N-phenylaminocarbonyl, pyridino-, pyrimidino, and benzotropane as GPR65 modulators

Abstract

One aspect of the present invention is a compound of formula (I) for use as a medicament [Formula 1] JPEG2023528073000334.jpg41120[In the formula, Ring A is a 5- or 6-membered aromatic or heteroaromatic ring, and the aromatic or heteroaromatic ring is selected from the group consisting of F, Cl, Br, I, CN, alkoxy, NR 11 R 11 , OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein the aryl and heteroaryl substituents may further be selected from F, Cl, Br, I, CN, alkoxy, NR 11 R 11 substituted with one or more substituents each independently selected from , OH, alkyl, haloalkyl, and aralkyl; Y is C=N-OH and CR 10 R 10 ' is selected from R 10 and R 10 each ' is independently selected from H, F, alkyl, and haloalkyl; R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I; R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl; R 11 and R 11 ' are each independently H, alkyl, haloalkyl, COR 12 , and SO2R 13 Selected from R 12 and R 13 and R are both alkyl], or a pharmaceutically acceptable salt or solvate thereof. A further aspect of the present invention relates to compounds of formula (I) for use in the fields of immuno-oncology, immunology and related applications, and to compounds of formula (I) per se.

Description

[Technical Field]

[0001] This invention relates to compounds capable of modulating GPR65. These compounds have potential therapeutic applications in the treatment of various disorders, including proliferative disorders and immune disorders. [Background technology]

[0002] GPR65 is a Gs-coupled G protein-coupled receptor (GPCR) primarily expressed in immune cells, activated by extracellular acidic pH, and causing an increase in cytoplasmic cyclic adenosine monophosphate (cAMP) (Non-Patent Literature 1). It has long been known that tumors typically undergo a switch from oxidative phosphorylation to aerobic glycolysis in their cellular metabolism, which in turn creates an acidic extracellular microenvironment (Non-Patent Literature 2). Recently, it has been shown that this acidic microenvironment triggers GPR65 activation in tumor-associated macrophages, leading to an increase in cytoplasmic cAMP, which in turn leads to the transcription of inducible cAMP early repressor (ICER). This, in turn, suppresses tumor necrosis factor alpha (TNFα) secretion, shifting macrophages toward an anti-inflammatory tumor-tolerant phenotype (Non-Patent Literature 3). Therefore, this GPR65-dependent pathway appears to correspond to a mechanism by which tumors utilize these acidic microenvironments to evade detection by the immune system.

[0003] Autoimmune diseases are also often associated with local acidic microenvironments (e.g., inflamed joints). Recent experiments have also suggested that GPR65 acts via ICER in CD4+ T cells to suppress IL-2, and thus bias cells toward an inflammatory Th17 phenotype associated with increased pathogenicity in the context of autoimmune diseases (Non-Patent Literature 4). This is supported by recent findings that ICER is required for Th17 differentiation (Non-Patent Literature 5) and that agonism of GPR65 leads to increased Th17 differentiation (Non-Patent Literature 6). Indeed, mutations at the location of GPR65 have been associated with several autoimmune diseases, such as multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, and Crohn's disease (Non-Patent Literature 7). One recent study found that mice with CD4+ T cells lacking GPR65 were protected from developing autoimmune encephalomyelitis (EAE) (Non-Patent Literature 7). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Wang, J. et al. (2004). TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor. Journal of Biological Chemistry, 45626-45633 [Non-Patent Document 2] Damaghi, M. et al. (2013). pH Sensing and Regulation in Cancer. Frontiers in Physiology [Non-Patent Document 3] Bohn, T. et al. (2018). Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nature Immunology, 1319-1326 [Non-Patent Document 4] Korn, T. et al. (2009). IL-17 and Th17 Cells. Annual Reviews in Immunology, 485-517 [Non-Patent Document 5] Yoshida, N. et al. (2016). ICER is requisite for Th17 differentiation. Nature Communications, 12993 [Non-Patent Document 6] Hernandez, J. (2018). GPR65, a critical regulator of Th17 cell pathogenicity, is regulated by the CRTC2 / CREB pathway. The Journal of Immunology, 200 (Supplement) [Non-Patent Document 7] Gaublomme, J. et al. (2015). Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell, 1400-1412 [Overview of the project] [Problems that the invention aims to solve]

[0005] Therefore, GPR65 appears to promote anti-inflammatory and tumor-tolerant phenotypes in tumor-associated macrophages, as well as inflammatory Th17 phenotypes in CD4+ T cells associated with autoimmune diseases, by acting via ICER. Thus, GPR65 signaling represents an interesting pathway for therapeutic interventions for both cancer and autoimmune diseases. Consequently, the need for developing novel small molecule GPR65 modulators remains. [Means for solving the problem]

[0006] The present invention seeks to provide compounds capable of modulating GPR65. As has become apparent from the above considerations, such compounds have potential therapeutic applications in the treatment of proliferative and immunological disorders, as well as various disorders including asthma and chronic obstructive pulmonary disease.

[0007] Description of the invention A first aspect of the present invention relates to a compound of formula (If), or a pharmaceutically acceptable salt or solvate thereof.

[0008] [ka] (If) [In the formula, Ring A is a pyridinyl ring or its tautomer, or a phenyl ring, each of which is H, F, Cl, Br, I, CN, alkoxy, or NR. 11 R 11 ', may be substituted with one or more substituents selected from OH, alkyl, phenyl, and haloalkyl, Y is CH2, C=N-OH, and CR 10 R 10 Selected from ', R 10 and R 10 Each of these is independently selected from H, F, alkyl, and haloalkyl. R a and R b Each is independently selected from H and alkyl, R1, R4, and R5 are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, F, Cl, Br, and I. R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, and CO2-alkyl, and the aryl, heteroaryl, and O-aryl groups may each be further substituted with one or more groups independently selected from halo, alkyl, and alkoxy. R11 and R 11 ’ are each independently H, alkyl, haloalkyl, COR 12 , CO2R 12 and SO2R 13 selected from, R 12 and R 13 are both independently alkyl].

[0009] The second aspect of the present invention relates to a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof

[0010]

Chemical formula

Chemical formula

[0011] A third aspect of the present invention relates to a compound of formula (Ie), or a pharmaceutically acceptable salt or solvate thereof.

[0012] [ka] (Ie) [In the formula, Ring A is, [ka] (wherein R6 and R8 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, OH, phenyl, and haloalkyl (more preferably CF3)), Y is CH2, C=N-OH, and CR 10 R 10 Selected from ', R 10 and R 10 Each of these is independently selected from H, F, alkyl, and haloalkyl. R a and R b Each is independently selected from H and alkyl, R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I. R2 and R3 are independently selected from F, Cl, Br, I, CN, methoxy, and haloalkyl. However, if Y is CH2, R a , R b R1, R4, R5, R6 and R8 are all assumed to be H. If R2 is Cl, then R3 is not CN. R2 and R3 are both assumed to be non-Cl.

[0013] Another aspect of the present invention relates to the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0014] [ka] (Ia) [In the formula, Ring A is a 5-membered or 6-membered aromatic or aromatic heterocycle, wherein the aromatic or aromatic heterocycle is composed of F, Cl, Br, I, CN, alkoxy, or NR. 11 R 11 ', OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl substituents may be substituted with one or more substituents selected from OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, and the aryl and heteroaryl substituents may further be F, Cl, Br, I, CN, alkoxy, NR 11 R 11 ', may be substituted with one or more substituents independently selected from OH, alkyl, haloalkyl, and aralkyl, Y is CH2, C=N-OH, and CR 10 R 10 Selected from ', R 10 and R 10 Each of these is independently selected from H, F, alkyl, and haloalkyl. R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I. R2 and R3 are independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl. R 11 and R 11 ' are independently H, alkyl, haloalkyl, and COR 12 , and SO2R 13 Selected from, R 12 and R 13 Both are alkyl groups. If Y is CH2, then ring A is, [ka] (In the formula, both R6 and R8 are H) - If R1, R4, and R5 are all H, then R2 and R3 are both not Cl. - If R1, R2, R4, and R5 are all H, then R3 is not Cl, - If R1, R3, R4, and R5 are all H, then R2 is not Cl, - If R2, R3, R4, and R5 are all H, then R1 is not Cl, - If R4 is Cl, and R2, R3, and R5 are all H, then R1 is not F.

[0015] Advantageously, the compounds claimed in this invention are capable of modulating GPR65, and therefore the compounds are of therapeutic interest in treating various disorders in the fields of oncology, immuno-oncology, and immunology.

[0016] Another aspect of the present invention relates to a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof.

[0017] [ka] (I C) [In the formula, Ring A is, [ka] (In the formula, R6 and R8 are independently H, F, Cl, Br, I, CN, alkoxy, NR) 11 R 11 ', selected from OH, alkyl, phenyl, and haloalkyl, provided that at least one of R6 and R8 is not H, Y is CH2, C=N-OH, and CR 10 R 10 Selected from ', R 10 and R 10 Each of these is independently selected from H, F, alkyl, and haloalkyl. R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I. R2 and R3 are independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl. R 11 and R 11 ' are independently H, alkyl, haloalkyl, and COR 12 , and SO2R 13 Selected from, R 12 and R 13 Both are alkyl groups.

[0018] Another aspect of the present invention relates to a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof.

[0019] [ka] (Id) [In the formula, Ring A is, [ka] (In the formula, R6 and R8 are independently H, F, Cl, Br, I, CN, alkoxy, NR) 11R 11 ’ is selected from OH, alkyl, phenyl, and haloalkyl), Y is CH2, C=N-OH, and CR 10 R 10 ’ is selected from, and R 10 and R 10 ’ are each independently selected from H, F, alkyl, and haloalkyl, R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I, R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl, provided that at least one of R2 and R3 is selected from CN, methoxy, and haloalkyl, R 11 and R 11 ’ are each independently selected from H, alkyl, haloalkyl, COR 12 , and SO2R 13 and are both alkyl]. 12 and R 13

[0020] Another aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament

[0021]

Chemical formula

[0022] Another aspect of the present invention relates to a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If) as described above for use as a medicament.

[0023] Another aspect of the present invention relates to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as described above for use in the treatment or prevention of a disorder selected from proliferative disorders, immune disorders, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).

[0024] Another aspect of the present invention relates to a compound of formula (I.1) for use as described above:

[0025]

Chemical formula

[0026] Another aspect of the present invention relates to a compound of formula (I.2) for use as described above:

[0027] [ka] (I.2) [In the formula, A, Y, and R1-R5 are as defined above.]

[0028] Another aspect of the present invention relates to a pharmaceutical composition comprising the compounds described above and a pharmaceutically acceptable diluent, excipient, or carrier.

[0029] Another aspect of the present invention relates to the above-described pharmaceutical composition for use as a pharmaceutical.

[0030] Another aspect of the present invention relates to the pharmaceutical composition described above for use in the treatment or prevention of disorders selected from proliferative disorders, immune disorders, asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS).

[0031] Another aspect of the present invention relates to a method for treating a disorder, comprising administering the compound or pharmaceutical composition described above to a target. [Modes for carrying out the invention]

[0032] The present invention relates to compounds capable of modulating GPR65.

[0033] "Alkyl" is defined herein as a linear or branched alkyl radical, preferably C 1-20 Alkyl, more preferably C 1-12 Alkyl, and more preferably C 1-10 Alkyl or C 1-6Alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl. More preferably, the alkyl is C 1-3 alkyl.

[0034] As used herein, the term "aryl" refers to a C 6-12 aromatic group and may be benzo-fused, for example, phenyl or naphthyl.

[0035] "Haloalkyl" is defined herein as a straight-chain or branched alkyl radical as defined above, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, which are substituted with one or more halogen atoms (which may be the same or different), for example, fluorine, chlorine, bromine, and iodine. Preferably, the haloalkyl is C 1-20 haloalkyl, more preferably C 1-12 haloalkyl, even more preferably C 1-10 haloalkyl or C 1-6 haloalkyl, or C 1-3 haloalkyl. Preferred examples are CF3 and CHF2, with CF3 being particularly preferred.

[0036] "Alkoxy" is defined herein as an oxygen atom bonded to an alkyl group as defined above, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, and hexoxy. Preferably, the alkoxy is C 1-20 alkoxy, more preferably C 1-12 alkoxy, even more preferably C 1-10 alkoxy or C 1-6 alkoxy, or C 1-3 alkoxy. A particularly preferred example is methoxy (-OCH3).

[0037] In this specification, "heteroaryl" refers to a monocyclic or bicyclic carbon atom comprising one or more heteroatoms (which may be the same or different), such as oxygen, nitrogen, or sulfur. 2-12 It is defined as an aromatic ring. Suitable examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, pyridinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and their benzo derivatives, such as benzofuranyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, etc.; or pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, isoquinolinyl, sinnolinyl, phthalazinyl, quinazolyl, quinoxalinyl, naphthilidinyl, etc.

[0038] In this specification, "aralkyl" is defined as an alkyl group defined above, which is substituted with one or more aryl groups as defined above.

[0039] In formulas (Ia), (Ib), (Ic), (Id), and (Ie), preferably, alkyl is C 1- C6 alkyl, haloalkyl is C 1- It is a C6 haloalkyl, and the alkoxy is C 1- It is a C6 alkoxy.

[0040] Structural representation of compounds The compounds of the present invention include a structure in which ring A is a substituted or otherwise substituted 5-membered or 6-membered aromatic or aromatic heterocycle that condenses with a nitrogen-containing portion of a bicyclic structure to form a tricyclic structure. The resulting tricyclic structure has two different stereoconfigurations, as illustrated below (for clarity, a crosslinking substituent R is used). a and R b (Omitted in the following display) can exist:

[0041] [ka] (I.1) (I.2)

[0042] For the sake of clarity, the present invention encompasses compounds of any of the above stereoconfigurations, as well as mixtures thereof, including racemic mixtures.

[0043] Alternatively, the structure can be represented as follows:

[0044] [ka] (I.3)

[0045] For the sake of clarity, the present invention encompasses compounds of the above configurations, their corresponding enantiomers, and mixtures thereof, including racemic mixtures. As used throughout, and for the sake of simplicity of representation, specific examples of compounds according to the present invention shown in configuration (I.3) above refer to mixtures of both enantiomers (in particular, racemic mixtures), whereas each enantiomer is shown in either configuration (I.1) or configuration (I.2), having, respectively, wedge-shaped or dashed bonded connections when synthesized or separated.

[0046] The compounds described herein contain a substituted five- or six-membered aromatic or aromatic heterocyclic A, which condense with the nitrogen-containing portion of a bicyclic structure to form a tricyclic structure. Any substituents may be halo, CN, alkoxy, or NR. 11 R 11’ The group is selected from OH, alkyl, phenyl, and haloalkyl. In some cases, ring A can exist in two or more tautomers. For example, if an aromatic heterocycle is substituted with an OH group, ring A can exist as two possible tautomers, as shown below:

[0047] [ka]

[0048] The 2-pyridone tautomer is considered the primary solid form. In solution, the energy difference between the two tautomers is considered minimal and depends on the polarity of the solvent. Those skilled in the art will recognize that other hydroxy-substituted nitrogen-containing heteroaromatic groups (e.g., pyrimidines, other pyridine positional isomers) can be similarly represented in the tautomers described above. The term "heteroaromatic," as used herein, encompasses all tautomers of a compound.

[0049] Preferably, ring A is as defined herein, and the dashed line indicates bonding to a ring containing N and Y: [ka]

[0050] Compound of formula (If) One aspect of the present invention relates to a compound of formula (If), or a pharmaceutically acceptable salt or solvate thereof.

[0051] [ka] (If) [In the formula, Ring A is a pyridinyl ring or its tautomer, or a phenyl ring, each of which is H, F, Cl, Br, I, CN, alkoxy, or NR. 11 R 11 ', may be substituted with one or more substituents selected from OH, alkyl, phenyl, and haloalkyl, Y is CH2, C=N-OH, and CR 10 R 10 Selected from ', R 10 and R 10 Each of these is independently selected from H, F, alkyl, and haloalkyl. R a and R b Each is independently selected from H and alkyl, R1, R4, and R5 are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, F, Cl, Br, and I. R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, and CO2-alkyl, and the aryl, heteroaryl, and O-aryl groups may each be further substituted with one or more groups independently selected from halo, alkyl, and alkoxy. R 11 and R 11 ' are independently H, alkyl, haloalkyl, and COR 12 CO2R 12 and SO2R 13 Selected from, R 12 and R 13 Both are independently alkyl.

[0052] In one preferred embodiment, ring A is a hydroxysubstituted pyridinyl group that may exist in a tautomer form, for example, as shown above in the section titled "Structural Representation of the Compound." Those skilled in the art will recognize that other positional isomers of the hydroxysubstituted pyridinyl group can be similarly represented in tautomer forms (see groups (viii) to (xii) and (xx) below).

[0053] In a preferred embodiment, ring A is selected from the following:

[0054] [ka] JPEG0007870548000023.jpg2383JPEG0007870548000024.jpg2161 [In the formula, R6, R7, R8, and R9 are each independently H, F, Cl, Br, I, CN, alkoxy, and NR.] 11 R 11 Selected from ', OH, alkyl, phenyl, and haloalkyl, R 14[is H or alkyl, more preferably H].

[0055] Further preferred embodiments are presented below in relation to the compound of formula (Ib). In particular, R 1-9 , R 14 A, Y, R a and R b A preferred definition of the group is given below for the compound of formula (Ib).

[0056] Compound of formula (Ib) One aspect of the present invention relates to a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof.

[0057] [ka] (Ib) [In the formula, Ring A is selected from (i) to (xx) groups: [ka] JPEG0007870548000027.jpg94120 (In the formula, R6, R7, R8, and R9 are each independently H, F, Cl, Br, I, CN, alkoxy, and NR.) 11 R 11 Selected from ', OH, alkyl, phenyl, and haloalkyl, R 14 (is H or alkyl), Y is CH2, C=N-OH, and CR 10 R 10 Selected from ', R 10 and R 10 Each of these is independently selected from H, F, alkyl, and haloalkyl. R a and R b Each is independently selected from H and alkyl, R1, R4, and R5 are each independently selected from H, CN, alkyl, haloalkyl, alkoxy, OH, F, Cl, Br, and I. R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, and CO2-alkyl, and the aryl, heteroaryl, and O-aryl groups may each be further substituted with one or more groups independently selected from halo, alkyl, and alkoxy. R 11 and R 11 ' are independently H, alkyl, haloalkyl, and COR 12 CO2R 12 and SO2R 13 Selected from, R 12 and R 13 Both are alkyl groups.

[0058] In one preferred embodiment, ring A is selected from groups (i) to (xviii).

[0059] In a preferred embodiment, ring A is selected from the (i), (ii), (iii), (iv), (v), (vi), (viii), (ix), (xiv), (xv), and (xix) groups, preferably selected from (i), (ii), (iii), (v), (vi), and (ix), and more preferably selected from (i), (ii), (vi), and (ix).

[0060] In a preferred embodiment, ring A is selected from (i), (ii), (iii), (iv), (vi), (vii), (viii), (ix), (xiii), (xiv), (xv), (xvi), (xvii), and (xviii).

[0061] In a preferred embodiment, ring A is selected from (i), (ii), (vi), (ix), (xiv), and (xv), and more preferably from (i), (ii), and (vi).

[0062] In a preferred embodiment, ring A is selected from (ii), (vi), and (ix).

[0063] In one preferred embodiment, ring A is (ii).

[0064] In one preferred embodiment, ring A is (vi).

[0065] In one preferred embodiment, ring A is (vi).

[0066] In a preferred embodiment, the compound is a compound of formula (Ib)-(ii):

[0067] [ka] (Ib)-(ii) [In the formula, Y, R a , R b [R1-R7 and R9 are as defined above]. In one preferred embodiment, R6, R7 and R9 are all H. In one particularly preferred embodiment, R9 is F, and R6 and R7 are both H.

[0068] In one preferred embodiment, the compound is the compound of formula (Ib)-(i):

[0069] [ka] (Ib)-(i) [In the formula, Y, R a , R b [R1 to R9 are as defined above]. In one preferred embodiment, R6, R7 and R9 are all H, and R8 is selected from H, OMe, OH, Cl, CN, F and NH2.

[0070] In one preferred embodiment, the compound is a compound of formula (Ib)-(vi):

[0071] [ka] (Ib)-(vi) [In the formula, Y, R a , R b [R1-R6, R8 and R9 are as defined above]. In one preferred embodiment, R6, R8 and R9 are each independently selected from H, F, Cl, NH2, Br and OMe, and more preferably selected from H and F. In one particularly preferred embodiment, R6, R8 and R9 are all H.

[0072] In one preferred embodiment, the compound is a compound of formula (Ib)-(ix):

[0073] [ka] (Ib)-(ix) [In the formula, Y, R a , R b , R1-R6, R9 and R 14 [is defined above]. In one preferred embodiment, both R6 and R9 are H, and R 14 is H or Me, more preferably Me. In one preferred embodiment, R6 is H, R9 is F, and R 14 is H or Me, and more preferably Me.

[0074] In one preferred embodiment, R a and R b Each is independently selected from H and methyl. In a preferred embodiment, R a and R b One of them is alkyl (more preferably methyl), and the other is H. In one particularly preferred embodiment, R a and R b Both are H.

[0075] In one preferred embodiment, R 11 and R 11' is selected from H and alkyl, more preferably selected from H and Me, and even more preferably R 11 and R 11 Both are H.

[0076] In one preferred embodiment, Y is CR 10 R 10 '(In the formula, R 10 and R 10 Each of the elements is independently selected from H, F, Me, and CF3, and more preferably selected from H, F, and Me. In one preferred embodiment, Y is selected from CH2, CHF, CHMe, and C=N-OH. In one preferred embodiment, Y is selected from CH2 and C=N-OH. More preferably, Y is CH2.

[0077] In one preferred embodiment, at least one of R1, R2, R3, R4, and R5 is not H.

[0078] In one preferred embodiment, one of R1, R2, R3, R4, and R5 is not H.

[0079] In one preferred embodiment, two of R1, R2, R3, R4, and R5 are not H.

[0080] In one preferred embodiment, three of R1, R2, R3, R4, and R5 are not H.

[0081] In one preferred embodiment, R2 and R3 are each independently selected from H, F, Cl, Br, CN, methoxy, OCF3, CF3, OCHF2, Me, Ph, pyrazolyl, oxazolyl, thiazolyl, OPh, NHCO-CH=CH2, and C2Me, and the Ph, OPh, pyrazolyl, oxazolyl, and thiazolyl groups may each be further substituted with one or more alkyl groups.

[0082] In one preferred embodiment, R2 and R3 are independently selected from H, F, Cl, Br, I, CN, methoxy, haloalkyl, haloalkoxy, and CO2-alkyl.

[0083] In a preferred embodiment, R3 is selected from H, F, Cl, Br, CN, methoxy, OCF3, CF3, OCHF2, Me, Ph, pyrazolyl, oxazolyl, thiazolyl, OPh, NHCO-CH=CH2, and CO2Me, and the Ph, OPh, pyrazolyl, oxazolyl, and thiazolyl groups may each be further substituted with one or more alkyl groups. Preferably, pyrazolyl is a 1H-pyrazole-1-yl group. Preferably, oxazolyl is an oxazole-5-yl group. Preferably, thiazolyl is a thiazolyl-4-yl group.

[0084] In a preferred embodiment, R2 is selected from H, F, Cl, Br, CN, Me, methoxy, OCF3, CF3, OCHF2, Ph, pyrazolyl, and CO2Me, and the Ph and pyrazolyl groups may each be further substituted with one or more alkyl groups. Preferably, the pyrazolyl is a 1H-pyrazole-1-yl group.

[0085] In one preferred embodiment, R2 and R3 are independently selected from F, Cl, Br, I, CN, CO2-alkyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0086] In one preferred embodiment, R2 and R3 are independently selected from F, Cl, Br, I, CN, and C1-C6 haloalkyl.

[0087] In one preferred embodiment, R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl.

[0088] In one preferred embodiment, R2 and R3 are each independently selected from Cl, Br, and CF3, and more preferably independently selected from Cl and CF3.

[0089] In one preferred embodiment, one of R2 and R3 is Cl, and the other is OCF3 or OCHF2.

[0090] In one preferred embodiment, one of R2 and R3 is Cl and the other is CO2Me.

[0091] In one preferred embodiment, both R2 and R3 are Cl, or one of R2 and R3 is Cl and the other is CF3.

[0092] In one preferred embodiment, both R2 and R3 are Cl.

[0093] In one preferred embodiment, one of R2 and R3 is Cl and the other is CF3.

[0094] In one preferred embodiment, one of R2 and R3 is Cl, and the other is selected from OCF3, CO2Me, OCHF2, and CF3.

[0095] In one preferred embodiment, R1, R4, and R5 are each independently selected from H, alkyl, alkoxy, OH, F, Cl, Br, and I.

[0096] In one preferred embodiment, R1, R4, and R5 are each independently selected from H, Me, OMe, OH, F, Cl, Br, and I.

[0097] In one preferred embodiment, R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I.

[0098] In one preferred embodiment, R5 is selected from H, F, Me, MeO, and Cl, preferably H or F, and more preferably H.

[0099] In one preferred embodiment, R5 is selected from H, F, and Cl, preferably H or F, and more preferably H.

[0100] In one preferred embodiment, R5 is selected from H, F, and CN, and is preferably H.

[0101] In one preferred embodiment, both R1 and R4 are H.

[0102] In one preferred embodiment, R1 is H, R2 is selected from H, F, Cl, Br, CN, Me, methoxy, OCF3, CF3, OCHF2, Ph, pyrazolyl, and CO2Me, R3 is selected from H, F, Cl, Br, CN, methoxy, OCF3, CF3, OCHF2, Me, Ph, pyrazolyl, oxazolyl, thiazolyl, OPh, NHCO-CH=CH2, and CO2Me, where the Ph, OPh, pyrazolyl, oxazolyl, and thiazolyl groups may each be further substituted with one or more alkyl groups, R4 is H or CF3, more preferably H, and R5 is selected from H, F, Me, MeO, Cl, OH, and CN, more preferably H or F, more preferably H. Preferably, for this embodiment, at least one of R2 and R3 is not H. Even more preferably, both R2 and R3 are not H.

[0103] In another preferred embodiment, one of R2 and R3 is selected from aryl, O-aryl, and heteroaryl, each of which may be substituted, the other of R2 and R3 is H, and R1, R4, and R5 are all H.

[0104] In one preferred embodiment, R6, R7, R8, and R9 are independently H, F, Cl, Br, CN, OMe, NR 11 R 11 Selected from ' and OH.

[0105] In one preferred embodiment, R6, R7, R8, and R9 are each independently selected from H, F, Cl, Br, CN, OMe, NH2, NHBu, NHCO2Bu, and OH.

[0106] In one preferred embodiment, R 14 is H or methyl. More preferably, R 14 H is H.

[0107] In one particularly preferred embodiment, the compound is a compound of formula (Ib.1):

[0108] [ka] (Ib.1) [In the formula, ring A, and Y and R1-R5 groups are as described in any of the embodiments above.]

[0109] In one preferred embodiment, the compound is in a pure form as an enantiomer. In one preferred embodiment, the compound is in the form of a mixture richly containing the compound of formula (Ib.1) as an enantiomer.

[0110] In another embodiment, the compound is the compound of formula (Ib.2):

[0111] [ka] (Ib.2) [In the formula, ring A, and Y and R1-R5 groups are as described in any of the embodiments above.]

[0112] In one preferred embodiment, the compound is in a pure form as an enantiomer. In one preferred embodiment, the compound is in the form of a mixture richly containing the compound of formula (Ib.2) as an enantiomer.

[0113] In one preferred embodiment, the compound is in the form of a mixture comprising the compound of formula (Ib.1) and its corresponding enantiomer of formula (Ib.2). In one preferred embodiment, the mixture is a racemic mixture, i.e., a 50:50 mixture of the compound of formula (Ib.1) and its corresponding enantiomer of formula (Ib.2).

[0114] Using a racemic mixture, the compounds of formula (Ib.1) or (Ib.2) can be separated by standard methods, such as chemical resolution using an optically active acid, or by column chromatography or reversed-phase column chromatography using a substantially optically active (or "chiral") stationary phase known to those skilled in the art, to prepare pure compounds of formula (Ib.1) or (Ib.2) as enantiomers. The racemic mixture can also be used to prepare enantiomer-rich mixtures of the compounds of formula (Ib.1) or (Ib.2). Mixtures rich in either the compound of formula (Ib.1) or (Ib.2) can also be obtained from a suitable enantiomer-rich precursor.

[0115] In one preferred embodiment of the present invention, the compound is in the form of a mixture containing an enantiomer, and the weight:weight ratio is at least about 2:1 or greater, preferably at least about 5:1 or greater, and most preferably at least about 10:1 or greater, preferring an enantiomer (utemer) that exhibits significant in vitro and / or in vivo activity.

[0116] In one particularly preferred embodiment, the compound is in the form of a mixture comprising the compound of formula (Ib.1) and its corresponding enantiomer of formula (Ib.2), wherein the weight:weight ratio of the compound of formula (Ib.1) to the compound of formula (Ib.2) is greater than 1.05:1, more preferably greater than 2:1, even more preferably greater than 5:1, and even more preferably greater than 10:1.

[0117] In one particularly preferred embodiment, the compound is in the form of a mixture comprising the compound of formula (Ib.1) and its corresponding enantiomer of formula (Ib.2), which is substantially rich in the compound of formula (Ib.1).

[0118] In one embodiment, the compound is in the form of a mixture comprising the compound of formula (Ib.1) and its corresponding enantiomer of formula (Ib.2), wherein the weight:weight ratio of the compound of formula (Ib.2) to the compound of formula (Ib.1) is greater than 1.05:1, more preferably greater than 2:1, even more preferably greater than 5:1, and even more preferably greater than 10:1.

[0119] In one embodiment, the compound is in the form of a mixture comprising the compound of formula (Ib.1) and its corresponding enantiomer of formula (Ib.2), and is substantially rich in the compound of formula (Ib.2).

[0120] In one preferred embodiment, the compound is as follows:

[0121] [ka] JPEG0007870548000035.jpg170131JPEG0007870548000036.jpg170134JPEG00078705480000 37.jpg189135JPEG0007870548000038.jpg185129JPEG0007870548000039.jpg183131JPEG000 7870548000040.jpg175132JPEG0007870548000041.jpg178134JPEG0007870548000042.jpg15 6131JPEG0007870548000043.jpg157134JPEG0007870548000044.jpg153135JPEG00078705480 00045.jpg168134JPEG0007870548000046.jpg160133JPEG0007870548000047.jpg195130JPE G0007870548000048.jpg192129JPEG0007870548000049.jpg178131JPEG0007870548000050.j pg185132JPEG0007870548000051.jpg187131JPEG0007870548000052.jpg152131JPEG0007870 548000053.jpg146132JPEG0007870548000054.jpg187130JPEG0007870548000055.jpg153130 The enantiomers thereof, as well as mixtures of the enantiomers including racemic mixtures, and pharmaceutically acceptable salts and solvates are selected from these.

[0122] Compounds of formula (Ie) Another aspect of the present invention relates to a compound of formula (Ie), or a pharmaceutically acceptable salt or solvate thereof.

[0123] [ka] (Ie) [In the formula, Ring A is, [ka] (wherein R6 and R8 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, OH, phenyl, and haloalkyl (more preferably CF3)), Y is CH2, C=N-OH, and CR 10 R 10 Selected from ', R 10 and R 10 Each of these is independently selected from H, F, alkyl, and haloalkyl. R a and R b Each is independently selected from H and alkyl, R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I. R2 and R3 are independently selected from F, Cl, Br, I, CN, methoxy, and haloalkyl. However, if Y is CH2, R a , R b R1, R4, R5, R6 and R8 are all assumed to be H. If R2 is Cl, then R3 is not CN. [Both R2 and R3 are not Cl.]

[0124] Therefore, in one embodiment, the compound of the present invention is a compound of formula (Ie), or a pharmaceutically acceptable salt or solvate thereof:

[0125] [ka] (Ie) [In the formula, Y, R a , R b R1-R5, R6 and R8 are as defined above. Preferably, when Y is CH2, R a , R bIf R1, R4, R5, R6 and R8 are H and R2 is Cl, then R3 is not CN. Preferably, if Y is CH2, then R a , R b R1, R4, R5, R6, and R8 are H, and R2 and R3 are neither Cl.

[0126] Another aspect of the present invention relates to the structure of formula (Ie) shown above (wherein Y, R a , R b (R1-R5, R6 and R8 are as defined above), however, [ka] This relates to compounds other than those specified, or their pharmaceutically acceptable salts or solvates.

[0127] Another aspect of the present invention relates to the structure of formula (Ie) shown above (wherein Y, R a , R b (R1-R5, R6 and R8 are as defined above), however, N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; and This relates to compounds other than N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide, or pharmaceutically acceptable salts or solvates thereof.

[0128] Another aspect of the present invention relates to the structure of formula (Ie) shown above (wherein Y, R a , R b (R1-R5, R6 and R8 are as defined above), however, N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide, and its enantiomers, and mixtures thereof; and This invention relates to compounds other than N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide, its enantiomers, and mixtures thereof, or pharmaceutically acceptable salts or solvates thereof.

[0129] In one preferred embodiment, R2 and R3 are each independently selected from F, Cl, Br, I, CN, and haloalkyl.

[0130] In one preferred embodiment, R2 is selected from F, Cl, Br, and CF3, and more preferably from Cl and CF3.

[0131] In one preferred embodiment, R3 is selected from F, Cl, Br, OMe, CN, and CF3, more preferably from F, Cl, Br, OMe, and CF3, and even more preferably from Cl and CF3.

[0132] In one preferred embodiment, one of R2 and R3 is selected from Cl and the other is CF3, or both R2 and R3 are Cl.

[0133] In one preferred embodiment, R1, R4, and R5 are all H.

[0134] In one preferred embodiment, Y is CR 10 R 10 ' and R 10 and R 10 Each of the elements is independently selected from H, F, Me, and CF3, more preferably from H, F, and Me. In one preferred embodiment, Y is selected from CH2, CHF, CHMe, and C=N-OH. In one preferred embodiment, Y is selected from CH2 and C=N-OH. In one preferred embodiment, Y is selected from CH2 and CHF. More preferably, Y is CH2.

[0135] In one preferred embodiment, R a and Rb Each is independently selected from H and methyl. In a preferred embodiment, R a and R b One of them is alkyl (more preferably methyl), and the other is H. In one particularly preferred embodiment, R a and R b Both are H.

[0136] In one preferred embodiment, at least one of R6 and R8 is not H.

[0137] In one preferred embodiment, R6 is H.

[0138] In a preferred embodiment, R8 is selected from H, CF3, phenyl, OH, and F.

[0139] In one preferred embodiment, R8 is OH, and ring A is: [ka] Or its corresponding tautomer. Preferably, R6 is H.

[0140] In one particularly preferred embodiment, the compound is of formula (Ie.1):

[0141] [ka] (Ie.1) (wherein ring A, and Y and R1-R5 groups are as described in any of the embodiments above for (Ie)).

[0142] In one preferred embodiment, the compound is in a pure form as an enantiomer. In one preferred embodiment, the compound is in the form of a mixture richly containing the compound of formula (Ie.1) as an enantiomer.

[0143] In another embodiment, the compound is given by formula (Ie.2):

[0144] [ka] (Ie.2) (wherein the formula, ring A, and Y and R1-R5 groups are as described in any of the embodiments above for (Ie)).

[0145] In one preferred embodiment, the compound is in a pure form as an enantiomer. In one preferred embodiment, the compound is in the form of a mixture richly containing the compound of formula (Ie.2) as an enantiomer.

[0146] In one preferred embodiment, the compound is in the form of a mixture comprising the compound of formula (Ie.1) and its corresponding enantiomer of formula (Ie.2). In one preferred embodiment, the mixture is a racemic mixture, i.e., a 50:50 mixture of the compound of formula (Ie.1) and its corresponding enantiomer of formula (Ie.2).

[0147] Using a racemic mixture, the compounds of formula (Ie.1) or (Ie.2) can be separated by standard methods, such as chemical resolution using an optically active acid, or by column chromatography or reversed-phase column chromatography using a substantially optically active (or "chiral") stationary phase known to those skilled in the art, to prepare pure compounds of formula (Ie.1) or (Ie.2) as enantiomers. The racemic mixture can also be used to prepare enantiomer-rich mixtures of the compounds of formula (Ie.1) or (Ie.2). Mixtures rich in either the compound of formula (Ie.1) or (Ie.2) can also be obtained from a suitable enantiomer-rich precursor.

[0148] In one preferred embodiment of the present invention, the compound is in the form of a mixture containing an enantiomer, and the weight:weight ratio is at least about 2:1 or greater, preferably at least about 5:1 or greater, and most preferably at least about 10:1 or greater, preferring an enantiomer (utemer) that exhibits significant in vitro and / or in vivo activity.

[0149] In one particularly preferred embodiment, the compound is in the form of a mixture comprising the compound of formula (Ie.1) and its corresponding enantiomer of formula (Ie.2), wherein the weight:weight ratio of the compound of formula (Ie.1) to the compound of formula (Ie.2) is greater than 1.05:1, more preferably greater than 2:1, even more preferably greater than 5:1, and even more preferably greater than 10:1.

[0150] In one particularly preferred embodiment, the compound is in the form of a mixture comprising the compound of formula (Ie.1) and its corresponding enantiomer of formula (Ie.2), which is substantially rich in the compound of formula (Ie.1).

[0151] In one embodiment, the compound is in the form of a mixture comprising the compound of formula (Ie.1) and its corresponding enantiomer of formula (Ie.2), wherein the weight:weight ratio of the compound of formula (Ie.2) to the compound of formula (Ie.1) is greater than 1.05:1, more preferably greater than 2:1, even more preferably greater than 5:1, and even more preferably greater than 10:1.

[0152] In one embodiment, the compound is in the form of a mixture comprising the compound of formula (Ie.1) and its corresponding enantiomer of (Ie.2), which is substantially rich in the compound of formula (Ie.2).

[0153] In one preferred embodiment, a compound of formula (Ie) selected from the following:

[0154] [ka] JPEG0007870548000064.jpg174128JPEG0007870548000065.jpg192129JPEG0007870548000066.jpg172133JPEG0007870548000067.jpg163132 and its enantiomers, as well as mixtures of its enantiomers including racemic mixtures, and pharmaceutically acceptable salts and solvates.

[0155] Compound of formula (Ia) One aspect of the present invention relates to a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof.

[0156] [ka] (Ia) [In the formula, Ring A is a 5-membered or 6-membered aromatic or aromatic heterocycle, wherein the aromatic or aromatic heterocycle is composed of F, Cl, Br, I, CN, alkoxy, or NR. 11 R 11 ', OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl substituents may be substituted with one or more substituents selected from OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, and the aryl and heteroaryl substituents may further be F, Cl, Br, I, CN, alkoxy, NR 11 R 11 ', may be substituted with one or more substituents independently selected from OH, alkyl, haloalkyl, and aralkyl, Y is CH2, C=N-OH, and CR 10 R 10 Selected from ', R 10 and R 10 Each of these is independently selected from H, F, alkyl, and haloalkyl. R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I. R2 and R3 are independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl. R11 and R 11 ' are independently H, alkyl, haloalkyl, and COR 12 , and SO2R 13 Selected from, R 12 and R 13 Both are alkyl groups. If Y is CH2, then ring A is, [ka] (In the formula, both R6 and R8 are H) - If R1, R4, and R5 are all H, then R2 and R3 are not both Cl. - If R1, R2, R4, and R5 are all H, then R3 is not Cl, - If R1, R3, R4, and R5 are all H, then R2 is not Cl, - If R2, R3, R4, and R5 are all H, then R1 is not Cl, - If R4 is Cl, and R2, R3, and R5 are all H, then R1 is not F.

[0157] In one preferred embodiment, the substituted aromatic or aromatic heterocycle is benzene, pyridine, pyridone, pyridine N-oxide, pyridazine, pyrimidine, pyrimidone, pyrazine, triazine, pyrrole, furan, thiophene, pyrazole, isoxazole, imidazole, oxazole, or thiazole ring. The term “heteroaromatic” also, as used herein, includes moieties that exist in tautomeristic forms, such as, but not limited to, pyridine, pyrimidone, etc. The aromatic or aromatic heterocycle A condenses with an adjacent nitrogen-containing bicyclic heterocycle group to form a condensed tricyclic ring system.

[0158] More preferably, the substituted aromatic or aromatic heterocycle is benzene, pyridine, pyridone, pyridine N-oxide, pyrimidine, pyrimidone, pyridazine, pyrazine, or an isoxazole ring.

[0159] In a preferred embodiment, ring A is F, Cl, Br, I, CN, C1-C6 alkoxy, NR 11 R 11 The ring is a benzene, pyridine, pyridone, pyridine N-oxide, pyrimidine, pyrimidone, pyridazine, pyrazine, or isoxazole ring, which may be substituted with one or more substituents selected from ', OH, C1-C6 alkyl, phenyl, and C1-C6 haloalkyl.

[0160] In one embodiment, ring A is [ka] JPEG0007870548000071.jpg63120 (wherein R6, R7, R8, and R9 are independently H, F, Cl, Br, I, CN, C1-C6 alkoxy, NR) 11 R 11 Selected from ', OH, C1-C6 alkyl, phenyl, and C1-C6 haloalkyl.

[0161] In one preferred embodiment, ring A is [ka] Selected from the following, more preferably selected from the following: [ka]

[0162] In one preferred embodiment, R 10 and R 10 Each of the elements is independently selected from H and C1-C6 alkyl, preferably C1-C6 alkyl is CH3.

[0163] In one preferred embodiment, Y is selected from CH2 and C=N-OH, and is preferably CH2.

[0164] In one preferred embodiment, R1 is selected from H and F, and is preferably H.

[0165] In one preferred embodiment, R2 and R3 are independently selected from F, Cl, Br, I, CN, and C1-C6 haloalkyl.

[0166] In one preferred embodiment, R2 and R3 are independently F, Cl, Br, I, CN, and CF, respectively. n H 3-n n is selected from the following, where n is 1, 2, or 3, preferably 3.

[0167] In one preferred embodiment, R2 and R3 are independently Cl, Br, and CF, respectively. n H 3-n n is selected from the following, where n is 1, 2, or 3, preferably 3.

[0168] In one preferred embodiment, R2 and R3 are each independently selected from Cl, Br, and CF3, preferably R2 and R3 are not both CF3, and more preferably R2 is Cl or Br and R3 is CF3.

[0169] In one preferred embodiment, R4 is selected from H and Cl, and is preferably H.

[0170] In one preferred embodiment, R5 is H.

[0171] In a preferred embodiment, R6 is H, F, Cl, CN, methoxy, CH3, NR 11 R 11 ', and selected from CF3, R 11 and R 11 Each of the elements is independently selected from H and C1-C6 alkyl groups, preferably both being H.

[0172] In one preferred embodiment, R6 is selected from H, F, Cl, CN, methoxy, and CH3, and is preferably H.

[0173] In a preferred embodiment, R7 is H, F, Cl, CN, methoxy, CH3, NR 11 R 11 ', and selected from CF3, R 11 and R 11 Each of the elements is independently selected from H and C1-C6 alkyl groups, preferably both being H.

[0174] In one preferred embodiment, R7 is selected from H, F, Cl, CN, methoxy, and CH3, preferably selected from H, F, or Cl, and more preferably H.

[0175] In a preferred embodiment, R8 is H, F, OH, CN, methoxy, NR 11 R 11 Selected from ', phenyl, CF3, CF2H, NHSO2CH3, NHCOCH3, and NHCHF2, R 11 and R 11 Each of the elements is independently selected from H and C1-C6 alkyl groups, preferably both being H.

[0176] In a preferred embodiment, R8 is selected from H, F, Cl, CN, phenyl, and OH, and is preferably selected from H, F, and OH.

[0177] In one preferred embodiment, R8 is OH.

[0178] In a preferred embodiment, R9 is H, F, Cl, CN, methoxy, CH3, NR 11 R 11 ', and selected from CF3, R 11 and R 11 Each of the elements is independently selected from H and C1-C6 alkyl groups, preferably both being H.

[0179] In a preferred embodiment, R9 is selected from H, F, Cl, CN, methoxy, and CH3, preferably selected from H, F, and CN, and more preferably H.

[0180] In one preferred embodiment, R6, R7, and R9 are H, if present.

[0181] In a particularly preferred embodiment, the compound of formula (Ia) is

[0182] [ka] (Ia) [In the formula, Ring A is, [ka] Selected from, Y is CH2, R1, R4, R5, R6, R7, and R9 are all H. R2 and R3 are each independently selected from Cl, Br, and CF3, preferably both R2 and R3 are not CF3, and more preferably R2 is Cl or Br and R3 is CF3. R8 is selected from H, F, Cl, CN, phenyl, and OH, preferably selected from H, F, and OH, and more preferably OH. Preferably, ring A [ka] In this case, R8 is H, and neither R2 nor R3 is Cl.

[0183] In a more preferred embodiment, the compound of formula (Ia) is

[0184] [ka] (Ia) [In the formula, Y is CH2, R1, R4, R5, and R6 are all H. R2 and R3 are each independently selected from Cl, Br, and CF3, preferably both R2 and R3 are not CF3, and more preferably R2 is Cl or Br and R3 is CF3. R8 is selected from H, F, Cl, CN, phenyl, and OH, preferably selected from H, F, and OH, and more preferably OH. Preferably, if R8 is H, then R2 and R3 are both not Cl.

[0185] In one particularly preferred embodiment, the compound is the compound of formula (Ia.1):

[0186] [ka] (Ia.1)

[0187] [In the formula, ring A, and Y and R1~R 13 The base is as described in any of the embodiments above. In one preferred embodiment, the compound is in a pure form as an enantiomer.

[0188] In another embodiment, the compound is the compound of formula (Ia.2):

[0189] [ka] (Ia.2) [In the formula, ring A, and Y and R1~R 13 The base is as described in any of the embodiments above. In one preferred embodiment, the compound is in a pure form as an enantiomer.

[0190] In one preferred embodiment, the compound is in the form of a mixture comprising the compound of formula (Ia.1) and its corresponding enantiomer of formula (Ia.2). In one preferred embodiment, the mixture is a racemic mixture, i.e., a 50:50 mixture of the compound of formula (Ia.1) and its corresponding enantiomer of formula (Ia.2).

[0191] Using a racemic mixture, the compounds of formula (Ia.1) or (Ia.2) can be separated by standard methods, such as chemical resolution using an optically active acid, or by column chromatography or reversed-phase column chromatography using a substantially optically active (or "chiral") stationary phase known to those skilled in the art, to prepare pure compounds of formula (Ia.1) or (Ia.2) as enantiomers. The racemic mixture can also be used to prepare enantiomer-rich mixtures of the compounds of formula (Ia.1) or (Ia.2). Mixtures rich in either the compound of formula (Ia.1) or (Ia.2) can also be obtained from a suitable enantiomer-rich precursor.

[0192] In one preferred embodiment of the present invention, the compound is in the form of a mixture containing an enantiomer, and the weight:weight ratio is at least about 2:1 or greater, preferably at least about 5:1 or greater, and most preferably at least about 10:1 or greater, preferring an enantiomer (utemer) that exhibits significant in vitro and / or in vivo activity.

[0193] In one particularly preferred embodiment, the compound is in the form of a mixture comprising the compound of formula (Ia.1) and its corresponding enantiomer of formula (Ia.2), wherein the weight:weight ratio of the compound of formula (Ia.1) to the compound of formula (Ia.2) is greater than 1.05:1, more preferably greater than 2:1, even more preferably greater than 5:1, and even more preferably greater than 10:1.

[0194] In one particularly preferred embodiment, the compound is in the form of a mixture comprising the compound of formula (Ia.1) and its corresponding enantiomer of formula (Ia.2), which is substantially rich in the compound of formula (Ia.1).

[0195] In one embodiment, the compound is in the form of a mixture comprising the compound of formula (Ia.1) and its corresponding enantiomer of formula (Ia.2), wherein the weight:weight ratio of the compound of formula (Ia.2) to the compound of formula (Ia.1) is greater than 1.05:1, more preferably greater than 2:1, even more preferably greater than 5:1, and even more preferably greater than 10:1.

[0196] In one embodiment, the compound is in the form of a mixture comprising the compound of formula (Ia.1) and its corresponding enantiomer of formula (Ia.2), and is substantially rich in the compound of formula (Ia.2).

[0197] In one preferred embodiment, the compound of formula (Ia) is selected from the following compounds shown herein: (1), (2), (3), (4), (5), (6), (7), (8), (11), (12), (13), (15), (16), (17), (18), (24), (25), (26), (27), (28), (29), (31), (32), (34), (35), (36), (37), (45), (46) and (47) and its enantiomers, as well as mixtures of its enantiomers including racemic mixtures, and pharmaceutically acceptable salts and solvates.

[0198] In another preferred embodiment, the compound of formula (Ia) is as follows: (±)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5R,8S)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide; (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide; (±)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide; (5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide; (±)-N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5R,8S)-N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (±)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5S,8R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide; (5R,8S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (±)-N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5R,8S)-N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (±)-N-(4-bromo-3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(4-bromo-3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5R,8S)-N-(4-bromo-3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (±)-N-(3-chloro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5S,8R)-N-(3-chloro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5R,8S)-N-(3-chloro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (±)-N-(3-bromo-4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(3-bromo-4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5R,8S)-N-(3-bromo-4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (±)-N-(3-bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(3-bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5R,8S)-N-(3-bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (±)-N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5R,8S)-N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxamide; (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-epimino-cyclohepta[d]pyrimidine-10-carboxamide; (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxamide; (±)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide; (5R,8S)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (±)-N-(3,4-dichlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5S,8R)-N-(3,4-dichlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5R,8S)-N-(3,4-dichlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (±)-N-(3,4-dichlorophenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5S,8R)-N-(3,4-dichlorophenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5R,8S)-N-(3,4-dichlorophenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (±)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide; (5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide; (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide; (±)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5S,8R)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5R,8S)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide; (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide; (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide; (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelen-10-carboxamide; (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide; (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide; (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide; (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide; (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide; (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide; (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide; (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide; (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide; (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide; (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (±)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5S,8R)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5R,8S)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(hydroxyimino)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(hydroxyimino)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(hydroxyimino)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (±)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; (5S,8R)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5R,8S)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (±)-N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide; (5S,8R)-N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; and (5R,8S)-N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide; The following are selected from pharmaceutically acceptable salts and solvates thereof.

[0199] Compound of formula (Ic) Another aspect of the present invention relates to a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof.

[0200] [ka] (I C) [In the formula, Ring A is, [ka] (In the formula, R6 and R8 are independently H, F, Cl, Br, I, CN, alkoxy, NR) 11 R 11 ', selected from OH, alkyl, phenyl, and haloalkyl, provided that at least one of R6 and R8 is not H, Y is CH2, C=N-OH, and CR 10 R 10 Selected from ', R 10 and R 10 Each of these is independently selected from H, F, alkyl, and haloalkyl. R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I. R2 and R3 are independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl. R 11 and R 11 ' are independently H, alkyl, haloalkyl, and COR 12 , and SO2R 13 Selected from, R 12 and R 13 Both are alkyl groups.

[0201] Y and R 1-13 The preferred definitions for the groups and the preferred stereochemistry of the ring systems are as presented above for the compounds of formulas (Ia), (Ib), (Ie), and (If).

[0202] In one preferred embodiment, R8 is an OH group, and ring A is in the form of a pyridine tautomer: [ka]

[0203] Examples of highly preferred compounds of formula (Ic) include the following compounds described herein: (24), (25), (26), (27), (28), (29), (31), (32), (45), (46), and (47), and their enantiomers, as well as mixtures of their enantiomers including racemic mixtures, and pharmaceutically acceptable salts and solvates.

[0204] Compound of formula (Id) Another aspect of the present invention relates to a compound of formula (Id), or a pharmaceutically acceptable salt or solvate thereof.

[0205] [ka] (Id) [In the formula, Ring A is, [ka] (In the formula, R6 and R8 are independently H, F, Cl, Br, I, CN, alkoxy, NR) 11 R 11 ', selected from OH, alkyl, phenyl, and haloalkyl, Y is CH2, C=N-OH, and CR 10 R 10 Selected from ', R 10 and R 10 Each of these is independently selected from H, F, alkyl, and haloalkyl. R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I. R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl, provided that at least one of R2 and R3 is selected from CN, methoxy, and haloalkyl. R 11 and R 11 ' are independently H, alkyl, haloalkyl, and COR 12 , and SO2R 13 Selected from, R 12 and R 13 Both are alkyl groups.

[0206] Y and R 1-13 The preferred definitions for the group and the preferred stereochemistry of the ring system are as presented above for the compound of formula (Ia).

[0207] Examples of highly preferred compounds of formula (Id) include the following compounds described herein: (1), (2), (3), (5), (8), (11), (13), (15), (18), (27), (28), (29), (32), (45), and (47), and their enantiomers, as well as mixtures of their enantiomers including racemic mixtures, and pharmaceutically acceptable salts and solvates.

[0208] method A further aspect of the present invention is a method for preparing a compound as defined herein, wherein the compound of formula II is used to prepare the compound of formula III (wherein R 1-5 A method comprising reacting with (Y and A as defined above) to form compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), or (If): [ka]

[0209] In one preferred embodiment, the reaction occurs in the presence of a base, preferably N,N-diisopropylethylamine (DIPEA) or triethylamine. Preferably, the reaction occurs in an organic solvent. Suitable organic solvents include, but are not limited to, dichloromethane, tetrahydrofuran, and dimethylformamide, or mixtures of two or more of these. Those skilled in the art will understand that other bases and solvents are also suitable.

[0210] therapeutic use Further aspects of the present invention relate to compounds described herein for use in pharmaceuticals. The compounds have specific uses in the fields of oncology, immuno-oncology, and immunology, which are described in more detail below. In preferred embodiments, the compounds of the present invention modulate GPR65, more preferably inhibit GPR65 signaling.

[0211] Another aspect of the present invention relates to the compounds described herein for use as pharmaceuticals, preferably for use in the treatment or prevention of disorders selected from proliferative disorders and immunodeficiencies.

[0212] Another aspect of the present invention relates to the compounds described herein for use in the treatment or prevention of asthma and / or chronic obstructive pulmonary disease (COPD). The GPR65 variant / SNP (rs6574978) has been shown to be associated with asthma / COPD syndrome with a nearly GWAS-significant p-value (1.18 x 10 e-7) (Hardin, M. et al. (2014). The clinical and genetic features of COPD-asthma overlap syndrome. Eur Respir J. 2014 Aug;44(2):341-50). Furthermore, pH-dependent GPR65 activation (pH is low / acidic in asthmatic lungs) promotes eosinophil survival in a cAMP-dependent manner and contributes to disease progression / exacerbation. It is also well known that asthma symptoms are reduced in GPR65 knockout mice (Kottyan, L. et al. (2009). Eosinophil viability is increased by acidic pH in a cAMP- and GPR65-dependent manner. Blood. 2009 Sep 24;114(13):2774-82).

[0213] Another aspect of the present invention relates to the compounds described herein for use in the treatment or prevention of acute respiratory distress syndrome (ARDS). GPR65 has been shown to be protective in a model of LPS-induced acute lung injury (Tsurumaki, H. et al (2015). Int J Mol Sci. Protective Role of Proton-Sensing TDAG8 in Lipopolysaccharide-Induced Acute Lung Injury. Dec 4;16(12):28931-42).

[0214] One aspect of the present invention relates to compounds described herein for use in the treatment of proliferative disorders, preferably cancer or leukemia.

[0215] In one preferred embodiment, cancer is a solid tumor and / or its metastases.

[0216] In another preferred embodiment, the cancer is selected from melanoma, elocellular carcinoma (RCC), gastric cancer, acute myeloid leukemia (AML), triple-negative breast cancer (TNBC), colorectal cancer, head and neck cancer, colorectal adenocarcinoma, pancreatic adenocarcinoma, lung cancer, sarcoma, ovarian cancer, and glioma, preferably glioblastoma (GBM).

[0217] Without being constrained by theory, it is understood that GPR65 modulators can prevent the increase in cytoplasmic cAMP in tumor-associated macrophages (TAMs), natural killer (NK) cells, and subsets of T cells that normally result from these exposures to the acidic tumor microenvironment and the concurrently occurring GPR65 activation. This reduction in cytoplasmic cAMP levels, in turn, reduces the levels of ICERs and pro-inflammatory mediators, such as CXCL10 and TNFα, preventing TAM polarization and other immune cell alterations associated with a non-inflammatory and tumor-tolerant environment. Therefore, GPR65 modulators are expected to lead to increased tumor visibility in the immune system and increase immune-mediated tumor clearance. This suggests that modulation of GPR65 activity may be an effective treatment for cancer, either as monotherapy, in combination with cancer immunotherapy (vaccines, drugs that promote T cell-mediated immune responses), or in patients who do not respond to immunomodulatory techniques such as PD1 / PDL-1 blockade.

[0218] Another aspect of the present invention relates to the compounds described herein for use in the treatment or prevention of immunodeficiencies, preferably autoimmune diseases.

[0219] In one embodiment, the autoimmune disease is selected from psoriasis, psoriatic arthritis, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), autoimmune thyroiditis (Hashimoto's disease), Graves' disease, uveitis (including intermediate uveitis), ulcerative colitis, Crohn's disease, autoimmune retinouveitis, systemic vasculitis, polymyositis dermatomyositis, systemic sclerosis (scleroderma), Sjögren's syndrome, ankylosing spondylitis and related spondyloarthropathy, sarcoidosis, autoimmune hemolytic anemia, immune thrombocytosis, autoimmune multilinear endocrine disorder, autoimmune myocarditis, type 1 diabetes, and atopic dermatitis.

[0220] In a particularly preferred embodiment, the autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and multiple sclerosis (MS).

[0221] Without being constrained by theory, it is understood that the GPR65 modulator prevents the upregulation of ICER in CD4+ T cells. This, in turn, is expected to prevent the suppression of ICER-related IL-2, which biases CD4+ T cells toward the inflammatory Th17 phenotype associated with increased pathogenicity in the context of autoimmune diseases. This is supported by the fact that mutations at the GPR65 site are associated with several autoimmune diseases, such as multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, and Crohn's disease (Gaublomme, J. et al. (2015). Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell, 1400-1412). This suggests that modulation of GPR65 activity may be an effective treatment for autoimmune diseases.

[0222] Another aspect relates to the compounds described herein for use in the treatment or prevention of disorders related to or associated with abnormal activity of GPR65.

[0223] Another aspect relates to the compounds described herein for use in the treatment or prevention of diseases or disorders related to GPR65.

[0224] Another aspect of the present invention relates to a method for treating the above-described disorders, comprising administering the compounds described herein to the subject.

[0225] Another aspect of the present invention relates to a method for treating a disease or disorder related to GPR65 in a subject. The method according to this aspect of the present invention is effective by administering a therapeutically effective amount of the compound of the present invention described above herein, either by itself or more preferably as part of a pharmaceutical composition, for example, mixed with a pharmaceutically acceptable carrier, as detailed below herein.

[0226] Another aspect of the present invention relates to a method for treating a subject having a condition that is alleviated by GPR65 modulation, the method comprising administering a therapeutically effective amount of the compound according to the present invention to the subject.

[0227] Another embodiment relates to a method for treating a pathological condition by mitigating the modulation of GPR65, comprising administering a therapeutically effective amount of the compound according to the present invention to the target.

[0228] Preferably, the subject is a mammal, and more preferably a human.

[0229] The term “method” refers to methods, means, techniques and procedures for accomplishing a given task, including but not limited to methods, means, techniques and procedures that are publicly known to practitioners of chemical, pharmacological, biological, biochemical and medical techniques, or that have been readily developed by them from known methods, means, techniques and procedures.

[0230] In this specification, the term “treat” includes inhibiting, substantially inhibiting, slowing or restoring the progression of a disease or disorder, substantially improving the clinical symptoms of a disease or disorder, or substantially preventing the appearance of the clinical symptoms of a disease or disorder.

[0231] In this specification, the term “prevent” primarily refers to methods for preventing an organism from acquiring a disability or disease in the initial stage.

[0232] The term "therapeutic dose" refers to the amount of compound administered that alleviates, to some extent, one or more symptoms of the disease or disorder being treated.

[0233] For any compound used in the present invention, the therapeutically effective dose, also referred to herein as the therapeutically effective dose, can also be initially predicted from a cell culture assay. For example, the dose can be formulated in an animal model and determined in cell culture. 50 or IC 100 A circulating concentration range including [specific values] can be achieved. Using such information, a useful dose in humans can be determined more accurately. The initial dose can also be predicted from in vivo data. Using these initial guidelines, a person skilled in the art can determine an effective dose in humans.

[0234] Furthermore, the toxicity and therapeutic effects of the compounds described herein are observed in cell cultures or experimental animals, for example, in LD50. 50 and ED 50 This can be determined by standard pharmaceutical procedures. The dose-to-toxicity ratio is the therapeutic index, LD50. 50 and ED 50 It can be expressed as a ratio between [a certain value] and [another value]. Compounds exhibiting a high therapeutic index are preferred. Data obtained from these cell culture assays and animal experiments can be used to formulate a dose range that is not toxic for use in humans. The dose of such compounds is preferably one that is only slightly toxic or non-toxic ED. 50The concentration is within the circulating concentration range, including [specific component]. The dose may vary within this range depending on the dosage form and route of administration used. The exact formulation, route of administration, and dose can be selected by the individual physician, taking into account the patient's condition (see, for example, Fingl et al, 1975, The Pharmacological Basis of Therapeutics, chapter 1, page 1).

[0235] Sufficient plasma levels of the active compound to maintain therapeutic effect can be obtained by individually adjusting the dosage and interval of administration. Typical patient doses for oral administration range from approximately 50 to 2000 mg / day, generally from approximately 100 to 1000 mg / day, preferably from approximately 150 to 700 mg / day, and most preferably from approximately 250 to 500 mg / day or 50 to 100 mg / day. Preferably, therapeutically effective serum levels are achieved by administering multiple doses daily. In the case of topical administration or selective uptake, the effective topical concentration of the drug may not be related to the plasma concentration. Those skilled in the art can optimize the therapeutically effective topical dose without excessive experimentation.

[0236] As used herein, “GPR65-related disease or disorder” means a disease or disorder characterized by inappropriate GPR65 activity. Inappropriate GPR65 activity refers to either an increase or decrease in GPR65 activity compared to activity in a healthy subject, as measured by an enzymatic or cellular assay. Inappropriate activity may also be due to overexpression of GPR65 in the affected tissue compared to healthy adjacent tissue.

[0237] Preferred diseases or disorders that the compounds described herein may be useful in preventing include proliferative disorders and immunological disorders as described earlier herein, as well as asthma and chronic obstructive pulmonary disease.

[0238] Therefore, the present invention further provides the use of the compounds defined herein in the preparation of pharmaceuticals for the treatment of diseases in which it is desirable to modulate GPR65. Such diseases include proliferative and immunological disorders as described earlier herein, as well as asthma and chronic obstructive pulmonary disease.

[0239] As used herein, the phrase “preparation of a pharmaceutical product” includes, in addition to these uses in any stage of such preparation of a pharmaceutical product, the direct use of the components of the present invention as a pharmaceutical product.

[0240] In one preferred embodiment, the compound prevents the expected increase in cytoplasmic cAMP levels following GPR65 activation at acidic pH. This prevention of cAMP accumulation, in turn, prevents downstream signaling via ICER, as described above. The “Human GPR65-Ring Adenylate (cAMP) Homogeneous Time-Resolved Fluorescence (HTRF) Antagonist Assay” described in the attached Examples, or simply the “cAMP Assay,” can be used to measure the potency of a GPR65 modulator, expressed as the concentration of the compound required to reduce the increase in cAMP concentration due to GPR65 activation by 50% (i.e., IC). 50 ).

[0241] In one preferred embodiment, the compound has an IC50 of less than approximately 25 μM in the cAMP assay. 50 The values ​​are shown. More preferably, the compound has an IC of less than about 10 μM, more preferably less than about 5 μM, even more preferably less than about 1 μM, and even more preferably less than about 0.1 μM in the cAMP assay. 50 Show the value.

[0242] In another preferred embodiment, the compound exhibits an hGPR65 IC50 value of less than 5 μM, more preferably less than 500 nM, in the assay described above.

[0243] Therapeutic use of compounds of formula I Further aspects of the present invention relate to compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, for use as pharmaceuticals.

[0244] [ka] (I) [In the formula, Ring A is a 5-membered or 6-membered aromatic or aromatic heterocycle, wherein the aromatic or aromatic heterocycle is composed of F, Cl, Br, I, CN, alkoxy, or NR. 11 R 11 ', OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl substituents may be substituted with one or more substituents selected from OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, and the aryl and heteroaryl substituents may further be F, Cl, Br, I, CN, alkoxy, NR 11 R 11 ', may be substituted with one or more substituents independently selected from OH, alkyl, haloalkyl, and aralkyl, Y is CH2, C=N-OH, and CR 10 R 10 Selected from ', R 10 and R 10 Each of these is independently selected from H, F, alkyl, and haloalkyl. R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I. R2 and R3 are independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl. R 11 and R 11 ' are independently H, alkyl, haloalkyl, and COR 12 , and SO2R 13 Selected from, R 12 and R 13 Both are alkyl groups.

[0245] Rings A, Y, and R 1-13The preferred definitions for the preferred stereochemistry of the groups and ring systems are as presented above for the compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), and (If).

[0246] Preferably, the compounds of formula (I) are intended for use in the treatment of proliferative disorders and autoimmune disorders, as well as in the treatment of asthma and chronic obstructive pulmonary disease. Details of appropriate proliferative disorders and autoimmune disorders are the same as those described above under the heading "Therapeutic Uses."

[0247] In one preferred embodiment, the compound of formula (I) for use described above is selected from the following: (1)-(8), (11)-(13), (15)-(18), (24)-(29), (31), (32), (34)-(37) and (45)-(53), and their enantiomers, as well as mixtures of their enantiomers including racemic mixtures, and pharmaceutically acceptable salts and solvates.

[0248] In one preferred embodiment, a compound of formula (I) selected from the following for use as described above:

[0249] [ka] JPEG0007870548000088.jpg188129JPEG0007870548000089.jpg164129JPEG0007870548000090.jpg194127JPEG00078705480000 91.jpg170127JPEG0007870548000092.jpg150127JPEG0007870548000093.jpg178129JPEG0007870548000094.jpg158129JPEG000 7870548000095.jpg193126JPEG0007870548000096.jpg167127JPEG0007870548000097.jpg161127JPEG0007870548000098.jpg16 9129JPEG0007870548000099.jpg178129JPEG0007870548000100.jpg160129JPEG0007870548000101.jpg169128JPEG00078705480 00102.jpg158128JPEG0007870548000103.jpg154131JPEG0007870548000104.jpg166128JPEG0007870548000105.jpg161130JPE G0007870548000106.jpg153127JPEG0007870548000107.jpg152128JPEG0007870548000108.jpg153128JPEG0007870548000109.j pg153129JPEG0007870548000110.jpg159130JPEG0007870548000111.jpg154128JPEG0007870548000112.jpg154129JPEG0007870 548000113.jpg167129JPEG0007870548000114.jpg153129JPEG0007870548000115.jpg153130JPEG0007870548000116.jpg102128

[0250] and its enantiomers, as well as mixtures of its enantiomers including racemic mixtures, and pharmaceutically acceptable salts and solvates.

[0251] Another aspect of the present invention relates to the compounds described above and their enantiomers, as well as mixtures of their enantiomers including racemic mixtures, and pharmaceutically acceptable salts and solvates for use as pharmaceuticals.

[0252] Another preferred embodiment is a compound according to the present invention selected from the following, or a compound according to the present invention for the use described above: N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(4-bromo-3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3-chloro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3-bromo-4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3-bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(3,4-dichlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(3,4-dichlorophenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(hydroxyimino)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(5-chloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide N-(3,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide 10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine 2-oxide 10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine 2-oxide 2-Chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annerene-10-carboxamide 1-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 1-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 2-Chloro-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo-[7]annelene-10-carboxamide 2-Cyano-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide 2-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annerene-10-carboxamide N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo-[7]annelene-10-carboxamide N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 1-Chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(4,5-dichloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo-[7]annelene-10-carboxamide tert-butyl-(10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-1-yl)carbamate N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide N-(4,5-dichloro-2-cyanophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine 2-oxide N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(4,5-dichloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(4,5-dichloro-2-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide 3-Bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 3-Chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(4-chloro-5-(trifluoromethyl)pyridine-2-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d-]pyrimidine-10-carboxamide N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-8-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(4,5-dichloro-2-methylphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(4,5-dichloro-2-methoxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 1-Fluoro-N-(2-fluoro-5-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 1-Fluoro-N-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 1-Fluoro-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[c]pyridine-10-carboxamide Methyl 2-chloro-4-(-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide)benzoate Methyl 2-chloro-5-(-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide)benzoate N-(3-chloro-4-(trifluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide Methyl 2-chloro-4-fluoro-5-(1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide)benzoate N-(4-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3-chloro-4-(difluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(3-chloro-4-(trifluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(4-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide Methyl 2-chloro-4-(3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide)benzoate Methyl 2-chloro-5-(3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide)benzoate Methyl 2-chloro-4-fluoro-5-(3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide)benzoate N-(3-chloro-4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(4,5-dichloro-2-fluorophenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-3,5-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide N-(4-bromo-5-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(5-bromo-4-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(4-bromo-3-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(3-bromo-4-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 1-Bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(4,5-dichloro-2-hydroxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(3-cyano-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 1-Fluoro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3-bromo-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3-chloro-2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 1-Fluoro-N-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 1-Fluoro-N-(3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide 1-Fluoro-N-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,5-bis(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c-]pyridine-10-carboxamide 1-Fluoro-N-(4-methyl-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(2,3-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(4-cyano-3-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3-chloro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3-cyano-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide 1-Fluoro-N-(3,4,5-trichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 1-Fluoro-N-(3-methyl-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(4-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide N-(3-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 1-Fluoro-N-(3-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3-bromo-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3,5-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(5-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide 1-Fluoro-N-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(4-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(4-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide N-(3-chloro-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide N-(4-acrylamido-3-chlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(4,5-dichloro-2-fluorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]-pyridine-10-carboxamide N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide N-(4-(1H-pyrazole-1-yl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide N-([1,1'-biphenyl]-3-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 1-Fluoro-N-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 1-Fluoro-N-(4-(thiazole-4-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide 1-Fluoro-N-(4-(4-methyloxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 1-Fluoro-N-(4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-2,5,6,7,8,9-hexahydro-1H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-([1,1'-biphenyl]-4-yl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(4,5-dichloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyridazine-10-carboxamide N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine-10-carboxamide 1,4-Dichloro-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine-10-carboxamide N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide N-(4-chloro-3-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide N-(4,5-dichloro-2-fluorophenyl)-1-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide N-(3-chloro-4-(trifluoromethyl)phenyl)-9-(hydroxyimino)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide N-(3,4-dichlorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (±)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (±)-N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (±)-N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(4-bromo-3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3-chloro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3-bromo-4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3-bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (±)-N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]-pyrimidine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (±)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(hydroxyimino)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(5-chloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (±)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (±)-N-(3,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide (±)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide (±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine 2-oxide (±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine 2-oxide (±)-2-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelen-10-carboxamide (±)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (±)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[c]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-2-chloro-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo-[7]annelene-10-carboxamide (±)-2-cyano-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelen-10-carboxamide (±)-2-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelen-10-carboxamide (±)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide (±)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-1-Chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4,5-dichloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-benzo[7]annelen-10-carboxamide tert-butyl((±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epimino-cyclohepta[c]pyridine-1-yl)carbamate (±)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-benzo[7]annelene-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (±)-N-(4,5-dichloro-2-cyanophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine 2-oxide (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4,5-dichloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4,5-dichloro-2-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-3-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (±)-3-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4-chloro-5-(trifluoromethyl)pyridine-2-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (±)-N-(3-cyano-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-fluoro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3-bromo-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3-chloro-2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-Fluoro-N-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-Fluoro-N-(3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-1-Fluoro-N-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(3,5-bis(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-fluoro-N-(4-methyl-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(2,3-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(4-cyano-3-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3-chloro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3-cyano-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-Fluoro-N-(3,4,5-trichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-1-fluoro-N-(3-methyl-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-Fluoro-N-(3-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3-bromo-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3,5-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(5-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-1-Fluoro-N-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(4-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(3-chloro-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(4-acrylamido-3-chlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4,5-dichloro-2-fluorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (±)-N-(4-(1H-pyrazole-1-yl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-([1,1'-biphenyl]-3-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-1-Fluoro-N-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-Fluoro-N-(4-(thiazole-4-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-1-fluoro-N-(4-(4-methyloxazole-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-fluoro-N-(4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-2,5,6,7,8,9-hexahydro-1H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (±)-N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-([1,1'-biphenyl]-4-yl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4,5-dichloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyridazine-10-carboxamide (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine-10-carboxamide (±)-1,4-dichloro-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine-10-carboxamide (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(4-chloro-3-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(3-cyano-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-fluoro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3-bromo-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3-chloro-2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-Fluoro-N-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-Fluoro-N-(3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-Fluoro-N-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(3,5-bis(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-fluoro-N-(4-methyl-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(2,3-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(4-cyano-3-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3-chloro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3-cyano-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-1-Fluoro-N-(3,4,5-trichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-1-fluoro-N-(3-methyl-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-Fluoro-N-(3-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3-bromo-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3,5-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(5-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-Fluoro-N-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(3-chloro-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(4-acrylamido-3-chlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4,5-dichloro-2-fluorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (±)-N-(4-(1H-pyrazole-1-yl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-([1,1'-biphenyl]-3-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-1-Fluoro-N-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-Fluoro-N-(4-(thiazole-4-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-1-fluoro-N-(4-(4-methyloxazole-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-fluoro-N-(4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-2,5,6,7,8,9-hexahydro-1H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (±)-N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-([1,1'-biphenyl]-4-yl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(4,5-dichloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyridazine-10-carboxamide (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine-10-carboxamide (±)-1,4-dichloro-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine-10-carboxamide (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (±)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(4-chloro-3-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (±)-N-(4,5-dichloro-2-fluorophenyl)-1-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-9-(hydroxyimino)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide cis-(±)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide trans-(±)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-8-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4,5-dichloro-2-methylphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-N-(4,5-dichloro-2-methoxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-Fluoro-N-(2-Fluoro-5-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-Fluoro-N-(2-Fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (±)-1-Fluoro-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(4-bromo-3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5R,8S)-N-(3-chloro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5R,8S)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]=pyrimidine-10-carboxamide (5R,8S)-N-(3-bromo-4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5R,8S)-N-(3-bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5R,8S)-N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (6S,9R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxamide (6S,9R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-epimino-cyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide (5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5R,8S,E)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(hydroxyimino)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(5-chloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5R,8S)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[c]pyridine 2-oxide (6S,9R)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine2-oxide (5R,8S)-2-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (6S,9R)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (6S,9R)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide (5R,8S)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c-]pyridine-10-carboxamide (6S,9R)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-2-chloro-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-benzo[7]annelen-10-carboxamide (5R,8S)-2-cyano-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5R,8S)-2-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-benzo[7]annelene-10-carboxamide (6S,9R)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide (5R,8S)-1-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[c]pyridine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-N-(4,5-dichloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-benzo[7]annelen-10-carboxamide tert-butyl((6S,9R)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epimino-cyclohepta[c]pyridine-1-yl)carbamate (5R,8S)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(3,4-dichlorophenyl)-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (6S,9R)-N-(4,5-dichloro-2-cyanophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine2-oxide (6S,9R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(4,5-dichloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epimino-cyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(3,4-dichlorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-N-(4,5-dichloro-2-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide (6S,9R)-3-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (6S,9R)-3-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(4-chloro-5-(trifluoromethyl)pyridine-2-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (6S,9R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (6S,9R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S,9S)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5S,8R)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(4-bromo-3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5S,8R)-N-(3-chloro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5S,8R)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5S,8R)-N-(3-bromo-4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5S,8R)-N-(3-bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5S,8R)-N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (6R,9S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxamide (6R,9S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-epimino-cyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d-]pyrimidine-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelene-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide (5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5S,8R,E)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(hydroxyimino)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(5-chloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5S,8R)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[c]pyridine 2-oxide (6R,9S)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine 2-oxide (5S,8R)-2-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (6R,9S)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (6R,9S)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide (5S,8R)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide (6R,9S)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-2-chloro-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-benzo[7]annelen-10-carboxamide (5S,8R)-2-cyano-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo-[7]annelen-10-carboxamide (5S,8R)-2-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-benzo[7]annelene-10-carboxamide (6R,9S)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-1-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-N-(4,5-dichloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-benzo[7]annelen-10-carboxamide tert-butyl((6R,9S)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epimino-cyclohepta[c]pyridine-1-yl)carbamate (5S,8R)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annelene-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-benzo[7]annelene-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(3,4-dichlorophenyl)-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (6R,9S)-N-(4,5-dichloro-2-cyanophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide (5S,8R)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[c]-pyridine2-oxide (6R,9S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(4,5-dichloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epimino-cyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(3,4-dichlorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-N-(4,5-dichloro-2-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide (6R,9S)-3-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide (6R,9S)-3-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(4-chloro-5-(trifluoromethyl)pyridine-2-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (6R,9S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (6R,9S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R,9R)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-8-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(4,5-dichloro-2-methylphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(4,5-dichloro-2-methoxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide (5R,8S)-1-fluoro-N-(2-fluoro-5-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-1-fluoro-N-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-1-fluoro-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide Methyl 2-chloro-4-((5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide)benzoate Methyl 2-chloro-5-((5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide)benzoate (5R,8S)-N-(3-chloro-4-(trifluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide Methyl 2-chloro-4-fluoro-5-((5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide)benzoate (5R,8S)-N-(4-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(3-chloro-4-(difluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(3-chloro-4-(trifluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(4-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide Methyl 2-chloro-4-((6S,9R)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide)benzoate Methyl 2-chloro-5-((6S,9R)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide)benzoate Methyl 2-chloro-4-fluoro-5-((6S,9R)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide)benzoate (5R,8S)-N-(3-chloro-4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S,9S)-N-(3,4-dichlorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(3,4-dichlorophenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(4,5-dichloro-2-fluorophenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-epimino-cyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (5S,6S,9R)-N-(3,4-dichlorophenyl)-3,5-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(4-bromo-5-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(5-bromo-4-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(4-bromo-3-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(3-bromo-4-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-1-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-N-(4,5-dichloro-2-hydroxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-(3,4-dichlorophenyl)-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-8-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(4,5-dichloro-2-methylphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(4,5-dichloro-2-methoxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide (5S,8R)-1-fluoro-N-(2-fluoro-5-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-1-fluoro-N-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-1-fluoro-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide Methyl 2-chloro-4-((5S,8R)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide)benzoate Methyl 2-chloro-5-((5S,8R)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide)benzoate (5S,8R)-N-(3-chloro-4-(trifluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide Methyl 2-chloro-4-fluoro-5-((5S,8R)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide)benzoate (5S,8R)-N-(4-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(3-chloro-4-(difluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(3-chloro-4-(trifluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(4-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide Methyl 2-chloro-4-((6R,9S)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide)benzoate Methyl 2-chloro-5-((6R,9S)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide)benzoate Methyl 2-chloro-4-fluoro-5-((6R,9S)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide)benzoate (5S,8R)-N-(3-chloro-4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R,9S)-N-(3,4-dichlorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(3,4-dichlorophenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(4,5-dichloro-2-fluorophenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-epimino-cyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (5S,6R,9S)-N-(3,4-dichlorophenyl)-3,5-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(4-bromo-5-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(5-bromo-4-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(4-bromo-3-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(3-bromo-4-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-1-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-N-(4,5-dichloro-2-hydroxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-(3,4-dichlorophenyl)-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(3-cyano-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-1-fluoro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(3-bromo-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(3-chloro-2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-1-fluoro-N-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-1-fluoro-N-(3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-1-fluoro-N-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-N-(3,5-bis(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-1-fluoro-N-(4-methyl-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(2,3-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-N-(2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(3-chloro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(3-cyano-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-1-fluoro-N-(3,4,5-trichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-1-fluoro-N-(3-methyl-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(4-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-N-(4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(3-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-1-fluoro-N-(3-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(3-bromo-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(3,5-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-N-(5-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-1-fluoro-N-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(4-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(4-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(3-chloro-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(4-acrylamido-3-chlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(4,5-dichloro-2-fluorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (5R,8S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (5R,8S)-N-(4-(1H-pyrazole-1-yl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-([1,1'-biphenyl]-3-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-1-fluoro-N-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c-]pyridine-10-carboxamide (5R,8S)-1-fluoro-N-(4-(thiazole-4-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-1-fluoro-N-(4-(4-methyloxazole-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-1-fluoro-N-(4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-2,5,6,7,8,9-hexahydro-1H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (5R,8S)-N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (6S,9R)-N-([1,1'-biphenyl]-4-yl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(4,5-dichloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine-10-carboxamide (5R,8S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine-10-carboxamide (5R,8S)-1,4-dichloro-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine-10-carboxamide (5R,8S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (5S,8R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (6R,9S)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide (5R,8S)-N-(4-chloro-3-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3-cyano-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-1-fluoro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3-bromo-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3-chloro-2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-1-fluoro-N-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-1-fluoro-N-(3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-1-fluoro-N-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3,5-bis(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-1-fluoro-N-(4-methyl-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(2,3-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-N-(2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-N-(4-cyano-3-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3-chloro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3-cyano-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-1-fluoro-N-(3,4,5-trichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-1-fluoro-N-(3-methyl-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(4-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-N-(4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-1-fluoro-N-(3-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3-bromo-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3,5-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-N-(5-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-1-fluoro-N-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(4-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide (5S,8R)-N-(4-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3-chloro-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(4-acrylamido-3-chlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(4,5-dichloro-2-fluorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (5S,8R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (5S,8R)-N-(4-(1H-pyrazole-1-yl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-([1,1'-biphenyl]-3-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-1-fluoro-N-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-1-fluoro-N-(4-(thiazole-4-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-1-fluoro-N-(4-(4-methyloxazole-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-1-fluoro-N-(4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-2,5,6,7,8,9-hexahydro-1H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (5S,8R)-N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (6R,9S)-N-([1,1'-biphenyl]-4-yl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(4,5-dichloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine-10-carboxamide (5S,8R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine-10-carboxamide (5S,8R)-1,4-dichloro-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine-10-carboxamide (5S,8R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (5S,8R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide (6S,9R)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(4-chloro-3-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(4,5-dichloro-2-fluorophenyl)-1-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(4,5-dichloro-2-fluorophenyl)-1-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (5R,8S,9S)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5R,8S,E)-N-(3-chloro-4-(trifluoromethyl)phenyl)-9-(hydroxyimino)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R,E)-N-(3-chloro-4-(trifluoromethyl)phenyl)-9-(hydroxyimino)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (5S,8R)-N-(4,5-dichloro-2-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide (5R,8S)-N-(4,5-dichloro-2-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide Methyl 2-chloro-4-((6S,9R)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epimino-cyclohepta[c]pyridine-10-carboxamide)benzoate Methyl 2-chloro-4-((6R,9S)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epimino-cyclohepta[c]pyridine-10-carboxamide)benzoate as well as pharmaceutically acceptable salts and solvates thereof.

[0253] In a preferred embodiment, the compounds according to the present invention, or compounds according to the present invention for use, exhibit an IC50 greater than 500 nM and less than 5 μM in a human GPR65-cyclic adenylate (cAMP) homogeneous time-resolved fluorescence (HTRF) antagonist assay, as described in the appendix examples. In a preferred embodiment, the compounds are selected from those indicated as “high” or “intermediate” in Table 1.

[0254] In a more preferred embodiment, the compound according to the present invention, or the compound according to the present invention for use, exhibits an IC50 of less than 500 nM in a human GPR65 cAMP HTRF antagonist assay, as described in the appended examples. In a preferred embodiment, the compound is selected from those indicated as “high” in Table 1.

[0255] Pharmaceutical composition For use according to the present invention, the compounds described herein or their physiologically acceptable salts, esters, or other physiologically functional derivatives may be presented as pharmaceutical formulations comprising the compound or its physiologically acceptable salts, esters, or other physiologically functional derivatives together with one or more pharmaceutically acceptable carriers, excipients, or diluents for the compound, and optionally other therapeutic and / or prophylactic components. The carrier(s) must be acceptable in the sense that they are compatible with the other components of the formulation and are not harmful to the recipient. The pharmaceutical compositions may be in amounts used in human and veterinary medicines for human or animal use.

[0256] Examples of such excipients suitable for various different forms of pharmaceutical compositions described herein can be found in “Handbook of Pharmaceutical Excipients, 2 nd This can be found in Edition, (1994), Edited by A Wade and PJ Weller. If a carrier, or more than one carrier, is present, each carrier must be acceptable in the sense that it is compatible with the other components of the formulation and not harmful to the recipient.

[0257] Acceptable carriers or diluents for therapeutic use are well known in the field of pharmacy and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985).

[0258] Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, and sorbitol. Examples of suitable diluents include ethanol, glycerol, and water.

[0259] The selection of pharmaceutical carriers, excipients, or diluents may be made with respect to the intended route of administration and standard pharmaceutical practices. Pharmaceutical compositions may include, or in addition to, any suitable binder(s), lubricants(s), suspending agents(s), coatings(s), solubilizers(s), buffers(s), flavoring agents(s), surfactants(s), thickeners(s), preservatives(s) (including antioxidants), and substances included for the purpose of conferring a formulation isotonic with the blood of the intended recipient.

[0260] Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flowing lactose, beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, and polyethylene glycol.

[0261] Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride.

[0262] Preservatives, stabilizers, dyes, and even flavorings may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0263] Pharmaceutical formulations include those suitable for oral, topical (including cutaneous, oral buccal, and sublingual), rectal, or parenteral (including subcutaneous, intradermal, intramuscular, and intravenous), nasal, and pulmonary administration, such as by inhalation. Where appropriate, formulations may be conveniently presented in separate dose units or prepared by any method well known in the field of pharmacy. All methods include the steps of combining the active compound with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, forming the product into the desired formulation.

[0264] Pharmaceutical formulations suitable for oral administration, in which the carrier is solid, are most preferably presented as unit-dose formulations, for example, as boluses, capsules, or tablets, each containing a predetermined amount of the active compound. Tablets can be prepared by compression or molding with optionally one or more adjuncts. Compressed tablets can be prepared by mixing the active compound in the form of a free fluid, such as a powder or granules, with optionally a binder, lubricant, inert diluent, surface surfactant, or dispersant, and compressing it in appropriate equipment. Wet tablets can be prepared by molding the active compound with an inert liquid diluent. Tablets may optionally be coated, and if uncoated, they may optionally be notched. Capsules can also be prepared by filling capsule shells with the active compound alone or mixed with one or more adjuncts, and then sealing them in the usual manner. Cachet formulations are similar to capsules, in which the active compound is sealed within a rice paper casing with optional adjuncts(s). The active compound may also be formulated as dispersible granules, which can be suspended in water before administration or sprinkled on food. The granules can also be packaged in sachets, for example. Formulations suitable for oral administration, in which the carrier is liquid, may be presented as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.

[0265] Oral formulations include controlled-release dosage forms, such as tablets in which the active compound is formulated within a suitable controlled-release matrix or coated with a suitable controlled-release film. Such formulations may be particularly advantageous for prophylactic use.

[0266] Pharmaceutical formulations suitable for rectal administration, in which the carrier is solid, are most preferably presented as unit-dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by mixing the active compound with a softened or molten carrier(s), followed by cooling and molding in a mold. Pharmaceutical formulations suitable for parenteral administration include a sterile solution or suspension of the active compound in an aqueous or oily vehicle.

[0267] The injectable preparations can be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in unit doses or in multi-dose containers that are sealed after formulation introduction until use is required. Alternatively, the active compound may be in powder form, prepared before use with a suitable vehicle, such as sterile, pyrogen-free water.

[0268] The active compound may also be formulated as a long-acting depot preparation, which can be administered by intramuscular injection or implantation, for example, subcutaneously or intramuscularly. The depot preparation may contain, for example, a suitable polymeric or hydrophobic material or an ion exchange resin. Such long-acting formulations are particularly advantageous for prophylactic use.

[0269] Formulations suitable for oral administration to the lungs are presented so as to deliver particles containing the active compound, preferably having a diameter in the range of 0.5 to 7 microns, to the recipient's bronchial trees.

[0270] One possibility is that such formulations may be conveniently presented for use in inhalation devices, preferably in the form of a finely ground powder, either as a perforable capsule made of gelatin, or as a self-propelled formulation comprising the active compound, a suitable liquid or gaseous spray, and optionally other components, such as surfactants and / or solid diluents. Suitable liquid sprays include propane and chlorofluorocarbons, as well as suitable gaseous sprays containing carbon dioxide. Self-propelled formulations in which the active compound is dispensed in the form of droplets of solution or suspension may also be available.

[0271] Such self-propelled formulations are similar to those known in the art and can be prepared by established procedures. Preferably, the self-propelled formulation is presented in a container equipped with either a manually operated or automatically functioning valve having the desired spray characteristics; advantageously, the valve is of the metering type, delivering a fixed amount, e.g., 25 to 100 microliters, each time it is in operation.

[0272] As a further possibility, the active compound may be in the form of a solution or suspension for use in an atomizer or nebulizer that utilizes an accelerated airflow or ultrasonic agitation to produce a fine droplet mist for inhalation.

[0273] Formulations suitable for nasal administration include preparations generally similar to those described above for pulmonary administration. When dispensed, such formulations should preferably have a particle diameter in the range of 10 to 200 microns to allow retention in the nasal cavity. This can be achieved, if necessary, by the use of powders of appropriate particle size or by the selection of a suitable valve. Other suitable formulations include nasal sprays containing coarse powders with a particle diameter in the range of 20 to 500 microns and 0.2 to 5% w / v of the active compound in an aqueous or oily solution or suspension for administration by rapid inhalation via nasal passage from a container held close to the nose.

[0274] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1 M and preferably 0.05 M phosphate buffer or 0.8% physiological saline. Furthermore, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils, e.g., olive oil, and organic esters for injection, e.g., ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions containing physiological saline and a buffering medium. Parenteral vehicles include sodium chloride solution, Ringer's glucose, glucose and sodium chloride, Ringer's lactate, or non-volatile oils. Preservatives and other additives, such as antimicrobial agents, antioxidants, chelating agents, and inert gases, may also be present.

[0275] Formulations suitable for topical application may be provided, for example, as gels, creams, or ointments. Such preparations can also be applied to wounds or ulcers by, for example, spreading them directly onto the surface of the wound or ulcer, or by holding them on appropriate support, such as a bandage, gauze, or mesh, and applying them to and over the area to be treated.

[0276] Liquid or powder formulations may also be provided that can be sprayed or sprinkled directly onto the area to be treated, such as a wound or ulcer. Alternatively, a carrier, such as a bandage, gauze, or mesh, may be sprayed or sprinkled with the formulation and then applied to the area to be treated.

[0277] A further aspect of the present invention provides a method for preparing the above-described pharmaceutical or veterinary compositions, comprising, for example, the step of binding an active compound(s) to a carrier by mixing.

[0278] Generally, formulations are prepared by uniformly and densely binding an activator to a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product. The present invention extends to methods for preparing pharmaceutical compositions, comprising combining or binding the compounds described herein with a pharmaceutically or veterinarily acceptable carrier or vehicle.

[0279] Salt / Ester The compounds of the present invention can exist as salts or esters, particularly as pharmaceutically and veterinarily acceptable salts or esters.

[0280] pharmaceutically acceptable salts of the compounds of the present invention include suitable acid addition or base salts thereof. A general overview of suitable pharmaceutically acceptable salts can be found in Bergeetal, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example, with strong inorganic acids such as mineral acids; with hydrohalic acids, such as hydrochloride, hydrobromide, and hydroiodide, sulfuric acid, sulfate phosphate, bisulfate, hemisulfate, thiocyanate, persulfate, and sulfonic acid; with strong organic carboxylic acids, such as unsubstituted or substituted (e.g., with halogens), alkane carboxylic acids with 1 to 4 carbon atoms, such as acetic acid; with saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or tetraphthalic acid; with hydroxycarboxylic acids, such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid; with amino acids, such as aspartic acid or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as unsubstituted or substituted (e.g., with halogens), (C1-C4)-alkylsulfonic acid, or arylsulfonic acid, such as methanesulfonic acid or p-toluenesulfonic acid. Even salts that are pharmaceutically or veterinarily unacceptable may still have value as intermediates.

[0281] Preferred salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipine, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentane, glucoheptane, glycerophosphate, oxalate, heptane, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropionate, picrinate, pivalate, propionate, tartrate, and lactate. Examples include tobionates, pivalates, camphorates, undecanoates and succinates; organic sulfonic acids, such as methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, camphorsulfonates, 2-naphthalenesulfonates, benzenesulfonates, p-chlorobenzenesulfonates and p-toluenesulfonates; and inorganic acids, such as hydrochlorides, hydrobroms, hydroiodides, sulfates, bisulfates, hemisulfates, thiocyanates, persulfates, phosphoric acids and sulfonic acids.

[0282] Esters are formed using either an organic acid or an alcohol / hydroxide, depending on the functional group being esterified. Organic acids include carboxylic acids, e.g., unsubstituted or substituted (e.g., with halogens) alkanecarboxylic acids with 1 to 12 carbon atoms, e.g., acetic acid; saturated or unsaturated dicarboxylic acids, e.g., oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or tetraphthalic acid; hydroxycarboxylic acids, e.g., ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid; amino acids, e.g., aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids, e.g., unsubstituted or substituted (e.g., with halogens), (C1-C4)-alkylsulfonic acids or arylsulfonic acids, e.g., methanesulfonic acid or p-toluenesulfonic acid. Suitable hydroxides include inorganic hydroxides, e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, and aluminum hydroxide. Examples of alcohols include alkane alcohols with 1 to 12 carbon atoms, which may be unsubstituted or substituted (e.g., with halogens).

[0283] Enantiomer / Tautomer In all embodiments of the present invention discussed above, the present invention includes, where appropriate, all enantiomers, diastereoisomers, and tautomers of the compounds of the present invention. Those skilled in the art will recognize compounds that possess optical properties (one or more chiral carbon atoms) or tautomerism. The corresponding enantiomers and / or tautomers can be isolated / prepared by methods known in the art.

[0284] Enantiomers are characterized by the absolute configuration of these chiral centers, which are explained by the R- and S-sequence rules of Cahn, Ingold, and Prelog. Such conventions are well known in the art (e.g., 'Advanced Organic Chemistry', 3). rd (See edition, ed. March, J., John Wiley and Sons, New York, 1985).

[0285] The compounds of the present invention containing chiral centers can be used as racemic mixtures, enantiomer-rich mixtures, or the racemic mixtures may be separated using well-known techniques, and the individual enantiomers may be used individually.

[0286] Stereoisomers and geometric isomers Some of the compounds of the present invention may exist as stereoisomers and / or geometric isomers. For example, they may possess one or more asymmetric and / or geometric centers, and thus may exist in two or three or more stereoisomeric and / or geometric forms. The present invention envisions the use of all of the individual stereoisomers and geometric isomers of these compounds, and mixtures thereof. The terms used in the claims encompass these forms, provided that the forms retain appropriate functional activity (though not necessarily to the same degree).

[0287] The present invention also includes all suitable isotopic variants of compounds or pharmaceutically acceptable salts thereof. An isotopic variant of a compound or pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but with an atomic weight different from that commonly found in nature. Examples of isotopes that can be incorporated into pharmaceuticals and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Cl is an example. Certain isotopic variants of drugs and their pharmaceutically acceptable salts, such as radioactive isotopes, for example, 3 H or 14 Those incorporating C are useful in drug and / or substrate tissue distribution experiments. Tritium-labeled, i.e., 3 H, and carbon-14, that is, 14 13C isotopes are particularly preferred due to the ease of their preparation and detection. Furthermore, isotopes, such as deuterium, i.e. 2 Substitution with hydrogen can be preferable in some situations because it may result in certain therapeutic benefits from greater metabolic stability, such as an increased in vivo half-life or a reduced dose. For example, the present invention includes compounds of general formula (I) in which any hydrogen atom is replaced by a deuterium atom. The isotopic variants of the present invention, of the agents of the present invention and their pharmaceutically acceptable salts, can generally be prepared by conventional procedures using appropriate isotopic variants of appropriate reagents.

[0288] Atropisomer Some of the compounds of the present invention can exist as atropisomers. Atropisomers are stereoisomers arising from bound rotation around a single bond, where a steric strain-induced energy difference or other inducement creates a sufficiently high barrier to rotation that allows for the isolation of individual conformational isomers. The present invention encompasses all such atropisomers. The present invention also covers rotational isomers of compounds.

[0289] Prodrug The present invention further includes compounds of the present invention in prodrug form, i.e., covalently bonded compounds that release an active parent drug in vivo. Such prodrugs are generally compounds of the present invention modified with one or more suitable groups so that the modification can be reversed upon administration to a human or mammalian subject. Reversal is usually carried out by enzymes naturally present in such subjects, however, such prodrugs may also be administered together with a second drug to carry out in vivo reversal. Examples of such modifications include esters (e.g., any of those described above), in which case reversal may be carried out by an esterase or the like. Other such systems are well known to those skilled in the art.

[0290] solvate The present invention also includes solvate forms of the compounds of the present invention. The terms used in the claims encompass these forms. Preferably, the solvate is a hydrate.

[0291] Combined use Further embodiments of the present invention relate to combinations comprising the compounds described herein and one or more additional activators. In particularly preferred embodiments, one or more compounds of the present invention are administered in combination with one or more additional activators, for example, commercially available existing drugs. In such cases, the compounds of the present invention may be administered simultaneously or sequentially following one or more other activators.

[0292] Drugs are generally more effective when used in combination. In particular, combination therapy is desirable to avoid overlapping primary toxicities, mechanisms of action, and resistance mechanisms. Furthermore, it is desirable to minimize the time interval between doses and administer most drugs at their maximum tolerated doses. The main advantage of combining chemotherapy drugs is that they can promote additive or possible synergistic effects through biochemical interactions and reduce the development of resistance.

[0293] Beneficial combinations can be suggested by studying the activity of the test compound with drugs that are known or presumed to be valuable in the treatment of specific disorders. This procedure can also be used to determine the order of drug administration, i.e., before, during, or after delivery. Such scheduling may be characteristic of all activators identified herein.

[0294] In the context of cancer, the compounds of the present invention can be used in combination with immunotherapies, such as cancer vaccines and / or other immune modulators, such as agents that block PD1 / PDL-1 interactions. Thus, in one preferred embodiment, the additional activator is an immunotherapy agent, more preferably a cancer immunotherapy agent. "Immunotherapy agent" refers to a treatment that uses the subject's own immune system to fight diseases such as cancer. For other disorders, the compounds of the present invention can be used in combination with agents that block or reduce inflammation, such as antibodies that target pro-inflammatory cytokines.

[0295] polymorphism The present invention further relates to the compounds of the present invention in various crystalline, polymorphic, and hydrated (anhydrous) forms. It is well established in the pharmaceutical industry that chemical compounds can be isolated in any of these forms by slightly altering the method of purification and / or isolation from the solvent used in the synthetic preparation of such compounds.

[0296] Administration The pharmaceutical compositions of the present invention can be administered rectally, nasally, intrabronchally, topically (including oral buccal and sublingual), vaginally, or parenterally (including subcutaneous, intramuscular, intravenous, intra-arterial, and intradermal), intraperitoneally, or intrathecally. Preferably, the formulation is an orally administered formulation. The formulation can be conveniently presented in the form of a unit dosage form, i.e., a unit dose, or a separate portion containing multiple units or subunits of a unit dose. For example, the formulation may be in the form of tablets and sustained-release capsules and may be prepared by any method well known in the art of pharmaceuticals.

[0297] Formulations for oral administration in the present invention can be presented as follows: separate units, e.g., capsules, gels, droplets, cachets, pills or tablets, each containing a predetermined amount of the activator; powders or granules; liquid formulations, emulsions or suspensions of the activator in aqueous or non-aqueous liquids; or oil-in-water or water-in-oil liquid emulsions; or as a bolus, etc. Preferably, these compositions contain 1 to 250 mg and more preferably 10 to 100 mg of the active ingredient per dose.

[0298] For compositions intended for oral administration (e.g., tablets and capsules), the term "acceptable carrier" includes vehicles, such as common excipients, such as binders, such as syrups, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sucrose, and starch; fillers and carriers, such as corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid; and lubricants, such as magnesium stearate, sodium stearate, and stearates of other metals, glycerol stearate, stearic acid, silicone fluids, talc wax, oils, and colloidal silica. Flavorings, such as peppermint, wintergreen oil, and cherry flavoring, may also be used. It may be desirable to add colorants to make the dosage form easily identifiable. Tablets may also be coated by methods well known in the art.

[0299] Tablets may optionally be prepared with one or more auxiliary components by compression or molding. Compressed tablets may optionally be prepared by compressing the activator into a free-flowing form, such as powder or granules, in a suitable apparatus, and mixing it with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant. Wet tablets may be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable apparatus. Tablets may be coated or etched, and may be formulated to provide sustained or controlled release of the activator.

[0300] Other formulations suitable for oral administration include flavored bases, lozenges containing the activator in ordinary sucrose and acacia or tragacanth; pastels containing the activator in an inert base, such as gelatin and glycerin, or in sucrose and acacia; and mouthwashes containing the activator in a suitable liquid carrier.

[0301] Other forms of administration include liquids and emulsions, which can be injected intravenously, intra-arterially, intrathecally, subcutaneously, intradermally, intraperitoneally, or intramuscularly, and are prepared from sterile or sterile-capable solutions. The injectable forms typically contain 10 to 1000 mg, preferably 10 to 250 mg, of the active ingredient per dose.

[0302] The pharmaceutical composition of the present invention may also be in the form of a suppository, pessary, suspension, emulsion, lotion, ointment, cream, gel, spray, liquid, or powder.

[0303] An alternative to transdermal administration is administration by the use of skin patches. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycol or liquid paraffin. The active ingredient can also be incorporated into an ointment consisting of a white wax or white soft paraffin base at a concentration of 1-10% by weight, together with stabilizers and preservatives as needed.

[0304] dose Those skilled in the art can easily determine an appropriate dose of one of the compositions of the present invention to administer to a subject without excessive experimentation. Typically, a physician determines the most appropriate actual dose for an individual patient, which depends on a variety of factors including the activity of the particular compound used, its metabolic stability and duration of action, age, weight, overall health, sex, diet, mode and timing of administration, elimination rate, concomitant drug use, severity of the particular condition, and the individual receiving treatment. The doses disclosed herein are illustrative of average cases. There may naturally be individual cases where a higher or lower dose range would be beneficial, and such dose ranges are within the scope of the present invention.

[0305] The dosage is further modified according to the mode of administration of the compound. For example, parenteral administration of the compound is usually preferred to achieve an "effective dose" for acute therapy. Intravenous infusion of the compound in 5% glucose in water or normal saline, or a similar formulation containing appropriate excipients, is most effective, but intramuscular bolus injection is also useful. Typically, the parenteral dose is about 0.01 to about 100 mg, preferably 0.1 to 20 mg, in a manner that maintains a plasma drug concentration at a concentration effective in modulating GPR65. The compound can be administered 1 to 4 times daily at levels that achieve a total daily dose of about 0.4 to about 400 mg. The precise amount of the therapeutically effective compound of the present invention, and the route by which such a compound is best administered, can be easily determined by those skilled in the art by comparing the blood concentration of the drug to the concentration required to have a therapeutic effect.

[0306] The compounds of the present invention can also be administered orally to a patient in a manner sufficient to achieve one or more of the therapeutic signs disclosed herein, in a concentration of the drug. Typically, pharmaceutical compositions containing the compounds are administered orally in doses of about 0.1 to about 500 mg or about 0.1 to about 50 mg, in a manner consistent with the patient's condition. Preferably, the oral dose is about 0.5 to about 50 mg or about 0.5 to about 20 mg.

[0307] When the compounds of the present invention are administered in accordance with the present invention, no unacceptable toxicological effects are expected. The compounds of the present invention, which may have good bioavailability, can be tested in one of several biological assays to determine the concentration of the compound required to have a given pharmacological effect.

[0308] The present invention will be further described with reference to the following figures and non-limiting examples. [Brief explanation of the drawing]

[0309] [Figure 1]This shows the X-ray crystal structure analyzed for (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (compound 52). [Figure 2] This shows the X-ray crystal structure analyzed for (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (compound 53). [Examples]

[0310] If the preparation of starting materials is not described, they are either commercially available, known in the literature, or readily obtainable by those skilled in the art using standard procedures. If it is indicated that a compound is prepared in the same manner as in previous examples or intermediates, it will be apparent to those skilled in the art that reaction times, equivalent amounts of reagents, solvents, concentrations, and temperatures may be modified according to the specific reaction, and that different workup or purification techniques may be necessary or desirable.

[0311] General scheme Abbreviation A list of some common abbreviations is provided below, but any other abbreviations not listed will be understood by those skilled in the art.

[0312] AcOH: Acetic acid; Boc: tert-butyloxycarbonyl; br.: broad; CAN: cerium ammonium nitrate; d: doublet; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; (ES+): electrospray ionization positive mode; Et3N: triethylamine; Depositphotos: ethyl acetate; EtOH: ethanol; h: time; HPLC: high-performance liquid chromatography; HCl: hydrochloric acid; Hz: Hertz; IPA: isopropylethylamine Pyryl alcohol; J: bond constant; l: liter; LDA: lithium diisopropylamide; M: molar concentration; m: multiplet; [M+H]+: protonated molecular ion; mCPBA: meta-chloroperoxybenzoic acid; MeCN: acetonitrile; MeOH: methanol; MHz: megahertz; min: minute; ml: milliliter; MS: mass spectrometry; MTBE: methyl tert-butyl ether; m / z: mass-charge ratio; NFSI: N-fluorobenzenesulfonimide; NMR: nuclear magnetic resonance; Pd-170: chloro(clotyl)(2-dicyclohexyl Pd-172: Chloro(clotyl)(2-dicyclohexylphosphino-2',4',6'-dimethoxy-1,1'-biphenyl)palladium(II); Pd-175: Allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate; Pd-178: Chloro(clotyl)(tricyclohexylphosphine)palladium(II); Pd 2(dba)3: Tris(dibenzylideneacetone)dipalladium(0); PDA: Photodiode array; PMP: para-methoxyphenyl; RT: Room temperature; Rt: Retention time; s: Singlet; SFC: Supercritical fluid chromatography; SCX: Solid-supported cation exchange (resin); S-Phos: 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl; t: Triplet; TFA: Trifluoroacetic acid; THF: Tetrahydrofuran; TLC: Thin-layer chromatography; ULC: Ultrahigh-performance liquid chromatography; UV: Ultraviolet light.

[0313] Other abbreviations are intended to convey these generally accepted meanings.

[0314] General experimental conditions All starting materials and solvents are either commercially available or prepared according to literature methods. Suitable isocyanate and aniline starting materials were obtained from Sigma Aldrich, Fluorochem, or Enamine stores, or synthesized as described herein. Suitable tricyclic amine starting materials were obtained from Enamine stores, or synthesized as described herein. Unless otherwise specified, the reaction mixtures were magnetically stirred, and the reactions were carried out at room temperature (approximately 20°C).

[0315] Silica gel chromatography was performed on automated flash chromatography systems such as the CombiFlash Companion, CombiFlash Rf system, or Reveleris X2 flash system, using RediSep® Rf, Reveleris®, or GraceResolv® pre-packed silica (230-400 mesh, 40-63 μm) cartridges.

[0316] Analytical UPLC-MS experiments to determine retention time and associated mass ions were performed using a Waters ACQUITY UPLC® H-class system equipped with an ACQUITY PDA detector and either an ACQUITY QDa mass spectrometer or a Waters SQD mass spectrometer, performing the analytical methods described below.

[0317] Analytical LC-MS experiments to determine retention time and associated mass ions were performed using an Agilent 1200 series HPLC system coupled to an Agilent 1956, 6100, or 6120 series single quadrupole mass spectrometer performing one of the analytical methods described below, or a Shimadzu LC-20AD series LC system and a Shimadzu-2020, single quadrupole mass spectrometer-based Shimadzu-2020-P2 system performing one of the analytical methods described below.

[0318] Analytical SFC experiments to determine retention times were performed using one of the analytical methods described below, with a column temperature of 40°C and a back pressure (ABPR) of 1750 psi, using the Waters SFC System UPC2 system.

[0319] Preparative HPLC purification was performed using either a Waters X-Bridge BEH C18, 5 μm, 19 × 50 mm column or a Waters Xbridge Prep OBD C18, 10 μm, 40 × 150 mm column, or a Phenomenex Gemini-NX C18, 3 μm, 30 × 75 mm column, with a concentration gradient of MeCN and 10 mM ammonium bicarbonate aqueous solution. Fractions were collected using a PDA or, in some cases, an SQD2 or ACQUITY QDa mass spectrometer, according to UV detection across the entire wavelength range.

[0320] Preparative SFC purification was performed using a Waters SFC prep15 system at a flow rate of 15 ml / min, employing either a 1 × 25 cm, 5 μm particle column or a Chiralpak® IG (Daicel) column (1 × 25 cm, 5 μm particle) that elutes to a mixture of CO2 and a co-solvent (MeOH, EtOH, or IPA). Fractions were collected using a PDA according to UV detection at 210–400 nm.

[0321] NMR spectra were recorded using either a Bruker Avance III HD 500MHz spectrometer or a Bruker Avance Neo 400MHz spectrometer using either the remaining non-deuterated solvent or tetramethylsilane as a reference, or a Varian Y 400MHz spectrometer using tetramethylsilane as a reference, or a QOne AS400 400MHz spectrometer using either the remaining non-deuterated solvent or tetramethylsilane as a reference.

[0322] In the absence of absolute stereochemistry clearly indicated by wedge and dashed bonds, the chemical structures disclosed throughout the examples (e.g., in the stereochemistry described above in (I.3)) should be interpreted as describing a racemate. To avoid ambiguity, the present invention encompasses compounds of any of these stereochemistrys as well as mixtures thereof.

[0323] Analysis method Method 1 - Basic 3-Minute Method Column: Waters ACQUITY UPLC (registered trademark) BEH C18, 1.7 μm at 40°C, 2.1 × 30 mm Detection: MS by UV and electrospray ionization at 210-400 nm unless otherwise indicated. Solvents: A: 10 mM ammonium bicarbonate aqueous solution, B: MeCN Concentration gradient:

[0324] [Table 1]

[0325] Method 2 - Basic 4-Minute Method Column: Waters X-Bridge BEH C18, 2.5 μm, 4.6 × 30 mm at 40°C Detection: MS by UV at 254 nm and electrospray ionization unless otherwise indicated. Solvents: A: 10 mM ammonium bicarbonate aqueous solution, B: MeCN Concentration gradient:

[0326] [Table 2]

[0327] Method 3 - Lux(registered trademark) Amylose-2 Column: Lux® Amylose-2, LC column at 40°C (150 × 2 mm, particle size 3 μm), flow rate 1.5 ml / min Detection: UV detection by DAD in the 220-400nm range. Solvent: Polar solvent, usually methanol, ethanol, or IPA concentration gradient or constant composition mixture in CO2:

[0328] Method 4 - CHIRALPAK® IG-3 (Daicel) column Column: CHIRALPAK® IG-3 (Daicel) column (2.1 × 150 mm, particle size 3 μm) and flow rate 1.5 ml / min Detection: UV detection by DAD in the 220-400nm range. Solvent: Polar solvent, usually methanol, ethanol, or IPA in CO2, with varying concentrations or compositional composition:

[0329] Method 5 - Basic 4-Minute Method Column: Gemini LC column C18 50×2mm, particle size 3μm at 40℃ Detection: MS by UV at 220 nm and electrospray ionization unless otherwise indicated. Solvents: A: 10 mM ammonium bicarbonate aqueous solution, B: MeCN Concentration gradient:

[0330] [Table 3]

[0331] Method 6 - Basic 4-Minute Method Column: Waters Sunfire, 3.5 μm at 25°C, 4.6 × 50 mm column Detection: MS by UV at 214 and 254 nm, and electrospray ionization, unless otherwise indicated. Solvents: A: 0.05% formic acid in water (volume / volume), B: 0.05% formic acid in MeCN (volume / volume) Concentration gradient:

[0332] [Table 4]

[0333] Experimental Scheme 1 Compound 1 (±)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

[0334] [ka]

[0335] To a solution of 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine (0.075 g, 0.465 mmol) and Et3N (97 μl, 0.698 mmol) in THF (4 ml), a solution of 1-isocyanato-4-(trifluoromethyl)benzene (0.131 g, 0.698 mmol) in THF (0.75 ml) was added. The resulting mixture was stirred at room temperature for 20 hours. MeOH (5 ml) was added, and the crude product was concentrated under vacuum. The product was purified by chromatography on RP Flash C18 (15-75% MeCN / 10 mM aqueous ammonium bicarbonate solution) to obtain (±)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide as a colorless solid. LC-MS (Method 1) showed a m / z of 349.3 (M+H) at 1.18 min. + (ES + ). 1H NMR(500MHz,DMSO-d6)δ9.14(s,1H), 8.96(s,1H), 8.61(s,1H), 7.68(d,J=8 .6Hz,2H), 7.58(d,J=8.6Hz,2H), 5.31(d,J=6.2Hz,1H), 4.84(t,J=6.5Hz,1 H), 3.36~3.33(m,1H), 2.79(d,J=18.4Hz,1H), 2.33~2.24(m,1H), 2.20(tt, J=12.2,6.2Hz,1H), 1.90(ddd,J=12.0,9.2,2.5Hz,1H), 1.81~1.72(m,1H).

[0336] The following compounds were prepared using appropriate starting materials, following the same procedure as described in Experimental Scheme 1. If the starting materials are not described in the literature, their synthesis is described below. Key points: (a) The reaction was carried out in DMF. (b) The reaction was carried out in DCM. (c) The reaction was carried out in a mixture of DMF and DCM. (d) The product was purified by mass separation HPLC (MeCN / 10 mM aqueous ammonium bicarbonate solution, C18). (e) The product was purified by silica gel chromatography (0.7 M ammonia / MeOH in DCM). (f) The reaction was carried out in DMF / THF. (g) The product was purified by silica gel chromatography (DCM in heptane). (h) The reaction was carried out using DIPEA instead of Et3N. (i) The product was purified by silica gel chromatography (SiO in isohexane). (j) ES - [MH] - , ES + No parental mass was observed in this case.

[0337] [Table 5] JPEG0007870548000123.jpg140127JPEG0007870548000124.jpg132128JPEG0007870548000125.jpg137126JPEG0007870548000126.jpg139125JPEG0007870548000127.jpg192127JPEG0007870548000128.jpg148127JPEG0007870548000129.jpg162127JPEG0007870548000130.jpg148125JPEG0007870548000131.jpg138127JPEG0007870548000132.jpg139125JPEG0007870548000133.jpg195125JPEG0007870548000134.jpg142126JPEG0007870548000135.jpg136127JPEG0007870548000136.jpg142125JPEG0007870548000137.jpg141126JPEG0007870548000138.jpg147127JPEG0007870548000139.jpg137126JPEG0007870548000140.jpg142128JPEG0007870548000141.jpg137127JPEG0007870548000142.jpg142127JPEG0007870548000143.jpg189129JPEG0007870548000144.jpg194127JPEG0007870548000145.jpg136125JPEG0007870548000146.jpg134125

[0338] Intermediate 1 (I-1)

[0339]

Chem.

[0340] Step 1: Dissolve tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-1a (10 g, 44 mmol) in 1,1-dimethoxy-N,N-dimethylmethaneamine (21 g, 24 ml, 0.18 mol), and heat the reaction mixture under reflux for 16 hours. Remove the solvent under vacuum. The product was purified by silica gel chromatography (0-5% in DCM (0.7 M ammonia / MeOH)) to obtain tert-butyl(E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-1b as a yellow solid. LC-MS (Method 2) at 1.60 min yielded m / z 281.2 [M+H] + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ7.25~7.14(m,1H), 5.20(d,J=5.7Hz,1H), 4.21(t,J=6.3Hz,1H), 3. 07(s,6H), 2.54(s,1H), 2.09(s,3H), 1.77(t,J=9.0Hz,1H), 1.68~1.56(m,1H), 1.38(s,9H).

[0341] Step 2: To a solution of 2,2,2-trifluoroacetimamide (192 mg, 132 μl, 1.71 mmol) in MeOH (10 ml), a solution of sodium methoxide in MeOH (661 μl, 5.4 M, 3.57 mmol) was added. A solution of tert-butyl(E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-1b (400 mg, 1.43 mmol) in MeOH (10 ml) was added, and the reaction mixture was heated at 80°C for 16 hours. Water (5 ml) and saturated ammonium chloride solution (5 ml) were added. The product was extracted with 20% IPA solution in chloroform (50 ml). The product was purified by silica gel chromatography (0-3% in DCM (0.7M ammonia / MeOH)) to obtain tert-butyl 2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-1c as a yellow oily substance. LC-MS (Method 2) showed a m / z of 330.1 [M+H] at 2.28 min. + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ5.12(d,J=5.8Hz,1H), 4.50(s,1H), 4.32(s,1H), 3.30(s,1H), 2.95~ 2.84(m,1H), 2.29~2.11(m,2H), 1.91(t,J=9.9Hz,1H), 1.77~1.68(m,1H), 1.41~1.23(m,9H).

[0342] Step 3: To a solution of tert-butyl 2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-1c (85 mg, 0.26 mmol) in DCM (2 ml), TFA (0.20 ml, 2.6 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The crude reaction mixture was concentrated under reduced pressure. 2 ml of 0.7 M ammonia in MeOH was added, and the solvent was removed under vacuum to obtain 2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine as a yellow oily substance, which was used in the subsequent steps without further purification. LC-MS (Method 2) m / z 230.0 [M+H] + (ES + ); in 1.20 minutes. Intermediate 2(I-2)

[0343] [ka]

[0344] Step 1: Using a procedure essentially similar to that for compound I-1c, tert-butyl(E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-1b was prepared to yield tert-butyl2-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-2a: LC-MS (Method 2) at 1.59 min, m / z 276.1 [M+H] + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ8.47(s,1H), 4.93(d,J=6.0Hz,1H), 4.44(s,1H), 3.21~3.12(m,1H), 2.67(d,J=18.2Hz,1H), 2.5 3(s,3H), 2.21(s,1H), 2.13(dq,J=11.8,5.8Hz,1H), 1.78(t,J=10.2Hz,1H), 1.66(dt,J=15.1,7.6Hz,1H), 1.34(s,9H).

[0345] Step 2: Using a procedure essentially similar to that in I-1, 2-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-2a was prepared to produce 2-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine I-2:LCMS (Method 2) m / z 176.1[M+H] + (ES + In 0.70 minutes. Intermediate 3(I-3)

[0346] [ka]

[0347] Step 1: Using essentially the same procedure as in I-1c, tert-butyl(E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-1b was prepared to produce tert-butyl 2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate (I-3a): LC-MS (Method 2) at 2.55 min, m / z 338.2 [M+H] + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ8.70(s,1H), 8.44~8.27(m,2H), 7.51(p,J=3.4,3.0Hz,3H), 5.02(d,J=5.9Hz,1H), 4.50(s,1H), 3.28(d ,J=23.9Hz,1H), 2.82(d,J=18.1Hz,1H), 2.32~2.11(m,2H), 1.87(t,J=10.1Hz,1H), 1.75(dd,J=12.7,6.4Hz,1H), 1.40(s,9H).

[0348] Step 2: Using a procedure essentially similar to that in I-1, 2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate (I-3a) was prepared to produce 2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine (I-3): LC-MS (Method 2) m / z 230.1 [M+H] + (ES + ); in 1.18 minutes. Intermediate 5 (I-5)

[0349] [ka]

[0350] Step 1: To a solution of urea (0.2 g, 4 mmol) in EtOH (10 ml), a solution of sodium ethoxide (2 ml, 21 wt / wt%, 4 mmol in EtOH) was added. Tert-butyl(E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate I-1b (1 g, 4 mmol) was added to EtOH (10 ml), and the reaction mixture was heated at 90°C for 16 hours. A saturated ammonium chloride solution (5 ml) was added, and the product was extracted with a 10% (0.7 M ammonia / MeOH) solution in DCM (2 × 35 ml). The product was purified by silica gel chromatography (0-10% in DCM (0.7M ammonia / MeOH)) to obtain tert-butyl2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-5a as a white solid. LC-MS (Method 2) showed a m / z of 278.1 (M+H) at 1.3 min. + (ES + ). 11H NMR (500MHz, DMSO-d6) δ11.68(s,1H), 7.96(s,1H), 4.79(d,J=6.0Hz,1H), 4.35(s,1H), 2.97(d,J=17.7Hz,1H), 2.16(s,1H), 2.02(dt,J=11.9,5.6Hz,1H), 1.78~1.69(m,1H), 1.67(d,J=17.0Hz,1H), 1.36(s,9H). 1 proton below the DMSO peak.

[0351] Step 2: To a solution of tert-butyl 2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-5a (361 mg, 1.30 mmol) in DCM (10 ml), TFA (1.00 ml, 13.0 mmol) was slowly added. The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum. 0.7 M ammonia in MeOH (5 ml) was added, and the mixture was concentrated under vacuum. The substance was purified by SCX elution with 0.7 M ammonia in MeOH to obtain 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-2-ol I-5 as a pale yellow solid. 1 H NMR(500MHz,DMSO-d6)δ7.79(s,1H), 7.27(s,1H), 6.67(s,1H), 4.05(d,J=5.7Hz,1H), 3.69(t,J=6.4Hz,1H), 2.88~2 .78(m,1H), 2.34(d,J=18.5Hz,1H), 1.91(d,J=4.4Hz,1H), 1.89~1.81(m,1H), 1.74~1.62(m,1H), 1.56~1.46(m,1H).

[0352] Intermediate 7(I-7) The synthesis method described in Schultz and Wolfe, Organic Letters, 2011, 13(11), 2962-2965, as shown in the following scheme, was used.

[0353] [ka]

[0354] Step 1: To a solution of 3-bromo-4-pyridinecarboxaldehyde (42.0 g, 225 mmol) in THF (250 ml), titanium(IV) ethoxide (93.6 ml, 451 mmol) was added all at once at room temperature. The mixture was stirred at room temperature for 5 minutes, and then (±)-tert-butylsulfinamide (30.1 g, 248 mmol) was added all at once. The resulting mixture was stirred at room temperature for 16 hours. Water (50 ml) was added at 0°C, and the product was extracted with ELISA (3 × 30 ml). The combined organic layers were concentrated under vacuum. The product was purified by silica gel chromatography (1-100% ELISA / petroleum ether) to obtain (E)-N-((3-bromopyridine-4-yl)methylene)-2-methylpropane-2-sulfinamide (I-7b) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.91(s,1H), 8.86(s,1H), 8.62(d,J=4.8Hz,1H), 7.83(d,J=5.2Hz,1H), 1.29(s,9H).

[0355] Step 2: To a solution of (E)-N-((3-bromopyridine-4-yl)methylene)-2-methylpropane-2-sulfinamide (I-7b) (53.4 g, 185 mmol) in THF (300 ml), buta-3-en-1-ylmagnesium bromide (0.5 M, 1.59 L) was added dropwise at 0°C. The mixture was heated to room temperature for 1 hour. Saturated ammonium chloride solution (200 ml) was added, and the product was extracted with ethyl acetate (3 × 50 ml). The combined organic matter was washed with water (30 ml) and saturated brine (30 ml). The organic matter was dried over sodium sulfate and concentrated under vacuum. The product was purified by silica gel chromatography (1% to 100% butyl / petroleum ether) to obtain N-(1-(3-bromopyridine-4-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-7c) as a yellow oily substance. 1H NMR(400MHz,CDCl3)δ8.68(s,1H), 8.51~8.48(m,1H), 7.31(d,J=5.2Hz,1H), 5.83~5.76(m,1H), 5.10(d,J=1.2Hz,1H), 5.0 5(d,J=5.2Hz,1H), 4.87~4.83(m,1H), 3.56(d,J=3.2Hz,1H), 2.16~2.09(m,2H), 1.95~1.88(m,2H), 1.20(d,J=11.2Hz,9H).

[0356] Step 3: To a solution of N-(1-(3-bromopyridine-4-yl)penta-4-en-1-yl)-2-methylpropan-2-sulfinamide (I-7c) (54.3 g, 157 mmol) in MeOH (326 ml), a solution of HCl in HCl (4 M, 117 ml) was added at 0°C. The mixture was heated to room temperature for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was filtered, the filter cake was washed with ELISA (2 × 10 ml), and dried under vacuum to obtain a pale yellow solid, which was then dissolved in water. The mixture was basicized to pH > 11 with aqueous NaOH solution and extracted with DCM (3 × 30 ml). The combined organic matter was washed with brine (30 ml) and dried over sodium sulfate to obtain 1-(3-bromopyridine-4-yl)penta-4-en-1-amine (I-7d) as a yellowish-brown oil. 1 H NMR (400MHz, CDCl3) δ8.64(s,1H), 8.48(d,J=5.6Hz,1H), 7.44(d,J=5.2Hz,1H), 5.86~5.81(m,1H), 5.07~ 4.98(m,2H), 4.32~4.29(m,1H), 2.20~2.13(m,2H), 1.81~1.83(m,1H), 1.52~1.64(m,1H), 1.52(br.s,2H).

[0357] Step 4: Et3N (20 ml, 143 mmol) was added dropwise to a solution of 1-(3-bromopyridine-4-yl)penta-4-en-1-amine (I-7d) (26.5 g, 110 mmol), (4-methoxyphenyl)boronic acid (25.1 g, 165 mmol), 4 Å molecular sieves (53.0 g), and Cu(OAc)2 (20.0 g, 110 mmol) in 1,4-dioxane (530 ml). The mixture was stirred at 35°C under O2 for 16 hours. The mixture was filtered, and the filter cake was washed with ELISA (3 × 15 ml). The filtrate was concentrated under vacuum. The product was purified by silica gel chromatography (1% to 100% ethyl acetate / petroleum ether) to obtain N-(1-(3-bromopyridine-4-yl)penta-4-en-1-yl)-4-methoxyaniline (I-7e) as a reddish-brown solid. 1 H NMR(400MHz,CDCl3)δ8.68(s,1H), 8.40(d,J=5.2Hz,1H), 7.34(d,J=4.8Hz,1H), 6.71~6.67(m,2H), 6.36(t,J=2.0,3.6Hz,2H), 5.87~5 .83(m,1H), 5.09~5.02(m,2H), 4.65~4.62(m,1H), 3.94(s,1H), 3.69(s,3H), 2.31~2.23(m,2H), 1.94~1.91(m,1H), 1.74~1.71(m,1H).

[0358] Step 5: Cool the flame-dried flask under a stream of N2 air, and add Pd2(dba)3 (3.61g, 3.95 mmol), S-Phos (3.24g, 7.89 mmol), and NaO tBu (5.69 g, 59.2 mmol) was added. The flask was purged with N2, and a solution of N-(1-(3-bromopyridine-4-yl)penta-4-en-1-yl)-4-methoxyaniline (I-7e) (13.7 g, 39.5 mmol) in toluene (274 ml) was added dropwise. The resulting mixture was heated at 90°C for 12 hours. The reaction mixture was filtered, and the filter cake was washed with ELISA (3 × 10 ml). The filtrate was concentrated under vacuum. The product was purified by silica gel chromatography (1%~100% ELISA / petroleum ether) to obtain 10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-7f) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ8.33(d,J=4.8Hz,1H), 8.17(s,1H), 7.08(d,J=5.2Hz,1H), 6.77~6.71(m,4H), 4.61(d,J=6.0Hz,1H), 4. 51(t,J=5.2,6.8Hz,1H), 3.70(s,3H), 3.21(dd,J=4.8,12.0Hz,1H), 2.43~2.35(m,3H), 1.95~1.91(m,1H), 1.79~1.78(m,1H).

[0359] Step 6: After cooling a solution of 10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-7f) (6.32 g, 23.7 mmol) in MeCN (237 ml) to 0°C, an aqueous solution of CAN (0.3 M, 316 ml) was added dropwise. After the addition was complete, the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated to dryness under vacuum to obtain 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-7 g) as a brownish oil, which was used in the subsequent steps without further purification.

[0360] Step 7: To a solution of 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-7g) (3.82g, 23.9 mmol) in THF (30 ml), K2CO3 (8.25g, 59.7 mmol) and di-tert-butyldicarbonate (26.0g, 119 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filter cake was washed with SiO2 (3 × 15 ml). Water (25 ml) was added to the filtrate. The aqueous layer was extracted with SiO2 (3 × 25 ml). The combined organic layers were dehydrated with sodium sulfate and concentrated under vacuum. The product was purified by silica gel chromatography (1% to 100% SiO2 / petroleum ether) to obtain tert-butyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxylate (I-7h) as a reddish-brown solid. 1 H NMR (400MHz, CDCl3) δ8.34~8.32(m,2H), 6.98(s,1H), 4.86(d,J=28.8Hz,1H), 4.58(s,1H), 3.36(s, 1H), 2.56(d,J=16.8Hz,1H), 2.24~2.18(m,2H), 1.86~1.81(m,1H), 1.64~1.65(m,1H), 1.42(s,9H).

[0361] Step 8: A solution of HCl in HCl (4M, 550 ml) was added to a solution of tert-butyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxylate (I-7h) (2.20 g, 8.45 mmol) in MeOH (400 ml) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum. The crude product was ground in MTBE (20 ml) at room temperature for 10 minutes. The mixture was filtered, the filtered cake was washed with MTBE (2 × 5 ml), and the cake was dried under vacuum to obtain 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine hydrochloride as a white solid. LC-MS (Method 5) showed m / z 161.2 (M+H) at 2.44 min. + (ES + ). 1H NMR(400MHz,CDCl3)δ9.92(s,1H), 9.65(s,1H), 8.64(d,J=18.0Hz,2H), 7.64(s,1H), 5.03(s,1H), 4.40 (s,1H), 3.39(s,1H), 3.00(d,J=17.6Hz,1H), 2.36~2.18(m,2H), 1.99~2.02(m,1H), 1.86~1.75(m,1H). Intermediate 8 (I-8)

[0362] [ka]

[0363] Step 1: Using essentially the same procedure as in I-7b, (E)-N-((4-bromopyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide (I-8b) was synthesized from 4-bromo-3-pyridinecarboxaldehyde (I-8a). 1 H NMR (400MHz, CDCl3) δ9.14(s,1H), 8.93(s,1H), 8.46(d,J=5.2Hz,1H), 7.61(d,J=5.2Hz,1H), 1.30(s,9H).

[0364] Step 2: Using essentially the same procedure as in I-7c, N-(1-(4-bromopyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-8c) was synthesized from (E)-N-((4-bromopyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide (I-8b). 1 H NMR(400MHz, CDCl3)δ:8.55(s,1H), 8.32~8.29(m,1H), 7.50(d,J=5.2Hz,1H), 5.85~5.76(m,1H) ), 5.10~5.02(m,2H), 4.92~4.90(m,1H), 3.57(d,J=3.6Hz,1H), 2.18~1.97(m,4H), 1.19(s,9H).

[0365] Step 3: Using essentially the same procedure as in I-7d, 1-(4-bromopyridine-3-yl)penta-4-en-1-amine (I-8d) was synthesized from N-(1-(4-bromopyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-8c). 1 H NMR (400MHz, CDCl3) δ8.66(s,1H), 8.29~8.24(m,1H), 7.48~7.45(t,J=8.8Hz,1H), 5.86~5.79(m,1H), 5.0 6~4.97(m,2H), 4.36~4.33(m,1H), 2.20~2.12(m,2H), 1.89~1.85(m,1H), 1.78~1.75(m,1H), 1.56(s,2H).

[0366] Step 4: Using essentially the same procedure as in I-7e, N-(1-(4-bromopyridine-3-yl)penta-4-en-1-amine (I-8d))-4-methoxyaniline (I-8e) was synthesized. 1 H NMR (400MHz, CDCl3) δ8.58(d,J=15.6Hz,1H), 8.26(s,1H), 7.49(d,J=5.2Hz,1H), 6.69(d,J=8.8Hz,2H), 6.44~6.41(m,2H), 5.88~5.82( m,1H), 5.08~5.01(m,2H), 4.72~4.68(m,1H), 3.86~3.84(m,1H), 3.69(s,3H), 2.30~2.21(m,2H), 2.02~1.89(m,1H), 1.88~1.76(m,1H).

[0367] Step 5: Using essentially the same procedure as in I-7f, 10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-8f) was synthesized from N-(1-(4-bromopyridine-3-yl)penta-4-en-1-yl)-4-methoxyaniline (I-8e). 1H NMR(400MHz,CDCl3)δ8.39(s,1H), 8.27(d,J=5.2Hz,1H), 6.84(d,J=4.4Hz,1H), 6.77~6.70(m,4H), 4.72(d,J=5.2Hz,1H), 4.65(d,J=5.2Hz,1H), 3.69(s,3H), 3.25~3.19(m,1H), 2.40(dd,J=3.6,7.2Hz,3H), 1.97~1.92(m,1H), 1.79~1.75(m,1H).

[0368] Step 6: Using essentially the same procedure as in I-7g, 6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-8g) was synthesized from 10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-8f).

[0369] Step 7: Using essentially the same procedure as in I-7h, tert-butyl-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxylate (I-8h) was prepared from 6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxylate (I-8h). 1 H NMR(400MHz,CDCl3)δ8.36(d,J=5.2Hz,1H), 8.31(s,1H), 7.01(d,J=4.8Hz,1H), 4.95(s,1H), 4.54(s,1H), 3.3 7(s,1H), 2.54(d,J=17.6Hz,1H), 2.33~2.16(m,2H), 1.93~1.81(m,1H), 1.70~1.59(m,1H), 1.47~1.35(m,9H).

[0370] Step 8: Using essentially the same procedure as in I-7, 6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxylate (I-8h) was synthesized from tert-butyl-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine hydrochloride (I-8). LC-MS (Method 5) showed m / z 161.2 (M+H) at 2.42 min.+ (ES + ). 1 H NMR(400MHz,CDCl3)δ10.26(s,1H), 9.90(s,1H), 8.79(s,1H), 8.71(d,J=6.0Hz,1H), 7.77(d,J=5.6Hz,1H), 5.10(d,J=6.0Hz,1 H), 4.36(s,1H), 3.54(dd,J=4.8,19.2Hz,1H), 3.19~3.07(m,1H), 2.41~2.18(m,2H), 2.08(t,J=11.2Hz,1H), 1.88~1.75(m,1H). Intermediate 9 (I-9)

[0371] [ka]

[0372] Step 1: Using essentially the same procedure as in I-7b, (E)-N-(2-bromo-4-methoxybenzylidene)-2-methylpropane-2-sulfinamide (I-9b) was synthesized from 2-bromo-4-methoxybenzaldehyde (I-9a). 1 H NMR (500MHz, d6-DMSO) δ8.73(s,1H), 8.01(d,J=8.8Hz,1H), 7.37(d,J=2.5Hz,1H), 7.13(dd,J=8.8,2.4Hz,1H), 3.88(s,3H), 1.18(s,9H).

[0373] Step 2: A solution of (E)-N-(2-bromo-4-methoxybenzylidene)-2-methylpropane-2-sulfinamide (13.0 g, 40.9 mmol) in THF (130 ml) was cooled to -78°C. Buta-3-en-1-ylmagnesium bromide (0.5 M in THF) (245 ml, 123 mmol) was added dropwise. The mixture was slowly warmed to room temperature and stirred at room temperature for 16 hours. A saturated aqueous solution of ammonium chloride (150 ml) was added, and the product was extracted with ELISA (2 × 100 ml). The organic matter was combined, dehydrated with magnesium sulfate, and concentrated under vacuum to obtain N-(1-(2-bromo-4-methoxyphenyl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-9c) as a light brown oil. The compound was used in the next step as a 2:1 mixture of diastereoisomers without any further purification.

[0374] Major diastereoisomers: 1 H NMR(500MHz,d6-DMSO)δ7.42(d,J=8.7Hz,1H), 7.11(d,J=2.5Hz,1H), 6.99(dd,J=8 .7,2.6Hz,1H), 5.82(ddt,J=16.9,10.2,6.5Hz,1H), 5.51(d,J=6.5Hz,1H), 5.06(d ,J=17.4Hz,1H), 4.98(d,J=10.8Hz,1H), 4.57(d,J=6.8Hz,1H), 3.76(s,3H), 2.19~ 2.08(m,1H), 2.07~1.97(m,1H), 1.94~1.84(m,1H), 1.78~1.67(m,1H), 1.05(s,9H).

[0375] Small amounts of diastereoisomers: 1H NMR(500MHz,d6-DMSO)δ7.51(d,J=8.7Hz,1H), 7.11(d,J=2.5Hz,1H), 6.99(dd,J=8.5,2.5Hz,1H), 5.87~5.78(m,2H), 5.09~4.9( m,2H), 4.56~4.45(m,1H), 3.77(s,3H), 2.23~2.09(m,1H), 2.08~1.97(m,1H), 1.83~1.70(m,1H), 1.68~1.59(m,1H), 1.10(s,9H).

[0376] Step 3: To a solution of N-(1-(2-bromo-4-methoxyphenyl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-9c) (16.5 g, 44.16 mmol) in MeOH (65 ml), a solution of HCl (4 M in 1,4-dioxane) (33 ml, 132.5 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2.5 hours. Water (200 ml) was added, and the aqueous solution was washed with ELISA (200 ml). The aqueous layer was adjusted to pH 8 by adding 2 M NaOH aqueous solution. The aqueous layer was then extracted with ELISA (2 × 100 ml). The organic matter was combined, dehydrated with magnesium sulfate, and concentrated under vacuum to obtain 1-(2-bromo-4-methoxyphenyl)penta-4-en-1-amine (I-9d) as a light brown liquid. The crude product was used in the next step without further purification.

[0377] Step 4: To a solution of 1-(2-bromo-4-methoxyphenyl)penta-4-en-1-amine(I-9d) (7.60 g, 28.1 mmol) in DCM (100 ml), (4-methoxyphenyl)boronic acid (12.8 g, 84.4 mmol), followed by copper(II) acetate (7.66 g, 42.2 mmol) and pyridine (11.4 ml, 141 mmol) were added. The blue mixture was vigorously stirred at room temperature for 72 hours. 2 M NaOH aqueous solution (100 ml) was added, and the mixture was stirred for 30 minutes. The copper salt was filtered through a Celite pad. Water (100 ml) was added, and the product was extracted with DCM (3 × 100 ml). The organic layers were combined, dehydrated with magnesium sulfate, and concentrated under vacuum. The product was purified by chromatography on silica gel (5-25% Â / isohexane) to obtain N-(1-(2-bromo-4-methoxyphenyl)penta-4-en-1-yl)-4-methoxyaniline (I-9e) as a yellow liquid. LC-MS (Method 2) showed a m / z of 255 (M-PMP) at 1.91 min. + (ES + ), 1 H NMR(500MHz,DMSO-d6)δ7.33(d,J=8.7Hz,1H), 7.12(d,J=2.6Hz,1H), 6.90(dd,J=8.7,2.6Hz,1H), 6. 62(d,J=8.9Hz,2H), 6.37(d,J=9.0Hz,2H), 5.92(d,J=8.1Hz,1H), 5.85(ddt,J=17.0,10.2,6.5,6.5Hz ,1H), 5.02(dq,J=17.2,1.8,1.7,1.7Hz,1H), 4.97(ddt,J=10.2,2.3,1.3,1.3Hz,1H), 4.51(td,J=8.2 ,8.2,5.0Hz,1H), 3.73(s,3H), 3.57(s,3H), 2.34~2.20(m,1H), 2.19~2.06(m,1H), 1.78~1.61(m,2H).

[0378] Step 5: Place Pd-178 (667 mg, 1.40 mmol) and NaO in a flask. tBu (2.02 g, 21.0 mmol) was added, and the flask was purged with nitrogen. A solution of N-(1-(2-bromo-4-methoxyphenyl)penta-4-en-1-yl)-4-methoxyaniline (I-9e) (5.26 g, 14.0 mmol) in degassed toluene (120 ml) was added by syringe at room temperature. The resulting mixture was heated at 95°C for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The Celite was washed with ELISA (100 ml). The filtrate was concentrated under vacuum. The product was purified by chromatography on silica gel (0-25% ELISA / isohexane) to obtain (±)-2-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelen (I-9f) as a pale pink oil. LCMS (Method 2) 1.27 min: m / z 296 (M+H) + (ES + ), 1 H NMR(500MHz,DMSO-d6)δ7.12(d,J=8.3Hz,1H), 6.76(d,J=9.1Hz,2H), 6.69(d,J=9.1Hz,2H), 6.65(dd,J=8.3,2.7Hz,1H), 6.48(d,J=2.6Hz,1H), 4.70(d, J=5.6Hz,1H), 4.54~4.38(m,1H), 3.64(s,3H), 3.61(s,3H), 3.10(dd,J=17. 0,4.7Hz,1H), 2.36(d,J=17.0Hz,1H), 2.30~2.13(m,2H), 1.80~1.63(m,2H).

[0379] Step 6: To a solution of (±)-2-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelen (I-9f) (680.0 mg, 2.30 mmol) in MeCN (25 ml), a solution of CAN (3.79 g, 6.91 mmol) in water (25 ml) was added dropwise over 30 minutes at 0°C. The mixture was stirred at 0°C for 1 hour and at room temperature for 1 hour. Water (10 ml) and 2 M NaOH (10 ml) were added, and the product was extracted with DCM (3 × 30 ml). The organic layers were combined and concentrated under vacuum to obtain (±)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelen (I-9) as a brownish oil. The compound was used without further purification. LCMS (Method 2) 1.56 min, m / z 190 (M+H) + (ES + ), 1 H NMR(500MHz,DMSO-d6)δ6.89(d,J=8.2Hz,1H), 6.61(dd,J=8.2,2.7Hz,1H), 6.58(d,J=2. 6Hz,1H), 4.04(d,J=5.1Hz,1H), 3.73~3.66(m,4H), 3.01(dd,J=16.6,5.0Hz,1H), 2.64(br s,1H), 2.44(d,J=16.6Hz,1H), 1.95~1.81(m,2H), 1.74~1.57(m,1H), 1.50~1.39(m,1H). Intermediate 10 (I-10)

[0380] [ka]

[0381] Step 1: (±)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelen(I-9) (267 mg, 1.24 mmol) was added to an aqueous HBr solution (48% in water) (1.4 ml, 48 wt / wt%, 12.41 mmol) at room temperature, and then refluxed for 6 hours. The mixture was diluted with MeOH (20 ml) and filtered to obtain a clear dark brown filtrate. SCX (7.00 g, 5.4 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. SCX was washed with MeOH (100 ml), and the product was eluted with 0.7 M ammonia in MeOH (50 ml). The eluate was concentrated under vacuum to obtain (±)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelen-2-ol as a dark brown oil. LCMS (Method 2) at 0.61 min: m / z 176 (M+H) + (ES + ), 1H NMR (500MHz, DMSO-d6) δ9.00 (s,1H), 6.77 (d,J=8.1Hz,1H), 6.44 (dd,J=8.1,2.5Hz,1H), 6.41 (d,J=2.5Hz,1H), 4.00 (d,J=5.3Hz,1H), 3.67 (t,J=5.8Hz,1H), 2.96 (dd,J=16.5,4.9Hz,1H), 2.37 (d,J=16.5,1H), 1.94~1.80 (m,2H), 1.68~1.59 (m,1H), 1.48~1.39 (m,1H), no exchangeable protons were observed. Intermediate 11 (I-11)

[0382] [ka]

[0383] Step 1: Pd-170 (1 mg, 1.45 μmol) and K2PO3 (23 mg, 145 μmol) were placed in a vial, sealed, and evacuated / backpacked with N2 (3 times). A solution of tert-butyl(±)-2-(((trifluoromethyl)sulfonyl)oxy)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annerene-10-carboxylate (40 mg, 97.0 μmol) and (2,4-dimethoxyphenyl)methaneamine (18 mg, 107 μmol) in 1,4-dioxane (1 ml) was added, and the reaction mixture was heated at 120°C for 16 hours. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and washed with ethyl acetate. The filtrate was concentrated under vacuum. The product was purified by silica gel chromatography (0%~100% SiO2 / isohexane) to obtain tert-butyl(±)-2-((2,4-dimethoxybenzyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annerene-10-carboxylate (I-11a) as a yellow oily substance. LC-MS (Method 1) showed a m / z of 447.1 (M+Na) at 1.82 min. + (ES + ), 1 ¹H NMR (500MHz, DMSO-d6) δ 7.18 (dd, J=8.3, 1.9Hz, 1H), 6.84 (br s, 1H), 6.53~6.33 (m, 4H), 4.90~4.72 (m, 1H), 4.60~4.37 (m, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.39~3.18 (m, 1H), 2.45 (d, J=16.5Hz, 1H), 2.30~2.02 (m, 3H), 1.79 (t, J=10.3Hz, 1H), 1.62 (br s, 2H), 1.39 (s, 9H). (-NH protons were not observed).

[0384] Step 2: To a solution of tert-butyl(±)-2-((2,4-dimethoxybenzyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelen-10-carboxylate (I-11a) (30 mg, 69.7 μmol) in DCM (1 ml), TFA (54 μl, 0.70 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum. The product was washed with MeOH and purified by ion exchange using SCX (0.5 g) eluted with 0.7 M ammonia in MeOH to obtain (±)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelen-2-amine (I-11) as a viscous yellow oily substance. LC-MS (Method 1) m / z 175.8 (M+H) + (ES + ), in 0.71 minutes. Intermediate 12 (I-12)

[0385] [ka]

[0386] Step 1: To a solution of 2-bromo-4-fluorobenzaldehyde I-12a (10.0 g, 49.3 mmol) in THF (170 ml), titanium(IV) ethoxide (20.7 ml, 98.5 mmol) was added all at once at room temperature. The mixture was stirred at room temperature for 5 minutes, and then (±)-tert-butylsulfinamide (5.97 g, 49.3 mmol) was added all at once. The resulting mixture was stirred at room temperature for 24 hours. Brine (100 ml) was added, the mixture was stirred for 10 minutes, and then filtered through Celite. The filtrate was extracted with ELISA (2 × 100 ml). The combined organic layers were washed with brine (3 × 100 ml), dehydrated with magnesium sulfate, and concentrated under vacuum to obtain (E)-N-(2-bromo-4-fluorobenzylidene)-2-methylpropane-2-sulfinamide as a pale yellow solid (I-12b). LCMS (Method 1) at 1.6 min: m / z 306.2, 308.1 (M+H) + (ES + ). 1H NMR (500MHz, DMSO-d6) δ8.77(s,1H), 8.11(dd,J=8.8,6.2Hz,1H), 7.81(dd,J=8.5,2.6Hz,1H), 7.45(td,J=8.2,2.6Hz,1H), 1.20(s,9H).

[0387] Step 2: To a solution of (E)-N-(2-bromo-4-fluorobenzylidene)-2-methylpropane-2-sulfinamide (13.00 g, 42.46 mmol) (I-12b) in THF (150 ml), buta-3-en-1-ylmagnesium bromide (2.17 M, 29.4 ml) was added dropwise at -78 °C. The mixture was heated to room temperature for 16 hours. Saturated ammonium chloride solution (50 ml) was added, and the product was extracted with ELISA (2 × 100 ml). The combined organic matter was dried over magnesium sulfate and concentrated under vacuum to obtain N-(1-(2-bromo-4-fluorophenyl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-12c) as an orange oil. LC-MS (Method 2) m / z 362.1, 364.1 (M+H) + (ES + ) In 2.48 minutes.

[0388] Step 3: To a solution of N-(1-(2-bromo-4-fluorophenyl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-12c) (15.0 g, 41.26 mmol) in MeOH (65 ml), a solution of 1,4-dioxane in HCl (4 M, 10.3 ml) at room temperature was added and the mixture was stirred for 2.5 hours. The reaction mixture was concentrated under vacuum. The residue was partitioned between water (200 ml) and ethyl acetate (200 ml). The aqueous phase was basicized to pH 8 with aqueous NaOH and extracted with ethyl acetate (2 × 100 ml). The organic layer was diluted with water (50 ml), basicized to pH 10 with NaOH, and extracted with ethyl acetate (3 × 100 ml). The combined organic compounds were dehydrated with magnesium sulfate and concentrated under vacuum to obtain 1-(2-bromo-4-fluorophenyl)penta-4-en-1-amine (I-12d) as a colorless oil. LC-MS (Method 2) at 2.20 min yielded m / z 258.0, 260.0 (M+H). + (ES+ ). 1 H NMR(500MHz,DMSO-d6)δ7.66(dd,J=8.7,6.4Hz,1H), 7.47(ddt,J=8.5,3.0,1.6Hz, 1H), 7.30~7.22(m,1H), 5.81(ddt,J=16.9,10.2,6.6Hz,1H), 5.09~4.92(m,1H), 4. 94 (ddt, J=10.3, 2.2, 1.1Hz, 1H), 4.13 (dd, J=8.1, 5.0Hz, 1H), 2.19~2.07 (m, 1H), 2.10~1.97 (m, 1H), 1.66~1.58 (m, 1H), 1.57~1.46 (m, 1H) (no replaceable -NH2 protons were observed).

[0389] Step 4: Pyridine (15.0 ml, 186 mmol) was added dropwise to a solution of 1-(2-bromo-4-fluorophenyl)penta-4-en-1-amine (9.60 g, 37.2 mmol) (I-12d), (4-methoxyphenyl)boronic acid (17.0 g, 112 mmol), and Cu(OAc)2 (10.1 g, 55.8 mmol) in DCM (100 ml). The mixture was stirred and exposed to air at room temperature for 16 hours. 2 M NaOH aqueous solution (100 ml) was added, the mixture was stirred for 30 minutes, and filtered through Celite. The filtrate was partitioned between water (100 ml) and DCM (100 ml) to separate the layers. The aqueous layer was further extracted with DCM (2 × 100 ml). The combined organic matter was dehydrated with magnesium sulfate and concentrated under vacuum. The product was purified by silica gel chromatography (0%~10% ethyl acetate / isohexane) followed by silica gel chromatography (0%~50% dimethyl silica gel / isohexane) to obtain N-(1-(2-bromo-4-fluorophenyl)penta-4-en-1-yl)-4-methoxyaniline (I-12e) as a colorless oil. LC-MS (Method 2) at 1.55 min yielded m / z values ​​of 364.3 and 366.6 (M+H). + (ES + ). 1H NMR(500MHz,DMSO-d6)δ7.52(dd,J=8.5,2.6Hz,1H), 7.47(dd,J=8.7,6.3Hz,1 H), 7.20(td,J=8.5,2.7Hz,1H), 6.67~6.60(m,2H), 6.40~6.33(m,2H), 6.00(d, J=8.0Hz,1H), 5.90~5.79(m,1H), 5.06~4.94(m,2H), 4.55(td,J=8.2,5.0Hz,1 H), 3.57(s,3H), 2.29(t,J=11.2Hz,1H), 2.21~2.10(m,1H), 1.79~1.64(m,2H).

[0390] Step 5: Place Pd-178 (448 mg, 939 μmol) and NaO in a three-necked flask. t Bu (3.99 g, 41.5 mmol) was added and the mixture was purged with N2. A solution of N-(1-(2-bromo-4-fluorophenyl)penta-4-en-1-yl)-4-methoxyaniline (I-12e) (3.42 g, 9.39 mmol) in toluene (30 ml) was added dropwise. The resulting mixture was heated at 95°C for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with ELISA (100 ml). The filtrate was concentrated under vacuum. The product was purified by silica gel chromatography (0%~5% ELISA / heptane) to obtain (±)-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelen (I-12f) as a pink oil. LCMS (Method 2) 2.52 min: m / z 384.1 (M+H) + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ7.26(dd,J=8.3,6.0Hz,1H), 6.90(td,J=8.7,2.7Hz,1H), 6.80~6.73(m,3H), 6.73~6.66(m,2H), 4.79(d,J=5.6H) z,1H), 4.44(t,J=5.8Hz,1H), 3.61(s,3H), 3.11(dd,J=17.3,4.8Hz,1H), 2.41(d,J=17.3Hz,1H), 2.26~2.18(m,2H), 1.84~1.62(m,2H).

[0391] Step 6: The solution of (±)-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annerene (I-12f) (2.15 g, 7.59 mmol) in MeCN (28 ml) was cooled to 0°C, and then the solution of CAN (12.5 g, 22.8 mmol) in water (100 ml) was added dropwise. After the addition was complete, the reaction mixture was stirred at 0°C for 1 hour, then warmed to room temperature and stirred for 1 hour. Water (30 ml) and 2 M sodium hydroxide aqueous solution (50 ml) were added, and the product was extracted with DCM (4 × 150 ml). The combined organic layers were dehydrated with magnesium sulfate and concentrated under vacuum. The crude residue was redissolved in MeOH, washed with MeOH, and purified by eluting SCX (15 g) with 0.7 M ammonia in MeOH to obtain (±)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annerene (I-12) as a brownish oily substance. LC-MS (Method 2) showed a m / z of 178.1 (M+H) at 1.65 min. + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ7.02(dd,J=6.3,1.9Hz,1H), 6.94~6.81(m,2H), 4.12~4.07(m,1H), 3.68(t,J=5.5Hz,1 H), 3.02(dd,J=16.8,5.0Hz,1H), 2.50~2.43(m,2H), 1.95~1.75(m,2H), 1.73~1.61(m,1H), 1.52~1.39(m,1H). Intermediate 13 (I-13)

[0392] [ka]

[0393] Step 1: To a solution of 3-chloro-2-fluoroisonicotinaldehyde I-13a (1.00 g, 6.27 mmol) in THF (17 ml), titanium(IV) ethoxide (2.63 ml, 12.5 mmol) was added all at once at room temperature. The mixture was stirred at room temperature for 5 minutes, and then (S)-tert-butylsulfinamide (760 mg, 6.27 mmol) was added all at once. The resulting mixture was stirred at room temperature for 16 hours. Brine (30 ml) was added, the mixture was stirred for 10 minutes, and then filtered through Celite. The filtrate was extracted with ELISA (2 × 20 ml). The combined organic matter was dehydrated with magnesium sulfate and concentrated under vacuum to obtain (S)-N-((3-chloro-2-fluoropyridine-4-yl)methylene)-2-methylpropane-2-sulfinamide (I-13b) as a pale yellow solid. LCMS (Method 1) 1.36 min: m / z 227.5 (M-Cl) + (ES + ). 1 H NMR (500MHz, DMSO-d6) δ8.81(s,1H), 8.33(dt,J=5.1,0.8Hz,1H), 7.90(d,J=5.1Hz,1H), 1.22(s,9H).

[0394] Step 2: To a solution of (S)-N-((3-chloro-2-fluoropyridine-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.38 g, 5.26 mmol) (I-13b) in THF (22 ml), buta-3-en-1-ylmagnesium bromide (0.5 M, 31.6 ml, 15.79 mmol) was added dropwise at -78 °C. The mixture was slowly warmed to room temperature and stirred for 72 hours. Saturated ammonium chloride solution (10 ml) was added, and the product was extracted with ELISA (3 × 10 ml). The combined organic matter was dried over magnesium sulfate and concentrated under vacuum. The product was purified by silica gel chromatography (0-100% siRNA / isohexane) to obtain (S)-N-((R)-1-(3-chloro-2-fluoropyridine-4-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-13c) as a pale yellow solid. LC-MS (Method 1) showed m / z 316.7, 319.1 (MH) at 1.39 min. -(ES - ). 1 H NMR(500MHz,DMSO-d6)δ8.21(dd,J=5.2,0.8Hz,1H), 7.53(d,J=5.2Hz,1H),5. 90(d,J=7.3Hz,1H), 5.81(dddd,J=17.3,10.2,7.1,6.1Hz,1H), 5.10(dq,J=17 .2,1.7Hz,1H), 5.02(ddt,J=10.2,2.3,1.2Hz,1H), 4.66(ddd,J=8.6,7.3,5.3 Hz,1H), 2.27~2.08(m,2H), 1.97~1.87(m,1H), 1.80~1.70(m,1H), 1.07(s,9H).

[0395] Step 3: (S)-N-((R)-1-(3-chloro-2-fluoropyridine-4-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-13c) (714 mg, 2.015 mmol) t To a solution in BuOH (7.2 ml), a solution of 1,4-dioxane in HCl (4 M, 3.0 ml, 12.09 mmol) was added at room temperature, and the mixture was stirred for 2.5 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (100 ml) and extracted with DCM (3 × 30 ml). The combined organic matter was dehydrated with magnesium sulfate and concentrated under vacuum to obtain a pale yellow liquid (I-13d) of (R)-1-(3-chloro-2-fluoropyridine-4-yl)penta-4-en-1-amine as an orange / brown oily substance. LC-MS (Method 1): m / z 215.4, 217.3 (M+H) at 1.17 min. + (ES + ), ¹H NMR (500MHz, DMSO-d6) δ 8.16 (dd, J=5.1, 0.9Hz, ¹H), 7.62 (d, J=5.1Hz, ¹H), 5.80 (ddt, J=16.9, 10.2, 6.6Hz, ¹H), 5.02 (dq, J=17.4, 1.8Hz, ¹H), 4.96 (ddt, J=10.2, 2.3, 1.3Hz, ¹H), 4.22 (dd, J=8.1, 5.1Hz, ¹H), 2.23~2.01 (m, ¹H), 1.76~1.50 (m, ¹H). No ¹NH protons were observed.

[0396] Step 4: Pyridine (1.2 ml, 15.0 mmol) was added dropwise to a solution of (R)-1-(3-chloro-2-fluoropyridine-4-yl)penta-4-en-1-amine(I-13d) (644.3 mg, 3.001 mmol), (4-methoxyphenyl)boronic acid (1.37 g, 9.0 mmol), and Cu(OAc)2 (820 mg, 4.50 mmol) in DCM (100 ml). The mixture was stirred and exposed to air at room temperature for 16 hours. 20 ml of 2 M NaOH aqueous solution was added, followed by 20 ml of water, and the mixture was extracted with DCM (3 × 20 ml). The combined organic matter was dehydrated with magnesium sulfate and concentrated under vacuum. The product was purified by silica gel chromatography (0%~100% DCM / isohexane) to obtain (R)-N-(1-(3-chloro-2-fluoropyridine-4-yl)penta-4-en-1-yl)-4-methoxyaniline (I-13e) as a yellow oily substance. LC-MS (Method 1): m / z 321.1, 323.4 (M+H) at 1.73 min. + (ES + ), 1 H NMR(500MHz,DMSO-d6)δ8.10(d,J=5.1Hz,1H), 7.41(d,J=5.1Hz,1H), 6.65(d,J=8.9Hz,2H), 6.38(d,J=8.9Hz,2H), 6.09(d,J=8.3Hz,1H), 5.84(dd t,J=17.0,10.2,6.6Hz,1H), 5.10~4.88(m,2H), 4.68(td,J=8.5,4.7Hz,1 H), 3.57(s,3H), 2.34~2.24(m,1H), 2.23~2.12(m,1H), 1.87~1.69(m,2H).

[0397] Step 5: Pd-178 (7.4 mg, 15.6 μmol) and sodium tert-butoxide (22.5 mg, 234 μmol) were placed in a three-necked flask and purged with N2. (R)-N-(1-(3-chloro-2-fluoropyridine-4-yl)penta-4-en-1-yl)-4-methoxyaniline (I-13e) (50.0 mg, 156 μmol) in toluene (1 ml) was added dropwise. The resulting mixture was heated at 95°C for 1.5 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with ELISA (3 × 20 ml). The filtrate was concentrated under vacuum. The product was purified by silica gel chromatography (0%~50% ethyl acetate / heptane) to obtain (5R,8S)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-13f) as a white solid. LC-MS (Method 1) showed a m / z of 285.3 (M+H) at 1.35 min. + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ7.95(d,J=4.9Hz,1H), 7.29(dd,J=5.0,1.7Hz,1H), 6.80(d,J=9.1Hz,2H), 6.71(d,J=9.1Hz,2H), 4.92(d,J=5.6Hz,1H), 4 .56(t,J=5.9Hz,1H), 3.61(s,3H), 2.92(dd,J=17.6,4.9Hz,1H), 2.35(d, J=17.5Hz,1H), 2.32~2.19(m,2H), 1.91~1.82(m,1H), 1.81~1.74(m,1H).

[0398] Step 6: After cooling the solution of (5R,8S)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-13f) (69 mg, 232 μmol) in MeCN (3.2 ml) to 0°C, the solution of CAN (381 mg, 696 μmol) in water (3.2 ml) was added dropwise. After the addition was complete, the reaction mixture was stirred at 0°C for 1 hour. 2M NaOH aqueous solution (5 ml) and water (5 ml) were added, and the mixture was extracted with DCM (3 × 10 ml). The combined organic matter was dehydrated with magnesium sulfate and concentrated under vacuum to obtain (5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-13) as a pale pink solid. LCMS (Method 1): m / z 179.2 (M+H) at 0.69 min + (ES + ), 1 H NMR(500MHz,DMSO-d6)δ7.91(dd,J=5.0,0.9Hz,1H), 7.04(dd,J=5.0,1.9Hz,1H), 4.17(d,J=5.3Hz,1H), 3.78(t,J=6.0Hz,1H), 2.85 (dd,J=17.1,5.2Hz,1H), 2.74(s,1H), 2.38(d,J=17.0Hz,1H), 2.01~1.85(m,2H), 1.73(t,J=9.1Hz,1H), 1.51(dt,J=9.4,5.4Hz,1H). Intermediate 14 (I-14)

[0399] [ka]

[0400] Step 1: Using essentially the same procedure as in I-12b, N-(2-bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfinamide I-14b was synthesized from 2-bromo-5-fluorobenzaldehyde I-14a. LC-MS (Method 2): m / z 305.9, 308.0 (M+H) at 2.80 min. + (ES + ), 1H NMR (500MHz, DMSO-d6) δ8.76(d,J=2.2Hz,1H), 7.86(dd,J=8.9,5.1Hz,1H), 7.80(dd,J=9.2,3.2Hz,1H), 7.56~7.36(m,1H), 1.20(s,9H).

[0401] Step 2: Using essentially the same procedure as in I-12c, N-(1-(2-bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfinamide I-14b) was synthesized as N-(1-(2-bromo-5-fluorophenyl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-14c. LC-MS (Method 2): m / z 362.0, 364.0 (M+H) at 2.47 min. + (ES + ), 1 H NMR(500MHz,DMSO-d6)δ7.61(ddd,J=8.7,5.4,4.2Hz,1H), 7.38(dd,J=10.2,3 .2Hz,1H), 7.13~7.04(m,1H), 5.87~5.79(m,1H), 5.69(d,J=7.2Hz,1H), 5.13~5 .02(m,1H), 5.02~4.95(m,1H), 4.62~4.46(m,1H), 2.26~2.17(m,1H), 2.17~2. 04(m,1H), 1.86(dtd,J=13.9,8.6,5.4Hz,1H), 1.80~1.60(m,1H), 1.06(s,9H).

[0402] Step 3: To a solution of N-(1-(2-bromo-5-fluorophenyl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-14c (13.6 g, 37.5 mmol) in MeOH (65 ml), a solution of 1,4-dioxane in HCl (4 M, 28 ml, 113 mmol) at room temperature was added and the mixture was stirred for 17 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in water (200 ml) and washed with ELISA (200 ml). The aqueous layer was basicized to pH 8 with 2 M NaOH solution and extracted with ELISA (2 × 100 ml). The combined organic matter was dehydrated with magnesium sulfate and concentrated under vacuum to obtain N-(1-(2-bromo-5-fluorophenyl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-14d as an orange / brownish oil. LCMS (Method 2): m / z 258.0, 260.0 (M+H) at 2.24 mins. + (ES + ), 1 H NMR(500MHz,DMSO-d6)δ7.57(dd,J=8.7,5.5Hz,1H), 7.48(dd,J=10.4,3.2Hz,1H), 7.03(td,J=8.4,3.2Hz,1H), 5.81(ddt,J=16.9,10.2,6.6Hz, 1H), 5.02(m,1H), 4.94(ddt,J=10.2,2.4,1.3Hz,1H), 4.12~4.00(m,1H) , 2.21~2.01(m,2H), 1.99(s,2H), 1.66~1.54(m,1H), 1.54~1.43(m,1H).

[0403] Step 4: Using essentially the same procedure as in I-12e, N-(1-(2-bromo-5-fluorophenyl)penta-4-en-1-amine I-14d was used to synthesize N-(1-(2-bromo-5-fluorophenyl)penta-4-en-1-yl)-4-methoxyaniline I-14e. LC-MS (Method 2): m / z 364.1, 366.0 (M+H) at 2.90 min. + (ES + ), 1H NMR(500MHz,DMSO-d6)δ7.61(dd,J=8.8,5.3Hz,1H), 7.26(dd,J=10.1,3.2Hz ,1H), 7.02(ddd,J=8.8,8.0,3.1Hz,1H), 6.67~6.61(m,2H), 6.41~6.34(m,2H ), 6.00(d,J=8.3Hz,1H), 5.90~5.81(m,1H), 5.06~4.94(m,2H), 4.58~4.50(m ,1H), 3.57(s,3H), 2.35~2.24(m,1H), 2.22~2.11(m,1H), 1.77~1.67(m,2H).

[0404] Step 5: Using a procedure essentially similar to that used for I-12f, (±)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annellene I-14f was synthesized from N-(1-(2-bromo-5-fluorophenyl)penta-4-en-1-yl)-4-methoxyaniline I-14e. LC-MS (Method 2): m / z 284.1 (M+H) + (ES + ); in 2.67 minutes.

[0405] Step 6: After cooling the solution of (±)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annelen I-14f (2.31 g, 8.15 mmol) in MeCN (100 ml) to 0°C, the solution of CAN (13.4 g, 24.5 mmol) in water (100 ml) was added dropwise. After the addition was complete, the reaction mixture was stirred at 0°C for 1 hour, then warmed to room temperature and stirred for 1 hour. 2M NaOH aqueous solution (100 ml) and DCM (100 ml) were added, the mixture was filtered through Celite, and washed with DCM (100 ml). The layers were separated, and the aqueous layer was extracted with DCM (2 × 100 ml). The combined organic compounds were dehydrated with magnesium sulfate and concentrated under vacuum to obtain (±)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annerene I-14 as a viscous, brownish-yellow oily substance. LC-MS (Method 2): m / z 178.5 (M+H) at 1.68 min. + (ES+ ), 1 ¹H NMR (400MHz, DMSO-d6) δ 7.02 (dd, J=8.3, 5.8Hz, 1H), 6.87 (ddd, J=18.0, 9.2, 2.8Hz, 2H), 4.09 (d, J=5.0Hz, 1H), 3.70 (t, J=5.8Hz, 1H), 2.98 (dd, J=16.6, 5.0Hz, 1H), 2.44 (d, J=16.4Hz, 1H), 1.96~1.82 (m, 2H), 1.70 (t, J=8.9Hz, 1H), 1.53~1.37 (m, 1H). (1H was obscured by the water peak). Intermediate 15 (I-15)

[0406] [ka]

[0407] Step 1: Using essentially the same procedure as in I-12b, N-(2-bromo-3-fluorobenzylidene)-2-methylpropane-2-sulfinamide I-15b was synthesized from 2-bromo-3-fluorobenzaldehyde I-15a. LC-MS (Method 2): m / z 305.9, 308.0 (M+H) at 2.42 min. + (ES + ), 1 H NMR (500MHz, DMSO-d6) δ8.81 (s, 1H), 7.88 (ddd, J=7.6, 1.8, 0.9Hz, 1H), 7.65~7.54 (m, 2H), 1.20 (s, 9H).

[0408] Step 2: Using essentially the same procedure as in I-12c, N-(1-(2-bromo-3-fluorobenzylidene)-2-methylpropane-2-sulfinamide I-15b) was synthesized to produce N-(1-(2-bromo-3-fluorophenyl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-15c. LC-MS (Method 2): m / z 362.0, 364.0 (M+H) at 2.44 min. + (ES + ), 1H NMR(500MHz,DMSO-d6)δ7.49~7.41(m,1H), 7.44~7.34(m,1H), 7.24(td,J=8.4,1.6Hz,1H), 5.86~5.77(m,1H), 5.71(d,J=7.0Hz,1H) ), 5.12~4.99(m,1H), 5.02~4.95(m,1H), 4.70~4.57(m,1H), 2.25~2.14(m,1H), 2.17~2.03(m,1H), 1.95~1.60(m,2H), 1.08(s,9H).

[0409] Step 3: Using essentially the same procedure as in I-14d, 1-(2-bromo-3-fluorophenyl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-15c was used to synthesize 1-(2-bromo-3-fluorophenyl)penta-4-en-1-amine I-15d. LC-MS (Method 2): m / z 258.0, 260.0 (M+H) at 2.18 min. + (ES + ), 1 H NMR(500MHz,DMSO-d6)δ7.46(dt,J=7.8,1.3Hz,1H), 7.40(td,J=7.9,5.6Hz, 1H), 7.20(ddd,J=8.9,8.0,1.6Hz,1H), 5.81(ddt,J=16.9,10.2,6.6Hz,1H), 5.06~4.98(m,1H), 4.94(ddt,J=10.2,2.4,1.3Hz,1H), 4.17(dd,J=8.2,4.9H z,1H), 2.20~1.96(m,2H), 1.96(s,2H), 1.67~1.61(m,1H), 1.56~1.49(m,1H).

[0410] Step 4: Pyridine (16.1 ml, 200 mmol) was added dropwise to a solution of 1-(2-bromo-3-fluorophenyl)penta-4-en-1-amine (10.3 g, 39.9 mmol)I-15d, (4-methoxyphenyl)boronic acid (18.2 g, 120 mmol), and Cu(OAc)2 (10.9 g, 59.9 mmol) in DCM (100 ml). The mixture was stirred and exposed to air at room temperature for 4 days. 2 M NaOH aqueous solution (100 ml) was added, the mixture was stirred for 30 minutes, and filtered through Celite. The filtrate was partitioned between water (100 ml) and DCM (100 ml) to separate the layers. The aqueous layer was further extracted with DCM (2 × 100 ml). The combined organic matter was dehydrated with magnesium sulfate and concentrated under vacuum. The product was purified by silica gel chromatography (0%~100% DCM / isohexane) to obtain N-(1-(2-bromo-3-fluorophenyl)penta-4-en-1-yl)-4-methoxyaniline I-15e as a sticky orange oily substance. 1 H NMR(500MHz,DMSO-d6)δ7.36~7.31(m,1H), 7.27(dd,J=8.0,1.7Hz,1H), 7.19(d dd,J=9.5,8.0,1.6Hz,1H), 6.66~6.58(m,2H), 6.40~6.33(m,2H), 6.04(d,J=8. 1Hz,1H), 5.87~5.82(m,1H), 5.06~4.94(m,2H), 4.61(td,J=8.1,5.2Hz,1H), 3. 56(s,3H), 2.30(dd,J=14.3,7.8Hz,1H), 2.23~2.12(m,1H), 1.80~1.67(m,2H).

[0411] Step 5: Using essentially the same procedure as in I-12f, (±)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annellene I-15f was synthesized from N-(1-(2-bromo-3-fluorophenyl)penta-4-en-1-yl)-4-methoxyaniline I-15e. LC-MS (Method 2): m / z 284.1 (M+H) at 2.56 min. + (ES + ), 1H NMR(400MHz,DMSO-d6)δ7.19~7.06(m,2H), 6.88(ddd,J=9.5,7.9,1.5Hz,1H), 6.83~6.74(m,2H), 6.73~6.65(m,2H), 4.83(d,J=5.3Hz) ,1H), 4.51(t,J=5.6Hz,1H), 3.60(s,3H), 2.96(dd,J=17.3,4.8Hz,1H), 2.37(d,J=17.4Hz,1H), 2.33~2.17(m,2H), 1.88~1.65(m,2H).

[0412] Step 6: Using essentially the same procedure as in I-12, (±)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annellene I-15 was synthesized from (±)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annellene I-15f. LC-MS (Method 2): m / z 178.1 (M+H) at 1.69 min. + (ES + ), 1 H NMR(500MHz,DMSO-d6)δ7.09(td,J=7.8,5.9Hz,1H), 6.90(ddd,J=9.5,8.2,1.1Hz,1H), 6.86(dd,J=7.5,1.1Hz,1H), 4.12(d,J=5.1Hz,1H), 3.75( t,J=6.0Hz,1H), 2.88(dd,J=16.9,5.2Hz,1H), 2.57(s,1H), 2.42(d,J=1 6.9Hz,1H), 1.97~1.85(m,2H), 1.70(t,J=9.0Hz,1H), 1.52~1.41(m,1H). Intermediate 16 (I-16)

[0413] [ka]

[0414] Step 1: Ti(OEt)4 (33.5 ml, 161 mmol) and tert-butylsulfinamide (10.8 g, 88.7 mmol) were added to a mixture of 2-bromonicotinaldehyde I-16a (15.0 g, 80.6 mmol) in THF (90.0 ml). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 ml) at 0°C and then extracted with SiO (3 × 75 ml). The combined organic matter was dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% SiO / petroleum ether) to obtain N-((2-bromopyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide I-16b as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.92(s,1H), 8.48(t,J=2.0Hz,1H), 8.31~8.29(m,1H), 7.40~7.37(m,1H), 1.25(t,J=3.2Hz,9H).

[0415] Step 2: To a solution of N-((2-bromopyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide I-16b (19.0 g, 65.7 mmol) in THF (107 ml), buta-3-en-1-ylmagnesium bromide (0.5 M, 302 ml) was added dropwise at 0°C. The mixture was warmed to room temperature for 1 hour. The reaction mixture was cooled to 0°C and water (50 ml) was carefully added. The product was extracted with ethyl acetate (3 × 100 ml). The combined organic layers were washed with brine (50 ml), dehydrated with sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to obtain N-(1-(2-bromopyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-16c as a yellow solid. 11H NMR (400MHz, CDCl3): δ 8.28 (t, J=2.8Hz, 1H), 7.69 (t, J=2.5Hz, 1H), 7.29~7.26 (m, 1H), 5.83~5.76 (t, J=2.4Hz, 1H), 5.08~5.00 (m, 2H), 4.84 (s, 1H), 2.23~2.10 (m, 2H), 1.97~1.93 (m, 2H), 1.18 (s, 9H). (NH was not observed.)

[0416] Step 3: To a solution of N-(1-(2-bromopyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-16c (11.2 g, 32.5 mmol) in MeOH (70 ml), HCl in ethyl phosphate (4 M, 24.4 ml, 97.6 mmol) was added at 0°C, and the mixture was heated to room temperature for 30 minutes. The reaction mixture was concentrated under vacuum, ground with MTBE (100 ml), the solid was filtered, washed with MTBE (2 × 100 ml), and dried under vacuum. The solid was dissolved in water (50 ml), cooled to 0°C, and the mixture was basicized to pH 11 with NaOH solution. The aqueous mixture was extracted with DCM (3 × 30 ml), the combined organic matter was washed with brine (30 ml), dehydrated with sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% siRNA / petroleum ether) to obtain 1-(2-bromopyridine-3-yl)penta-4-en-1-amine I-16d as a yellow solid. 1 ¹H NMR (400MHz, CDCl3) δ 8.26~8.22 (m,1H), 7.87~7.78 (m,1H), 7.26 (t,J=5.6Hz,1H), 5.85~5.76 (m,1H), 5.05~4.96 (m,2H), 4.35~4.30 (m,1H), 2.21~2.10 (m,2H), 1.83 (t,J=6.4Hz,1H), 1.70~1.64 (m,1H). (NH2 was not observed.)

[0417] Step 4: Et3N (4.56 ml, 32.8 mmol) was added dropwise to a mixture of 1-(2-bromopyridine-3-yl)penta-4-en-1-amine I-16d (6.50 g, 26.9 mmol), (4-methoxyphenyl)boronic acid (7.66 g, 50.4 mmol), 4 Å molecular sieves (12.1 g), and Cu(OAc)2 (11.4 g, 63.0 mmol) in 1,4-dioxane (100 ml). The resulting mixture was stirred at 35°C under O2 for 16 hours. The reaction mixture was filtered, and the solid was washed with ELISA (3 × 10 ml). The filtrate was dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% siRNA / petroleum ether) to obtain N-(1-(2-bromopyridine-3-yl)penta-4-en-1-yl)-4-methoxyaniline I-16e as a reddish-brown solid. 1 ¹H NMR (400MHz, CDCl3) δ 8.26~8.23 (m,1H), 7.83~7.70 (m,1H), 7.26~7.18 (m,1H), 6.69 (d,J=4.8Hz,1H), 6.41~6.38 (m,2H), 5.86 (d,J=6.8Hz,2H), 5.08~5.00 (m,2H), 4.64 (t,J=4.4Hz,1H), 3.69 (s,3H), 2.31~2.22 (m,2H), 1.98 (d,J=6.8Hz,1H), 1.73 (t,J=8.4Hz,1H). (NH was not observed)

[0418] Step 5: Place Pd2(dba)3 (131 mg, 0.144 mmol), tricyclohexylphosphonium; tetrafluoroborate (106 mg, 0.288 mmol), and NaO in a three-necked flask. tBu (207 mg, 2.16 mmol) was added and the mixture was purged with argon. A solution of N-(1-(2-bromopyridine-3-yl)penta-4-en-1-yl)-4-methoxyaniline I-16e (0.50 g, 1.44 mmol) in 1,4-dioxane (1.8 ml) was added, and the resulting mixture was heated at 95°C for 12 hours. The reaction mixture was filtered, and the solid was washed with ethyl acetate (3 × 10 ml). The filtrate was dehydrated with sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to obtain (±)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine I-16f as a pale reddish-brown solid. 1 H NMR (400MHz, CDCl3) δ8.32~8.31(m,1H), 7.45~7.43(m,1H), 6.75(t,J=2.8Hz,1H), 6.72(t,J=6.4Hz,4H), 4.67(d,J=6.8Hz,1H) , 4.53(t,J=6.4Hz,1H), 3.69(s,3H), 3.36(d,J=17.6Hz,1H), 2.61(d,J=17.6Hz,1H), 2.38(t,J=5.6Hz,1H), 1.94~1.83(m,2H).

[0419] Step 6: (±)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine I-16 was synthesized from (±)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine I-16f using essentially the same procedure as in I-14. LC-MS (Method 1): m / z 160.9 (M+H) + (ES + In 0.62 minutes. Intermediate 17 (I-17)

[0420] [ka]

[0421] Step 1: Using essentially the same procedure as in I-13b, (S)-N-((4-bromo-6-fluoropyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide I-17b was synthesized from 4-bromo-6-fluoronicotinaldehyde I-17a. LC-MS (Method 2): m / z 307.0, 308.9 (M+H) at 2.05 min. + (ES + ), 1 H NMR (500MHz, DMSO-d6) δ8.81(s,1H), 8.73(s,1H), 7.88(d,J=2.4Hz,1H), 1.21(s,9H).

[0422] Step 2: To a solution of ((S)-N-((4-bromo-6-fluoropyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide I-17b (7.00 g, 22.8 mmol) in THF (114 ml), buta-3-en-1-ylmagnesium bromide (2.54 M, 17.9 ml, 45.6 mmol) was added dropwise at -78°C. The mixture was slowly warmed to room temperature and stirred for 16 hours. Saturated ammonium chloride solution (10 ml) was added, and the product was sorbed with ELISA. Extraction was performed using 2 × 10 ml. The combined organic matter was dried over magnesium sulfate and concentrated under vacuum. The product was purified by silica gel chromatography (0-10% IPA / isohexane) to obtain a 2:1 mixture of diastereomers of (±)-N-(1-(4-bromo-6-fluoropyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-17c as a pale yellow oil. LC-MS (Method 1) m / z 363.3, 365.4 (M+H) + (ES + ), at 1:39 and 1:42.

[0423] Major diastereomers: 1H NMR (500MHz, DMSO-d6) δ 8.43 (s, 1H), 7.60 (d, J=2.6Hz, 1H), 6.00 (d, J=9.5Hz, 1H), 5.82 (ddt, J=16.7, 10.3, 6.6Hz, 1H), 5.12~4.97 (m, 2H), 4.64~4.50 (m, 1H), 2.26~2.14 (m, 1H), 2.16~2.05 (m, 1H), 1.94~1.78 (m, 1H), 1.78~1.66 (m, 1H), 1.13 (s, 9H).

[0424] Small amounts of diastereomer: 1H NMR (500MHz, DMSO-d6) δ 8.33 (s, 1H), 7.61 (d, J=2.5Hz, 1H), 5.82 (ddt, J=16.7, 10.3, 6.6Hz, 1H), 5.76 (d, J=7.0Hz, 1H), 5.12~4.97 (m, 2H), 4.64~4.50 (m, 1H), 2.26~2.14 (m, 1H), 2.16~2.05 (m, 1H), 2.03~1.92 (m, 1H), 1.94~1.78 (m, 1H), 1.07 (s, 9H).

[0425] Step 3: Using essentially the same procedure as in I-13d, (±)-N-(1-(4-bromo-6-fluoropyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-17c was used to synthesize (±)-1-(4-bromo-6-fluoropyridine-3-yl)penta-4-en-1-amine I-17d. LC-MS (Method 1) showed m / z 259.2, 261.2 (M+H) at 1.21 min. + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ8.41(s,1H), 7.55(d,J=2.7Hz,1H), 5.82(ddt,J=16.9,10.2,6.6Hz,1H), 5.03(dq,J=17.2,1.8Hz,1H ), 4.95(ddt,J=10.2,2.3,1.3Hz,1H), 4.12(dd,J=8.2,4.9Hz,1H), 2.25~1.98(m,4H), 1.75~1.64(m,1H), 1.64~1.54(m,1H).

[0426] Step 4: Using essentially the same procedure as in I-13e, (±)-N-(1-(4-bromo-6-fluoropyridine-3-yl)penta-4-en-1-yl)-4-methoxyaniline I-17e was synthesized from (±)-1-(4-bromo-6-fluoropyridine-3-yl)penta-4-en-1-yl)-4-methoxyaniline I-17e. LC-MS (Method 1) at m / z 1.76 min yielded 365.0, 367.1 (M+H). + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ8.21(s,1H), 7.61(d,J=2.5Hz,1H), 6.66(d,J=8.9Hz,2H), 6.40(d,J=9.0Hz,2H), 6.04(d,J=8.3Hz,1H), 5.86(ddt,J= 17.0,10.2,6.6Hz,1H), 5.08~4.90(m,2H), 4.59(td,J=8.5,4.8Hz,1H) , 3.58(s,3H), 2.35~2.26(m,1H), 2.23~2.13(m,1H), 1.92~1.71(m,2H).

[0427] Step 5: Place Pd-178 (0.29g, 0.61 mmol) and NaO in a three-necked flask. tBu (0.88 g, 9.2 mmol) was added and the mixture was purged with N2. A solution of N-(1-(4-bromo-6-fluoropyridine-3-yl)penta-4-en-1-yl)-4-methoxyaniline I-17e (2.3 g, 6.1 mmol) in toluene (66 ml) was added dropwise. The resulting mixture was heated at 95°C for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the solid was washed with ELISA (150 ml). The filtrate was concentrated under vacuum. The product was purified by silica gel chromatography (0%~50% siRNA / isohexane) to obtain a mixture of enantiomers, which was dissolved in DCM:methanol (1:4) to a concentration of 30 mg / ml. This mixture was then separated by chiral SFC on a Waters prep15 at 40°C, 100 bar, on a LuxC3 column (21.2 mm × 250 mm, particle size 5 μm) using 40% methanol, and a flow rate of 50 ml / min, after UV detection at 210 nm. (6S,9R)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-17f) was obtained as a pale yellow solid. LCMS (Method 1) showed a m / z of 285.3 (M+H)+(ES+) at 1.35 min. 1H NMR (500MHz, DMSO-d6) δ 8.10 (s, 1H), 6.79 (t, J=9.7Hz, 3H), 6.70 (d, J=9.1Hz, 2H), 4.95 (d, J=5.5Hz, 1H), 4.47 (t, J=6.0Hz, 1H), 3.61 (s, 3H), 3.11 (dd, J=18.2, 4.9Hz, 1H), 2.31~2.19 (m, 2H), 1.88~1.55 (m, 2H). The 1H peak was obscured by the remaining DMSO peak. And (6R,9S)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-17g) was obtained as a pale yellow solid. LCMS (Method 1) showed m / z 285.3 (M+H)+(ES+) at 1.35 min. 1H NMR (500MHz, DMSO-d6) δ 8.10 (s, 1H), 6.79 (t, J=9.7Hz, 3H), 6.70 (d, J=9.1Hz, 2H), 4.95 (d, J=5.5Hz, 1H), 4.47 (t, J=6.0Hz, 1H), 3.61 (s, 3H), 3.11 (dd, J=18.2, 4.9Hz, 1H), 2.31~2.19 (m, 2H), 1.88~1.55 (m, 2H). The 1H peak was obscured by the remaining DMSO peak.

[0428] Step 6: Using essentially the same procedure as in I-13, (6S,9R)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-17) was synthesized from (6S,9R)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-17f). LC-MS (Method 1) m / z 179.2 (M+H) + (ES + ), in 0.71 minutes. Intermediate 18 (I-18)

[0429] [ka]

[0430] (6S,9R)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-17 (300 mg, 1.68 mmol) was dissolved in HBr (1.90 ml, 48 wt / wt% water, 16.8 mmol) and heated at 100°C for 18 hours. The reaction mixture was cooled to room temperature, diluted with MeOH, loaded onto an SCX cartridge (20 g), and the product was eluted with ammonia solution in MeOH (0.7 M) to obtain (6S,9R)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridine-3-one (I-18) as a grayish-white solid. LC-MS (Method 1) m / z 176.9 (M+H) + (ES + ), in 0.41 minutes, Intermediate 19 (I-19)

[0431] [ka]

[0432] Step 1: To a solution of 4-chloro-3-fluoropyridine I-19a (25.9 ml, 190 mmol) in THF (120 ml), LDA (2 M, 114 ml, 228 mmol) was added at -70°C. The mixture was stirred at -70°C for 3 hours, then DMF (17.5 ml, 228 mmol) in THF (50 ml) was added. The mixture was slowly warmed to room temperature and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C and saturated ammonium chloride (100 ml) was added. The aqueous layer was adjusted to pH 6 with HCl (1 M) and extracted with MTBE (3 × 100 ml). The combined organic layers were washed with brine (100 ml), dehydrated with sodium sulfate, and concentrated under vacuum to obtain 4-chloro-5-fluoronicotinaldehyde I-19b as a yellow oil. 1 H NMR (400MHz, CDCl3) δ10.4(s,1H), 8.87(s,1H), 8.69(s,1H).

[0433] Step 2: Using a procedure essentially similar to that in I-16b, N-((4-chloro-5-fluoropyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide I-19c was synthesized from 4-chloro-5-fluoronicotinaldehyde I-19b. 1 H NMR (400MHz, CDCl3) δ9.02(s,1H), 8.93(s,1H), 8.59(s,1H), 1.30(s,9H).

[0434] Step 3: To a solution of (E)-N-((4-chloro-5-fluoropyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide I-19c (27.0 g, 102 mmol) in THF (150 ml), buta-3-en-1-ylmagnesium bromide (0.5 M, 822 ml) was added at 0°C. The mixture was heated and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C and water (50 ml) was added. The product was extracted with ELISA (3 × 100 ml). The organic layer was separated, washed with water (100 ml) and brine (100 ml), dehydrated with sodium sulfate, and concentrated under vacuum. The product was ground with petroleum ether (50 ml), the solid was filtered, and washed with petroleum ether (2 × 20 ml). The solid was dried under vacuum to obtain N-(1-(4-chloro-5-fluoropyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-19d as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.43(s,2H), 5.84~5.76(m,1H), 5.10~5.03(m,2H), 4.94~4.90(m,1H), 3.58(d,J=2.4Hz,1H), 2.22~2.01(m,4H), 1.20(s,9H).

[0435] Step 4: Using essentially the same procedure as in I-16d, 1-(4-chloro-5-fluoropyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-19d was used to synthesize 1-(4-chloro-5-fluoropyridine-3-yl)penta-4-en-1-amine I-19e. 1¹H NMR (400MHz, CDCl3) δ 8.52 (s,1H), 8.38 (s,1H), 5.83~5.77 (m,1H), 5.05~4.97 (m,2H), 4.39~4.35 (m,1H), 2.16~2.11 (m,2H), 1.86~1.60 (m,2H). (NH2 was not observed.)

[0436] Step 5: Using essentially the same procedure as in I-16e, N-(1-(4-chloro-5-fluoropyridine-3-yl)penta-4-en-1-amine I-19e)-4-methoxyaniline I-19f was synthesized. 1 H NMR (400MHz, CDCl3) δ8.43(s,1H), 8.37(s,1H), 6.72~6.69(m,2H), 6.44(t,J=3.6Hz,2H), 5.85~5.81(m,1H) , 5.09~5.03(m,2H), 4.76(t,J=4.8Hz,1H), 3.96(s,1H), 3.70(s,3H), 2.30~2.22(m,2H), 1.97~1.87(m,2H).

[0437] Step 6: Using essentially the same procedure as in I-16f, (±)-4-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-19g was synthesized from N-(1-(4-bromo-5-fluoropyridine-3-yl)penta-4-en-1-yl)-4-methoxyaniline I-19f. 1 H NMR(400MHz,CDCl3)8.25(s,1H), 8.17(s,1H), 6.77~6.73(m,4H), 4.79(d,J=6.0Hz,1H), 4.52(t,J= 5.2,1H), 3.71(s,3H), 3.15~3.09(m,1H), 2.48~2.40(m,3H), 1.99~1.94(m,1H), 1.78~1.70(m,1H).

[0438] Step 7: After cooling the solution of (±)-4-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-19 g (0.150 g, 528 μmol) in MeCN (10 ml) to 0°C, the solution of CAN (925 mg, 1.69 mmol) in water (10 ml) was added dropwise. After the addition was complete, the reaction mixture was stirred at 0°C for 1 hour. Further, CAN (925 mg, 1.69 mmol) in water (3 ml) was added, and the reaction mixture was stirred for another hour. The substance was loaded onto an SCX cartridge (20 g), washed with MeOH (40 ml), and the product was eluted using a 0.7 M ammonia solution in MeOH (100 ml) to obtain (6S,9R)-4-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine as a yellow oily substance I-19. LC-MS (Method 1): m / z 178.9 (M+H) + (ES + In 0.71 minutes. Intermediate 20 (I-20)

[0439] [ka]

[0440] Step 1: To a solution of (6S,9R)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-17f (100.0 mg, 351.7 μmol) in MeOH (1 ml), sodium methoxide (5.4 M in MeOH, 391 μl, 2.11 mmol) was added, and the reaction mixture was heated at 65°C for 48 hours. The reaction mixture was diluted with DCM (20 ml) and water (50 ml). The layers were separated, and the aqueous layer was extracted with DCM (3 × 30 ml). The combined organic compounds were dehydrated with magnesium sulfate and concentrated under vacuum to obtain (6S,9R)-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-20a as a pale yellow oily substance. LC-MS (Method 2) m / z 297.1 (M+H) + (ES + ), in 2.14 minutes.

[0441] Step 2: Using a procedure essentially similar to that in I-13, (6S,9R)-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-20a was synthesized to produce (6S,9R)-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-20. LC-MS (Method 1) m / z 191.1 (M+H) + (ES + ), in 1.33 minutes. Intermediate 21 (I-21)

[0442] [ka]

[0443] Step 1: Using essentially the same procedure as in I-7b, (S)-N-((4-bromopyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide I-21a was synthesized from 4-bromo-3-pyridinecarboxaldehyde (I-8a) and (S)-tert-butylsulfinamide. 1 H NMR (400MHz, CDCl3) δ9.13(s,1H), 8.92(s,1H), 8.46(d,J=5.2Hz,1H), 7.60(d,J=5.6Hz,1H), 1.29(s,9H).

[0444] Step 2: Using essentially the same procedure as in I-7c, (S)-N-((R)-1-(4-bromopyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-21b and (S)-N-((S)-1-(4-bromopyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-22a were synthesized from (S)-N-((4-bromopyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-22a. 1H NMR(400MHz,CDCl3)δ:8.52(s,1H), 8.29(d,J=5.6Hz,1H), 7.50(t,J=9.6Hz,1H), 5.83~5.76(m,1 H), 5.09~5.01(m,2H), 4.91~4.89(m,1H), 3.60(t,J=2.8Hz,1H), 2.19~1.96(m,4H), 1.18(s,9H).

[0445] Step 3: Using essentially the same procedure as in I-7d, (R)-1-(4-bromopyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-21b was used to synthesize (R)-1-(4-bromopyridine-3-yl)penta-4-en-1-amine I-21c. 1 ¹H NMR (400MHz, CDCl3): δ 8.70 (s, 1H), 8.27~8.22 (m, 1H), 7.45 (t, J=5.6Hz, 1H), 5.88~5.80 (m, 1H), 5.07~4.98 (m, 2H), 4.37~4.33 (m, 1H), 2.22~2.13 (m, 2H), 1.90~1.75 (m, 2H). (NH2 was not observed.)

[0446] Step 4: Using a procedure essentially similar to that in I-7e, (R)-N-(1-(4-bromopyridine-3-yl)penta-4-en-1-amine I-21c)-4-methoxyaniline I-21d was synthesized. 1 ¹H NMR (400MHz, CDCl3): δ 8.68 (s, 1H), 8.40 (d, J=5.2Hz, 1H), 7.34 (d, J=5.2Hz, 1H), 6.70 (d, J=9.2Hz, 2H), 6.39~6.36 (m, 2H), 5.87~5.83 (m, 1H), 5.09~5.02 (m, 2H), 4.66~4.63 (m, 1H), 3.95 (s, 1H), 3.87 (s, 3H), 2.33~2.25 (m, 2H), 1.95~1.93 (m, 1H), 1.75~1.71 (m, 1H), (NH was not observed).

[0447] Step 5: Pd2(dba)3 (0.68g, 0.75 mmol), tricyclohexylphosphonium tetrafluoroborate (551mg, 1.50 mmol), and NaO t Bu (5.69 g, 59.2 mmol) was dissolved in toluene (50 ml). The flask was purged with N2, and (R)-N-(1-(4-bromopyridine-3-yl)penta-4-en-1-yl)-4-methoxyaniline I-21d (2.6 g, 7.5 mmol) was added dropwise. The resulting mixture was heated at 90°C for 12 hours. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (3 × 50 ml). The filtrate was concentrated under vacuum. The product was purified by silica gel chromatography (10%~100% ethyl acetate / petroleum ether) to obtain (6S,9R)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-21e. 1 H NMR(400MHz,CDCl3)δ8.40(s,1H), 8.28(d,J=5.2Hz,1H), 6.85(d,J=5.2Hz,1H), 6.77~6.71(m,4H), 4.73(d,J=5.2Hz, 1H), 4.46(t,J=5.2Hz,1H), 3.69(s,3H), 3.25~3.20(m,1H), 2.42~2.35(m,3H), 1.97~1.93(m,1H), 1.79~1.77(m,1H).

[0448] Step 6: To a solution of (6S,9R)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-21e) (1.08 g, 4.05 mmol) in MeCN (50 ml), a solution of CAN (6.67 g, 12.2 mmol) in water (50 ml) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 1 hour, and then the reaction mixture was warmed to room temperature for 1 hour. The reaction mixture was cooled to 0°C, and CAN (4.45 g, 8.11 mmol) in an additional volume of water (20 ml) was added, and the mixture was stirred at 0°C for 1 hour. A solution of 2 M NaOH (50 ml) was added, and the resulting mixture was filtered through a Celite pad. The layers were separated, and the aqueous layer was extracted with DCM (3 × 100 ml). The combined organic compounds were dehydrated with magnesium sulfate and concentrated under vacuum to obtain (6S,9R)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-21 as a grayish-white solid. 1 H NMR(500MHz,DMSO-d6)δ8.27~8.18(m,2H), 7.04(d,J=5.0Hz,1H), 4.17(d,J=5.7Hz,1H), 3.71(s,1H), 2.99(dd,J=17. 4,5.0Hz,1H), 2.72(s,1H), 2.47(dd,J=17.2,1.1Hz,1H), 1.98~1.86(m,2H), 1.71(t,J=8.9Hz,1H), 1.49~1.42(m,1H). Intermediate 22 (I-22)

[0449] [ka]

[0450] Step 1: Using essentially the same procedure as in I-7d, (S)-N-((S)-1-(4-bromopyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-22a was used to synthesize (S)-1-(4-bromopyridine-3-yl)penta-4-en-1-amine I-22b. 1¹H NMR (400MHz, CDCl3) δ 8.56 (d, J=7.2Hz, 1H), 8.25 (d, J=5.2Hz, 1H), 7.45 (d, J=5.2Hz, 1H), 5.87~5.79 (m, 1H), 5.06~4.97 (m, 2H), 4.36~4.33 (m, 1H), 2.20~2.12 (m, 2H), 1.89~1.85 (m, 1H), 1.78~1.75 (m, 1H). (NH2 was not observed.)

[0451] Step 2: Using a procedure essentially similar to that in I-7e, (S)-N-(1-(4-bromopyridine-3-yl)penta-4-en-1-amine I-22b)-4-methoxyaniline I-22c was synthesized. 1 H NMR(400MHz,CDCl3)δ:8.57(s,1H), 8.26(s,1H), 7.50(s,1H), 6.70(d,J=2.4Hz,2H), 6.45~6.42(m,2H), 5.86~5.82( m,2H), 4.73~4.71(m,2H), 4.69~4.67(m,1H), 3.70(s,3H), 2.31~2.23(m,2H), 1.96~1.94(m,1H), 1.85~1.82(m,1H).

[0452] Step 3: Using a procedure essentially similar to that in I-21e, (6S,9R)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine)I-22d was synthesized from (S)-N-(1-(4-bromopyridine-3-yl)penta-4-en-1-yl)-4-methoxyaniline I-22c. 1 H NMR (400MHz, CDCl3) δ8.66(s,1H), 8.29~8.24(m,1H), 7.48~7.45(t,J=8.8Hz,1H), 5.86~5.79(m,1H), 5.0 6~4.97(m,2H), 4.36~4.33(m,1H), 2.20~2.12(m,2H), 1.89~1.85(m,1H), 1.78~1.75(m,1H), 1.56(s,2H).

[0453] Step 4: Using essentially the same procedure as in I-21, (6S,9R)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-22 was synthesized from 1-(4-bromopyridine-3-yl)penta-4-en-1-amine I-22d. 1 1H NMR (500MHz, DMSO-d6) δ 8.23 ​​(d, J=5.0Hz, 1H), 8.19 (s, 1H), 7.03 (d, J=5.0Hz, 1H), 4.16 (d, J=5.7Hz, 1H), 3.70 (t, J=6.0Hz, 1H), 2.99 (dd, J=17.4, 5.1Hz, 1H), 2.00~1.86 (m, 2H), 1.70 (t, J=8.9Hz, 1H), 1.49~1.41 (m, 1H). (NH was not observed, 1CH below the DMSO peak) Intermediate 23 (I-23)

[0454] [ka]

[0455] Step 1: Using essentially the same procedure as in I-7b, (S)-N-((3-bromopyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide I-23b was synthesized from 3-bromo-4-pyridine carboxyaldehyde I-7a. 1 H NMR (400MHz, CDCl3) δ8.92(s,1H), 8.87(s,1H), 8.64~8.63(m,1H), 7.85~7.84(m,1H), 1.30(s,3H).

[0456] Step 2: To a solution of (S)-N-((3-bromopyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide (I-23b) (6.00 g, 20.7 mmol) in THF (120 ml), (3-methylbuta-3-en-1-yl)magnesium bromide (0.5 M in THF, 124 ml) was added, and the mixture was stirred at 20°C for 1 hour. A saturated NH4Cl solution (50 ml) was added, and the product was extracted with ELISA (3 × 20 ml). The combined organic matter was washed with water (20 ml) and brine (200 ml), dried over sodium sulfate, and concentrated under vacuum. The product was purified by silica gel chromatography (1% to 100% butyl / petroleum ether) to obtain (S)-N-((R)-1-(3-bromopyridine-3-yl)-4-methylpenta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-23c as a yellow oily substance. 1 H NMR (400MHz, CDCl3) δ8.72~8.64(m,1H), 8.61(s,1H), 7.33~7.32(m,1H), 4.85 ~4.81(m,1H), 4.77~4.73(m,2H), 2.14~1.93(m,4H), 1.72(s,3H), 1.19,(s,9H)

[0457] Step 3: Using a procedure essentially similar to that in I-7d, (R)-1-(3-bromopyridine-3-yl)-4-methylpenta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-23c was used to synthesize (R)-1-(3-bromopyridine-3-yl)-4-methylpenta-4-en-1-amine I-23d. 1 H NMR (400MHz, CDCl3) δ8.64~8.61(m,1H), 8.49~8.45(m,1H), 7.43(t,J=4.8Hz,1H), 4.72~ 4.69(m,2H), 4.30~4.24(m,1H), 2.14~2.05(m,2H), 1.87~1.70(m,1H), 1.68~1.64(m,1H).

[0458] Step 4: Using a procedure essentially similar to that in I-7e, (R)-N-(1-(3-bromopyridine-3-yl)-4-methylpenta-4-en-1-amine I-23d)-4-methoxyaniline I-23e was synthesized. 1 H NMR(400MHz,CDCl3)δ8.70(s,1H), 8.42(s,1H), 7.37(s,1H), 6.70(d,J=8.8Hz,2H), 6.36(t,J=8.8Hz,2H), 4.7 5(d,J=25.5Hz,2H), 4.65~4.62(m,1H), 3.70(s,3H), 2.26~2.20(m,2H), 2.12~1.98(m,3H), 1.77~1.75(m,4H).

[0459] Step 5: Using essentially the same procedure as in I-21e, (5R,8S)-10-(4-methoxyphenyl)-8-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-23f was synthesized from (R)-N-(1-(3-bromopyridine-3-yl)-4-methylpenta-4-en-1-yl)-4-methoxyaniline I-23e. 1 H NMR(400MHz,CDCl3)δ8.42(s,1H), 8.22(s,1H), 7.09(d,J=4.8Hz,1H), 6.81(d,J=8.8Hz,2H), 6.67(d,J=8.8Hz,2H), 4.44(d,J=6.4Hz,2H), 3 .71(s,3H), 2.72~2.68(m,1H), 2.49~2.45(m,1H), 2.33~2.30(m,1H), 2.05~2.02(m,1H), 1.99~1.93(m,2H), 1.72~1.70(m,1H), 1.56(s,3H).

[0460] Step 6: Using a procedure essentially similar to that in I-21, (5R,8S)-8-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-23f) was synthesized from (5R,8S)-8-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-23f). LC-MS (Method 2) m / z 175 (M+H) + (ES + ), in 1.15 minutes. Intermediate 24 (I-24)

[0461] [ka]

[0462] Step 1: 1-Cyclopropylethane-1-ol (11.3 ml, 116 mmol) was dissolved in an aqueous HBr solution (45 ml, 47 wt / wt%) at 0°C. The mixture was heated to room temperature for 12 hours. The product was distilled under vacuum (60°C, 750 Torr) to obtain a mixture of (E)-5-bromopenta-2-ene I-24b and (Z)-5-bromopenta-2-ene I-24c as a yellow oil. 1 H NMR (400MHz, CDCl3) δ5.58~5.52(m,1H), 5.43~5.36(m,1H), 3.37~3.33(m,2H), 2.56~2.50(m,2H), 1.67~1.65(m,3H).

[0463] Step 2: To a solution of I2 (1.69 ml, 8.39 mmol) and Mg (8.66 g, 356 mmol) in THF (250 ml), a mixture of (E)-5-bromopenta-2-ene I-24b and (Z)-5-bromopenta-2-ene I-24c (25.0 g, 167 mmol) in THF (100 ml) was added at room temperature of 20 °C. The mixture was stirred at 40 °C for 1 hour. The crude mixture of (E)-penta-3-en-1-ylmagnesium bromide I-24d and (Z)-penta-3-en-1-ylmagnesium I-24e was used in the next step without any post-treatment or further purification.

[0464] Step 3: Using a procedure essentially similar to that in I-7c, (S)-N-((R,E)-1-(3-bromopyridine-4-yl)hexa-4-en-1-yl)-2-methylpropane-2-sulfinamide I-24f and (S)-N-((R,Z)-1-(3-bromopyridine-4-yl)hexa-4-en-1-yl)-2-methylpropane-2-sulfinamide I-24g were synthesized from a mixture of (S,E)-N-((3-bromopyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide I-23b and (E)-penta-3-en-1-ylmagnesium bromide I-24d and (Z)-penta-3-en-1-ylmagnesium I-24e. The data for I-24f as I-24g was obtained from only a small portion of the mixture. 1 H NMR (400MHz, CDCl3) δ8.67(s,1H), 8.48(d,J=5.2Hz,1H), 5.50~5.39(m,2H), 4.88~4.81(m,1H) ), 3.59(d,J=3.6Hz,1H), 2.11~2.03(m,3H), 1.93~1.90(m,2H), 1.64~1.63(m,3H), 1.16(s,9H)

[0465] Step 4: Using essentially the same procedure as in I-7d, (R,E)-1-(3-bromopyridine-4-yl)hexa-4-en-1-yl)-2-methylpropane-2-sulfinamide I-24f and (S)-N-((R,Z)-1-(3-bromopyridine-4-yl)hexa-4-en-1-yl)-2-methylpropane-2-sulfinamide I-24g were used to synthesize (R,E)-1-(3-bromopyridine-4-yl)hexa-4-en-1-amine I-24h and (R,Z)-1-(3-bromopyridine-4-yl)hexa-4-en-1-amine I-24i.

[0466] Step 5: Using essentially the same procedure as in I-7e, ((R,E)-N-(1-(3-bromopyridine-4-yl)hexa-4-en-1-amine I-24h and (R,Z)-1-(3-bromopyridine-4-yl)hexa-4-en-1-amine I-24i) were used to synthesize ((R,E)-N-(1-(3-bromopyridine-4-yl)hexa-4-en-1-yl)-4-methoxyaniline I-24j and (R,Z)-N-(1-(3-bromopyridine-4-yl)hexa-4-en-1-yl)-4-methoxyaniline I-24k). The data for I-24j as I-24k were obtained from only a small portion of the mixture. 1 H NMR (400MHz, CDCl3) δ8.69(s,1H), 8.41(s,1H), 7.39(s,1H), 6.70~6.67(m,2H), 6.38~6.36(m, 2H), 5.50~5.41(m,2H), 4.63~4.60(m,1H), 3.68(s,3H), 2.19~2.15(m,2H), 1.71~1.64(m,4H).

[0467] Step 6: Add NaO to the solution of ((R,E)-N-(1-(3-bromopyridine-4-yl)hexa-4-en-1-yl)-4-methoxyaniline I-24j and (R,Z)-N-(1-(3-bromopyridine-4-yl)hexa-4-en-1-yl)-4-methoxyaniline I-24k (0.54 g, 1.49 mmol) in dioxane (5 ml) at room temperature. t Bu (287 mg, 2.99 mmol) and Pd-178 (71.3 mg, 149 mmol) were added. The mixture was heated at 105°C for 16 hours. The reaction mixture was filtered, and the filter cake was washed with toluene (3 × 50 ml). The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (30-60% MeCN / 10 mM NH4HCO3) to obtain (5R,8S,9R)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-24l as a white solid, and (5R,8S,9S)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-24k as a white solid. (5R,8S,9R)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-24l: 1 H NMR(400MHz,CDCl3)δ8.37(s,2H), 7.06~7.01(m,1H), 6.88~6.78(m,4H), 4.67(d,J=5.2Hz,1H), 4.14(d,J=6.0,1H), 3.75(s,3H), 2.81(d,J=7.6Hz,1H), 2.23~2.16(m,2H), 1.79~1.74(m,1H), 1.58~1.50(m,1H), 1.37(d,J=7.6Hz,3H). (5R,8S,9S)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-24k: 1 H NMR (400MHz, CDCl3) δ8.35~8.32(m,2H), 7.05(d,J=5.2Hz,1H), 6.99~6.73(m,4H), 4.57(d,J=7.6Hz,1H), 4.22~4.19(m ,1H), 3.70(s,3H), 3.35~3.32(m,1H), 2.34~2.31(m,1H), 2.22~2.13(m,1H), 1.98~1.83(m,2H), 1.31(d,J=8.0Hz,3H).

[0468] Step 7: To a solution of (5R,8S,9S)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-24k (11.0 mg, 39.2 μmol) in MeCN (0.55 ml), a solution of CAN (65 mg, 118 μmol) in water (0.55 ml) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour. Water (10 ml) and 2 M NaOH (10 ml) were added, and the product was extracted with DCM (3 × 20 ml). The combined organic matter was concentrated under vacuum to obtain (5R,8S,9S)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-24 as a colorless oil. The product was used in the next step without further purification or analysis. Intermediate 25 (I-25)

[0469] [ka]

[0470] Step 1: To a solution of 2,3-difluoropyridine I-25a (50.0 g, 434 mmol) in hexane (275 ml) and THF (450 ml), n-BuLi (2.5 M in hexane, 173 ml) was added at -70°C. The mixture was stirred at -70°C for 2 hours, then 1,1,2-trichloro-1,2,2-trifluoroethane (52 ml, 434 mmol) was added at -70°C, and the resulting mixture was stirred at -70°C for 1 hour. Aqueous ammonium chloride solution (300 ml) was added at 0°C, and the product was extracted with pharmaceutically acceptable ammonium chloride (3 × 100 ml). The combined organic matter was washed with brine (100 ml), dried over sodium sulfate, and concentrated under vacuum to obtain 4-chloro-2,3-difluoropyridine I-25b as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.92(d,J=5.2Hz,1H), 7.29(d,J=2.0Hz,1H).

[0471] Step 2: To a solution of 4-chloro-2,3-difluoropyridine I-25b (17 g, 113 mmol) in THF (170 ml), a solution of LDA in THF / n-heptane / ethylbenzene (2 M, 68 ml) was added at -90°C. The mixture was heated to ~70°C for 2 hours. DMF (10.5 ml, 136 mmol) in THF (170 ml) was slowly added at -90°C. The resulting mixture was slowly heated to room temperature and stirred at room temperature for 1 hour. 1 M aqueous HCl (200 ml) was added at 0°C. The product was extracted with MTBE (3 × 100 ml). The combined organic matter was washed with brine (100 ml), dehydrated with sodium sulfate, and concentrated under vacuum to obtain 4-chloro-5,6-difluoronicotinaldehyde I-25c as a yellow oil. 1 H NMR (400MHz, CDCl3) δ10.3(s,1H), 8.52(s,1H).

[0472] Step 3: Using essentially the same procedure as in I-7b, N-((4-chloro-5,6-difluoronicotinaldehyde-3-yl)methylene)-2-methylpropane-2-sulfinamide I-25d was synthesized from 4-chloro-5,6-difluoronicotinaldehyde I-25c. 1 H NMR (400MHz, CDCl3) δ8.89(d,J=2.4Hz,1H), 8.64(s,1H), 1.31(s,9H).

[0473] Step 4: Using essentially the same procedure as in I-7c, N-(1-(4-chloro-5,6-difluoropyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-25e was synthesized from N-((4-chloro-5,6-difluoropyridine-3-yl)methylene)-2-methylpropane-2-sulfinamide I-25d. 1 H NMR (400MHz, CDCl3) δ8.00(s,1H), 5.81~5.76(m,1H), 5.09~4.99(m,2H), 4.84~4. 68(m,1H), 3.73~3.56(m,1H), 2.13~2.11(m,2H), 2.00~1.97(m,2H), 1.17(s,9H).

[0474] Step 5: Using essentially the same procedure as in I-7d, 1-(4-chloro-5,6-difluoropyridine-3-yl)penta-4-en-1-yl)-2-methylpropane-2-sulfinamide I-25e was used to synthesize 1-(4-chloro-5,6-difluoropyridine-3-yl)penta-4-en-1-amine I-25f. 1 H NMR (400MHz, CDCl3) δ8.11(s,1H), 5.84~5.76(m,1H), 5.06~4.98(m,2H), 4.33~4.30(m,1H), 2.18~2.12(m,2H), 1.85~1.73(m,2H).

[0475] Step 6: Using essentially the same procedure as in I-7e, N-(1-(4-chloro-5,6-difluoropyridine-3-yl)penta-4-en-1-amine I-25f)-4-methoxyaniline I-25g was synthesized. 1 H NMR (400MHz, CDCl3) δ8.00(s,1H), 6.71~6.69(m,2H), 6.42~6.39(m,2H), 5.84~5.79(m,1H) , 5.08~5.03(m,2H), 4.67~4.65(m,1H), 3.70(s,3H), 2.29~2.20(m,2H), 1.95~1.86(m,2H).

[0476] Step 7: Dissolve 25 g (0.30 g, 885 μmol) of N-(1-(4-chloro-5,6-difluoropyridine-3-yl)penta-4-en-1-yl)-4-methoxyaniline I in 10 ml of 1,4-dioxane at room temperature. t Bu (127 mg, 1.32 mmol) and Pd-178 (42 mg, 88.5 µl) were added. The resulting mixture was heated at 95°C for 16 hours. The reaction mixture was filtered. The filtered cake was washed with ethyl acetate (3 × 10 ml), the combined organic matter was dehydrated with sodium sulfate, and concentrated under vacuum. The product was purified by chromatography on silica (1-100%, ethyl acetate / petroleum ether) to obtain (±)-3,4-difluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-25h as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.79(s,1H), 6.74~6.70(m,4H), 4.80~4.78(m,1H), 4.52~4.49(m,1H) , 3.71(s,3H), 3.17~3.13(m,1H), 2.55~2.38(m,2H), 1.96~1.91(m,1H), 1.75~1.70(m,1H).

[0477] Step 8: Using essentially the same procedure as in I-24, (±)-3,4-difluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-25h was synthesized from (±)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-25h. 1 H NMR(500MHz,DMSO-d6)δ7.75(d,J=1.6Hz,1H), 4.31~4.26(m,1H), 3.76(t,J=5.9Hz,1H), 3.00~2.91(m, 1H), 2.74(s,1H), 2.59(dd,J=18.0,1.3Hz,1H), 2.00~1.87(m,2H), 1.78~1.66(m,1H), 1.57~1.46(m,1H) Intermediate 26 (I-26)

[0478] [ka]

[0479] Step 1: To a solution of (±)-3,4-difluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-25h (145 mg, 480 μmol) in MeOH (5 ml), a solution of sodium methoxide in MeOH (133 μl, 5.4 M, 719 μmol) was added. The reaction mixture was heated at 65°C for 18 hours. The reaction mixture was diluted with MeOH (5 ml), an additional amount of sodium methoxide in MeOH (133 μl, 5.4 M, 719 μmol) was added, and the reaction mixture was stirred at 65°C for a further 3 hours. The reaction mixture was diluted with DCM (30 ml), water (10 ml) was added, and the layers were separated. The aqueous solution was extracted with DCM (3 × 20 ml), the combined organic layer was dehydrated with sodium sulfate, and concentrated under vacuum to obtain (±)-4-fluoro-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-26a as a brownish oil. 1H NMR(500MHz,DMSO-d6)δ7.88(s,1H), 6.84~6.78(m,2H), 6.73~6.68(m,2H), 4.92(d,J=5.3Hz,1H), 4.51(t,J=5.9Hz,1H), 3. 85(s,3H), 3.61(d,J=2.4Hz,3H), 2.97(dd,J=18.0,5.0Hz,1H), 2.46(s,1H), 2.25(q,J=6.5,4.5Hz,2H), 1.88~1.70(m,2H).

[0480] Step 2: Using a procedure essentially similar to that in I-24, (±)-4-fluoro-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-26b was synthesized from (±)-4-fluoro-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-26a. 1 H NMR(500MHz,DMSO-d6)δ7.66(s,1H), 4.20(d,J=4.9Hz,1H), 3.87(s,3H), 3.73(t,J=5.9Hz,1H), 2.88(dd,J=1 7.6,5.2Hz,1H), 2.70(s,1H), 2.53(d,J=1.3Hz,1H), 1.95~1.86(m,2H), 1.74~1.64(m,1H), 1.54~1.44(m,1H).

[0481] Step 3: The solution of (±)-4-fluoro-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-26b (190 mg, 999 μmol) in an aqueous HBr solution (2.8 M, 48 wt%, 25.0 mmol) was refluxed for 16 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in MeOH and loaded onto an SCX cartridge (10 g). The cartridge was washed with MeOH, and the product was eluted with a 0.7 M ammonia solution in MeOH. The filtrate was concentrated under vacuum to obtain (±)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridine-3-one I-26 as a brown solid. LC-MS (Method 1) showed m / z 177.2 (M+H) at 0.40 min. +(ES + ). ...

Claims

1. Compounds of formula (If), or pharmaceutically acceptable salts or solvates thereof, 【Chemistry 1】 [In the formula, Ring A is a pyridinyl ring or its tautomer, or a phenyl ring, each of which is H, F, Cl, Br, I, CN, alkoxy, NR １１ R １１ ', may be substituted with one or more substituents selected from OH, alkyl, phenyl, and haloalkyl, Y is C=N-OH and CR １０ R １０ Selected from ', R １０ and R １０ Each of these is independently selected from H, F, and alkyl. R ａ and R ｂ Each is independently selected from H and alkyl, R １ 、R ４ 、and R ５ are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, F, Cl, Br, and I, R ２ and R ３ These are, independently, H, F, Cl, Br, I, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, and CO ２ - Selected from alkyl groups, the aryl, heteroaryl, and O-aryl groups may each be further substituted with one or more groups independently selected from halo, alkyl, and alkoxy groups. R １１ and R １１ ' are independently H, alkyl, haloalkyl, and COR １２ CO ２ R １２ and SO ２ R １３ Selected from, R １２ and R １３ Both are independently alkyl.

2. The compound according to claim 1, wherein ring A is selected from the following: 【Chemistry 2】 [In the formula, R ６ , R ７ , R ８ , and R ９ These are H, F, Cl, Br, I, CN, alkoxy, and NR, respectively, independently. １１ R １１ Selected from ', OH, alkyl, phenyl, and haloalkyl, R １４ [is H or alkyl].

3. Compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof. 【Transformation 3】 [In the formula, Ring A 【Chemistry 4】 The following is the basis: 【Transformation 5】 Selected from, When the bond indicated by the wavy line represents a bond to a ring containing N and Y of ring A; 【Transformation 6】 (In the formula, R ６ , R ７ , R ８ , and R ９ These are H, F, Cl, Br, I, CN, alkoxy, and NR, respectively, independently. １１ R １１ Selected from ', OH, alkyl, phenyl, and haloalkyl, R １４ (is selected from H or alkyl), and Y is C=N-OH and CR １０ R １０ Selected from ', R １０ and R １０ Each of these is independently selected from H, F, and alkyl. R ａ and R ｂ Each is independently selected from H and alkyl, R １ , R ４ , and R ５ Each of these is independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, F, Cl, Br, and I. R ２ and R ３ These are, independently, H, F, Cl, Br, I, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, and CO ２ - Selected from alkyl groups, the aryl, heteroaryl, and O-aryl groups may each be further substituted with one or more groups independently selected from halo, alkyl, and alkoxy groups. R １１ and R １１ ' are independently H, alkyl, haloalkyl, and COR １２ CO ２ R １２ and SO ２ R １３ Selected from, R １２ and R １３ Both are independently alkyl.

4. R １４ The compound according to claim 2 or 3, wherein H is present.

5. The compound according to claim 3 or 4, wherein ring A is selected from (i), (ii), (iii), (iv), (v), (vi), (viii), (ix), (xiv), (xv), and (xix).

6. The compound according to claim 5, wherein ring A is selected from (i), (ii), (iii), (v), (vi), and (ix).

7. The compound according to claim 6, wherein ring A is selected from (i), (ii), (vi), and (ix).

8. A compound according to any one of claims 1 to 7, which is a compound of formula (Ib)-(ii): 【Transformation 5】 [In the formula, Y, R ａ , R ｂ , R １ ~R ５ R is as defined in claim 1 or 3, ６ , R ７ and R ９ [This is as defined in claim 2 or 3].

9. A compound according to any one of claims 1 to 7, which is a compound of formula (Ib)-(i): 【Transformation 6】 [In the formula, Y, R ａ , R ｂ , R １ ~R ５ R is as defined in claim 1 or 3, ６ ~R ９ [This is as defined in claim 2 or 3].

10. A compound according to any one of claims 1 to 7, which is a compound of formula (Ib)-(vi): 【Transformation 7】 [In the formula, Y, R ａ , R ｂ , R １ ~R ５ R is as defined in claim 1 or 3, ６ , R ８ and R ９ [This is as defined in claim 2 or 3].

11. A compound according to any one of claims 1 to 7, which is a compound of formula (Ib)-(ix): 【Transformation 8】 [In the formula, Y, R ａ , R ｂ , R １ ~R ５ R is as defined in claim 1, ６ , R ９ and R １４ [This is as defined in claim 2].

12. Y is CH ２ A compound according to any one of claims 1 to 11, selected from and C=N-OH.

13. Y is CH ２ The compound according to claim 12.

14. R ２ and R ３ are each independently H, F, Cl, Br, CN, methoxy, OCF ３ , CF ３ , OCHF ２ , Me, Ph, pyrazolyl, oxazolyl, thiazolyl, OPh, NHCO-CH=CH ２ and CO ２ Me, and the Ph, OPh, pyrazolyl, oxazolyl and thiazolyl groups may each be further substituted with one or more alkyl groups, the compound according to any one of claims 1 to 13.

15. R ２ and R ３ are each independently selected from F, Cl, Br, I, CN, C １ -C ６ haloalkyl, C １ -C ６ haloalkoxy and CO ２ -alkyl, and a compound according to any one of claims 1 to 14.

16. R ２ and R ３ However, each is independent of Cl, Br, and CF ３ A compound selected from any one of claims 1 to 15.

17. R ２ and R ３ However, Cl and CF are independent of each other. ３ A compound according to claim 16, selected from the above.

18. R ２ and R ３ Both are Cl, or R ２ and R ３ One of them is Cl and the other is OCF ３ CO ２ Me, OCHF ２ and CF ３ A compound according to any one of claims 1 to 17, selected from the above.

19. R １ and R ４ The compound according to any one of claims 1 to 18, wherein both are H.

20. R ５ The compound according to any one of claims 1 to 19, wherein the compound is selected from H, F, Me, MeO, Cl, OH, and CN.

21. R ５ The compound according to claim 20, wherein the compound is H or F.

22. R ５ The compound according to claim 21, wherein H is present.

23. R ６ , R ７ , R ８ , and R ９ However, each is independent of H, F, Cl, Br, CN, OMe, NH ２ , NHBu, NHCO ２ A compound according to any one of claims 2 to 22, selected from Bu and OH.

24. A compound according to any one of claims 1 to 23, which is a compound of formula (Ib.1): 【Chemistry 9】 [In the formula, A, Y and R １ ~R ５ [This is as defined in any of claims 1 to 23.]

25. below: 【Chemistry 10】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 Compounds according to any one of claims 3 to 24, selected from, and their enantiomers, as well as mixtures of their enantiomers including racemic mixtures, and pharmaceutically acceptable salts and solvates.

26. Compounds of formula (Ie), or pharmaceutically acceptable salts or solvates thereof, 【Chemistry 11】 [In the formula, Ring A is, 【Chemistry 12】 (In the formula, R ６ and R ８ Each of these is independently selected from H, F, Cl, Br, I, CN, alkoxy, OH, phenyl, and haloalkyl. Y is C=N-OH and CR １０ R １０ Selected from ', R １０ and R １０ Each of these is independently selected from H, F, and alkyl. R ａ and R ｂ Each is independently selected from H and alkyl, R １ , R ４ , and R ５ Each of these is independently selected from H, F, Cl, Br, and I. R ２ and R ３ Each of these is independently selected from Cl, Br, I, CN, and haloalkyl, However, Y is CH ２ If R ａ , R ｂ , R １ , R ４ , R ５ , R ６ and R ８ Assume that all are H, R ２ If Cl, then R ３ It is not CN, R ２ and R ３ [Both are not Cl].

27. R ２ and R ３ The compound according to claim 26, wherein each is independently selected from Cl, Br, I, CN, and haloalkyl.

28. R ２ However, Cl, Br and CF ３ A compound according to claim 26 or 27, selected from the above.

29. R ２ However, Cl and CF ３ A compound according to claim 28, selected from the above.

30. R ３ However, Cl, Br, CN and CF ３ A compound according to claim 26, selected from the above.

31. R ３ However, Cl and CF ３ A compound according to claim 30, selected from the above.

32. R １ , R ４ and R ５ The compound according to any one of claims 26 to 31, wherein all of the atoms are H.

33. Y is CH ２ A compound according to any one of claims 26 to 32, selected from and CHF.

34. Y is CH ２ The compound according to claim 33.

35. R ６ A compound according to any one of claims 26 to 34, wherein is H.

36. R ８ H, CF ３ A compound according to any one of claims 26 to 35, selected from phenyl, OH, and F.

37. R ８ is OH, and ring A is 【Chemistry 13】 The compound according to any one of claims 26 to 36.

38. Compound of formula (Ie. 1): 【Chemistry 14】 (In the formula, A, Y and R １ ~R ５ The compound according to any one of claims 26 to 37, wherein (is as defined in any one of claims 26 to 37).

39. below: 【Chemistry 15】 【change】 【change】 【change】 【change】 Compounds selected from, and their enantiomers, as well as mixtures of their enantiomers including racemic mixtures, and pharmaceutically acceptable salts and solvates.

40. A pharmaceutical composition comprising a compound according to any one of claims 1 to 39, and a pharmaceutically acceptable diluent, excipient, or carrier.

41. A compound according to any one of claims 1 to 39 for use as a pharmaceutical.

42. A pharmaceutical composition comprising a compound of formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable diluent, excipient, or carrier, 【Chemistry 16】 [In the formula, Ring A is, 【Chemistry 17】 (In the formula, R ６ and R ８ Each of these is independently selected from H, F, Cl, Br, I, CN, alkoxy, OH, phenyl, and haloalkyl. Y is C=N-OH and CR １０ R １０ Selected from ', R １０ and R １０ Each of these is independently selected from H, F, and alkyl. R ａ and R ｂ Each is independently selected from H and alkyl, R １ , R ４ , and R ５ Each of these is independently selected from H, F, Cl, Br, and I. R ２ and R ３ Each of these is independently selected from F, Cl, Br, I, CN, alkoxy, and haloalkyl. However, Y is CH ２ If R ａ , R ｂ , R １ , R ４ , R ５ , R ６ and R ８ Assume that all are H, R ２ If Cl, then R ３ It is not CN, R ２ and R ３ [Both are not Cl].

43. The pharmaceutical composition according to claim 40 or 42 for use in the treatment or prevention of a disorder selected from proliferative disorders, immune disorders, asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS).

44. A pharmaceutical composition for use according to claim 43, wherein the use comprises modulating GPR65.

45. A pharmaceutical composition for use according to claim 44, wherein use comprises inhibiting GPR65 signaling.

46. A pharmaceutical composition for use according to claim 43, wherein the disorder is a proliferative disorder.

47. A pharmaceutical composition for use according to claim 46, wherein the proliferative disorder is cancer.

48. The pharmaceutical composition for use according to claim 47, wherein the cancer is a solid tumor and / or its metastases.

49. The pharmaceutical composition for use according to claim 46, wherein the proliferative disorder is a cancer selected from melanoma, elliptic carcinoma (RCC), gastric cancer, acute myeloid leukemia (AML), triple-negative breast cancer (TNBC), colorectal cancer, head and neck cancer, colorectal adenocarcinoma, pancreatic adenocarcinoma, sarcoma, lung cancer, ovarian cancer, and glioma.

50. A pharmaceutical composition for use according to claim 49, wherein the cancer is glioblastoma (GBM).

51. A pharmaceutical composition for use according to claim 43, wherein the disorder is an immune disorder.

52. A pharmaceutical composition for use according to claim 51, wherein the immune deficiency is an autoimmune disease.

53. The pharmaceutical composition for use according to claim 52, wherein the autoimmune disease is selected from psoriasis, psoriatic arthritis, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), autoimmune thyroiditis (Hashimoto's disease), Graves' disease, uveitis (including intermediate uveitis), ulcerative colitis, Crohn's disease, autoimmune retinouveitis, systemic vasculitis, polymyositis dermatomyositis, systemic sclerosis (scleroderma), Sjögren's syndrome, ankylosing spondylitis and related spondyloarthropathy, sarcoidosis, autoimmune hemolytic anemia, immune platelet disorder, and autoimmune multilinear endocrine disorder.

54. The pharmaceutical composition for use according to claim 53, wherein the autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and multiple sclerosis (MS).

55. A pharmaceutical composition for use according to claim 43, wherein the disorder is selected from asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS).

56. A pharmaceutical composition according to claim 40 or 42 for use in the treatment or prevention of diseases or disorders related to GPR65.

57. Use of a compound defined in any of claims 1 to 39 or 41, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment or prevention of a disease or disorder related to GPR65 in a subject.

58. Use of a compound defined in any of claims 1 to 39 or 41, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment or prevention of a disorder selected from proliferative disorders, immune disorders, asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS).

59. Compounds selected from the following for use in the treatment or prevention of disorders selected from proliferative disorders, immune disorders, asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS): [Chemistry 18] 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 and its enantiomers, as well as mixtures of its enantiomers including racemic mixtures, and pharmaceutically acceptable salts and solvates.

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