N-phenylaminocarbonylpyridyl-, pyrimidyl and benzo-tropane as modulators of GPR65

Abstract

One aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as a medicament, wherein: ring A is a 5- or 6-membered aromatic ring or heteroaromatic ring, wherein the aromatic ring or heteroaromatic ring is optionally selected from F, Cl, Br, I, CN, alkoxy, NR 11 R 11 One or more substituents of ', OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein said aryl and heteroaryl substituents are optionally each independently selected from F, Cl, Br, I, CN, alkoxy, NR 11 R 11 One or more substituents selected from ', OH, alkyl, haloalkyl, and aralkyl; Y is selected from C=N-OH and CR 10 R 10' , where 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; and R 11 and R 11 Each is independently selected from H, alkyl, haloalkyl, COR 12 and SO2R 13 , where R 12 and R 13 All are alkyl groups. The invention also relates to the use of compounds of formula (I) in immuno-oncology, immunology, and related applications, as well as to compounds of formula (I) themselves.

Description

Technical Field

[0001] This invention relates to compounds capable of modulating GPR65. These compounds have potential therapeutic applications in treating a variety of conditions, including proliferative and immune disorders. Background Technology

[0002] GPR65 is a Gs-coupled G protein-coupled receptor (GPCR) primarily expressed in immune cells, and it is activated by acidic extracellular pH to increase cytoplasmic cyclic adenosine monophosphate (cAMP) (Wang, 2004). It is well known that tumors typically undergo a metabolic shift from oxidative phosphorylation to aerobic glycolysis, which in turn creates an acidic extracellular microenvironment (Damaghi, 2013). Recently, it has been shown that this acidic microenvironment induces GPR65 activation in tumor-associated macrophages, leading to increased cytoplasmic cAMP and resulting in the transcription of an inducible early cAMP repressor (ICER). This, in turn, inhibits the secretion of tumor necrosis factor-α (TNFα), causing macrophages to favor an anti-inflammatory, tumor-permissive phenotype (Bohn, 2018). Therefore, this GPR65-dependent pathway appears to represent a mechanism by which tumors utilize their acidic microenvironment to evade immune system detection.

[0003] Autoimmune diseases are often associated with acidic local microenvironments (e.g., inflamed joints). Recent studies have also shown that GPR65 acts through ICER in CD4+ T cells to suppress IL-2, thereby biasing cells toward an inflammatory Th17 phenotype, which is associated with increased pathogenicity in autoimmune disease conditions (Korn, 2009). Supporting this is the recent finding that ICER is essential for Th17 differentiation (Yoshida, 2016), and that the agonistic effect of GPR65 leads to increased Th17 differentiation (Hernandez, 2018). In fact, 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, 2015). A recent study found that mice with CD4+ T cells lacking GPR65 were protected from developing autoimmune encephalomyelitis (EAE) (Gaublomme, 2015).

[0004] Therefore, GPR65 appears to function via ICER to promote an anti-inflammatory and tumor-permissive phenotype in tumor-associated macrophages and an inflammatory Th17 phenotype in CD4+ T cells associated with autoimmune diseases. Thus, GPR65 signaling represents an attractive pathway for therapeutic interventions in cancer and autoimmune diseases. Consequently, there is an ongoing need to develop novel small-molecule GPR65 modulators.

[0005] The present invention aims to provide compounds capable of modulating GPR65. As can be clearly seen from the above discussion, these compounds have potential therapeutic applications in treating a variety of conditions, including proliferative and immune disorders, as well as asthma and chronic obstructive pulmonary disease. Summary of the Invention

[0006] The first aspect of the present invention relates to compounds of formula (If) or pharmaceutically acceptable salts or solvates thereof.

[0007]

[0008] in:

[0009] Ring A is a pyridyl ring or its tautomer, or a benzene ring, each optionally selected from H, F, Cl, Br, I, CN, alkoxy, NR. 11 R 11 One or more substituents of ', OH, alkyl, phenyl and haloalkyl are used;

[0010] Y is selected from CH2, C=N-OH and CR. 10 R 10 ', where R 10 and R 10 Each is independently selected from H, F, alkyl, and haloalkyl;

[0011] R a and R b Each is independently selected from H and alkyl groups;

[0012] R1, R4, and R5 are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, F, Cl, Br, and I;

[0013] 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, wherein the aryl, heteroaryl, and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, and alkoxy groups; and

[0014] R 11 and R 11 Each is independently selected from H, alkyl, haloalkyl, COR 12 CO2R 12 and SO2R 13 , where R 12 and R 13 Each is an alkyl group independently.

[0015] The second aspect of the invention relates to compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof.

[0016]

[0017] in:

[0018] Ring A is selected from group (i)-(xx):

[0019]

[0020] R6, R7, R8, and R9 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, and NR. 11 R 11 ', OH, alkyl, phenyl and haloalkyl, and R 14 It is H or alkyl;

[0021] Y is selected from CH2, C=N-OH and CR. 10 R 10 ', where R 10 and R 10 Each is independently selected from H, F, alkyl, and haloalkyl;

[0022] R a and R b Each is independently selected from H and alkyl groups;

[0023] R1, R4, and R5 are each independently selected from H, CN, alkyl, haloalkyl, alkoxy, OH, F, Cl, Br, and I;

[0024] 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, wherein the aryl, heteroaryl, and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, and alkoxy; and

[0025] R 11 and R 11 Each is independently selected from H, alkyl, haloalkyl, COR 12 CO2R 12 and SO2R 13 , where R 12 and R 13 Each is an alkyl group independently.

[0026] The third aspect of the invention relates to compounds of formula (Ie) or pharmaceutically acceptable salts or solvates thereof.

[0027]

[0028] in:

[0029] Ring A is

[0030]

[0031] R6 and R8 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, OH, phenyl and haloalkyl (more preferably CF3);

[0032] Y is selected from CH2, C=N-OH and CR. 10 R 10 ', where R 10 and R 10 Each is independently selected from H, F, alkyl, and haloalkyl;

[0033] R a and R b Each is independently selected from H and alkyl groups;

[0034] R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I; and

[0035] R2 and R3 are each independently selected from F, Cl, Br, I, CN, methoxy and haloalkyl;

[0036] The condition is that when Y is CH2 and R a R b When R1, R4, R5, R6, and R8 are all H:

[0037] When R2 is Cl, R3 is not CN; and

[0038] R2 and R3 are not both Cl.

[0039] Another aspect of the present invention relates to compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof.

[0040]

[0041] in:

[0042] Ring A is a 5- or 6-membered aromatic ring or heteroaromatic ring, wherein the aromatic ring or heteroaromatic ring is optionally selected from F, Cl, Br, I, CN, alkoxy, NR. 11 R 11 One or more substituents of ', OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein said aryl and heteroaryl substituents are optionally each independently selected from F, Cl, Br, I, CN, alkoxy, NR 11 R 11 One or more substituents selected from ', OH, alkyl, haloalkyl, and aralkyl;

[0043] Y is selected from CH2, C=N-OH and CR. 10 R 10 ', where R 10 and R 10 Each is independently selected from H, F, alkyl, and haloalkyl;

[0044] R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I;

[0045] R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl; and

[0046] R 11 and R 11 Each is independently selected from H, alkyl, haloalkyl, COR 12 and SO2R 13 , where R 12 and R 13 All are alkyl groups;

[0047] Where Y is CH2 and ring A has the following structure:

[0048]

[0049] Both R6 and R8 are H.

[0050] - When R1, R4, and R5 are all H, R2 and R3 are not all Cl;

[0051] -When R1, R2, R4, and R5 are all H, R3 is not Cl;

[0052] - When R1, R3, R4, and R5 are all H, R2 is not Cl;

[0053] - When R2, R3, R4, and R5 are all H, R1 is not Cl;

[0054] - When R4 is Cl and R2, R3 and R5 are all H, R1 is not F.

[0055] Advantageously, the compound currently claimed is able to modulate GPR65, thereby making the compound therapeutically significant in treating a variety of diseases, such as in the fields of oncology, immuno-oncology, and immunology.

[0056] Another aspect of the present invention relates to compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof.

[0057]

[0058] in:

[0059] Ring A is

[0060]

[0061] R6 and R8 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, and NR. 11 R 11 ', OH, alkyl, phenyl and haloalkyl, provided that at least one of R6 and R7 is not H;

[0062] Y is selected from CH2, C=N-OH and CR. 10 R 10 ', where R 10 and R 10 Each is independently selected from H, F, alkyl, and haloalkyl;

[0063] R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I;

[0064] R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl; and

[0065] R 11 and R 11 Each is independently selected from H, alkyl, haloalkyl, COR 12 and SO2R 13 , where R 12 and R 13 All are alkyl groups.

[0066] Another aspect of the present invention relates to compounds of formula (Id) or pharmaceutically acceptable salts or solvates thereof.

[0067]

[0068] in:

[0069] Ring A is

[0070]

[0071] R6 and R8 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, and NR. 11 R 11 ', OH, alkyl, phenyl and haloalkyl;

[0072] Y is selected from CH2, C=N-OH and CR. 10 R 10 ', where R 10 and R 10 Each is independently selected from H, F, alkyl, and haloalkyl;

[0073] R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I;

[0074] 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; and

[0075] R 11 and R 11 Each is independently selected from H, alkyl, haloalkyl, COR 12 and SO2R 13 , where R 12 and R 13 All are alkyl groups.

[0076] Another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as a medicine.

[0077]

[0078] in:

[0079] Ring A is a 5- or 6-membered aromatic ring or heteroaromatic ring, wherein the aromatic ring or heteroaromatic ring is optionally selected from F, Cl, Br, I, CN, alkoxy, NR. 11 R 11 One or more substituents of ', OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein said aryl and heteroaryl substituents are optionally each independently selected from F, Cl, Br, I, CN, alkoxy, NR 11 R 11 One or more substituents selected from ', OH, alkyl, haloalkyl, and aralkyl;

[0080] Y is selected from CH2, C=N-OH and CR. 10 R 10 ', where R 10 and R 10 Each is independently selected from H, F, alkyl, and haloalkyl;

[0081] R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I;

[0082] R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl; and

[0083] R 11 and R 11 Each is independently selected from H, alkyl, haloalkyl, COR 12 and SO2R 13 , where R12 and R 13 All are alkyl groups;

[0084] Another aspect of the present invention relates to the use of compounds of the above formulas (Ia), (Ib), (Ic), (Id), (Ie) or (If) as pharmaceuticals.

[0085] Another aspect of the invention relates to the use of compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) in the treatment or prevention of conditions selected from proliferative disorders, immune disorders, asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS).

[0086] Another aspect of the present invention relates to the use of the above-mentioned compound, which has the formula (I.1):

[0087]

[0088] A, Y, and R1-R5 are as defined above.

[0089] Another aspect of the present invention relates to the use of the above-mentioned compound, which has the formula (I.2):

[0090]

[0091] A, Y, and R1-R5 are as defined above.

[0092] Another aspect of the present invention relates to pharmaceutical compositions comprising the above-described compounds and pharmaceutically acceptable diluents, excipients, or carriers.

[0093] Another aspect of the present invention relates to the use of the above-described pharmaceutical composition as a medicine.

[0094] Another aspect of the present invention relates to the use of the above-described pharmaceutical composition for the treatment or prevention of diseases selected from proliferative diseases, immune diseases, asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS).

[0095] Another aspect of the present invention relates to a method of treating a condition, including administering the above-described compound or pharmaceutical composition to a subject.

[0096] Detailed description

[0097] This invention relates to compounds capable of modulating GPR65.

[0098] "alkyl" is defined herein as a straight-chain or branched alkyl radical, preferably C10. 1-20 Alkyl, more preferably C 1-12 Alkyl, or even more preferably C 1-10 Alkyl or C1-6 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. More preferably, the alkyl group is C10. 1-3 alkyl.

[0099] The term "aryl" as used in this article refers to C 6-12 Aromatic groups, which can be benzofused groups, such as phenyl or naphthyl.

[0100] "Haloalkyl" is defined herein as a straight-chain or branched alkyl group as defined above, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, wherein the alkyl group is substituted with one or more halogen atoms (which may be the same or different), such as fluorine, chlorine, bromine, and iodine. Preferably, the haloalkyl group is C10. 1-20 Haloalkyl, more preferably C 1-12 Halogenated alkyl, or even more preferably C10, 1-10 Halogenated alkyl or C 1-6 Halogenated alkyl, or C 1-3 Halogenated alkyl groups. Preferred examples are CF3 and CHF2, with CF3 being particularly preferred.

[0101] "Alkoxy" is defined herein as a group in which an oxygen atom is bonded to an alkyl group as defined above, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, and hexoxy. Preferably, the alkoxy group is C10. 1-20 Alkoxy, more preferably C 1-12 Alkoxy, or even more preferably C 1-10 Alkoxy or C 1-6 alkoxy, or C 1-3 Alkyl group. A particularly preferred example is methoxy (-OCH3).

[0102] "Heteroaryl" is defined herein as a monocyclic or bicyclic C18 group comprising one or more heteroatoms (which may be the same or different). 2-12 Aromatic ring, wherein the heteroatom is, for example, oxygen, nitrogen, or sulfur. Examples of suitable heteroaryl groups include thiophene, furanyl, pyrrole, pyridinyl, oxazolyl, thiazolyl, imidazole, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and their benzo[a] derivatives, such as benzofuranyl, benzothiophene, benzimidazolyl, indolyl, isoindolyl, indolyl, etc.; or pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and their benzo[a] derivatives, such as quinolinyl, isoquinolinyl, cenolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthidyl, etc.

[0103] "Aryl group" is defined herein as an alkyl group as defined above that is substituted with one or more aryl groups as defined above.

[0104] In formulas (Ia), (Ib), (Ic), (Id), and (Ie), the preferred alkyl group is C1-C6 alkyl, the preferred haloalkyl group is C1-C6 haloalkyl, and the preferred alkoxy group is C1-C6 alkoxy.

[0105] Structural representation of compounds

[0106] The compounds of the present invention comprise the following structure: ring A is an optionally substituted 5- or 6-membered aromatic ring or heteroaromatic ring, which is fused with a bicyclic nitrogen-containing portion to form a tricyclic structure. The resulting tricyclic structure can exist in two different configurations as shown below (for clarity, the bridging substituent R is omitted in the following representations). a and R b ):

[0107]

[0108] For the avoidance of doubt, the present invention includes compounds of any of the above configurations and mixtures thereof, including racemic mixtures.

[0109] Alternatively, the structure can be represented as follows:

[0110]

[0111] For the avoidance of doubt, the present invention includes compounds of the above configuration, their corresponding enantiomers, and mixtures thereof, including racemic mixtures. As used throughout, and for ease of representation, specific examples of the compounds of the present invention described in the above configuration (I.3) refer to mixtures of two enantiomers (particularly racemic ones), wherein the respective enantiomers (in cases where these enantiomers have been synthesized or isolated) are respectively depicted as having a wedge-shaped bond or a dashed bond in configuration (I.1) or configuration (I.2).

[0112] The compounds described herein include optionally substituted 5- or 6-membered aromatic or heteroaromatic ring A, which is fused with a bicyclic nitrogen-containing moiety to form a tricyclic structure. Optional substituents are selected from halogens, CN, alkoxy groups, and NR groups. 11 R 11 ', OH, alkyl, phenyl, and haloalkyl. In some cases, ring A can exist in more than one tautomer form. For example, when the heteroaromatic ring is substituted with an OH group, ring A can exist as two possible tautomers, as shown below:

[0113]

[0114] 2-Pyridone tautomers are considered the predominant solid-state form. In solution, the energy difference between the two tautomers is understood to be very small and depends on the polarity of the solvent. Those skilled in the art will understand that other hydroxyl-substituted N-containing heteroaromatic groups (e.g., pyrimidines, other pyridine regioisomers) can be similarly represented in the tautomer forms shown above. The term "heteroaromatic" as used herein includes all tautomer forms of the compound.

[0115] Preferably, loop A is as defined herein, wherein the wavy line indicates a connection to the loops including N and Y:

[0116]

[0117] Formula (If) compound

[0118] One aspect of the present invention relates to compounds of formula (If) or pharmaceutically acceptable salts or solvates thereof.

[0119]

[0120] in:

[0121] Ring A is a pyridyl ring or its tautomer, or a benzene ring, each optionally selected from H, F, Cl, Br, I, CN, alkoxy, NR. 11 R 11 One or more substituents of ', OH, alkyl, phenyl and haloalkyl are used;

[0122] Y is selected from CH2, C=N-OH and CR. 10 R 10 ', where R 10 and R 10 Each is independently selected from H, F, alkyl, and haloalkyl;

[0123] R a and R b Each is independently selected from H and alkyl groups;

[0124] R1, R4, and R5 are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, F, Cl, Br, and I;

[0125] 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, wherein the aryl, heteroaryl, and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, and alkoxy groups; and

[0126] R 11 and R 11Each is independently selected from H, alkyl, haloalkyl, COR 12 CO2R 12 and SO2R 13 , where R 12 and R 13 Each is an alkyl group independently.

[0127] In a preferred embodiment, ring A is a hydroxyl-substituted pyridyl group, which may be present in tautomeric form, for example, as described in the section entitled "Structural Representation of the Compound" above. Those skilled in the art will recognize that other regioisomers of the hydroxyl-substituted pyridyl group may similarly be represented in tautomeric form (see groups (viii)-(xii) and (xx) below).

[0128] In a preferred embodiment, ring A is selected from the following:

[0129]

[0130] R6, R7, R8, and R9 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, and NR. 11 R 11 ', OH, alkyl, phenyl and haloalkyl, and R 14 It is H or an alkyl group, more preferably H.

[0131] Further preferred embodiments of the compound of formula (Ib) are listed below. In particular, the group R... 1-9 R 14 A, Y, R a and R b The preferred form is defined as the compound of formula (Ib).

[0132] Compound of formula (Ib)

[0133] One aspect of the present invention relates to compounds of formula (Ib) or pharmaceutically acceptable salts or solvates thereof.

[0134]

[0135] in:

[0136] Ring A is selected from group (i)-(xx):

[0137]

[0138]

[0139] R6, R7, R8, and R9 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, and NR. 11 R11 ', OH, alkyl, phenyl and haloalkyl, and R 14 It is H or alkyl;

[0140] Y is selected from CH2, C=N-OH and CR. 10 R 10 ', where R 10 and R 10 Each is independently selected from H, F, alkyl, and haloalkyl;

[0141] R a and R b Each is independently selected from H and alkyl groups;

[0142] R1, R4, and R5 are each independently selected from H, CN, alkyl, haloalkyl, alkoxy, OH, F, Cl, Br, and I;

[0143] 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, wherein the aryl, heteroaryl, and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, and alkoxy; and

[0144] R 11 and R 11 Each is independently selected from H, alkyl, haloalkyl, COR 12 CO2R 12 and SO2R 13 , where R 12 and R 13 Each is an alkyl group independently.

[0145] In a preferred embodiment, ring A is selected from group (i)-(xviii).

[0146] In a preferred embodiment, ring A is selected from groups (i), (ii), (iii), (iv), (v), (vi), (viii), (ix), (xiv), (xv), and (xix), and is preferably selected from (i), (ii), (iii), (v), (vi), and (ix), and more preferably selected from (i), (ii), (vi), and (ix).

[0147] In a preferred embodiment, ring A is selected from (i), (ii), (iii), (iv), (vi), (vii), (viii), (ix), (xiii), (xiv), (xv), (xvi), (xvii), and (xviii).

[0148] In a preferred embodiment, ring A is selected from (i), (ii), (vi), (ix), (xiv) and (xv), more preferably from (i), (ii) and (vi).

[0149] In a preferred embodiment, ring A is selected from (ii), (vi), and (ix).

[0150] In a preferred embodiment, ring A is (ii).

[0151] In a preferred embodiment, ring A is (vi).

[0152] In a preferred embodiment, ring A is (vi).

[0153] In a preferred embodiment, the compound has formula (Ib)-(ii):

[0154]

[0155] Among them, Y and R a R b R1-R7 and R9 are as defined above. In a preferred embodiment, R6, R7 and R9 are all H. In a particularly preferred embodiment, R9 is F, and R6 and R7 are both hydrogen.

[0156] In a preferred embodiment, the compound has formula (Ib)-(i):

[0157]

[0158] Among them, Y and R a R b R1-R9 are as defined above. In a preferred embodiment, R6, R7 and R9 are all H, and R8 is selected from H, OMe, OH, Cl, CN, F and NH2.

[0159] In a preferred embodiment, the compound has the formula (Ib)-(vi):

[0160]

[0161] Among them, Y and R a R b R1-R6, R8, and R9 are as defined above. In a preferred embodiment, R6, R8, and R9 are each independently selected from H, F, Cl, NH2, Br, and OMe, more preferably from H and F. In a particularly preferred embodiment, R6, R8, and R9 are all H.

[0162] In a preferred embodiment, the compound has the formula (Ib)-(ix):

[0163]

[0164] Among them, Y and R a R b R1-R6, R9 and R 14 As defined above. In a preferred embodiment, both R6 and R9 are H, and R 14 It is H or Me, more preferably Me. In a preferred embodiment, R6 is H, R9 is F, and R 14 It is H or Me, with Me being preferred.

[0165] In a 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 an alkyl group (more preferably methyl), and the other is H. In a particularly preferred embodiment, R a and R b All are H.

[0166] In a preferred embodiment, R 11 and R 11 'Selected from H and alkyl, more preferably selected from H and Me, even more preferably R' 11 Both R1 and R1' are H.

[0167] In a preferred embodiment, Y is CR 10 R 10 ', where 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 a preferred embodiment, Y is selected from CH2, CHF, CHMe, and C=N-OH. In a preferred embodiment, Y is selected from CH2 and C=N-OH. More preferably, Y is CH2.

[0168] In a preferred embodiment, at least one of R1, R2, R3, R4 and R5 is not H.

[0169] In a preferred embodiment, one of R1, R2, R3, R4, and R5 is not H.

[0170] In a preferred embodiment, two of R1, R2, R3, R4, and R5 are not H.

[0171] In a preferred embodiment, three of R1, R2, R3, R4, and R5 are not H.

[0172] In a 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 CO2Me, wherein the Ph, OPh, pyrazolyl, oxazolyl and thiazolyl groups are each optionally further substituted by one or more alkyl groups.

[0173] In a preferred embodiment, R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, haloalkyl, haloalkoxy and CO2-alkyl.

[0174] 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, wherein Ph, OPh, pyrazolyl, oxazolyl, and thiazolyl are each optionally further substituted by one or more alkyl groups. Preferably, the pyrazolyl group is 1H-pyrazol-1-yl. Preferably, the oxazolyl group is oxazol-5-yl. Preferably, the thiazolyl group is thiazolyl-4-yl.

[0175] In a preferred embodiment, R2 is selected from H, F, Cl, Br, CN, Me, methoxy, OCF3, CF3, OCHF2, Ph, pyrazolyl, and CO2Me, wherein the Ph and pyrazolyl groups are each optionally further substituted by one or more alkyl groups. Preferably, the pyrazolyl group is 1H-pyrazol-1-yl.

[0176] In a preferred embodiment, R2 and R3 are each independently selected from F, Cl, Br, I, CN, CO2 alkyl, C1-C6 haloalkyl and C1-C6 haloalkoxy.

[0177] In a preferred embodiment, R2 and R3 are each independently selected from F, Cl, Br, I, CN and C1-C6 haloalkyl groups.

[0178] In a preferred embodiment, R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl.

[0179] In a preferred embodiment, R2 and R3 are each independently selected from Cl, Br and CF3, and more preferably independently selected from Cl and CF3.

[0180] In a preferred embodiment, one of R2 and R3 is Cl, and the other is OCF3 or OCHF2.

[0181] In a preferred embodiment, one of R2 and R3 is Cl, and the other is CO2Me.

[0182] In a preferred embodiment, both R2 and R3 are Cl, or one of R2 and R3 is Cl and the other is CF3.

[0183] In a preferred embodiment, both R2 and R3 are Cl.

[0184] In a preferred embodiment, one of R2 and R3 is Cl, and the other is CF3.

[0185] In a preferred embodiment, one of R2 and R3 is Cl, and the other is selected from OCF3, CO2Me, OCHF2, and CF3.

[0186] In a preferred embodiment, R1, R4, and R5 are each independently selected from H, alkyl, alkoxy, OH, F, Cl, Br, and I.

[0187] In a preferred embodiment, R1, R4, and R5 are each independently selected from H, Me, OMe, OH, F, Cl, Br, and I.

[0188] In a preferred embodiment, R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I.

[0189] In a preferred embodiment, R5 is selected from H, F, Me, MeO and Cl, preferably H or F, and more preferably H.

[0190] In a preferred embodiment, R5 is selected from H, F and Cl, preferably H or F, and more preferably H.

[0191] In a preferred embodiment, R5 is selected from H, F and CN, and is preferably H.

[0192] In a preferred embodiment, both R1 and R4 are H.

[0193] In a 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, wherein Ph, OPh, pyrazolyl, oxazolyl, and thiazolyl are each optionally further substituted by one or more alkyl groups; R4 is H or CF3, more preferably H; R5 is selected from H, F, Me, MeO, Cl, OH, and CN, and is preferably H or F, more preferably H. Preferably, for this embodiment, at least one of R2 and R3 is not H. Even more preferably, neither R2 nor R3 is H.

[0194] In another preferred embodiment, one of R2 and R3 is selected from aryl, O-aryl and heteroaryl, each of which is optionally substituted, and the other of R2 and R3 is H, and R1, R4 and R5 are all H.

[0195] In a preferred embodiment, R6, R7, R8, and R9 are each independently selected from H, F, Cl, Br, CN, OMe, and NR. 11 R 11 'and OH.

[0196] In a preferred embodiment, R6, R7, R8 and R9 are each independently selected from H, F, Cl, Br, CN, OMe, NH2, NHBu, NHCO2Bu and OH.

[0197] In a preferred embodiment, R 14 It is H or methyl. More preferably, R 14 It's H.

[0198] In a particularly preferred embodiment, the compound has formula (Ib.1):

[0199]

[0200] Wherein ring A and groups Y and R1-R5 are as described in any of the above embodiments.

[0201] In a preferred embodiment, the compound is in the form of a pure enantiomer. In another preferred embodiment, the compound is in the form of a mixture of enantiomer-enriched (Ib.1) compounds.

[0202] In another embodiment, the compound has formula (Ib.2):

[0203]

[0204] Wherein ring A and groups Y and R1-R5 are as described in any of the above embodiments.

[0205] In a preferred embodiment, the compound is in the form of a pure enantiomer. In another preferred embodiment, the compound is in the form of a mixture of enantiomer-enriched (Ib.2) compounds.

[0206] In a 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 another 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).

[0207] The racemic mixture can be used to prepare enantiomerically pure compounds of formula (Ib.1) or (Ib.2) by separating them using standard methods, such as chemical resolution by optically active acids or column chromatography or reversed-phase column chromatography using substantially optically active (or “chiral”) stationary phases known to those skilled in the art. The racemic mixture can also be used to prepare enantiomer enrichment mixtures of compounds of formula (Ib.1) or (Ib.2). Mixtures enriched with compounds of formula (Ib.1) or (Ib.2) can also be obtained from precursors enriched with appropriate enantiomers.

[0208] In a preferred embodiment of the invention, the compound is in the form of a mixture comprising enantiomers, wherein the weight:weight ratio is at least about 2:1 or higher, preferably at least about 5:1 or higher, most preferably at least about 10:1 or higher, which is conducive to enantiomers (preferably enantiomers) exhibiting significant activity in vitro and / or in vivo.

[0209] In a particularly preferred embodiment, the compound is present 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, even more preferably greater than 10:1.

[0210] In a particularly preferred embodiment, the compound is present in the form of a mixture comprising the compound of formula (Ib.1) and its corresponding enantiomer of formula (Ib.2), which is substantially enriched in the compound of formula (Ib.1).

[0211] In one embodiment, the compound is in the form of a mixture comprising a 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, even more preferably greater than 10:1.

[0212] In one embodiment, the compound is in the form of a mixture comprising a compound of formula (Ib.1) and its corresponding enantiomer of formula (Ib.2), which is substantially rich in the compound of formula (Ib.2).

[0213] In a preferred embodiment, the compound is selected from substances, their enantiomers, mixtures of their enantiomers, and pharmaceutically acceptable salts and solvates thereof, wherein the mixtures of their enantiomers include racemic mixtures:

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237] Compound of formula (Ie)

[0238] Another aspect of the present invention relates to compounds of formula (Ie) or pharmaceutically acceptable salts or solvates thereof.

[0239]

[0240] in:

[0241] Ring A is

[0242]

[0243] R6 and R8 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, OH, phenyl and haloalkyl (more preferably CF3);

[0244] Y is selected from CH2, C=N-OH and CR. 10 R 10 ', where R 10 and R 10 Each is independently selected from H, F, alkyl, and haloalkyl;

[0245] R a and R b Each is independently selected from H and alkyl groups;

[0246] R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I; and

[0247] R2 and R3 are each independently selected from F, Cl, Br, I, CN, alkoxy, and haloalkyl; and

[0248] The condition is that when Y is CH2 and R a R b When R1, R4, R5, R6, and R8 are all H:

[0249] When R2 is Cl, R3 is not CN; and

[0250] R2 and R3 are not both Cl.

[0251] Therefore, in one embodiment, the compound of the present invention is a compound of formula (Ie) or a pharmaceutically acceptable salt or solvate thereof:

[0252]

[0253] Among them, Y and R a R b R1-R5, R6, and R8 are defined as described above. Preferably, when Y is CH2, R... a R b R1, R4, R5, R6, and R8 are H; when R2 is Cl, R3 is not CN. Preferably, when Y is CH2, R... a R b R1, R4, R5, R6, and R8 are all H, while R2 and R3 are not all Cl.

[0254] Another aspect of the present invention relates to compounds having the structure of the above formula (Ie) or pharmaceutically acceptable salts or solvates thereof, wherein Y, R a R b R1-R5, R6, and R8 are as defined above, provided that the compound is not:

[0255]

[0256] Another aspect of the present invention relates to compounds having the structure of the above formula (Ie) or pharmaceutically acceptable salts or solvates thereof, wherein Y, R a R b R1-R5, R6, and R8 are as defined above, provided that the compound is not:

[0257] N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]-pyrimidine-10-carboxamide; and

[0258] N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide.

[0259] Another aspect of the present invention relates to compounds having the structure of the above formula (Ie) or pharmaceutically acceptable salts or solvates thereof, wherein Y, R a R b R1-R5, R6, and R8 are as defined above, provided that the compound is not:

[0260] N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged iminecycloheptane[d]-pyrimidine-10-carboxamide, its enantiomers, and mixtures thereof; and

[0261] N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptyl[d]pyrimidine-10-carboxamide, its enantiomers, and mixtures thereof.

[0262] In a preferred embodiment, R2 and R3 are each independently selected from F, Cl, Br, I, CN and haloalkyl.

[0263] In a preferred embodiment, R2 is selected from F, Cl, Br and CF3, and more preferably from Cl and CF3.

[0264] In a preferred embodiment, R3 is selected from F, Cl, Br, OMe, CN and CF3, more preferably from F, Cl, Br and OMe and CF3, and even more preferably from Cl and CF3.

[0265] In a preferred embodiment, one of R2 and R3 is selected from Cl, and the other is CF3, or both R2 and R3 are Cl.

[0266] In a preferred embodiment, R1, R4, and R5 are all H.

[0267] In a preferred embodiment, Y is CR 10 R 10 ', where 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 a preferred embodiment, Y is selected from CH2, CHF, CHMe, and C=N-OH. In a preferred embodiment, Y is selected from CH2 and C=N-OH. In a preferred embodiment, Y is selected from CH2 and CHF. More preferably, Y is CH2.

[0268] In a 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 an alkyl group (more preferably methyl), and the other is H. In a particularly preferred embodiment, R a and R b All are H.

[0269] In a preferred embodiment, at least one of R6 and R8 is not H.

[0270] In a preferred embodiment, R6 is H.

[0271] In a preferred embodiment, R8 is selected from H, CF3, phenyl, OH and F.

[0272] In a preferred embodiment, R8 is OH, and ring A is the following structure or its corresponding tautomer:

[0273]

[0274] Preferably, R6 is H.

[0275] In a particularly preferred embodiment, the compound has formula (Ie.1):

[0276]

[0277] Wherein ring A and groups Y and R1-R5 are as described in any of the embodiments of (Ie) above.

[0278] In a preferred embodiment, the compound is in the form of a pure enantiomer. In another preferred embodiment, the compound is in the form of a mixture of enantiomers enriched with the compound of formula (Ie.1).

[0279] In another embodiment, the compound has formula (Ie.2):

[0280]

[0281] Wherein ring A and groups Y and R1-R5 are as described in any of the embodiments of (Ie) above.

[0282] In a preferred embodiment, the compound is in the form of a pure enantiomer. In another preferred embodiment, the compound is in the form of a mixture of enantiomers enriched with the compound of formula (Ie.2).

[0283] In a preferred embodiment, the compound is a mixture comprising the compound of formula (Ie.1) and its corresponding enantiomer of formula (Ie.2). In another 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).

[0284] Compounds of formula (Ie.1) or (Ie.2) can be separated by standard methods. Racemic mixtures can be used to prepare enantiomerically pure compounds of formula (Ie.1) or (Ie.2), for example by chemical resolution using optically active acids, or by column chromatography or reversed-phase column chromatography using substantially optically active (or “chiral”) stationary phases known to those skilled in the art. Racemic mixtures can also be used to prepare enantiomer enrichment mixtures of compounds of formula (Ie.1) or (Ie.2). Mixtures enriched from compounds of formula (Ie.1) or (Ie.2) can also be obtained from precursors enriched from suitable enantiomers.

[0285] In a preferred embodiment of the invention, the compound is in the form of a mixture comprising enantiomers, wherein the weight:weight ratio is at least about 2:1 or higher, preferably at least about 5:1 or higher, most preferably at least about 10:1 or higher, which is conducive to enantiomers (preferably enantiomers) exhibiting significant activity in vitro and / or in vivo.

[0286] In a particularly preferred embodiment, the compound is in the form of a mixture comprising a 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, more preferably greater than 5:1, and more preferably greater than 10:1.

[0287] In a particularly preferred embodiment, the compound is present in the form of a mixture comprising the compound of formula (Ie.1) and its corresponding enantiomer of formula (Ie.2), which is substantially enriched in the compound of formula (Ie.1).

[0288] In one embodiment, the compound exists 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, even more preferably greater than 10:1.

[0289] In one embodiment, the compound exists in the form of a mixture comprising the compound of formula (Ie.1) and its corresponding enantiomer of formula (Ie.2), which is substantially enriched in the compound of formula (Ie.2).

[0290] In a preferred embodiment, the compound of formula (Ie) is selected from substances, their enantiomers, mixtures of their enantiomers, pharmaceutically acceptable salts and solvates thereof, wherein the mixture of their enantiomers comprises racemic mixtures:

[0291]

[0292]

[0293]

[0294]

[0295]

[0296] Compound of formula (Ia)

[0297] One aspect of the present invention relates to compounds of formula (Ia) or pharmaceutically acceptable salts or solvates thereof.

[0298]

[0299] in:

[0300] Ring A is a 5- or 6-membered aromatic ring or heteroaromatic ring, wherein the aromatic ring or heteroaromatic ring is optionally selected from F, Cl, Br, I, CN, alkoxy, NR. 11 R 11 One or more substituents of ', OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein said aryl and heteroaryl substituents are optionally each independently selected from F, Cl, Br, I, CN, alkoxy, NR 11 R 11 One or more substituents selected from ', OH, alkyl, haloalkyl, and aralkyl;

[0301] Y is selected from CH2, C=N-OH and CR. 10 R 10 ', where R 10 and R 10 Each is independently selected from H, F, alkyl, and haloalkyl;

[0302] R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I;

[0303] R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl; and

[0304] R 11 and R 11 Each is independently selected from H, alkyl, haloalkyl, COR 12 and SO2R 13 , where R 12 and R 13 All are alkyl groups;

[0305] Where Y is CH2 and ring A is:

[0306]

[0307] Both R6 and R8 are H.

[0308] - When R1, R4, and R5 are all H, R2 and R3 are not all Cl;

[0309] -When R1, R2, R4, and R5 are all H, R3 is not Cl;

[0310] - When R1, R3, R4, and R5 are all H, R2 is not Cl;

[0311] - When R2, R3, R4, and R5 are all H, R1 is not Cl;

[0312] - When R4 is Cl and R2, R3 and R5 are all H, R1 is not F.

[0313] In a preferred embodiment, the optionally substituted aromatic or heteroaromatic ring is a benzene, pyridine, pyridinone, pyridine N-oxide, pyridazine, pyrimidine, pyrimidinone, pyrazine, triazine, pyrrole, furan, thiophene, pyrazole, isoxazole, imidazole, oxazole, or thiazole ring. The term "heteroaromatic" as used herein also includes portions present in tautomeric form, such as, but not limited to, pyridine, pyrimidinone, etc. The aromatic or heteroaromatic ring A is fused with an adjacent nitrogen-containing bicyclic heterocyclic group to form a fused tricyclic ring system.

[0314] More preferably, the optionally substituted aromatic or heteroaromatic ring is benzene, pyridine, pyridinone, pyridine N-oxide, pyrimidine, pyrimidinone, pyridazine, pyrazine, or isoxazole ring.

[0315] In a preferred embodiment, ring A is a benzene, pyridine, pyridone, pyridine N-oxide, pyrimidine, pyrimidinone, pyridazine, pyrazine, or isoxazole ring, optionally surrounded by one or more elements selected from F, Cl, Br, I, CN, C1-C6 alkoxy, NR. 11 R 11 Substitution with ', OH, C1-C6 alkyl, phenyl and C1-C6 haloalkyl groups.

[0316] In one implementation, ring A is selected from:

[0317]

[0318] R6, R7, R8, and R9 are each independently selected from H, F, Cl, Br, I, CN, C1-C6 alkoxy groups, and NR. 11 R 11 ', OH, C1-C6 alkyl, phenyl and C1-C6 haloalkyl.

[0319] In a preferred embodiment, ring A is selected from:

[0320]

[0321] Better selections are:

[0322]

[0323] In a preferred embodiment, R 10 and R 10 Each is independently selected from H and C1-C6 alkyl groups, preferably C1-C6 alkyl groups being CH3.

[0324] In a preferred embodiment, Y is selected from CH2 and C=N-OH, and is preferably CH2.

[0325] In a preferred embodiment, R1 is selected from H and F, and is preferably H.

[0326] In a preferred embodiment, R2 and R3 are each independently selected from F, Cl, Br, I, CN and C1-C6 haloalkyl groups.

[0327] In a preferred embodiment, R2 and R3 are each independently selected from F, Cl, Br, I, CN, and CF. n H 3-n , where n is 1, 2 or 3, and preferably 3.

[0328] In a preferred embodiment, R2 and R3 are each independently selected from Cl, Br, and CF. n H 3-n , where n is 1, 2 or 3, and preferably 3.

[0329] In a preferred embodiment, R2 and R3 are each independently selected from Cl, Br or CF3, preferably wherein R2 and R3 are not both CF3, and more preferably wherein R2 is Cl or Br and R3 is CF3.

[0330] In a preferred embodiment, R4 is selected from H and Cl, and is preferably H.

[0331] In a preferred embodiment, R5 is H.

[0332] In a preferred embodiment, R6 is selected from H, F, Cl, CN, methoxy, CH3, NR. 11 R 11 'and CF3, where R 11 and R 11 Each is independently selected from H and C1-C6 alkyl groups, and preferably all of them are H.

[0333] In a preferred embodiment, R6 is selected from H, F, Cl, CN, methoxy, and CH3, and is preferably H.

[0334] In a preferred embodiment, R7 is selected from H, F, Cl, CN, methoxy, CH3, NR. 11 R 11 'and CF3, where R 11 and R 11 Each is independently selected from H and C1-C6 alkyl groups, and preferably all of them are H.

[0335] In a preferred embodiment, R7 is selected from H, F, Cl, CN, methoxy, and CH3, preferably H, F, or Cl, and more preferably H.

[0336] In a preferred embodiment, R8 is selected from H, F, OH, CN, methoxy, NR. 11 R 11 ', phenyl, CF3, CF2H, NHSO2CH3, NHCOCH3 and NHCHF2, wherein R 11 and R 11 Each is independently selected from H and C1-C6 alkyl groups, and preferably all of them are H.

[0337] In a preferred embodiment, R8 is selected from H, F, Cl, CN, phenyl and OH, and is preferably selected from H, H and OH.

[0338] In a preferred embodiment, R8 is OH.

[0339] In a preferred embodiment, R9 is selected from H, F, Cl, CN, methoxy, CH3, NR. 11 R 11 'and CF3, where R 11 and R 11 Each is independently selected from H and C1-C6 alkyl groups, and preferably all of them are H.

[0340] In a preferred embodiment, R9 is selected from H, F, Cl, CN, methoxy, and CH3, preferably from H, F, and CN, and more preferably from H.

[0341] In a preferred embodiment, R6, R7, and R9 are H, if present.

[0342] In a particularly preferred embodiment, the compound of formula (Ia) is...

[0343]

[0344] in:

[0345] Ring A is selected from:

[0346]

[0347] Y is CH2;

[0348] R1, R4, R5, R6, R7, and R9 are all H;

[0349] R2 and R3 are each independently selected from Cl, Br, or CF3, preferably wherein R2 and R3 are not both CF3, and more preferably wherein R2 is Cl or Br and R3 is CF3; and

[0350] R8 is selected from H, F, Cl, CN, phenyl and OH, preferably H, F and OH, and more preferably OH;

[0351] Preferably, when ring A is:

[0352]

[0353] Furthermore, when R8 is H, R2 and R3 are not both Cl.

[0354] In a more preferred embodiment, the compound of formula (Ia) is:

[0355]

[0356] in:

[0357] Y is CH2;

[0358] R1, R4, R5, and R6 are all H;

[0359] R2 and R3 are each independently selected from Cl, Br, or CF3, preferably wherein R2 and R3 are not both CF3, more preferably wherein R2 is Cl or Br and R3 is CF3; and

[0360] R8 is selected from H, F, Cl, CN, phenyl and OH, preferably H, F and OH, and more preferably OH;

[0361] When R8 is H, R2 and R3 are not both Cl.

[0362] In a particularly preferred embodiment, the compound has formula (Ia.1):

[0363]

[0364] Among them, ring A and group Y and R1-R 13 As described in any of the above embodiments. In a preferred embodiment, the compound is in its enantiomerically pure form.

[0365] In another embodiment, the compound has formula (Ia.2):

[0366]

[0367] Among them, ring A and group Y and R1-R 13 As described in any of the above embodiments. In a preferred embodiment, the compound is in its enantiomerically pure form.

[0368] In a 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 another 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).

[0369] The racemic mixture can be used to prepare enantiomers of pure compounds of formula (Ia.1) or (Ia.2) by separating compounds of formula (Ia.1) or (Ia.2) using standard methods, such as chemical resolution by optically active acids or column chromatography or reversed-phase column chromatography using substantially optically active (or “chiral”) stationary phases known to those skilled in the art. The racemic mixture can also be used to prepare mixtures enriched with enantiomers of compounds of formula (Ia.1) or (Ia.2). Mixtures enriched with compounds of formula (Ia.1) or (Ia.2) can also be obtained from precursors enriched with suitable enantiomers.

[0370] In a preferred embodiment of the invention, the compound is in the form of a mixture comprising enantiomers, wherein the weight:weight ratio is at least about 2:1 or higher, preferably at least about 5:1 or higher, most preferably at least about 10:1 or higher, which is conducive to enantiomers (preferably enantiomers) exhibiting significant activity in vitro and / or in vivo.

[0371] In a particularly preferred embodiment, the compound is present 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, even more preferably greater than 10:1.

[0372] In a particularly preferred embodiment, the compound exists in the form of a mixture comprising the compound of formula (Ia.1) and its corresponding enantiomer of formula (Ia.2), which is substantially enriched in the compound of formula (Ia.1).

[0373] In one embodiment, the compound is in the form of a mixture comprising a compound of formula (Ia.1) and its corresponding enantiomer of formula (Ia.2), wherein the 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, even more preferably greater than 10:1.

[0374] In one embodiment, the compound exists as a mixture comprising the compound of formula (Ia.1) and its corresponding enantiomer of formula (Ia.2), which is substantially enriched in the compound of formula (Ia.2).

[0375] In a preferred embodiment, the compound of formula (Ia) is selected from the following compounds shown herein, their enantiomers, mixtures of their enantiomers, and pharmaceutically acceptable salts and solvates thereof, wherein the mixtures of their enantiomers comprise racemic mixtures:

[0376] (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).

[0377] In another preferred embodiment, the compound of formula (Ia) is selected from the following substances and their pharmaceutically acceptable salts and solvates:

[0378] (±)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0379] (5S,8R)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0380] (5R,8S)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0381] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0382] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0383] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0384] (±)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0385] (5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0386] (5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0387] (±)-N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide;

[0388] (5S,8R)-N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0389] (5R,8S)-N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0390] (±)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0391] (5S,8R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0392] (5R,8S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0393] (±)-N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0394] (5S,8R)-N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0395] (5R,8S)-N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide;

[0396] (±)-N-(4-bromo-3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0397] (5S,8R)-N-(4-bromo-3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin [d]-pyrimidine-10-carboxamide;

[0398] (5R,8S)-N-(4-bromo-3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin [d]-pyrimidine-10-carboxamide;

[0399] (±)-N-(3-chloro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]-pyrimidine-10-carboxamide;

[0400] (5S,8R)-N-(3-chloro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin [d]-pyrimidine-10-carboxamide;

[0401] (5R,8S)-N-(3-chloro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]-pyrimidine-10-carboxamide;

[0402] (±)-N-(3-bromo-4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0403] (5S,8R)-N-(3-bromo-4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin [d]-pyrimidine-10-carboxamide;

[0404] (5R,8S)-N-(3-bromo-4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin [d]-pyrimidine-10-carboxamide;

[0405] (±)-N-(3-bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0406] (5S,8R)-N-(3-bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]-pyrimidine-10-carboxamide;

[0407] (5R,8S)-N-(3-bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]-pyrimidine-10-carboxamide;

[0408] (±)-N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0409] (5S,8R)-N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide;

[0410] (5R,8S)-N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0411] (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0412] (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptamethrin-10-carboxamide;

[0413] (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0414] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0415] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0416] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptapyrimidine-10-carboxamide;

[0417] (±)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0418] (5S,8R)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0419] (5R,8S)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide;

[0420] (±)-N-(3,4-dichlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin [d]-pyrimidine-10-carboxamide;

[0421] (5S,8R)-N-(3,4-dichlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide;

[0422] (5R,8S)-N-(3,4-dichlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0423] (±)-N-(3,4-dichlorophenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]-pyrimidine-10-carboxamide;

[0424] (5S,8R)-N-(3,4-dichlorophenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0425] (5R,8S)-N-(3,4-dichlorophenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0426] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0427] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0428] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0429] (±)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0430] (5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0431] (5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0432] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0433] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-1-carboxamide;

[0434] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-1-carboxamide;

[0435] (±)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin [d]-pyrimidine-10-carboxamide;

[0436] (5S,8R)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin [d]-pyrimidine-10-carboxamide;

[0437] (5R,8S)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin [d]-pyrimidine-10-carboxamide;

[0438] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0439] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-1-carboxamide;

[0440] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-1-carboxamide;

[0441] (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide;

[0442] (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide;

[0443] (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide;

[0444] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide;

[0445] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide;

[0446] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide;

[0447] (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide;

[0448] (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide;

[0449] (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide;

[0450] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]-pyridine-10-carboxamide;

[0451] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptane[c]pyridine-10-carboxamide;

[0452] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptane[c]pyridine-10-carboxamide;

[0453] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0454] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0455] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide;

[0456] (±)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin [d]-pyrimidine-10-carboxamide;

[0457] (5S,8R)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin [d]-pyrimidine-10-carboxamide;

[0458] (5R,8S)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0459] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(oxime)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide;

[0460] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(oxime)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[d]pyrimidine-10-carboxamide;

[0461] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(oxime)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide;

[0462] (±)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0463] (5S,8R)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]-pyrimidine-10-carboxamide;

[0464] (5R,8S)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]-pyrimidine-10-carboxamide;

[0465] (±)-N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxamide;

[0466] (5S,8R)-N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide; and

[0467] (5R,8S)-N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide.

[0468] Compound of formula (Ic)

[0469] Another aspect of the present invention relates to compounds of formula (Ic) or pharmaceutically acceptable salts or solvates thereof.

[0470]

[0471] in:

[0472] Ring A is

[0473]

[0474] R6 and R8 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, and NR. 11 R 11 ', OH, alkyl, phenyl and haloalkyl, provided that at least one of R6 and R8 is not H;

[0475] Y is selected from CH2, C=N-OH and CR. 10 R10 ', where R 10 and R 10 Each is independently selected from H, F, alkyl, and haloalkyl;

[0476] R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I;

[0477] R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl; and

[0478] R 11 and R 11 Each is independently selected from H, alkyl, haloalkyl, COR 12 and SO2R 13 , where R 12 and R 13 All are alkyl groups.

[0479] Groups Y and R 1-13 The preferred definitions and preferred configurations of the ring system are as described above for compounds of formulas (Ia), (Ib), (Ie) and (If).

[0480] In a preferred embodiment, R8 is OH, and ring A is in the form of a pyridine tautomer:

[0481]

[0482] Highly preferred compounds of formula (Ic) include the following compounds described herein: (24), (25), (26), (27), (28), (29), (31), (32), (45), (46) and (47), their enantiomers, mixtures of their enantiomers, and pharmaceutically acceptable salts and solvates thereof, wherein the mixtures of their enantiomers include racemic mixtures.

[0483] Formula (Id) compound

[0484] Another aspect of the present invention relates to compounds of formula (Id) or pharmaceutically acceptable salts or solvates thereof.

[0485]

[0486] in:

[0487] Ring A is

[0488]

[0489] R6 and R8 are each independently selected from H, F, Cl, Br, I, CN, alkoxy, and NR. 11 R 11', OH, alkyl, phenyl and haloalkyl;

[0490] Y is selected from CH2, C=N-OH and CR. 10 R 10 ', where R 10 and R 10 Each is independently selected from H, F, alkyl, and haloalkyl;

[0491] R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I;

[0492] 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; and

[0493] R 11 and R 11 Each is independently selected from H, alkyl, haloalkyl, COR 12 and SO2R 13 , where R 12 and R 13 All are alkyl groups.

[0494] Groups Y and R 1-13 The preferred definition and preferred configuration of the ring system are as described above for compound (Ia).

[0495] Highly preferred compounds of formula (Id) include the following compounds as described herein: (1), (2), (3), (5), (8), (11), (13), (15), (18), (27), (28), (29), (32), (45) and (47), their enantiomers, mixtures of their enantiomers, and pharmaceutically acceptable salts and solvates thereof, wherein the mixtures of their enantiomers include racemic mixtures.

[0496] method

[0497] Another aspect of the invention relates to a method for preparing compounds as defined herein, the method comprising reacting a compound of formula II with a compound of formula III, wherein R 1-5 Y and A, as defined above, form compounds of the formula (Ia), (Ib), (Ic), (Id), (Ie), or (If):

[0498]

[0499] In a preferred embodiment, the reaction is carried out in the presence of a base, preferably N,N-diisopropylethylamine (DIPEA) or triethylamine. Preferably, the reaction is carried out in an organic solvent. Suitable organic solvents include, but are not limited to, dichloromethane, tetrahydrofuran, and dimethylformamide, or mixtures of two or more thereof. Those skilled in the art will understand that other bases and solvents will also be suitable.

[0500] Therapeutic applications

[0501] Another aspect of the invention relates to the use of the compounds described herein in pharmaceuticals. As described in more detail below, the compounds have particular use in the fields of oncology, immuno-oncology, and immunology. In a preferred embodiment, the compounds of the invention regulate GPR65, more preferably inhibit GPR65 signaling.

[0502] Another aspect of the invention relates to the use of the compounds described herein as medicines, preferably for the treatment or prevention of diseases selected from proliferative and immune disorders.

[0503] Another aspect of the invention relates to compounds described herein for the treatment or prevention of asthma and / or chronic obstructive pulmonary disease (COPD). A GPR65 variant / SNP (rs6574978) has been shown to be associated with asthma / COPD syndrome with a nearly GWAS significant p-value (1.18 x 10e-7) (Hardin 2014). Furthermore, pH-dependent GPR65 activation (low / acidic pH in asthmatic lungs) promotes eosinophil survival in a cAMP-dependent manner, leading to disease progression / exacerbation. GPR65 KO mice are also known to have reduced asthma symptoms (Kottyan 2009).

[0504] Another aspect of the invention relates to the use of the compounds described herein for the treatment or prevention of acute respiratory distress syndrome (ARDS). GPR65 has been shown to have a protective effect in LPS-induced acute lung injury models (Tsurumaki 2015).

[0505] One aspect of the invention relates to the use of the compounds described herein for the treatment of proliferative disorders. Preferably, the proliferative disorder is cancer or leukemia.

[0506] In a preferred embodiment, the cancer is a solid tumor and / or its metastatic tumor.

[0507] In another preferred embodiment, the cancer is selected from the following: melanoma, renal cell carcinoma (RCC), gastric cancer, acute myeloid leukemia (AML), triple-negative breast cancer (TNBC), colorectal cancer, head and neck cancer, colorectal adenocarcinoma, pancreatic cancer, lung cancer, sarcoma, ovarian cancer, and glioma, preferably glioblastoma (GBM).

[0508] Unwilling to be bound by theory, it is proposed that GPR65 modulators can prevent the increase of cytoplasmic cAMP in tumor-associated macrophages (TAMs), natural killer (NK) cells, and T cell subsets, which is typically due to their exposure to the acidic tumor microenvironment and associated GPR65 activation. This reduction in cytoplasmic cAMP levels, in turn, reduces the levels of ICERs and pro-inflammatory mediators (such as CXCL10 and TNFα), prevents TAM polarization, and alters in other immune cells associated with non-inflammatory and tumor-permissive environments. Therefore, GPR65 modulators hold promise for increasing tumor visibility to the immune system, thereby enhancing immune-mediated tumor clearance. This suggests that modulating GPR65 activity may be an effective approach to cancer treatment, whether as a monotherapy, in combination with cancer immunotherapies (vaccines, agents that promote T cell-mediated immune responses), or in patients unresponsive to immunomodulatory approaches (such as PD1 / PDL-1 blockade).

[0509] Another aspect of the invention relates to the use of the compounds described herein for the treatment or prevention of immune disorders, preferably autoimmune diseases.

[0510] In one implementation, the autoimmune disease is selected from: psoriasis, psoriatic arthritis, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), autoimmune thyroiditis (Hashimoto's thyroiditis), Graves' disease, uveitis (including intermediate uveitis), ulcerative colitis, Crohn's disease, autoimmune uveoretinitis, systemic vasculitis, polymyositis dermatomyositis, systemic sclerosis (scleroderma), Sjögren's syndrome, ankylosing spondylitis and related spondyloarthropathy, sarcoidosis, autoimmune hemolytic anemia, immune thrombocytopenic purpura, autoimmune polyendocrine disorders, autoimmune myocarditis, type I diabetes, and atopic dermatitis.

[0511] In a particularly preferred embodiment, the autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and multiple sclerosis (MS).

[0512] Not wanting to be bound by theory, it is proposed that GPR65 regulators would prevent the upregulation of ICER in CD4+ T cells. In turn, this would hopefully prevent ICER-related IL-2 inhibition, which biases CD4+ T cells toward the inflammatory Th17 phenotype associated with increased pathogenicity in autoimmune diseases. This is supported by the fact that mutations at the GPR65 locus are associated with a variety of autoimmune diseases, such as multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, and Crohn's disease (Gaublomme, 2015). This suggests that regulating GPR65 activity may be an effective approach for treating autoimmune diseases.

[0513] On the other hand, the compounds described herein are used to treat or prevent conditions caused by, related to, or accompanied by abnormal activity against GPR65.

[0514] On the other hand, it relates to the use of the compounds described herein for the treatment or prevention of GPR65-related diseases or conditions.

[0515] Another aspect of the present invention relates to a method of treating the condition described above, comprising administering the compound described herein to a subject.

[0516] Another aspect of the invention relates to a method for treating a subject with a GPR65-related disease or condition. The method according to this aspect of the invention is achieved by administering a therapeutically effective amount of the compound of the invention to the subject in need, either as described above, or, more preferably, as part of a pharmaceutical composition mixed with, for example, a pharmaceutically acceptable carrier.

[0517] Another aspect of the present invention relates to a treatment method for alleviating the condition of a subject by modulating GPR65, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of the present invention.

[0518] Another aspect of the invention relates to a treatment method that alleviates the condition of a subject by modulating GPR65, wherein the method comprises administering a therapeutically effective amount of the compound of the invention to the subject.

[0519] On the other hand, there are treatment methods that alleviate the condition by modulating GPR65, wherein the method includes administering a therapeutically effective amount of the compound of the present invention to a subject.

[0520] Preferably, the subject is a mammal, more preferably a human.

[0521] The term "method" refers to the manner, means, technique, and process used to accomplish a given task, including (but not limited to) those known manner, means, techniques, and processes, or those manner, means, techniques, and processes that are readily developed by those skilled in the art of chemistry, pharmacy, biology, biochemistry, and medicine from known manner, means, techniques, and processes.

[0522] In this article, the term "treatment" includes eliminating, substantially inhibiting, slowing down, or reversing the development of a disease or condition, substantially improving the clinical symptoms of a disease or condition, or substantially preventing the occurrence of the clinical symptoms of a disease or condition.

[0523] In this article, the term "prevention" refers to methods used to initially prevent an organism from developing symptoms or diseases.

[0524] The term "therapeutic effective dose" refers to the amount of a compound applied that will, to a certain extent, alleviate one or more symptoms of the disease or condition being treated.

[0525] For any compound used in this invention, the therapeutically effective amount also refers herein to an effective therapeutic dose, which can be preliminarily estimated by cell culture assays. For example, a dose can be established in animal models to achieve a range of circulating concentrations, including the IC50 determined by cell culture. 50 or IC 100 This information can be used to more accurately determine the effective dose for human use. The initial dose can also be estimated using in vivo data. Using this initial guidance, those skilled in the art can determine the effective dose for human use.

[0526] In addition, standard pharmaceutical procedures performed in cell cultures or laboratory animals (e.g., by determining LD50) 50 and ED 50 The toxicity and efficacy of the compounds described herein can be determined. The dose ratio between toxicity and efficacy is the therapeutic index and can be expressed as LD50. 50 With ED 50 The ratio between these values. Compounds exhibiting a high therapeutic index are preferred. Data obtained from these cell culture experiments and animal studies can be used to determine dosage ranges that do not produce toxicity for human use. The dosage of the compound is preferably at cyclic concentrations with only minimal or no toxicity (including ED). 50The dosage may vary within this range depending on the dosage form and administration method used. The exact dosage form, administration method, and dosage can be selected by a private physician based on the patient's condition (see, for example, Fingl et al., 1975, The Pharmacological Basis of Therapeutics, Chapter 1, page 1).

[0527] The dosage and interval can be individually adjusted to provide sufficient plasma levels to maintain the therapeutically effective active compound. Typical patient doses for oral administration range from about 50-2000 mg / day, typically about 100-1000 mg / day, preferably about 150-700 mg / day, most preferably about 250-500 mg / day, or 50-100 mg / day. Preferably, therapeutically effective serum levels are achieved through multiple daily doses. In cases of topical application or selective uptake, the effective local concentration of the drug may be independent of plasma concentration. Those skilled in the art will be able to optimize the therapeutically effective local dose without excessive experimentation.

[0528] As used herein, “GPR65-related disease or condition” refers to a disease or condition characterized by inappropriate GPR65 activity. For example, inappropriate GPR65 activity compared to that in healthy subjects refers to an increase or decrease in GPR65 activity as measured by enzyme or cell assays. Overexpression of GPR65 in diseased tissues compared to healthy adjacent tissues may also lead to inappropriate activity.

[0529] The preferred diseases or conditions for which the compounds described herein may be used for prevention include the proliferative and immune disorders mentioned above, as well as asthma and chronic obstructive pulmonary disease.

[0530] Therefore, this invention further provides the use of the compounds defined herein in the preparation of medicaments for treating diseases requiring modulation of GPR65. Such diseases include the proliferative and immune disorders described above, as well as asthma and chronic obstructive pulmonary disease.

[0531] As used herein, the phrase “preparation of a medicament” includes the use of the components of the invention directly as a medicament, as well as their use at any stage of the preparation of such a medicament.

[0532] In a preferred embodiment, the compound inhibits the expected increase in cytoplasmic cAMP levels following GPR65 activation at acidic pH. As described above, this inhibition of cAMP accumulation, in turn, inhibits downstream signaling via ICER. As described in the appended Examples section, the “human GPR65 cyclic adenosine monophosphate (cAMP) homogeneous time-resolved fluorescence (HTRF) antagonist detection,” or simply “cAMP detection,” can be used to determine the potency of a GPR65 modulator, expressed as the concentration of the compound required to reduce the increase in cAMP concentration upon GPR65 activation by 50% (i.e., IC50). 50 ).

[0533] In a preferred embodiment, the compound exhibits an IC50 in cAMP detection. 50 The value is less than about 25 μM. More preferably, the compound exhibits an IC50 value in cAMP detection. 50 The value is 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.

[0534] In another preferred embodiment, in the above-described detection, the compound exhibits hGPR65 IC 50 The value is less than 5 μM, more preferably less than 500 nM.

[0535] Therapeutic uses of Formula I compounds

[0536] Another aspect of the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as a medicine:

[0537]

[0538] in:

[0539] Ring A is a 5- or 6-membered aromatic ring or heteroaromatic ring, wherein the aromatic ring or heteroaromatic ring is optionally selected from F, Cl, Br, I, CN, alkoxy, NR. 11 R 11 One or more substituents of ', OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein said aryl and heteroaryl substituents are optionally each independently selected from F, Cl, Br, I, CN, alkoxy, NR 11 R 11 One or more substituents selected from ', OH, alkyl, haloalkyl, and aralkyl;

[0540] Y is selected from CH2, C=N-OH and CR. 10 R 10' , where R 10 and R 10Each is independently selected from H, F, alkyl, and haloalkyl;

[0541] R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I;

[0542] R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl; and

[0543] R 11 and R 11 Each is independently selected from H, alkyl, haloalkyl, COR 12 and SO2R 13 , where R 12 and R 13 All are alkyl groups.

[0544] Ring A and groups Y and R 1-13 The preferred definitions and preferred configurations of the ring system are as described above for compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), and (If).

[0545] Compounds of formula (I) are preferably used to treat proliferative disorders and autoimmune disorders, as well as asthma and chronic obstructive pulmonary disease. Details regarding suitable proliferative disorders and autoimmune disorders are the same as those described in the above heading, "Therapeutic Applications."

[0546] In a preferred embodiment, the compound of formula (I) used for the above-described purposes is selected from the following substances and their enantiomers, mixtures of their enantiomers, and pharmaceutically acceptable salts and solvates thereof, wherein the mixtures of their enantiomers include racemic mixtures:

[0547] (1)-(8), (11)-(13), (15)-(18), (24)-(29), (31), (32), (34)-(37) and (45)-(53).

[0548] In a preferred embodiment, the compound of formula (I) used for the above-described purposes is selected from the following substances and their enantiomers, mixtures of their enantiomers, and pharmaceutically acceptable salts and solvates thereof, wherein the mixtures of their enantiomers include racemic mixtures:

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578] Another aspect of the invention relates to the use of the above-mentioned compounds and their enantiomers, mixtures of their enantiomers, and pharmaceutically acceptable salts and solvates thereof as pharmaceuticals, wherein the mixtures of their enantiomers include racemic mixtures.

[0579] In another preferred embodiment, the compound according to the invention or the compound used for the above purposes is selected from the following substances and their pharmaceutically acceptable salts and solvates:

[0580] N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide

[0581] N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[d]pyrimidine-10-carboxamide

[0582] N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[d]pyrimidine-10-carboxamide

[0583] N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0584] N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgedimine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0585] N-(3,4-Difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0586] N-(4-Bromo-3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptamethrin-10-carboxamide

[0587] N-(3-chloro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptamethrin-10-carboxamide

[0588] N-(3-Chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptamethrin-10-carboxamide

[0589] N-(3-Bromo-4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptamethrin-10-carboxamide

[0590] N-(3-Bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptapyrimidine-10-carboxamide

[0591] N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[d]pyrimidine-10-carboxamide

[0592] N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0593] N-(3,4-Dichlorophenyl)-6,7,8,9-Tetrahydro-5H-6,9-bridged imine cycloheptamethrin-10-carboxamide

[0594] N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0595] N-(3,4-Dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptamethrin[d]pyrimidine-10-carboxamide

[0596] N-(3,4-Dichlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-5,8-bridgedimine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0597] N-(3,4-Dichlorophenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptamethrin[d]pyrimidine-10-carboxamide

[0598] N-(3-chloro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide

[0599] N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridgedimine cycloheptyl[d]pyrimidine-10-carboxamide

[0600] N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridgedimine cycloheptamethrin-10-carboxamide

[0601] N-(3,4-Dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0602] N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0603] N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0604] N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0605] N-(3,4-Dichlorophenyl)-6,7,8,9-Tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0606] N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-bridgediminecyclohepta[c]pyridine-10-carboxamide

[0607] N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[d]pyrimidine-10-carboxamide

[0608] N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[d]pyrimidine-10-carboxamide

[0609] N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[d]pyrimidine-10-carboxamide

[0610] N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide

[0611] N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide

[0612] N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgedimine cycloheptamethrin-10-carboxamide

[0613] N-(3,4-Dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgedimine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0614] N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(oxime)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0615] N-(3,4-Dichlorophenyl)-6,7,8,9-Tetrahydro-5H-5,8-bridgediminecycloheptamethrin-10-carboxamide

[0616] N-(4-Chlorophenyl)-6,7,8,9-Tetrahydro-5H-5,8-bridgediminecycloheptamethrin-10-carboxamide

[0617] N-(3-Chlorophenyl)-6,7,8,9-Tetrahydro-5H-5,8-bridgediminecycloheptamethrin-10-carboxamide

[0618] N-(5-chloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-cycloheptane[d]pyrimidine-10-carboxamide

[0619] N-(3,4-Dichlorophenyl)-6,7,8,9-Tetrahydro-5H-5,8-bridgediminecycloheptamethrin-10-carboxamide

[0620] N-(3,4-Dichlorophenyl)-6,7,8,9-Tetrahydro-5H-5,8-bridgediminecycloheptamethrin-10-carboxamide

[0621] N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[0622] N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[0623] N-(3,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0624] N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0625] 10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-2-oxide

[0626] 10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]-pyridine-2-oxide

[0627] 2-Chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0628] 1-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0629] 3-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0630] 1-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0631] 3-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0632] 1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0633] 3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0634] N-(3,4-Dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0635] N-(3,4-Dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0636] N-(3,4-Dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0637] 2-Chloro-N-(3-Chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo-[7] arbutin-10-carboxamide

[0638] 2-Cyano-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0639] 2-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0640] N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0641] N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo-[7] arbutin-10-carboxamide

[0642] N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0643] 1-Chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0644] N-(3,4-Dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0645] N-(4,5-dichloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0646] N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0647] N-(3-chloro-4-(trifluoromethyl)phenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo-[7] arunculene-10-carboxamide

[0648] tert-butyl-(10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-bridged iminecycloheptane[c]pyridin-1-yl)carbamate

[0649] N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0650] N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0651] N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0652] N-(3,4-Dichlorophenyl)-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-bridgediminecycloheptan[c]-pyridine-10-carboxamide

[0653] N-(3,4-Dichlorophenyl)-6,7,8,9-Tetrahydro-5H-5,8-bridgediminecycloheptane[b]pyridine-10-carboxamide

[0654] N-(4,5-dichloro-2-cyanophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0655] N-(3,4-Dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0656] 10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-2-oxide

[0657] N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0658] N-(4,5-dichloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0659] N-(3,4-dichlorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0660] N-(4,5-dichloro-2-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0661] 3-Bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0662] 3-Chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0663] N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0664] N-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[0665] N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0666] N-(3,4-Dichlorophenyl)-6,7,8,9-Tetrahydro-5H-6,9-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0667] N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0668] N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0669] N-(3,4-Dichlorophenyl)-6,7,8,9-Tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0670] N-(3,4-Dichlorophenyl)-6,7,8,9-Tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0671] N-(3,4-Dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0672] N-(3,4-Dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0673] N-(3,4-Dichlorophenyl)-6,7,8,9-Tetrahydro-5H-6,9-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0674] N-(3,4-Dichlorophenyl)-6,7,8,9-Tetrahydro-5H-6,9-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0675] N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgedimine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0676] N-(3,4-Dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d-]pyrimidine-10-carboxamide

[0677] N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgedimine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0678] N-(3-chloro-4-(trifluoromethyl)phenyl)-8-methyl-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0679] N-(4,5-dichloro-2-methylphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0680] N-(4,5-dichloro-2-methoxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0681] 1-Fluoro-N-(2-Fluoro-5-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0682] 1-Fluoro-N-(2-Fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0683] 1-Fluoro-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta-[c]pyridine-10-carboxamide

[0684] 2-Chloro-4-(-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carbamate) methyl benzoate

[0685] 2-Chloro-5-(-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carbamate) methyl benzoate

[0686] N-(3-chloro-4-(trifluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0687] 2-Chloro-4-fluoro-5-(1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]-pyridine-10-carbamate) methyl benzoate

[0688] N-(4-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0689] N-(3-chloro-4-(difluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0690] N-(3-chloro-4-(trifluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0691] N-(4-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0692] Methyl 2-chloro-4-(3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptane[c]pyridine-10-carbamate)benzoate

[0693] Methyl 2-chloro-5-(3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptane[c]pyridine-10-carbamate)benzoate

[0694] Methyl 2-chloro-4-fluoro-5-(3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptane[c]-pyridine-10-carboxamido)benzoate

[0695] N-(3-chloro-4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0696] N-(3,4-Dichlorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0697] N-(3,4-dichlorophenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[0698] N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0699] N-(4,5-dichloro-2-fluorophenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0700] N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0701] N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0702] N-(3,4-Dichlorophenyl)-3,5-difluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[0703] N-(4-bromo-5-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0704] N-(5-bromo-4-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0705] N-(4-Bromo-3-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0706] N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0707] N-(3-Bromo-4-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[0708] N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0709] N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0710] 1-Bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0711] N-(4,5-dichloro-2-hydroxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0712] N-(3,4-dichlorophenyl)-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0713] N-(3-cyano-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0714] 1-Fluoro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged iminecycloheptane[c]pyridine-10-carboxamide

[0715] N-(3-bromo-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0716] N-(3-chloro-2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0717] 1-Fluoro-N-(3-Fluorophenyl)-6,7,8,9-Tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0718] 1-Fluoro-N-(3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[0719] 1-Fluoro-N-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[0720] N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[0721] N-(3,5-bis(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c-]pyridine-10-carboxamide

[0722] 1-Fluoro-N-(4-methyl-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0723] N-(2,3-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0724] N-(2,4-Difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0725] N-(4-cyano-3-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0726] N-(3-chloro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0727] N-(3-cyano-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgedimine cycloheptan[c]-pyridine-10-carboxamide

[0728] 1-Fluoro-N-(3,4,5-trichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0729] 1-Fluoro-N-(3-methyl-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0730] N-(4-Bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0731] N-(4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgedimine cycloheptan[c]pyridine-10-carboxamide

[0732] N-(3-Bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0733] 1-Fluoro-N-(3-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0734] N-(3-Bromo-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0735] N-(3,5-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0736] N-(5-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgedimine cycloheptan[c]-pyridine-10-carboxamide

[0737] 1-Fluoro-N-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0738] N-(4-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0739] N-(4-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0740] N-(3-chloro-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgedimine cycloheptan[c]-pyridine-10-carboxamide

[0741] N-(4-Acrylamido-3-chlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0742] N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0743] N-(4,5-dichloro-2-fluorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgedimine cyclohepta[b]-pyridine-10-carboxamide

[0744] N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptyl[b]pyridine-10-carboxamide

[0745] N-(4-(1H-pyrazol-1-yl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[0746] N-([1,1'-biphenyl]-3-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[0747] 1-Fluoro-N-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0748] 1-Fluoro-N-(4-(thiazolyl-4-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[0749] 1-Fluoro-N-(4-(4-methyloxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0750] 1-Fluoro-N-(4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0751] N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-2,5,6,7,8,9-hexahydro-1H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[0752] N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0753] N-([1,1'-biphenyl]-4-yl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptane[c]pyridine-10-carboxamide

[0754] N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[0755] N-(4,5-dichloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptamethrin[d]pyridazine-10-carboxamide

[0756] N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[d]pyridazine-10-carboxamide

[0757] 1,4-Dichloro-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0758] N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptyl[b]pyridine-10-carboxamide

[0759] N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptyl[b]pyridine-10-carboxamide

[0760] N-(3,4-Dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0761] N-(4-chloro-3-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0762] N-(4,5-dichloro-2-fluorophenyl)-1-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[c]pyridine-10-carboxamide

[0763] N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[d]pyrimidine-10-carboxamide

[0764] N-(3-chloro-4-(trifluoromethyl)phenyl)-9-(oxime)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0765] N-(3,4-Dichlorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0766] (±)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0767] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0768] (±)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[d]pyrimidine-10-carboxamide

[0769] (±)-N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0770] (±)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0771] (±)-N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0772] (±)-N-(4-bromo-3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0773] (±)-N-(3-chloro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptamethidine-10-carboxamide

[0774] (±)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0775] (±)-N-(3-bromo-4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0776] (±)-N-(3-bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0777] (±)-N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0778] (±)-N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0779] (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptamethrin-10-carboxamide

[0780] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0781] (±)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-[d]pyrimidine-10-carboxamide

[0782] (±)-N-(3,4-dichlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0783] (±)-N-(3,4-dichlorophenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0784] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide

[0785] (±)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0786] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0787] (±)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0788] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0789] (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0790] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[c]-pyridine-10-carboxamide

[0791] (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0792] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta-[c]pyridine-10-carboxamide

[0793] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0794] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0795] (±)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[d]pyrimidine-10-carboxamide

[0796] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0797] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0798] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0799] (±)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0800] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(oxime)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0801] (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0802] (±)-N-(4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0803] (±)-N-(3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0804] (±)-N-(5-chloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0805] (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0806] (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0807] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[0808] (±)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[0809] (±)-N-(3,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0810] (±)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0811] (±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-2-oxide

[0812] (±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-bridgediminecyclohepta[c]-pyridine-2-oxide

[0813] (±)-2-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0814] (±)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0815] (±)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0816] (±)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0817] (±)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0818] (±)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0819] (±)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta-[c]pyridine-10-carboxamide

[0820] (±)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0821] (±)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0822] (±)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0823] (±)-2-chloro-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo-[7] arunculene-10-carboxamide

[0824] (±)-2-cyano-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0825] (±)-2-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0826] (±)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0827] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0828] (±)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[0829] (±)-1-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0830] (±)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0831] (±)-N-(4,5-dichloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[0832] (±)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0833] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-benzo[7]annulen-10-carboxamide

[0834] tert-butyl((±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-bridged iminecycloheptane[c]pyridin-1-yl)carbamate

[0835] (±)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0836] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-benzo[7]annulen-10-carboxamide

[0837] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0838] (±)-N-(3,4-dichlorophenyl)-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-bridgediminecycloheptan[c]-pyridine-10-carboxamide

[0839] (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[0840] (±)-N-(4,5-dichloro-2-cyanophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0841] (±)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0842] (±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-2-oxide

[0843] (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0844] (±)-N-(4,5-dichloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0845] (±)-N-(3,4-dichlorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0846] (±)-N-(4,5-dichloro-2-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]-pyridine-10-carboxamide

[0847] (±)-3-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0848] (±)-3-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0849] (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0850] (±)-N-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[0851] (±)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[0852] (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0853] (±)-N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0854] (±)-N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0855] (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0856] (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0857] (±)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0858] (±)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0859] (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0860] (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0861] (±)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0862] (±)-N-(3-cyano-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0863] (±)-1-Fluoro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0864] (±)-N-(3-bromo-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0865] (±)-N-(3-chloro-2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0866] (±)-1-Fluoro-N-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0867] (±)-1-Fluoro-N-(3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[0868] (±)-1-Fluoro-N-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0869] (±)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]-pyridine-10-carboxamide

[0870] (±)-N-(3,5-bis(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0871] (±)-1-Fluoro-N-(4-methyl-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[c]pyridine-10-carboxamide

[0872] (±)-N-(2,3-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]-pyridine-10-carboxamide

[0873] (±)-N-(2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[0874] (±)-N-(4-cyano-3-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0875] (±)-N-(3-chloro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0876] (±)-N-(3-cyano-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0877] (±)-1-Fluoro-N-(3,4,5-trichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0878] (±)-1-Fluoro-N-(3-methyl-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0879] (±)-N-(4-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0880] (±)-N-(4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0881] (±)-N-(3-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0882] (±)-1-Fluoro-N-(3-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[c]pyridine-10-carboxamide

[0883] (±)-N-(3-bromo-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[c]pyridine-10-carboxamide

[0884] (±)-N-(3,5-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[0885] (±)-N-(5-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]-pyridine-10-carboxamide

[0886] (±)-1-Fluoro-N-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[c]pyridine-10-carboxamide

[0887] (±)-N-(4-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0888] (±)-N-(4-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]-pyridine-10-carboxamide

[0889] (±)-N-(3-chloro-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]-pyridine-10-carboxamide

[0890] (±)-N-(4-Acrylamido-3-chlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0891] (±)-N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0892] (±)-N-(4,5-dichloro-2-fluorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[0893] (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[0894] (±)-N-(4-(1H-pyrazol-1-yl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0895] (±)-N-([1,1'-biphenyl]-3-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]-pyridine-10-carboxamide

[0896] (±)-1-Fluoro-N-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[c]pyridine-10-carboxamide

[0897] (±)-1-Fluoro-N-(4-(thiazolyl-4-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[0898] (±)-1-Fluoro-N-(4-(4-methyloxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0899] (±)-1-Fluoro-N-(4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[0900] (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-2,5,6,7,8,9-hexahydro-1H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[0901] (±)-N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[c]pyridine-10-carboxamide

[0902] (±)-N-([1,1'-biphenyl]-4-yl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptane[c]pyridine-10-carboxamide

[0903] (±)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[0904] (±)-N-(4,5-dichloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptamethrin[d]-pyridazine-10-carboxamide

[0905] (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[d]pyridazine-10-carboxamide

[0906] (±)-1,4-Dichloro-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[d]pyridazine-10-carboxamide

[0907] (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[0908] (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[0909] (±)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[0910] (±)-N-(4-chloro-3-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0911] (±)-N-(3-cyano-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0912] (±)-1-Fluoro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0913] (±)-N-(3-bromo-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0914] (±)-N-(3-chloro-2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0915] (±)-1-Fluoro-N-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0916] (±)-1-Fluoro-N-(3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0917] (±)-1-Fluoro-N-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0918] (±)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]-pyridine-10-carboxamide

[0919] (±)-N-(3,5-bis(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0920] (±)-1-Fluoro-N-(4-methyl-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[c]pyridine-10-carboxamide

[0921] (±)-N-(2,3-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]-pyridine-10-carboxamide

[0922] (±)-N-(2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[0923] (±)-N-(4-cyano-3-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0924] (±)-N-(3-chloro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0925] (±)-N-(3-cyano-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]-pyridine-10-carboxamide

[0926] (±)-1-Fluoro-N-(3,4,5-trichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0927] (±)-1-Fluoro-N-(3-methyl-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0928] (±)-N-(4-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0929] (±)-N-(4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0930] (±)-N-(3-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0931] (±)-1-Fluoro-N-(3-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[c]pyridine-10-carboxamide

[0932] (±)-N-(3-bromo-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[c]pyridine-10-carboxamide

[0933] (±)-N-(3,5-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0934] (±)-N-(5-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0935] (±)-1-Fluoro-N-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0936] (±)-N-(4-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0937] (±)-N-(4-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]-pyridine-10-carboxamide

[0938] (±)-N-(3-chloro-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]-pyridine-10-carboxamide

[0939] (±)-N-(4-Acrylamido-3-chlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0940] (±)-N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0941] (±)-N-(4,5-dichloro-2-fluorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[0942] (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[0943] (±)-N-(4-(1H-pyrazol-1-yl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0944] (±)-N-([1,1'-biphenyl]-3-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]-pyridine-10-carboxamide

[0945] (±)-1-Fluoro-N-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[c]pyridine-10-carboxamide

[0946] (±)-1-Fluoro-N-(4-(thiazolyl-4-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[0947] (±)-1-Fluoro-N-(4-(4-methyloxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0948] (±)-1-Fluoro-N-(4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[0949] (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-2,5,6,7,8,9-hexahydro-1H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[0950] (±)-N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecyclohepta[c]pyridine-10-carboxamide

[0951] (±)-N-([1,1'-biphenyl]-4-yl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptane[c]pyridine-10-carboxamide

[0952] (±)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]-pyridine-10-carboxamide

[0953] (±)-N-(4,5-dichloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptamethrin[d]-pyridazine-10-carboxamide

[0954] (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[d]pyridazine-10-carboxamide

[0955] (±)-1,4-Dichloro-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[d]pyridazine-10-carboxamide

[0956] (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[0957] (±)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[0958] (±)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[0959] (±)-N-(4-chloro-3-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0960] (±)-N-(4,5-dichloro-2-fluorophenyl)-1-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0961] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-9-(oxime)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0962] cis-(±)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0963] trans-(±)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-[d]pyrimidine-10-carboxamide

[0964] (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-8-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0965] (±)-N-(4,5-dichloro-2-methylphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0966] (±)-N-(4,5-dichloro-2-methoxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[0967] (±)-1-Fluoro-N-(2-Fluoro-5-(trifluoromethyl)phenyl)-6,7,8,9-Tetrahydro-5H-5,8-bridgediminecyclohepta[c]pyridine-10-carboxamide

[0968] (±)-1-Fluoro-N-(2-Fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-Tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[0969] (±)-1-Fluoro-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0970] (5R,8S)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-[d]pyrimidine-10-carboxamide

[0971] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0972] (5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0973] (5R,8S)-N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0974] (5R,8S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0975] (5R,8S)-N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0976] (5R,8S)-N-(4-bromo-3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0977] (5R,8S)-N-(3-chloro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0978] (5R,8S)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[d]=pyrimidine-10-carboxamide

[0979] (5R,8S)-N-(3-bromo-4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0980] (5R,8S)-N-(3-bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-cycloheptane[d]pyrimidine-10-carboxamide

[0981] (5R,8S)-N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0982] (5R,8S)-N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0983] (6S,9R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptamethrin-10-carboxamide

[0984] (6S,9R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptamethrin-10-carboxamide

[0985] (5R,8S)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0986] (5R,8S)-N-(3,4-dichlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-[d]pyrimidine-10-carboxamide

[0987] (5R,8S)-N-(3,4-dichlorophenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0988] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0989] (5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0990] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0991] (5R,8S)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[0992] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[0993] (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[0994] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[0995] (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[0996] (6S,9R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta-[c]pyridine-10-carboxamide

[0997] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-[d]pyrimidine-10-carboxamide

[0998] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-[d]pyrimidine-10-carboxamide

[0999] (5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta-[d]pyrimidine-10-carboxamide

[1000] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide

[1001] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide

[1002] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide

[1003] (5R,8S)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1004] (5R,8S,E)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(oxime)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1005] (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1006] (5R,8S)-N-(4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1007] (5R,8S)-N-(3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1008] (5R,8S)-N-(5-chloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1009] (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1010] (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1011] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1012] (5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1013] (5R,8S)-N-(3,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1014] (5R,8S)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1015] (5R,8S)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta-[c]pyridine-2-oxide

[1016] (6S,9R)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]-pyridine-2-oxide

[1017] (5R,8S)-2-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1018] (6S,9R)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1019] (6S,9R)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1020] (5R,8S)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1021] (5R,8S)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1022] (5R,8S)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1023] (5R,8S)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1024] (6S,9R)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c-]pyridine-10-carboxamide

[1025] (6S,9R)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1026] (5R,8S)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1027] (5R,8S)-2-chloro-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-benzo[7]annulen-10-carboxamide

[1028] (5R,8S)-2-cyano-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1029] (5R,8S)-2-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1030] (5R,8S)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1031] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-benzo[7]annulen-10-carboxamide

[1032] (6S,9R)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta-[c]pyridine-10-carboxamide

[1033] (5R,8S)-1-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta-[c]pyridine-10-carboxamide

[1034] (5R,8S)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1035] (5R,8S)-N-(4,5-dichloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1036] (5R,8S)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1037] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-benzo[7]annulen-10-carboxamide

[1038] tert-butyl((6S,9R)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-bridged iminecycloheptane[c]pyridin-1-yl)carbamate

[1039] (5R,8S)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1040] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[1041] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1042] (6S,9R)-N-(3,4-dichlorophenyl)-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-bridgediminecycloheptan[c]-pyridine-10-carboxamide

[1043] (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[1044] (6S,9R)-N-(4,5-dichloro-2-cyanophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1045] (6S,9R)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1046] (5R,8S)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-2-oxide

[1047] (6S,9R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1048] (6S,9R)-N-(4,5-dichloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1049] (6S,9R)-N-(3,4-dichlorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1050] (5R,8S)-N-(4,5-dichloro-2-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1051] (6S,9R)-3-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1052] (6S,9R)-3-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1053] (5R,8S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1054] (5R,8S)-N-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[1055] (6S,9R)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1056] (6S,9R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1057] (5S,8R)-N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1058] (5R,8S)-N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1059] (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1060] (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1061] (5R,8S)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1062] (5S,8R)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1063] (6S,9R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1064] (6R,9S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1065] (5R,8S,9S)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1066] (5S,8R)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1067] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1068] (5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1069] (5S,8R)-N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1070] (5S,8R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1071] (5S,8R)-N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1072] (5S,8R)-N-(4-bromo-3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1073] (5S,8R)-N-(3-chloro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1074] (5S,8R)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1075] (5S,8R)-N-(3-bromo-4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1076] (5S,8R)-N-(3-bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1077] (5S,8R)-N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide

[1078] (5S,8R)-N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1079] (6R,9S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptamethrin-10-carboxamide

[1080] (6R,9S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptamethrin-10-carboxamide

[1081] (5S,8R)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1082] (5S,8R)-N-(3,4-dichlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-[d]pyrimidine-10-carboxamide

[1083] (5S,8R)-N-(3,4-dichlorophenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-[d]pyrimidine-10-carboxamide

[1084] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1085] (5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1086] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1087] (5S,8R)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d-]pyrimidine-10-carboxamide

[1088] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1089] (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7] arbutin-10-carboxamide

[1090] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1091] (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1092] (6R,9S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta-[c]pyridine-10-carboxamide

[1093] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-[d]pyrimidine-10-carboxamide

[1094] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-[d]pyrimidine-10-carboxamide

[1095] (5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta-[d]pyrimidine-10-carboxamide

[1096] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide

[1097] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptapyrimidine-10-carboxamide

[1098] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1099] (5S,8R)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1100] (5S,8R,E)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(oxime)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1101] (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1102] (5S,8R)-N-(4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1103] (5S,8R)-N-(3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1104] (5S,8R)-N-(5-chloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1105] (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1106] (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1107] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1108] (5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1109] (5S,8R)-N-(3,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1110] (5S,8R)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1111] (5S,8R)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta-[c]pyridine-2-oxide

[1112] (6R,9S)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta-[c]pyridine-2-oxide

[1113] (5S,8R)-2-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1114] (6R,9S)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1115] (6R,9S)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1116] (5S,8R)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1117] (5S,8R)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1118] (5S,8R)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1119] (5S,8R)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1120] (6R,9S)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta-[c]pyridine-10-carboxamide

[1121] (6R,9S)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta-[c]pyridine-10-carboxamide

[1122] (5S,8R)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1123] (5S,8R)-2-chloro-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-benzo[7]annulen-10-carboxamide

[1124] (5S,8R)-2-cyano-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo-[7] arunculene-10-carboxamide

[1125] (5S,8R)-2-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1126] (5S,8R)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1127] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-benzo[7]annulen-10-carboxamide

[1128] (6R,9S)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1129] (5S,8R)-1-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1130] (5S,8R)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1131] (5S,8R)-N-(4,5-dichloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1132] (5S,8R)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1133] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-benzo[7]annulen-10-carboxamide

[1134] tert-butyl((6R,9S)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-bridged iminecycloheptane[c]pyridin-1-yl)carbamate

[1135] (5S,8R)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]-arunne-10-carboxamide

[1136] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-benzo[7]annulen-10-carboxamide

[1137] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1138] (6R,9S)-N-(3,4-dichlorophenyl)-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta-[c]pyridine-10-carboxamide

[1139] (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[1140] (6R,9S)-N-(4,5-dichloro-2-cyanophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1141] (6R,9S)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta-[c]pyridine-10-carboxamide

[1142] (5S,8R)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-cyclohepta-[c]-pyridine-2-oxide

[1143] (6R,9S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1144] (6R,9S)-N-(4,5-dichloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1145] (6R,9S)-N-(3,4-dichlorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1146] (5S,8R)-N-(4,5-dichloro-2-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1147] (6R,9S)-3-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta-[c]pyridine-10-carboxamide

[1148] (6R,9S)-3-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1149] (5S,8R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1150] (5S,8R)-N-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[1151] (6R,9S)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1152] (6R,9S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1153] (5R,8S)-N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1154] (5S,8R)-N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1155] (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1156] (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1157] (5S,8R)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1158] (5R,8S)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1159] (6R,9S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1160] (6S,9R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1161] (5S,8R,9R)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1162] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-8-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1163] (5R,8S)-N-(4,5-dichloro-2-methylphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1164] (5R,8S)-N-(4,5-dichloro-2-methoxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1165] (5R,8S)-1-fluoro-N-(2-fluoro-5-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1166] (5R,8S)-1-fluoro-N-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1167] (5R,8S)-1-fluoro-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1168] 2-Chloro-4-((5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carbamate) methyl benzoate

[1169] 2-Chloro-5-((5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carbamate) methyl benzoate

[1170] (5R,8S)-N-(3-chloro-4-(trifluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1171] 2-Chloro-4-fluoro-5-((5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carbamate) methyl benzoate

[1172] (5R,8S)-N-(4-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1173] (6S,9R)-N-(3-chloro-4-(difluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1174] (6S,9R)-N-(3-chloro-4-(trifluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1175] (6S,9R)-N-(4-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1176] 2-Chloro-4-((6S,9R)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]-pyridine-10-carbamate) methyl benzoate

[1177] 2-Chloro-5-((6S,9R)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]-pyridine-10-carbamate) methyl benzoate

[1178] 2-Chloro-4-fluoro-5-((6S,9R)-3-oxo-3,5,6,7,8,9-hexahydro-2H--6,9-diaminocyclo-heptyl[c]pyridine-10-carbamate)methyl benzoate

[1179] (5R,8S)-N-(3-chloro-4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1180] (5R,8S,9S)-N-(3,4-dichlorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1181] (6S,9R)-N-(3,4-dichlorophenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1182] (6S,9R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1183] (6S,9R)-N-(4,5-dichloro-2-fluorophenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1184] (6S,9R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1185] (6S,9R)-N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1186] (5S,6S,9R)-N-(3,4-dichlorophenyl)-3,5-difluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1187] (6S,9R)-N-(4-bromo-5-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1188] (6S,9R)-N-(5-bromo-4-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1189] (6S,9R)-N-(4-bromo-3-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1190] (6S,9R)-N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1191] (6S,9R)-N-(3-bromo-4-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1192] (6S,9R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1193] (6R,9S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1194] (5R,8S)-1-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1195] (5R,8S)-N-(4,5-dichloro-2-hydroxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1196] (6S,9R)-N-(3,4-dichlorophenyl)-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1197] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-8-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1198] (5S,8R)-N-(4,5-dichloro-2-methylphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1199] (5S,8R)-N-(4,5-dichloro-2-methoxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[1200] (5S,8R)-1-fluoro-N-(2-fluoro-5-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1201] (5S,8R)-1-fluoro-N-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1202] (5S,8R)-1-fluoro-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1203] 2-Chloro-4-((5S,8R)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carbamate) methyl benzoate

[1204] 2-Chloro-5-((5S,8R)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carbamate) methyl benzoate

[1205] (5S,8R)-N-(3-chloro-4-(trifluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1206] 2-Chloro-4-fluoro-5-((5S,8R)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carbamate) methyl benzoate

[1207] (5S,8R)-N-(4-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1208] (6R,9S)-N-(3-chloro-4-(difluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1209] (6R,9S)-N-(3-chloro-4-(trifluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1210] (6R,9S)-N-(4-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1211] 2-Chloro-4-((6R,9S)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]-pyridine-10-carbamate) methyl benzoate

[1212] Methyl 2-chloro-5-((6R,9S)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]-pyridine-10-carbamate)benzoate

[1213] 2-Chloro-4-fluoro-5-((6R,9S)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptane[c]pyridine-10-carbamate) methyl benzoate

[1214] (5S,8R)-N-(3-chloro-4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1215] (5S,8R,9S)-N-(3,4-dichlorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1216] (6R,9S)-N-(3,4-dichlorophenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1217] (6R,9S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1218] (6R,9S)-N-(4,5-dichloro-2-fluorophenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1219] (6R,9S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1220] (6R,9S)-N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1221] (5S,6R,9S)-N-(3,4-dichlorophenyl)-3,5-difluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1222] (6R,9S)-N-(4-bromo-5-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1223] (6R,9S)-N-(5-bromo-4-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1224] (6R,9S)-N-(4-bromo-3-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1225] (6R,9S)-N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1226] (6R,9S)-N-(3-bromo-4-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1227] (6R,9S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1228] (5S,8R)-1-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1229] (5S,8R)-N-(4,5-dichloro-2-hydroxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1230] (6R,9S)-N-(3,4-dichlorophenyl)-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1231] (5R,8S)-N-(3-cyano-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1232] (5R,8S)-1-fluoro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[1233] (5R,8S)-N-(3-bromo-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1234] (5R,8S)-N-(3-chloro-2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1235] (5R,8S)-1-fluoro-N-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1236] (5R,8S)-1-fluoro-N-(3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1237] (5R,8S)-1-fluoro-N-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1238] (5R,8S)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[1239] (5R,8S)-N-(3,5-bis(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1240] (5R,8S)-1-fluoro-N-(4-methyl-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1241] (5R,8S)-N-(2,3-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1242] (5R,8S)-N-(2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1243] (5R,8S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1244] (5R,8S)-N-(3-chloro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1245] (5R,8S)-N-(3-cyano-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1246] (5R,8S)-1-fluoro-N-(3,4,5-trichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptan[c]pyridine-10-carboxamide

[1247] (5R,8S)-1-fluoro-N-(3-methyl-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1248] (5R,8S)-N-(4-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1249] (5R,8S)-N-(4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1250] (5R,8S)-N-(3-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1251] (5R,8S)-1-fluoro-N-(3-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1252] (5R,8S)-N-(3-bromo-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1253] (5R,8S)-N-(3,5-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1254] (5R,8S)-N-(5-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1255] (5R,8S)-1-fluoro-N-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1256] (5R,8S)-N-(4-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1257] (5R,8S)-N-(4-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1258] (5R,8S)-N-(3-chloro-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[1259] (5R,8S)-N-(4-acrylamido-3-chlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[1260] (5R,8S)-N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1261] (5R,8S)-N-(4,5-dichloro-2-fluorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[1262] (5R,8S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[1263] (5R,8S)-N-(4-(1H-pyrazol-1-yl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1264] (5R,8S)-N-([1,1'-biphenyl]-3-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[1265] (5R,8S)-1-fluoro-N-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c-]pyridine-10-carboxamide

[1266] (5R,8S)-1-fluoro-N-(4-(thiazolyl-4-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[1267] (5R,8S)-1-fluoro-N-(4-(4-methyloxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[1268] (5R,8S)-1-fluoro-N-(4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1269] (5R,8S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-2,5,6,7,8,9-hexahydro-1H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[1270] (5R,8S)-N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1271] (6S,9R)-N-([1,1'-biphenyl]-4-yl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptane[c]pyridine-10-carboxamide

[1272] (5R,8S)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[1273] (5R,8S)-N-(4,5-dichloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-cycloheptane[d]pyridazine-10-carboxamide

[1274] (5R,8S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-cycloheptane[d]pyridazine-10-carboxamide

[1275] (5R,8S)-1,4-dichloro-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-cycloheptane[d]pyridazine-10-carboxamide

[1276] (5R,8S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[1277] (5S,8R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[1278] (6R,9S)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1279] (5R,8S)-N-(4-chloro-3-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1280] (5S,8R)-N-(3-cyano-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1281] (5S,8R)-1-fluoro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[1282] (5S,8R)-N-(3-bromo-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1283] (5S,8R)-N-(3-chloro-2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1284] (5S,8R)-1-fluoro-N-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1285] (5S,8R)-1-fluoro-N-(3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1286] (5S,8R)-1-fluoro-N-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1287] (5S,8R)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[1288] (5S,8R)-N-(3,5-bis(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1289] (5S,8R)-1-fluoro-N-(4-methyl-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1290] (5S,8R)-N-(2,3-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]-pyridine-10-carboxamide

[1291] (5S,8R)-N-(2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1292] (5S,8R)-N-(4-cyano-3-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1293] (5S,8R)-N-(3-chloro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1294] (5S,8R)-N-(3-cyano-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1295] (5S,8R)-1-fluoro-N-(3,4,5-trichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1296] (5S,8R)-1-fluoro-N-(3-methyl-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1297] (5S,8R)-N-(4-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1298] (5S,8R)-N-(4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1299] (5S,8R)-N-(3-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1300] (5S,8R)-1-fluoro-N-(3-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1301] (5S,8R)-N-(3-bromo-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1302] (5S,8R)-N-(3,5-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1303] (5S,8R)-N-(5-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1304] (5S,8R)-1-fluoro-N-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1305] (5S,8R)-N-(4-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]-pyridine-10-carboxamide

[1306] (5S,8R)-N-(4-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1307] (5S,8R)-N-(3-chloro-4-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1308] (5S,8R)-N-(4-acrylamido-3-chlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminecycloheptane[c]pyridine-10-carboxamide

[1309] (5S,8R)-N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1310] (5S,8R)-N-(4,5-dichloro-2-fluorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[1311] (5S,8R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[1312] (5S,8R)-N-(4-(1H-pyrazol-1-yl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1313] (5S,8R)-N-([1,1'-biphenyl]-3-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[1314] (5S,8R)-1-fluoro-N-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1315] (5S,8R)-1-fluoro-N-(4-(thiazolyl-4-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1316] (5S,8R)-1-fluoro-N-(4-(4-methyloxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[1317] (5S,8R)-1-fluoro-N-(4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1318] (5S,8R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-2,5,6,7,8,9-hexahydro-1H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[1319] (5S,8R)-N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1320] (6R,9S)-N-([1,1'-biphenyl]-4-yl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptane[c]pyridine-10-carboxamide

[1321] (5S,8R)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine-10-carboxamide

[1322] (5S,8R)-N-(4,5-dichloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-cycloheptane[d]pyridazine-10-carboxamide

[1323] (5S,8R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-cycloheptane[d]pyridazine-10-carboxamide

[1324] (5S,8R)-1,4-dichloro-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgedimine-cycloheptane[d]pyridazine-10-carboxamide

[1325] (5S,8R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[1326] (5S,8R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine-10-carboxamide

[1327] (6S,9R)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1328] (5S,8R)-N-(4-chloro-3-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1329] (5R,8S)-N-(4,5-dichloro-2-fluorophenyl)-1-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1330] (5S,8R)-N-(4,5-dichloro-2-fluorophenyl)-1-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1331] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1332] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1333] (5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1334] (5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1335] (5S,8R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1336] (5R,8S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1337] (5R,8S)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxamide

[1338] (5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1339] (5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxamide

[1340] (5R,8S,9S)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1341] (5R,8S,E)-N-(3-chloro-4-(trifluoromethyl)phenyl)-9-(oxime)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1342] (5S,8R,E)-N-(3-chloro-4-(trifluoromethyl)phenyl)-9-(oxime)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-bridged imine cycloheptamethrin-10-carboxamide

[1343] (5S,8R)-N-(4,5-dichloro-2-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1344] (5R,8S)-N-(4,5-dichloro-2-cyanophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine-10-carboxamide

[1345] 2-Chloro-4-((6S,9R)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptane[c]pyridine-10-carbamate) methyl benzoate

[1346] Methyl 2-chloro-4-((6R,9S)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-bridged imine cycloheptane[c]pyridine-10-carbamoyl)benzoate.

[1347] In a preferred embodiment, as described in the appended examples, the compound according to the invention or the compound for use according to the invention shows an IC50 >500 nM and <5 μM in the detection of human GPR65 cyclic adenosine monophosphate (cAMP) homogeneous time-resolved fluorescence (HTRF) antagonist. 50 In a preferred embodiment, the compound is selected from those marked "high" or "medium" in Table 1.

[1348] In a more preferred embodiment, as described in the appended examples, the compound according to the invention or the compound for use according to the invention shows an IC50 of <500 nM in the human GPR65 cAMP HTRF antagonist assay. 50 In a preferred embodiment, the compound is selected from those marked "high" in Table 1.

[1349] Pharmaceutical Composition

[1350] For the purposes described herein, the compounds, or physiologically acceptable salts, esters, or other physiologically functional derivatives thereof, may be prepared into pharmaceutical formulations comprising the compounds, or physiologically acceptable salts, esters, or other physiologically functional derivatives thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents used therein, and optionally other therapeutic and / or prophylactic ingredients. One or more carriers must be acceptable in the sense of compatibility with other components of the formulation and harmlessness to the recipient. The pharmaceutical compositions may be used for human or animal purposes in human medicine and veterinary medicine.

[1351] Examples of such suitable excipients for the various forms of pharmaceutical compositions described herein can be found in the "Handbook of Pharmaceutical Excipients," 2nd edition, (1994), edited by A. Wade and P.J. Weller. A carrier, or each carrier if more than one is present, must be acceptable in the sense of compatibility with other components of the formulation and harmlessness to the recipient.

[1352] Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical industry and described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Company (ARGennaro, ed., 1985).

[1353] Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, and sorbitol. Examples of suitable diluents include ethanol, glycerol, and water.

[1354] The choice of drug carrier, excipient, or diluent can be made based on the intended route of administration and standard pharmaceutical practice. A pharmaceutical composition may include any suitable one or more binders, lubricants, suspending agents, coating agents, solubilizers, buffers, flavoring agents, surfactants, thickeners, preservatives (including antioxidants), etc., and substances included to make the formulation isotonic with the blood of the intended recipient as a carrier, excipient, or diluent. Alternatively, a pharmaceutical composition may include, in addition to a carrier, excipient, or diluent, any suitable one or more binders, lubricants, suspending agents, coating agents, solubilizers, buffers, flavoring agents, surfactants, thickeners, preservatives (including antioxidants), etc., and substances included to make the formulation isotonic with the blood of the intended recipient.

[1355] Examples of suitable binders include starch, gelatin, natural sugars (such as glucose, anhydrous lactose, free-flowing lactose, β-lactose, and corn flavoring), natural and synthetic gums (such as gum arabic, tragacanth, or sodium alginate), carboxymethyl cellulose, and polyethylene glycol.

[1356] Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride.

[1357] Preservatives, stabilizers, dyes, and even flavorings may be added to pharmaceutical compositions. Examples of preservatives include sodium benzoate, esters of sorbic acid and p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[1358] Pharmaceutical formulations include those suitable for oral, topical (including transdermal, oral, and sublingual), rectal or parenteral (including subcutaneous, intradermal, intramuscular, and intravenous), and nasal and pulmonary (e.g., via inhalation) administration. Where appropriate, formulations may be conveniently provided in discrete dose units and may be prepared by any method known in the pharmaceutical field. All methods involve the step of combining the active compound with a liquid carrier and / or a finely chopped solid carrier, and then, if necessary, shaping the product into the desired formulation.

[1359] Pharmaceutical formulations suitable for oral administration (where the carrier is solid) are preferably provided in the form of unit-dose formulations (such as pills, capsules, or tablets, each containing a predetermined amount of active compound). Tablets can be obtained by compression or molding, optionally with one or more adjuvants. Compressed tablets can be prepared by compressing an active compound in free-flowing form (such as powder or granules) optionally with a binder, lubricant, inert diluent, surfactant, or dispersant in a suitable machine. Molded tablets can be obtained by molding an active compound with an inert liquid diluent. Tablets can optionally be coated, and if not coated, can optionally be scored. Capsules can be prepared by filling a capsule shell with the active compound alone or with a mixture of one or more adjuvants, and then sealing it in the usual manner. Flat capsules are similar to capsules, wherein the active compound and any one or more adjuvants are sealed in a rice paper sleeve. The active compound can also be formulated as dispersible granules, which, for example, can be suspended in water or sprinkled on food before administration. Capsules can be packaged in, for example, sachets. Formulations suitable for oral administration with a liquid carrier may be provided as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water emulsions.

[1360] Formulations intended for oral administration include controlled-release dosage forms (e.g., tablets), in which the active compound is formulated in a suitable controlled-release matrix or coated with a suitable controlled-release membrane. Such formulations are particularly convenient for prophylactic use.

[1361] Pharmaceutical formulations suitable for rectal administration (where the carrier is solid) are preferably provided in the form of unit-dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be readily formed by mixing the active compound with one or more softened or melted carriers, then cooling and molding in a mold. Pharmaceutical formulations suitable for parenteral administration include sterile solutions or suspensions of the active compound in aqueous or oily carriers.

[1362] Injectable formulations are suitable for bolus or continuous infusion. These formulations are conveniently provided in single-dose or multi-dose containers, which are then sealed after introduction until use. Alternatively, the active compound may be in powder form, reconstituted with a suitable carrier such as sterile, pyrogen-free water prior to use.

[1363] The active compound can also be formulated into a long-acting depot preparation, which can be administered by intramuscular injection or implantation (e.g., subcutaneous or intramuscular). Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion exchange resins. Such long-acting preparations are particularly convenient for prophylactic use.

[1364] A formulation suitable for pulmonary administration via the buccal space is provided, enabling the delivery of particles containing the active compound and ideally ranging in diameter from 0.5 micrometers to 7 micrometers into the recipient's bronchial tree.

[1365] As one possibility, such formulations may be in the form of fine powders, which can be readily provided in a permeable capsule (e.g., a suitable gelatin capsule) for use in an inhalation device, or in the form of a self-propelled formulation comprising an active compound, a suitable liquid or gaseous propellant, and optional other components such as surfactants and / or solid diluents. Suitable liquid propellants include propane and chlorofluorocarbons, and suitable gaseous propellants include carbon dioxide. Self-propelled formulations in which the active compound is dispensed in the form of droplets of solution or suspension may also be used.

[1366] Such self-propelled formulations are similar to those known in the art and can be prepared by established procedures. Suitably, the self-propelled formulation is provided in a container equipped with a manually operable or automatically operated valve having the desired spray characteristics; advantageously, the valve is metering, thereby delivering a fixed volume, for example, 25 microliters to 100 microliters, with each operation of the valve.

[1367] As another possibility, the active compound may be in the form of a solution or suspension for use in a sprayer or atomizer, thereby employing accelerated airflow or ultrasonic agitation to produce a fine droplet mist for inhalation.

[1368] Suitable formulations for nasal administration include those substantially similar to those described for pulmonary administration. When dispensing such formulations, they should ideally have a particle size in the range of 10 to 200 micrometers to allow them to remain in the nasal cavity; this can be achieved by appropriately using powders of suitable particle size or selecting a suitable valve. Other suitable formulations include: coarse powders in the range of 20 to 500 micrometers for rapid inhalation administration through the nostrils from a container near the nose; and nasal drops comprising an aqueous or oily solution or suspension of the active compound at a concentration of 0.2% w / v to 5% w / v.

[1369] 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 can be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Aqueous carriers include water, alcohol / aqueous solutions, emulsions, or suspensions, including physiological saline and buffer media. Parenteral carriers include sodium chloride solution, Ringer's glucose, glucose and sodium chloride, sodium lactate Ringer's injection, or fixed oil. Preservatives and other additives, such as antimicrobial agents, antioxidants, chelating agents, inert gases, etc., may also be present.

[1370] Preparations suitable for topical application may be provided in the form of gels, creams, or ointments, for example. Such preparations may be applied to wounds or ulcers by applying the preparation directly to the surface of the wound or ulcer or by placing it on a suitable support (such as a bandage, gauze, mesh, etc.) and then applying it to cover the area to be treated.

[1371] Liquid or powder formulations are also available, which can be sprayed or applied directly to the treatment site, such as a wound or ulcer. Alternatively, the formulation can be sprayed or applied onto a carrier such as a bandage, gauze, or mesh before being applied to the treatment site.

[1372] According to another aspect of the present invention, a method for preparing the above-mentioned pharmaceutical composition or veterinary drug composition is provided, the method comprising combining one or more active compounds with a carrier, for example by mixing.

[1373] Typically, the above-mentioned formulations are prepared by uniformly and closely binding the active agent with a liquid carrier and / or a finely chopped solid carrier, and then shaping the product if necessary. This invention extends to methods for preparing pharmaceutical compositions comprising combining or integrating the compounds described herein with pharmaceutically or veterinarily acceptable carriers or excipients.

[1374] Salt / Ester

[1375] The compounds of the present invention can exist in the form of salts or esters, particularly in the form of pharmaceutically and veterinarily acceptable salts or esters.

[1376] Pharmaceutically acceptable salts of the compounds of the present invention include suitable acid addition salts or basic salts thereof. A review of suitable pharmaceutical salts can be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed from, for example, the following acids: strong inorganic acids, such as mineral acids, such as hydrohalic acids (e.g., hydrochloric acid, hydrobromic acid, and hydroiodic acid), sulfuric acid, phosphoric acid, sulfates, hydrogen sulfates, hemisulfates, thiocyanates, persulfates, and sulfonic acids; strong organic carboxylic acids, such as unsubstituted or substituted (e.g., halogenated) alkane carboxylic acids having 1 to 4 carbon atoms, such as acetic acid; saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or tetraphthalic acid; hydroxycarboxylic acids, such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid; amino acids, such as aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids, such as unsubstituted or substituted (e.g., halogenated) (C1-C4) alkyl sulfonic acids, or aryl sulfonic acids, such as methanesulfonic acid or p-toluenesulfonic acid. Salts that are pharmaceutically and veterinarily unacceptable as intermediates may still be valuable.

[1377] Preferred salts include, for example, acetates, trifluoroacetates, lactates, gluconates, citrates, tartrates, maleates, malates, pantothenates, adipates, alginates, aspartates, benzoates, butates, digluconates, cyclopentanoates, glucono-p-gluconates, glyceryl phosphates, oxalates, heptaates, hexanoates, fumarates, nicotinates, palmoates, pectinates, 3-phenylpropionates, picrates, neopentanoates, propionates, tartrates, lacturonates, pivotates, camphorates, undecanoates, and succinates; organic sulfonates, such as methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, camphorsulfonates, 2-naphthalenesulfonates, benzenesulfonates, p-chlorobenzenesulfonates, and p-toluenesulfonates; and inorganic acid salts, such as hydrochlorides, hydrobromates, hydroiodates, sulfates, hydrogen sulfates, hemisulfates, thiocyanates, persulfates, phosphates, and sulfonates.

[1378] Esters are formed based on the functional group of esterification by using organic acids or alcohols / hydroxides. Organic acids include carboxylic acids, such as unsubstituted or substituted (e.g., halogenated) alkane carboxylic acids having 1 to 12 carbon atoms (e.g., acetic acid); saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or tetraphthalic acid; hydroxycarboxylic acids, such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid; amino acids, such as aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids, such as unsubstituted or substituted (e.g., halogenated) (C1-C4) alkyl sulfonic acids or aryl sulfonic acids, such as methanesulfonic acid or p-toluenesulfonic acid. Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and aluminum hydroxide. Alcohols include unsubstituted or substituted (e.g., halogenated) alkane alcohols having 1 to 12 carbon atoms.

[1379] Enantiomers / Tautomers

[1380] In all aspects discussed above, this invention (appropriately) includes all enantiomers, diastereomers, and tautomers of the compounds of this invention. Those skilled in the art will recognize compounds exhibiting optical activity (one or more chiral carbon atoms) or tautomerism. The corresponding enantiomers and / or tautomers can be isolated / prepared using methods known in the art.

[1381] Enantiomers are characterized by the absolute configuration of their chiral centers and are represented according to the R- and S-ordering rules of Cahn, Ingold, and Prelog. This convention is well known in the art (e.g., see 'Advanced Organic Chemistry', 3). rd edition, ed. March, J., John Wiley and Sons, New York, 1985).

[1382] The compounds of the present invention, including chiral centers, can be used as racemic mixtures, mixtures rich in enantiomers, or racemic mixtures can be separated using known techniques so that individual enantiomers can be used alone.

[1383] Stereoisomers and Geometric Isomers

[1384] Some compounds of the present invention may exist in stereoisomers and / or geometric isomers; for example, they may have one or more asymmetric centers and / or geometric centers, and thus may exist in two or more stereoisomers and / or geometric isomers. The present invention covers the use of all individual stereoisomers and geometric isomers of those compounds, as well as mixtures thereof. The terms used in the claims include these forms, provided that said forms retain suitable functional activity (although not necessarily to the same degree).

[1385] This invention also includes all suitable isotopic variations of the compound or its pharmaceutically acceptable salt. An isotopic variation of the compound or its pharmaceutically acceptable salt is defined as a compound or its pharmaceutically acceptable salt in which at least one atom is replaced by an atom having the same atomic number but a different atomic weight than those commonly found in nature. Examples of isotopes that can be introduced into drugs and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, [list of isotopes]. 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. Certain isotopic variants of drugs and their pharmaceutically acceptable salts are useful in studies of drug and / or basal tissue distribution, such as those involving the introduction of radioactive isotopes (e.g., ...). 3 H or 14 C) isotopic variations. For ease of preparation and detection, tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred. Furthermore, isotopes (e.g., deuterium, i.e., 2 Substitution of H) can provide a degree of therapeutic advantage due to its greater metabolic stability, such as a prolonged half-life in vivo or a reduced dose requirement, and may therefore be preferred in some cases. For example, the present invention comprises compounds of general formula (I) in which all hydrogen atoms are substituted with deuterium atoms. Typically, isotopic variants of the drugs of the present invention and pharmaceutically acceptable salts thereof can be prepared by conventional methods using appropriate isotopic variants of suitable drugs.

[1386] Resistive isomers

[1387] Some compounds of this invention can exist as trans-restricted isomers. Trans-restricted isomers are stereoisomers resulting from hindered rotation around a single bond, wherein a sufficiently high rotational barrier is created due to energy differences caused by steric strain or other contributing factors, thereby isolating individual conformational isomers. This invention includes all such trans-restricted isomers. This invention also covers rotational isomers of compounds.

[1388] Prodrug

[1389] The present invention also includes compounds of the invention in prodrug form, i.e., compounds covalently bonded to an active parent drug released in vivo. Such prodrugs are typically compounds of the invention in which one or more suitable groups are modified such that the modification is reversible upon administration to a human or mammalian subject. Reversal is typically carried out by enzymes naturally present in such subjects, but it is also possible to revert in vivo by administering a second drug with such a prodrug. Examples of such modifications include esters (e.g., any of those described above), wherein reversibility can be achieved by esterases or the like. Other such systems are well known to those skilled in the art.

[1390] solvates

[1391] The invention also includes the compounds of the invention in solvate form. The terms used in the claims include these forms. Preferably, the solvate is an hydrate.

[1392] joint

[1393] Another aspect of the invention relates to combinations comprising the compounds described herein and one or more additional active agents. In a particularly preferred embodiment, one or more compounds of the invention are administered in combination with one or more additional active agents (e.g., commercially available pharmaceuticals). In this case, the compounds of the invention may be administered sequentially, simultaneously, or sequentially with one or more additional active agents.

[1394] When administered in combination, drugs are generally more effective. In particular, combination therapy is advantageous to avoid overlap in major toxicities, mechanisms of action, and resistance mechanisms. Furthermore, it is desirable to administer the maximum amount of drug at the maximum tolerated dose with the shortest possible time interval between such doses. A major advantage of combining with chemotherapy drugs is that, through biochemical interactions, an additive effect or potential synergistic effect can be promoted, and the development of drug resistance can also be reduced.

[1395] By studying the activity of test compounds with drugs known or suspected of playing an important role in the treatment of specific conditions, beneficial combinations can be indicated. This method can also be used to determine the order of drug administration—that is, before, simultaneously with, or after administration. This timing arrangement can be characteristic of all the active agents identified herein.

[1396] In the case of cancer, the compounds of the present invention can be used in combination with immunotherapies (such as cancer vaccines) and / or other immunomodulators (such as drugs that block PD1 / PDL-1 interaction). Therefore, in a preferred embodiment, the additional active agent is an immunotherapeutic agent, more preferably a cancer immunotherapeutic agent. "Immunotherapeutic agent" refers to a treatment that utilizes the subject's own immune system to fight diseases such as cancer. For other conditions, the compounds of the present invention can be used in combination agents that block or reduce inflammation (such as antibodies targeting pro-inflammatory cytokines).

[1397] Polymorphs

[1398] This invention also relates to compounds of this invention in various crystalline, polymorphic, and (anhydrous) hydrated forms. Methods in the pharmaceutical field have been well established that compounds in any of these forms can be isolated by slightly altering the purification methods and / or the separation methods of the solvents used to synthesize such compounds.

[1399] Application method

[1400] The pharmaceutical compositions of the present invention are suitable for rectal, nasal, bronchial, topical (including oral and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intra-arterial, and intradermal), intraperitoneal, or intrathecal administration. Preferred formulations are those for oral administration. The formulations can be conveniently provided in unit dosage forms (i.e., in the form of discrete portions comprising unit doses) or in unit doses of multiple units or subunits. As examples, the formulations can be in the form of tablets and sustained-release capsules and can be prepared by any method known in the pharmaceutical field.

[1401] The oral formulations of the present invention may be provided in the following forms: discrete units containing a predetermined amount of active ingredient, such as capsules, pills, drops, sachets, pellets, or tablets; powders or granules; solutions, emulsions, or suspensions of the active ingredient in aqueous or non-aqueous liquids; or oil-in-water emulsions or water-in-oil emulsions; or pills, etc. Preferably, these compositions comprise 1 mg to 250 mg of active ingredient per dose, and more preferably 10 mg to 100 mg of active ingredient.

[1402] For oral compositions (e.g., tablets and capsules), the term "acceptable carrier" includes excipients such as common excipients, such as binders like syrups, gum arabic, gelatin, sorbitol, tragacanth gum, polyvinylpyrrolidone (polyvinyl ether), 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 alginate; and lubricants such as magnesium stearate, sodium stearate and other metal stearates, glyceryl stearate stearate, silicone oil, talc, oils, and colloidal silica. Flavoring agents such as peppermint, wintergreen oil, cherry flavoring, etc., may also be used. It may be advantageous to add coloring agents to make the dosage form easily identifiable. Tablet coating may also be performed using methods known in the art.

[1403] Tablets can be obtained by compression or molding, optionally with one or more additional ingredients. Compressed tablets can be prepared by compressing an active agent in free-flowing form (such as powder or granules), optionally with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, in a suitable machine. Molded tablets can be obtained by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored, and can be formulated as sustained-release or controlled-release active agents.

[1404] Other formulations suitable for oral administration include: tablets containing an active agent in a flavoring matrix (typically sucrose and gum arabic or tragacanth); soft tablets containing an active agent in an inert matrix (such as gelatin and glycerin, or sucrose and gum arabic); and mouthwashes containing an active agent in a suitable liquid carrier.

[1405] Other forms of administration include solutions or emulsions that can be injected intravenously, intra-arterially, intrathecally, subcutaneously, intradermally, intraperitoneally, or intramuscularly, prepared from sterile or sterilizable solutions. Injectable formulations typically contain 10-1000 mg, preferably 10-250 mg, of the active ingredient per dose.

[1406] The pharmaceutical compositions of the present invention may also be in the form of suppositories, vaginal suppositories, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or powders.

[1407] Alternative methods of transdermal application include the use of skin patches. For example, the active ingredient can be incorporated into a cream composed of an aqueous emulsion of polyethylene glycol or liquid paraffin. The active ingredient can also be incorporated into an ointment composed of a paraffin or white soft paraffin matrix at a concentration between 1% and 10% by weight, with stabilizers and preservatives added as needed.

[1408] dose

[1409] Those skilled in the art can readily determine the appropriate dosage of one of the compositions of the present invention for administration to a subject without excessive trial. Typically, a physician can determine the most suitable actual dosage for an individual patient, which depends on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of said compound, age, weight, general health condition, sex, diet, route and time of administration, excretion rate, drug combinations, severity of the specific condition, and the individual receiving treatment. The dosages disclosed herein are examples of average cases. Individual examples are possible where higher or lower dosage ranges should be used, which are within the scope of the invention.

[1410] The dosage can be further adjusted according to the administration method of the compound. For example, parenteral administration of the compound is generally preferred to achieve an "effective dose" for acute treatment. While intramuscular bolus injection is also useful, intravenous infusion of the compound in 5% glucose or saline solution, or similar formulations with suitable excipients, is most effective. Typically, the parenteral dose is from about 0.01 mg to about 100 mg; preferably between 0.1 mg and 20 mg, in a manner that maintains the drug concentration in the plasma at a level that effectively regulates GPR65. The compound is administered once to four times daily at a level that achieves a total daily dose of about 0.4 mg to about 400 mg. Those skilled in the art can readily determine the precise therapeutically effective dose of the compound of the present invention, as well as the preferred route of administration, by comparing the blood levels of the drug with the concentrations required to achieve a therapeutic effect.

[1411] The compounds of the present invention can also be administered orally to patients in a manner that achieves a concentration sufficient to meet one or more therapeutic targets disclosed herein. Typically, the oral dose of the pharmaceutical composition comprising the compound is between about 0.1 mg and 500 mg, or between about 0.1 mg and about 50 mg, and the administration method must be consistent with the patient's condition. Preferably, the oral dose is between about 0.5 mg and 50 mg, or between about 0.5 mg and about 20 mg.

[1412] When the compounds of the present invention are administered according to the present invention, unacceptable toxic effects are not expected. The compounds of the present invention, which may have good bioavailability, can be detected using one of several bioassay techniques, thereby determining the concentration of the compound required to achieve a given pharmaceutical effect.

[1413] The invention is further described with reference to the following figures and non-limiting embodiments. Attached Figure Description

[1414] Figure 1The analytical X-ray crystal structure of (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide (compound 52) was described.

[1415] Figure 2 The resolved X-ray crystal structure of 5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxamide (compound 53) was described. Detailed Implementation

[1416] Example

[1417] Unless otherwise specified, the preparation of the raw materials is commercially available, known in the literature, or readily obtainable by a person skilled in the art using standard methods. When it is indicated that the compound is prepared using a method similar to that used for the preceding embodiments or intermediates, a person skilled in the art will understand that, for each specific reaction, the reaction time, reagent equivalence, solvent, concentration, and temperature can be adjusted, and different work-ups or purification techniques may be required or advantageously employed.

[1418] Overall Plan

[1419] abbreviation

[1420] Below is a list of some commonly used abbreviations—if other abbreviations not listed are used, those skilled in the art will understand them.

[1421] AcOH: Acetic acid; Boc: tert-butoxycarbonyl; br: broad peak; CAN: cerium ammonium nitrate; d: bimodal; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; (ES + ): Electrospray ionization positive mode; Et3N: Triethylamine; EtOAc: Ethyl acetate; EtOH: Ethanol; h: hour; HPLC: High performance liquid chromatography; HCl: Hydrochloric acid; Hz: Hertz; IPA: Isopropanol; J: Coupling constant; l: L; LDA: Lithium diisopropylamino; M: Mole; m: Multiplet; [M+H] + Protonated molecular ion; mCPBA: m-chloroperoxybenzoic acid; MeCN: acetonitrile; MeOH:

[1422] Methanol; MHz; min; ml; MS; MTBE

[1423] Methyl tert-butyl ether; m / z: mass-to-charge ratio; NFSI: N-fluorobis(benzene)sulfonamide; NMR: nuclear magnetic resonance; Pd-170: (crotonyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium chloride (II); Pd-172: (crotonyl)(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)palladium chloride (II); Pd-175: allyl[2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl]palladium trifluoromethanesulfonate (II); Pd-178: (crotonyl)(tricyclohexylphosphine)palladium(II) chloride; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0); PDA: photodiode array; PMP: p-methoxyphenyl; RT: room temperature; Rt: retention time; s: singlet; SFC: supercritical fluid chromatography; SCX: solid-supported cation exchange (resin); S-Phos: 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl; t: triplet; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TLC: thin-layer chromatography; UPLC: ultra-high performance liquid chromatography; UV: ultraviolet light.

[1424] Other abbreviations are intended to express their generally accepted meaning.

[1425] Overall experimental conditions

[1426] All starting materials and solvents were obtained from commercial sources or prepared according to literature methods. Suitable isocyanates and anilines were obtained from Sigma-Aldrich, Fluorochem, or Enamine stores, or synthesized as described herein. Suitable tricyclic amines were obtained from Enamine stores or synthesized as described herein. Unless otherwise stated, the reaction mixture was magnetically stirred and reacted at room temperature (approximately 20°C).

[1427] Perform silica column chromatography on an automated rapid chromatography system, such as the CombiFlash Companion or CombiFlash Rf system, or use... Rf or Or GraceResolv TM The Reveleris X2 rapid system is pre-loaded with silica (230-400 mesh, 40-63 μm) columns.

[1428] Use the Waters ACQUITY-- meter equipped with an ACQUITY PDA detector and an ACQUITY QDa mass spectrometer or a Waters SQD mass spectrometer. The H-Class system was used to perform UPLC-MS experiments to determine retention time and associated mass ions, following the analytical methods described below.

[1429] Perform analytical LC-MS experiments to determine retention times and associated mass ions as follows: Use an Agilent 1200 series HPLC system connected to an Agilent 1956, 6100, or 6120 series single quadrupole mass spectrometer and run one of the analytical methods described below; or use a Shimadzu-2020-P2 consisting of a Shimadzu LC-20AD series LC system and a Shimadzu-2020 single quadrupole mass spectrometer and run one of the analytical methods described below.

[1430] SFC experiments were performed using one of the analytical methods described below, with the Waters SFC system UPC2 (column temperature 40°C, back pressure (ABPR) 1750 psi) to determine retention time.

[1431] Preparative HPLC purification was performed using a Waters X-Bridge BEH C18 column (5 μm, 19 x 50 mm), a Waters X-Bridge Prep OBDC18 column (10 μm, 40 x 150 mm), or a Phenomenex Gemini NX C18 column (3 μm, 30 x 75 mm) with a MeCN and 10 mm ammonium bicarbonate aqueous gradient. Fractions were collected after UV detection at all wavelengths using a PDA and, in some cases, an SQD2 or ACQUITY QDa mass spectrometer.

[1432] SFC preparation and purification were performed using the Waters SFC prep 15 system, which features Phenomenex. Cellulose-4, 1x25cm column, 5μm particle size column or An IG (Daicel Ltd.) column (1x25cm, 5μm particle size) was used at a flow rate of 15ml / min, eluted with a mixture of CO2 and a co-solvent (MeOH, EtOH, or IPA). The fraction was collected after UV detection using a PDA at 210–400nm.

[1433] NMR spectra were recorded using a Bruker Avance III HD 500MHz instrument or a Bruker Avace Neo 400MHz instrument, with residual non-deuterated solvent or tetramethylsilane as a reference, or a VarianY 400MHz instrument with tetramethylsilane as a reference, or a QOne AS400 400MHz spectrometer with residual non-deuterated solvent or tetramethylsilane as a reference.

[1434] Where absolute stereochemistry is not explicitly indicated by wedge and dashed bonds, the chemical structures disclosed throughout the embodiments (e.g., in the configuration (I.3) described above) shall be interpreted as describing racemates. For the avoidance of doubt, the invention includes compounds of any configuration and mixtures thereof.

[1435] Analytical methods

[1436] Method 1 – Basic 3-Minute Method

[1437] Column: Waters ACQUITY BEH C18, 1.7μm, 2.1x30mm, 40℃

[1438] Detection: Unless otherwise specified, UV detection is performed in the range of 210-400 nm, and mass spectrometry is performed by electrospray ionization.

[1439] Solvents: A: 10mM ammonium bicarbonate aqueous solution, B: MeCN

[1440] gradient:

[1441] time ％A ％B Flow rate (ml / min) 0.00 95 5 0.77 0.11 95 5 0.77 2.15 5 95 0.77 2.56 5 95 0.77 2.83 95 5 0.77 3.00 95 5 0.77

[1442] Method 2 – Basic 4-Minute Method

[1443] Column: Waters X-Bridge BEH C18, 2.5μm, 4.6x30mm, 40℃

[1444] Detection: Unless otherwise specified, UV detection is performed at 254 nm, and mass spectrometry is performed by electrospray ionization.

[1445] Solvents: A: 10mM ammonium bicarbonate aqueous solution; B: MeCN

[1446] gradient:

[1447] time ％A ％B Flow rate (ml / min) 0.0 95.0 5.0 2.5 3.0 5.0 95.0 2.5 3.01 5.0 95.0 4.5 3.6 5.0 95.0 4.5 3.7 95.0 5.0 2.5 4.0 95.0 5.0 2.5

[1448] Method 3 – Amylose-2

[1449] column: Amylose-2, LC column (150x2mm, 3μm particle size), temperature 40℃, flow rate 1.5ml / min

[1450] Detection: UV detection of DAD at 220–400 nm

[1451] Solvent: A gradient or isocratic mixture of polar solvents, typically a CO2 solution of methanol, ethanol, or IPA.

[1452] Method 4 – IG-3 (Daicel Ltd.) pillar

[1453] column: IG-3 (Daicel Ltd.) column (2.1 x 150 mm, 3 μm particle size), flow rate 1.5 ml / min

[1454] Detection: UV detection of DAD at 220–400 nm

[1455] Solvent: A gradient or isocratic mixture of polar solvents, typically a CO2 solution of methanol, ethanol, or IPA.

[1456] Method 5 – The Basic 4-Minute Method

[1457] Column: Gemini LC column C18 50x2mm, particle size 3μm, 40℃

[1458] Detection: Unless otherwise specified, UV detection is performed at 220 nm, and MS is performed by electrospray ionization.

[1459] Solvents: A: 10mM ammonium bicarbonate aqueous solution, B: MeCN

[1460] gradient:

[1461] time ％A ％B Flow rate (ml / min) 0.0 100 0 0.6 0.4 100 0 0.6 3.00 10 90.0 0.6 3.85 0 100 0.6 3.86 100 0 0.6 4.0 100 0 0.6

[1462] Method 6 – The Basic 4-Minute Method

[1463] Column: Waters Sunfire, 3.5μm, 4.6×50mm column, 25℃

[1464] Detection: Unless otherwise specified, UV detection was performed at 214 and 254 nm, and MS was performed by electrospray ionization.

[1465] Solvent:

[1466] A: 0.05% formic acid aqueous solution (v / v) B: 0.05% formic acid (MeCN) (v / v)

[1467] gradient:

[1468]

[1469]

[1470] Experimental Scheme 1

[1471] Compound 1(±)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin[d]pyrimidine-10-carboxamide

[1472]

[1473] A solution of 1-isocyano-4-(trifluoromethyl)benzene (0.131 g, 0.698 mmol) in THF (0.75 ml) was added to a solution of 6,7,8,9-tetrahydro-5H-5,8-bridged imine-cyclohepta[d]pyrimidine (0.075 g, 0.465 mmol) and Et3N (97 μl, 0.698 mmol). The resulting mixture was stirred at room temperature for 20 hours. The crude product was concentrated under vacuum by adding MeOH (5 ml). The product was purified by RP Flash C18 chromatography (15-75% MeCN / 10 mM ammonium bicarbonate aqueous solution) to give (±)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine-cyclohepta[d]pyrimidine-10-carboxamide as a colorless solid. LC-MS (Method 1) m / z 349.3 (M+H) + (ES + At 1.18 minutes. 1 H 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).

[1474] The following compounds were prepared using suitable raw materials in a manner similar to that described in Experimental Scheme 1. Where the raw materials are not described in the literature, the synthetic methods are as follows.

[1475] Key points: (a) Reaction in DMF, (b) Reaction in DCM, (c) Reaction in a mixture of DMF and DCM, (d) Purification of the product by mass spectrometry-guided HPLC (MeCN / 10mM ammonium bicarbonate aqueous solution, C18), (e) Purification of the product by silica gel chromatography (0.7M ammonia / MeOH in DCM solution), (f) Reaction in DMF / THF, (g) Purification of the product by silica gel chromatography (Heptane solution of DCM), (h) Reaction using DIPEA instead of Et3N, (i) Purification of the product by silica gel chromatography (Isohexane solution of EtOAc), (j) ES - [MH] - In ES + No parent mass was observed.

[1476]

[1477]

[1478]

[1479]

[1480]

[1481]

[1482]

[1483]

[1484]

[1485]

[1486]

[1487]

[1488]

[1489]

[1490]

[1491]

[1492]

[1493]

[1494]

[1495]

[1496]

[1497]

[1498]

[1499]

[1500]

[1501]

[1502] Intermediate 1 (I-1)

[1503]

[1504] Step 1: 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester I-1a (10 g, 44 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethylmethylamine (21 g, 24 ml, 0.18 mol), and the reaction mixture was heated under reflux for 16 hours. The solvent was removed under vacuum. The product was purified by silica gel chromatography (0–5% (0.7 M ammonia / MeOH) in DCM solution) to give (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester I-1b as a yellow solid. LCMS (Method 2) m / z 281.2 [M+H] + (ES + At 1.60 minutes. 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).

[1505] Step 2: Add a MeOH solution of sodium methoxide (661 μl, 5.4 M, 3.57 mmol) to a MeOH solution of 2,2,2-trifluoroacetamidine (192 mg, 132 μl, 1.71 mmol) (10 mL). Add a MeOH solution of (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester I-1b (400 mg, 1.43 mmol) (10 mL). Heat the reaction mixture to 80 °C for 16 hours. Add water (5 mL) and a saturated ammonium chloride solution (5 mL). Extract the product with a chloroform solution of 20% IPA (50 mL). The product was purified by silica gel chromatography (0–3% (0.7 M ammonia / MeOH) in DCM solution) to give 2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxylic acid tert-butyl ester I-1c, which was a yellow oil. LCMS (Method 2) m / z 330.1 [M+H] + (ES + At 2.28 minutes. 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).

[1506] Step 3: Add TFA (0.20 ml, 2.6 mmol) to a solution of 2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin [d]pyrimidine-10-carboxylic acid tert-butyl ester I-1c (85 mg, 0.26 mmol) in DCM (2 ml). Stir the reaction mixture at room temperature for 16 hours. Concentrate the crude reaction mixture under reduced pressure. Add 2 ml of 0.7 M ammonia in MeOH solution, remove the solvent under vacuum, and give 2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin [d]pyrimidine as a yellow oil, which can be used without further purification in subsequent steps. LCMS (Method 2) m / z 230.0 [M+H] + (ES + At 1.20 minutes.

[1507] Intermediate 2 (I-2)

[1508]

[1509] Step 1: Using essentially the same steps as compound I-1c, 2-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged iminecyclohepta[d]pyrimidine-10-carboxylic acid tert-butyl ester I-2a was prepared from (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester I-1b. LCMS (Method 2) m / z 276.1 [M+H] + (ES + At 1.59 minutes. 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).

[1510] Step 2: Using essentially the same steps as I-1, 2-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[d]pyrimidine-10-carboxylic acid tert-butyl ester I-2a was prepared to produce 2-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[d]pyrimidine I-2. LCMS (Method 2) m / z 176.1 [M+H] + (ES + At 0.70 minutes.

[1511] Intermediate 3 (I-3)

[1512]

[1513] Step 1: Using essentially the same steps as I-1c, 2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[d]pyrimidine-10-carboxylic acid tert-butyl ester (I-3a) was prepared from (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester I-1b: LCMS (Method 2) m / z 338.2 [M+H] + (ES + At 2.55 minutes. 1HNMR(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).

[1514] Step 2: Using essentially the same steps as in I-1, 2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[d]pyrimidine-10-carboxylic acid tert-butyl ester (I-3a) was prepared to produce 2-phenyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[d]pyrimidine (I-3): LCMS (Method 2), m / z 230.1 [M+H] + (ES + At 1.18 minutes.

[1515] Intermediate 5 (I-5)

[1516]

[1517] Step 1: Add a solution of sodium ethoxide (2 ml, 21% w / w EtOH solution, 4 mmol) to a solution of urea (0.2 g, 4 mmol) in 10 ml of EtOH. Add a solution of (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester I-1b (1 g, 4 mmol) in 10 ml of EtOH. Heat the reaction mixture to 90 °C for 16 hours. Add a saturated ammonium chloride solution (5 ml) and extract the product with 10% (0.7 M ammonia / MeOH) DCM solution (2 x 35 ml). The product was purified by silica gel chromatography (0–10% (0.7 M ammonia / MeOH) in DCM solution) to give 2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxylic acid tert-butyl ester I-5a as a white solid. LCMS (Method 2) m / z 278.1 (M+H) + (ES + At 1.3 minutes. 1¹H NMR (500MHz, DMSO-d⁶) δ 11.68 (s, ¹H), 7.96 (s, ¹H), 4.79 (d, J = 6.0 Hz, ¹H), 4.35 (s, ¹H), 2.97 (d, J = 17.7 Hz, ¹H), 2.16 (s, ¹H), 2.02 (dt, J = 11.9, 5.6 Hz, ¹H), 1.78–1.69 (m, ¹H), 1.67 (d, J = 17.0 Hz, ¹H), 1.36 (s, 9H). One proton is located below the DMSO peak.

[1518] Step 2: TFA (1.00 ml, 13.0 mmol) was slowly added to a DCM (10 ml) solution of 2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-10-carboxylic acid tert-butyl ester I-5a (361 mg, 1.30 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum. A 0.7 M ammonia solution in MeOH (5 ml) was added, and the mixture was concentrated under vacuum. The material was purified by SCX elution with a 0.7 M ammonia solution in MeOH to provide 6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptamethrin-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).

[1519] Intermediate 7 (I-7)

[1520] The following scheme uses the synthesis method described in Schultz and Wolfe, Organic Letters, 2011, 13(11), 2962-2965.

[1521]

[1522] Step 1: A portion of titanium ethoxide (IV) (93.6 ml, 451 mmol) was added to a solution of 3-bromo-4-pyridinecarboxaldehyde (42.0 g, 225 mmol) in THF (250 ml) at room temperature. The mixture was stirred at room temperature for 5 minutes, and then a portion of (±)-tert-butylsulfinamide (30.1 g, 248 mmol) was added. 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 EtOAc (3 x 30 ml). The combined organic layers were concentrated under vacuum. The product was purified by silica gel chromatography (1-100% EtOAc / petroleum ether) to give (E)-N-((3-bromopyridin-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).

[1523] Step 2: At 0°C, but-3-en-1-yl magnesium bromide (0.5 M, 1.59 L) was added dropwise to a THF (300 mL) solution of (E)-N-((3-bromopyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (I-7b) (53.4 g, 185 mmol). The mixture was heated to room temperature over 1 hour. A saturated ammonium chloride solution (200 mL) was added, and the product was extracted with EtOAc (3 x 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%-100% EtOAc / petroleum ether) to give N-(1-(3-bromopyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-7c) as a yellow oil. 1 H 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).

[1524] Step 3: At 0°C, a solution of HCl in EtOAc (4M, 117ml) was added to a MeOH (326ml) solution of N-(1-(3-bromopyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-7c) (54.3g, 157mmol). 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 EtOAc (2 x 10ml), and dried under vacuum to give a pale yellow solid, which was then dissolved in water. The mixture was alkalized with NaOH solution to pH > 11 and extracted with DCM (3 x 30ml). The combined organic matter was washed with brine (30ml) and dried with sodium sulfate to give 1-(3-bromopyridin-4-yl)pent-4-en-1-amine (I-7d) as a yellow-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).

[1525] Step 4: Add 1-(3-bromopyridin-4-yl)pent-4-en-1-amine (I-7d) (26.5 g, 110 mmol), (4-methoxyphenyl)boronic acid (25.1 g, 165 mmol), Molecular sieve (53.0 g) and Cu(OAc)₂ (20.0 g, 110 mol) were added dropwise to a solution of 1,4-dioxane (530 mL) with Et₃N (20 mL, 143 mmol). The mixture was stirred at 35 °C in O₂ for 16 hours. The mixture was filtered, and the filter cake was washed with EtOAc (3 x 15 mL). The filtrate was concentrated under vacuum. The product was purified by silica gel chromatography (1%–100% EtOAc / petroleum ether) to give N-(1-(3-bromopyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-7e) as a reddish-brown solid. 1H 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).

[1526] Step 5: Cool the flame-dried flask under a stream of N2 and add Pd2(dba)3 (3.61 g, 3.95 mmol), S-Phos (3.24 g, 7.89 mmol), and NaOtBu (5.69 g, 59.2 mmol). Purge the flask with N2 and add dropwise a solution of N-(1-(3-bromopyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-7e) (13.7 g, 39.5 mmol) in toluene (274 ml). Heat the resulting mixture to 90 °C for 12 hours. Filter the reaction mixture and wash the filter cake with EtOAc (3 x 10 ml). Concentrate the filtrate under vacuum. The product was purified by silica gel chromatography (1%-100% EtOAc / petroleum ether) to give 10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine (I-7f), which was a light 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).

[1527] Step 6: Cool a solution of 10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminocycloheptane[c]pyridine (I-7f) (6.32 g, 23.7 mmol) in MeCN (237 ml) to 0 °C, and then add dropwise an aqueous solution of CAN (0.3 M, 316 ml). After the addition is complete, stir the reaction mixture at 0 °C for 1 hour. Concentrate the reaction mixture under vacuum to dryness to obtain 6,7,8,9-tetrahydro-5H-5,8-bridgediminocycloheptane[c]pyridine (I-7 g) as a brown oil, which can be used in subsequent steps without any further purification.

[1528] Step 7: Add K₂CO₃ (8.25 g, 59.7 mmol) and di-tert-butyl dicarbonate (26.0 g, 119 mmol) to a THF (30 mL) solution of 6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine (I-7 g) (3.82 g, 23.9 mmol). Stir the mixture at room temperature for 16 hours. Filter the reaction mixture and wash the filter cake with EtOAc (3 x 15 mL). Add water (25 mL) to the filtrate. Extract the aqueous layer with EtOAc (3 x 25 mL). Dry the combined organic layers with sodium sulfate and concentrate under vacuum. Purify the product by silica gel chromatography (1%-100% EtOAc / petroleum ether) to give tert-butyl 6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxylic acid as a reddish-brown solid (I-7 h). 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).

[1529] Step 8: At room temperature, a solution of HCl in EtOAc (4 M, 550 mL) was added to a solution of 6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine-10-carboxylic acid tert-butyl ester (I-7h) (2.20 g, 8.45 mmol) in MeOH (400 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum. The crude product was milled with MTBE (20 mL) at room temperature for 10 minutes. The mixture was filtered, the filter cake was washed with MTBE (2 x 5 mL), and the filter cake was dried under vacuum to give 6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine hydrochloride as a white solid. LCMS (Method 5) m / z 161.2 (M+H) + (ES+ At 2.44 minutes. 1 H 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).

[1530] Intermediate 8 (I-8)

[1531]

[1532] Step 1: Using essentially the same steps as I-7b, synthesize (E)-N-((4-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (I-8b) 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).

[1533] Step 2: Using essentially the same steps as I-7c, synthesize N-(1-(4-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (I-8c) from (E)-N-((4-bromopyridin-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).

[1534] Step 3: Using essentially the same steps as I-7d, synthesize 1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-8c) from N-(1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-8c) 1H 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).

[1535] Step 4: Using essentially the same steps as I-7e, synthesize N-(1-(4-bromopyridin-3-yl)pent-4-en-1-amine (I-8d) from 1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline (I-8e). 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).

[1536] Step 5: Using essentially the same steps as I-7f, synthesize 10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptane[c]pyridine (I-8f) from N-(1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline (I-8e). 1 H 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).

[1537] Step 6: Using essentially the same steps as I-7g, synthesize 6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine (I-8f) from 10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptan[c]pyridine (I-8f).

[1538] Step 7: Using essentially the same steps as I-7h, prepare tert-butyl 6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptane[c]pyridine (I-8g) from 6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptane[c]pyridine (I-8g). 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).

[1539] Step 8: Using essentially the same steps as I-7, synthesize 6,7,8,9-tetrahydro-5H-6,9-bridged iminecycloheptane[c]pyridine-10-carboxylic acid tert-butyl ester (I-8h) from 6,7,8,9-tetrahydro-5H-6,9-bridged iminecycloheptane[c]pyridine hydrochloride (I-8). LCMS (Method 5) m / z 161.2 (M+H) + (ES + At 2.42 minutes. 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).

[1540] Intermediate 9 (I-9)

[1541]

[1542] Step 1: Using essentially the same steps as I-7b, synthesize (E)-N-(2-bromo-4-methoxybenzyl)-2-methylpropane-2-sulfinamide (I-9b) 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).

[1543] Step 2: Cool a solution of (E)-N-(2-bromo-4-methoxyphenyl)-2-methylpropane-2-sulfinamide (13.0 g, 40.9 mmol) in THF (130 mL) to -78°C. Add dropwise but-3-en-1-yl magnesium bromide (0.5 M THF solution) (245 mL, 123 mmol). Slowly heat the mixture to room temperature and stir at room temperature for 16 hours. Add saturated ammonium chloride aqueous solution (150 mL) and extract the product with EtOAc (2 x 100 mL). Combine the organic compounds, dry with magnesium sulfate, and concentrate under vacuum to give N-(1-(2-bromo-4-methoxyphenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-9c) as a light brown oil. This compound, as a 2:1 mixture of diastereomers, can proceed to the next step without further purification.

[1544] Major diastereomers: 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).

[1545] Minor diastereomers: 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).

[1546] Step 3: At room temperature, HCl (33 ml, 132.5 mmol) was added to a solution of N-(1-(2-bromo-4-methoxyphenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-9c) (16.5 g, 44.16 mmol) in MeOH (65 ml). The reaction mixture was stirred at room temperature for 2.5 hours. Water (200 ml) was added, and the aqueous solution was washed with EtOAc (200 ml). The aqueous layer was adjusted to pH 8 by adding 2 M NaOH aqueous solution. The aqueous layer was then extracted with EtOAc (2 x 100 ml). The organic matter was combined, dried over magnesium sulfate, and concentrated under vacuum to give 1-(2-bromo-4-methoxyphenyl)pent-4-en-1-amine (I-9d) as a light brown liquid. The crude product can be used in the next step without further purification.

[1547] Step 4: To a solution of 1-(2-bromo-4-methoxyphenyl)pent-4-en-1-amine (I-9d) (7.60 g, 28.1 mmol) in DCM (100 mL), add (4-methoxyphenyl)boronic acid (12.8 g, 84.4 mmol), followed by copper acetate (II) (7.66 g, 42.2 mmol) and pyridine (11.4 mL, 141 mmol). Stir the blue mixture vigorously at room temperature for 72 hours. Add 2 M NaOH aqueous solution (100 mL) and stir the mixture for 30 minutes. Filter the copper salt through a diatomaceous earth mat. Add water (100 mL) and extract the product with DCM (3 x 100 mL). Combine the organic layers, dry with magnesium sulfate, and concentrate under vacuum. The product was purified by silica gel chromatography (5-25% EtOAc / isohexane) to give N-(1-(2-bromo-4-methoxyphenyl)pent-4-en-1-yl)-4-methoxyaniline (I-9e) as a yellow liquid. LCMS (Method 2) m / z 255 (M-PMP) + (ES + At 1.91 minutes, 1H 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).

[1548] Step 5: Add Pd-178 (667 mg, 1.40 mmol) and NaOtBu (2.02 g, 21.0 mmol) to the flask and purge the flask with nitrogen. Add a solution of degassed toluene (120 mL) of N-(1-(2-bromo-4-methoxyphenyl)pent-4-en-1-yl)-4-methoxyaniline (I-9e) (5.26 g, 14.0 mmol) using a syringe at room temperature. Heat the resulting mixture at 95 °C for 2 hours. Cool the reaction mixture to room temperature and filter through diatomaceous earth. Wash the diatomaceous earth with EtOAc (100 mL). Concentrate the filtrate under vacuum. The product was purified by silica gel chromatography (0-25% EtOAc / isohexane) to give (±)-2-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]annulene (I-9f), which was a light pink oil. LCMS (Method 2) m / z 296 (M+H) + (ES + At 1.27 minutes, 1H 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).

[1549] Step 6: At 0 °C, an aqueous solution (25 ml) of CAN (3.79 g, 6.91 mmol) was added dropwise to a MeCN (25 ml) solution of (±)-2-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]annulene (I-9f) (680.0 mg, 2.30 mmol) over 30 minutes. The mixture was stirred at 0 °C for 1 hour and then at room temperature for 1 hour. Water (10 ml) and 2M NaOH (10 ml) were added, and the product was extracted with DCM (3 x 30 ml). The organic layers were combined and concentrated under vacuum to give (±)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]annulene (I-9) as a brown oil. This compound was ready for use without further purification. LCMS (Method 2) m / z 190(M+H) + (ES + At 1.56 minutes, 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).

[1550] Intermediate 10 (I-10)

[1551]

[1552] Step 1: (±)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]annuclear (I-9) (267 mg, 1.24 mmol) was added to an aqueous HBr solution (48% aqueous solution) (1.4 ml, 48% w / w, 12.41 mmol) at room temperature and then refluxed for 6 hours. The mixture was diluted with MeOH (20 ml) and filtered to give a clear, dark brown filtrate. SCX (7.00 g, 5.4 mmol) was added and the mixture was stirred further at room temperature for 1 hour. SCX was washed with MeOH (100 ml) and the product was eluted with a solution of 0.7 M ammonia in MeOH (50 ml). The eluent was concentrated under vacuum to give (±)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]annuclear-2-ol as a dark brown oil. LCMS (Method 2) m / z 176 (M+H) + (ES + At 0.61 minutes, 1 ¹H NMR (500MHz, DMSO-d⁶) δ 9.00 (s, ¹H), 6.77 (d, J = 8.1 Hz, ¹H), 6.44 (dd, J = 8.1, 2.5 Hz, ¹H), 6.41 (d, J = 2.5 Hz, ¹H), 4.00 (d, J = 5.3 Hz, ¹H), 3.67 (t, J = 5.8 Hz, ¹H), 2.96 (dd, J = 16.5, 4.9 Hz, 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), 1 invisible exchangeable proton.

[1553] Intermediate 11 (I-11)

[1554]

[1555] Step 1: Pd-170 (1 mg, 1.45 μmol) and K2PO3 (23 mg, 145 μmol) were placed in vials, sealed, and purged / backfilled with N2 (3 times). A solution of (±)-2-(((trifluoromethyl)sulfonyl)oxy)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]anthene-10-carboxylic acid tert-butyl ester (40 mg, 97.0 μmol) and (2,4-dimethoxyphenyl)methylamine (18 mg, 107 μmol) in 1,4-dioxane (1 ml) was added, and the reaction mixture was heated to 120 °C for 16 hours. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth pad washed with EtOAc. The filtrate was concentrated under vacuum. The product was purified by silica gel chromatography (0%-100% EtOAc / isohexane) to obtain (±)-2-((2,4-dimethoxybenzyl)amino)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]annulene-10-carboxylic acid tert-butyl ester (I-11a), which was a yellow oil. LC-MS (Method 1) m / z 447.1 (M+Na) + (ES + At 1.82 minutes, 1 ¹H NMR (500MHz, DMSO-d⁶) δ 7.18 (dd, J = 8.3, 1.9 Hz, 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 = 16.5 Hz, 1H), 2.30–2.02 (m, 3H), 1.79 (t, J = 10.3 Hz, 1H), 1.62 (br s, 2H), 1.39 (s, 9H). (-NH protons are not visible).

[1556] Step 2: Add TFA (54 μl, 0.70 mmol) to a solution of (±)-2-((2,4-dimethoxybenzyl)amino)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]annulen-10-carboxylic acid tert-butyl ester (I-11a) (30 mg, 69.7 μmol) in DCM (1 ml), and stir the reaction mixture overnight at room temperature. Concentrate the reaction mixture under vacuum. Wash with MeOH using SCX (0.5 g) and elute with 0.7 M ammonia in MeOH solution. Purify the product by ion exchange to give (±)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]annulen-2-amine (I-11) as a viscous yellow oil. LC-MS (Method 1) m / z 175.8 (M+H) + (ES +At 0.71 minutes.

[1557] Intermediate 12 (I-12)

[1558]

[1559] Step 1: A portion of titanium ethoxide (IV) (20.7 ml, 98.5 mmol) was added to a THF (170 ml) solution of 10.0 g (49.3 mmol) of 2-bromo-4-fluorobenzaldehyde I-12a at room temperature. The mixture was stirred at room temperature for 5 minutes, and then a portion of (±)-tert-butylsulfinamide (5.97 g, 49.3 mmol) was added. The resulting mixture was stirred at room temperature for 24 hours. Brine (100 ml) was added, and the mixture was stirred for 10 minutes, then filtered through diatomaceous earth. The filtrate was extracted with EtOAc (2 x 100 ml). The combined organic layers were washed with brine (3 x 100 ml), dried over magnesium sulfate, and concentrated under vacuum to give (E)-N-(2-bromo-4-fluorobenzyl)-2-methylpropane-2-sulfinamide (I-12b) as a pale yellow solid. LCMS (Method 1) m / z 306.2, 308.1 (M+H) + (ES + At 1.6 minutes, 1 H 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).

[1560] Step 2: At -78°C, but-3-en-1-yl magnesium bromide (2.17 M, 29.4 mL) was added dropwise to a THF (150 mL) solution of (E)-N-(2-bromo-4-fluorophenyl)-2-methylpropane-2-sulfinamide (13.00 g, 42.46 mmol) (I-12b). The mixture was heated to room temperature over 16 hours. A saturated ammonium chloride solution (50 mL) was added, and the product was extracted with EtOAc (2 x 100 mL). The combined organic matter was dried over magnesium sulfate and concentrated under vacuum to give N-(1-(2-bromo-4-fluorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-12c) as an orange oil. LCMS (Method 2) m / z 362.1, 364.1 (M+H) + (ES + At 2.48 minutes.

[1561] Step 3: At room temperature, a solution of 1,4-dioxane in HCl (4M, 10.3 mL) was added to a solution of N-(1-(2-bromo-4-fluorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-12c) (15.0 g, 41.26 mmol) in MeOH (65 mL) and stirred for 2.5 h. The reaction mixture was concentrated under vacuum. The residue was partitioned between water (200 mL) and EtOAc (200 mL). The aqueous phase was alkalized to pH 8 with NaOH solution and extracted with EtOAc (2 x 100 mL). The organic layer was diluted with water (50 mL), alkalized to pH 10 with NaOH, and extracted with ethyl acetate (3 x 100 mL). The combined organics were dried over magnesium sulfate and concentrated under vacuum to give 1-(2-bromo-4-fluorophenyl)pent-4-en-1-amine (I-12d) as a colorless oil. LCMS (Method 2) m / z 258.0, 260.0 (M+H) + (ES + At 2.20 minutes. 1 ¹H NMR (500MHz, DMSO-d⁶) δ 7.66 (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) (Exchangeable -NH₂ protons are not visible).

[1562] Step 4: Pyridine (15.0 ml, 186 mmol) was added dropwise to a solution of 1-(2-bromo-4-fluorophenyl)pent-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 under air at room temperature for 16 hours. 2 M NaOH aqueous solution (100 ml) was added, and the mixture was stirred for 30 minutes and filtered through diatomaceous earth. The filtrate was partitioned between water (100 ml) and DCM (100 ml), and the layers were separated. The aqueous layer was further extracted with DCM (2 x 100 ml). The combined organic matter was dried over magnesium sulfate and concentrated under vacuum. The product was purified by silica gel chromatography (0%-10% EtOAc / isohexane) followed by silica gel chromatography (0%-50% DMC / isohexane) to give N-(1-(2-bromo-4-fluorophenyl)pent-4-en-1-yl)-4-methoxyaniline (I-12e) as a colorless oil. LCMS (Method 2) m / z 364.3, 366.6 (M+H) + (ES + At 1.55 minutes. 1 H 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).

[1563] Step 5: Add Pd-178 (448 mg, 939 μmol) and NaOtBu (3.99 g, 41.5 mmol) to a three-necked flask and purge with N2. Add dropwise a solution of N-(1-(2-bromo-4-fluorophenyl)pent-4-en-1-yl)-4-methoxyaniline (I-12e) (3.42 g, 9.39 mmol) in toluene (30 ml). Heat the resulting mixture to 95 °C for 2 hours. Cool the reaction mixture to room temperature and filter through diatomaceous earth, washing with EtOAc (100 ml). Concentrate the filtrate under vacuum. Purify the product by silica gel chromatography (0%-5% EtOAc / heptane) to give (±)-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]annulene (I-12f) as a pink oil. LCMS (Method 2) m / z 384.1 (M+H) + (ES + At 2.52 minutes, 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).

[1564] Step 6: Cool a solution of (±)-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]annulene (I-12f) (2.15 g, 7.59 mmol) in MeCN (28 ml) to 0 °C, and then add dropwise an aqueous solution of CAN (12.5 g, 22.8 mmol) (100 ml). After the addition is complete, stir the reaction at 0 °C for 1 hour, then heat to room temperature and stir for 1 hour. Add water (30 ml) and 2M sodium hydroxide aqueous solution (50 ml), and extract the product with DCM (4 x 150 ml). The combined organic layers are dried with magnesium sulfate and concentrated under vacuum. The crude residue was redissolved in MeOH and purified by washing with MeOH using SCX (15 g) and eluting with 0.7 M ammonia in MeOH solution to obtain (±)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]annulene (I-12), a brown oil. LCMS (Method 2) m / z 178.1 (M+H) + (ES +At 1.65 minutes, 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, 5.0 Hz, 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).

[1565] Intermediate 13 (I-13)

[1566]

[1567] Step 1: A portion of titanium ethoxide (IV) (2.63 ml, 12.5 mmol) was added to a THF (17 ml) solution of 3-chloro-2-fluoroisonicotinaldehyde (I-13a) (1.00 g, 6.27 mmol) at room temperature. The mixture was stirred at room temperature for 5 minutes, and then a portion of (S)-tert-butylsulfinamide (760 mg, 6.27 mol) was added. The resulting mixture was stirred at room temperature for 16 hours. Brine (30 ml) was added, and the mixture was stirred for 10 minutes, then filtered through diatomaceous earth. The filtrate was extracted with EtOAc (2 x 20 ml). The combined organic matter was dried over magnesium sulfate and concentrated under vacuum to give (S)-N-((3-chloro-2-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (I-13b) as a pale yellow solid. LCMS (Method 1) m / z 227.5 (M-Cl) + (ES + At 1.36 minutes. 1 H NMR (500MHz, DMSO-d6) δ8.81 (s, 1H), 8.33 (dt, J = 5.1, 0.8 Hz, 1H), 7.90 (d, J = 5.1 Hz, 1H), 1.22 (s, 9H).

[1568] Step 2: At -78°C, but-3-en-1-yl magnesium bromide (0.5 M, 31.6 mL, 15.79 mmol) was added dropwise to a THF (22 mL) solution of (S)-N-((3-chloro-2-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.38 g, 5.26 mmol) (I-13b). The mixture was slowly heated to room temperature and stirred for 72 hours. A saturated ammonium chloride solution (10 mL) was added, and the product was extracted with EtOAc (3 x 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% EtOAc / isohexane) to give (S)-N-((R)-1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-13c) as a pale yellow solid. LCMS (Method 1) m / z 316.7, 319.1 (MH) - (ES - At 1.39 minutes. 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).

[1569] Step 3: At room temperature, a solution of 1,4-dioxane in HCl (4M, 3.0ml, 12.09mmol) was added to a solution of (S)-N-((R)-1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-13c) (714 mg, 2.015 mmol) in tBuOH (7.2 ml), 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 x 30 ml). The combined organic matter was dried over magnesium sulfate and concentrated under vacuum to give (R)-1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-amine (I-13d) as a pale yellow liquid and an orange / brown oil. LCMS (Method 1): m / z 215.4, 217.3 (M+H) + (ES + At 1.17 minutes,1 ¹H NMR (500MHz, DMSO-d⁶) δ 8.16 (dd, J = 5.1, 0.9 Hz, 1H), 7.62 (d, J = 5.1 Hz, 1H), 5.80 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.02 (dq, J = 17.4, 1.8 Hz, 1H), 4.96 (ddt, J = 10.2, 2.3, 1.3 Hz, 1H), 4.22 (dd, J = 8.1, 5.1 Hz, 1H), 2.23–2.01 (m, 2H), 1.76–1.50 (m, 2H), 2NH protons not observed.

[1570] Step 4: Add pyridine (1.2 ml, 15.0 mmol) dropwise to a solution of (R)-1-(3-chloro-2-fluoropyridin-4-yl)pent-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). Stir the mixture with air at room temperature for 16 hours. Add 2M NaOH aqueous solution (20 ml), then add water (20 ml), and extract the mixture with DCM (3 x 20 ml). Dry the combined organic matter with magnesium sulfate and concentrate under vacuum. Purify the product by silica gel chromatography (0%–100% DCM / isohexane) to give (R)-N-(1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-13e) as a yellow oil. LCMS (Method 1): m / z 321.1, 323.4 (M+H) + (ES + At 1.73 minutes, 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).

[1571] Step 5: Pd-178 (7.4 mg, 15.6 μmol) and sodium tert-butoxide (22.5 mg, 234 μmol) were added to a three-necked flask and purged with N2. A toluene solution (1 mL) of (R)-N-(1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-13e) (50.0 mg, 156 μmol) was added dropwise. The resulting mixture was heated to 95 °C for 1.5 hours. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth, washed with EtOAc (3 x 20 mL). The filtrate was concentrated under vacuum. The product was purified by silica gel chromatography (0%–50% EtOAc / heptane) to give (5R,8S)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine (I-13f) as a white solid. LCMS (Method 1) m / z 285.3 (M+H) + (ES + At 1.35 minutes. 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).

[1572] Step 6: A solution of (5R,8S)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridgediminocyclohepta[c]pyridine (I-13f) (69 mg, 232 μmol) in MeCN (3.2 mL) was cooled to 0 °C, and then an aqueous solution of CAN (381 mg, 696 μmol) (3.2 mL) was added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 1 hour. 2 M NaOH aqueous solution (5 mL) and water (5 mL) were added, and the mixture was extracted with DCM (3 x 10 mL). The combined organic matter was dried over magnesium sulfate and concentrated under vacuum to give (5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridgediminocyclohepta[c]pyridine (I-13) as a light pink solid. LCMS (Method 1): m / z 179.2 (M+H) + (ES + At 0.69 minutes, 1H 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).

[1573] Intermediate 14 (I-14)

[1574]

[1575] Step 1: Using essentially the same procedure as I-12b, N-(2-bromo-5-fluorobenzaldehyde)-2-methylpropane-2-sulfinamide I-14b was synthesized from 2-bromo-5-fluorobenzaldehyde I-14a. LCMS (Method 2): m / z 305.9, 308.0 (M+H) + (ES + At 2.80 minutes, 1 H 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).

[1576] Step 2: Using essentially the same steps as I-12c, N-(1-(2-bromo-5-fluorobenzyl)-2-methylpropane-2-sulfinamide (I-14c) was synthesized from N-(2-bromo-5-fluorobenzyl)-2-methylpropane-2-sulfinamide I-14b. LCMS (Method 2): m / z 362.0, 364.0 (M+H) + (ES + At 2.47 minutes, 1H 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).

[1577] Step 3: At room temperature, a solution of HCl in 1,4-dioxane (4M, 28ml, 113mmol) was added to a MeOH (65ml) solution of N-(1-(2-bromo-5-fluorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-14c (13.6g, 37.5mmol) and stirred for 17 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in water (200ml) and washed with EtOAc (200ml). The aqueous layer was alkalized to pH 8 with 2M NaOH solution and extracted with EtOAc (2 x 100ml). The combined organic matter was dried over magnesium sulfate and concentrated under vacuum to give N-(1-(2-bromo-5-fluorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-14d as an orange / brown oil. LCMS (Method 2): m / z 258.0, 260.0 (M+H) + (ES + At 2.24 minutes, 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).

[1578] Step 4: Using essentially the same steps as I-12e, N-(1-(2-bromo-5-fluorophenyl)pent-4-en-1-amine (I-14d) was synthesized from N-(1-(2-bromo-5-fluorophenyl)pent-4-en-1-yl)-4-methoxyaniline I-14e. LCMS (Method 2): m / z 364.1, 366.0 (M+H) + (ES + At 2.90 minutes, 1 H 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).

[1579] Step 5: Using essentially the same steps as I-12f, (±)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]annulene (I-14f) was synthesized from N-(1-(2-bromo-5-fluorophenyl)pent-4-en-1-yl)-4-methoxyaniline I-14e. LCMS (Method 2): m / z 284.1 (M+H) + (ES + At 2.67 minutes.

[1580] Step 6: Cool a solution of (±)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]annulene I-14f (2.31 g, 8.15 mmol) in MeCN (100 ml) to 0 °C, and then add dropwise an aqueous solution of CAN (13.4 g, 24.5 mmol) (100 ml). After the addition is complete, stir the reaction at 0 °C for 1 hour, then heat it to room temperature and stir for 1 hour. Add 2 M NaOH aqueous solution (100 ml) and DCM (100 ml), filter the mixture through diatomaceous earth, and wash with DCM (100 ml). Separate the layers and extract the aqueous layer with DCM (2 x 100 ml). The combined organic matter was dried with magnesium sulfate and concentrated under vacuum to obtain (±)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]annulene I-14, a viscous brown oil. LCMS (Method 2): m / z 178.5 (M+H) + (ES + At 1.68 minutes, 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 peak is blocked by water).

[1581] Intermediate 15 (I-15)

[1582]

[1583] Step 1: Using essentially the same procedure as I-12b, N-(2-bromo-3-fluorobenzaldehyde)-2-methylpropane-2-sulfinamide I-15b was synthesized from 2-bromo-3-fluorobenzaldehyde I-15a. LCMS (Method 2): m / z 305.9, 308.0 (M+H) + (ES + At 2.42 minutes, 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).

[1584] Step 2: Using essentially the same steps as I-12c, N-(1-(2-bromo-3-fluorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-15c was synthesized from N-(2-bromo-3-fluorophenyl)-2-methylpropane-2-sulfinamide I-15b. LCMS (Method 2): m / z 362.0, 364.0 (M+H) + (ES + At 2.44 minutes, 1 H 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).

[1585] Step 3: Using essentially the same procedure as for I-14d, 1-(2-bromo-3-fluorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-15c was synthesized into 1-(2-bromo-3-fluorophenyl)pent-4-en-1-amine I-15d. LCMS (Method 2): m / z 258.0, 260.0 (M+H) + (ES + At 2.18 minutes, 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).

[1586] Step 4: Pyridine (16.1 ml, 200 mmol) was added dropwise to a solution of 1-(2-bromo-3-fluorophenyl)pent-4-en-1-amine (10.3 g, 39.9 mmol) I-15d, (4-methoxyphenyl)boric acid (18.2 g, 120 mmol), and Cu(OAc)2 (10.9 g, 59.9 mmol) in DCM (100 ml). The mixture was stirred under air at room temperature for 4 days. 2 M NaOH aqueous solution (100 ml) was added, and the mixture was stirred for 30 minutes and filtered through diatomaceous earth. The filtrate was partitioned between water (100 ml) and DCM (100 ml), and the layers were separated. The aqueous layer was further extracted with DCM (2 x 100 ml). The combined organic matter was dried over 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)pent-4-en-1-yl)-4-methoxyaniline I-15e, which was a viscous orange oil. 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).

[1587] Step 5: Using essentially the same steps as I-12f, (±)-1-fluoro-10-(4-methoxyphenyl)pent-4-en-1-yl)-4-methoxyaniline I-15e was synthesized from N-(1-(2-bromo-3-fluorophenyl)pent-4-en-1-yl)-4-methoxyaniline I-15e. LCMS (Method 2): m / z 284.1 (M+H) + (ES + At 2.56 minutes, 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).

[1588] Step 6: Using essentially the same steps as I-12, (±)-1-fluoro-6,7,8,8,9-tetrahydro-5H-5,8-bridged imine benzo[7]annulene I-15f was synthesized from (±)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-8,8-bridged imine benzo[7]annulene I-15f. LCMS (Method 2): m / z 178.1 (M+H) + (ES + At 1.69 minutes, 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).

[1589] Intermediate 16 (I-16)

[1590]

[1591] Step 1: To a mixture of 2-bromoisonitanaldehyde I-16a (15.0 g, 80.6 mmol) in THF (90.0 mL), Ti(OEt)4 (33.5 mL, 161 mmol) and tert-butylsulfinamide (10.8 g, 88.7 mmol) were added. 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 EtOAc (3 x 75 mL). The combined organic matter was dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to give N-((2-bromopyridin-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).

[1592] Step 2: At 0°C, but-3-en-1-yl magnesium bromide (0.5 M, 302 mL) was added dropwise to a THF (107 mL) solution of N-((2-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-16b (19.0 g, 65.7 mmol). The mixture was heated 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 EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to give N-(1-(2-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-16c as a yellow solid. 1 ¹H NMR (400MHz, CDCl₃) δ 8.28 (t, J = 2.8 Hz, 1H), 7.69 (t, J = 2.5 Hz, 1H), 7.29–7.26 (m, 1H), 5.83–5.76 (t, J = 2.4 Hz, 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) (NH₃ not observed).

[1593] Step 3: At 0°C, add a solution of HCl in EtOAc (4M, 24.4ml, 97.6mmol) to a MeOH (70ml) solution of N-(1-(2-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-16c (11.2g, 32.5mmol) and heat the mixture to room temperature for 30 minutes. Concentrate the reaction mixture under vacuum, grind with MTBE (100ml), filter to collect the solid, wash with MTBE (2 x 100ml) and dry under vacuum. Dissolve the solid in water (50ml), cool to 0°C, and alkalize the mixture to pH 11 with NaOH solution. Extract the aqueous mixture with DCM (3 x 30ml), wash the combined organic matter with brine (30ml), dry with sodium sulfate and concentrate under vacuum. The residue was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to give 1-(2-bromopyridin-3-yl)pent-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 = 5.6 Hz, 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 = 6.4 Hz, 1H), 1.70–1.64 (m, 1H) (NH₂ not observed).

[1594] Step 4: Add 1-(2-bromopyridin-3-yl)pent-4-en-1-amine I-16d (6.50 g, 26.9 mmol), (4-methoxyphenyl)boronic acid (7.66 g, 50.4 mmol), Et3N (4.56 ml, 32.8 mmol) was added dropwise to a mixture of molecular sieve (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 and O2 for 16 hours. The reaction mixture was filtered, and the solid was washed with EtOAc (3 x 10 ml). The filtrate was dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to give N-(1-(2-bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-16e as a reddish-brown solid. 1¹H 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 = 4.8 Hz, 1H), 6.41–6.38 (m, 2H), 5.86 (d, J = 6.8 Hz, 2H), 5.08–5.00 (m, 2H), 4.64 (t, J = 4.4 Hz, 1H), 3.69 (s, 3H), 2.31–2.22 (m, 2H), 1.98 (d, J = 6.8 Hz, 1H), 1.73 (t, J = 8.4 Hz, 1H). (NH₃ not observed)

[1595] Step 5: In a three-necked flask, add Pd2(dba)3 (131 mg, 0.144 mmol), tricyclohexylphosphine tetrafluoroborate (106 mg, 0.288 mmol), and NaOtBu (207 mg, 2.16 mmol), and purge with argon. Add a solution of N-(1-(2-bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-16e (0.50 g, 1.44 mmol) in 1,4-dioxane (1.8 mL), and heat the resulting mixture to 95 °C for 12 hours. Filter the reaction mixture and wash the solids with EtOAc (3 x 10 mL). Dry the filtrate with sodium sulfate and concentrate under vacuum. The residue was purified by silica gel chromatography (0-100% EtOAc / petroleum ether) to give (±)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine I-16f as a light 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).

[1596] Step 6: Using essentially the same steps as I-14, (±)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine I-16f was synthesized from (±)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[b]pyridine. LCMS (Method 1): m / z 160.9 (M+H) + (ES +At 0.62 minutes.

[1597] Intermediate 17 (I-17)

[1598]

[1599] Step 1: Using essentially the same procedure as I-13b, (S)-N-((4-bromo-6-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-17b was synthesized from 4-bromo-6-fluoroisononin I-17a. LCMS (Method 2): m / z 307.0, 308.9 (M+H) + (ES + At 2.05 minutes, 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).

[1600] Step 2: At -78°C, but-3-en-1-yl magnesium bromide (2.54 M, 17.9 mL, 45.6 mmol) was added dropwise to a THF (114 mL) solution of ((S)-N-((4-bromo-6-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-17b (7.00 g, 22.8 mmol) . The mixture was slowly heated to room temperature and stirred for 16 hours. A saturated ammonium chloride solution (10 mL) was added, and Et was used to... OAc (2 x 10 ml) extraction product. The combined organic compounds were dried over magnesium sulfate and concentrated under vacuum. The product was purified by silica gel chromatography (0-10% IPA / isohexane) to give a 2:1 mixture of diastereomers of (±)-N-(1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-17c, appearing as a pale yellow oil. LCMS (Method 1) m / z 363.3, 365.4 (M+H) + (ES + (), at 1.39 and 1.42 minutes.

[1601] Major diastereomers: 1H NMR (500MHz, DMSO-d6) δ8.43(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),5.1 2–4.97(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).

[1602] Minor diastereomers: 1 H NMR (500MHz, DMSO-d6) δ8.33(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),5.1 2–4.97(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).

[1603] Step 3: Using essentially the same procedure as for I-13d, (±)-1-(4-bromo-6-fluoropyridin-3-yl)pentyl-4-en-1-yl)-2-methylpropane-2-sulfinamide I-17c was synthesized into (±)-1-(4-bromo-6-fluoropyridin-3-yl)pentyl-4-en-1-amine I-17d. LCMS (Method 1) m / z 259.2, 261.2 (M+H) + (ES + At 1.21 minutes. 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).

[1604] Step 4: Using essentially the same steps as for I-13e, synthesize (±)-N-(1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-amine I-17d from (±)-1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-17e. LCMS (Method 1) m / z 365.0, 367.1 (M+H) + (ES + At 1.76 minutes. 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).

[1605] Step 5: Add Pd-178 (0.29 g, 0.61 mmol) and NaOtBu (0.88 g, 9.2 mmol) to a three-necked flask and purge with N2. Add dropwise a solution of N-(1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-17e (2.3 g, 6.1 mmol) in toluene (66 mL). Heat the resulting mixture to 95 °C for 2 hours. Cool the reaction mixture to room temperature and filter through diatomaceous earth. Wash the solids with EtOAc (150 mL). Concentrate the filtrate under vacuum. The product was purified by silica gel chromatography (0%-50% EtOAc / isohexane) to obtain an enantiomer mixture dissolved in 30 mg / ml DCM:methanol (1:4), which was then separated by chiral SFC on a Waters prep 15 column. UV detection was performed at 210 nm, 40 °C, and 100 bar on a Lux C3 column (21.2 mm x 250 mm, 5 μm particle size) using 40% methanol to obtain (6S,9R)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged iminecycloheptane[c]pyridine (I-17f) as a pale yellow solid. LCMS (Method 1) m / z 285.3 (M+H) + (ES + At 1.35 minutes, 1¹H 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), 1H is obscured by residual DMSO peaks.

[1606] And (6R,9S)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine (I-17g), a pale yellow solid. LCMS (Method 1) m / z 285.3 (M+H) + (ES + At 1.35 minutes, 1 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), 1H is obscured by residual DMSO peaks.

[1607] Step 6: Using essentially the same steps as in I-13, (6S,9R)-3-fluoro-6,7,8,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine (I-17) was synthesized from (6S,9R)-3-fluoro-6,7,8,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine (I-17f). LCMS (Method 1) m / z 179.2 (M+H) + (ES + ), 0.71 minutes.

[1608] Intermediate 18 (I-18)

[1609]

[1610] (6S,9R)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine I-17 (300 mg, 1.68 mmol) was dissolved in HBr (1.90 mL, 48% w / w aqueous solution, 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 column (20 g), and eluted with a methanolic solution of ammonia (0.7 M) to give (6S,9R)-2,5,6,7,8,9-hexahydro-3H-6,9-bridged imine cyclohepta[c]pyridine-3-one (I-18) as a grayish-white solid. LCMS (Method 1) m / z 176.9 (M+H) + (ES + At 0.41 minutes.

[1611] Intermediate 19 (I-19)

[1612]

[1613] Step 1: At -70°C, LDA (2M, 114ml, 228mmol) was added to a THF (120ml) solution of 25.9ml (190mmol) of 4-chloro-3-fluoropyridine I-19a. The mixture was stirred at -70°C for 3 hours, and then a THF (50ml) solution of 17.5ml (228mmol) of DMF was added. The mixture was slowly heated to room temperature and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C and saturated ammonium chloride (100ml) was added. The aqueous layer was adjusted to pH 6 with HCl (1M) and extracted with MTBE (3 x 100ml). The combined organic layers were washed with brine (100ml), dried over sodium sulfate, and concentrated under vacuum to give 4-chloro-5-fluoroisononiaaldehyde I-19b as a yellow oil. 1 H NMR (400MHz, CDCl3) δ10.4(s,1H),8.87(s,1H),8.69(s,1H).

[1614] Step 2: Using essentially the same steps as I-16b, synthesize N-((4-chloro-5-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-19c from 4-chloro-5-fluoroisononiaaldehyde I-19b. 1 H NMR (400MHz, CDCl3) δ9.02(s,1H),8.93(s,1H),8.59(s,1H),1.30(s,9H).

[1615] Step 3: At 0°C, add but-3-en-1-ylmagnesium bromide (0.5M, 822ml) to a THF (150ml) solution of (E)-N-((4-chloro-5-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-19c (27.0g, 102mmol). Heat the mixture and stir at room temperature for 1 hour. Cool the reaction mixture to 0°C and add water (50ml). Extract the product with EtOAc (3 x 100ml). Separate the organic layer, wash with water (100ml) and brine (100ml), dry with sodium sulfate and concentrate under vacuum. Grind the product with petroleum ether (50ml), filter and wash with petroleum ether (2 x 20ml), and collect the solid. Vacuum drying of the solid yielded N-(1-(4-chloro-5-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-19d, which was 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).

[1616] Step 4: Using essentially the same steps as I-16d, synthesize 1-(4-chloro-5-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-19d from N-(1-(4-chloro-5-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-19d. 1 ¹H NMR (400 MHz, 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 not observed)

[1617] Step 5: Using essentially the same steps as I-16e, synthesize N-(1-(4-(4-(4-chloro-5-fluoropyridin-3-yl)pent-4-en-1-amine I-19e) from 1-(4-chloro-5-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-19f. 1H 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).

[1618] Step 6: Using essentially the same steps as I-16f, synthesize (±)-4-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptane[c]pyridine I-19g from N-(1-(4-bromo-5-fluoropyridin-3-yl)pent-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).

[1619] Step 7: A solution of (±)-4-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine I-19 g (0.150 g, 528 μmol) in MeCN (10 mL) was cooled to 0 °C, and then an aqueous solution of CAN (925 mg, 1.69 mmol) was added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 1 hour. A further aqueous solution of CAN (925 mg, 1.69 mmol) in water (3 mL) was added and the mixture was stirred for 1 hour. The material was packed into an SCX column (20 g), washed with MeOH (40 mL), and eluted with a 0.7 M ammonia solution of MeOH (100 mL) to give (6S,9R)-4-fluoro-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine I-19 as a yellow oil. LCMS (Method 1): m / z 178.9 (M+H) + (ES + At 0.71 minutes.

[1620] Intermediate 20 (I-20)

[1621]

[1622] Step 1: Add sodium methoxide (5.4 M MeOH solution, 391 μl, 2.11 mmol) to a MeOH solution of (6S,9R)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine I-17f (100.0 mg, 351.7 μmol) and heat the reaction mixture at 65 °C for 48 hours. Dilute the reaction mixture with DCM (20 mL) and water (50 mL). Separate the layers and extract the aqueous layer with DCM (3 x 30 mL). Dry the combined organic matter with magnesium sulfate and concentrate under vacuum to give (6S,9R)-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine I-20a as a pale yellow oil. LCMS (Method 2) m / z 297.1 (M+H) + (ES + At 2.14 minutes.

[1623] Step 2: Using essentially the same steps as I-13, (6S,9R)-3-methoxy-6,7,8-9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine I-20a was synthesized from (6S,9R)-3-methoxy-6,7,8-9-tetrahydro-56H-6,9-bridged imine cyclohepta[c]pyridine. LCMS (Method 1) m / z 191.1 (M+H) + (ES + At 1.33 minutes.

[1624] Intermediate 21 (I-21)

[1625]

[1626] Step 1: Using essentially the same steps as I-7b, synthesize (S)-N-((4-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-21a 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).

[1627] Step 2: Using essentially the same steps as I-7c, synthesize (S)-N-((R)-1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-21b and (S)-N-((S)-1-(4-bromopyridin-3-yl)pent-4-en-1-yl)2-methylpropane-2-sulfinamide I-22a from (S)-N-((S)-1-(4-bromopyridin-3-yl)pent-4-en-1-yl)2-methylpropane-2-sulfinamide I-22a. 1 H 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).

[1628] Step 3: Using essentially the same steps as I-7d, synthesize (R)-1-(4-bromopyridin-3-yl)pentyl-4-en-1-yl)-2-methylpropane-2-sulfinamide I-21b from (S)-N-((R)-1-(4-bromopyridin-3-yl)pentyl-4-en-1-yl)-2-methylpropane-2-sulfinamide I-21b. 1 H NMR (400MHz, CDCl3) δ8.70 (s, 1H), 8.27-8.22 (m, 1H), 7.45 (t, J = 5.6Hz, 1H), 5.88-5.8 0(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).

[1629] (NH2 was not observed)

[1630] Step 4: Using essentially the same steps as I-7e, synthesize (R)-N-(1-(4-bromopyridin-3-yl)pent-4-en-1-amine I-21c from (R)-1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-21d. 1¹H NMR (400MHz, CDCl₃) δ 8.68 (s, 1H), 8.40 (d, J = 5.2 Hz, 1H), 7.34 (d, J = 5.2 Hz, 1H), 6.70 (d, J = 9.2 Hz, 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), (NH₃ not observed).

[1631] Step 5: Add a 50 mL solution of Pd2(dba)3 (0.68 g, 0.75 mmol), tricyclohexylphosphine tetrafluoroborate (551 mg, 1.50 mmol), and NaOtBu (5.69 g, 59.2 mmol) in toluene to the flask. Purge the flask with N2 and add dropwise (R)-N-(1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-21d (2.6 g, 7.5 mmol). Heat the resulting mixture to 90 °C for 12 hours. Filter the reaction mixture and wash the filter cake with EtOAc (3 x 50 mL). Concentrate the filtrate under vacuum. The product was purified by silica gel chromatography (10%-100% EtOAc / petroleum ether) to give (6S,9R)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[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).

[1632] Step 6: At 0°C, a solution of CAN (6.67 g, 12.2 mmol) in water (50 ml) was added dropwise to a solution of (6S,9R)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine (I-21e) (1.08 g, 4.05 mmol) in MeCN (50 ml). The reaction mixture was stirred at 0°C for 1 hour, and then heated to room temperature for 1 hour. The reaction mixture was cooled to 0°C, and another portion of the CAN (4.45 g, 8.11 mmol) aqueous solution (20 ml) was added. The mixture was stirred at 0°C for 1 hour. 2M NaOH solution (50 ml) was added, and the mixture was filtered through a diatomaceous earth mat. The layers were separated, and the aqueous layer was extracted with DCM (3 x 100 ml). The combined organic compounds were dried with magnesium sulfate and concentrated under vacuum to obtain (6S,9R)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cyclohepta[c]pyridine I-21, which was 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).

[1633] Intermediate 22 (I-22)

[1634]

[1635] Step 1: Using essentially the same steps as I-7d, synthesize (S)-1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-22a from (S)-N-((S)-1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-22a. 1 H NMR (400MHz, CDCl3) δ 8.56 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 5.2 Hz, 1H), 7.45 (d, J = 5.2 Hz, 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 not observed).

[1636] Step 2: Using essentially the same steps as I-7e, synthesize (S)-N-(1-(4-bromopyridin-3-yl)pent-4-en-1-amine I-22b from (S)-1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-22c. 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).

[1637] Step 3: Using essentially the same steps as I-21e, (6S,9R)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptane[c]pyridine I-22d was synthesized from (S)-N-(1-(4-bromopyridin-3-yl)pent-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).

[1638] Step 4: Using essentially the same steps as I-21, (6S,9R)-6,7,8,9-tetrahydro-5H-6,9-bridged imine cycloheptane[c]pyridine I-22 was synthesized from 1-(4-bromopyridin-3-yl)pent-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) (NH₄⁺ was not observed; 1CH₂ was observed below the DMSO peak).

[1639] Intermediate 23 (I-23)

[1640]

[1641] Step 1: Using essentially the same steps as I-7b, synthesize (S)-N-((3-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-23b from 3-bromo-4-pyridinecarboxaldehyde 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).

[1642] Step 2: To a THF (120 ml) solution of (S)-N-((3-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (I-23b) (6.00 g, 20.7 mmol), magnesium bromide (0.5 M THF solution, 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 EtOAc (3 x 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 (EtOAc / petroleum ether 1%-100%) to obtain a yellow oily substance (S)-N-((R)-1-(3-bromopyridin-3-yl)-4-methylpent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-23c. 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).

[1643] Step 3: Using essentially the same steps as I-7d, synthesize (R)-1-(3-bromopyridin-3-yl)-4-methylpent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-23c from (S)-N-((R)-1-(3-bromopyridin-3-yl)-4-methylpent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-23c. 1H 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).

[1644] Step 4: Using essentially the same steps as I-7e, synthesize (R)-N-(1-(3-bromopyridin-3-yl)-4-methylpent-4-en-1-amine I-23d from (R)-1-(3-bromopyridin-3-yl)-4-methylpent-4-en-1-yl)-4-methoxyaniline I-23e from (R)-1-(3-bromopyridin-3-yl)-4-methylpent-4-en-1-yl)-4-methoxyaniline. 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).

[1645] Step 5: Using essentially the same steps as I-21e, synthesize (5R,8S)-10-(4-methoxyphenyl)-8-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptane[c]pyridine I-23f from (R)-N-(1-(3-bromopyridin-3-yl)-4-methylpent-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).

[1646] Step 6: Using essentially the same steps as I-21, (5R,8S)-8-methyl-6,7,8,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine (I-23) was synthesized from (5R,8S)-10-(4-methoxyphenyl)-8-methyl-6,7,8,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine (I-23f). LCMS (Method 2) m / z 175 (M+H) + (ES + At 1.15 minutes.

[1647] Intermediate 24 (I-24)

[1648]

[1649] Step 1: At 0 °C, 1-cyclopropylethane-1-ol (11.3 ml, 116 mmol) was dissolved in an aqueous HBr solution (45 ml, 47% w / w). The mixture was heated to room temperature for 12 hours. The product was distilled under vacuum (60 °C, 750 Torr) to give a mixture of (E)-5-bromopent-2-ene I-24b and (Z)-5-bromopent-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).

[1650] Step 2: At 20°C, add a mixture of (E)-5-bromopent-2-ene I-24b and (Z)-5-bromopent-2-ene I-24c (25.0 g, 167 mmol) in 100 ml of THF to a THF solution of I2 (1.69 ml, 8.39 mmol) and Mg (8.66 g, 356 mmol). Stir the mixture at 40°C for 1 hour. The crude mixture of (E)-pent-3-en-1-ylmagnesium bromide I-24d and (Z)-pent-3-en-1-ylmagnesium I-24e can be used for the next step without any treatment or further purification.

[1651] Step 3: Using essentially the same steps as I-7c, synthesize (S)-N-((R,E)-1-(3-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-23b, (E)-pent-3-en-1-ylmagnesium bromide I-24d, and (Z)-pent-3-en-1-ylmagnesium I-24e from a mixture of (S,E)-N-((R,Z)-1-(3-bromopyridin-4-yl)hex-4-en-1-yl)-2-methylpropane-2-sulfinamide I-24f and (S)-N-((R,Z)-1-(3-bromopyridin-4-yl)hex-4-en-1-yl)-2-methylpropane-2-sulfinamide I-24g. The data for I-24f and I-24g are a small fraction 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).

[1652] Step 4: Using essentially the same steps as I-7d, synthesize (R,E)-1-(3-bromopyridin-4-yl)hex-4-en-1-yl)-2-methylpropane-2-sulfinamide I-24f and (S)-N-((R,Z)-1-(3-bromopyridin-4-yl)hex-4-en-1-yl)2-methylpropane-2-sulfinamide I-24g to synthesize (R,E)-1-(3-bromopyridin-4-yl)hex-4-en-1-amine I-24h and (R,Z)-1-(3-bromopyridin-4-yl)hex-4-en-1-amine I-24i.

[1653] Step 5: Using essentially the same steps as I-7e, combine (R,E)-1-(3-bromopyridin-4-yl)hex-4-en-1-amine I-24h and (R,Z)-1-(3-bromopyridin-4-yl)hex-4-en-1-amine I-24i with (R,E)-N-(1-(3-bromopyridin-4-yl)hex-4-en-1-yl)-4-methoxyaniline I-24j and (R,Z)-N-(1-(3-bromopyridin-4-yl)hex-4-en-1-yl)-4-methylaniline I-24k. The data for I-24j and I-24k are a small fraction of the mixture. 1H 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).

[1654] Step 6: At room temperature, add NaOtBu (287 mg, 2.99 mmol) and Pd-178 (71.3 mg, 149 μmol) to a solution of ((R,E)-N-(1-(3-bromopyridin-4-yl)hex-4-en-1-yl)-4-methoxyaniline I-24j and (R,Z)-N-(1-(3-bromopyridin-4-yl)hex-4-en-1-yl)-4-methylaniline I-24k (0.54 g, 1.49 mmol) in dioxane (5 mL). Heat the mixture at 105 °C for 16 hours. Filter the reaction mixture and wash the filter cake with EtOAc (3 x 50 mL). Concentrate the filtrate under vacuum. Analyze the residue by preparative HPLC (30-60% MeCN / 10 mM). Purification with NH4HCO3 yielded (5R,8S,9R)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine I-24l, a white solid, and (5R,8S,9S)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cycloheptan[c]pyridine I-24k, both white solids.

[1655] (5R,8S,9S)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[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).

[1656] (5R,8S,9S)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-bridged imine cyclohepta[c]pyridine I-24k: 1H 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...

Claims

1. A compound of formula (If) or a pharmaceutically acceptable salt thereof, (If) in: Ring A is a pyridyl ring or its tautomer, or a benzene ring, each optionally selected from H, F, Cl, Br, I, CN, C. 1-6 Alkoxy, NR 11 R 11 '、OH、C 1-6 Alkyl, phenyl and C 1-6 One or more substituents of the haloalkyl group are used for substitution; Y is selected from C=N-OH and CR 10 R 10 ', where R 10 and R 10 Each is independently selected from H, F, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R a and R b Each is independently selected from H and C. 1-6 alkyl; R1, R4, and R5 are each independently selected from H, CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl halogens, OH, F, Cl, Br, and I; R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, and C. 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl, C 6-12 Aryl, heteroaryl, O-C 6-12 Aryl, NHCO-CH=CH2 and CO2-C 1-6 Alkyl, wherein the C 6-12 Aryl, heteroaryl and O-C 6-12 Each aryl group is optionally and independently selected from halogenated, C 1-6 Alkyl and C 1-6 One or more alkoxy groups are substituted; and R 11 and R 11 Each is independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and CO2R 12 , where R 12 C 1-6 alkyl; Here, heteroaryl is defined as a monocyclic or bicyclic C containing one or more heteroatoms. 2-12 An aromatic ring, wherein the one or more heteroatoms may be the same or different, and wherein the one or more heteroatoms are selected from oxygen, nitrogen or sulfur.

2. The compound according to claim 1, wherein ring A is selected from the following: R6, R7, R8, and R9 are each independently selected from H, F, Cl, Br, I, CN, and C. 1-6 Alkoxy, NR 11 R 11 '、OH、C 1-6 Alkyl, phenyl and C 1-6 Halogenated alkyl groups, and R 14 Is it H or C? 1-6 alkyl.

3. A compound of formula (Ib), or a pharmaceutically acceptable salt thereof, (Ib) in: Ring A is selected from group (i)-(xx): R6, R7, R8, and R9 are each independently selected from H, F, Cl, Br, I, CN, and C. 1-6 Alkoxy, NR 11 R 11 '、OH、C 1-6 Alkyl, phenyl and C 1-6 Halogenated alkyl groups, and R 14 For H or C 1-6 alkyl; Y is selected from C=N-OH and CR 10 R 10 ', where R 10 and R 10 Each is independently selected from H, F, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R a and R b Each is independently selected from H and C. 1-6 alkyl; R1, R4, and R5 are each independently selected from H, CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl halogens, OH, F, Cl, Br, and I; R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, and C. 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl, C 6-12 Aryl, heteroaryl, OC 6-12 Aryl, NHCO-CH=CH2 and CO2-C 1-6 Alkyl, wherein the C 6-12 Aryl, heteroaryl and OC 6-12 Each aryl group may optionally be further independently selected from halogenated, C-shaped, or other alkyl groups. 1-6 Alkyl and C 1-6 One or more alkoxy groups are substituted; and R 11 and R 11 Each is independently selected from H and C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and CO2R 12 , where R 12 C 1-6 alkyl; Here, heteroaryl is defined as a monocyclic or bicyclic C containing one or more heteroatoms. 2-12 An aromatic ring, wherein the one or more heteroatoms may be the same or different, and wherein the one or more heteroatoms are selected from oxygen, nitrogen or sulfur.

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

5. The compound according to claim 4, wherein ring A is selected from (i), (ii), (iii), (v), (vi) and (ix).

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

7. The compound according to any one of claims 1 to 6, wherein it is of formula (Ib)-(ii): (Ib)-(ii) Among them, Y and R a R b R1-R5 are as defined in claim 1, and R6, R7 and R9 are as defined in claim 2.

8. The compound according to any one of claims 1 to 6, wherein it is of formula (Ib)-(i): (Ib)-(i) Among them, Y and R a R b R1-R5 are as defined in claim 1, and R6-R9 are as defined in claim 2.

9. The compound according to any one of claims 1 to 6, wherein it is of formula (Ib)-(vi): (Ib)-(vi) Among them, Y and R a R b R1-R5 are as defined in claim 1, and R6, R8 and R9 are as defined in claim 2.

10. The compound according to any one of claims 1 to 6, wherein it is of formula (Ib)-(ix): (Ib)-(ix) Among them, Y and R a R b R1-R5 as defined in claim 1, and R6, R9 and R 14 As defined in claim 2.

11. The compound according to any one of claims 1 to 6, wherein Y is selected from CH2 and C=N-OH.

12. The compound according to claim 11, wherein Y is CH2.

13. The compound according to any one of claims 1 to 6, wherein 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 CO2Me, wherein the Ph, OPh, pyrazolyl, oxazolyl, and thiazolyl groups are each optionally surrounded by one or more C 1-6 The alkyl group is further substituted.

14. The compound according to any one of claims 1 to 6, wherein R2 and R3 are each independently selected from F, Cl, Br, I, CN, C1-C6 haloalkyl, C1-C6 haloalkoxy and CO2-C 1-6 alkyl.

15. The compound according to any one of claims 1 to 6, wherein R2 and R3 are each independently selected from Cl, Br and CF3.

16. The compound according to claim 15, wherein R2 and R3 are each independently selected from Cl and CF3.

17. The compound according to any one of claims 1 to 6, wherein R2 and R3 are both Cl, or one of R2 and R3 is Cl and the other is selected from OCF3, CO2Me, OCHF2 and CF3.

18. The compound according to any one of claims 1 to 6, wherein R1 and R4 are both H.

19. The compound according to any one of claims 1 to 6, wherein R5 is selected from H, F, Me, MeO, Cl, OH and CN.

20. The compound according to claim 19, wherein R5 is H or F.

21. The compound according to claim 20, wherein R5 is H.

22. The compound according to any one of claims 2 to 6, wherein R6, R7, R8 and R9 are each independently selected from H, F, Cl, Br, CN, OMe, NH2, NHBu, NHCO2Bu and OH.

23. The compound according to claim 1 or 2, wherein it is of formula (Ib.1) or a mixture of enantiomer-enriched compounds of formula (Ib.1): (Ib.1) 24. The compound according to any one of claims 3 to 6, wherein it is of formula (Ib.1) or a mixture of enantiomer-enriched compounds of formula (Ib.1): (Ib.1) 25. The compound according to claim 3, wherein the compound is selected from the following substances and their enantiomers, mixtures of their enantiomers, and pharmaceutically acceptable salts thereof, wherein the mixtures of their enantiomers include racemic mixtures:

26. A compound of formula (Ie) or a pharmaceutically acceptable salt thereof, (Ie) in: Ring A is R6 and R8 are each independently selected from H, F, Cl, Br, I, CN, and C. 1-6 Alkoxy, OH, phenyl and C 1-6 Halogenated alkyl groups; Y is selected from C=N-OH and CR 10 R 10 ', where R 10 and R 10 Each is independently selected from H, F, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R a and R b Each is independently selected from H and C. 1-6 alkyl; R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I; and R2 and R3 are each independently selected from Cl, Br, I, CN, and C. 1-6 Halogenated alkyl groups; The condition is that when Y is CH2 and R a R b When R1, R4, R5, R6, and R8 are all H: When R2 is Cl, R3 is not CN; and R2 and R3 are not both Cl.

27. The compound according to claim 26, wherein R2 and R3 are each independently selected from Cl, Br, I, CN, and C. 1-6 Halogenated alkyl groups.

28. The compound according to claim 26, wherein R2 is selected from Cl, Br and CF3.

29. The compound according to claim 28, wherein R2 is selected from Cl and CF3.

30. The compound according to claim 26, wherein R3 is selected from Cl, Br, CN and CF3.

31. The compound according to claim 30, wherein R3 is selected from Cl and CF3.

32. The compound according to claim 26, wherein R1, R4 and R5 are all H.

33. The compound according to claim 26, wherein Y is selected from CH2 and CHF.

34. The compound according to claim 33, wherein Y is CH2.

35. The compound according to claim 26, wherein R6 is H.

36. The compound according to claim 26, wherein R8 is selected from H, CF3, phenyl, OH and F.

37. The compound according to claim 26, wherein R8 is OH, and ring A is: 。 38. The compound according to any one of claims 26 to 37, wherein it is of formula (Ie.1) or a mixture of enantiomer-enriched formula (Ie.1) compounds: (Ie.1).

39. A compound selected from the group consisting of substances and their enantiomers, mixtures of their enantiomers, and pharmaceutically acceptable salts thereof, wherein the mixtures of their enantiomers comprise racemic mixtures:

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

41. The pharmaceutical composition of claim 40, comprising a pharmaceutically acceptable diluent.

42. Use of the compound according to any one of claims 1 to 39 or the pharmaceutical composition according to claim 40 in the preparation of a medicament for treating or preventing GPR65-related conditions selected from cancer, autoimmune diseases, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).

43. The use according to claim 42, wherein the use includes adjusting GPR65.

44. The use according to claim 43, wherein the use includes suppressing GPR65 signal conduction.

45. The use according to claim 42, wherein the GPR65-related condition is cancer.

46. ​​The use according to claim 45, wherein the cancer is a solid tumor and / or its metastatic tumor.

47. According to the use described in claim 45, the cancer is selected from the following: melanoma, renal cell carcinoma (RCC), gastric cancer, acute myeloid leukemia (AML), triple-negative breast cancer (TNBC), colorectal cancer, head and neck cancer, colorectal adenocarcinoma, pancreatic cancer, sarcoma, lung cancer, ovarian cancer, and glioma.

48. The use according to claim 47, wherein the cancer is glioblastoma (GBM).

49. The use according to claim 42, wherein the GPR65-related condition is an autoimmune disease.

50. The use according to claim 49, wherein the autoimmune disease is selected from: psoriasis, psoriatic arthritis, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), autoimmune thyroiditis, Graves' disease, uveitis, ulcerative colitis, Crohn's disease, autoimmune uveoretinitis, systemic vasculitis, polymyositis dermatomyositis, scleroderma, Sjögren's syndrome, ankylosing spondylitis and related spondyloarthropathy, sarcoidosis, autoimmune hemolytic anemia, immune thrombocytopenic purpura, and autoimmune polyendocrine disorders.

51. The use according to claim 50, wherein the autoimmune thyroiditis is Hashimoto's thyroiditis.

52. The use according to claim 50, wherein the uveitis is intermediate uveitis.

53. The use according to claim 50, wherein the scleroderma is systemic sclerosis.

54. The use according to claim 50, wherein the autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and multiple sclerosis (MS).

55. The use according to claim 42, wherein the GPR65-related condition is selected from asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS).

56. Use of compounds selected from the following, their enantiomers, mixtures of their enantiomers, and pharmaceutically acceptable salts thereof, in the preparation of medicaments for the treatment or prevention of GPR65-related conditions selected from cancer, autoimmune diseases, asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS), wherein the mixtures of their enantiomers comprise racemic mixtures:

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