RU2848371C1 - N-phenylaminocarbonylpyridine-, pyrimidine- and benzotropane as gpr65 modulators - Google Patents

Abstract

FIELD: compounds of formula (If) or a pharmaceutically acceptable salt thereof

SUBSTANCE: wherein ring A is a pyridinyl ring or its tautomeric form or a phenyl ring, and is selected from groups (i)-(xvii), (xix), (xx):

as well as a pharmaceutical composition having GPR65 signalling pathway inhibitory activity, and their use in the manufacture of a medicament for treating or preventing a GPR65-associated disease or disorder in a subject.

EFFECT: new compounds that can be used to treat or prevent GPR65-associated disease.

46 cl, 2 dwg, 1 tbl

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to compounds capable of modulating GPR65. These compounds may find medical use in the treatment of a number of disorders, including proliferative and immune disorders.

LEVEL OF TECHNOLOGY

GPR65 is a Gs-coupled receptor (GPCR) that is primarily expressed in immune cells and is activated at acidic extracellular pH, causing an increase in cytoplasmic cyclic adenosine monophosphate (cAMP) (Wang, 2004). It has long been known that tumors typically undergo a switch in cellular metabolism from oxidative phosphorylation to aerobic glycolysis, which in turn leads to an acidic extracellular microenvironment (Damaghi, 2013). Recently, it was shown that this acidic microenvironment induces GPR65 activation in tumor-associated macrophages, resulting in an increase in cytoplasmic cAMP, which leads to the transcription of the inducible early repressor of cAMP (ICER). This, in turn, suppresses the secretion of tumor necrosis factor alpha (TNFα), shifting macrophages toward an anti-inflammatory, tumor-permissive phenotype (Bohn, 2018). Therefore, this GPR65-dependent pathway appears to be a mechanism by which tumors exploit their acidic microenvironment to evade immune detection.

Autoimmune diseases are also often associated with an acidic local microenvironment (e.g., with inflamed joints). Recent studies also suggest that GPR65 acts through ICER in CD4+ T cells to suppress IL-2 and, consequently, shift cells toward an inflammatory Th17 phenotype, which, in the context of autoimmune disease, is associated with increased pathogenicity (Korn, 2009). This is supported by recent findings that ICER is required for Th17 differentiation (Yoshida, 2016) and that GPR65 agonism leads to increased Th17 differentiation (Hernandez, 2018). Indeed, mutations in the GPR65 locus are associated with several autoimmune diseases, such as multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, and Crohn's disease (Gaublomme, 2015). One recent study found that mice with CD4+ T cells that were deficient in GPR65 were protected from developing autoimmune encephalomyelitis (EAE) (Gaublomme, 2015).

Thus, GPR65 appears to act through ICER, activating an anti-inflammatory and antitumor phenotype in tumor-associated macrophages and an inflammatory Th17 phenotype in CD4+ T cells, which is associated with autoimmune disease. Consequently, the GPR65 signaling pathway represents a promising therapeutic target for the treatment of both cancer and autoimmune diseases. Therefore, there is an ongoing need to develop new small-molecule modulators of GPR65.

The present invention addresses the challenge of developing compounds capable of modulating GPR65. From the above discussion, it is clear that such compounds could find medical application in the treatment of various diseases, including proliferative and immune disorders, as well as asthma and chronic obstructive pulmonary disease.

ESSENCE OF THE INVENTION

The first aspect of the invention relates to a compound of formula (If) or a pharmaceutically acceptable salt or solvate thereof,

Where:

ring A is a pyridinyl ring or a tautomer thereof, or a phenyl ring, each of which may be optionally substituted with one or more substituents selected from H, F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, phenyl and haloalkyl;

Y is selected from _CH2 , C=N-OH and _CR10R10 ', where _R10 and _R10 ' are each independently selected from H, _F , alkyl and haloalkyl;

R _a and R _b are each independently selected from H and alkyl;

R ₁ , R ₄ , and R ₅ are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, F, Cl, Br, and I;

R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl and CO ₂ -alkyl, wherein said aryl, heteroaryl and O-aryl groups are each optionally further substituted with one or more groups optionally selected from halogen, alkyl and alkoxy; and

R ₁₁ and R ₁₁ ' are each independently selected from H, alkyl, haloalkyl, COR ₁₂ , CO ₂ R ₁₂ and SO ₂ R ₁₃ , where R ₁₂ and R ₁₃ are both independently alkyl.

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

Where:

ring A is selected from groups (i)-(xx):

wherein R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from H, F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, phenyl and haloalkyl, and R ₁₄ is H or alkyl;

Y is selected from _CH2 , C=N-OH and _CR10R10 ', where _R10 and _R10 ' are each independently selected from H, _F , alkyl and haloalkyl;

R _a and R _b are each independently selected from H and alkyl;

R ₁ , R ₄ , and R ₅ are each independently selected from H, CN, alkyl, haloalkyl, alkoxy, OH, F, Cl, Br, and I;

R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl and CO ₂ -alkyl, wherein said aryl, heteroaryl and O-aryl groups are each optionally further substituted with one or more groups optionally selected from halogen, alkyl and alkoxy; and

R ₁₁ and R ₁₁ ' are each independently selected from H, alkyl, haloalkyl, COR ₁₂ , CO ₂ R ₁₂ and SO ₂ R ₁₃ , where R ₁₂ and R ₁₃ are both independently alkyl.

The third aspect of the invention relates to a compound of formula (Ie) or a pharmaceutically acceptable salt or solvate thereof,

Where:

ring A is

where R ₆ and R ₈ are each independently selected from H, F, Cl, Br, I, CN, alkoxy, OH, phenyl and haloalkyl (more preferably CF ₃ );

Y is selected from _CH2 , C=N-OH and _CR10R10 ', where _R10 and _R10 ' are each independently selected from H, _F , alkyl and haloalkyl;

R _a and R _b are each independently selected from H and alkyl;

R ₁ , R ₄ , and R ₅ are each independently selected from H, F, Cl, Br, and I; and

R ₂ and R ₃ are each independently selected from F, Cl, Br, I, CN, methoxy and haloalkyl;

provided that when Y is CH₂, and R_a, R_b, R₁, R₄, R₅, R₆and R₈all represent H:

R ₃ is not CN when R ₂ is Cl; and

R ₂ and R ₃ are both not Cl.

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

Where:

ring A is a 5 or 6 membered aromatic or heteroaromatic ring, wherein said aromatic or heteroaromatic ring is optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, haloalkyl, aralkyl, aryl and heteroaryl, and wherein said aryl and heteroaryl substituents are in turn optionally substituted with one or more substituents, each of which is independently selected from F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, haloalkyl and aralkyl;

Y is selected from _CH2 , C=N-OH and _CR10R10 ', where _R10 and _R10 ' are each independently selected from H, _F , alkyl and haloalkyl;

R ₁ , R ₄ and R ₅ are each independently selected from H, F, Cl, Br and I;

R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, CN, methoxy and haloalkyl; and

R ₁₁ and R ₁₁ ' are each independently selected from H, alkyl, haloalkyl, COR ₁₂ and SO ₂ R ₁₃ , where R ₁₂ and R ₁₃ are both alkyl;

where when Y is CH ₂ , and ring A is:

where R ₆ and R ₈ are both H,

- R ₂ and R ₃ are not both Cl when R ₁ , R ₄ and R ₅ are all H;

- R ₃ is not Cl when R ₁ , R ₂ , R ₄ and R ₅ are all H;

- R ₂ is not Cl when R ₁ , R ₃ , R ₄ and R ₅ are all H;

- R ₁ is not Cl when R ₂ , R ₃ , R ₄ and R ₅ are all H;

- R ₁ is not F when R ₄ is Cl, and R ₂ , R ₃ , and R ₅ are all H.

Preferably, the compounds claimed in the present invention would be capable of modulating GPR65 and would therefore be of therapeutic interest in the treatment of various diseases, for example in the field of oncology, immuno-oncology and immunology.

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

Where:

ring A is

wherein R ₆ and R ₈ are each independently selected from H, F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, phenyl, and haloalkyl, provided that at least one of R ₆ and R ₈ is not H;

Y is selected from _CH2 , C=N-OH and _CR10R10 ', where _R10 and _R10 ' are each independently selected from H, _F , alkyl and haloalkyl;

R ₁ , R ₄ , and R ₅ are each independently selected from H, F, Cl, Br, and I;

R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, CN, methoxy and haloalkyl; and

R ₁₁ and R ₁₁ ' are each independently selected from H, alkyl, haloalkyl, COR ₁₂ and SO ₂ R ₁₃ , where R ₁₂ and R ₁₃ are both alkyl.

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

Where:

ring A is

where R ₆ and R ₈ are each independently selected from H, F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, phenyl, and haloalkyl;

Y is selected from _CH2 , C=N-OH and _CR10R10 ', where _R10 and _R10 ' are each independently selected from H, _F , alkyl and haloalkyl;

R ₁ , R ₄ , and R ₅ are each independently selected from H, F, Cl, Br, and I;

R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, CN, methoxy and haloalkyl, provided that at least one of R ₂ and R ₃ is selected from CN, methoxy and haloalkyl; and

R ₁₁ and R ₁₁ ' are each independently selected from H, alkyl, haloalkyl, COR ₁₂ and SO ₂ R ₁₃ , where R ₁₂ and R ₁₃ are both alkyl.

Another aspect of the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof,

Where:

ring A is a 5 or 6 membered aromatic or heteroaromatic ring, wherein said aromatic or heteroaromatic ring is optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, haloalkyl, aralkyl, aryl and heteroaryl, and wherein said aryl and heteroaryl substituents are in turn optionally substituted with one or more substituents, each of which is independently selected from F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, haloalkyl and aralkyl;

Y is selected from _CH2 , C=N-OH and _CR10R10 ', where _R10 and _R10 ' are each independently selected from H, _F , alkyl and haloalkyl;

R ₁ , R ₄ , and R ₅ are each independently selected from H, F, Cl, Br, and I;

R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, CN, methoxy and haloalkyl; and

R ₁₁ and R ₁₁ ' are each independently selected from H, alkyl, haloalkyl, COR ₁₂ and SO ₂ R ₁₃ , where R ₁₂ and R ₁₃ are both alkyl;

for use as a medicinal product.

Another aspect of the invention relates to a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If) as described above for use as a medicinal product.

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

Another aspect of the invention relates to the above-described compound for use, which has the formula (I.1):

where A, Y and R ₁ -R ₅ are defined above.

Another aspect of the invention relates to the above-described compound for use, which has the formula (I.2):

(I.2)

where A, Y and R ₁ -R ₅ are defined above.

Another aspect of the invention relates to a pharmaceutical composition comprising the compound described above and a pharmaceutically acceptable diluent, excipient or carrier.

Another aspect of the invention relates to the above-described pharmaceutical composition for use as a medicinal product.

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

Another aspect of the invention relates to a method of treating a disorder comprising administering to a subject the compound or pharmaceutical composition described above.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds that are capable of modulating GPR65.

"Alkyl" is defined in the invention as a linear or branched alkyl radical, preferably C _1-20 alkyl, more preferably C _1-12 alkyl, even more preferably C _1-10 alkyl or C _1-6 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl. More preferably, alkyl is C _1-3 alkyl.

As used herein, the term "aryl" refers to a C _6-12 aromatic group which may be benzo-fused, such as phenyl or naphthyl.

"Haloalkyl" is defined in the invention as a linear or branched alkyl radical as defined above, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, which is substituted by one or more halogen atoms (which may be the same or different), such as fluorine, chlorine, bromine and iodine. Preferably, the haloalkyl is a C _1-20 haloalkyl, more preferably a C _1-12 haloalkyl, even more preferably a C _1-10 haloalkyl or a C _1-6 haloalkyl, or a C _1-3 haloalkyl. Preferred examples are CF ₃ and CHF ₂ , with CF ₃ being particularly preferred.

"Alkoxy" is defined in the invention as an oxygen atom attached to an alkyl group as defined above, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy and hexoxy. Preferably, alkoxy is C _1-20 alkoxy, more preferably C _1-12 alkoxy, even more preferably C _1-10 alkoxy or C _1-6 alkoxy, or C _1-3 alkoxy. A particularly preferred example is methoxy (-OCH ₃ ).

"Heteroaryl" is defined herein as a monocyclic or bicyclic C _2-12 aromatic ring comprising one or more heteroatoms (which may be the same or different) such as oxygen, nitrogen or sulfur. Examples of suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyridinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and benzo derivatives thereof such as benzofuranyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl and the like; or pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like, and their benzo derivatives such as quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl and the like.

"Aralkyl" is defined herein as an alkyl group, as defined above, substituted by one or more aryl groups, as defined above.

In formulas (Ia), (Ib), (Ic), (Id) and (Ie), it is preferred that alkyl is C1 _{- C6} alkyl, haloalkyl is C1 _{- C6} haloalkyl, and alkoxy is C1 _{- C6} alkoxy.

Representation of the compound structure

The compounds of the invention include a structure in which ring A is an optionally substituted 5- or 6-membered aromatic or heteroaromatic ring fused with a bicyclic nitrogen-containing moiety to form a tricyclic structure. The resulting tricyclic structure can exist in two different configurations, depicted below (for convenience, the bridging substituents R _a and R _b are not shown in the following presentations):

For the avoidance of doubt, the invention includes compounds in one of the two configurations given above, as well as mixtures thereof, including racemic mixtures.

Alternatively, the structure could be represented, for example, as follows:

For the avoidance of doubt, the invention includes compounds of the above configuration, as well as their corresponding enantiomers and mixtures thereof, including racemic mixtures. For ease of presentation, specific examples of compounds of the invention used in the invention, depicted in the above configuration (I.3), refer to mixtures of both enantiomers (in particular, to the racemate), while the corresponding enantiomers, when synthesized and separated, are depicted either in the configuration (I.1) or in the configuration (I.2), with bonds depicted as a solid wedge or as a dotted wedge, respectively.

The compounds described in the invention contain an 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. Optimal substituents are selected from halogen, CN, alkoxy, NR ₁₁ R _11' , OH, alkyl, phenyl, and haloalkyl. In some cases, ring A may exist in more than one tautomeric form. As an illustration, in the case where the heteroaromatic ring is substituted with an OH group, ring A can exist in the form of two possible tautomers, depicted below:

The 2-pyridone tautomer is believed to be the dominant form in the solid state. In solution, the energy difference between the two tautomeric forms is very small and depends on the polarity of the solvent. It is obvious to those skilled in the art that other hydroxy-substituted N-containing heteroaromatic groups (e.g., pyrimidine, other regioisomers of pyridine) can similarly exist in the tautomeric form shown above. As used herein, the term "heteroaromatic compound" encompasses all tautomeric forms of the compounds.

Preferred is the ring A defined in the invention, in which the wavy lines indicate attachment to a ring containing N and Y:

Compounds of formula (If)

One aspect of the invention relates to a compound of formula (If) or a pharmaceutically acceptable salt or solvate thereof,

Where:

ring A is a pyridinyl ring or a tautomer thereof, or a phenyl ring, each of which may be optionally substituted with one or more substituents selected from H, F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, phenyl and haloalkyl;

Y is selected from _CH2 , C=N-OH and _CR10R10 ', where _R10 and _R10 ' are each independently selected from H, _F , alkyl and haloalkyl;

R _a and R _b are each independently selected from H and alkyl;

R ₁ , R ₄ and R ₅ are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, F, Cl, Br and I;

R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl and CO ₂ -alkyl, wherein said aryl, heteroaryl and O-aryl groups are each optionally further substituted with one or more groups optionally selected from halogen, alkyl and alkoxy; and

R ₁₁ and R ₁₁ ' are each independently selected from H, alkyl, haloalkyl, COR ₁₂ , CO ₂ R ₁₂ and SO ₂ R ₁₃ , where R ₁₂ and R ₁₃ are both independently alkyl.

In one preferred embodiment, ring A is a hydroxy-substituted pyridinyl group, which may exist in a tautomeric form, such as that depicted above in the section entitled "Structural Representation of Compounds." It will be apparent to those skilled in the art that other regioisomers of hydroxy-substituted pyridinyl groups may similarly be represented in tautomeric form (see groups (viii)-(xii) and (xx) below).

In a preferred embodiment, ring A is selected from the following rings:

where R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from H, F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, phenyl and haloalkyl, and R ₁₄ is H or alkyl, more preferably H.

Still other preferred embodiments are presented below with respect to compounds of formula (Ib). In particular, preferred definitions for the groups R _1-9 , R ₁₄ , A, Y, R _a and R _b are presented below for compounds of formula (Ib).

Compounds of formula (Ib)

One aspect of the invention relates to a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof,

Where:

ring A is selected from groups (i)-(xx):

wherein R ₆ , R ₇ , R ₈ , and R ₉ are each independently selected from H, F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, phenyl, and haloalkyl, and R ₁₄ is H or alkyl;

Y is selected from _CH2 , C=N-OH and _CR10R10 ', where _R10 and _R10 ' are each independently selected from H, _F , alkyl and haloalkyl;

R _a and R _b are each independently selected from H and alkyl;

R ₁ , R ₄ , and R ₅ are each independently selected from H, CN, alkyl, haloalkyl, alkoxy, OH, F, Cl, Br, and I;

R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl and CO ₂ -alkyl, wherein said aryl, heteroaryl and O-aryl groups are each optionally further substituted with one or more groups optionally selected from halogen, alkyl and alkoxy; and

R ₁₁ and R ₁₁ ' are each independently selected from H, alkyl, haloalkyl, COR ₁₂ , CO ₂ R ₁₂ and SO ₂ R ₁₃ , where R ₁₂ and R ₁₃ are both alkyl.

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

In one 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 is even more preferably selected from (i), (ii), (vi) and (ix).

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

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

In one preferred embodiment, ring A is selected from (ii), (vi) and (ix).

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

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

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

In one preferred embodiment, the compound has formula (Ib)-(ii):

where Y, R _a , R _b , R ₁ -R ₇ and R ₉ are as defined above. In one preferred embodiment, R ₆ , R ₇ and R ₉ are all H. In one particularly preferred embodiment, R ₉ is F and R ₆ and R ₇ are both H.

In one preferred embodiment, the compound has formula (Ib)-(i):

where Y, R _a , R _b , R ₁ -R ₉ are defined above. In one preferred embodiment, R ₆ , R ₇ and R ₉ are all H, and R ₈ is selected from H, OMe, OH, Cl, CN, F and NH ₂ .

In one preferred embodiment, the compound has the formula (Ib)-(vi):

wherein Y, R _a , R _b , R ₁ -R ₆ , R ₈ and R ₉ are as defined above. In one preferred embodiment, R ₆ , R ₈ and R ₉ are each independently selected from H, F, Cl, NH ₂ , Br and OMe, and more preferably from H and F. In one particularly preferred embodiment, R ₆ , R ₈ and R ₉ are all H.

In one preferred embodiment, the compound has formula (Ib)-(ix):

where Y, R _a , R _b , R ₁ -R ₆ , R ₉ and R ₁₄ are as defined above. In one preferred embodiment, R ₆ and R ₉ are both H, and R ₁₄ is H or Me, more preferably Me. In one preferred embodiment, R ₆ is H, R ₉ is F, and R ₁₄ is H or Me, more preferably Me.

In one preferred embodiment, R _a and R _b are each independently selected from H and methyl. In one preferred embodiment, one of R _a and R _b is alkyl (more preferably methyl) and the other is H. In one particularly preferred embodiment, R _a and R _b are both H.

In one preferred embodiment, R ₁₁ and R ₁₁ ' are selected from H and alkyl, and more preferably selected from H and Me, even more preferably R ₁₁ and R ₁₁ ' are both H.

In one preferred embodiment, Y is CR ₁₀ R ₁₀ ', where R ₁₀ and R ₁₀ ' are each independently selected from H, F, Me and CF ₃ , and more preferably selected from H, F and Me. In one preferred embodiment, Y is selected from CH ₂ , CHF, CHMe and C=N-OH. In one preferred embodiment, Y is selected from CH ₂ and C=N-OH. More preferably, Y is CH ₂ .

In one preferred embodiment, at least one of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ is not H.

In one preferred embodiment, one of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ is not H.

In one preferred embodiment, two of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are not H.

In one preferred embodiment, three of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are not H.

In one preferred embodiment, R ₂ and R ₃ are each independently selected from H, F, Cl, Br, CN, methoxy, OCF ₃ , CF ₃ , OCHF ₂ , Me, Ph, pyrazolyl, oxazolyl, thiazolyl, OPh, NHCO-CH=CH ₂ and CO ₂ Me, wherein said Ph, OPh, pyrazolyl, oxazolyl and thiazolyl groups are each optionally further substituted with one or more alkyl groups.

In one preferred embodiment, R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, CN, methoxy, haloalkyl, haloalkoxy, and CO ₂ -alkyl.

In one preferred embodiment, R ₃ is selected from H, F, Cl, Br, CN, methoxy, OCF ₃ , CF ₃ , OCHF ₂ , Me, Ph, pyrazolyl, oxazolyl, thiazolyl, OPh, NHCO-CH=CH ₂ and CO ₂ Me, wherein said Ph, OPh, pyrazolyl, oxazolyl and thiazolyl groups are each optionally further substituted with one or more alkyl groups. Preferably, the pyrazolyl group is a 1H-pyrazol-1-yl group. Preferably, the oxazolyl group is an oxazol-5-yl group. Preferably, the thiazolyl group is a thiazol-4-yl group.

In one preferred embodiment, R ₂ is selected from H, F, Cl, Br, CN, Me, methoxy, OCF ₃ , CF ₃ , OCHF ₂ , Ph, pyrazolyl and CO ₂ Me, wherein said Ph and pyrazolyl groups are each optionally further substituted with one or more alkyl groups. Preferably, the pyrazolyl group is a 1H-pyrazol-1-yl group.

In one preferred embodiment, R ₂ and R ₃ are each independently selected from F, Cl, Br, I, CN, CO ₂ -alkyl, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy.

In one preferred embodiment, R ₂ and R ₃ are each independently selected from F, Cl, Br, I, CN, and C ₁ -C ₆ haloalkyl.

In one preferred embodiment, R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl.

In one preferred embodiment, R ₂ and R ₃ are each independently selected from Cl, Br, and CF ₃ , and more preferably, independently selected from Cl and CF ₃ .

In one preferred embodiment, one of R ₂ and R ₃ is Cl and the other is OCF ₃ or OCHF ₂ .

In one preferred embodiment, one of R ₂ and R ₃ is Cl and the other is CO ₂ Me.

In one preferred embodiment, R ₂ and R ₃ are both Cl, or one of R ₂ and R ₃ is Cl and the other is CF ₃ .

In one preferred embodiment, R ₂ and R ₃ are both Cl.

In one preferred embodiment, one of R ₂ and R ₃ is Cl and the other is CF ₃ .

In one preferred embodiment, one of R ₂ and R ₃ is Cl and the other is selected from OCF ₃ , CO ₂ Me, OCHF ₂ and CF ₃ .

In one preferred embodiment, R ₁ , R ₄ and R ₅ are each independently selected from H, alkyl, alkoxy, OH, F, Cl, Br and I.

In one preferred embodiment, R ₁ , R ₄ and R ₅ are each independently selected from H, Me, OMe, OH, F, Cl, Br and I.

In one preferred embodiment, R ₁ , R ₄ and R ₅ are each independently selected from H, F, Cl, Br and I.

In one preferred embodiment, R ₅ is selected from H, F, Me, MeO and Cl, and is preferably selected from H or F, more preferably from H.

In one preferred embodiment, R ₅ is selected from H, F and Cl, and is preferably selected from H or F, more preferably from H.

In one preferred embodiment, R ₅ is selected from H, F and CN, and is preferably selected from H.

In one preferred embodiment, R ₁ and R ₄ are both H.

In one preferred embodiment, R ₁ is H; R ₂ is selected from H, F, Cl, Br, CN, Me, methoxy, OCF ₃ , CF ₃ , OCHF ₂ , Ph, pyrazolyl and CO ₂ Me; R ₃ is selected from H, F, Cl, Br, CN, methoxy, OCF ₃ , CF ₃ , OCHF ₂ , Me, Ph, pyrazolyl, oxazolyl, thiazolyl, OPh, NHCO-CH=CH ₂ and CO ₂ Me, wherein said Ph, OPh, pyrazolyl, oxazolyl and thiazolyl groups are each optionally further substituted with one or more alkyl groups; R ₄ is H or CF ₃ , more preferably H; R ₅ is selected from H, F, Me, MeO, Cl, OH and CN, and preferably from H or F, more preferably from H. It is preferred, in relation to this embodiment, when at least one of R ₂ and R ₃ is not H. It is even more preferred when both R ₂ and R ₃ are not H.

In another preferred embodiment, one of R ₂ and R ₃ is selected from aryl, O-aryl, and heteroaryl, each of which is optionally substituted, and the other of R ₂ and R ₃ is H, and R ₁ , R ₄ , and R ₅ all represent H.

In one preferred embodiment, R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from H, F, Cl, Br, CN, OMe, NR ₁₁ R ₁₁ ' and OH.

In one preferred embodiment, R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from H, F, Cl, Br, CN, OMe, NH ₂ , NHBu, NHCO ₂ Bu and OH.

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

In one particularly preferred embodiment, the compound has formula (Ib.1):

wherein ring A and groups Y and R ₁ -R ₅ are as described in any of the above embodiments.

In one preferred embodiment, the compound is in enantiomerically pure form. In one preferred embodiment, the compound is in the form of a mixture that is enantiomerically enriched in the compound of formula (Ib.1).

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

wherein ring A and groups Y and R ₁ -R ₅ are as described in any of the above embodiments.

In one preferred embodiment, the compound is in enantiomerically pure form. In one preferred embodiment, the compound is in the form of a mixture that is enantiomerically enriched in the compound of formula (Ib.2).

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

Racemic mixtures can be used to prepare enantiomerically pure compounds of formula (Ib.1) or (Ib.2) by separating the compounds of formula (Ib.1) or (Ib.2) using standard techniques, such as those known to those skilled in the art by chemical resolution using an optically active acid or by column chromatography or reversed-phase column chromatography using a substantially optically active (or "chiral") stationary phase. Racemic mixtures can also be used to prepare enantiomerically enriched mixtures of compounds of formula (Ib.1) or (Ib.2). Mixtures enriched in one of the compounds of formula (Ib.1) or (Ib.2) can also be obtained from the corresponding enantiomerically enriched precursor compounds.

In one preferred embodiment of the invention, the compound is in the form of a mixture comprising enantiomers, wherein the weight ratio is at least about 2:1 or greater, preferably at least about 5:1 or greater, most preferably at least about 10:1 or greater in favor of the enantiomer that exhibits significant in vitro and/or in vivo activity (in favor of the eutomer).

In one particularly preferred 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 ratio of said compound of formula (Ib.1) to said compound of formula (Ib.2) is greater than 1.05:1, more preferably greater than 2:1, even more preferably greater than 5:1, and even more preferably greater than 10:1.

In one particularly preferred 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 enriched in said compound of formula (Ib.1).

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 ratio of said compound of formula (Ib.2) to said compound of formula (Ib.1) is greater than 1.05:1, more preferably greater than 2:1, even more preferably greater than 5:1, and even more preferably greater than 10:1.

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 enriched in said compound of formula (Ib.2).

In one preferred embodiment, the compound is selected from the following compounds:

and its enantiomers, and mixtures of its enantiomers, including racemic mixtures, and its pharmaceutically acceptable salts and solvates.

Compounds of formula (Ie)

Another aspect of the invention relates to a compound of formula (Ie) or a pharmaceutically acceptable salt or solvate thereof,

Where:

ring A is

where R ₆ and R ₈ are each independently selected from H, F, Cl, Br, I, CN, alkoxy, OH, phenyl and haloalkyl (more preferably from CF ₃ );

Y is selected from _CH2 , C=N-OH and _CR10R10 ', where _R10 and _R10 ' are each independently selected from H, _F , alkyl and haloalkyl;

R _a and R _b are each independently selected from H and alkyl;

R ₁ , R ₄ and R ₅ are each independently selected from H, F, Cl, Br and I; and

R ₂ and R ₃ are each independently selected from F, Cl, Br, I, CN, methoxy and haloalkyl;

provided that when Y is CH₂, and R_a, R_b, R₁, R₄, R₅, R₆and R₈all represent H:

R ₃ is not CN when R ₂ is Cl; and

R ₂ and R ₃ are both not Cl.

Thus, in one embodiment, the compound of the invention has formula (Ie), or a pharmaceutically acceptable salt or solvate thereof:

where Y, R_a, R_b, R₁-R₅, R₆and R₈defined above. Preferably, Y is CH₂, R_a, R_b, R₁, R₄, R₅, R₆and R₈represent H, R₃does not represent CN when R₂represents Cl. Preferably, Y represents CH₂, R_a, R_b, R₁, R₄, R₅, R₆and R₈represent H, R₂and R₃both do not represent Cl.

Another aspect of the invention relates to a compound or a pharmaceutically acceptable salt or solvate thereof having a structure of formula (Ie) above, wherein Y, R _a , R _b , R ₁ -R ₅ , R ₆ and R ₈ are as defined above, with the proviso that the compound is not:

.

Another aspect of the invention relates to a compound or a pharmaceutically acceptable salt or solvate thereof having a structure of formula (Ie) above, wherein Y, R _a , R _b , R ₁ -R ₅ , R ₆ and R ₈ are as defined above, with the proviso that the compound is not:

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

N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide.

Another aspect of the invention relates to a compound or a pharmaceutically acceptable salt or solvate thereof having a structure of formula (Ie) above, wherein Y, R _a , R _b , R ₁ -R ₅ , R ₆ and R ₈ are as defined above, with the proviso that the compound is not:

N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]-pyrimidine-10-carboxamide and its enantiomers and mixtures of its enantiomers; and

N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide, and its enantiomers and mixtures of its enantiomers.

In one preferred embodiment, R ₂ and R ₃ are each independently selected from F, Cl, Br, I, CN, and haloalkyl.

In one preferred embodiment, R ₂ is selected from F, Cl, Br and CF ₃ , and more preferably is selected from Cl and CF ₃ .

In one preferred embodiment, R ₃ is selected from F, Cl, Br, OMe, CN and CF ₃ , more preferably selected from F, Cl, Br, OMe and CF ₃ , and even more preferably selected from Cl and CF ₃ .

In one preferred embodiment, one of R ₂ and R ₃ is selected from Cl and the other is CF ₃ , or R ₂ and R ₃ are both Cl.

In one preferred embodiment, R ₁ , R ₄ and R ₅ are all H.

In one preferred embodiment, Y is CR ₁₀ R ₁₀ ', where R ₁₀ and R ₁₀ ' are each independently selected from H, F, Me and CF ₃ , and more preferably selected from H, F and Me. In one preferred embodiment, Y is selected from CH ₂ , CHF, CHMe and C=N-OH. In one preferred embodiment, Y is selected from CH ₂ and C=N-OH. In one preferred embodiment, Y is selected from CH ₂ and CHF. More preferably, Y is CH ₂ .

In one preferred embodiment, R _a and R _b are each independently selected from H and methyl. In one preferred embodiment, one of R _a and R _b is alkyl (more preferably methyl) and the other is H. In one particularly preferred embodiment, R _a and R _b are both H.

In one preferred embodiment, at least one of R ₆ and R ₈ is not H.

In one preferred embodiment, R ₆ is H.

In one preferred embodiment, R ₈ is selected from H, CF ₃ , phenyl, OH and F.

In one preferred embodiment, R ₈ is OH and ring A is:

or its corresponding tautomer. Preferably, R ₆ is H.

In one particularly preferred embodiment, the compound has formula (Ie.1):

wherein ring A and groups Y and R ₁ -R ₅ are as described in any of the above embodiments for (Ie).

In one preferred embodiment, the compound is in enantiomerically pure form. In one preferred embodiment, the compound is in the form of a mixture that is enantiomerically enriched in the compound of formula (Ie.1).

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

wherein ring A and groups Y and R ₁ -R ₅ are as described in any of the above embodiments for (Ie).

In one preferred embodiment, the compound is in enantiomerically pure form. In one preferred embodiment, the compound is in the form of a mixture that is enantiomerically enriched in the compound of formula (Ie.2).

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

Racemic mixtures can be used to prepare enantiomerically pure compounds of formula (Ie.1) or (Ie.2) by separating the compounds of formula (Ie.1) or (Ie.2) using standard methods, such as those known to those skilled in the art by chemical resolution using an optically active acid or by using column chromatography or reversed-phase column chromatography using a substantially optically active (or "chiral") stationary phase. Racemic mixtures can also be used to prepare enantiomerically enriched mixtures of compounds of formula (Ie.1) or (Ie.2). Mixtures enriched in one of the compounds of formula (Ie.1) or (Ie.2) can also be obtained from the corresponding enantiomerically enriched precursor compounds.

In one preferred embodiment of the invention, the compound is in the form of a mixture comprising enantiomers, wherein the weight ratio is at least about 2:1 or greater, preferably at least about 5:1 or greater, most preferably at least about 10:1 or greater in favor of the enantiomer that exhibits significant in vitro and/or in vivo activity (in favor of the eutomer).

In one 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 ratio of said compound of formula (Ie.1) to said compound of formula (Ie.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.

In one 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), which is substantially enriched in said compound of formula (Ie.1).

In one 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 ratio of said compound of formula (Ie.2) to said 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.

In one 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), which is substantially enriched in said compound of formula (Ie.2).

In one preferred embodiment, the compound of formula (Ie) is selected from the following compounds:

and their enantiomers and mixtures of their enantiomers, including racemic mixtures, and their pharmaceutically acceptable salts and solvates.

Compounds of formula (Ia)

One aspect of the invention relates to a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof,

Where:

ring A is a 5 or 6 membered aromatic or heteroaromatic ring, wherein said aromatic or heteroaromatic ring is optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, haloalkyl, aralkyl, aryl and heteroaryl, and wherein said aryl and heteroaryl substituents are in turn optionally substituted with one or more substituents, each of which is independently selected from F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, haloalkyl and aralkyl;

Y is selected from _CH2 , C=N-OH and _CR10R10 ', where _R10 and _R10 ' are each independently selected from H, _F , alkyl and haloalkyl;

R ₁ , R ₄ , and R ₅ are each independently selected from H, F, Cl, Br, and I;

R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, CN, methoxy and haloalkyl; and

R ₁₁ and R ₁₁ ' are each independently selected from H, alkyl, haloalkyl, COR ₁₂ , and SO ₂ R ₁₃ , where R ₁₂ and R ₁₃ are both alkyl;

where when Y is CH ₂ and ring A is:

where R ₆ and R ₈ are both H,

- R ₂ and R ₃ are not both Cl when R ₁ , R ₄ and R ₅ are all H;

- R ₃ is not Cl when R ₁ , R ₂ , R ₄ and R ₅ are all H;

- R ₂ is not Cl when R ₁ , R ₃ , R ₄ and R ₅ are all H;

- R ₁ is not Cl when R ₂ , R ₃ , R ₄ and R ₅ are all H;

- R ₁ is not F when R ₄ is Cl, and R ₂ , R ₃ , and R ₅ are all H.

In one preferred embodiment, the optionally substituted aromatic or heteroaromatic ring is a benzene, pyridine, pyridone, pyridine N-oxide, pyridazine, pyrimidine, pyrimidone, pyrazine, triazine, pyrrole, furan, thiophene, pyrazole, isoxazole, imidazole, oxazole or thiazole ring. The term "heteroaromatic" as used herein also includes moieties that exist in tautomeric form, such as, but not limited to, pyridine, pyrimidone and other similar moieties. The aromatic or heteroaromatic ring A is fused with an adjacent nitrogen-containing bicyclic heterocyclic group to form a fused tricyclic ring system.

More preferably, the optionally substituted aromatic or heteroaromatic ring is a benzene, pyridine, pyridone, N-oxide pyridine, pyrimidine, pyrimidone, pyridazine, pyrazine or isoxazole ring.

In one preferred embodiment, ring A is a benzene, pyridine, pyridone, N-oxide pyridine, pyrimidine, pyrimidone, pyridazine, pyrazine or isoxazole ring, which is optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, C ₁ -C ₆ alkoxy, NR ₁₁ R ₁₁ ', OH, C ₁ -C ₆ alkyl, phenyl and C ₁ -C ₆ haloalkyl.

In one embodiment, ring A is selected from:

where R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from H, F, Cl, Br, I, CN, C ₁ -C ₆ alkoxy, NR ₁₁ R ₁₁ ', OH, C ₁ -C ₆ alkyl, phenyl and C ₁ -C ₆ haloalkyl.

In one preferred embodiment, ring A is selected from:

And, more preferably, choose from:

In one preferred embodiment, R ₁₀ and R ₁₀ ' are each independently selected from H and C ₁ -C ₆ alkyl, preferably wherein the C ₁ -C ₆ alkyl is CH ₃ .

In one preferred embodiment, Y is selected from CH ₂ and C=N-OH, and preferably when selected from CH ₂ .

In one preferred embodiment, R ₁ is selected from H and F, and preferably when selected from H.

In one preferred embodiment, R ₂ and R ₃ are each independently selected from F, Cl, Br, I, CN, and C ₁ -C ₆ haloalkyl.

In one preferred embodiment, R ₂ and R ₃ are each independently selected from F, Cl, Br, I, CN, and CF _n H _3-n , wherein n is 1, 2, or 3, and preferably is 3.

In one preferred embodiment, R ₂ and R ₃ are each independently selected from Cl, Br and CF _n H _3-n , where n is 1, 2 or 3, and preferably is 3.

In one preferred embodiment, R ₂ and R ₃ are each independently selected from Cl, Br or CF ₃ , preferably where R ₂ and R ₃ are not both CF ₃ , and more preferably where R ₂ is Cl or Br and R ₃ is CF ₃ .

In one preferred embodiment, R ₄ is selected from H and Cl, and preferably from H.

In one preferred embodiment, R ₅ is H.

In one preferred embodiment, R₆selected from H, F, Cl, CN, methoxy, CH₃, NR₁₁R₁₁’ and CF₃, where R₁₁And R₁₁’ each independently chooses from H and C₁-C₆alkyl, and preferably when both are H.

In one preferred embodiment, R ₆ is selected from H, F, Cl, CN, methoxy and CH ₃ , and is preferably selected from H.

In one preferred embodiment, R₇selected from H, F, Cl, CN, methoxy, CH₃, NR₁₁R₁₁’ and CF₃, where R₁₁And R₁₁’ each independently chooses from H and C₁-C₆alkyl, and preferably when both are H.

In one preferred embodiment, R ₇ is selected from H, F, Cl, CN, methoxy and CH ₃ , preferably from H, F or Cl, and more preferably from H.

In one preferred embodiment, R ₈ is selected from H, F, OH, CN, methoxy, NR ₁₁ R ₁₁ ', phenyl, CF ₃ , CF ₂ H, NHSO ₂ CH ₃ , NHCOCH ₃ and NHCHF ₂ , wherein R ₁₁ and R ₁₁ ' are each independently selected from H and C ₁ -C ₆ alkyl and, preferably, both are H.

In one preferred embodiment, R ₈ is selected from H, F, Cl, CN, phenyl and OH, preferably from H, F and OH.

In one preferred embodiment, R ₈ is OH.

In one preferred embodiment, R₉selected from H, F, Cl, CN, methoxy, CH₃, NR₁₁R₁₁’ and CF₃, where R₁₁And R₁₁’ each independently chooses from H and C₁-C₆alkyl, and preferably when both are H.

In one preferred embodiment, R ₉ is selected from H, F, Cl, CN, methoxy and CH ₃ , preferably from H, F, and CN, and more preferably from H.

In one preferred embodiment, R₆, R₇and R₉, in case of their presence, represent H.

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

Where:

ring A is selected from:

Y represents CH ₂ ;

R ₁ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₉ are all H;

R ₂ and R ₃ are each independently selected from Cl, Br or CF ₃ , preferably when R ₂ and R ₃ are not both CF ₃ , and more preferably when R ₂ is Cl or Br and R ₃ is CF ₃ ; and

R ₈ is selected from H, F, Cl, CN, phenyl and OH, preferably from H, F, and OH, and more preferably from OH;

Preferably, ring A is:

and R ₈ is H, R ₂ and R ₃ are both not Cl.

In an even more preferred embodiment, the compound of formula (Ia) is

(Ia)

Where:

Y are CH ₂ ;

R ₁ , R ₄ , R ₅ and R ₆ are all H;

R ₂ and R ₃ are each independently selected from Cl, Br or CF ₃ , preferably when R ₂ and R ₃ are not both CF ₃ , and more preferably when R ₂ is Cl or Br and R ₃ is CF ₃ ; and

R ₈ is selected from H, F, Cl, CN, phenyl and OH, preferably from H, F and OH, and more preferably from OH;

preferably, when R ₈ are H, R ₂ and R ₃ are both not Cl.

In one particularly preferred embodiment, the compound has formula (Ia.1):

wherein ring A and groups Y and R ₁ -R ₁₃ are as described in any of the above embodiments. In one preferred embodiment, the compound is in enantiomerically pure form.

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

wherein ring A and groups Y and R ₁ -R ₁₃ are as described in any of the above embodiments. In one preferred embodiment, the compound is in enantiomerically pure form.

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

Racemic mixtures can be used to prepare enantiomerically pure compounds of formula (Ia.1) or (Ia.2) by separating the compounds of formula (Ia.1) or (Ia.2) by standard methods, for example, those known to those skilled in the art by chemical resolution using an optically active acid or by using column chromatography or reversed-phase column chromatography using a substantially optically active (or "chiral") stationary phase. Racemic mixtures can also be used to prepare enantiomerically enriched mixtures of compounds of formula (Ia.1) or (Ia.2). Mixtures enriched in one of the compounds of formula (Ia.1) or (Ia.2) can also be obtained from the corresponding enantiomerically enriched precursor compounds.

In one preferred embodiment of the invention, the compound is in the form of a mixture comprising enantiomers, wherein the weight ratio is at least about 2:1 or greater, preferably at least about 5:1 or greater, most preferably at least about 10:1 or greater in favor of the enantiomer that exhibits significant in vitro and/or in vivo activity (in favor of the eutomer).

In one particularly preferred 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 said compound of formula (Ia.1) to said 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.

In one particularly preferred 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), which is substantially enriched in said compound of formula (Ia.1).

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 said compound of formula (Ia.2) to said 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.

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), which is substantially enriched in said compound of formula (Ia.2).

In one preferred embodiment, the compound of formula (Ia) is selected from the following compounds provided in the invention:

(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), including racemic mixtures, and their pharmaceutically acceptable salts and solvates.

In another preferred embodiment, the compound of formula (Ia) is selected from the following compounds:

(±)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

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

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

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

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

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

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

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

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

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

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

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

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

(5S,8R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

(5R,8S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

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

(5S,8R)-N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

(5R,8S)-N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

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

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

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

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

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

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

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

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

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

(±)-N-(3-bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

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

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

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

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

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

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

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

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

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

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

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

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

(5S,8R)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

(5R,8S)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

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

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

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

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

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

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

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

(5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

(5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

(±)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

(5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

(5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

(±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

(5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

(5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

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

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

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

(±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

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

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

(±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-benzo[7]annulene-10-carboxamide;

(5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide;

(5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide;

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

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

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

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

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

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

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

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

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

(±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

(5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

(5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

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

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

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

(±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(hydroxyimino)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide;

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

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

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

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

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

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

(5S,8R)-N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide; and

(5R,8S)-N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide;

and its pharmaceutically acceptable salts and solvates.

Compounds of formula (Ic)

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

Where:

ring A is

wherein R ₆ and R ₈ are each independently selected from H, F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, phenyl, and haloalkyl, provided that at least one of R ₆ and R ₈ is not H;

Y is selected from _CH2 , C=N-OH and _CR10R10 ', where _R10 and _R10 ' are each independently selected from H, _F , alkyl and haloalkyl;

R ₁ , R ₄ and R ₅ are each independently selected from H, F, Cl, Br and I;

R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, CN, methoxy and haloalkyl; and

R ₁₁ and R ₁₁ ' are each independently selected from H, alkyl, haloalkyl, COR ₁₂ and SO ₂ R ₁₃ , where R ₁₂ and R ₁₃ are both alkyl.

Preferred definitions for the Y and R _1-13 groups and preferred ring system configurations are given above for compounds of formula (Ia), (Ib), (Ie) and (If).

In one preferred embodiment, R ₈ is OH and ring A is in the form of the pyridine tautomer:

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

Compounds of formula (Id)

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

Where:

ring A is

where R ₆ and R ₈ are each independently selected from H, F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, phenyl, and haloalkyl;

Y is selected from _CH2 , C=N-OH and _CR10R10 ', where _R10 and _R10 ' are each independently selected from H, _F , alkyl and haloalkyl;

R ₁ , R ₄ and R ₅ are each independently selected from H, F, Cl, Br and I;

R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, CN, methoxy and haloalkyl, provided that at least one of R ₂ and R ₃ is selected from CN, methoxy and haloalkyl; and

R ₁₁ and R ₁₁ ' are each independently selected from H, alkyl, haloalkyl, COR ₁₂ , and SO ₂ R ₁₃ , where R ₁₂ and R ₁₃ are both alkyl.

Preferred definitions for the Y and R _1-13 groups and preferred ring system configurations are given above for compounds of formula (Ia).

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

METHOD

Another aspect of the invention relates to a method for preparing a compound described in the invention, wherein said method comprises reacting a compound of formula II with a compound of formula III, wherein R ^1-5 , Y and A are defined above, to form a compound of formula (Ia), (Ib), (Ic), (Id), (Ie) or (If):

In one 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 solvents include, but are not limited to, dichloromethane, tetrahydrofuran, and dimethylformamide, or mixtures of two or more thereof. Those skilled in the art will recognize that other suitable bases and solvents can also be used.

THERAPEUTIC USE

Another aspect of the invention relates to the use of the compounds described herein in medicine. The compounds may find particular application in the fields of oncology, immuno-oncology, and immunology, which are described in more detail below. In a preferred embodiment, a compound of the invention modulates GPR65, and more preferably inhibits the GPR65 signaling pathway.

Yet another aspect of the invention relates to the use of the compounds described in the invention as a medicinal product, preferably for use in the treatment or prevention of a disorder selected from a proliferative disorder and an immune disorder.

Another aspect of the invention relates to the use of the compounds described herein in the treatment or prevention of asthma and/or chronic obstructive pulmonary disease (COPD). In gene-wide association studies (GWAS), the GPR65/SNP variant (rs6574978) was shown to be associated with asthma/COPD syndrome with a nearly significant p-value (1.18×10 ^-7 ) (Hardin, 2014). Furthermore, GPR65 activation upon exposure to pH (the pH is low/acidic in the lungs in asthma) promotes eosinophil viability in a cAMP-dependent manner, which leads to disease progression/exacerbation. Furthermore, GPR65 knockout mice are known to exhibit milder asthma symptoms (Kottyan, 2009).

Another aspect of the invention relates to the use of the compounds described herein in the treatment or prevention of acute respiratory distress syndrome (ARDS). GPR65 has been shown to exert a protective effect in a model of lipopolysaccharide (LPS)-induced acute lung injury (Tsurumaki, 2015).

One aspect of the invention relates to the use of a compound described herein in the treatment of a proliferative disorder. The proliferative disorder is preferably cancer or leukemia.

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

In another preferred embodiment, the cancer is selected from 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 adenocarcinoma, lung cancer, sarcoma, ovarian cancer and gliomas, preferably glioblastoma (GBM).

Without committing to any theory, it should be noted that GPR65 modulators are able to prevent the increase in cytoplasmic cAMP in tumor-associated macrophages (TAMs), natural killer cells (NK cells), and T cell subsets, which is typically a consequence of their exposure to the acidic tumor microenvironment and the concomitant activation of GPR65. This reduction in cytoplasmic cAMP, in turn, reduces the levels of ICER and proinflammatory mediators such as CXCL10 and TNFα, preventing TAM polarization and alterations in other immune cells associated with a non-inflammatory, tumor-favoring environment. Therefore, GPR65 modulators are expected to enhance tumor recognition by the immune system, leading to enhanced immune-mediated tumor elimination. This suggests that modulation of GPR65 activity may be an effective cancer treatment as a standalone therapy or in combination with cancer immunotherapy (vaccines, agents that stimulate T-cell-mediated immune responses), or in patients who do not respond to immunomodulatory approaches such as PD1/PDL-1 blockade.

Another aspect of the invention relates to the use of the invention described in the treatment or prevention of an immune disorder, preferably an autoimmune disease.

In one embodiment, the autoimmune disease is selected from psoriasis, psoriatic arthritis, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), autoimmune thyroiditis (Hashimoto's thyroiditis), Graves' disease, uveitis (including intermediate uveitis), ulcerative colitis, Crohn's disease, autoimmune uveoretinitis, systemic vasculitis, polymyositis-dermatomyositis, systemic sclerosis (scleroderma), Sjogren's syndrome, ankylosing spondylitis and related spondyloarthropathies, sarcoidosis, autoimmune hemolytic anemia, immune platelet disorders, autoimmune polyendocrinopathies, autoimmune myocarditis, type I diabetes, and atopic dermatitis.

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

Without committing to any theory, it is worth noting that GPR65 modulators are able to prevent ICER upregulation in CD4+ T cells. This, in turn, is expected to prevent ICER-associated IL-2 suppression, which shifts CD4+ T cells toward the inflammatory Th17 phenotype, which is associated with increased pathogenicity in the context of autoimmune disease. This is supported by the fact that mutations in the GPR65 locus are associated with several autoimmune diseases, such as multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, and Crohn's disease (Gaublomme, 2015). This suggests that modulating GPR65 activity could be an effective treatment for autoimmune diseases.

Another aspect relates to the use of a compound described in the invention in the treatment or prevention of a disorder caused by, associated with, or accompanied by abnormal activity in relation to GPR65.

Another aspect relates to the use of a compound described in the invention in the treatment or prevention of a GPR65-associated disease or disorder.

Another aspect of the invention relates to a method of treating the disorder described above, comprising administering a compound described in the invention to a subject.

Another aspect of the invention relates to a method for treating a GPR65-associated disease or disorder in a subject. The method according to this aspect of the present invention is carried out by administering to a subject in need thereof a therapeutically effective amount of the above-described compound of the present invention, either in pure form or, more preferably, as a component of a pharmaceutical composition mixed, for example, with a pharmaceutically acceptable carrier, as described in detail below.

Yet another aspect of the invention relates to a method of treating a subject whose disease state can be alleviated by modulating GPR65, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of the invention.

Another aspect relates to a method of treating a disease condition that can be alleviated by modulating GPR65, wherein the method comprises administering to a subject a therapeutically effective amount of a compound of the invention.

Preferably, the subject is a mammal, more preferably a human.

The term "method" refers to a course of action, means, techniques, and procedures for performing a given task, including, but not limited to, those courses of action, means, techniques, and procedures that are either known or that can be readily developed from known courses of action, means, techniques, and procedures by persons skilled in the art of chemistry, pharmacology, biology, biochemistry, and medicine.

In the invention, the term "treating" includes stopping, substantially inhibiting, slowing, or reversing the progression of a disease or disorder, substantially alleviating the clinical symptoms of a disease or disorder, or substantially preventing the manifestation of clinical symptoms of a disease or disorder.

In the invention, the term "prevention" refers primarily to a method of increasing the body's resistance to an acquired disorder or disease.

The term "therapeutically effective amount" refers to that amount of the compound administered that results in some relief of one or more symptoms of the disease or disorder being treated.

For any compound used in this invention, the therapeutically effective amount, also referred to herein as the therapeutically effective dose, can be initially estimated by conducting cell culture studies. For example, the dose can be estimated in animal models by determining the circulating concentration range, which includes the IC ₅₀ or IC ₁₀₀ determined in cell culture. This information can be used to more accurately determine doses for use in humans. Initial doses can also be estimated based on in vivo data. Using these initial guidelines, one of ordinary skill in the art can determine the effective dose for use in humans.

In addition, the toxicity and therapeutic efficacy of the compounds described in the invention can be determined by standard pharmaceutical methods in cell cultures or on experimental animals, for example, by determining the LD50 and ED50 values. The ratio between the doses of toxic and therapeutic effect is the therapeutic index, which can be expressed as the ratio of LD50 and ED50. Compounds that are characterized by high therapeutic index values are preferred. Data obtained as a result of these analyses on cell cultures and studies on animals can be used to determine a range of doses that are not toxic when administered to humans. Preferably, the dosage of such compounds is within a range of circulating concentrations that include the ED50 value when little or no toxicity is observed. The dosage may vary within this range depending on the dosage form used and the route of administration used. The exact composition of the dosage form, route of administration, and dosage may be selected by the treating physician depending on the patient's condition (see, for example, Fingl et al, 1975, The Pharmacological Basis of Therapeutics, chapter 1, page 1).

The dosage amount and dosage interval can be adjusted in each individual case to ensure plasma levels of the active compound sufficient to maintain the therapeutic effect. Typical oral doses for patients range from about 50 to 2000 mg/day, typically from about 100 to 1000 mg/day, preferably from about 150 to 700 mg/day, and most preferably from about 250 to 500 mg/day or from 50 to 100 mg/day. Preferably, therapeutically effective serum levels can be achieved by administering multiple doses daily. In cases of local application or selective absorption of the drug, the effective local concentration of the drug may be independent of the plasma concentration. One skilled in the art is able to select optimal therapeutically effective local doses without any experimentation.

As used herein, the term "GPR65-associated disease or disorder" refers to a disease or disorder characterized by inappropriate GPR65 activity. Inappropriate GPR65 activity refers to either an increase or decrease in GPR65 activity, as measured by enzymatic or cellular assays, for example, compared to the activity in a healthy subject. Inappropriate activity may also be due to overexpression of GPR65 in diseased tissue compared to healthy adjacent tissue.

Preferred diseases or disorders for which the compounds described in the invention can be used for the prevention or treatment include the proliferative disorders and immune disorders described above, as well as asthma and chronic obstructive pulmonary disease.

Accordingly, the present invention further provides the use of the compounds described herein in the preparation of a medicament for the treatment of a disease requiring modulation of GPR65. Such diseases include the proliferative and immune disorders described above, as well as asthma and chronic obstructive pulmonary disease.

As used in the invention, the phrase "preparation of a medicinal product" includes the use of the components of the invention directly as a medicinal product in addition to their use at any stage of the preparation of such medicinal product.

In one preferred embodiment, the compound prevents the increase in cytoplasmic cAMP levels expected following GPR65 activation at an acidic pH. This prevention of cAMP accumulation, in turn, prevents downstream signaling through ICER, as described above. The "homogeneous time-resolved fluorescence (HTRF) assay for cyclic adenosine monophosphate (cAMP) produced by a human GPR65 antagonist" or simply the "cAMP assay" described in the accompanying examples can be used to measure the activity of GPR65 modulators, which is expressed as the concentration of the compound required to reduce the increase in cAMP concentration upon GPR65 activation by 50% (i.e., the IC ₅₀ value).

In one preferred embodiment, the compound is characterized by an _IC50 value in the cAMP assay of less than about 25 μM. More preferably, the compound is characterized by an _IC50 value in the cAMP assay of less than about 10 μM, more preferably less than about 5 μM, even more preferably less than about 1 μM, and even more preferably less than about 0.1 μM.

In another preferred embodiment, the compound has an IC ₅₀ value for hGPR65 in the above assay of less than <5 μM, more preferably less than <500 nM.

Therapeutic use of compounds of formula I

Another aspect of the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof,

Where:

ring A is a 5 or 6 membered aromatic or heteroaromatic ring, wherein said aromatic or heteroaromatic ring is optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, haloalkyl, aralkyl, aryl and heteroaryl, and wherein said aryl and heteroaryl substituents are in turn optionally substituted with one or more substituents, each of which is independently selected from F, Cl, Br, I, CN, alkoxy, NR ₁₁ R ₁₁ ', OH, alkyl, haloalkyl and aralkyl;

Y is selected from _CH2 , C=N-OH and _CR10R10 ', where _R10 and _R10 ' are each independently selected from H, _F , alkyl and haloalkyl;

R ₁ , R ₄ and R ₅ are each independently selected from H, F, Cl, Br and I;

R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, CN, methoxy and haloalkyl; and

R ₁₁ and R ₁₁ ' are each independently selected from H, alkyl, haloalkyl, COR ₁₂ and SO ₂ R ₁₃ , where R ₁₂ and R ₁₃ are both alkyl;

for use as a medicinal product.

Preferred definitions for ring A and groups Y and R _1-13 and preferred configurations of the ring system are given above for compounds of formula (Ia), (Ib), (Ic), (Id), (Ie) and (If).

Preferably, the compounds of formula (I) are used in the treatment of proliferative disorders and autoimmune disorders, as well as asthma and chronic obstructive pulmonary disease. The detailed description of the corresponding proliferative disorders and autoimmune disorders is the same as the description provided above in the section entitled "Therapeutic Uses."

In one preferred embodiment, the compound of formula (I) for the above-described use is selected from the following compounds:

(1)-(8), (11)-(13), (15)-(18), (24)-(29), (31), (32), (34)-(37) and (45)-(53) and their enantiomers and mixtures of their enantiomers, including racemic mixtures, and their pharmaceutically acceptable salts and solvates.

In one preferred embodiment, the compound of formula (I) for the above-described use is selected from the following compounds:

and their enantiomers and mixtures of their enantiomers, including racemic mixtures, and their pharmaceutically acceptable salts and solvates.

Another aspect of the invention relates to the above-described compounds and their enantiomers and mixtures of their enantiomers, including racemic mixtures, and their pharmaceutically acceptable salts and solvates, for use as a medicinal product.

In another preferred embodiment, the compound of the invention or for the use described above is selected from the following compounds:

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

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

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

N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide

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

N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide

N-(4-bromo-3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide

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

N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide

N-(3-bromo-4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide

N-(3-bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide

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

N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide

N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epimino-cyclohepta[d]pyrimidine-10-carboxamide

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

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

N-(3,4-dichlorophenyl)-2-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

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

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

N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-benzo[7]annulene-10-carboxamide

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

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

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

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

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

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

N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexa-hydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexa-hydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

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

N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

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

N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide

N-(4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclo-hepta[d]pyrimidine-10-carboxamide

N-(3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclo-hepta[d]pyrimidine-10-carboxamide

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

N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide

N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclo-hepta[d]pyrimidine-10-carboxamide

N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

N-(3,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

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

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

2-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

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

N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

2-cyano-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

2-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

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

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

1-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

N-(3-chloro-4-(trifluoromethyl)phenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo-[7]annulene-10-carboxamide

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

N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

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

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

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

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

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

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

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

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

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

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

3-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

3-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

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

N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclo-hepta[c]pyridine-10-carboxamide

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

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

N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclo-hepta[c]pyridine-10-carboxamide

N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclo-hepta[c]pyridine-10-carboxamide

N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclo-hepta[c]pyridine-10-carboxamide

N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclo-hepta[c]pyridine-10-carboxamide

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

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

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

N-(3-chloro-4-(trifluoromethyl)phenyl)-8-methyl-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

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

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

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

methyl 2-chloro-4-(-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamido)benzoate

methyl 2-chloro-5-(-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamido)benzoate

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

methyl 2-chloro-4-fluoro-5-(1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamido)benzoate

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

N-(3-chloro-4-(difluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexa-hydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

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

Methyl 2-chloro-5-(3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamido)benzoate

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

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

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

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

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

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

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

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

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

N-(4-bromo-5-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexa-hydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

N-(5-bromo-4-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexa-hydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

N-(4-bromo-3-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

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

N-(3-bromo-4-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

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

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

1-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

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

1-fluoro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

1-fluoro-N-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide

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

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

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

N-(3,5-biphenyltrifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c-]pyridine-10-carboxamide

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

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

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

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

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

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

1-fluoro-N-(3,4,5-trichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

1-fluoro-N-(3-methyl-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

N-(4-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide

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

N-(3-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine-10-carboxamide

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

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

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

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

1-fluoro-N-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

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

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

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

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

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

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

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

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

1-fluoro-N-(4-(thiazol-4-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

1-fluoro-N-(4-(4-methyloxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

1-fluoro-N-(4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

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

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

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

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

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

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

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

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

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

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

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

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

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

N-(3-Chloro-4-(trifluoromethyl)phenyl)-9-(hydroxyimino)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

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

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

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

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

(±)-N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

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

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

(±)-N-(4-bromo-3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

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

(±)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(±)-N-(3-bromo-4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(±)-N-(3-bromo-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

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

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

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

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

(±)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide

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

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

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

(±)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-phenyl-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

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

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

(±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-benzo[7]annulene-10-carboxamide

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

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

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

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

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

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

(±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

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

(±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(hydroxyimino)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide

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

(±)-N-(4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclo-hepta[d]pyrimidine-10-carboxamide

(±)-N-(3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclo-hepta[d]pyrimidine-10-carboxamide

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

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

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

(±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(±)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(±)-N-(3,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

(±)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

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

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

(±)-2-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

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

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

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

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

(±)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(±)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta-[c]pyridine-10-carboxamide

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

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

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

(±)-2-chloro-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminobenzo-[7]annulene-10-carboxamide

(±)-2-cyano-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

(±)-2-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

(±)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

(±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

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

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

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

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

(±)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

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

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

(±)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

(±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-erimino-benzo[7]annulene-10-carboxamide

(±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

(±)-N-(4,5-dichloro-2-cyanophenyl)-3-oxo-3,5,6,7,8,9-hexa-hydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

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

(±)-N-(4,5-dichloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexa-hydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(±)-N-(3,5-bis(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(±)-1-fluoro-N-(4-methyl-3-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

(±)-N-(4-cyano-3-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(±)-N-(3-chloro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

(±)-1-fluoro-N-(3-methyl-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(±)-1-fluoro-N-(4-(thiazol-4-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(±)-1-fluoro-N-(4-(4-methyloxazol-5-yl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(±)-1-fluoro-N-(4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

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

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

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

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

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

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

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

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

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

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

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

(±)-N-(3-cyano-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

(±)-N-(3-bromo-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

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

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

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

(±)-N-(3,5-bis(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(±)-1-fluoro-N-(4-methyl-3-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

(±)-N-(4-cyano-3-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(±)-N-(3-chloro-5-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

(±)-1-fluoro-N-(3-methyl-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(±)-1-fluoro-N-(4-(thiazol-4-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(±)-1-fluoro-N-(4-(4-methyloxazol-5-yl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(±)-1-fluoro-N-(4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

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

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

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

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

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

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

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

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

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

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

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

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

(±)-N-(3-Chloro-4-(trifluoromethyl)phenyl)-9-(hydroxyimino)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

cis-(±)-N-(3,4-Dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

trans-(±)-N-(3,4-Dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide

(±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-8-methyl-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

(±)-N-(4,5-dichloro-2-methoxyphenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(±)-1-fluoro-N-(2-fluoro-5-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(±)-1-fluoro-N-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(±)-1-fluoro-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide

(5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5R,8S)-N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5R,8S)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5R,8S)-N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

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

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

(5R,8S)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]=pyrimidine-10-carboxamide

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

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

(5R,8S)-N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5R,8S)-N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(6S,9R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxamide

(6S,9R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

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

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

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

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

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

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

(5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

(5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide

(5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide

(5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide

(5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide

(5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

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

(5R,8S,E)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(hydroxyimino)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5R,8S)-N-(4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide

(5R,8S)-N-(3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide

(5R,8S)-N-(5-chloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5R,8S)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5R,8S)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[c]pyridine 2-oxide

(6S,9R)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine 2-oxide

(5R,8S)-2-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(6S,9R)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

(6S,9R)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c-]pyridine-10-carboxamide

(6S,9R)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-2-chloro-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-erimino-benzo[7]annulene-10-carboxamide

(5R,8S)-2-cyano-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5R,8S)-2-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-erimino-benzo[7]annulene-10-carboxamide

(6S,9R)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide

(5R,8S)-1-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[c]pyridine-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-N-(4,5-dichloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-erimino-benzo[7]annulene-10-carboxamide

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

(5R,8S)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

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

(6S,9R)-N-(3,4-dichlorophenyl)-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide

(6S,9R)-N-(4,5-dichloro-2-cyanophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine 2-oxide

(6S,9R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(4,5-dichloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(3,4-dichlorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-N-(4,5-dichloro-2-cyanophenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-3-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

(6S,9R)-3-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

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

(5R,8S)-N-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

(6S,9R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(6S,9R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S,9S)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

(5S,8R)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

(5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(3,5-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(3,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

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

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

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

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

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

(5S,8R)-N-(3-bromo-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(3,4-dibromophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(6R,9S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxamide

(6R,9S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-2-(trifluoromethyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

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

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

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

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

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

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

(5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

(5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide

(5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide

(5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide

(5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxamide

(5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5R,8S)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

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

(5S,8R,E)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-9-(hydroxyimino)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(4-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(3-chlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(5-chloro-2-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5S,8R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5S,8R)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[c]pyridine 2-oxide

(6R,9S)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine 2-oxide

(5S,8R)-2-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(6R,9S)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

(6R,9S)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

(5S,8R)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5S,8R)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5S,8R)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide

(6R,9S)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5S,8R)-2-chloro-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-erimino-benzo[7]annulene-10-carboxamide

(5S,8R)-2-cyano-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo-[7]annulene-10-carboxamide

(5S,8R)-2-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-erimino-benzo[7]annulene-10-carboxamide

(6R,9S)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

(5S,8R)-1-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5S,8R)-N-(4,5-dichloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-erimino-benzo[7]annulene-10-carboxamide

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

(5S,8R)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide

(5S,8R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-erimino-benzo[7]annulene-10-carboxamide

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

(6R,9S)-N-(3,4-dichlorophenyl)-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide

(6R,9S)-N-(4,5-dichloro-2-cyanophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide

(5S,8R)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[c]-pyridine 2-oxide

(6R,9S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(4,5-dichloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(3,4-dichlorophenyl)-4-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

(5S,8R)-N-(4,5-dichloro-2-cyanophenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-3-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide

(6R,9S)-3-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

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

(5S,8R)-N-(4-chloro-5-(trifluoromethyl)pyridin-2-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

(6R,9S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(6R,9S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R,9R)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

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

(5R,8S)-N-(4,5-dichloro-2-methylphenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-N-(4,5-dichloro-2-methoxyphenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-1-fluoro-N-(2-fluoro-5-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

(5R,8S)-1-fluoro-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

methyl 2-chloro-4-((5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamido)benzoate

methyl 2-chloro-5-((5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamido)benzoate

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

methyl 2-chloro-4-fluoro-5-((5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamido)benzoate

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

(6S,9R)-N-(3-chloro-4-(difluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(3-chloro-4-(trifluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(4-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

Methyl 2-chloro-4-((6S,9R)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamido)benzoate

Methyl 2-chloro-5-((6S,9R)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamido)benzoate

Methyl 2-chloro-4-fluoro-5-((6S,9R)-3-oxo-3,5,6,7,8,9-hexa-hydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamido)benzoate

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

(5R,8S,9S)-N-(3,4-dichlorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(3,4-dichlorophenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(4,5-dichloro-2-fluorophenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,6S,9R)-N-(3,4-dichlorophenyl)-3,5-difluoro-6,7,8,9-tetra-hydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(4-bromo-5-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(5-bromo-4-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(4-bromo-3-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexa-hydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(3-bromo-4-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexa-hydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-1-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-N-(4,5-dichloro-2-hydroxyphenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-(3,4-dichlorophenyl)-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

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

(5S,8R)-N-(4,5-dichloro-2-methylphenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-N-(4,5-dichloro-2-methoxyphenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-1-fluoro-N-(2-fluoro-5-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

(5S,8R)-1-fluoro-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

methyl 2-chloro-4-((5S,8R)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamido)benzoate

methyl 2-chloro-5-((5S,8R)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamido)benzoate

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

methyl 2-chloro-4-fluoro-5-((5S,8R)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamido)benzoate

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

(6R,9S)-N-(3-chloro-4-(difluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(3-chloro-4-(trifluoromethoxy)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(4-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

Methyl 2-chloro-4-((6R,9S)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamido)benzoate

Methyl 2-chloro-5-((6R,9S)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamido)benzoate

Methyl 2-chloro-4-fluoro-5-((6R,9S)-3-oxo-3,5,6,7,8,9-hexa-hydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamido)benzoate

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

(5S,8R,9S)-N-(3,4-dichlorophenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(3,4-dichlorophenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(4,5-dichloro-2-fluorophenyl)-3,4-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,6R,9S)-N-(3,4-dichlorophenyl)-3,5-difluoro-6,7,8,9-tetra-hydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(4-bromo-5-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(5-bromo-4-chloro-2-fluorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(4-bromo-3-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexa-hydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(3-bromo-4-chlorophenyl)-3-oxo-3,5,6,7,8,9-hexa-hydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-4-fluoro-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-1-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5S,8R)-N-(4,5-dichloro-2-hydroxyphenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-(3,4-dichlorophenyl)-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

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

(5R,8S)-1-fluoro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

(5R,8S)-N-(3-chloro-2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-1-fluoro-N-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-1-fluoro-N-(3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-1-fluoro-N-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-N-(3,5-bis(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-1-fluoro-N-(4-methyl-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-N-(2,3-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-N-(2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

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

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

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

(5R,8S)-1-fluoro-N-(3,4,5-trichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-1-fluoro-N-(3-methyl-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-N-(4-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-N-(4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-N-(3-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-1-fluoro-N-(3-(trifluoromethoxy)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

(5R,8S)-N-(3,5-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-N-(5-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-1-fluoro-N-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

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

(5R,8S)-N-(4-acrylamido-3-chlorophenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

(5R,8S)-N-(4,5-dichloro-2-fluorophenyl)-2-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide

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

(5R,8S)-N-(4-(1H-pyrazol-1-yl)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-N-([1,1'-biphenyl]-3-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5R,8S)-1-fluoro-N-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c-]pyridine-10-carboxamide

(5R,8S)-1-fluoro-N-(4-(thiazol-4-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-1-fluoro-N-(4-(4-methyloxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-1-fluoro-N-(4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-2,5,6,7,8,9-hexahydro-1H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide

(5R,8S)-N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(6S,9R)-N-([1,1'-biphenyl]-4-yl)-3-oxo-3,5,6,7,8,9-hexa-hydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

(5R,8S)-1,4-dichloro-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine-10-carboxamide

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

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

(6R,9S)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide

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

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

(5S,8R)-1-fluoro-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

(5S,8R)-N-(3-chloro-2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-1-fluoro-N-(3-fluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5S,8R)-1-fluoro-N-(3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-1-fluoro-N-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-N-(3,5-bis(trifluoromethyl)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-1-fluoro-N-(4-methyl-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-N-(2,3-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5S,8R)-N-(2,4-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

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

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

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

(5S,8R)-1-fluoro-N-(3,4,5-trichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-1-fluoro-N-(3-methyl-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-N-(4-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5S,8R)-N-(4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-N-(3-bromophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5S,8R)-1-fluoro-N-(3-(trifluoromethoxy)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

(5S,8R)-N-(3,5-difluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine-10-carboxamide

(5S,8R)-N-(5-chloro-2-fluorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-1-fluoro-N-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

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

(5S,8R)-N-(4-acrylamido-3-chlorophenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

(5S,8R)-N-(4,5-dichloro-2-fluorophenyl)-2-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide

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

(5S,8R)-N-(4-(1H-pyrazol-1-yl)phenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-N-([1,1'-biphenyl]-3-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-1-fluoro-N-(4-phenoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-1-fluoro-N-(4-(thiazol-4-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-1-fluoro-N-(4-(4-methyloxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-1-fluoro-N-(4-(oxazol-5-yl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-2,5,6,7,8,9-hexahydro-1H-5,8-epiminocyclohepta[b]pyridine-10-carboxamide

(5S,8R)-N-(4,5-dichloro-2-fluorophenyl)-4-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(6R,9S)-N-([1,1'-biphenyl]-4-yl)-3-oxo-3,5,6,7,8,9-hexa-hydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(5S,8R)-N-([1,1'-biphenyl]-4-yl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

(5S,8R)-1,4-dichloro-N-(5-chloro-2-fluoro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine-10-carboxamide

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

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

(6S,9R)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

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

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

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

(5R,8S)-N-(3-Chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(3-Chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5R,8S)-N-(4-Chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(4-Chloro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5S,8R)-N-(4-Fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5R,8S)-N-(4-Fluoro-3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

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

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

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

(5R,8S,9S)-N-(3,4-Dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

(5R,8S,E)-N-(3-chloro-4-(trifluoromethyl)phenyl)-9-(hydroxy-imino)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

(5S,8R,E)-N-(3-chloro-4-(trifluoromethyl)phenyl)-9-(hydroxyimino)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]-pyrimidine-10-carboxamide

(5S,8R)-N-(4,5-Dichloro-2-cyanophenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(5R,8S)-N-(4,5-Dichloro-2-cyanophenyl)-1-fluoro-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

Methyl 2-chloro-4-((6S,9R)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamido)benzoate

Methyl 2-chloro-4-((6R,9S)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamido)benzoate

and their pharmaceutically acceptable salts and solvates.

In one preferred embodiment, the compound or compound for use according to the invention is characterized by an _IC50 value of >500 nM and <5 μM in the homogeneous time-resolved fluorescence (HTRF) assay of cyclic adenosine monophosphate (cAMP) produced by the human GPR65 antagonist described in the accompanying examples. In one preferred embodiment, the compound is selected from compounds whose activity is designated in Table 1 as "high" or "moderate".

In a more preferred embodiment, the compound or compound for use according to the invention is characterized by an _IC50 value of <500 nM in the homogeneous time-resolved fluorescence (HTRF) assay of cyclic adenosine monophosphate (cAMP) produced by the human GPR65 antagonist described in the accompanying examples. In one preferred embodiment, the compound is selected from the compounds whose potency is designated as "high" in Table 1.

PHARMACEUTICAL COMPOSITIONS

For use in the present invention, the compounds or their physiologically acceptable salts, esters, or other physiologically functional derivatives described herein may be presented as a pharmaceutical composition comprising the compounds or their physiologically acceptable salts, esters, or other physiologically functional derivatives together with one or more pharmaceutically acceptable carriers, excipients, or diluents and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and not have a deleterious effect on the recipient. The pharmaceutical composition may be intended for use in humans or animals in human and veterinary medicine.

Examples of such suitable excipients for the various forms of pharmaceutical compositions described in the invention can be found in the Handbook of Pharmaceutical Excipients, 2nd Edition, (1994), Edited by A. Wade and P.J. Weller. The carrier, or if more than one carrier is present, each carrier, must be acceptable in the sense of being compatible with the other ingredients of the composition and not having a deleterious effect on the recipient.

Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro ed. 1985).

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

The choice of a pharmaceutical carrier, excipient, or diluent may be made taking into account the intended route of administration and generally accepted pharmaceutical practice. The pharmaceutical composition may contain, as a carrier, excipient, or diluent, or in addition to them, any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s), buffer(s), flavoring(s), surfactant(s), thickener(s), preservative(s) (including antioxidants), and other similar substances, as well as substances introduced to impart isotonic properties to the composition similar to the properties of the blood of the intended recipient.

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

Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and other similar substances.

Preservatives, stabilizers, colorants, and even flavorings may be added to a pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and p-hydroxybenzoic acid esters. Antioxidants and suspending agents may also be added.

Pharmaceutical compositions include those suitable for oral, topical (including dermal, buccal, and sublingual), rectal, parenteral (including subcutaneous, intradermal, intramuscular, and intravenous), nasal, and pulmonary administration, for example, by inhalation. The dosage form, if desired, may be presented in discrete unit doses and may be prepared by any of the methods well known in the pharmaceutical art. All methods include the step of admixing the active compound with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired dosage form.

Pharmaceutical compositions suitable for oral administration, in which the carrier is a solid, are most preferably presented in unit-dose dosage forms such as boluses, capsules, or tablets, each containing a predetermined amount of the active compound. A tablet can be made by compression or molding, optionally together with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active compound in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersing agent. Molded tablets can be made by molding the active compound with an inert liquid diluent. Tablets can be optionally coated and, if uncoated, optionally scored. Capsules can be prepared by filling the active compound, alone or mixed with one or more excipients, into capsule shells and then closing them in the usual manner. Cachets are similar to capsules in which the active compound, along with any excipient(s), is sealed in a rice paper wrapper. The active compound can also be prepared in the form of dispersible granules, which can be, for example, suspended in water before use or sprinkled on food. The granules can be packaged, for example, in a cachet. Dosage forms used for oral administration in which the carrier is a liquid can be presented as a solution or suspension in an aqueous or nonaqueous liquid, or as an oil-in-water liquid emulsion.

Oral dosage forms include controlled-release dosage forms, such as tablets, in which the active compound is formulated in an appropriate release-controlling matrix or coated with an appropriate release-controlling film. Such dosage forms can be particularly useful for prophylactic use.

Dosage forms for rectal administration in which the carrier is a solid are most preferably presented as single-dose suppositories. Suitable carriers include cocoa butter and other substances commonly used in pharmaceuticals. Suppositories can be easily prepared by mixing the active compound with the softened or melted carrier(s), followed by cooling and molding. Dosage forms used for parenteral administration include sterile solutions or suspensions of the active compound in aqueous or oily vehicles.

Injectable medications may be intended for bolus injection or continuous infusion. These medications are conveniently prepared in single-dose containers or multi-dose containers, which are sealed after administration until needed for the next dose. Alternatively, the active compound may be in powder form, which is mixed with a suitable vehicle, such as sterile, pyrogen-free water, before use.

The active compound can also be formulated as prolonged-release depot preparations, which can be administered by intramuscular injection or by implantation, for example, subcutaneously or intramuscularly. Depot preparations may include, for example, suitable polymeric or hydrophobic materials or ion-exchange resins. Such prolonged-release preparations are particularly suitable for prophylactic use.

Dosage forms used for pulmonary administration through the oral cavity are represented by forms in which particles containing the active compound and preferably having a diameter in the range of 0.5 to 7 microns are delivered to the bronchial tree of the recipient.

As one possible embodiment, such compositions are finely divided powders that are conveniently formulated either in the form of a pierceable capsule, preferably, for example, made of gelatin, for use in an inhalation device, or, alternatively, in the form of a self-propelling formulation containing the active compound, a suitable liquid or gaseous propellant, and, optionally, other ingredients such as a surfactant and/or a solid diluent. Suitable liquid propellants include propane and chlorofluorocarbons, and suitable gaseous propellants include carbon dioxide. Self-propelling formulations in which the active compound is distributed as droplets of a solution or suspension may also be used.

Such self-propelling formulations are similar to those known in the art and can be prepared using known methods. They are conveniently presented in a container equipped with either a manually operated or automatically actuated valve having the required aerosol generation characteristics; preferably, the valve is of a type that allows for the delivery of a measured, fixed volume, for example, 25 to 100 microliters, with each actuation.

Alternatively, the active compound may be in the form of a solution or suspension for use in a nebulizer or spray device that uses an accelerated air stream or ultrasonic agitation to produce an aerosol of fine droplets for inhalation.

Dosage forms suitable for nasal administration include those generally similar to those described above for pulmonary administration. Desirably, when dosing, such forms have a particle diameter in the range of 10 to 200 microns to ensure retention in the nasal cavity, and this can be achieved, where appropriate, by using a powder with an appropriate particle size or by selecting an appropriate valve. Other suitable forms include coarse powders with a particle diameter of 20 to 500 microns for administration by rapid inhalation through the nasal passage from a container held close to the nose, and nasal drops containing 0.2 to 5% w/v of the active compound in an aqueous or oily solution or suspension.

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% saline. Furthermore, such pharmaceutically acceptable carriers may 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, alcoholic/aqueous solutions, emulsions, or suspensions, including saline and buffered media. Media for parenteral administration include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Preservatives and other additives may also be present, such as antimicrobials, antioxidants, chelating agents, inert gases and other similar additives.

Topical dosage forms can be prepared, for example, as gels, creams, or ointments. Such preparations can be applied, for example, to a wound or ulcer, either by directly spreading them on the wound or ulcer surface or by applying them to a suitable base, such as a dressing, gauze, mesh, or other similar materials, which can then be applied to the area to be treated.

Liquid or powder dosage forms may also be offered, which can be sprayed or sprinkled directly onto the treatment area, i.e., the wound or ulcer. Alternatively, a carrier such as a bandage, gauze, mesh, or other similar carrier can be sprayed or impregnated with the composition and then applied to the treatment area.

According to a further aspect of the invention, a method for preparing the pharmaceutical or veterinary composition described above is provided, wherein the method comprises mixing the active compound(s) with a carrier, for example by stirring.

Typically, dosage forms are prepared by uniformly and thoroughly mixing the active agent with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product. The invention includes methods for preparing a pharmaceutical composition that involve conjugating or associating a compound described herein with a pharmaceutically or veterinarily acceptable carrier or medium.

SALTS/ESTERS

The compounds of the invention may be presented in the form of salts or esters, in particular pharmaceutically acceptable or veterinarily acceptable salts or esters.

Pharmaceutically acceptable salts of the compounds of the invention include the suitable acid addition salts or base addition salts thereof. A review of suitable pharmaceutical salts can be found in Berge et al., J Pharm Sci, 66, 119 (1977). Salts can be formed, for example, with strong inorganic acids, such as mineral acids, for example hydrohalic acids, such as hydrochloric, hydrobromic and hydroiodic acids, sulfuric acid, phosphoric acid and sulfonic acids; with strong organic carboxylic acids, such as unsubstituted or substituted (e.g. by halogen) alkanecarboxylic acids with 1 to 4 carbon atoms, such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic acid; with hydroxycarboxylic acids, such as ascorbic, glycolic, lactic, malic, tartaric or citric acid; with amino acids, such as aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as unsubstituted or substituted (e.g. by halogen) (C1-C4)-alkyl or aryl sulfonic acids, such as methane- or p-toluenesulfonic acid. Salts that are not acceptable from a pharmaceutical or veterinary point of view may nevertheless be used as intermediates.

Preferred salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, tartrate, lactobionate, pivalate, camphorate, undecanoate and succinate, salts of organic sulfonic acids such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, camphorsulfonate, 2-naphthalenesulfonate, benzenesulfonate, p-chlorobenzenesulfonate and p-toluenesulfonate; and salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, salts of phosphoric and sulfonic acids.

Esters are formed with either organic acids or alcohols/hydroxides, depending on the functional group being esterified. Organic acids include carboxylic acids, such as unsubstituted or substituted (e.g., by halogen) alkanecarboxylic acids with 1-12 carbon atoms, such as acetic acid; saturated or unsaturated dicarboxylic acids, such as oxalic, malonic, succinic, maleic, fumaric, phthalic, or terephthalic acids; hydroxycarboxylic acids, such as ascorbic, glycolic, lactic, malic, tartaric, or citric acids; amino acids, such as aspartic or glutamic acids; benzoic acid; or organic sulfonic acids, such as unsubstituted or substituted (e.g., by halogen) (C1-C4)-alkyl or aryl sulfonic acids, such as methane- or p-toluenesulfonic acid. Suitable hydroxides include inorganic hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and aluminum hydroxide. Alcohols include alkyl alcohols with 1-12 carbon atoms, which may be unsubstituted or substituted (e.g., by halogen).

Enantiomers/Tautomers

In all aspects of the present invention discussed above, the invention includes, where appropriate, all enantiomers, diastereoisomers, and tautomers of the compounds of the invention. Those skilled in the art are familiar with which compounds possess optical properties (the presence of one or more chiral carbon atoms) or tautomeric characteristics. The corresponding enantiomers and/or tautomers can be isolated/prepared using methods known in the art.

Enantiomers are characterized by the absolute configuration of their chiral centers and are described according to the rules of precedence in the Cahn-Ingold-Prelog system for determining R- and S-nomenclature. Such methodologies are well known in the art (e.g., see "Advanced Organic Chemistry," 3rd edition, ed. March, J., John Wiley and Sons, New York, 1985).

The compounds of the invention containing a chiral center may be used in the form of a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known methods and only one individual enantiomer may be used.

STEREOISOMERS AND GEOMETRIC ISOMERS

Some of the compounds of the invention may exist in the form of stereoisomers and/or geometric isomers, for example, they may have one or more asymmetric centers and/or geometric centers and, therefore, may exist in two or more stereoisomeric and/or geometric forms. The present invention contemplates the use of all individual stereoisomers and geometric isomers of these compounds and mixtures thereof. The terms used in the claims encompass these forms, provided that said forms retain the corresponding functional activity (although not necessarily to the same extent).

The present invention also includes all suitable isotopic variants of the compound or a pharmaceutically acceptable salt thereof. An isotopic variant of a compound of the present invention or a pharmaceutically acceptable salt thereof is defined as a variant in which at least one atom is replaced by an atom with the same atomic number, but with an atomic mass different from the atomic mass typically found in nature. Examples of isotopes that can be introduced into the compound and its pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 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, respectively. Specific isotopic variations of the compound and its pharmaceutically acceptable salts, such as those incorporating a radioactive isotope such as ³ H or ¹⁴ C, can be used in drug and/or substrate tissue distribution studies. Tritium, i.e., ³ H, and carbon-14, i.e., ¹⁴ C, are particularly preferred due to their ease of preparation and detection. In addition, substitution with isotopes such as deuterium, i.e., ² H, may provide certain therapeutic advantages related to greater metabolic stability, such as an increased half-life in vivo, or reduced dosage requirements, and may therefore be preferred in some circumstances. For example, the invention includes compounds of general formula (I) in which any hydrogen atom is replaced by a deuterium atom. Isotopic variations of the compound of the present invention and its pharmaceutically acceptable salts of the present invention can generally be prepared by conventional methods using the corresponding isotopic variations of suitable reagents.

ATROPOISOMERS

Some of the compounds of the invention may exist as atropisomers. Atropisomers are stereoisomers that arise from hindered rotation about a single bond, where energy differences due to steric strain or other factors create a barrier to rotation that is high enough to allow the isolation of individual conformers. The invention encompasses all of these atropisomers. The invention also encompasses rotamers of the compounds.

PRODRUGS

Furthermore, the invention further includes the compounds of the present invention in prodrug form, i.e., covalently linked compounds that release the active parent drug in vivo. Such prodrugs are typically compounds of the invention in which one or more relevant groups have been modified in such a way that this modification can be reversed upon administration to a human or mammal. Conversion to the parent compound is typically accomplished by an enzyme naturally present in the human or mammal, although it is also possible to administer a second agent along with such a prodrug to accomplish the reverse conversion in vivo. Examples of such modifications include the formation of an ester (e.g., any of those described above), where the reverse conversion can be accomplished by an esterase, and other similar conversions. Other such systems are well known to those skilled in the art.

SOLVATES

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

COMBINATIONS

Another aspect of the invention relates to a combination comprising a compound described herein and one or more additional active drugs. In a particularly preferred embodiment, one or more compounds of the invention are administered in combination with one or more additional active drugs, such as existing drugs available on the pharmaceutical market. In such cases, the compounds of the invention may be administered sequentially, simultaneously, or one after another with one or more other active drugs.

Generally, drugs exhibit greater efficacy when administered in combination. In particular, combination therapy is desirable in cases where it is necessary to prevent overlap between the primary toxicities, mechanism of action, and resistance mechanism(s). Furthermore, it is also desirable to administer most drugs at their maximum tolerated doses with minimal time intervals between doses. The main advantages of using combination chemotherapeutic agents are that combination therapy can promote additive or potentially synergistic effects through biochemical interactions and can also reduce the likelihood of resistance.

A beneficial combination may be suggested by testing the activity of test compounds in combination with drugs known or suspected to play an important role in the treatment of a specific disorder. This approach can also be used to determine the order of drug administration—pre-, concomitantly, or post-administration. This regimen may be a distinguishing feature for all active drugs identified in the invention.

For cancer, the compounds of the invention can be used in combination with immunotherapeutic agents, such as cancer vaccines, and/or other immunomodulators, such as agents that block the PD1/PDL-1 interaction. Thus, in one preferred embodiment, the additional active drug is an immunotherapeutic agent, more preferably an anticancer immunotherapeutic agent. "Immunotherapeutic agent" refers to a treatment that utilizes a subject's own immune system to combat diseases such as cancer. For other disorders, the compounds of the invention can be used in combination with drugs that block or reduce inflammation, such as antibodies targeting proinflammatory cytokines.

POLYMORPHS

Furthermore, the invention further relates to the compounds of the present invention in their various crystalline forms, polymorphic forms, and anhydrous or aqueous forms. It is well known in the pharmaceutical industry that chemical compounds can be isolated in any of these forms by slightly altering the purification method or isolation from the solvents used in the synthesis of such compounds.

INTRODUCTION

The pharmaceutical compositions of the present invention may be intended for rectal, nasal, intrabronchial, topical (including buccal and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, and intradermal), intraperitoneal, or intrathecal administration. Preferably, the dosage form is an oral dosage form. For convenience, the dosage forms may be presented as unit dose dosage forms, i.e., in the form of discrete portions containing a single dose or a component of a single dose. For example, the dosage forms may be tablets and extended-release capsules, and they may be prepared by any method well known in the pharmaceutical art.

The oral dosage forms of the present invention may be presented as discrete units such as capsules, gelatin capsules, drops, cachets, pills or tablets, each containing a predetermined amount of the active agent, in the form of a powder or granules, in the form of a solution, emulsion or suspension of the active agent in an aqueous liquid or non-aqueous liquid, or in the form of an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, or in the form of a bolus and other similar forms. Preferably, these compositions contain from 1 to 250 mg and, more preferably, from 10 to 100 mg of the active ingredient per dose.

In the case of compositions for oral administration (e.g., tablets and capsules), the term "acceptable carrier" includes such media as commonly known excipients, for example, binders, for example, syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sucrose and starch; fillers and carriers, for example, corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants, such as magnesium stearate, sodium stearate and other metal stearates, glycerol stearate, stearic acid, silicone fluid, talc waxes, oils and colloidal silicon dioxide. Flavorings such as peppermint, oil of wintergreen, cherry flavoring, and other similar flavorings may also be used. It may be desirable to add a coloring agent to make the dosage form easily recognizable. Tablets may also be coated using methods well known in the art.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent. Tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the active agent.

Other forms suitable for oral administration include lozenges containing the active agent in a flavored base, usually sucrose, acacia, or tragacanth; pastilles containing the active agent in an inert base such as gelatin and glycerol, or sucrose and acacia; and mouthwashes containing the active agent in a suitable liquid carrier.

Other forms of administration include solutions or emulsions that can be administered intravenously, intraarterially, intrathecally, subcutaneously, intradermally, intraperitoneally, or intramuscularly, and which are prepared from sterile or sterilizable solutions. Injectable forms typically contain 10 to 1000 mg, preferably 10 to 250 mg, of the active ingredient per dose.

The pharmaceutical compositions of the present invention may also be in the form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or powders.

An alternative method of transdermal administration is the use of a transdermal patch. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. The active ingredient can also be incorporated at a concentration of 1 to 10% by weight into an ointment consisting of a white wax or white soft paraffin base, along with any stabilizers and preservatives that may be required.

DOSAGE

A person skilled in the art can readily determine, without undue experimentation, the appropriate dose of one of the specific compositions for administration to a subject. Generally, a physician must determine the specific dose that will be most appropriate for a particular patient, and this will depend on a number of factors, including the activity of the specific compound used, the metabolic stability and duration of action of that compound, age, body weight, general health, gender, diet, route and time of administration, rate of elimination, drug combination, and the severity of the specific condition of the individual being treated. The doses described herein are provided as examples for an average case. Of course, there may be specific cases requiring higher or lower dosage ranges, and such cases are within the scope of the present invention.

The dosage amount may be further modified depending on the route of administration of the compound. For example, to achieve an "effective amount" in emergency therapy, parenteral administration of the compound is generally preferred. The most effective is intravenous infusion of the compound in 5% dextrose in water or saline or a similar composition with suitable excipients, although intramuscular bolus injection may also be used. Typically, to maintain plasma drug concentrations at levels effective for modulating GPR65, the parenteral dose is from about 0.01 to about 100 mg; preferably, from 0.1 to 20 mg. The compounds may be administered one to four times daily at a dose that achieves a total daily dose of from about 0.4 to about 400 mg. The precise amount of the compound of the invention that is therapeutically effective and the route by which such compound is best administered can be determined without difficulty by one skilled in the art by comparing the blood level of the drug with the concentration required to achieve a therapeutic effect.

The compounds of the present invention can also be administered to a patient orally, such that the concentration of the drug is sufficient to achieve one or more therapeutic effects disclosed in the invention. Typically, a pharmaceutical composition containing the compound is administered orally at a dose of about 0.1 to about 500 mg or about 0.1 to about 50 mg, depending on the patient's condition. Preferably, the oral dose is about 0.5 to about 50 mg or about 0.5 to about 20 mg.

No unacceptable toxicological effects are expected when the compounds of the present invention are administered in accordance with the present invention. Compounds of the present invention, which may have sufficiently high bioavailability, can be tested in one of several biological assays to determine the concentration of the compound required to exhibit a given pharmacological effect.

The invention is further described with reference to the following figures and non-limiting examples.

FIGURES

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

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

EXAMPLES

In cases where the preparation of the starting materials is not described, they are commercially available, known in the literature, or can be readily synthesized by those skilled in the art using standard methods. In cases where compounds are indicated to have been prepared by analogy with previously given examples or by analogy with the previously described preparation of intermediate compounds, it is obvious to those skilled in the art that the reaction time, number of equivalents of reagents, solvent, concentration, and temperature may be varied for each specific reaction, and that it may be necessary or desirable to use different methods for isolating or purifying the resulting compounds.

General synthesis schemes

Conventional abbreviations

A list of some commonly used abbreviated symbols is given below - in case of using other abbreviated symbols that are not given in the invention, they are well known to those skilled in the art.

AcOH: Acetic acid; Boc: Tert-butyloxycarbonyl br.: Broad; CAN: Ammonium cerium nitrate; d: Doublet; DCM: Dichloromethane; DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; DMSO: Dimethyl sulfoxide; (ES+): Positive ion electrospray ionization; _Et3N : Triethylamine; EtOAc: Ethyl acetate; EtOH: Ethanol; h: Hours; HPLC: High performance liquid chromatography; HCl: Hydrochloric acid; Hz: Hertz; IPA: Isopropyl alcohol; J: Coupling constant; l: Liter; LDA: Lithium diisopropylamide; M: Molar; m: Multiplet [M+H]+: Protonated molecular ion; mCPBA: meta-chloroperoxybenzoic acid; MeCN: acetonitrile; MeOH: methanol; MHz: megahertz; min: minutes; ml: milliliters; MS: mass spectrometry; MTBE: methyl tert-butyl ether; m/z: mass-to-charge ratio; NFSI: N-fluorobenzenesulfonimide; NMR: nuclear magnetic resonance; Pd-170: chloro(crotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II); Pd-172: chloro(crotyl)(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)palladium(II); Pd-175: Allyl (2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-tri-isopropyl-1,1'-biphenyl)palladium(II) triflate; Pd-178: Chloro-(crotyl)(tricyclohexylphosphine)palladium(II); Pd ₂ (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-dicyclohexylphosphino-2',6'-dimethoxybiphenyl; t: Triplet; TFA: Trifluoroacetic Acid; THF: tetrahydrofuran; TLC: thin layer chromatography; UPLC: ultra-performance liquid chromatography; UV: ultraviolet.

Other abbreviated symbols are assumed to have their generally accepted meanings.

General conditions for conducting experiments

All starting materials and solvents were either purchased from the manufacturers or synthesized according to literature procedures. The corresponding starting materials, isocyanate and aniline, were purchased from Sigma Aldrich, Fluorochem, or Enamine or synthesized as described herein. The corresponding starting material, tricyclic amine, was purchased from Enamine or synthesized as described herein. Reaction mixtures were stirred magnetically, and reactions were carried out at room temperature (approximately 20°C) unless otherwise noted.

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

UPLC-MS analyses to determine retention times and associated ion masses were performed using a Waters ACQUITY UPLC® H-Class system equipped with an ACQUITY PDA detector and an ACQUITY QDa or Waters SQD mass spectrometer using the analytical method described below.

LC-MS (liquid chromatography with mass spectrometry) analyses for retention times and associated ion masses were performed using an Agilent 1200 Series HPLC system coupled to an Agilent 1956, 6100, or 6120 Series single quadrupole mass spectrometer using one of the analytical methods described below, or using a Shimadzu-2020-P2 system consisting of a Shimadzu LC-20AD liquid chromatography system and a Shimadzu-2020 single quadrupole mass spectrometer using one of the analytical methods described below.

SFC analyses for retention times were performed using a Waters SFC UPC2 system with a column temperature of 40°C and an ABPR of 12.06 MPa using one of the analytical methods described below.

Preparative HPLC purification was performed on either a Waters X-Bridge BEH C18, 5 μm, 19 × 50 mm, a Waters Xbridge Prep OBD C18, 10 μm, 40 × 150 mm, or a Phenomenex Gemini-NX C18, 3 μm, 30 × 75 mm column using a gradient of MeCN and 10 mM aqueous ammonium bicarbonate. Fractions were collected after UV detection at all wavelengths using a photodiode array detector and, in some cases, an SQD2 or ACQUITY QDa mass spectrometer.

Preparative SFC purification was performed using a Waters SFC prep 15 system using either a Phenomenex Lux® Cellulose-4 column, 1×25 cm, 5 μm particle size, or a Chiralpak® IG column (Daicel Ltd.), 1×25 cm, 5 μm particle size, at a flow rate of 15 mL/min, eluting with a mixture of _CO2 and a cosolvent (MeOH, EtOH, or IPA). Fractions were collected after UV detection at 210–400 nm using a photodiode array detector.

NMR spectra were recorded on either a Bruker Avance III HD 500 MHz or a Bruker Avance Neo 400 MHz instrument using either residual non-deuterated solvent or tetramethylsilane as ethanol, or on a Varian Y 400 MHz instrument using tetramethylsilane as the standard, or on a QOne AS400 400 MHz spectrometer using either residual non-deuterated solvent or tetramethylsilane as the standard.

In the absence of absolute stereochemistry specifically indicated by the bonds depicted as wedge-shaped and dotted lines, the chemical structures described in the examples (e.g., in configuration (I.3) described above) should be interpreted as representing a racemate. For the avoidance of doubt, the invention includes compounds in any configuration, as well as mixtures thereof.

Methods of analysis

Method 1 - The Basic Method with a 3-Minute Cycle

Column: Waters ACQUITY UPLC® BEH C18, 1.7 µm, 2.1 x 30 mm at 40°C

Detection: UV at 210-400 nm unless otherwise stated, MS in electrospray ionization mode

Solvents: A: 10 mM aqueous ammonium bicarbonate, B: MeCN

Gradient:

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

Method 2 - The Basic Method with a 4-Minute Cycle

Column: Waters X-Bridge BEH C18, 2.5 µm, 4.6 x 30 mm at 40°C

Detection: UV at 254 nm unless otherwise stated, MS in electrospray ionization mode

Solvents: A: 10 mM aqueous ammonium bicarbonate solution B: MeCN

Gradient:

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

Method 3 - Lux® Amylose-2 Column

Column: Lux® Amylose-2, LC (150×2 mm, particle size 3 µm) at 40°C and flow rate of 1.5 ml/min

Detection: UV detection using a diode array detector (DAD) at 220-400 nm

Solvents: Gradient or isocratic mixture of polar solvent, usually methanol, ethanol, or IPA in _CO2

Method 4 - CHIRALPAK ^® IG-3 Column (Daicel Ltd.)

Column: CHIRALPAK ^® IG-3 (Daicel Ltd.) (2.1×150 mm, 3 µm particle size) and flow rate of 1.5 ml/min

Detection: UV detection using a diode array detector (DAD) at 220-400 nm

Solvents: Gradient or isocratic mixture of polar solvent, usually methanol, ethanol, or IPA in _CO2

Method 5 - The Basic Method with a 4-Minute Cycle

Column: Gemini LC Column C18 50×2 mm, particle size 3 µm at 40°C

Detection: UV at 220 nm unless otherwise stated, MS in electrospray ionization mode

Solvents: A: 10 mM aqueous ammonium bicarbonate, B: MeCN

Gradient:

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

Method 6 - The Basic Method with a 4-Minute Cycle

Column: Waters Sunfire, 3.5 µm, 4.6 x 50 mm at 25°C

Detection: UV at 214 and 254 nm unless otherwise stated, MS in electrospray ionization mode

Solvents: A: 0.05% formic acid in water (v/v) B: 0.05% formic acid in MeCN (v/v)

Gradient:

Time %A %B Flow rate (ml/min) 0.00 85 15 1.0 0.50 85 15 1.0 4.00 0 100 1.0 4.50 0 100 1.0 4.51 85 15 1.0 5.00 85 15 1.0

Experimental design 1

Connection 1. (±)-N-(4-(Trifluoromethyl)phenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

To a solution of 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine (0.075 g, 0.465 mmol) and _Et3N (97 µL, 0.698 mmol) in THF (4 mL) was added a solution of 1-isocyanato-4-(trifluoromethyl)benzene (0.131 g, 0.698 mmol) in THF (0.75 mL). The resulting mixture was stirred at room temperature for 20 h. MeOH (5 mL) was added, and the crude product was concentrated in vacuo. The product was purified by chromatography on RP Flash C18 (15-75% MeCN/10 mM aqueous ammonium bicarbonate) to afford (±)-N-(4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide as a colorless solid. LC-MS (Method 1) m/z 349.3 (M+H) ⁺ (ES ⁺ ); at 1.18 min. ¹ H NMR (500 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.96 (s, 1H), 8.61 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H), 5.31 (d, J=6.2 Hz, 1H), 4.84 (t, J=6.5 Hz, 1H), 3.36-3.33 (m, 1H), 2.79 (d, J=18.4 Hz, 1H), 2.33-2.24 (m, 1H), 2.20 (tt, J=12.2, 6.2 Hz, 1H), 1.90 (ddd, J=12.0, 9.2, 2.5 Hz, 1H), 1.81-1.72 (m, 1H).

The following compounds were prepared using the appropriate starting materials in a manner similar to that described in Experimental Scheme 1. If the starting materials are not described in the literature, their synthesis is described below.

Explanation: (a) The reaction was performed in DMF (b) The reaction was performed in DCM (c) The reaction was performed in a mixture of DMF and DCM (d) The product was purified by mass-targeted HPLC (MeCN/10 mM aqueous ammonium bicarbonate, C18) (e) The product was purified by silica gel chromatography (0.7 M ammonia/MeOH in DCM) (f) The reaction was performed in DMF/THF (g) The product was purified by silica gel chromatography (DCM in heptane) (h) The reaction was performed using DIPEA instead of Et ₃ N (i) The product was purified by silica gel chromatography (EtOAc in isohexane) (j) ES ^- [MH] ^- , the original mass was not detected in ES ⁺ .

Intermediate compound 1 (I-1)

Step 1. tert-Butyl 3-oxo-8-azabicyclo[3,2,1]octane-8-carboxylate I-1a (10 g, 44 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethylmethanamine (21 g, 24 mL, 0.18 mol), and the reaction mixture was heated at reflux for 16 h. The solvent was removed under vacuum. The product was purified by silica gel chromatography (0-5% (0.7 M ammonia/MeOH) in DCM) to afford tert-butyl (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3,2,1]octane-8-carboxylate I-1b as a yellow solid. LCMS (method 2) m/z 281.2 [M+H] ⁺ (ES ⁺ ); at 1.60 min. ¹ H NMR (500 MHz, DMSO-d6) δ 7.25-7.14 (m, 1H), 5.20 (d, J=5.7 Hz, 1H), 4.21 (t, J=6.3 Hz, 1H), 3.07 (s, 6H), 2.54 (s, 1H), 2.09 (s, 3H), 1.77 (t, J=9.0 Hz, 1H), 1.68-1.56 (m, 1H), 1.38 (s, 9H).

Stage 2. To the solution To 2,2,2-trifluoroacetimidamide (192 mg, 132 μL, 1.71 mmol) in MeOH (10 mL) was added a solution of sodium methoxide in MeOH (661 μL, 5.4 M, 3.57 mmol). A solution of tert-butyl (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3,2,1]octane-8-carboxylate I-1b (400 mg, 1.43 mmol) in MeOH (10 mL) was added, and the reaction mixture was heated to 80°C for 16 h. Water (5 mL) and saturated ammonium chloride solution (5 mL) were added. The product was extracted with 20% IPA in chloroform (50 mL). The product was purified by silica gel chromatography (0-3% (0.7 M ammonia/MeOH) in DCM) to afford tert-butyl 2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-1c as a yellow oil. LCMS (Method 2) m/z 330.1 [M+H]⁺(ES⁺); at 2.28 min.¹H NMR (500 MHz, DMSO-d6) δ 5.12 (d, J=5.8 Hz, 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=9.9 Hz, 1H), 1.77-1.68 (m, 1H), 1.41-1.23 (m, 9H).

Step 3. To a solution of tert-butyl 2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-1c (85 mg, 0.26 mmol) in DCM (2 mL) was added TFA (0.20 mL, 2.6 mmol). The reaction mixture was stirred at room temperature for 16 h. The crude reaction mixture was concentrated under reduced pressure. 2 mL of 0.7 M ammonia in MeOH was added, and the solvent was removed in vacuo to give 2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine as a yellow oil, which was used in the next steps without further purification. LCMS (method 2) m/z 230.0 [M+H] ⁺ (ES ⁺ ); at 1.20 min.

Intermediate compound 2 (I-2)

Stage 1. tert-butyl 2-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-2a was prepared from tert-butyl (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo-[3,2,1]octane-8-carboxylate I-1b using essentially the same method as that used to prepare compound I-1c: LCMS (Method 2) m/z 276.1 [M+H]⁺(ES⁺); at 1.59 min.¹H NMR (500 MHz, DMSO-d6) δ 8.47 (s, 1H), 4.93 (d, J=6.0 Hz, 1H), 4.44 (s, 1H), 3.21-3.12 (m, 1H), 2.67 (d, J=18.2 Hz, 1H), 2.53 (s, 3H), 2.21 (s, 1H), 2.13 (dkv, J=11.8, 5.8 Hz, 1H), 1.78 (t, J=10.2 Hz, 1H), 1.66 (dt, J=15.1, 7.6 Hz, 1H), 1.34 (s, 9H).

Stage 2:2-Methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine I-2 was prepared from tert-butyl 2-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-2a, using essentially the same method as that used to prepare the compoundI-1: LCMS (method 2) m/z 176.1 [M+H]⁺(ES⁺); at 0.70 min.

Intermediate compound 3 (I-3)

Step 1. tert-butyl 2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate (I-3a) was prepared from tert-butyl (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo-[3,2,1]octane-8-carboxylate I-1b using essentially the same method as that used to prepare compoundI-1c: LCMS (method 2) m/z 338.2 [M+H]⁺(ES⁺); at 2.55 min.¹H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.44-8.27 (m, 2H), 7.51 (p, J=3.4, 3.0 Hz, 3H), 5.02 (d, J=5.9 Hz, 1H), 4.50 (s, 1H), 3.28 (d, J=23.9 Hz, 1H), 2.82 (d, J=18.1 Hz, 1H), 2.32-2.11 (m, 2H), 1.87 (t, J=10.1 Hz, 1H), 1.75 (dd, J=12.7, 6.4 Hz, 1H), 1.40 (s, 9H).

Stage 2. 2-Phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclo-hepta[d]pyrimidine (I-3) was prepared from tert-butyl 2-phenyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate (I-3a) using essentially the same method as that used to prepare compound I-1: LCMS (Method 2) m/z 230.1 [M+H]⁺(ES⁺); at 1.18 min.

Intermediate compound 5 (I-5)

Step 1. To a solution of urea (0.2 g, 4 mmol) in EtOH (10 mL) was added sodium ethoxide solution (2 mL, 21% by weight in EtOH, 4 mmol). Tert-butyl (E)-2-((dimethylamino)methylene)-3-oxo-8-azabicyclo[3,2,1]octane-8-carboxylate I-1b (1 g, 4 mmol) in EtOH (10 mL) was added, and the reaction mixture was heated to 90 °C for 16 h. Saturated ammonium chloride solution (5 mL) was added, and the product was extracted with 10% solution (0.7 M ammonia/MeOH) in DCM (2×35 mL). The product was purified by silica gel chromatography (0-10% (0.7 M ammonia/MeOH) in DCM) to afford tert-butyl 2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-5a as a white solid. LCMS (Method 2) m/z 278.1 (M+H) ⁺ (ES ⁺ ), at 1.3 min. ¹ H NMR (500 MHz, 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). 1 proton under the DMSO peak.

Stage 2. To the solution To tert-butyl 2-hydroxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate I-5a (361 mg, 1.30 mmol) in DCM (10 mL) was added TFA (1.00 mL, 13.0 mmol) slowly. The resulting mixture was stirred at room temperature. The reaction mixture was concentrated in vacuo. 0.7 M ammonia in MeOH (5 mL) was added, and the mixture was concentrated in vacuo. The material was purified by strong cation exchange (SCX) chromatography eluting with 0.7 M ammonia in MeOH to afford 6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidin-2-olI-5in the form of a pale yellow solid.¹H NMR (500 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.27 (s, 1H), 6.67 (s, 1H), 4.05 (d, J=5.7 Hz, 1H), 3.69 (t, J=6.4 Hz, 1H), 2.88-2.78 (m, 1H), 2.34 (d, J=18.5 Hz, 1H), 1.91 (d, J=4.4 Hz, 1H), 1.89-1.81 (m, 1H), 1.74-1.62 (m, 1H), 1.56-1.46 (m, 1H).

Intermediate compound 7 (I-7)

The following scheme uses the synthetic method described by Schultz and Wolfe, Organic Letters, 2011, 13(11), 2962-2965.

Step 1. To a solution of 3-bromo-4-pyridinecarboxaldehyde (42.0 g, 225 mmol) in THF (250 mL) was added titanium(IV) ethoxide (93.6 mL, 451 mmol) in one portion at room temperature. The mixture was stirred at room temperature for 5 min, then (±)-tert-butylsulfinamide (30.1 g, 248 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 16 h. Water (50 mL) was added at 0°C, and the product was extracted with EtOAc (3×30 mL). The combined organic layers were concentrated in vacuo. The product was purified by silica gel chromatography (1–100% EtOAc/petroleum ether) to afford (E)-N-((3-bromopyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (I-7b) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.91 (s, 1H), 8.86 (s, 1H), 8.62 (d, J=4.8 Hz, 1H), 7.83 (d, J=5.2 Hz, 1H), 1.29 (s, 9H).

Step 2. To a solution of (E)-N-((3-bromopyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (I-7b) (53.4 g, 185 mmol) in THF (300 mL) was added dropwise but-3-en-1-yl magnesium bromide (0.5 M, 1.59 L) at 0°C. The mixture was warmed to room temperature over 1 h. Saturated ammonium chloride solution (200 mL) was added, and the product was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo. 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.68 (s, 1H), 8.51-8.48 (m, 1H), 7.31 (d, J=5.2 Hz, 1H), 5.83-5.76 (m, 1H), 5.10 (d, J=1.2 Hz, 1H), 5.05 (d, J=5.2 Hz, 1H), 4.87-4.83 (m, 1H), 3.56 (d, J=3.2 Hz, 1H), 2.16-2.09 (m, 2H), 1.95-1.88 (m, 2H), 1.20 (d, J=11.2 Hz, 9H).

Step 3. To a solution of N-(1-(3-bromopyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-7c) (54.3 g, 157 mmol) in MeOH (326 mL) was added a solution of HCl in EtOAc (4 M, 117 mL) at 0 °C. The mixture was warmed to room temperature over 30 min. The reaction mixture was concentrated in vacuo. The residue was filtered, and the filter cake was washed with EtOAc (2 × 10 mL) and dried in vacuo to give a pale yellow solid, which was then dissolved in water. The mixture was basified to pH > 11 with NaOH solution and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate to give 1-(3-bromopyridin-4-yl)pent-4-ene-1-amine (I-7d) as a yellowish-brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.64 (s, 1H), 8.48 (d, J=5.6 Hz, 1H), 7.44 (d, J=5.2 Hz, 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).

Stage 4. To a solution of 1-(3-bromopyridin-4-yl)pent-4-ene-1-amine (I-7d) (26.5 g, 110 mmol), (4-methoxyphenyl)boronic acid (25.1 g, 165 mmol), 4 Å molecular sieves (53.0 g) and Cu(OAc)₂(20.0 g, 110 mmol) in 1,4-dioxane (530 ml) was added dropwise Et₃N (20 mL, 143 mmol). The mixture was stirred at 35°C under O₂for 16 h. The mixture was filtered, and the filter cake was washed with EtOAc (3×15 mL). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (1%-100% EtOAc/petroleum ether) to afford N-(1-(3-bromopyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-7e) as a reddish-brown solid.¹H NMR (400 MHz, CDCl₃) δ 8.68 (s, 1H), 8.40 (d, J=5.2 Hz, 1H), 7.34 (d, J=4.8 Hz, 1H), 6.71-6.67 (m, 2H), 6.36 (t, J=2.0, 3.6 Hz, 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).

Step 5. The flame-dried flask was cooled under N ₂ and charged with Pd ₂ (dba) ₃ (3.61 g, 3.95 mmol), S-Phos (3.24 g, 7.89 mmol), and NaO ^t Bu (5.69 g, 59.2 mmol). The flask was purged with N ₂ , and 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) was added dropwise. The resulting mixture was heated to 90 °C for 12 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (3×10 mL). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (1%-100% EtOAc/petroleum ether) to afford 10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-7f) as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (d, J=4.8 Hz, 1H), 8.17 (s, 1H), 7.08 (d, J=5.2 Hz, 1H), 6.77-6.71 (m, 4H), 4.61 (d, J=6.0 Hz, 1H), 4.51 (t, J=5.2, 6.8 Hz, 1H), 3.70 (s, 3H), 3.21 (dd, J=4.8, 12.0 Hz, 1H), 2.43-2.35 (m, 3H), 1.95-1.91 (m, 1H), 1.79-1.78 (m, 1H).

Step 6. A solution of 10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-7f) (6.32 g, 23.7 mmol) in MeCN (237 mL) was cooled to 0 °C, then an aqueous solution of CAN (0.3 M, 316 mL) was added dropwise. After complete addition, the reaction mixture was stirred for 1 h at 0 °C. The reaction mixture was concentrated to dryness in vacuo to give 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-7g) as a brown oil, which was used in the next step without further purification.

Step 7. To a solution of 6,7,8,9-tetrahydro-5H-5,8-epiminocyclo-hepta[c]pyridine (I-7g) (3.82 g, 23.9 mmol) in THF (30 mL) were added K ₂ CO ₃ (8.25 g, 59.7 mmol) and di-tert-butyl dicarbonate (26.0 g, 119 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (3×15 mL). Water (25 mL) was added to the filtrate. The aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (1%-100% EtOAc/Petroleum ether) to afford tert-butyl 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[c]pyridine-10-carboxylate (I-7h) as a reddish-brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34-8.32 (m, 2H), 6.98 (s, 1H), 4.86 (d, J=28.8 Hz, 1H), 4.58 (s, 1H), 3.36 (s, 1H), 2.56 (d, J=16.8 Hz, 1H), 2.24-2.18 (m, 2H), 1.86-1.81 (m, 1H), 1.64-1.65 (m, 1H), 1.42 (s, 9H).

Step 8. A solution of HCl in EtOAc (4 M, 550 mL) was added to a solution of tert-butyl 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxylate (I-7h) (2.20 g, 8.45 mmol) in MeOH (400 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum. The crude product was triturated with MTBE (20 mL) at room temperature for 10 min. The mixture was filtered, the filter cake was washed with MTBE (2×5 mL), and the cake was dried under vacuum to afford 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine hydrochloride as a white solid. LCMS (Method 5) m/z 161.2 (M+H) ⁺ (ES ⁺ ), at 2.44 min. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.92 (s, 1H), 9.65 (s, 1H), 8.64 (d, J=18.0 Hz, 2H), 7.64 (s, 1H), 5.03 (s, 1H), 4.40 (s, 1H), 3.39 (s, 1H), 3.00 (d, J=17.6 Hz, 1H), 2.36-2.18 (m, 2H), 1.99-2.02 (m, 1H), 1.86-1.75 (m, 1H).

Intermediate compound 8 (I-8)

Stage 1. (E)-N-((4-Bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (I-8b) was synthesized from 4-bromo-3-pyridinecarboxaldehyde (I-8a) using essentially the same method as that used to prepare compound I-7b.¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 8.93 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 7.61 (d, J=5.2 Hz, 1H), 1.30 (s, 9H).

Step 2. N-(1-(4-Bromopyridin-3-yl)pent-4-en-1-yl)-2-methyl-propane-2-sulfinamide (I-8c) was synthesized from (E)-N-((4-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (I-8b) using essentially the same method as that used to prepare compound I-7c. ^1H NMR (400 MHz, CDCl ₃ ) δ: 8.55 (s, 1H), 8.32-8.29 (m, 1H), 7.50 (d, J=5.2 Hz, 1H), 5.85-5.76 (m, 1H), 5.10-5.02 (m, 2H), 4.92-4.90 (m, 1H), 3.57 (d, J=3.6 Hz, 1H), 2.18-1.97 (m, 4H), 1.19 (s, 9H).

Step 3. 1-(4-Bromopyridin-3-yl)pent-4-en-1-amine (I-8d) was synthesized from N-(1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-8c) using essentially the same method as that used to prepare compound I-7d. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.66 (s, 1H), 8.29-8.24 (m, 1H), 7.48-7.45 (t, J=8.8 Hz, 1H), 5.86-5.79 (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), 1.56 (s, 2H).

Step 4. N-(1-(4-Bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline (I-8e) was synthesized from 1-(4-bromopyridin-3-yl)pent-4-en-1-amine (I-8d) using essentially the same method as that used to prepare compound I-7e. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.58 (d, J=15.6 Hz, 1H), 8.26 (s, 1H), 7.49 (d, J=5.2 Hz, 1H), 6.69 (d, J=8.8 Hz, 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).

Stage 5. 10-(4-Methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-8f) was synthesized from N-(1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline (I-8e) using essentially the same method as that used to prepare compound I-7f.¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1H), 8.27 (d, J=5.2 Hz, 1H), 6.84 (d, J=4.4 Hz, 1H), 6.77-6.70 (m, 4H), 4.72 (d, J=5.2 Hz, 1H), 4.65 (d, J=5.2 Hz, 1H), 3.69 (s, 3H), 3.25-3.19 (m, 1H), 2.40 (dd, J=3.6, 7.2 Hz, 3H), 1.97-1.92 (m, 1H), 1.79-1.75 (m, 1H).

Stage 6. 6,7,8,9-Tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-8g) was synthesized from 10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-8f) using essentially the same method as that used to prepare compound I-7g.

Stage 7. Tert-butyl 6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxylate (I-8h) was prepared from 6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-8g) using essentially the same method as that used to prepare compound I-7h.¹H NMR (400 MHz, CDCl₃) δ 8.36 (d, J=5.2 Hz, 1H), 8.31 (s, 1H), 7.01 (d, J=4.8 Hz, 1H), 4.95 (s, 1H), 4.54 (s, 1H), 3.37 (s, 1H), 2.54 (d, J=17.6 Hz, 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).

Stage 8. 6,7,8,9-Tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine hydrochloride (I-8) was synthesized from tert-butyl 6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxylate (I-8h) using essentially the same method as that used to prepare compound I-7. LCMS (Method 5) m/z 161.2 (M+H)⁺(ES⁺), at 2.42 min.¹H NMR (400 MHz, CDCl₃) δ 10.26 (s, 1H), 9.90 (s, 1H), 8.79 (s, 1H), 8.71 (d, J=6.0 Hz, 1H), 7.77 (d, J=5.6 Hz, 1H), 5.10 (d, J=6.0 Hz, 1H), 4.36 (s, 1H), 3.54 (dd, J=4.8, 19.2 Hz, 1H), 3.19-3.07 (m, 1H), 2.41-2.18 (m, 2H), 2.08 (t, J=11.2 Hz, 1H), 1.88-1.75 (m, 1H).

Intermediate compound 9 (I-9)

Stage 1. (E)-N-(2-Bromo-4-methoxybenzylidene)-2-methylpropane-2-sulfinamide (I-9b) was synthesized from 2-bromo-4-methoxybenzaldehyde (I-9a) using essentially the same method as that used to prepare compound I-7b.¹H NMR (500 MHz, d6-DMSO) δ 8.73 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.37 (d, J=2.5 Hz, 1H), 7.13 (dd, J=8.8, 2.4 Hz, 1H), 3.88 (s, 3H), 1.18 (s, 9H).

Stage 2. Solution (E)-N-(2-bromo-4-methoxybenzylidene)-2-methylpropane-2-sulfinamide (13.0 g, 40.9 mmol) in THF (130 mL) was cooled to -78°C. But-3-en-1-ylmagnesium bromide (0.5 M in THF) (245 mL, 123 mmol) was added dropwise. The mixture was slowly warmed to room temperature, and the mixture was stirred at room temperature for 16 h. Saturated aqueous ammonium chloride solution (150 mL) was added, and the product was extracted with EtOAc (2×100 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to afford N-(1-(2-bromo-4-methoxyphenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-9c) as a light brown oil. The compound was used in the next step without further purification as a 2:1 mixture of diastereoisomers.

Major diastereoisomer: ¹ H NMR (500 MHz, d6-DMSO) δ 7.42 (d, J=8.7 Hz, 1H), 7.11 (d, J=2.5 Hz, 1H), 6.99 (dd, J=8.7, 2.6 Hz, 1H), 5.82 (ddt, J=16.9, 10.2, 6.5 Hz, 1H), 5.51 (d, J=6.5 Hz, 1H), 5.06 (d, J=17.4 Hz, 1H), 4.98 (d, J=10.8 Hz, 1H), 4.57 (d, J=6.8 Hz, 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).

Minor diastereoisomer: ¹ H NMR (500 MHz, d6-DMSO) δ 7.51 (d, J=8.7 Hz, 1H), 7.11 (d, J=2.5 Hz, 1H), 6.99 (dd, J=8.5, 2.5 Hz, 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).

Stage 3. To the solution 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) was added a solution of HCl (4 M in 1,4-dioxane) (33 mL, 132.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2.5 h. Water (200 mL) was added, and the aqueous solution was washed with EtOAc (200 mL). The pH of the aqueous layer was adjusted to pH 8 by adding 2 M aqueous NaOH. The aqueous layer was then extracted with EtOAc (2×100 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to yield 1-(2-bromo-4-methoxyphenyl)pent-4-ene-1-amine (I-9d) as a pale brown liquid. The crude product was used in the next step without further purification.

Step 4. To a solution of 1-(2-bromo-4-methoxyphenyl)pent-4-ene-1-amine (I-9d) (7.60 g, 28.1 mmol) in DCM (100 mL) was added (4-methoxyphenyl)boronic acid (12.8 g, 84.4 mmol), followed by copper(II) acetate (7.66 g, 42.2 mmol) and pyridine (11.4 mL, 141 mmol). The blue mixture was vigorously stirred at room temperature for 72 h. Aqueous 2M NaOH (100 mL) was added, and the mixture was stirred for 30 min. Copper salts were filtered through a pad of celite. Water (100 mL) was added, and the product was extracted with DCM (3 × 100 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo. The product was purified by silica gel chromatography (5–25% EtOAc/isohexane) to afford N-(1-(2-bromo-4-methoxy-phenyl)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 min,¹H NMR (500 MHz, DMSO-d6) δ 7.33 (d, J=8.7 Hz, 1H), 7.12 (d, J=2.6 Hz, 1H), 6.90 (dd, J=8.7, 2.6 Hz, 1H), 6.62 (d, J=8.9 Hz, 2H), 6.37 (d, J=9.0 Hz, 2H), 5.92 (d, J=8.1 Hz, 1H), 5.85 (ddt, J=17.0, 10.2, 6.5, 6.5 Hz, 1H), 5.02 (dq, J=17.2, 1.8, 1.7, 1.7 Hz, 1H), 4.97 (ddt, J=10.2, 2.3, 1.3, 1.3 Hz, 1H), 4.51 (td, J=8.2, 8.2, 5.0 Hz, 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).

Stage 5. Pd-178 (667 mg, 1.40 mmol) and NaO were added to the flask.^tBu (2.02 g, 21.0 mmol) was added and the flask was purged with nitrogen. A solution of N-(1-(2-bromo-4-methoxyphenyl)pent-4-en-1-yl)-4-methoxyaniline (I-9e) (5.26 g, 14.0 mmol) in degassed toluene (120 mL) was added via syringe at room temperature. The resulting mixture was heated at 95°C for 2 h. The reaction mixture was cooled to room temperature and filtered through celite. Celite was washed with EtOAc (100 mL). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0-25% EtOAc/isohexane) to afford (±)-2-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene (I-9f) as a pale pink oil. LCMS (Method 2) m/z 296 (M+H)⁺(ES⁺), at 1.27 min,¹H NMR (500 MHz, DMSO-d6) δ 7.12 (d, J=8.3 Hz, 1H), 6.76 (d, J=9.1 Hz, 2H), 6.69 (d, J=9.1 Hz, 2H), 6.65 (dd, J=8.3, 2.7 Hz, 1H), 6.48 (d, J=2.6 Hz, 1H), 4.70 (d, J=5.6 Hz, 1H), 4.54-4.38 (m, 1H), 3.64 (s, 3H), 3.61 (s, 3H), 3.10 (dd, J=17.0, 4.7 Hz, 1H), 2.36 (d, J=17.0 Hz, 1H), 2.30-2.13 (m, 2H), 1.80-1.63 (m, 2H).

Step 6. To a solution of (±)-2-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene (I-9f) (680.0 mg, 2.30 mmol) in MeCN (25 mL) was added dropwise a solution of CAN (3.79 g, 6.91 mmol) in water (25 mL) over 30 min at 0 °C. The mixture was stirred at 0 °C for 1 h and at room temperature for 1 h. Water (10 mL) and 2M NaOH (10 mL) were added, and the product was extracted with DCM (3×30 mL). The organic layers were combined and concentrated in vacuo to afford (±)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-epimino-benzo[7]annulene (I-9) as a brown oil. This compound was used without further purification. LCMS (Method 2) m/z 190 (M+H) ⁺ (ES ⁺ ), at 1.56 min, ¹ H NMR (500 MHz, DMSO-d6) δ 6.89 (d, J=8.2 Hz, 1H), 6.61 (dd, J=8.2, 2.7 Hz, 1H), 6.58 (d, J=2.6 Hz, 1H), 4.04 (d, J=5.1 Hz, 1H), 3.73-3.66 (m, 4H), 3.01 (dd, J=16.6, 5.0 Hz, 1H), 2.64 (br s, 1H), 2.44 (d, J=16.6 Hz, 1H), 1.95-1.81 (m, 2H), 1.74-1.57 (m, 1H), 1.50-1.39 (m, 1H).

Intermediate compound 10 (I-10)

Step 1. (±)-2-Methoxy-6,7,8,9-tetrahydro-5H-5,8-epimino-benzo[7]annulene (I-9) (267 mg, 1.24 mmol) was added to an aqueous solution of HBr (48% solution in water) (1.4 mL, 48% by weight, 12.41 mmol) at room temperature, and then heated under reflux for 6 h. The mixture was diluted with MeOH (20 mL) and filtered to obtain a clear dark brown filtrate. SCX (7.00 g, 5.4 mmol) was added, and the mixture was then stirred at room temperature for 1 h. SCX was washed with MeOH (100 mL), and the product was eluted with 0.7 M ammonia in MeOH (50 mL). The eluant was concentrated under vacuum to give (±)-6,7,8,9-tetrahydro-5H-5,8-epimino-benzo[7]annulen-2-ol as a dark brown oil. LCMS (Method 2) m/z 176 (M+H) ⁺ (ES ⁺ ), at 0.61 min, ¹ H NMR (500 MHz, 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 replaceable proton is not visible

Intermediate compound 11 (I-11)

Step 1. A vial was charged with Pd-170 (1 mg, 1.45 μmol) and K ₂ PO ₃ (23 mg, 145 μmol), sealed, and evacuated/backfilled with N ₂ (3 times). A solution of tert-butyl (±)-2-(((tri-fluoromethyl)sulfonyl)oxy)-6,7,8,9-tetrahydro-5H-5,8-epimino-benzo[7]annulene-10-carboxylate (40 mg, 97.0 μmol) and (2,4-dimethoxyphenyl)methanamine (18 mg, 107 μmol) in 1,4-dioxane (1 mL) was added, and the reaction mixture was heated to 120 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0%-100% EtOAc/isohexane) to afford tert-butyl (±)-2-((2,4-dimethoxybenzyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate (I-11a) as a yellow oil. LC-MS (method 1) m/z 447.1 (M+Na) ⁺ (ES ⁺ ) at 1.82 min, ¹ H NMR (500 MHz, 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 proton is not visible).

Step 2. To a solution of tert-butyl (±)-2-((2,4-dimethoxybenzyl)amino)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate (I-11a) (30 mg, 69.7 μmol) in DCM (1 mL) was added TFA (54 μL, 0.70 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The product was purified by ion exchange using SCX (0.5 g), washing with MeOH and eluting with 0.7 M ammonia in MeOH to give (±)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[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 min.

Intermediate compound 12 (I-12)

Step 1. To a solution of 2-bromo-4-fluorobenzaldehyde I-12a (10.0 g, 49.3 mmol) in THF (170 mL) was added titanium(IV) ethoxide (20.7 mL, 98.5 mmol) in one portion at room temperature. The mixture was stirred at room temperature for 5 min, then (±)-tert-butylsulfinamide (5.97 g, 49.3 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 24 h. Brine (100 mL) was added, and the mixture was stirred for 10 min, then filtered through Celite. The filtrate was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (3×100 mL), dried over magnesium sulfate, and concentrated in vacuo to afford (E)-N-(2-bromo-4-fluorobenzylidene)-2-methylpropane-2-sulfinamide as a pale yellow solid (I-12b). LCMS (Method 1) m/z 306.2, 308.1 (M+H) ⁺ (ES ⁺ ), at 1.6 min. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.77 (s, 1H), 8.11 (dd, J=8.8, 6.2 Hz, 1H), 7.81 (dd, J=8.5, 2.6 Hz, 1H), 7.45 (td, J=8.2, 2.6 Hz, 1H), 1.20 (s, 9H).

Step 2. To a solution of (E)-N-(2-bromo-4-fluorobenzylidene)-2-methyl-propane-2-sulfinamide (13.00 g, 42.46 mmol) (I-12b) in THF (150 mL) was added but-3-en-1-yl magnesium bromide (2.17 M, 29.4 mL) dropwise at -78°C. The mixture was warmed to room temperature over 16 h. Saturated ammonium chloride solution (50 mL) was added, and the product was extracted with EtOAc (2×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo 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 min.

Step 3. 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) was added a solution of HCl in 1,4-dioxane (4 M, 10.3 mL) at room temperature and stirred for 2.5 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between water (200 mL) and EtOAc (200 mL). The aqueous phase was basified to pH 8 with NaOH and extracted with EtOAc (2×100 mL). The organic layer was diluted with water (50 mL), basified to pH 10 with NaOH, and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford 1-(2-bromo-4-fluorophenyl)pent-4-ene-1-amine (I-12d) as a colorless oil. LCMS (Method 2) m/z 258.0, 260.0 (M+H) ⁺ (ES ⁺ ), at 2.20 min. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.66 (dd, J=8.7, 6.4 Hz, 1H), 7.47 (ddt, J=8.5, 3.0, 1.6 Hz, 1H), 7.30-7.22 (m, 1H), 5.81 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.09-4.92 (m, 1H), 4.94 (ddt, J=10.3, 2.2, 1.1 Hz, 1H), 4.13 (dd, J=8.1, 5.0 Hz, 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 -NH ₂ protons are not visible).

Stage 4. To a solution of 1-(2-bromo-4-fluorophenyl)pent-4-ene-1-amine (9.60 g, 37.2 mmol) (I-12d), (4-methoxyphenyl)boronic acid (17.0 g, 112 mmol) and Cu(OAc)₂Pyridine (15.0 mL, 186 mmol) was added dropwise to a mixture of 10.1 g (10.1 g, 55.8 mmol) of ethyl acetate in DCM (100 mL). The mixture was stirred at room temperature under air for 16 h. 2 M aqueous NaOH (100 mL) was added, the mixture was stirred for 30 min, and filtered through Celite. The filtrate was partitioned between water (100 mL) and DCM (100 mL), and the layers were separated. The aqueous layer was then extracted with DCM (2×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (0%-10% EtOAc/isohexane), followed by silica gel chromatography (0%-50% DCM/isohexane) to afford 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 min.¹H NMR (500 MHz, DMSO-d₆) δ 7.52 (dd, J=8.5, 2.6 Hz, 1H), 7.47 (dd, J=8.7, 6.3 Hz, 1H), 7.20 (td, J=8.5, 2.7 Hz, 1H), 6.67-6.60 (m, 2H), 6.40-6.33 (m, 2H), 6.00 (d, J=8.0 Hz, 1H), 5.90-5.79 (m, 1H), 5.06-4.94 (m, 2H), 4.55 (td, J=8.2, 5.0 Hz, 1H), 3.57 (s, 3H), 2.29 (t, J=11.2 Hz, 1H), 2.21-2.10 (m, 1H), 1.79-1.64 (m, 2H).

Step 5. Pd-178 (448 mg, 939 μmol) and NaO were charged into a three-necked flask.^tBu (3.99 g, 41.5 mmol) and purged with N₂A 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) was added dropwise. The resulting mixture was heated to 95°C for 2 h. The reaction mixture was cooled to room temperature and filtered through celite, washing with EtOAc (100 mL). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0%-5% EtOAc/heptane) to afford (±)-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene (I-12f) as a pink oil. LCMS (method 2) m/z 384.1 (M+H)⁺(ES⁺), at 2.52 min.¹H NMR (500 MHz, DMSO-d₆) δ 7.26 (dd, J=8.3, 6.0 Hz, 1H), 6.90 (td, J=8.7, 2.7 Hz, 1H), 6.80-6.73 (m, 3H), 6.73-6.66 (m, 2H), 4.79 (d, J=5.6 Hz, 1H), 4.44 (t, J=5.8 Hz, 1H), 3.61 (s, 3H), 3.11 (dd, J=17.3, 4.8 Hz, 1H), 2.41 (d, J=17.3 Hz, 1H), 2.26-2.18 (m, 2H), 1.84-1.62 (m, 2H).

Stage 6. A solution of (±)-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene (I-12f) (2.15 g, 7.59 mmol) in MeCN (28 mL) was cooled to 0 °C, then a solution of CAN (12.5 g, 22.8 mmol) in water (100 mL) was added dropwise. After complete addition, the reaction mixture was stirred for 1 h at 0 °C, then warmed to room temperature and stirred for 1 h. Water (30 mL) and 2 M aqueous sodium hydroxide solution (50 mL) were added, and the product was extracted with DCM (4×150 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The crude residue was redissolved in MeOH and purified using SCX (15 g), washing with MeOH and eluting with 0.7 M ammonia in MeOH to give (±)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo-[7]annulene (I-12) as a brown oil. LCMS (Method 2) m/z 178.1 (M+H)⁺(ES⁺), at 1.65 min.¹H NMR (500 MHz, DMSO-d₆) δ 7.02 (dd, J=6.3, 1.9 Hz, 1H), 6.94-6.81 (m, 2H), 4.12-4.07 (m, 1H), 3.68 (t, J=5.5 Hz, 1H), 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).

Intermediate compound 13 (I-13)

Stage 1. To a solution of 3-chloro-2-fluoroisonicotinaldehyde I-13a (1.00 g, 6.27 mmol) in THF (17 mL) was added titanium(IV) ethoxide (2.63 mL, 12.5 mmol) in one portion at room temperature. The mixture was stirred at room temperature for 5 min, then (S)-tert-butylsulfinamide (760 mg, 6.27 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 16 h. Brine (30 mL) was added, and the mixture was stirred for 10 min, then filtered through Celite. The filtrate was extracted with EtOAc (2×20 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo 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 min.¹H NMR (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.33 (dt, J=5.1, 0.8 Hz, 1H), 7.90 (d, J=5.1 Hz, 1H), 1.22 (s, 9H).

Step 2. To a solution of (S)-N-((3-chloro-2-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.38 g, 5.26 mmol) (I-13b) in THF (22 mL) was added but-3-en-1-yl magnesium bromide (0.5 M, 31.6 mL, 15.79 mmol) dropwise at -78°C. The mixture was slowly warmed to room temperature and stirred for 72 h. Saturated ammonium chloride solution (10 mL) was added, and the product was extracted with EtOAc (3×10 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (0-100% EtOAc/isohexane) to afford (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 min. ¹ H NMR (500 MHz, DMSO-d6) δ 8.21 (dd, J=5.2, 0.8 Hz, 1H), 7.53 (d, J=5.2 Hz, 1H), 5.90 (d, J=7.3 Hz, 1H), 5.81 (dddd, J=17.3, 10.2, 7.1, 6.1 Hz, 1H), 5.10 (dqv, J=17.2, 1.7 Hz, 1H), 5.02 (ddt, J=10.2, 2.3, 1.2 Hz, 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).

Step 3. 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) was added a solution of HCl in 1,4-dioxane (4 M, 3.0 mL, 12.09 mmol) at room temperature and stirred for 2.5 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (100 mL) and extracted with DCM (3×30 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give (R)-1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-amine as a pale yellow liquid (I-13d). LCMS (Method 1): m/z 215.4, 217.3 (M+H) ⁺ (ES ⁺ ); at 1.17 min, ¹ H NMR (500 MHz, 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 (dqv, 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), 2 NH protons were not detected.

Stage 4. 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-methoxy-phenyl)boronic acid (1.37 g, 9.0 mmol) and Cu(OAc)₂(820 mg, 4.50 mmol) in DCM (100 mL) was treated dropwise with pyridine (1.2 mL, 15.0 mmol). The mixture was stirred at room temperature under air for 16 h. 2 M aqueous NaOH (20 mL) was added, followed by water (20 mL), and the mixture was extracted with DCM (3×20 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (0%–100% DCM/isohexane) to afford (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 min,¹H NMR (500 MHz, DMSO-d6) δ 8.10 (d, J=5.1 Hz, 1H), 7.41 (d, J=5.1 Hz, 1H), 6.65 (d, J=8.9 Hz, 2H), 6.38 (d, J=8.9 Hz, 2H), 6.09 (d, J=8.3 Hz, 1H), 5.84 (ddt, J=17.0, 10.2, 6.6 Hz, 1H), 5.10-4.88 (m, 2H), 4.68 (td, J=8.5, 4.7 Hz, 1H), 3.57 (s, 3H), 2.34-2.24 (m, 1H), 2.23-2.12 (m, 1H), 1.87-1.69 (m, 2H).

Step 5. Pd-178 (7.4 mg, 15.6 μmol) and sodium tert-butoxide (22.5 mg, 234 μmol) were charged into a three-necked flask and purged with N₂A solution of (R)-N-(1-(3-chloro-2-fluoro-pyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-13e) (50.0 mg, 156 μmol) in toluene (1 mL) was added dropwise. The resulting mixture was heated to 95°C for 1.5 h. The reaction mixture was cooled to room temperature and filtered through celite, washing with EtOAc (3×20 mL). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0%-50% EtOAc/heptane) to afford (5R,8S)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-13f) as a white solid. LCMS (Method 1) m/z 285.3 (M+H)⁺(ES⁺), at 1.35 min.¹H NMR (500 MHz, DMSO-d6) δ 7.95 (d, J=4.9 Hz, 1H), 7.29 (dd, J=5.0, 1.7 Hz, 1H), 6.80 (d, J=9.1 Hz, 2H), 6.71 (d, J=9.1 Hz, 2H), 4.92 (d, J=5.6 Hz, 1H), 4.56 (t, J=5.9 Hz, 1H), 3.61 (s, 3H), 2.92 (dd, J=17.6, 4.9 Hz, 1H), 2.35 (d, J=17.5 Hz, 1H), 2.32-2.19 (m, 2H), 1.91-1.82 (m, 1H), 1.81-1.74 (m, 1H).

Step 6. A solution of (5R,8S)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-13f) (69 mg, 232 μmol) in MeCN (3.2 mL) was cooled to 0 °C, then a solution of CAN (381 mg, 696 μmol) in water (3.2 mL) was added dropwise. After complete addition, the reaction mixture was stirred for 1 h at 0 °C. 2 M aqueous NaOH (5 mL) and water (5 mL) were added, and the mixture was extracted with DCM (3×10 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford (5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-13) as a pale pink solid. LCMS (Method 1): m/z 179.2 (M+H) ⁺ (ES ⁺ ); at 0.69 min, ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (dd, J=5.0, 0.9 Hz, 1H), 7.04 (dd, J=5.0, 1.9 Hz, 1H), 4.17 (d, J=5.3 Hz, 1H), 3.78 (t, J=6.0 Hz, 1H), 2.85 (dd, J=17.1, 5.2 Hz, 1H), 2.74 (s, 1H), 2.38 (d, J=17.0 Hz, 1H), 2.01-1.85 (m, 2H), 1.73 (t, J=9.1 Hz, 1H), 1.51 (dt, J=9.4, 5.4 Hz, 1H).

Intermediate compound 14 (I-14)

Step 1. N-(2-Bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfinamide I-14b was synthesized from 2-bromo-5-fluorobenzaldehyde I-14a using essentially the same method as that used to prepare compound I-12b. LCMS (Method 2): m/z 305.9, 308.0 (M+H) ⁺ (ES ⁺ ); at 2.80 min, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.76 (d, J=2.2 Hz, 1H), 7.86 (dd, J=8.9, 5.1 Hz, 1H), 7.80 (dd, J=9.2, 3.2 Hz, 1H), 7.56-7.36 (m, 1H), 1.20 (s, 9H).

Step 2. N-(1-(2-Bromo-5-fluorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-14c was synthesized from N-(2-bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfinamide I-14b using essentially the same method as that used to prepare compound I-12c. LCMS (Method 2): m/z 362.0, 364.0 (M+H) ⁺ (ES ⁺ ); at 2.47 min, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.61 (dd, J=8.7, 5.4, 4.2 Hz, 1H), 7.38 (dd, J=10.2, 3.2 Hz, 1H), 7.13-7.04 (m, 1H), 5.87-5.79 (m, 1H), 5.69 (d, J=7.2 Hz, 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, 5.4 Hz, 1H), 1.80-1.60 (m, 1H), 1.06 (s, 9H).

Step 3. To a solution of N-(1-(2-bromo-5-fluorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-14c (13.6 g, 37.5 mmol) in MeOH (65 mL) was added a solution of HCl in 1,4-dioxane (4 M, 28 mL, 113 mmol) at room temperature and stirred for 17 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in water (200 mL) and washed with EtOAc (200 mL). The aqueous layer was basified to pH 8 with 2 M aqueous NaOH and extracted with EtOAc (2×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford 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 min, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.57 (dd, J=8.7, 5.5 Hz, 1H), 7.48 (dd, J=10.4, 3.2 Hz, 1H), 7.03 (td, J=8.4, 3.2 Hz, 1H), 5.81 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.02 (m, 1H), 4.94 (ddt, J=10.2, 2.4, 1.3 Hz, 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).

Stage 4. N-(1-(2-Bromo-5-fluorophenyl)pent-4-en-1-yl)-4-methoxyaniline I-14e was synthesized from N-(1-(2-bromo-5-fluorophenyl)pent-4-en-1-amine I-14d using essentially the same method as that used to obtain compound I-12e. LCMS (Method 2): m/z 364.1, 366.0 (M+H)⁺(ES⁺); at 2.90 min,¹H NMR (500 MHz, DMSO-d₆) δ 7.61 (dd, J=8.8, 5.3 Hz, 1H), 7.26 (dd, J=10.1, 3.2 Hz, 1H), 7.02 (ddd, J=8.8, 8.0, 3.1 Hz, 1H), 6.67-6.61 (m, 2H), 6.41-6.34 (m, 2H), 6.00 (d, J=8.3 Hz, 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).

Step 5. (±)-3-Fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene I-14f was synthesized from N-(1-(2-bromo-5-fluorophenyl)pent-4-en-1-yl)-4-methoxyaniline I-14e using essentially the same method as that used to prepare compound I-12f. LCMS (Method 2): m/z 284.1 (M+H) ⁺ (ES ⁺ ); at 2.67 min.

Stage 6. A solution of (±)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene I-14f (2.31 g, 8.15 mmol) in MeCN (100 mL) was cooled to 0 °C, then a solution of CAN (13.4 g, 24.5 mmol) in water (100 mL) was added dropwise. After complete addition, the reaction mixture was stirred for 1 h at 0 °C, then warmed to room temperature and stirred for 1 h. 2 M aqueous NaOH (100 mL) and DCM (100 mL) were added, and the mixture was filtered through Celite, washing with DCM (100 mL). The layers were separated, and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford (±)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene I-14 as a viscous brown oil. LCMS (Method 2): m/z 178.5 (M+H)⁺(ES⁺); at 1.68 min,¹H NMR (400 MHz, DMSO-d₆) δ 7.02 (dd, J=8.3, 5.8 Hz, 1H), 6.87 (ddd, J=18.0, 9.2, 2.8 Hz, 2H), 4.09 (d, J=5.0 Hz, 1H), 3.70 (t, J=5.8 Hz, 1H), 2.98 (dd, J=16.6, 5.0 Hz, 1H), 2.44 (d, J=16.4 Hz, 1H), 1.96-1.82 (m, 2H), 1.70 (t, J=8.9 Hz, 1H), 1.53-1.37 (m, 1H). (1H is closed by the water peak).

Intermediate connection 15 (I-15)

Step 1. N-(2-Bromo-3-fluorobenzylidene)-2-methylpropane-2-sulfinamide I-15b was synthesized from 2-bromo-3-fluorobenzaldehyde I-15a using essentially the same method as that used to prepare compound I-12b. LCMS (Method 2): m/z 305.9, 308.0 (M+H) ⁺ (ES ⁺ ); at 2.42 min, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.81 (s, 1H), 7.88 (ddd, J=7.6, 1.8, 0.9 Hz, 1H), 7.65-7.54 (m, 2H), 1.20 (s, 9H).

Step 2. N-(1-(2-Bromo-3-fluorophenyl)pent-4-en-1-yl)-2-methyl-propane-2-sulfinamide I-15c was synthesized from N-(2-bromo-3-fluorobenzylidene)-2-methylpropane-2-sulfinamide I-15b using essentially the same method as that used to prepare compound I-12c. LCMS (Method 2): m/z 362.0, 364.0 (M+H) ⁺ (ES ⁺ ); at 2.44 min, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.49-7.41 (m, 1H), 7.44-7.34 (m, 1H), 7.24 (td, J=8.4, 1.6 Hz, 1H), 5.86-5.77 (m, 1H), 5.71 (d, J=7.0 Hz, 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).

Step 3. 1-(2-Bromo-3-fluorophenyl)pent-4-en-1-amine I-15d was synthesized from N-(1-(2-bromo-3-fluorophenyl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-15c using essentially the same method as that used to prepare compound I-14d. LCMS (Method 2): m/z 258.0, 260.0 (M+H) ⁺ (ES ⁺ ); at 2.18 min, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.46 (dt, J=7.8, 1.3 Hz, 1H), 7.40 (td, J=7.9, 5.6 Hz, 1H), 7.20 (ddd, J=8.9, 8.0, 1.6 Hz, 1H), 5.81 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.06- 4.98 (m, 1H), 4.94 (ddt, J=10.2, 2.4, 1.3 Hz, 1H), 4.17 (dd, J=8.2, 4.9 Hz, 1H), 2.20-1.96 (m, 2H), 1.96 (s, 2H), 1.67-1.61 (m, 1H), 1.56-1.49 (m, 1H).

Stage 4. To a solution of 1-(2-bromo-3-fluorophenyl)pent-4-ene-1-amine (10.3 g, 39.9 mmol) I-15d, (4-methoxyphenyl)boronic acid (18.2 g, 120 mmol) and Cu(OAc)₂(10.9 g, 59.9 mmol) in DCM (100 mL) was treated dropwise with pyridine (16.1 mL, 200 mmol). The mixture was stirred at room temperature under air for 4 days. 2 M NaOH aqueous solution (100 mL) was added, the mixture was stirred for 30 min and filtered through Celite. The filtrate was partitioned between water (100 mL) and DCM (100 mL), and the layers were separated. The aqueous layer was then extracted with DCM (2×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (0%–100% DCM/isohexane) to afford N-(1-(2-bromo-3-fluorophenyl)pent-4-en-1-yl)-4-methoxyaniline I-15e as a thick orange oil.¹H NMR (500 MHz, DMSO-d₆) δ 7.36-7.31 (m, 1H), 7.27 (dd, J=8.0, 1.7 Hz, 1H), 7.19 (ddd, J=9.5, 8.0, 1.6 Hz, 1H), 6.66-6.58 (m, 2H), 6.40-6.33 (m, 2H), 6.04 (d, J=8.1 Hz, 1H), 5.87-5.82 (m, 1H), 5.06-4.94 (m, 2H), 4.61 (td, J=8.1, 5.2 Hz, 1H), 3.56 (s, 3H), 2.30 (dd, J=14.3, 7.8 Hz, 1H), 2.23-2.12 (m, 1H), 1.80-1.67 (m, 2H).

Step 5. (±)-1-Fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene I-15f was synthesized from N-(1-(2-bromo-3-fluorophenyl)pent-4-en-1-yl)-4-methoxyaniline I-15e using essentially the same method as that used to prepare compound I-12f. LCMS (Method 2): m/z 284.1 (M+H) ⁺ (ES ⁺ ); at 2.56 min, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.19-7.06 (m, 2H), 6.88 (ddd, J=9.5, 7.9, 1.5 Hz, 1H), 6.83-6.74 (m, 2H), 6.73-6.65 (m, 2H), 4.83 (d, J=5.3 Hz, 1H), 4.51 (t, J=5.6 Hz, 1H), 3.60 (s, 3H), 2.96 (dd, J=17.3, 4.8 Hz, 1H), 2.37 (d, J=17.4 Hz, 1H), 2.33-2.17 (m, 2H), 1.88-1.65 (m, 2H).

Step 6. (±)-1-Fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene I-15 was synthesized from (±)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene I-15f using essentially the same method as that used to prepare compound I-12. LCMS (Method 2): m/z 178.1 (M+H) ⁺ (ES ⁺ ); at 1.69 min, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.09 (td, J=7.8, 5.9 Hz, 1H), 6.90 (dd, J=9.5, 8.2, 1.1 Hz, 1H), 6.86 (dd, J=7.5, 1.1 Hz, 1H), 4.12 (d, J=5.1 Hz, 1H), 3.75 (t, J=6.0 Hz, 1H), 2.88 (dd, J=16.9, 5.2 Hz, 1H), 2.57 (s, 1H), 2.42 (d, J=16.9 Hz, 1H), 1.97-1.85 (m, 2H), 1.70 (t, J=9.0 Hz, 1H), 1.52-1.41 (m, 1H).

Intermediate connection 16 (I-16)

Stage 1. To a mixture of 2-bromonicotinaldehyde I-16a (15.0 g, 80.6 mmol) in THF (90.0 mL) was added Ti(OEt)₄(33.5 ml, 161 mmol) and tert-butylsulfinamide (10.8 g, 88.7 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water (100 mL) at 0 °C and then extracted with EtOAc (3×75 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to afford N-((2-bromopyridin-3-yl)-methylene)-2-methylpropane-2-sulfinamide I-16b in the form of a solid yellow substance.¹H NMR (400 MHz, CDCl₃) δ 8.92 (s, 1H), 8.48 (t, J=2.0 Hz, 1H), 8.31-8.29 (m, 1H), 7.40-7.37 (m, 1H), 1.25 (t, J=3.2 Hz, 9H).

Stage 2. To a solution of N-((2-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-16b (19.0 g, 65.7 mmol) in THF (107 mL) was added dropwise with but-3-en-1-yl magnesium bromide (0.5 M, 302 mL) at 0 °C. The mixture was warmed to room temperature over 1 h. The reaction mixture was cooled to 0 °C and water (50 mL) was carefully added. The product was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo. 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. ¹H NMR (400 MHz, 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). (NH was not detected)

Step 3. To a solution of N-(1-(2-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-16c (11.2 g, 32.5 mmol) in MeOH (70 mL) was added HCl in EtOAc (4 M, 24.4 mL, 97.6 mmol) at 0 °C, and the mixture was warmed to room temperature over 30 min. The reaction mixture was concentrated in vacuo, triturated with MTBE (100 mL), and the solid was collected by filtration, washed with MTBE (2 × 100 mL), and dried in vacuo. The solids were dissolved in water (50 mL), cooled to 0 °C, and the mixture was basified to pH 11 with NaOH solution. The aqueous mixture was extracted with DCM (3 × 30 mL), and the combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to give 1-(2-bromopyridin-3-yl)-pent-4-ene-1-amine I-16d as a yellow solid.¹H NMR (400 MHz, 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 detected)

Stage 4. To a mixture of 1-(2-bromopyridin-3-yl)pent-4-ene-1-amine I-16d (6.50 g, 26.9 mmol), (4-methoxyphenyl)boronic acid (7.66 g, 50.4 mmol), 4 Å molecular sieves (12.1 g), and Cu(OAc)₂(11.4 g, 63.0 mmol) in 1,4-dioxane (100 ml) was added dropwise Et₃N (4.56 mL, 32.8 mmol). The resulting mixture was stirred at 35°C under O₂for 16 h. The reaction mixture was filtered, and the solid was washed with EtOAc (3×10 mL). The filtrate was dried over sodium sulfate and concentrated in vacuo. 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.¹H NMR (400 MHz, 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). (NH was not detected)

Stage 5. Pd was loaded into a three-necked flask.₂(dba)₃ (131 mg, 0.144 mmol), tricyclohexylphosphonium tetrafluoroborate (106 mg, 0.288 mmol) and NaO^tBu (207 mg, 2.16 mmol) and The mixture was purged with argon. 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) was added, and the resulting mixture was heated to 95°C for 12 h. The reaction mixture was filtered, and the solid was washed with EtOAc (3×10 mL). The filtrate was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to afford (±)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine I-16f as a pale reddish-brown solid.¹H NMR (400 MHz, CDCl₃) δ 8.32-8.31 (m, 1H), 7.45-7.43 (m, 1H), 6.75 (t, J=2.8 Hz, 1H), 6.72 (t, J=6.4 Hz, 4H), 4.67 (d, J=6.8 Hz, 1H), 4.53 (t, J=6.4 Hz, 1H), 3.69 (s, 3H), 3.36 (d, J=17.6 Hz, 1H), 2.61 (d, J=17.6 Hz, 1H), 2.38 (t, J=5.6 Hz, 1H), 1.94-1.83 (m, 2H).

Stage 6. (±)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[b]pyridine I-16 was synthesized from (±)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine I-16f using essentially the same method as that used to prepare compound I-14. LCMS (Method 1): m/z 160.9 (M+H)⁺(ES⁺); at 0.62 min.

Intermediate compound 17 (I-17)

Step 1. (S)-N-((4-bromo-6-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-17b was synthesized from 4-bromo-6-fluoronicotinaldehyde I-17a using essentially the same method as that used to prepare compound I-13b. LCMS (Method 2): m/z 307.0, 308.9 (M+H) ⁺ (ES ⁺ ); at 2.05 min, ¹ H NMR (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.73 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 1.21 (s, 9H).

Step 2. To a solution of ((S)-N-((4-bromo-6-fluoropyridin-3-yl)-methylene)-2-methylpropane-2-sulfinamide I-17b (7.00 g, 22.8 mmol) in THF (114 mL) was added but-3-en-1-yl magnesium bromide (2.54 M, 17.9 mL, 45.6 mmol) dropwise at -78 °C. The mixture was slowly warmed to room temperature and stirred for 16 h. Saturated ammonium chloride solution (10 mL) was added, and the product was extracted with EtOAc (2×10 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (0-10% IPA/isohexane) to give a 2:1 mixture diastereomers of (±)-N-(1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-17c as a pale yellow oil. LCMS (method 1) m/z 363.3, 365.4 (M+H) ⁺ (ES ⁺ ), at 1.39 and 1.42 min.

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

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

Step 3. (±)-1-(4-Bromo-6-fluoropyridin-3-yl)pent-4-en-1-amine I-17d was synthesized from (±)-N-(1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-17c using essentially the same method as that used to prepare compound I-13d. LCMS (Method 1) m/z 259.2, 261.2 (M+H) ⁺ (ES ⁺ ), at 1.21 min. ¹ H NMR (500 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.55 (d, J=2.7 Hz, 1H), 5.82 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.03 (dqv, J=17.2, 1.8 Hz, 1H), 4.95 (ddt, J=10.2, 2.3, 1.3 Hz, 1H), 4.12 (dd, J=8.2, 4.9 Hz, 1H), 2.25-1.98 (m, 4H), 1.75-1.64 (m, 1H), 1.64-1.54 (m, 1H).

Step 4. (±)-N-(1-(4-Bromo-6-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-17e was synthesized from (±)-1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-amine I-17d using essentially the same method as that used to prepare compound I-13e. LCMS (Method 1) m/z 365.0, 367.1 (M+H) ⁺ (ES ⁺ ), at 1.76 min. ¹ H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.61 (d, J=2.5 Hz, 1H), 6.66 (d, J=8.9 Hz, 2H), 6.40 (d, J=9.0 Hz, 2H), 6.04 (d, J=8.3 Hz, 1H), 5.86 (ddt, J=17.0, 10.2, 6.6 Hz, 1H), 5.08-4.90 (m, 2H), 4.59 (td, J=8.5, 4.8 Hz, 1H), 3.58 (s, 3H), 2.35-2.26 (m, 1H), 2.23-2.13 (m, 1H), 1.92-1.71 (m, 2H).

Step 5. Pd-178 (0.29 g, 0.61 mmol) and NaO were charged into a three-necked flask.^tBu (0.88 g, 9.2 mmol) and purged with N₂A 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) was added dropwise. The resulting mixture was heated to 95°C for 2 h. The reaction mixture was cooled to room temperature and filtered through celite, washing the solid with EtOAc (150 mL). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0%-50% EtOAc/isohexane) to afford a mixture of enantiomers, which were dissolved to 30 mg/mL in DCM:methanol (1:4) and then separated by chiral SFC on a Waters prep 15 liquid chromatograph with UV detection at 210 nm, 40°C, 10 MPa on a Lux C3 column (21.2 mm x 250 mm, 5 μm particle size), flow rate 50 mL/min, using 40% methanol, to afford (6S,9R)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-17f) as a pale yellow solid. LCMS (method 1) m/z 285.3 (M+H)+ (ES+), at 1.35 min. ¹H NMR (500 MHz, DMSO-d6) δ 8.10 (s, 1H), 6.79 (t, J=9.7 Hz, 3H), 6.70 (d, J=9.1 Hz, 2H), 4.95 (d, J=5.5 Hz, 1H), 4.47 (t, J=6.0 Hz, 1H), 3.61 (s, 3H), 3.11 (dd, J=18.2, 4.9 Hz, 1H), 2.31-2.19 (m, 2H), 1.88-1.55 (m, 2H), 1H overlapped with the peak of residual DMSO,

and (6R,9S)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-17g) as a pale yellow solid. LCMS (Method 1) m/z 285.3 (M+H)+ (ES+), at 1.35 min. 1H NMR (500 MHz, DMSO-d6) δ 8.10 (s, 1H), 6.79 (t, J=9.7 Hz, 3H), 6.70 (d, J=9.1 Hz, 2H), 4.95 (d, J=5.5 Hz, 1H), 4.47 (t, J=6.0 Hz, 1H), 3.61 (s, 3H), 3.11 (dd, J=18.2, 4.9 Hz, 1H), 2.31-2.19 (m, 2H), 1.88-1.55 (m, 2H), 1H overlapped with residual DMSO peak.

Step 6. (6S,9R)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-17) was synthesized from (6S,9R)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-17f) using essentially the same method as that used to prepare compound I-13. LCMS (Method 1) m/z 179.2 (M+H) ⁺ (ES ⁺ ), at 0.71 min.

Intermediate compound 18 (I-18)

(6S,9R)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine I-17 (300 mg, 1.68 mmol) was dissolved in HBr (1.90 mL, 48% by weight in water, 16.8 mmol) and heated at 100 °C for 18 h. The reaction mixture was cooled to room temperature, diluted with MeOH, loaded onto an SCX cartridge (20 g), and the product was eluted with ammonia in MeOH (0.7 M) to afford (6S,9R)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridin-3-one (I-18) as a yellowish-white solid. LCMS (method 1) m/z 176.9 (M+H) ⁺ (ES ⁺ ), at 0.41 min,

Intermediate compound 19 (I-19)

Step 1. To a solution of 4-chloro-3-fluoropyridine I-19a (25.9 mL, 190 mmol) in THF (120 mL) was added LDA (2 M, 114 mL, 228 mmol) at -70 °C. The mixture was stirred at -70 °C for 3 h, then DMF (17.5 mL, 228 mmol) in THF (50 mL) was added. The mixture was slowly warmed to room temperature and stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, and saturated aqueous ammonium chloride solution (100 mL) was added. The aqueous layer was adjusted to pH 6 with HCl (1 M) and extracted with MTBE (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo to give 4-chloro-5-fluoronicotinaldehyde I-19b as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.4 (s, 1H), 8.87 (s, 1H), 8.69 (s, 1H).

Step 2. N-((4-Chloro-5-fluoropyridin-3-yl)methylene)-2-methyl-propane-2-sulfinamide I-19c was synthesized from 4-chloro-5-fluoro-nicotinaldehyde I-19b using essentially the same method as that used to prepare compound I-16b. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.02 (s, 1H), 8.93 (s, 1H), 8.59 (s, 1H), 1.30 (s, 9H).

Step 3. To a solution of (E)-N-((4-chloro-5-fluoropyridin-3-yl)-methylene)-2-methylpropane-2-sulfinamide I-19c (27.0 g, 102 mmol) in THF (150 mL) was added but-3-en-1-yl magnesium bromide (0.5 M, 822 mL) at 0 °C. The mixture was warmed and stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C and water (50 mL) was added. The product was extracted with EtOAc (3×100 mL). The organic layer was separated, washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated in vacuo. The product was triturated with petroleum ether (50 mL), and the solid was collected by filtration, washing with petroleum ether (2 x 20 mL). The solid was dried under vacuum to give N-(1-(4-chloro-5-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-19d as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (s, 2H), 5.84-5.76 (m, 1H), 5.10-5.03 (m, 2H), 4.94-4.90 (m, 1H), 3.58 (d, J = 2.4 Hz, 1H), 2.22-2.01 (m, 4H), 1.20 (s, 9H).

Step 4. 1-(4-Chloro-5-fluoropyridin-3-yl)pent-4-en-1-amine I-19e was synthesized from N-(1-(4-chloro-5-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-19d using essentially the same method as that used to prepare compound I-16d.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 detected)

Stage 5. N-(1-(4-Chloro-5-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-19f was synthesized from 1-(4-chloro-5-fluoropyridin-3-yl)pent-4-en-1-amine I-19e using essentially the same method as that used to prepare compound I-16e.¹H NMR (400 MHz, CDCl₃)δ 8.43 (s, 1H), 8.37 (s, 1H), 6.72-6.69 (m, 2H), 6.44 (t, J=3.6 Hz, 2H), 5.85-5.81 (m, 1H), 5.09-5.03 (m, 2H), 4.76 (t, J=4.8 Hz, 1H), 3.96 (s, 1H), 3.70 (s, 3H), 2.30-2.22 (m, 2H), 1.97-1.87 (m, 2H).

Step 6. (±)-4-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-19g was synthesized from N-(1-(4-bromo-5-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-19f using essentially the same method as that used to prepare compound I-16f. ^1H NMR (400 MHz, CDCl ₃ ) 8.25 (s, 1H), 8.17 (s, 1H), 6.77-6.73 (m, 4H), 4.79 (d, J=6.0 Hz, 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).

Step 7. A solution of (±)-4-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-19g (0.150 g, 528 μmol) in MeCN (10 mL) was cooled to 0°C, then a solution of CAN (925 mg, 1.69 mmol) in water (10 mL) was added dropwise. After complete addition, the reaction mixture was stirred for 1 h at 0°C. Then CAN (925 mg, 1.69 mmol) in water (3 mL) was added, and the reaction mixture was stirred for 1 h. The material was loaded onto an SCX cartridge (20 g), washed with MeOH (40 mL), and the product was eluted using 0.7 M ammonia in MeOH (100 mL) to give (6S,9R)-4-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine as a yellow oil I-19. LCMS (Method 1): m/z 178.9 (M+H) ⁺ (ES ⁺ ); at 0.71 min.

Intermediate connection 20 (I-20)

Step 1. To a solution of (6S,9R)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-17f (100.0 mg, 351.7 μmol) in MeOH (1 mL) was added sodium methoxide (5.4 M in MeOH, 391 μL, 2.11 mmol), and the reaction mixture was heated at 65°C for 48 h. The reaction mixture was diluted with DCM (20 mL) and water (50 mL). The layers were separated, and the aqueous layer was extracted with DCM (3×30 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford (6S,9R)-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetra-hydro-5H-6,9-epiminocyclohepta[c]pyridine I-20a as a pale yellow oil. LCMS (Method 2) m/z 297.1 (M+H) ⁺ (ES ⁺ ), at 2.14 min.

Stage 2. (6S,9R)-3-Methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-20 was synthesized from (6S,9R)-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-20a using essentially the same method as that used to prepare compound I-13. LCMS (Method 1) m/z 191.1 (M+H)⁺(ES⁺), at 1.33 min.

Intermediate compound 21 (I-21)

Step 1. (S)-N-((4-Bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-21a was synthesized from 4-bromo-3-pyridinecarboxaldehyde (I-8a) and (S)-tert-butylsulfinamide using essentially the same method as that used to prepare compound I-7b. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.13 (s, 1H), 8.92 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 7.60 (d, J=5.6 Hz, 1H), 1.29 (s, 9H).

Step 2. (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 were synthesized from (S)-N-((4-bromopyridin-3-yl)methylene)-2-methyl-propane-2-sulfinamide I-21a using essentially the same method as that used to prepare compound I-7c. ^1H NMR (400 MHz, CDCl ₃ ) δ: 8.52 (s, 1H), 8.29 (d, J=5.6 Hz, 1H), 7.50 (t, J=9.6 Hz, 1H), 5.83-5.76 (m, 1H), 5.09-5.01 (m, 2H), 4.91-4.89 (m, 1H), 3.60 (t, J=2.8 Hz, 1H), 2.19-1.96 (m, 4H), 1.18 (s, 9H).

Step 3. (R)-1-(4-Bromopyridin-3-yl)pent-4-en-1-amine I-21c was synthesized from (S)-N-((R)-1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-21b using essentially the same method as that used to prepare compound I-7d. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.70 (s, 1H), 8.27-8.22 (m, 1H), 7.45 (t, J=5.6 Hz, 1H), 5.88-5.80 (m, 1H), 5.07-4.98 (m, 2H), 4.37-4.33 (m, 1H), 2.22-2.13 (m, 2H), 1.90-1.75 (m, 2H). (NH ₂ was not detected)

Step 4. (R)-N-(1-(4-Bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-21d was synthesized from (R)-1-(4-bromopyridin-3-yl)pent-4-en-1-amine I-21c using essentially the same method as that used to prepare compound I-7e. ¹ H NMR (400 MHz, CDCl ₃ ) 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), (NH not detected)

Step 5. A flask containing a solution of Pd ₂ (dba) ₃ (0.68 g, 0.75 mmol), tricyclohexylphosphonium tetrafluoroborate (551 mg, 1.50 mmol), and NaO ^t Bu (5.69 g, 59.2 mmol) in toluene (50 mL) was purged with N ₂ , and (R)-N-(1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-21d (2.6 g, 7.5 mmol) was added dropwise to the flask. The resulting mixture was heated to 90 °C for 12 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (3×50 mL). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (10%-100% EtOAc/petroleum ether) to afford (6S,9R)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-21e. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.40 (s, 1H), 8.28 (d, J=5.2 Hz, 1H), 6.85 (d, J=5.2 Hz, 1H), 6.77-6.71 (m, 4H), 4.73 (d, J=5.2 Hz, 1H), 4.46 (t, J=5.2 Hz, 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).

Stage 6. To a solution of (6S,9R)-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-21e) (1.08 g, 4.05 mmol) in MeCN (50 mL) was added dropwise a solution of CAN (6.67 g, 12.2 mmol) in water (50 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then the reaction mixture was warmed to room temperature over 1 h. The reaction mixture was cooled to 0 °C and an additional portion of CAN (4.45 g, 8.11 mmol) in water (20 mL) was added, and the mixture was stirred at 0 °C for 1 h. 2 M NaOH (50 mL) was added, and the resulting mixture was filtered through a pad of celite. The layers were separated, and the aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford (6S,9R)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-21 as a yellowish-white solid.¹H NMR (500 MHz, DMSO-d₆) δ 8.27-8.18 (m, 2H), 7.04 (d, J=5.0 Hz, 1H), 4.17 (d, J=5.7 Hz, 1H), 3.71 (s, 1H), 2.99 (dd, J=17.4, 5.0 Hz, 1H), 2.72 (s, 1H), 2.47 (dd, J=17.2, 1.1 Hz, 1H), 1.98-1.86 (m, 2H), 1.71 (t, J=8.9 Hz, 1H), 1.49-1.42 (m, 1H).

Intermediate connection 22 (I-22)

Stage 1. (S)-1-(4-Bromopyridin-3-yl)pent-4-en-1-amine I-22b was synthesized from (S)-N-((S)-1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-22a using essentially the same method as that used to prepare compound I-7d.¹H NMR (400 MHz, 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 detected)

Step 2. (S)-N-(1-(4-Bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-22c was synthesized from (S)-1-(4-bromopyridin-3-yl)pent-4-en-1-amine I-22b using essentially the same method as that used to prepare compound I-7e. ^1H NMR (400 MHz, CDCl ₃ ) δ: 8.57 (s, 1H), 8.26 (s, 1H), 7.50 (s, 1H), 6.70 (d, J=2.4 Hz, 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).

Step 3. (6S,9R)-10-(4-Methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine) I-22d was synthesized from (S)-N-(1-(4-bromopyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-22c using essentially the same method as that used to prepare compound I-21e. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.66 (s, 1H), 8.29-8.24 (m, 1H), 7.48-7.45 (t, J=8.8 Hz, 1H), 5.86-5.79 (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), 1.56 (s, 2H).

Step 4. (6S,9R)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclo-hepta[c]pyridine I-22 was synthesized from 1-(4-bromopyridin-3-yl)pent-4-en-1-amine I-22d using essentially the same method as that used to prepare compound I-21. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.23 (d, J = 5.0 Hz, 1H), 8.19 (s, 1H), 7.03 (d, J = 5.0 Hz, 1H), 4.16 (d, J = 5.7 Hz, 1H), 3.70 (t, J = 6.0 Hz, 1H), 2.99 (dd, J = 17.4, 5.1 Hz, 1H), 2.00-1.86 (m, 2H), 1.70 (t, J = 8.9 Hz, 1H), 1.49-1.41 (m, 1H). (NH not detected, 1CH under DMSO peak)

Intermediate compound 23 (I-23)

Stage 1. (S)-N-((3-Bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-23b was synthesized from 3-bromo-4-pyridinecarboxaldehyde I-7a using essentially the same method as that used to prepare compound I-7b. ¹H NMR (400 MHz, CDCl₃) δ 8.92 (s, 1H), 8.87 (s, 1H), 8.64-8.63 (m, 1H), 7.85-7.84 (m, 1H), 1.30 (s, 3H).

Step 2. To a solution of (S)-N-((3-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide(I-23b)(6.00 g, 20.7 mmol) in THF (120 mL) was added (3-methylbut-3-en-1-yl)magnesium bromide (0.5 M in THF, 124 mL), then the mixture was stirred at 20°C for 1 h. A saturated aqueous solution of NH₄Cl (50 mL), and the product was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (200 mL), dried over sodium sulfate, and concentrated in vacuo. The product was purified by silica gel chromatography (EtOAc/petroleum ether 1%-100%) to afford (S)-N-((R)-1-(3-bromopyridin-3-yl)-4-methylpent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-23c as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.72-8.64 (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)

Stage 3. (R)-1-(3-Bromopyridin-3-yl)-4-methylpent-4-en-1-amine I-23d was synthesized from (S)-N-((R)-1-(3-bromopyridin-3-yl)-4-methyl-pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-23c using essentially the same method as that used to prepare compound I-7d. ¹H NMR (400 MHz, CDCl₃) δ 8.64-8.61 (m, 1H), 8.49-8.45 (m, 1H), 7.43 (t, J=4.8 Hz, 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).

Stage 4. (R)-N-(1-(3-Bromopyridin-3-yl)-4-methylpent-4-en-1-yl)-4-methoxyaniline I-23e was synthesized from (R)-1-(3-bromopyridin-3-yl)-4-methylpent-4-en-1-amine I-23d using essentially the same method as that used to prepare compound I-7e. ¹H NMR (400 MHz, CDCl₃) δ 8.70 (s, 1H), 8.42 (s, 1H), 7.37 (s, 1H), 6.70 (d, J=8.8 Hz, 2H), 6.36 (t, J=8.8 Hz, 2H), 4.75 (d, J=25.5 Hz, 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).

Step 5. (5R,8S)-10-(4-Methoxyphenyl)-8-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-23f was synthesized from (R)-N-(1-(3-bromopyridin-3-yl)-4-methylpent-4-en-1-yl)-4-methoxyaniline I-23e using essentially the same method as that used to prepare compound I-21e. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42 (s, 1H), 8.22 (s, 1H), 7.09 (d, J=4.8 Hz, 1H), 6.81 (d, J=8.8 Hz, 2H), 6.67 (d, J=8.8 Hz, 2H), 4.44 (d, J=6.4 Hz, 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).

Step 6. (5R,8S)-8-Methyl-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine (I-23) was synthesized from (5R,8S)-10-(4-methoxyphenyl)-8-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclo-hepta[c]pyridine (I-23f) using essentially the same method as that used to prepare compound I-21. LCMS (method 2) m/z 175 (M+H)⁺(ES⁺), at 1.15 min.

Intermediate connection 24 (I-24)

Step 1. 1-Cyclopropylethan-1-ol (11.3 mL, 116 mmol) was dissolved in aqueous HBr (45 mL, 47% by weight) at 0°C. The mixture was warmed to room temperature over 12 h. The product was distilled under vacuum (60°C, 0.01 MPa) to give (E)-5-bromopent-2-ene mixture I-24b and (Z)-5-bromopent-2-ene I-24c as a yellow oil.¹H NMR (400 MHz, CDCl₃) δ 5.58-5.52 (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).

Step 2. To a solution of I ₂ (1.69 mL, 8.39 mmol) and Mg (8.66 g, 356 mmol) in THF (250 mL) at 20 °C was added a mixture of (E)-5-bromopent-2-ene I-24b and (Z)-5-bromopent-2-ene I-24c (25.0 g, 167 mmol) in THF (100 mL) at room temperature. The mixture was stirred at 40 °C for 1 h. The crude mixture of (E)-pent-3-en-1-ylmagnesium bromide I-24d and (Z)-pent-3-en-1-ylmagnesium I-24e was used in the next step without isolation or further purification.

Step 3. (S)-N-((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 were synthesized from (c, E)-N-((3-bromopyridin-3-yl)methylene)-2-methyl-propane-2-sulfinamide I-23b and a mixture of (E)-pent-3-en-1-ylmagnesium bromide I-24d and (Z)-pent-3-en-1-ylmagnesium I-24e using essentially the same method as that used to prepare compound I-7c. Data are given for I-24f, since I-24g was a minor component of the mixture.¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 8.48 (d, J=5.2 Hz, 1H), 5.50-5.39 (m, 2H), 4.88-4.81 (m, 1H), 3.59 (d, J=3.6 Hz, 1H), 2.11-2.03 (m, 3H), 1.93-1.90 (m, 2H), 1.64-1.63 (m, 3H), 1.16 (s, 9H)

Stage 4. (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 were synthesized from (S)-N-((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 using essentially the same method as that used to prepare compound I-7d.

Stage 5. ((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-methoxyaniline I-24k were synthesized from (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 using essentially the same method as that used to prepare compound I-7e. Data are given for I-24j, since I-24k was a minor component of the mixture. ¹H NMR (400 MHz, CDCl₃) δ 8.69 (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).

Stage 6. 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-methoxyaniline I-24k (0.54 g, 1.49 mmol) in dioxane (5 ml) was added NaO^tBu (287 mg, 2.99 mmol) and Pd-178 (71.3 mg, 149 μmol) were added at room temperature. The mixture was heated at 105°C for 16 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (3×50 mL). The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (30-60% MeCN/10 mM NH₄HCO₃) to obtain (5R,8S,9R)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-24l as a white solid and (5R,8S,9S)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine I-24k as a white solid.

(5R,8S,9R)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-24l: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 2H), 7.06-7.01 (m, 1H), 6.88-6.78 (m, 4H), 4.67 (d, J=5.2 Hz, 1H), 4.14 (d, J=6.0, 1H), 3.75 (s, 3H), 2.81 (d, J=7.6 Hz, 1H), 2.23-2.16 (m, 2H), 1.79-1.74 (m, 1H), 1.58-1.50 (m, 1H), 1.37 (d, J=7.6 Hz, 3H).

(5R,8S,9S)-10-(4-methoxyphenyl)-9-methyl-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-24k: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35-8.32 (m, 2H), 7.05 (d, J=5.2 Hz, 1H), 6.99-6.73 (m, 4H), 4.57 (d, J=7.6 Hz, 1H), 4.22-4.19 (m, 1H), 3.70 (s, 3H), 3.35-3.32 (m, 1H), 2.34-2.31 (m, 1H), 2.22-2.13 (m, 1H), 1.98-1.83 (m, 2H), 1.31 (d, J=8.0 Hz, 3H).

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

Intermediate connection 25 (I-25)

Step 1. To a solution of 2,3-difluoropyridine I-25a (50.0 g, 434 mmol) in hexane (275 mL) and THF (450 mL) was added n-BuLi (2.5 M in hexane, 173 mL) at -70 °C. The mixture was stirred at -70 °C for 2 h, then 1,1,2-trichloro-1,2,2-trifluoropentane (52 mL, 434 mmol) was added at -70 °C, and the resulting mixture was stirred at -70 °C for 1 h. Aqueous ammonium chloride solution (300 mL) was added at 0 °C, and the product was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo to give 4-chloro-2,3-difluoropyridine I-25b as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92 (d, J=5.2 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H).

Step 2. To a solution of 4-chloro-2,3-difluoropyridine I-25b (17 g, 113 mmol) in THF (170 mL) was added a solution of LDA in THF/n-heptane/ethylbenzene (2 M, 68 mL) at -90°C. The mixture was warmed to -70°C for 2 h. DMF (10.5 mL, 136 mmol) in THF (170 mL) was slowly added at -90°C. The resulting mixture was slowly warmed to room temperature and stirred at room temperature for 1 h. 1 M aqueous HCl (200 mL) was added at 0°C. The product was extracted with MTBE (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo to give 4-chloro-5,6-difluoronicotinaldehyde I-25c as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.3 (s, 1H), 8.52 (s, 1H).

Step 3. N-((4-Chloro-5,6-difluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-25d was synthesized from 4-chloro-5,6-difluoronicotinaldehyde I-25c using essentially the same method as that used to prepare compound I-7b. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.89 (d, J=2.4 Hz, 1H), 8.64 (s, 1H), 1.31 (s, 9H).

Step 4. N-(1-(4-Chloro-5,6-difluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-25e was synthesized from N-((4-chloro-5,6-difluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide I-25d using essentially the same method as that used to prepare compound I-7c. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (s, 1H), 5.81-5.76 (m, 1H), 5.09-4.99 (m, 2H), 4.84-4.68 (m, 1H), 3.73-3.56 (m, 1H), 2.13-2.11 (m, 2H), 2.00-1.97 (m, 2H), 1.17 (s, 9H).

Step 5: 1-(4-Chloro-5,6-difluoropyridin-3-yl)pent-4-en-1-amine I-25f was synthesized from N-(1-(4-chloro-5,6-difluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropan-2-sulfinamide I-25e using essentially the same method as the method used for obtaining compound I-7d. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 5.84-5.76 (m, 1H), 5.06-4.98 (m, 2H), 4.33-4.30 (m, 1H), 2.18-2.12 (m, 2H), 1.85-1.73 (m, 2H).

Step 6. N-(1-(4-Chloro-5,6-difluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-25g was synthesized from 1-(4-chloro-5,6-difluoropyridin-3-yl)pent-4-en-1-amine I-25f using essentially the same method as that used to prepare compound I-7e. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 6.71-6.69 (m, 2H), 6.42-6.39 (m, 2H), 5.84-5.79 (m, 1H), 5.08-5.03 (m, 2H), 4.67-4.65 (m, 1H), 3.70 (s, 3H), 2.29-2.20 (m, 2H), 1.95-1.86 (m, 2H).

Step 7. To a solution of N-(1-(4-chloro-5,6-difluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline I-25g (0.30 g, 885 μmol) in 1,4-dioxane (10 mL) were added NaO ^t Bu (127 mg, 1.32 mmol) and Pd-178 (42 mg, 88.5 μmol) at room temperature. The resulting mixture was heated at 95°C for 16 h. The reaction mixture was filtered. The filter cake was washed with EtOAc (3×10 mL), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (1-100%, EtOAc/petroleum ether) to give (±)-3,4-difluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epimino-cyclohepta[c]pyridine I-25h as a yellow solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.79 (s, 1H), 6.74-6.70 (m, 4H), 4.80-4.78 (m, 1H), 4.52-4.49 (m, 1H), 3.71 (s, 3H), 3.17-3.13 (m, 1H), 2.55-2.38 (m, 2H), 1.96-1.91 (m, 1H), 1.75-1.70 (m, 1H).

Step 8. (±)-3,4-Difluoro-6,7,8,9-tetrahydro-5H-6,9-epimino-cyclohepta[c]pyridine I-25 was synthesized from (±)-3,4-difluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-25h using essentially the same method as that used to prepare compound I-24. ¹H NMR (500 MHz, DMSO-d₆) δ 7.75 (d, J=1.6 Hz, 1H), 4.31-4.26 (m, 1H), 3.76 (t, J=5.9 Hz, 1H), 3.00-2.91 (m, 1H), 2.74 (s, 1H), 2.59 (dd, J=18.0, 1.3 Hz, 1H), 2.00-1.87 (m, 2H), 1.78-1.66 (m, 1H), 1.57-1.46 (m, 1H)

Intermediate connection 26 (I-26)

Step 1. To a solution of (±)-3,4-difluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-25h (145 mg, 480 μmol) in MeOH (5 mL) was added a solution of sodium methoxide in MeOH (133 μL, 5.4 M, 719 μmol). The reaction mixture was heated to 65°C for 18 h. The reaction mixture was diluted with MeOH (5 mL), and an additional portion of sodium methoxide in MeOH (133 μL, 5.4 M, 719 μmol) was added, and the reaction mixture was stirred at 65°C for another 3 h. The reaction mixture was diluted with DCM (30 mL) and water (10 mL) was added, and the layers were separated. The aqueous layers were extracted with DCM (3×20 mL), and the combined organic layer was dried over sodium sulfate and concentrated in vacuo to afford (±)-4-fluoro-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine I-26a as a brown oil. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.88 (s, 1H), 6.84-6.78 (m, 2H), 6.73-6.68 (m, 2H), 4.92 (d, J=5.3 Hz, 1H), 4.51 (t, J=5.9 Hz, 1H), 3.85 (s, 3H), 3.61 (d, J=2.4 Hz, 3H), 2.97 (dd, J=18.0, 5.0 Hz, 1H), 2.46 (s, 1H), 2.25 (q, J=6.5, 4.5 Hz, 2H), 1.88-1.70 (m, 2H).

Step 2. (±)-4-Fluoro-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-26b was synthesized from (±)-4-fluoro-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epimino-cyclohepta[c]pyridine I-26a using essentially the same method as that used to prepare compound I-24.¹H NMR (500 MHz, DMSO-d₆) δ 7.66 (s, 1H), 4.20 (d, J=4.9 Hz, 1H), 3.87 (s, 3H), 3.73 (t, J=5.9 Hz, 1H), 2.88 (dd, J=17.6, 5.2 Hz, 1H), 2.70 (s, 1H), 2.53 (d, J=1.3 Hz, 1H), 1.95-1.86 (m, 2H), 1.74-1.64 (m, 1H), 1.54-1.44 (m, 1H).

Stage 3. Solution of (±)-4-fluoro-3-methoxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-26b (190 mg, 999 μmol) in aqueous HBr (2.8 M, 48% by weight, 25.0 mmol) was heated under reflux for 16 h. The reaction mixture was concentrated under vacuum. The residue was dissolved in MeOH, loaded onto an SCX cartridge (10 g), the cartridge was washed with MeOH, and the product was eluted with 0.7 M ammonia in MeOH. The filtrate was concentrated under vacuum to afford (±)-2,5,6,7,8,9-hexahydro-3H-6,9-epiminocyclohepta[c]pyridin-3-one I-26 as a brown solid. LCMS (Method 1) m/z 177.2 (M+H)⁺(ES⁺), at 0.40 min.¹H NMR (500 MHz, DMSO-d₆) δ 11.07 (s, 1H), 7.02 (s, 1H), 6.00 (s, 1H), 4.01 (d, J=5.5 Hz, 1H), 3.60 (t, J=6.1 Hz, 1H), 2.82 (dd, J=17.6, 5.1 Hz, 1H), 2.42-2.34 (m, 1H), 1.90-1.77 (m, 2H), 1.63-1.55 (m, 1H), 1.48-1.39 (m, 1H).

Intermediate connection 27 (I-27)

Stage 1. Towards the solution (6S,9R)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-17f (100 mg, 352 μmol) in THF (3.5 mL) was added a solution of LDA (2 M in THF) (194 μL, 387 μmol) at 0°C, and the reaction mixture was stirred at 0°C for 1 h. A solution of NFSI (222 mg, 703 μmol) in THF (1 mL) was added, and the reaction mixture was stirred at 0°C for 5 min and warmed to room temperature over 16 h. The reaction mixture was diluted with EtOAc (5 mL) and water (10 mL) was added. The layers were separated. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford a brown oil. The product was purified by silica gel chromatography (0–100% EtOAc/isohexane) to afford (5S,6S,9R)-3,5-difluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine I-27a as a pale yellow oil. LCMS (Method 5) m/z 303.1 (M+H)⁺(ES⁺), at 2.30 min.¹H NMR (500 MHz, CDCl₃) δ 8.08 (s, 1H), 6.94 (d, J=2.3 Hz, 1H), 6.86-6.63 (m, 4H), 5.70 (ddd, J=50.9, 5.0, 1.3 Hz, 1H), 4.87-4.69 (m, 1H), 4.61 (t, J=5.8 Hz, 1H), 3.72 (s, 3H), 2.46-2.27 (m, 1H), 2.28-2.10 (m, 2H), 1.79 (ddd, J=11.6, 8.6, 2.8 Hz, 1H)

Stage 2. (5S,6S,9R)-3,5-difluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-27 was synthesized from (5S,6S,9R)-3,5-difluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epimino-cyclohepta[c]pyridine I-27a using essentially the same method as that used to prepare compound I-24.

Intermediate connection 28 (I-28)

Step 1. (6R,9S)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epimino-cyclohepta[c]pyridine (I-28) was synthesized from (6R,9S)-3-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (I-17g) using essentially the same method as that used to prepare compound I-13. LCMS (method 1) m/z 179.2 (M+H) ⁺ (ES ⁺ ), at 0.71 min, ¹ H NMR (500 MHz, Chloroform-d) δ 7.80 (s, 1H), 6.58 (d, J=2.0 Hz, 1H), 4.28 (d, J=5.6 Hz, 1H), 3.93-3.69 (m, 1H), 3.10 (ddd, J=17.8, 5.2, 1.5 Hz, 1H), 2.57 (d, J=17.8 Hz, 1H), 2.14-1.91 (m, 3H), 1.90-1.77 (m, 1H), 1.67-1.42 (m, 1H).

Experiment 2 design

Connection 45. (±)-N-(3-Chloro-4-(trifluoromethyl)phenyl)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide.

Step 1. 2-Amino-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide 45b was synthesized from 2-amino-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidin-2-amine 45a using essentially the same method as that used to prepare compound 1. LCMS (Method 1): m/z 398.1, 400.0 (M+H) ⁺ (ES ⁺ ); at 1.19 min. ¹ H NMR (500 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.01 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.62 (dd, J=8.8, 2.1 Hz, 1H), 6.45 (s, 2H), 5.12 (d, J=5.9 Hz, 1H), 4.71 (dd, J=7.9, 5.0 Hz, 1H), 3.11 (ddd, J=18.3, 5.3, 1.4 Hz, 1H), 2.23 (kv, J=11.3, 10.8 Hz, 1H), 2.11 (tt, J=11.8, 6.2 Hz, 1H), 1.84-1.66 (m, 2H). (1 H was covered by the residual solvent peak).

Step 2. To a solution of 2-amino-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide 45b (100 mg, 251 μmol) in THF (2 mL) was added tetrafluoroboric acid in water (2.34 mL, 48% by weight, 15.1 mmol), and the resulting mixture was cooled to 0 °C. A solution of sodium nitrite (34.7 mg, 503 μmol) in water (2 mL) was added dropwise, and the reaction mixture was stirred at 0 °C for 1 h, then warmed to room temperature over 16 h. The reaction mixture was recooled to 0°C, and an additional portion of sodium nitrite (34.7 mg, 503 μmol) in water (2 mL) was added. The reaction mixture was stirred for 1 h. The reaction mixture was added to an ice-cold solution of NaHCO ₃ (10 mL), and the product was extracted with 10% MeOH in DCM (3×50 mL). The solvent was dried over sodium sulfate, filtered, and concentrated in vacuo. The product was purified by mass-targeted HPLC (20-50% MeCN/10 mM aqueous ammonium bicarbonate, C18) to afford (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide as a light yellow solid. LC-MS (Method 1) m/z 399.3, 401.3 (M+H) ⁺ (ES ⁺ ); at 1.15 min. ¹ H NMR (500 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.62 (d, J=1.7 Hz, 1H), 7.89 (d, J=2.1 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 5.39 (d, J=6.1 Hz, 1H), 4.83 (t, J=6.4 Hz, 1H), 3.38 (m, 1H), 2.84 (d, J=18.8 Hz, 1H), 2.32-2.23 (m, 1H), 2.18 (dt, J=11.7, 5.7 Hz, 1H), 1.91 (t, J=10.7 Hz, 1H), 1.78 (dd, J=17.8, 10.6 Hz, 1H).

The following compound was prepared using the appropriate starting materials in a method similar to that described in Experimental Scheme 2.

Experimental design 3

Compound 47. (±)-N-(3-Chloro-4-(trifluoromethyl)phenyl)-9-(hydroxyimino)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide

To a solution of 2-amino-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide 45b (200 mg, 503 μmol) in AcOH (5 mL) was added dropwise a solution of sodium nitrite (208 mg, 3.02 mmol) in water (2 mL). The reaction mixture was stirred for 2 h. An additional portion of water (2 mL) was added, and the reaction mixture was stirred for 72 h. The precipitate was washed with water and dried under vacuum to give (±)-N-(3-chloro-4-(trifluoromethyl)phenyl)-9-(hydroxyimino)-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide 47 as a yellow solid. LC-MS (Method 1) m/z 428.3, 430.3 (M+H) ⁺ (ES ⁺ ); at 1.15 min. ¹ H NMR (500 MHz, DMSO-d6) δ 12.40 (s, 1H), 11.82 (s, 1H), 9.42 (s, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.55 (dd, J=8.5, 2.1 Hz, 1H), 5.80 (d, J=6.8 Hz, 1H), 5.23 (s, 1H), 2.35-2.24 (m, 2H), 1.80 (d, J=9.3 Hz, 1H), 1.71 (d, J=11.6 Hz, 1H). (1NH was not detected)

Experimental Design 4

Compound 11. (±)-N-(3-chloro-4-cyanophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

To a solution of 4-amino-2-chlorobenzonitrile (47 mg, 0.31 mmol) in THF (1 mL) was added a solution of triphosgene (37 mg, 0.12 mmol) in THF (1 mL), then Et ₃ N (130 μL, 0.93 mmol). The resulting mixture was stirred at room temperature for 30 min. A solution of 6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine (50 mg, 0.31 mmol) in DMF (0.5 mL) was added, and the resulting mixture was stirred at room temperature for 72 h. A solution of 2 M NaOH (2 mL) was added, and the product was extracted with DCM (3 mL). The organic phases were passed through a hydrophobic frit, and the filtrate was concentrated in vacuo. The product was purified by product-directed HPLC (20-50% MeCN/10 mM aqueous ammonium bicarbonate, C18) to afford (±)-N-(5-(trifluoromethyl)pyrazin-2-yl)-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine-10-carboxamide as an off-white solid. LC-MS (Method 1) m/z 340.3, 342.3 (M+H) ⁺ (ES ⁺ ) at 1.05 min, ¹ H NMR (500 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.96 (s, 1H), 8.61 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.59 (dd, J=8.7, 2.0 Hz, 1H), 5.31 (d, J=6.2 Hz, 1H), 4.84 (t, J=6.5 Hz, 1H), 3.37-3.34 (m, 1H), 2.80 (d, J=18.4 Hz, 1H), 2.34-2.14 (m, 2H), 1.96-1.86 (m, 1H), 1.81-1.72 (m, 1H).

The following compounds were prepared using the appropriate starting materials in a manner similar to that described in Experimental Scheme 4. In cases where the starting materials are not described in the literature, their synthesis is described below.

Explanations: (a) The reaction was carried out in DCM. (b) Purification was done by silica gel chromatography (EtOAc/isohexane). (c) Purification was done by silica gel chromatography (0.7 M ammonia in MeOH/DCM) (d) (MH) ^- ES ^(-) , since no ionization occurred at ES ⁽⁺⁾ (e) LCMS method 6 (f) Purification was done by preparative TLC (MeOH/DCM)

Intermediate connection 29 (I-29)

Step 1. To a solution of 2-chloro-4-nitroaniline I-29a (1.00 g, 5.79 mmol) and sodium bicarbonate (1.46 g, 17.4 mmol) in MeCN (10 mL) was added acryloyl chloride (706 µL, 8.69 mmol) at 0°C over 5 min. The reaction mixture was warmed to room temperature over 16 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (3×20 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford N-(2-chloro-4-nitrophenyl)acrylamide I-29b as a yellow solid. This compound was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.37 (d, J=2.6 Hz, 1H), 8.31 (d, J=9.1 Hz, 1H), 8.23 (dd, J=9.1, 2.6 Hz, 1H), 6.77 (dd, J=17.0, 10.3 Hz, 1H), 6.36 (dd, J=17.0, 1.8 Hz, 1H), 5.88 (dd, J=10.2, 1.8 Hz, 1H).

Step 2. To a solution of N-(2-chloro-4-nitrophenyl)acrylamide (1.40 g, 5.232 mmol) in a mixture of EtOH (30 mL) and water (6 mL) was added iron powder (585 mg, 10.46 mmol), followed by 1 mL of saturated ammonium chloride solution. The reaction mixture was heated at 80°C for 4 h. The reaction mixture was cooled to room temperature and filtered through celite. Celite was washed with EtOH and ethyl acetate. The filtrate was concentrated in vacuo, and the residue was partitioned between 10% MeOH in DCM (50 mL) and water (50 mL). The layers were separated, and the aqueous layer was extracted with 10% MeOH in DCM (2 × 30 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to afford N-(4-amino-2-chlorophenyl)acrylamide I-29 as a yellow oil. This compound was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.18 (d, J=8.6 Hz, 1H), 6.65 (d, J=2.5 Hz, 1H), 6.56-6.35 (m, 2H), 6.18 (dd, J=17.1, 2.1 Hz, 1H), 5.69 (dd, J=10.2, 2.1 Hz, 1H), 5.33 (s, 2H)

Intermediate connection 30 (I-30)

Step 1. (E)-N-((2-Chloro-6-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (I-30b) was synthesized from 2-chloro-6-fluoronicotinaldehyde (I-30a) using essentially the same method as that used to prepare compound I-7b. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 8.93 (s, 1H), 8.48 (t, J=8.4 Hz, 1H), 7.02-6.99 (m, 1H), 1.28 (m, 9H).

Step 2. N-(1-(2-Chloro-6-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-30c) was synthesized from (E)-N-((2-chloro-6-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (I-30b) using essentially the same method as that used to prepare compound I-7c. ¹H NMR: (400 MHz, CDCl₃) δ 7.82-7.87 (m, 1H), 6.87-6.90 (m, 1H), 5.76 (t, J=10.4 Hz, 1H), 5.01-5.05 (m, 2H), 4.98-4.84 (m, 1H), 5.82-3.79 (m, 1H), 2.20- 2.05 (m, 2H), 1.94-1.88 (m, 2H) 1.16-1.22 (m, 9H)

Stage 3. 1-(2-Chloro-6-fluoropyridin-3-yl)pent-4-en-1-amine (I-30d) was synthesized from N-(1-(2-Chloro-6-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-30c) using essentially the same method as that used to prepare compound I-7d. ¹H NMR: (400 MHz, CDCl₃) δ 8.00 (t, J=8.4 Hz, 1H), 6.87-6.90 (m, 1H), 5.72-5.83 (m 1H), 5.96-5.05 (m, 2H), 4.36 (t, J=5.6 Hz, 1H) 2.09-2.15 (m, 2H), 1.65-1.69 (m, 2H), 1.48 (s, 2H).

Step 4. N-(1-(2-Chloro-6-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline (I-30e) was synthesized from 1-(2-chloro-6-fluoropyridin-3-yl)pent-4-ene-1-amine (I-30d) using essentially the same method as that used to prepare compound I-7e. ¹H NMR: (400 MHz, CDCl3) δ 7.88 (t, J=8.0 Hz, 1H), 6.78-6.83 (m, 1H), 6.70 (t, J=4.4 Hz, 2H), 6.40 (d, J=4.4 Hz, 2H), 5.80-5.87 (m, 1H), 5.01-5.05 (m, 2H), 3.70 (s, 3H), 2.19-2.31 (m, 2H), 1.77-1.92 (m, 2H), 1.43 (s, 1H) (1 replaceable NH not detected)

Step 5. To a solution of N-(1-(2-chloro-6-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline (I-30e) (3.00 g, 9.35 mmol) in toluene (60 mL) were added NaO ^t Bu (1.35 g, 14.0 mmol) and Pd-172 (567 mg, 935 μmol) at 20 °C. The mixture was stirred at 110 °C for 16 h. The reaction mixture was concentrated in vacuo. The product was purified by silica gel chromatography (EtOAc/petroleum ether 1%-100%) to give (±)-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-30f) as a yellow solid. ^1H NMR: (400 MHz, CDCl3) δ 7.55 (t, J=8.0 Hz, 1H), 6.68-6.77 (m, 5H), 4.72 (d, J=2.4 Hz, 1H), 4.52 (d, J=5.6 Hz, 1H), 3.71 (s, 3H), 3.28 (dd, J=8.8, 4.4 Hz, 1H), 2.53 (d, J=8.8 Hz, 1H), 2.42-2.56 (m, 3H), 1.82-1.96 (m, 2H).

Step 6. (±)-2-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-30) was synthesized from (±)-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-30f) using essentially the same method as that used to prepare compound I-9. ¹ H NMR (400 MHz, DMSO-d6) δ 7.60 (t, J=8.3 Hz, 1H), 6.90-6.76 (m, 1H), 4.19 (d, J=5.6 Hz, 1H), 3.84-3.68 (m, 1H), 3.02 (dd, J=17.7, 5.2 Hz, 1H), 2.79 (s, 1H), 2.45 (s, 1H), 2.00-1.82 (m, 2H), 1.77-1.65 (m, 1H), 1.58-1.39 (m, 1H)

Intermediate connection 31 (I-31)

Step 1. To a solution of (±)-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (113 mg, 397 μmol) in MeOH (4 mL) was added a solution of sodium methoxide in methanol (110 μL, 5.4 molar, 596 μmol). The resulting mixture was heated at 65°C for 20 h. THF (1 mL) was added, followed by additional sodium methoxide (110 μL, 5.4 molar, 596 μmol). The reaction mixture was stirred at 65°C for another 24 h. The reaction mixture was cooled. The solid was filtered and washed with MeOH (2×5 mL), and the solid was dried under vacuum to afford (±)-2-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-31a) as a white solid. LC-MS (Method 1) m/z 297.1 (M+H) ⁺ (ES ⁺ ); at 1.68 min.

Step 2. (±)-2-Methoxy-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[b]pyridine (I-31b) was synthesized from (±)-2-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-31a) using essentially the same method as that used to prepare compound I-9. ¹ H NMR (400 MHz, Chloroform-d) δ 7.17 (d, J=8.2 Hz, 1H), 6.45 (d, J=8.2 Hz, 1H), 4.17 (d, J=5.5 Hz, 1H), 3.97-3.89 (m, 1H), 3.86 (s, 3H), 3.21-3.05 (m, 1H), 2.59 (d, J=17.7 Hz, 1H), 2.35 (s, 1H), 2.19-2.00 (m, 2H), 1.89-1.78 (m, 1H), 1.68-1.57 (m, 1H).

Step 3. (±)-1,5,6,7,8,9-Hexahydro-2H-5,8-epiminocyclohepta[b]pyridin-2-one (I-31) was synthesized from (±)-2-methoxy-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[b]pyridine (I-31b) using essentially the same method as that used to prepare compound I-10. ¹ H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.15 (d, J=9.1 Hz, 1H), 6.04 (d, J=9.1 Hz, 1H), 3.91 (d, J=5.3 Hz, 1H), 3.80-3.59 (m, 1H), 2.80 (dd, J=17.5, 4.9 Hz, 1H), 2.18 (d, J=17.5 Hz, 1H), 2.06-1.58 (m, 3H), 1.55-1.26 (m, 1H), 1 replaceable proton not visible.

Intermediate connection 32 (I-32)

Step 1. To a solution of 3-bromo-5-fluoroisonicotinaldehyde I-32a (4.5 g, 22.2 mmol) and (S)-2-methylpropane-2-sulfinamide (2.7 g, 22.2 mmol) in DCM (50 mL) was added cesium carbonate (7.2 g, 22.2 mmol). After stirring at room temperature for 16 h, the reaction mixture was filtered, and the filter cake was washed with DCM (50 mL). The filtrate was concentrated under reduced pressure to give (S)-N-((3-bromo-5-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide I-32b as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.77 (d, J=1.6 Hz, 1H), 8.63 (s, 1H), 1.22 (s, 9H)

Stage 2. (S)-N-((R)-1-(3-Bromo-5-fluoropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-32c) was synthesized from (S)-N-((3-bromo-5-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (I-32b) using essentially the same method as that used to prepare compound I-13c. ¹H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.54 (d, J=1.6 Hz, 1H), 5.84-5.72 (m, 2H), 5.08-4.97 (m, 2H), 4.79 (q, J=6.4 Hz, 1H), 2.18-2.10 (m, 2H), 2.05-2.00 (m, 1H), 1.99-1.87 (m, 1H), 1.01 (s, 9H).

Stage 3. To a solution of (S)-N-((R)-1-(3-bromo-5-fluoropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-32c) (5.4 g, 14.9 mmol) in^tA solution of HCl in dioxane (4 M, 19 mL) was added to BuOH (60 mL) at 0°C. The reaction mixture was stirred at room temperature for 2.5 h. Water (50 mL) was added, and the mixture was extracted with EtOAc (3×50 mL). The aqueous layer was basified with saturated aqueous sodium bicarbonate solution and extracted with EtOAc (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford (R)-1-(3-bromo-5-fluoropyridin-4-yl)pent-4-ene-1-amine (I-32d) as a yellow oil.¹H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.50 (d, J=2.4 Hz, 1H), 5.84-5.74 (m, 1H), 5.03-4.92 (m, 2H), 4.19 (t, J=7.2 Hz, 1H), 2.15-2.10 (m, 3H), 2.02-1.93 (m, 1H), 1.88-1.70 (m, 2H).

Step 4. To a solution of (R)-1-(3-bromo-5-fluoropyridin-4-yl)pent-4-ene-1-amine (3 g, 11.6 mmol) (I-32d) in DCM (40 mL) were added (4-methoxyphenyl)boronic acid (5.3 g, 34.8 mmol), copper(II) acetate (3.15 g, 17.4 mmol), and Et ₃ N (8.1 mL, 58 mmol). The dark blue mixture was vigorously stirred at room temperature in the presence of air for 20 h. 2 M aqueous NaOH (20 mL) was added, and the resulting biphasic mixture was filtered, and the filter cake was washed with DCM. The layers were separated, and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers _{were dried over Na2SO4 and} concentrated in vacuo. The product was purified by silica gel chromatography (10% EtOAc/petroleum ether) to afford (R)-N-(1-(3-bromo-5-fluoropyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-32e) as a yellow oil. ^1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.45 (d, J=2.0 Hz, 1H), 6.64 (d, J=8.8 Hz, 2H), 6.47 (d, J=8.8 Hz, 2H), 5.88-5.77 (m, 2H), 5.06-5.00 (m, 2H), 4.81-4.75 (m, 1H), 3.57 (s, 3H), 2.32-2.26 (m, 1H), 2.15-2.01 (m, 2H), 1.98 -1.80 (m, 1H).

Step 5. (5R,8S)-4-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine (I-32f) was synthesized from (R)-N-(1-(3-bromo-5-fluoropyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-32e) using essentially the same method as that used to prepare compound I-13f. ¹ H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.04 (s, 1H), 6.77-6.71 (m, 4H), 5.04 (d, J=5.6 Hz, 1H), 4.55 (t, J=6.4 Hz, 1H), 3.60 (s, 3H), 3.06 (dd, J= 4.8, 4.8 Hz, 1H), 2.52-2.47 (m, 1H), 2.35-2.24 (m, 2H), 1.90-1.85 (m, 1H), 1.78-1.73 (m, 1H)

Stage 6. (5R,8S)-4-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine (I-32) was synthesized from (5R,8S)-4-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]-pyridine (I-32f) using essentially the same method as that used to prepare compound I-13.¹H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.11 (s, 1H), 4.38 (d, J=1.6 Hz, 1H), 3.76 (t, J=6.4 Hz, 1H), 3.02 (dd, J= 4.2, 4.2 Hz, 1H), 2.56-2.50 (m, 1H), 2.02-1.89 (m, 2H), 1.76-1.71 (m, 1H), 1.52 -1.46 (m, 1H)

Intermediate connection 33 (I-33)

Stage 1. N-((3-Chloro-2-fluoropyridin-4-yl)methylene)-2-methyl-propane-2-sulfinamide (I-33b) was synthesized from 3-chloro-2-fluoro-isonicotinaldehyde (I-33a) using essentially the same method as that used to prepare compound I-32b.¹H NMR (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.33 (d, J=5.1 Hz, 1H), 7.90 (d, J=5.1 Hz, 1H), 1.22 (s, 9H).

Stage 2. A solution of but-3-en-1-ylmagnesium bromide in THF (133 mL, 0.5 M, 66.55 mmol) was slowly added to a solution of N-((3-chloro-2-fluoropyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (I-33b) (14.6 g, 55.46 mmol) in THF (150 mL) at -78 °C. The reaction mixture was slowly warmed to room temperature over 16 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (150 mL) and extracted with EtOAc (2×200 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to give N-(1-(3-chloro-2-fluoro-pyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-33c) as an orange oil. LC-MS (Method 2) m/z 319.0, 321.0 (M+H)⁺(ES⁺); at 2.12 min.

Step 3. 1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-amine (I-33d) was synthesized from N-(1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide (I-33c) using essentially the same method as that used to prepare compound I-13d. ¹ H NMR (500 MHz, DMSO-d6) δ 8.16 (dd, J=5.1, 0.9 Hz, 1H), 7.62 (d, J=5.1 Hz, 1H), 5.86-5.74 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.02 (dkv, J=17.2, 1.8 Hz, 1H), 4.98-4.92 (m, 1H), 4.20 (dd, J=8.2, 5.0 Hz, 1H), 3.31 (s, 1H), 2.27 (br. s, 2H), 2.20-2.02 (m, 1H), 1.69-1.51 (m, 2H).

Step 4. N-(1-(3-Chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-33e) was synthesized from 1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-amine (I-33d) using essentially the same method as that used to prepare compound I-32e. ¹ H NMR (500 MHz, DMSO-d6) δ 8.10 (dd, J=5.2, 0.8 Hz, 1H), 7.41 (d, J=5.1 Hz, 1H), 6.69-6.61 (m, 2H), 6.42-6.35 (m, 2H), 6.09 (d, J=8.3 Hz, 1H), 5.80-5.81 (m, 1H), 5.07-4.96 (m, 2H), 4.68 (td, J=8.5, 4.7 Hz, 1H), 3.57 (s, 3H), 2.29 (dd, J=14.3, 8.4 Hz, 1H), 2.24-2.13 (m, 1H), 1.86-1.70 (m, 2H).

Step 5. (±)-1-Fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-33f) was synthesized from N-(1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (I-33e) using essentially the same method as that used to prepare compound I-7f. ¹ H NMR (500 MHz, DMSO-d6) δ 7.95 (d, J=5.0 Hz, 1H), 7.28 (d, J=4.9 Hz, 1H), 6.85-6.76 (m, 2H), 6.71 (d, J=8.6 Hz, 2H), 4.92 (d, J=5.4 Hz, 1H), 4.56 (s, 1H), 3.61 (s, 3H), 2.92 (d, J=16.4 Hz, 1H), 2.35 (d, J=17.4 Hz, 1H), 2.33-2.27 (m, 2H), 1.88-1.75 (m, 2H)

Step 6. (±)-1-Fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-33) was synthesized from (±)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine (I-33f) using essentially the same method as that used to prepare compound I-14. ¹ H NMR (400 MHz, DMSO-d6) δ 7.91 (dd, J=5.0, 1.0 Hz, 1H), 7.04 (dd, J=5.0, 1.9 Hz, 1H), 4.17 (d, J=5.4 Hz, 1H), 3.78 (t, J=5.9 Hz, 1H), 3.04-2.68 (m, 2H), 2.38 (d, J=17.1 Hz, 1H), 1.93 (ddt, J=8.6, 5.9, 2.6 Hz, 2H), 1.73 (t, J=9.0 Hz, 1H), 1.63-1.34 (m, 1H).

Intermediate connection 34 (I-34)

Stage 1. A flask containing palladium(II) trifluoroacetate (270 mg, 812 μmol), Xantphos (940 mg, 1.62 mmol), and benzoic acid (496 mg, 4.06 mmol) was evacuated and filled with N₂(3 times). Toluene (100 mL) was added, followed by cyclohepta-1,3,5-triene (I-34a) (16.8 mL, 162 mmol), and the flask was evacuated and filled with N₂(3 times). The mixture was stirred at room temperature for 2-3 minutes, then a solution of 4-methoxyaniline (5.00 g, 40.6 mmol) in toluene (50 mL), which had been purged with N, was added.₂for 2 minutes. The reaction mixture was heated at 110°C for 3 hours and cooled overnight. The organic phases were washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (0-10% EtOAc/isohexane) to afford (±)-8-(4-methoxyphenyl)-8-azabicyclo[3,2,1]oct-2-ene (I-34 b) in the form of a transparent orange oil.¹H NMR (500 MHz, CDCl₃) δ 6.88 (d, J=8.6 Hz, 2H), 6.84-6.78 (m, 2H), 6.07 (m, 1H), 5.50-5.38 (m, 1H), 4.28-4.19 (m, 1H), 4.08 (t, J=5.3 Hz, 1H), 3.76 (s, 3H), 2.57 (d, J=18.0 Hz, 1H), 2.42-2.42 (m, 1H), 2.20-2.08 (m, 1H), 2.06-1.97 (m, 1H), 1.91-1.62 (m, 2H)

Step 2. (±)-8-(4-Methoxyphenyl)-8-azabicyclo[3,2,1]oct-2-ene (I-34b) (1.03 g, 4.07 mmol) and 3,6-dichloro-1,2,4,5-tetrazine (737 mg, 4.88 mmol) were dissolved in xylenes (40 mL), and the mixture was stirred at 100°C for 72 h. The reaction mixture was cooled to room temperature, and the solvent was concentrated in vacuo. The product was purified by silica gel chromatography (0-50% EtOAc/isohexane) to afford (±)-1,4-dichloro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine (I-34c) as a pale brown solid. ¹ H NMR (400 MHz, DMSO-d6) δ 6.85-6.64 (m, 4H), 5.00 (d, J=5.8 Hz, 1H), 4.64 (t, J=5.7 Hz, 1H), 3.62 (s, 3H), 2.91 (dd, J=18.9, 5.0 Hz, 1H), 2.40-2.20 (m, 2H), 2.04-1.91 (m, 1H), 1.89-1.75 (m, 1H) (1H under DMSO peak)

Stage 3. (±)-1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine (I-34) was synthesized from (±)-1,4-dichloro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine (I-34c) using essentially the same method as that used to prepare compound I-14.¹H NMR (400 MHz, DMSO-d6) δ 4.31 (d, J=5.1 Hz, 1H), 3.83 (s, 1H), 2.92 (d, J=4.4 Hz, 1H), 2.44 (d, J=18.6 Hz, 1H), 2.07-1.93 (m, 2H), 1.82 (t, J=9.2 Hz, 1H), 1.61-1.46 (m, 1H). (The replaceable -NH proton is not visible.)

Intermediate connection 35 (I-35)

To a solution of (±)-1,4-dichloro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyridazine (I-34) (84 mg, 0.37 mmol) in EtOH (2 mL) was added Et ₃ N (200 μL, 1.5 mmol), then Pd/C (86 mg, 5% by weight, 37 μmol). The reaction mixture was stirred for 16 h at room temperature under H ₂ atmosphere (0.5 MPa). The reaction mixture was filtered and concentrated in vacuo. The resulting residue was dissolved in DCM (30 mL) and washed with distilled water (5 mL). 2 M NaOH solution was added to the aqueous solution until pH ~10 was reached. The aqueous solution was extracted with DCM (3×20 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give (±)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyridazine as a pale yellow oil, which was used without further purification. ¹ H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J=1.9 Hz, 2H), 4.16 (d, J=6.1 Hz, 1H), 3.78 (t, J=5.9 Hz, 1H), 2.97 (dd, J=17.9, 5.0 Hz, 1H), 2.51-2.43 (m, 1H), 2.02-1.86 (m, 2H), 1.75 (t, J=9.1 Hz, 1H), 1.54-1.38 (m, 1H). (The replaced -NH proton was not detected)

Intermediate connection 36 (I-35)

Step 1. To a solution of diisopropylamine (9.2 mL, 60 mmol) in dried THF (20 mL) at -70°C was added a solution of n-BuLi in hexanes (2.5 M, 26.5 mL, 60 mmol). The mixture was stirred at -70°C for 0.5 h. A solution of 3-chloro-2-(trifluoromethyl)pyridine I-36a (8 g, 40 mmol) in THF (80 mL) was slowly added to the reaction mixture, and the mixture was stirred at -70°C for 1 h. A solution of DMF (8.5 mL, 110 mmol) in THF (30 mL) was slowly added, and the mixture was stirred at -70°C for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (60 mL), and the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The product was purified by silica gel chromatography (20% EtOAc/petroleum ether) to afford 3-chloro-2-(trifluoromethyl)isonicotinaldehyde I-36b as a yellow solid. ¹ H NMR: (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.90 (d, J = 4.8 Hz, 1H), 8.07 (d, J = 4.8 Hz, 1H)

Step 2. (S)-N-((3-Chloro-2-(trifluoromethyl)pyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide I-36c was synthesized from 3-chloro-2-(trifluoromethyl)isonicotinaldehyde I-36b using essentially the same method as that used to prepare compound I-32b. ¹ H NMR: (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.82 (d, J=4.8 Hz, 1H), 8.23 (d, J=4.8 Hz, 1H), 1.23 (s, 9H).

Stage 3. (S)-N-((R)-1-(3-Chloro-2-(trifluoromethyl)pyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-36d was synthesized from (S)-N-((3-chloro-2-(trifluoromethyl)pyridin-4-yl)-methylene)-2-methylpropane-2-sulfinamide I-36c using essentially the same method as that used to prepare compound I-13c.¹H NMR (400 MHz, DMSO-d6): δ 8.69 (d, J=4.8 Hz, 1H), 7.89 (d, J=4.8 Hz, 1H), 5.93 (d, J=7.2 Hz, 1H), 5.85-5.74 (m, 1H), 5.13-4.99 (m, 2H), 4.78-4.72 (m, 1H), 2.27-2.13 (m, 2H), 1.96-1.86 (m, 1H), 1.81-1.72 (m, 1H), 1.07 (s, 9H).

Stage 4. (R)-1-(3-Chloro-2-(trifluoromethyl)pyridin-4-yl)pent-4-en-1-amine I-36e was synthesized from (S)-N-((R)-1-(3-chloro-2-(trifluoromethyl)pyridin-4-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide I-36d using essentially the same method as that used to prepare compound I-32d.¹H NMR (400 MHz, DMSO-d6): δ 8.63 (d, J=4.8 Hz, 1H), 8.00 (d, J=4.8 Hz, 1H), 5.85-5.75 (m, 1H), 5.05-4.93 (m, 2H), 4.30-4.27 (m, 1H), 2.22-2.05 (m, 4H), 1.69-1.51 (m, 2H).

Step 5. (R)-N-(1-(3-chloro-2-(trifluoromethyl)pyridin-4-yl)-pent-4-en-1-yl)-4-methoxyaniline I-36f was synthesized from (R)-1-(3-chloro-2-(trifluoromethyl)pyridin-4-yl)pent-4-en-1-amine I-36e using essentially the same method as that used to prepare compound I-32d. ^1H NMR (400 MHz, DMSO-d6): δ 8.59 (d, J=4.8 Hz, 1H), 7.77 (d, J=4.8 Hz, 1H), 6.66-6.63 (m, 2H), 6.40-6.36 (m, 2H), 6.13 (d, J=8.4 Hz, 1H), 5.89-5.79 (m, 1H), 5.05-4.97 (m, 2H), 4.77 (kv, J=8.8 Hz, 1H), 3.56 (s, 3H), 2.36-2.16 (m, 2H), 1.80-1.74 (m, 2H)

Step 6. A mixture of (R)-N-(1-(3-chloro-2-(trifluoromethyl)pyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline I-36f (2 g, 5.4 mmol), NaO ^t Bu (778 mg, 8.1 mmol), Pd ₂ (dba) ₃ CHCl ₃ (559 mg, 0.54 mmol), and tricyclohexylphosphine (302 mg, 1.08 mmol) in toluene (30 mL) was stirred at 95 °C for 4 h under N ₂ . The mixture was cooled to room temperature, filtered, and the filter cake was washed with EtOAc (3×20 mL). The filtrate was concentrated in vacuo, and the product was purified by silica gel chromatography (10% EtOAc/petroleum ether) to afford (5R,8S)-10-(4-methoxyphenyl)-1-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-36g as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6): δ 8.43 (d, J=4.8 Hz, 1H), 7.62 (d, J=4.8 Hz, 1H), 6.84-6.80 (m, 2H), 6.73-6.69 (m, 2H), 5.00 (d, J=6.0 Hz, 1H), 4.57 (t, J=5.2 Hz, 1H), 3.61 (s, 3H), 3.20 (dd, J=4.8, 4.8 Hz, 1H), 2.58 (d, J=17.6 Hz, 1H), 2.32-2.23 (m, 2H), 1.87-1.74 (m, 2H)

Step 7. (5R,8S)-1-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-36 was synthesized from (5R,8S)-10-(4-methoxyphenyl)-1-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine I-36g using essentially the same method as that used to prepare compound I-14. ¹ H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J=4.8 Hz, 1H), 7.37 (d, J=4.8 Hz, 1H), 4.24 (d, J=5.2 Hz, 1H), 3.81-3.77 (m, 1H), 3.12 (dd, J=5.2, 5.2 Hz, 1H), 2.64-2.59 (m, 1H), 1.98-1.91 (m, 2H), 1.73 (t, J= 9.6 Hz, 1H), 1.51-1.46 (m, 1H).

Experimental design 5

Compound 58. (±)-10-((3,4-Dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine 2-oxide

To a solution of (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 36 (50 mg, 0.14 mmol) in DCM (1 mL) was added mCPBA (62 mg, 0.29 mmol, 80% by weight) at 0°C. The reaction mixture was warmed to room temperature for 16 h. Water was added (10 mL), and the product was extracted with DCM (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated in vacuo. The product was purified by preparative TLC (eluted with 25% MeOH/EtOAc) to afford (±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine 2-oxide 58 as a white solid. LC-MS (Method 1) m/z 364.1, 366.1 (M+H)⁺(ES⁺) at 1.07 min,¹H NMR: (400 MHz, CDCl₃) δ 8.01-7.96 (m, 2 H), 7.60 (d, J=2.7 Hz, 1 H), 7.33 (d, J=8.8 Hz, 1 H), 7.22 (dd, J=8.8, 2.7 Hz, 1 H), 7.04-7.00 (m, 1 H), 6.73 (s, 1 H), 5.03 (d, J=6.2 Hz, 1 H), 4.66- 4.59 (m, 1 H), 3.37 (dd, J=17.0, 4.9 Hz, 1 H), 2.62 (d, J=17.2 Hz, 1 H), 2.47-2.36 (m, 1 H), 2.36-2.25 (m, 1 H), 2.00-1.91 (m, 1 H), 1.84-1.74 (m, 1 H)

The following compound was prepared using the appropriate starting materials in a method similar to that described in Experimental Scheme 5

Experimental Design 6

Compound 59. (±)-10-((3,4-Dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine 2-oxide

(±)-10-((3,4-Dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine 2-oxide 59 was synthesized from (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide 59a using essentially the same method as that used to prepare compound 58. LC-MS (Method 1) m/z 364.0, 366.1 at 1.07 min (M+H)⁺(ES⁺),¹H NMR: (400 MHz, CDCl₃-d) δ 8.06 (s, 2H), 7.91 (dd, J=6.6, 1.5 Hz, 1H), 7.73 (d, J=2.2 Hz, 1H), 7.40-7.35 (m, 1H), 7.33-7.28 (m, 1H), 6.98 (d, J=6.4 Hz, 1H), 5.15 (d, J=5.5 Hz, 1H), 4.82 (t, J=5.8 Hz, 1H), 3.31 (dd, J=17.9, 4.9 Hz, 1H), 2.62 (d, J=17.9 Hz, 1H), 2.42-2.24 (m, 2H), 2.03-1.92 (m, 1H), 1.77-1.67 (m, 1H)

Experimental design 7

Connection 60. (±)-2-Chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

Stage 1. Towards the solution (±)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-2-ol I-10 (176 mg, 0.93 mmol) in DCM (5 mL) was added di-tert-butyl dicarbonate (224 mg, 1.03 mmol) at 0 °C and then warmed to room temperature over 1 h. Saturated aqueous sodium bicarbonate (10 mL) was added, and the product was extracted with DCM (3×10 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to afford tert-butyl (±)-2-hydroxy-6,7,8,9-tetra-hydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate 60a as a pale brown solid. The crude product was used in the next step without further purification. LC-MS (method 2) m/z 274 (M-H)^-(ES^-) at 2.02 min.

Step 2. To a solution of tert-butyl (±)-2-hydroxy-6,7,8,9-tetra-hydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate 60a (247 mg, 0.83 mmol) in DMF (7.3 mL) was added DIPEA (0.44 mL, 2.50 mmol), followed by 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (447 mg, 1.25 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc (20 mL), and a 2:1 mixture of water and brine (50 mL) was added. The product was extracted with EtOAc (2×20 mL). The organic layers were combined and washed with water (5×20 mL) and brine (20 mL). The organic layers were dried over magnesium sulfate and concentrated in vacuo. The product was purified by silica gel chromatography (0–50% EtOAc/isohexane) to afford tert-butyl (±)-2-(((trifluoromethyl)sulfonyl)oxy)-6,7,8,9-tetra-hydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate 60b as a pale yellow oil. LC-MS (method 2) m/z 308 (M+H-Boc) ⁺ (ES ⁺ ) at 1.86 min, ¹ H NMR (500 MHz, DMSO-d6) δ 7.39-7.31 (m, 1H), 7.24 (d, J=7.5 Hz, 2H), 4.90 (br s, 1H), 4.37 (br s, 1H), 3.30-3.15 (m, 1H), 2.67 (d, J=17.3 Hz, 1H), 2.24-2.06 (m, 2H), 1.82-1.70 (m, 1H), 1.67-1.56 (m, 1H), 1.43-1.22 (m, 9H).

Step 3. Pd-175 (11 mg, 14 μmol), potassium chloride (34 mg, 0.46 mmol), and potassium fluoride (6.6 mg, 0.11 mmol) were added to a microwave reaction vial, sealed, evacuated, and filled with _N2 (3×). A solution of tert-butyl (±)-2-(((trifluoromethyl)sulfonyl)oxy)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate 60b (93 mg, 0.23 mmol) in 1,4-dioxane (3 mL) was added, and the resulting mixture was heated to 130 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through a pad of celite, washing with EtOAc (20 mL). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0-15% EtOAc/isohexane) to afford tert-butyl (±)-2-chloro-6,7,8,9-tetra-hydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate 60c as a colorless oil. LC-MS (Method 2) m/z 194.7 (M+H-Boc) ⁺ (ES ⁺ ) at 1.82 min, ¹ H NMR (500 MHz, _CDCl3 ) δ 7.16-7.02 (m, 2H), 6.98 (d, J=8.1 Hz, 1H), 4.87 (s, 1H), 4.50 (s, 1H), 3.34 (s, 1H), 2.52 (d, J=16.7 Hz, 1H), 2.18 (tdd, J=18.0, 15.8, 9.0 Hz, 2H), 1.88-1.74 (m, 1H), 1.73-1.53 (m, 1H), 1.40 (s, 9H)

Stage 4. A solution of HCl in 1,4-dioxane (294 μL, 4 M, 1.17 mmol) was added dropwise to a mixture of tert-butyl (±)-2-chloro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate 60c (11.5 mg, 11.7 μmol), and the solution was stirred for 16 h at room temperature. An additional portion of HCl in 1,4-dioxane (294 μL, 4 M, 1.17 mmol) was added, and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo. The resulting mixture was dissolved in DCM (0.2 mL). 1,2-Dichloro-4-isocyanatobenzene (16.6 mg, 88.1 μmol) and DIPEA (31 μL, 180 μmol) were added. The resulting mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with 10% MeOH in DCM (2 mL) and washed with water (2 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The product was purified by reversed-phase mass-targeted HPLC (45-75% MeCN/(0.1% ammonia in water) to afford (±)-2-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide 60 as a colorless solid. LC-MS (Method 1) m/z 381.2, 383.4 (M+H)⁺(ES⁺) at 1.79 min,¹H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.46 (s, 2H), 7.18 (s, 3H), 5.17 (d, J=6.0 Hz, 1H), 4.69 (t, J=6.2, 6.2 Hz, 1H), 3.33-3.26 (m, 1H), 2.64 (d, J=17.2 Hz, 1H), 2.27-2.06 (m, 2H), 1.78 (t, J=10.4, 10.4 Hz, 1H), 1.67 (dt, J=15.2, 7.6, 7.6 Hz, 1H).

Experimental Design 8

Compound 61. (±)-1-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

Step 1. To a solution of (±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine 2-oxide 59 (50 mg, 137 μmol) and tert-butylamine (87 μL, 824 μmol) in trifluorotoluene (2.4 mL) and DCM (0.6 mL) was added p-tolylsulfonyl 4-methylbenzenesulfonate (112 mg, 343 μmol) at 0°C. The reaction mixture was stirred at 0°C for 6 h. The mixture was warmed to room temperature and concentrated in vacuo. The product was purified by preparative TLC (50% EtOAc/petroleum ether) and then purified by preparative HPLC (55-85% MeCN/10 mm NH₄HCO₃) to give (±)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 61-a as a white solid and (±)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 62-a as a white solid.

61-a ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.92 (d, J=5.1 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.17 (dd, J=8.8, 2.7 Hz, 1H), 6.32 (d, J=2.4 Hz, 1H), 6.30 (s, 1H), 4.88 (d, J=5.7 Hz, 1H), 4.54-4.45 (m, 1H), 3.94 (br s, 1H), 3.34 (dd, J=17.2, 4.6 Hz, 1H), 2.48 (d, J=17.0 Hz, 1H), 2.44-2.22 (m, 1H), 2.28-2.16 (m, 1H), 1.96-1.88 (m, 1H), 1.82-1.72 (m, 1H), 1.51 (s, 9H)

62-a ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.83 (s, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.18 (dd, J=8.7, 2.5 Hz, 1H), 6.35 (s, 1H), 6.20 (s, 1H), 4.79 (d, J=5.1 Hz, 1H), 4.64 (t, J=5.8 Hz, 1H), 4.57-4.34 (m, 1H), 3.35 (dd, J=17.2, 4.6 Hz, 1H), 2.51 (d, J=17.2 Hz, 1H), 2.37-2.22 (m, 2H), 1.95 (t, J=9.2 Hz, 1H), 1.78-1.67 (m, 1H), 1.41 (s, 9H)

Step 2. To a solution of (±)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridine-10-carboxamide 61a (25 mg, 60 μmol) in DCM (1 mL) was added TFA (0.3 mL, 4.05 mmol) at room temperature. The resulting mixture was heated to 50 °C for 6 h. The reaction mixture was concentrated in vacuo. The residue was diluted with water (5 mL) and DCM (3 mL). The pH was adjusted to 10 with aqueous 50% NaOH. The product was extracted with DCM (3 × 3 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over sodium sulfate, and concentrated in vacuo. The product was purified by preparative HPLC (35-55% MeCN/10 mM NH ₄ HCO ₃ ) to afford (±)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 61 as a white solid. LC-MS (Method 1) m/z 363.1, 365.1 (M+H) ⁺ (ES ⁺ ) at 1.23 min, ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.78 (d, J=5.5 Hz, 1H), 7.60 (d, J=2.5 Hz, 1H), 7.32-7.28 (m, 1H), 7.25-7.19 (m, 1H), 6.80 (br s, 1H), 6.51 (d, J=5.50 Hz, 1H), 5.52-5.24 (m, 1H), 5.10 (d, J=5.75 Hz, 1H) 4.69-4.57 (m, 1H), 3.88 (s, 1H), 3.43 (dd, J=17.7, 4.5 Hz, 1H), 2.56 (d, J=17.7 Hz, 1H), 2.48-2.37 (m, 1H), 2.29 (ddd, J=17.9, 11.7, 6.2 Hz, 1H), 1.82-1.71 (m, 1H), 2.02-1.95 (m, 1H)

Experimental design 9

Compound 62. (±)-3-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(±)-3-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 62 was synthesized from (±)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 62-a using essentially the same method as that used to prepare compound 61. LC-MS (Method 1) m/z 363.1, 365.1 (M+H) ⁺ (ES ⁺ ) at 1.21 min, ¹ H NMR: (400 MHz, CDCl ₃ -d) δ 7.77 (s, 1H), 7.60 (d, J=2.43 Hz, 1H), 7.32-7.28 (m, 1H), 7.20 (dd, J=8.8, 2.4 Hz, 1H), 6.62 (br.s, 1H), 6.28 (s, 1H), 4.86 (d, J=5.5 Hz, 1H), 4.67-4.62 (m, 1H), 3.35 (dd, J=17.4, 4.6 Hz, 1H), 2.53 (d, J=17.4 Hz, 1H), 2.38-2.22 (m, 2H), 1.90 (br.s, 1H), 1.76-1.67 (m, 1H). (NH ₂ protons were not detected)

Experimental design 10

Compound 63 (±)-1-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide, compound 65 (±)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide and compound 66 (±)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

Stage 1. (±)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 65 and (±)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 66 were synthesized from (±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine 2-oxide 58 using essentially the same method as that used to prepare compound 61a and 62a.

65 LC-MS (Method 1) m/z 419.2, 421.1 (M+H) ⁺ (ES ⁺ ) at 1.77 min, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (d, J=5.1 Hz, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.18 (dd, J=8.7, 2.5 Hz, 1H), 6.34 (d, J=5.1 Hz, 1H), 6.31 (s, 1H), 4.77-4.72 (m, 1H), 4.67 (d, J=5.6 Hz, 1H), 3.89 (s, 1H), 3.01 (dd, J=15.9, 4.8 Hz, 1H), 2.39-2.25 (m, 2H), 2.09-1.99 (m, 2 H), 1.80-1.72 (m, 1 H), 1.46 (s, 9 H)

66 LC-MS (Method 1) m/z 419.1, 421.1 (M+H) ⁺ (ES ⁺ ) at 1.66 min, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (s, 1H), 7.86-7.79 (m, 1H), 7.60 (d, J=2.5 Hz, 1H), 7.33-7.30 (m, 1H), 7.23-7.18 (m, 1H), 6.33 (s, 1H), 6.19 (s, 1H), 4.83 (d, J=6.1 Hz, 1H), 4.57 (d, J=4.5 Hz, 1H), 3.34-3.23 (m, 1H), 2.54 (d, J=16.0 Hz, 1H), 2.39-2.20 (m, 2H), 1.95 (t, J=10.2 Hz, 1H), 1.85-1.74 (m, 1H), 1.42 (s, 9H).

Step 2. (±)-1-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 63 was synthesized from (±)-1-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 65 using essentially the same method as that used to prepare compound 61. LC-MS (Method 1) m/z 363.1, 365.1 (M+H) ⁺ (ES ⁺ ) at 1.98 min, ¹ H NMR (400 MHz, CDCl3-d) δ 7.94 (d, J=5.1 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.18 (dd, J=8.7, 2.5 Hz, 1H), 6.51 (d, J=5.1 Hz, 1H), 6.35 (s, 1H), 4.81-4.77 (m, 1H), 4.78 (d, J=6.2 Hz, 1H), 4.73 (t, J=6.0 Hz, 1H), 4.34 (s, 2H), 3.12 (dd, J=16.1, 4.9 Hz, 1H), 2.43-2.26 (m, 2H), 2.22 (d, J=16.1Hz, 1H). 2.06-1.98 (m, 1H), 1.83-1.74 (m, 1H).

Experimental Design 11

Compound 64. (±)-3-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(±)-3-Amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 64 was synthesized from (±)-3-(tert-butylamino)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 66 using essentially the same method as that used to prepare compound 61. LC-MS (Method 1) m/z 363.1, 365.1 (M+H) ⁺ (ES ⁺ ) at 1.21 min, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83 (s, 1 H), 7.61 (d, J=2.4 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.20 (dd, J=8.7, 2.5 Hz, 1H), 6.35 (s, 1H), 6.29 (s, 1H), 4.85 (d, J=6.2 Hz, 1H), 4.57 (t, J=6.2 Hz, 1H), 4.33 (s, 2H), 3.31 (dd, J=16.0, 4.7 Hz, 1H), 2.57 (d, J=16.1 Hz, 1H), 2.41-2.21 (m, 2H), 2.00-1.90 (m, 1H), 1.84-1.75 (m, 1H)

Experimental design 12

Compound 67. (±)-N-(3,4-Dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

To a solution of (±)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetra-hydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 62 (10 mg, 27.52 μmol) in HF:pyridine (0.5 ml, 5.55 mmol, 70% HF) was added dropwise with a solution of NaNO₂(4.75 mg, 68.82 μmol) in water (0.25 mL) at 0°C for 5 min. After stirring at 0°C for 0.5 h, the reaction mixture was warmed to room temperature over 2.5 h. Water was added. (5 ml), and the product was extracted with EtOAc (3×2 ml). The combined organic layers were washed with brine (2×5 mL), dried over sodium sulfate and concentrated in vacuo. The product was purified by preparative HPLC (35-55% MeCN/10 mm NH₄HCO₃) to give (±)-N-(3,4-dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 67 as a white solid. LC-MS (Method 1 m/z 364.5, 366.5, 368.4 (M-H)^-(ES^-) at 1.47 min,¹H NMR: (400 MHz, CDCl₃) δ 8.00 (s, 1H), 7.59 (d, J=2.6 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.18 (dd, J=8.7, 2.5 Hz, 1H), 6.72 (s, 1H), 6.40 (s, 1H), 5.04 (d, J=5.6 Hz, 1H), 4.64 (br t, J=6.1 Hz, 1H), 3.48 (dd, J=17.7, 4.3 Hz, 1H), 2.71 (d, J=17.7 Hz, 1H), 2.47-2.27 (m, 2H), 2.05-1.91 (m, 1H), 1.82-1.71 (m, 1H).

Experimental design 13

Compound 68. (±)-N-(3,4-Dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

(±)-N-(3,4-Dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 68 was synthesized from (±)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 61 using essentially the same method as that used to prepare compound 67. LC-MS (Method 1) m/z 366.1, 368.1, (M+H)⁺(ES⁺) at 1.43 min,¹H NMR: (400 MHz, CDCl₃) δ 8.01 (dd, J=5.1, 0.7 Hz, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.19 (dd, J=8.7, 2.6 Hz, 1H), 6.96 (d, J=4.5 Hz, 1H), 6.46 (s, 1H), 5.17 (d, J=5.8 Hz, 1H), 4.75-4.68 (m, 1H), 3.49 (dd, J=17.8, 4.7 Hz, 1H), 2.66 (d, J=17.7 Hz, 1H), 2.47-2.27 (m, 2H), 2.11-1.99 (m, 1H), 1.82-1.69 (m, 1H).

Experimental design 14

Compound 69. (±)-N-(3,4-Dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(±)-N-(3,4-Dichlorophenyl)-3-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 69 was synthesized from (±)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 64, using essentially the same method as that used to prepare compound 67.LC-MS (method 1) m/z 366.1, 368.1(M+H)⁺(ES⁺) at 1.42 min,¹H NMR (400 MHz, CDCl₃) δ 7.97 (s, 1 H), 7.60 (d, J=2.6 Hz, 1 H), 7.33 (d, J=8.8 Hz, 1 H), 7.19 (dd, J=8.7, 2.6 Hz, 1 H), 6.73 (d, J=2.7 Hz, 1 H), 6.38 (s, 1 H), 5.03 (d, J=6.2 Hz, 1 H), 4.65-4.57 (m, 1 H), 3.41 (d, J=16.4 Hz, 1 H), 2.70 (d, J=16.6 Hz, 1 H), 2.47-2.27 (m, 2 H), 1.94-2.03 (m, 1 H), 1.86-1.76 (m, 1 H).

Experimental design 15

Compound 71. (±)-2-Chloro-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

To a solution of tert-butyl (±)-2-chloro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate 60c (19 mg, 65.4 μmol) in DCM (1 mL) was added dropwise TFA (50 μL, 654 μmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (1 mL). In a separate flask, a solution of 3-chloro-4-(trifluoromethyl)aniline (14 mg, 71.9 μmol) was added to a solution of triphosgene (9 mg, 30 μmol) in DCM (1 mL). Triethylamine (28 μL, 203 μmol) was added, and the resulting mixture was stirred for 10 min. This solution was then added to the TFA salt solution, and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with 10% MeOH in DCM (8 mL) and saturated sodium bicarbonate solution (5 mL). The product was extracted with 10% MeOH in DCM (2×8 mL). The combined organic layers were passed through a hydrophobic frit and concentrated under reduced pressure. The product was purified by preparative HPLC (45-75% MeCN/0.1% NH₄OH in water) to obtain (±)-2-chloro-N-(3-chloro-4-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]-annulene-10-carboxamide 71 as a colorless solid. LC-MS (method 1) m/z 415.6, 417.5 (M+H)⁺(ES⁺) at 1.82 min,¹H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.64-7.58 (m, 1H), 7.19 (d, J=1.2 Hz, 3H), 5.20 (d, J=6.0 Hz, 1H), 4.73 (t, J=6.4 Hz, 1H), 2.66 (d, J=17.4 Hz, 1H), 2.27-2.09 (m, 2H), 1.83-1.75 (m, 1H), 1.73-1.64 (m, 1H). (1 proton is covered by the residual water peak)

Experimental design 16

Compound 72. (±)-2-Cyano-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide

Step 1. A vial was charged with Pd-170 (1.0 mg, 1.5 μmol), potassium carbonate (3.4 mg, 25 μmol), and potassium ferrocyanate trihydrate (21 mg, 49 μmol), sealed, and evacuated/backfilled with _N2 (3 times). A solution of tert-butyl (±)-2-chloro-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate (29 mg, 99 μmol) 60c in 1,4-dioxane:water (1:1, 0.3 mL) was added, and the reaction mixture was heated to 120 °C for 17 h. The reaction mixture was cooled to room temperature and filtered through a pad of celite, washing with EtOAc (10 mL). The filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (0%-50% EtOAc/isohexane) to afford tert-butyl (±)-2-cyano-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate (72-1) as a viscous colorless oil. LC-MS (Method 1) m/z 185.3 (M-Boc+H) ⁺ (ES ⁺ ) at 1.54 min,

Step 2. To a solution of tert-butyl (±)-2-cyano-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxylate (72-1) (20 mg, 70 μmol) in DCM (1 mL) was added TFA (54 μL, 0.70 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum. The resulting mixture was dissolved in DCM (1 mL). 1,2-dichloro-4-isocyanatobenzene (15 mg, 77 μmol) and DIPEA (37 μL, 210 μmol) were added. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with 10% MeOH in DCM (8 mL) and washed with saturated aqueous sodium bicarbonate (5 mL). The aqueous layer was extracted with 10% MeOH in DCM (2×8 mL), and the combined organic layers were dried with a hydrophobic frit and concentrated in vacuo. The product was purified by reversed-phase mass-targeted HPLC (35-65% MeCN/(0.1% ammonia in water)) to afford (±)-2-cyano-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminobenzo[7]annulene-10-carboxamide (72) as a colorless solid. LC-MS (Method 1) m/z 370.3, 372.6 (MH) ^- (ES ^- ) at 1.57 min, ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.95 (s, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 9.2 Hz, 2H), 7.50-7.41 (m, 2H), 7.37 (d, J=7.7 Hz, 1H), 5.23 (d, J=6.0 Hz, 1H), 4.73 (s, 1H), 2.70 (d, J=17.3 Hz, 1H), 2.18 (dd, J=12.1, 6.4 Hz, 2H), 1.80 (t, J=10.0 Hz, 1H), 1.72-1.63 (m, 1H) (urea-NH was not detected).

Experimental design 17

Compound 76. (±)-N-(3,4-Dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

To a solution of (±)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetra-hydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 62 (5 mg, 13.76 µmol) in H₂SO₄(0.5 ml, 1.41 mmol, 15%) NaNO solution was added dropwise₂(2.85 mg, 41.29 μmol) in water (0.2 mL) at 0°C for 5 min. The reaction mixture was stirred at 0°C for 3 h. The reaction mixture was poured into water. (3 ml) and basified with ammonium hydroxide to pH 8, and the mixture was extracted with DCM (3×3 ml). The combined organic phase was washed with brine (2×5 ml), dried over sodium sulfate and concentrated in vacuo. The product was purified by reverse-phase HPLC (5-95% (0.018% TFA in MeCN)/(0.037% TFA in water)) to afford (±)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexa-hydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 76 as a white solid. LC-MS (Method 1) m/z 364.1, 366.1 (M+H)⁺(ES⁺) at 1.09 min,¹H NMR (400 MHz, CDCl₃-d) δ 11.98-11.17 (m, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.35-7.30 (m, 1H), 7.29 (br d, J=2.5 Hz, 1H), 7.05 (s, 1H), 7.01 (s, 1H), 6.34 (s, 1H), 4.90 (br d, J=5.5 Hz, 1H), 4.57 (t, J=6.0 Hz, 1H), 3.24 (d, J=13.8 Hz, 1H), 2.59 (d, J=17.9 Hz, 1H), 2.39-2.16 (m, 2H), 1.85 (t, J=10.2 Hz, 1H), 1.78-1.68 (m, 1H).

Experimental design 18

Compound 77. (±)-1-Chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

To a solution of (±)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetra-hydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (63) (15 mg, 41.29 μmol) in HCl (1.62 mL, 16.77 mmol, 37% by weight) was added a solution of NaNO₂(14.25 mg, 206.47 μmol) in water (0.25 mL) and CuCl (4.09 mg, 41.29 μmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (5 mL), basified with aqueous NaOH (15% w/w) to pH 7, and extracted with DCM (3 × 3 mL). The combined organic phases were washed with brine (2 × 5 mL), dried over sodium sulfate, and concentrated in vacuo. The product was purified by reverse-phase HPLC (35-100% MeCN/(10 mm NH₄HCO₃in water)) to obtain (±)-1-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 77 as a white solid. LC-MS (method 1) m/z 382.0, 384.0 (M+H)⁺(ES⁺) at 2.63 min,¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J=4.9 Hz, 1 H), 7.59 (d, J=2.6 Hz, 1 H), 7.32 (d, J=8.8 Hz, 1 H), 7.20 (dd, J=8.8, 2.6 Hz, 1 H), 7.01 (s, 1 H), 7.04 (d, J=4.9 Hz, 1 H), 6.47 (s, 1 H), 5.04 (d, J=6.4 Hz, 1 H), 4.67-4.58 (m, 1 H), 3.31 (dd, J=17.7, 4.8 Hz, 1 H), 2.74-2.64 (m, 1 H), 2.48-2.26 (m, 1 H), 2.02-1.93 (m, 1 H), 1.87-1.77 (m, 1 H).

Experimental design 19

Compound 82. tert-butyl ((±)-10-((3,4-dichlorophenyl)-carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]-pyridin-1-yl)carbamate

The following synthesis scheme was used, described in the publication by Fier, Kim and Cohen, J. Am. Chem. Soc., 2020, 142, (19), 8614-8618

To a solution of (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 59a (20 mg, 57.43 μmol) and trimethylsilyl N-trimethylsilylethanimidate (35.05 mg, 172.30 μmol) in 1,4-dioxane (0.23 ml) was added tert-butyl ((3-chloro-5,6-dicyanopyrazin-2-yl)oxy)carbamate (25.47 mg, 86.15 μmol) at room temperature, and the reaction mixture was heated at 80 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with ice-cold AcOH (0.23 mL) and zinc (18.8 mg, 287 μmol) was added simultaneously. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (5 mL), neutralized with aqueous NaOH (15% by weight) to pH 7, and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated in vacuo. The product was purified by reverse-phase HPLC (45-100% MeCN/(10 mm NH₄HCO₃in water)) to obtain tert-butyl ((±)-10-((3,4-dichlorophenyl)carbamoyl)-6,7,8,9-tetrahydro-5H-6,9-epimino-cyclohepta[c]pyridin-1-yl)carbamate 82 as a yellow solid. LC-MS (method 1) m/z 363.1 (M-Boc+H)⁺(ES⁺) at 1.69 min,¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 8.15 (br d, J=4.0 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.59 (dd, J=8.8, 2.4 Hz, 1H), 7.29 (s, 1H), 7.27-7.26 (m, 1H), 7.26-7.26 (m, 1H), 6.97 (br d, J=4.6 Hz, 1H), 6.94 (s, 1H), 5.15 (d, J=6.0 Hz, 1H), 4.93-4.83 (m, 1H), 3.51 (br. dd, J=17.9, 4.9 Hz, 1H), 2.57 (d, J=17.4 Hz, 1H), 2.44-2.26 (m, 2H), 1.97-1.86 (m, 1H), 1.72-1.66 (m, 1H), 1.60 (s, 9H).

Experimental design 20

Compound 99. (±)-3-Bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetra-hydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

A mixture of (±)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (62) (5 mg, 2.75 μmol) and POBr ₃ (4 mg, 13.75 μmol) was stirred at 110°C for 2 h. The reaction mixture was cooled to 0°C and aqueous NaOH solution (35% by weight) was added until pH 10. The mixture was extracted with EtOAc (3×5 mL), and the organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, and concentrated in vacuo. The product was purified by reverse phase HPLC (50-100% MeCN/(10 mM NH ₄ HCO ₃ in water)) to afford (±)-3-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (99) as a white solid. LCMS (Method 1) m/z 426.0, 428.0, 430.0 (M+H) ⁺ (ES ⁺ ), at 1.51 min, ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (s, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.28-7.27 (m, 1H), 7.18 (dd, J=2.6, 8.8 Hz, 1H), 6.38 (br s, 1H), 5.00 (d, J=5.9 Hz, 1H), 4.64 (d, J=5.1 Hz, 1H), 3.44 (dd, J=4.4, 17.9 Hz, 1H), 2.65 (d, J=17.6 Hz, 1H), 2.46-2.29 (m, 2H), 1.98 (t, J=9.5 Hz, 1H), 1.83-1.71 (m, 1H).

Experimental Design 21

Connection 100. (±)-3-Chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

To a solution of (±)-3-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetra-hydro-5H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (62) (3.5 mg, 9.64 μmol) and CuCl (954 μg, 9.64 μmol) in HCl (0.5 ml) were added dropwise to a solution of NaNO₂(3.3 mg, 48.2 μmol) in water (0.2 mL) at 0°C. The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was diluted with water. (5 ml) and basified by dropwise addition of ammonium hydroxide to pH 9. The aqueous mixture was extracted with EtOAc (3×5 ml), and the combined organic layers were washed with brine (2×5 mL), dried over sodium sulfate and concentrated in vacuo. The product was purified by reverse-phase HPLC (45-100% MeCN/(10 mm NH₄HCO₃in water)) to give (±)-3-chloro-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta-[c]pyridine-10-carboxamide (100) as a white solid. LCMS (Method 1) m/z 382.0, 384.0, 386.0 (M+H)⁺(ES⁺), at 1.48 min,¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.18 (dd, J=2.5, 8.7 Hz, 1H), 7.12 (s, 1H), 6.37 (s, 1H), 5.02 (d, J=5.7 Hz, 1H), 4.63 (t, J=6.0 Hz, 1H), 3.45 (dd, J=4.9, 17.6 Hz, 1H), 2.66 (d, J=17.6 Hz, 1H), 2.48-2.27 (m, 2H), 2.05-1.91 (m, 1H), 1.83-1.69 (m, 1H).

Experimental design 22

Compound 109. (±)-N-(3,4-Dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

(±)-N-(3,4-dichlorophenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 109 was synthesized from (±)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 63, using essentially the same method as that used to prepare compound 67. LCMS (Method 1) m/z 366.1, 368.0 (M+H)⁺(ES⁺), at 1.45 min,¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, J=5.0 Hz, 1H), 7.60 (d, J=2.6 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.19 (dd, J=8.8, 2.6 Hz, 1H), 7.02-6.97 (m, 1 H), 6.38 (s, 1 H), 5.06 (d, J=6.5 Hz, 1H), 4.66-4.59 (m, 1 H), 3.31 (dd, J=17.6, 4.28 Hz, 1 H)

Experimental design 23

Compound 113. Cis-(±)-N-(3,4-Dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

Step 1. A solution of tert-butyl 2-fluoro-3-oxo-8-azabicyclo[3,2,1]octane-8-carboxylate (220 mg, 904 μmol) and DMF-DMA (3 mL, 23 mmol) was stirred at 110 °C for 3 h. The reaction mixture was cooled to room temperature and poured onto ice (30 mL). The product was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over sodium sulfate, and concentrated in vacuo to give tert-butyl 2-((dimethylamino)methylene)-4-fluoro-3-oxo-8-azabicyclo[3,2,1]octane-8-carboxylate 113b as a yellow oil. The crude product was used in the next step without further purification.

Stage 2. To a solution of formamidine acetate (17 mg, 161 μmol) in EtOH (2 mL) was added sodium ethoxide (9.9 mg, 145 μmol) at room temperature. After stirring at room temperature for 30 min, a solution of tert-butyl 2-((dimethylamino)methylene)-4-fluoro-3-oxo-8-azabicyclo[3,2,1]octane-8-carboxylate 113b (60 mg, 160 μmol) in EtOH (1 mL) was added, and the reaction mixture was stirred at 80 °C for 16 h. The mixture was cooled to room temperature and poured into water (50 mL), extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate, and concentrated in vacuo. The product was purified by preparative TLC (25% EtOAc/petroleum ether) to afford cis-tert-butyl 9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate 113c as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 1H), 8.67 (s, 1H), 5.23 (d, J=4.6 Hz, 1H), 5.16-4.86 (m, 2H), 2.36 (d, J=10.4 Hz, 1H), 2.17 (br. s, 1H), 1.70-1.64 (m, 2H), 1.47-1.44 (m, 9H)

and trans-tert-butyl 9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate 114c as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ -d) δ 9.19 (s, 1H), 8.55 (s, 1H), 5.90-5.64 (m, 1H), 5.17-4.72 (m, 2H), 2.29-2.18 (m, 3H), 1.85-1.78 (m, 1H), 1.46-1.44 (m, 9H)

Stage 3. A solution of cis-tert-butyl 9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxylate 113c (170 mg, 609 μmol) in 4 M HCl/EtOAc (10 mL, 40 mmol) was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to give cis-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine hydrochloride 113d as a yellow solid. The material was used in the next step without further purification.¹H NMR (400 MHz, CD₃OD) δ 9.33 (s, 1H), 8.95 (s, 1H), 5.61-5.42 (m, 1H), 5.20 (d, J=5.7 Hz, 1H), 4.78-4.70 (m, 1H), 2.51-2.39 (m, 2H), 2.12-2.04 (m, 1H), 1.91-1.79 (m, 1H), (NH not detected)

Stage 4.To a solution of cis-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine hydrochloride 113d (120 mg, 556 μmol) in DCM (5 mL) was added 1,2-dichloro-4-isocyanatobenzene (105 mg, 556 μmol) and DIPEA (291 μL, 1.67 mmol) at 0°C. The reaction mixture was then warmed to room temperature over 16 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over sodium sulfate, and concentrated in vacuo. The product was purified by preparative HPLC (20-50% MeCN/(10 mm NH₄HCO₃in water) to give cis-(±)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide as a white solid. LCMS (Method 1) m/z 365.2, 367.2 (M-H)^-(ES^-) at 1.23 min,¹H NMR (500 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.13 (s, 1H), 8.91 (s, 1H), 7.81 (d, J=2.5 Hz, 1H), 7.48 (d, J=8.9 Hz, 1H), 7.42 (dd, J=8.9, 2.5 Hz, 1H), 5.41 (d, J=6.2 Hz, 1H), 5.31 (dd, J=48.5, 1.9 Hz, 1H), 5.21 (t, J=10.1 Hz, 1H), 2.25 (d, J=11.4 Hz, 1H), 2.14-1.95 (m, 1H), 1.72-1.59 (m, 1H), 1.54 (dt, J=16.2, 8.4 Hz, 1H)

Experimental design 24

Compound 114. trans-(±)-N-(3,4-Dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

Step 1. trans-9-Fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[d]pyrimidine hydrochloride 114d was synthesized from trans-tert-butyl 9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta-[d]pyrimidine-10-carboxylate 114c using essentially the same method as that used to prepare compound 113d.¹H NMR (400 MHz, CD₃OD) δ 9.30-9.26 (m, 1H), 8.85 (s, 1H), 6.12-5.89 (m, 1H), 5.14 (d, J=5.6 Hz, 1H), 4.72 (br t, J=6.4 Hz, 1H), 2.53-2.28 (m, 3H), 2.25-2.14 (m, 1H), (NH not detected)

Step 2. trans-(±)-N-(3,4-dichlorophenyl)-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide 114 was synthesized from trans-9-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine hydrochloride 114d using essentially the same method as that used to prepare compound 113.LCMS (method 1) m/z 365.3, 367.2 (M-H)^-(ES^-) at 1.30 min.¹H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.15 (s, 1H), 8.79 (d, J=1.1 Hz, 1H), 7.83 (d, J=2.5 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.9, 2.5 Hz, 1H), 5.92 (dd, J=49.5, 5.5 Hz, 1H), 5.40 (d, J=4.9 Hz, 1H), 5.03 (t, J=6.0 Hz, 1H), 2.22-2.12 (d, J=7.9 Hz, 2H), 2.08-1.97 (s, 1H), 1.84 (t, J=9.4 Hz, 1H).

Separation of enantiomers by chiral chromatography

It should be noted that the enantiomers of the compounds described above can be isolated using well-known methods, including, but not limited to, chiral chromatography. For example, a racemic mixture can be dissolved in a solvent such as methanol, then separated by chiral SFC on a Waters prep 15 system with UV detection using a diode array detector (DAD) at 210-400 nm, 40°C, 12.0 MPa on a Chiralpak® IG column (Daicel Ltd.) (1×25 cm, particle size 5 μm), flow rate 15 mL/min, using 50% ethanol in 0.1% DEA, to obtain both enantiomers as separated pure compounds.

For example, (±)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (compound 48) was dissolved at a concentration of 100 mg/mL in methanol and then separated by chiral SFC on a Waters prep 15 system with UV detection using a diode array detector (DAD) at 210-400 nm, 40°C, 120 MPa on a Chiralpak® IG column (Daicel Ltd.) (1×25 cm, particle size 5 μm), flow rate 15 mL/min, using 50% ethanol in 0.1% DEA to give (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (compound 52) and (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide (compound 53) both as colorless solids. LCMS and NMR data for compounds 52 and 53 are given in the table below.

Explanation: (a) m/z of ES ^-

Experimental design 25

Compound 133. (5R,8S)-N-(3-Chloro-4-(difluoromethoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

To a solution of (5R,8S)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epimino-cyclohepta[c]pyridine I-13 (30 mg, 0.16 mmol) and Et₃N (65 μL, 0.47 mmol) in DCM (1 mL) was added a solution of triphosgene (46 mg, 0.16 mmol) in 1 mL of DCM. The resulting mixture was stirred at room temperature for 5 min. In a separate flask, 3-chloro-4-(difluoromethoxy)aniline, HCl (40 mg, 0.17 mmol) was dissolved in DCM (1 mL), Et₃N (48 mg, 65 µL, 3 eq, 0.47 mmol) was added and the mixture was stirred until a homogeneous solution was formed. The carbamoyl chloride solution was added dropwise to the aniline solution. The mixture was stirred at room temperature for 4 h. Then LiHMDS (52 mg, 0.31 mmol) was added and the reaction mixture was stirred for 18 h. The reaction mixture was concentrated in vacuo. The product was purified by silica gel chromatography (0-70% EtOAc/isohexane) to afford (5R,8S)-N-(3-chloro-4-(difluoro-methoxy)phenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclo-hepta[c]pyridine-10-carboxamide 133 as a pale brown solid. LCMS (method 1) m/z 398.4, 400.4 (M+H)⁺(ES⁺) at 1.39 min,¹H NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.01 (d, J=5.0 Hz, 1H), 7.76 (d, J=2.6 Hz, 1H), 7.43 (dd, J=9.0, 2.6 Hz, 1H), 7.30-7.16 (m, 2H), 7.05 (t, J=73.6 Hz, 1H), 5.23 (d, J=6.3 Hz, 1H), 4.80 (t, J=6.3 Hz, 1H), 3.21-3.07 (m, 1H), 2.58 (d, J=17.3 Hz, 1H), 2.31-2.06 (m, 2H), 1.92-1.79 (m, 1H), 1.78-1.67 (m, 1H).

Experimental design 26

Compound 148. (±)-1-Bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

Stage 1. To a solution of (±)-1-amino-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 63 (7 mg, 19 μmol) in H₂SO₄(0.8 ml, 15% by weight) NaNO solution was added dropwise₂(3 mg, 42 μmol) in water (0.2 mL) at 0°C. The reaction mixture was stirred at room temperature for 6 h. Water (5 mL) was added, and the aqueous solution was basified with aqueous NaOH (15%) to pH 8. The product was extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over sodium sulfate, and concentrated in vacuo. The product was purified by preparative HPLC (20-55% MeCN/10 mm NH₄HCO₃) to give (±)-N-(3,4-dichlorophenyl)-1-oxo-2,5,6,7,8,9-hexahydro-1H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 148-1 as a white solid.¹H NMR (400 MHz, CDCl₃) δ 11.03 (br.s, 1H), 7.65 (d, J=2.2 Hz, 1H), 7.34-7.30 (m, 1H), 7.24-7.17 (m, 2H), 6.63 (br.s, 1H), 6.12 (d, J=6.6 Hz, 1H), 4.87 (d, J=6.4 Hz, 1H), 4.56-4.47 (m, 1H), 3.11 (br. dd, J=4.2, 17.9 Hz, 1H), 2.49 (d, J=17.9 Hz, 1H), 2.44-2.32 (m, 1H), 2.24 (tt, J=6.1, 12.0 Hz, 1H), 2.05-1.94 (m, 1H), 1.86-1.75 (m, 1H)

Step 2. A solution of (±)-N-(3,4-dichlorophenyl)-1-oxo-2,5,6,7,8,9-hexahydro-1H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide (8 mg, 22 μmol) and phosphorus(V) oxybromide (31 mg, 110 μmol) was stirred at 110°C for 3 h. The reaction mixture was poured into water (5 mL) and basified with aqueous NaOH (15% by weight) to pH 9. The product was extracted with EtOAc (3×3 mL). The combined organic layers were washed with brine (2×5 mL), dried over sodium sulfate, and concentrated in vacuo. The product was purified by preparative HPLC (40-70% MeCN/10 mM NH ₄ HCO ₃ ) to afford (±)-1-bromo-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 148 as a white solid. LCMS (Method 1) m/z 428.1, 430.1 (M+H) ⁺ (ES ⁺ ) at 1.55 min, ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.20 (d, J=4.9 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.20 (dd, J=2.5, 8.7 Hz, 1H), 7.06 (d, J=4.9 Hz, 1H), 6.43 (s, 1H), 5.01 (d, J=6.4 Hz, 1H), 4.65-4.58 (m, 1H), 3.28 (dd, J=5.2, 17.5 Hz, 1H), 2.66 (d, J=17.6 Hz, 1H), 2.47-2.27 (m, 2H), 2.01-1.92 (m, 1H), 1.88-1.78 (m, 1H)

Experimental design 27

Compound 149. (5R,8S)-N-(4,5-Dichloro-2-hydroxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide

A solution of (5R,8S)-N-(4,5-dichloro-2-methoxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 118 (20.0 mg, 50.5 μmol) in DCM (0.5 mL) was cooled to -78 °C. A solution of tribromoborane in DCM (66 μL, 1 M, 65.6 μmol) was added dropwise at -78 °C, and the mixture was stirred at -78 °C for 5 min, then warmed to 0 °C for 1 h. The reaction mixture was cooled to -78 °C and anhydrous MeOH (1 mL) was added. The reaction mixture was warmed to room temperature over 30 min. The reaction mixture was concentrated in vacuo. The product was purified by chromatography on RP Flash C18 (5-40% MeCN/10 mM aqueous ammonium bicarbonate) to afford (5R,8S)-N-(4,5-dichloro-2-hydroxyphenyl)-1-fluoro-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[c]pyridine-10-carboxamide 149 as a pale yellow solid. LCMS (Method 1) m/z 382.1, 384.0 (M+H) ⁺ (ES ⁺ ) at 0.74 min. 1H NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.00 (d, J=5.0 Hz, 1H), 7.71 (s, 1H), 7.21 (dd, J=5.1, 1.6 Hz, 1H), 6.98 (s, 1H), 5.20 (d, J=6.2 Hz, 1H), 5.00-4.52 (m, 1H), 3.19 (dd, J=17.3, 5.0 Hz, 1H), 2.57 (d, J=17.3 Hz, 1H), 2.21 (dtd, J=23.8, 12.1, 7.2 Hz, 2H), 1.91-1.80 (m, 1H), 1.79-1.69 (m, 1H), 1 replaceable proton is not visible.

Experimental design 28

Compound 150. (6S,9R)-N-(3,4-Dichlorophenyl)-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide

To a solution of (6S,9R)-N-(3,4-dichlorophenyl)-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide (35 mg, 96 μmol) in DMF (2 mL) were added MeI (6.0 μL, 96 μmol) and K ₂ CO ₃ (40 mg, 0.29 mmol). The reaction mixture was stirred for 16 h. An additional portion of MeI (3 μL, 48 μmol) was added, and the reaction mixture was stirred for another 16 h. Saturated aqueous sodium bicarbonate (5 mL) was added, and the product was extracted with 20% 0.7 M ammonia/MeOH in DCM. The organic phases were concentrated in vacuo. The product was purified by chromatography on RP Flash C18 (15-50% MeCN/10 mM ammonium bicarbonate) to afford (6S,9R)-N-(3,4-dichlorophenyl)-2-methyl-3-oxo-3,5,6,7,8,9-hexa-hydro-2H-6,9-epiminocyclohepta[c]pyridine-10-carboxamide 150 as a pure white solid. LCMS (Method 1) m/z 378.3, 380.3 (M+H) ⁺ (ES ⁺ ) at 1.16 min. ^1H NMR (500 MHz, DMSO-d6) δ 8.88 (s, 1H), 7.84 (d, J=2.1 Hz, 1H), 7.51 (s, 1H), 7.50-7.42 (m, 2H), 6.16 (s, 1H), 5.03 (d, J=6.0 Hz, 1H), 4.60 (t, J=6.4 Hz, 1H), 3.35 (s, 3H), 3.10 (dd, J=17.9, 5.0 Hz, 1H), 2.56 (d, J=17.8 Hz, 1H), 2.17 (t, J=10.5 Hz, 1H), 2.08 (tt, J=12.0, 6.5 Hz, 1H), 1.73 (t, J=10.4 Hz, 1H), 1.64 (d, J=8.3 Hz, 1H).

Determination of absolute stereochemistry

The absolute stereochemistry of the compounds of the invention was determined by X-ray structural analysis.

Description of equipment and data recording

The data were recorded on a Rigaku Oxford Diffraction XtaLAB Synergy four-circle diffractometer equipped with a HyPix-6000HE antistatic high-performance area detector.

Cryogenic system: Oxford Cryostream 800

Cu: λ=1.54184 Å, 50 watt, microfocus source with multilayer mirror (μ-CMF).

Distance from crystal to CCD detector: d=35 mm

Tube voltage: 50 kV

Tube current: 1 mA

An example of stereochemistry determination by X-ray structural analysis for compounds 52 and 53 is given below. It should be kept in mind that similar methods can be used to identify the absolute stereochemistry of other compounds.

Compound 52. (5R,8S)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

A total of 13407 reflections were recorded in the 2θ range from 10.794 to 133.11. The limiting indices were: -12 ≤ h ≤ 12, -7 ≤ k ≤ 7, -13 ≤ l ≤12; which yielded 2535 individual reflections (Rint=0.0996). The structure was solved using the SHELXT program (Sheldrick, GM 2015. Acta Cryst. A71, 3-8) and refined using the SHELXL program (in comparison with F ² ) (Sheldrick, GM 2015. Acta Cryst. C71, 3-8). The total number of refined parameters was 208, compared to 2535 obtained data. All reflections were included in the refinement procedure. The F ² goodness of fit criterion was 1.038 with the final R value for [I > 2σ (I)] R ₁ = 0.0934 and wR _{2 =} 0.2203. The largest values for the differential peak and hole were 1.28 and -0.56 Å ^-3 , respectively. The resulting molecular modeling diagram (Oak Ridge Thermal Ellipsoid Plot (ORTEP)) of the crystal structure for compound 52 is shown in Figure 1.

Compound 53. (5S,8R)-N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidine-10-carboxamide

A total of 11,160 reflections were recorded over a 2θ range from 7.75 to 133.182. The limiting indices were: -12 ≤ h ≤ 12, -7 ≤ k ≤ 7, -13 ≤ l ≤ 10; which yielded 2,527 individual reflections (Rint=0.0914). The structure was solved using SHELXT (Sheldrick, GM 2015. Acta Cryst. A71, 3-8) and refined using SHELXL (compared to ^F2 ) (Sheldrick, GM 2015. Acta Cryst. C71, 3-8). The total number of refined parameters was 208, compared to 2,527 obtained data. All reflections were included in the refinement procedure. The F ² goodness of fit criterion was 1.066 with the final R value for [I > 2σ (I)] R ₁ = 0.0947 and wR ₂ = 0.2243. The largest values for the differential peak and hole were 0.87 and -0.39 Å ^-3 , respectively. The resulting molecular modeling diagram (Oak Ridge Thermal Ellipsoid Plot (ORTEP)) of the crystal structure for compound 53 is shown in Figure 2.

A method for studying the human GPR65 antagonist by the method of homogeneous time-resolved fluorescence (HTRF) analysis of the produced cyclic adenosine monophosphate (cAMP),

IC ₅₀ values were obtained according to the following procedure.

Human astrocytoma 1321N1 cells stably expressing recombinant human GPR65 (1321N1-hrGPR65 cells, EuroscreenFast) were cultured according to the manufacturer's instructions.

Compounds were tested for their ability to antagonize GPR65 by measuring the concentration of cytoplasmic cAMP after treating cells at pH 7.2 to activate the GPR65 signaling pathway and adding the test compound. The extent to which the added compound suppressed the expected increase in cAMP concentration upon GPR65 activation characterizes its activity. The analysis was performed according to the EuroscreenFast assay method as follows.

On the day of the assay, test compounds were added by acoustic dispensing into white, small-volume 384-well microtiter plates. The pH of KRH buffer (5 mM KCl, 1.25 mM MgSO ₄ , 124 mM NaCl, 25 mM HEPES, 13.3 mM glucose, 1.25 mM KH ₂ PO ₄ , and 1.45 mM CaCl ₂ ) was adjusted to pH 6.5, pH 7.6, and pH 8.4 with NaOH. 1321N1-hGPR65 cells were rapidly thawed and diluted in KRH, pH 7.6, then centrifuged at 300 xg for 5 min and resuspended in assay buffer (KRH, pH 7.6, supplemented with 1 mM 3-isobutyl-1-methylxanthine (IBMX) and 200 μM ethylenediaminetetraacetic acid (EDTA)). Cells were added to plates at a density of 2,000 cells per well in a volume of 5 μl. The assay plates were briefly centrifuged at 100 xg and then incubated at room temperature for 30 min. Cells were stimulated by adding 5 μl of KRH, pH 6.5, to achieve an assay pH of 7.2, while control wells were supplemented with 5 μl of KRH, pH 8.4, to achieve an assay pH of 7.9. Assay plates were briefly centrifuged at 100 xg and then incubated at room temperature for 30 min.

cAMP accumulation was determined using a cAMP HTRF kit (Cisbio). d2-labeled cAMP and cryptate-labeled anti-cAMP antibody in lysis and detection buffer (Cisbio) were added to the assay plates, and the plates were incubated at room temperature for 1 h. HTRF measurements were performed using a Pherastar FSX instrument. Acceptor and donor emission signals were measured at 665 nm and 620 nm, respectively, and HTRF ratios were calculated as 665 nm signal/620 nm signal × 104. Data were normalized to high and low controls, and four-parameter logistic regression was used to determine hGPR65 _IC50 values for the test compounds, which are listed in Table 1.

Table 1. Activity of selected compounds according to the invention 1 Average 46 High 2 High 47 Average 3 Average 48 High 4 Average 49 Low 5 Low 50 Low 6 Low 51 Average 7 High 52 High 8 Low 53 Low 11 Average 54 Average 12 Average 55 Average 13 Low 56 Average 15 High 57 Average 16 High 58 High 17 High 59 Low 18 High 60 High 24 Low 61 Average 25 Low 62 Low 26 Average 63 Low 27 Low 64 Average 28 Low 65 Average 29 Average 66 Average 31 High 67 Average 32 High 68 Average 34 Average 69 Average 35 High 71 Average 36 High 72 Average 37 Average 73 Low 38 High 74 High 39 Low 75 High 42 High 76 High 43 High 77 High 44 Low 78 High 45 High 79 High 80 Average 120 High 81 Average 122 High 82 Average 123 High 83 Average 124 High 84 Average 125 High 85 High 126 High 86 Low 127 High 87 Low 128 High 88 High 129 High 91 High 130 Average 92 High 131 Average 93 High 132 Average 94 High 133 High 95 Average 134 High 98 High 135 Average 99 Low 136 Average 100 Average 137 Average 101 High 138 High 103 High 139 High 104 Average 140 High 105 Low 141 High 106 High 142 High 107 Low 143 High 108 High 144 High 109 High 145 High 110 Low 146 High 111 Average 147 High 112 Low 148 Average 113 Average 149 High 114 Average 150 Average 115 Average 151 High 116 Average 152 Average 117 High 153 High 118 Average 154 Average 119 High 155 Average 156 High 178 High 157 High 179 Average 158 High 180 High 159 Average 181 High 160 High 182 High 161 Average 183 Average 162 Average 184 High 163 High 185 High 164 High 186 Average 165 Average 187 Average 166 High 188 Average 167 High 189 High 168 High 190 High 169 Average 191 High 170 High 192 High 171 High 193 Average 172 High 194 Average 173 Average 195 Average 174 High 196 High 175 Average 197 Average 176 Average 198 Average 177 High 199 High 200 Average

High = IC ₅₀ <500 nM; Medium = IC ₅₀ >500 nM and <5 µM; Low >5 µM

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Those skilled in the art will readily appreciate the possibility of various modifications and variations of the described aspects within the scope and spirit of the invention. Although the invention has been described with reference to specific preferred embodiments, it should be understood that the claimed invention is in no way limited to such specific embodiments. Furthermore, it is intended that various modifications of the described embodiments of the invention that are obvious to those skilled in the art be included within the scope of the following claims.

Claims (152)

1. A compound of formula (If) or a pharmaceutically acceptable salt thereof, wherein ring A is a pyridinyl ring or a tautomer thereof or a phenyl ring, each of which may be optionally substituted with one or more substituents 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 haloalkyl; Y is selected from C=N-OH and CR ₁₀ R ₁₀ ', where R ₁₀ and R ₁₀ ' are each independently selected from H, F and C _1-6 alkyl; R _a is selected from H and C _1-6 alkyl; R _b represents H; R ₁ , R ₄ and R ₅ are each independently selected from H, CN, C _1-6 alkyl, C _1-6 alkoxy, OH, F, Cl, Br and I; R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, CN, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, phenyl, oxazolyl, pyrazolyl, thiazolyl, OC _6-10 aryl, NHCO-CH=CH ₂ and CO ₂ ^_ C _1-6 alkyl, wherein said oxazolyl group is each optionally further substituted with one or more C _1-6 alkyl groups; and R ₁₁ and R ₁₁ ' are each independently selected from H, C _1-6 alkyl and CO ₂ R ₁₂ , where R ₁₂ is C _1-6 alkyl. 2. The compound according to item 1, wherein ring A is selected from the following compounds: where R ₆ , R ₇ , R ₈ and R ₉ are each independently 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 haloalkyl and R ₁₄ is H or alkyl, more preferably H. 3. A compound of formula (Ib) or a pharmaceutically acceptable salt thereof, where ring A is selected from groups (i)-(xvii), (xix), (xx): wherein R ₆ , R ₇ , R ₈ and R ₉ are each independently 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 haloalkyl and R ₁₄ is H or C _1-6 alkyl, more preferably H; Y is selected from C=N-OH and CR ₁₀ R ₁₀ ', where R ₁₀ and R ₁₀ ' are each independently selected from H, F and C _1-6 alkyl; R _a is selected from H and C _1-6 alkyl; R _b represents H; R ₁ , R ₄ and R ₅ are each independently selected from H, CN, C _1-6 alkyl, C _1-6 alkoxy, OH, F, Cl, Br and I; R ₂ and R ₃ are each independently selected from H, F, Cl, Br, I, CN, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, phenyl, oxazolyl, pyrazolyl, thiazolyl, OC _6-12 aryl, NHCO-CH=CH ₂ and CO ₂ -C _1-6 alkyl, wherein said oxazolyl group is each optionally further substituted with C _1-6 alkyl; and R ₁₁ and R ₁₁ ' are each independently selected from H, C _1-6 alkyl and CO ₂ R ₁₂ , where R ₁₂ is C _1-6 alkyl. 4. The compound of claim 3, wherein ring A is selected from (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 is even more preferably selected from (i), (ii), (vi) and (ix). 5. A compound according to any one of the preceding claims, which has the formula (Ib)-(ii) where Y, R _a , R _b , R ₁ -R ₅ are defined in paragraph 1 and R ₆ , R ₇ and R ₉ are defined in paragraph 2. 6. A compound according to any one of claims 1 to 4, which has the formula (Ib)-(i) where Y, R _a , R _b , R ₁ -R ₅ are defined in paragraph 1 and R ₆ -R ₉ are defined in paragraph 2. 7. A compound according to any one of claims 1-4, which has the formula (Ib)-(vi) where Y, R _a , R _b , R ₁ -R ₅ are defined in paragraph 1 and R ₆ , R ₈ and R ₉ are defined in paragraph 2. 8. A compound according to any one of paragraphs 1-4, which has the formula (Ib)-(ix) where Y, R _a , R _b , R ₁ -R ₅ are defined in paragraph 1 and R ₆ , R ₉ and R ₁₄ are defined in paragraph 2. 9. A compound according to any one of the preceding claims, wherein Y is selected from CH ₂ and C=N-OH and is preferably selected from CH ₂ . 10. A compound according to any one of the preceding claims, wherein R ₂ and R ₃ are each independently selected from H, F, Cl, Br, CN, methoxy, OCF ₃ , CF ₃ , OCHF ₂ , Me, Ph, pyrazolyl, oxazolyl, thiazolyl, OPh, NHCO-CH=CH ₂ and CO ₂ Me, wherein said oxazolyl group is each optionally further substituted with one or more C _1-6 alkyl groups. 11. A compound according to any one of claims 1-9, wherein R ₂ and R ₃ are each independently selected from F, Cl, Br, I, CN, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy and CO ₂ -C _1-6 alkyl. 12. A compound according to any one of the preceding claims, wherein R ₂ and R ₃ are each independently selected from Cl, Br and CF ₃ and more preferably each independently selected from Cl and CF ₃ . 13. A compound according to any one of the preceding claims, wherein R ₂ and R ₃ are both Cl or one of R ₂ and R ₃ is Cl and the other is selected from OCF ₃ , CO ₂ Me, OCHF ₂ and CF ₃ . 14. A compound according to any one of the preceding claims, wherein R ₁ and R ₄ are both H. 15. A compound according to any one of the preceding claims, wherein R ₅ is selected from H, F, Me, MeO, Cl, OH and CN and is preferably selected from H or F, more preferably is selected from H. 16. A compound according to any one of claims 2 to 15, wherein R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from H, F, Cl, Br, CN, OMe, NH ₂ , NHBu, NHCO ₂ Bu and OH. 17. A compound according to any of the preceding claims, having formula (Ib.1) where A, Y and R ₁ -R ₅ are as defined in any one of claims 1 to 16, or which is in the form of a mixture which is enantiomerically enriched in the compound of formula (Ib.1). 18. A compound selected from the following compounds: and their pharmaceutically acceptable salts. 19. A compound of formula (Ie) or a pharmaceutically acceptable salt thereof, where ring A represents where R ₆ and R ₈ are each independently selected from H, F, Cl, Br, I, CN, C _1-6 alkoxy, OH, phenyl, and C _1-6 haloalkyl; Y is selected from C=N-OH and CR ₁₀ R ₁₀ ', where R ₁₀ and R ₁₀ ' are each independently selected from H, F and C _1-6 alkyl; R _a is selected from H and C _1-6 alkyl; R _b represents H; R ₁ , R ₄ and R ₅ are each independently selected from H, F, Cl, Br and I; and R ₂ and R ₃ are each independently selected from Cl, Br, I, CN and C _1-6 haloalkyl; provided that when Y is _CH2 and R _a , R _b , R ₁ , R ₄ , R ₅ , R ₆ and R ₈ are all H: R ₃ is not CN when R ₂ is Cl; and R ₂ and R ₃ are both not Cl. 20. The compound of claim 19, wherein R ₂ and R ₃ are each independently selected from Cl, Br, I, CN and C _1-6 haloalkyl. 21. The compound according to claim 19 or 20, wherein R ₂ is selected from Cl, Br and CF ₃ and more preferably is selected from Cl and CF ₃ . 22. The compound according to claim 19, wherein R ₃ is selected from Cl, Br, CN and CF ₃ , more preferably selected from Cl and CF ₃ . 23. A compound according to any one of claims 19 to 22, wherein R ₁ , R ₄ and R ₅ are all H. 24. A compound according to any one of claims 19 to 23, wherein Y is selected from CH ₂ and CHF and is preferably selected from CH ₂ . 25. A compound according to any one of claims 19 to 24, wherein R ₆ is H. 26. A compound according to any one of claims 19-25, wherein R ₃ is selected from H, CF ₃ , phenyl, OH and F. 27. A compound according to any one of paragraphs 19-26, wherein R ₈ is OH and ring A is: 28. A compound according to any one of paragraphs 19-27, which has the formula (Ie.1) where A, Y and R ₁ -R ₅ are as defined in any of claims 19 to 27, or which is in the form of a mixture which is enantiomerically enriched in the compound of formula (Ie.1). 29. A compound selected from the following compounds: and their pharmaceutically acceptable salts. 30. A pharmaceutical composition having GPR65 signaling pathway inhibitory activity, comprising an effective amount of a compound according to any one of claims 1-29 and a pharmaceutically acceptable diluent, excipient or carrier. 31. A compound according to any one of claims 1-29 or a pharmaceutical composition according to claim 30 for use as a medicinal product. 32. A compound according to any one of claims 1-29 or a pharmaceutical composition according to claim 30 for use in the treatment or prevention of a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS). 33. A compound or pharmaceutical composition for use according to claim 32, wherein the use comprises modulating GPR65, preferably wherein the use comprises inhibiting the GPR65 signaling pathway. 34. A compound or pharmaceutical composition for use according to claim 32, wherein the disorder is a proliferative disorder. 35. A compound or pharmaceutical composition for use according to claim 34, wherein the proliferative disorder is cancer and preferably is a solid tumor and/or metastases thereof. 36. A compound or pharmaceutical composition for use according to claim 34, wherein the proliferative disorder is a cancer selected from 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 adenocarcinoma, sarcoma, lung cancer, ovarian cancer and glioma, preferably glioblastoma (GBM). 37. The compound or pharmaceutical composition for use according to claim 32, wherein the disorder is an immune disorder. 38. The compound or pharmaceutical composition for use according to claim 37, wherein the immune disorder is an autoimmune disorder. 39. A compound or pharmaceutical composition for use according to claim 38, wherein 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), Sjogren's syndrome, ankylosing spondylitis and related spondyloarthropathies, sarcoidosis, autoimmune hemolytic anemia, immunological platelet disorders and autoimmune polyendocrinopathies. 40. A compound or pharmaceutical composition for use according to claim 39, wherein the autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease and multiple sclerosis (MS). 41. A compound or pharmaceutical composition for use according to claim 32, wherein the use comprises treating or preventing a disorder selected from asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS). 42. A method for treating a disorder mediated by the GPR65 signaling pathway, comprising administering to a subject a compound according to any one of claims 1-29 or a pharmaceutical composition thereof according to claim 30. 43. A compound according to any one of claims 1-29 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 30 for use in the treatment or prevention of a GPR65-associated disease or disorder. 44. Use of a compound as defined in any one of claims 1-29, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment or prevention of a GPR65-associated disease or disorder in a subject. 45. The use according to claim 44 in the preparation of a medicinal product for the treatment or prevention of a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS). 46. Use of a compound selected from the following compounds: and pharmaceutically acceptable salts for the treatment or prevention of a disease mediated by the GPR65 signaling pathway, or a disorder mediated by the GPR65 signaling pathway selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).