BRPI0613309A2 - compound, pharmaceutical composition, method for the manufacture of a pharmaceutical composition, method for preventing, ameliorating or treating a cannabinoid receptor-mediated disease, disorder or syndrome, selective cb2 agonist, use of a compound and process for preparing a compound - Google Patents

Abstract

COMPOSITION, PHARMACEUTICAL COMPOSITION, METHOD FOR MANUFACTURING A PHARMACEUTICAL COMPOSITION, METHOD FOR AVOIDING, IMPROVING OR TREATING A DISEASE, MEDIUM-RECEIVED SYNDROME FOR A COMPONENT PREABLE TO BEABONOID SELECTED COMPONENT The present invention relates to novel cannabinoid receptor modulators, in particular cannabinoid receptor 1 (CE1) or cannabinoid receptor 2 (CB2) modulators, and uses thereof to treat cannabinoid receptor modulated diseases, conditions and / or disorders ( pain, neurodegenerative disorders, eating disorders, weight loss or control, and obesity).

Description

"COMPOUND, PHARMACEUTICAL COMPOSITION, METHOD FOR MANUFACTURING A PHARMACEUTICAL COMPOSITION, METHOD FOR AVOIDING, IMPROVING OR TREATING A DISEASE, AUSINDROME MEDIATED BY RECEIVER OF CANABINOID, A COMPONENTS OF PAIN, A COMPONENT OF USE

Field of the invention

The present invention relates to novel cannabinoid receptor modulators, in particular cannabinoid receptor 1 (CB1) or cannabinoid receptor 2 (CB2) modulators, and uses thereof to treat cannabinoid receptor modulated diseases, conditions and / or disorders (such as pain). , neurodegenerative disorders, eating disorders, weight loss or control, and obesity).

Background

The endogenous cannabinoid system comprises two major receptors, CB1 and CB2, and a number of ligands including anandamide and virodamine demonstrating increased cannabinoid receptor activity (Jonathan A. W & Louis J. A, Obes. Man., 5-19, 2005). Anandamide, which is produced post synaptically, is the main fatty acid involved in the system. It gains access to extracellular space and activates CBllocated cannabinoid receptors on presynaptic nerve terminals. This activation causes presynaptic inhibition of γ-aminobutyric acid or glutamate through inhibition of calcium channels while simultaneously interfering with gallbladder release and activating potassium channels.

However, anandamide is prone to rapid enzymatic hydrolysis. This represents a serious disadvantage in its use as a drug because, inter alia, substances that are susceptible to hydrolytic cleavage may undergo changes in the gastrointestinal tract.

CB1 receptors are predominantly located in the brain and other neurons, while CB2 receptors are predominantly located in immune cells. Stimulation of these receptors is known to affect central and peripheral action on lipid and glucose metabolism in adipose tissue and most notably, helps regulate food intake, energy balance and nicotine dependence as well as regulate fear and anxiety.

There is evidence to suggest that CBl agonists or antagonists, respectively, increase or decrease the motivation to work for palatable ingestion (Gallate JEe McGregorI S, Psychopharmacology, 142, 302-308, 1999 and Gallate JE, Saharov T, Mallet PEe McGregorI S, 1999, Eur. J. Pharmacol., 370, 233-240, 1999). Cannabinoids appear to directly stimulate feeding by actions on appetite processes, making food stimulation more salient and rapidly inducing sealiment even in satiated animals (Williams CMeKirkham TC, Physiol. Behav., 76, 241-250, 2002).

Current data reveal that cannabinoids mediated suppression of inflammation in vitro and in vivo by stimulation of CB2 receptors (Ehrhart J et al., J. Neuroinflammation, 2, 29, 2 005). Inflammatory mediators such as nitric oxide, cytokines, echymiocins play an important role in neuron cell damage associated with microglial cells. Activated microglial cells have been involved in a number of neurodegenerative disorders, including Alzheimer's disease, multiple sclerosis, HIV and dementia.

Compounds capable of modulating cannabinoid (CB) receptor activity may be used to treat CB receptor-mediated disorders, diseases or disorders including appetite, metabolism, diabetes, obesity, glaucoma-associated intraocular pressure, mood disorders, seizures , substance abuse, learning disorders, cognitive disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders, inflammation, cell growth disorders, eye diseases, allergies and reactions allergic disorders, pain, anxiety, psychotic disorders, pathological conditions of the brain, gastrointestinal disorders, nausea, vomiting, dizziness, urinary and fertility problems, cardiovascular diseases, neuroinflammatory disorders, diseases of the nervous system, syndromes, diseases and disorders, dermatological disorders, d isturbia associated with leukocyte activation, autoimmune diseases, nephrological pathologies, delayed or immediate hypersensitivity, parasitic, eviral and bacterial infectious diseases.

At present, various CB modulators have been characterized as agonists, inverse agonists or antagonists for CB1 and / or CB2 receptors. These modulators include naphthalen-1-yl- (4-pentyloxy-naphthalen-1-yl) methanone (believed to be SAB-378), 4- (2,4-dichlorophenylamino) -N- (tetrahydro-pyran-4-ylmethyl) -2-trifluoromethyl benzamide (GW-842166X), N- (1-piperidinyl) -5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazol-2-carboxamide (SR141716A), 3 - (4-chlorophenyl-N '- (4-chlorophenyl) sulfonyl-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazol-1-carboxamide (SLV-319), and (R) - (+ ) - [2,3-dihydro-5-methyl-3- [4-morphonylnylmethyl] -pyrrolo [1,2,3-de] -1,4-benzoxazin-6-yl] (1-naphthyl) methanone ( WIN 55212-2).

<formula> formula see original document page 48 </formula> <formula> formula see original document page 5 </formula>

These modulators have reached various stages of clinical testing for the treatment of pain, neurodegenerative disorders, psychotic disorders, syndromes, neurological disorders or disorders, eating disorders, Alzheimer's disease, alcohol dependence, diabetes, obesity and / or quitting smoking.

U.S. Patent Nos. 5,624,941, 6,028,084, and 6,509,367, PCT Publications Nos. WO 98/31227, WO 98/41519, WO98 / 43636 and WO 98/43635, and European Publication no. EP0 658 546 disclose certain substituted pyrazoles having activity against cannabinoid receptors. U.S. Pat. Nos. 6,355,631 and 6,479,479 and the PCT publications in WO 01/64632, 01/64633, and 01/64634 disclose certain azetidine derivatives which are cannabinoid antagonists.

Other decanabinoid receptor modulating compounds are disclosed in U.S. Patent Nos. 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, e5,532,237, and PCT publications in WO 97/29079, WO98 / 37061, WO 99 WO 00/10967, WO 00/10968, WO01 / 58869, WO 01/70700, WO 02/076949, WO 03/026647, WO03 / 026648, WO 03/027069, WO 03/022776, WO 03/027114 , WO03 / 077847, WO 03/088968, WO 04/13120, WO 04/69837, WO04 / 058145, WO 04/26301, WO 04/058744, WO 04/096763 and WO06 / 030124.

There is an unmet need for alcohol abuse treatment. The health risks associated with alcohol abuse include motor control and decision making, cancer, liver disease, birth defects, heart disease, drug / drug interactions, suggesting that endogenous cannabinoid tone plays a critical role in controlling ethanol intake. CB1 receptor antagonist SR-141716A has been shown to block voluntary admission of ethanol in rats and mice (See, Arnonr, M. et al., "Selective Inhibition of Sucrose and Ethanol Intake by SR141716, an Antagonist of Central Cannabinoid (CB) Receptors" selective admission of sucrose and ethanol by SR141716, a central cannabinoid receptor antagonist (CB)], Psycopharmacol., 132, 104-106 (1997)). For an exam, see Hungund, B.L. and B.S. Basavaraj appa, "AreAnadamide and Cannabinoid Receptors Involved in EthanolTolerance? A Review of the Evidence." [Are anadamide and cannabinoid receptors involved in tolerance to ethanol? An Examination of Evidence], Alcohol & Alcoholism, 35 (2) 126-133, 2000.

Current treatments for alcohol abuse or dependence generally suffer from non-compliance or potential hepatotoxicity. There is an unmet need for more effective treatment of alcohol abuse / dependence.

There is also a need for safer and more effective therapeutic treatments for cannabinoid receptor-modulated diseases, conditions and / or disorders (such as pain, obesity), including those modulated by CB1 or CB2 receptors.

Summary of the invention

The present invention relates to cannabinoid receptor modulators of the formula:

<formula> formula see original document page 6 </formula> and analogues thereof, pharmaceutically acceptable salts thereof, pharmaceutically acceptable esters thereof, regioisomers thereof, stereoisomers thereof, enantiomers thereof, diastereomers thereof, polymorphs thereof, and pharmaceutically acceptable solvates thereof same where:

each of the dotted lines in formula (1) independently represents an optional double bond;

UeV are independently C or N;

W, X and Y are independently C, Ν, O, X or -C (O) except that at least two of U, V, W, X or Y are independently selected from N, O, -C (O) - or S;

R, R1 and R2 may be the same or different and are independently hydrogen, nitro, cyano, formyl, acetyl, halogen, -OR3, -SR3, oxo, thio, unsubstituted or substituted alkyls, unsubstituted or substituted alkenyl, cycloalkyl substituted or unsubstituted, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl group unsubstituted or substituted heterocyclylalkyl, -NR 3 R 4, -C (= B) -R 3, -C (O) O-R 3, -C (O) NR 3 R 4, -S (O) m-NR 3 R 4, or a protecting group or R 1 and R 2 can be joined together to form an optionally substituted saturated or unsaturated 3- to 7-membered cyclic ring, which may be optionally preferably include at least two heteroatoms selected from 0, NR3 or S;

each occurrence of R3 and R4 may be the same or different and are independently hydrogen, halo, cyano, -0Ra, SRa, oxo, thio, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyls, substituted or unsubstituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, unsubstituted or unsubstituted heteroaryl substituted or unsubstituted heteroaryl substituted cycloalkenylalkyl group (= B) -Ra, -C (O) O-Ra, -C (O) NRaRb, -S (O) m-Ra, -S (O) m-RaRb, -RaRb, or a group of R3 and R 4, when attached to a common atom, may be joined to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may be l may optionally include at least two heteroatoms selected from 0, NR3 or S;

each occurrence of Ra and Rb may be the same or different and independently be hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C (O) -Rc, -C (O) O-Rc, -C (O ) RcRd, -S (O) m-Rc, -S (O) m-RcRd, -RcRd, -ORc, -SRc, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyls, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, heterosubstituted or unsubstituted, heterosubstituted or unsubstituted heterocyclic group or not replaced;

each occurrence of Rc and Rd may be the same or different and be independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted alkynyl or cycloalkyl substituted or unsubstituted, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, heterosubstituted or unsubstituted, heterosubstituted or unsubstituted, substituted or unsubstituted group not replaced;

each occurrence of B is independently O, S or NR3, ρ and m are independently O, 1 or 2;

A is

<formula> formula see original document page 9 </formula> <formula> formula see original document page 10 </formula> <formula> formula see original document page 11 </formula> <formula> formula see original document page 12 </ formula>

Where:

each of the dotted lines in A independently represents an optional double bond;

R5, R6i R7, R8, R9, R10, R11, R12, R13, and R14 are independently hydrogen, nitro, cyano, formyl, acetyl, halogen, -OR15, -SR15, oxo, thio, unsubstituted or substituted alkyls, or substituted alkenyl. substituted, unsubstituted or substituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl unsubstituted, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR15R16, -C (= B) -R15, -C (O) O-R15, -C (O) NR15R16, -S (O) m-R15, -S (O) mNR15R16, or a protecting group;

R5 and R6 may be joined together to form an optionally substituted 3- to 11-membered saturated or unsaturated bicyclic or monocyclic annulus, which may optionally include at least one selected heteroatoms of O, NR3 or S;

R 9 and R 10 may be joined together to form an optionally substituted 3- to 11-membered saturated or unsaturated bicyclic or monocyclic ring which may optionally include at least one heteroatoms selected from O, NR 3 or S; R 5 and R 9 may be joined together to form a optionally substituted saturated or unsaturated 3- to 11-membered bicyclic or monomer which may optionally include at least one heteroatom selected from), NR3 or S;

R 7 and R 10 may be joined together to form an optionally substituted 3- to 11-membered saturated or unsaturated bicyclic or mono- ring which may optionally include at least one heteroatom selected from), NR 3 or S;

each occurrence of R15 and R16 may be the same or different and are independently hydrogen, nitro, halo, cyano, -OR3, -SR3, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl substituted or unsubstituted, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyls, substituted or unsubstituted cycloalkenylalkyls, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic heteroaryl, substituted or unsubstituted heteroaryl group unsubstituted, C (= B) -R 3, -C (O) O-R 3, -C (O) NR 3 R 4, -S (O) m-R 3, -S (O) m-NR 3 R 4 or R 15 and R 16 when bound to a common atom may be joined together to form an optionally substituted 3- to 7-membered saturated or unsaturated cyclic ring, which may be optionally include at least two heteroatoms selected from 0, NR3 or S where R3 and R4 are as defined above: η is 1, 2, 3, or 4; and

a, b, c, d and e are integers independently selected from 0 to 4, with the proviso that the compound does not have the formula: where R1 and R2 are as defined above.

Preferred is a compound of formula (1) wherein UeC is C.

It is further preferred where YeX are N, and W is C.

It is further preferred where B in the group -C (B) NR 1 R 2 is O.

It is further preferred where R is hydrogen, unsubstituted or substituted alkyls, substituted or unsubstituted aryl.

It is further preferred where R is methyl, phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2- (4-chlorophenyl) phenyl or 5-chloropyridin-2-yl.

It is further preferred where R1 is hydrogen.

It is further preferred where R2 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroarylalkyl group. , or NR3 R4.

It is further preferred where R2 is t-butyl, n-pentyl, cyclopentyl, cycloheyl, adamantan-1-yl, 2-methyladamantan-2-yl, 3-hydroxy adamantan-1-yl, 1,3,3-trimethylbicyclo [ 2.2.1] hepta-2-yl, 1-phenylcyclopropyl, cyclohexylmethyl, phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 2-methoxy phenyl, 4-tert-butylphenyl, 2,4-difluorophenyl benzyl, 2- chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, 2,4-difluorobenzyl, 2,6-difluorobenzyl, 2-bromobenzyl, 4-bromobenzyl, 4-trifluoromethylbenzyl, 1-phenylethyl, 1- methyl-1-phenylethyl, 2-phenylethyl, 1- (2-chlorophenyl) ethyl, 2- (4-fluorophenyl) ethyl, 1-phenylpropyl, 1-ethyl-1-phenylpropyl, 1- (2-chlorophenyl) 1-methylethyl methyl phenylethanate, 2-hydroxy-1-phenylethyl, piperidinyl, morpholinyl, pyridinyl, 1,2,4-triazol-4-yl, 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl.

It is further preferred where R1 and R2 are joined together to form an optionally substituted 3- to 7-membered saturated or unsaturated cyclic ring, which may optionally include at least two O, NR3 or S-selected heteroatoms.

It is further preferred where R 1 and R 2 together with the nitrogen atom to which they are attached are formampiperidin-1-yl or morpholinyl (e.g. morpholin-1-yl).

It is further preferred where R2 is NR3R4; wherein each occurrence of R3 and R4 may be the same or different and be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, heterosubstituted or unsubstituted group or R3 and R4 may be joined together. itself to form an optionally substituted 3- to 7-membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from 0, NR3 or S.

It is further preferred where R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted cycloalkyl.

It is further preferred where R3 is methyl, phenyl or cyclohexyl. It is further preferred where R4 is selected from substituted or unsubstituted aryls, substituted or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyl.

It is further preferred where R 4 is phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4- difluorophenyl, 2-bromophenyl, 3-chloropyridin-2-yl, 5-chloropyridin-2-yl or cyclohexyl.

It is further preferred where R2 is -NR3R4, wherein R3 and R4 are joined together to form an optionally substituted 3 to 7 membered cyclic unsaturated or unsaturated ring, which may optionally include at least two heteroatoms selected from O, NR3 or S.

It is further preferred where R3 and R4 are joined together to form piperidin-1-yl or morphonyl-4-yl.

It is further preferred where A is:

<formula> formula see original document page 16 </formula> <formula> formula see original document page 17 </formula>

Where:

(g)

R5 to R are independently hydrogen or methyl; eR8 is substituted or unsubstituted phenyl.

Additionally preferred is where R 8 is 4-chlorophenyl.

Additionally preferred is where a = b = c = d = e = 1.

More preferably, UeV are C, X and Y are N, W is -C (O) NR 1 R 2.

It is further preferred ρ = 1.

According to one embodiment, trimethyl-bicyclo [2.2.IOheptane and ρ represents unsubstituted phenyl.

According to a preferred embodiment, Y is N, U is C, one is from W, V, and X is N and the remaining two are C, B in the group -C (B) NR1R2 is O, and A, R, R1 , and R 2 are as defined above.

Another configuration is a decannabinoid receptor modulator of formula IA, <formula> formula see original document page 18 </formula>

or an analog thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable ester thereof, tautomer thereof, regioisomer thereof, stereoisomer thereof, enantiomer thereof, diastereomer thereof, polymorph thereof, or pharmaceutically acceptable solvate thereof,

R, R1 and R2 may be the same or different and are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted arylalkyl, substituted heterocyclic group or substituted heteroaryl group or unsubstituted or substituted or unsubstituted heteroarylalkyl or R 1 and R 2 may be joined together to form an optionally substituted 3- to 7-membered saturated or unsaturated cyclic ring which may optionally include at least two O, NR 3 or S or NR 3 R 4 heteroatoms;

each occurrence of R3 and R4 may be the same or different and are independently hydrogen, unsubstituted or substituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclic group or R3 and R4 may be joined together to form an optionally substituted 3- to 7-membered or unsubstituted cyclic ring which may optionally

where include at least two heteroatoms selected from NR3 or S;

ρ is 1; and

A is

<formula> formula see original document page 19 </formula> where:

each of the dotted lines in A is independently an optional double bond, and each occurrence of R 5 R 6, R 7, R 8, R 9, R 10, R 11, R 12 / R 13 and R 14 is the same or different and selected from hydrogen, substituted or unsubstituted alkyl or aryl substituted or substituted. not replaced;

with the exception that the modulator does not have the formula:

<formula> formula see original document page 18 </formula>

where R1 and R2 are as defined above.

According to one embodiment, when A is 1,7,7-trimethyl-bicyclo [2.2.1] heptane and ρ is 1, then R does not represent unsubstituted phenyl.

According to a preferred embodiment, R is aryl substituted or unsubstituted.

It is further preferred where R is halogen substituted aryl, substituted or unsubstituted alkyl, unsubstituted or substituted alkoxy or unsubstituted substituted aryl.

It is further preferred where R is 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-methylphenyl, 4-methoxyphenyl or 2- (4). -chlorophenyl) phenyl.

It is further preferred where R is 2,4-dichlorophenyl or 2,4-difluorophenyl.

Another preferred embodiment is a cannabinoid receptor modulator of Formula 1 (a) to 1 (g). <formula> formula see original document page 21 </formula> <formula> formula see original document page 22 </formula>

above and R in

where R, R 1, R 2 and R 8 are as defined formula 1 (c) is unsubstituted phenyl.

According to a preferred embodiment, R is a grouped phenyl substituted with at least one halogen atom.

More preferably, R is a common substituted phenyl group or two halogen atoms (e.g., 2,4-difluorophenyl or 2,4-dichlorophenyl).

Still another embodiment is a selective CB2 agonist (ie, a CB2 agonist that does not substantially inhibit or activate the CB1 receptor) having the formula:

<formula> formula see original document page 22 </formula>

where R, R1, and R2 are as defined above. R is preferably a substituted or unsubstituted aryl, more preferably substituted or unsubstituted phenyl, and even more preferably a substituted phenyl. Even more desirably, R is a grouped phenyl substituted with one or two halogen atoms (e.g., 2,4-difluorophenyl or 2,4-dichlorophenyl). These compounds are particularly useful in the treatment of CB2 receptor agonizing mediated disorders including, but not limited to, ophthalmic disorders, respiratory disorders, immune disorders (such as autoimmune disorders), inflammation, pain (such as neuropathic pain) and neurodegenerative related syndromes.

Accordingly, the present invention also includes methods for treating any of these disorders in a subject requiring the same by administering a therapeutically effective amount of one or more compounds of formula 1 (b).

Representative compounds of the present invention listed below are illustrative in nature and do not limit the scope of the invention.

101. N (7) -Piperidine-5- (2-bromophenyl) -5,6-diazatetracyclo [7.3.1.13,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

102. N (7) -Benzyl-5- (2-bromophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

103. N (7) -Morphino-5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

104. N (7) - (3-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

105. N (7) - (4-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

106. N (7) -Cyclohexyl-5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

107. N (7) - (N-cyclohexyl-N-methylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

108. N (7) -Cyclohexylmethyl-5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.11311-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, 109. N (7) - (Adamantan-1-yl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide,

110. N (7) - (IS, 2endo-1,3,3-Trimethyl-bicyclo [2.2.1] hepta-2-yl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13 '11. O4 '] tetradeca-4 (8) -6-diene-7-carboxamide,

111. N (7) - (2-Chlorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

112. N (7) - (4-Chlorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide,

113. N (7) - (4-Fluorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. 0 '] tetradeca-4 (8) -6-diene-7-carboxamide,

114. N (7) - (2,4-Difluorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

115. N (7) - (2,6-Difluorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7 -carboxamide,

116. N (7) - (4-Trifluoromethylbenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

117. N (7) - (I-Phenylethyl)) - 5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

118. N (7) - (R 1 -Phenylethyl)) - 5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11.O4,8] tetradeca-4 (8), 6-diene-7 -carboxamide,

119. N (7) - (1-Methyl-1-phenylethyl)) - 5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

120. N (7) - (2-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13ill-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide , 121. N (7) - (N'-phenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13ill-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

122. N (7) - (N'-phenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13-11O4'8] tetradeca-4 (8), 6-diene-7 hydrochloride -carboxamide,

123. N (7) - (2-Chlorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

124. N (7) - (2-Chlorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo hydrochloride [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

125. N (7) - [(4-chlorophenyl) amino)] - 5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

126. N (7) - (2,4-Dichlorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

127. N (7) - [(2,4-Dichlorophenyl-N'-methylamino] -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8) , 6-diene-7-carboxamide,

128. N (7) - [(2,4-Dichlorophenyl-N'-methylamino] -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 hydrochloride (8), 6-diene-7-carboxamide,

129. N (7) - (2,4-Dichlorophenyl-N'-cyclohexylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

130. N (7) - (4-Fluorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide ,

131. N (7) - (4-Fluorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7 hydrochloride -carboxamide,

132. N (7) - (2,4-Difluorophenylamino] -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7 -carboxamide,

133. N (7) - (3-fluorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

134. N (7) - (3-Chloro-2-pyridylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

135. N (7) - (5-Chloro-2-pyridylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

136. N (7) - (2-Phenylethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. 0 '] tetradeca-4 (8) -6-diene-7-carboxamide,

137. N (7) - (N ', N'-Diphenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

138. N7- [1- (2-Chlorophenyl) ethyl] -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

139. N (7) -Benzyl-5- (4'-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4 '] tetradeca-4 (8) -6-diene-7-carboxamide,

140. N (7) -Piperidine-5- (4'-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide,

141. 7- (4'-Chlorophenyl) -6,7-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -5-dien-5-yl-piperidinomethanone,

142. N (7) -Phenyl-5- (4'-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide,

143. N (7) -Piperidine-5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, 144. N (7) - (Adamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.0 '] tetradeca-4 (8) -S-diene-7-carboxamide ,

145. N (7) - (IS, 2endo-1,3,3-Trimethyl-bicyclo [2.2.1] hepta-2-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7 . 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide,

146. N (7) - (S-1-phenylethyl)) - 5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

147. N (7) - (R 1 -phenylethyl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7 -carboxamide,

148. N (7) - (1-Methyl-1-phenylethyl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11.O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

149. N (7) - (2-Chlorobenzyl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

150. N (7) - (2,4-Dichlorophenylamino) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

151. N (7) - [1- (2-Chlorophenyl) ethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

152. N (7) - [(S) -1-Phenylpropyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

153. N7- [1- (2-Chlorophenyl) -1-methylethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.13lll-O4'8] tetradeca-4 (8), 6 -diene-7-carboxamide,

154. Methyl (2R) -2- [7- (2,4-difluorophenyl) -6,7-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 5-dien-5-ylcarboxamido] -2-phenylethanate,

155. Methyl (2S) -2- [7- (2,4-difluorophenyl) -6,7-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 5-dien-5-ylcarboxamido] -2-phenylethanate,

156. N7- (3-Hydroxyiadamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

157. N (7) - (I-Methyl-1-phenylethyl) -5- (4-fluorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene Carboxamide,

158. N (7) - (Adamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide,

158a. N7- (Adamantan-2-yl) -5- (4-fluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

159. N7- (1,3,3-Trimethylbicyclo [2.2.1] hepta-2-yl) -5- (4-fluorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

160. N (7) -Piperidine-5- (4-methylphenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

161. N (7) - (2,4-Dichlorophenylamino) -5- (4-methylphenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7 -carboxamide,

162. N (7) - (2-Chlorobenzyl) -5- (4-methylphenyl) -5,6-diazatetracyclo [7.3.1.13'11.O4'8] tetradeca-4 (8), 6-diene-7- carboxamide,

163. N (7) -Piperidine-5- (4-methoxyphenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

164. N7- (2-Chlorobenzyl) -5- (4-methoxyphenyl) -5,6-diazatetracyclo [7.3.1.13ill-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

165. N (7) - (2,4-Dichlorophenylamino) -5- (4-methoxyphenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

166. N (7) -Piperidine-5 - [(2-chlorophenyl) phenyl] -5,6-diazatetracyclo [7.3.1. 13-14-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

167. N (7) - [(2,4-Dichlorophenyl) amino] -5-phenyl-5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

168. N (7) -Phenyl-5-phenyl-5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide,

169. N (7) -piperidine-5-phenyl-5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide,

170. N (7) -Benzyl-5-phenyl-5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide,

171. N (7) -phenyl-6,7-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -5-dien-5-yl-piperidinomethanone,

172. N (7) - (4-Fluorobenzyl) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7 -carboxamide,

173. N (7) -Phenylamino-5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

174. N (7) - (2-Chlorophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

175. N (7) - (2,4-Dichlorophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

176. N (7) - (2-Bromophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11.O4'8] tetradeca-4 (8), 6-diene- 7-carboxamide,

177. N (7) - (N ', N'-Diphenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

178. N (7) - (2-Phenylethyl) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, 179. N (7) -Benzyl-5- (2 ', 4'-dichlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide,

180. N (7) piperidine-5- (2 ', 4'-dichlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

181. N (7) - (2,4-Dichlorophenylamino) -5- (2-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

182. N (7) -Benzyl-5- (2'-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide,

183. N (7) -cyclohexy-5- (2'-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4 '] tetradeca-4 (8) -6-diene-7-carboxamide,

184. N (7) -piperidine-5- (2'-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4 '] tetradeca-4 (8) -6-diene-7-carboxamide,

185. N7- (2-Chlorobenzyl) -5- (5-chloro-2-pyridyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

186. N (7) -Benzyl-5,6-diazatetracyclo [7. 3,11,11. O4 '] tetradeca-4 (8) -6-diene-7-carboxamide,

187. N (7) piperidino-5,6-diazatetracyclo [7. 3.1.1 '.0'] tetradeca-4 (8) -6-diene-7-carboxamide,

188. 7,7-diazatetracyclo [7. 3,11,11. O4 '] tetradeca-4 (8) -5-dien-5-yl-piperidinomethanone,

189a. N (7) piperidine-6-methyl-5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide,

189b. N (7) piperidine-5-methyl-5,6-diazatetracyclo [7.3.1.13'11. O4 '] tetradeca-4 (8) -6-diene-7-carboxamide,

190a. N (7) - (1-methyl-1-phenylethyl) -6-pentyl-5,6-diazatetracyclo [7. 3,11,11. Q4'8] tetradeca-4,7-diene-7-carboxamide,

190b.N (7) - (1-methyl-1-phenylethyl) -5-pentyl-5,6-diazatetracyclo [7.3.1. 13 ''. O4 '] tetradeca-4 (8) -6-diene-7-carboxamide,

191. N (7) - [(IR) -2-Hydroxy-1-phenylethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 ( 8), 6-diene-7-carboxamide,

192. N (7) - [(IS) -2-Hydroxy-1-phenylethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

201. N (3) -Piperidine-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

202. N (3) -Cyclohexyl-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

203. N (3) -Benzyl-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

204 N (3) -Phenylamino-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

205. N (3) -Piperidine-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

206. N (3) -Cyclohexyl-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

207. N (3) -Benzyl-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

208. N (3) -Phenylamino-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

209. N (3) -Piperidine-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

210. 1- (4-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-yl piperidino methanone,

211. N (3) -Cyclohexyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

212. N (3) -Cyclopentyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

213. N (3) - [(N-Cyclohexyl-N-methyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole-3-one carboxamide,

N (3) -Phenyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (3-Chlorophenyl) - 1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-Chlorophenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (3-Bromophenyl) -1- (4-chlorophenyl) -4,5,6, 7-Tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2-Methoxyphenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4 , 7-methane-indazol-3-carboxamide, N (3) - (4-tert-Butylphenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane indazol-3-carboxamide, N (3) -Benzyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2-Chlorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-Chlorobenzyl) -1 - (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2,4-Dichlorobenzyl) -1- (4-chlorophenyl ) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2-Bromobenzyl) -1- (4-chlorophenyl) -4,5,6 7-tetrahydro-1H-4,7-methane-indazol-3-carb oxamide, N (3) - (4-Bromobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-Fluorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-Trifluoromethylbenzyl) -1 - (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

N (3) -Phenylamino-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

N (3) - [(4-Chlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [ (2,4-Dichlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

N (3) - [(3,4-Dichlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

N (3) - [(2-Fluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

N (3) - [(3-Fluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

N (3) - [(4-Fluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

N (3) - [(2,4-Difluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

N (3) - (N ', N'-Diphenylamino-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Cyclohexyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Cyclohexylmethyl-I- (2,4 -dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (N, N-Dicyclohexylamino) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

N (3) - (4H-1,2,4-triazol-4-yl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole -3-carboxamide,

N (3) - (1,3,3-Trimethylbicyclo [2.2.1] hepta-2-yl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7 -methane-indazol-3-carboxamide,

N (3) - (Adamantan-yl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - Phenyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2,4-Difluorophenyl) -1 - (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

N (3) - (2-Fluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-Fluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2,4- Difluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

N (3) - (2,6-Difluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

N (3) - (2-Chlorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-Chlorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2,4- Dichlorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

N (3) - [S- (1-phenylethyl)] -1- (2,4-dichlorophenyl) -4,5,6,7tetrahydro-1H-4,7-methane-indole-3-carboxamide, N (3) - [R- (1-phenylethyl)] -1- (2,4-dichlorophenyl) -4,5,6,7tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2-phenylethyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [2- ( 4-fluorophenyl) ethyl] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

N (3) -Phenylamino-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(2- Chlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

N (3) - [N- (2-Chlorophenyl) -N-methylamino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole-3 -carboxamide,

N (3) - [(4-Chlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

260. N (3) - [(2,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole-3-one carboxamide,

261. N (3) - [(2,4-dichlorophenyl) -N-methylamino] -1- (2,4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole -3-carboxamide,

262. N (3) - [(3,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole-3-one carboxamide,

263. N (3) - [(2-Bromophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

264. N (3) - [(2-Fluorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

265. N (3) - [(2,4-Difluorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole-3-one carboxamide,

266. N (3) - [(3-Fluorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

267. N (3) - [(3-chloropyridin-2-yl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-25 indazol-3-carboxamide,

268. N (5) -piperidine-3- (2 ', 4'-dichlorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide;

269. N (5) -benzyl-3- (2 ', 4'-dichlorophenyl) -3,4-diazatricyclo [5.2.1.0] deca-2 (6), 4-diene-5-carboxamide,

270. N (3) -Piperidine-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

271. N (3) -Cyclohexyl-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

272. N (3) -Benzyl-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, 273. N (3) -Phenylamino-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1'-4,7-methane-indazol-3-carboxamide,

274. N (3) -Piperidine-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1'-4,7-methane-indazol-3-carboxamide,

275. N (3) -Cyclohexyl-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1'-4,7-methane-indazol-3-carboxamide /

276. N (3) -Benzyl-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

277. N (3) -Phenylamino-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

278. N (3) - [(2-Fluorophenyl) amino] -1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

279. N (3) -Cyclohexyl-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

280. N (3) -Benzyl-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

281. N5- (Adamantan-2-yl) -3- (4-fluorophenyl) -3,4-diazatricyclo [5.2.1.O2'6] deca-2 (6), 4-diene-5-carboxamide,

282. N5- (1-Methyl-1-phenylethyl) -3- (4-fluorophenyl) -3,4-diazatricyclo [5.2.1.O2,6] deca-2 (6), 4-diene-5-carboxamide ,

283. N5- (Adamantan-1-yl) -3- (4-fluorophenyl) -3,4-di azatrazone [5.2.1.O2'6] deca-2 (6), 4-diene-5-one carboxamide,

284. N (3) -Phenylamino-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

285. N (3) -Phenylamino-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

286. N (3) - [(2-Chlorophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

287. N (3) - [(2-bromophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, 288 N (3) - [(2-Fluorophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

289. N (3) -Piperidine-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

290. N (3) -Cyclohexyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, 2 91. N (3) - (Cyclohexylmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

292. N (3) - [S- (I-Phenylethyl)] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide ,

293. N (3) - (R-1-phenylethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

294. N (3) - (1-Methyl-1-phenylethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide ,

295. N5- [1- (2-Chlorophenyl) -1-methylethyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide,

296. N (3) - (1,3,3-Trimethylbicyclo [2.2.1] hepta-2-yl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4 7-methane-indazol-3-carboxamide,

297. N5- (2-Chlorobenzyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide,

298. N5- (4-Chlorobenzyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide,

299. N5- (1-Ethyl-1-phenylpropyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 . 1. O2'6] deca-2 (6), 4-diene-5-carboxamide,

300. N5 - [(IS) -1-Phenylpropyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02,6] deca-2 (6), 4-diene-5-carboxamide ,

301. Methyl (2S) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1.O.2'6] deca-2 (6), 3-dien-3-ylcarboxamido ] -2-phenylethanate,

302. N5 - [(IS) -2-Hydroxy-1-phenylethyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.O.2'6] deca-2 (6), 4-diene-5-carboxamide,

303. N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

304. (4R, 7S) - or (4S, 7R) -N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4, 7-methane-indazol-3-carboxamide,

305. (4S, 7R) or (4R, 7S) -N (3) - (ter-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4.7 -methane-indazol-3-carboxamide,

306. N5-n-Pentyl-3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide,

307. N5- (2,4-Dichlorobenzyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide,

308. N5- (1-phenylcyclopropyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide,

309. N5- (2-Adamantyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide,

310. N5- (2-Methyl-2-adamantyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.O2'6] deca-2 (6), 4-diene-5 -carboxamide,

311. N7- (3-Hydroxyiadamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide,

312. 4- [5- (2,4-Difluorophenyl) -4,5-diazatricyclo [5.2.1.O2'6] deca-2 (6), 3-dien-3-ylcarboxamido] morpholine,

313. N (3) - (ter-Pentyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

314. N (3) -Cyclopropanmethyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

315. N (3) -Cyclobutyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

316. N (3) - (Tetrahydro-2H-4-pyranmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide ,

317. N (3) -Cyclopropyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

318. N (3) - (4-methylpiperazine) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

319. Methyl (2R) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1.0.2,6] deca-2 (6), 3-dien-3-ylcarboxamido] - 2-phenylethanate,

320. N (3) - [(IR) -2-Hydroxy-1-phenylethyl] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole -3-carboxamide,

321. N (3) - (tert-Butyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

322. N (3) - (Tetrahydro-2-furanylmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

323. N (3) - (tert-Butyl) -1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-imido-1-3-carboxamide,

324. N (3) - (tert-Butyl) -1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

325. N (3) - (tert-Butyl) -1- (3,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

326. Methyl (2S) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1.0.2,6] deca-2 (6), 3-dien-3-ylcarboxamido] - 2- (4-fluorophenyl) etanoate,

327. N (3) - (tert-Butyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

328. N (3) - (4-Hydroxyphenyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

329. N (3) - (tert-Butyl) -1- (2-ethoxy, 4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, 330 . N (3) - (2-furylmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

331. N (3) - (2 -1iophenomethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

332. N (3) - [(IS) -2-Hydroxy-1- (4-fluorophenyl) ethyl] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4, 7-methane-indazol-3-carboxamide,

333. Methyl- (2S) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5. 2 .1. THE . 2'6] deca-2 (6), 3-dien-3-ylcarboxamido] -4-methylpentanoate,

334. N (3) - (Adamantan-yl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

335a. N (3) - (tert-butyl) -1- (4-fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

335b. N (3) - (tert-butyl) -2- (4-fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

336a.N (3) - (tert-butyl) -1- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

336b.N (3) - (tert-butyl) -2- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

337. N (3) - (2-hydroxyethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

338. N (3) - (thienylethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

339. N (3) - (Isopropyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

340. N (3) - [(1S) -2-Methoxy-1-phenylethyl] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole -3-carboxamide,

401. N (3) -Phenyl-1- (2,4-dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide ,

402. N (3) - [(2-Fluorophenyl) amino] -1- (2,4-Dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7- methane-indazol-3-carboxamide,

403. N (3) - [(2,4-Difluorophenyl) amino] -1- (2,4-dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4, 7-methane-indazol-3-carboxamide,

404. N (3) - [(3-chloropyridin-2-yl) amino] -1- (2,4-

Dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

405. N (3) - (Adamantan-1-yl) -1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane -indazol-3-carboxamide,

406. N (3) - (1,3,3-Trimethylbicyclo [2.2.1] hepta-2-yl) -1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6 , 7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide,

407. N (3) - (1-Methyl-1-phenylethyl)) -1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4, 7-methane-indazol-3-carboxamide,

408. (4R, 7S) -N (3) -ter-Butyl-1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methane-indazole -3-carboxamide,

409. Methyl (2R) -2- [1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-one carboxamido] -2-phenylethanate,

410. N (3) - [(IR) -2-Hydroxy-1-phenylethyl] -1- (2,4-difluorophenyl) -7,8,8-trimethyl) -4,5,6,7-tetrahydro- 1H-4,7-methane-indazol-3-carboxamide,

411. (4S, 7R) -N (3) -ter-Butyl-1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methane-indazole -3-carboxamide,

412. N (3) -pentyl-1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-β-methane-indazol-3-carboxamide

501. N (12) -Benzyl-10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxamide,

502. N (12) -Piperidine-10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxamide,

503. N (12) -Piperidine-10- (2,4-dichlorophenyl) -10,11-diazatetracyclo hydrochloride [6. 5 2 . O2'7. O9'13] pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxamide, 504. N (12) - [(N'-Cyclohexyl-N'-methyl) amino] -10- (2,4-dichlorophenyl) -10,11-

diazatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxamide,

505. N (12) - {N '- [(2,4-Dichlorophenyl) -N'-methyl] amino} -10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxamide,

506. N (12) - (Adamantan-yl) -10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxamide,

507. N12- (1,3,3-Trimethylbicyclo [2.2.1] hepta-2-yl) -10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2 (7), 3,5,9 (13), 11-pentaene-12-carboxamide,

508. N12- (1-Methyl-1-phenylethyl) -10- (2,4, dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7. Pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxamide,

509. N12- (1-Methyl-1-phenylethyl) -10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxamide,

601. N (12) -Benzyl-16- (4-chlorophenyl) -10- (2,4-dichlorophenyl) -15,17-dioxo-10,11,16-triazapentacyclo [6.5.5. O2'7. O9'13. O14'18] octadeca-2,4,6,9 (13), 11-pentaene-12-carboxamide,

602. N (12) -Piperidine-16- (4-chlorophenyl) -10- (2,4-dichlorophenyl) -15,17-dioxo-10,11,16-triazapentacyclo [6.5.5. O2'7. O9'13. O14'18] octadeca-2,4,6,9 (13), 11-pentaene-12-carboxamide,

701. N12-Benzyl-10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6.5.1. O2.7. O9'13] tetradeca-2,4,6,9 (13), 11-pentaeno-12-carboxamide,

702. N (12) -ter-Butyl-10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6. 5 .1. O2'7. O9'13] tetradeca-2,4,6,9 (13), 11-pentaene-12-carboxamide, 701. Ν12- (I-Methyl-1-phenylethyl) -10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6. 5 .1. O2'7. O9'13] tetradeca-2,4,6,9 (13), 11-pentaeno-12-carboxamide, 801. N5- (tert-Butyl) -3- (2,4-difluorophenyl) -3,4-

diazatricyclo [5.2.2. O2.6] undeca-2 (6), 4-diene-5-carboxamide,

8 02. N (5) - (ter-Pentyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.2.O2'6] undeca-2 (6), 4-diene-5 -carboxamide.

<table> table see original document page 143 </column> </row> <table>] <table> table see original document page 44 </column> </row> <table>] <table> table see original document page 45 </column> </row> <table>] <table> table see original document page 46 </column> </row> <table>] <table> table see original document page 47 </column> </ row > <table>] <table> table see original document page 48 </column> </row> <table>] <table> table see original document page 49 </column> </row> <table>] <table> table see original document page 50 </column> </row> <table>]

Table (Ib)

<table> table see original document page 50 </column> </row> <table>] <table> table see original document page 51 </column> </row> <table>] <table> table see original document page 52 </column> </row> <table>] <table> table see original document page 53 </column> </row> <table>] <table> table see original document page 54 </column> </ row > <table>] <table> table see original document page 55 </column> </row> <table>] <table> table see original document page 56 </column> </row> <table>] <table> table see original document page 57 </column> </row> <table>] <table> table see original document page 58 </column> </row> <table>] <table> table see original document page 59 </ column> </row> <table>] <table> table see original document page 60 </column> </row> <table>] <table> table see original document page 61 </column> </row> <table >] <table> table see original document page 62 </column> </row> <table>] Table Ic

<table> table see original document page 63 </column> </row> <table>] <table> table see original document page 64 </column> </row> <table>] <table> table see original document page 65 </column> </row> <table>] Table (If)

<table> table see original document page 66 </column> </row> <table>]

Table (Ig)

Another embodiment of the invention is a pharmaceutical composition comprising at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). <table> table see original document page 66 </column> </row> <table>] Preferably the pharmaceutical composition comprises an effective amount (s) of the present invention.

Still another invention is a method for preventing, ameliorating a cannabinoid receptor mediated disease, disorder or syndrome (such as a CB1 or CB2 receptor interaction mediated disease, disorder or syndrome) in a subject needing to understand administering therapeutically effective amount to the subject. of a compound of the present invention.

Such conditions include, but are not limited to, appetite disorders, metabolism disorders, catabolism disorders, diabetes, obesity, ophthalmic disorders, social-related disorders, mood disorders, seizures, substance abuse, learning disorders, cognition, memory disorders, organ contraction, spasmomuscular, respiratory disorders, disorders and diseases, disorders of locomotor activity, movement disorders, immune disorders (such as autoimmune disorders), inflammation, cell growth, pain-related and neurodegenerative syndromes.

A preferred condition is pain, ophthalmic disorders, respiratory disorders, immune disorders (such as autoimmune disorders), inflammation, cell growth, and neurodegenerative related syndromes.

Still another embodiment is a method for preventing, ameliorating, or treating an appetite disorder, social disorder, autoimmune syndrome, disorder or disorder related to inflammation, or neurodegenerative pain, or substance abuse, in a subject subject thereto by administering to the subject. a therapeutically effective amount of a compound of the present invention.

Still another invention is a method for preventing, ameliorating an appetite-related disease, disorder or syndrome such as obesity, an overweight condition, anorexia, bulimia, cachexia, dysregulated appetite, an obesity-related syndrome, disorder, disease or symptom (including , but not limited to, obesity as a result of genetics, diet, intake volume, syndrome, metabolic disorder or disease, hypothalmic disorder or disease, age, abnormally high fat distribution, abnormal deadening compartment distribution, a compulsive eating disorder, or a motivational disorder that includes the desire to consume sugars, carbohydrates, alcohols, or drugs or any ingredient of reduced hedonic value and / or activity) in a subject needing to administer to the subject a therapeutically effective amount of a compound of the present invention.

Still another embodiment is a method for preventing, ameliorating, or treating a socially related disease, disorder or syndromes, including, but not limited to, depression and its types, bipolar depression, unipolar depression, ourecurrent single major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features or early postpartum, seasonal affective disorder, early or late onset dysthymic disorders with or without atypical features, neurotic depression and social phobia, dementia accompanying depression, anxiety, psychosis, social affective disorders, and / or disorders cognitive, in a subject requiring the same by administering to the subject a therapeutically effective amount of a compound of the present invention.

Still another embodiment is a method for preventing, ameliorating, or treating an autoimmune disease, disorder, or syndrome related to, but not limited to, psoriasis, lupus erythematosus, connective endowed diseases, Sjogren's syndrome, spodylarthritis, rheumatoid arthritis, arthritis. reaction, undifferentiated spondyloarthritis, Behcet's disease, autoimmune hemolytic anemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloses, graft rejection or diseases affecting the plasma cell line, allergic diseases (such as delayed or immediate hypersensitivity, allergic rhinitis, dermatitis contact or parasitic infectious allergic conjunctivitis), viral or bacterial diseases (such as AIDS and meningitis), inflammatory diseases (such as but not limited to joint disease, arthritis, arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel disease (IBD) irritable bowel disease (IBS)) and osteoporosis in a subject needing the same by administering to the subject a therapeutically effective amount of a compound of the present invention.

Still another invention is a method for preventing, ameliorating pain or a neurodegenerative-related syndrome, disorder or disorder, including, but not limited to, central and peripheral trajectory mediated pain, bone and joint pain, pain associated with migraine headache, pain cancer, dental pain, menstrual cramps, labor pain, chronic inflammatory pain, allergy associated pain, arthritis, dermatitis or immunodeficiency, chronic dorneuropathic (including pain associated with diabetic neuropathy, sciatica, nonspecific low back pain, fibromyalgia, and related neuropathy post herpetic neuralgia, trigeminal neuralgia, resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions, Hodgkin's disease, severe myangia, nephrotic syndrome, scleroderma etiroiditis, in a subject requiring the same by administering therapeutically effective amount to the subject. of a compound of the present invention Vention

Still another method is a method for preventing, ameliorating, a substance-related syndrome, disorder or disease such as, but not limited to, drug abuse and drug suppression in which, for example, the substance of abuse or dependence is alcohol, amphetamines, amphetamine-like substances, caffeine, marijuana, cocaine, hallucinogens, inhalants, opioids, nicotine (and / or tobacco products), abuse of heroin, barbiturates, phencyclidine (or compostimilar to phencyclidine), sedative-hypnotics, benzodiazepines, or combinations of substance abuse, in a subject needing the same by administering to the subject a therapeutically effective amount of a compound of the present invention.

Still another embodiment is a method for reducing smoking anxiety in a subject requiring same by administering to the subject a therapeutically effective amount of a compound of the present invention.

Still another embodiment is a method for treating addiction, addiction, nicotine suppression or assisting in trimming or reducing the use of smoke in a subject requiring the same by administering to the subject a therapeutically effective amount of a compound of the present invention.

Still another embodiment is a method for preparing a compound of formula (1), where Y is N, U is C, one of W, V, eX is N and the remaining two are C, B is O, and A, R, R1 , R2 and r are as defined above. The method includes the step of coupling an amine of the formula HNR1R2 with a compound of the formula:

<formula> formula see original document page 70 </formula> where L2 is a leaving group to form the compound of formula (1).

Still another embodiment is a method for preparing a compound of formula (1), wherein WeY are N, U7 V, and X are C, B is O, and A, R, R1, R2 and ρ are as defined above. The method includes the steps of:

(a) oxidize a compound of formula K.

<formula> formula see original document page 71 </formula>

to produce a compound of formula B:

B

(b) subjecting the compound of formula B to reductive amination to form the vicinal diamine of formula C:

<formula> formula see original document page 71 </formula>

(c) monoacylating the vicinal diamine of formula C to form a mono N-acyl diamine of formula D:

<formula> formula see original document page 71 </formula>

where pg is a protecting group.

(d) subjecting the compound of formula D to cyclization to form a compound of formula E: (e) dehydrogenating the compound of formula E to form a compound of formula F:

<formula> formula see original document page 72 </formula>

(f) deriving the compound of form F to form compound G1, compound G2, or a mixture thereof:

<formula> formula see original document page 72 </formula>

(g) hydrolyzing compound G1, compound G2, or both to form compound H1, compound H2, or both:

<formula> formula see original document page 72 </formula>

(h) coupling an amine of the formula HNR1R2 with a compound H1, compound H2, or both to form the compound of formula (1).

Still another embodiment is a method for preparing a compound of formula (1), wherein XeY are N, U, V, and W are C, B is 0, and A, R, R1, R2 and ρ are as defined above. The method includes the steps of: (a) deprotonating a compound of formula K:

followed by acylation to produce a compound of formula L:

<formula> formula see original document page 73 </formula>

(b) reacting the compound of formula L with a hydrazinating formula RNHNH2 to form compound M, compound N, or both:

(c) hydrolyzing and coupling compound M, compound N, or both with an amine of formula HNR 1 R 2 to form the compound of formula (1).

Still another embodiment is a method for preparing a compound of formula (1), where VeY are N, U, W, and X are C, B is O, ρ is 0 or I7 and A, R7 R1 and R2 are as defined above. The method includes the steps of:

(a) convert a compound of formula O: to a compound of formula P:

<formula> formula see original document page 74 </formula>

(b) couple compound P with an amine of formula Q:

(c) deprotecting the compound of formula R followed by condensation to form a compound of formula S:

<formula> formula see original document page 74 </formula>

(d) hydrolyze and couple the compound of formula S with an amine of formula HNR 1 R 2 to form the compound of formula

Brief Description of the Drawings

Figure 1 is a bar graph of the mean percent reversal of neuropathic hyperalgesia (± SEM) as measured by the Seltzer model (protocol V) 0.5 and 1 hour after vehicle dosing, 100 mg / kg gabapentin, or 0.01, 0.1, 0.3, or 1 mg / kg of the compound of Example 2 94.

Figure 2 is a bar graph of the mean percent reversal of neuropathic hyperalgia (± SEM) as measured to form a compound of formula R:

<formula> formula see original document page 74 </formula> chronic restriction injury to sciatic nerve model (protocol VI) 0.5 and 1 hour after vehicle dosing, gabapentin 100 mg / kg, or 0.1 mg / kg of the compound of Example 294.

Figure 3 is a bar graph of the mean maximum possible percenteanalgesia (MPE) percentage (± SEM) as measured by the Tail-Flick method (protocol VII) 1, 3, 6, 12, and 18 hours after vehicle dosing, 3 mg. / kg (ip) WIN55212-2, or 0.3, 1, or 3 mg / kg (ip) of the compound of

Example 294.

Detailed Description of the Invention

The term "aryl" refers to aromatic radicals having 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.

The term "arylalkyl" refers to an above-defined aryl group attached directly to an above-defined alkyl group eg -CH 2 C 6 H 5 and -C 2 H 5 C 6 H 5.

The term "heterocyclic ring" refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For the purposes of this invention, the ring radical may be a monocyclic, bicyclic or tricyclic system which may include fused, bridged or spiro ring systems, and nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized. for various oxidation states.

In addition, the nitrogen atoms may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e. heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include, but are not limited to: azetidinyl, acridinyl, benzodioxolyl, benzofuranyl, carbazolyl, cinolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, phthalazinyl quinoxalinyl, quinolinyl, isoquinylinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl pyrrolidyl, pyrimidinyl, pyrimidinyl, pyridylazole oxasolidinyl, triazolyl, indanyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolinidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahidroindolyl benzoyldiazolyl, octahidroindolyl benzoyl benzoo xazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, detiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanil, and isochromanil. The heterocyclic forward radical may be attached to the backbone on any heteroatom or carbon atom that results in the creation of a stable backbone.

The term "heteroaryl" refers to an aromatic heterocyclic ring heteroaryl radical. The heteroaryl ring radical may be attached to the backbone on any heteroatom or carbon atom that results in the creation of a stable backbone.

The term "heteroarylalkyl" refers to a heteroaryl forward moiety attached directly to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom that results in the creation of a stable structure.

The term "heterocyclyl" refers to a heterocyclic ring radical as defined above. The heterocyclic ring radical may be attached to the backbone to any heteroatom or carbon atom that results in the creation of a stable backbone.

The term "heterocyclylalkyl" refers to a heterocyclic forward radical attached directly to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom that results in the creation of a stable structure.

The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a simple bond, e.g. e.g. methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).

The term "alkenyl" refers to an aliphatic hydrocarbon group containing a double carbon carbon bond and which may have a straight or branched chain having 2 to about 10 carbon atoms, e.g. ethenyl, 1-propenyl, 2 -propienyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

The term "alkynyl" refers to a straight or branched hydrocarbyl radical having at least one carbon-carbon triple bond and having from 2 to about 12 carbon atoms (with radicals having from 2 to about 10 carbon atoms being preferred), e.g., ethinyl, propynyl, and butynyl.

The term "alkoxy" denotes an alkyl group attached via an oxygen bond to the rest of the molecule. Representative examples of such groups are -OCH3 and -OCH5.

The term "cycloalkyl" denotes a nonaromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronaphthyl, adamantyl enorbonyl groups, bridged cyclic groups or spirobutyl groups, e.g., spiro (4,4) non-2-yl.

The term "cycloalkylalkyl" refers to a cyclic ring containing radical having from 3 to about 8 carbon atoms directly attached to an alkyl group. The group cycloalkyl may be attached to the backbone at any carbon atom in the alkyl group resulting in the creation of a stable backbone. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

The term "cycloalkylaryl" refers to a cyclic ring containing radical having from 3 to about 8 carbon atoms, attached directly to any aryl group.

Non-limiting examples of such groups include phenylcyclopropyl, phenylcyclobutyl and phenylcyclopentyl.

The term "cycloalkenyl" refers to a cyclic ring containing radical having from 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.

Unless otherwise specified, the term "substituted" as used herein refers to the substitution with any or any of the following substituents: hydroxy, halogen, carboxy, cyano, nitro, oxo (= 0), thio (= S), alkyl substituted or unsubstituted, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyls, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aminoalkyl, aryl substituted or unsubstituted, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substantially guanidines, -COORx, -C (O) Rx, -C (S) Rx, -C (O) NRxRy, -C (O) ONRxRy, -NRxCONRyRz, -N (Rx) SORy, - (= NN (Rx) R y), NRxC (O) ORy, -NRxRy, -NRxC (O) Ry, -NRxC (S) Ry, -NRxC (S) RyR2, -SONRxRy, -SO2NRxRy, -ORx, -ORxC (O) NRyRz, - ORxC (O) ORy, OC (O) Rx, -OC (O) NRxRy, -RxNRyC (O) Rz, -RxORy, -RC (O) ORy, -RxC (O) NRyRz, -RxC (O) Ry, -RxOC (O) Ry, -SRx, -SORx, -SO2Rx, and -ONO2, where Rx, Ry and Rz are independently selected from hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxy, substituted alkynyls, substituted alkynyls substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aminos, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring. According to one embodiment, the substituents on the "substituted" groups mentioned above cannot be further substituted. For example, when the substituent or "alkyl substituted" is "substituted with aryl" the substituent on the "substituted with aryl" may not be "substituted with alkenyl".

The term "protecting group" or PG refers to a substituent that is employed to block or protect a particular functionality. Other functional groups in the compound may remain active. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects amino acid functionality in the compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonylFmoc). Similarly, a "hydroxy protecting group" refers to a substituent on a blocked hydroxy group that protects hydroxy functionality. Suitable dehydroxy protecting groups include, but are not limited to, acetyl and silyl. A "carboxy protecting group" refers to a carboxy group substituent that blocks or protects carboxy functionality. Suitable decarboxy protecting groups include, but are not limited to, CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (ρ-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfenyl) ethyl, 2- (diphenylphosphino) ethyl, and nitroethyl. For an overview of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

The term "cannabinoid receptor" refers to any of the hitherto known or unknown subtypes of the cannabinoid receptor class, including CB1 and / or CB2 receptors, which may be linked by a cannabinoid modulator compound of the present invention.

The term "modulator" further refers to the use of a compound of the invention as a CB receptor agonist (e.g. CB1 and / or CB2), partial agonist, antagonist or inverse antagonist.

The term "treating" or "treating" a condition, disorder or condition includes:

(1) prevent or delay the onset of clinical symptoms of the condition, disorder or condition by developing in a subject who may be plagued with or predisposed to the condition, disorder or condition, but does not yet experience or exhibit clinical or subclinical symptoms of the condition, disorder or condition.

(2) inhibit the condition, disorder or condition, i.e., or reduce the development of a disease or the clinical or subclinical menosymphoma thereof; or

(3) relieve disease, ie, cause regression of the condition, disorder or condition or at least one of its 30 clinical or subclinical symptoms.

The benefit to a subject being treated is either statistically significant or at least noticeable to the subject or to the physician.

The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., pets including dogs and cats) and non-domestic animals (such as wild animals). A "therapeutically effective amount" means that amount of a compound which, when administered to a subject to treat a condition, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and response of the subject being treated.

Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and η), organic base salts (such as N, N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, meformine, benzylamine, trialkylamine, and thiamine), chiral base salts (such as alkylphenylamine, glycinol and phenylglycol), natural amino acid salts (such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine), unnatural amino acid salts (such as substituted D-isomers or amino acids), guanidine salts, substituted guanidine salts (where substituents are selected from nitro, amino, alkyl, alkenyl, or alkynyl), ammonium salts, substituted ammonium salts, and aluminum salts. Other pharmaceutically acceptable salts include acid addition salts (where appropriate) such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluoroacetate), tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulfonates, benzoates, benzoates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates. Still other pharmaceutically acceptable salts include, but are not limited to, quaternary ammonium salts of the inventive compounds with alkyl halides or alkyl sulfates (such as MeI or (Me) 2SO4).

Pharmaceutically acceptable solvates include hydrates and other crystallization solvents (such as alcohols). The compounds of the present invention may form low standard molecular weight solvent solvates by methods known in the art.

Pharmaceutical Compositions

The pharmaceutical composition of the present invention comprises at least one compound of the present invention and a pharmaceutically acceptable carrier (such as a pharmaceutically acceptable carrier or diluent).

Preferably, the pharmaceutical composition comprises a therapeutically effective amount of the compound (s) of the present invention. The compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or diluent) or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sache, paper or other container.

Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxy ethoxylated castor oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl esters of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acids, ediglyceride monoglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydromethylene epolivinylpyrrolidone cellulose.

The carrier or diluent may include a sustained deliberation material such as glyceryl monostearate or glyceryl distearate alone or mixed with a wax.

The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, osmotic pressure influencing salts, buffers, sweetening agents, flavoring agents, colorants, or any of the foregoing combinations. The pharmaceutical composition of the invention may be formulated to provide rapid, sustained, or delayed release of the active ingredient upon administration to a subject employing methods known in the art.

The pharmaceutical compositions of the present invention may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20th Ed., 2003 (Lippincott Williams & Wilkins). For example, the active compound may be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sache, paper, or other container. When an optor serves as a diluent, it may be a materialsolid, semi-solid, or liquid that acts as a vehicle, excipient, or medium for the active compound. The compound may be adsorbed onto a solid granular container, for example in a sache.

Pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.

The route of administration may be any route that effectively carries the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parentereal, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as a topical ointment). The oral route is preferred.

Solid oral formulations include, but are not limited to, tablets, capsules (soft or gelatin), dragees (containing the active ingredient in powder or pellet form), bundles and lozenges. Tablets, dragees, or capsules having talc and / or a carbohydrate or binder carrier or the like are particularly suitable for oral application. Preferred carriers for tablets, pills, or capsules include lactose, corn starch, and / or potato starch. A syrup or elixir may be used in cases where a sweetened vehicle may be nailed.

A typical tablet which may be prepared by any conventional tabletting technique may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mg cellulose microcrystalline (Avicel®), 70 mg modified cellulose gum (Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approx. 9 mg Mywacett 9-40 T and approx. 0.9 mg acylated demonoglyceride.

Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.

Particularly suitable for parenteral application are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

Treatment Methods

The present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment, amelioration, and / or prevention of cannabinoid (CB) receptor-modulated diseases, conditions, and / or disorders, especially those modulated by the CB1 or CB2 receptor, including those discussed below.

The present invention further provides a method for treating a cannabinoid (CB) receptor-modulated disease, condition and / or disorder, and in particular the CB1 or CB2 receptor, in a subject needing to administer to the subject a therapeutically effective amount of a compound or composition. of the present invention.

Diseases, conditions, and / or disorders that are modulated by a CB receptor include, but are not limited to, appetite disorders, metabolism disorders, catabolism disorders, diabetes, obesity, social-related disorders, mood disorders, seizures, substance abuse, learning disorders, cognitive disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders (such as autoimmune disorders), inflammation, cell growth, pain (such as neuropathic pain) and neurodegenerative-related syndromes, disorders and diseases.

Appetite-related syndromes, disorders or diseases include, but are not limited to, obesity, overweight, anorexia, bulimia, cachexia, dysregulated appetite, and the like. Syndromes, disorders or diseases related to obesity include, but are not limited to, obesity as a result of degeneracy, diet, intake volume, metabolic disorder or disorder, hypothalmic disorder or disorder, age, abnormal distribution of adipose mass, abnormal distribution of fat compartment, compulsive eating disorders, motivational disorders that include the desire to consume sugars, carbohydrates, alcohols or drugs or any ingredient with hedonic value and the like. Symptoms associated with syndromes, disorders, and obesity-related illnesses include, but are not limited to, reduced activity.

Metabolism-related syndromes, disorders or diseases include, but are not limited to, metabolic syndrome, dyslipidemia, elevated blood pressure, insulin sensitivity or resistance, hyperinsulinemia, hypercholesterolemia, hyperlipidemias, atherosclerosis, hypertriglyceridemia, arteriosclerosis, other cardiovascular diseases, osteoarthritis, sleep disorders (rhythmocircadian disorders, dyssonia, insomnia, sleep apnea, and apharolepsy), cholelithiasis, hepatomegaly, steatosis, abnormal levels of alanine aminotransferase, polycystic disease, inflammation, and the like.

Diabetes-related syndromes, disorders or diseases include, but are not limited to, glucose dysregulation, insulin resistance, glucose intolerance, hyperinsulinemia, dyslipidemia, hypertension, obesity, hyperglycemia and the like.

Catabolism-related syndromes, disorders or diseases include, but are not limited to, catabolism in connection with pulmonary dysfunction and ventilatory dependence; cardiac dysfunction, eg, associated with valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure.

Ophthalmic diseases include, but are not limited to, glaucoma, intraocular pressure associated with glaucoma, retinitis, retinopathies, uveitis, acute ocular injury (eg conjunctivitis).

Osocial or mood related syndromes, disorders or diseases include, but are not limited to, depression (including, but not limited to, bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical or postpartum onset, seasonal affective disorder, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression and social phobia, dementia accompanying depression, psychosis, social-affective disorders, cognitive disorders and the like).

Substance abuse-related syndromes, disorders or diseases include, but are not limited to, alcohol, amphetamines (or substances similar to amphetamines), caffeine, marijuana, cocaine, halucinogens, opioids, nicotine (and / or tobacco products), heroin abuse , barbiturates, phenicylidine (or compounds similar to phenyclidine), sedative hypnotics, benzodiazepines, or combinations of any of the above. The pharmaceutical compounds and compositions may also be used to treat symptoms of substance-induced suppression and anxiety or tumor disorder.

The present invention further provides a method for treating addiction, addiction, nicotine suppression, or assisting in stopping or decreasing smoking in a subject requiring the same by administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of the present invention.

Syndromes, disorders or disorders related to learning, cognition or memory that may be treated with the compounds of the present invention include, but are not limited to, memory loss or impairment as a result of age, disease, side effects of medications (adverse events) or the like. . Decreased memory is a primary symptom of dementia and may also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovascular disease, and trauma. cognitive decline related to age. Dementias are usually diseases that include memory loss and additional intellectual impairment separated from memory. The compounds and pharmaceutical compositions of the present invention are also useful for treating attention deficit-related cognitive impairment, such as attention deficit disorder.

Muscle spasm syndromes, disorders or diseases include, but are not limited to, multiple sclerosis, cerebral palsy, and the like.

Syndromes, disorders, or disorders of motor activity and movement include, but are not limited to, stroke, Parkinson's disease, multiple sclerosis, epilepsy, and the like.

Respiratory-related syndromes, disorders or diseases include, but are not limited to, respiratory tract diseases, obstructive chronic obstructive pulmonary disorder, emphysema, asthma, bronchitis, and the like.

Kidney dysfunction nephritis that can be treated with the modulators of the present invention includes, but is not limited to, mesangial proliferative glomerulonephritis, nephritic syndrome, liver dysfunction (hepatitis, cirrhosis).

Syndromes, disorders or disorders related to autoimmune or inflammation include, but are not limited to, psoriasis, lupus erythematosus, connective tissue diseases, Sjogren's syndrome, spondyloarthritis, rheumatoid arthritis, reaction arthritis, undifferentiated spondyloarthritis, autohemiasis, immune, multiple sclerosis, amyotropic lateral sclerosis, amyloidosis, graft rejection or diseases affecting the plasma cell line; allergic diseases: delayed or immediate hypersensitivity, allergic rhinitis, contact dermatitis or parasitic infectious allergic conjunctivitis, viral or bacterial diseases (such as AIDS and meningitis), inflammatory diseases (such as but not limited to joint arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS)) and osteoporosis.

Cell growth related syndromes, disorders or diseases include, but are not limited to, unregulated mammalian cell proliferation, breast cancer cell proliferation, prostate cancer cell proliferation and the like.

Wrist-related syndromes, disorders or diseases include, but are not limited to, central and peripheral pathway-mediated pain, bone and joint pain, pain associated with migraine headache, cancer pain, dental pain, menstrual cramps, childbirth, inflammatory-type pain, allergies, arthritis, arthritis, dermatitis, immunodeficiency, chronic neuropathic pain (eg pain associated with diabetic neuropathy, sciatica, nonspecific low back pain, fibromyalgia, HIV-related neuropathy; postherpetic neuralgia, neuralgia triplets, and pain resulting from trauma, amputation, cancer, toxins, or chronic inflammatory conditions), Hodgkin's disease, myasthenia gravis, nephrotic syndrome, scleroderma, and similar thyroiditis.

Syndromes, disorders or diseases related to neurodegenerative diseases include, but are not limited to, Parkinson's disease, multiple sclerosis, epilepsy, ischemia or secondary biochemical collateral injury or traumatic brain injury, brain inflammation, eye injury or stroke and the like.

The compounds of this invention may also be used in conjunction with other pharmaceutical agents for treating the diseases, conditions and / or disorders described herein. Therefore, treatment methods which include administering compounds of the present invention in combination with other pharmaceutical agents are also provided. Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention include, but are not limited to, anti-obesity agents such as polypoprotein-B secretion inhibitors / microsomal detrigliceride transfer protein (apo-B / MTP), steroidal 11β-hydroxy inhibitors dehydrogenase-1 (Ιΐβ-HSD type 1), peptide YY3-36 or analogs thereof, MCR-4 agonists, cholecystokinin A (CCK-A) agonists, monoamine uptake inhibitors (such as sibutramine), agonist sympathomimetics, β3 adrenergic receptors, dopamine receptor agonists (such as comobromocriptine), melanocyte stimulating hormone receptor analogues, 5HT2C receptor agonists / demelanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin receptor agonists, antagonists , lipase inhibitors (such as tetrahydrolipstatin, ie Orlistat), drugs (such as bombesin agonist), neuropeptide Y receptor antagonists, agentstyromimetics, dehydroepiandrosterone or a damesma analog, deglucocorticoid receptor agonists or antagonists, orexin receptor antagonists, peptide-1 receptor agonists such as glucagon (GLP-1) ), Protein Tyrosine Phosphatase (PTP-IB) inhibitors, dipetidyl peptidase IV (DPP-IV) inhibitors, ciliary neurotrophic factors (such as Axokine® available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Process & Gamble Company, Cincinnati, Ohio) , human agouti-related protein (AGRP) inhibitors, ghrelin receptor antagonists, inverted histamine receptor antagonists or antagonists, and neuromedine U receptor antagonists. Other antiobesity agents, including the preferred agents listed below, are well known, or will be apparent to you. in the light of this disclosure, any ordinary experience in the technique.

Especially preferred are anti-obesity agents such as Orlistat, sibutramine, bromocriptine, ephedrine, leptin, peptide YY3.36 or an analog thereof (including the complete YY peptide), and pesudoephedrine.

Preferably, the compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensitive diet.

Antiobesity agents for use in the combinations, pharmaceutical compositions, and methods of the invention may be prepared using methods known to one of ordinary skill in the art, for example, sibutramine may be prepared as described in U.S. patent. no. 4.92 9.629; bromocriptine may be prepared as described in patents 3,752,814 and 3,752,888; Orlistat may be prepared as described in U.S. Patent Nos. 5,274,143; 5,420,305, 5,540,917, and 5,643, 874; and PYY 3-36 (including analogs) may be prepared as described in U.S. Patent Publication no. 2002/0141985 International Publication No. WO 03/027637. All references cited above are incorporated herein by reference.

Other suitable pharmaceutical agents that may be administered in combination with the compounds of the present invention include agents designed to treat smoking abuse (e.g., denicotin receptor partial agonists, debupropion (also known as the Zyban®) hypochloride substitution therapies) and nicotine), agents for treating erectile dysfunction (eg dopaminergic agents such as apomorphine), ADD / ADHD agents (eg Ritalin® (methylphenid hypochloride), Strattera® (atomoxetine hypochloride), Concerta® ( methylphenidate) and Adderall® (amphetamine aspartate; deanfetamine sulfate; dextroamphetamine saccharate; and dextroamphetamine sulfate)), and agents for treating alcoholism, such as opioid antagonists (eg maltrexone (also known under the trade name ReVia® ) enalmefene), disulfiram (also known under the tradename Antabuse®), and acamprosate (also known under the trade name Campral®)). In addition, agents for reducing alcohol suppression symptoms may also be co-administered, such as benzodiazepines, beta blockers, clonidine, carbamazepine, pregabalin, egabapentin (Neurontin®). Treatment for alcoholism is preferably administered in combination with behavioral therapy including such components as motivational reinforcement therapy, cognitive behavioral therapy, referral to self-help groups, including Alcoholics Anonymous (AA).

Other pharmaceutical agents which may be useful include antihypertensive agents; antidepressants (eg fluoxetine hypochloride (Prozac®)); enhancers of cognition (e.g., donepezil hypochloride (Aircept®) and other acetylcholinesterase inhibitors); neuroprotective agents (e.g., memantine); antipsychotic medications (eg ziprasidone (Geodon®), risperidone (Risperdal®), and olanzapine (Zyprexa®)); insulin and insulin analogs (e.g., LysPro insulin); GLP-I (7-37) (insulinotropin) and GLP-I (7-36) -NH2; sulfonylureas and analogs thereof; chloropropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, Glipizida®, glimepiride, repaglinide, meglitinide; biguanides: metformin, phenformin, buformin; Î ± 2 -imidazoline antagonists: midaglizole, isaglidol, deriglidol, idazoxane, fluparoxane; other insulin secretagogues: linoglyride, A-4166; glitazones: ciglitazone, Actos® (pioglitazone), englitazone, troglitazone, darglitazone, Avandia® (BRL 4,9653); fatty acid oxidation inhibitors: clomoxir, etomoxir; α-glucosidase inhibitors: acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945; β-agonists: BRL 35135, BRL37344, RO 16-8714, ICI D7114, CL 316.243; dephosphodiesterase inhibitors: L-386,398; delipid reducing agents: benfluorex; fenfluramine; vanadate and vanadium complexes (e.g., Naglivan®) and peroxovanadium complexes; amylin antagonists; deglucagon antagonists; gluconeogenesis inhibitors; deomatostatin analogs; antipolytic agents: nicotinic acid, acipimox, WAG 994, pramlinitide (Symlin®), AC 2993, nateglinide, aldose reductase inhibitors (eg, zopolrestat), glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, sodium hydrogen detoxifier inhibitors type 1 (NHEO1) and / or cholesterol biosynthesis inhibitors or cholesterol absorption inhibitors, especially a HMG-CoA reductase inhibitor, or a HMG-CoA synthase inhibitor, or a HMG-COA reductase or synthase gene expression inhibitor, a sequester bile acid, a fibrate, an aCAT inhibitor, a squalene synthetase inhibitor, an anti-oxidant or niacin. The compounds of the present invention may also be administered in common combination naturally occurring compound which acts to lower plasma cholesterol levels. Such naturally occurring compounds are commonly called nutraceuticals and include, for example, garlic extract, Goodia plant extracts, and niacin.

The compounds of the present invention (including the pharmaceutical compositions and processes used therein) may be used alone or in combination with other pharmaceutical agents in the manufacture of a medicament for therapeutic applications described herein.

General Method of Preparation

The compound of formula (1) may be synthesized by the schemes illustrated below.

The compounds of formula (1), where WeY are N; U, V and X are C; B is O; ρ is 0 or 1; and R, R1 and R2 are as described in the general description, can be synthesized as shown in scheme 1. <formula> formula see original document page 94 </formula>

In the above scheme, the compound of formula K may be oxidized (for example with SeO2 (selenium dioxide)) to provide a compound of formula B, which may then be subjected to reductive amination (e.g. under standard conditions (e.g. hydrogenation in the presence of NH 4 OAc, Pd / C)) to obtain the vicinal diamine of formula C. Compound C may be monoacylated (e.g. with an acid chloride of formula pgOCH 2 COCl or an anhydride of formula (pgOCH 2)). CO (where pg is an alcohol protecting group, eg benzyl or methoxymethyl (MOM))) to obtain an N-acyl diamine of formula D. The compound of formula D may be subjected to intramolecular cyclization to provide the compound E. Compound E may be dehydrogenated (e.g. using an oxidizing agent (such as ceric ammonium nitrate or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ))) to produce the compound of formula F. Compound F is converted to compounds Gle / or G2. For example, derivatization of compound F by alkylation, alkylation or arylation would provide the compounds of formula G1 and / or G2 which may be separated. The compound of formula G1 and / or G2 thus obtained may be hydrolyzed to form compound (s) H1 and / or H2.

Compounds H1 and / or H2 may be coupled with an amine (e.g., HNR1R2) to form a compound of formula (1). Suitable amines include, but are not limited to, N, N'-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (EDC) and benzotriazol-1-yloxytronium dimethylammonium hexafluorophosphate (dimethylammonium).

In another embodiment, the compounds of formula (1) where X and Y are N; UeV are C; B is O; ρ is O or 1; R, R1 and R2 are as described in the general description, can be synthesized as shown in scheme 2.

Scheme 2

<formula> formula see original document page 95 </formula>

In the above scheme, the compound of formula K may be deprotonated, e.g., using a base (such as LiHMDS or LDAO, followed by acylation, e.g., using dediethyl oxalate, to obtain the compound of formula L.). L may then be treated with a substituted hydrazine (such as RNHNH2) to obtain the compound (s) of formula M and / or N. The compound (s) of formula M and / or N thus obtained may be hydrolyzed and coupled with an amine (e.g., HNR1R2) to form a compound of formula (1). Suitable amines include, but are not limited to , N, N'-Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide (EDC) hydrochloride and benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate (BOP).

In yet another embodiment, the compounds of formula (1) wherein VeY are nitrogen; U, W and X are carbon; B is oxygen; ρ is O or 1 and R, R1 and R2 are as described in the general description, can be synthesized as shown in scheme 3.

Scheme 3

<formula> formula see original document page 96 </formula>

In the above scheme, compound of formula 0 is converted to a compound of formula Ρ. Compound P is then coupled with an amine of formula Q, for example, thermally or catalysed by reagents such as Hg (OAc) 2, to form a compound of formula R. Compound R is unprotected and condensed to form a compound of formula S. Deprotection and subsequent intramolecular condensation of compound R is preferably performed in the presence of an acid (such as TsOH, MsOH, TfOH or CF 3 COOH). The compound of general formula S may be hydrolyzed and coupled with an amine (e.g., HNR 1 R 2) to form a compound of formula (1). Suitable amines include, but are not limited to, N, N'-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (EDC) and benzotriazol-1-yloxytris (dimethylammonium) hexafluorophosphate (dimethyl) BOP).

It should be understood that the present invention encompasses all isomers of compounds of formula (I) and their pharmaceutically acceptable derivatives, including all geometrical forms, optical tautomeric 10e, and mixtures thereof (e.g., racemic mixtures). Where additional chiral centers are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures of the same. The different isomeric forms may be separated or resolved from one another by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereo-specific or asymmetric syntheses. The present invention also includes isotopically labeled compounds, which are identical to those cited in the following formulas I, except that one or more atoms are substituted by one atom having an atomic mass or a different mass number than the atomic mass usually found in nature. . Examples of isotopes which may be incorporated into the compounds of the invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, 20 and chlorothal isotopes such as 3 H, 11 C, 14 C, 18 F, 123 I and 125 I.

The compounds of the present invention and pharmaceutically acceptable salts of the above-mentioned isotope-containing compounds and / or other isotopes of other atoms are within the scope of the present invention. The isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as 3 H, 14 C are incorporated, are useful in drug and / or substrate tissue distribution assays. Titrates, i.e. 3 H, and carbon-14, i.e. 14 C isotopes, are particularly preferred for their ease of preparation and detection. Isotopes 11C and 8F are particularly useful in PET (positron emission tomography), and 125I isotopes are particularly useful in SPECT (photon emission computed tomography), all useful in brain imaging. In addition, replacement with heavier isotopes such as Deuterium, i.e. 2H, may provide certain therapeutic advantages resulting from increased metabolic stability, for example increased in vivo half-life or reduced dosage requirements and may therefore be preferred in some circumstances. The following isotopically labeled compounds of formula I of this invention may generally be prepared by performing the procedures disclosed in the Schemes and / or Examples below, replacing a readily available isotopically labeled reagent with a non-isotopically labeled reagent.

The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated. This invention includes within its scope stoichiometric hydrates or solvates as well as compounds containing varying amounts of water and / or solvent. Settings of the present invention are illustrated by the following examples. It should be understood, however, that embodiments of the invention are not limited to the specific details of these examples, as other variations thereof will be known, or apparent in light of the present disclosure, to one of ordinary technical experience.

Experimental section

Abbreviations and notations: The following abbreviations and notations were used in the following text. M.p .: melting point. BOP reagent: (Benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate. FC: Flash Chromatography. J: Coupling constants expressed in Hz units. THF: tetrahydrofuran. Et 3 N: triethyl amine. BuLi: butyl lithium. LiHMDS: lithium hexamethyl disilazide.

Intermediate 1

5- (2-Bromophenyl) -5,6-diazatetracyclo acid [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylic

Step 1: Ethyl 2-oxo- (5-oxotricyclo [4. 3.1.1. 3'8] undeca-4-yl) acetate

A 1.6 M solution of n-BuLi in hexane was added to a solution of hexamethyldisilazane (1.27 mL, 5.4 mmol) in diethyl ether (10.0 mL) at -78 ° C and stirred at room temperature for 15 min. To this mixture was added a solution of homoadamantanone [900 mg, 5.4 mmol, prepared according to: Black, R. M. and Gill, G. B., J. Chem. Soc. (C), 1970, 671] in diethyl ether (27.0 ml) and stirring at -78 ° C was continued for an additional 45 min. Dediethyl oxalate (0.98 mL, 6.5 mmol) was added and the mixture was allowed to slowly warm to 25 ° C. After stirring overnight, water (25 ml) was added to the solution and the separated layers. The aqueous layer was washed twice with diethyl ether (20 mL), acidified with 1 N HCl and extracted with diethyl ether (3 x 20 mL), the organic layer was dried over Na 2 SO 4, filtered and evaporated. Flash chromatography (97: 3 petroleum ether / ethyl acetate) afforded the title compound as a yellow oil (589 mg, 36%). 1H-NMR (δ ppm, CDCl3, 300 MHz): 15.75 (s, 1H); 4.33 (q, J = 7.2, 2H); 2.80 (br. T, J = 6. 1H); 2.75-2.70 (m, 1H); 2.13-85 (m, 8H); 1.81-1.69 (m, 4 H); 1.36 (m, t, J = 7.2, 3H). IR (cm -1 pure): 3423 (br), 2982 (w), 2919 (s), 2851 (m), 1741 (s), 1599 (s, br.).

Step 2: Ethyl 5- (2-bromophenyl) -5,6-diazatetracyclo [7.3.1.13-11O4'8] tetradeca-4 (8), 6-diene-7-carboxylate

A solution of intermediate 1 (2.0 g, 7.56 mmol), 2-bromophenylhydrazine hydrochloride (1.86 g, 8.32 mmol) and ethanol (30 mL) was refluxed for 1 h. After cooling, the solid precipitate was collected by filtration and dried to afford the title product in pure form (2.04 g, 65%). 1H-NMR (δ ppm, CDCl3, 300MHz): 7.67 (dd, J = 7.8, 1.2, 1H); 7.42-7.26 (m, 3H); 4.40 (g, J = 7.2, 2H); 3.79 (br. T, J = 5.4, 1H); 2.54 (br. T, J = 7.2, 1H); 2.18 (br. S, 2H); 2.14-1.92 (m, 4H); 1.92-1.60 (m, 6H); 1.39 (t, J = 7.2, 3H).

Step 3: 5- (2-Bromophenyl) -5,6-diazatetracyclic acid [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylic

A solution of Ethyl 5- (2-bromophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylate in ethanol: water (20: 1) was refluxed with KOH (270 mg, 4.82 mmol) for 2 h. After removal of ethanol, the residue was dissolved in water and acidified to pH 4.0 with 1N aqueous HCl. The precipitate was filtered and dried to afford intermediate 1, (715 mg, 77%) was obtained. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.71 (dd, J = 7.8, 1.5, 1H); 7.50-7.32 (m, 3H); 3.79 (br. T, J = 5.1.1H); 2.56 (br. T, J = 5.0, 1H); 2.19 (s, 2H); 2.12 - 1.90 (m, 4H); 1.90-1.66 (m, 6H).

Intermediates 2 to 11 were prepared according to the procedure as described in steps 2 and 3 of intermediate 1 using Ethyl 2-oxo- (5-oxotricyclo [4.3.1.1. 3'8] undeca-4-yl) acetate, phenyl or (unsubstituted) pyridyl hydrazine and alkali.

Intermediate 2

5- (4-chlorophenyl) -5,6-diazatetracyclo acid [7. 3,11,11. O4,8] tetradeca-4 (8), 6-diene-7-carboxylic

Step 1: Ethyl 5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11,04,8] tetradeca-4 (8), 6-diene-7-carboxylate

Yield: 54%. 1 H-NMR (δ ppm, CDCl 3, 300 MHz): 7,43,7.30 (AB, J = 10,4H); 4.40 (q, J = 7.5, 2H); 3.79 (t, J = 5.1, 1H); 3.0 (t, J = 5.4, 1H); 2.21 (br. S, 2H); 2.06-1.77 (m, 10H); 1.40 (t, J = 7.5, 3H). Step 2: 5- (4-Chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11, O4'8] tetradeca-4 (8), 6-diene-7-carboxylic

Yield: 89%. 1H-NMR (δ ppm, DMSO-d6): 7.59 (d, J = 8.7, 2H); 7.39 (d, J = 8.7, 2H); 3.76 (br. S, 1H); 2.97 (br. S, 1H); 2.14 (br. S, 2H); 1.67-1.98 (m, 10H).

Intermediate 3

5- (2,4-Difluorophenyl) -5,6-diazatetracyclo [7.3.1.13ill-O4'8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Step 1: Ethyl 5- (2,4-Difluorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxylate

Yield: 96%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.40 (m, 1H); 7.02-6.90 (m, 2H); 4.38 (q, J = 7.2, 2H); 3.76 (br. S, 1H); 2.66 (br. S, 1H); 2.17 (br s, 2H), 2.05-1.70 (m, 10H), 1.37 (t, J = 7.2, 3H).

Step 2: 5- (2,4-Difluorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Yield: 95%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 12.80 (br. S, 1H); 7.70-7.55 (m, 2H); 7.30 (br. T, J = 7.5.1H); 3.66 (br. S, 1H); 2.63 (br. S, 1H); 2.13 (s, 2H); 2.00-1.71 (m, 10H).

Intermediate 4

5- (4-Fluorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Step 1: Ethyl 5- (4-Fluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11.O4'8] tetradeca-4 (8), 6-diene-7-carboxylate

Yield: 55%. 1H-NMR (δ ppm, CDCl3, 300MHz): 7.38-7.31 (m, 2H); 7.18-7.11 (m, 2H); 4.39 (q, J = 7.5, 2H); 3.78 (br. S, 1H); 2.95 (br. S, 1H); 2.20 (br. S, 2H); 2.06-1.76 (m, 10H); 1.39 (t, J = 7.2, 3H).

Step 2: 5- (4-Fluorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Yield: 81%. 1H-NMR (δ ppm, DMSO-d6, 300 MHz): 12.60 (br. S, 1H); 7.47-7.35 (m, 4H); 3.67 (br. S, 1H); 2.91 (br. S, 1H); 2.14 (br. S, 2H); 1.98-1.71 (m, 10H).

Intermediate 5

5- (4-Methylphenyl) -5,6-diazatetracyclo acid [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylic

Step 1: Ethyl 5- (4-methylphenyl) -5,6-diazatetracyclo [7.3.1.13'11.O4'8] tetradeca-4 (8), 6-diene-7-carboxylate

Yield: 91%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.23 (s, 4H); 4.39 (q, J = 7.2, 2H); 3.79 (br. T, J = 5.7, 1H); 3.00 (br. S, 1H); 2.41 (s, 3H); 2.19 (br. S, 2H); 2.07-1.95 (m, 2H); 1.95-1.73 (m, 8H); 1.40 (t, J = 7.2, 3H).

Step 2: 5- (4-Methylphenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Yield: 99%. 1H-NMR (δ ppm, DMSO-d6, 300 MHz): 12.60 (br. S, 1H); 7.34 (d, J = 8.1, 2H); 7.26 (d, J = 8.1H); 3.68 (br. S, 1H); 2.94 (br. S, 1H); 2.37 (s, 3H); 2.12 (br. S, 2H); 2.05-1.62 (m, 10H).

Intermediate 6

5- (4-Methoxyphenyl) -5,6-diazatetracyclo [7.3.1.13'11.O4'8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Step 1: Ethyl 5- (4-Methoxyphenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylate

Yield: 78%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.29 (d, J = 9.0); 6.96 (d, J = 9.0, 2H); 4.39 (q, J = 7.2, 2H); 3.79 (br. T, J = 5.0, 1H); 2.96 (br. S, 1H); 2.19 (br. S, 1H); 2.08-1.96 (m, 2H); 1.96-1.74 (m, 8H); 1.39 (t, J = 7.2, 3H).

Step 2: 5- (4-Methoxyphenyl) -5,6-diazatetracyclic acid [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylic Yield: 95%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.28 (d, J = 9.0, 2H); 6.98 (d, J = 9.0, 2H); 3.86 (s, 3H); 3.78 (t, J = 5.4, 1H); 2.99 (br. S, 1H); 2.21 (br. S, 2H); 2.10-1.70 (m, 10H).

Intermediate 7

5-phenyl-5,6-diazatetracyclo acid [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylic

Step 1: Ethyl 5-phenyl-5,6-diazatetracyclo [7.3.1.13'11.O4'8] tetradeca-4 (8), 6-diene-7-carboxylate

Yield: 63%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.32 (m, 5H); 4.40 (q, J = 7.5, 2H); 3.80 (t, J = 5.4, 1H); 3.02 (br, t, J = 4.8, 1H); 2.22 (br. S, 2H); 2.07-1.95 (m, 2H); 1.95-1.76 (m, 8H); 1.40 (t, J = 7.5.3H).

Step 2: 5-Phenyl-5,6-diazatetracyclo [7.3.1.13ill-O4'8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Yield: 91%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.58-7.42 (m, 3H); 7.37 (dd, J = 7.8, 1.2, 2H); 3.80 (t, J = 5.4, 1H); 3.06 (br. S, 1H); 2.22 (br. S, 2H); 2.10-1.75 (m, 10H).

Intermediate 8

5- (2,4-Dichlorophenyl) -5,6-diazatetracyclic acid [7. 3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylic

Step 1: Ethyl 5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylate

Yield: 71%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.52 (s, 1H); 7.34 (s, 2H); 4.39 (q, J = 6.9, 2H); 3.79 (br. T, J = 5.4, 1H); 2.55 (br. T, J = 4.6, 1H); 2.19 (br. S, 2H); 2.10-1.60 (m, 10H); 1.39 (t, J = 6.9, 3H).

Step 2: 5- (2,4-Dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13ill-O4'8] tetradeca-4 (8), 6-diene-7-carboxylic acid

Yield: 95%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.57 (d, J = 1.8, 1H); 7.38 (dd, J = 8.4, 1.8, 1Η); 7.32 (d, J = 8.4, 1H); 3.78 (br. T, J = 5.4, 1H); 2.57 (br. T, J = 4.6, 1H); 2.20 (br. S, 2H); 2.10-2.65 (m, 10H).

Intermediate 9

5- (2-chlorophenyl) -5,6-diazatetracyclo acid [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylic

Step 1: Ethyl 5- (2-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxylate

Yield: 56%. 1 H-NMR (ppm, CDCl 3, 300 MHz): 7.53-7.48 (m, 1H); 7.45-7.32 (m, 3H); 4.40 (q, J = 7.5, 2H); 3.80 (t, J = 5.7, 1H); 2.57 (br. T, J = 5.4, 1H); 2.17 (m, 2H); 2.08-1.65 (m, 10H); 1.39 (t, J = 7.5, 3H).

Step 2: 5- (2-Chlorophenyl) -5,6-diazatetracyclo acid [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylic

Yield: 96%. 1H-NMR (δ ppm, DMSO-d6, 300 MHz): 12.66 (br. S, 1H); 7.72 (d, J = 8.1, 1H); 7.70-7.51 (m, 3H); 3.68 (t, J = 5.1, 1H); 2.46 (br. S, 1H); 2.13 (br. S, 2H); 2.03-1.64 (m, 10H).

Intermediate 10

5- (5-chloropyridyl) -5,6-diazatetracyclo acid [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylic

Step 1: Ethyl 5- (5-chloropyridyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxylate

Yield: 28%. 1H-NMR (δ ppm, DMSO-d6, 300MHz): 8.46-8.44 (d, J = 2.7, 1H); 8.08 (dd, J = 8.7, 2.7, 1H); 7.74 (d, J = 8.7,1H); 4.21 (q, J = 6.9, 2H); 3.13-3.06 (m, 2H); 2.12-1.62 (m, 12H); 1.12 (t, J = 7.2, 3H).

Step 2: 5- (5-Chloropyridyl) -5,6-diazatetracyclo acid [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylic

Yield: 78%. 1H-NMR (δ ppm, DMSO-d6, 300 MHz): 13.25 (br. S, 1H), 8.44 (d, J = 2.5, 1H); 8.06 (dd, J = 8.0,2.5, 1H); 7.70 (d, J = 8.1, 1H); 3.22 (br. S, 1H); 3.05 (br. S, 1H); 2.12-1.64 (m, 12H).

Intermediate 11

5,6-diazatetracyclic acid [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylic

Step 1: Ethyl 5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylate

Yield: 97%. 1H-NMR (δ ppm, CDCl3): 4.36 (q, J = 7.2H); 3.61 (br. T, J = 5.4, 1H); 3.10 (br. S, 1H); 2.16 (br. S, 2H); 2.08-1.95 (m, 4H); 1.85-1.70 (m, 6H); 1.38 (t, J = 7.2, 2H).

Step 2: 5,6-Diazatetracyclo Acid [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylic

Yield: 79%. 1H-NMR (δ ppm, DMS0-d6): 12.78 (br. S, 1H); 3.54 (br. S, 1H); 2.97 (br. S, 1H); 2.09 (br s, 2H); 1.97-1.85 (m, 4H); 1.77 (br. S, 2H); 1.68 (t, J = 12.0, 4H).

Intermediate 12a and Intermediate 12b

Ethyl 6-methyl-5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylate (intermediate 12a) and Ethyl 5-methyl-5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylate (Intermediate 12b):

A solution of 5,6-diazatetracyclo acid [7.3.1.13 · 11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylic acid (100 mg, 0.38 mmol) in DMF (2 ml) was treated with NaH (50% dispersion in mineral oil, 20 mg, 0, 4 mmol) and stirred at room temperature for 45 minutes and then iodomethane (60 mg, 0.026 mmol) was added to the mixture. Stirring was continued for an additional 1.5 h. Mixture poured into water, extracted with dried ethyl acetate over anhydrous sodium sulfate. Evaporation and separation by flash chromatography afforded Intermediate 12a and Intermediate 12b.

Intermediate 12a: Yield: 36%. 1H-NMR (δ ppm, CDCl3): 4.37 (q, J = 7.2, 2H); 3.82 (s, 3H); 3.71 (t, J = 5.4,1H); 3.00 (br. T, J = 4.8, 1H); 2.18 (br s, 2H); 2.10-1.80 (m, 4H); 1.80 (br. T, J = 12.3, 6H); 1.39 (t, J = 7.2, 3H) .13 C-NMR (δ ppm, CDCl3): 161.02, 158.50, 132.17.127.49, 60.58, 39.36, 36.29 , 35.35, 34.69, 32.41, 28.63, 27.15, 14.21.

Intermediate 12b: Yield: 36%. 1H-NMR (δ ppm, CDCl3): 4.34 (q, J = 7.2, 2H); 4.02 (s, 3H); 3.54 (t, J = 5.7, 1H); 3.03 (t, J = 5.1, 1H); 2.14 (br. S, 2H); 2.07-1.93 (m, 4H); 1.84-1.67 (m, 6H); 1.37 (t, J = 7.2, 3H) .13 C-NMR (δ ppm, CDCl3): 163.32, 150.32, 136.54, 130.80, 60.32, 36.78, 36 , 14, 34.65, 33.65, 29.57, 28.68, 26.46,14,40.

Intermediate 13a and Intermediate 13b

6-Pentyl-5,6-diazatetracyclic acid [7. 3,11,11. O4'8] tetradeca-4,7-diene-7-carboxylic acid (Intermediate 13a) and 5-Pentyl-5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8) -6-diene acid -7-carboxylic acid (Intermediate 13b)

Step 1: Ethyl 6-pentyl-5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4,7-diene-7-carboxylate (Intermediate 13aa) and Ethyl 5-pentyl-5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxylate (Intermediate 13bb):

Intermediates 13aa and 13bb were prepared by a procedure similar to that described for intermediates 12a and 12b, using intermediate 11 (1.00g, 3.84 mmol), DMF (3 ml) and 1-bromo-n-pentane ((53 μΐ 4.20 mmol).

Intermediate 13aa: 1 H-NMR (δ ppm, CDCl 3, 300 MHz): 4.39-4.28 (m, 4H); 3.53 (t, J = 5.4, 1H); 3.04 (t, J = 5.4.1H); 2.13 (br. S, 2H); 2.04-1.94 (m, 4H); 1.84-1.66 (m, 8H); 1.37 (t, J = 6.9, 3H); 1.30-1.24 (m, 4H); 0.88 (t, J = 6.9, 3H).

Intermediate 13bb: 1H-NMR (δ ppm, CDCl3, 300 MHz): 4.37 (q, J = 6.9, 2H); 4.07 (t, J = 7.5, 2H); 3.71 (br. S, 1H); 2.98 (br. S, 1H); 2.18 (br. S, 2H); 2.02-1.92 (m, 4Η); 1.85-1.71 (m, 8Η); 1.38 (t, J = 6.9, 3Η); 1.40-1.24 (m, 4Η); 0.89 (t, J = 7.2, 3Η).

Step 2: 6-Pentyl-5,6-diazatetracyclic acid [7. 3,11,11. O4'8] tetradeca-4,7-diene-7-carboxylic acid (Intermediate 13a) and 5-Pentyl-5,6-diazatetracyclic acid [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxylic (Intermediate 13b)

Intermediate 13aa (400 mg, 1.21 mmol) and Intermediate 13bb (400 mg, 1.21 mmol), KOH (136 mg, 2.42 mmol), ethanol (10 mL) and H 2 O (0.5 mL) produced the intermediate 13a (270 mg, 73%). 1H-NMR (δ ppm, CDCl3, 300 MHz): 4.39 (t, J = 7.8, 2H); 3.64 (br. S, 1H); 3.07 (br. S, 1H); 2.14 (br.s, 2H); 2.04-1.94 (m, 4H); 1.79-1.72 (m, 8H); 1.35-1.28 (m, 4H); 0.89 (t, J = 7.5, 3H) and intermediate 13b (290mg, 79%). 1H-NMR (δ ppm, CDCl3, 300 MHz): 4.06 (t, J = 7.2, 2H); 3.70 (br. S, 1H); 2.98 (br. S, 1H); 2.18 (br.s, 2H); 2.02-1.93 (m, 4H); 1.84-1.68 (m, 8H); 1.40-1.24 (m, 4H); 0.89 (t, J = 7.2, 3H).

Intermediates 14 to 21 were prepared according to the procedure as described in step 2 and step 3 of intermediate 1, using Ethyl 2-oxo-2- (3-oxobicyclo [2,2,1] hepta-2-yl) acetate, phenyl hydrazine (unsubstituted) and appropriate alkali.

Intermediate 14

1-Phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Step 1: Ethyl 2-oxo-2- (3-oxobicyclo [2,2,1] hepta-2-yl) acetate

The title product was prepared by a procedure similar to that described in step 1 of the middle 1 starting from hexamethyldisilazane (4.2 mL, 20.0 mmol), ether (91 mL), nBuLi (2.3 M in hexane, 1163 mL , 27.3 mmol), norcanfor (2.0 g, 18.2 mmol) and diethyl oxalate (2.96 ml, 21.82 mmol) the title product was obtained.

Yield: 56%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 1141 (br.s, 1H); 4.35 (q, J = 7.2, 2H); 3.81 (br. S, 1H); 2.81 (br. S, 1H); 2.05-1.85 (m, 3H); 1.80 (br. D, J = 10.5.1H); 1.59 (br. T, J = 7.2, 2 Η); 1.41 (t, J = 7.2, 3H).

Step 2: Ethyl 1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate

Yield: 52%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.73 (d, J = 8.7, 2H); 7.47 (t, J = 7.2, 2H); 7.33 (t, J = 7.2.1H); 4.42 (q, J = 7.2, 2H); 3.72 (br. S, 1H); 3.68 (br.s, 1H); 2.13 (br. D, J = 8.7, 1H); 2.05-1.95 (m, 2H); 1.72 (d, J = 8.7, 1H); 1.42 (t, J = 7.2, 3H); 1.30-1.18 (m, 2H).

Step 3: 1-Phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Yield: 79%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.73 (d, J = 7.8, 2H); 7.50 (t, J = 7.8, 2H); 7.36 (t, J = 7.5.1H); 3.75 (s, 1H); 3.72 (s, 1H); 2.17 (br. D, J = 9.0.1H); 2.10-1.93 (m, 2H); 1.74 (d, J = 8.7, 1H); 1.38-1.08 (m, 2H).

Intermediate 15

1- (2-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Step 1: Ethyl 1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate

Yield: 87%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.72-7.60 (m, 2H); 7.41-7.33 (m, 2H); 4.42 (q, J = 7.2, 2H); 3.69 (s, 1H); 3.40 (s, 1H); 2.14 (br. D, J = 9.0, 1H); 2.05-1.82 (m, 2H); 1.72 (d, J = 9.3, 1H); 1.30 (t, J = 7.2, 3H); 1.35-1.12 (m, 2H).

Step 2: 1- (2-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Yield: 93%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.59-7.50 (m, 2H); 7.45-7.33 (m, 2H); (dt, J = 8.7, 1.8, 2H); 3.72 (s, 1H); 3.42 (s, 1H); 2.17 (br. D, J = 8.7, 1H); 2.10-1.85 (m, 2H); 1.74 (d, J = 8.7, 1H); 1.38-1.18 (m, 2H).

Intermediate 16

1- (4-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Step 1: Ethyl 1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate

Yield: 72%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.60 (d, J = 8.7, 2H); 7.43 (d, J = 8.7, 2H); 4.42 (q, J = 7.2H); 3.69 (br. S, 1H); 3.66 (br. S, 1H); 2.14 (br. D, J = 8.7, 1H); 2.10-1.95 (m, 2H); 1.72 (br. D, J = 8.7, 1H), 1.42 (t, J = 7.2, 3H), 1.30-1.15 (m, 2H).

IR (KBr, cm -1): 2977 (m), 2871 (m), 1716 (s), 1502 (s), 1373 (s), 1230 (s), 1092 (s), 831 (m).

Step 2: 1- (4-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Yield: 74.5%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.70 (d, J = 6.7, 2H); 7.50 (d, J = 6.7, 2H); 3.70 (s, 2H); 2.16 (br. D, J = 8.7, 1H); 2.10-1.94 (m, 2H); 1.74 (br.d., J = 8.7,1H); 1.2 (m, 2H). IR (KBr, cm -1): 3460 (vs); 2943 (m), 2873 (m), 1705 (vs), 1684 (vs), 1500 (vs), 1357 (s?), 1252 (vs), 1093 (vs), 835 (s).

Intermediate 17

1- (2,4-Dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Step 1: Ethyl 1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate

Yield: 51%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.53 (d, J = 2.4, 1H); 7.49 (d, J = 8.4, 1H); 7.36 (dd, J = 8.4,2.4, 1H); 4.41 (q, J = 7.2, 2H); 3.69 (br. S, 1H); 3.38 (br. S, 1H); 2.14 (br. D, J = 9.0, 1H); 2.07-1.82 (m, 2H); 1.70 (br. D, J = 9.0, 1H); 1.41 (t, J = 7.2, 3H); 1.29-1.13 (m, 2H).

Step 2: 1- (2,4-Dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Yield: 87%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.56 (d, J = 2.1, 1H); 7.48 (d, J = 8.4, 1H); 7.38 (dd, J = 8.4,2.1, 1H); 3.71 (br. S, 1H); 3.41 (br. S, 1H); 2.16 (br.d., J = 8.7,1H); 2.07-1.82 (m, 2H); 1.72 (br. D, J = 8.7.1H); 1.31-1.14 (m, 2H).

Intermediate 18

1- (2-Bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid Step 1: Ethyl 1- (2-bromophenyl) -4,5,6,7 -tetrahydro-1H-4,7-methane-indazol-3-carboxylate

Yield: 79%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.69 (dd, J = 7.8, 1.5, 1H); 7.50 (dd, J = 7.8, 2.1, 1H); 7.44 (td, J = 7.8, 1.5, 1H); 7.32 (td, J = 7.8, 2.1, 1H); 4.41 (q, J = 7.2, 2H); 3.69 (br. S, 1H); 3.39 (br. S, 1H); 2.18 (br. D, J = 9.0, 1H); 2.05-1.81 (m, 2H); 1.70 (d, J = 8.7, 1H); 1.41 (t, J = 7.2, 3H); 1.30-1.12 (m, 2H).

Step 2: 1- (2-Bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Yield: 92%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.71 (dd, J = 8.4, 1.5, 1H); 7.53-7.40 (m, 2H); 7.34 (td, J = 7.8, 2.1, 1H); 3.73 (br. S, 1H); 3.41 (br. S, 1H); 2.19 (br. D, J = 8.7, 1H); 2.04-1.82 (m, 2H); 1.73 (d, J = 7.2, 1.5, 1H); 1.32-1.15 (m, 2H).

Intermediate 19

1- (4-Bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Step 1: Ethyl 1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate

Yield: 81%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.65-7.50 (m, 4H); 4.42 (q, J = 7.2, 2H); 3.69 (s, 2H); 3.67 (s, 2H); 2.13 (br. D, J = 8.7, 1H); 2.06-1.95 (m, 2H); 1.74 (d, J = 8.7, 1H); 1.42 (t, J = 7.2, 3H); 1.28-1.15 (m, 2H).

Step 2: 1- (4-Bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Yield: 83%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.62 (s, 4H); 3.71 (s, 2H); 2.17 (br. D, J = 9.0, 1H); 2.06-2.01 (m, 2H); 1.75 (d, J = 9.0, 1H); 1.30-1.17 (m, 2H).

Intermediate 20

1- (4-Fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Step 1: Ethyl 1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate

Yield: 86%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.69 (dd, J = 9.0, 4.8, 2Η); 7.15 (t, J = 9.0, 2Η); 4.42 (q, J = 7.2, 2H); 3.67 (br. S, 2H); 3.40 (br s, 1H); 2.16 (br.d., J = 8.7,1H); 2.03-1.85 (m, 2H); 1.72 (br. D, J = 9.0.1H); 1.43 (t, J = 7.2, 3H); 1.32-1.17 (m, 2H).

Step 2: 1- (4-Fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Yield: 60%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.70 (dd, J = 8.7, 4.8, 2H); 7.18 (t, J = 8.7, 2H); 3.70 (s, 2H); 2.17 (br. D, J = 8.7, 1H); 2.10-1.90 (m, 2H); 1.74 (d, J = 8.7, 1H); 1.35-1.18 (m, 2H).

Intermediate 21

1- (2,4-Difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Step 1: Ethyl 1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane indazol-3-carboxylate

Yield: 81%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.80-7.68 (m, 1H); 7.05-6.95 (m, 2H); 4.42 (q, J = 7.2, 2H); 3.67 (br. S, 1H); 3.47 (br. S, 1H); 2.12-2.08 (br. D, J = 8.7, 1H); 2.03-1.90 (m, 2H); 1.72-1.65 (br. D, J = 8.7.1H); 1.41 (t, J = 7.2, 3H); 1.30-1.17 (m, 2H).

Step 2: 1- (2,4-Difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Yield: 78%. 153-156 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.80-7.70 (m, 1H); 7.10-6.97 (m, 2H); 3.70 (br.s, 1H); 3.50 (br. S, 1H); 2.12 (d, J = 7.2, 1H); 2.08-1.86 (m, 2H); 1.72 (d, J = 8.7,1H); 1.35-1.17 (m, 2H).

Optical Resolution 1- (2,4-Difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid:

Intermediate 21

Intermediate 21a

A paste of intermediate 21 (racemic, 15.0 g, 51.72mmol) in acetonitrile (LR grade) (150 ml) was treated with (S) - (-) - α-methylbenylamine (3.66 ml, 28.44 mmol), stirred at RT for 5-10 min and the mixture was heated at reflux for 15 min. Methanol (24 mL) was added slowly until a clear solution resulted and heating was continued for an additional 30 min after which time the mixture was allowed to slowly cool to RT. The separated crystals were collected by filtration and washed with 9: 1 comacetonitrile / MeOH (-15 ml). The acid was recovered from the diastereomeric salt by dissolving in CH 2 Cl 2 and extracting with aq. 1 Ν. Repeating the same procedure several times provided a mixture (100mg) enriched in the delayed elution enantiomer [Intermediate 21a, Rt = 38.20 min on a CHIRALCEL AS-H column (dimensions: 250 χ 4.6 mm, particle size: 5μ) using a 90: 10: 0.1 mixture of n-hexane: isopropanol: trifluoroacetic acid as the eluent at a flow rate of 1 ml / min]. 114-115 ° C; e.e = 92%.

Intermediate 21b

The mother liquor obtained in the first step of the process described above was evaporated, distributed between CH 2 Cl 2 and aq. 1N and the layers were separated. Drying (Na 2 SO 4) and evaporation of the organic layer afforded a mixture of two enantiomeric acids (9g) enriched in the fast eluting enantiomer (Rt = 34.65 min under the same conditions described above; e.e = 34%). The mixture was enriched in this enantiomer to a 91% ee (Intermediate 21b, yield = 72 mg) by replacing (S) - (-) - α-methylbenylamine with (R) - (+) -α-methylbenylamine in the above process for the enantiomer delayed elution. 110-112 ° C.

Intermediates 22 and 23 were prepared according to the process as described in step 2 and step 3 of intermediate 1 using Ethyl 2- (3-hydroxy-4,7,7-trimethylbicyclo [2,2,1] hepta-2-en Suitable 2-yl-2-oxoacetate, unsubstituted phenylhydrazine and alkali.

Intermediate 22

1- (2,4-Dichlorophenyl) - 7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Step 1: Ethyl 2- (3-hydroxy-4,7,7-trimethylbicyclo [2,2,1] hepta-2-en-2-yl-2-oxoacetate

A solution of DL-camphor (5 g, 33 mmol) in toluene (25 mL) was added to a slurry of sodium hydride (60% dispersion, 1.34 g, 56 mmol) and diethyl oxalate (6.69 g 49 mmol) in toluene (30 ml) at 60 ° C and the mixture stirred at the same temperature for 1 hour. The reaction mixture was quenched on ice, acidified with 1 N HCl, extracted with ethyl acetate and the organic layers dried over Na 2 SO 4 and the solvent removed under vacuum to afford the title product (7.3 g, 88%) which was used without purification. in the next step.

Yield: 88%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 1139 (br. S, 1H); 4.35 (q, J = 7.2, 2H); 3.29 (d, J = 4.2.1H); 2.30-2.04 (m, 1H); 1.70-1.40 (m, 1H); 1.46 (br. D, J = 8.7, 2H); 1.38 (t, J = 7.2, 3H); 1.01, 0.97, 0.83 (3s, 9H).

Step 2: Ethyl 1- (2,4-dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate

Yield: 42%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.53 (s, 1H); 7.36 (s, 2H); 4.40 (q, J = 7.2, 2H); 3.16 (d, J = 3.6, 1H); 2.13 (m, 1H); 1.40 (t, J = 7.2, 3H); 1.26 (m, 2H); 0.88 (s, 6H); 0.83 (s, 3H).

Step 3: 1- (2,4-Dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid

Yield: 72%. 1H-NMR (δ ppm, DMSO-ds, 300 MHz): 12.80 (br. S, 1H); 7.95 (d, J = 2.1, 1H); 7.67 (d, J = 8.7.1H); 7.63 (dd, J = 8.7, 2.1, 1H); 3.01 (d, J = 3.6, 1H); 2.13-2.06 (m, 1H); 1.79 (br. T, J = 8.7, 1H); 1.32 (br.t, J = 9.3, 1H); 1.16-1.00 (m, 1H); 0.88 (s, 3H); 0.84 (s, 3H); 0.77 (s, 3H).

Intermediate 23

3- (2,4-Difluorophenyl) -1,10,10-trimethyl-3,4-diazatriciclo acid [5.2 .1. O2'6] deca-2 (6), 4-diene-5-carboxylic

Step 1: Ethyl 3- (2,4-difluorophenyl) -1,10,10-trimethyl-3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxylate

Yield: 42%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.58-7.48 (m, 1H); 7.03-6.80 (m, 2H); 4.40 (q, J = 7.2, 2H); 3.15 (d, J = 4.2, 1H); 2.20-2.08 (m, 1H); 1.88-1.76 (m, 1H); 1.40 (t, J = 7.2, 3H); 1.40-1.08 (m, 2H); 0.99, Ο, 92, Ο, 79 (3s, 9Η).

Step 2: 3- (2,4-Difluorophenyl) -1,10,10-trimethyl-3,4-diazatricylic acid [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxylic

Yield: 72%. 1H-NMR (δ ppm, DMS0-d6, 300 MHz): 12.80 (br. S, 1H); 7.80-7.57 (m, 2H); 7.29 (br. T, J = 8.4.1H); 3.01 (d, J = 3.6, 1H); 2.08-2.02 (m, 1H); 1.79 (br.t, J = 9.6, 1H); 1.32 (br. T, J = 9.0, 1H); 1.06 (br. T, J = 9.0 1H); 0.91, 0.88, 0.73 (3s, 9H).

Intermediates 24 and 25 were prepared according to the process as described in steps 2 and step 3 of intermediate 1 using Ethyl 2-oxo-2- (10-oxotricyclo [6.2.2. O2'7] dodeca-2,4 , 6-trien-9-yl) acetate, (unsubstituted) phenyl hydrazine and appropriate alkali.

Intermediate 24

10- (2,4-dichlorophenyl) -10,11-diazatetracyclic acid [6.5.2. O2'7. O9.13] pentadeca-2, 4,6,9 (13), 11-pentaene-12-carboxylic

Step 1: Ethyl 2-oxo-2- (10-oxotricyclo [6.2.2.0.0] 7] dodeca-2,4,6-trien-9-yl) acetate.

The title product was prepared by a procedure similar to that described for step 1 of intermediate1. From tricycle [6. 2 . 2 . O2.7] dodeca-2,4,6-trien-9-one [prepared by one of the methods available in the art of organic synthesis, e.g. as described in Hales et al. Tetrahedron, 1995, 51, 7777-7790] (2.5 g, 14.53 mmol), hexamethyldisilazane (4.9 mL, 23.2 mmol), n-BuLi (10 mL, 23.4 mmol) 2.34 M and diethyl oxalate (3.18 mL, 21.18 mmol) the desired product was obtained (2.3 g, 63%).

Yield: 63%. 1H-NMR (δ ppm, CDCl3, 400 MHz): 12.9 (s, 1H); 7.20-7.15 (m, 4H); 4.91 (s, 1H); 4.31 (q, J = 7.2.2H); 3.79 (s, 1H); 2.00-1.90 (m, 2H); 1.73-1.60 (m, 2H); 1.34 (t, J = 7.2, 3H).

Step 2: Ethyl 10 - (2,4-dichlorophenyl) -10,11-diazatetracyclo [6.5.2. O2'7. O9'13] pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxylate

Yield: 91%. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.58 (d, J = 2.2, 1H); 7.45 (d, J = 8.5,1H); 7.38 (dd, J = 8.5,2,0,1H); 7.33 (br. D, J = 7.0, 1H); 7.16 (br. D, J = 7.08, 1H); 7.13 (td, J = 7.6, 1.5, 1H); 7.08 (td, J = 7.5, 1.5, 1H); 4.91 (s, 1H); 4.45 (q, J = 7.2, 2H); 4.29 (s, 1H); 1.81-1.72 (m, 4H); 1.43 (t, J = 7.2, 3H).

Step 3: 10- (2,4-Dichlorophenyl) -10,11-diazatetracyclic acid [6.5.2. O2'7. O9.13] pentadeca-2, 4,6,9 (13), 11-pentaene-12-carboxylic

1H-NMR (ppm, CDCl3, 400 MHz): 7.60 (d, J = 2.1, 1H); 7.45 (d, J = 8.5, 1H); 7.41 (dd, J = 8.5, 2.1, 1H); 7.35 (br. D, J = 6.8, 1H); 7.17 (br. D, J = 7.2, 1H); 7.14 (td, J = 7.5, 1.3, 1H); 7.09 (td, J = 7.5, 1.3, 1H); 4.94 (s, 1H); 4.32 (s, 1H); 1.82-1.73 (m, 4H).

Intermediate 25

10- (2,4-difluorophenyl) -10,11-diazatetracyclic acid [6. 5 2 . O2'7. O9'13] pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxylic

Step 1: Ethyl 10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2, 4,6,9 (13), 11-pentaene-12-carboxylate

Yield: 71%. 1H-NMR (δ ppm, CDCl3, 300MHz): 7.67-7.57 (m, 1H); 7.34 (d, J = 6.9, 1H); 7.20-7.01 (m, 5H); 4.90 (s, 1H); 4.44 (q, J = 6.9, 2H); 4.39 (br. S, 1H); 1.79 (s, 4H); 1.45 (t, J = 6.9, 3H).

Step 2: 10- (2,4-Difluorophenyl) -10,11-diazatetracyclo acid [6. 5 2 . O2'7. O9'13] pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxylic

Yield: 86%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.68-7.58 (m, 1H); 7.35 (d, J = 7.2, 1H); 7.21-7.04 (m, 5H); 4.94 (s, 1H); 4.41 (br. S, 1H); 1.81 (br. S, 4H)

Intermediate 26 was prepared according to the procedure described in steps 2 and step 3 of intermediate 1 using Ethyl 9endo, 13endo-2- [11- (4-chlorophenyl) -10,12,15-trioxo-11-azatetracyclo [6. 5 2 . O2-709.13] pentadeca-2,4,6-trien-14-yl] -2-oxoacetate (unsubstituted) phenyl hydrazine and appropriate alkali.

Intermediate 26 Acid 13Endo, 14endo-16- (4-chlorophenyl) -15,17-dioxo-10- (2,4-dichlorophenyl) -10,11,16-triazapentacyclo [6,5,5,0,27]. O9'13. O14'18] octadeca-2,4,6,9 (13), 11-pentaene-12-carboxylic

Step 1: 9-Endo, 13-endo-11- (4-chlorophenyl) -11-azatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2,4,6-triene-10,12,14-trione

A solution of 11-oxatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2,4,6-triene-10,12,14-trione [prepared as described by Takeda et al., Tetrahedron 1970, 26, 1435-1451] (1.0 g, 4.11 mmol), 4-chloroaniline (1.2 g, 9.05 mmol) in xylene was refluxed for 6 h. Water was added to the browning mixture and extracted with EtOAc. The organic layers were dried over Na 2 SO 4 and the solvent evaporated. The residue after FC (AcOEt-petroleum ether 4: 96-16: 84) afforded the title product (930 mg, 65%) Yield: 65%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.40-7.222 (m, 6H); 6.47 (d, J = 8.7, 2H); 4.18 (dd, J = 3,3,1H); 4.07-4.02 (m, 1H); 3.59 (dd, J = 8.7, 3.3, 1H); 3.49 (dd, J = 8.4, 3.3, 1H); 2.56 (dd, J = 20.4, 2.1, 1H); 2.43 (dd, J = 20.4, 3.3, 1H).

Step 2: Ethyl 9endo, 13endo-2- [1- (4-chlorophenyl) -10,12,15-trioxo-azatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2,6,6-trien-14-yl] -2-oxoacetate

The title product was prepared by a procedure similar to that described for step 1 of intermediate1. From 9-Endo, 13-endo-11- (4-chlorophenyl) -11-azatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2,4,6-triene-10,12,14-trione (800 mg, 2.28 mmol), hexamethyldisilazane (0.68 mL, 3.2 mmol), n-BuLi (15% in hexane, 1.31 ml, 3.1 mmol) and diethyl oxalate (0.62 ml, 4.6 mmol) the title product (530 mg, 52%) was obtained pure after FC. Yield: 52%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 13.0 (br. S, 1H); 7.36-7.20 (m, 6H); 6.47 (d, J = 7.2, 2H); 5.54 (br. S, 1H); 4.49-4.38 (m, 3H); 3.54 (br s, 2H), 1.45 (t, J = 7.2, 3H).

Step 3: Ethyl 13endo, 14endo-16-4-chlorophenyl) -15,17-dioxo-10- (2,4-dichlorophenyl) -10,11,16-triazapentacyclo [6,5,5,220]. O9'13. O14'18] octadeca-2,4,6,9 (13), 11-pentaene-12-carboxylate.

Yield: 66%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.63 (d, J = 2.4, 1H); 7.51 (d, J = 8.4, 1H); 7.47-7.35 (m, 3H); 7.30-7.15 (m, 4H); 6.44 (d, J = 9.0, 2H); 5.44 (d, J = 3.0, 1H); 4.83 (d, J = 2.7, 1H); 4.49 (q, J = 7.2, 2H); 3.56 (dd, J = 8.7, 3.3, 1H); 3.48 (br. D, J = 8.7, 1H); 1.46 (t, J = 7.2, 3H).

Step 4: 13Endo, 14endo-16- (4-chlorophenyl) -15,17-dioxo-10- (2,4-dichlorophenyl) -10,11,16-triazapentacyclo [6,5,5,0,07] acid. O9'13. O14'18] octadeca-2,4,6,9 (13), 11-pentaene-12-carboxylic

Yield: 76%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.66 (d, J = 2.4, 1H); 7.54-7.40 (m, 3H); 7.28-7.19 (m, 5H); 6.45 (d, J = 8.7, 2H); 5.50 (d, J = 3.0, 1H); 4.87 (d, J = 3.0, 1H); 3.59 (dd, J = 8.7, 3.0, 1H); 3.50 (br. D, J = 8.7, 1H).

Intermediate 27

10- (2,4-Difluorophenyl) -10,11-diazatetracyclo acid [6, 5, 1, 02-7. O9'13] tetradeca-2,4,6,9 (13), 11-pentaene-12-carboxylic

Step 1: Ethyl 2-oxo-2- (10-oxotricyclo [6,2,1,0,7] undeca-2 (7), 3,5-trien-9-yl) acetate

The title product was prepared by a procedure similar to that described for step 1 of intermediate22, from Benzonorbornanone (2.4 g, 15.18 mmol), sodium hitride (60% dispersion, 619 mg, 25 mmol) and oxalate. of diethyl (3.09 ml, 22.7 mmol) the title product (2.6 g, 52%) was obtained. 1H-NMR (δ ppm, CDCl3, 300MHz): 10.63 (br. S, 1H); 7.75-7.20 (m, 5H); 4.81 (d, J = 1.5, 1H); 4.35 (q, J = 7.2, 2H); 3.75 (d, J = 1.5, 1H) 2.57 (dt, J = 9.3, 1.8, 1H); 2.42 (d, J = 8.7, 1.5, 1H); 1.43 (t, J = 7.2, 3H).

Step 2: Ethyl 10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6, 5, 1, 02.7. O9'13] tetradeca-2,4,6,9 (13), 11-pentaene-12-carboxylate The title product was prepared by a procedure similar to that described for step 3 of intermediate 20. From Ethyl (2Z) -hydroxy (10-oxotricyclo [6,1,10,27] undeca-2,4,6-trien-9-ylidene) acetate (1.0 g, 3.87 mmol) 2,4-difluorophenylhydrazine hydrochloride (838 mg, 4.64 mmol) ethanol (13.0 ml) and acetic acid (15.0 ml) the title product (1.21 g, 85%) was obtained. 1H-NMR (δ ppm, CDCl3, 300MHz): 7.79-7.69 (m, 1H); 7.35-7.26 (m, 2H); 7.05-6.94 (m, 4H), 4.52 (br. S, 1H), 4.41 (q, J = 7.5, 2H); 4.32 (br. S, 1H); 3.00 (br. D, J = 8.1, 1H); 2.85 (dt, J = 8.1, 1.5, 1H); 1.41 (t, J = 7.5, 3H).

Step 3: 10- (2,4-Difluorophenyl) -10,11-diazatetracyclo acid [6, 5.1, 02-7. O9'13] tetradeca-2,4,6,9 (13), 11-pentaene-12-carboxylic

The title product was prepared by a procedure similar to that described for intermediate. From

Ethyl 10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6,5,1,0,7]. O9'13] tetradeca-2,4,6,9 (13), 11-pentaene-12-carboxylate KOH (367 mg, 6.5 mmol), ethanol (10.4 mL) and H 2 O (0.5 mL) The title product (810 mg, 73%) was obtained. 1H-NMR (δ ppm, DMS0-d6, 300 MHz): 12.95 (m, 1H); 7.78-7.57 (m, 2H); 7.32-7.25 (m, 3H); 6.98-6.89 (m, 2H); 4.43 (s, 2H); 2.89 (d, J = 8.1, 1H); 2.71 (d, J = 8.1, 1H).

Intermediates 28 to 30 were prepared according to the procedure as described in step 2 and step 3 of intermediate 1 using ethyl 2-hydroxy-2- (3-oxabicyclo [2,2,2] octa-2-yliden) phenyl acetate appropriate (unsubstituted) hydrazine and alkali.

Intermediate 28

3- (2,4-Difluorophenyl) -3,4-diazatriciclo acid [5. 2 . 2 . O2'6] undeca-2 (6), 4-diene-5-carboxylic acid

Step 1: Ethyl 2-hydroxy-2- (3-oxabicyclo [2,2,2] octa-2-yliden) acetate

A solution of bicyclo [2,2,2] octan-2-one (2.4 g, 19.35 mmol) in toluene (20 mL) was added to a sodium hydride slurry (60% dispersion, 603 mg, 25 mL). , 16 mmol) diethyl eoxalate (3.15 mL, 23.22 mmol) in toluene (10 mL) at 60 ° C and the mixture stirred at the same temperature for 1 hour. The reaction mixture was quenched on ice, acidified with 1 N HCl, extracted with ethyl acetate and the organic layers dried over Na 2 SO 4 and the solvent was removed under vacuum to afford Intermediate 28 (1.2 g, 27%) which was used without purification. for the next step. 1H-NMR (δ ppm, CDCl3, 300 MHz): 13.80 (br. S, 1H); 4.36 (q, J = 6.9, 2H); 3.57 (br. S, 1H); 2.52 (br. S, 1H); 1.82-1.60 (m, 8H); 1.38 (t, J = 6.9, 3H).

Step 2: Ethyl-3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 . 2 . O2,6] undeca-2 (6), 4-diene-5-carboxylate:

Yield: 48%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.60 (m, 1H); 7.06-6.94 (m, 2H); 4.43 (q, J = 7.2, 2H); 3.70 (br. S, 1H); 3.15 (br. S, 1H); 1.78 (d, 7.8, 4H); 1.45-1.36 (m, 7H).

Step 3: 3- (2,4-Difluorophenyl) -3,4-diazatriciclo [5.2.2.O2'6] undeca-2 (6), 4-diene-5-carboxylic acid:

Yield: .90%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.72-7.60 (m, 1H); 7.09-6.98 (m, 2H); 3.73 (br. S, 1H); 3.18 (br. S, 1H); 1.80 (d, J = 6.6, 4H); 1.40 (d, J = 7.8, 4H).

Intermediate 2 9

3- (3,4-Dichlorophenyl) -3,4-diazatriciclo acid [5.2.1. 02'6] deca-2 (6), 4-diene-5-carboxylic acid

Step 1: Ethyl 3- (3,4-dichlorophenyl) -3,4-diazatricyclo [5.2.1. 02'6] deca-2 (6), 4-diene-5-carboxylate

Yield: 69%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.90 (d, J = 2.1, 1H); 7.59 (dd, J = 7.5, 2.1, 1H); 7.52 (d, J = 8.7,1H); 4.42 (q, J = 7.5, 2H); 3.71 (br. S, 1H); 3.66 (br. S, 1H); 2.14 (d, J = 8.7,1H); 2.00 (d, J = 8.4.2H); 1.73 (d, J = 9.3, 1H); 1.42 (t, J = 7.5, 3H); 1.20 (d, J = 6.9, 2H). Step 2: 3- (3,4-Dichlorophenyl) -3,4-diazatriciclo acid [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxylic Yield: 90%. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.92-7.87 (m, 1H); 7.62-7.52 (m, 2H); 3.73 (br. S, 1H); 3.71 (br. S, 1H); 2.16 (d, J = 6.6, 1H); 2.03 (d, J = 6,3,2H); 1.76 (d, J = 8.7, 1H); 1.23 (d, J = 6.0, 2H).

Intermediate 30

3- (2-Ethoxy-4-fluorophenyl) -3,4-diazatriciclo acid [5.2.1. O2'6] deca-2 (6), 4-diene-5-carboxylic

Step1: Ethyl 3- (2-ethoxy-4-fluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxylate

1H-NMR (δ ppm, CDCl3, 300 MHz): 7.53 (q, J = 6.3, 1H); 6.78-6.66 (m, 2H); 4.40 (q, J = 6.9, 2H); 4.10-4.00 (m, 2H); 3.65 (br. S, 1H); 3.35 (br. S, 1H); 2.08 (d, J = 8.1, 1H); 2.00-1.80 (m, 2H); 1.66 (d, J = 9.0, 1H); 1.44-1.32 (m, 6H); 1.24 (d, J = 6.0, 2H).

Step 2: 3- (2-Ethoxy-4-fluorophenyl) -3,4-diazatriciclo acid [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxylic

Yield: 91%. 1H-NMR (δ ppm, DMS0-ds, 300 MHz): 12.62 (br. S, 1H); 7.48 (t, J = 7.8,1H); 7.18 (d, J = 8.4.1H); 6.94-6.86 (m, 1H); 4.17 (d, J = 6.6, 2H); 3.49 (br.s, 1H); 3.34 (br. S, 1H); 2.00-1.88 (m, 3H); 1.63 (d, J = 7.8, 1H); 1.30 (t, J = 6.6,1H); 1.09 (t, J = 10.5, 2H).

Intermediates 31a and 31b, 32a and 32b were prepared according to the procedure as described for intermediates 12a and 12b followed by hydrolysis as described for intermediates 13a and 13b using Ethyl 2-oxo-2- (3-oxobicyclo [2,2,1 ] hepta-2-yl) acetate, dehydrazine hydrate, methyl benzyl 4-bromide and defluoro benzyl 4-bromide respectively.

Intermediate 31a

Step 1: Ethyl 4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate:

Yield: 1.30 g, 66%. 1H-NMR (δ ppm, CDCl3): 4.36 (q, J = 6.9, 2H); 3.58 (br. S, 1H); 3.45 (br s, 1H), 2.02-1.92 (m, 3H); 1.71 (d, J = 9.0, 1H); 1.38 (t, J = 6.9.3H); 1.30-1.20 (m, 2H). Step2: Ethyl 1- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate: (Intermediate 31aa) and

Ethyl 2- (4-methylbenzyl) -4,5,6,7-tetrahydro-2H-4,7-methane-indazol-3-carboxylate (Intermediate 31bb)

Intermediate 31aa: 1 H-NMR (δ ppm, CDCl 3, 300 MHz): 7.15 (s, 4H); 5.28 (d, J = 4.8, 2H); 4.38 (q, 7.2, 2H); 3.54 (br. S, 1H); 2.97 (br. S, 1H); 2.34 (s, 3H); 1.98-1.78 (m, 3H); 1.52 (d, J = 8.7,1H); 1.39 (t, J = 6.9, 3H); 1.12-0.98 (m, 1H); 0.82-0.68 (m, 1H).

Intermediate 31bb: 1 H-NMR (δ ppm, CDCl 3, 300 MHz): 7.20-7.05 (m, 4H); 5.72 (d, J = 15.6,1H); 5.49 (d, 14.7, 1H); 4.38-4.25 (m, 2H); 3.52 (br. S, 1H); 3.41 (br. S, 1H); 2.29 (s, 3H); 2.22 (br. S, 1H); 1.99-1.80 (m, 2H); 1.66 (d, J = 7.2, 1H); 1.35 (t, J = 6.9, 3H); 1.26-1.19 (m, 2H)

Step 3a: 3- (4-Methylbenzyl) -3,4-diazatriciclo acid [5.2.1. 02'6] deca-2 (6), 4-diene-5-carboxylic:

Intermediate 31a (294 mg, 82%). 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.15 (s, 4H); 5.27 (d, J = 3.6, 2H); 3.57 (br.s, 1H); 3.03 (br. S, 1H); 2.34 (s, 3H); 1.96-1.81 (m, 2H); 1.74-1.65 (m, 1H); 1.55 (d, J = 9.0, 1H); 1.12-1.02 (m, 1H); 0.83-0.74 (m, 1H).

Step 3b: 2- (4-Methylbenzyl) -4,5,6,7-tetrahydro-2H-4,7-methane-indazol-3-carboxylic acid:

Intermediate 31b: (68 mg, 85%). 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.10 (d, J = 3.3, 4H); 5.72 (d, 15.0, 1H); 5.49 (d, J = 14.4, 1H); 3.58 (br. S, 1H); 3.42 (br. S, 1H); 2.29 (s, 3H); 1.99-1.88 (m, 3H); 1.67 (d, J = 8.7, 1H), 1.23 (d, J = 10.5, 2H).

Intermediates 32a and 32b

Step 1: Ethyl 1- (4-fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate (Intermediate 32aa) and

Ethyl 2- (4-fluorobenzyl) -4,5,6,7-tetrahydro-2H-4,7-methane-indazol-3-carboxylate (Intermediate 32bb)

Intermediates 32aa: 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.28-7.20 (m, 2Η); 7.03 (t, J = 8.7, 2Η); 5.29 (d, J = 3.3, 2H); 4.38 (q 6.9.2H); 3.55 (br. S, 1H); 3.02 (br.s, 1H); 1.98-1.79 (m, 2H); 1.70-1.62 (m, 1H); 1.55 (d, J = 9.0, 1H); 1.39 (t, J = 6.9, 3H); 1.14-0.98 (m, 1H); 0.82-0.68 (m, 1H).

Intermediate 32bb: 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.24-7.17 (m, 2H); 6.95 (t, J = 8.4, 2H); 5.72 (d, J = 15.6.1H); 5.48 (d, 15.0, 1H); 4.29 (q, J = 7.2, 2H); 3.51 (br.s, 1H); 3.40 (br s, 1H); 1.94 (d, J = 6.0, 3H); 1.66 (d, J = 9.0, 1H); 1.35 (t, J = 7.2, 3H), 1.28-1.18 (m, 2H).

Step 2a: 1- (4-Fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid:

Intermediate 32a: (294 mg, 72%). 1H-NMR (δ ppm, DMSO-d6, 300 MHz): 12.42 (br. S, 1H); 7.36-7.25 (m, 2H); 7.20 (t, J = 9.0, 2H); 5.31 (br. S, 2H); 3.39 (br. S, 1H); 3.32 (br. S, 1H); 1.90-1.70 (m, 3H); 1.55 (d, J = 8.7.1H); 0.99-0.80 (m, 1H); 0.79-0.62 (m, 1H).

Step 2b: 2- (4-Fluorobenzyl) -4,5,6,7-tetrahydro-2H-4,7-methane-indazol-3-carboxylic acid:

Intermediate 32b: (55 mg, 60%). 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.25-7.17 (m, 2H); 6.96 (t, J = 8.7, 2H); 5.72 (d, J = 14.4, 1H); 5.50 (d, 15.3, 1H); 3.59 (br. S, 1H); 3.43 (br. S, 1H); 1.84 (d, J = 6.9, 3H); 1.69 (d, J = 8.4, 1H); 1.23 (d, J = 10.2, 2H).

Example 101

N (7) -Piperidine-5- (2-bromophenyl) -5,6-diazatetracyclo [7.3.1.13ll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide.

A solution of intermediate 1 (300 mg, 0.78 mmol) in DMF (3 mL) was treated with BOP reagent (319 mg, 0.72 mmol) and Et 3 N (0.10 mL, 0.99 mmol) at room temperature. 15 minutes after which time N-aminopiperidine (80 μΐ, 0.90mmol) was added to the mixture and stirred at room temperature for 1 h. The mixture was poured into water and the formed precipitate was collected by filtration, dried and flash chromatographed to achieve pure title compound (270 mg, 74%). M. p .: 244 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.72 (d, J = 7.6, 1Η); 7.65 (br. S, 1H); 7.50-7.30 (m, 3H; 3.97 (br. S, 1H); 2.85 (br. S, 4H); 2.51 (br. S, 1H); 2.16 (br s, 2H); 2, δ-δ, 50 (m, 14H); 1.40 (br. s, 2H). IR (cm -1, KBr): 3311 (w), 2913 (s), 2844 (m), 2793 (m), 1687 (s), 1570 (w), 1522 (s), 1489 (m), 1479 (m), 1440 (m), 1352 (m), 1227 (m), 1214 (m) MS (m / z) 469.4 ([M + H] +).

Example 102

N (7) -Benzyl-5- (2-bromophenyl) -5,6-diazatetracyclo [7.3.1.13'11.O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 1 (300 mg, 0.78 mmol), DMF (3 mL), Et 3 N (0.10 mL, 0.99 mmol), BOP reagent (319 mg 0.72 mmol) and benzylamine (80μl, 0.72 mmol) provided the title compound (280mg, 76%). M.p .: 201 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.70 (d, J = 7.5, 1H); 7.44 (dd, J = 7.5, 1.5, 1H); 7.41-7.20 (m, 8H); 4.63 (dd, J = 14.4, 6.0, 1H); 4.50 (dd, J = 16.5, 5.4, 1H); 4.00 (br. T, J = 5.1, 1H); 2.52 (br. T, J = 5.1, 1H); 2.13 (br. S, 2H); 2.13-1.92 (m, 4H); 1.92-1.65 (m, 6H). IR (cm -1, KBr): 3428 (m), 2908 (s), 2845 (m), 1672 (s), 1566 (m), 1522 (s), 1498 (s), 1472 (s), 1351 (m), 1087 (m), 1024 (m), 1010 (m), 778 (m), 763 (m), 726 (m), 698 (m) MS (m / z): 476.4 ( [M + H] +).

Example 103

N (7) -Morpholine-5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (40 μΐ, 0.29 mmol), BOP reagent (129 mg 0.29 mmol) and N-aminomorpholine (28 μΐ, 0.29 mmol) yielded the title compound (97 mg, 78%). Mp: 220 ° C. 1 H-NMR (δ ppm, CDCl 3, 300 MHz): 7.75 (br. S, 1H); 7.47 (d, J = 8.1, 2H); 7.29 (d, J = 8.1, 2H); 3.96 (br. S, 1H); 3.85 (t, J = 4.5.4Η); 2.99 (br. S, 1H); 2.95 (t, J = 4.5, 5H); 2.20 (br.s, 2H); 2.10-1.76 (m, 10H). IR (KBr, cm -1): 2915 (s), 2848 (m), 1674 (s), 1532 (m), 1498 (s), 1304 (m), 1267 (m), 1219 (m), 1112 (s), 1091 (s), 895 (m), 838 (s) MS (m / z): 427.3 ([M + H] +).

Example 104

N (7) - (3-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (48 μΐ, 0.34 mmol), BOP reagent (128 mg 0.29 mmol) and 3-aminomethylpyridine (30 μΐ, 0.29 mmol) provided the title compound (98 mg, 78%). M.P .: 180 ° C. 1H-NMR (δppm, DMSO-d6, 300 MHz): 8.76 (t, J = 6.0, 1H); 8.52 (br.s, 1H); 8.43 (dd, J = 4.8, 1.5, 1H); 7.70 (d, J = 8.1H); 7.62 (d, J = 8.4, 2H); 7.46 (d, J = 8.4, 2H); 7.34 (dd, J = 8.1, 4.8, 1H); 4.39 (d, J = 6.0, 2H); 3.80 (br.s, 1H); 2.95 (br. S, 1H); 2.14 (br. S, 2H), 2.00-1.69 (m, 10H). MS (m / z): 433.2 ([M + H] +).

Example 105

N (7) - (4-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (48 μΐ, 0.34 mmol), BOP reagent (128 mg 0.29 mmol) and 4-aminomethylpyridine ((30 μΐ, 0.29 mmol) provided the title compound (119 mg, 94%). MP: 167-168 ° C. 1H NMR (δ ppm, DMSO-d6 300 MHz): 8.79 (t, J = 6.3, 1H), 8.48 (d, J = 4.5, 2H), 7.65 (dd, J = 7.5, 1.5 7.48 (dd, J = 7.5, 1.5, 2H), 7.27 (d, J = 4.5, 2H), 4.39 (d, J = 5.7, 2H); 3.80 (br. S, 1H); 2.97 (br. S, 1H); 2.14 (br.s, 2H); 2.00-1.68 (m, 10H). (cm -1, KBr): 3212 (m), 2913 (s), 2850 (m), 1656 (s), 1529 (m), 1498 (s), 1419 (m), 1363 (m), 1232 ( m), 1160 (m), 1084 (m), 842 (m) MS (m / z): 433.1 ([Μ + Η] +).

Example 106

N (7) -Cyclohexyl-5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (40 μΐ, 0.29 mmol), BOP reagent (129 mg 0.29 mmol) and cyclohexylamine (40 µl, 0.29 mmol) provided the title compound (110 mg, 89%). Mp 162 ° C. 1H-NMR (δ ppm, CDCl3, 300MHz): 7.47 (d, J = 8.7, 2H); 7.30 (d, J = 8.7, 2H); 6.85 (d, J = 8.7, 1H); 4.01 (br. T, J = 5.5, 1H); 4.00-3.80 (m, 1H); 2.99 (br. T, J = 5.6, 1H); 2.20 (br s, 2H): 2.08-1.68 (m, 12H); 1.48-1.10 (m, 8H). IR (cm -1, KBr): 3336 (m), 2928 (s), 2909 (s), 2846 (m), 1649 (s), 1537 (s), 1498 (s), 1366 (m), 1231 (m), 1164 (m), 1088 (m), 838 (m) MS (m / z): 424.1 ([M + H] +).

Example 107

N (7) - (N-cyclohexy-N-methylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (250 mg, 0.72 mmol), DMF (3 mL), Et 3 N (0.22.0 mL, 1.60 mmol), BOP reagent (322 mg 0.72 mmol) and 3-N-cyclohexyl-N-methyl hydrazine (140 mg, 1.10 mmol) yielded the title compound (215 mg, 65%). 219 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.64 (br. S, 1H); 7.46 (d, J = 9.0.2H), 7.31 (d, J = 9.0, 2.1, 2H), 3.97 (br. S, 1H); 2.98 (br. S, 1H), 2.69 (s, 3H), 2.62 (br. S, 1H); 2.19 (br. S, 2H); 2.05-1.70 (m, 14H); 1.40-1.00 (m, 6H). IR (cm -1, KBr): MS (m / z): 453.20 ([M + H] +).

Example 108

N (7) -Cyclohexylmethyl-5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (100 mg, 0.29 mmol), Et 3 N (40 μπιΐ, 0.29 mmol), BOP reagent (129 mg, 0.29 mmol) and cyclohexanomethylamine (38 μΐ, 0.23 mmol) provided the title compound (93 mg, 73%). M.P .: 117 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.46 (d, J = 8.1, 2H); 7.29 (d, J = 8.1, 2H); 7.03 (br. S, 1H); 4.01 (br. S, 1H); 3.22 (t, J = 6.6, 2H); 3.00 (br.s, 1H); 2.20 (br. S, 2H); 2.10-1.50 (m, 15H); 1.40-1.10 (m, 4H), 1.10-0.85 (m, 2H). IR (cm -1, KBr): 3441 (m), 2924 (s), 2849 (m), 1670 (s), 1528 (m), 1499 (s), 1477 (m), 1364 (m), 1214 (m), 1232 (m), 1162 (w), 1087 (m), 838 (m) MS (m / z): 438.2 ([M + H] +).

Example 109

N (7) - (Adamantan-1-yl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (120 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (58 μΐ, 0.42 mmol), BOP reagent (154 mg 0.35 mmol) and 1-adamantylamine (52 mg, 0.35 mmol) provided the title compound (117 mg, 70%). M. p .: 249-252 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.47 (d, J = 8.7, 2H); 7.29 (d, J = 8.7.2H); 6.73 (br. S, 1H); 4.00 (br s, 1H); 2.98 (br. S, 1H); 2.23-1.54 (m, 27H). IR (cm -1, KBr): 3389 (s), 2904 (s), 2849 (m), 1674 (s), 1561 (w), 1527 (s), 1499 (s), 1479 (m), 1455 (m), 1364 (m), 1356 (m), 1232 (m), 1219 (m), 1170 (w), 1090 (m), 1014 (w), 837 (m) MS (m / z) : 476.2 ([M + H] +).

Example 110

N (7) - (IS, 2endo-1,3,3-Trimethyl-bicyclo [2,2,1] hepta-2-yl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (120 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (58 μΐ, 0.42 mmol), BOP reagent (154 mg 0.35 mmol) and 1,3,3-Trimethyl-bicyclo [2,2,1] hepta-2-ylamine (53 mg, 0.80 mmol) provided the title compound (135 mg, 80%) . M. p .: 229 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.91 (s, 1H); 7.47 (d, J = 8.7, 2H); 7.39 (d, J = 8.1, 2H); 7.34-7.20 (m, 3H); 6.99 (t, J = 8.8,1H); 3.86 (br. T, J = 4.8, 1H); 3.35 (s, 3H); 3.00 (br s, 1H); 2.17 (br. S, 2H); 2.00-1.70 (m, 10H). IR (cm -1, KBr): 3396 (s), 2909 (s), 2845 (m), 1685 (s), 1587 (m), 1563 (m), 1498 (s), 1475 (s), 1464 (s), 1438 (s), 1366 (m), 1223 (m), 1152 (m), 1092 (s), 1083 (m), 1014 (m), 837 (s) MS (m / z) : 478.3 ([M + H] +).

Example 111

N (7) - (2-Chlorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (40 µl, 0.29 mmol), BOP reagent (129 mg 0.29 mmol) and 2-chlorobenzylamine (35 μΐ, 0.29 mmol) yielded the title compound (102 mg, 75%). Mp 162-164 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.18 (m, 9H); 4.67 (d, J = 6,3,2H); 3.99 (br. T, J = 4.8, 1H); 3.00 (br. T, J = 4.8.1H); 2.20 (br. S, 2H); 2.00-1.70 (m, 10H). IR (KBr, cm -1): 3422 (m), 2916 (s), 2845 (m), 1670 (s), 1564 (m), 1531 (s), 1497 (s), 1478 (s), 1442 ( m), 1360 (m), 1249 (m), 1232 (m), 1163 (m), 1085 (s), 1047 (m), 1012 (m), 976 (m), 835 (m). m / z): 466.0 ([M + H] +).

Example 112

N (7) - (4-Chlorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (100 mg, 0.29 mmol), Et 3 N (40 μΐ, 0.29 mmol), BOP reagent (129 mg, 0.29 mmol) and 4 -chlorobenzylamine (36 μΐ, 0.29 mmol) provided the title compound (115 mg, 85%). MP: 198 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.45 (d, J = 8.7, 2H); 7.40-7.20 (m, 7H); 4.54 (d, J = 6.3, 2H); 4.00 (br. S, 1H); 3.00 (br s, 1H); 2.21 (br. S, 2H); 2.95, 95 (m, 2H); 1.95-1.70 (m, 8H). IR (cm -1, KBr): 3317 (m), 2914 (s), 2847 (m), 1657 (s), 1538 (s), 1498 (s), 1365 (m), 1247 (m), 1087 (m), 1015 (m); 839 (m) MS (m / z): 466.3 ([M + H] +).

Example 113

N (7) - (4-Fluorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11.O4,8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (40 μΐ, 0.29 mmol), BOP reagent (129 mg 0.29 mmol) and 4-fluorobenzylamine (33 μΐ, 0.29 mmol) provided the title compound (96 mg, 73%). M.p .: 201 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.44 (d, J = 8.4, 2H); 7.30-7.25 (m, 5H); 7.00 (t, J = 8.4, 2H); 4.54 (d, J = 6.0, 2H); 4.01 (br. S, 1H); 3.00 (br s, 1H); 2.20 (br. S, 2H); 2.05-1.95 (m, 2H); 1.95-1.80 (m, 8H). IR (cm -1, KBr): 3345 (m), 2921 (s), 2900 (m), 2850 (m), 1648 (s), 1542 (s), 1508 (s), 1364 (m), 1354 (m), 1258 (m), 1233 (m), 1217 (s), 1155 (m), 1087 (m), 834 (s). MS (m / z): 450.0 ([M + H] +).

Example 114

N (7) - (2,4-Difluorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (150 mg, 0.43 mmol), DMF (2.0 mL), Et 3 N (60 µl, 0.43 mmol), BOP reagent (193 mg 0.43 mmol) and 2,4-difluorobenzylamine (52 μΐ, 0.43 mmol) yielded the title compound (195 mg, 96%). 185 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.49-7.27 (m, 6H); 6.90-6.75 (m, 2H); 4.57 (d, J = 6.3, 2H); 3.98 (t, J = 5.7, 1H); 2.99 (br. T, J = 5.4, 1H), 2.20 (br. S, 2H), 2.05-1.80 (m, 10H). IR (cm -1, KBr): 3428 (s), 2920 (m), 2898 (m), 1673 (s), 1535 (s), 1500 (s), 1430 (s), 1229 (m), 1161 (m), 1064 (m), 986 (m), 835 (m), 960 (m), 861 (m) MS (m / z): 468.10 ([M + H] +).

Example 115

N (7) - (2,6-Difluorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (150 mg, 0.43 mmol), DMF (2.0 mL), Et 3 N (60 μΐ, 0.43 mmol), BOP reagent (193 mg 0.43 mmol) and 2,6-difluorobenzylamine (52 μΐ, 0.43 mmol) yielded the title compound (178 mg, 87%). 166-167 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.44 (d, J = 8.7, 2H); 7.30-7.20 (m, 3H); 6.88 (t, J = 7.8, 2H), 4.68 (d, J = 5.7, 2H), 4.00 (br. T, J = 5.4, 1H); 2.98 (br. S, 1H), 2.19 (br. S, 2H), 2.05-1.60 (m, 10H). IR (cm -1, KBr): 3427 (m), 2930 (m), 2905 (m), 1681 (s), 1594 (m), 1563 (m), 1530 (s), 1499 (s), 1471 (s), 1364 (m), 1260 (m), 1161 (m), 1087 (s), 994 (s), 839 (m) MS (m / z): 468.10 ([M + H] +).

Example 116

N (7) - (4-Trifluoromethylbenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (100 mg, 0.29 mmol), Et 3 N (40 μΐ, 0.29 mmol), BOP reagent (129 mg, 0.29 mmol) and 4 - (trifluoromethyl) benzylamine (42 Dl, 0.27 mmol) provided the title compound (115mg, 79%). M. p .: 228 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.57 (d, J = 8.6, 2H); 7.46-7.39 (m, 4H); 7.37 (br. T, J = 5.4, 1H); 7.28 (d, J = 8.7, 2H); 4.63 (d, J = 6.0, 2H); 3.99 (br. T, J = 4.2, 1H); 3.00 (br s, 1H); 2.21 (br. S, 2H); 2.05-1.96 (m, 2H); 1.96-1.84 (m, 8H). IR (cm -1, KBr): 3350 (m), 2916 (s), 2850 (m), 1647 (s), 1618 (m), 1541 (s), 1498 (s), 1325 (s), 1256 (m), 1232 (m), 1159 (s), 1124 (s), 1112 (s), 1086 (s), 1065 (s), 1015 (m), 978 (m), 850 (m), 834 (m)

Example 117

N (7) - (I-Phenylethyl)) - 5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (150 mg, 0.43 mmol), DMF (2.0 mL), Et 3 N (60 μΐ, 0.43 mmol), BOP reagent (193 mg 0.43 mmol) and S - (-) - Phenylethylamine (58 μΐ, 0.43 mmol) provided the title compound (130 mg, 67%). 85-86 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.40 (m, 5H); 736-7.20 (m, 4H); 5.27 (quintet, 7.2, 1H); 4.00 (t, J = 5.6, 1H); 2.98 (t, J = 5.6, 1H), 2.19 (br. S, 2H), 2.10-1.75 (m, 10H), 1.57 (d, J = 6.9 , 3H). IR (cm -1, KBr): 3410 (m), 2913 (s), 2845 (m), 1667 (s), 1526 (s), 1498 (s), 1478 (s), 1363 (m), 1219 (m), 1160 (m), 1084 (s), 1014 (m), 835 (m), 699 (m) MS (m / z): 446.10 ([M + H] +).

Example 118

N (7) - (R-1-Phenylethyl)) - 5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (46 μΐ, 0.32 mmol), BOP reagent (136 mg 0.32 mmol) and R-phenylethylamine (39 mg, 0.32 mmol) provided the title compound (90 mg, 69%). Mp 65-70 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.18 (m, 10H); 5.35-5.18 (m, 1H); 4.00 (br. S, 1H); 2.98 (br. S, 1H); 2.19 (br. S, 2H); 2.10-1.71 (m, 10H); 1.57 (d, J = 6.9, 3H). IR (cm -1, KBr): 3408 (s), 3062 (w), 3029 (w), 2914 (s), 2845 (s), 1667 (s), 1596 (w), 1585 (w), 1526 (s), 1498 (s), 1478 (s), 1441 (s), 1406 (m), 1363 (τη), 1353 (w), 1271 (m), 1232 (s), 1218 (m), 1159 (m), 1083 (s), 1033 (m), 1013 (m), 933 (w), 835 (m) MS (m / z): 446.3 ([Μ + Η] +).

Example 119

N (7) - (1-Methyl-1-phenylethyl)) - 5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (46 μΐ, 0.32 mmol), BOP reagent (136 mg 0.32 mmol) and α, α-dimethylbenzylamine (48 mg, 0.36 mmol) provided the title compound (90 mg, 67%). M.p .: 181 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.47 (br. D, J = 8.7, 4H); 7.36-7.28 (m, 5H); 7.22 (br. T, J = 7.2, 1H); 3.92 (br. S, 1H); 3.35 (s, 3H); 2.99 (br. S, 1H); 2.18 (br s, 2H); 2.00-1.74 (m, 10H); 1.79 (s, 6H). IR (cm -1, KBr): 3407 (m), 3090 (w), 3060 (w), 3024 (w), 2965 (w), 2898 (s), 2845 (m), 1675 (s), 1563 (w), 1497 (s), 1479 (s), 1438 (m), 1407 (w), 1379 (w), 1362 (m), 1340 (w), 1254 (w), 1231 (w), 1219 (w), 1194 (w), 1159 (w), 1085 (m), 1031 (w), 1015 (m), 834 (m) MS (m / z): 460.1 (25, [M + H] +) 342.3 (100).

Example 120

N (7) - (2-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (48 μΐ, 0.34 mmol), BOP reagent (128 mg 0.29 mmol) and 2-aminomethylpyridine ((30 μΐ, 0.29 mmol) provided the title compound (98 mg, 78%). MP: 187 ° C. 1H NMR (δppm, DMSO-d6, 300 MHz ): 8.66 (t, J = 6.0, 1H); 8.49 (br.d, J = 5.1, 1H); 7.76 (td, J = 7.6, 1.8; 7.64 (d, J = 9.0, 2H); 7.51 (d, J = 9.0, 2H); 7.31 (d, J = 7.6, 1H); 26 (m, 1H); 4.50 (d, J = 6.0, 2H); 3.82 (br. S, 1H); 2.98 (br. S, 1H); 2.15 (br. s, 2H), 2.00-1.70 (m, 10H) .IV (cm -1, KBr): 2918 (m), 2847 (m), 1781 (s), 1496 (s), 1443 (m ), 1366 (m), 1230 (m), 1113 (m), 1089 (m), 1059 (m), 835 (m) MS (m / z): 433.2 ([M + H] +) .

Example 121

N (7) - (N'-phenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13 ^ 1-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (200 mg, 0.29 mmol), Et 3 N (80 μΐ, 0.58 mmol), BOP reagent (258 mg, 0.58 mmol) and phenylhydrazine (60 μΐ, 0.58mmol) provided the title compound (185 mg, 73%). MP: 103-105 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.59 (s, 1H); 7.48 (d, J = 8.7, 2H); 7.33 (d, J = 8.7, 2H); 7.22 (t, J = 7.5, 2H); 6.94 (d, J = 8.7, 2H); 6.88 (t, J = 7.5, 1H); 3.89 (br. T, J = 4.7, 1H); 3.03 (br. S, J = 3.5, 1H); 2.20 (br. S, 2H); 2.00-1.75 (m, 10H). IR (cm -1, KBr): 3279 (m), 2912 (s), 2845 (m), 1678 (s), 1603 (m), 1497 (s), 1467 (m), 1353 (m), 1232 (m), 1090 (m), 1012 (m), 835 (m) MS (m / z): 433.1 ([M + H] +).

Example 12 2

N (7) - (N'-phenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo hydrochloride [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

A solution of Example 121 (100 mg, 0.23 mmol) in ether (2.0 mL) was treated with a saturated solution of HCl in ether (2.0 mL) at RT and stirred at RT for 1 hour and solid precipitated. filtered to yield the title compound (90 mg, 73%). 135-136 ° C. 1H-NMR (δ ppm, DMSO-ds, 300 MHz): 9.95 (s, 1H); 7.65 (d, J = 9.0, 2H); 7.52 (d, J = 9.0, 2H); 7.13 (t, J = 7.8, 2H); 6.74 (d, J = 7.5, 2H); 6.69 (t, J = 7.5, 1H); 3.67 (br. S, 1H); 3.02 (br. S, 1H); 2.15 (br. S, 2H); 2.00-1.71 (m, 10H). IR (cm -1, KBr): 3419 (br. S), 3020 (m), 1642 (s), 1498 (m), 1216 (m), 1092 (w), 1014 (w), 836 (m) MS (m / z): 433.3 ([+ +] +).

Example 12 3

N (7) - (2-Chlorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (200 mg, 0.58 mmol), Et 3 N (90 μΐ, 0.64 mmol), BOP reagent (258 mg, 0.58 mmol) and 2-chlorophenylhydrazine hydrochloride (104 mg, 0.58 mmol) provided the title compound (168 mg, 62%). M.P .: 155 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 8.60 (s, 1H); 7.49 (d, J = 8.7,2H); 7.38-7.20 (m, 3H); 7.11 (t, J = 7.2,1H); 7.04 (dd, J = 7.5, 1.5, 1H); 6.82 (t, J = 7.6, 1H); 6.56 (br. S, 1H); 3.90 (br. S, 1H); 3.03 (br. S, 1H); 2.20 (br. S, 2H); 2.01-1.70 (m, 10H). IR (cm -1, KBr): 3376 (m), 3310 (m), 2909 (m), 1683 (s), 1597 (m), 1563 (w), 1498 (s), 1470 (s), 1423 (w), 1364 (m), 1212 (m), 1088 (m), 1026 (m), 835 (m) MS (m / z): 467.9 ([M + H] +).

Example 124

N (7) - (2-Chlorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo hydrochloride [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (250 mg, 0.73 mmol), DMF (3 mL), Et 3 N (0.12.0 mL, 0.86 mmol), BOP reagent ( 322 mg, 0.73 mmol) and N- (2-chlorophenyl) -N-methylhydrazine hydrochloride (220 mg, 0.80 mmol) provided the title compound (210 mg, 60%). M. p .: 229 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.91 (s, 1H); 7.47 (d, J = 8.7, 2H); 7.39 (d, J = 8.1, 2H); 7.34-7.20 (m, 3H); 6.99 (t, J = 8.8,1H); 3.86 (br. T, J = 4.8, 1H); 3.35 (s, 3H); 3.00 (br s, 1H); 2.17 (br. S, 2H); 2.00-1.70 (m, 10H). IR (cm -1, KBr): 3396 (s), 2909 (s), 2845 (m), 1685 (s), 1587 (m), 1563 (m), 1498 (s), 1475 (s), 1464 (s), 1438 (s), 1366 (m), 1223 (m), 1152 (m), 1092 (s), 1083 (m), 1014 (m), 837 (s).

N (7) - [(4-chlorophenyl) amino)] - 5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (100 mg, 0.29 mmol), Et 3 N (0.27 mL, 1.94 mmol), BOP reagent (129 mg, 0.29 mmol) and 4-chlorophenylhydrazine hydrochloride (52 mg, 0.29 mmol) provided the title compound (105 mg, 77%). 208-210 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.58 (s, 1H); 7.49 (d, J = 8.4.2H); 7.33 (d, J = 8.4, 2H); 7.18 (d, J = 8.7, 2H); 6.88 (d, J = 8.7, 2H); 6.00 (br s, 1H); 3.87 (br. S, 1H); 3.03 (br. S, 1H); 2.20 (s, 2H); 2.00-1.70 (m, 10H). IR (cm -1, KBr): 3282 (m), 2912 (s), 2845 (m), 1670 (s), 1596 (m), 1498 (s), 1470 (s), 1253 (m), 1231 (m), 1091 (s), 1013 (m), 834 (m) MS (m / z): 467.2 ([M + H] +).

Example 126

N (7) - (2,4-Dichlorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (200 mg, 0.58 mmol), Et 3 N (90 μΐ, 0.65 mmol), BOP reagent (258 mg, 0.58 mmol) and 2,4-dichlorophenylhydrazine hydrochloride (125 mg, 0.59 mmol) provided the title compound (226 mg, 77%). 214-215 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.60 (s, 1H); 7.49 (d, J = 8.7,2H); 7.40-7.22 (m, 3H); 7.11 (dd, J = 8.7, 2.4, 1H); 6.97 (d, J = 8.7,1H); 6.49 (br. S, 1H); 3.87 (br. T, J = 4.61, 1H); 3.03 (br. S, 1H); 2.20 (br. S, 2H); 2.04-1.70 (m, 10H). IR (cm -1, KBr): 3300 (m), 2907 (m), 2845 (m), 1681 (s), 1498 (s), 1471 (s), 1232 (m), 1089 (m), 863 (m), 837 (m).

Example 127

N (7) - [(2,4-Dichlorophenyl-N'-methylamino] -5- (4-chlorophenyl) -5,6-diazatetracyclo [7,3,11,11,10,48] tetradeca-4 (8 ), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (300 mg, 0.88 mmol), DMF (3.0 mL), Et 3 N (0.15 mL, 1.05 mmol), BOP reagent ( 387 mg, 0.88 mmol) and N- (2,4-dichlorophenyl) -N-methylhydrazine (296 mg, 0.97 mmol) provided the title compound (220 mg, 49%). Mp: 192 ° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.90 (s, 1H); 7.44 (dt, J = 8.8, 2.0, 2H); 7.29-7.26 (m, 4H); 7.17 (dd, J = 8.4, 2.4, 1H); 3.80 (br s, 1H); 3.30 (s, 3H); 2.97 (br.s, 1H); 2.15 (s, 2H); 1.86-1.75 (m, 10H). IR (cm -1, KBr): 3396 (s), 2909 (s), 2845 (m), 1685 (s), 1587 (m), 1563 (m), 1498 (s), 1475 (s), 1464 (s), 1438 (s), 1366 (m), 1223 (m), 1152 (m), 1092 (s), 1083 (m), 1014 (m), 837 (s). MS (m / z): 514.9 ([M + H] +).

Example 128

N (7) - [(2,4-Dichlorophenyl-N'-methylamino] -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 hydrochloride (8 ), 6-diene-7-carboxamide.

A solution of Example 127 (100 mg, 0.19 mmol) in ether (2.0 mL) was treated with ether, saturated with HCl (2.0 mL) and kept at RT for 1 hour and precipitated solid was filtered to yield the title compound. title compound (102 mg, 95%). M.p .: 203 ° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.86 (s, 1H); 7.53 (d, J = 7.2, 2H); 7.42-7.36 (m, 3H); 7.33 (d, J = 1.7, 1H); 7.20 (dd, J = 8.8, 1.7, 1H); 3.29 (s, 3H); 2.99 (br. S, 1H); 2.21 (s, 2H); 1.88 (m, 4H); 1.88-1.80 (m, 6H). IR (cm -1, KBr): 3386 m), 3197 (m), 2916 (s), 2901 (s), 2845 (m), 1687 (s), 1474 (s), 1439 (s), 1260 ( m), 1323 (m), 1241 (m), 1124 (m), 1106 (m), 1089 (s), 1012 (m), 938 (m), 845 (m), 829 (m). m / z): 515.0 ([M-HCl + H] +).

Example 129

N (7) - (2,4-Dichlorophenyl-N'-cyclohexylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (200 mg, 0.58 mmol), Et 3 N (0.26 mL) , 1.87 mmol), BOP reagent (258 mg, 0.58 mmol) and N-cyclohexyl-N- (2,4-dichlorophenyl) hydrazine hydrochloride (427 mg, 1.28 mmol) provided the title compound (162 mg, 48%) MP: 95 - 96 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.72 (s, 1H); 7.47 (d, J = 8.4, 2H); 7.42 (d, J = 8.7,1H); 7.40 - 7.20 (m, 3H); 7.17 (dd, J = 8.7, 2.4, 1H), 3.86 (br. T, J = 5.2, 1H); 3.75 (br. S, 1H); 2.99 (br. S, 1H); 2.17 (s, 2H), 2.00-1.70 (m, 14H), 1.43-1.10 (m, 6H). IR (cm -1, KBr): 3400 (m), 2919 (s), 2850 (s), 1683 (s), 1564 (w), 1498 (s), 1474 (s), 1363 (m), 1233 (m), 1218 (m), 1100 (m), 1062 (m), 833 (m), 753 (w) MS (m / z): 583.1 ([M + H] +).

Example 13 0

N (7) - (4-Fluorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (200 mg, 0.58 mmol), Et 3 N (0.16 mL, 1.15 mmol), BOP reagent (258 mg, 0.58 mmol) ) and 4-fluorophenylhydrazine hydrochloride (95 mg, 0.58 mmol) provided the title compound (218 mg, 83%). 125-127 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.59 (s, 1H); 7.48 (d, J = 8.6,2H); 7.32 (d, J = 8.6, 2H); 7.00-6.80 (m, 4H); 3.88 (br.s, 1H); 3.03 (br. S, 1H); 2.20 (br. S, 2H); 2.05-1.70 (m, 10H). IR (cm -1, KBr): 3263 (m), 2912 (s), 2847 (m), 1671 (s), 1508 (s), 1498 (s), 1475 (m), 1234 (m), 1219 (m), 1088 (m), 884 (w), 831 (m) MS (m / z): 451.0 ([M + H] +).

Example 131

N (7) - (4-Fluorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo hydrochloride [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide.

A solution of Example 130 (100 mg, 0.22 mmol) in ether (2.0 mL) was treated with a saturated solution of ether HCl (2.0 mL) at RT and stirred at RT for 1 hour and the solid precipitated was diluted and washed with ether to yield the title compound (106 mg, 98%). M.p .: 175 ° C.

1H-NMR (δ ppm, DMS0-d6, 300 MHz): 9.99 (s, 1H); 7.64 (d, J = 8.5, 2H); 7.50 (d, J = 8.5, 2H); 6.98 (t, J = 8.7,2H); 6.74 (dd, J = 8.7, 4.8, 2H); 3.67 (br. S, 1H); 3.01 (br. S, 1H); 2.15 (s, 2H); 2.00-1.70 (m, 10H). IR (cm -1, KBr): 3247 (br.m), 2916 (m), 2844 (m), 1694 (s), 1507 (s), 1498 (s), 1234 (s), 1089 (m) , 1014 (m), 990 (w), 836 (m) MS (m / z): 451.0 ([M + H] +).

Example 132

N (7) - (2,4-Difluorophenylamino] -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7- carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (200 mg, 0.58 mmol), Et 3 N (22 μΐ, 1.58 mmol), BOP reagent (258 mg, 0.58 mmol) and hydrochloride of 2,4-difluorophenylhydrazine (105 mg, 0.58 mmol) gave 20 NMR (δ ppm, CDCl 3, 300 MHz): 8.56 (s, 1H); 7.49 (d, J = 9.0, 2H); 7.32 (d, J = 9.0, 2H); 7.01 (m, 1H); 6.86-6.74 (m, 2H); 6.24 (br. S, 1H); 3.87 (br. T, J = 4.6, 1H); 3.03 (br. S, 1H); 2.20 (br. S, 2H); 2.02-1.78 (m, 10H).

IR (cm -1, KBr): 3276 (w), 2912 (m), 2846 (w), 1683 (s), 1499 (s), 1467 (m), 1137 (m), 1114 (m), 848 (m), 836 (m) .MS (m / z): 469.1 ([M + H] +).

Example 133

N (7) - (3-fluorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (250 mg, 0.72 mmol), DMF (3 mL), Et 3 N (0.22.0 mL, 1.60 mmol), BOP reagent (322 mg 0.72 mmol) and 3-fluorophenylhydrazine hydrochloride (119 μΐ, 0.72 mmol) yielded the title compound (165 mg, 50%). M.p .: 203 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 8.58 (s, 1 H); 7.51 (d, J = 9.0.2H); 7.33 (d, J = 9.0, 2H), 7.16 (q, J = 6.6, 1H); 6.72-6.53 (m, 3H); 3.88 (br s, 1H); 3.03 (br. S, 1H); 2.21 (br. S, 2H); 2.05-1.80 (m, 10H). IR (cm -1, KBr): 3259 (m), 2913 (s), 1617 (s), 1601 (m), 1498 (s), 1442 (m), 1269 (m), 1234 (m), 1140 (m), 1089 (s), 1012 (m), 832 (m), 760 (m), 679 (m) MS (m / z): 451.10 ([M + H] +).

Example 134

N (7) - (3-Chloro-2-pyridylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11. O4,8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (150 mg, 0.44 mmol), DMF (1.5 mL), Et 3 N (68 µΐ, 0.48 mmol), BOP reagent (203 mg 0.46 mmol) and 3-chloro-2-hydrazinopyridine (69 mg, 0.48 mmol) provided the title compound (170 mg, 83%). 200-203 ° C. 1H-NMR (δ ppm, DMSO-dg, 300 MHz): 9.85 (s, 1H); 8.46 (s, 1H); 8.0 (dd, J = 4.5, 1.5, 1H); 7.69 (dd, J = 7.5, 1.5, 1H); 7.66 (d, J = 8.7, 2H); 7.51 (d, J = 9.0, 2H); 6.75 (dd, J = 7.8, 4.8, 1H); 3.73 (br. S, 1H); 3.02 (br. S, 1H); 2.15 (br. S, 2H); 2.00-1.70 (m, 10H). IR (cm -1, KBr): 3382 (m), 2902 (m), 2846 (m), 1683 (m), 1664 (m); 1589 (s), 1498 (s), 1455 (s), 1401 (m), 1229 (m), 1117 (m), 1089 (m), 1030 (m), 833 (m). MS (m / z): 468.10 ([M + H] +).

Example 135

N (7) - (5-Chloro-2-pyridylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7 -carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (150 mg, 0.44 mmol), DMF (1.5 mL), Et 3 N (68 µΐ, 0.48 mmol), BOP reagent (203 mg 0.46 mmol) and 5-chloro-2-hydrazinopyridine (70 mg, 0.49 mmol) provided the title compound (170 mg, 83%). 130-135 ° C. 1H-NMR (δ ppm, DMS0-d6, 300 MHz): 10.02 (s, 1H); 8.62 (s, 1H); 8.06 (d, J = 2.4, 1H); 7.66 (d, J = 8.5, 2H); 7.60 (dd, J = 8.7, 2.5, 1H); 7.51 (d, J = 8.5, 2H); 6.60 (d, J = 8.7.1H); 3.69 (br. S, 1H); 3.01 (br. S, 1H); 2.15 (br. S, 2H); 2.00-1.70 (m, 10H). IR (cm -1, KBr): 3285 (m), 2909 (s), 2847 (m), 1671 (s), 1595 (m), 1498 (s), 1477 (s), 1364 (m), 1255 (m), 1233 (m), 1089 (m), 1012 (m), 832 (m) MS (m / z): 468.10 ([M + H] +).

Example 136

N (7) - (2-Phenylethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (100 mg, 0.29 mmol), Et 3 N (40 μΐ, 0.29 mmol), BOP reagent (129 mg, 0.29 mmol) and phenothylamine (36 μΐ, 0.29 mmol) provided the title compound (105 mg, 81%). M. p .: 144 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.46 (d, J = 8.7.2H); 7.35-7.18 (m, 7H); 7.07 (br. T, J = 7.5, 1H); 3.99 (br. T, J = 4.7, 1H); 3.63 (q, J = 7.5, 2H); 3.00 (br. T, J = 4.7, 1H); 2.90 (t, J = 7.5, 2H); 2.20 (br. S, 2H); 2.05-1.95 (m, 2H); 1.94-1.75 (m, 8H). IR (cm -1, KBr): 3398 (m), 2913 (s), 2843 (m), 1673 (s), 1538 (s), 1498 (s), 1483 (s), 1382 (m), 1231 (m), 1086 (m), 998 (m), 839 (m) MS (m / z): 446.1 ([M + H] +).

Example 137

N (7) - (N ', N'-Diphenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (300 mg, 0.88 mmol), DMF (3 mL), Et 3 N (0.27 mL, 1.94 mmol), BOP reagent (387 mg 0.88 mmol) and N, N-diphenylhydrazine hydrochloride (192 mg, 0.87 mmol) provided the title compound (370 mg, 83%). M. p .: 214 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 9.04 (s, 1H); 7.47 (d, J = 8.4.2H); 7.33 (d, J = 8.4, 2H); 7.28-7.20 (m, 8H); 7.00 (t, J = 8.4, 2H); 3.94 (br. S, 1H); 3.03 (br. S, 1H); 2.20 (s, 2H); 2.05-1.80 (m, 10H). IR (cm -1) KBr): 3384 (m), 2912 (m), 2900 (m), 1702 (s), 1591 (τη), 1497 (s), 1466 (τη), 1277 (w), 1235 (w), 1092 (m), 1012 (w) MS (m / z): 509.4 ([Μ + ΗΓ).

Example 138

Ν (7) - [1- (2-Chlorophenyl) ethyl] -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 2 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (48 μΐ, 0.34 mmol), BOP reagent (141 mg 0.31 mmol) and (±) -1- (2-chlorophenylethylamine (48 μ, 0.29 mmol) provided the title compound (104 mg, 77%). Mp: 198 ° C. 1H NMR (δppm (CDCl 3, 300 MHz): 7.48-7.18 (m, 8H); 5.27 (quintet, J = 7.2, 1H); 3.99 (br. S, 1H); 2.98 ( br, s, 1H), 2.18 (br. s, 2H), 2.06-1.74 (m, 10H), 1.56 (d, J = 7.2, 3H).

IR (cm -1, KBr): 3400 (m), 2915 (s), 2880 (s), 1666 (s), 1498 (s), 1528 (s), 1480 (s), 1362 (m), 1229 (m), 1085 (m), 1012 (w), 834 (m), 696 (m).

Example 13 9

N (7) -Benzyl-5- (4'-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized according to the procedure described for Example 101 using Intermediate 2 (100 mg, 0.29 mmol), DMF (1 mL), triethylamine (0.04 mL, 0.29 mmol), BOP reagent. (128 mg, 0.29 mmol) and benzylamine (0.031 mL, 0.291 mmol) to provide the title compound (72 mg, 57%). M. p .: 160-166 ° C. 1H-NMR (δ ppm, CDCl3): 7.45 (d, J = 8.4, 2H); 7.39-7.21 (m, 7H); 4.58 (d, J = 6.0, 2H); 4.02 (t, J = 5.4, 1H); 3.00 (br. T, J = 4.7, 1H); 2.20 (br. D, 2H); 2.04-1.77 (m, 10H). IR (cm -1, KBr): 3471 (m), 3403 (m), 2919 (s), 2884 (m), 1672 (s), 1534 (m), 1499 (s).

Example 14 0

N (7) -Piperidine-5- (4'-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized according to the procedure described for Example 101 using intermediate 2 (100 mg, 0.291 mmol), triethylamine (0.04 ml, 0.29 mmol), BOP reagent (128 mg, 0.29 mmol) and 1-aminopiperidine (0.031ml, 0.291 mmol) to provide the title compound (85 mg, 68%). 185-188 ° C. 1H-NMR (δ ppm, CDCl3): 7.67 (br. S, 1H); 7.46 (d, J = 8.7, 2H) 7.29 (d, J = 8.7, 2H); 3.99 (br. T, J = 5.4, 1H); 2.99 (br. T, 1H); 2.85 (br. S, 4H); 2.19 (br. S, 2H); 2.06-1.69 (m, 14H); 1.44-1.38 (m, 2H). IR (cm -1, KBr): 3436 (m), 3320 (m), 2921 (s), 2853 (m), 1694 (m), 1668 (s), 1499 (m).

Example 141

7- (4'-Chlorophenyl) -6,7-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -5-dien-5-yl-piperidinomethanone

The title compound was synthesized according to the procedure described for Example 101 using intermediate 2 (100 mg, 0.291 mmol), triethylamine (0.04 ml, 0.29 mmol), BOP reagent (128 mg, 0.29 mmol) epiperidine. (0.028 mL, 0.291 mmol) to afford the title compound (85 mg, 71%). M. p .: 151-153 ° C. 1H-NMR (δ ppm, CDCl3): 7.43 (d, J = 9.0); 7.31 (d, J = 9.0); 3.70 (br. S, 2H); 3.55 (t, J = 5.1, 2H); 3.00-3.10 (m, 2H); 2.21 (br. S, 2H); 2.05-1.78 (m, 10H); 1.75-1.50 (m, 18H). IR (cm -1, KBr): 2913 (m), 1634 (s), 1498 (m).

Example 142

N (7) -Phenyl-5- (4'-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized according to the procedure described for Example 101 using intermediate 2 (100 mg, 0.291 mmol), triethylamine (0.04 ml, 0.29 mmol), BOP reagent (128 mg, 0.29 mmol) and aniline (0.026 mL, 0.29 mmol) to afford the title compound (95 mg, 77%). M.P .: 188-190 ° C. 1H-NMR (δ ppm, CDCl3): 8.78 (br. S, 1H); 7.67 (d, J = 8.4, 2H); 7.50 (d, J = 8.7, 2H); 7.30-7.37 (m, 4H); 7.12 (t, J = 8.4, 1H); 4.05 (t, J = 5.4, 1H); 3.02 (t, J = 4.8, 1H); 2.22 (br.s, 2H); 2.10-1.75 (m, 10H). IR (cm -1, KBr): 3365 (m), 2915 (m), 2844 (m), 1682 (s), 1532 (s), 1498 (s).

Example 143

N (7) -Piperidine-5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 3 (100 mg, 0.30 mmol), DMF (1.0 mL), Et 3 N (42 μΐ, 0.31 mmol), BOP reagent (135 mg 0.31 mmol) and N-aminopiperidine (33 μΐ, 0.31 mmol) provided the title compound (96 mg, 73%). 215 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.61 (br. S, 1H); 7.49-7.40 (m, 1H); 7.05-6.95 (m, 2H); 3.96 (br. S, 1H); 2.86 (br. S, 4H); 2.65 (br. S, 1H); 2.18 (br s, 2H), 2.04-1.90 (m, 2H); 1.85-1.62 (m, 12H); 1.42 (br. S, 2H). IR (cm -1, KBr): MS (m / z): 427.20 ([M + H] +)

Example 144

N (7) - (Adamant an-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 3 (150 mg, 0.44 mmol), DMF (1.0 mL), Et 3 N (72 μΐ, 0.52 mmol), BOP reagent (192 mg 0.44 mmol) and 1-adamantylamine (65 mg, 0.44 mmol) provided the title compound (156 mg, 75%). M. p .: 221-224 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.38 (m, 1H); 7.06-6.93 (m, 2H); 6.68 (br. S, 1H); 3.97 (br. S, 1H); 3.35 (br s, 3H); 2.22-1.54 (m, 27H). IR (cm -1, KBr): 3394 (m), 2915 (s), 2850 (s), 1669 (s), 1611 (m), 1566 (m), 1520 (s), 1483 (m), 1440 (m), 1359 (m), 1353 (m), 1273 (m), 1225 (m), 1220 (τη), 1140 (m), 1092 (m), 1082 (m), 966 (m), 850 (m) .MS (m / z): 478.2 ([M + H] +).

N (7) - (IS, 2endo-1,3,3-Trimethyl-bicyclo [2,2,1] hepta-2-yl) -5- (2,4-difluorophenyl) -5,6-

diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 3 (150 mg, 0.44 mmol), DMF (1.0 mL), Et 3 N (72 µl, 0.52 mmol), BOP reagent (192 mg 0.44 mmol) and 2-amino-1,3,3-trimethyl-bicyclo [2,2,1] heptane (66 mg, 0.44 mmol) provided the title compound (176 mg, 84%). M. p .: 235-23.8 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.51-7.42 (m, 1H); 7.07-6.95 (m, 3H); 3.98 (br. S, 1H); 3.72 (d, J = 6.0.1H); 2.67 (br. S, 1H); 2.18 (br. S, 2H); 2.06-1.54 (m, 13H); 1.54-1.28 (m, 2H); 1.28-1.14 (m, 2H); 1.16, 1.10.0.85 (3s, 9H). IR (cm -1, KBr): 3419 (s), 2927 (s), 2905 (s), 2870 (m), 1669 (s), 1567 (m), 1515 (s), 1480 (m), 1442 (m), 1366 (m), 1275 (m), 1226 (m), 1226 (τη), 1097 (m), 1080 (m), 967 (m), 858 (m), 845 (m). (m / z): 480.320 ([M + H] +).

Example4 6

N (7) - (N-phenylethyl)) - 5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7- carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 3 (150 mg, 0.46 mmol), DMF (1.5 mL), Et 3 N (75 μΐ, 0.51 mmol), BOP reagent ( 214 mg, 0.53 mmol) and SI-phenylethylamine (65 μΐ, 0.50 mmol) provided the title compound30 (120 mg, 58%). M.p .: 123-128 ° C. 7.50-7.13 (m, 7H); 7.06-6.94 (m, 2H); 5.27 (quintet, J = 7.2, 1H); 3.97 (br. S, 1H); 2.65 (br. S, 1H); 2.17 (br. S, 2H); 2.06-1.74 (m, 10H); 1.56 (d, J = 7.2, 3H). IR (cm -1, KBr): 3404 (m), 2911 (s), 2846 (m), 1668 (s), 1519 (s), 35 1480 (m), 1439 (m), 1367 (w), 1352 (w), 1275 (m), 1227 (m), 1145 (m), 1081 (m), 966 (w), 854 (m) MS (m / z): 448.2 ([M + H ] +). Example 147

N (7) - (R-1-phenylethyl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 3 (150 mg, 0.46 mmol), DMF (1.5 mL), Et 3 N (75 μΐ, 0.51 mmol), BOP reagent (214 mg 0.53 mmol) and R 1 -phenylethylamine (65 μΐ, 0.50 mmol) provided the title compound (125 mg, 61%). M.p .: 123-128 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.12 (m, 7H); 7.06-6.94 (m, 2H); 5.27 (quintet, J = 7.5, 1H); 3.97 (br. S, 1H); 2.65 (br.s, 1H); 2.17 (br. S, 2H); 2.07-1.70 (m, 10H); 1.56 (d, J = 7.5, 3H). IR (cm -1, KBr): 3404 (m), 2911 (s), 2846 (m), 1669 (s), 1519 (s), 1480 (m), 1439 (m), 1367 (w), 1352 (w), 1275 (m), 1227 (m), 1145 (m), 1081 (w), 966 (m), 853 (m) MS (m / z): 448.2 ([M + H] +).

Example 148

N (7) - (1-Methyl-1-phenylethyl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11.O4'8] tetradeca-4 (8), 6- diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 3 (150 mg, 0.46 mmol), DMF (1.5 mL), Et 3 N (75 μΐ, 0.51 mmol), BOP reagent (214 mg 0.53 mmol) and α, α-dimethylbenzylamine (68 mg, 0.51 mmol) provided the title compound (70 mg, 33%). 150-152 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.60-7.41 (m, 3H); 7.33 (t, J = 7.2, 2H); 7.22 (t, J = 7.2,1H); 7.05-6.95 (m, 2H); 3.89 (br s, 1H); 2.65 (br. S, 1H); 2.16 (br. S, 2H); 2.00-1.54 (m, 10H); 1.78 (s, 6H). IR (cm -1, KBr): 3419 (m), 2906 (m), 1678 (s), 1519 (s), 1276 (m), 1261 (m), 1134 (m), 968 (m), 848 (m) MS (m / z): 462.2 (100, [M + H] +), 344.1 (90).

Example 149

N (7) - (2-Chlorobenzyl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13ill-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 3 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (48 µl, 0.34 mmol), BOP reagent (128 mg 0.29 mmol) and 2-chlorobenzylamine (55 µl, 0.46 mmol) provided the title compound (152 mg, 71%). M.p .: 136 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.51-7.39 (m, 3H); 7.35 (dd, J = 7.5, 2.4, 1H); 7.24-7.18 (m, 2H); 7.05-6.95 (m, 2H); 4.67 (d, J = 6.0, 2H); 3.98 (t, J = 5.4, 1H); 2.67 (br. S, 1H); 2.19 (br. S, 2H), 2.10-1.95 (m, 2H); 1.95-1.65 (m, 10H). IR (cm -1, KBr): 3329 (m), 2918 (s), 2849 (m), 1648 (s), 1537 (m), 1515 (m), 1442 (m), 1220 (m), 1083 (m), 1051 (m), 750 (m) MS (m / z): 468.0 ([M + H] +).

Example 150

N (7) - (2,4-Dichlorophenylamino) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7 -carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 3 (150 mg, 0.46 mmol), DMF (2.0 mL), Et 3 N (63 µΐ, 0.46 mmol), BOP reagent (203 mg 0.46 mmol) and dichlorophenylhydrazine 2,4-hydrochloride (98 mg, 0.46 mmol) provided the title compound (107 mg, 47%). M. p .: 162 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.70 (br. S, 1H); 7.48 (m, 1H); 7.30 (d, J = 1.2, 1H); 7.16-6.96 (m, H); 3.87 (br. S, 1H); 2.71 (br. S, 1H); 2.19 (br. S, 2H), 2.05-1.70 (m, 10H). IR (cm -1, KBr): 3394 (br. S, s), 2916 (s), 1683 (s), 1519 (m), 1274 (m), 1216 (m), 1145 (s), 1118 ( s), 1099 (m), 967 (m), 850 (m), 817 (m) MS (m / z): 503.0 ([M + H] +).

Example 151

N (7) - [1- (2-Chlorophenyl) ethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 3 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (48 μΐ, 0.34 mmol), BOP reagent (141 mg 0.31 mmol) and (±) -1- (2-chlorophenyldiethylamine (48 µl, 0.29 mmol) provided the title compound (60 mg, 41%). Mp: 143-146 ° C. 1H-NMR (δ ppm, CDCl 3, 300 MHz): 7.46-7.14 (m, 5H); 7.04-6.94 (m, 2H); 5.26 (quintet, J = 7.2, 1H) 3.97 (br. S, 1H); 2.65 (br. S, 1H); 2.17 (br. S, 2H); 2.04-1.70 (m, 10H); 1.56 (d, J = 7.2, 3H) IR (cm -1, KBr): 3419 (m), 2915 (s), 2847 (m), 1666 (s), 1612 (m), 1519 (sO, 1481 (m), 1442 (m), 1368 (w), 1353 (w), 1273 (m), 1219 (m), 1144 (m), 1082 (m), 967 (m), 852 (m).

Example 152

N (7) - [(S) -1-Phenylpropyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 3 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (48 μΐ, 0.34 mmol), BOP reagent (141 mg 0.31 mmol) and (s) -1-phenylpropylamine (41 μΐ, 0.29 mmol) provided the title compound (84 mg, 63%). M.P .: 127-129 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.10 (m, 1H); 7.34-7.15 (m, 6H); 7.05-6.90 (m, 2H); 4.99 (q, J = 7.5, 1H); 3.96 (t. J = 6.2,1H); 2.64 (br. S, 1H); 2.16 (br. S, 2H); 2.04-1.70 (m, 12H); 0.94 (t, J = 7.2, 3H). IR (cm -1, KBr): 3410 (m), 3325 (m), 2916 (s), 2848 (m), 1666 (s), 1612 (m), 1519 (s), 1481 (m), 1442 (m), 1367 (w), 1353 (w), 1273 (m), 1226 (m), 1217 (m), 1144 (m), 1083 (m), 1030 (w), 966 (w), 966 (m), 852 (w), 756 (s), 700 (m) MS (m / z): 462.1 ([M + H] +).

Example 153

N7- [1- (2-Chlorophenyl) -1-methylethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7,33,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 3 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (45 μΐ, 0.31 mmol), BOP reagent (141 mg 0.31 mmol) and 2- (2-chlorophenyl) prop-2-ylamine (73 mg, 0.43 mmol) provide the title compound (95 mg, 66%). 145-147 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.57 (dd, J = 7.5, 1.2, 1H); 7.52-7.39 (m, 2H); 7.32 (dd, J = 7.8, 1.5, 1H); 7.26-7.20 (m, 1H); 7.16 (td, J = 7.8, 1.5, 1H), 7.08-6.94 (m, 2H); 3.82 (br. T. J = 6.2, 1H); 2.64 (br. S, 1H); 2.14 (br. S, 2H); 1.95-1.74 (m, 10H); 1.88 (s, 6H). IR (cm -1, KBr): 3419 (m), 2919 (m), 2892 (m), 2841 (m), 1674 (s), 1515 (s), 1441 (m), 1384 (w), 1362 (w), 1274 (m), 1249 (m), 1226 (m), 1139 (m), 1083 (m), 1039 (m), 967 (m), 843 (m), 727 (m). (m / z): 496.2 ([M + H] +).

Example 154

Methyl (2R) -2- [7- (2,4-difluorophenyl) -6,7-diazatetracyclo [7. 3,11.11. O4'8] tetradeca-4 (8), 5-dien-5-ylcarboxamido] -2-phenylethanate

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 3 (200 mg, 0.58 mmol), DMF (2.0 mL), Et 3 N (193 μΐ, 1.39 mmol), BOP reagent (282 mg 0.64 mmol) and (R) - (+) -2-phenylglycine methyl ester hydrochloride (117 mg, 0.58 mmol) gave the title compound (140 mg, 57%). MP: 138-141 ° C . 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.78 (d, J = 7.2, 1H); 7.49-7.30 (m, 6H); 7.10-6.90 (m, 2H); 5.72 (d, J = 7.5, 1H); 3.91 (t. J = 6.1,1H); 3.74 (s, 3H); 2.66 (br. S, 1H); 2.16 (br. S, 2H); 2.00-1.70 (m, 10H) .IV (cm -1, KBr): 3411 (m), 2915 (s), 2848 (m), 1744 (s), 1671 (s), 1613 (m ), 1570 (m), 1519 (m), 1478 (m), 1478 (m), 1441 (m), 1352 (w), 1367 (w), 1352 (w), 1322 (m), 1273 (m ), 1209 (m), 1081 (m), 967 (w), 851 (w), 754 (m), 698 (m). MS (m / z): 492.1 ([M + H] +).

Example 155

Methyl (2S) -2- [7- (2,4-difluorophenyl) -6,7-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 5-dien-5-ylcarboxamido] -2-phenylethanate

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 3 (500 mg, 1.45 mmol), DMF (4.0 mL), Et 3 N (480 μΐ, 3.48 mmol), BOP reagent (706 mg (1.59 mmol) and (S) - (+) -2-phenylglycine methyl ester hydrochloride (293 mg, 1.45 mmol) provided the title compound (525 mg, 73%). . 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.78 (d, J = 6.9, 1H); 7.52-7.25 (m, 6H); 7.05-6.90 (m, 2H); 5.71 (d, J = 7.2, 1H); 3.90 (t. J = 6.2,1H); 3.74 (s, 3H); 2.66 (br. S, 1H); 2.16 (br. S, 2H); 2.04-1.70 (m, 10H) .IV (cm -1, KBr): 3432 (m), 3413 (m), 2919 (s), 2849 (m), 1755 (s), 1740 (s) ), 1672 (s), 1614 (m), 1570 (m), 1522 (s), 1479 (m), 1439 (m), 1223 (m), 1308 (m), 1326 (m), 1274 (m ), 1259 (m), 1207 (m), 1161 (m), 1143 (m), 1082 (m), 1029 (w), 967 (m), 845 (m), 697, MS (m / z) : 492.1 ([M + H] +).

Example 156

N7- (3-Hydroxyiadamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 3 (200 mg, 0.58 mmol), DMF (2.0 mL), Et 3 N (88 μΐ, 0.63 mmol), BOP reagent (282 mg 0.63 mmol) and 3-amino-1-adamantanol (97 mg, 0.58 mmol) provided the title compound (143 mg, 51%). 240-243 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.48-7.38 (m, 1H); 7.05-6.94 (m, 2H); 6.74 (br. S, 1H); 3.94 (br. S, 1H); 2.64 (br. S, 1H); 2.28 (br. S, 2H); 2.17 (br. S, 2H); 2.11 (br s, 2H), 2.04-1.56 (m, 21H). IR (cm -1, KBr): 3385 (m), 2911 (s), 2849 (m), 1657 (s), 1610 (w), 1560 (w), 1520 (m), 1482 (m), 1441 (w), 1441 (w), 1362 (w), 1352 (w), 1273 (w), 1253 (w), 1227 (m), 1150 (m), 1132 (m), 1101 (w), 1084 (w), 1048 (w), 1025 (w), 966 (m), 872 (m) MS (m / z): 494.0 ([M + H] +).

Example 157

N (7) - (1-Methyl-1-phenylethyl) -5- (4-fluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 4 (100 mg, 0.30 mmol), DMF (1.5 mL ), Et 3 N (50 μΐ, 0.36 mmol), BOP reagent (148 mg, 0.33 mmol) and α, α-dimethylbenzylamine (49 mg, 0.36 mmol) provided the title compound (92 mg, 68%). 180-182 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.47 (d, J = 7.8, 2H); 7.38-7.14 (m, 8H); 3.91 (br. S, 1H); 2.95 (br. S, 1H); 2.17 (br. S, 2H); 1.97-1.76 (m, 16H). IR (cm -1, KBr): 3412 (m), 3064 (w), 2981 (w), 2916 (s), 2846 (m), 1672 (s), 1565 (w), 1512 (s), 1482 (m), 1439 (m), 1382 (w), 1363 (w), 1257 (m), 1215 (s), 1155 (m), 1084 (m), 844 (m). MS (m / z): 443.9 (100%), 444.9 ([M + H] +).

Example 158

N (7) - (Adamantan-1-yl) -5- (4-fluorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 4 (150 mg, 0.46 mmol), DMF (1.5 mL), Et 3 N (76 μΐ, 0.55 mmol), BOP reagent (223 mg 0.50 mmol) and 1-adamantylamine (69 mg, 0.46 mmol) provided the title compound (150 mg, 71%). 214-216 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.36-7.26 (m, 2H); 7.20-7.12 (m, 2H); 6.73 (br. S, 1H); 3.99 (br. S, 1H); 2.94 (br. S, 1H), 2.19-1.55 (m, 27H). IR (cm -1, KBr): 3392 (m), 2905 (s), 2847 (m), 1671 (s), 1560 (w), 1529 (m), 1512 (s), 1481 (m), 1454 (w), 1441 (w), 1357 (m), 1219 (m), 1092 (m), 841 (m) MS (m / z): 460.3 ([M + H] +).

Example 158a

N7- (Adamantan-2-yl) -5- (4-fluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 4 (100 mg, 0.36 mmol), DMF (1.0 mL), Et 3 N (124 µl, 0.88 mmol), BOP reagent (170 mg 0.38 mmol) and 2-adamantylamine hydrochloride (103 mg, 0.55 mmol) provided the title compound (120 mg, 80%). 196-198 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.69-7.63 (m, 2H); 7.17 (t, J = 8.1, 2H); 4.23 (d, J = 8.4, 1H); 3.75 (br. S, 1H); 3.65 (br. S, 1H), 2.14-1.87 (m, 14H), 1.78-1.54 (m, 4H), 1.26-1.21 (m, 2H). IR (cm -1, KBr): 3414 (s), 2979 (w), 2901 (s), 2851 (s), 1663 (s), 1542 (s), 1517 (s), 1488 (s), 1454 (m), 1445 (m), 1347 (w), 1255 (w), 1224 (m), 1213 (s), 1159 (m), 1126 (m), 1091 (m), 953 (w), 833 (m) MS (m / z): 406.2 ([M + H] +).

Example 159

N7- (1,3,3-Trimethylbicyclo [2,2,1] hepta-2-yl) -5- (4-fluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 4 (100 mg, 0.30 mmol), DMF (1.5 mL), Et 3 N (103 μl, 0.73 mmol), BOP reagent (142 mg 0.32 mmol) and 1S, 2endo-amino-1,3,3-trimethyl-bicyclo [2.2.1] heptane (86 mg, 0.46 mmol) provided the title compound (101 mg, 71%) Mp: 139-141 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.38-7.31 (m, 2H); 7.21-7.04 (m, 3H); 4.00 (br s, 1H); 3.73 (d, J = 9.6,1H); 2.98 (br. S, 1H), 2.19 (br. S, 1H), 2.05-1.66 (m, 14H), 1.51-1.39 (m, 2H), 1, 25-1.08 (m, 1H), 1.21, 1.01, 0.85 (3s, 9H). IR (cm -1, KBr): 3418 (s), 2927 (s), 2904 (s), 2870 (m), 1670 (s), 1607 (w), 1560 (m), 1510 (s), 1525 (s), 1479 (m), 1440 (m), 1375 (w), 1355 (w), 1365 (w), 1220 (m), 1159 (m), 1151 (m), 1089 (m), 1029 (m) 838 (m) MS (m / z): 462.3 ([M + H] +).

Example 160

N (7) -Piperidine-5- (4-methylphenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 5 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (46 μΐ, 0.33 mmol), BOP reagent (137 mg 0.31 mmol) and 1-aminopiperidine (35 μΐ, 0.33 mmol) yielded the title compound (70 mg, 56%). 228-232 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.70 (br. S, 1H); 7.28 (d, J = 9.0, 2H) 7.23 (d, J = 9.0, 2H); 3.99 (br. T, J = 4.83, 1H); 2.99 (br. S, 1H); 2.85 (br. S, 4H); 2.42 (s, 3H); 2.18 (br. S, 2H); 2.04-1.95 (m, 2H); 1.95-1.65 (m, 12H); 1.41 (br. S, 2H). IR (cm -1, KBr): 3306 (m), 2949 (s), 2937 (s), 2911 (s), 2849 (s), 2790 (m), 1690 (s), 1563 (w), 1518 (s), 1488 (m), 1462 (m), 1349 (m), 1216 (m), 1127 (m), 1108 (m), 987 (m), 830 (m) MS (m / z) : 405.20 ([M + H] +).

Example 161

N (7) - (2,4-Dichlorophenylamino) -5- (4-methylphenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 5 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (46 μΐ, 0.33 mmol), BOP reagent (137 mg 0.31 mmol) and 2,4-dichlorophenylhydrazine hydrochloride (70 mg, 0.32 mmol) provided the title compound (110 mg, 73%). M.P .: 208-215 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 9.42 (br. S, 1H); 7.38-7.20 (m, 7H); 7.14-7.00 (m, 1H); 3.96 (br. S, 1H); 3.04 (br. S, 1H); 2.45 (s, 3H); 2.40-1.80 (m, 12H) .IV (cm -1, KBr): 3314 (m), 3247 (m), 2914 (s), 2846 (m), 1674 (s), 1661 (s) ), 1515 (s), 1477 (s), 1478 (s), 1390 (m), 1363 (m), 1254 (m), 1235 (m), 1216 (m), 1089 (m), 1079 (m ), 862 (m), 825 (s) MS (m / z): 481.10 ([M + H] +).

Example 162

N (7) - (2-Chlorobenzyl) -5- (4-methylphenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 5 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (46 µl, 0.33 mmol), BOP reagent (137 mg 0.31 mmol) and 2-chlorobenzylamine (40 μΐ, 0.36 mmol) provided the title compound (80 mg, 58%). M.P .: 127-130 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.70 (br. S, 1H); 7.48 (br. D, J = 6.9.1H); 7.38-7.16 (m, 7H); 4.68 (d, J = 6.0, 2H); 4.02 (br.t, J = 4.6, 1H); 3.00 (br s, 1H); 2.42 (s, 3H); 2.20 (br. S, 2H); 2.10-1.70 (m, 10H). IR (cm -1, KBr): 3410 (m), 2915 (s), 2904 (s), 2842 (m), 1663 (s), 1526 (s), 1517 (s), 1478 (s), 1465 (s), 1439 (s), 1365 (m), 1352 (m), 1232 (m), 1215 (m), 1085 (m), 829 (m), 756 (m) MS (m / z) : 446.10 ([M + H] +).

Example 163

N (7) -Piperidine-5- (4-methoxyphenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 6 (100 mg, 0.27 mmol), DMF (2.0 mL), Et 3 N (44 μΐ, 0.32 mmol), BOP reagent (129 mg 0.32 mmol) and 1-aminopiperidine (29 µg, 0.29 mmol) provided the title compound (65 mg, 58%). MP: 156 ° C (melts). 1 H-NMR (δ ppm, CDCl 3, 300 MHz): 7.22 (d, J = 6.9, 3H); 6.98 (d, J = 6.9, 2H); 3.86 (br s, 3H); 3.74 (br s, 1H); 3.01 (br. S, 1H), 2.38-1.70 (m, 20H). IR (cm -1, KBr): 3284 (m), 2917 (s), 2849 (s), 1655 (s), 1609 (m), 1519 (s), 1471 (s), 1440 (s), 1353 (m), 1298 (m), 1256 (s), 1231 (s), 1147 (m), 1071 (m), 1010 (m), 891 (m), 814 (s), MS (m / z) : 421.20 ([M + H] +).

Example 164

N7- (2-Chlorobenzyl) -5- (4-methoxyphenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 6 (100 mg, 0.27 mmol), DMF (1.0 mL), Et 3 N (44 μΐ, 0.32 mmol), BOP reagent (129 mg 0.32 mmol) and 2-chlorobenzylamine (32 μΐ, 0.27 mmol) yielded the title compound (85 mg, 69%). Mp 178 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.45 (m, 2H); 7.37-7.10 (m, 5H); 6.98 (br.d., J = 7.5, 2H); 4.67 (br. S, 2H); 4.00 (br s, 1H); 3.86 (br s, 3H); 2.96 (br. S, 1H); 2.19 (br. S, 2H), 2, δ-δ, 40 (m, 10H). IR (cm -1, KBr): 3395 (s), 2904 (m), 2848 (m), 1667 (s), 1531 (s), 1515 (s), 1444 (s), 1353 (s), 1242 (S), 1230 (s), 1222 (s), 1231 (s), 1162 (m), 985 (m), 839 (m) MS (m / z): 462.10 ([M + H] +).

Example 165

N (7) - (2,4-Dichlorophenylamino) -5- (4-methoxyphenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 6 (100 mg, 0.36 mmol), DMF (1.0 mL), Et 3 N (44 µΐ, 0.32 mmol), BOP reagent (125 mg 0.28 mmol) and 2,4-dichlorophenylhydrazine hydrochloride (57 mg, 0.27 mmol) provided the title compound (78 mg, 56%). M. p .: 199 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 8.75 (br. S, 1H); 7.36-7.27 (m, 3H); 7.10 (dd, J = 9.0, 1.8, 1H); 7.06-6.94 (d, J = 9.0.1H); 6.97 (br. S, 1H); 6.50 (br. S, 1H); 3.87 (br. S, 4H); 3.00 (br. S, 1H); 2.19 (br. S, 2H), 2.02-1.80 (m, 10H) .IV (cm -1, KBr): 3359 (s), 3020 (w), 2912 (s), 2844 ( m), 1678 (s), 1517 (s), 1473 (s), 1247 (s), 1229 (s), 1075 (m), 1020 (m), 837 (s) MS (m / z): 497.10 ([M + H] +).

Example 166

N (7) -Piperidine-5 - [(2-chlorophenyl) phenyl] -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

A solution of Example 101 (170 mg, 0.36 mmol) in dioxane (4.0 mL) was treated with 4-chlorophenyl boronic acid (62 mg, 0.33 mmol), Pd (PF3) 2Cl2 (6 mg, 0.009 mml). ) and sodium carbonate (115 mg, 1.08 mmol) and refluxed for 7 h. The solvent was evaporated and the residue dissolved in AcOEt was washed with water. The organic layer was dried over Na 2 SO 4, filtered and the solvent removed. The residue was subjected to FC to provide about 70% (as analyzed by HPLC) of pure product which was further purified by preparative TLC to afford the title compound (70 mg, 39%). HPLC purity: 99.8%. Mp 206 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.59-7.38 (m, 4H); 7.27 (d, J = 8.4, 2H); 6.99 (d, J = 8.4, 2H); 3.84 (br. S, 1H); 3.35 (s, 3H); 2.89 (br. S, 4H); 2.35 (br. S, 1H); 2.00-1.70 (m, 18H). MS (m / z): 501.2 ([M + H] +).

Example 167

N (7) - [(2,4-Dichlorophenyl) amino] -5-phenyl-5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101 using Intermediate 7 (100 mg, 0.33 mmol), DMF (1.0 mL), Et 3 N (50 µl, 0.36 mmol), BOP reagent ( 151 mg, 0.34 mmol) 2,4-dichlorophenylhydrazine hydrochloride (77 mg, 0.36 mmol) to afford the title compound (110 mg, 71%). 166-170 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.60 (s, 1H); 7.56-7.42 (m, 3H); 7.39 (dd, J = 7.5, 2.1.2H); 7.29 (d, J = 2.2, 2H); 7.12 (dd, J = 9.0, 2.2, 1H); 6.80 (d, J = 9.0, 1H); 6.55 (br. S, 1H); 3.90 (t, J = 6.0, 1H); 3.15 (br. S, 1H); 2.20 (s, 2H); 2.04 -1.74 (m, 10H). IR (cm -1, KBr): 3371 (s), 3307 (m), 2910 (s), 2848 (m), 1683 (s), 1596 (m), 1564 (m), 1501 (m), 1463 (s), 1450 (s), 1393 (m), 1361 (m), 1231 (m), 1214 (m), 1075 (m), 1018 (m), 872 (m). MS (m / z): 467.1 ([M + H] +).

Example 168

N (7) -Phenyl-5-phenyl-5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized according to the procedure described for Example 101 using intermediate 7 (100 mg, 0.32 mmol), DMF (2 mL), triethylamine (0.05 mL, 0.35 mmol), BOP reagent ( 151 mg, 0.34 mmol) and aniline (33 Dl, 0.35 mmol) to afford the title compound (70 mg, 56%). Mp 178-181 ° C. 1H-NMR (δ ppm, CDCl3): 8.82 (br.s, 1H); 7.67 (d, J = 7.8,2H); 7.56-7.29 (m, 7H); 7.09 (t, J = 7.5); 4.06 (br. T, J = 5, 1H); 3.07 (br.t, J = 4.3, 1H); 2.22 (br. S, 2H); 2.09-1.98 (m, 2H); 1.98-1.76 (m, 8H). IR (cm -1, KBr): 3449 (br., M), 3384 (m), 2922 (m), 2904 (m), 2844 (m), 1689 (s), 1601 (m), 1591 (m ), 1528 (s), 1502 (s).

Example 169

N (7) -piperidine-5-phenyl-5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized according to the procedure described for Example 101 using intermediate 7 (155 mg, 0.5 mmol), DMF (2 mL), triethylamine (77 μ, 0.55 mmol), BOP reagent (235 mg 0.53 mmol) and 1-aminopiperidine (60 μΐ, 0.55 mmol) to provide the title compound (120 mg, 61%). 1H-NMR (δ ppm, CDCl3): 7.69 (br. S, 1H); 7.53-7.32 (m, 5H); 4.00 (br. T, J = 5.5, 1H); 3.02 (br. T, J = 4.6, 1H); 2.84 (br. T, J = 4.8, 4H); 2.19 (br. S, 2H); 2.05-1.68 (m, 14H); 1.44-1.36 (m, 2H). IR (cm -1, KBr): 3345 (m), 3306 (m), 2941 (s), 2920 (s), 2906 (s), 1687 (s), 1525 (m), 1500 (m).

Example 170

N (7) -Benzyl-5-phenyl-5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized according to the procedure described for Example 101 using intermediate 7 (100 mg, 0.32 mmol), DMF (2 mL), triethylamine (0.05 mL, 0.35 mmol), BOP reagent ( 151 mg, 0.34 mmol) and benzylamine (39 μΐ, 0.35 mmol) to provide the title compound (70 mg, 55%). Mp: 7-139 ° C. 1H-NMR (δ ppm, CDCl3): 7.51-7.21 (m, 11 H); 4.58 (d, J = 5.7, 2H); 4.03 (br. T, JK = 5.1H); 3.03 (br.t, J = 4.3, 1H); 2.20 (br. S, 2H); 2.08-1.98 (m, 2H); 1.98-1.76 (m, 8H). IR (cm -1, KBr): 3405 (m), 3361 (m), 2916 (s), 2900 (s), 2844 (m), 1659 (s), 1541 (s), 1504 (m).

Example 171N (7) -phenyl-6,7-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -5-dien-5-yl-piperidino methanone

The title compound was synthesized according to the procedure described for Example 101 using intermediate 7 (100 mg, 0.32 mmol), DMF (2 mL), triethylamine (0.05 mL, 0.35 mmol), BOP reagent ( 151 mg, 0.34 mmol) and piperidine (36 μΐ, 0.35 mmol) to provide the title compound (50 mg, 50%). M.P .: 123-125 ° C. 1H-NMR (δ ppm, CDCl3): 7.49-7.35 (m, 5 H); 3.71 (br. S, 2H); 3.57 (t, J = 5.4, 2H); 3.11 (br. S, 1H); 3.05 (br. S, 1H); 2.21 (br. S, 2H); 2.04-1.74 (m, 10H); 1.70-1.51 (m, 8H). IR (cm -1, KBr): 2916 (s), 2845 (m), 1630 (s), 1597 (m), 1500 (m).

Example 172

N (7) - (4-Fluorobenzyl) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 8 (100 mg, 0.28 mmol), DMF (1.0 mL), Et 3 N (41 μΐ, 0.29 mmol), BOP reagent (123 mg). 0.28 mmol) and 4-fluorobenzylamine (37 mg, 33 μΐ, 0.29 mmol) provided the title compound (95 mg, 74%). Mp: 68-70 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.54 (d, J = 2.4.1H); 7.38-7.15 (m, 5H); 7.00 (t, J = 8.4, 2H); 4.53 (dd, J = 14.1, 5.7, 2H)); 3.98 (br. S, 1H), 2.53 (br. S, 1H); 2.18 (br. S, 2H); 2.00-1.61 (m, 10H). IR (cm -1, KBr): 3415 (m), 3307 (m), 2913 (s), 2846 (m), 1667 (s), 1537 (s), 1509 (s), 1498 (s), 1441 (m), 1352 (m), 1220 (s), 1156 (m), 1088 (m), 1071 (m), 824 (s). MS (m / z): 484.1 ([M + H] +).

Example 173

N (7) -Phenylamino-5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 8 (100 mg, 0.28 mmol), DMF (1.0 mL), Et 3 N (41 μΐ, 0.29 mmol), BOP reagent (123 mg). 0.29 mmol) and phenylhydrazine (29 µl, 0.29 mmol) provided the title compound (80 mg, 65%). Mp 162-163 ° C. 1H-NMR (δ ppm, CDCl3, 300MHz): 8.53 (s, 1H); 7.59 (d, J = 2.4, 1H); 7.42 (dd, J = 8.4, 2.1, 1H); 7.35 (d, J = 8.4, 1H); 7.22 (t, J = 8.4.2H); 6.95 (d, J = 8.4, 2H); 6.89 (t, J = 7.2,1H); 3.87 (br. S, 1H); 2.57 (br. S, 1H); 2.18 (br. S, 2H); 2.00-1.67 (m, 10H). IR (cm -1, KBr): 3292 (m), 2911 (s), 2845 (m), 1670 (s), 1603 (m), 1566 (m), 1525 (m), 1496 (s), 1477 (m), 1441 (m), 1351 (m), 1232 (m), 1219 (m), 1133 (m), 1121 (m), 1104 (m), 1086 (m), 887 (m) 825 ( m) MS (m / z) 467.8 ([M + H] +).

Example 174

N (7) - (2-Chlorophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 8 (100 mg, 0.27 mmol), DMF (1.0 mL), Et 3 N (94 μΐ, 0.66 mmol), BOP reagent (129 mg 0.29 mmol) and de-chlorophenylhydrazine hydrochloride (52 mg, 0.29 mmol) provided the title compound (88 mg, 66%). M.P .: 100C. 1H-NMR (δppm, CDCl3, 300 MHz): 8.54 (s, 1H); 7.59 (d, J = 2.1.1H); 7.42 (dd, J = 8.4, 2.4, 1H); 7.34 (d, J = 8.4, 1H); 7.28 (dd, J = 8.1, 1.6, 1H); 7.15 (td, J = 8.1, 1.6, 1H); 7.04 (dd, J = 8.1, 1.5, 1H); 6.82 (td, J = 8.1, 1.5, 1H); 6.55 (br. S, 1H); 3.87 (br. T, J = 5.1, 1H); 2.58 (br. T, J = 5.1, 1H); 2.18 (br. S, 2H); 2.05-1.63 (m, 8H); 1.35-1.20 (m, 2H). IR (cm -1, KBr): 3217 (m), 2916 (s), 2847 (m), 1678 (s), 1668 (s), 1595 (m), 1498 (s), 1475 (s), 1441 (s), 1361 (m), 1232 (m), 1218 (m), 1133 (m), 1106 (m), 1084 (m), 1063 (m), 937 (w), 826 (m). (m / z) 501.0 ([M + H] +).

Example 175

N (7) - (2,4-Dichlorophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1. N-11-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 8 (100 mg, 0.27 mmol), DMF (1.0 mL), Et 3 N (82 μΐ, 0.59 mmol), BOP reagent (123 mg). 0.28 mmol) and 2,4-dichlorophenylhydrazine hydrochloride (62 mg, 0.29 mmol) provided the title compound (95 mg, 67%). M.P .: 153 - 156 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.52 (br. S, 1H); 7.59 (d, J = 1.8, 1H); 7.42 (dd, J = 8.1, 1.8, 1H); 7.36-7.24 (m, 2H); 7.12 (dd, J = 8.7, 2.4, 1H); 6.97 (d, J = 8.7,1H); 6.48 (br. S, 1H); 3.85 (br. S, 1H); 2.57 (br. S, 1H); 2.18 (br. S, 2H); 2.00-1.60 (m, 10H). IR (cm -1) KBr): 3307 (m), 2920 (s), 2905 (s); 2848 (m), 1682 (s), 1495 (s), 1469 (s), 1388 (m), 1353 (m), 890 (m), 864 (m) MS (m / z): 535.1 ([M + H] +).

Example 176

N (7) - (2-Bromophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 8 (100 mg, 0.27 mmol), DMF (1.0 mL), Et 3 N (82 μΐ, 0.59 mmol), BOP reagent (123 mg). 0.28 mmol) and 2-bromophenylhydrazine hydrochloride (62 mg, 0.29 mmol) yielded the title compound (70 mg, 48%). 196-199 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.56 (br. S, 1H); 7.59 (d, J = 1.8, 1H); 7.45 (br. T, J = 8.1, 2H); 7.41 (d, J = 8.1,1H); 7.19 (t, J = 7.8,1H); 7.02 (d, J = 7.8,1H); 6.75 (t, J = 7.8,1H); 6.52 (br. S, 1H); 3.87 (br. S, 1H); 2.57 (br. S, 1H); 2.18 (br. S, 2H); 2.00-1.60 (m, 8H); 1.30-1.26 (m, 2H). IR (cm -1, KBr): 3216 (m), 2915 (s), 2847 (m), 1685 (s), 1595 (m), 1566 (m), 1497 (s), 1441 (m), 1387 (m), 1352 (m), 1263 (m), 1232 (m), 1218 (m), 1129 (m), 1105 (m), 1085 (m), 1062 (m), 1019 (m), 936 (w), 889 (w), 866 (w), 825 (m) MS (m / z): 545.1 ([M + H] +).

Example 177Ν (7) - (N ', Ν'-Diphenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13ill-O4'8] tetradeca-4 (8), 6- diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 8 (100 mg, 0.27 mmol), DMF (1.0 mL), Et 3 N (74 μΐ, 0.53 mmol), BOP reagent (123 mg). 0.28 mmol) and N, N-diphenylhydrazine hydrochloride (141 mg, 0.64 mmol) provided the title compound (85 mg, 59%). Mp: 176-180 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.96 (s, 1H); 7.57 (d, J = 2.1.1H); 7.40 (dd, J = 8.4, 2.1, 1H); 7.35-7.21 (m, 9H); 7.01 (br. T, J = 8.4, 2H); 3.91 (br. S, 1H), 2.57 (br. S, 1H); 2.18 (br. S, 2H); 2.00 -1.73 (m, 10H). IR (cm -1, KBr): 3392 (m), 2915 (m), 2881 (m), 2845 (m), 1686 (s), 1590 (m), 1493 (s), 1462 (m), 1386 (m), 1354 (m), 1340 (m), 1311 (m), 1292 (m), 1273 (m), 1204 (m), 1150 (m), 1102 (m), 1088 (m), 1076 (w), 1028 (w), 866 (w), 822 (w) MS (m / z): 543.3 ([M + H] +).

Example 178

N (7) - (2-Phenylethyl) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 8 (100 mg, 0.28 mmol), DMF (1.0 mL), Et 3 N (41 μΐ, 0.29 mmol), BOP reagent (123 mg). 0.29 mmol) and phenothilamine (37 μΐ, 0.29 mmol) provided the title compound (90 mg, 71%). 63-66 ° C. 1H-NMR (δ ppm, CDCl3, 300MHz): 7.56 (d, J = 2.1, 1H); 7.38 (dd, J = 8.4, 2.1, 1H); 7.40-7.18 (m, 6H); 7.02 (t, J = 7.2,1H); 3.97 (br. S, 1H); 3.61 (q, J = 7.2, 2H); 2.90 (t, J = 8.1, 2H); 2.54 (br. S, 1H); 2.18 (br. S, 2H); 2.00-1.65 (m, 10H). IR (cm -1, KBr): 3413 (m), 2912 (s), 2845 (m), 1667 (s), 1535 (s), 1497 (s), 1478 (s), 1352 (m), 1233 (m), 1219 (m), 1162 (m), 1103 (m), 1088 (m), 996 (m), 866 (w), 699 (m).

MS (m / z): 480.1 ([M + H] +).

Example 179N (7) -Benzyl-5- (2 ', 4'-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13ill-O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

A solution of intermediate 8 (100 mg, 0.27 mmol) in DMF (2 mL) was treated with BOP reagent (123 mg, 0.28 mmol) ethylethylamine (41 μΐ, 0.29 mmol) at room temperature for 15 minutes. After which time benzylamine (32 μΐ, 0.29 mmol) was added to the mixture and stirred at room temperature for 1 h. The mixture was poured into water and the precipitate formed was collected by filtration, dried and purified by flash chromatography to afford pure title compound (90 mg, 73%). Mp: 65-66 ° C. 1H-NMR (δ ppm, CDCl3): 7.54 (d, J = 2.4, 1H); 7.40-7.18 (m, 8H); 4.62 (dd, J = 14.7, 6.0, 1H); 4.52 (dd, J = 14.7, 6.0, 1H); 4.0 (t, J = 5.4, 1H); 2.53 (br.s, 1H); 2.18 (br. S, 2H); 1.05-2.10 (m, 10H). IR (cm -1, KBr): 3413 (m), 2914 (s), 2846 (m), 1664 (s), 1534 (s).

Example 180

N (7) piperidino-5- (2 ', 4'-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. 04'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized according to the procedure described for Example 101 using intermediate 8 (160 mg, 0.42 mmol), DMF (2 mL), triethylamine (0.06 mL, 0.41 mmol), BOP reagent ( 187 mg, 0.42 mmol) and 1-aminopiperidine (0.05 mL, 0.46 mmol) to provide the title compound (106 mg, 52%). Mp: 101-104 ° C. 1H-NMR (δ ppm, CDCl3): 7.58 (br. S, 1H); 7.56 (d, J = 2.1, 1H); 7.38 (dd, J = 8.7, 2.4, 1H); 7.31 (d, J = 8.7,1H); 3.96 (br. T, J = 5.4, 1H); 2.84 (br. S, 4H); 2.53 (br. S, 1H); 2.17 (br. S, 2H); 1.05-2.10 (m, 14H); 1.72-1.9 (m, 2H). IR (cm -1, KBr): 3413 (m), 2914 (s), 2846 (m), 1664 (s), 1534 (s).

Example 181

N (7) - (2,4-Dichlorophenylamino) -5- (2-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 9 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (45 μΐ, 0.32 mmol), BOP reagent (136 mg, 0.31 mmol) and 2,4-dichlorophenylhydrazine hydrochloride (69 mg, 0.32 mmol) provided the title compound (95 mg, 65%). M.P .: 233-240 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.60 (s, 1H);

7.57 (dd, J = 7.6, 1, 6, 2H); 7.48 (td, J = 8.8, 2.4, 1H); 7.47-7.37 (m, 2H); 7.29 (d, J = 2.4, 1H); 7.11 (dd, J = 8.8, 2.4, 1H) 6.98 (d, J = 8.8, 1H); 3.87 (br. T, J = 5.6, 1H); 2.60 (br. T, J = 5.6, 1H); 2.20 (br s, 2H); 2.10-1.60 (m, 10H). IR (cm -1, KBr): 3386 (m), 3343 (m), 2907 (m), 2870 (m), 2847 (m), 1694 (s), 1497 (m), 1469 (m), 1349 (m), 1277 (m), 1259 (m), 1232 (m), 1216 (m), 1087 (m), 1058 (m), 1014 (m), 859 (m) MS (m / z) : 501.1 ([M + H] +).

Example 182

N (7) -Benzyl-5- (2-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13ill-O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized according to the procedure described for Example 101 using intermediate 9 (100 mg, 0.29 mmol), DMF (2 mL), triethylamine (46 μ, 0.32 mmol), BOP reagent (136 mg 0.32 mmol) and benzylamine (36 μΐ, 0.32 mmol) to provide the title compound (83 mg, 65%). M.P .: 159-161 ° C. 1H-NMR (δ ppm, CDCl3): 7.52 (d, J = 7.5, 1H); 7.47-7.24 (m, 8 H); 4.62 (dd, J = 15.0, 6.0, 1H); 4.51 (dd, J = 15.0, 6.0, 1H); 4.01 (br. S, 1H); 2.55 (br.s, 1H); 2.18 (br. S, 2H); 210-1.54 (m, 10H). IR (cm -1, KBr): 3412 (m), 3427 (m), 2909 (s), 2845 (m), 1672 (s), 1567 (m), 1524 (s), 1498 (s), 1474 (s); 1455 (s).

Example 183

N (7) -cyclohexyl-5- (2-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized according to the procedure described for Example 101 using intermediate 9 (100 mg, 0.29 mmol), DMF (2 mL), triethylamine (45 μΐ, 0.32 mmol), BOP reagent (136 mg 0.32 mmol) and cyclohexylamine (37 μΐ, 0.32 mmol) to provide the title compound (95 mg, 77%). M.P .: 218-220 ° C. 1H-NMR (δρρτη, CDCl 3): 7.55-7.52 (m, 1H); 7.42-7.35 (m, 3 H); 6.80 (br. D, J = 8.1, 1H); 4.00 (br. T, J = 5.4, 1H); 3.97-3.83 (m, 1H); 2.54 (br.s, 1H); 2.17 (br.s, 2H); 1.99 (br.s, 6H); 1.92-1.52 (m, 8H); 1.55-1.05 (m, 6H). IR (cm -1, KBr): 3409 (m), 2921 (s), 2904 (s), 2849 (m), 1667 (s), 1567 (m), 1527 (s), 1494 (s), 1479 (s) .

Example 184

N (7) -piperidine-5- (2'-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized according to the procedure described for Example 101 using intermediate 9 (100 mg, 0.29 mmol), DMF (2 mL), triethylamine (45 μ 1, 0.32 mmol), BOP reagent (136 mg, 0.32 mmol) and 1-aminopiperidine (35 μΐ, 0.32 mmol) to provide the title compound (90 mg, 72%). 251-254 ° C. 1H-NMR (δppm, CDCl3): 7.62 (br. S, 1H); 7.54 (d, J = 8.7,1H); 7.53-7.35 (m, 3H); 3.98 (br. S, 1H); 2.84 (t, J = 4.8, 4H); 2.54 (br. S, 1H); 2.17 (br. S, 2H); 1.98 (t, J = 12.6, 4H); 1.93-1.50 (m, 10H); 1.44-1.34 (m, 2H). IR (cm -1, KBr): 3314 (m), 2905 (s), 2844 (m), 2804 (m), 1686 (s), 1567 (m), 1525 (s), 1492 (s), 1480 (s).

Example 185

N7- (2-Chlorobenzyl) -5- (5-chloro-2-pyridyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 10 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (40 μΐ, 0.29 mmol), BOP reagent (128 mg 0.29 mmol) and 2-chloro-benzylamine (31 mg, 0.29 mmol) provided the title compound (64 mg, 49%). M.P .: 187-189 ° C. 1H-NMR (δ ppm, DMSO-d6, 300 MHz): 8.81 (t, J = 6.3, 1H), 8.60 (d, J = 2.6, 1H); 8.19 (dd, J = 8.6, 2.6, 1H); 7.96 (d, 8.6, 1H); 7.46-7.42 (m, 1H); 7.38-7.27 (m, 3H); 4.48 (d, J = 6.0.2H); 4.04 (s, 1H); 3.78 (m, 1H); 2.14 (br. S, 2H); 1.95-1.68 (m, 10H).

Example 186

N (7) -Benzyl-5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized according to the procedure described for Example 101 using intermediate 11 (100 mg, 0.43 mmol), DMF (1 mL), triethylamine (0.06 mL, 0.43 mmol), BOP reagent ( 190 mg, 0.43 mmol) and benzylamine (0.05 mL, 0.43 mmol) to provide the title compound (96 mg, 69%). M.P .: 218-219 ° C. 1H-NMR (δ ppm, DMSO-d6): 12.70 (br. S, 1H); 8.44 (br. S, 1H); 7.30 (m, 5H); 4.36 (br s, 2H); 3.71 (br. S, 1H); 2.97 (br.s, 1H); 2.10 (br s, 2H); 1.91 (br.s, 4H); 1.77 (br.s, 2H); 1.65 (t, J = 13.2, 10H). IR (cm -1 KBr): 3434 (s), 2924 (s), 2854 (m), 1634 (m).

Example 187

N (7) -Piperidine-5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

A solution of intermediate 11 (160 mg, 0.68 mmol) in DMF (3 mL) was treated at room temperature with EPCI (198 mg, 1.02 mmol), HOBt (93 mg, 0.68 mmol), triethylamine (0 mL). 19 mL, 1.36 mmol), DMAP (8 mg) and 1-aminopiperidine (0.081 mL, 0.68 mmol) for 16 h. Dilution of the mixture with water, extraction with ethyl acetate, drying over Na 2 SO 4, evaporation and purification by flash chromatography afforded the title compound (134 mg, 63%). Mp: 295-297 ° C. 1H-NMR (δ ppm, DMS0-d6): 12.61 (br. S, 1H); 8.61 (br. S, 1H); 3.65 (br s, 1H); 3.00 (br.s, 1H); 2.10 (br s, 2H); 1.99-1.51 (m, 14H); 1.33 (br.s, 2H). IR (cm -1, KBr): 3314 (m), 3199 (s), 3155 (m); 3085 (m), 3003 (m), 2907 (s), 2843 (s), 2805 (m), 1653 (s), 1590 (m), 1543 (m), 1509 (m).

Example 188

6,7-Diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -5-dien-5-yl-piperidinomethanone:

The title compound was synthesized according to the procedure described for Example 101 using intermediate 11 (100 mg, 0.43 mmol), DMF (1 mL), triethylamine (0.06 mL, 0.43 mmol), BOP reagent ( 190 mg, 0.43 mmol) and piperidine (43D1, 0.43 mmol) to provide the title compound (84 mg, 66%). Mp: 263-264 ° C. 1H-NMR (δ ppm, CDCl3): 3.57 (br. S, 4H); 3.05 (br. S, 1H); 2.92 (br.s, 1H); 2.17 (br. S, 2H); 2.10-1.50 (m, 16H). IR (cm -1, KBr): 3436 (m), 3198 (s), 3155 (m); 2924 (s), 2905 (s), 2888 (s), 1607 (s), 1598 (s), 1583 (s) .

Example 189a

N (7) -Piperidine-6-methyl-5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

A 0.27 M solution of KOH in 4: 3 ethanol-water (3.5 mL) was added to a solution of intermediate 12a (123 mg, 0.45 mmol) and refluxed for 3 h. After mixing the mixture to approximately half of its initial volume, it was acidified with aq HCl. The solid preprecipitate was filtered, dried and dissolved in DMF (3ml). The solution was treated with DMAP (5mg), EPCI (100mg, 0.5mmol), HOBt (47mg, 0.35mmol), 1-aminopiperidine (39mg, 0.35mmol) and triethylamine (0, 08ml, 0.56 mmol) at room temperature for 15h. Dilution of the mixture with water, extraction with ethyl acetate, drying over Na 2 SO 4 and purification by flash chromatography afforded the title compound (48 mg, 33%) M.p .: 188.9 ° C. 1H-NMR (δ ppm, DMSO-d6): 6.27 (br. S, 1H); 3.88 (s, 3H); 3.06-2.92 (m, 2H); 2.87 (t, J = 5.4, 4H); 2.15 (br. S, 2H); 2.10-1.91 (m, 4H); 1.90-1.70 (IOH); 1.55-1.40 (m, 2H). IR (cm -1, KBr): 3440 (br., M); 3227 (m), 2918 (s), 2844 (s), 1636 (s), 1557 (m), 1532 (m).

N (7) -Piperidine-5-methyl-5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized according to the procedure described for Example 189a using intermediate 12b (173 mg, 0.63 mmol), ethanol (2 mL), 0.27 M KOH in ethanol-water 4: 3 (3 , 5 ml), DMF (3 ml), DMAP (8 mg), EPCI (167 mg, 0.87 mmol), HOBt (78 mg, 0.58 mmol), 1-aminopiperidine (58 mg, 0.35 mmol) ethylethylamine (0.13 ml, 0.93 mmol) to afford the title compound in pure form (148mg, 72%). Mp: 218.7 ° C. 1H-NMR (δ ppm, DMS0-ds): 7.56 (br. S, 1H); 3.89 (t, J = 5.4,1H); 3.74 (s, 3H); 2.97 (t, J = 5.1, 1H); 2.85 (t, J = 5.1, 4H); 2.162.00-1.88 (m, 4H); 1.90-1.66 (10H); 1.47-1.36 (m, 2H).

Example 190a

N (7) - (I-Methyl-1-phenylethyl) -6-pentyl-5,6-diazatetracyclo [7.3.1.133-1-O4'8] tetradeca-4,7-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 189a.

Intermediate 13a (100 mg, 0.33 mmol), DMF (1.0 mL), Et3N (52 μΐ, 0.36 mmol), BOP reagent (160 mg, 0.36 mmol) and α, α-dimethylbenzylamine (53 mg 0.39 mmol) provided the title compound (100 mg, 72%). Mp 66-69 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.46-7.40 (m, 2H); 7.58 (t, J = 7.2, 2H); 7.30-7.20 (m, 2H); 5.83 (br. S, 1H); 4.14 (t, J = 7.8, 2H); 3.11 (br. T, J = 5.2, 1H); 3.03 (br. T, J = 5.2, 1H); 2.15 (br. S, 1H); 2.08-1.94 (m, 4H); 1.79 (s, 6H); 1.80-1.70 (m, 6H); 1.32-1.20 (m, 4H); 0.87 (t, J = 7.5, 3H).

Example 190b

N (7) - (I-Methyl-1-phenylethyl) -5-pentyl-5,6-diazatetracyclo [7. 3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 189b. Intermediate 13b (100 mg, 0.33 mmol), DMF (1.0 mL), Et 3 N (52 µl, 0.36 mmol), BOP reagent ( 160 mg, 0.36 mmol) and α-dimethylbenzylamine (53 mg, 0.39 mmol) provided the title compound (95 mg, 68%). 99-102 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.44 (m, 2H); 7.32 (t, J = 7.2, 2H); 7.24-7.16 (m, 2H); 3.97 (t, J = 7.5, 2H); 3.82 (br. S, 1H); 2.94 (br. S, 1H); 2.13 (br. S, 2H); 2.00-1.84 (m, 4H); 1.78 (s, 6H); 1.80-1.68 (m, 6H); 1.40-1.24 (m, 4H); 0.91 (t, J = 7.2, 3H).

Example 191

N (7) - [(IR) -2-Hydroxy-1-phenylethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

To a solution of Example 154 (290 mg, 0662 mmol) in TF (3 mL) was added LiBH 4 (32 mg, 1.52 mmol) and the mixture was refluxed overnight. After solvent evaporation, the oily residue was diluted with water and acidified with 1N HCl extracted with ethyl acetate and the combined organic layers were washed with brine and dried over Na 2 SO 4. FC (3: 7 AcOEt / depetroleum ether) provided the title compound (150 mg, 61%). Mp 161-162 ° C. 1H-NMR (δ ppm, DMS0-d6, 300 MHz): 8.24 (d, J = 7.5, 1H); 7.76-7.58 (m, 2H); 7.38-7.20 (m, 6H); 5.02-4.92 (m, 2H); 3.77 (br. S, 1H); 3.70-3.64 (m, 2H); 2.62 (br. S, 1H); 2.12 (br. S, 2H); 1.98-1.68 (m, 10H). IR (cm -1, KBr): 3403 (m), 3007 (w), 2916 (s), 2848 (m), 1656 (s), 1612 (w), 1519 (s), 1483 (m), 1443 (m), 1368 (m), 1353 (m), 1273 (m), 1225 (m) 1144 (m), 1082 (m), 966 (m), 851 (m) MS (m / z): 452.17 (M + H +).

Example 192

N (7) - [(IS) -2-Hydroxy-1-phenylethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 191. The product of Example 155 (400 mg, 0.81 mmol), TF (5 mL) and LiBH4 (35 mg, 1.62 mmol) provided the title compound. (130 mg, 34%). M.P .: 158 - 159 ° C. 1H-NMR (δ ppm, DMS0-d6, 300 MHz): 8.24 (d, J = 8.1, 1H); 7.71 (q, 8.4, 1H); 7.61 (t, J = 8.4, 1H); 7.38-7.20 (m, 6H); 5.00-4.94 (m, 2H), 3.78 (br.s, 1H); 3.72-3.64 (m, 2H); 2.62 (br. S, 1H); 2.11 (br. S, 2H); 2.00-1.65 (m, 10H). MS (m / z): 452.17 (M + H +).

Example 201

N (3) -Piperidine-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 14 (100 mg, 0.39 mmol), DMF (1.0 mL), Et 3 N (66 µΐ, 0.47 mmol), BOP reagent (191 mg 0.43 mmol) and 1-aminopiperidine (42 μΐ, 0.39 mmol) provided the title compound (45 mg, 34%). Mp: 144 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.68 (d, J = 7.8, 2H); 7.68 (br. S, 1H); 7.48 (t, J = 7.8,1H); 7.32 (t, J = 7.8, 1H); 3.75 (br. S, 1H); 3.70 (br. S, 1H); 2.91 (br. S, 4H); 2.11 (br. D, J = 8.1, 1H); 1.98 (br. D, J = 9.3, 2H); 1.80-1.50 (m, 5H); 1.45 (br s, 2H); 1.24 (br. D, J = 8.1H). IR (KBr, cm -1): 3302 (m), 2987 (m), 2940 (s), 2856 (m), 2790 (m), 1686 (s), 1597 (m), 1537 (s), 1513 (s), 1489 (s), 1444 (m), 1339 (m), 1270 (m), 1225 (m), 1140 (m), 1127 (m), 1075 (w), 1036 (w), 918 (m), 893 (m), 832 (w) MS (m / z): 337.1 ([M + H] +).

Example 2 02

N (3) -Cyclohexyl-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 14 (100 mg, 0.39 mmol), DMF (1.0 mL), Et 3 N (66 μΐ, 0.48 mmol), BOP reagent (191 mg 0.43 mmol) and cyclohexylamine (45 μΐ, 0.39 mmol) yielded the title compound (99mg, 75%). M.p .: 107 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.68 (d, J = 8.1, 2H); 7.48 (t, J = 8.1, 2H); 7.33 (t, J = 7.8,1H); 6.80 (br. D, J = 8.4, 1H); 3.97-3.95 (m, 1H); 3.75 (br. S, 1H); 3.69 (br. S, 1H); 2.12 (br. D, J = 8.7, 1H); 2.11-1.90 (m, 4Η); 1.79-1.65 (m, 4Η); 1.48-1.15 (m, 7Η). IR (KBr, cm -1): 3327 (m), 2936 (m), 2856 (m), 1655 (s), 1595 (m), 1549 (s), 1508 (s), 1490 (s), 1462 (s), 1448 (m), 1352 (s), 1272 (m), 1249 (m), 1226 (m), 1164 (m), 1140 (m), 1121 (m). MS (m / z): 336.1 ([M + H] +).

Example 2 03

N (3) -Benzyl-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 14 (100 mg, 0.39 mmol), DMF (1.0 mL), Et 3 N (66 µΐ, 0.48 mmol), BOP reagent (191 mg 0.43 mmol) and benzyl amine (45 µl, 0.39 mmol) provided the title compound (87 mg, 65%). 115 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.66 (d, J = 7.5, 2H); 7.47 (t, J = 7.8, 2H); 7.40-7.26 (m, 7H); 4.64 (d, J = 5.4, 2H); 3.78 (br. S, 1H); 3.71 (br. S, 1H); 2.15 (br. D, J = 8.4, 1H); 2.00 (br. D, J = 8.7, 2H); 1.73 (br. D, J = 8.4, 1H); 1.30-1.14 (m, 2H) .IV (KBr, cm -1): 3376 (m), 2995 (m), 2966 (m), 2948 (m), 2863 (m), 1652 (s ), 1595 (s), 1552 (s), 1354 (s), 1277 (m), 1256 (m), 1235 (s), 1157 (m), 1122 (m), 1070 (m), 988 (m MS (m / z): 344.1 ([M + H] +).

Example 204

N (3) -Phenylamino-I-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 14 (100 mg, 0.39 mmol), DMF (1.0 mL), Et 3 N (66 μΐ, 0.48 mmol), BOP reagent (191 mg 0.43 mmol) and phenylhydrazine (38 µl, 0.39 mmol) provided the title compound (111 mg, 82%). M.p .: 189 ° C. 1H-NMR (δ ppm, CDCl3, 300MHz): 8.59 (br. S, 1H); 7.71 (d, J = 8.1, 2H); 7.50 (t, J = 8.1, 2H); 7.35 (t, J = 8.1, 1H); 7.24 (t, J = 7.8, 2H), 6.96 (d, J = 7.8, 2H); 6.90 (t, J = 7.8,1H); 3.73 (br.s, 2H); 2.14 (br. D, J = 8.7, 1H); 1.90-2.10 (m, 2H); 1.73 (d, J = 8.4, 1H); 1.31-1.14 (m, 2H). IR (KBr, cm -1): 3413 (m), 3393 (m), 3273 (s), 2970 (m), 2955 (m), 2868 (w), 1682 (s), 1599 (m) and 1541 ( m), 1506 (s), 1476 (s), 1458 (s), 1349 (m), 1273 (m), 1226 (m), 1132 (m), 1085 (m), 1066 (m), 895 ( m) .345.1 ([M + H] +).

Example 205

N (3) -Piperidine-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate15 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (58 μΐ, 0.42 mmol), BOP reagent (169 mg 0.38 mmol) and 1aminopiperidine (38 μΐ, 0.35 mmol) provided the title compound (100 mg, 78%). M.p .: 232 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.60-7.47 (m, 3H); 7.42-7.35 (m, 2H); 3.76 (br. S, 1H); 3.37 (br. S, 1H); 2.80 (br. S, 4H); 2.13 (br. D, J = 9.3, 1H); 2.11-1.86 (m, 2H); 1.75-1.62 (m, 5H); 1.42-1.18 (m, 4H). IR (KBr, cm -1): 3314 (w), 2999 (w), 2938 (s), 2867 (w), 2781 (m), 1682 (s), 1540 (s), 1511 (s), 1484 (s), 1450 (m), 1342 (m), 1276 (w), 1257 (w), 1227 (m), 1123 (m), 1083 (m), 1035 (m), 987 (m), 893 (w) MS (m / z): 371.1 ([M + H] +).

Example 206

N (3) -Cyclohexyl-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate15 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (58 μΐ, 0.42 mmol), BOP reagent (169 mg 0.38 mmol) and cyclohexylamine (40 μΐ, 0.39 mmol) yielded the title compound (92 mg, 72%). Mp: 171 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.45 (m, 2H); 7.45-7.35 (m, 2H); 6.73 (br. D, J = 7.2, 1H); 3.95-3.82 (m, 1H); 3.77 (br. S, 1H); 3.37 (br.S, 1H); 2.13 (br. D, J = 9.3, 1H); 2.11-1.86 (m, 4H); 1.70-1.66 (m, 4H); 1.42-1.18 (m, 7H). IR (KBr, cm -1): 3407 (m), 3393 (m), 2996 (m), 2934 (s), 2850 (s), 1662 (s), 1549 (s), 1513 (s), 1506 (s), 1483 (s), 1447 (s), 1342 (s), 1223 (s), 1125 (s), 1085 (m), 965 (m), 950 (m) .MS (m / z) : 370.1 ([M + H] +).

Example 207

N (3) -Benzyl-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate15 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (58 μΐ, 0.42 mmol), BOP reagent (169 mg 0.38 mmol) and benzyl amine (37 μΐ, 0.34 mmol) yielded the title compound (60mg, 46%). 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.55-7.15 (m, 10H); 4.60 (br s, 2H); 3.79 (br. S, 1H); 3.38 (br.S, 1H); 2.16 (br. D, J = 7.8, 1H); 1.99-1.88 (m, 2H); 1.70 (d, J = 8.7, 1H); 1.31-1.20 (m, 2H). IR (Neat, cm -1): 3414 (m), 2994 (m), 2968 (m), 2949 (m), 1664 (s), 1550 (s), 1513 (s), 1485 (s), 1455 (s), 1347 (m), 1275 (m), 1251 (m), 1235 (m), 1161 (m), 1141 (m), 1121 (m) MS (m / z): 378.1 ( [M + H] +).

Example 208

N (3) -Phenylamino-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate15 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (58 μΐ, 0.42 mmol), BOP reagent (169 mg 0.38 mmol) and phenyl hydrazine (34 µl, 0.34 mmol) provided the title compound (105 mg, 80%). M. p .: 205 ° C. 1H-NMR (δ ppm, CDCl3, 300MHz): 8.51 (s, 1H); 7.60-7.51 (m, 2H); 7.52-7.40 (m, 2H); 7.23 (t, J = 7.8, 2H); 6.95 (d, J = 7.8, 2H); 6.90 (t, J = 7.5, 1H); 3.74 (br s, 1H); 3.41 (br. S, 1H); 2.15 (br.d., J = 8.7,1H); 2.00-1.85 (m, 2H); 1.70 (br. D, J = 8.7.1H); 1.32-1.20 (m, 2H). IR (KBr, cm -1): 3283 (s), 2993 (m), 2958 (m), 1675 (s), 1591 (m), 1603 (m), 1542 (m), 1513 (s), 1497 (s), 1439 (m), 1348 (m), 1281 (m), 1238 (m), 1137 (m), 1123 (m), 1082 (m), 1062 (m), 889 (m). (m / z): 379.0 ([M + H] +).

Example 2 09

N (3) -Piperidine-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (48 μΐ, 0.35 mmol), BOP reagent (152 mg 0.35 mmol) and 1-aminopiperidine (37 μΐ, 0.35 mmol) yielded the title compound (68 mg, 53%). Mp: 78-81 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.63 (d, J = 8.7, 2H); 7.44 (d, J = 8.7, 2H); 3.75 (s, 1H); 3.67 (s, 1H); 2.91 (br. S, 4H); 2.11 (br.d., J = 8.7, 1H); 2.00 (br. D, J = 9.6, 2H); 1.80-1.65 (m, 5H); 1.45 (m, 2H); 1.20 (m, 2H). IR (KBr, cm -1): 3408 (m), 2931 (m), 2871 (m), 2779 (m), 1692 (s), 1540 (m), 1506 (s), 1489 (s), 1347 (m), 1268 (m), 1227 (m), 1085 (m) MS (m / z): 371.2 ([M + H] +).

Example 210

1- (4-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-yl piperidino methanone

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.39 mmol), BOP reagent (160 mg 0.36 mmol) and piperidine (38μΐ, 0.38 mmol) provided the title compound (80 mg, 65%). 96-98 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.63 (d, J = 8.7, 2H); 7.41 (d, J = 8.7, 2H); 3.92-3.75 (m, 4H), 3.69 (br. S, 1H), 3.57 (s, 1H), 2.13 (d, J = 6.9.1H), 1, 97 (d, J = 9.0, 2H), 1.80-1.60 (m, 7H), 1.24 (d, J = 8.7, 2H). IR (cm -1, KBr): 2932 (s), 2861 (m), 1613 (s), 1503 (s), 1467 (m), 1422 (m), 1371 (m), 1352 (m), 1271 (m), 1246 (m), 1156 (w), 1132 (m), 1088 (m), 825 (m) MS (m / z): 356.0 ([M + H] +) Example 211

N (3) -Cyclohexyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et 3 N (48μΐ, 0.35mmol), BOP reagent (152mg, 0 , 35 mmol) and cyclohexylamine (39 μΐ, 0.35 mmol) to afford the title compound (98mg, 77%). 155-158 ° C. 1H-NMR (δ ppm, CDCl3, 300MHz): 7.64 (d, J = 8.7, 2H); 7.43 (d, J = 8.7, 2H); 6.76 (br. D, J = 8.7, 1H); 4.02-3.87 (m, 1H); 3.75 (s, 1H); 3.67 (s, 1H); 2.12 (br. D, J = 8.1, 1H); 2.10-1.90 (m, 4H); 1.80-1.57 (m, 4H); 1.48-1.18 (m, 7H) IR (KBr, cm -1): 3411 (m), 2926 (s), 2848 (m), 1666 (s), 1598 (w), 1545 (s) , 1505 (s), 1486 (s), 1349 (m), 1248 (w), 1223 (m), 1159 (m), 1122 (m), 1086 (m), 829 (m), 506 (m) MS (m / z): 370.3 ([M + H] +).

Example 212

N (3) -Cyclopentyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.39 mmol), BOP reagent (160 mg 0.36 mmol) eccyclopentylamine (38 μΐ, 0.38 mmol) yielded the title compound (95 mg, 77%). Mp: 176-178 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.63 (d, J = 8.7, 2H); 7.43 (d, J = 8.7,2H); 6.81 (d, J = 7.5, 1H); 4.38 (sextet, J = 7.5, 1H); 3.76 (s, 1H), 3.66 (s, 1H), 2.20-1.90 (d, J = 8.7, 5H ) 1.8-1.40 (m, 7H); 1.28-1.20 (m, 2H). IR (cm -1, KBr): 3288 (m), 2964 (s), 2868 (m), 1643 (s), 1552 (s), 1505 (s), 1489 (s), 1442 (m), 1406 (m), 1364 (m), 1347 (m), 1275 (m), 1252 (m), 1243 (m), 1158 (m), 1129 (m), 1089 (m), 1008 (m), 836 (m) MS (m / z): 356.0 ([M + H] +).

Example 213

N (3) - [(N-Cyclohexyl-N-methyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (300 mg, 1.039 mmol), DMF (3 mL), Et 3 N (173 μΐ, 1.25 mmol), BOP reagent (459 mg, 1.039 mmol) and N-methyl-N-cyclohexylhydrazine (132 mg, 1.04 mmol) yielded the title compound (285mg, 69%). MP: 62 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.63 (d, J = 8.7, 2H); 7.62 (br. S, 1H); 7.44 (d, J = 9.0, 2H); 3.77 (s, 1H); 3.67 (s, 1H); 2.73 (br. S, 3H); 2.13 (br. D, J = 8.7, 1H); 2.10-1.90 (m, 4H); 1.72 (br. D, J = 8.7, 1H); 1.80-1.15 (m, 11H) .IV (KBr, cm -1) 3258 (m), 2930 (s), 2854 (s), 1678 (s), 1596 (m), 1544 (s) , 1501 (s), 1447 (s), 1350 (s), 1274 (m), 1233 (m), 1159 (m), 1121 (m), 1090 (s), 1051 (m), 1006 (m) 915 (m), 866 (m), 831 (s) MS (m / z): 399.1 ([M + H] +).

Example 214

N (3) -Phenyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et 3 N (48μΐ, 0.35mmol), BOP reagent (152mg, 0.35 mmol) and aniline (31 μΐ, 0.35 mmol) provided the title compound (80 mg, 64%). M.p .: 137-140 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.70 (s, 1H); 7.69 (t, J = 9.9, 4H); 7.48 (d, J = 9.0.2H); 7.36 (t, J = 7.9, 2H); 7.12 (t, J = 7.4, 1H); 3.80 (s, 1H); 3.71 (s, 1H); 2.17 (br. D, J = 9.0, 1H); 2.95, 95 (m, 2H); 1.76 (br. D, J = 9.0, 1H); 1.38-1.19 (m, 2H). IR (KBr, cm -1): 3283 (m), 2933 (w), 2865 (w), 1663 (s), 1597 (s), 1542 (s), 1500 (s), 1433 (m), 1350 (m), 1240 (m), 1089 (m), 833 (m), 759 (m), 507 (w) .MS (m / z): 364.3 ([M + H] +).

Example 215

N (3) - (3-Chlorophenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.38 mmol), BOP reagent (162 mg 0.37 mmol) and 3-chloroaniline (49 mg, 0.38 mmol) provided the title compound (110mg, 78%). 158-161 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.71 (br. S, 1H); 7.87 (t, J = 1.8, 1H); 7.67 (d, J = 8.7, 2H); 7.54 (br. D, J = 8.1, 1H); 7.48 (d, J = 8.7,2H); 7.28 (t, J = 8.1, 1H); 7.09 (br. D, J = 8.1, 1H); 3.80 (br. S, 1H); 3.71 (br. S, 1H); 2.17 (br. D, J = 9.0.1H); 2.12-1.97 (m, 2H); 1.76 (d, J = 8.7, 1H); 1.32-1.20 (m, 2H). IR (cm -1, KBr): 3295 (s), 3187 (w), 3059 (w), 2987 (m), 2960 (m), 2984 (m), 2866 (m), 1677 (s), 1593 (s), 1551 (m), 1497 (s), 1484 (s), 1410 (m), 1400 (m), 1355 (m), 1308 (m), 1297 (w), 1234 (m), 1220 (m), 1157 (w), 1141 (m), 1091 (m), 1077 (w), 1048 (w), 1008 (m), 997 (m) 875 (m), 825 (m). MS (m / z): 398.2 ([M + H] +).

Example 216

N (3) - (4-Chlorophenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.39 mmol), BOP reagent (160 mg 0.36 mmol) and 4-chloroaniline (49 mg, 0.39 mmol) yielded the title compound (80mg, 58%). 182-184 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.69 (s, 1H); 7.67 (d, J = 8.7, 4H); 7.47 (d, J = 8.7,2H); 7.32 (d, J = 8.7, 2H); 3.80 (s, 1H), 3.71 (s, 1H), 2.16 (d, J = 8.7, 1H); 2.03 (d, J = 7.2, 2H); 1.76 (d, J = 8.7, 1H); 1.26 (d, J = 7.5, 2H). IR (cm -1, KBr): 3306 (m), 2989 (w), 2971 (w), 2945 (m), 2868 (w), 1673 (s), 1660 (s), 1594 (s), 1545 (s), 1498 (s), 1407 (s), 1397 (m), 1310 (m), 1284 (m), 1240 (m), 1089 (s), 1008 (m), 828 (s). (m / z): 398.0 ([M + H] +).

Example 217

N (3) - (3-Bromophenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.39 mmol), BOP reagent (160 mg 0.36 mmol) and 3-bromoaniline (42 μΐ, 0.38 mmol) provided the title compound (90mg, 59%). Mp: 176-178 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.69 (s, 1H); 8.00 (d, J = 2.1, 1H); 7.66 (d, J = 7.5.2H); 7.61 (br. D, J = 7.5, 1H); 7.47 (d, J = 7.5, 2H); 7.25-7.17 (m, 2H); 3.80 (s, 1H), 3.71 (s, 1H), 2.16 (d, J = 8.7, 1H); 2.03 (d, J = 7.8, 2H); 1.76 (d, J = 1.26 (d, J = 7.2, 2H) IR (cm -1, KBr): 3292 (w), 2865 (w), 1675 (s), 1587 (s ), 1497 (s), 1409 (m), 1397 (m), 1355 (m), 1306 (m), 1233 (m), 1091 (m), 874 (w), 825.

Example 218

N (3) - (2-Methoxyphenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazo1-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (48 μΐ, 0.35 mmol), BOP reagent (153 mg 0.35 mmol) and o-anisidine (39μΐ, 0.35 mmol) provided the title compound (100mg, 74%). 149-151 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 9.32 (br. S, 1H); 8.54 (dd, J = 8.1, 2.1, 1H); 7.69 (d, J = 9.0, 2H); 7.47 (d, J = 9.0, 2H); 7.10-7.02 (m, 2H); 6.92 (dd, J = 7.8, 1.5, 1H); 3.94 (s, 3H); 3.81 (br. S, 1H); 3.71 (br. S, 1H); 2.17 (d, J = 7.8,1H); 2.02 (br.d., J = 8.4, 2H); 1.76 (d, J = 8.7, 1H); 1.40-1.18 (m, 2H). IR (KBr, cm -1): 3380 (m), 2873 (w), 1684 (s), 1601 (m), 1541 (s), 1499 (s), 1479 (s), 1461 (s), 1349 (m), 1247 (m), 1219 (m), 1118 (m), 1089 (m), 1044 (m), 1027 (m), 838 (m) MS (m / z): 394.2 ( [M + H] +).

Example 219

N (3) - (4-tert-Butylphenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.39 mmol), BOP reagent (160 mg , 0.36 mmol) and 4-tert-butylaniline (62 μ.8, 0.3.8 mmol) yielded the title compound (100 mg, 69%). 76-78 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.65 (s, 1H); 7.67 (d, J = 8.7, 2H); 7.63 (d, J = 8.7, 2H); 7.47 (d, J = 8.7, 2H); 7.37 (d, J = 9.0, 2H); 3.81 (s, 1H); 3.70 (s, 1H); 2.16 (d, J = 9.0, 1H); 2.02 (d, J = 8.4, 2H); 1.75 (d, J = 9.0, 1H); 1.33 (s, 9H); 1.40-1.20 (m, 2H). IR (cm -1, KBr): 2962 (m), 2868 (m), 1685 (s), 1589 (m), 1537 (s), 1519 (s), 1492 (s), 1407 (m), 1349 (πι), 1243 (m), 1219 (m), 1134 (w), 1121 (w), 1091 (w), 1047 (w), 1009 (w), 830 (s). MS (m / z): 420.1 ([Μ + Η] +).

Example 220

Ν (3) -Benzyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1'-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate16 (100mg, 0.35mmol), DMF (1.0ml), Et3N (48μΐ, 0.35mmol), BOP reagent (152mg, 0 , 35 mmol) and benzylamine (37μΐ, 0.35 mmol) provided the title compound (67mg, 51%). 112-125 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.61 (d, J = 9.0, 2H); 7.45-7.20 (m, 8H); 4.63 (br. D, J = 5.7, 2H); 3.78 (s, 1H); 3.68 (s, 1H); 2.14 (br. D, J = 8.5, 1H); 2.05-1.90 (m, 2H); 1.73 (br. D, J = 8.5, 1H); 1.35-1.17 (m, 2H). IR (KBr, cm -1): 3318 (m), 2995 (m), 2930 (m), 1652 (s), 1548 (s), 1501 (s), 1352 (m), 1275 (m), 1239 (m), 1120 (m), 1089 (m), 830 (m), 701 (w), 508 (w) MS (m / z): 378.3 ([M + H] +).

Example 221

N (3) - (2-Chlorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (48 μΐ, 0.35 mmol), BOP reagent (152 mg 0.35 mmol) and 2-chlorobenzylamine (41 μΐ, 0.35 mmol) provided the title compound (91 mg, 64%). 119-122 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.63 (d, J = 9.0, 2H); 7.43 (d, J = 9.0, 2H); 7.51-7.20 (m, 5H); 4.72 (d, J = 6.3, 2H); 3.76 (S (1H)); 3.67 (s, 1H); 2.12 (br d, J = 8.6, 1H); 2.10-1.90 (m, 2H); 1.73 (br. D, J = 8.6,1H); 1.35-1.19 (m, 2H). IR (KBr, cm -1): 3319 (m), 2955 (m), 2868 (m), 1651 (s), 1595 (m), 1547 (m), 1490 (s), 1442 (m), 1352 (m), 1277 (m), 1237 (m), 1160 (m), 1123 (m), 1091 (m), 1007 (m), 993 (m), 835 (m) MS (m / z) : 412.0 ([M + H] +). Example 222

N (3) - (4-Chlorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (48 μΐ, 0.35 mmol), BOP reagent (152 mg 0.35 mmol) and 4-chlorobenzylamine (42 μΐ, 0.35 mmol) yielded the title compound (104 mg, 73%). 157-160 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.61 (d, J = 8.7, 2H); 7.42 (d, J = 8.7,2H); 7.31 (s, 4H); 7.23 (br. S, 1H); 4.59 (d, J = 5.6, 2H); 3.77 (s, 1H); 3.68 (s, 1H); 2.14 (br. D, J = 8.6.1H); 2.10-1.90 (m, 2H); 1.73 (br. D, J = 8.6.1H); 1.35-1.18 (m, 2H). IR (KBr, cm -1): 3324 (m), 2979 (m), 2951 (m), 2875 (m), 1649 (s), 1560 (s), 1513 (s), 1444 (m), 1406 (m), 1354 (m), 1244 (m), 1160 (m), 1144 (m), 1092 (s), 1007 (m), 980 (m), 946 (m), 835 (s), 626 (m), 509 (w) MS (m / z): 412.0 ([M + H] +).

Example 223

N (3) - (2,4-Dichlorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (48 μΐ, 0.35 mmol), BOP reagent (152 mg 0.35 mmol) and 2,4-dichlorobenzylamine (46μ1, 0.35 mmol) provided the title compound (104 mg, 67%). 108-111 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.62 (d, J = 8.7, 2H); 7.50-7.30 (m, 4H); 7.34 (br. S, 1H); 4.70 (d, J = 6.3, 2H); 3.75 (s, 1H); 3.68 (s, 1H); 2.13 (br. D, J = 9.0, 1H); 2, δ-90, (m, 2H); 1.73 (br d, J = 9.0, 1H); 1.40-1.18 (m, 2H) IR (KBr, cm -1): 3294 (m), 2988 (w), 2949 (w), 1652 (s), 1554 (m), 1502 (s) , 1491 (s), 1356 (m), 1252 (m), 1092 (m), 831 (s) MS (m / z): 447.9 ([M + H] +).

Example 224

N (3) - (2-Bromobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamideThe title compound was synthesized by a similar procedure. that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (0.10 mL, 0.69 mmol), BOP reagent (0.153 g, 0.35 mmol) and 2-bromobenzylamine hydrochloride (77 mg, 0.35 mmol) to provide the title compound (105 mg, 67%). Mp: 141 - 142 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.60-7.50 (m, 3H); 7.50-7.22 (m, 5H); 7.14 (td, J = 7.8, 1.5, 1H); 4.70 (d, J = 6.3, 2H); 3.80 (s, 1H); 3.70 (s, 1H); 2.14 (br.d., J = 8.7, 1H); 2.10-1.80 (m, 2H); 1.70 (br. D, J = 8.7.1H); 1.35-1.15 (m, 2H). IR (KBr, cm -1): 3322 (m), 2954 (w), 2867 (w), 1651 (s), 1548 (m), 1503 (s), 1350 (m), 1277 (w), 1236 (w), 1091 (s), 835 (m) MS (m / z): 458.1 ([M + H] +).

Example 225

N (3) - (4-Bromobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (0.096 mL, 0.69 mmol), BOP reagent (0.153 g, 0.35 mmol) 4-bromobenzylamine hydrochloride (77 mg, 0.35 mmol) provided the title compound (118 mg, 64%). Mp 181-183 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.60 (d, J = 6.9, 2H); 7.50-7.40 (m, 4H); 7.30-7.20 (m, 2H); 4.60 (br. D, J = 5.1, 2H); 3.80 (s, 1H); 3.70 (s, 1H); 2.14 (br. D, J = 9.0, 1H); 2.07-1.92 (m, 2H); 1.70 (br. D, J = 9.0, 1H); 1.30-1.15 (m, 2H). IR (KBr, cm -1): 3325 (m), 2979 (m), 2950 (m), 1648 (s), 1558 (m), 1505 (s), 1489 (s), 1353 (m), 1253 (m), 1092 (m), 835 (s) .MS (m / z): 458.0 ([M + H] +).

Example 226

N (3) - (4-Fluorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (48 μΐ, 0.35 mmol), BOP reagent (152 mg 0.35 mmol) and 4-fluorobenzylamine (39 μΐ, 0.35 mmol) yielded the title compound (95 mg, 69%). 104-107 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.61 (d, J = 9.0, 2H); 7.42 (d, J = 9.0, 2H); 7.35 (dd, J = 8.6, 5.7, 2H); 7.21 (br. S, 1H); 7.02 (t, J = 8.6, 2H); 4.59 (d, J = 6.0, 2H); 3.77 (s, 1H); 3.68 (s, 1H); 2.13 (br. D, J = 8.7, 1H); 2, δ-90, (m, 2H); 1.73 (br. D, J = 9.0, 1H); 1.40-1.18 (m, 2H). IR (KBr, cm -1): 3314 (m), 2968 (m), 2940 (m), 2872 (w), 1647 (s), 1554 (m), 1509 (s), 1357 (m), 1218 (m), 1091 (S), 832 (S), 626 (w), 564 (w) MS (m / z): 396.1 ([M + H] +).

Example 22 7

N (3) - (4-Trifluoromethylbenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (48 μΐ, 0.35 mmol), BOP reagent (152 mg 0.35 mmol) and 4-trifluoromethylbenzylamine (49 μΐ, 0.35 mmol) to provide the title compound (104 mg, 68%). 165-168 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.67-7.57 (m, 4H); 7.48 (d, J = 8.7, 2H); 7.43 (d, J = 8.7, 2H) 7.30 (br. T, J = 6.0, 1H); 4.68 (d, J = 5.7, 2H); 3.77 (s, 1H); 3.69 (s, 1H); 2.13 (br. D, J = 8.4, 1H); 2.10-1.90 (m, 2H); 1.73 (br. D, J = 7.2, 1H); 1.30-1.18 (m, 2H). IR (KBr, cm -1): 3323 (m), 2969 (m), 2953 (m), 2874 (w), 1648 (s), 1557 (m), 1504 (s), 1439 (m), 1406 (m), 1417 (m), 1325 (s), 1282 (m), 1245 (m), 1161 (s), 1122 (s), 1110 (s), 1092 (s), 1064 (s), 847 (m), 832 (m), 625 (w), 509 (w) .MS (m / z): 446.0 ([M + H] +).

Example 228

N (3) -Phenylamino-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (48 μΐ, 0.35 mmol), BOP reagent (152 mg 0.35 mmol) and phenylhydrazine (34 μΐ, 0.35 mmol) provided the title compound (92 mg, 70%). Mp 138-141 ° C. 1H-NMR (δ ppm, CDCl3, 300MHz): 8.55 (s, 1H); 7.67 (d, J = 8.5, 2H); 7.46 (d, J = 8.5, 2H); 7.24 (t, J = 7.5, 2H); 6.95 (d, J = 8.4, 2H) 6.90 (t, J = 7.5); 3.71 (br. S, 2H); 2.13 (br. D, J = 8.1, 1H); 2.10-1.95 (m, 2H); 1.73 (br. D, J = 8.7, 1H); 1.40-1.18 (m, 2H). IR (KBr, cm -1): 3258 (m), 2951 (m), 1660 (s), 1603 (s), 1500 (s), 1358 (m), 1306 (m), 1277 (m), 1127 (m), 1092 (s), 892 (w), 828 (m), 749 (m), 691 (m), 510 (m) MS (m / z): 379.0 ([M + H] +).

Example 229

N (3) - [(4-Chlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (48 μΐ, 0.35 mmol), BOP reagent (152 mg 0.35 mmol) and 4-chlorophenylhydrazine hydrochloride (61 mg, 0.35 mmol) to provide the title compound (98 mg, 69%). M. p .: 220-225Â ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.60 (s, 1H); 7.66 (d, J = 9.0, 2H); 7.47 (d, J = 9.0, 2H); 7.18 (d, J = 8.6, 2H); 6.87 (d, J = 8.6, 2H); 3.71 (s, 2H); 2.13 (br. D, J = 8.7, 1H); 2.10-1.90 (m, 2H); 1.73 (br. D, J = 9.0, 1H); 1.38-1.18 (m, 2H). IR (KBr, cm -1): 3256 (m), 2995 (m), 2950 (m), 2870 (m), 1661 (s), 1595 (m), 1500 (s), 1357 (m), 1278 (m), 1236 (m), 1128 (m), 1092 (s), 894 (w), 826 (m), 658 (w), 610 (w), 503 (w). MS (m / z) : 413.0 ([M + H] +).

Example 23 0

N (3) - [(2,4-Dichlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (57 μΐ, 0.42 mmol), BOP reagent (152 mg 0.35 mmol) and 2,4-dichlorophenylhydrazine hydrochloride (73 mg, 0.35 mmol) provided the title compound (53 mg, 34%). Mp = 180-182 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.54 (d, J = 3.0, 1H); 7.66 (d, J = 8.7, 2H); 7.47 (d, J = 8.7, 2H); 7.31 (d, J = 2.1.1H); 7.11 (dd, J = 8.7, 2.1, 1H); 6.96 (d, J = 8.7, 1H), 6.51 (d, J = 3.0, 1H); 3.71 (br. S, 2H); 2.13 (br. D, J = 7.8, 1H); 2.0 (m, 2H); 1.74 (br. D, J = 9.0, 1H); 1.232-1.25 (m, 2H). IR (KBr, cm -1): 3301 (m), 2993 (m), 2873 (m), 1674 (s), 1595 (w), 1542 (m), 1499 (s), 1352 (m), 1304 (m), 1232 (m), 1021 (m), 1049 (m), 814 (m).

Example 231

N (3) - [(3,4-Dichlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0 mL), Et 3 N (0.193 mL, 1.38 mmol), BOP reagent (306 mg, 0.69 mmol) 3,4-dichlorophenylhydrazine hydrochloride (148 mg, 0.69 mmol) provided the title compound (222 mg, 64.5%). 235-237 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.50 (s, 1H); 7.67 (d, J = 9.0, 2H); 7.48 (d, J = 9.0.2H); 7.28 (d, J = 8.4, 1H); 7.05 (d, J = 2.4, 1H); 6.79 (dd, J = 8.4, 2.4, 1H); 6.19 (br. S, 1H); 3.70 (s, 2H); 2.14 (br. D, J = 8.5, 1H); 2.10-1.90 (m, 2H); 1.7 (br. D, J = 8.5,1H); 1.30-1.18 (m, 2H). IR (KBr, cm -1): 3250 (m), 2995 (w), 2968 (w), 2946 (w), 2869 (m), 1667 (s), 1650 (s), 1598 (m), 1500 (s), 1475 (s), 1353 (m), 1277 (m), 1092 (m), 828 (m), 610 (w) MS (m / z): 449.0 ([M + H] +).

Example 232

N (3) - [(2-Fluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0 mL), Et 3 N (0.193 mL, 1.38 mmol), BOP reagent (306 mg, 0.69 mmol) and 2-fluorophenylhydrazine hydrochloride (113 mg, 0.69 mmol) provided the title compound (240 mg, 87%). M.p .: 91 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.50 (s, 1H); 7.65 (d, J = 7.2, 2H); 7.46 (d, J = 7.2, 2H); 6.95-7.10 (m, 3H); 6.80-6.90 (m, 1H); 6.40 (br. S, 1H); 3.70 (br.s, 2H); 2.14 (br. D, J = 9.0, 1H); 2.05-1.90 (m, 2H); 1.70 (br. D, J = 9.0, 1H); 1.30-1.17 (m, 2H). IR (KBr, cm -1): 3292 (m), 2925 (m), 2870 (m), 1676 (s), 1502 (s), 1351 (m), 1276 (m), 1194 (m), 1091 (s), 831 (s). MS (m / z): 397.0 ([M + H] +).

Example 233

N (3) - [(3-Fluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0 mL), Et 3 N (0.193 mL, 1.38 mmol), BOP reagent (306 mg, 0.69 mmol) and 3-fluorophenylhydrazine hydrochloride (113 mg, 0.69 mmol) afforded the title compound (158 mg, 58%). MP: 199 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.50 (s, 1H), 7.70 (d, J = 9.0, 2H); 7.50 (d, J = 9.0, 2H); 7.30-7.10 (m, 1H); 6.70-6.50 (m, 3H); 6.20 (br. S, 1H); 3.70 (s, 2H); 2.14 (br. D, J = 9.0, 1H); 2.10-1.90 (m, 2H); 1.73 (br. D, J = 9.0, 1H); 1.35-1.18 (m, 2H). IR (KBr, cm -1): 3257 (m), 2952 (w), 2872 (w), 1663 (s), 1619 (m), 1597 (m), 1501 (s), 1358 (m), 1266 (m), 1092 (m), 827 (m) MS (m / z): 397.1 ([M + H] +).

Example 234

N (3) - [(4-Fluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0 mL), Et 3 N (0.193 mL, 1.38 mmol), BOP reagent (306 mg, 0.69 mmol) and 4-fluorophenylhydrazine hydrochloride (113 mg, 0.69 mmol) provided the title compound (179 mg, 65%). MP: 212 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.50 (s, 1H); 7.70 (d, J = 9.0, 2H); 7.50 (d, J = 9.0, 2H); 7.00-6.80 (m, 4H); 3.70 (s, 2H); 2.14 (br. D, J = 9.0, 1H); 2.07-1.90 (m, 2Η); 1.73 (br. D, J = 9.0, 1H); 1.35-1.18 (m, 2H). IR (KBr, cm -1): 3268 (m), 2986 (w), 2950 (w), 1663 (m), 1502 (s), 1359 (m), 1214 (w), 1092 (m), 827 (m), 504 (w) MS (m / z): 397.0 ([M + H] +).

Example 235

N (3) - [(2,4-Difluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0 mL), Et 3 N (0.19 mL, 1.38 mmol), BOP reagent ( 306 mg, 0.69 mmol) and 2,4-difluorophenylhydrazine hydrochloride (113 mg, 0.69 mmol) to provide the title compound (160 mg, 56%). M.P .: 118 -12 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.50 (br. S, 1H); 7.70 (d, J = 8.7, 2H); 7.50 (d, J = 8.7, 2H); 7.10-6.70 (m, 3H); 6.25 (br. S, 1H); 3.70 (s, 2H); 2.14 (br.d., J = 8.7, 1H); 2.08-1.95 (m, 2H); 1.70 (br. D, J = 8.7, 1H); 1.35-1.20 (m, 2H). IR (KBr, cm -1): 3422 (m), 3286 (m), 2925 (m), 2871 (w), 1666 (m), 1501 (s), 1093 (m), 961 (m), 831 (m) MS (m / z): 417.1 ([M + H] +).

Example 236

N (3) - (N ', N'-Diphenylamino-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (200 mg, 0.69 mmol), DMF (2.0 mL), Et 3 N (0.19 mL, 1.38 mmol), BOP reagent ( 306 mg, 0.69 mmol) and N, N-diphenylhydrazine hydrochloride (113 mg, 0.69 mmol) provided the title compound (250 mg, 79.4%). 193-195 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.98 (s, 1H); 7.66 (d, J = 9.0, 2H); 7.45 (d, J = 9.0, 2H); 7.40-7.20 (m, 8H); 7.00 (m, 2H); 3.74 (br s, 1H); 3.71 (br. S, 1H); 2.14 (br. D, J = 8.7, 1H); 2.05-1.95 (m, 2H); 1.70 (br. D, J = 8.7.1H); 1.30-1.18 (m, 2H). IR (KBr, cm -1): 3232 (w), 2924 (m), 1664 (m), 1590 (m), 1497 (s), 1357 (m), 1223 (m), 1092 (m), 828 (w) MS (m / z): 455.0 ([M + H] +).

Example 237N (3) -Cyclohexyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1'-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (43 μΐ, 0.31 mmol), BOP reagent (136 mg 0.31 mmol) and cyclohexylamine (33 μΐ, 0.31 mmol) provided the title compound (104 mg, 83%). 157-160 ° C. 1H-NMR (δ ppm, CDCl3, 300MHz): 7.55 (s, 1H); 7.46 (d, J = 8.0, 1H); 7.37 (d, J = 8.0, 1H); 6.70 (br. D, J = 8.1, 1H); 4.05 - 3.85 (m, 1H); 3.75 (br. S, 1H); 3.36 (br. S, 1H); 2.13 (d, J = 8.1.1H); 2.00-1.85 (m, 4H); 1.70-1.58 (m, 4H); 1.46-1.15 (m, 7H). IR (KBr, cm -1): 3398 (m), 2923 (m), 2850 (m), 1658 (s), 1543 (s), 1520 (s), 1485 (m), 1343 (m), 1249 (m), 1122 (m), 1105 (m), 836 (m).

Example 23 8

N (3) -Cyclohexylmethyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (51 μΐ, 0.37 mmol), BOP reagent (136 mg 0.31 mmol) and cyclohexanomethylamine (40 μΐ, 0.31 mmol) provided the title compound (90 mg, 69%). 111-113 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.56 (br. S, 1H); 7.45 (d, J = 8.7,1H); 7.39 (br. D, J = 8.7, 1H); 6.88 (br. T, J = 6.3, 1H): 3.77 (br. S, 1H); 3.36 (br. S, 1H); 3.32-3.18 (m, 2H); 2.13 (br. D, J = 8.6, 1H); 2.00-1.50 (m, 9H); 1.25-1.11 (m, 5H); 1.00-0.80 (m, 2H). IR (KBr, cm -1): 3291 (m), 2922 (s), 2948 (m), 1643 (s), 1553 (m), 1501 (s), 1486 (s), 1445 (m), 1351 (m), 1274 (m), 1241 (m), 1107 (m), 1074 (m), 869 (m), 831 (m), 800 (m), 623 (m) .MS (m / z) : 418.1 ([M + H] +).

Example 239

N (3) - (N, N-Dicyclohexylamino) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (51 μΐ, 0.37 mmol), BOP reagent (136 mg 0.31 mmol) and N, N-dicyclohexylhydrazine (121 mg, 0.31 mmol) provided the title compound (70 mg, 45%). M.P .: 127-130 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.56 (d, J = 2.1, 1H); 7.48 (d, J = 8.7,1H); 7.35 (dd, J = 8.7, 2.1, 1H); 7.33 (br.s, 1H); 3.78 (s, 1H); 3.37 (s, 1H); 2.84 (br. S, 2H); 2.12 (br. D, J = 8.4, 1H); 1.97-1.80 (m, 6H); 1.80-1.58 (m, 6H); 1.40-1.00 (m, 13H). IR (KBr, cm -1): 3328 (m), 2932 (s), 2854 (s), 1693 (s), 1537 (m), 1501 (m), 1482 (m), 1345 (m), 1229 (m), 1102 (m), 1079 (m), 867 (m), 837 (m) MS (m / z): 501.50 ([M + H] +).

Example 240

N (3) - (4H-1,2,4-triazol-4-yl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole -3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (42 μΐ, 0.31 mmol), BOP reagent (136 mg 0.31 mmol) and 4-amino-1,2,4-triazole (26 mg, 0.31 mmol) provided the title compound (38 mg, 32%). M. p .: 231-233 ° C. 1H-NMR (δ ppm, DMS0-d6, 300 MHz): 1195 (s, 1H); 8.72 (s, 2H); 8.0 (d, J = 2.1, 1H); 7.71 (d, J = 8.4, 1H); 7.67 (dd, J = 8.4,2,1, 1H); 3.58 (br. S, 1H); 3.41 (s, 1H); 2.05 (br. D, J = 8.7, 1H); 1.98-1.90 (m, 2H); 1.71 (d, J = 8.7, 1H); 1.24-1.08 (m, 2H). IR (KBr, cm -1): 3125 (w), 3090 (m), 2997 (m), 2876 (m), 1699 (s), 1506 (s), 1350 (m), 1129 (m), 1065 (s), 923 (w), 826 (w) MS (m / z): 389.3 ([M + H] +).

Example 241

N (3) - (1,3,3-Trimethyl bicyclo [2,2,1] hepta-2-yl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H 4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (51 μΐ, 0.37 mmol), BOP reagent (136 mg 0.31 mmol) and (IS) -2endo-amino-1,3,3-trimethylbicyclo [2.2.1] heptane [prepared as described by Suchocki et al. In J. Med. Chem.1991,34,1003- 1010 (46 mg, 0.34 mmol)] provided the title compound (76 mg, 54%). 156-159 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.56 (d, J = 2.1, 1H); 7.47 (d, J = 8.4, 1H); 7.38 (dd, J = 8.4, 2.1, 1H); 6.91 (br. D, J = 8.4, 1H); 3.76 (br s, 2H); 3.38 (br. S, 1H); 2.12 (br.d., J = 7.5,1H); 2.00-1.84 (m, 2H); 1.80-1.58 (m, 4H); 1.02 (m, 12H); 0.85 (s, 3H). IR (KBr, cm -1): 3420 (m), 2954 (s), 2869 (m), 1677 (s), 1538 (s), 1483 (s), 1386 (m), 1229 (m), 1161 (m), 1113 (m), 1078 (s), 823 (w), 798 (w) MS (m / z): 458.10 ([M + H] +).

Example 242

N (3) - (Adamantan-yl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (0.51 μΐ, 0.37 mmol), BOP reagent ( 136 mg, 0.31 mmol) and 1-adamantylamine (46 mg, 0.31 mmol) provided the title compound (108 mg, 76%). Mp 201-204 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.55 (d, J = 1.8, 1H); 7.45 (d, J = 8.4.2H); 7.37 (dd, J = 8.4, 1.8, 1H); 6.60 (br. S, 1H); 3.75 (br. S, 1H); 3.35 (br. S, 1H); 2.13 (br. S, 10H); 2.02-1.80 (m, 2H); 1.70 (br. S, 7H); 1.40-1.13 (m, 2H). IR (cm -1, KBr): 3400 (s), 2907 (s), 2851 (m), 1667 (s), 1542 (s), 1516 (s), 1483 (s), 1452 (m), 1359 (m), 1289 (w), 1230 (m), 1105 (m), 862 (w), 832 (m) MS (m / z): 456.3 ([M + H] +).

Example 243

N (3) -Phenyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (42 μΐ, 0.30 mmol), BOP reagent (121 mg 0.31 mmol) and aniline (28 μΐ, 0.31 mmol) provided the title compound (90 mg, 71%). Mp 66-68 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.63 (br. S, 1H); 7.68 (d, J = 8.1, 2H); 7.59 (d, J = 2.1.1H); 7.49 (d, J = 8.4, 1H); 7.41 (dd, J = 8.4, 2.1, 1H); 7.34 (t, J = 8.1, 2H); 7.11 (t, J = 7.5,1H); 3.81 (br.s, 1H); 3.39 (br. S, 1H); 2.16 (br. D, J = 9.0, 1H); 2.05-1.86 (m, 2H); 1.73 (d, J = 8.7,1H); 1.35-1.15 (m, 2H). IR (KBr, cm -1): 3382 (m), 2948 (m), 2869 (m), 1681 (s), 1596 (s), 1542 (s), 1500 (s), 1434 (s), 1380 (m), 1347 (m), 1321 (m), 1282 (m), 1237 (m), 1218 (τη), 1159 (m), 1096 (m), 1077 (m), 810 (m). (m / z): 398.1 ([M + H] +).

Example 244

N (3) - (2,4-Difluorophenyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (57 μΐ, 0.37 mmol), BOP reagent (136 mg 0.31 mmol) and 2,4-difluoroaniline (31 μΐ, 0.31 mmol) yielded the title compound (62 mg, 46%). 152-155 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.79 (br. S, 1H); 8.50-8.40 (m, 1H); 7.59 (d, J = 2.1, 1H); 7.48 (d, J = 8.4, 1H); 7.41 (dd, J = 8.4, 2.1, 1H); 6.95-6.82 (m, 2H); 3.79 (br. S, 1H); 3.40 (br. S, 1H); 2.17 (br. D, J = 8.7, 1H); 2.10-1.90 (m, 2H); 1.73 (d, J = 8.7,1H); 1.35-1.15 (m, 2H). IR (KBr, cm -1): 3389 (s), 2993 (m), 2874 (m), 1685 (s), 1543 (s), 1505 (s), 1428 (m), 1345 (m), 1123 (m), 1102 (m), 1085 (m), 961 (w), 852 (w), 619 (w) MS (m / z): 434.0 ([M + H] +).

Example 245

N (3) - (2-Fluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (51 μΐ, 0.37 mmol), BOP reagent (136 mg 0.31 mmol) and 2-fluorobenzylamine (35 μΐ, 0.31 mmol) provided the title compound (55 mg, 41%). 54 ° C (melts). 1 H-NMR (δ ppm, CDCl 3, 300 MHz): 7.55 (br. S, 1H); 7.50-7.30 (m, 3H); 7.28-7.20 (m, 2H); 7.15-7.00 (m, 2H); 4.65 (br. D, J = 5.1, 2H); 3.77 (br. S, 1H); 3.37 (br. S, 1H); 2.12 (br. D, J = 7.5, 1H); 1.99-1.84 (m, 2H); 1.69 (br.d., J = 8.4, 1H); 1.28-1.15 (m, 2H). IR (KBr, cm -1): 3419 (m), 2950 (m), 2874 (m), 1668 (s), 1548 (s), 1487 (s), 1455 (s), 1346 (m), 1275 (m), 1229 (s), 1107 (s), 832 (m) MS (m / z): 430.10 ([M + H] +).

Example 246

N (3) - (4-Fluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (43 μΐ, 0.31 mmol), BOP reagent (136 mg 0.31 mmol) and 4-fluorobenzylamine (35 μΐ, 0.31 mmol) provided the title compound (90 mg, 68%). 106-108 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.55 (d, J = 2.1, 1H); 7.41 (d, J = 8.4, 1H); 7.39-7.25 (m, 3H); 7.15 (br. T, J = 6.6.1H); 7.00 (t, J = 8.7, 2H); 4.54 (dd, J = 17.0, 6.6, 1H) 4.59 (dd, J = 17.0, 6.6, 1H); 3.77 (br. S, 1H); 3.36 (br.s, 1H); 2.12 (br. D, J = 9.0, 1H); 2.10-1.82 (m, 2H); 1.70 (br. D, J = 9.0, 1H); 1.32-1.10 (m, 2H). IR (KBr, cm -1): 3277 (m), 2951 (m), 2979 (m), 2871 (m), 1648 (s), 1551 (m), 1510 (s), 1350 (m), 1273 (m), 1223 (s), 1108 (m), 1076 (w), 833 (m) MS (m / z): 432.1 ([M + H] +).

Example 247

N (3) - (2,4-Difluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (51 μΐ, 0.37 mmol), BOP reagent (136 mg 0.31 mmol) and 2,4-difluorobenzylamine (36 μΐ, 0.31 mmol) provided the title compound (93 mg, 67%). Mp 73-76 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.55 (d, J = 1.8, 1H); 7.40 (m, 3H); 7.20 (br. S, 1H); 6.90-6.75 (m, 2H); 4.50-4.70 (m, 2H); 3.77 (br. S, 1H); 3.36 (br. S, 1H); 2.12 (br. D, J = 8.7, 1H); 2.02-1.86 (m, 2H); 1.69 (d, J = 8.7, 1H); 1.14 (br. D, J = 9.0, 2H). IR (KBr, cm -1): 3421 (w), 3283 (m), 2996 (m), 2926 (w), 1648 (s), 1552 (m), 1505 (s), 1487 (s), 1455 (s), 1280 (m), 1138 (m), 1117 (m), 1098 (m), 832 (m), 964 (w), 851 (w), 832 (w). MS (m / z) : 448.10 ([M + H] +).

Example 248

N (3) - (2,6-Difluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (0.51 μΐ, 0.37 mmol), BOP reagent ( 136 mg, 0.31 mmol) and 2,6-difluorobenzylamine (36 mg, 0.31 mmol) provided the title compound (74 mg, 53%). 130-133 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.33 (m, 2H); 7.29-7.06 (m, 2H); 6.94-6.82 (m, 2H); 4.78-4.61 (m, 2H); 3.78 (br. S, 1H); 3.35 (br. S, 1H); 2.10 (br. D, J = 8.7, 1H); 2.04-1.81 (m, 2H); 1.68 (d, J = 8.7, 1H); 1.38-1.10 (m, 2H) .IV (cm -1, KBr): 3305 (m), 2988 (w), 2971 (w), 2945 (w), 2868 (w), 1672 (s ), 1660 (s), 1593 (s), 1545 (s), 1498 (s), 1406 (m), 1397 (m), 1355 (m), 1310 (w), 1240 (m), 1218 (w ), 1120 (w), 1189 (s), 1048 (w), 1008 (w), 829 (s) MS (m / z): 448.1 ([M + H] +).

Example 249

N (3) - (2-Chlorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (43 μΐ, 0.31 mmol), BOP reagent (136 mg 0.31 mmol) and 2-chlorobenzylamine (37 μΐ, 0.31 mmol) provided the title compound (102 mg, 74%). 117-120 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.55 (d, J = 2.4, 1H); 7.50-7.30 (m, 4H); 7.30-7.16 (m, 3H); 4.67 (dd, J = 17.6, 6.3, 1H) 4.72 (dd, J = 17.0, 6.3, 1H); 3.77 (br. S, 1H); 3.36 (br.s, 1H); 2.12 (br. D, J = 8.6, 1H); 2.00 -1.86 (m, 2H); 1.68 (br. D, J = 8.6, 1H); 1.31-1.13 (m, 2H). IR (KBr, cm -1): 3309 (m), 2998 (m), 2968 (m), 2951 (m), 2925 (m), 2869 (m), 1640 (s), 1564 (s), 1504 (s), 1487 (s), 1442 (m), 1346 (m), 1281 (m), 1241 (m), 1110 (m), 1056 (m), 870 (m), 832 (m). (m / z): 448.1 ([Μ + Η] +).

Example 250

N (3) - (4-Chlorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1'-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (43 μΐ, 0.31 mmol), BOP reagent (136 mg, 0.31 mmol) and 4-chlorobenzylamine (37 μΐ, 0.31 mmol) provided the title compound (108 mg, 78%). Mp: 139-142 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.56 (d, J = 2.2, 1H); 7.42 (d, 8.4, 1H); 7.36 (dd, J = 8.4, 2.2, 1H); 7.29 (s, 4H); 7.16 (br. T, J = 5.1, 1H); 4.65-4.47 (m, 2H); 3.77 (br. S, 1H); 3.36 (br. S, 1H); 2.12 (br. D, J = 8.6, 1H); 2, δ-δ, 85 (m, 2H); 1.70 (br. D, J = 8.6, 1H); 1.32-1.15 (m, 2H). IR (KBr, cm -1): 3290 (m), 2934 (m), 2869 (m), 1652 (s), 1553 (s), 1489 (s), 1436 (m), 1351 (m), 1276 (m), 1249 (m), 1142 (m), 1076 (m), 851 (m), 799 (m), 707 (m), 654 (m), 623 (m) MS (m / z) : 448.2 ([M + H] +).

Example 251

N (3) - (2,4-Dichlorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (43 μΐ, 0.31 mmol), BOP reagent (136 mg 0.31 mmol) and 2,4-dichlorobenzylamine (41 μΐ, 0.31 mmol) provided the title compound (118 mg, 79%). 57-59 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.56 (s, 1H); 7.45-7.37 (m, 4H); 7.27-7.20 (m, 3H); 4.60 (br. D, J = 4.8, 2H); 3.76 (s, 1H); 3.37 (s, 1Η); 2.12 (br. D, J = 8.4, 1H); 2.05-1.86 (m, 2H); 1.71-1.65 (br. D, J = 8.4, 1H); 1.26-1.13 (m, 2H). IR (KBr, cm -1): 3337 (m), 2948 (m), 2870 (m), 1737 (m), 1666 (s), 1545 (s), 1483 (s), 1381 (m), 1347 (m), 1236 (s), 1104 (s), 1078 (m), 1046 (m), 865 (m), 832 (s) .MS (m / z): 482.3 ([M + H] +).

Example 2 52

N (3) - [S- (1-phenylethyl)] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (51 μΐ, 0.37 mmol), BOP reagent (136 mg 0.31 mmol) and S - (-) - 1-phenylethylamine (39 μΐ, 0.31 mmol) provided the title compound (74 mg, 66%). 91-94 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.56 (d, J = 2.1, 1H); 7.47-7.20 (m, 7H); 7.08 (d, J = 7.5,1H); 5.38-5.22 (m, 1H); 3.75 (br. S, 1H); 3.35 (br. S, 1H); 2.11 (br. T, J = 8.7, 1H); 2.00-1.80 (m, 2H); 1.69 (br. S, 1H); 1.58 (d, J = 6.9.3H); 1.40-1.08 (m, 1H). MS (m / z): 426.10 ([M + H] +).

Example 2 53

N (3) - [R- (1-phenylethyl)] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (51 μΐ, 0.37 mmol), BOP reagent (136). mg, 0.31 mmol) and R - (+) - 1-phenothilamine (33 μΐ, 0.31 mmol) provided the title compound (66 mg, 50%). 89-92 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.55 (d, J = 2.1, 1H); 7.50-7.20 (m, 7H); 7.08 (d, J = 7.8,1H); 5.30 (m, 1H); 3.75 (br. S, 1H); 3.35 (br. S, 1H); 2.10 (t, J = 9.0, 1H); 2.00-1.80 (m, 2H); 169 (br. S, 1H); 1.58 (d, J = 6.9, 3H); 1.40-1.10 (m, 2H). IR (KBr, cm -1): 3411 (m), 3247 (m), 2972 (m), 2952 (m), 2870 (m), 1638 (s), 1545 (m), 1502 (s), 1483 (s), 1448 (m), 1378 (m), 1359 (m), 1239 (m), 1262 (m), 1138 (m), 1101 (m), 1076 (m), 815 (w), 699 (m) MS (m / z): 426.0 ([M + H] +).

Example 254

N (3) - (2-phenylethyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (43 μΐ, 0.31 mmol), BOP reagent (136 mg 0.31 mmol) and phenothilamine (38 µl, 0.31 mmol) provided the title compound (70 mg, 53%) as a waxy solid. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.55 (d, J = 1.8, 1H); 7.43 (d, J = 8.4, 1H); 7.36 (dd, J = 8.4, 1.8, 1H); 7.35-7.19 (m, 5H); 6.91 (br.s, 1H); 3.75 (br. S, 1H); 3.70-3.60 (m, 2H); 3.36 (br. S, 1H); 2.90 (t, J = 7.2, 2H); 2.12 (br. D, J = 8.6, 1H); 2.01-1.84 (m, 2H); 1.69 (br. D, J = 8.6, 1H); 1.31-1.13 (m, 2H).

Example 255

N (3) - [2- (4-fluorophenyl) ethyl] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (43 μΐ, 0.31 mmol), BOP reagent (136 mg 0.31 mmol) and 4-fluorophenothilamine (40 μΐ, 0.31 mmol) yielded the title compound (100 mg, 73%) as a glass paste. 1 H-NMR (δ ppm, CDCl 3, 300 MHz): 7, 56 (d, J = 2.1, 1H) 7.41 (d, J = 8.4, 1H); 7.37 (d, J = 8.4, 2.1, 1H); 7.19 (dd, J = 8.4, 5.4, 2H); 6.98 (t, J = 8.7, 2H); 6.90 (br.t, J = 4.6, 1H); 3.75 (br. S, 1H); 3.71-3.57 (m, 2H); 3.36 (br. S, 1H); 2.90 (t, J = 7.5, 2H); 2.12 (br. D, J = 8.7, 1H); 2.20-1.86 (m, 2H); 1.69 (br. D, J = 8.7, 1H); 1.31-1.13 (m, 2H).

Example 256

N (3) -Phenylamino-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (51 μΐ, 0.37 mmol), BOP reagent (136 mg 0.31 mmol) and defenylhydrazine hydrochloride (30 μΐ, 0.31 mmol) provided the title compound (84 mg, 66%). 182-185 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.48 (br. S, 1H); 7.58 (d, J = 1.8, 1H); 7.48 (d, J = 8.5,1H); 7.40 (dd, J = 8.5, 1.8.1H); 7.26-7.20 (m, 3H); 7.00-6.82 (m, 3H); 3.73 (br. S, 1H); 3.40 (br. S, 1H); 2.13 (br. D, J = 8.1, 1H); 1.97-1.90 (m, 2H); 1.71 (br. D, J = 9.0, 1H); 1.30-1.15 (m, 2H). IR (KBr, cm -1): 3251 (s), 2996 (m), 2947 (m), 2870 (m), 1663 (s), 1604 (m), 1542 (m), 1498 (s), 1483 (s), 1352 (m), 1279 (m), 1230 (m), 1231 (m), 1111 (m), 1083 (m), 1060 (m), 937 (m), 899 (m), 889 (m) 867 (m) MS (m / z): 413.0 ([M + H] +).

Example 257

N (3) - [(2-Chlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (107 μΐ, 0.77 mmol), BOP reagent (136 mg 0.31 mmol) and 2-chlorophenylhydrazine hydrochloride (55 mg, 0.31 mmol) provided the title compound (78 mg, 57%). Mp: 180-183 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.49 (br. S, 1H); 7.59 (d, J = 2.4, 1H); 7.48 (d, J = 8.4, 1H); 7.41 (dd, J = 8.4, 2.4.1H); 7.29 (d, J = 8.0, 1H); 7.14 (t, J = 7.8,1H); 7.03 (d, J = 8.1, 1H); 6.83 (t, J = 8.0, 1H); 6.55 (br. S, 1H); 3.73 (br. S, 1H); 3.40 (br s, 1H); 2.13 (br. D, J = 9.0, 1H); 2.01-1.87 (m, 2H); 1.70 (br. D, J = 9.0, 1H); 1.30-1.16 (m, 2H). IR (KBr, cm -1): 3255 (br., M), 2959 (w), 2874 (w), 1667 (s), 1508 (s), 1346 (m), 1279 (m), 1110 (m ), 1079 (m), 1066 (m), 862 (w). MS (m / z): 448.9 ([M + H] +).

Example 258

N (3) - [N- (2-Chlorophenyl) -N-methylamino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole-3 -carboxamide The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (0.51 μΐ, 0.37 mmol), BOP reagent (136 mg, 0.31 mmol) and N- (2-chlorophenyl) -N-methylhydrazine hydrochloride (59 mg, 0.31 mmol) provided the title compound (104 mg, 70%). 121-124 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.82 (br. S, 1H); 7.56 (d, J = 2.1, 2H); 7.45 (d, J = 8.4, 1H); 7.42 (dd, J = 8.1, 1.5, 1H); 7.38 (dd, J = 8.4, 2.1, 1H); 7.31 (dd, J = 8.1, 1.5, 1H); 7.24 (td, J = 8.1, 1.5, 1H); 6.99 (td, J = 8.1, 1.5 1H); 3.70 (br. S, 1H); 3.37 (br. S, 4H); 2.09 (br. D, J = 8.4, 1H); 2.00-1.82 (m, 2H); 1.67 (br.d., J = 8.7, 1H); 1.30-1.10 (m, 2H). IR (cm -1, KBr): 3404 (s), 3253 (m), 2951 (w), 2868 (w), 1654 (s), 1587 (w), 1545 (w), 1500 (s), 1484 (s), 1475 (s), 1443 (m), 1348 (w), 1276 (m), 1236 (m), 1122 (m), 1107 (m), 1052 (m), 832 (s). (m / z): 461.0 ([M + H] +).

Example 2 59

N (3) - [(4-Chlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (200 mg, 0.62 mmol), DMF (2.0 mL), Et 3 N (189 μΐ, 1.36 mmol), BOP reagent (273 mg 0.62 mmol) and 4-chlorophenylhydrazine hydrochloride (110 mg, 0.62 mmol) provided the title compound (195 mg, 70%). 141-144 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.47 (s, 1H); 7.59 (d, J = 1.8, 1H); 7.48 (d, J = 8.3, 1H); 7.40 (dd, J = 8.3, 1.8.1H); 7.18 (d, J = 8.7, 2H); 6.87 (d, J = 8.7, 2H); 6.17 (br. S, 1H); 3.72 (s, 1H); 3.40 (s, 1H); 2.15 (br. D, J = 8.7, 1H); 1.99-1.88 (m, 2H); 1.70 (br. D, J = 8.7, 1H); 1.26-1.19 (m, 2H). IR (KBr, cm -1): 3271 (s), 2991 (m), 1667 (m), 1596 (m), 1505 (m), 1491 (m), 1348 (m), 1276 (m), 1230 (m), 1080 (m), 1065 (m), 889 (m), 824 (s) MS (m / z): 447.0 ([M + H] +).

Example 2 60

N (3) - [(2,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (200 mg, 0.62 mmol), DMF (2.0 mL), Et 3 N (189 μΐ, 1.36 mmol), BOP reagent (273 mg 0.62 mmol) and 2,4-dichlorophenylhydrazine hydrochloride (132 mg, 0.62 mmol) to provide the title compound (205 mg, 69%). M. p .: 187 - 190 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.47 (d, J = 3.0, 1H); 7.59 (d, J = 2.1, 1H); 7.47 (d, J = 8.6, 1H) 7.40 (dd, J = 8.6, 2.1, 1H); 7.30 (d, J = 2.4, 1H); 7.11 (dd, J = 8.7, 1H); 6.95 (d, J = 9.0, 1H); 6.49 (d, J = 3.0, 1H); 3.71 (s, 1H); 3.39 (s, 1H); 2.12 (br. D, J = 9.3, 1H); 1.97-1.90 (m, 2H); 1.70 (br. D, J = 9.3, 1H); 1.25-1.15 (m, 2H). IR (KBr, cm -1): 3348 (m), 3191 (m), 2984 (m), 2968 (m), 2873 (w), 1661 (s), 1588 (m), 1557 (m), 1495 (s), 1343 (m), 1279 (m), 1108 (m), 1078 (m), 1068 (m), 861 (m).

Example 261

N (3) - [(2,4-dichlorophenyl) -N-methylamino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole-3 -carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (0.51 μΐ, 0.37 mmol), BOP reagent ( 136 mg, 0.31 mmol) and N- (2,4-dichlorophenyl) -N-methylhydrazine (59 mg, 0.31 mmol) provided the title compound (97 mg, 63%). 135-138 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.81 (br. S, 1H); 7.57 (d, J = 1.8, 1H); 7.42 (d, J = 8.3, 1H); 7.40 (dd, J = 8.3, 1.8, 1H); 7.35 (d, J = 8.3, 1H); 7.31 (d, J = 2.4.1H); 7.21 (dd, J = 8.3, 2.4, 1H); 3.69 (br. S, 1H); 3.35 (br. S, 4H); 2.09 (br. D, J = 9.0, 1H); 2.00-1.80 (m, 2H); 1.67 (br. D, J = 9.0, 1H); 1.35-1.20 (m, 2H). IR (cm -1, KBr): 3348 (s), 3081 (w), 2963 (m), 2871 (w), 1683 (s), 1586 (w), 1565 (w), 1533 (m), 1505 1482 (s), 1470 (s), 1438 (m), 1345 (m), 1122 (m), 1105 (m), 1085 (m), 1464 (s), 1049 (m), 814 (m) MS (m / z): 495.0 ([Μ + Η] +).

Example 262

N (3) - [(3,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (200 mg, 0.619 mmol), DMF (2.0 mL), Et 3 N (189 μΐ, 1.361 mmol), BOP reagent (273 mg, 0.619 mmol) ) 3,4-Dichlorophenylhydrazine hydrochloride (132 mg, 0.619 mmol) provided the title compound (205 mg, 69%). MP: 176-179 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.48 (s, 1H); 7.59 (d, J = 2.1, 1H); 7.48 (d, J = 8.4, 1H); 7.40 (dd, J = 8.4, 2.1, 1H); 7.26 (d, J = 8.7,1H); 7.03 (d, J = 2.7, 1H); 6.77 (dd, J = 8.7, 2.7, 1H); 6.22 (br. S, 1H); 3.72 (br. S, 1H); 3.40 (br s, 1H); 2.13 (br. D, J = 9.0, 1H); 2.03-1.88 (m, 2H); 1.70 (br d, J = 9.0, 1H); 1.30-1.16 (m, 2H). IR (KBr, cm -1): 3314 (m), 2951 (m), 2870 (m), 1678 (s), 1602 (m), 1511 (s), 1475 (s), 1384 (m), 1339 (m), 1253 (m), 1225 (m), 1126 (s), 1062 (s), 863 (m), 819 (s) MS (m / z): 481.0 ([M + H] +).

Example 2 63

N (3) - [(2-Bromophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (103 μΐ, 0.74 mmol), BOP reagent (136 mg 0.31 mmol) and 2-bromophenylhydrazine hydrochloride (69 mg, 0.31 mmol) yielded the title compound (115 mg, 76%). 159 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 8.50 (d, J = 3.3, 1H); 7.59 (d, J = 2.4, 1H); 7.50-7.39 (m, 3 H); 7.20 (t, J = 7.7, 1H); 7.01 (d, J = 6.9, 1H); 6.77 (t, J = 7.5, 1H); 6.52 (d, J = 3.3, 1H); 3.73 (s, 1H); 3.40 (s, 1H); 2.14 (br. D, J = 8.7, 1H); 2.02-1.91 (m, 2H); 1.70 (br d, J = 8.7, 1H); 1.30-1.19 (m, 2H). IR (KBr, cm -1): 3256 (m), 2925 (m), 2859 (m), 1666 (s), 1505 (s), 1344 (m), 1278 (m), 1232 (m), 1110 (m), 1079 (m), 1064 (m), 742 (m) MS (m / z): 491.0 ([Μ + Η] +).

Example 264

N (3) - [(2-Fluorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (200 mg, 0.62 mmol), DMF (2.0 mL), Et 3 N (0.2.0 mL, 1.49 mmol), BOP reagent (273 mg, 0.62 mmol) 2-fluorophenylhydrazine hydrochloride (100 mg, 0.62 mmol) provided the title compound (96 mg, 72%). MP: 131 - 134 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.51 (br.s, 1H); 7.59 (d, J = 2.1, 1H); 7.48 (d, J = 8.6, 1H) 7.40 (dd, J = 8.6, 2.1, 1H); 7.10-6.95 (m, 3H); 6.90-6.80 (m, 1H); 3.73 (br. S, 1H); 3.40 (br s, 1H); 2.14 (br. D, J = 9.0, 1H); 2.02-1.85 (m, 2H); 1.70 (d, J = 9.0, 1H); 1.30-1.15 (m, 2H). IR (KBr, cm -1): 3256 (br. S), 2989 (m), 2959 (m), 2873 (w), 1666 (s), 1618 (m), 1508 (s), 1456 (m) 1345 (m), 1279 (m), 1243 (m), 1194 (m), 1099 (s), 1063 (m), 863 (m).

Example 265

N (3) - [(2,4-Difluorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (150 mg, 0.46 mmol), DMF (2.0 mL), Et 3 N (154 μΐ, 1.11 mmol), BOP reagent (205 mg 0.46 mmol) and 2,4-difluorophenylhydrazine hydrochloride (83 mg, 0.46 mmol) gave the title compound (143 mg, 69%). 157-160 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.50 (br. S, 1H); 7.59 (d, J = 1.8, 1H); 7.47 (d, J = 8.4, 1H); 7.39 (dd, J = 8.4,1,8, 1H); 7.00 (dt, J = 9.0, 5.4, 1H); 6.82 (td, J = 8.4,2.7, 1H); 6.72 (br. T, J = 8.1, 1H); 3.72 (br. S, 1H); 3.40 (br. S, 1H); 2.13 (br. D, J = 8.4, 1H); 2.05-1.85 (m, 2H); 1.70 (d, J = 8.4, 1H); 1.30-1.15 (m, 2H). IR (KBr, cm -1): 3358 (m), 3198 (m), 3061 (m), 2989 (m), 2874 (m), 1664 (s), 1565 (m), 1520 (s), 1468 (m), 1382 (m), 1320 (m), 1281 (m), 1262 (m), 1207 (m), 1123 (m), 1108 (m), 1077 (m), 959 (m), 798 (m) MS (m / z): 449.0 ([Μ + Η] +).

Example 266

N (3) - [(3-Fluorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1'-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (103 μΐ, 0.74 mmol), BOP reagent (136 mg 0.31 mmol) and 3-fluorophenylhydrazine hydrochloride (50 mg, 0.31 mmol) yielded the title compound (98 mg, 74%). Mp 190 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 8.46 (s, 1H); 7.59 (d, J = 2.4.1H); 7.49 (d, J = 8.4, 1H); 7.40 (dd, J = 8.7, 2.4, 1H); 7.21-7.13 (m, 1H); 6.77-6.47 (m, 3H); 6.20 (br. S, 1H); 3.73 (s, 1H); 3.40 (s, 1H); 2.14 (br. D, J = 8.6, 1H); 2.02-1.88 (m, 2H); 1.70 (br. D, J = 8.6, 1H); 1.31-1.16 (m, 2H). IR (KBr, cm -1): 3411 (s), 3277 (s), 2986 (m), 2940 (m), 2870 (m), 1670 (s), 1615 (s), 1544 (s), 1504 (s), 1469 (s), 1444 (s), 1475 (s), 1341 (m), 1273 (m), 1237 (m), 1105 (m), 1081 (m), 835 (m). (m / z): 431.1 ([M + H] +).

Example 2 67

N (3) - [(3-chloropyridin-2-yl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-one carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.30 mmol), DMF (1.0 mL), Et 3 N (51 μΐ, 0.32 mmol), BOP reagent (129 mg 0.32 mmol) and 3-chloro-2-hydrazinopyridine (44 mg, 0.31 mmol) to provide the title compound (50 mg, 36%). 95 ° C (melts) 1 H-NMR (δ ppm, CDCl 3, 300 MHz): 9.40 (br. S, 1H); 8.10 (br. D, J = 4.8, 1H); 7.60 (br. D, J = 7.8, 2H); 7.58-7.50 (m, 1H); 7.39 (br. D, J = 8.1, 2H); 6.78 (dt, J = 7.5, 2.4, 1H); 3.72 (br. S, 1H); 3.41 (br. S, 1H); 2.15 (t, J = 8.7, 1H), 2.00-1.85 (m, 2H); 1.69 (br. D, J = 8.7, 1H); 1.20-1.10 (m, 2H). IR (cm -1, KBr): 3368 (br.m), 2954 (m), 2870 (m), 1677 (s), 1591 (s), 1537 (m), 1498 (s), 1470 (s) , 1406 (m), 1252 (m), 1227 (m), 1125 (s), 1080 (m), 1033 (m), 866 (w), 832 (m), MS (m / z): 448, 0 ([Μ + Η] +).

Example 2 68

N (5) -piperidine-3- (2 ', 4'-dichlorophenyl) -3,4-diazatricyclo [5. 2 .1. O2.6] deca-2 (6), 4-diene-5-carboxamide

The title compound was synthesized according to the procedure described for Example 101 using intermediate 17 (100 mg, 0.31 mmol), DMF (1 mL), triethylamine (0.04 mL, 0.31 mmol), BOP reagent ( 136 mg, 0.31 mmol) and 1-aminopiperidine (0.033 mL, 0.31 mmol) to provide the title compound (62 mg, 50%). 1H-NMR (δppm, CDCl3): 7.56 (d, J = 2.1, 1H); 7.45 (d, J = 8.4.1H); 7.37 (dd, J = 8.4, 2.1, 1H); 3.76 (br. S, 1H); 3.36 (br. S, 1H); 2.91 (br. S, 4H); 2.12 (br. D, J = 10.2.1H); 2.04-1.82 (m, 2H); 1.81-1.56 (m, 5H); 1.50-1.38 (m, 2H); 1.34-1.10 (m, 2H).

Example 269

N (5) -benzyl-3- (2 ', 4'-dichlorophenyl) -3,4-diazatricyclo [5. 2 .1. O2.6] deca-2 (6), 4-diene-5-carboxamide

The title compound was synthesized according to the procedure described for Example 101 using intermediate 17 (100 mg, 0.31 mmol), DMF (1 mL), triethylamine (0.04 mL, 0.31 mmol), BOP reagent ( 136 mg, 0.31 mmol) and benzylamine (0.033 mL, 0.31 mmol) to afford the title compound (94 mg, 74%). 1H-NMR (δppm, CDCl3): 7.55 (d, J = 2.1, 1H); 7.42 (d, J = 8.4.1H); 7.37-7.23 (m, 6H); 7.15 (br. S, 1H); 4.63 (dd, J = 110, 5.0, 1H); 4.57 (dd, J = 110, 5.0, 1H); 3.78 (br. S, 1H); 3.36 (br. S, 1H); 2.13 (br. D, J = 8.4, 1H); 2.04-1.82 (m, 2H); 1.70 (br. D, J = 8.4, 1H); 1.35-1.11 (m, 2H).

Example 270

N (3) -Piperidine-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 18 (100 mg, 0.30 mmol), DMF (1.0 mL), Et 3 N (50 μΐ, 0.36 mmol), BOP reagent (146 mg 0.33 mmol) and 1-aminopiperidine (32 μΐ, 0.30 mmol) provided the title compound (52 mg, 42%). M. p .: 236 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.73 (d, J = 8.4, 1H); 7.58 (br. S, 1H); 7.39-7.46 (m, 2H); 7.36-7.30 (m, 1H); 3.77 (br. S, 1H); 3.35 (br. S, 1H); 2.85 (br. S, 4H); 2.15 (br. D, J = 7.8, 1H); 2.00-1.71 (m, 6H); 1.44-1.16 (m, 5H). IR (KBr, cm -1): 3308 (m), 3000 (m), 2940 (s), 2864 (m), 2793 (m), 1685 (s), 1540 (s), 1511 (s), 1484 (s), 1449 (m), 1340 (w), 1229 (m), 1133 (m), 1123 (m), 1036 (m), 986 (m), 904 (m), 832 (w). (m / z): 415.1 ([M + H] +).

Example 271

N (3) -Cyclohexyl-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 18 (100 mg, 0.30 mmol), DMF (1.0 mL), Et 3 N (50 μΐ, 0.36 mmol), BOP reagent (146 mg 0.33 mmol) and cyclohexylamine (39 μΐ, 0.34 mmol) provided the title compound (100 mg, 80%). Mp 178 ° C. 1H-NMR (δ ppm, CDCl3, 300MHz): 7.26 (d, J = 8.1, 1H); 7.51-7.40 (m, 2H); 7.33 (br.t, J = 8.1, 1H); 6.73 (br. D, J = 8.4, 1H); 3.85-4.05 (m, 1H); 3.77 (br. S, 1H); 3.35 (br. S, 1H); 2.15 (br. D, J = 7.2, 1H); 2.00-1.85 (m, 4H); 1.80-1.65 (m, 4H); 1.50-1.14 (m, 7H). IR (KBr, cm -1): 3413 (m), 2938 (s), 2854 (m), 1662 (s), 1541 (s), 1512 (s), 1480 (s), 1450 (s), 1341 (m), 1299 (m), 1222 (m), 1159 (m), 1125 (m) MS (m / z): 414.0 ([M + H] +).

Example 272

N (3) -Benzyl-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 18 (100 mg, 0.30 mmol), DMF (1.0 mL), Et 3 N (50 μΐ, 0.36 mmol), BOP reagent (146 mg 0.33 mmol) and benzylamine (32μΐ, 0.30 mmol) provided the title compound (60mg, 47%). M.F .: 1010C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.70 (d, J = 8.4, 1H); 7.45-7.16 (m, 9H); 4.61 (m, 2H); 3.79 (br. S, 1H); 3.56 (br. S, 1H); 2.16 (br. D, J = 8.7.1H); 2.05-1.80 (m, 2H); 1.70 (br. D, J = 8.7, 1H); 1.35-1.15 (m, 2H). IR (KBr, cm -1): 3419 (w), 3020 (s), 2401 (w), 1661 (w), 1549 (w), 1516 (w), 1484 (w), 1427 (w), 1343 (w) 1216 (s) MS (m / z): 422.0 ([M + H] +).

Example 273

N (3) -Phenylamino-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 18 (100 mg, 0.30 mmol), DMF (1.0 mL), Et 3 N (50 μΐ, 0.36 mmol), BOP reagent (146 mg 0.33 mmol) and phenylhydrazine (30 μΐ, 0.30 mmol) provided the title compound (101 mg, 80%). 219 ° C. 1H-NMR (δ ppm, CDCl3, 300MHz): 8.51 (br. S, 1H); 7.50 (d, J = 7.8,1H); 7.60-7.41 (m, 2H); 7.36 (br. T, J = 8.4, 1H); 7.34 (t, J = 7.8H); 6.95 (d, J = 7.8, 2H); 6.89 (t, J = 7.5, 1H); 3.73 (br. S, 1H); 3.39 (br. S, 1H); 2.16 (br. D, J = 7.2, 1H); 2.00-1.85 (m, 2H); 7.70 (d, J = 8.7, 1H); 1.28-1.20 (m, 2H). IR (KBr, cm -1): 3283 (m), 2992 (m), 2959 (m), 2863 (w), 1675 (s), 1603 (m), 1542 (m), 1511 (s), 1497 (s), 1438 (m), 1348 (m), 1281 (m), 1240 (m), 1136 (m), 1123 (m), 1084 (m), 1029 (m), 888 (m). (m / z): 423.0 ([M + H] +).

Example 274

N (3) -Piperidine-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate19 (100 mg, 0.30 mmol), DMF (1.0 mL), Et 3 N (50 μΐ, 0.36 mmol), BOP reagent (146). mg, 0.33 mmol) and 1-aminopiperidine (33 μΐ, 0.30 mmol) provided the title compound (124 mg, 99%). M.p .: 173 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.60 (br. S, 4H); 3.70 (br. S, 1H); 3.65 (br. S, 1H); 2.90 (br. S, 4H); 2.20 (br. D, J = 7.14.1H); 2.00 (br. D, J = 8.6, 2H); 1.90 -1.60 (m, 6H); 1.30-1.20 (m, 3H). IR (KBr, cm -1): 3408 (w), 3308 (w), 2929 (s), 2859 (m), 2780 (m), 1692 (s), 1591 (m), 1541 (s), 1503 (S), 1489 (s), 1440 (m), 1401 (m), 1348 (s), 1268 (m), 1226 (s), 1154 (m), 1122 (s), 1064 (m), 1006 (m) 827 (s) MS (m / z): 415.1 ([M + H] +).

Example 2 75

N (3) -Cyclohexyl-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate19 (100 mg, 0.30 mmol), DMF (1.0 mL), Et 3 N (50 μΐ, 0.36 mmol), BOP reagent (146 mg 0.33 mmol) and cyclohexylamine (34 μΐ, 0.30 mmol) provided the title compound (91 mg, 73%). Mp: 164 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.58 (s, 4H); 6.75 (br. D, J = 8.1, 1H); 3.93 (m, 1H); 3.75 (br. S, 1H); 3.67 (br. S, 1H); 2.12 (br. D, J = 8.4.1H); 2.10-1.90 (m, 4H); 1.80-1.70 (m, 3H); 1.60-1.20 (m, 8H). IR (KBr, cm -1): 3410 (m), 2922 (m), 2848 (m), 1667 (s), 1591 (w), 1546 (s), 1504 (s), 1486 (s), 1450 (m), 1349 (m), 1224 (m), 1160 (m), 1122 (m), 1065 (m), 1006 (m), 827 (m) MS (m / z): 414.1 ( [M + H] +).

Example 276

N (3) -Benzyl-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate19 (100 mg, 0.30 mmol), DMF (1.0 mL), Et 3 N (50 μΐ, 0.36 mmol), BOP reagent (146 mg 0.33 mmol) and benzyl amine (33 μΐ, 0.30 mmol) yielded the title compound (107mg, 85%). M.p .: 89 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.56 (br. S, 4H); 7.40-7.22 (m, 6H); 4.64 (d, J = 5.4, 2H); 3.80 (br. S, 1H); 3.68 (br. S, 1H); 2.14 (br. D, J = 8.1.1H); 2.00 (br. D, J = 5.7, 2H); 1.74 (d, J = 8.4, 1H); 1.26-1.20 (m, 2H). IR (KBr, cm -1): 3321 (m), 2937 (m), 2868 (m), 1649 (s), 1590 (m), 1551 (s), 1499 (s), 1455 (m), 1347 (s), 1275 (m), 1241 (m), 1121 (m), 1070 (m), 1005 (m), 975 (m), 825 (m) MS (m / z): 422.1 ( [M + H] "). Example 2 77

N (3) -Phenylamino-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate19 (100 mg, 0.30 mmol), DMF (1.0 mL), Et 3 N (50 μΐ, 0.36 mmol), BOP reagent (146 mg 0.33 mmol) and phenylhydrazine (29 μΐ, 0.30 mmol) provided the title compound (90mg, 71%). M.p .: 138 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.54 (br. S, 1H); 7.61 (s, 4H); 7.24 (t, J = 7.8, 2H); 6.95 (d, J = 8.4, 2H); 6.90 (t, J = 7.2, 1H); 3.72 (br., 2H); 2.13 (br. D, J = 8.0, 1H); 1.99 (br. D, J = 7.8,2H); 1.73 (br. D, J = 8.0, 1H); 1.40-1.15 (m, 2H). IR (KBr, cm -1): 3262 (m), 2948 (m), 2869 (m), 1666 (s), 1603 (s), 1591 (s), 1545 (m), 1497 (s), 1401 (m), 1357 (m), 1279 (m), 1252 (m), 1227 (m), 1124 (m), 1083 (m), 1070 (m), 1005 (m), 894 (m). (m / z): 422.9 ([M + H] +).

Example 278

N (3) - [(2-Fluorophenyl) amino] -1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate19 (100 mg, 0.30 mmol), DMF (1.0 mL), Et 3 N (63 μΐ, 0.45 mmol), BOP reagent (146 mg 0.33 mmol) and 2-fluorophenylhydrazine hydrochloride (48 mg, 0.30 mmol) provided the title compound (50 mg, 38%). M.p .: 123 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 8.57 (br. S, 1H); 7.61 (s, 4H); 7.10-6.70 (m, 3H); 7.00-6.80 (m, 1H); 3.71 (s, 2H); 2.17 (br. D, J = 8.4, 1H); 2.10-1.90 (m, 2H); 1.73 (d, J = 8.7,1H); 1.35-1.15 (m, 2H). MS (m / z): 441.1 ([M + H] +).

Example 279

N (3) -Cyclohexyl-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate20 (100 mg, 0.37 mmol), DMF (1.0 mL), Et 3 N (61 μΐ, 0.44 mmol), BOP reagent (178 mg 0.40 mmol) and cyclohexylamine (42 μΐ, 0.37 mmol) provided the title compound (72 mg, 56%). M.P .: 127 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.64-7.62 (m, 2H); 7.17 (t, J = 8.4, 2H); 6.75 (br. D, J = 7.7, 1H); 4.05-3.80 (m, 1H); 3.75 (br. S, 1H); 3.64 (br. S, 1H); 2.20-1.90 (br. S, 5H); 1.74-1.66 (m, 5H); 1.44-1.10 (m, 6H). IR (KBr, cm -1): 3352 (m), 3310 (w), 2934 (m), 2834 (m), 1656 (s), 1642 (s), 1517 (s), 1499 (s), 1451 (m), 1350 (m), 1276 (w), 1252 (w), 1223 (s), 1163 (m), 1123 (m), 842 (m) MS (m / z): 354.1 ( [M + H] +).

Example 280

N (3) -Benzyl-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate20 (100 mg, 0.37 mmol), DMF (1.0 mL), Et 3 N (61 μΐ, 0.44 mmol), BOP reagent (178 mg 0.40 mmol) and benzylamine (39μΐ, 0.36 mmol) provided the title compound (43mg, 33%). 104 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.62 (br. S, 2H); 7.38-7.00 (m, 8H); 4.63 (br. D, J = 5.1, 2H); 3.78 (br. S, 1H); 3.66 (br. S, 1H); 2.12 (br.d., J = 8.4, 1H); 1.90-2.10 (m, 2H); 1.73 (d, J = 8.4.1H); 1.40-1.10 (m, 2H). IR (KBr, cm -1): 3411 (m), 3009 (w), 2869 (w), 1670 (s), 1543 (s), 1500 (s), 1492 (s), 1454 (m), 1416 (m), 1349 (s), 1276 (m), 1226 (s), 1212 (s), 1164 (m), 1124 (m), 954 (w); 835 (s) MS (m / z) : 362.1 ([M + H] +).

Example 281

N5- (Adamantan-2-yl) -3- (4-fluorophenyl) -3,4-diazatricyclo [5.2.1. O2'6] deca-2 (6), 4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate20 (100 mg, 0.36 mmol), DMF (1.0 mL), Et 3 N (124μ1, 0.88 mmol), BOP reagent (170 mg, 0.38 mmol) and 2-adamantylamine hydrochloride (103 mg, 0.55 mmol) provided the title compound (120 mg, 80%). 196-198 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.69-7.63 (m, 2H); 7.17 (t, J = 8.1, 2Η); 4.23 (d, J = 8.4, 1H); 3.75 (br. S, 1H); 3.65 (br. S, 1H), 2.14-1.87 (m, 14H), 1.78-1.54 (m, 4H), 1.26-1.21 (m, 2H). IR (cm -1, KBr): 3414 (s), 2979 (w), 2901 (s), 2851 (s), 1663 (s), 1542 (s), 1517 (s), 1488 (s), 1454 (m), 1445 (m), 1347 (w), 1255 (w), 1224 (m), 1213 (s), 1159 (m), 1126 (m), 1091 (m), 953 (w), 833 (m) MS (m / z): 406.2 ([M + H] +).

Example 282

N5- (1-Methyl-1-phenylethyl) -3- (4-fluorophenyl) -3,4-diazatricyclo [5.2.1. O2'6] deca-2 (6), 4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate20 (100 mg, 0.36 mmol), DMF (1.0 mL), Et 3 N (41 μΐ, 0.40 mmol), BOP reagent (170 mg 0.38 mmol) and α, α-dimethylbenzylamine (75 mg, 0.55 mmol) provided the title compound (77 mg, 54%). 119-122 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.68-7.62 (m, 2H); 7.51-7.46 (m, 2H); 7.37-7.30 (m, 2H); 7.27-7.13 (m, 3H); 3.70 (br. S, 1H); 3.63 (br. S, 1H); 2.08 (d, J = 9.0, 1H), 1.95 (d, J = 7.8, 2H); 1.84 (s, 6H); 1.68 (d, J = 8.4, 1H), 1.23 (d, J = 12.0, 2H). IR (cm -1, KBr): 3358 (m), 2972 (m), 2927 (m), 2870 (m), 1664 (s), 1605 (w), 1542 (m), 1515 (s), 1489 (m), 1383 (w), 1357 (m), 1276 (m) 1219 (m), 1136 (m), 1117 (m), 1093 (m), 1031 (w), 1088 (w), 949 ( w), 858 (w), 839 (m) MS (m / z): 390.0 (M + H +).

Example 283

N5- (Adamant an-1-yl) -3- (4-fluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate20 (100 mg, 0.36 mmol), DMF (1.0 mL), Et 3 N (41 μΐ, 0.40 mmol), BOP reagent (170 g 0.38 mmol) and 1-adamantylamine (83 mg, 0.54 mmol) provided the title compound (127 mg, 85%). M.P .: 189-191 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.66-7.60 (m, 2H); 7.19-7.12 (m, 2H); 6.66 (br. S, 1H); 3.74 (br. S, 1H); 3.63 (br. S, 1H); 2.15-2.10 (m, 9H) 1.97 (d, J = 8.7, 2H); 1.75-1.68 (m, 8H); 1.30-1.20 (m, 2Η). IR (cm -1, KBr): 3361 (m), 2986 (m), 2909 (m), 1658 (s), 1517 (s), 1550 (s), 1493 (s), 1412 (m), 1308 (w), 1289 (w), 1278 (w), 1256 (s), 868 (m) MS (m / z): 406.1 ([Μ + Η] +).

Example 284

N (3) -Phenylamino-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate20 (100 mg, 0.37 mmol), DMF (1.0 mL), Et 3 N (61 μΐ, 0.44 mmol), BOP reagent (178 mg 0.40 mmol) and phenylhydrazine (36 μΐ, 0.37 mmol) provided the title compound (72 mg, 54%). M. p .: 163 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.55 (s, 1H); 7.69 (dd, J = 9.3, 5.2, 2H); 7.27-7.16 (m, 4H); 6.95 (d, J = 7.5, 2H); 6.90 (t, J = 7.2, 1H); 3.73 (br. S, 1H); 3.69 (br. S, 1H); 2.15 (br. D, J = 9.0, 1H); 2.06-1.99 (m, 2H); 1.73 (d, J = 8.7,1H); 1.25 (br. D, J = 7.2, 2H). IR (KBr, cm -1): 3376 (m), 2991 (m), 2952 (m), 2871 (m), 1674 (s), 1604 (s), 1517 (s), 1497 (s); 1441 (m), 1350 (m), 1279 (m), 1223 (s), 1154 (m), 1127 (m), 1093 (m), 1083 (m), 1066 (m), 1041 (w), 889 (m), 841 (m) .MS (m / z): 363.1 ([M + H] +).

Example 285

N (3) -Phenylamino-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.36 mmol), DMF (1.0 mL), Et 3 N (44 μΐ, 0.32 mmol), BOP reagent (125 mg 0.28 mmol) and phenylhydrazine (34 μΐ, 0.34 mmol) provided the title compound (87 mg, 44%). Mp: 161 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.50 (br. S, 1H); 7.70 (m, 1H); 7.24 (t, J = 7.8, 2H); 7.09-6.99 (m, 2H); 6.99-6.86 (m, 3H); 3.72 (br. S, 1H); 3.48 (br. S, 1H); 2.09 (br. D, J = 8.4, 1H); 1.97 (br. D, J = 9.3, 2H); 1.69 (br. D, J = 8.7, 1H); 1.27 (br. D, J = 9.3, 2H). IR (cm -1, KBr): 3274 (s), 2991 (m), 2957 (m), 1672 (s), 1605 (s), 1525 (s), 1497 (s), 1441 (m), 1352 (s), 2849 1445 (m), (s), 1219 (m), 1273 (s), 1230 (τη), 1146 (m), 1126 (m), 1085 (m), 966 (m), 889 (m) 851 (m) MS (m / z): 381.0 ([Μ + Η] +).

Example 286

N (3) - [(2-Chlorophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (114 μΐ, 0.83 mmol), BOP reagent (152 mg 0.34 mmol) and 2-chlorophenylhydrazine hydrochloride (61 mg, 0.34 mmol) provided the title compound (108 mg, 76%). M.P .: 126-129 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.55 (br. S, 1H); 7.75-7.65 (m, 1H); 7.29 (d, J = 7.2,1H); 7.14 (t, J = 8.1,1H); 7.04 (br. T, J = 8.1, 3H); 6.83 (t, J = 6.9, 1H); 3.71 (br. S, 1H); 3.49 (br. S, 1H); 2.09 (d, J = 9.0, 1H); 1.97 (d, J = 9.0, 2H); 1.70 (d, J = 9.0, 1H); 1.26 (br. D, J = 8.4.2H). IR (KBr, cm -1): 3247 (br.m), 2956 (m), 2873 (m), 1670 (s), 1595 (m), 1524 (s), 1494 (s), 1439 (m) 1349 (m), 1270 (s), 1254 (m), 1141 (m), 1048 (m), 1034 (m), 964 (m), 887 (w), 848 (m), 750 (s) MS (m / z): 415.10 ([M + H] +).

Example 287

N (3) - [(2-bromophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (114 μΐ, 0.83 mmol), BOP reagent (152 mg 0.34 mmol) and 2-bromophenylhydrazine hydrochloride (76 mg, 0.34 mmol) provided the title compound (125 mg, 79%). 134-137 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.57 (br. S, 1H); 7.74-7.65 (m, 1H); 7.46 (d, J = 7.8,1H); 7.19 (t, J = 7.8,1H); 7.10-6.90 (m, 3H); 6.77 (t, J = 8.1, 1H); 3.72 (br. S, 1H); 3.49 (br. S, 1H); 2.12 (br. D, J = 8.7, 1H); 1.97 (br. D, J = 9.0, 2H); 1.70 (br. D, J = 8.7, 1H); 1.27 (br. D, J = 9.0, 2H). IR (KBr, cm -1): 3327 (s), 3295 (m), 2969 (m), 2869 (m), 1656 (s), 1609 (m), 1594 (m), 1524 (s), 1481 (s), 1449 (m), 1353 (m), 1271 (s), 129 (m), 1093 (s), 1071 (m), 1046 (m), 1021 (m), 846 (s).

Example 288

N (3) - [(2-Fluorophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (114 · μΐ, 0.83 mmol), BOP reagent (152 mg, 0.34 mmol) and 2-fluorophenylhydrazine hydrochloride (55 mg, 0.34 mmol) provided the title compound (94 mg, 69%). Mp: 172-175 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.54 (br. S, 1H); 7.71 (dt, J = 8.4, 2.4, 1H); 7.10-6.96 (m, 5H); 6.90-6.80 (m, 1H); 3.72 (br. S, 1H); 3.49 (br. S, 1H); 2.11 (br. D, J = 7.2.1H); 1.97 (d, J = 9.3, 2H); 1.71 (d, J = 9.0, 1H); 1.30-1.25 (m, 2H). IR (KBr, cm -1): 3339 (s), 2989 (m), 2871 (m), 1685 (s), 1614 (m), 1523 (s), 1498 (s), 1439 (s), 1271 (m), 1233 (m), 1192 (m), 1143 (m), 1061 (m), 1027 (m), 966 (m), 862 (m) MS (m / z): 399.10 ([M + H] +).

Example 289

N (3) -Piperidine-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (58 μΐ, 0.42 mmol), BOP reagent (166 mg 0.38 mmol) and 1-aminopiperidine (37 μΐ, 0.34 mmol) provided the title compound (42 mg, 33%). Mp: 143 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.72-7.61 (m, 1H); 7.58 (br. S, 1H); 7.02 (t, J = 8.4, 2H); 3.75 (br. S, 1H); 3.44 (br.s, 1H); 2.88 (br.s, 4H); 2.09 (br. D, J = 8.7, 1H); 2.10-1.90 (m, 2H); 1.78-1.65 (m, 5H); 1.50-1.34 (m, 2H); 1.34-1.08 (m, 2H). IR (KBr, cm -1): 3263 (m), 2994 (m), 2942 (m), 2872 (m), 2853 (m), 1658 (s), 1611 (m), 1521 (s), 1444 1353 (m), 1269 (s), 1233 (m), 1143 (m), 1121 (m), 1089 (m), 965 (m), 907 (m) MS (m / z) : 373.2 ([M + H] +) Example 290

N (3) -Cyclohexyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (57 μΐ, 0.42 mmol), BOP reagent (166 mg 0.38 mmol) and cyclohexylamine (39 μΐ, 0.34 mmol) provided the title compound (41 mg, 32%). M.p .: 119 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.60 (m, 1H); 7.01 (t, J = 7.8, 2H); 6.72 (br. D, J = 8.1, 1H); 4.03-3.85 (m, 1H); 3.75 (br. S, 1H); 3.44 (br. S, 1H); 2.10-1.95 (m, 5H); 1.80-1.42 (m, 5H); 1.40-1.15 (m, 6H). IR (KBr, cm -1): 3294 (m), 2995 (m), 2933 (s), 2853 (m), 1641 (s), 1610 (m), 1548 (s), 1520 (s), 1499 (s), 1451 (m), 1352 (m), 1269 (m), 1251 (m), 1239 (m), 1160 (m), 1142 (m), 1122 (m), 1090 (m), 964 (m) 851 (m) MS (m / z): 372.1 ([M + H] +).

Example 291

N (3) - (Cyclohexylmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (57 μΐ, 0.41 mmol), BOP reagent (152 mg 0.34 mmol) and 2-cyclohexylmethyl amine (44 μΐ, 0.34 mmol) provided the title compound (87 mg, 65%). 94-97 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.67 (m, 1H); 7.01 (t, J = 8.1H); 6.91 (br. S, 1H); 3.75 (br. S, 1H); 3.44 (br. S, 1H); 3.26 (t, J = 6.6, 2H); 2.08 (br. D, J = 8.7, 1H); 2.05-1.85 (m, 2H); 1.83-1.50 (m, 6H); 1.26-1.18 (m, 6H), 1.05-0.85 (m, 2H). IR (KBr, cm -1): 3379 (m), 2926 (s), 2848 (m), 1655 (s), 1556 (m), 1519 (s), 1499 (m), 1450 (m), 1271 (m), 1241 (m), 1142 (m), 1088 (m), 962 (w), 852 (w) MS (m / z): 386.20 ([M + H] +).

Example 292

N (3) - [S- (I-Phenylethyl)] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (57 µΐ, 0.41 mmol), BOP reagent (152 mg, 0, 34 mmol) and S - (-) - 1-phenothylamine (44 μΐ, 0.34 mmol) provided the title compound (85 mg, 63%). 54-57 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.66 (dt, J = 9.0, 5.7, 1H); 7.40-7.20 (m, 5H); 7.11 (br. D, J = 7.5, 1H); 7.00 (t, J = 8.7,2H); 5.35-5.28 (m, 1H); 3.74 (br s, 1H); 3.44 (br. S, 1H); 2.07 (br. T, J = 8.6, 1H); 1.94 (br s, 2H); 1.70-1.55 (m, 4H); 1.33-1.25 (m, 2H). IR (KBr, cm -1): 3412 (m), 3310 (w), 2971 (m), 2872 (m), 1664 (s), 1611 (m), 1523 (s), 1493 (s), 1447 (s), 1359 (m), 1271 (s), 1232 (m), 1180 (m), 1144 (s), 1121 (m), 1091 (m), 965 (m), 850 (m). (m / z): 394.0 ([M + H] +).

Example 293

N (3) - (R-1-phenylethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.38 mmol), BOP reagent (152 mg 0.36 mmol) and RI-phenylethylamine (44 μ, 0.37 mmol) provided the title compound (75 mg, 56%). Mp 40-45 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.72-7.60 (m, 1H); 7.46-7.19 (m, 5H) 7.15-6.90 (m, 3H); 5.31 (br. S, 1H); 3.74 (br. S, 1H) 3.43 (br. S, 1H); 2.07 (br. S, 1H); 1.95 (br s, 2H) 1.72-1.51 (m, 4H); 1.44-1.17 (m, 2H). IR (cm -1) KBr) 3412 (s), 3062 (m), 3029 (m), 2970 (s), 29230 (s), 2872 (m), 1663 (s), 1610 (s), 1523 ( s), 1493 (s), 1447 (s), 1358 (m), 1326 (m), 1270 (s), 1252 (s), 1232 (s), 1210 (m), 1160 (s), 1143 ( s), 1121 (s), 1191 (s), 965 (m) 850 (m), 831 (m) MS (m / z): 394.2 (87, [M + H] +); 2 (100). Example 2 94

N (3) - (1-Methyl-1-phenylethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.38 mmol), BOP reagent (152 mg 0.36 mmol) and α, α-dimethylbenzylamine (56 mg, 0.41 mmol) provided the title compound (80 mg, 58%). 105 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.69 (dt, J = 9.6, 6.0, 1H); 7.49 (d, J = 7.8, 2H); 7.34 (t, J = 7.8, 2H); 7.28-7.18 (m, 2H); 7.06-6.96 (m, 2H); 3.70 (br. S, 1H); 3.43 (br. S, 1H); 2.06 (br. D, J = 8.7, 1H); 2.00-1.86 (m, 2H); 1.66 (br. D, J = 8.4, 1H); 1.35-1.17 (m, 2H). IR (cm -1, KBr): 3334 (s), 2965 (s), 2929 (s), 2873 (m), 1656 (s), 1609 (s), 1522 (s), 1495 (s), 1449 1385 (m), 1362 (m), 1326 (w), 1308 (m), 1271 (s), 1252 (s), 1237 (s), 1194 (m), 1156 (w), 1143 (m), 1121 (m), 1106 (m), 1091 (m), 965 (m) 848 (m), 831 (m). MS (m / z): 408.1 (40, [M + H] +); 290.3 (100).

Example 295

N5- [1- (2-Chlorophenyl) -1-methylethyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2.6] deca-2 (6), 4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.37 mmol), BOP reagent (152 mg 0.37 mmol) and 2- (2-chlorophenyl) prop-2-ylamine (87 mg, 0.51 mmol) provide the title compound (87 mg, 57%). Mp: 176-179 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.75-7.60 (m, 1H); 7.58 (d, J = 7.8,1H); 7.41-7.12 (m, 4H); 7.06-6.95 (m, 2H); 3.64 (s, 1H); 3.42 (s, 1H); 2.04 (d, J = 8.4, 1H); 1.95-1.85 (m, 8H), 1.62 (d, J = 9.3, 1H), 1.23 (d, J = 9.0, 2H). IR (cm -1, KBr): 3413 (m), 2975 (m), 2871 (m), 1675 (s), 1613 (w), 1522 (s), 1491 (m), 1447 (m), 1383 (w), 1362 (w), 1270 (s), 1244 (m), 1144 (m), 1091 (w), 1037 (w), 965 (w), 853 (w), 755 (w). (m / z): 442.1 ([M + H] +).

Example 296

N (3) - (1,3,3-Trimethylbicyclo [2,2,1] hepta-2-yl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4 7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (120 mg, 0.41 mmol), DMF (1.0 mL), Et 3 N (137 μΐ, 0.99 mmol), BOP reagent (182 mg 0.44 mmol) and DE, 2endo-1,3,3-trimethyl-bicyclo [2.2.1] hepta-2-ylamine hydrochloride (77 mg, 0.41 mmol) provided the title compound (86mg, 49%). 114-117 ° C. 1H-NMR (δ ppm, DMS0-d6, 300MHz): 7.86-7.76 (m, 1H), 7.60 (br. T, J = · 9.3, 1H); 7.29 (br. T, J = 8.1, 1H); 7.00 (d, J = 9.6, 1H); 3.63 (d, J = 9.3, 1H); 3.52 (br. S, 1H); 3.46 (br. S, 1H); 2.05-1.85 (m, 3H); 1.75-1.55 (m, 4H); 1.50-1.35 (m, 2H); 1.25-0.95 (m, 10H); 0.77 (d, J = 5.1, 3H). IR (cm -1, KBr): 3390 (m), 2952 (s), 2873 (m), 1658 (s), 1607 (w), 1520 (s), 1496 (s), 1451 (m), 1475 (m), 1368 (w), 1329 (m), 1252 (m), 1232 (m), 1158 (m), 1148 (m), 964 (m), 822 (w). MS (m / z) : 426.3 ([M + H] +).

Example 297

N5- (2-Chlorobenzyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2 '6] deca-2 (6), 4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (57 μΐ, 0.41 mmol), BOP reagent (167 mg 0.37 mmol) and 2-chlorobenzylamine (41 μΐ, 0.34 mmol) provided the title compound (100 mg, 68%). 102-105 ° C. 1H-NMR (δ ppm, DMSO-d6, 300 MHz): 8.67-8.73 (m, 1H), 7.89-7.77 (m, 1H); 7.66-7.57 (m 1H); 7.44 (d, J = 7.2, 1H); 7.34-7.30 (m, 4H); 4.49 (br s, 2H); 3.55 (br. S, 1H); 3.47 (br. S, 1H); 2.00-1.92 (m, 3H); 1.66 (d, J = 8.7, 1H); 1.17-1.05 (m, 2H). IR (cm -1, KBr): 3337 (m), 2965 (m), 2868 (w), 1657 (m), 1645 (s), 1623 (m), 1526 (s), 1271 (m), 1243 (w), 1234 (w), 1160 (m), 846 (m), 738 (w).

Example 298

N5- (4-Chlorobenzyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (50 μΐ, 0.37 mmol), BOP reagent (159 mg, 0.36 mmol) and 4-chloro-benzylamine (63 μΐ, 0.51 mmol) provided the title compound (96 mg, 67%). M.p .: 121-125 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.67-7.57 (m, 1H); 7.30-7.25 (m, 4H); 7.20-7.15 (m, 1H); 7.05-6.95 (m, 2H); 4.57 (d, J = 4.8.2H); 3.76 (br. S, 1H); 3.45 (br s, 1H); 2.09 (d, J = 9.0, 1H); 2.00-1.93 (m, 2H); 1.69 (d, J = 9.0, 1H); 1.28-1.24 (m, 2H). IR (cm -1, KBr): 3310 (m), 2964 (m), 2939 (m), 2874 (m), 1644 (s), 1607 (w), 1557 (s), 1520 (s), 1491 (s), 1454 (m), 1407 (w), 1358 (m), 1326 (w), 1272 (m), 1254 (m), 1232 (m), 1160 (m), 1142 (m), 1088 (m), 1013 (m), 962 (m), 853 (m) MS (m / z): 412.25 (100%), 414.2 ([M + H] +).

Example 299

N5- (1-Ethyl-1-phenylpropyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2 '6] deca-2 (6), 4-diene-5-carboxamide The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL ), Et 3 N (54 μΐ, 0.37 mmol), BOP reagent (152 mg, 0.34 mmol) and α, α-diethylbenzylamine (72 mg, 0.44 mmol) provided the title compound (85 mg, 86%). Mp 45-48 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.76-7.66 (m, 1H), 7.42-7.10 (m, 6H); 7.07-6.96 (m, 2H); 3.70 (br. S, 1H); 3.45 (br s, 1H); 2.23 (q, J = 7.2, 4H); 2.06 (d, J = 9.0, 1H); 1.93 (d, J = 8.4, 2H); 1.66 (d, J = 8.7, 1H); 1.26 (d, J = 5.4, 2H); 0.78 (t, J = 7.2, 6H). IR (cm -1, KBr): 3407 (m), 3059 (m), 2968 (s), 2975 (s), 2935 (s), 1681 (s), 1610 (m), 1583 (s), 1524 (s), 1491 (m), 1447 (m), 1377 (w), 1327 (w), 1270 (m), 1234 (m), 1144 (m), 1091 (m), 965 (m), 850 (m), 756 (m), 698 (m) MS (m / z): 436.0 [M + H] +.

Example 300

N5 - [(IS) -1-Phenylpropyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.02,6] deca-2 (6), 4-diene-5-carboxamide The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.37 mmol), BOP reagent (152 mg, 0, 34 mmol) and (s) - (a) -ethylbenzyl amine (51 mg, 0.37 mmol) provided the title compound (70 mg, 50%). 100-103 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.71-7.62 (m, 1H), 7.39-7.25 (m, 5H); 7.23-6.96 (m, 3H ); 5.05 (quintet, J = 7.8, 1H); 3.72 (br. S, 1H); 3.43 (br. S, 1H); 2.10-1.85 (m, 5H); 1.66 (d, J = 9.0, 1H); 1.27-1.19 (m, 2H); 1.00-0.92 (m, 3H) .IV (cm -1, KBr): 3282 (m), 2968 (m), 2874 (m), 1641 (s), 1614 (m), 1522 (s ), 1494 (s), 1454 (m), 1359 (m), 1269 (m), 1231 (m) 1159 (m), 1140 (m), 1120 (m), 1094 (m), 963 (m) , 847 (m), 701 (m) MS (m / z): 290 (100%), 408.2 (M + H +).

Example 301

Methyl (2S) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1.O.2'6] deca-2 (6), 3-dien-3-ylcarboxamido] - 2-phenylethanate

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 21 (510 mg, 1.76 mmol), DMF (4.0 mL), Et 3 N (580 μΐ, 4.20 mmol), BOP reagent (777 mg (1.76 mmol) and (S) - (+) -2-phenylglycine methyl ester hydrochloride (354 mg, 1.76 mmol) provided the title compound (420 mg, 55%). PP: 72 - 75 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.47 (d, J = 7.5, 1H), 7.86-7.81 (m, 1H); 7.61 (t, J = 8.4, 1H); 7.45-7.29 (m, 6H); 5.65 (d, J = 6.9, 1H); 3.66 (s, 3H); 3.52 (br. S, 1H); 3.47 (br. S, 1H); 1.94 (br. S, 3H); 1.67 (br. S, 1H); 1.25-1.05 (m, 2H); IR (cm -1, KBr): 3412 (m), 2953 (m), 2872 (m), 1745 (s), 1674 (s), 1610 (m), 1524 (s), 1488 (s), 1452 (m), 1358 (m), 1328 (w), 1295 (w) 1270 (s), 1211 (m), 1160 (m), 1144 (m), 1121 (m), 1092 (m), 965 ( m), 850 (w), 698 (m) MS (m / z): 438.2 (M + H +).

Example 302

N5 - [(IS) -2-Hydroxy-1-phenylethyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.O.2'6] deca-2 (6), 4 -diene-5-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 191. To a solution of Example 301 (290 mg, 0662 mmol) in TF (3 mL) was added LiBH4 (32 mg, 1.52 mmol) and the mixture was refluxed to during the night. After solvent evaporation, the oily residue was diluted with water and acidified with 1N HCl extracted with ethyl acetate and the combined organic layers were washed with brine and dried over Na 2 SO 4. FC (3: 7 AcOEt / petroleum ether) provided the title compound (170 mg, 63%). M.p .: 91 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.71-7.61 (m, 1H); 7.46-7.29 (m, 6H); 7.00 (t, J = 8.4, 2H); 5.23 (br. Q, J = 5.1, 1H); 3.98 (br. S, 2H); 3.73 (br. S, 1H); 3.44 (br. S, 1H); 2.92 (br. S, 1H); 2.14-1.93 (m, 3H); 1.69 (d, J = 8.7, 1H) / 1.32-1.24 (m, 2H). MS (m / z): 410.1 (M + H +).

Example 303

N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide [N5- (tert-butyl) butyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1.O26] deca-2 (6), 4-diene-5-carboxamide]

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (57 μΐ, 0.40 mmol), BOP reagent (165 mg 0.37 mmol) and 2-amino-2-methylpropane (36 μΐ, 0.34 mmol) provided the title compound (31 mg, 26%). 109-111 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.71-7.62 (m, 1H), 7.04-6.97 (m, 2H); 6.74 (br. S, 1H); 3.75 (br. S, 1H); 3.43 (br s, 1H); 2.10-2.04 (m, 1H); 2.01-1.90 (m, 2H); 1.67 (d, J = 8.4.1H); 1.46 (s, 9H); 1.33-1.19 (m, 2H). IR (cm -1, KBr): 3323 (m), 2968 (m), 1652 (s), 1609 (s), 1547 (s), 1522 (s), 1495 (w), 1448 (m), 1391 (w), 1360 (m), 1272 (m) 1258 (w), 1145 (w), 1109 (m), 965 (m), 849 (m) MS (m / z): 346.0 (M + H +).

Example 304 and Example 305 (4R, 7S) and (4S, 7R) N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4 , 7 - methane-indazol-3-carboxamide Preparation I: The title compound was synthesized by a similar procedure to that described for Example 101. Intermediate 21a (delayed elution enantiomer, 100mg, 0.34 mmol), DMF (1.0 mL ), Et3N (57 μΐ, 0.41 mmol), BOP reagent (167 mg, 0.37 mmol) and 2-amino-2-methylpropane (36 μΐ, 0.34 mmol) provided the title compound (91mg, 76%). HPLC: Rt (CHIRALCEL 0D-H column, dimensions: 250χ 4.6 mm, particle size: 5μ, eluent: isopropanole 0.2% in n-hexane, flow rate: 1 ml / min) = 26.59min; e.e = 92.3%. 89-92 ° C. 1 H-NMR (δ ppm, CDCl 3, 300 MHz): 7.72-7.60 (m, 1H), 7.04-6.96 (m, 2H); 6.74 (br.s, 1H); 3.75 (br. S, 1H); 3.43 (br. S, 1H); 2.07 (d, J = 8.1, 1H); 2.01-1.90 (m, 2H); 1.67 (d, J = 8.7, 1H); 1.46 (s, 9H); 1.33-1.19 (m, 2H).

Preparation II: The title compound was synthesized by a similar procedure to that described for Example101. Intermediate 21b (fast eluting enantiomer, 70mg, 0.24 mmol), DMF (1.0 mL), Et3N (38 μΐ, 0.28 mmol), BOP reagent (118 mg, 0.26 mmol) and 2- Amino-2-methylpropane (25 μΐ, 0.24 mmol) provided the title compound (63mg, 75%). HPLC: Rt (CHIRALCEL OD-H column, dimensions: 250χ 4.6 mm, particle size: 5μ, eluent: isopropanole 0.2% in n-hexane, flow rate: 1 ml / min) = 24.73min; e.e .: 90%. 89-90 ° C. Example 305 eracryptquiryl at 25 ° C in chloroform (C = 0.5). 1H-NMR (δppm, CDCl3, 300 MHz): 7.72-7.62 (m, 1H), 7.00 (t, J = 10.8, 2H); 6.74 (br. S, 1H); 3.75 (br. S, 1H); 3.43 (br.s, 1H); 2.07 (d, J = 8.4, 1H); 2.01-1.89 (m, 2H); 1.67 (d, J = 8.1, 1H); 1.46 (s, 9H); 1.33-1.19 (m, 2H).

Example 306

N5-n-Pentyl-3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2 '6] deca-2 (6), 4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.37 mmol), BOP reagent (152 mg 0.34 mmol) and n-pentylamine (32 mg, 0.37 mmol) provided the title compound (50mg, 40%). Mp 75-78 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.61 (m, 1H), 7.01 (t, J = 8.4, 2H), 6.83 (br. S, 1H ); 3.75 (br. S, 1H); 3.43-3.36 (m, 3H); 2.08 (d, J = 8.7, 1H), 2.02-1.89 (m, 2H), 1.68 (d, J = 8.7, 1H), 1.62-1.56 (m 2H); 1.38-1.24 (m, 6H); 0.94 (t, J = 7.2, 3H) .IV (cm -1, KBr): 3338 (m), 2960 (m), 2932 (m), 2872 (m), 2857 (m), 1648 (s), 1607 (w), 1552 (s), 1453 (s), 1519 (m), 1356 (m), 1251 (m), 1235 (m) 1159 (m), 1142 (m), 1112 ( w), 1144 (m), 1087 (m), 1013 (m), 853 (m), 624 (m) .MS (m / z): 360.1 (M + H +).

Example 307

N5- (2,4-Dichlorobenzyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.37 mmol), BOP reagent (152 mg 0.34 mmol) and 2,4-dichlorobezylamine (66 mg, 0.34 mmol) provided the title compound (110 mg, 71%). 105-108 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.69-7.60 (m, 1H), 7.44 (d, J = 7.8, 1H); 7.39 (d, J = 1.8, 2H); 7.29-7.19 (m, 2H); 7.00 (t, J = 8.1, 2H); 4.65 (d, J = 6.3, 2H); 3.74 (br s, 1H); 3.45 (br s, 1H); 2.08 (d, J = 8.4, 1H); 1.98-1.93 (m, 2H); 1.68 (d, J = 8.4, 1H); 1.56 (d, J = 8.4, 2H). IR (cm -1, KBr): 3394 (m), 2973 (m), 2933 (m), 2871 (m), 1660 (s), 1607 (w), 1551 (w), 1587 (m), 1519 (s), 1493 (m), 1350 (m), 1326 (w), 1270 (m) 1231 (m), 1162 (m), 1142 (m), 1125 (m), 1091 (m), 1050 ( m), 985 (w), 961 (m), 856 (m), 824 (m) MS (m / z): 448.1 (M + H +).

Example 308

N5- (1-phenylcyclopropyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2 '6] deca-2 (6), 4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.37 mmol), BOP reagent (152 mg 0.34 mmol) and α, α-cyclopropylbenzylamine (59 mg, 0.44 mmol) provided the title compound (55 mg, 40%). 90 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.72-7.61 (m, 1H), 7.51 (br. S, 1H); 7.35-7.14 (m, 5H); 7.06-6.96 (m, 2H); 3.73 (br. S, 1H); 3.44 (br. S, 1H); 2.06 (d, J = 8.7,1H); 2.00-1.92 (m, 2H); 1.67 (d, J = 8.7, 1H); 1.43-1.23 (m, 6H). IR (cm -1, KBr): 3407 (w), 3296 (m), 3088 (w), 3056 (w), 2953 (m), 1660 (s), 1607 (m), 1522 (s), 1491 (m), 1453 (m), 1355 (m), 1322 (w), 1270 (m), 1230 (m), 1158 (m), 1142 (m), 1089 (m), 965 (m), 851 (w) MS (m / z): 406.1 [M + H] +.

Example 309

N5- (2-Adamantyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2.6] deca-2 (6), 4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (54 μ 1, 0.37 mmol), BOP reagent (152 mg, 0.34 mmol) and 2-adamantanamine hydrochloride (71 mg, 0.37 mmol) provided the title compound (123 mg, 84%). 159-161 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.74-7.64 (m, 1H), 7.21 (d, J = 7.8.1H), 7.05-6.95 (m 2H); 4.23 (d, J = 8.4, 1H); 3.73 (br.s, 1H) / 3.44 (br.s, 1H); 2.10-1.79 (m, 13H); 1.77-1.55 (m, 7H). IR (cm -1, KBr): 3414 (m), 2909 (s), 2855 (m), 1659 (s), 1614 (w), 1603 (w), 1545 (s), 1530 (s), 1494 (m), 1470 (w), 1448 (w), 1346 (w) 1290 (s), 1272 (m), 1226 (m), 1154 (m), 1122 (m), 967 (m), 869 ( m) MS (m / z): 424.3 (M + H +).

Example 310

N5- (2-Methyl-2-adamantyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2.6] deca-2 (6), 4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.37 mmol), BOP reagent (152 mg 0.34 mmol) and 2-methyl-2-adamantylamine (73 mg, 0.44 mmol) provided the title compound (110 mg, 73%). Mp 60 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.71-7.63 (m, 1Η), 7.02-6.95 (m, 2Η); 6.82 (br.s, 1H); 3.74 (br s, 1H); 3.44 (br. S, 1H); 2.30 (br s, 2H); 2.04-1.79 (m, 9H); 1.73-1.62 (m, 10H); 1.25 (s, 3H) .IV (cm -1, KBr): 3406 (m), 2920 (s), 2861 (s), 1672 (s), 1610 (m), 1543 (s), 1524 ( s), 1493 (s), 1446 (s), 1377 (w), 1368 (w), 1353 (m), 1270 (s), 1256 (m), 1227 (m), • 1161 (m), 1144 (m), 1105 (m), 965 (m), 849 (m), 815 (w), 578 (m) MS (m / z): 438.1.

Example 311

N7- (3-Hydroxyiadamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 21 (200 mg, 0.68 mmol), DMF (2.0 mL), Et 3 N (110 μΐ, 0.82 mmol), BOP reagent (335 mg 0.75 mmol) and 3-amino-1-adamantanol (115 mg, 0.68 mmol) provided the title compound (185 mg, 55%). 180-182 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.61 (m, 1H); 7.04-6.96 (m, 2H); 6.69 (br. S, 1H); 3.72 (br. S, 1H); 3.43 (br. S, 1H); 2.30 (br. S, 2H); 2.13 (br. S, 2H); 2.10-1.94 (m, 7H); 1.73-1.51 (m, 8H); 1.33-1.19 (m, 2H). IR (cm -1, KBr): 3418 (s), 3369 (s), 2913 (s), 2885 (s), 1651 (s), 1610 (m), 1548 (s), 1519 (s), 1495 (s), 1455 (m), 1421 (w), 1359 (m), 1341 (w), 1314 (m), 1270 (s), 1233 (s), 1145 (m), 1115 (m), 1102 (m), 1049 (w), 1032 (w), 965 (m), 846 (m). MS (m / z): 440.1 ([M + H] +).

Example 312

4- [5- (2,4-Difluorophenyl) -4,5-diazatricyclo [5. 2 .1. O2,6] deca-2 (6), 3-dien-3-ylcarboxamido] morpholine

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (53 μΐϊΐΐ, 0.37 mmol), BOP reagent (159 mg 0.36 mmol) and 4-morpholinamine (115 mg, 0.68 mmol) provided the title compound (100mg, 78%). 106-110 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.61 (m, 2Η); 7.06-6.98 (m, 2Η); 3.85 (t, J = 4.5.4Η); 3.74 (br s, 1H); 3.44 (br. S, 1H); 2.96 (t, J = 4.5, 4H); 2.08 (d, J = 8.7,1H); 1.97-1.94 (m, 2H); 1.69 (d, J = 9.0, 1H); 1.27-1.23 (m, 2H). IR (cm -1, KBr): 3435 (m), 3262 (m), 3085 (w), 2954 (m), 2925 (m), 2870 (m), 1670 (s), 1614 (m), 1523 (s), 1498 (m), 1450 (m), 1387 (w), 1357 (m), 1326 (w), 1269 (s), 1232 (s), 1145 (m), 1108 (m), 1093 (m), 1002 (m), 966 (m), 847 (m) MS (m / z): 375.2 ([M + H] +).

Example 313

N (3) - (ter-Pentyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (53 μΐ, 0.37 mmol), BOP reagent (159 mg 0.36 mmol) and ter-amyl amine (60 μΐ, 0.52 mmol) provided the title compound (109mg, 88%). Mp: 78-80 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.71-7.61 (m, 1H); 7.04-7.02 (m, 2H); 6.66 (br. S, 1H); 3.74 (br. S, 1H); 3.43 (br s, 1H); 2.07 (d, J = 8.4.1H); 1.98-1.78 (m, 4H); 1.67 (d, J = 9.0, 1H); 1.41 (s, 6H); 1.26-1.20 (m, 2H); 0.91 (t, J = 7.2, 3H). MS (m / z): 360.2 ([M + H] +).

Example 314

N (3) -Cyclopropanmethyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (116 μΐ, 0.83 mmol), BOP reagent (159 mg 0.36 mmol) and deamino methyl cyclopropane hydrochloride (55 mg, 0.51 mmol) provided the title compound (101 mg, 85%). 113-115 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.72-7.62 (m, 1H); 7.06-6.92 (m, 3H); 3.75 (br. S, 1H); 3.44 (br s, 1H); 3.28 (t, J = 5.7, 2H); 2.08 (d, 7.8, 1H); 1.96 (br s, 2H); 1.68 (d, J = 9.3, 1H); 1.26 (br s, 2H); 1.06-1.02 (m, 1H); 0.52 (d, J = 7.5, 2H); 0.26 (d, J = 4.2, 2H). MS (m / z): 344.1 ([Μ + Η] +).

Example 315

N (3) -Cyclobutyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1'-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (116 μΐ, 0.83 mmol), BOP reagent (160 mg 0.36 mmol) and decyclobutyl amine hydrochloride (115 mg, 0.68 mmol) provided the title compound (92 mg, 77%). M.p .: 123-125 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.62 (m, 1H); 7.06-6.96 (m, 3H); 4.56 (quintet, J = 7.5, 1H); 3.74 (br s, 1H); 3.43 (br s, 1H); 2.46-2.36 (m, 2H); 2.07 (d, J = 7.8, 1H), 2.04-1.95 (m, 5H); 1.78-1.60 (m, 2H); 1.25 (br. S, 2H).

MS (m / z): 344.2 ([M + H] +).

Example 316

N (3) - (Tetrahydro-2H-4-pyranmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.37 mmol), BOP reagent (160 mg 0.36 mmol) and tetrahydro-2H-4-pyranylmethylamine (60 mg, 0.51 mmol) provided the title compound (103 mg, 77%). Mp 107-109 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.60 (m, 1H); 7.05-6.96 (m, 3H); 4.10-3.94 (m, 2H); 3.75 (br. S, 1H); 3.46-3.29 (m, 5H), 2.12-2.02 (m, 1H); 2.00-1.62 (m, 5H); 1.44-1.20 (m, 5H). MS (m / z): 386.0 ([M + H] +).

Example 317

N (3) -Cyclopropyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.37 mmol), BOP reagent (160 mg 0.36 mmol) eciclopropylamine (36 μΐ, 0.51 mmol) provided the title compound (103 mg, 86%). 59-61 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.62 (m, 1 H); 7.00 (t, J = 9.9.2Η); 6.90 (br. S, 1H); 3.75 (br. S, 1H); 3.43 (br s, 1H); 2.88-2.84 (m, 1H); 2.07 (d, J = 8.7,1H); 2.02-1.90 (m, 2H); 1.68 (d, J = 8.7, 1H); 1.32-1.15 (m, 2H); 0.82 (d, J = 5.1, 2H); 0.62 (br. S, 2H). MS (m / z): 328.0 ([M + H] +).

Example 318

N (3) - (4-methylpiperazine) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (51 μΐ, 0.37 mmol), BOP reagent (165 mg 0.37 mmol) and N-amino-N-methylpiperazine (61 μΐ, 0.51 mmol) gave the title compound (97 mg, 72%). 154-156 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.62 (m, 1H); 7.58 (br s, 1H); 7.08-6.96 (m, 2H); 3.74 (br. S, 1H); 3.44 (br. S, 1H); 3.03 (br. S, 4H); 2.76 (br. S, 4H); 2.41 (s, 3H); 2.08 (d, J = 9.3, 1H); 2.00-1.94 (m, 2H); 1.68 (d, J = 8.1,1H); 1.30-1.24 (m, 2H).

Example 319

Methyl (2R) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1.O.2'6] deca-2 (6), 3-dien-3-ylcarboxamido] - 2-phenylethanate:

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 21 (300 mg, 1.03 mmol), DMF (3.0 mL), Et 3 N (343 μΐ, 2.48 mmol), BOP reagent (502 mg , 1.13 mmol) and R - (-) -2-phenylglycinmethylester hydrochloride (208 mg, 1.03 mmol) provided the title compound (334 mg, 74%). MP: 61-63 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.78-7.64 (m, 2H); 7.45 (d, J = 7.8, 2H); 7.40-7.31 (m, 3H); 7.04-6.95 (m, 2H); 5.76 (dd, J = 2.1, 7.2, 1H); 3.76 (2s, 3H); 3.71 (br. S, 1H); 3.44 (br. S, 1H); 2.11-2.01 (m, 1H); 1.99-1.90 (m, 2H); 1.66 (d, J = 8.7, 1H); 1.30-1.21 (m, 2H) .IV (cm -1, KBr): 3411 (m), 3065 (w), 2953 (m), 2872 (w), 1744 (s), 1672 (s) ), 1610 (m), 1541 (s), 1523 (s), 1489 (s), 1454 (m), 1358 (m), 1328 (w), 1295 (w), 1271 (s), 1213 (m ), 1160 (m), 1145 (m), 1122 (m), 1093 (w), 966 (m), 851 (m). MS (m / z): 480, 24 ([Μ + Η] +) .

Example 320

N (3) - [(IR) -2-Hydroxy-1-phenylethyl] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole-3 -carboxamide

The title compound was synthesized by a procedure similar to that described for Example 191. Example 319 (235 mg, 0.54 mmol), TF (4 mL) and LiBH4 (24 mg, 1.09 mmol) provided the title compound ( 153 mg, 69%). M.P .: 68-70 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.25 (d, J = 9.0.1H); 7.87-7.82 (m, 1H); 7.63-7.58 (m, 1H); 7.36-7.22 (m, 6H); 5.05-4.94 (m, 2H); 3.73-3.67 (m, 2H); 3.50 (br. S, 1H); 3.45 (br s, 1H); 2.05-1.84 (m, 3H); 1.70-1.62 (m, 1H); 1.24-1.20 (m, 2H). MS (m / z): 452.17 (M + H +).

Example 321

N (3) - (tert-Butyl) -1- (4-chlorohenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 16 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (52 μΐ, 0.38 mmol), BOP reagent (157 mg 0.35 mmol) and 2-amino-2-methylpropane (53 μΐ, 0.51 mmol) provided the title compound (56 mg, 47%). 170-173 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.62 (d, J = 8.7, 2H); 7.43 (d, J = 8.7,2H); 6.78 (br. S, 1H); 3.75 (br. S, 1H); 3.65 (br. S, 1H); 2.08-1.99 (m, 1H); 2.02-1.94 (m, 2H); 1.70 (d, J = 8.4, 1H); 1.47 (s, 9H); 1.28-0.99 (m, 2H).

Example 322

N (3) - (Tetrahydro-2-furanylmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et3N (54 μΐ, 0.37 mmol), BOP reagent (160 mg, 0.36 mmol) ) and tetrahydro-2-furanylmethylamine (54 μΐ, 0.51 mmol) provided the title compound (82 mg, 64%). 91-93 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.74-7.62 (m, 1 H); 7.15 (br. S, 1H); 7.08-6.94 (m, 2H); 4.12-4.00 (m, 1H); 3.94-3.86 (m, 1H); 3.80-3.68 (m, 3H); 3.50-3.30 (m, 2H), 2.10-1.85 (m, 6H); 1.72-1.58 (m, 1H); 1.25 (br. S, 3H). MS (m / z): 374.2 ([M + H] +).

Example 323

N (3) - (tert-Butyl) -1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate20 (100 mg, 0.36 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.40 mmol), BOP reagent (170 g 0.38 mmol) and t-butylamine (57μΐ, 0.55 mmol) provided the title compound (102 mg, 85%). M.p .: 131-133 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.66-7.60 (m, 2H); 7.20-7.12 (m, 2H); 6.78 (br. S, 1H); 3.76 (br. S, 1H); 3.63 (br. S, 1H); 2.15-2.10 (m, 1H); 2.00-1.92 (m, 2H); 1.74-1.68 (m, 1H); 1.47 (s, 9H); 1.30-1.16 (m, 2H). MS (m / z): 328.15 ([M + H] +).

Example 324

N (3) - (tert-Butyl) -1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate19 (100 mg, 0.30 mmol), DMF (1.0 mL), Et 3 N (45 μΐ, 0.33 mmol), BOP reagent (139 mg 0.31 mmol) and 2-amino-2-methylpropane (47 μΐ, 0.45 mmol) yielded the title compound (87 mg, 75%). 157-159 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.57 (s, 4H); 6.78 (br. S, 1H); 3.75 (br. S, 1H); 3.65 (br. S, 1H); 2.18-2.07 (m, 1H); 2.02-1.92 (m, 2H); 1.70 (d, J = 9.0, 1H); 1.47 (s, 9H); 1.28-0.99 (m, 2H).

Example 325

N (3) - (tert-Butyl) -1- (3,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 29 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (47 μΐ, 0.34 mmol), BOP reagent (143 mg 0.32 mmol) and 2-amino-2-methylpropane (48 μΐ, 0.46 mmol) provided the title compound (77 mg, 66%). 205-207 ° C. 1H-NMR (δ ppm, CDCl3, 300MHz): 7.83 (a, 1H); 7.52 (s, 2H); 6.77 (br. S, 1H); 3.75 (br. S, 1H); 3.67 (br. S, 1H); 2.11 (d, J = 8.7, 1H); 1.99 (d, 6.3, 2H); 1.71 (d, J = 8.7,1H); 1.48 (s, 9H); 1.28-1.16 (m, 2H).

Example 326

Methyl (2S) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5. 2 .1. 0 2'6] deca-2 (6), 3-dien-3-ylcarboxamido] -2- (4-fluorophenyl) etanoate

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 21 (400 mg, 1.37 mmol), DMF (4.0 mL), Et 3 N (450 μΐ, 3.31 mmol), BOP reagent (670 mg (1.51 mmol) and (S) - (-) - 2- (4-fluorophenyl) glycine methyl ester hydrochloride (302 mg, 1.37 mmol) provided the title compound (543 mg, 86%). 51 - 52 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.78-7.68 (m, 2H); 7.44-7.41 (m, 2H); 7.06-6.95 (m, 4H); 5.63 (d, J = 6.9,1H); 3.77, 3.76 (2s, 3H); 3.70 (brs, 1H); 3.44 (br. S, 1H); 2.10-2.02 (m, 1H); 2.00-1.90 (m, 2H); 1.67 (d, J = 7.8, 1H); 1.30-1.19 (m, 2H).

Example 327

N (3) - (tert-Butyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 17 (100 mg, 0.30 mmol), DMF (1.0 mL), Et 3 N (48 μΐ, 0.34 mmol), BOP reagent (144 mg 0.32 mmol) and 2-amino-2-methylpropane (48 μΐ, 0.46 mmol) provided the title compound (90 mg, 77%). 129-131 ° C. 1H-NMR (δ ppm, CDCl3, 300MHz): 7.55 (d, J = 2.4, 1H); 7.45 (d, J = 8.4, 1H); 7.37 (dd, J = 8.4, 2.1, 1H); 6.71 (br. S, 1H); 3.76 (br. S, 1H); 3.34 (br. S, 1H); 2.11 (d, J = 9.0, 1H); 2.02-1.82 (m, 2H); 1.68 (d, J = 8.7, 1H); 1.45 (s, 9H); 1.33-1.12 (m, 2H).

Example 328N (3) - (4-Hydroxyphenyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (51 μΐ, 0.37 mmol), BOP reagent (160 mg 0.36 mmol) and 4-amino-phenol (56 mg, 0.51 mmol) provided the title compound (112mg, 85%). M.P .: 189-191 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.56 (br. S, 1H); 7.75-7.64 (m, 1H); 7.52 (d, J = 9,3,2H); 7.08-6.99 (m, 2H); 6.82 (d, J = 8.7, 2H); 5.30 (br.s, 1H); 3.79 (br. S, 1H); 3.47 (br. S, 1H); 2.11 (d, J = 8.7,1H); 2.00-1.94 (m, 2H); 1.71 (d, J = 8.7,1H); 1.32-1.22 (m, 2H).

Example 329

N (3) - (tert-Butyl) -1- (2-ethoxy, 4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 30 (100 mg, 0.31 mmol), DMF (1.0 mL), Et 3 N (50 μΐ, 0.34 mmol), BOP reagent (146 mg 0.33 mmol) and 2-amino-2-methylpropane (40 μΐ, 0.37 mmol) provided the title compound (96 mg, 82%). 117-120 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.54-7.44 (m, 1H), 6.82-6.69 (m, 3H); 4.12-4.00 (m, 2H ); 3.73 (br. S, 1H); 3.31 (br. S, 1H); 2.06 (d, J = 8.1, 1H); 1.98-1.82 (m, 2H); 1.65 (d, J = 8.4, 1H); 1.45 (s, 9H); 1.38 (t, J = 6.9, 3H); 1.28-1.20 (m, 2H).

Example 330

N (3) - (2-furylmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (57 μΐ, 0.41 mmol), BOP reagent (167 mg 0.37 mmol) and furfurylamine (38 μΐ, 0.41 mmol) provided the title compound (98mg, 77%). 99-100 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.71-7.61 (m, 1H); 7.36 (br. S, 1H); 7.19-7.11 (m, 1H); 7.00 (t, J = 8.4, 2Η); 6.30 (d, J = 7.5, 2H); 4.60 (d, J = 5.1, 2H); 3.76 (br. S, 1H); 3.44 (br. S, 1H); 2.08 (d, J = 7.5, 1H); 2.02-1.90 (m, 2H), 1.68 (d, J = 8.1, 1H), 1.32-1.22 (m, 2H).

Example 331

N (3) - (2-thiophenomethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (57 μΐ, 0.37 mmol), BOP reagent (167 mg 0.37 mmol) and 2-thiophenomethylamine (42 μΐ, 0.41 mmol) provided the title compound (106 mg, 80%). 103-105 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.70-7.58 (m, 1H); 7.24-7.12 (m, 2H); 7.05-6.94 (m, 4H); 4.78 (d, J = 4.5, 2H); 3.77 (br. S, 1H); 3.44 (br. S, 1H); 2.08 (d, J = 6.3, 1H); 2.02-1.89 (m, 2H), 1.69 (d, J = 9.0, 1H); 1.34-1.20 (m, 2H). Example 332

N (3) - [(IS) -2-Hydroxy-1- (4-fluorophenyl) ethyl] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7- methane indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 191. Example 326 (400 mg, 0.87 mmol), TF (6 mL) and LiBH4 (38 mg, 1.75 mmol) provided the title compound ( 288 mg, 76%). Mp 116-119 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.65 (q, J = 8.4.1H); 7.49-7.41 (m, 1H); 7.40-7.32 (m, 2H); 7.08-6.96 (m, 4H); 5.24-5.18 (m, 1H); 3.96 (d, J = 5.1, 2H); 3.72 (br.s, 1H); 3.44 (br. S, 1H); 2.12-2.02 (m, 2H); 1.99-1.92 (m, 2H); 1.68 (d, J = 8.7, 1H); 1.28-1.20 (m, 2H).

Example 333

Methyl- (2S) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1.O.2,6] deca-2 (6), 3-dien-3-ylcarboxamido] -4-methylpentanoate:

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (104 μΐ, 0.74 mmol), BOP reagent (159 mg 0.37 mmol) and L-Ieucine methyl ester hydrochloride (75 mg, 0.50 mmol) provided the title compound (87 mg, 60%) as a waxy solid. 1 H NMR (δ ppm, CDCl 3, 300 MHz) : 7.78-7.65 (m, 1H); 7.21-7.10 (m, 1H); 7.12-6.95 (m, 2H); 4.90-4.75 (m, 1H); 3.75 (s, 4H); 3.45 (br s, 1H); 2.12-2.02 (m, 1H); 2.00-1.90 (m, 2H); 1.80-1.60 (m, 6H); 1.34-1.18 (m, 2H), 1.02-0.90 (m, 4H).

Example 334

N (3) - (Adamantan-yl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate21 (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (50 μΐ, 0.37 mmol), BOP reagent (159 mg 0.36 mmol) and 1-adamantylamine (78 mg, 0.51 mmol) provided the title compound (88 mg, 60%). Mp 146-148 ° C. 1H-NMR (δ ppm, CDCl3, 300MHz): 7.72-7.60 (m, 1H); 7.04-6.94 (m, 2H); 6.61 (br. S, 1H); 3.73 (br. S, 1H); 3.42 (br. S, 1H); 2.20-2.03 (m, 10H); 1.98-1.92 (m, 2H); 1.80-1.52 (m, 4H); 1.44-1.19 (m, 5H).

Example 335a

N (3) - (tert-butyl) -1- (4-fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 32a (100 mg, 0.34 mmol), DMF (1.0 mL), Et 3 N (55 μΐ, 0.39 mmol), BOP reagent (162 mg 0.36 mmol) and 2-amino-2-methylpropane (44 μΐ, 0.41 mmol) provided the title compound (85 mg, 71%) as an oil. 1 H-NMR (δ ppm, CDCl 3, 300 MHz): 7.24-7.14 (m, 2H); 7.04 (t, J = 8.4, 2H); 6.67 (br. S, 1H); 5.18 (s, 2H); 3.64 (br. S, 1H); 3.03 (br. S, 1H); 1.98-1.65 (m, 3H); 1.55 (d, J = 8.7, 1H); 1.45 (s, 9H); 1.18-1.08 (m, 1H); 0.86-0.74 (m, 1H).

Example 335b

N (3) - (tert-butyl) -2- (4-fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide The title compound was synthesized by a similar procedure. that described for Example 101. Intermediate 32b (50 mg, 0.17 mmol), DMF (1.0 mL), Et 3 N (30 μΐ, 0.19 mmol), BOP reagent (80 mg, 0.18 mmol) and 2- Amino-2-methylpropane (20 μΐ, 0.19 mmol) provided the title compound (40 mg, 67%). 130-134 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.30-7.20 (m, 2H); 6.94 (t, J = 8.7,2H); 5.80 (d, J = 14.7,1H); 5.72 (br. S, 1H); 5.43 (d, J = 14.4, 1H); 3.40 (br s, 1H); 3.29 (br s, 1H), 1.98-1.88 (m, 3H); 1.68 (d, J = 8.4, 1H); 1.42 (s, 9H); 1.21 (d, J = 9.6, 2H).

Example 33 6a

N (3) - (tert-butyl) -1- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 31a (100 mg, 0.35 mmol), DMF (1.0 mL), Et 3 N (55 μΐ, 0.39 mmol), BOP reagent (164 mg 0.37 mmol) and 2-amino-2-methylpropane (56 μΐ, 0.53 mmol) provided the title compound (71 mg, 65%). 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.16 (d, J = 8.1, 2H); 7.10 (d, J = 8.1, 2H); 6.69 (br. S, 1H); 5.17 (s, 2H); 3.63 (br. S, 1H); 2.99 (br. S, 1H); 2.34 (s, 3H), 1.94-1.78 (m, 2H); 1.72-1.64 (m, 1H); 1.53 (d, J = 8.7, 1H); 1.45 (s, 9H); 1.18-1.08 (m, 1H); 0.90-0.78 (m, 1H).

Example 33 6b

N (3) - (tert-butyl) -2- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 32b (68 mg, 0.24 mmol), DMF (1.0 mL), Et 3 N (38 µΐ, 0.26 mmol), BOP reagent (111 mg 0.25 mmol) and 2-amino-2-methylpropane (38 μΐ, 0.41 mmol) provided the title compound (44 mg, 54%). Mp 142-144 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.18 (d, J = 7.8, 2H); 7.07 (d, J = 7.8,2H); 5.80 (d, J = 14.7,1H); 5.71 (br. S, 1H); 5.41 (d, J = 14.7,1H); 3.39 (br. S, 1H); 3.28 (br s, 1H); 2.28 (s, 3Η); 1.98-1.89 (m, 3Η); 1.70-1.62 (m, 1Η); 1.42 (s, 9Η), 1.20 (d, J = 9.0, 2Η).

Example 4 01

N (3) -Phenyl-1- (2,4-dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate22 (100 mg, 0.27 mmol), DMF (1.0 mL), Et 3 N (43 μΐ, 0.30 mmol), BOP reagent (127 mg 0.29 mmol) and aniline (28 μΐ, 0.30 mmol) provided the title compound (85 mg, 71%) .P. F.: 112 - 115 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.64 (br.s, 1H); 7.67 (d, J = 7.8, 2H); 7.59 (br. S, 1H); 7.47-7.25 (m, 4H); 7.09 (t, J = 7.5,1H); 3.29 (d, J = 3.6.1H); 2.22-2.08 (m, 1H); 1.83 (br. T, J = 9.3, 1H); 1.43-1.20 (m, 2H); 0.93 (s, 6H); 0.85 (s, 3H). IR (cm -1, KBr): 3274 (s), 3251 (s), 2955 (m), 2928 (s), 2869 (m), 1663 (s), 1517 (s), 1546 (s), 1533 (m), 1596 (s), 1502 (s), 1474 (m), 1436 (s), 1388 (m), 1345 (m), 1323 (s), 1252 (m), 1220 (m), 1229 (m), 1129 (m), 1117 (m), 1102 (m), 1077 (m), 1062 (s), 1014 (m), 1001 (m) MS (m / z): 440.3 ( [M + H] +).

Example 402

N (3) - [(2-Fluorophenyl) amino] -1- (2,4-Dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methanesulfonamide indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 22 (100 mg, 0.27 mmol), DMF (1.0 mL), Et 3 N (43 μΐ, 0.30 mmol), BOP reagent (127 mg 0.29 mmol) and 2-fluorophenylhydrazine (49 mg, 0.30 mmol) to afford the title compound (85 mg, 83%). Mp 72-80 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.54 (br. S, 1H); 7.60 (br. S, 1H); 7.42 (d, J = 8.4, 1H); 7.38 (d, J = 8.7,1H); 7.14-6.95 (m, 3H); 6.87-6.78 (m, 1H); 3.21 (d, J = 3.3, 1H); 2.20-2.06 (m, 1H); 1.82 (br. T, J = 9.0, 1H); 1.41-1.18 (m, 2H) 0.93 (s, 3H); 0.91 (s, 3H); 0.82 (s, 3H). IR (cm -1, KBr): 3413 (m), 2912 (s), 2845 (m), 1667 (s), 1535 (s), 1497 (s), 1478 (s), 1352 (m), 1233 (m), 1219 (τη), 1162 (m), 1103 (m), 1088 (τη), 996 (τη), 866 (w) MS (τη / ζ): 473.10 ([Μ + Η] +) Example 403

N (3) - [(2,4-Difluorophenyl) amino] -1- (2,4-Dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1Η-4,7- methane indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate22 (100 mg, 0.27 mmol), DMF (1.0 mL), Et 3 N (43 μΐ, 0.31 mmol), BOP reagent (127 mg 0.29 mmol) and 3,5-difluorophenylhydrazine hydrochloride (55 mg, 0.31 mmol) provided the title compound (90 mg, 67%). Mp: 145-148 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.78 (br. S, 1H); 7.60 (d, J = 1.8, 1H); 7.45-7.35 (m, 2H); 7.10-6.98 (m, 1H); 6.86-6.70 (m, 2H); 3.22 (d, J = 3.6, 1H); 2.20-2.05 (m, 1H); 1.88-1.80 (m, 1H); 1.40-1.20 (m, 2H); 0.93.0.88, 0.82 (3s, 9H). IR (cm -1, KBr): 3339 (m), 3269 (m), 2979 (m), 2961 (m), 1678 (s), 1508 (s), 1472 (m), 1211 (m), 1132 (m), 1102 (m), 959 (m), 844 (m) MS (m / z): 491.10 ([M + H] +).

Example 404

N (3) - [(3-chloropyridin-2-yl) amino] -1- (2,4-dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4, 7-methane-indazol-3-arboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate22 (100 mg, 0.27 mmol), DMF (1.0 mL), Et 3 N (43 μΐ, 0.31 mmol), BOP reagent (127 mg 0.29 mmol) and 3-chloro-2-hydrazinopyridine (45 mg, 0.31 mmol) to provide the title compound (75 mg, 56%). Mp 142-145 ° C. 1H-NMR (δ ppm, DMSO-d6, 300 MHz): 9.88 (br. S, 1H); 8.42 (br. S, 1H); 8.00 (d, J = 9.6, 2H); 7.30-7.55 (τη, 3H); 6.75 (br.s, 1H); 3.05 (br. S, 1H); 2.09 (br. S, 1H); 1.80 (br. S, 1H); 1.40-1.05 (m, 2H); 0.88, 0.86, 0.80 (3s, 9H). IR (cm -1) KBr): 3339 (m), 3269 (m), 2961 (m), 2979 (m), 1678 (s), 1508 (s), 1472 (τη), 1437 (m), 1312 (m), 1211 (m), 1132 (m), 1102 (m), 959 (m), 844 (m) MS (m / z): 490.00 ([Μ + Η] +).

Example 405

N (3) - (Adamantan-1-yl) -1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazole -3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 23 (120 mg, 0.36 mmol), DMF (1.0 mL), Et 3 N (60 μΐ, 0.43 mmol), BOP reagent (159 mg 0.36 mmol) and 1-adamantylamine (54 mg, 0.36 mmol) provided the title compound (120 mg, 71%). Mp 162-165 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.50-7.40 (m, 1H); 7.03-6.93 (m, 2H), 6.59 (s, 1H); 3.21 (d, J = 3.6, 1H); 2.13-2.07 (m, 9H); 1.84-1.63 (m, 7H); 1.37-1.24 (m, 3H); 0.97 (s, 3H); 0.90 (s, 3H); 0.77 (s, 3H). IR (cm -1, KBr): 3299 (m), 2958 (m), 2910 (s), 1652 (s), 1614 (m), 1605 (m), 1548 (s), 1524 (s), 1499 (s), 1454 (m), 1358 (m), 1324 (w), 1269 (m), 1224 (m), 1202 (m), 1143 (m), 1121 (w), 1017 (w), 981 (w) 945 (w), 847 (m) MS (m / z): 466.2 ([M + H] +).

Example 406

N (3) - (1,3,3-Trimethylbicyclo [2,2,1] hepta-2-yl) -1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6 7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 23 (120 mg, 0.36 mmol), DMF (1.0 mL), Et 3 N (120 μΐ, 0.86 mmol), BOP reagent (159 mg 0.36 mmol) and DE, 2endo-1,3,3-trimethyl-bicyclo [2.2.1] hepta-2-ylamine hydrochloride (68mg, 0.36 mmol) provided the title compound (95 mg , 57%). Mp 171-173 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.56-7.45 (m, 1H), 7.05-6.90 (m, 2H); 6.89 (d, J = 9.0.1H); 3.76 (d, J = 9.0, 1H); 3.22 (t, J = 3.9, 1H); 2.19-2.06 (m, 1H); 1.86-1.62 (m, 4H); 1.54-0.74 (m, 24H). IR (cm -1, KBr): 3419 (m), 2954 (s), 2871 (s), 1672 (s), 1612 (m), 1542 (s), 1521 (s), 1493 (s), 1388 (m), 1328 (w), 1318 (w), 1220 (m), 1176 (w), 1117 (s), 1087 (m), 1018 (m), 962 (m), 859 (m), 791 (w) MS (m / z): 468.3 ([Μ + Η] +).

Example 407

N (3) - (I-Methyl-1-phenylethyl)) -1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7- methane indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 23 (120 mg, 0.36 mmol), DMF (1.0 mL), Et 3 N (60 μΐ, 0.43 mmol), BOP reagent (159 mg 0.36 mmol) and 2-phenylprop-2-ylamine (48 mg, 0.36 mmol) provided the title compound (107 mg, 66%). 114-117 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.82-7.73 (m, 1H); 7.66-7.54 (m, 2H); 7.39 (d, J = 7.8, 2H); 7.35-7.26 (m, 3H); 7.22-7.15 (m, 1H); 2.95 (br. D, J = 2.7, 1H); 2.12-2.05 (m, 1H); 1.85-1.74 (m, 1H); 1.65 (d, J = 9.6, 2H); 1.30-0.95 (m, 1H); 0.90 (s, 3H); 0.85 (s, 3H); 0.71 (s, 3H). IR (cm -1, KBr): 3390 (m), 2973 (m), 2931 (m), 2871 (m), 1605 (w), 1583 (w), 1542 (s), 1526 (s), 1494 (s), 1446 (m), 1392 (w), 1378 (w), 1360 (w), 1319 (w), 1268 (m), 1108 (m), 928 (m), 870 (m), 766 (m) MS (m / z): 450.0 ([M + H] +).

Example 408

N (3) -ter-Butyl-1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 23 (100 mg, 0.30 mmol), DMF (1.0 mL), Et 3 N (46 μΐ, 0.33 mmol), BOP reagent (139 mg 0.31 mmol) and tert-Butylamine (32 mg, 0.45 mmol) provided the title compound (90mg, 77%). 150-154 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.53-7.43 (m, 1H); 7.03-6.95 (m, 2H); 6.71 (br. S, 1H); 3.22 (d, J = 3.9, 1H); 2.13-2.06 (m, 1H); 1.84-1.76 (m, 1H); 1.45 (s, 9H); 1.32-1.24 (m, 2H); 0.97, 0.90, 0.78 (3s, 9H). IR (cm -1, KBr): 3402 (s), 3070 (w), 2966 (s), 2873 (m), 1671 (s), 1613 (m), 1549 (m), 1500 (s), 1472 (w), 1448 (m), 1390 (m), 1364 (m), 1322 (m), 1268 (s), 1219 (m), 1139 (s), 1116 (m), 1090 (m), 1018 (m), 961 (m), 861 (m), 846 (m) MS (m / z): 388.2 ([M + H] +).

Methyl (2R) -2- [1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamido] -2-phenylethanate:

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 23 (300 mg, 0.90 mmol), DMF (4.0 mL), Et 3 N (284 μΐ, 0.33 mmol), BOP reagent (418 mg 0.94 mmol) and (R) - (-) - 2-phenylglycine methyl ester hydrochloride (272 mg, 1.35 mmol) provided the title compound (290 mg, 67%). MP: 107-109 ° C . 1H-NMR (δ ppm, DMSO-d6, 300 MHz): 8.42-8.36 (m, 1H); 7.78-7.72 (m, 1H); 7.63-7.56 (m, 1H); 7.44-7.28 (m, 6H); 5.64 (d, J = 7.5, 1H); 3.65, 3.64 (2s, 3H); 3.03 (br. S, 1H); 2.12-2.02 (m, 1H); 1.84-1.76 (m, 1H); 1.26-1.20 (m, 1H); 1.12-1.00 (m, 1H); 0.91, 0.88 (2s, 6H); 0.74, 0.70 (2s, 3H). MS (m / z): 480.24 ([M + H] +).

Example 410

N (3) - [(IR) -2-Hydroxy-1-phenylethyl] -1- (2,4-difluorophenyl) -7,8,8-trimethyl) -4,5,6,7-tetrahydro-1H- 4,7-methane-indazol-3-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 192. Example 409 (170 mg, 034 mmol), TF (3 mL) and LiBH4 (15 mg, 0.68 mmol) provided the title compound (120 mg , 75%). M.P .: 68-70 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.52-7.42 (m, 1H); 7.40-7.30 (m, 6H); 7.04-6.94 (m, 2H); 5.26-5.16 (m, 1H); 4.04-3.94 (m, 2H); 3.20 (d, J = 3.6, 1H); 3.02 (br. S, 1H); 2.13-2.06 (m, 1H); 1.84-1.76 (m, 1H); 1.34-1.20 (m, 2H); 0.98, 0.91 (2s, 6H); 0.79, 0.76 (2s, 3H). MS (m / z): 452.17 (M + H +).

Example 411

(4S, 7R) -N (3) -ter-Butyl-1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-β-methane-indazole-3 -carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 23 (100 mg, 0.30 mmol), DMF (1.0 mL), Et 3 N (45 μΐ, 0.33 mmol), BOP reagent (139 mg 0.31 mmol) and 2-amino-2-methylpropane (47 μΐ, 0.45 mmol) gave the title compound (65 mg, 56%). M. p .: 173-175 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.54-7.44 (m, 1H); 7.04-6.94 (m, 2H); 6.73 (br. S, 1H); 3.22 (d, J = 3.6, 1H); 2.13-2.06 (m, 1H); 1.85-1.76 (m, 1H); 1.45 (s, 9H); 1.33-1.24 (m, 2H); 0.97, 0.90, 0.78 (3s, 9H).

Example 501

N (12) -Benzyl-10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7 'O9'13] pentadeca-2, 4,6,9 (13), 11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 24 (90 mg, 0.23 mmol), DMF (1.0 mL), Et 3 N (36 µΐ, 0.26 mmol), BOP reagent (103 mg 0.23 mmol) and benzylamine (25μΐ, 0.23 mmol) yielded the title compound (40 mg, 33%). P . F.: 164 - 166 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.60 (s, 1H); 7.40-7.22 (m, 8H); 7.20 - 7.00 (m, 4 H); 5.06 (s, IHO; 4.60 (d, J = 6.3, 2H); 4.28 (s, 1H); 1.70 (m, 4H) MS (m / z): 474.0 ([M + H] +).

Example 502

N (12) -Piperidine-10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6.5.2. O2-7O9'13] pentadeca-2, 4,6,9 (13), 11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 24 (90 mg, 0.23 mmol), DMF (1.0 mL), Et 3 N (36 µΐ, 0.26 mmol), BOP reagent (105 mg 0.24 mmol) and 1-aminopiperidine (26 μΐ, 0.23 mmol) yielded the title compound (40 mg, 37%). 164-166 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.61 (s, 1H); 7.44-7.32 (m, 3H); 7.16 - 7.05 (m, 4 H); 5.02 (s, 1H); 4.27 (s, 1H); 2.83 (br. S, 4H); 2.20-1.70 (m, 8H); 1.41 (br. S, 2H). IR (cm -1, KBr): 2934 (s), 2854 (m), 1648 (s), 1551 (m), 1509 (s), 1488 (s), 1441 (s), 1381 (m), 1355 (m), 1342 (m), 1146 (m), 1097 (m), 1070 (m), 898 (m), 818 (w). MS (m / z): 467.0 ([M + H] +). Example 503

N (12) -Piperidine Hydrochloride -10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6.5.5. O2-7O9'13] pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxamide

A solution of Example 502 (250 mg, 0.53 mmol) in ether (5 mL) was treated with HCl-saturated ether (10 mL) and kept at RT for 1 hour and the precipitated solid was concentrated to yield the title compound (200 mg , 74%). 100-110 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.61 (s, 1H); 7.58 (br. S, 1H); 7.41 (s, 2H); 7.33 (d, J = 7.5,1H); 7.15-7.00 (m, 3H); 5.03 (br. S, 1H); 4.27 (br. S, 1H); 2.86 (br. S, 4H); 1.80-1.70 (m, 8H); 1.43 (br. S, 2H).

Example 504

N (12) - [(N'-Cyclohexyl-N'-methyl) amino] -10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6.5.2. O2'7. 09'13] pentadeca-2,4,6,9 (13), 11-pentaeno-12-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 24 (100 mg, 0.26 mmol), DMF (1.0 mL), Et 3 N (40 μΐ, 0.29 mmol), BOP reagent (121 mg 0.27 mmol) and N-cyclohexyl-N-methyl hydrazine (37 mg, 0.29 mmol) to provide the title compound (70 mg, 55%). M.P .: 127-132 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.62 (s, 1H); 7.52 (br s, 1H); 7.42-7.20 (m, 3H); 7.20-7.00 (m, 3H); 5.05 (s, 1H); 4.28 (s, 1H); 2.69 (s, 3H); 2.82-2.55 (m, 1H); 1.96 (br s, 2H); 1.88-1.70 (m, 6H); 1.40-1.00 (m, 6H). IR (cm -1, KBr): 3422 (s), 2930 (s), 2854 (s), 1667 (s), 1508 (s), 1474 (s), 1381 (m), 1354 (m), 1280 (m), 1248 (w), 1134 (m), 1118 (m), 1083 (m), 1012 (m), 815 (m) MS (m / z): 495.1 ([M + H] +).

Example 505

N (12) - {N '- [(2,4-Dichlorophenyl) -N'-methyl] amino} -10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2, 4,6,9 (13), 11-pentaene-12-carboxamide The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 24 (100 mg, 0.26 mmol), DMF (1.0 mL), Et 3 N (40 μΐ, 0.29 mmol), BOP reagent (120 mg, 0.27 mmol) and N- (2,4-dichlorophenyl) -N-methylhydrazine (88 mg, 0.46 mmol) to provide the title compound (80 mg, 55%). Mp: 220-223 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.82 (s, 1H); 7.61 (d, J = 1.2, 1H); 7.42-7.24 (m, 6 H); 7.15-7.05 (m, 3H); 4.94 (s, 1H); 4.28 (s, 1H); 3.33 (s, 3H); 1.79-1.69 (m, 4H). IR (cm -1, KBr): 3376 (s), 3005 (w), 2964 (m), 2867 (m), 1682 (s), 1546 (m), 1500 s), 1471 (s), 1352 (m), 1271 (m), 1241 (m), 1116 (m), 1100 (m), 811 (m), 759 (m) MS (m / z) 556.9 ([M + H] + ).

Example 506

N (12) - (Adamantan-yl) -10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7O9'13] pentadeca-2, 4,6,9 (13), 11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 24 (100 mg, 0.26 mmol), DMF (1 mL), Et 3 N (40 μΐ, 0.28 mmol), BOP reagent (121 mg, 0 , 27 mmol) and 1-adamantylamine (43 mg, 0.28 mmol) provided the title compound (80 mg, 59%). 120-124 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.60 (s, 1H); 7.46-7.31 (m, 3H); 7.20-6.99 (m, 3H); 6.59 (br. S 3H); 5.04 (br s, 1H); 4.26 (br.s, 1H); 2.12 (br. S, 9H); 1.90-1.54 (m, 10H). IR (cm -1, KBr): 3396 (m), 2906 (s), 2849 (s), 1670 (s), 1548 (s), 1537 (s), 1508 (s), 1483 (s), 1457 (m), 1356 (m), 1279 (w), 1167 (m), 1072 (m), 818 (m). MS (m / z): 540.2 (100, [M + Na] +), 518, 2 (25, [M + H] +).

Example 507

N12- (1,3,3-Trimethylbicyclo [2,2,1] hepta-2-yl) -10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7 'O9'13] pentadeca-2 (7), 3,5,9 (13), 11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 24 (100 mg, 0.26 mmol), DMF (1.0 mL), Et 3 N (40 μΐ, 0.28 mmol), BOP reagent (120 mg 0.27 mmol) and 1S, 2endo-amino-1,3,3-trimethyl-bicyclo [2.2.1] heptane (43 mg, 0.28 mmol) provided the title compound (95 mg, 70%) . M.P .: 82-85 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.60 (br., S, 1H), 7.43-7.07 (m, 6H); 6.92 (d, J = 7.8,1H); 5.04 (br.s, 1H); 4.29 (br. S, 1H); 3.77 (br. S, 1H); 1.92-1.58 (m, 8H); 1.42-0.76 (m, 12H).

Example 508

N12- (1-Methyl-1-phenylethyl) -10- (2,4, dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7. O913] pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 24 (100 mg, 0.26 mmol), DMF (1.0 mL), Et 3 N (41 μΐ, 0.28 mmol), BOP reagent (120 mg 0.27 mmol) and α, α-dimethylbenzylamine (56 mg, 0.41 mmol) provided the title compound (70 mg, 53%). Mp 190 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.61 (br. S, 1H); 7.45-7.05 (m, 12H); 4.98 (br. S, 1H); 4.26 (br. S, 1H); 1.80 (s, 3H); 1.77 (s, 3H); 1.75-1.58 (m, 4H).

Example 509

N12- (1-Methyl-1-phenylethyl) -10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6.5.2. O2'7. O913] pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 25 (100 mg, 0.28 mmol), DMF (1.0 mL), Et 3 N (44 μΐ, 0.31 mmol), BOP reagent (131 mg 0.29 mmol) and α, α-dimethylbenzylamine (58 mg, 0.42 mmol) provided the title compound (78 mg, 58%). 175-178 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.64-7.54 (m, 1H); 7.43 (d, J = 7.5, 2H); 7.35-7.02 (m, 10H); 4.98 (br. S, 1H); 4.35 (br.s, 1H); 1.81, 1.77 (2s, 6H); 1.80-1.68 (m, 4H). IR (cm -1, KBr): 3403 (s), 3077 (m), 2961 (m), 2973 (m), 1665 (s), 1609 (m), 1526 (s), 1493 (s), 1471 (m), 1446 (m), 1383 (w), 1361 (w), 1328 (w), 1269 (m), 1256 (m), 1160 (m), 1146 (m), 1095 (m), 846 (m), 758 (m), 699 (m) MS (m / z): 470.2 ([Μ + Η] +).

Example 601

N (12) -Benzyl-16- (4-chlorophenyl) -10- (2,4-dichlorophenyl) -15,17-dioxo-10,11,16-triazapentacyclo [6,5,5,0,0'7'09 '13'014'18] octadeca-2,4,6,9 (13), 11-pentaene-12-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 26 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (49 μΐ, 0.35 mmol), BOP reagent (130 mg 0.29 mmol) and α, α-dimethylbenzylamine (47 mg, 0.35 mmol) provided the title compound (90 mg, 67%). 84-87 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.92-7.79 (m, 2H), 7.71-7.61 (m, 1H); 7.41-7.15 (m, 8H); 6.98-6.90 (m, 2H); 4.43 (br s, 1H); 4.36 (s, 1H); 2.88 (d, J = 7.8, 1H); 2.70 (d, J = 7.5, 1H); 1.66.1.64 (2s, 6H); IR (cm -1, KBr): 3404 (m), 2974 (w), 2933 (w), 2867 (w), 1679 (s), 1608 (w), 1522 (s), 1507 (m), 1447 (m), 1382 (w), 1362 (w), 1347 (w), 1270 (m), 1257 (m), 1209 (m), 1133 (m), 1029 (w), 1006 (w), 965 (m), 847 (m), 786 (w), 761 (m). MS (m / z): 456.2 [M + H] +); 338.1 (100).

Example 602

N (12) -Piperidine-16- (4-chlorophenyl) -10- (2,4-dichlorophenyl) -15,17-dioxo-10,11,16-triazapentacyclo [6,5,5,2'0'09 '13'014'18] octadeca-2,4,6,9 (13), 11-pentaeno-12-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 26 (100 mg, 0.18 mmol), DMF (1.0 mL), Et 3 N (30 μΐ, 0.20 mmol), BOP reagent (85 mg 0.19 mmol) and 1-aminopiperidine (22 μΐ, 0.20 mmol) provided the title compound (35 mg, 31%). Mp: 150 ° C. 1H-NMR (δppm, CDCl3, 300 MHz): 7.66 (s, 1H); 7.60 (br. S, 1H); 7.46-7.40 (m, 3H); 7.26 - 7.17 (m, 5H); 6.44 (d, J = 8.4.2H); 5.58 (d, J = 3.3, 1H); 4.81 (d, J = 3.3, 1H); 3.58 (dd, J = 8.4, 3.3, 1H); 3.46 (dd, J = 8.1, 3.3, 1H); 2.89-1.20 (m, 10Η). IR (cm -1, KBr): MS (m / z): 646.2 ([M + H] +).

Example 701

N12-Benzyl-10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6, 5, 1, O2-7O9'13] tetradeca-2, 4, 6,9 (13), 11-pentaeno-12 -carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 27 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (49 μΐ, 0.35 mmol), BOP reagent (130 mg 0.29 mmol) and benzyl amine (32 μΐ, 0.29 mmol) provided the title compound (90mg, 71%). Mp 65-67 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 8.70 (br. S, 1H); 7.85-7.75 (m, 1H); 7.65 (t, J = 9.0.1H); 7.23-7.30 (m, 8H); 6.95 (br. D, J = 2.9, 2H); 4.39-4.47 (m, 4H); 2.89 (d, J = 7.5, 1H); 2.73 (d, J = 7.5.1H). IR (cm -1, KBr): 3404 (m), 3063 (w), 2974 (w), 2933 (w), 2867 (w), 1679 (s), 1608 (w), 1522 (s), 1507 (s), 1447 (m), 1382 (w), 1362 (w), 1347 (w), 1270 (m), 1257 (m), 1209 (m), 1133 (m), 965 (m), 847 (w) 761 (m) MS (m / z): 428.2 [M + H] +.

Example 702

N (12) -ter-Butyl-10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6, 5, 1, 2'709'13] tetradeca-2,4,6,9 (13), 11-pentaeno-12-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 27 (100 mg, 0.29 mmol), DMF (1.0 mL), Et 3 N (49 μΐ, 0.35 mmol), BOP reagent (143 mg 0.32 mmol) and 2-amino-2-methylpropane (31 μΐ, 0.29 mmol) provided the title compound (91 mg, 78%). M. p .: 59 ° C. 1H-NMR (δ ppm, CDCl3, 300MHz): 7.72-7.62 (m, 1H); 7.41 (d, J = 5.7,1H); 7.32-7.26 (m, 1H); 7.07-6.92 (m, 4H); 6.65 (br. S, 1H); 4.62 (br.s, 1H); 4.29 (br. S, 1H); 2.96 (d, J = 7.5, 1H); 2.82 (d, J = 7.5, 1H); 1.43 (s, 9H).

Example 801

N5- (tert-Butyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 . 2 . O2,6] undeca-2 (6), 4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 28 (100 mg, 0.32 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.35 mmol), BOP reagent (159 mg 0.36 mmol) and 2-amino-2-methylpropane (34 μΐ, 0.32 mmol) provided the title compound (96 mg, 81%). 105-108 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.62-7.54 (m, 1H); 7.08-6.99 (m, 2H); 6.82 (br. S, 1H); 3.83 (br. S, 1H); 3.11 (br. S, 1H); 1.75 (d, J = 6.6, 4H); 1.52-1.26 (m, 4H); 1.47 (s, 9H).

Example 802

N (5) - (ter-Pentyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 . 2 . O2'6] undeca-2 (6), 4-diene-5-carboxamide

The title compound was synthesized by a procedure similar to that described for Example 101. Intermediate 28 (100 mg, 0.32 mmol), DMF (1.0 mL), Et 3 N (54 μΐ, 0.39 mmol), BOP reagent (159 mg 0.36 mmol) and ter-amyl amine (38 μΐ, 0.32 mmol) provided the title compound (81mg, 66%). 102-105 ° C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.66-7.54 (m, 1H); 7.10-6.96 (m, 2H); 6.74 (br. S, 1H); 3.82 (br. S, 1H); 3.13 (br. S, 1H); 1.89-1.70 (m, 6H); 1.42 (s, 6H); 1.48-1.43 (m, 2H); 1.30-1.20 (m, 2H); 0.92 (t, J = 7.2, 3H). MS (m / z): 374.1 ([M + H] +).

Protocols

I. In vitro protocol for CBl derate receptor binding using brain membrane

In this assay, [3H] SR141716A (5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-N- (1-piperidyl) pyrazol-3-carboxamide) was used to bind the CBl receptor present a rat brain membrane preparation which may be displaced by unlabeled ligands having affinity for the CB1 receptor.

The assay was performed according to the modified method of Thomas et al., 1998 (JPET 285: 285-292). The total reaction mixture (250 ml) contained either Tris-BSA buffer (50 mM Tris, pH 7.4 with 1.5% BSA) or unlabeled SR141716A (1 mM) or test samples (1 mM), [3H] SR141716A (2 nM) and 100 mg rat brain membrane. Non-specific binding was defined by 1 mM SR141716A. Assay mix was incubated at 37 ° C for 1 hour. Sanding was then stopped by rapid vacuum filtration using Whatman GF / B-96 microfilter plate. A scintillation cocktail was added and radioactive counts were measured using a Topcount beta scintillation contactor.

Standard and test sample dilutions were produced in an assay buffer containing either ethanol or DMSO at a final concentration of 1%.

The percentage displacement (%) by a test ligand was compared by comparing the specific limit values. Assay results are shown in Table II below.

In this assay, [3H] -CP-55,940 ((-) - 3- [2-hydroxyl-4- (1,1-dimethylheptyl) phenyl] -4- [3-hydroxypropyl] cyclohexan-1-ol) was used as the radioligand to bind membrane-expressed human CBlh receptors from CHO cells (nCB1-CHO cell alignment was generated in the laboratory itself) which can be displaced by unlabeled ligands having affinity for the CB1 receptor.

The assay was performed according to the modified method of Ross et al., 1999 (Br. J. Pharmacol. 128, 735-743).

The reaction was prepared in a total volume of 200 μΐ in PEI (Poly (ethyleneimine)) (0.2%) pre-coated Millipore GFB (Glass Fiber-B) filter plates. 1 mM raw materials of test compounds were prepared in DMSO and tested at a final concentration of 300 mM. Non-specific binding was determined by CP-55,940 0.5 μΜ. The total reaction mixture contained Tris-BSA buffer (50 mM Tris, 5 mM MgCl2, 1 mM EDTA, pH 7.4 with 0.1% BSA), unlabeled CP-55.940 (0.5 μΜ) or test samples, [3H] -CP-55,940 k (0.75 nM) and 50 μg human CBl receptor preparation. The assay mixture (with or without test compound) was incubated at 370 ° C for 1 hour. The reaction was stopped by rapid vacuum filtration and radioactivity on the filters was measured by the liquid scintillation count. Assay results are shown in Table II below. III. In vitro protocol for CB2 derate receptor binding using spleen membrane

In this assay, [3H] CP55.940 was used to bind the CB2 receptor present in a rat spleen membrane preparation that can be displaced by unlabeled ligands having affinity for the CB2 receptor. The assay was performed according to the modified Rinaldi method. Carmona et al., 1998 (JPET 284: 644-650). Total reaction mixture (250 mL) contained either Tris-BSA buffer (50 mM Tris, pH 7.4 with 1.5% BSA) or unlabeled (N - [(IS) -endo-1,3,3-trimethylbicyclo [SR144528]). 2.2.1] heptan-2-yl] -5- (4-chloro-3-methylphenyl) -1- (4-methyl-benzyl) -pyrazol-3-carboxamide]) (1 mM) or test samples (300 nM ), [3H] CP55,940 (1 nM) and 100 mg of rat brain membrane. Non-specific binding was defined by 1 mM SR144528. The assay mixture was incubated at 37 ° C for 1 hour. The reaction was then quenched by rapid vacuum filtration using a Whatman GF / B-96 microfilter plate. A scintillation cocktail was added and radioactive counts were measured using a Topcount beta scintillation counter.

Standard and test sample dilutions were produced in an assay buffer containing either ethanol or DMSO at a final concentration of 1% .0 percentage displacement (%) by a foilculated test binder comparing specific limit values. Assay results are shown in Table II below.

IV. Protocol for in vitro assay using hCB2-CHO membranes:

In this assay, [3H] -CP-55,940 was used as an oriolioligant to bind CHO cell membrane-expressed human CB2 receptor (the laboratory-derived hCB2-CH0 cell line) that can be displaced by unlabeled ligands having affinity for the CB2 receptor .

The assay was performed according to the modified method of Ross et al., 1999 (Br. J. Pharmacol. 128, 735-743). The reaction was prepared in a total volume of 200 μΐ pre-coated Millipore GFB filter plates. PEI (0.2%). Raw materials of 1 mM test compounds were prepared in DMSO and tested at a final concentration of 300 nM. Non-specific binding was determined by CP-55,940 at 0.5 μΜ. The total reaction mixture contained Tris-BSA buffer (50 mM Tris, 5 mM MgCl2, 1 mM EDTA, pH 7.4 with 0.1% BSA), unlabeled CP-55.940 (0.5 μΜ) or test samples. . [3H] -CP-55,940 (0.75 nM) and 25-50 μg human CB2 receptor preparation. The mixed assay (with or without test compound) was incubated at 30 ° C for 1 hour. The reaction was stopped by rapid vacuum filtration and radioactivity on the filters was measured by liquid scintillation counting.

The percent displacement (%) by a test ligand was compared by comparing the specific limit values. Assay results are shown in Table II below.

V. Neuropathic Hyperalgesia Model - Partial Nerve Nerve Linkage (Seltzer Model)

This protocol was performed with the compound of Example 294 at 0.01, 0.1, 0.3, and 1 mg / kg (I.P.), and 100 mg / kg gabapentin (I.P.) to evaluate the ability of the compound of

Example 2 94 in reducing neuropathic hyperalgesia. The Seltzer method is also generally described in Seltzer et al., Pain [Dor] 1990, 43: 205-18.

1. Rats were anesthetized using ketamine / xylazine (40/5 mg / kg / ml, i.p.). After anesthetic induction, the left thigh was shaved and cleaned.

2. The left ciliary nerve was exposed at the mid-thigh level through a small incision.

Nerve 3.0 was detached from the adherent muscle tissue.

4. Half of the nerve thickness was firmly ligated after bifurcation of the common sciatic nerve using silk sutures 7.0.

5. The wound was closed with muscle sutures and the skin and povidone were applied.

6. Animals were allowed to recover for 12 to 15 days post-binding. Mechanical hyperalgesia was examined in the rat dorneuropathic model using the paw pressure technique (Ugo Basile Analgesimeter, Cat. No. 37215, Comerio, Italy).

8. Paw removal limits were recorded for both hind ipsilateral quantocontralateral hind paws before (pre-dose) and 0.5 and 1 hour after drug or vehicle administration (post-dose).

9. The cut was set at 150 g pressure and the pontofinal was taken as paw removal or vocalization.

Data analysis:

Removal threshold latency values (natural, pre-dose and post-dose) are represented as mean ± SEM. SeeWalker KM, Urban LA, Medhurst SJ, Patel S, Panesar M, FoxAJ, and McIntyre P., "The VRl antagonist capsazepinereverses mechanical hyperalgesia in models ofinflammatory and neuropathic pain" , J. Pharmacol.Expt. The R. 304: 56-62, 2003. The percentage inversion of neuropathic mechanical hyperalgesia was calculated from the removal limit latency values according to the following formula:

Inversion% = [(Ipsilateral post-dose - Ipsilateral pre-dose) / (Contralateral pre-dose - Ipsilateral pre-dose)] χ 100%

Statistical analyzes of the data were performed on one-way ANOVA percentage inversion values followed by Tukey post hoc test using GraphPad Prism software.

Results are shown in Figure 1. The decomposed 1 mg / kg of Example 294 significantly reversed neuropathic hyperalgesia in this model.

SAW. Chronic Constriction Injury (ICC) for Ciatio Nerve Model (ICC Model)

This protocol was performed with the compound of Example 294 at 0.1 mg / kg (p.o.) and gabapentin at 100 mg / kg (i.p.) to assess the ability of the compound of Example 294 to reduce neuropathic hyperalgesia. This method is also generally described in Miletic G and Miletic V, "Long-termchanges in sciatic-evoked A-fiber dorsal horn fieldpotentials accompany loose ligation of the sciatic nervein rats" [Long-term changes in fiber-A-dorsal tip camp potentials by sciatica accompany loose sciatic nerve ligation in rats ", Pain [Dor] 84: 353-359, 2000.

1. Rats were anesthetized using ketamine / xylazine (40/5 mg / kg / ml, i.p.). After anesthetic induction, the left thigh was shaved and cleaned.

2. The left ciliary nerve was exposed at mid-thigh level through a small incision.3.0 nerve was detached from the adherent muscle tissue.

4. Four loose Ethicon 4-0 (Johnson & Johnson) chromic gut ligatures within 1 mm were placed near the nerve after the common sciatic nerve bifurcation.

5. The wound was closed with muscle sutures and the skin and povidone were applied.

6. Animals were used for experiment after 7 days of binding.

7. Mechanical hyperalgesia was examined in the rat dorneuropathic model using the paw pressure technique (Ugo Basile Analgesimeter, Cat. No. 37215, Comerio, Italy).

8. Paw removal limits were recorded for both hind ipsilateral quantocontralateral hind paws before (pre-dose) and 0.5 and 1 hour after drug or vehicle administration (post-dose).

9. The cut was set at 150 g pressure and the pontofinal was taken as paw removal or vocalization.

Data analysis was performed as described on protocol V. The results are shown in figure 2.

VII. Tail-Flick analgesia test in mice

Tail-Flick (basal) latency was measured in vehicle-treated natural 55 ° C mice, WIN 55212-2 (CB1 receptor umagonist) (3 mg / kg ip), or Example 294 (0.3, 1, or 3 mg / kg ip) using a water bath (Julabo, Germany). See Murielle J., Arnone M, FinanceO., Soubrie P., and Le'Fur G., SR147778 (5- (4-Bromophenyl) -1- (2,4-dichlorophenyl) -4-ethyl-N- ( 1-peperidinyl) -1H-pyrazol-3-carboxamide), A New Potent and Selective Antagonist of the CB1 Cannabinoid Recipient: Biochemical and Pharmacological Characterization "[SR147778 (5- (4-Bromophenyl) -1- (2,4-dichlorophenyl) - 4-Ethyl-N- (1-peperidinyl) -1H-pyrazol-3-carboxamide), A Potent Newly Elective Cannabinoid Receptor Antagonist CB1: Biochemical and Pharmacological Characterization ", J. Pharmaeol.exp. Ther., 310: 905- 914, 2004. Intraperitoneal (ip) injections of vehicle, standard or test drug were given to analgesia by measuring Tail-Fliek latency (reaction) at 1, 3, 6, 12, and 18 hours post-dosing. removal was set at 10 seconds and the end point was taken as the Tail-Flick tail response.

Data analysis

Tail-Flick latency values (baseline and reaction) were represented as mean ± SEM. Maximum analgesia (% MPE) was calculated according to the following formula:

Maximum possible analgesic effect% = [(daring latency - basal latency) / (Removal latency basal latency)] χ 100

Data analysis was performed on the MPEpercentual values by a one-way ANOVA followed by Tukey post hoc porteste. Results are shown in Figure 3.

VIII. Protocol for GTPyS Binding Assay (CB1 Assay Functional in Rat Cerebellar Mambran) In this GTPyS binding assay, total, basal and non-specific binding were determined. See Griffin G., Atkinson P.J., Showalter V.M., Martin B.R. and AboodM.E., "Evaluation of cannabinoid receptor agonists andantagonists using the Guanosine-5'-0- (3- (35S) thio) -triphosphates binding assay in rat cerebellar membranes" [Evaluation of decanabinoid receptor agonists and antagonists using Guanosine-5'-O- (3- (35S) thio) triphosphate binding assay on dermal cerebellar membranes], J. Pharmacol Exp Ther 285: 553-560, 1998. Three wells for total binding, three wells for basal binding , and three wells for nonspecific binding at 0.2 nM radioligant concentration were used. Basal binding was defined by GDP 50 μΜ (guanosine diphosphate) and non-specific binding was defined by unlabeled GTPyS10 μΜ. 10 μg of rat cerebellum membrane, 50 μΜ deGDP, WIN-55212-2 or test compound (1 μΜ or 300 nM), 10 μΜ unlabeled GTPyS, and 0.2 nM of [35SJGRPyS were added to a 96 µl plate wells and the final reaction mix volume was produced with GTPyS buffer (3 mM anhydrous Tris 50 TtiM2, 0.2 mM EGTA and pH 7.4 NaCl) to 200 μΐ. The plates were incubated at 30 ° C for 1 hour. Then the reaction was stopped by filtration using a Whatman GF / B-96 microfilter plate. Three washes were given using Tris-HCl. Brain membrane-bound radioactivity was retained on the filter discs to which scintillation fluid was added (Microscint OS). Then the plates were read for radioactivity counts using a Beta Scintillation Counter (Packard Instruments, IL, USA).

The cerebellar brain membrane was prepared as follows:

1. Sacrifice the mouse and remove the entire brain and cerebellum separation as quickly as possible and keep it on ice.

2. Take the weight of the cerebellum and homogenize in 30 ml homogenizing buffer (50 mM Tris-HCl containing 1mM EDTA and 5% sucrose, pH 7.5) using cold condition homogenizer.

3. Centrifuge the homogenized cerebellum at 18,000 rpm (38000 g) for 15 min at 4 ° C.

4. Resuspend the pellet in 5 ml of 50 mM Tris-HCL containing 1 mM EDTA and keep on ice for 30 min.

5. Pass the membrane through an insulin syringe to ensure uniform suspension.

6. Centrifuge the membrane at 18,000 rpm at 4 ° C for 20 min.

7. Reconstitute the pellet in 3 ml GTPyS buffer and estimate the protein by BCA assay and store the membrane in 1000 μg aliquots of protein.

CBl agonist and antagonist activity selection assay

Test compounds were selected at a final concentration of 1 μΜ or 300 nM in the absence and presence of 1 μΜ of WIN 55.212-2 in the same manner as described in the GTPyS binding assay.

An agonist will stimulate GTPyS binding over basal.

An antagonist will inhibit WIN-55212-2 (CB1 agonist) and induce GTPγS binding stimulation without significantly altering basal binding.

An inverse agonist will decrease basal GTPγS binding / or produce more than 100% inhibition of agonist-induced stimulation (WIN-55212-2).

A partial agonist produces only partial basal over stimulation and also partially inhibits GTPyS binding deagonist stimulation (WIN-55212-2).

Data analysis

Percent GTPyS binding stimulation for test compound at 1 μΜ or 300 nM concentration in the absence and presence of WIN 55-221-2 1 μΜ was calculated by comparing it with baseline specific limit values (basal binding - non-specific binding).

Results are shown in Table III below.

IX. Assay to determine agonist and antagonist activity for CB1 and CB2 receptors

1. CB1 / CB2 receptor antagonism expressed in CHO cells

H-CB1 / CHO or h-CB2 / CH0 cells were developed in HAM F12 DMEM (Sigma) with 10% FBS (Hyclone), 1% penicillin-streptomycin solution and 400 μg / ml G418 (Sigma). 5000 cells were well-fed into a 96-well plate and incubated for 24 hours at 37 ° C in 5% CO 2. On the day of the assay, the cells were washed with heated Krebs buffer containing 0.1% fatty acid free BSA (FAF) and resuspended in the same 1XM IBMX containing buffer. Test antagonist or reference compound (Am 251 (1- (2,4-dichlorophenyl) -5- (4-iodophenyl) -4-methyl-N- (1-piperidyl) pyrazol-3-carboxamide) for CB1 and SR 144528 for CB2) diluted in FAFBSA + IBMX + Krebs buffer was added to the cells and incubated for 10 minutes at room temperature. CP 55940 (final concentration of 30 nM for the CBl test and 10 nM of the same for the CB2 test) was added to the cells followed by forskolin (final concentration 10 μΜ) and incubated for 30 minutes at room temperature. At the end of incubation, the cells were lysed using the cAMP and cAMP enzyme kit lysis reagent was quantified by the chemiluminescence method described in the manufacturer's instructions (DiscoveRX). EC50 values were calculated from dose-response curves by nonlinear regression analysis using PRISM software.

2. CB1 / CB2 receptor agonism expressed in CHOC hCB1 / CHO or h-CB2 / CH0 cells were developed in HAM F12 DMEM (Sigma) medium with 10% FBS (Hyclone), 1% and 400% penicillin-streptomycin solution µg / ml of G418 (Sigma). 5000 cells were well-fed into a 96-well plate and incubated for 24 hours at 370 ° C in 5% CO2. On the day of evaluation, cells were washed with heated Krebs Buffer containing 0.1% fatty acid free BSA (FAF) and resuspended in the same buffer containing 1 mM IBMX. Test compound or CP55.940 as reference compound (30 nM final concentration for CB1 test and 10 nM same for CB2 test) diluted in FFB + IBMX + Krebs buffer was added to cells followed by addition of forskolin (final concentration of 10 μΜ) and incubated for 30 minutes at room temperature. At the end of incubation, cells were lysed using cAMP and cAMP assay kit lysis reagent was quantified by the chemiluminescence method described in the manufacturer's instructions (DiscoverRZ). EC50 values were calculated from dose response curves by nonlinear regression analysis using PRISM software.

Results are shown in Table IV below.

Table II

<table> table see original document page 251 </column> </row> <table> <table> table see original document page 251 </column> </row> <table> <table> table see original document page 253 < / column> </row> <table> <table> table see original document page 254 </column> </row> <table> <table> table see original document page 255 </column> </row> <table> <table> table see original document page 256 </column> </row> <table> Table III

<table> table see original document page 257 </column> </row> <table> <table> table see original document page 259 </column> </row> <table> <table> table see original document page 259 < / column> </row> <table> <table> table see original document page 260 </column> </row> <table>

NT = not tested

While the invention has been described herein with reference to particular embodiments, it should be understood that these configurations are merely illustrative of the principles and applications of the present invention. It should therefore be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be foreseen without departing from the spirit and scope of the present invention as set forth in the appended claims.

All publications, patents and patent applications in this patent application are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated herein by reference.

Claims (51)

1. A compound having the formula: <formula> formula see original document page 261 </formula> an analogue thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer thereof, an enantiomer thereof, a diastereomer thereof, a polymorph thereof, or a pharmaceutically acceptable solvate thereof, wherein one of the dotted lines in formula (1) is independently an optional double bond; C, N, W, X and Y are independently C, Ν, O, X or -C (O) except that at least two of U, V, W, X or Y are independently selected from N, 0, -C ( O) - or S; R, R 1 and R 2 may be the same or different and independently hydrogen, nitro, cyano, formyl, acetyl, halogen, -OR 3, -SR 3, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted alkynyl or unsubstituted, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted, substituted or unsubstituted heterocyclylalkyl, -NR 3 R 4, -C (= B) -R 3, -C (O) O-R 3, -C (O) NR 3 R 4, -S (O) m-NR 3 R 4, or a protecting group or R 1 and R 2 may be joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR 3 or S, each occurrence of R 3 and R 4 may be the same or different and are independently hydrogen, halo, cyano, -ORa, SRa, oxo, thio, substituted or unsubstituted alkyl, alkenyl s substituted or unsubstituted, substituted or unsubstituted alkynyls, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted, substituted or unsubstituted, unsubstituted or unsubstituted arylalkyl, heterosubstituted or unsubstituted arylalkyl group substituted, unsubstituted or substituted heterocyclic group, unsubstituted or substituted heterocyclylalkyl, -C (= B) -Ra, -C (O) O-Ra, -C (O) NRaRb, -S (O) m-Ra, -S ( O) m-NRaRb, -NRaRb, or a protecting group of R3 and R4, when attached to a common atom, may be joined to form an optionally substituted saturated or unsaturated 3- to 7-membered cyclic ring, which may optionally include at least two selected heteroatomers. O, NR3 or S, each occurrence of Ra and Rb may be the same or different and are independently hydrogen , halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C (O) -Rc, -C (O) O-Rc, -C (O) NRcRd, -S (O) m-Rc, -S (O) m-NRcRd, -NRcRd, -ORc, -SRc, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyls, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocyclyl group, or substituted or unsubstituted heterocyclylalkyl group, and each occurrence of Rc may be equal to or equal to Rc; differently and independently are hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, uncle, a protecting group, substituted or unsubstituted alkyl, alkenylsu. substituted or unsubstituted, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted, substituted or unsubstituted aryl, unsubstituted or unsubstituted, substituted or unsubstituted arylalkyl group unsubstituted, heterocyclylalkylsubstituted or unsubstituted, or heteroarylalkylsubstituted or unsubstituted, each occurrence of B being independently O, S or NR3; ρ independently being O, 1 or 2; to be <formula> formula see original document page 263 </ formula > <formula> formula see original document page 264 </formula> where: each of the dotted lines in A independently represents an optional double bond; R5, R6, R7, R8, R9, R10, R11, R12, R13 independently of hydrogen, nitro, cyan, formyl, acetyl, halog nio, -0R "°, -SRx3, oxo, thio, substituted or unsubstituted alkyls, unsubstituted or substituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl unsubstituted, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR15R16, -C (= B) -R15, -C ( O) O-R15, -C (O) NR15R16, -S (O) m-R15, -S (O) rNNR15R16, or a protecting group, R5 and R6 may be joined together to form a saturated or bicyclic or mono-ring. optionally substituted 3 to 11 membered unsaturated moiety which may optionally include at least one heteroatoms selected from O, NR3 or S; R9 and R10 may be bonded together to form an optionally substituted 3- to 11-membered saturated or unsaturated ring or monocyclic ring which may optionally include at least one heteroatoms selected from O, NR3 or S; each occurrence of R15 and R16 may be the same or different and are independently hydrogen, nitro, halo, cyano, -OR3, -SR3, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkylsubstituted or unsubstituted, cycloalkylsubstituted or unsubstituted, cycloalkenylsubstituted or unsubstituted unsubstituted, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, C (= B) -R3, -C (O ) O-R3, -C (O) NR 3 R 4, -S (O) m-R 3, -S (O) m-NR 3 R 4 or R 15 and R 16, when attached to a common atom, may be joined together to form an optionally saturated or unsaturated 3- to 7-membered cyclic ring substituted, which may optionally include at least two heteroatoms selected from O, NR3 or S wherein R3 and R4 are as defined above: n is 1, 2, 3, or 4; ea, b, c, d e e are integers independently selected from 0 to 4, with the proviso that the compound does not have the formula: where R1 and R2 are as defined above. Compound according to claim 1, characterized in that U and V are C. Compound according to either of claims 1 or 2, characterized in that W is Ce Y and X are N. Compound according to any one of claims 1, 2 or 3, characterized in that R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. Compound according to claim 4, characterized in that R is methyl, phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 2,4 -fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2- (4-chlorophenyl) phenyl or 5-chloropyridin-2-yl. Compound according to claim 1-4 or 5, characterized in that R 1 is hydrogen. Compound according to Claim 1-5 or 6, characterized in that R 2 is unsubstituted or substituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted heterocyclic group or unsubstituted, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heteroarylalkyl, or NR3R4. Compound according to claim 7, characterized in that R2 is t-butyl, n-pentyl, cyclopentyl, cyclohexyl, adamantan-1-yl, 2-methyladamantan-2-yl, 3-hydroxy adamantan-1 -yl, 1,3,3-trimethylbicyclo [2.2.1] hepta-2-yl, 1-phenylcyclopropyl, cyclohexylmethyl, phenyl, 3-chlorophenyl, 4-chlorophenyl, -3-bromophenyl, 2-methoxy phenyl, 4-ester -butylphenyl, 2,4-difluorophenyl benzyl, 2-chlorobenzyl, 4-chlorobenzyl, -2,4-dichlorobenzyl, 2-fluorobenzyl, 4-fluorobenzyl, -2,4-difluorobenzyl, 2,6-difluorobenzyl, 2-bromobenzyl, -4-bromobenzyl, 4-trifluoromethylbenzyl, 1-phenylethyl, 1-methyl-1-phenylethyl, 2-phenylethyl, 1- (2-chlorophenyl) ethyl, -2- (4-fluorophenyl) ethyl, 1-phenylpropyl, 1- ethyl-1-phenylpropyl, 1- (2-chlorophenyl) 1-methylethyl, methyl phenylethane, 2-hydroxy-1-phenylethyl, piperidinyl, morpholinyl, pyridinyl, 1,2,4-triazol-4-yl, 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl. Compound according to claim 7, characterized in that R2 is NR3R4; where R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryls or substituted or unsubstituted cycloalkyl and R4 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or unsubstituted or cycloalkyl. Compound according to claim 9, characterized in that R3 is methyl, phenyl, cyclohexyl and R4 is phenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl. , 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-bromophenyl, 3-chloropyridin-2-yl, 5-chloropyridin-2-yl or cyclohexyl, or R3 and R4 are joined together. itself to form piperidin-1-yl or morpholin-4-yl. A compound according to claims 1-4 or 5, wherein R 1 and R 2 are joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring which may optionally include at least two heteroatoms selected from O, NR3 or S. Compound according to Claim 11, characterized in that R 1 and R 2 are joined together to form piperidin-1-yl or morpholin-1-yl. Compound according to claim 1-11 or 12, characterized in that A is <formula> formula see original document page 268 </formula> Compound according to claim 13, characterized in that each occurrence of R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, and R 14 is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl. substituted; a, b, c, and d are 1 and each of the dotted lines in A represents an optional double bond. Compound according to claim 14, characterized in that each of R 5, R 6, R 7, R 8, R 9, and R 14 independently represent hydrogen or methyl. Compound according to claim 14, characterized in that R 8 represents 4-chloro-phenyl. Compound according to claim 1-13 or 14, characterized in that B is oxygen. 18. A compound having Formula IA <formula> formula see original document page 269 </formula> an analogue thereof, pharmaceutically acceptable salt thereof, pharmaceutically acceptable ester thereof, tautomer thereof, regioisomer thereof, stereoisomer thereof , enantiomer thereof, diastereomer thereof, polymorph thereof, or pharmaceutically acceptable solvate thereof, wherein R, R 1 and R 2 may be the same or different and are independently hydrogen, substituted or unsubstituted alkylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heteroaryl group or substituted or unsubstituted heteroarylalkyl or R1 and R2 may be joined together to form a 3- to 7-membered saturated or unsaturated cyclic ring which may optionally include at least two heteroatoms selected from O, NR3 or S or NR3R4, each occurrence of R3 and R4 may be the same or different and independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl. substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclic group or R3 and R4 may be joined together to form an optionally substituted 3- to 7-membered cyclic unsaturated or unsaturated ring which may optionally include at least two heteroatoms selected from 0, NR3 or S; ρ be 1; eWhen <formula> formula see original document page 270 </formula> one of the dotted lines in A is independently an optional double bond, and each occurrence of R5, R6, R7, R8, R9, R10, R11, R12, R13 or R14 is the same or different and selected from hydrogen, unsubstituted or unsubstituted alkyl or unsubstituted aryl, with the proviso that the compound does not have the formula: where R1 and R2 are as defined above . Compound according to Claim 18, characterized in that the compound of Formula 1 (A) is: <formula> formula see original document page 271 </formula> Compound according to Claim 1, characterized in that the compound is selected from: N (7) -Piperidine-5- (2-bromophenyl) -5,6-diazatetracyclo [7.3.1.13ill-O4'8 ] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) -Benzyl-5- (2-bromophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) -morpholine-5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (3-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (4-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) -cyclohexyl-5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (N-cyclohexyl-N-methylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3. 1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) -cyclohexylmethyl-5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (Adamantan-1-yl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13 ' 11 O4'8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) - (1S, 2endo-1,3,3-Trimethyl-bicyclo [2.2.1] hepta-2-yl) - 5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4 '] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) - (2-Chlorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4' 8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (4-Chlorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) - (4-Fluorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) - (2,4-Difluorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2,6-Difluorobenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (4-Trifluoromethylbenzyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (I-phenylethyl)) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (R-1-phenylethyl)) 5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (1-Methyl-1-phenylethyl)) - 5- (4-chlorophenyl) -5,6-diazatetracyclo [7 . 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2-Pyridylmethyl) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (N'-phenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.I3 '11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (N'-phenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo hydrochloride [7.3. 1.131-1-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2-Chlorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13 '11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2-Chlorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo hydrochloride [7.3.1.13 11-O4'8] tetradeca - 4 (8), 6-diene-7-carboxamide, N (7) - [(4-chlorophenyl) amino)] - 5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11.O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2,4-Dichlorophenylamino) -5- (4-chlorophenyl) -5,6 -diazatetracyclo [7.3.1.13ill-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - [(2,4-Dichlorophenyl-N'-methylamino] -5- (4 (chlorophenyl) -5,6-diazatetracyclo [7,3,11,11,10,48] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - [(2,4) hydrochloride -Dichlorophenyl-N'-methylamino] -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2,4-Dichlorophenyl-N'-cyclohexylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6 -diene-7-carboxamide, N (7) - (4-Fluorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11.04'8] tetradeca-4 (8), 6 -diene-7-carboxamide, hydr N (7) - (4-Fluorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca - 4 (8), 6-diene-7-carboxamide, N (7) - (2,4-Difluorophenylamino] -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13 '11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (3-fluorophenylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13 11-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (3-Chloro-2-pyridylamino) -5- (4-chlorophenyl) -5,6-diazatetracyclo [ 7.3.1.13ill-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (5-Chloro-2-pyridylamino) -5- (4-chlorophenyl) -5,6 -diazatetracyclo [7,3,11,11,10,48] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2-phenylethyl) -5- (4-chlorophenyl) -5 , 6-diazatetracyclo [7.3.1.13'11.04'8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) - (N ', N'-Diphenylamino) -5- (4- chlorophenyl) -5,6-diazatetracyclo [7.3.1.13ill-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - [1- (2-Chlorophenyl) ethyl] -5 - (4-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13ll1-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) -Benzyl-5- (4'- chlorophenyl) -5,6-diazatetracyclo [7.3.1.13ill-O4'8] tetradeca-4 ( 8) -6-diene-7-carboxamide, N (7) -piperidine-5- (4'-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04 '] tetradeca-4 (8) -6-diene -7-carboxamide, 7- (4'-Chlorophenyl) -6,7-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -5-dien-5-yl-piperidinomethanone, N (7) -phenyl-5- (4'-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) -piperidine-5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (Adamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3. 1.13'11. Q4'8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) - (IS, 2endo-1,3,3-Trimethyl-bicyclo [2.2.1] hepta-2-yl) - 5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) - (Sl-phenylethyl)) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13 '11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (R 1 -phenylethyl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13ill -O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (1-Methyl-1-phenylethyl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2-Chlorobenzyl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13 ' 11 O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2,4-Dichlorophenylamino) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - [1- (2-Chlorophenyl) ethyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - [(S) -I-Phenylpropyl] -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [ 7 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N7- [1- (2-Chlorophenyl) -1-methylethyl] -5- (2,4-difluorophenyl) -5,6- diazatetracyclo [7. 3.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, Methyl (2R) -2- [7- (2,4-difluorophenyl) -6,7-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 5-dien-5-ylcarboxamido] -2-phenylethanate, Methyl (2S) -2- [7- (2,4-difluorophenyl) -6,7-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 5-dien-5-ylcarboxamido] -2-phenylethanate, N7- (3-Hydroxyadeatan-1-yl) -5- (2,4-difluorophenyl) -5,6- diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (1-Methyl-1-phenylethyl) -5- (4-fluorophenyl) -5,6-diazatetracyclo [7.3. 1.1311-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (Adamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide, N7- (Adamantan-2-yl) -5- (4-fluorophenyl) -5,6-diazatetracyclo [7.3.1.13ill-O4 ' 8] tetradeca-4 (8), 6-diene-7-carboxamide, N7- (1,3,3-Trimethylbicyclo [2.2.1] hepta-2-yl) -5- (4-fluorophenyl) -5,6 -diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) -piperidine-5- (4-methylphenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2,4-Dichlorophenylamino) -5- (4-methylphenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2-Chlorobenzyl) -5- (4-methylphenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4 '8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) -piperidine-5- (4-methoxyphenyl) -5,6-diazatetracyclo [7. 3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N7- (2-Chlorobenzyl) -5- (4-methoxyphenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2,4-Dichlorophenylamino) -5- (4-methoxyphenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) -piperidine-5 - [(2-chlorophenyl) phenyl] -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - [(2,4-Dichlorophenyl) amino] -5-phenyl-5,6-diazatetracyclo [7.3.1.13lll- O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) -phenyl-5-phenyl-5,6-diazatetracyclo [7. 3.1.1 '' .O4'8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) -piperidine-5-phenyl-5,6-diazatetracyclo [7.3.1.13ill-O4'8 ] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) -Benzyl-5-phenyl-5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) - 6-diene-7-carboxamide; -7-phenyl-6,7-diazatetracyclo [7.3.1.1'0 '] tetradeca-4 (8) -5-dien-5-yl-piperidinomethanone; N (7) - (4-Fluorobenzyl) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) -Phenylamino-5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2 -Chlorophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - ( 2,4-Dichlorophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7 ) - (2-Bromophenylamino) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N ( 7) - (N ', N'-Diphenylamino) -5- (2,4- dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2-phenylethyl) -5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13 ' 11 O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) -Benzyl-5- (2 ', 4'-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) -piperidine-5- (2 ', 4'-dichlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - (2,4-Dichlorophenylamino) -5- (2-chlorophenyl) -5,6-diazatetracyclo [7. 3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) -Benzyl-5- (2'-chlorophenyl) -5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) -cyclohexyl-5- (2'-chlorophenyl) -5,6-diazatetracyclo [7. 3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) -piperidine-5- (2'-chlorophenyl) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide, N7- (2-Chlorobenzyl) -5- (5-chloro-2-pyridyl) -5,6-diazatetracyclo [7. 3,11,11. O4 8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) -Benzyl-5,6-diazatetracyclo [7.3.1.1 '.0'] tetradeca-4 (8) -6-diene- 7-carboxamide, N (7) -piperidine-5,6-diazatetracyclo [7.3.1.13 '".O4'8] tetradeca-4 (8) -6-diene-7-carboxamide, -6,7-diazatetracyclo [7 3.1.14'11.04'8] tetradeca-4 (8) -5-dien-5-yl-piperidinomethanone; N (7) -piperidine-6-methyl-5,6-diazatetracyclo [7.3. 1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) -piperidine-5-methyl-5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) - (1-methyl-1-phenylethyl) -6-pentyl-5,6-diazatetracyclo [7.3.1.13'11.04 ' 8] tetradeca-4,7-diene-7-carboxamide, N (7) - (1-methyl-1-phenylethyl) -5-pentyl-5,6-diazatetracyclo [7.3.1.13'11.04.4 ] tetradeca-4 (8) -6-diene-7-carboxamide, N (7) - [(IR) -2-Hydroxy-1-phenylethyl] -5- (2,4-difluorophenyl) -5,6- diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxamide, N (7) - [(IS) -2-Hydroxy-1-phenylethyl] -5- (2 (4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13lll-O4 ' 8] tetradeca-4 (8), 6-diene-7-carboxamide, and pharmaceutically acceptable salts thereof. Compound according to Claim 1, characterized in that the compound is selected from: N (3) - Piperidine-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane indazol-3-carboxamide, N (3) -Cyclohexyl-1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Benzyl-1- phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -phenylamino-1-phenyl-4,5,6,7-tetrahydro-1H-4 7-methane-indazol-3-carboxamide, N (3) -piperidine-1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide , N (3) -Cyclohexyl -1- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Benzyl-I- (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -phenylamino-1- (2-chlorophenyl) -4,5,6 , 7-Tetrahydro-1H-4-,7-methane-indazol-3-carboxamide, N (3) -Piperidine-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4 7-Methane-indazol-3-carboxamide, -1- (4-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-yl piperidino methanone, N (3) - Cyclohexyl-1- (4-chlorophenyl) -4,5,6,7-te trahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -cyclopentyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane -indazol-3-carboxamide, N (3) - [(N-Cyclohexyl-N-methyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7- methane-indazol-3-carboxamide, N (3) -Phenyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3 ) - (3-Chlorophenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1'-4,7-methane-indazol-3-carboxamide, N (3) - (4-Chlorophenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (3-Bromophenyl) -1- (4-chlorophenyl ) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2-Methoxyphenyl) -1- (4-chlorophenyl) -4,5,6 , 7-Tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-tert-Butylphenyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro 1H-4,7-methane-indazol-3-carboxamide, N (3) -Benzyl-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methan-i nda ζo1-3 -carboxamide, N (3) - (2-Chlorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3 -carboxamide, N (3) - (4-Chlorob Enzyme) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2,4-Dichlorobenzyl) -1 - (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2-Bromobenzyl) -1- (4-chlorophenyl) - 4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-Bromobenzyl) -1- (4-chlorophenyl) -4,5,6, 7-Tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-Fluorobenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H- 4,7-methane-indazol-3-carboxamide, N (3) - (4-Trifluoromethylbenzyl) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole -3-carboxamide, N (3) -Phenylamino-1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(4-Chlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(2, 4-Dichlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(3,4- Dichlorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(2-Fluorophenyl) amino] -1- (4-cl orophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(3-Fluorophenyl) amino] -1- (4-chlorophenyl) -4 , 5,6,7-Tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(4-Fluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6 , 7-Tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(2,4-Difluorophenyl) amino] -1- (4-chlorophenyl) -4,5,6,7 -tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (N ', N'-Diphenylamino) -1- (4-chlorophenyl) -4,5,6,7-tetrahydro 1H-4,7-methane-indazol-3-carboxamide, N (3) -cyclohexyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane- indazol-3-carboxamide, N (3) -Cyclohexylmethyl-1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3 ) - (N, N-Dicyclohexylamino) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4H-1,2,4-triazol-4-yl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide , N (3) - (1,3,3-Trimethyl bicyclo [2.2.1] hepta-2-yl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4 7-methane-indazol-3-carboxamide, N ( 3) - (Adamantan-yl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -phenyl 1- (2,4-Dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2,4-Difluorophenyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2-Fluorobenzyl) -1- (2,4- dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-Fluorobenzyl) -1- (2,4-dichlorophenyl) -4, 5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2,4-Difluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6 , 7-Tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2,6-Difluorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7- tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2-Chlorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4 , 7-Methane-indazol-3-carboxamide, N (3) - (4-Chlorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane indazol-3-carboxamide, N (3) - (2,4-Dichlorobenzyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3 -carboxamide, N (3) - [S- (1-phenylethyl )] - 1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1β-4,7-methane-indazol-3-carboxamide, N (3) - [R- (1-phenylethyl) ] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2-phenylethyl) -1- ( 2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [2- (4-fluorophenyl) ethyl] -1- ( 2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -phenylamino-1- (2,4-dichlorophenyl) -4 , 5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(2-Chlorophenyl) amino] -1- (2,4-dichlorophenyl) -4, 5,6,7-Tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [N- (2-Chlorophenyl) -N-methylamino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(4-Chlorophenyl) amino] -1- (2,4-dichlorophenyl) -4 , 5,6,7-tetrahydro-1H-4,7-methane-indazole-3-carboxamide, N (3) - [(2,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) - 4,5,6,7-Tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(2,4-dichlorophenyl) -N-methylamino] -1- (2,4- chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-m tano-indazol-3-carboxamide, N (3) - [(3,4-Dichlorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7 -methane-indazol-3-carboxamide, N (3) - [(2-Bromophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane -indazol-3-carboxamide, N (3) - [(2-Fluorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole -3-carboxamide, N (3) - [(2,4-Difluorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methanesulfonamide indazol-3-carboxamide, N (3) - [(3-fluorophenyl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazoline 3-carboxamide, N (3) - [(3-chloropyridin-2-yl) amino] -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane -indazol-3-carboxamide, N (5) -piperidine-3- (2 ', 4'-dichlorophenyl) -3,4-diazatricyclo [5.2.1. O2'6] deca-2 (6), 4-diene-5-carboxamide, N (5) -benzyl-3- (2 ', 4'-dichlorophenyl) -3,4-diazatricyclo [5.2.1. O2'6] deca-2 (6), 4-diene-5-carboxamide, N (3) piperidine-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H - 4.7 -methane-indazol-3-carboxamide, N (3) -cyclohexyl-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Benzyl-1- (2-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -phenylamino-1- (2-) bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) piperidine-1- (4-bromophenyl) -4,5,6,7 -tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -cyclohexyl-1- (4-bromophenyl) -4,5,6,1-tetrahydro-1H-4,7- methane-indazol-3-carboxamide, N (3) -Benzyl-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3 ) -Phenylamino-1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(2-Fluorophenyl) amino] -1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Cyclohexyl-1- (4-fluorophenyl) -4, 5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Benzyl-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-1 4.7 - methane-indazol-3-carboxamide, N5- (Adamantan-2-yl) -3- (4-fluorophenyl) -3,4-diazatricyclo [5. 2.1. O2'6] deca-2 (6), 4-diene-5-carboxamide, N5- (I-Methyl-1-phenylethyl) -3- (4-fluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide, N5- (Adamantan-1-yl) -3- (4-fluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide, N (3) -phenylamino-1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H - 4.7 -methane-indazol-3-carboxamide, N (3) -Phenylamino-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide , N (3) - [(2-Chlorophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(2-bromophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3 ) - [(2-Fluorophenyl) amino] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Piperidine-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -cyclohexyl-I- (2, 4-Difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (Cyclohexylmethyl) -1- (2,4-difluorophenyl) -4 , 5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [S- (I-phenylethyl)] -1- (2,4-difluorophenyl) -4, 5,6,7-Tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (R 1 -phenylethyl) -1- (2,4-difluorophenyl) -4,5,6,7 -tetrah idro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (1-Methyl-1-phenylethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro -1H-4,7-methane-indazol-3-carboxamide, N5- [1- (2-Chlorophenyl) -1-methylethyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide, N (3) - (1,3,3-Trimethylbicyclo [2.2.1] hepta-2-yl) -1- (2.4 -difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N5- (2-Chlorobenzyl) -3- (2,4-difluorophenyl) -3,4 -diazatricyclo [5.2.1. O2'6] deca-2 (6), 4-diene-5-carboxamide, N5- (4-Chlorobenzyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1. O2'6] deca-2 (6), 4-diene-5-carboxamide, N5- (1-Ethyl-1-phenylpropyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1 . O2'6] deca-2 (6), 4-diene-5-carboxamide, N5 - [(IS) -1-phenylpropyl] -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1 . O2'6] deca-2 (6), 4-diene-5-carboxamide, Methyl (2S) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1. O2'6] deca-2 (6), 3-dien-3-ylcarboxamido] -2-phenylethanate, N5 - [(IS) -2-Hydroxy-1-phenylethyl] -3- (2,4-difluorophenyl) - 3,4-diazatricyclo [5.2.1. O2'6] deca-2 (6), 4-diene-5-carboxamide, N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro- 1H-4,7-methane-indazol-3-carboxamide, (4R, 7S) -N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro -1Η-4,7-methane-indazol-3-carboxamide, (4S, 7R) -N (3) - (tert-Butyl) -1- (2,4-difluorophenyl) -4,5,6,7- tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N5-n-Pentyl-3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide, N5- (2,4-Dichlorobenzyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.1. O2'6] deca-2 (6), 4-diene-5-carboxamide, N5- (1-phenylcyclopropyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide, N5- (2-Adamantyl) -3- (2,4-difluorophenyl) -3,4-diazatryl [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide, N5- (2-Methyl-2-adamantyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2 .1. O2'6] deca-2 (6), 4-diene-5-carboxamide, N7- (3-Hydroxyiadamantan-1-yl) -5- (2,4-difluorophenyl) -5,6-diazatetracyclo [7.3.1.13 '11.04'8] tetradeca-4 (8), 6-diene-7-carboxamide, -4- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1.02,6] deca- 2 (6), 3-dien-3-ylcarboxamido] morpholine, N (3) - (ter-Pentyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4, 7-methane-indazol-3-carboxamide, N (3) -Cyclopropanmethyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide , N (3) -Cyclobutyl-1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (Tetrahydro) -2H-4-pyranmethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) -Cyclopropyl- 1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (4-methylpiperazine) -1- (2, 4-Difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, Methyl (2R) -2- [5- (2,4-difluorophenyl) -4,5 -diazatricyclo [5. 2 .1. 0.2'6] deca-2 (6), 3-dien-3-ylcarboxamido] -2-phenylethanate, N (3) - [(IR) -2-Hydroxy-1-phenylethyl] -1- (2, 4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (tert-Butyl) -1- (4-chlorophenyl) -4 , 5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (Tetrahydro-2-furanylmethyl) -1- (2,4-difluorophenyl) -4, 5,6,7-Tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (tert-Butyl) -1- (4-fluorophenyl) -4,5,6,7-tetrahydro -1H-4,7-methane-indazol-3-carboxamide, N (3) - (tert-Butyl) -1- (4-bromophenyl) -4,5,6,7-tetrahydro-1H-4,7 -methane-indazol-3-carboxamide, N (3) - (tert-Butyl) -1- (3,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-2-one 3-carboxamide, Methyl (2S) -2- [5- (2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1.O.2'6] deca-2 (6), 3-dien-3 -ylcarboxamido] -2- (4-fluorophenyl) etanoate, N (3) - (tert-Butyl) -1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7- methane-indazol-3-carboxamide, N (3) - (4-Hydroxyphenyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3 -carboxamide, N (3) - (ter-Buti l) -1- (2-ethoxy, 4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole-3-carboxamide, N (3) - (2-furylmethyl) - 1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2-thiophenomethyl) -1- (2, 4-Difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(IS) -2-Hydroxy-1- (4-fluorophenyl) ethyl] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole-3-carboxamide, methyl (2S) -2- [5- ( 2,4-difluorophenyl) -4,5-diazatricyclo [5.2.1.O.2,6] deca-2 (6), 3-dien-3-ylcarboxamido] -4-methylpentanoate, N (3) - (Adamantan -1-yl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (tert-butyl) -1 - (4-fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (tert-butyl) -2- (4-fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (tert-butyl) -1- (4-methylbenzyl) -4,5,6 , 7-Tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (2-hydroxyethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro 1-4, 7- methane-indazol-3-carboxamide, N (3) - (thienylethyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide , N (3) - (Isopropyl) -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [ (IS) -2-Methoxy-1-phenylethyl] -1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N ( 3) - (tert-Butyl) -2- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, and pharmaceutically acceptable salts thereof. Compound according to Claim 1, characterized in that the compound is selected from: N (3) -Phenyl-1- (2,4-dichlorophenyl) -7,8,8-trimethyl-4,5, 6,7-Tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(2-Fluorophenyl) amino] -1- (2,4-Dichlorophenyl) -7,8,8- trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(2,4-Difluorophenyl) amino] -1- (2,4-dichlorophenyl ) --7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - [(3-chloropyridin-2-yl ) amino] -1- (2,4-Dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N ( 3) - (Adamantan-1-yl) -1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3 -carboxamide, N (3) - (1,3,3-Trimethylbicyclo [2.2.1] hept-2-yl) -1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5, 6,7-Tetrahydro-1H-4,7-methane-indazol-3-carboxamide, N (3) - (1-Methyl-1-phenylethyl)) -1- (2,4-difluorophenyl) -7,8, 8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamide, (4R, 7S) -N (3) -t Butyl-1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-methane-indazol-3-carboxamide, Methyl (2R) -2 - [ 1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxamido] -2-phenylethylanoate, N (3) - [(IR) -2-Hydroxy-1-phenylethyl] -1- (2,4-difluorophenyl) -7,8,8-trimethyl) -4,5,6,7-tetrahydro-1H- 4,7-methane-indazol-3-carboxamide, N (3) -pentyl-1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-β- methane-indazol-3-carboxamide, (4S, 7R) -N (3) -ter-Butyl-1- (2,4-difluorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro -1H-methane-indazole-3-carboxamide, and pharmaceutically acceptable salts thereof. Compound according to Claim 1, characterized in that the compound is selected from: N (12) -Benzyl-10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxamide, N (12) -piperidine-10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2, 4,6,9 (13), 11-pentaeno-12-carboxamide, N (12) -Piperidine-10- (2,4-dichlorophenyl) -10,11-diazatetracyclo hydrochloride ^. 5 2 . O2'7. Pentadeca - 2,4,6,9 (13), 11-pentaeno-12-carboxamide, N (12) - [(N'-Cyclohexyl-N'-methyl) amino] -10- (2 , 4-dichlorophenyl) -10,11-diazatetracyclo [6.5.2. O2'7. O9'13] pentadeca-2,4,6,9 (13), 11-pentaeno-12-carboxamide, N (12) - {N '- [(2,4-Dichlorophenyl) -N'-methyl] amino} (2,4-dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7. Pentadeca-2, 4,6,9 (13), 11-pentaeno-12-carboxamide, N (12) - (Adamantan-yl) -10- (2,4-dichlorophenyl) -10,11- diazatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2, 4,6,9 (13), 11-pentaeno-12-carboxamide, N 12 - (1,3,3-Trimethylbicyclo [2.2.1] hepta-2-yl) -10- ( 2,4-dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7. Pentadeca-2 (7), 3,5,9 (13), 11-pentaene-12-carboxamide, N 12- (I-Methyl-1-phenylethyl) -10- (2,4, dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7. O9 "13] pentadeca-2, 4,6,9 (13), 11-pentaene-12-carboxamide, N 12- (1-Methyl-1-phenylethyl) -10- (2,4-difluorophenyl) -10,11 -diazatetracyclo [6.5.5.2-0.7.09.13] pentadeca-2, 4,6,9 (13), 11-pentaene-12-carboxamide, and pharmaceutically acceptable salts thereof. Compound according to Claim 1, characterized in that the compound is selected from: N (12) -Benzyl-16- (4-chlorophenyl) -10- (2,4-dichlorophenyl) -15,17 -dioxo-10,11,16-triazapentacyclo [6. 5 5 O2'7. O9'13. O14'18] octadeca - 2,4,6,9 (13), 11-pentaeno-12-carboxamide or N (12) -piperidine-16- (4-chlorophenyl) -10- (2,4-dichlorophenyl) - -15,17-dioxo-10,11,16-triazapentacyclo [6. 5 5 O2'7. O9'13. O14'18] octadeca - 2,4,6,9 (13), 11-pentaeno-12-carboxamide, and pharmaceutically acceptable salts thereof. Compound according to Claim 1, characterized in that the compound is selected from: N12-Benzyl-10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6. 5 .1. O2'7. O9'13] tetradeca-2, 4,6,9 (13), 11-pentaene-12-carboxamide, N 12- (I-Methyl-1-phenylethyl) -10- (2,4-difluorophenyl) -10,11 -diazatetracyclo [6. 5 .1. O2'7. O9'13] tetradeca-2, 4,6,9 (13), 11-pentaeno-12-carboxamide, N (12) -tert-Butyl-10- (2,4-difluorophenyl) -10,11-diazatetracyclo [ 6 5 .1. O2'7. O9'13] tetradeca-2, 4,6,9 (13), 11-pentaene-12-carboxamide, and pharmaceutically acceptable salts thereof. Compound according to Claim 1, characterized in that the compound is selected from: N5- (tert-Butyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.2. O2'6] undeca-2 (6), 4-diene-5-carboxamide, N (5) - (tert-Pentyl) -3- (2,4-difluorophenyl) -3,4-diazatricyclo [5.2.2. O2'6] undeca-2 (6), 4-diene-5-carboxamide, and pharmaceutically acceptable salts thereof. Compound according to Claim 1, characterized in that the compound is selected from: 5- (2-bromophenyl) -5,6-diazatetracyclo [7.3.1.13,11.04'8] tetradeca-4 acid (8) , 6-diene-7-carboxylic acid, 5- (4-chlorophenyl) -5,6-diazatetracyclo [7,3,1.13 '", O4'8] tetradeca-4 (8), 6-diene-7-carboxylic acid 5- (2,4-Difluorophenyl) -5,6-diazatetracyclo [7.3.1.13'11.04'8] tetradeca-4 (8), 6-diene-7-carboxylic acid, 5- (4-Fluorophenyl acid) ) -5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylic acid 5- (4-methylphenyl) -5,6-aiazatetracyclo [7.3. 1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylic acid 5- (4-Methoxyphenyl) -5,6-diazatetracyclo [7. 3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylic acid, 5-phenyl-5,6-diazatetracyclo [7,3,1.13'11, O4'8] tetradeca-4 (8), 6-diene-7 -carboxylic acid 5- (2,4-dichlorophenyl) -5,6-diazatetracyclo [7,3,1.13 '", O4'8] tetradeca-4 (8), 6-diene-7-carboxylic acid (2-chlorophenyl) -5,6-diazatetracyclo [7,3,1.13 ' ", O4'8] tetradeca-4 (8), 6-diene-7-carboxylic acid, 5- (5-chloropyridyl) -5,6-diazatetracyclo [7,3,1.13" ", O4'8] tetradeca- 4 (8), 6-diene-7-carboxylic acid, 5,6-diazatetracyclo [7,3,1.1 ', 0'] tetradeca - 4 (8), 6-diene-7-carboxylic acid, 6-Pentyl acid -5,6-diazatetracyclo [7. 3.1.1 ''. Q4'8] tetradeca-4,7-diene-7-carboxylic acid 5-Pentyl-5,6-diazatetracyclo [7.3.1.1 3, 11.04'8] tetradeca-4 (8) -6-diene-7-carboxylic acid, I-Phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid 1- (2-Chlorophenyl) -4,5 6,7-Tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid 1- (4-Chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid 3-carboxylic acid 1- (2,4-Dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid 1- (2-Bromophenyl) -4, 5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid 1- (4-Bromophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole -3-carboxylic acid 1- (4-Fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid 1- (2,4-Difluorophenyl) -4-acid , 5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid (R or S) 1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-- 1H-4,7-methane-indazol-3-carboxylic acid (S or R) 1- (2,4-difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole -3-carboxylic acid 1- ( 2,4-Dichlorophenyl) -7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylic acid 3- (2,4-difluorophenyl) - 1,10,10-trimethyl-3,4-diazatricyclo [5.2.2. O2'6] deca-2 (6), 4-diene-5-carboxylic acid, 10- (2,4-dichlorophenyl) -10,11-diazatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2, 4,6,9 (13), 11-pentaene-12-carboxylic acid, 10- (2,4-difluorophenyl) -10,11-diazatetracyclo [6.5.2. O2'7. O9'13] pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxylic acid, 13Endo, 14endo-16- (4-chlorophenyl) -15,17-dioxo-10- (2,4 dichlorophenyl) -10,11,16-triazapentacyclo [6.5.5. O2'7. O9'13. O14'18] octadeca - 2,4,6,9 (13), 11-pentaene-12-carboxylic acid, 10- (2,4-Difluorophenyl) -10,11diazatetracyclo [6. 5 .1. O2'7. O9'13] tetradeca-2,4,6,9 (13), 11-pentaene-12-carboxylic acid 3- (2,4-difluorophenyl) -3,4diazatriciclo acid [5.2.2. O2'6] undeca-2 (6), 4-diene-5-carboxylic acid 3- (3,4-dichlorophenyl) -3,4diazatriciclo acid [5.2.1. O2'6] deca-2 (6), 4-diene-5-carboxylic acid 3- (2-ethoxy-4-fluorophenyl) -3,4diazatriciclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxylic acid 2- (4-Methylbenzyl) -4,5,6,7-tetrahydro-2H-4,7-methaneindazole-3-carboxylic acid, 3- (4-Methylbenzyl) -3,4-diazatriciclo acid [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxylic acid, 2- (4-Fluorobenzyl) -4,5,6,7-tetrahydro-2H-4,7-methane-indazol-3-carboxylic acid, 1- (4-Fluorobenzyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazole-3-carboxylic acid, and pharmaceutically acceptable salts thereof. Compound according to Claim 1, characterized in that the compound is selected from Ethyl 5- (2-bromophenyl) -5,6diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylate, Ethyl 5- (4-chlorophenyl) -5,6diazatetracyclo [7, 3, 1.13'11, O4'8] tetradeca-4 (8) 6-Diene-7-carboxylate, 1-Ethyl 5- (2,4-Difluorophenyl) -5,6diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylate, Ethyl 5- (4-Fluorophenyl) -5,6diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylate, Ethyl 5- (4-methylphenyl) -5,6diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4 (8), 6-diene-7-carboxylate, Ethyl 5- (4-Methoxyphenyl) -5,6-diazatetracyclo [7.3.1.13 '". Θ"' 8] tetradeca-4 (8 ), 6-diene-7-carboxylate, Ethyl 5-phenyl-5,6-diazatetracyclo [7,3,1.13 '", O4'8] tetradeca-4 (8), 6-diene-7-carboxylate, Ethyl 5 - (2,4-dichlorophenyl) -5,6-diazatetracyclo [7,3,1.13 '', O4'8] tetradeca-4 (8), 6-diene-7-carboxylate, Ethyl 5- (2- chlorophenyl) -5,6-diazatetracyclo [7,3,11,11,10,48] tetradeca-4 (8), 6-diene-7-carboxylate, Ethyl 5- (5-chloropyridyl) -5,6-diazatetracyclo [7,3,1.13'11, O4'8] tetradeca-4 (8), 6-diene-7-carboxylate, Ethyl 5,6-diazatetracyclo [7,3,1.1 ', 0'] tetradeca-4 (8 ), 6-diene-7-carboxylate, Ethyl 6-methyl-5,6-diazatetracyclo [7,3,1.13'11, O4'8] tetradeca-4 (8), 6-diene-7-carboxylate, Ethyl 5 -methyl-5,6-diazatetracyclo [7,3,1.13'11,04,48] tetradeca-4 (8), 6-diene-7-carboxylate, Ethyl 6-pentyl-5,6-diazatetracyclo [7. 3,11,11. O4'8] tetradeca-4,7-diene-7-carboxylate, Ethyl 5-pentyl-5,6-diazatetracyclo [7.3.1.13'11. O4'8] tetradeca-4 (8) -6-diene-7-carboxylate, Ethyl 1-phenyl-4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate, Ethyl 1 - (2-chlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methanindazol-3-carboxylate, Ethyl 1- (4-chlorophenyl) -4,5,6,7-tetrahydro 1H-4,7-methane-indazol-3-carboxylate, Ethyl 1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3-carboxylate, Ethyl 1- (2-bromophenyl) -4,5,6,7-tetrahydro-1'-4,7-methaneindazol-3-carboxylate, Ethyl 1- (4-bromophenyl) -4,5,6,7-tetrahydro-1Η -4,7-methaneindazole-3-carboxylate, Ethyl 1- (4-fluorophenyl) -4,5,6,7-tetrahydro-1H-4,7-methaneindazole-3-carboxylate, Ethyl 1- (2,4- difluorophenyl) -4,5,6,7-tetrahydro-1H-4,7methane-indazol-3-carboxylate, Ethyl 1- (2,4-dichlorophenyl) -7,8,8-trimethyl-4,5,6, 7tetrahydro-1H-4,7-methane-indazole-3-carboxylate, Ethyl 3- (2,4-difluorophenyl) -1,10,10-trimethyl-3,4-diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxylate, Ethyl 10- (2,4-dichlorophenyl) -10,11diazatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2, 4,6,9 (13), 11-pentaeno-12-carboxylate, Ethyl 10- (2,4-difluorophenyl) -10,11diazatetracyclo [6. 5 2 . O2'7. O9'13] pentadeca-2,4,6,9 (13), 11-pentaene-12-carboxylate, Ethyl 13endo, 14endo-16- (4-chlorophenyl) -15,17-dioxo-10- (2,4-dichlorophenyl ) -10,11,16-triazapentacyclo [6. 5 5 O2'7. O9'13. O14'18] octadeca-2,4,6,9 (13), 11-pentaene-12-carboxylate, Ethyl 10- (2,4-difluorophenyl) -10,11diazatetracyclo [6. 5 .1. O2'7. O9'13] tetradeca-2, 4,6,9 (13), 11-pentaeno-12-carboxylate, Ethyl-3- (2,4-difluorophenyl) -3,4-diazatricyclo [5. 2 . 2 . O2'6] undeca-2 (6), 4-diene-5-carboxylate, Ethyl 3- (3,4-dichlorophenyl) -3,4diazatricyclo [5.2.1. O2,6] deca-2 (6), 4-diene-5-carboxylate, Ethyl 3- (2-ethoxy-4-fluorophenyl) -3,4diazatricyclo [5. 2 .1. O2'6] deca-2 (6), 4-diene-5-carboxylate, Ethyl 4,5,6,7-tetrahydro-1H-4,7-methane-indazol-3carboxylate, Ethyl 2- (4-methylbenzyl) -4,5,6,7-tetrahydro-2H-4,7-methaneindazole-3-carboxylate, Ethyl 1- (4-methylbenzyl) -4,5,6,7-tetrahydro-1H-4,7-methaneindazole 3-carboxylate, Ethyl 2- (4-fluorobenzyl) -4,5,6,7-tetrahydro-2H-4,7-methane-indazol-3-carboxylate, Ethyl 1- (4-fluorobenzyl) -4,5, 6,7-Tetrahydro-1H-4,7-methane-indazol-3-carboxylate, and pharmaceutically acceptable salts thereof. Compound according to Claim 1, characterized in that the compound is selected from: Ethyl 2-oxo- (5-oxotricyclo [4.3.1.1.3'8] undeca-4-yl) acetate, Ethyl 2- oxo-2- (3-oxobicyclo [2.2.1] hepta-2-yl) acetate Ethyl 2- (3-hydroxy-4,7,7-trimethyl bicyclo [2.2.1] hepta-2-en-2-yl -2-oxoacetate, Ethyl 2-oxo-2- (10-oxotricyclo [6.2 .2.0 O7] dodeca-2,4,6-trien-9-yl) acetate, Ethyl 9endo, 13endo-2- [11 - (4-chlorophenyl) -10,12,15-trioxo-11-azatetracyclo [6.5.2.0-2.7.09.13] pentadeca-2,4,6-trien-14-yl] -2-oxoacetate, Ethyl 2-oxo-2- (10-oxotricyclo [6.2.1.O2'7] undeca-2 (7), 3,5-trien-9-yl) acetate, Ethyl 2-hydroxy-2- (3-oxabicyclo) [2.2.2] octa-2-yliden) acetate, -9-Endo, 13-endo-11- (4-chlorophenyl) -11-azatetracyclo [6.5.0.02.7.09.9] pentadeca- 2,4,6-triene-10,12,14-trione, and pharmaceutically acceptable salts thereof. Pharmaceutical composition, characterized in that it comprises a compound as defined in any one of claims 1-29, either as a free base or in a pharmaceutically acceptable salt form and a pharmaceutically acceptable excipient. Pharmaceutical composition according to claim 30, characterized in that the pharmaceutically acceptable excipient is a carrier or diluent. A method for the manufacture of a pharmaceutical composition comprising mixing a compound as defined in any one of claims 1-29 either as a free base or a pharmaceutically acceptable salt form and a pharmaceutically acceptable excipient. Use of a compound as defined in any one of claims 1 to 29, characterized in that it is used to prepare a drug to prevent, ameliorate, treat a cannabinoid-mediated disease, disorder or syndrome. Use of a compound according to claim 33, wherein the cannabinoid receptor disease, disorder or syndromes are selected from appetite disorders, metabolism disorders, catabolism disorder, diabetes, obesity, ophthalmic disorders, disorders related to social, mood disorders, seizures, substance abuse, learning disorders, cognitive disorders, memory disorders, organ contraction, muscle twitch, respiratory disorders, disorders and diseases, disorders of locomotor activity, movement disorders, immune disorders (such as autoimmune disorders), inflammation, cell growth, pain-related or neurodegenerative syndromes. Use of a compound according to claim 34, characterized in that the cannabinoid receptor disease, disorder or syndromes are selected from appetite disorders, osocial-related disorders, syndromes, disorders and diseases, and abuse related to self-abuse. immune or inflammation, neurodegenerative pain. Use of a compound according to claim 35, wherein the disease, disorder or appetite-related syndrome includes obesity, overweight, anorexia, bulimia, cachexia, irregular appetite, syndromes, disorders, diseases or symptoms related to obesity including obesity as a result of genetics; diet; admission volume of foodstuffs; metabolic syndrome, disorder or disease, hypothalamic disorder or disease; age, abnormal distribution of fat mass; abnormal distribution of adipose compartment; compulsive eating disorders, motivational disorders which include the desire to consume sugars; carbohydrates; alcohols or drugs or any ingredient with reduced activity, hedonic value. Use of a compound according to claim 35, characterized in that the disease, disorder or social-related syndrome is depression and includes bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic characteristics, catatonic characteristics, melancholic, atypical characteristics or seasonal affective disorder, postpartum onset, early or late onset dysthymic disorders with daring atypical features, neurotic and phobiasocial depression, dementia accompanying depression, anxiety, psychosis, social affective disorders, cognitive disorders. Use of a compound according to claim 35, characterized in that the disease, disorder or inflammation-related syndrome or syndromes include psoriasis, lupus erythematosus, connective tissue disorders, Sjogren's syndrome, ankylosing spondyloarthritis, rheumatoid arthritis, reaction arthritis, non-differentiated spondylartrithen, Behcet's disease, autoimmune hemolytic anemia, multiple sclerosis, amyotropic lateral sclerosis, amyloids, graft rejection or diseases affecting the plasma cell line; delayed or immediate hypersensitivity, rhinitealergic, contact dermatitis or allergic conjunctivitis, parasitic, viral or bacterial infectious diseases (such as AIDS and meningitis), inflammatory diseases (such as, but not limited to, arthritis, rheumatoid arthritis , osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS)) and osteoporosis. Use of a compound according to claim 35, characterized in that pain and neurodegenerative syndromes, disorders and illnesses include pain mediated by central and peripheral pathways, bone and joint pain, pain associated with migraine headache, cancer pain, menstrual cramps, labor pain, chronic inflammatory pain, allergies, rheumatoid arthritis, dermatitis, immunodeficiency, chronic neuropathic pain, including pain associated with diabetic neuropathy; sciatic; low back pain not specific; fibromyalgia; HIV-related neuropathy; postherpetic neuralgia; trigeminal neuralgia; resulting from physical trauma, dental pain, amputation, cancer, toxins or chronic inflammatory conditions, Hodgkin's disease, myasthenia gravis, nephrotic syndrome, scleroderma and thyroiditis. The use of a compound according to claim 35, wherein the substance abuse syndromes, disorders or diseases include drug abuse and drug suppression in which the substance of abuse or dependence includes alcohol, amphetamines, substances similar to amphetamines, caffeine, marijuana, cocaine, halucinogens, inhalants, opioids, nicotine, heroin abuse, barbiturates, phencyclidine or its derivatives, sedative hypnotics, benzodiazepines, substance abuse combinations. Use of a compound according to claim 35, characterized in that ophthalmic diseases include glaucoma, intraocular pressure associated with glaucoma, retinitis, retinopathies, uveitis, acute injury to ocular tissue. 42. Selective CB2 agonist, characterized in that it has the formula: <formula> formula see original document page 299 </formula> where R, R1 and R2 may be the same or different and are independently hydrogen, nitro, cyano, formyl, acetyl. , halogen, -OR3, -SR3, oxo, thio, unsubstituted or substituted alkyls, unsubstituted or substituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl substituted, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR3R4, -C (= B) -R3, -C (O ) O-R3, -C (O) NR3R4, -S (O) m-NR3R4, or a protecting group or R1 and R2 may be joined together to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from 0, NR3 or S, each occurrence of R3 and R4 may be the same or different and are independently hydrogen, halo , cyano, -0Ra, SRa, oxo, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl substituted or unsubstituted, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted heterocyclylalkyl, -C (= B) -Ra, -C (O) O-Ra, -C (O) NRaRb , -S (O) m-Ra, -S (O) m-NRaRb, -NRaRb, or a protecting group of R3 and R4, when attached to a common atom, can be joined to form a saturated or unsaturated cyclic ring of 3 to 7. optionally substituted members, which may optionally include at least two heteroatoms selected from 0, NR3 or S; each occurrence of Ra and Rb may be the same or different and are independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C (O) -Rc, -C (O) O-Rc, -C (O) NRcRd, -S (O) m-Rc, -S (O) m-NRcRd, -NRcRd, -0RC, -SRc, a group protective, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyls, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl substituted, unsubstituted or substituted heterocyclic group, substituted or unsubstituted heterocyclylalkyls, or substituted or unsubstituted heteroarylalkyls, each occurrence of Rc and Rd may be the same or different and are independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, one group protective, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyls, unsubstituted or substituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted, aryl substituted unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic group, unsubstituted or substituted heterocyclylalkyl, or unsubstituted or substituted heteroarylalkyl, each occurrence of B being independent nently O, S or NR; m independently be O, 1 or 2. 43. Selective CB2 agonist according to claim 42, characterized in that R is a substituted or unsubstituted aryl. 44. Selective CB2 agonist, characterized in that R is a phenyl group substituted with one or two halogen atoms. Use of a compound as defined in any one of claims 42 to 44, wherein it is used to prepare a medicament for treating an ophthalmic disorder, respiratory disorder, autoimmune disorder, inflammation, pain-related or neurodegenerative syndrome. Use of a compound, characterized in that it is used in an effective amount as defined in any one of claims 42-44. Use according to claim 46, characterized in that the pain is neuropathic pain. A process for preparing a compound as defined in claim 1, wherein Y is N, U is C, one is W, V, and X is N and the remaining two are C, and B is 0, characterized in that the step comprises: couple an amine of the formula NHR1R2 with a compound of the formula: where L2 is a leaving group to form the compound of formula (1). A process for preparing a compound as defined in claim 1, wherein WeY are N, U, V, and X are C, and B is O, comprising the steps of: (a) oxidizing a compound of formula K: <formula> formula see original document page 302 </formula> to produce a compound of formula B: <formula> formula see original document page 302 </formula> (b) subject the compound of formula B to reductive amination to form the vicinal diamine of formula C: <formula> formula see original document page 302 </formula> (c) monoacylate the vicinal diamine of formula C to form a mono N-acyl diamine of formula D: <formula> formula see original document page 302 </ formula > where pg is a protecting group: (d) cyclizing the compound of formula D to form a compound of formula E: <formula> formula see original document page 302 </formula> (e) dehydrogenating the compound of formula E to form formula F compound: <formula> formula see original document page 303 </formula> (f) derive the compound of formula F to form compound G1, compound G2, or a mixture thereof: (g) hydrolyze compound G1, compound G2, or both to form compound H1, (h) Couple an amine of the formula HNR1R2 with compound H1, compound H2, or both to form compound of formula (1). Process for the preparation of compounds of formula IA: wherein A, R, R1 and R2 are equal to those defined in claim 1, characterized in that it comprises the steps of: a ) deprotonate a compound of formula K: <formula> formula see original document page 304 </formula> followed by acylation to produce a compound of formula L: <formula> formula see original document page 304 </formula> (b) react the compound of formula L with a hydrazinating formula RNHNH2 to form compound M, compound N, or both: (c) hydrolyze and couple compound M, compound N, or both with a amine of formula HNR 1 R 2 to form the compound of formula (1). 51. A process for preparing a compound of formula 1, wherein VeY is N, U, W, and X are C, B is O, and ρ is 0 or 1, characterized in that it comprises the steps of: (a) converting a compound of formula O: <formula> formula see original document page 304 </formula> for a compound of formula P: <formula> formula see original document page 304 </formula> (b) couple compound P with an amine of the <formula> formula see original document page 305 </formula> to form a compound of formula R: <formula> formula see original document page 305 </formula> (c) deprotonate the compound of formula R followed by condensation to form a compound of formula S: <formula> formula see original document page 305 </formula>; and (d) hydrolyzing and coupling the compound of formula S with an amine of the formula HNR 1 R 2 to form the compound of formula (1).