HK1019443B - Substituted indazole derivatives and their use as inhibitors phosphodiesterase (pde) type iv and the production of tumor necrosis factor (tnf) - Google Patents

Description

Substituted indazole derivatives and their use as Phosphodiesterase (PDE) type IV and inhibitors of the production of Tumor Necrosis Factor (TNF)

Background

The present invention relates to a series of novel indazole analogs that are selective inhibitors of Phosphodiesterase (PDE) type IV and the production of Tumor Necrosis Factor (TNF), and thus are useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases in which TNF production is implicated. The invention also relates to methods of using the compounds in the treatment of the above-mentioned diseases in mammals, especially humans, and to pharmaceutical compositions containing the compounds.

Since cyclic Adenosine Monophosphate (AMP) was identified as an intracellular second messenger, see e.w.sutherland and t.w.rall pharmacological reviews (pharmacol. rev.) 12, 265, (1960), inhibition of phosphodiesterase has become a regulatory target and therapeutic measure in methods of treating a number of diseases. Recently, a unique class of PDEs has been identified, see e.g. TiPS 11, 150 (1990) by j.a. beavo et al, and their selective inhibition has led to improvements in drug therapy, see e.g. c.d. nicholson, m.s. hahid TiPS 12, 19 (1991). In particular, it has been recognized that the release of inflammatory mediators can be inhibited by the inhibition of type IV PDEs, see m.w. verghese et al journal of molecular and cellular cardiology 12 (supplement II), S61, (1989), and also the ability to relax airway smooth muscle (t.j. torphy, "New antiasthmatic drug guidance (Directions for New Anti-Asthma Drugs)" s.r.o' Donnell and c.g. a.persson, editors 1988, 37 Birkhauser-Verlag). Thus, compounds that inhibit type IV PDEs, but are only minimally active on other PDE types, inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular or antiplatelet effects.

TNF has been identified in association with a variety of infectious and autoimmune diseases, see w.friends, joint european society for biochemistry (FEBS Letters) 285, 199 (1991). Furthermore, TNF has been shown to be the major mediator of the inflammatory response seen in sepsis and septic shock, see C.E. Spooner et al, Clinical immunology and immunopathology 62, S11 (1992).

Summary of The Invention

The present invention relates to compounds of formula I and pharmaceutically acceptable salts thereof,wherein:

r is hydrogen, C₁-C₆Alkyl, - (CH)₂)_n(C₃-C₇Cycloalkyl) in which n is 0 to 2, (C)₁-C₆Alkoxy) C₁-C₆Alkyl radical, C₂-C₆Alkenyl, - (CH)₂)_n(C₃-C₉Heterocyclyl) wherein n is 0 to 2, or- (Z')_b(Z”)_c(C₆-C₁₀Aryl) in which b and C are independently 0 or 1, Z' is C₁-C₆Alkylene or C₂-C₆Alkenylene radical, Z "being O, S, SO₂Or NR₉Wherein said alkyl, alkenyl, alkoxyalkyl, heterocyclyl and aryl moieties of said group R may be substituted with 1 to 3 substituents independently selected from halogen, hydroxy, C₁-C₅Alkyl radical, C₂-C₅Alkenyl radical, C₁-C₅Alkoxy radical, C₃-C₆Cycloalkoxy, trifluoromethyl, nitro, CO₂R₉、C(O)NR₉R₁₀、NR₉R₁₀And SO₂NR₉R₁₀；

R₁Is hydrogen, C₁-C₇Alkyl radical, C₂-C₃Alkenyl, phenyl, C₃-C₇Cycloalkyl or (C)₃-C₇Cycloalkyl) C₁-C₂Alkyl radical, wherein the radical R₁The alkyl, alkenyl and phenyl groups of (a) may be substituted with 1 to 3 substituents independently selected from methyl, ethyl, trifluoromethyl and halogen;

R₂is selected fromAndwherein the dotted lines in formulae (Ia) and (Ib) represent single or double bonds;

m is 0 to 4;

R₃is H, halogen, cyano, C which may be substituted by 1 to 3 halogen radicals₁-C₄Alkyl radical, CH₂NHC(O)C(O)NH₂Can be substituted by R₁₁、R₁₇、CH₂OR₉、NR₉R₁₀、CH₂NR₉R₁₀、CO₂R₉、C(O)NR₉R₁₀、C≡CR₁₁C (Z) H or CH ═ CR₁₁R₁₁A substituted cyclopropyl group;

R₄is H, C (Y) R₁₄，CO₂R₁₄，C(Y)NR₁₇R₁₄，CN，C(NR₁₇)NR₁₇R₁₄，C(NOR₉)R₁₄，C(O)NR₉NR₉C(O)R₉，C(O)NR₉NR₁₇R₁₄，C(NOR₁₄)R₉，C(NR₉)NR₁₇R₁₄，C(NR₁₄)NR₉R₁₀，C(NCN)NR₁₇R₁₄，C(NCN)S(C₁-C₄Alkyl), CR₉R₁₀OR₁₄，CR₉R₁₀SR₁₄，CR₉R₁₀S(O)_nR₁₅Wherein n is 0 to 2, CR₉R₁₀NR₁₄R₁₇，CR₉R₁₀NR₁₇SO₂R₁₅，CR₉R₁₀NR₁₇C(Y)R₁₄，CR₉R₁₀NR₁₇CO₂R₁₅，CR₉R₁₀NR₁₇C(Y)NR₁₇R₁₄，CR₉R₁₀NR₁₇C(NCN)NR₁₇R₁₄，CR₉R₁₀NR₁₇C(CR₉NO₂)S(C₁-C₄Alkyl), CR₉R₁₀CO₂R₁₅，CR₉R₁₀C(Y)NR₁₇R₁₄，CR₉R₁₀C(NR₁₇)NR₁₇R₁₄，CR₉R₁₀CN，CR₉R₁₀C(NOR₁₀)R₁₄，CR₉R₁₀C(NOR₁₄)R₁₀，CR₉R₁₀NR₁₇C(NR₁₇)S(C₁-C₄Alkyl), CR₉R₁₀NR₁₇C(NR₁₇)NR₁₇R₁₄，CR₉R₁₀NR₁₇C(O)C(O)NR₁₇R₁₄，CR₉R₁₀NR₁₇C(O)C(O)OR₁₄Tetrazolyl, thiazolyl, imidazolyl, imidazolidinyl, pyrazolyl, thiazolidinyl, oxazolyl, oxazolidinyl, triazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, CR₉R₁₀(tetrazolyl), CR₉R₁₀(thiazolyl), CR₉R₁₀(imidazolyl group), CR₉R₁₀(imidazolidinyl), CR₉R₁₀(pyrazolyl), CR₉R₁₀(thiazolidinyl), CR₉R₁₀(oxazolyl), CR₉R₁₀(oxazolidinyl), CR₉R₁₀(triazolyl), CR₉R₁₀(isoxazolyl), CR₉R₁₀(oxadiazolyl), CR₉R₁₀(thiadiazolyl), CR₉R₁₀(morpholinyl), CR₉R₁₀(piperidinyl group), CR₉R₁₀(piperazinyl) or CR₉R₁₀(pyrrolyl), wherein R is₄Said heterocyclyl and heterocyclyl portions of substituents may be substituted with 1 to 3R₁₄Substituent group substitution;

R₅is R₉、OR₉、CH₂OR₉Cyano, C (O) R₉、CO₂R₉、C(O)NR₉R₁₀Or NR₉R₁₀Provided that R is R if the dotted line in formula (Ia) represents a double bond₅Is absent;

or R₄And R₅Together form ═ O or ═ R₈；

Or R₅Is hydrogen and R₄Is OR₁₄，SR₁₄，S(O)_nR₁₅Wherein n is0 to 2, SO₂NR₁₇R₁₄，NR₁₇R₁₄，NR₁₄C(O)R₉，NR₁₇C(Y)R₁₄，NR₁₇C(O)OR₁₅，NR₁₇C(Y)NR₁₇R₁₄，NR₁₇SO₂NR₁₇R₁₄，NR₁₇C(NCN)NR₁₇R₁₄，NR₁₇SO₂R₁₅，NR₁₇C(CR₉NO₂)NR₁₇R₁₄，NR₁₇C(NCN)S(C₁-C₄Alkyl), NR)₁₇C(CR₉NO₂)S(C₁-C₄Alkyl), NR)₁₇C(NR₁₇)NR₁₇R₁₄，NR₁₇C(O)C(O)NR₁₇R₁₄Or NR₁₇C(O)C(O)OR₁₄；

Each R₆Independently selected from methyl and ethyl groups which may be substituted with 1 to 3 halogen groups;

R₇is OR₁₄，SR₁₄，SO₂NR₁₇R₁₄，NR₁₇R₁₄，NR₁₄C(O)R₉，NR₁₇C(Y)R₁₄，NR₁₇C(O)OR₁₅，S(O)_nR₁₂Wherein n is 0 to 2, OS (O)₂R₁₂，OR₁₂，OC(O)NR₁₃R₁₂，OC(O)R₁₃，OCO₂R₁₃，O(CR₁₂R₁₃)_mOR₁₂Wherein m is 0 to 2, CR₉R₁₀OR₁₄，CR₉R₁₀NR₁₇R₁₄，C(Y)R₁₄，CO₂R₁₄，C(Y)NR₁₇R₁₄，CN，C(NR₁₇)NR₁₇R₁₄，C(NOR₉)R₁₄，C(O)NR₉NR₉C(O)R₉，C(O)NR₉NR₁₇R₁₄，C(NOR₁₄)R₉，C(NR₉)NR₁₇R₁₄，C(NR₁₄)NR₉R₁₀，C(NCN)NR₁₇R₁₄，C(NCN)S(C₁-C₄Alkyl), tetrazolyl, thiazolyl, imidazolyl, imidazolidinyl, pyrazolyl, thiazolidinyl, oxazolyl, oxazolidinyl, triazolyl, isoxazolyl, oxadiazolyl or thiadiazolyl, wherein R is₇The heterocyclic group of (A) may be substituted by 1 to 3R₁₄Substituent group substitution;

R₈is ═ NR₁₅、＝NCR₉R₁₀(C₂-C₆Alkenyl), ═ NOR₁₄、＝NOR₁₉、＝NOCR₉R₁₀(C₂-C₆Alkenyl) ═ NNR₉R₁₄、＝NNR₉R₁₉、＝NCN、＝NNR₉C(Y)NR₉R₁₄、＝C(CN)₂、＝CR₁₄CN、＝CR₁₄CO₂R₉、＝CR₁₄C(O)NR₉R₁₄、＝C(CN)NO₂、＝C(CN)CO₂(C₁-C₄Alkyl), - (C (CN) OCO₂(C₁-C₄Alkyl), (C), (CN) (C)₁-C₄Alkyl), - (C (CN) C (O) NR₉R₁₄2- (1, 3-dithiane), 2- (1, 3-dithiolane), dimethylthioketal, diethylthioketal, 2- (1, 3-dioxolane), 2- (1, 3-dioxane), 2- (1, 3-oxathiolane), dimethylketal, or diethylketal;

each R₉And R₁₀Independently hydrogen or C which may be substituted by up to three fluorine atoms₁-C₄An alkyl group;

each R₁₁Independently is fluorine or R₁₀；

Each R₁₂Independently is C₁-C₆Alkyl radical, C₂-C₃Alkenyl radical, C₃-C₇Cycloalkyl group, (C)₃-C₇Cycloalkyl) C₁-C₂Alkyl radical, C₆-C₁₀Aryl or C₃-C₉Heterocyclyl, wherein the radical R₁₂May be substituted with 1 to 3 substituents independently selected from methyl, ethyl, trifluoromethyl andhalogen;

each R₁₃Independently is hydrogen or R₁₂；

Each R₁₄Independently is hydrogen or R₁₅Or if R is₁₄And R₁₇As NR₁₇R₁₄When present, then R₁₇And R₁₄May form together with the nitrogen a 5 to 7 membered ring which may additionally contain at least one heteroatom selected from O, N and S;

each R₁₅Independently is C₁-C₆Alkyl or- (CR)₉R₁₀)_nR₁₆Wherein n is 0 to 2, R₁₆And said C₁-C₆The alkyl group may be substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, NR₁₀R₁₇，C(O)R₉，OR₉，C(O)NR₁₀R₁₇，OC(O)NR₁₀R₁₇，NR₁₇C(O)NR₁₇R₁₀，NR₁₇C(O)R₁₀，NR₁₇C(O)O(C₁-C₄Alkyl radical), C (NR)₁₇)NR₁₇R₁₀，C(NCN)NR₁₇R₁₀，C(NCN)S(C₁-C₄Alkyl), NR)₁₇C(NCN)S(C₁-C₄Alkyl), NR)₁₇C(NCN)NR₁₇R₁₀，NR₁₇SO₂(C₁-C₄Alkyl), S (O)_n(C₁-C₄Alkyl) where n is 0 to 2, NR₁₇C(O)C(O)NR₁₇R₁₀，NR₁₇C(O)C(O)R₁₇Thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl and C which may be substituted by one to three fluorine atoms₁-C₂An alkyl group;

each R₁₆Independently is C₃-C₇Cycloalkyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, thienyl, thiazolyl, quinolinyl, naphthyl, or phenyl;

each R₁₇Independently is OR₉Or R₁₀；

R₁₈Is H, C (Y) R₁₄，CO₂R₁₄，C(Y)NR₁₇R₁₄，CN，C(NR₁₇)NR₁₇R₁₄，C(NOR₉)R₁₄，C(O)NR₉NR₉C(O)R₉，C(O)NR₉NR₁₇R₁₄，C(NOR₁₄)R₉，C(NR₉)NR₁₇R₁₄，C(NR₁₄)NR₉R₁₀，C(NCN)NR₁₇R₁₄，C(NCN)S(C₁-C₄Alkyl), CR₉R₁₀OR₁₄，CR₉R₁₀SR₁₄，CR₉R₁₀S(O)_nR₁₅Wherein n is 0 to 2, CR₉R₁₀NR₁₄R₁₇，CR₉R₁₀NR₁₇SO₂R₁₅，CR₉R₁₀NR₁₇C(Y)R₁₄，CR₉R₁₀NR₁₇CO₂R₁₅，CR₉R₁₀NR₁₇C(Y)NR₁₇R₁₄，CR₉R₁₀NR₁₇C(NCN)NR₁₇R₁₄，CR₉R₁₀NR₁₇C(CR₉NO₂)S(C₁-C₄Alkyl), tetrazolyl, thiazolyl, imidazolyl, imidazolidinyl, pyrazolyl, thiazolidinyl, oxazolyl, oxazolidinyl, triazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, wherein said heterocyclyl may be substituted with 1 to 3R₁₄Substituent group substitution;

R₁₉is-C (O) R₁₄、-C(O)NR₉R₁₄、-S(O)₂R₁₅or-S (O)₂NR₉R₁₄；

Each Y is independently ═ O or ═ S; and

z is O or NR₁₇、＝NCN、＝C(CN)₂、＝CR₉CN、＝CR₉NO₂、＝CR₉CO₂R₉、＝CR₉C(O)NR₉R₁₀、＝C(CN)CO₂(C₁-C₄Alkyl) or ═ C (CN) C (O) NR₉R₁₀。

The invention also relates to intermediates useful in the preparation of compounds of formula I, including compounds of the formula:and

wherein X is bromine, -C (O) O (C)₁-C₆Alkyl), -CH₂CN, carboxy, -CH₂OH or-C (O) H, R and R₁As defined above for the compounds of formula I.

The term "halogen" as used herein, unless otherwise indicated, refers to fluorine, chlorine, bromine or iodine. Preferred halogen groups are fluorine, chlorine and bromine.

The term "alkyl" as used herein, unless otherwise specified, includes saturated monovalent hydrocarbon radicals having straight or branched moieties.

As used herein, the term "alkoxy", unless otherwise indicated, includes O-alkyl, wherein "alkyl" is as defined above.

As used herein, unless otherwise indicated, the term "alkenyl" includes unsaturated alkyl groups having one or more double bonds, wherein "alkyl" is as defined above.

The term "cycloalkyl" as used herein, unless otherwise indicated, includes saturated monovalent cyclic hydrocarbon radicals including cyclobutyl, cyclopentyl and cycloheptyl.

As used herein, the term "aryl" includes, unless otherwise indicated, organic functional groups derived from aromatic hydrocarbons by removal of one hydrogen, such as phenyl or naphthyl.

As used herein, the term "heterocyclyl", unless otherwise indicated, includes aromatic and non-aromatic heterocompounds containing one or more heteroatoms selected from O, S and NA cyclic group. The heterocyclic group includes benzo-fused ring systems and ring systems substituted with oxygen. R for formula Ia₄For substituents, C₃-C₉The heterocyclic group may be attached to C through a nitrogen atom, or preferably through a carbon atom₁-C₆On the alkyl group. C₃An example of a heterocyclic radical is thiazolyl, C₉An example of a heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazinyl. Examples of aromatic heterocyclic groups are pyridyl (pyridinyl), imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl and thiazolyl. Heterocyclic groups having one fused benzene ring include benzimidazolyl.

Where certain heterocyclic groups are specifically enumerated or encompassed by substituents of compounds of formula I, it is to be understood that all suitable isomers of such heterocyclic groups are also included therein. For example in the substituent R₄In the definition of "thiazolyl" the term includes 2-, 4-or 5-thiazolyl; the term "imidazolyl" includes 2-, 4-, or 5-imidazolyl; the term "pyrazolyl" includes 3-, 4-or 5-pyrazolyl; the term "oxazolyl" includes 2-, 4-or 5-oxazolyl; the term "isoxazolyl" includes 3-, 4-, or 5-isoxazolyl, and the like. Likewise, in the substituent R₁₆In the definition of (1), "pyridyl" includes 2-, 3-or 4-pyridyl.

Preferred compounds of formula I include those wherein R₂Is a radical of the formula (Ia) in which R is₃And R₅Is of the cis structure:

other preferred compounds of formula I include those wherein R₂A group of formula (Ia) wherein the dotted line in formula (Ia) represents a single bond, R₃And R₄Is cis.

Other preferred compounds of formula I include those wherein R is cyclohexyl, cyclopentyl, methylenecyclopropyl, isopropyl, phenyl, or 4-fluorophenyl.

Other preferred compounds of formula I include those wherein R₁Is C which may be substituted by up to three fluorine atoms₁-C₂Alkyl compounds, more preferably, R₁Is ethyl.

Other preferred compounds of formula I include those wherein R₂A group of formula (Ia) wherein the dotted line in formula (Ia) represents a single bond.

Other preferred compounds of formula I include those wherein R₂A group of formula (Ia) wherein the dotted line in formula (Ia) represents a single bond, R₃Is cyano.

Other preferred compounds of formula I include those wherein R₂A group of formula (Ia) wherein the dotted line in formula (Ia) represents a single bond, m is 0, R₅Is hydrogen.

Other preferred compounds of formula I include those wherein R₂A group of formula (Ia) wherein the dotted line in formula (Ia) represents a single bond, R₄Is carboxy, -CH₂OH or-CH₂C(O)NH₂。

Preferred compounds of formulae X, XIV and XIX include those wherein R₁Is ethyl.

Other preferred compounds of formulae X and XIX include those wherein R is cyclohexyl, cyclopentyl, methylenecyclopropyl, isopropyl, phenyl, or 4-fluorophenyl. Particularly preferred compounds include:

1- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) -4-oxo-cyclohexanecarbonitrile;

trans-4-cyano-4- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) -cyclohexanecarboxylic acid methyl ester;

cis-4-cyano-4- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) -cyclohexanecarboxylic acid methyl ester;

1- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) -4-oxo-cyclohexanecarbonitrile;

cis-4-cyano-4- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) -cyclohexanecarboxylic acid methyl ester;

trans-4-cyano-4- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) -cyclohexanecarboxylic acid methyl ester;

cis-4-cyano-4- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) -cyclohexanecarboxylic acid;

trans-4-cyano-4- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) -cyclohexanecarboxylic acid;

1- (cyclohexyl-3-ethyl-1H-indazol-6-yl) -cis-4-hydroxymethylcyclohexanecarbonitrile;

cis-4-cyano-4- (1- (cyclohexyl-3-ethyl) -1H-indazol-6-yl) -cyclohexanecarboxamide; and

trans-4-cyano-4- (1- (cyclohexyl-3-ethyl) -1H-indazol-6-yl) -cyclohexanecarboxamide.

The term "pharmaceutically acceptable salts" as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula I. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of carboxylates, and hydrochlorides of amino groups. Other pharmaceutically acceptable salts of amino groups are hydrobromide, sulphate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulphonate and p-toluenesulphonate.

Certain compounds of formula I may have asymmetric centers and thus exist in different enantiomeric configurations. All optical isomers and stereoisomers of the compounds of formula I and mixtures thereof are considered to be within the scope of the present invention. For compounds of formula I, the invention includes the use of racemates, single enantiomeric configurations, single diastereomeric configurations or mixtures thereof. The compounds of formula I may also exist in tautomeric forms. The present invention relates to the use of all these tautomers and mixtures thereof.

The invention further relates to a pharmaceutical composition for inhibiting Phosphodiesterase (PDE) type IV or producing Tumor Necrosis Factor (TNF) in a mammal, comprising a pharmaceutically effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The invention further relates to a method for inhibiting Phosphodiesterase (PDE) type IV or producing Tumor Necrosis Factor (TNF) by administering to a patient an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof.

The present invention further relates to a pharmaceutical composition for the prevention or treatment of asthma, arthritis, rheumatoid arthritis, gouty arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions in a mammal; sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammation, silicosis, lung sarcoma, bone resorption disease, reperfusion injury, graft-versus-host reaction, allograft rejection, fever and myalgia due to infection (e.g., bacterial, viral or fungal infection), cachexia secondary to influenza, infection or malignancy, cachexia secondary to Acquired Immune Deficiency Syndrome (AIDS), AIDS, HIV, ARC (AIDS-related complex), keloid formation, scar tissue formation, Crohn's disease (Crohn's disease), ulcerative colitis, pyresis, multiple sclerosis, type I diabetes, autoimmune diabetes, systemic lupus erythematosus, bronchitis, chronic obstructive airway disease, psoriasis, Bechet's disease, Henoch's disease, chronic glomerulonephritis, intestinal inflammation, leukaemia, allergic rhinitis or dermatitis, which comprises a pharmaceutically effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The invention further relates to a method of treating or preventing the above mentioned diseases or conditions by administering to a patient an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof.

Within the scope of formula I, certain "aminal" -like "or" acetal-like "chemical structuresThe structure may be unstable. Such a structure may result when two heteroatoms are attached to the same carbon atom. For example, if R is C substituted by hydroxy₁-C₆Alkyl, the hydroxyl group may be attached to the same carbon atom as the nitrogen atom from which R extends. It is to be understood that compounds which are unstable as such are not within the scope of the present invention.

Detailed description of the invention

The following reaction schemes 1-4 illustrate the preparation of the compounds of the present invention. R and R in these schemes are unless otherwise indicated₁The definition is the same as above.

Scheme 1 Flow 1 (continue) Scheme 2 Scheme 3 Flow 3 (continue) Flow 3 (continue) Scheme 4

The preparation of compounds of formula I can be carried out by those skilled in the art following one or more of the synthetic procedures outlined in schemes 1-4 above, and with reference to the following examples. In step 1 of scheme 1, the carboxylic acid of formula II may be obtained from known commercial sources or may be prepared according to methods well known to those skilled in the art, and subjected to standard nitration conditions (HNO)₃/H₂SO₄Nitration at 0 ℃ C. and the nitro derivative of formula III obtained in step 2 of scheme 1, by standard hydrogenation (H under pressure) at room temperature (20-25 ℃ C.)₂-Pd/C) for several hours (2-10 hours) to obtain the compound of formula IV. In step 3 of scheme 1, aminobenzoic acid of formula IV is reacted with a base, such as sodium carbonate, under aqueous conditions and heated slightly until most is dissolved. The reaction mixture was cooled to a lower temperature (about 0 ℃) and treated with aqueous sodium nitrate solution. After about 15 minutes, the reaction mixture is slowly transferred to a suitable vessel containing crushed ice and a strong acid, such as hydrochloric acid. The reaction mixture is stirred for 10-20 minutes and then added to a solution of excess tert-butylmercaptan in an aprotic solvent, such as ethanol, at room temperature. By addition of an inorganic base, preferably saturated Na₂CO₃Aqueous solution, the reaction mixture is acidified to pH 4-5 and the reaction mixture is stirred at room temperature for 1-3 hours. Brine was added to the reaction mixture, which was then filtered to give the thioether of formula V.

In step 4 of scheme 1, a thioether of formula V is reacted with a strong base, preferably potassium tert-butoxide, in dimethyl sulfoxide (DMSO) at room temperature to convert the thioether of formula V to the corresponding indazole carboxylic acid of formula VI. After stirring for several hours (1-4 hours), the reaction mixture is acidified with a strong acid, such as hydrochloric acid or sulfuric acid, and then extracted by conventional methods. In step 5 of scheme 1, the indazole carboxylic acid of formula VI is converted to the corresponding ester of formula VII according to conventional methods well known to those skilled in the art. In step 6 of scheme 1, the ester of formula VII is subjected to conventional alkylation conditions (strong base/various alkylating agents and optionally a copper catalyst such as CuBr) in a polar aprotic solvent such as Tetrahydrofuran (TNF), N-methylpyrrolidinone, or Dimethylformamide (DMF) at room temperature or elevated temperature (25-200 deg.C)₂) Alkylation of the ester to give the compound of formula VIII is carried out for about 6 to 24 hours, preferably about 12 hours. In step 7 of scheme 1, the compound of formula VIII is converted to the corresponding alcohol of formula IX according to the following conventional procedures for reducing esters to alcohols well known to those skilled in the art. Preferably, the reduction is carried out at low temperature (about 0 ℃) in a polar aprotic solvent with a metal hydride reducing agent, such as lithium aluminum hydride. In step 8 of scheme 1, the formula (II a) is prepared according to conventional methods well known to those skilled in the artThe alcohol of IX is oxidized to the corresponding aldehyde of formula X. For example, the oxidation can be carried out in an anhydrous solvent, preferably dichloromethane, with a catalytic amount of tetrapropylammonium perruthenate and an excess of N-methylmorpholine-N-oxide, as described in british chemical society, communications chemistry, 1625 (1987).

Scheme 2 provides an alternative method for preparing aldehydes of formula X. In step 1 of scheme 2, the compound of formula XI is nitrated using conventional nitration conditions (nitric and sulfuric acids) to provide the compound of formula XII. In step 2 of scheme 2, the nitro derivative of formula XII is reduced to the corresponding amine of formula XIII according to conventional methods well known to those skilled in the art. Preferably, the compound of formula XII is reduced to the amine of formula XIII with anhydrous stannous chloride in an anhydrous aprotic solvent, such as ethanol. In step 3 of scheme 2, the corresponding diazonium fluoroacid (fluoroforms) salt is prepared as described in A.roe Organic reactions (organics reactions) volume 5, Wiley, New York, Inc. 1949, pp.198-206, and then phase transfer catalyzed cyclization is carried out as described in R.A. Bartsch and I.W. Yang journal of heterocyclic chemistry (J.het.chem.) 21, 1063(1984) to convert the amine of formula XIII to the corresponding indazole of formula XIV. In step 4 of scheme 2, the alkylation of the compound of formula XIV is carried out using standard procedures known to those skilled in the art (i.e., strong base, polar aprotic solvent, and alkyl halide) to provide an N-alkylated compound of formula XV. In step 5 of scheme 2, the metal halide metathesis reaction of formula XV compound is carried out with alkyllithium, such as n-butyllithium, in a polar aprotic solvent, such as THF, at low temperature (-50 ℃ to-100 ℃ (preferably-78 ℃), followed by completion of the reaction with DMF at low temperature and then warming to room temperature to give the aldehyde compound of formula X.

Scheme 3 illustrates a method for preparing a compound of formula XXII, i.e. wherein R₂A compound of formula I which is a cyclic moiety of formula (Ia). In step 1 of scheme 3, the aldehyde moiety of the compound of formula X is converted to an appropriate leaving group, such as halogen, mesylate, or other leaving group familiar to those skilled in the art, and the resulting compound is then reacted with sodium cyanate in a polar solvent, such as DMF, to provide the compound of formula XVI. In scheme 3In step 2, the compound of formula XVI is reacted with methyl acrylate (or related derivative, due to the addition of R) in an aprotic solvent, such as ethylene glycol dimethyl ether (DME), at elevated temperature, preferably at reflux temperature₂Group i) under basic conditions to give compounds of formula XVII. In step 3 of scheme 3, a compound of formula XVII is converted to a compound of formula XVIII using a strong base, such as sodium hydride, and a polar aprotic solvent, such as DMF or THF, at elevated temperature, preferably at reflux temperature.

In step 4 of scheme 3, the compound of formula XVIII is decarboxylated by conventional methods, e.g., with sodium chloride in DMSO at a temperature of about 140 ℃ to provide the compound of formula XIX. In step 5 of scheme 3, the compound of formula XIX is derivatized to the corresponding dithian-2-ylidenecyclohexanecarbonitrile of formula XX by reaction with 2-lithium-1, 3-dithiane. In step 6 of scheme 3, the compound of formula XX is converted to the corresponding ester of formula XXI using mercuric (II) chloride and perchloric acid in a polar aprotic solvent, such as methanol. In step 7 of scheme 3, a compound of formula XXI is converted to the corresponding carboxylic acid of formula XXII by hydrolysis using standard hydrolysis methods, such as aqueous sodium hydroxide in a polar solvent, or as described in T.Green and P.G.M.Wets, Protecting Groups in Organic synthesis, 2 nd edition, John Wiley and Sons publishing company (1991), New York, using any of a number of well known hydrolysis methods well known to those skilled in the art. The synthetic procedure described in scheme 3 is similar to that provided in PCT published applications WO 93/19751 and WO 93/17949 for the preparation of the corresponding catechol-containing compounds.

Wherein R is₂Other compounds of formula I selected from moieties (Ia), (Ib), (Ic) and (Id) may be prepared from one or more of the intermediate compounds described in schemes I-III. In particular, aldehydes of the formula X or ketone compounds of the formula XIX can be used for preparing various compounds of the formula I. The corresponding non-indazole analogs provided in PCT published applications WO 93/19748, WO 93/19749, WO 93/09751, WO 93/19720, WO93/19750, WO 95/03794, WO95/09623, WO 95/09624, WO 95/09627, WO 95/09836 and WO 95/09837 can be used in the synthesis ofMixing R of any different formulae (Ia), (Ib), (Ic) and (Id)₂Partially introduced into one or more of the intermediate compounds mentioned above. For example, for step 1 of scheme 4, a carboxylic acid of formula XXII can be converted to an alcohol of formula XXIII by reduction of the carboxylic acid with various metal hydrides in a polar solvent as described in example 9 below, following the synthesis of the corresponding non-indazole analogs provided in PCT published applications WO 93/19747, WO 93/19749, and WO 95/09836. Further, for step 2 of scheme 4, a carboxylic acid of formula XXII can be converted to the corresponding carboxamide of formula XXIV by converting the carboxylic acid of formula XXII to an acid chloride intermediate using conventional synthetic methods and then reacting the acid chloride with ammonia in an aprotic solvent. Other carboxamide analogs of formula XXIV can be prepared by reacting the acid chloride intermediate with various primary or secondary amines according to conventional methods well known to those skilled in the art, as described in the above-mentioned PCT published application.

Other compounds of formula I can be prepared from intermediate compounds of formula XIX according to the synthetic methods for the corresponding non-indazole analogs provided in the above-mentioned PCT published applications. Compounds of formula I, wherein R is R, can be prepared from keto intermediates of formula XIX by reaction with a base such as lithium diisopropylamide in a polar aprotic solvent such as THF and excess N-phenyltrifluoromethanesulfonamide as described in PCT published application WO 93/19749₂Is a moiety of formula (Ia)₄And R₅One is H. Compounds of formula I can be prepared from keto intermediates of formula XIX, wherein R is₂Is a moiety of the formula Ia, R₄Is hydrogen, R₅is-CO₂CH₃or-CO₂H: by reaction with triflic anhydride in the presence of a tertiary amine base, and by reaction of the resulting triflate with (triphenylphosphine) palladium and carbon monoxide in the presence of an alcohol or amine, to give the methyl ester compound of the formula I, in which R is₅is-CO₂CH₃(ii) a Hydrolysis of the methyl ester compound using standard hydrolysis methods, such as with sodium or potassium hydroxide in aqueous methanol/tetrahydrofuran, affords the corresponding carboxylic acid compound. The synthetic methods of the corresponding non-indazole analogs of PCT published application WO 93/19749 further describeSuch a synthesis method.

Other compounds of formula I can be prepared from intermediate compounds of formula XIX according to the methods for the synthesis of the corresponding non-indazole analogs of the above-disclosed PCT applications. Compounds of formula I wherein R is R may be prepared by reaction of an intermediate of formula XIX with a suitable reducing agent such as lithium borohydride, dipentyl borane, lithium tris (t-butoxy) aluminum or sodium borohydride in a suitable non-reactive solvent such as 1, 2-dimethoxyethane, THF or ethanol₂Is a moiety of formula (Ia)₅Is hydrogen, R₄Is a hydroxyl group. Compounds of formula I wherein R is prepared by reacting an intermediate of formula XIX with an ammonium salt, such as ammonium formate, methylamine hydrochloride or dimethylamine hydrochloride, in the presence of sodium cyanoborohydride in a suitable solvent, such as ethanol, can be prepared₂Is a moiety of formula (Ia)₅Is hydrogen, R₄is-NH₂、-NHCH₃or-N (CH)₃)₂。

Alternatively, the corresponding alcohol of formula I (R) is reacted in the presence of an imide or phthalimide₄＝OH，R₅H) with an azadicarboxylate complex and then in an alcoholic solvent, such as ethanol, to produce a compound of formula I, wherein R is₂Is a moiety of the formula Ia, R₄Is amino, R₅Is hydrogen. In a suitable aprotic solvent, reacting R therein₄Metal salts of the corresponding compounds with thiols, e.g. NaSR, as leaving groups, e.g. mesylate, tosylate, bromide or chloride₁₄Reaction to produce a compound of formula I, wherein R₂Is a moiety of formula (Ia)₅Is H, R₄is-SR₁₄. In the presence of thiolacetic acid, reacting the corresponding alcohol (R)₄Where OH) with phosphines, e.g. complexes of triphenylphosphine with nitrilocarboxylic acid esters, and subsequent hydrolysis of the resulting thioglycolates, the corresponding compounds of the formula I can be obtained, where R is₄is-SH. Furthermore, R can be converted to R by standard alcohol conversion methods well known to those skilled in the art₄Compounds of such a structure that are hydroxyl groups interconvert. By one or more of the synthetic methods of the corresponding non-indazole analogs of PCT published applications WO 93/19751 and WO 93/19749, wherein R is₂Is a moiety of formula (Ia), R₅Is hydrogen and R₄Is hydroxy, -SH or-NH₂The above compounds of formula I may be converted into various other compounds of formula I.

Compounds of formula I, wherein R is R, can be prepared from intermediates of formula XIX according to one or more of the syntheses of the corresponding non-indazole analogs provided in PCT published application WO 93/19720₂The dotted line represents a double bond for the moiety of formula (Ia). Compounds of formula I, wherein R is R, can be prepared from the corresponding ketone intermediates of formula XIX according to one or more of the synthetic methods for the preparation of the corresponding non-indazole analogs provided in PCT published application WO93/19750₂Is a moiety of formula (Ia)₄And R₅Together form ═ O or ═ R₈Wherein R is₈The definition is the same as above. Other compounds of formula I, wherein R is R, can be prepared from intermediates of formula XIX according to one or more of the syntheses of the corresponding non-indazole analogs provided in PCT published application WO 93/19748₂Is a moiety of formula (Ia)₄And R₅Together form ═ R₈。

Compounds of formula I, wherein R is R, can be prepared from one or more of the above intermediates, a bromoindazole intermediate of formula XV, according to one or more of the synthetic methods of the corresponding non-indazole analogs provided in PCT published applications WO 95/09627, WO 95/09624, WO95/09623, WO 95/09836 and WO 95/03794, wherein R is₂Is a moiety of formula (Ib). Compounds of formula I, wherein R is R, can be prepared from intermediates of formula XV according to one or more of the synthetic methods of the corresponding non-indazole analogs provided in PCT published applications WO 95/09624 and WO 95/09837₂Is a moiety of formula (Ic). Compounds of formula I, wherein R is R, can be prepared from bromo indazole intermediates of formula XV according to one or more of the synthetic methods for the preparation of the corresponding catechol-containing analogs provided in PCT published applications WO 95/09627, WO95/09623 and WO 95/09624₂Are moieties of formula (Id).

Pharmaceutically acceptable acid addition salts of the compounds of the present invention include, but are not limited to, those with HCl, HBr, HNO₃、H₂SO₄、H₃PO₄、CH₃SO₃H、p-CH₃C₆H₄SO₃H、CH₃CO₂H. Gluconic acid, tartaric acid, maleic acid and succinic acid. In the invention, for example, R₃Is CO₂R₉、R₉Pharmaceutically acceptable cationic salts of compounds of formula I that are hydrogen include, but are not limited to, salts of sodium, potassium, calcium, magnesium, ammonium, N' -dibenzylethylenediamine, N-methylglucamine (meglumine), ethanolamine, trimethylamine, and diethanolamine.

When administered to humans for the treatment or prevention of inflammation, the oral dosage of a compound of formula I or a pharmaceutically acceptable salt thereof (the active compound) is generally in the range of 0.1-1000mg per day for an average adult patient (70 kg). Each tablet or capsule will generally contain from 0.1 to 100mg of the active compound in a suitable pharmaceutically acceptable excipient or carrier. The intravenous dose is generally in the range of 0.1 to 10mg per single dose as required. For intranasal or inhalational administration, the dosage is generally formulated as a 0.1 to 1% (w/v) solution. Conventionally, the physician will determine the actual dosage which will be most suitable for each individual patient, which will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the general case, although in practice, slightly higher or lower dosage ranges will be acceptable, and all such dosages are within the scope of the invention.

In the administration to a human to inhibit TNF, a variety of conventional routes of administration may be employed, including oral, parenteral, topical and rectal (suppositories). In general, the daily oral or parenteral dose of the active compound is between about 0.1 and 25mg/kg of the subject's body weight, preferably about 0.3 to 5 mg/kg. However, depending on the physical condition of the subject, it may be necessary to adjust the dose appropriately. In any event, the person responsible for administration will determine the appropriate dosage for a particular subject.

For use in humans, the active compounds of the present invention may be administered alone, but will generally be administered in admixture with a pharmaceutical diluent or carrier selected with due consideration of the route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules, alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They can be injected parenterally; for example, intravenous, intramuscular or subcutaneous injection. For parenteral administration, they are best used in the form of sterile aqueous solutions which may contain other substances; for example, contains sufficient salt or glucose to render the solution isotonic.

In addition, in the treatment of skin inflammation, the active compounds can be administered topically, according to standard pharmaceutical practice, with the aid of creams, jellies, gels, pastes and ointments.

The active compounds may also be administered to mammals other than humans. The dosage administered to a mammal will depend on the species of animal and the disease or condition being treated. The active compounds can be administered to the animal in the form of capsules, pellets, tablets or liquid drenches. The active compounds can also be administered to the animal by injection or as an implant. These formulations are prepared in a conventional manner according to standard veterinary practice. Alternatively, the compound may be administered with animal feed, for which purpose a concentrated feed additive or premix may be prepared for mixing with normal animal feed.

The ability of a compound of formula I or a pharmaceutically-acceptable salt thereof to inhibit PDE IV can be determined by the following assay.

Thirty to forty grams of human lung tissue was placed in 50ml Tris/phenylmethylsulfonyl chloride (PMSF)/sucrose buffer pH 7.4 using a Tekmar Tissumizer^(Tekmar, Kemper road 7143, Cincinnati, Ohio 45249) for 30 seconds at full speed. The homogenized product was centrifuged at 48000Xg for 70 minutes at 4 ℃. The supernatant was filtered twice through a 0.22 μm filter and loaded onto a mono-Q FPLC column (Pharmacia LKB Biotechnology, centre Dart 800, Piscataway, N.J. 08854) previously run at pH 7.4, Tris/PMSF buffer equilibration. The sample was first run through the column at a flow rate of 1 ml/min, followed by washing and elution at a flow rate of 2 ml/min. The samples were eluted using a stepwise increasing NaCl gradient in Tris/PMSF buffer at pH 7.4. Fractions of 8ml were collected. Assaying these fractions for specific PDEs_IVThe activity is measured by³H]Hydrolysis of cAMP and the known PDE_IVInhibitors (e.g., cyclopentyloxymethoxyphenylpyrrolidone) inhibit the ability of the hydrolysis reaction. The appropriate fractions were pooled, diluted with ethylene glycol (2ml ethylene glycol/5 ml enzyme preparation) and stored at-20 ℃ before use.

Compounds were dissolved in dimethyl sulfoxide (DMSO) at a concentration of 10mM and diluted 1: 25 with water (400. mu.M compound, 4% DMSO). A further series of dilutions was made in 4% DMSO to give the desired concentration. The final DMSO concentration in the tube was 1%. The following reagents were added in duplicate to a 12X 75mm glass tube in order (all concentrations are given as the final concentration in the tube).

i)25 μ l of compound or DMSO (1%, for controls and blanks)

ii) 25. mu.l of Tris buffer pH 7.5

iii)[³H]cAMP(1μM)

IV) 25. mu.l of PDE IV enzyme (for blanks, enzymes were thermostated in boiling water for 5 minutes in advance)

The reaction tube was shaken and then placed in a water bath (37 ℃) for 30 minutes, and the reaction was terminated by placing the tube in a boiling water bath for 4 minutes. Wash buffer (0.5ml, 0.1M 4- (2-hydroxyethyl) -1-piperazine-ethanesulfonic acid (HEPES)/0.1M naci, pH 8.5) was added to each tube on an ice bath. The contents of each tube were added to an AFF-Gel 601 column (Biorad laboratories, post office 1229, 85A Marcus Drive, Melville, N.Y. 11741) (borate affinity Gel, bed volume 1ml) which was previously equilibrated with wash buffer. [³H]The cAMP is washed with 2X 6ml of a washing buffer solution³H]The 5' AMP was eluted with 4ml of 0.25M acetic acid. After vortexing, add to 3ml scintillation fluid in a suitable vialAdding 1ml of the eluent, vortexing and counting³H]。IC₅₀Defined as inhibition of 50%³H]The cAMP is specifically hydrolyzed into³H]Compound concentration of 5' AMP.

The ability of compound I or a pharmaceutically acceptable salt thereof to inhibit the production of TNF and thereby demonstrate their efficacy in the treatment of diseases involving TNF production is demonstrated by the following in vitro assays:

peripheral blood (100ml) from human volunteers was collected in ethylenediaminetetraacetic acid (EDTA). Mononuclear cells were isolated with FICOLL/3, 5-diacetamido-2, 4, 6-triiodosodium benzoate (FICOLL/Hypaque) and washed three times in incomplete HBSS. The cells were resuspended in preheated RPMI (containing 5% FCS, glutamine, pen/step and nystatin) to a final concentration of 1X 10⁶Each cell per ml. Monocytes were plated at 1X 10 in 1.0ml⁶The cells were placed in a tray in a 24-well basin. The cells were incubated at 37 deg.C (5% carbon dioxide) and allowed to attach to the dish for 2 hours, after which the non-attached cells were removed by gentle washing. Test compounds (10. mu.l) were then added to the cells, each at 3-4 concentrations, and the temperature was maintained for 1 hour. LPS (10. mu.l) was added to the appropriate wells. The plates were kept at 37 ℃ overnight (18 hours). At the end of the incubation period, a sandwich ELISA (R) was used&D Quantikine kit) for TNF analysis. IC was performed for each compound based on linear regression analysis₅₀And (4) measuring.

The following examples further illustrate the invention. In the following examples, "DMF" refers to dimethylformamide, "THF" refers to tetrahydrofuran, "DMSO" refers to dimethyl sulfoxide, and "DMAP" refers to 4-dimethylaminopyridine.

Example 1

A.3-nitro-4-propylbenzoic acid

A9.44 g (57.5mmol, 1.0 eq) portion of 4-propylbenzoic acid was dissolved in 50ml of concentrated H₂SO₄And cooled in an ice bath. 4.7ml (74.7mmol, 1.3 equivalents) of concentrated HNO are added dropwise over a period of 1-2 minutes₃In 10ml of concentrated H₂SO₄The solution of (1). After stirring at 0 ℃ for 1 hour, the reaction mixture was poured into a 1L beaker half-filled with ice. After stirring for 10 minutes, the white solid formed is filtered off and washed with H₂O washing 1 time and drying to obtain 12.01g (100%) of the target compound: mp 106-; IR (KBr)3200-3400, 2966, 2875, 2667, 2554, 1706, 1618, 1537, 1299, 921cm^-1；¹H NMR(300MHz，DMSO-d₆)δ0.90(t，3H，J＝7.4Hz)，1.59(m，2H).2.82(m，2H)，7.63(d，1H，J＝8.0Hz)，8.12(dd，1H.J＝1.7，8.0Hz)，8.33(d，1H，J＝1.7Hz)；¹³C NMR(75.5MHz，DMSO-d₆)δ14.2，23.7，34.2，125.4，130.5，132.9，133.6，141.4，149.5，165.9；C₁₀H₁₁NO₄·1/4H₂Calculated value of O: c, 56.20; h, 5.42; n, 6.55. found: c, 56.12; h, 5.31; and N, 6.81.

B.3-amino-4-propylbenzoic acid

11.96g (57.2mmol) of 3-nitro-4-propylbenzoic acid are mixed with 1.5g of 10% Pd/C moistened with 50% water in 250ml of CH at room temperature₃The mixture in OH was placed on a Parr hydrogenation apparatus at 25psi H₂Shaking the mixture. After 1 hour, the reaction mixture was filtered through celite, and the filtrate was concentrated and dried to give 9.80g (96%) of a light yellow crystalline solid: mp 139.5-142.5 ℃; IR (Kbr)3200, 3369, 3298, 2969, 2874, 2588, 1690, 1426, 916, 864cm^-1；¹H NMR(300Mhz，DMSO-d₆)δ0.90(t，3H，J＝7.2Hz)，1.52(m，2H)，2.42(m，2H)，5.08(br s，2H)，6.96(d，1H，J＝7.8Hz)，7.05(dd，1H，J＝1.7，7.8Hz)，7.20(d，1H，J＝1.7Hz)；MS(Cl，NH₃)m/z 180(M+H⁺Base peak); c₁₀H₁₃NO₂·1/3H₂Calculated value of O: c, 64: 85 parts by weight; n, 7.89; n, 7.56 found: c, 64.69; h, 7.49; and N, 7.86.

C.3-carboxy-6-propylbenzenediazotert-butyl sulfide

8.80g (49.1mmol, 1.0 eq) of 3-amino-4-propylbenzoic acid with 2.34g (22.1mmol, 0.45 eq) of sodium carbonate in 55ml of H are heated slowly with an air heating gun₂Mixture in O until most was dissolved. The reaction mixture was cooled in an ice bath and 3.73g (54.0mmol, 1.0 eq) of sodium nitrite in 27ml of H were added dropwise₂Solution in O. After 15 minutes, the reaction mixture was transferred to a dropping funnel and added over 10 minutes to a beaker containing 55g of crushed ice and 10.6ml of concentrated HCl. After stirring for 10 min, the contents of the beaker were transferred to a dropping funnel and added over 5 min to a room temperature solution of 5.31ml (47.1mmol, 0.96 eq.) of tert-butylmercaptan in 130ml of ethanol. Adding saturated Na₂CO₃The pH of the aqueous solution was adjusted to 4-5 and the reaction mixture was stirred at room temperature for 1 hour. 200ml of brine were added and the mixture was filtered. 1 XH for solid₂O wash and dry overnight to give 12.25g (89%) brown/rust colored powder (note-malodor): mp 102 ℃ (dec); IR (KBr)3200-^-1；¹H NMR(300MHz，DMSO-d₆) δ 0.84(t, 3H, J ═ 7.3Hz), 1.48(m, 2H), 1.55(s, 9H), 2.42(m, 2H), 7.29(d, 1H, J ═ 1.6Hz), 750 (d, 1H, J ═ 8.0Hz), 7.86(dd, 1H, J ═ 1.7, 7.9Hz), 13.18(br s, 1H); MS (thermal spraying, NH)₄OAc) M/z 281(M + H +, base); c₁₄H₂CN₂O₂S calculated value: c, 59.96; h, 7.19; n, 9.99 found: c, 59.71; h, 7.32; n, 10.02

3-ethyl-1H-indazole-6-carboxylic acid

To a room temperature solution of 44.6g (398mmol, 9.3 equivalents) of potassium tert-butoxide in 200ml of DMSO, a solution of 12.0g (42.8mmol, 1.0 equivalent) of 3-carboxy-6-propylbenzenediazo tert-butyl sulfide in 150ml of DMSO is added dropwise over 15 minutes. After stirring at room temperature for 2 hours, the reaction mixture was poured into 1.5L of 1N HCl at 0 ℃ and stirred for 5 minutes, then extracted with 2X 350ml of ethyl acetate. The ethyl acetate extracts (note-foul) were combined and washed with 2X 250ml H₂O washing over MgSO₄Drying. Filtering, concentrating the filtrate, drying to obtain a brown solid, adding 1L of 1: 3 Et₂Trituration with O/hexane and drying gave 7.08g (87%) of a brown crystalline powder: mp248-251 ℃; IR (KBr)3301, 3300-2400, 2973, 2504, 1702, 1455, 1401, 1219cm^-1；¹H NMR(300MHz，DMSO-d₆)δ1.31(1，3H，J＝7.6Hz)，2.94(q，2H，J＝7.6Hz)，7.63(dd，1H，J＝1.1，8.4Hz)，7.81(d，1H，J＝8.4Hz)，8.06(d，1H，J＝1.1Hz)12.95(br s，1H)；MS(Cl，NH₃) M/z 191(M + H +, base); c₁₀H₁₀N₂O₂Calculated values: c, 63.14; h, 5.30; n, 14.73. found: c, 62.66; h, 5.42; n, 14.80.

E.3-Ethyl-1H-indazole-6-carboxylic acid methyl ester

To a solution of 7.92g (41.6mmol, 1.0 eq) of 3-ethyl-1H-indazole-6-carboxylic acid, 16.9ml (416mmol, 10 eq) of methanol and 5.59g (45.8mmol, 1.1 eq) of DMAP in 250ml of CH₂Cl₂To the room temperature solution in (1.1 equiv) was added 8.78g (45.8 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in one portion. After 18 hours of reaction at room temperature, the reaction mixture was concentrated to 150ml, diluted with 500ml of ethyl acetate, diluted with 2X 100ml of 1N HCl, 1X 100ml of H₂O, 1X 100ml brine, Na₂SO₄And (5) drying. Filtration, concentration of the filtrate, and drying gave 7.8g of a brown solid which was purified on a silica gel column (30% to 50% ethyl acetate/hexane gradient elution) to give 6.41g (75%) of a brown solid: mp107-108 ℃; IR (KBr)3100-2950, 1723, 1222cm^-1；¹H NMR(300MHz，CDCl₃)δ8.19(m，1H)，7.7-7.8(m，2H)，3.96(s，3H)，3.05(q，2H，J＝7.7Hz)，1.43(t，3H，7.7Hz)；MS(Cl，NH₃)m/z 205(M+H⁺Base peak); c₁₁H₁₂N₂O₂Calculated values: c, 64.70; h, 5.92; n, 13.72. found: c, 64.88; h, 6.01; and N, 13.96.

F1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid methyl ester

To 5.7g (27.9mmol, 1.0 mm)Amount) 3-Ethyl-1H-indazole-6-carboxylic acid methyl ester to a room temperature solution in 125ml anhydrous DMF 1.17g (29.4mmol, 1.05 equiv) of sodium hydride in a 60% oil dispersion was added all at once. After 20 min, 3.89ml (36.6mmol, 1.3 eq) of cyclopentyl bromide were added dropwise and the reaction mixture was stirred at room temperature overnight. The mixture was then poured into 1L H₂In O, extracted with 3X 450ml of ethyl acetate. The organic extracts were combined and washed with 3X 400ml H₂O, 1X 200ml brine, Na₂SO₄And (5) drying. Filtration, concentration of the filtrate and drying gave an amber oil which was purified on a silica gel column (10% ethyl acetate/hexane, wt.%) to give 5.48g (72%) of a clear oil:¹H NMR(300MHz，CDCl₃) δ 8.16(d, 1H, J ═ 1.0Hz), 7.7(m, 2H), 5.00 (quintuple, 1H, J ═ 7.5Hz), 3.97(s, 3H), 3.01(q, 2H, J ═ 7.6Hz), 2.2(m, 4H), 2.0(m, 2H), 1.8(m, 2H), 1.39(t, 3H, J ═ 7.6 Hz); c₁₆H₂₀N₂O₂HRMS calculated of (a): 272.1526. measured value: 272.15078.

g (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) methanol

To a 0 ℃ solution of 1.02g (7.05mmol, 1.0 equiv) of methyl 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylate in 50ml of THF was added 7ml (7.0mmol, 1.0 equiv) of a 1.0M solution of lithium aluminum hydride in THF. After 20 minutes, 1ml of methanol was carefully added and the reaction mixture was poured into 500ml of 5% H₂SO₄Of (5), extracted with 3X 50ml of ethyl acetate. The organic extracts were combined and washed with 2X 40ml H₂O, 1X 40ml brine, Na₂SO₄And (5) drying. Filtration, concentration of the filtrate, and drying gave 1.58g of a clear oil which was purified on a silica gel column to give 1.539 (89%) of a clear oil: IR (CHCl)₃)3606，3411，3009，2972，2875，1621，1490cm^-1；¹H NMR(300Mhz，CDCl₃) δ 7.65(d, 1H, J ═ 8.0Hz), 7.42(s, 1H), 7.05(dd, 1H, J ═ 1.0, 8.2Hz), 4.92 (quintuple, 1H, J ═ 7.7Hz), 4.84(s, 2H), 2.98(q, 2H, J ═ 7.6Hz), 2.2(m, 4H), 2.0(m, 2H), 1.7(m, 3H), 1.38(t, 3H, J ═ 7.6 Hz); MS (thermal spraying, NH)₄OAc)m/z 245(M+H⁺Base peak); c₁₅H₂₀N₂HRMS calcd for O + H: 245, 1654. found: 245, 1675.

1-cyclopentyl-3-ethyl-1H-indazole-6-carbaldehyde (carbaldehyde)

To a solution of 1.47g (6.02mmol, 1.0 eq) of (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) methanol, 1.06g (9.03mmol, 1.5 eq) of N-methylmorpholine N-oxide and 3.01g of 4A molecular sieve in 12ml of anhydrous CH₂Cl₂106mg (0.301mmol, 0.05 eq) of tetrapropylammonium perruthenate (VII) are added to the room-temperature suspension. After 30 minutes, the reaction mixture was filtered through a short column of silica gel (with CH)₂Cl₂Elution). The product containing fractions were concentrated and the residue chromatographed on a column of silica gel (15% ethyl acetate/hexane, quick) to give 924mg (63%) of a pale yellow solid: mp 41 ℃; IR (KBr)3053, 2966, 2872, 2819 and 1695cm^-1；¹H NMR(300MHz，CDCl₃) δ 10.13(s, 1H), 7.93(d, 1H, J ═ 0.9Hz), 7.77(d, 1H, J ═ 8.4Hz), 7.60(dd, 1H, J ═ 1.2, 8.4Hz), 5.00 (quintuple, 1H, J ═ 7.5Hz), 3.01(q, 2H, J ═ 7.6Hz), 2.2(m, 4H), 2.0(m, 2H), 1.7(m, 2H), 1.39(t, 3H, J ═ 7.5 Hz); MS (Cl, NH)₃)m/z 243(M+H⁺Radical peak) C₁₅H₁₈N₂Calculated value of O: c, 74.35; h, 7.49; n, 11.56 found: c, 74.17; h, 7.58; n, 11.79.

Example 2

A.4-bromo-2-nitro-1-propylbenzene

To 600ml of concentrated H₂SO₄And 200ml of H₂To a 10 ℃ solution of O was added 125g (628mmol, 1.0 eq) of 1-bromo-4-propylbenzene in one portion. 43.2ml (691mmol, 1.1 equiv.) of concentrated HNO are added dropwise over 30 minutes under vigorous mechanical stirring₃(69-71%, 16M) in 150ml of concentrated H₂SO₄With 50ml H₂Room temperature mixture in O. The ice bath was warmed to room temperature and the reaction was stirred at room temperature for 68 hours. The reaction mixture was poured into a bag loosely and completely covered with crushed iceWrapped in 4L beakers. After stirring for 1 hour, the mixture was transferred to a 4L separatory funnel and extracted with 4X 800ml isopropyl ether. The organic extracts were combined and washed with 3X 800ml H₂O, 1X 500ml brine, Na₂SO₄And (5) drying. Filtration, concentration of the filtrate and drying gave 150ml of yellow liquid which was purified by silica gel chromatography (2 columns, 3kg of silica gel each, 2% ethyl acetate/hexane) to give 63.9g (42%) of yellow liquid. The desired isomer is the less polar of the two, and the ratio of the two is 1: 1. bp108 ℃ and 2.0 mm; IR (CHCl)₃)3031，2966，2935，2875，1531，1352cm^-1；¹H NMR(300MHZ，CDCl₃)δ8.01(d，1H，J＝2.1Hz)，7.62(dd，1H，J＝2.1，8.3Hz)，7.23(d，1H，J＝8.3Hz)，2.81(m，2H)，1.67(m，2H)，0.98(t，3H，J＝7.4Hz)；¹³C NMR(75.5MHz，CDCl₃)δ13.94，23.74，34.43，119.6，127.4，133.3，135.7，136.4，149.8；GCMS(EI)m/z 245/243(M⁺) 147 (base peak): c₉H₁₀NO₂HRMS calcd for BR + H: 243.9973. measured value: 243.9954.

b.5-bromo-2-propylaniline

To a solution of 51.9g (213mmol, 1.0 eq) of 4-bromo-2-nitro-1-propylbenzene in 1200ml absolute ethanol and 12ml (6 eq) of H₂To the room temperature solution in O was added 121g (639mmol, 3.0 equiv.) of stannous chloride (anhydrous) in one portion. After 24 hours of reaction at room temperature, the majority of the ethanol was removed in a rotary evaporator. The residue was poured into a 4L beaker, three quarters of which was filled with crushed ice and H₂And O. 150g of NaOH granules were added in portions with stirring until the pH was 10 and most of the tin hydroxide had dissolved. The mixture was split in half and each half was extracted with 2X 750ml ethyl acetate. All four ethyl acetate extracts were combined and washed with 1X 500ml of 1N NaOH, H₂Washed with brine and then H₂SO₄And (5) drying. Filtration, concentration of the filtrate and drying gave a yellow liquid which was purified on a 1.2kg silica gel column (1: 12 ethyl acetate/hexane) to give 41.83g (92%) of a pale yellow liquid:

1R(CHCl₃)3490，3404，3008，2962，2933，2873，1620，1491cm^-1；¹H NMR(300MHz，CDCl₃)δ6.8-6.9(m，3H)，3.90 br s，2H)，2.42(m，2H0，1.62(m，2H)，0.99(t，3H，J＝7.3Hz)；GCMS(EI)m/z 215/213(M⁺) 186/184 (base peak); c₉H₁₂Calculated NBr: c, 50.49; h, 5.65; n, 6.54. found: c, 50.77; h, 5.70; and N, 6.50.

C.6-bromo-3-ethyl-1H-indazole

49.22g (230mmol, 1.0 eq) of 5-bromo-2-propylaniline were placed in a 3L flask and cooled in an ice bath. 57.5ml (690mmol, 3.0 equiv.) of concentrated HCl in 165ml of H are added₂The resulting solid material was ground in O at 0 ℃ until a fine white suspension was obtained. 100ml of H are then added₂O, then 15.9g (230mmol, 1.0 eq) of sodium nitrite in 75ml of H are added dropwise over a period of 10 minutes₂Solution in O. The ice bath was removed and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was then filtered through a sintered glass funnel pre-cooled to 0 ℃. The filtrate was cooled in an ice bath and 32.8g (313mmol, 1.36 eq) of ammonium tetrafluoroborate in 110ml of H were added dropwise over a period of 10 minutes with mechanical stirring₂0 ℃ solution/suspension in O. The resulting thick white suspension (aryldiazonium tetrafluoroborate) was stirred at 0 ℃ for 1.5 hours. The mixture was then filtered and the solid was washed with 1X 200ml of 5% NH₄BF₄Aqueous solution (cooled to 0 ℃ C.), 1X 150ml CH₃OH (cooled to 0 ℃ C.) and Et 1X 200ml further₂And O washing. Drying at room temperature under high vacuum for 1 hour gave 54.47g (76%) of the diazonium salt as an off-white solid.

1500ml of ethanol-free chloroform were placed in a 3L flask, followed by the addition of 34.16g (348mmol, 2.0 equivalents) of potassium acetate (pulverized and dried) and 2.3g (8.7mmol, 0.05 equivalents) of 18-crown-6. After 10 minutes the diazonium salt was added all at once and the reaction mixture was stirred at room temperature under nitrogen for 18 hours. The mixture was then filtered and the solid was taken up in CHCl₃Washing was carried out 2 times and the filtrate was concentrated to give 47g of crude product (brown crystals).Purification by chromatography on silica gel (1.23kg silica gel, 15%, 20%, 40% ethyl acetate/hexane gradient) gave 21.6g (second step 55%, total 42%) of brown crystals: mp 112-; IR (KBr)3205, 3008, 2969, 2925, 1616, 1340, 1037cm^-1；¹H NMR(300MHz，CDCl₃)δ9.86(br s，1H)，7.61(d，1H，J＝1.3Hz)，7.57(d，1H，J＝8.4Hz)，7.24(dd，1H，J＝1.5，8.6Hz)，2.99(q，2H，J＝7.6Hz)，1.41(t，3H，J＝7.6Hz)；MS(Cl，NH₃)m/z 227/225(M+H⁺Base peak); c₉H₉N₂Calculated Bt C, 48.02; h, 4.03; n, 12.45. found: c, 48.08; h, 387; n, 12.45.

D.6-bromo-1-cyclopentyl-3-ethyl-1H-indazole

To a solution of 13.17g (58.5mmol, 1.0 eq) of 6-bromo-3-ethyl-1H-indazole in 500ml of anhydrous DMF at 10 ℃ was added 2.46g (61.4mmol, 1.05 eq) of sodium hydride in 60% oil dispersion per 0.5 g. The mixture was stirred at room temperature for 20 minutes, then a solution of 8.8ml (81.9mmol, 1.4 equivalents) of cyclopentyl bromide in 10ml of anhydrous DMF was added dropwise. After 18 hours, the reaction mixture was poured into 2L H₂In O, extracted with 2X 1L of ethyl acetate. The organic extracts were combined and washed with 2X 750ml H₂O, 1X 500ml brine, Na₂SO₄And (5) drying. Filtration, concentration of the filtrate, and drying gave 20.7g of crude product, which was purified on a silica gel column (1.1kg silica gel, 3% ethyl acetate/hexane) to give 10.6g (62%) of an amber liquid: IR (CHCl)₃)2972，2875，1606，1501，1048cm^-1；¹H NMR(300MHz，CDCl₃) δ 7.56(d, 1H, J ═ 1.3Hz), 7.52(d, 1H, J ═ 8.7Hz), 7.17(dd, 1H, J ═ 1.5, 8.5Hz), 4.83 (quintuple, 1H, J ═ 7.6Hz), 2.95(q, 2H, J ═ 7.6Hz), 2.15(m, 4H), 2.0(m, 2H), 1.65(m, 2H), 1.36(t, 3H, J ═ 7.7 Hz); MS (thermolpray, NH)₄OAc)m/z 295/293(M+H⁺Base peak); c₁₄H₁₇N₂Calculated Br: c, 57.35; h, 5.84; n, 9.55. found: c, 57.48; h, 5.83; and N, 9.90.

E.1-cyclopentyl-3-ethyl-1H-indazole-6-aldehyde

To a solution of 8.32g (28.4mmol, 1.0 eq) of 6-bromo-1-cyclopentyl-3-ethyl-1H-indazole in 200ml of anhydrous THF at-78 ℃ was added 11.6ml (28.4mmol, 1.0 eq) of n-BuLi in 2.45M hexane. After 30 min, 8.8ml (114mmol, 4.0 eq.) of anhydrous DMF was added dropwise at-78 ℃ and the reaction mixture was stirred for a further 30 min at-78 ℃. The mixture was warmed to room temperature over 1 hour and then 125ml 1N HCl was added. After stirring for 10 minutes, most of the THF was removed on a rotary evaporator. The residue is taken up in 500ml of H₂Diluted with O and extracted with 2X 250ml of ethyl acetate. The organic extracts were combined and washed with 1X 100ml H₂O, 1X 100ml brine, Na₂SO₄And (5) drying. Filtration, concentration of the filtrate, and drying gave a yellow oil which was purified on a silica gel column (15% ethyl acetate/hexane, wt. -%) to give 4.70g (68%) of a yellow crystalline solid:¹H NMR(300Hz，CDCl₃) Equivalent spectrum to the compound from example 8.

F (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) acetonitrile

To a room temperature suspension of 5.65g (23.3mmol, 1.0 equiv.) of 1-cyclopentyl-3-ethyl-1H-indazol-6-al-dehyde and 3.84g (44.3mmol, 1.9 equiv.) of lithium bromide in 115ml of anhydrous acetonitrile was added dropwise 4.44ml (35.0mmol, 1.5 equiv.) of trimethylsilyl chloride. After 15 min, the reaction mixture was cooled in an ice bath and 6.84ml (38.7mmol, 1.66 equivalents) of 1, 1, 3, 3-tetramethyldisiloxane were added dropwise, allowing the temperature of the reaction to rise to room temperature over 2 h. The reaction mixture was heated to reflux for 6 hours, then cooled to room temperature and quenched with 300ml CH₂Cl₂Diluting with diatomaceous earth^(Celite^) And (5) filtering. The filtrate was concentrated and dried at room temperature under high vacuum to give 13.08g of a brown oily solid.

The solid was dissolved in 200ml of anhydrous DMF, 259g (52.9mmol, 2.27 eq) of sodium cyanide were added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into 500ml H₂In O, extracted with 3X 200ml of ethyl acetate. Combining the organic extractsUsing 3X 200mlH₂O, 1X 200ml brine, Na₂SO₄And (5) drying. Filtration, concentration of the filtrate, and drying gave a brown oil which was purified on a silica gel column (10% -20% ethyl acetate/hexanes gradient) to give 2.98g of impure product and 2.05g of recovered (impure) starting material.

The recovered product was again subjected to the reaction conditions described above except that 50ml of 1, 1, 3, 3-tetramethyldisiloxane was used, followed by 50ml of DMF and 940mg of sodium cyanide. Silica gel chromatography gave 0.62g of impure product which was then combined with 2.98g of above and purified again by chromatography (10% ethyl acetate/hexane) to give 3.27g (55%) of a yellow oil: IR (CHCl)₃)3062，2972，2874，2255，1623cm^-1；¹H NMR(300MHz，CDCl₃) δ 7.66(d, 1H, J ═ 8.3Hz), 7.39(s, 1H), 6.97(dd, 1H, J ═ 1.1, 8.4Hz), 4.90 (quintuple peak, 1H, J ═ 7.6Hz), 3.89(s, 2H), 2.98(q, 2H, J ═ 7.6Hz), 2.2(m, 4H), 2.0(m, 2H), 1.7(m, 2H), 1.37gt, 3H, J ═ 7.4 Hz); MS (Cl, NH)₃)m/z 254(M+H⁺Base peak); c₁₆H₁₉N₃Calculated values: c, 75.86; h, 7.56; n, 16.59. found: c, 7584; h, 7.94; and N, 16.60.

G.4-cyano-4- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) pimelic acid dimethyl ester

To a room temperature solution of 3.19g (12.6mmol, 1.0 equiv) of (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) acetonitrile in 100ml of anhydrous acetonitrile was added 530 μ l (1.26mmol, 0.1 equiv) of trinitrotoluene b (triton b) in 40% methanol. The reaction mixture was heated to reflux and 11.3ml (126mmol, 10.0 equiv.) of methyl acrylate were added dropwise. After 15 minutes, the reaction mixture was cooled to room temperature and concentrated on a rotary evaporator. The residue was diluted with 300ml of diethyl ether, washed with 1X 50ml of 1N HCl, 1X 50ml of brine and then with Na₂SO₄And (5) drying. Filtration, concentration of the filtrate, and drying gave a brown oil which was purified on a silica gel column (20% ethyl acetate/hexane, quick) to give 4.00g (75%) of a yellow oil: IR (CHCl)₃)3031，2972，2955，2874，2250，1735cm^-1；¹H NMR(300MHz，CDCl₃) δ 7.68(d, 1H, J ═ 8.5Hz), 7.49(s, 1H), 6.97(d, 1H, J ═ 8.5 Hz); 4.93 (quintuple, 1H, J ═ 7.6Hz), 3.58(s, 6H), 2.97(q, 2H), J ═ 7.7Hz, 2.45(m, 6H), 2.2(m, 6H), 2.0(m, 2H), 1.8m, 2H), 1.37(t, 3H, J ═ 7.7 Hz); MS (Cl, NH)₃)m/z 426(M+H⁺Base peak); c₂₄H₃₁N₃O₄Calculated values: c, 67.74; h, 7.34; n.9.88. found: c.67.76;

h (. + -.) -5-cyano-5- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) -2-oxo-cyclohexanecarboxylic acid methyl ester

To a room temperature solution of 3.93g (9.24mmol, 1.0 equiv.) of 4-cyano-4- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) pimelic acid dimethyl ester in 100ml of anhydrous 1, 2-dimethoxyethane was added 924mg (23.1mmol, 2.5 equiv.) of sodium hydride in 60% oil dispersion in one portion. The reaction mixture was heated to reflux under nitrogen for 1.5 hours and then cooled to room temperature. After 18 hours, the reaction mixture is taken up with 50ml of H₂The reaction was quenched, poured into 200ml ethyl acetate and washed with 1X 100ml 1N HCl. The aqueous layer was extracted with 1X 50ml of ethyl acetate. The organic extracts were combined, washed with 1X 50ml of brine and then Na₂SO₄And (5) drying. Filtration, concentration of the filtrate, and drying gave a yellow oil which was purified on a silica gel column (10% ethyl acetate/hexanes) to give 2.78g (76%) of a white amorphous solid: IR (KRr)2954, 2871, 2240, 1663, 1619cm^-1；¹H NMR(300MHz，CDCl₃) δ 12.27(s, 1H), 7.70(d, 1H, J ═ 8.5Hz), 7.57(s, 1H), 7.15(dd, 1H, J ═ 1.6, 8.5Hz), 4.93 (quintuple, 1H, J ═ 7.6Hz), 3.78(s, 3H), 3.05(m, 1H), 2.98(q, 2H, J ═ 7.6Hz), 2.9(m, 1H), 2.75(m, 1H), 2.6(m, 1H), 2.35(m, 2H), 2.2(m, 4H), 2.0(m, 2H), 1.75(m, 2H), 1.38(t, 3H, J ═ 7.6 Hz); MS (Cl, NH)₃)m/z 394(M+H⁺Base peak); c₂₃H₂₇N₃O₃Calculated values: c, 70.22; h, 6.92; n, 10.68. found: c, 70.07; h, 7.01; and N, 10.70.

1- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) -4-oxo-cyclohexanecarbonitrile

Under nitrogen, 2.72g (6.91mmol, 1.0 equivalent) (+ -) -5-cyano-5- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) -2-oxo-cyclohexanecarboxylic acid methyl ester was mixed with 2.58g (44.2mmol, 6.4 equivalents) sodium chloride in 50ml dimethyl sulfoxide and 4ml H₂The mixture in O was heated in an oil bath at 140 ℃. After 3 hours, the reaction mixture was cooled to room temperature and stirred for 72 hours. The reaction mixture was poured into 250ml of H₂In O, extracted with 2X 150ml of ethyl acetate. The organic extracts were combined and washed with 2X 100ml H₂O, 1X 100ml brine, Na₂SO₄And (5) drying. The crude product was purified on a silica gel column (20% ethyl acetate/hexane) to give 1.82g (78%) of a white crystalline solid: mp 81-89 ℃; IR (KBr)2969, 2951, 2872, 2236, 1716cm^-1；¹H NMR(300MHz，CDCl₃) δ 7.71(d, 1H, J ═ 8.5Hz), 7.58(s, 1H), 7.16(dd, 1H, J ═ 1.5, 8.5Hz), 4.93 (quintuple peak, 1H, J ═ 7.6Hz), 3.0(m, 4H), 2.7(m, 4H), 2.45(m, 2H), NH₄OAc)m/z 336(M+H⁺Base peak); c₂₁H₂₅N₃Calculated value of O: c, 75.20; h, 7.51; n, 12.53. found: c, 74.06; h, 7.59; n, 12.41; c₂₁H₂₅N₃HRMS calcd for O + H: 336.20778. found 336.2088.

Example 3

1- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) -4- [1, 3] dithian-2-ylidene-cyclohexanecarbonitrile

To a solution of 1.88ml (9.89mmol, 2.1 equivalents) 2-trimethylsilyl-1, 3-dithiane in 80ml anhydrous THF at 0 deg.C was added dropwise a solution of 3.94ml (9.84mmol, 2.09 equivalents) n-BuLi in 2.5M hexane. After 25 minutes of reaction at 0 ℃, the reaction mixture was cooled to-78 ℃ and a solution of 1.58g (4.71mmol, 1.0 eq) of 1- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) -4-oxo-cyclohexanecarbonitrile in 40ml anhydrous THF was added. After 1 hour at-78 ℃ the reaction was terminated by adding 50ml of brineThe mixture was allowed to react, then the temperature was raised to room temperature and 100ml of H was used₂Diluted with O and 1X 100ml CH₂Cl₂And 1X 50ml of brine, over Na₂SO₄And (5) drying. Filtration, concentration of the filtrate, and drying gave a clear oil which was purified on a silica gel column (10% ethyl acetate/hexane) to give 1.51g (73%) of a white amorphous solid: IR (KBr)2962, 2870, 2232, 1620, 1569, 1508, 1434, 1217cm^-1；¹H NMR(300MHz，CDCl₃) δ 7.67(d, 1H, J ═ 8.5Hz), 7.53(s, 1H), 7.15(dd, 1H, J ═ 1.5, 8.6Hz), 4.92 (quintuple, 1H, J ═ 7.6Hz), 3.36(m, 2H), 3.0(m, 6H), 2.42(m, 2H), 2.34(m, 2H), 2.2(m, 6H), 2.0(m, 4H), 1.8(m, 2H), 1.37(t, 3H, J ═ 7.5 Hz); MS (Cl, NH)₃)m/z 438(M+H⁺Base peak); c₂₅H₃₁N₃S₂Calculated values: c, 68.60; h, 7.14; n, 9.60 found: c, 68.26; h, 7.29; and N, 9.58.

Trans-4-cyano-4- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) cyclohexanecarboxylic acid methyl ester and cis-4-cyano-4- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) cyclohexanecarboxylic acid methyl ester

Under a nitrogen atmosphere, 1.45g (3.31mmol, 1.0 equivalent) of 1- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) -4- [1, 3]A mixture of dithiane-2-ylidene-cyclohexanecarbonitrile, 3.59g (13.2mmol, 4.0 equivalents) of mercury (II) chloride and 1.48ml (16.9mmol, 5.1 equivalents) of 70% perchloric acid in 60ml of methanol is heated to reflux. After 2 hours, the reaction mixture was cooled to room temperature and quenched with 250ml CH₂Cl₂Diluting with diatomaceous earth^And (5) filtering. The filtrate was taken up with 1X 100ml of saturated NaHCO₃Aqueous solution, 1X 75ml of 10% aqueous sodium sulfite solution, 1X 100ml of H₂O washing with Na₂SO₄And (5) drying. Filtration, concentration of the filtrate, and drying gave a clear oil which was purified on a silica gel column (15% ethyl acetate/hexanes) to give 340mg (27%) of the trans isomer (less polar) as a white solid, and 794mg (63%) of the cis isomer (more polar) as a white solid: trans isomer data: mp 79-82 ℃; IR (KBr)29u73, 2949, 2890, 2871,2235，1721，1618，1484，1453，1217，1170cm^-1；¹H NMR(300MHz，CDCl₃) δ 7.67(d, 1H, J ═ 8.4Hz), 7.52(s, 1Y), 7.14(dd, 1H, J ═ 1.4, 8.5Hz), 4.93 (quintuple, 1H, J ═ 7.6Hz), 3.74(s, 3H), 2.97(q, 2H, J ═ 7.6Hz), 2.85(m 1H0, 2.3(m, 2H), 2.2(m, 10H), 2.0(m, 2H), 1.75(m, 2H), 1.37(t, 3H, J ═ 7.6 Hz); MS (Cl, NH)₃)m/z 380(M+H⁺Base peak); c₂₃H₂₉N₃O₂for calculating the value: c, 72.79; h, 7.70; n, 11.07. found: c, 73.05; h, 7.80; n, 11.03. cis isomer data: mp112-114 ℃; IR (KBr)3065, 2952, 2866, 2234, 1731, 1622, 1487, 1445, 1220, 1204cm^-1；¹H NMR(300MHz，CDCl₃) δ 7.68(d, 1H, J ═ 8.5Hz), 7.55(s, 1H), 7.14(dd, 1H, J ═ 1.3, 8.4Hz), 4.93 (quintuple peak, 1H, J ═ 7.6Hz), 3.73(s, 3H), 2.98(q, 2H, J ═ 7.6Hz), 2.42(m, 1H), 2.36(m, 1H), 1.9-2.3(m, 13H), 1.8(m, 2H), 1.37(t, 3H, J ═ 7.5 Hz); MS (Cl, NH)₃)m/z 380(M+H⁺Base peak); c₂₃H₂₉N₃O₂Calculated values: c, 72.79; h, 7.70; n, 11.07. found: c, 72.93; h, 7.56; n, 10.92.

Example 4

Trans-4-cyano-4- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) cyclohexanecarboxylic acid

A mixture of 337mg (0.888mmol, 1.0 eq) of methyl trans-4-cyano-4- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) cyclohexanecarboxylate in 10ml of methanol, 2ml of THF and 2.7ml (2.66mmol, 3.0 eq) of 1N NaOH was stirred at room temperature. After 3 hours, the reaction mixture is concentrated on a rotary evaporator and 100ml of H are used₂Diluted with O, acidified to pH 1 and extracted with 2X 70ml of ethyl acetate. The organic extracts were combined and washed with 1X 50ml of H₂O, 1X 50ml brine, Na₂SO₄And (5) drying. Filtering, concentrating the filtrate, drying to obtain a white solid, purifying with silica gel column (5% CH)₃OH/CH₂Cl₂) Purification above gave 197mg (61%) of a white amorphous solid: IR (KBr)3200-2500, 3060, 2963, 2871, 2245, 1729, 1702, 1621, 1453, 1219cm^-1；¹H NMR(300MHz，DMSO-d₆) δ 12.4(br s, 1H), 7.77(d, 1H, J ═ 8.5Hz), 7.69(s, 1H), 7.20(dd, 1H, J ═ 1.3, 8.5 Hz); 5.17 (quintuple, 1H, J ═ 7.6Hz), 2.90(q, 2H, J ═ 7.6Hz), 2.75(m, 1H), 1.9-2.3(m, 16H), 1.7(m, 2H), 1.28(t, 3H, J ═ 7.6 Hz); MS (Cl, NH)₃)m/z 366(M+H⁺Base peak); c₂₂H₂₇N₃O₂Calculated values: c, 72.29; h, 7.45; n, 11.50. found: c, 71.98; h, 7.75; n, 11.21.

Example 5

Cis-4-cyano-4- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) cyclohexanecarboxylic acid

A mixture of 831mg (2.19mmol, 1.0 eq) of methyl cis-4-cyano-4- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) cyclohexanecarboxylate in 20ml of methanol, 4ml of THF and 6.6ml (6.57mmol, 3.0 eq) of 1N NaOH was stirred at room temperature. After 1.5 hours, the reaction mixture is concentrated on a rotary evaporator and 100ml of H are used₂Diluted with O, acidified to pH 1 and extracted with 2X 70ml of ethyl acetate. The organic extracts were combined and washed with 1X 50ml of H₂O, 1X 50ml brine, Na₂SO₄And (5) drying. Filtration, concentration of the filtrate, drying to give 0.80g of a white solid, on silica gel column (5% CH)₃OH/CH₂Cl₂) Purification as above gave 730mg (91%) of a white crystalline solid. Recrystallization from ethyl acetate/hexane gave 538mg of white crystals:

mp 197-199℃；IR(KBr)3200-2600，3061，2961，2948，2939，2871，2245，1732，1625，1451，1255，1185，1169cm^-1；¹H NMR(300MHz，DMSO-d₆) δ 12.35(br s, 1H), 7.77(d, 1H, J ═ 8.6Hz), 7.73(s, 1H0, 7.27(dd, 1H, J ═ 1.5, 8.5Hz), 5.13 (quintuple, 1H, J ═ 7.5Hz), 2.90(q, 2H, J ═ 7.6Hz), 2.42(m, 1H), 2.73 (s, 1H, J ═ 8.6Hz), 5.13 (quintuple, 1H, J ═ 7.5Hz), 2.90(q, 2H, J ═ 7.6Hz).30(m，2H)，1.7-2.1(m，14H)，1.29(t，3H，J＝7.5Hz)；MS(Cl，NH₃)m/z 366(M+H⁺Base peak); c₂₂H₂₇N₃O₂Calculated values: c, 72.29; h, 7.45; n, 11.50 calculated: c, 72.01; h, 7.60; n, 11.29.

Example 6

A.6-bromo-1-cyclohex-2-enyl-3-ethyl-1H-indazole

To a room temperature solution of 11.35g (50.4mmol, 1.0 equiv.) of 6-bromo-ethyl-1H-indazole in 300ml of anhydrous DMF was added 2.12g (52.9mmol, 1.05 equiv.) of sodium hydride in 60% oil dispersion in four portions over 10 minutes. After stirring for 20 minutes, 9.0ml (70.6mmol, 1.4 equivalents) of 3-bromocyclohexene was added dropwise and the reaction was concentrated and dried under high vacuum at room temperature to give 7.52g of an orange-yellow solid.

The solid was dissolved in anhydrous DMF, 1.56g (31.8mmol, 2.27 equivalents) of sodium cyanide were added and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was then poured into 400ml of H₂In O, extracted with 3X 200ml of ethyl acetate. The organic extracts were combined and washed with 3X 150ml H₂O, 1X 150ml brine, Na₂SO₄And (5) drying. Filtration, concentration of the filtrate, and drying gave a yellow oil which was purified on a silica gel column (5% -10% ethyl acetate/hexanes gradient) to give 1.40g (38%) of a yellow-green oil: MS (Cl, NH)₃)268(M+H⁺Base peak); c₁₇H₂₁N₃Analysis calculated value: c, 76.38; h, 7.92; n, 15.72. Measured value: c, 76.43; h, 7.53; n, 15.39.

B6-bromo-1-cyclohexyl-3-ethyl-1H-indazole

A mixture of 10.22g (33.5mmol, 1.0 eq.) of 6-bromo-1-cyclohex-2-enyl-3-ethyl-1H-indazole and 1.5g of 10% Pt/C in 1L cyclohexane was placed on Parr^On a hydrogenation apparatus at room temperature at 2-5psi H₂Shaking the mixture. After 1 hour, the reaction mixture was passed through celite^Filtering, and rotary evaporating the filtrateConcentrated on the vessel and purified by chromatography (5% ethyl acetate/hexanes, flash) to give 9.70g (94%) of a light yellow oil: MS (Cl, NH)₃)m/z309/307(M+H⁺Base peak); c₁₅H₁₉N₃Calculated Br analysis: c, 58.64; h, 6.23; and N, 9.12. Measured value: c, 58.56; h, 6.29; n, 8.77.

C1-cyclohexyl-3-ethyl-1H-indazole-6-aldehyde

This compound was prepared according to the method of example 2.e. using 5.02g (16.3mmol, 1.0 eq) of 6-bromo-1-cyclohexyl-3-ethyl-1H-indazole as starting material to give 3.65g (87%) of a light yellow oil: MS (Cl, NH)₃)m/z 257(M+H⁺Base peak); c₁₆H₂₀N₂Calculated value of O analysis: c, 74.97; h, 7.87; n, 10.93. Measured value: c, 75.00; h, 7.70; n, 10.74.

D- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) acetonitrile

To a room temperature suspension of 3.58g (14.0mmol, 1.0 equiv.) of 1-cyclohexyl-3-ethyl-1H-indazol-6-al-dehyde and 2.31g (26.6mmol, 1.9 equiv.) of lithium bromide in 100ml of anhydrous acetonitrile was added dropwise 2.7ml (21.0mmol, 1.5 equiv.) of trimethylsilyl chloride. After 15 minutes, the reaction mixture was cooled in an ice bath and 4.1ml (23.2mmol, 1.66 equivalents) of 1, 1, 3, 3-tetramethyldisiloxane were added dropwise, allowing the temperature of the reaction to rise to room temperature over 30 minutes. The reaction mixture was heated to reflux for 3 hours, then cooled to room temperature and quenched with 300ml CH₂Cl₂Diluting with diatomaceous earth^And (5) filtering. The filtrate was concentrated and dried under high vacuum at room temperature to give 7.52g of an orange-yellow solid.

The solid was dissolved in 100ml of anhydrous DMF, 1.56g (31.8mmol, 2.27 equivalents) of sodium cyanide were added and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then poured into 400ml of H₂In O, extracted with 3X 200ml of ethyl acetate. The organic extracts were combined and washed with 3X 150ml H₂O, 1X 150ml brine, Na₂SO₄And (5) drying. Filtering, concentrating the filtrate, and drying to obtain yellowThe oil was purified on a silica gel column (5% -10% ethyl acetate/hexanes gradient) to give 1.40g (38%) of a yellow-green oil: MS (Cl, NH)₃)268(M+H⁺Base peak); c₁₇H₂₁N₃Analysis calculated value: c, 76.38; h, 7.92; n, 15.72. Measured value: c, 76.43; h, 7.53; n, 15.39.

4-cyano-4- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) pimelic acid dimethyl ester

This compound was prepared as in example 2.g. using 1.33g (4.98mmol, 1.0 eq) of (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) acetonitrile as the starting material to give 1.38g (63%) of a yellow oil; MS (Cl, NH)₃)m/z 440(M+H⁺Base peak); c₂₅H₃₃N₃O₄Analysis calculated value: c, 68.32; h, 7.57; n, 9.56. Measured value: c, 68.18; h, 7.52; and N, 9.28.

F5-cyano-5- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) -2-oxo-cyclohexanecarboxylic acid methyl ester

This compound was prepared as in example 2.H. using 1.33g (3.03mmol, 1.0 equivalent) of dimethyl 4-cyano-4- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) pimelate as starting material to give 983mg (80%) of a white amorphous solid: MS (Cl, NH)₃)m/z 408(M+H⁺Base peak); c₂₄H₂₉N₃O₃Analysis calculated value: c, 70.75; h, 7.18; n, 10.31. Measured value: c, 70.75; h, 7.33; n, 10.19.

1- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) -4-oxo-cyclohexanecarbonitrile

This compound was prepared as in example 2. i.using 933mg (2.29mmol, 1.0 eq) of 5-cyano-5- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) -2-oxo-cyclohexanecarboxylic acid methyl ester as starting material to give 588mg (74%) of a white amorphous solid: MS (Cl, NH)₃)m/z350(M+H⁺Base peak); c₂₂H₂₇N₃Calculated value of O analysis: c, 75.62; h, 7.79; and N, 12.03.Measured value: c, 75.57; h, 7.90; and N, 12.15.

Example 7

Cis-4-cyano-4- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) cyclohexanecarboxylic acid methyl ester and trans-4-cyano-4- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) cyclohexanecarboxylic acid methyl ester

These compounds were prepared according to the method of example 3.b. using 540mg (1.20mmol, 1.0 equivalent) of 1- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) -4- [1, 3] dithian-2-ylidene-cyclohexanecarbonitrile as starting material to give 117mg (25%) of the trans isomer and 233mg (50%) of the cis isomer, the former being a white oily solid and the latter being a white crystalline solid:

trans isomer data:¹H NMR(300MHz，CDCl3)δ7.68(d，1H，J＝8.4Hz)，7.50(d，1H，J＝0.8Hz)，7.13(dd，1H，J＝1.6，8.5Hz)，4.34(m，1H)，3.74(s，3H)，2.98(q，2H，J+7.6Hz)，2.85(m，1H)，2.3(m，2H)，1.9-2.2(m，12H)，1.8(m，2H)，1.55(m，2H)，1.37(t，3H，J＝7.6Hz)；MS(Cl，NH₃)m/z 394(M+H⁺base peak); c₂₄H₃₁N₃O₂Calculated values: c, 73.25; h, 7.95; n, 10.68, found C, 73.07; h, 8.12; n, 10.89. cis isomer data: 1H NMR (300MHz, CDCl)₃)δ7.68(d.1H，J＝8.4Hz)，7.53(d，1H，J＝0.9Hz)，7.14(dd，1H，J＝1.6，8.5Hz)，4.34(m，1H)，3.74(s，3H)，2.98(，2H，J＝7.6Hz)，2.43(m，1H)，1.9-2.3(m，15H)，1.8(m，1H)，1.5(m，2H)，1.37(t，3H，JJ＝7.6Hz)；MX(Cl，NH₃)m/z 394(M+⁺Base peak); c₂₄H₃₁N₃O₇Calculated values: c, 73.25; h, 7.95; n, 10.68 found: c, 73.17; h, 7.89; n, 10.43.

Example 8

Cis-4-cyano-4- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) cyclohexanecarboxylic acid

This compound was prepared according to the method of example 5, using 201mg (0.511mmol, 1.0 eq) of cis-4-cyano-4- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) cyclohexanecarboxylic acid methyl ester as starting material, to give 178mg (92%) of a white crystalline solid, which was recrystallized from ethyl acetate/hexane to give 153mg of a white crystalline powder: mp192-194 ℃; c₂₃H₂₉N₃O₂Analysis calculated value: c, 72.79; h, 7.70; n, 11.07. Measured value: c, 72.25; h, 7.99; n, 10.97.

Example 9

1- (cyclohexyl-3-ethyl-1H-indazol-6-yl) -cis-4-hydroxymethylcyclohexanecarbonitrile

To a solution of the product from example 8 (220mg, 0.58mmol) in anhydrous tetrahydrofuran (5ml) was added dropwise a solution of borane in tetrahydrofuran (1M, 1.3ml, 1.3mmol) with stirring. The mixture was stirred at 0 ℃ for one hour, and then methanol (1ml) was slowly added to terminate the reaction. The mixture was poured into water (100ml) and extracted with ethyl acetate (2X 100 ml). The organic extracts were combined, washed with water (1X 20ml), brine (1X 20ml), dried over magnesium sulphate and concentrated to give an oil. Another identical experiment was carried out using the product from example 8 (100mg, 0.26mmol) and borane in tetrahydrofuran (1M, 0.6ml, 0.58 mmol). The crude products from both runs were combined and chromatographed on silica gel eluting with 2.5% methanol in dichloromethane (v/v) to give an oil. Recrystallization from ethyl acetate/hexane gave 214mg of a white solid (67%), mp117-9 ℃. Mass Spectrum (m/e): 367(M +1, 20), 366(M +, 100).

Example 10

Cis-4-cyano-4- (1- (cyclohexyl-3-ethyl) -1H-indazol-6-yl) cyclohexanecarboxamide A mixture of the product from example 8 (150mg, 0.4mmol), thionyl chloride (36. mu.l, 0.49mmol) and dimethylformamide (5. mu.l) in anhydrous dichloromethane (3ml) was refluxed for four hours. The mixture was cooled to 0 ℃ and anhydrous ammonia gas was introduced while chloroform (200ml) was added, which was washed with water (1X 40ml), dried over magnesium sulfate, and concentrated to give a solid. Recrystallization from ethyl acetate/hexane gave 125mg of a white solid (83%), mp180-2 ℃. Mass Spectrum (m/e): (M +1, 20), 379(M +, 100).

Example 11

Trans-4-cyano-4- (1- (cyclohexyl-3-ethyl) -1H-indazol-6-yl) cyclohexanecarboxamide

The title compound was prepared following a synthetic procedure analogous to that provided in example 4. The melting point of the isolated product was 140-143 ℃.

Claims (15)

1. A compound of formula I or a pharmaceutically acceptable salt thereof,wherein:

   r is hydrogen, C₁-C₆Alkyl, - (CH)₂)_n(C₃-C₇Cycloalkyl) in which n is 0 to 2, (C)₁-C₆Alkoxy) C₁-C₆Alkyl radical, C₂-C₆Alkenyl, - (CH)₂)_n(C₃-C₉Heterocyclyl) wherein n is 0 to 2, or- (Z')_b(Z”)_c(C₆-C₁₀Aryl) in which b and C are independently 0 or 1, Z' is C₁-C₆Alkylene or C₂-C₆Alkenylene radical, Z "being O, S, SO₂Or NR₉Wherein said alkyl, alkenyl, alkoxyalkyl, heterocyclyl and aryl moieties of said group R may be substituted with 1 to 3 substituents independently selected from halogen, hydroxy, C₁-C₅Alkyl radical, C₂-C₅Alkenyl radical, C₁-C₅Alkoxy radical, C₃-C₆Cycloalkoxy, trifluoromethyl, nitro, CO₂R₉、C(O)NR₉R₁₀、NR₉R₁₀And SO₂NR₉R₁₀；

   R₁Is hydrogen, C₁-C₇Alkyl radical, C₂-C₃Alkenyl, phenyl, C₃-C₇Cycloalkyl or (C)₃-C₇Cycloalkyl) C₁-C₂Alkyl radical, wherein the radical R₁The alkyl, alkenyl and phenyl groups of (a) may be substituted with 1 to 3 substituents independently selected from methyl, ethyl, trifluoromethyl and halogen;

   R₂is selected fromAndwherein the dotted lines in formulae (Ia) and (Ib) represent single or double bonds;

   m is 0 to 4;

   R₃is H, halogen, cyano, C which may be substituted by 1 to 3 halogen radicals₁-C₄Alkyl radical, CH₂NHC(O)C(O)NH₂Can be substituted by R₁₁、R₁₇、CH₂OR₉、NR₉R₁₀、CH₂NR₉R₁₀、CO₂R₉、C(O)NR₉R₁₀、C≡CR₁₁C (Z) H or CH ═ CR₁₁R₁₁Substituted ringPropyl;

   R₄is H, C (Y) R₁₄，CO₂R₁₄，C(Y)NR₁₇R₁₄，CN，C(NR₁₇)NR₁₇R₁₄，C(NOR₉)R₁₄，C(O)NR₉NR₉C(O)R₉，C(O)NR₉NR₁₇R₁₄，C(NOR₁₄)R₉，C(NR₉)NR₁₇R₁₄，C(NR₁₄)NR₉R₁₀，C(NCN)NR₁₇R₁₄，C(NCN)S(C₁-C₄Alkyl), CR₉R₁₀OR₁₄，CR₉R₁₀SR₁₄，CR₉R₁₀S(O)_nR₁₅Wherein n is 0 to 2, CR₉R₁₀NR₁₄R₁₇，CR₉R₁₀NR₁₇SO₂R₁₅，CR₉R₁₀NR₁₇C(Y)R₁₄，CR₉R₁₀NR₁₇CO₂R₁₅，CR₉R₁₀NR₁₇C(Y)NR₁₇R₁₄，CR₉R₁₀NR₁₇C(NCN)NR₁₇R₁₄，CR₉R₁₀NR₁₇C(CR₉NO₂)S(C₁-C₄Alkyl), CR₉R₁₀CO₂R₁₅，CR₉R₁₀C(Y)NR₁₇R₁₄，CR₉R₁₀C(NR₁₇)NR₁₇R₁₄，CR₉R₁₀CN，CR₉R₁₀C(NOR₁₀)R₁₄，CR₉R₁₀C(NOR₁₄)R₁₀，CR₉R₁₀NR₁₇C(NR₁₇)S(C₁-C₄Alkyl), CR₉R₁₀NR₁₇C(NR₁₇)NR₁₇R₁₄，CR₉R₁₀NR₁₇C(O)C(O)NR₁₇R₁₄，CR₉R₁₀NR₁₇C(O)C(O)OR₁₄Tetrazolyl, thiazolyl, imidazolyl, imidazolidinyl, pyrazolyl, thiazoleAlkyl, oxazolyl, oxazolidinyl, triazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, CR₉R₁₀(tetrazolyl), CR₉R₁₀(thiazolyl), CR₉R₁₀(imidazolyl group), CR₉R₁₀(imidazolidinyl), CR₉R₁₀(pyrazolyl), CR₉R₁₀(thiazolidinyl), CR₉R₁₀(oxazolyl), CR₉R₁₀(oxazolidinyl), CR₉R₁₀(triazolyl), CR₉R₁₀(isoxazolyl), CR₉R₁₀(oxadiazolyl), CR₉R₁₀(thiadiazolyl), CR₉R₁₀(morpholinyl), CR₉R₁₀(piperidinyl group), CR₉R₁₀(piperazinyl) or CR₉R₁₀(pyrrolyl), wherein R is₄Said heterocyclyl and heterocyclyl portions of substituents may be substituted with 1 to 3R₁₄Substituent group substitution;

   R₅is R₉、OR₉、CH₂OR₉Cyano, C (O) R₉、CO₂R₉、C(O)NR₉R₁₀Or NR₉R₁₀Provided that R is R if the dotted line in formula (Ia) represents a double bond₅Is absent;

   or R₄And R₅Together form ═ O or ═ R₈；

   Or R₅Is hydrogen and R₄Is OR₁₄，SR₁₄，S(O)_nR₁₅Wherein n is 0 to 2, SO₂NR₁₇R₁₄，NR₁₇R₁₄，NR₁₄C(O)R₉，NR₁₇C(Y)R₁₄，NR₁₇C(O)OR₁₅，NR₁₇C(Y)NR₁₇R₁₄，NR₁₇SO₂NR₁₇R₁₄，NR₁₇C(NCN)NR₁₇R₁₄，NR₁₇SO₂R₁₅，NR₁₇C(CR₉NO₂)NR₁₇R₁₄，NR₁₇C(NCN)S(C₁-C₄Alkyl), NR)₁₇C(CR₉NO₂)S(C₁-C₄Alkyl), NR)₁₇C(NR₁₇)NR₁₇R₁₄，NR₁₇C(O)C(O)NR₁₇R₁₄Or NR₁₇C(O)C(O)OR₁₄；

   Each R₆Independently selected from methyl and ethyl groups which may be substituted with 1 to 3 halogen groups;

   R₇is OR₁₄，SR₁₄，SO₂NR₁₇R₁₄，NR₁₇R₁₄，NR₁₄C(O)R₉，NR₁₇C(Y)R₁₄，NR₁₇C(O)OR₁₅，S(O)_nR₁₂Wherein n is 0 to 2, OS (O)₂R₁₂，OR₁₂，OC(O)NR₁₃R₁₂，OC(O)R₁₃，OCO₂R₁₃，O(CR₁₂R₁₃)_mOR₁₂Wherein m is 0 to 2, CR₉R₁₀OR₁₄，CR₉R₁₀NR₁₇R₁₄，C(Y)R₁₄，CO₂R₁₄，C(Y)NR₁₇R₁₄，CN，C(NR₁₇)NR₁₇R₁₄，C(NOR₉)R₁₄，C(O)NR₉NR₉C(O)R₉，C(O)NR₉NR₁₇R₁₄，C(NOR₁₄)R₉，C(NR₉)NR₁₇R₁₄，C(NR₁₄)NR₉R₁₀，C(NCN)NR₁₇R₁₄，C(NCN)S(C₁-C₄Alkyl), tetrazolyl, thiazolyl, imidazolyl, imidazolidinyl, pyrazolyl, thiazolidinyl, oxazolyl, oxazolidinyl, triazolyl, isoxazolyl, oxadiazolyl or thiadiazolyl, wherein R is₇The heterocyclic group of (A) may be substituted by 1 to 3R₁₄Substituent group substitution;

   R₈is ═ NR₁₅、＝NCR₉R₁₀(C₂-C₆Alkenyl), ═ NOR₁₄、＝NOR₁₉、＝NOCR₉R₁₀(C₂-C₆Alkenyl) ═ NNR₉R₁₄、＝NNR₉R₁₉、＝NCN、＝NNR₉C(Y)NR₉R₁₄、＝C(CN)₂、＝CR₁₄CN、＝CR₁₄CO₂R₉、＝CR₁₄C(O)NR₉R₁₄、＝C(CN)NO₂、＝C(CN)CO₂(C₁-C₄Alkyl), - (C (CN) OCO₂(C₁-C₄Alkyl), (C), (CN) (C)₁-C₄Alkyl), - (C (CN) C (O) NR₉R₁₄2- (1, 3-dithiane), 2- (1, 3-dithiolane), dimethylthioketal, diethylthioketal, 2- (1, 3-dioxolane), 2- (1, 3-dioxane), 2- (1, 3-oxathiolane), dimethylketal, or diethylketal;

   each R₉And R₁₀Independently hydrogen or C which may be substituted by up to three fluorine atoms₁-C₄An alkyl group;

   each R₁₁Independently is fluorine or R₁₀；

   Each R₁₂Independently is C₁-C₆Alkyl radical, C₂-C₃Alkenyl radical, C₃-C₇Cycloalkyl group, (C)₃-C₇Cycloalkyl) C₁-C₂Alkyl radical, C₆-C₁₀Aryl or C₃-C₉Heterocyclyl, wherein the radical R₁₂May be substituted with 1 to 3 substituents independently selected from methyl, ethyl, trifluoromethyl and halogen;

   each R₁₃Independently is hydrogen or R₁₂；

   Each R₁₄Independently is hydrogen or R₁₅Or if R is₁₄And R₁₇As NR₁₇R₁₄When present, then R₁₇And R₁₄May form together with the nitrogen a 5 to 7 membered ring which may additionally contain at least one heteroatom selected from O, N and S;

   each R₁₅Independently is C₁-C₆Alkyl or- (CR)₉R₁₀)_nR₁₆Wherein n is 0 to 2, R₁₆And said C₁-C₆The alkyl group may be substituted with 1 to 3 substituents independently selected from halogen, nitroCyano radicals, NR₁₀R₁₇，C(O)R₉，OR₉，C(O)NR₁₀R₁₇，OC(O)NR₁₀R₁₇，NR₁₇C(O)NR₁₇R₁₀，NR₁₇C(O)R₁₀，NR₁₇C(O)O(C₁-C₄Alkyl radical), C (NR)₁₇)NR₁₇R₁₀，C(NCN)NR₁₇R₁₀，C(NCN)S(C₁-C₄Alkyl), NR)₁₇C(NCN)S(C₁-C₄Alkyl), NR)₁₇C(NCN)NR₁₇R₁₀，NR₁₇SO₂(C₁-C₄Alkyl), S (O)_n(C₁-C₄Alkyl) where n is 0 to 2, NR₁₇C(O)C(O)NR₁₇R₁₀，NR₁₇C(O)C(O)R₁₇Thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl and C which may be substituted by one to three fluorine atoms₁-C₂An alkyl group;

   each R₁₆Independently is C₃-C₇Cycloalkyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, thienyl, thiazolyl, quinolinyl, naphthyl, or phenyl;

   each R₁₇Independently is OR₉Or R₁₀；

   R₁₈Is H, C (Y) R₁₄，CO₂R₁₄，C(Y)NR₁₇R₁₄，CN，C(NR₁₇)NR₁₇R₁₄，C(NOR₉)R₁₄，C(O)NR₉NR₉C(O)R₉，C(O)NR₉NR₁₇R₁₄，C(NOR₁₄)R₉，C(NR₉)NR₁₇R₁₄，C(NR₁₄)NR₉R₁₀，C(NCN)NR₁₇R₁₄，C(NCN)S(C₁-C₄Alkyl), CR₉R₁₀OR₁₄，CR₉R₁₀SR₁₄，CR₉R₁₀S(O)_nR₁₅Wherein n is 0 to 2, CR₉R₁₀NR₁₄R₁₇，CR₉R₁₀NR₁₇SO₂R₁₅，CR₉R₁₀NR₁₇C(Y)R₁₄，CR₉R₁₀NR₁₇CO₂R₁₅，CR₉R₁₀NR₁₇C(Y)NR₁₇R₁₄，CR₉R₁₀NR₁₇C(NCN)NR₁₇R₁₄，CR₉R₁₀NR₁₇C(CR₉NO₂)S(C₁-C₄Alkyl), tetrazolyl, thiazolyl, imidazolyl, imidazolidinyl, pyrazolyl, thiazolidinyl, oxazolyl, oxazolidinyl, triazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, wherein said heterocyclyl may be substituted with 1 to 3R₁₄Substituent group substitution;

   R₁₉is-C (O) R₁₄、-C(O)NR₉R₁₄、-S(O)₂R₁₅or-S (O)₂NR₉R₁₄；

   Each Y is independently ═ O or ═ S; and

   z is O or NR₁₇、＝NCN、＝C(CN)₂、＝CR₉CN、＝CR₉NO₂、＝CR₉CO₂R₉、＝CR₉C(O)NR₉R₁₀、＝C(CN)CO₂(C₁-C₄Alkyl) or ═ C (CN) C (O) NR₉R₁₀。
2. The compound of claim 1, wherein R is cyclohexyl, cyclopentyl, methylenecyclopropyl, isopropyl, phenyl, or 4-fluorophenyl.
3. The compound of claim 2, wherein R₁Is C which may be substituted by up to three fluorine atoms₁-C₂An alkyl group.
4. A compound of claim 3, wherein R₁Is ethyl.
5. A compound of claim 3, wherein R₂Is a group of formula (Ia) wherein the dotted line represents a single bond.
6. The compound of claim 5, wherein R₃Is cyano.
7. The compound of claim 6, wherein m is 0, R₅Is hydrogen.
8. The compound of claim 6, wherein R₄Is carboxy, -CH₂OH or-CH₂C(O)NH₂。
9. The compound of claim 1, wherein R₂Is a radical of the formula (Ia) in which R₃And R₅Is of the cis structure:
10. the compound of claim 1, wherein R₂Is a group of the formula Ia in which the dotted line represents a single bond, R₃And R₄Is cis.
11. The compound of claim 1 selected from the group consisting of:

    1- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) -4-oxo-cyclohexanecarbonitrile;

    trans-4-cyano-4- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) cyclohexanecarboxylic acid methyl ester;

    cis-4-cyano-4- (1-cyclopentyl-3-ethyl-1H-indazol-6-yl) cyclohexanecarboxylic acid methyl ester;

    1- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) -4-oxo-cyclohexanecarbonitrile;

    cis-4-cyano-4- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) cyclohexanecarboxylic acid methyl ester;

    trans-4-cyano-4- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) cyclohexanecarboxylic acid methyl ester;

    cis-4-cyano-4- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) cyclohexanecarboxylic acid;

    trans-4-cyano-4- (1-cyclohexyl-3-ethyl-1H-indazol-6-yl) cyclohexanecarboxylic acid;

    1- (cyclohexyl-3-ethyl-1H-indazol-6-yl) -cis-4-hydroxymethylcyclohexanecarbonitrile;

    cis-4-cyano-4- (1- (cyclohexyl-3-ethyl) -1H-indazol-6-yl) cyclohexanecarboxamide; and

    trans-4-cyano-4- (1- (cyclohexyl-3-ethyl) -1H-indazol-6-yl) cyclohexanecarboxamide.
12. 12. A pharmaceutical composition for inhibiting Phosphodiesterase (PDE) type IV or producing Tumor Necrosis Factor (TNF) in a mammal comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
13. 13. The use of a compound of claim 1 for the manufacture of a medicament for inhibiting Phosphodiesterase (PDE) type IV or producing Tumor Necrosis Factor (TNF) in a mammal.
14. 14. A pharmaceutical composition for preventing or treating asthma, arthritis, rheumatoid arthritis, gouty arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions in a mammal; sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammation, silicosis, pulmonary sarcoma, bone resorption disease, reperfusion injury, graft-to-host reaction, allograft rejection, fever and myalgia due to infection, cachexia secondary to infection or malignancy, cachexia secondary to Acquired Immune Deficiency Syndrome (AIDS), AIDS, HIV, ARC (AIDS-related complex), keloid formation, scar tissue formation, Crohn's disease (Crohn's disease), ulcerative colitis, pyresis, multiple sclerosis, type I diabetes, autoimmune diabetes, systemic lupus erythematosus, bronchitis, chronic obstructive airway disease, psoriasis, Bechet's disease, allergic purpura nephritis, chronic glomerulonephritis, inflammation of the bowel, a leukemia, allergic rhinitis or dermatitis comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
15. 15. Use of a compound of claim 1 for the preparation of a medicament for treating asthma, arthritis, rheumatoid arthritis, gouty arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammation, silicosis, pulmonary sarcoma, bone resorption disease, reperfusion injury, graft-to-host reaction, allograft rejection, fever and myalgia due to infection, cachexia secondary to infection or malignancy, cachexia secondary to Acquired Immune Deficiency Syndrome (AIDS), AIDS, HIV, ARC (AIDS-related complex), keloid formation, scar tissue formation, Crohn's disease (Crohn's disease), ulcerative colitis, pyresis, multiple sclerosis, type I diabetes, autoimmune diabetes, systemic lupus erythematosus, bronchitis, chronic obstructive airway disease, psoriasis, Bechet's disease, allergic purpura nephritis, chronic glomerulonephritis, inflammation of the bowel, application in drugs for treating leukemia, allergic rhinitis or dermatitis.