JPH10511395A - 1,3,3- (Trisubstituted) cyclohexane monomers and related compounds - Google Patents

Abstract

  (57) [Summary] The present invention relates to certain 1,3,3- (trisubstituted) cyclohexane monomers and related compounds useful for treating allergic and inflammatory diseases and inhibiting the production of tumor necrosis factor (TNF).

Description

DETAILED DESCRIPTION OF THE INVENTION       1,3,3- (Trisubstituted) cyclohexane monomers and related compounds Field of the invention   The present invention provides novel 1,3,3- (trisubstituted) cyclohexane monomers and related compounds, Pharmaceutical compositions containing these compounds, and allergic and inflammatory diseases The use of these in the treatment of cancer and the inhibition of the production of tumor necrosis factor (TNF) You. Background of the Invention   Bronchial asthma is characterized by reversible narrowing of the airway and hyperresponsiveness of the airway to external stimuli. It is a complex multifactorial disease that is characterized by:   Due to the fact that several mediators are involved in the development of asthma, Identification of new therapeutic agents has become difficult. Thus, eliminating the action of one mediator Leaves no substantial effect on all three factors in chronic asthma It is thought to be. Other than "mediator solution", the condition of this disease To regulate the activity of cells involved in physiology.   One such method is cAMP (adenosine cyclic 3 ', 5'-mode). (No phosphate). Cyclic A MPs mediate biological responses to a wide range of hormones, neurotransmitters and drugs Krebs Endocrinology Proc eedings of the 4th International Congress Excerpta Medica, 17-29,1973] . When an appropriate agent binds to a specific cell surface receptor, adenylate cyclase Is activated, it is Mg⁺²-Convert ATP to cAMP at a fast rate.   Cyclic AMP is involved in the pathophysiology of exogenous (allergic) asthma Regulates most, if not all, activities of cells. The increase in cAMP is As such, 1) relaxation of airway smooth muscle, 2) inhibition of mast cell mediator release. Harm, 3) inhibition of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) monocytes and And have beneficial effects, including inhibition of macrophage activation. Accordingly Activate adenylate cyclase or inhibit phosphodiesterase The compound is effective in controlling inappropriate activation of airway smooth muscle and various inflammatory cells It is. The major cellular mechanism of cAMP inactivation is the cyclic nucleotide phosphodiestera. 3'-phos by one or more of a series of isoenzymes called Lies in the hydrolysis of the homodiester bond.   PD, a unique cyclic nucleotide phosphodiesterase (PDE) isoenzyme EIV may be responsible for cAMP degradation in airway smooth muscle and inflammatory cells [Torphy, Phosphodiesterase Isozymes: Pote Unique Targets for Novel Anti-Azematic Agents (“Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthma tic Agents ”in New Drugs for Asthma, Barnes, ed.IBC Technical Services L td., 1989)]. Studies show that inhibition of this enzyme only results in relaxation of airway smooth muscle Not only inhibit monocyte and neutrophil activation, but also hypertrophic cells, basophils and And suppresses degranulation of neutrophils. Moreover, the benefits of PDE IV inhibitors The most significant effect is that the adenylate cyclase activity of the target cells is When elevated by the appropriate hormone or autakoid, it is significantly enhanced. this Such PDE IV inhibitors include prostaglandin E_TwoAnd prostacyclin ( High levels of adenylate cyclase activator), effective in asthmatic lungs is there. Such compounds offer a unique solution for pharmacotherapy of bronchial asthma. And has a remarkable therapeutic effect superior to currently marketed drugs.   The compounds of the present invention also inhibit the production of tumor necrosis factor (TNF), a serum glycoprotein. Inhibit. Excessive or unregulated TNF production can lead to multiple sclerosis, autoimmune diabetes and And many autoimmune diseases such as systemic lupus erythematosus, as well as rheumatoid arthritis H, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritis; sepsis , Septic shock, endotoxin shock, gram negative sepsis, toxic shock syndrome, Adult respiratory distress syndrome, cerebral malaria, chronic pneumonia, silicosis, pulmonary sarcoidosis, Bone resorption disease, reperfusion injury, graft-versus-host reaction, allograft rejection, flu D Fever and muscle pain due to infections such as Kixy, a cachexia, AID derived from human acquired immunodeficiency syndrome (AIDS) S, ARC (AIDS-related syndrome), keloid formation, scar tissue formation, Crohn's disease Are associated with the transmission or relapse of a number of diseases, including ulcerative colitis, or fever.   AIDS occurs as a result of infection of T lymphocytes with the human immunodeficiency virus (HIV). This. At least three types of HIV: HIV-1, HIV-2 and HI V-3 has been identified. HIV infection results in impaired T-cell mediated immunity and infection Individuals develop severe opportunistic infections and / or abnormal tumors. HIV is T Activation of T lymphocytes is required to enter the lymphocytes. HIV-1 or H Viruses such as IV-2 infect T lymphocytes after T cell activation, and Expression and / or replication of various viral proteins may be responsible for such T cell activation. More mediated or maintained. Once activated T lymphocytes become infected with HIV T lymphocytes to allow HIV gene expression and / or HIV replication Must be kept activated.   Cytokines, especially TNF, play a role in maintaining T lymphocyte activation Cell-mediated HIV protein expression and / or viral replication activated by Related to manufacturing. Thus, in individuals infected with HIV, cytokines, especially TNF Interference of cytokine activity, such as by inhibiting production, is a measure of T cell activation. Helps to limit the prevalence of HIV infectivity against uninfected cells And delay or eliminate the progression of immune dysfunction induced by HIV infection Bring. Monocytes, macrophages, and related cells such as stellate cells and Rear cells are also involved in maintaining HIV infection. These cells, such as T cells, A target for viral replication, the level of viral replication depends on the activation state of the cell . [Rosenberg et al., The Immunopathogenesis of HI Application, The Immunopathogenesis of HIV Infection, Advances in Immunology), 57 (1989)]. Monokines, such as TNF, are used in HIV in monocytes and / or macrophages. It has been shown to activate replication [Poli et al., Proceedings of B National Academy of Sciences (Proc. Natl. Acad. Sci.) 87: 782-7 84 (1990)], therefore, inhibition of monokine production or activity is As described above for vesicles, it helps limit HIV progression.   TNF also provides cytomegalovirus (CMV), influenza virus, Other viral infections, such as adenovirus and herpes virus, as described above. It is related to various roles for various reasons.   TNF has also been associated with yeast and fungal infections. Especially Candida al Vicance (Candida albicans) is expressed in human monocytes and natural killer cells. It has been shown to induce TNF production in vitro. [Riipi et al. , Infection and Immunity, 58 (9): 2750-54 (1990); and Safari et al., Journal of Infexia. S. Daizys (Journal of Infectious Diseases), 164: 389-95 (1991) checking ... In addition, Wasan et al., Antimicrovial Argents Ann. Antimicrobial Agents and Chemotherapy, 35 (10): 204 6-48 (1991); and Luke et al., Journal of Infectious Dizzy Jiz, 162: 211-214 (1990)].   The ability to control the adverse effects of TNF has been demonstrated in mammals in need of such use. It is facilitated by using a compound that inhibits TNF. Excessive and / or excessive TNF Or TNF-mediated diseases aggravated or induced by unregulated production There remains a need for compounds that are useful in such applications. Summary of the Invention   In a first aspect, the present invention provides a compound of formula (I): [Where,   R₁Is-(CR_FourR_Five)_nC (O) O (CR_FourR_Five)_mR₆,-(CR_FourR_Five)_nC (O) NR_Four(C R_FourR_Five)_mR₆,-(CR_FourR_Five)_nO (CR_FourR_Five)_mR₆Or-(CR_FourR_Five)_rR₆(here The alkyl moiety is unsubstituted or substituted with one or more fluorines. Has been replaced);   m is 0 to 2;   n is 0-4;   r is 0-6;   R_FourAnd R_FiveIs independently hydrogen or C_1-2Selected from alkyl;   R₆Is hydrogen, methyl, hydroxyl, aryl, halo-substituted aryl, aryl Oxy C_1-3Alkyl, halo-substituted aryloxy C_1-3Alkyl, indanyl, i Ndenyl, C_7-11Polycycloalkyl, tetrahydrofuranyl, furanyl, tet Lahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydro Thiopyranyl, thiopyranyl, C_3-6Cycloalkyl or one or two C containing a saturated bond_4-6Cycloalkyl (where cycloalkyl or hetero The ring moiety is unsubstituted or has 1 to 3 methyl groups, 1 ethyl group Or substituted with one hydroxyl group).   However,   a) R₆When is hydroxyl, m is 2; or   b) R₆When is hydroxyl, r is 2 to 6; or   c) R₆Is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2- When it is tetrahydrofuranyl or 2-tetrahydrothienyl, m is 1 or Is 2; or   d) R₆Is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2- R is not 1 when it is tetrahydrofuranyl or 2-tetrahydrothienyl And 6;   e) When n is 1 and m is 0,-(CR_FourR_Five)_nO (CR_FourR_Five)_mR₆In R₆Is a group other than H;   X is YR_Two, Halogen, fluorine, NR_FourR_FiveOr formylamine;   Y is O or S (O)_m';   m 'is 0, 1 or 2;   X_TwoIs O or NR₈Is;   X_ThreeIs hydrogen or X;   R_TwoIs -CH optionally substituted with one or more fluorine._ThreeYou And -CH_TwoCH_ThreeSelected from the group consisting of:   R_ThreeIs COOR₁₄, C (O) NR_FourR₁₄Or R₇Is;   s is 0-4;   W is alkyl having 2 to 6 carbons, alkenyl having 2 to 6 carbons or 2 to 6 carbons Alkynyl;   Z is CR₈R₈OR₁₄, CR₈R₈OR_Fifteen, CR₈R₈SR₁₄, CR₈R₈SR_Fifteen, C R₈R₈S (O)_m'R₇, CR₈R₈NR_TenR₁₄, CR₈R₈NR_TenS (O)_TwoNR_TenR₁₄, CR₈R₈NR_TenS (O)_TwoR₇, CR₈R₈NR_TenC (Y ') R₁₄, CR₈R₈NR_TenC (O ) OR₇, CR₈R₈NR_TenC (Y ') NR_TenR₁₄, CR₈R₈NR_TenC (NCN) NR_Ten R₁₄, CR₈R₈NR_TenC (CR_FourNO_Two) NR_TenR₁₄, CR₈R₈NR_TenC (NCN) S R₉, CR₈R₈NR_TenC (CR_FourNO_Two) SR₉, CR₈R₈C (O) OR₁₄, CR₈R₈C (Y ') NR_TenR₁₄, CR₈R₈C (NR_Ten) NR_TenR₁₄, CR₈R₈CN, CR₈R₈( Tetrazolyl), CR₈R₈(Imidazolyl), CR₈R₈(Imidazolidinyl), CR₈R₈(Pyrazolyl), CR₈R₈(Thiazolyl), CR₈R₈(Thiazolidinyl ), CR₈R₈(Oxazolyl), CR₈R₈(Oxazolidinyl), CR₈R₈(G Riazolyl), CR₈R₈(Isoxazolyl), CR₈R₈(Oxadiazolyl), CR₈R₈(Thiadiazolyl), CR₈R₈(Morpholinyl), CR₈R₈(Piperige Nil), CR₈R₈(Piperazinyl), CR₈R₈(Pyrrolyl), CR₈R₈C (NO R₈) R₁₄, CR₈R₈C (NOR₁₄) R₈, CR₈R₈NR_TenC (NR_Ten) SR₉, CR₈ R₈NR_TenC (NR_Ten) NR_TenR₁₄, CR₈R₈NR_TenC (O) C (O) NR_TenR₁₄Also Is CR₈R₈NR_TenC (O) C (O) OR₁₄Is;   X_FiveIs H, R₉, OR₈, CN, C (O) R₈, C (O) OR₈, C (O) NR₈R₈Also Is NR₈R₈Is;   X_FourIs H, R₉, OR₈, CN, C (O) R₈, C (O) OR₈, C (O) NR₈R₈Also Is NR₈R₈Is;   Y ′ is O or S;   R₇Is-(CR_FourR_Five)_qR₁₂Or C_1-6Alkyl (where R₁₂Or C_1-6Al The kill group may be unsubstituted, unsubstituted, Substituted one or more times by methyl or ethyl substituted by fluorine ), -F, -Br, -Cl, -NO_Two, -NR_TenR₁₁, -C (O) R₈, -C O_TwoR₈, -O (CH_Two)_qR₈, -CN, -C (O) NR_TenR₁₁, -O (CH_Two)_qC (O) NR_TenR₁₁, -O (CH_Two)_qC (O) R₉, -NR_TenC (O) NR_TenR₁₁, -NR_TenC ( O) R₁₁, -NR_TenC (O) OR₉, -NR_TenC (O) R₁₃, -C (NR_Ten) NR_TenR₁₁ , -C (NCN) NR_TenR₁₁, -C (NCN) SR₉, -NR_TenC (NCN) SR₉, − NR_TenC (NCN) NR_TenR₁₁, -NR_TenS (O)_TwoR₉, -S (O)_m'R₉, -NR_TenC (O) C (O) NR_TenR₁₁, -NR_TenC (O) C (O) R_TenOr R₁₃Is;   q is 0, 1 or 2;   R₁₂Is R₁₃, C_3-7Cycloalkyl, or (2-, 3- or 4-pyridyl ), Pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, pi Perazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl ), Quinolinyl, naphthyl and phenyl. Or a substituted aryl or heteroaryl group;   R₁₂Is R₁₃, C_3-7Cycloalkyl, (2-, 3- or 4-pyridyl), pyri Midyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazini , Piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), Selected from norinyl, naphthyl or phenyl;   R₈Is hydrogen or R₉Is;   R₉Is a C which may be substituted by 1 to 3 fluorines_1-4Alkyl;   R_TenIs OR₈Or R₁₁Is;   R₁₁Is hydrogen or C which may be substituted by 1 to 3 fluorines_1-4Archi Or R_TenAnd R₁₁Is -NR_TenR₁₁Are nitrogen and Together carbon or carbon and at least one selected from O, N or S Forming a 5- to 7-membered ring consisting of another heteroatom;   R₁₃Is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazo Ryl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, iso Selected from the group consisting of xazolyl, oxadiazolyl or thiadiazolyl An unsubstituted or substituted heteroaryl group;₁₃Is R₁₂Or R₁₃Replaced by Each ring is connected via a carbon atom to form a second R₁₃The rings are each substituted Or the methyl may be substituted with one or three fluoro atoms. One or two C_1-2Substituted with alkyl;   R₁₄Is hydrogen or R₇Or R₈And R₁₄Is NR₈R₁₄Place like If they are, together with nitrogen, selected from carbon or carbon and O, N or S. Forming a 5- to 7-membered ring having one or more other heteroatoms;   R_FifteenIs C (O) R₁₄, C (O) NR_FourR₁₄, S (O)_TwoR₇Or S (O)_TwoNR_FourR₁₄so is there;   However,   f) R₇Is C which may be substituted by 1 to 3 fluorines_1-4Other than alkyl Is the base) Or a pharmaceutically acceptable salt thereof.   The present invention also relates to a compound of formula (I) and a pharmaceutically acceptable carrier or diluent. And a pharmaceutical composition comprising:   The present invention also relates to the enzymatic activity (or contact) of PDE IV in mammals, including humans. Mediation or inhibition of the compound of formula (I) as shown below. Administering a compound to a mammal in need thereof.   The invention further provides administering to a mammal, including a human, an effective amount of a compound of formula (I). A method for treating allergic and inflammatory diseases.   The present invention also provides an effective amount of a compound of formula (I), including humans in need thereof. Also provided is a method of treating asthma, comprising administering to a milk animal.   The present invention also provides a method of inhibiting TNF production in a mammal, including a human, comprising: Administering an effective TNF inhibiting amount of a compound of formula (I) to a mammal in need of such treatment To a method consisting of: This is a method that is sensitive to the treatment. For the prophylactic treatment or prevention of TNF-mediated disease states.   The present invention is also a method of treating a human infected with the human immunodeficiency virus (HIV). Thus, such humans can be administered a compound of formula (I) in an amount effective to inhibit TNF. And a method consisting of:   The compounds of formula (I) are useful in the treatment of other viral infections. Una virus is sensitive to upregulation by TNF. Or induces TNF production in vivo.   In addition, the compounds of formula (I) are also useful in the treatment of yeast and fungal infections. Such yeasts and fungi may be upregulated by TNF. Are sensitive to or cause TNF production in vivo. Detailed description of the invention   The present invention also relates to the enzymatic activity of PDE IV in mammals in need thereof (and Is a method for mediating or inhibiting catalytic activity) and in mammals in need thereof And inhibiting TNF production by treating the mammal with an effective amount of a compound of formula (I). Administering a substance.   Phosphodiesterase IV inhibitors are useful for asthma, chronic bronchitis, atopic dermatitis, Hives, allergic rhinitis, allergic conjunctivitis, spring catarrh, eosinophilic granuloma , Psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, myocardium Or brain reperfusion injury, chronic glomerulonephritis, endotoxin shock and adult respiratory distress Useful in treating a variety of allergic and inflammatory diseases, including symptomatic groups. In addition, PDE IV inhibitors are used for central nervous system such as diabetes insipidus and depression and multi-infarct dementia. It is also useful in treating systemic disorders.   Viruses relevant for treatment according to the invention are those which produce TNF as a result of infection Or the TNF inhibitor of formula (I) directly or indirectly reduces replication It is susceptible to inhibition, such as less. Such a virus is HIV- 1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza Virus, adenovirus and herpes virus, such as, but not limited to But not limited to herpes zoster and herpes simplex No.   The invention more particularly relates to mammals afflicted with human immunodeficiency virus (HIV). A method of treating an animal, comprising administering to a mammal such a mammal a TNF-inhibiting amount of Formula (I). A method comprising administering a compound.   The compounds of the present invention may be used in veterinary animals other than humans in need of suppression of TNF production. Also used in connection with treatment. T undergoing therapeutic or prophylactic treatment in animals NF-mediated diseases include those conditions mentioned above, especially viral infections. This Examples of such viruses are feline immunodeficiency virus (FIV) or, for example, equine infectious Anemia virus, goat arthritis virus, visna virus, maedi virus and Includes, but is not limited to, retroviral infections, including other lentiviruses Not done.   The compounds of the present invention may also be used to inhibit yeast and fungi from upregulation by TNF. Sites that are susceptible to in vivo or cause TNF production in vivo It is also useful in treating such yeast and fungal infections. Good treatment A preferred condition is fungal meningitis. In addition, the compounds of formula (I) are And may be administered in combination with other medicaments used for fungal infections. Fungal feeling The medicine selected for the infection is called polymyxin, such as polymycin B Compound species, clotrimazole, econazole, miconazole and ketoconazo Species called imidazoles such as fluconazole and itranazole And other triazoles; amphotericin, especially amphotericin And a class of compounds called liposomal amphotericin B. It is not limited to this.   The compounds of formula (I) also require treatment with antifungal, antibacterial or antiviral agents. By administering to a mammal in need thereof an effective amount of a compound of formula (I), Used to inhibit and / or reduce sex. Preferably, the compound of formula (I) The compound inhibits or reduces the toxicity of amphotericin-type compounds, especially amphotericin B. Administered to reduce.   As used herein, “C_1-3Alkyl "," C_1-4Alkyl "," C_1-6A The term "alkyl" or "alkyl" group refers to one to ten straight or branched chain It means to include both groups, and unless otherwise limited, methyl, ethyl , N-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert -And the like, but are not limited thereto.   "Alkenyl" means a straight chain of 1 to 6 carbons, unless the chain length is limited. Or branched, both vinyl, 1-propenyl, 2-propenyl, 2-p Including but not limited to lopinyl or 3-methyl-2-propenyl .   The term "cycloalkyl" or "cycloalkylalkyl" is Pill, cyclopropylmethyl, cyclopentyl or cyclohexyl I mean a group of 7 carbon atoms.   “Aryl” or “aralkyl” refers to phenyl, benzyl, unless otherwise specified. An aromatic ring of 6 to 10 carbon atoms, such as phenethyl or naphthyl, or Means a ring system. Preferably, the aryl is a single ring, ie, phenyl. A Alkyl chains are intended to include both straight-chain or branched groups having 1 to 4 carbon atoms. And   "Heteroaryl" is an aromatic ring system containing one or more heteroatoms For example, imidazolyl, triazolyl, oxazolyl, pyridyl, pyrimidyl , Pyrazolyl, pyrrolyl, furanyl or thienyl.   "Halo" refers to any halogen, i.e., chloro, fluoro, bromo or yo. Means mode.   "Inhibition of IL-1 production" or "inhibition of TNF production" is:   a) by whole cells, including but not limited to monocytes or macrophages, In vivo in humans by inhibiting the release of IL-1 in vivo Reduce excess levels of each IL-1 or TNF below normal levels. When;   b) In vivo translation of respective IL-1 or TNF levels in humans Down-regulating translation or transcription levels below normal levels; Or   c) suppresses direct synthesis of IL-1 or TNF levels as a post-translational event Down regulation by Means   The term “TNF-mediated disease or condition” means that TNF produces TNF itself. Or other services such as, but not limited to, IL-1 or IL-6. Any medical condition that acts either by inducing the release of itokines means. Thus, for example, IL-1 is the main element and its production and action Conditions that are elicited or secreted in response to TNF are TNF-mediated diseases It is considered a state. TNF-β (also known as lymphotoxin) Structurally similar to TNF-α (also known as cachectin) Since each elicits a similar biological response and binds to the same cellular receptor, TNF -Α and TNF-β are both inhibited by the compounds of the present invention. Therefore, this specification In the book, unless otherwise specified, they are collectively referred to as "TNF". Preferably Inhibits TNF-α.   "Cytokines" affect the function of cells and are involved in immune, inflammatory or hematopoietic responses. Means any secreted polypeptide that is a molecule that regulates interactions between cells I do. Cytokines, regardless of which cells produce them, monokines and Includes but is not limited to lymphokines.   Inhibition according to the invention for use in the treatment of humans infected with HIV Itokine has (a) T cell activation and / or activated T cell mediated HIV inheritance Initiation and / or maintenance of offspring expression and / or replication, and / or (b) Any problems associated with cytokine-mediated diseases such as hexy or muscle wasting It must be a linked cytokine. Preferably, the cytokine is TN F-α.   In the case of the present invention, preferred compounds are as follows:   R₁When is an alkyl substituted with one or more halogen, The fins are preferably fluorine and chlorine, more preferably one or more fluors. C substituted with nitrogen_1-4Alkyl. Preferred halo-substituted alkyl chain lengths are 1 Or 2 carbons, most preferably -CF_Three, -CH_TwoF, -CHF_Two, -CF_TwoCHF_Two, -CH_TwoCF_ThreeAnd -CH_TwoCHF_TwoIt is. Preferred R₁Replace The group is CH_Two-Cyclopropyl, CH_Two-C_5-6Having cycloalkyl and OH groups Or not have C_4-6Cycloalkyl, C_7-11Polycycloalkyl, (3- also Is 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, 1 or Is benzyl which may be further substituted by fluorine or C_1-2Alkyl, − (CH_Two)_1-3C (O) O (CH_Two)_0-2CH_Three,-(CH_Two)_1-3O (CH_Two)_0-2CH_Threeand − (CH_Two)_2-4OH.   R₁The group is (CR_FourR_Five) Group, R_FourAnd R_FiveThe groups are independently hydrogen or Is alkyl. This is (CR_FourR_Five)_nOr (CR_FourR_Five)_mIndividual mess like The methylene repeating units allow each of the methylene repeating units to be branched For example, n is 2 (CR_FourR_Five)_nIs, for example, -CH_TwoCH (CH_Three)- Can be. Each hydrogen atom of a methylene repeat unit or a branched hydrocarbon is replaced May be substituted with fluorine independently of each other, If preferred R₁A substitution can be obtained.   R₁Is C_7-11When the polycycloalkyl is, for example, bicyclo [2.2 .1] Heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl , Tricyclo [5.2.1.0^2'6Decyl and the like; (Saccamano) et al., WO 87/06576 (published November 5, 1987). Have been.   W is preferably an alkyl, alkenyl or alkynyl having 2 to 4 carbon atoms. And when it is alkenyl or alkynyl, one or two double or There are triple bonds.   Z is preferably CR₈R₈OR₁₄, CR₈R₈OR_Fifteen, CR₈R₈SR₁₄, CR₈ R₈SR_Fifteen, CR₈R₈S (O)_m'R₇, CR₈R₈NR_TenR₁₄, CR₈R₈NS (O)_TwoNR_TenR₁₄, CR₈R₈NS (O)_TwoR₇, CR₈R₈NR_TenC (O) R₁₄, CR₈R₈ NR_TenC (O) OR₇, CR₈R₈NR_TenC (O) NR_TenR₁₄, CR₈R₈NR_TenC (N CN) NR_TenR₁₄, CR₈R₈NR_TenC (CR_FourNO_Two) NR_TenR₁₄, CR₈R₈NR_Ten C (NCN) SR₉, CR₈R₈NR_TenC (CR_FourNO_Two) SR₉, CR₈R₈C (O) OR₁₄ , CR₈R₈C (O) NR_TenR₁₄, CR₈R₈C (NR_Ten) NR_TenR₁₄, CR₈R₈CN, CR₈R₈(Oxazolyl), CR₈R₈(Thiadiazolyl), CR₈R₈C (NOR₈ ) R₁₄, CR₈R₈C (NOR₁₄) R₈, CR₈R₈NR_TenC (NR_Ten) SR₉, CR₈R₈ NR_TenC (NR_Ten) NR_TenR₁₄, CR₈R₈NR_TenC (O) C (O) NR_TenR₁₄Or C R₈R₈NR_TenC (O) C (O) OR₁₄R of Z₈The group is H and the R of Z₁₄Is R_Four Is most preferred.   X_FourIs preferably H, OH, OCH_Three, CN, C (O) R₈, C (O) OH, C ( O) OCH_Three, C (O) NH_Two, CON (CH_Three)_Two, NH_TwoOr N (CH_Three)_TwoIt is. Most Also preferred X_FourThe groups are H, OH, CN, C (O) OH, C (O) NH_TwoOr NH_TwoIn You.   Preferred X groups are those wherein X is YR_Two, Y are oxygen. Preferred X_TwoThe group is oxygen is there. Preferred X_ThreeThe group is hydrogen. Preferred R_TwoThe group is optionally substituted C not substituted or substituted with one or more halogens_1-2Alkyl It is. Halogen atoms are preferably fluorine and chlorine, more preferably fluorine. Is prime. More preferred R_TwoThe group is R_TwoIs methyl, or fluoro-substituted alkyl, Especially C_1-2Alkyl, for example -CF_Three, -CHF_TwoOr -CH_TwoCHF_TwoThe original one It is. CHF_TwoAnd CH_ThreeGroups are most preferred.   Preferred R₇The group is unsubstituted or substituted-(CH_Two)_0-2(2-, 3- or 4-pi Lysyl), (CH_Two)_1-2(2-imidazolyl), (CH_Two)_Two(4-morpholinyl), (CH_Two )_Two(4-piperazinyl), (CH_Two)_1-2(2-thienyl), (CH_Two)_1-2(4-thiazoli ), Unsubstituted or substituted pyrimidinyl, and substituted or unsubstituted (CH_Two)_0-2 Phenyl.   -NR_TenR₁₁Part R_TenAnd R₁₁But together with the nitrogen to which they are bound Containing at least one other heteroatom selected from O, N or S When forming a 5- to 7-membered ring, preferred rings are 1-imidazolyl, 2- ( R₈) -1-Imidazolyl, 1-pyrazolyl, 3- (R₈) -1-Pyrazolyl, 1- Triazolyl, 2-triazolyl, 5- (R₈) -1-triazolyl, 5- (R₈) − 2-triazolyl, 5- (R₈) -1-tetrazolyl, 5- (R₈) -2-Tetrazori , 1-tetrazolyl, 2-tetrazolyl, morpholinyl, piperazinyl, 4- (R₈) -1-piperazinyl or pyrrolyl ring, including but not limited to .   -NR_TenR₁₄Part R_TenAnd R₁₄Together with the nitrogen to which they are bound Containing at least one other heteroatom selected from, O, N or S When forming a 7-membered ring, preferred rings are 1-imidazolyl, 1-pyrazoli , 1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl , Morpholinyl, piperazinyl and pyrrolyl rings, including but not limited to Not. Each ring is, if possible, on a possible nitrogen or carbon, R described in the specification₇May be substituted with a group. Examples of such carbon substitutions are: 2- (R₇) -1-imidazolyl, 4- (R₇) -1-imidazolyl, 5- (R₇) -1 -Imidazolyl, 3- (R₇) -1-pyrazolyl, 4- (R₇) -1-Pyrazolyl, 5 − (R₇) -1-pyrazolyl, 4- (R₇) -2-triazolyl, 5- (R₇) -2-to Liazolyl, 4- (R₇) -1-triazolyl, 5- (R₇) -1-Triazolyl, 5 − (R₇) -1-tetrazolyl, and 5- (R₇) -2-tetrazolyl, , But is not limited to this. R₇Possible nitrogen substitution by 1- (R₇) -2-tetrazo Lil, 2- (R₇) -1-tetrazolyl, 4- (R₇) -1-piperazinyl However, it is not limited to these. If possible, the ring is R₇One or more times Numerical substitution may be performed.   NR containing heterocyclic ring_TenR₁₄A preferred group for is 5- (R₁₄) -1-Tet Lazolyl, 2- (R₁₄) -1-imidazolyl, 5- (R₁₄) -2-tetrazolyl also Is 4- (R₁₄) -1-piperazinyl.   R₁₃Preferred rings for are (2-, 4- or 5-imidazolyl), (3- , 4- or 5-pyrazolyl), (4- or 5-triazolyl [1,2,3]), ( 3- or 5-triazolyl [1,2,4]), (5-tetrazolyl), (2-, 4- Ma Or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl [1,2,4]), (2-oxadiazolyl [1,3,4]), ( 2-thiadiazolyl [1,3,4]), (2-, 4- or 5-thiazolyl), (2 -, 4- or 5-oxazolidinyl), (2-, 4- or 5-thiazolidinyl) ) Or (2-, 4- or 5-imidazolidinyl).   R₇The group is optionally imidazolyl, pyrazolyl, triazolyl, tetrazolyl When optionally substituted with a heterocyclic ring such as ril or thiazolyl, a heterocyclic ring The ring itself is 1- (R₈) -2-imidazolyl, 1- (R₈) -4-imidazolyl, 1- (R₈) -5-imidazolyl, 1- (R₈) -3-pyrazolyl, 1- (R₈) -4- Pyrazolyl, 1- (R₈) -5-Pyrazolyl, 1- (R₈) -4-triazolyl or 1- (R₈) -5 on a possible nitrogen or carbon atom, such as 5-triazolyl₈By It may be replaced. If possible, the ring may be R or R₈Replaced by May be.   R₁Is -CH_Two-Cyclopropyl, -CH_TwoC_5-6Cycloalkyl, unsubstituted or -C substituted with OH_4-6Cycloalkyl, tetrahydrofuran-3-yl , (3- or 4-cyclopentenyl), unsubstituted or one or more fluorine Benzyl or C substituted with_1-2Alkyl or-(CH_Two)_2-4OH R;_TwoIs methyl or fluoro-substituted alkyl; W is ethynyl or 1,3 -Butadiynyl: R_ThreeIs R₇(Where R₇Is unsubstituted or substituted aryl Or heteroaryl ring); X is YR_TwoAnd Z is CR₈R₈OR_Fifteen Or CR₈R₈NR_TenR₁₄Compounds of formula (I) are preferred.   Most preferably, R₁Is -CH_Two-Cyclopropyl, cyclopentyl, 3-hi Droxycyclopentyl, methyl or CF_TwoH is; X is YR_TwoAnd Y is Oxygen; X_TwoIs oxygen; X_ThreeIs hydrogen; R_TwoIs CF_TwoWith H or methyl W is ethynyl or 1,3-butadiynyl; R_ThreeIs substituted or unsubstituted It is a compound that is a pyrimidinyl ring.   For example, as a compound:   Cis- [3- (3-Cyclopentyloxy-4-methoxyphenyl) -3- (4-pyridylethynyl) -1- (hydroxymethyl) cyclohexane], and And   Cis- [3- (3-cyclopentyloxy-4-methoxyphenyl) -3- ( 4-pyridylethynyl) -1- (aminomethyl) cyclohexane] Is mentioned.   All compounds of formula (I) are required to inhibit TNF production, including humans. In mammals, macrophages, monocytes or macrophages are preferably Useful in methods of inhibiting the production of TNF by spheres. All of the formula (I) The compounds are useful for inhibiting or mediating the enzymatic or catalytic activity of PDE IV, and Useful in the treatment of more mediated conditions.   Pharmaceutically acceptable salts of the compounds of the present invention, if they can be prepared, will also It is explicitly included. These salts are acceptable for their use in pharmaceutical applications You can do it. The salt retains the biological activity of the parent compound and is useful in treating disease. Has no harmful or toxic effects in applications and uses in   Pharmaceutically acceptable salts are prepared according to standard methods. Parent dissolved in a suitable solvent The compound is treated with an excess of an organic or inorganic acid in the case of an acid addition salt of a base and If the child has, for example, COOH, it is treated with an excess of an organic or inorganic base.   The pharmaceutical composition of the present invention comprises a pharmaceutical carrier or diluent and an amount of a compound of formula (I). Consists of The compound is present or intended in an amount that produces a physiological response. May require the user to take two or more units in order to perform any treatment It can be present in even smaller amounts. These compositions can be in solid, liquid or gaseous form Can be formed as Alternatively, when one of these three forms is administered, for example, When delivering the body by aerosol means, or spray or aerosol It may be converted to another form as in the case of delivering with a file.   The nature of the composition and the pharmaceutical carrier or diluent may, for example, be parenteral, local, or topical. It will depend on the oral, inhalation or the intended route of administration.   For topical administration, the pharmaceutical composition may be applied to a skin suitable for application to the skin, eyes, ears, or nose. Forms of ointments, ointments, liniments, lotions, pastes, aerosols and drops It is.   For parenteral administration, the pharmaceutical composition may be sterile injectable, such as an ampoule or aqueous. Or in the form of a non-aqueous liquid suspension.   For oral administration, the pharmaceutical composition may be a tablet, capsule, powder, pellet, troche , Lozenges, syrups, liquids or emulsions.   When the pharmaceutical composition is used in the form of a solution or suspension, a suitable pharmaceutical carrier or diluent may be used. Examples of excipients include, for example, water in the case of an aqueous system; Phosphorus, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil , Liquid paraffin and its mixture with water; lactose, kaori for solid systems And mannitol; for aerosol systems, dichlorodifluoromethane, Includes rotrifluoroethane and compressed carbon dioxide. A pharmaceutical carrier or In addition to diluents, the compositions of the present invention may contain other ingredients, such as stabilizers, antioxidants, It may contain preservatives, lubricants, suspending agents, viscosity modifiers, etc .; The component should not have a detrimental effect on the therapeutic effect of the composition of the invention.   Pharmaceutical preparations described in this way, according to the usual techniques of pharmacists, It will be the desired end product.   In these compositions, the amount of carrier or diluent will vary but, preferably, the active ingredient will Most of the suspension or solution. If the diluent is a solid, this is the solid active ingredient It may be present in less than, equal to, or greater than a minute.   In general, the compounds of the present invention will exhibit nontoxic levels of leukotriene-induced disease. Administered to the subject in a composition comprising an amount sufficient to inhibit the weather. Local treatment Formulations contain approximately 0.01-5.0% by weight of the active ingredient, and may be applied to the affected area as needed. Apply as a preventive or therapeutic agent. For oral, or other ingestion or injection formulation If administered, the dosage of the composition ranges from 50 mg to 1000 mg for each administration. Selected from the enclosed active ingredients. For convenience, administer an equal dose 1 to 5 times a day And the daily dose is selected from about 50 mg to about 5000 mg.   When these compounds are administered according to the present invention, unacceptable toxicological effects are Unthinkable.   The following examples illustrate the invention. These examples are not intended to Is not limited. Hereinafter, the matters held by the inventor are referred to in the claims. I do. Manufacturing method   Synthetic scheme described in the original text   Compounds of formula (I) are represented by Z and X_FourZ and Z as defined for formula (I) And X_FourOr Z and X_FourTerminal acetylene which is a group convertible to, for example, Compound1-Scheme 1With a suitable halide R_ThreeX (where R_ThreeIs the formula (I) R as defined_ThreeOr R_ThreeAnd a suitable catalyst For example, copper (I) halide in the presence of triphenylphosphine and divalent Or a suitable solvent such as an amine in the presence of a palladium compound or a zero-valent palladium compound. Brandsma et al. [Synthesis Communications (Syn.Comm.), 1990] , 20, 1889] by reacting as described herein. Prepared, formula2-Scheme 1Is obtained. formula1-Scheme 1The compound of U.S. Patent Application Serial No. 08 / 131,054 (filed October 1, 1993) and And related applications PCT / US94 / 10816 (filed on September 23, 1994) Can be prepared by methods analogous to those described in a) Pd (PPh_Three)_Four, PPh_Three, CuI, R_ThreeX, piperidine   Alternatively, Z, X_FourAnd R_ThreeZ, X as defined for formula (I)_FourYou And R_ThreeOr Z, X_FourOr R_ThreeA compound of the formula (I) which is a group convertible into Object is, for example, a compound1-Scheme 2Co-pending US from corresponding ketones such as Patent Application No. 08/131054 (filed October 1, 1993) and related patent applications Synthesis described in application PCT / US94 / 10816 (filed on Sep. 23, 1994) The synthesis of such ketone starting materials is described in co-pending US application 08/130215 (filed October 1, 1993) and PCT / US94 / 1 0815 (filed September 23, 1994) or co-pending USSN 08/130 213 and PCT application PCT / US94 / 10767 (10/1993, respectively). On March 1, 1994 and on September 23, 1994).   Alternatively, acid capture using a suitable metal salt, such as a copper salt and a catalytic amount of a palladium salt. A suitable alcohol as a scavenger in the presence of a suitable base, such as sodium acetate, For example, in methanol, the method of Tsuji et al. [Tetrahedron Letters (Tet) .Lett.), 1980, 21, 849]. Compound1-Scheme 3To oxidative carbonylation,2-Scheme 3Compound of The compound is then converted to a ketone as described above and subjected to standard esthetic procedures. The independent manipulation of the carboxylic acid ester using the (I) It may be converted to another compound. The synthesis of such ketone starting materials is simultaneous No. 08/130215 (filed October 1, 1993) and PCT / US94 / 10815 (filed September 23, 1994). a) PdCl_Two, CuCl_Two, NaO_TwoCCH_Three, CO, CH_ThreeOH; same as in scheme 2   Similarly, for example, compounds1-Scheme 4(Z and X_FourIs determined with respect to formula (I). Z and X defined_FourOr Z or X_FourIs a group that can be converted to And a suitable metal salt such as a copper salt with a catalytic amount of a palladium salt. Used together, in the presence of a suitable base such as sodium acetate as an acid scavenger, In a suitable alcohol such as ethanol, the method of Tsuji et al. [Tetrahedron. Oxidative carbohydrates as described in Letters (Tet. Lett.), 1980, 21, 849]. Nylation, the formula2-Scheme 4Is obtained. Manipulation of the carboxylic acid ester group using thiol exchange or amidation conditions provides the compound of formula (I) May be converted to other compounds. a) PdCl_Two, CuCl_Two, NaO_TwoCCH_Three, CO, CH_ThreeOH   The preparation of the remaining compounds of formula (I) is as described in the methods described above and in the examples below. Can be achieved in a similar manner.   Some of the compounds of formula (I) have different physical and biological properties It may exist in different diastereomeric forms, and such isomers are standard chromatographic Separation can be achieved by torography. Experimental example Example                                  Example 1 Cis- [3- (3-cyclopentyloxy-4-methoxyphenyl) -3- (4 -Pyridylethynyl) -1- (hydroxymethyl) cyclohexane]   Cis- [3- (3-cyclopentyloxy-4-methoxyphenyl) -3- ( 4-pyridylethynyl) cyclohexane-1-carboxylic acid] (0.22 g, 0.5 2 mmol, of a co-pending US application filed on the same day, identified as P50296 Methanol (0.025 ml) and borohydride Tetrahydrofuran (2.0 ml) containing titanium (0.02 g, 0.78 mmol) ) Is stirred overnight at room temperature under an argon atmosphere. The reaction mixture is salified Partition between methylene and acidic water, extract three times, dry (magnesium sulfate), and evaporate. Fire. Purify by flash column chromatography to obtain the product.                                  Example 2 Cis- [3- (3-cyclopentyloxy-4-methoxyphenyl) -3- (4 -Pyridylethynyl) -1- (aminomethyl) cyclohexane]   Under an argon atmosphere, cis- [3- (3-cyclopentyloxy-4-methoxy) Phenyl) -3- (4-pyridylethynyl) -1- (hydroxymethyl) cyclo Hexane] (0.067 g, 0.16 mmol) in tetrahydrofuran (2 ml) The medium solution was triphenylphosphine (0.04 g, 0.16 mmol), phthal (0.02 g, 0.16 mmol) followed by diethyl azodicarboxy Silate (0.03 ml, 0.16 mmol) is added dropwise. Whey reaction flask And stir the mixture at room temperature for 30 hours. Evaporate solvent and flush residue The product was purified by column chromatography to give the product phthalimide. Was dissolved in ethanol (0.5 ml) under an argon atmosphere, and hydrazine hydrate ( (0.08 ml, 0.15 mmol) for 3 days. Filter the precipitate by filtration Remove and add the filtrate to a silica column to elute the product. Practical example                                  Example A   Inhibitory effect of compounds of formula (I) on in vitro TNF production by human monocytes   The inhibitory effect of the compounds of formula (I) on in vitro TNF production by human monocytes is Badger et al., EPO Publication No. 0411754A2 (1991). February 6, 1990) and Hanna, WO 90/15534 (December 1990) 27)).                                  Example B   Using two experimental models of endotoxin shock, the in vitro for compounds of formula (I)  In vivo TNF activity was measured. Protocols used in these experimental models The method is described in Badger et al., EPO Publication No. 0411754A2 (19). February 6, 1991) and Hanna, WO 90/15534 (1990 (December 27).   The compound of Example 1 of the present invention is a serum level of TNF induced by endotoxin injection. Showed a positive in vivo response in the reduction of                                  Example C                           Isolation of PDE isoenzyme   The phosphodiesterase inhibitory activity and selectivity of the compounds of the present invention Can be determined using any of the PDE isoenzymes. Used as a source of different isoenzymes The following tissues are: 1) PDE Ib, porcine aorta; 2) PDE Ic Guinea pig heart; 3) PDE III, guinea pig heart; 4) PDE IV, human only Bulb; and 5) PDE V (also referred to as "Ia"), canine trachea. PDE Ia, Ib, Ic and III are partially purified using standard chromatography techniques [ Torphy and Cieslinski, Molecular Hu Pharmacol., 37: 206-214, 1990]. Anio with PDE IV Exchange, followed by continuous use of heparin-Sepharose chromatography And purify for kinetic identity [Torphy et al., Journal O. J. Biol. Chem., 267: 1798-1804, 1992] .   Phosphodiesterase activity is measured by Torphy and Seeslinski (Cieslinski) [Molecular Pharmacol., 37 : 206-214, 1990]. The present specification relates to formula (I) Positive ICs in the nanomolar to μM range for the compounds of the examples described in₅₀Is measured Have been.

────────────────────────────────────────────────── ─── Continuation of front page    (72) Inventor Carpinski, Joseph M             United States 19,644 Pennsylvania             Pottstown, North Charlotte Su             Treat 308 (72) Inventors Ryan, M Dominic             United States 19,644 Pennsylvania             Pottstown, Foxtail Dry             No. 2146 (72) Inventor Bender, Paul E             United States 08003 New Jersey               Cherry Hill, Lilac Rain             No. 504

Claims (1)

[Claims]   1. Formula (I): [Where,   R₁Is-(CR_FourR_Five)_nC (O) O (CR_FourR_Five)_mR₆,-(CR_FourR_Five)_nC (O) NR_Four(C R_FourR_Five)_mR₆,-(CR_FourR_Five)_nO (CR_FourR_Five)_mR₆Or-(CR_FourR_Five)_rR₆(here The alkyl moiety is unsubstituted or substituted with one or more fluorines. Has been replaced);   m is 0 to 2;   n is 0-4;   r is 0-6;   R_FourAnd R_FiveIs independently hydrogen or C_1-2Selected from alkyl;   R₆Is hydrogen, methyl, hydroxyl, aryl, halo-substituted aryl, aryl Oxy C_1-3Alkyl, halo-substituted aryloxy C_1-3Alkyl, indanyl, i Ndenyl, C_7-11Polycycloalkyl, tetrahydrofuranyl, furanyl, tet Lahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydro Thiopyranyl, thiopyranyl, C_3-6Cycloalkyl or one or two C containing a saturated bond_4-6Cycloalkyl (where cycloalkyl or hetero The ring moiety is unsubstituted or has 1 to 3 methyl groups, 1 ethyl group Or substituted with one hydroxyl group).   However,   a) R₆When is hydroxyl, m is 2; or   b) R₆When is hydroxyl, r is 2 to 6; or   c) R₆Is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2- When it is tetrahydrofuranyl or 2-tetrahydrothienyl, m is 1 or Is 2; or   d) R₆Is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2- R is not 1 when it is tetrahydrofuranyl or 2-tetrahydrothienyl And 6;   e) When n is 1 and m is 0,-(CR_FourR_Five)_nO (CR_FourR_Five)_mR₆In R₆Is a group other than H;   X is YR_Two, Halogen, fluorine, NR_FourR_FiveOr formylamine;   Y is O or S (O) m ';   m 'is 0, 1 or 2;   X_TwoIs O or NR₈Is;   X_ThreeIs hydrogen or X;   R_TwoIs -CH optionally substituted with one or more fluorine._Threeand -CH_TwoCH_ThreeSelected from the group consisting of:   R_ThreeIs COOR₁₄, C (O) NR_FourR₁₄Or R₇Is;   s is 0-4;   W is alkyl having 2 to 6 carbons, alkenyl having 2 to 6 carbons or 2 to 6 carbons Alkynyl;   Z is CR₈R₈OR₁₄, CR₈R₈OR_Fifteen, CR₈R₈SR₁₄, CR₈R₈SR_Fifteen, C R₈R₈S (O) m'R₇, CR₈R₈NR_TenR₁₄, CR₈R₈NR_TenS (O)_TwoNR_TenR₁₄, CR₈R₈NR_TenS (O)_TwoR₇, CR₈R₈NR_TenC (Y ') R₁₄, CR₈R₈NR_TenC (O ) OR₇, CR₈R₈NR_TenC (Y ') NR_TenR₁₄, CR₈R₈NR_TenC (NCN) NR_Ten R₁₄, CR₈R₈NR_TenC (CR_FourNO_Two) NR_TenR₁₄, CR₈R₈NR_TenC (NCN) S R₉, CR₈R₈NR_TenC (CR_FourNO_Two) SR₉, CR₈R₈C (O) OR₁₄, CR₈R₈C (Y ') NR_TenR₁₄, CR₈R₈C (NR_Ten) NR_TenR₁₄, CR₈R₈CN, CR₈R₈( Tetrazolyl), CR₈R₈(Imidazolyl), CR₈R₈(Imidazolidinyl), CR₈R₈(Pyrazolyl), CR₈R₈(Thiazolyl), CR₈R₈(Thiazolidinyl ), CR₈R₈(Oxazolyl), CR₈R₈(Oxazolidinyl), CR₈R₈(G Riazolyl), CR₈R₈(Isoxazolyl), CR₈R₈(Oxadiazolyl), CR₈R₈(Thiadiazolyl), CR₈R₈(Morpholinyl), CR₈R₈(Piperige Nil), CR₈R₈(Piperazinyl), CR₈R₈(Pyrrolyl), CR₈R₈C (NO R₈) R₁₄, CR₈R₈C (NOR₁₄) R₈, CR₈R₈NR_TenC (NR_Ten) SR₉, CR₈ R₈NR_TenC (NR_Ten) NR_TenR₁₄, CR₈R₈NR_TenC (O) C (O) NR_TenR₁₄Also Is CR₈R₈NR_TenC (O) C (O) OR₁₄Is;   X_FiveIs H, R₉, OR₈, CN, C (O) R₈, C (O) OR₈, C (O) NR₈R₈Also Is NR₈R₈Is;   X_FourIs H, R₉, OR₈, CN, C (O) R₈, C (O) OR₈, C (O) NR₈R₈Also Is NR₈R₈Is;   Y ′ is O or S;   R₇Is-(CR_FourR_Five)_qR₁₂Or C_1-6Alkyl (where R₁₂Or C_1-6Al The kill group may be unsubstituted, unsubstituted, Substituted one or more times by methyl or ethyl substituted by fluorine ), -F, -Br, -Cl, -NO_Two, -NR_TenR₁₁, -C (O) R₈, -CO_Two R₈, -O (CH_Two)_qR₈, -CN, -C (O) NR_TenR₁₁, -O (CH_Two)_qC (O) N R_TenR₁₁, -O (CH_Two)_qC (O) R₉, -NR_TenC (O) NR_TenR₁₁, -NR_TenC (O ) R₁₁, -NR_TenC (O) OR₉, -NR_TenC (O) R₁₃, -C (NR_Ten) NR_TenR₁₁, -C (NCN) NR_TenR₁₁, -C (NCN) SR₉, -NR_TenC (NCN) SR₉, -N R_TenC (NCN) NR_TenR₁₁, -NR_TenS (O)_TwoR₉, -S (O)_m'R₉, -NR_TenC ( O) C (O) NR_TenR₁₁, -NR_TenC (O) C (O) R_TenOr R₁₃Is;   q is 0, 1 or 2;   R₁₂Is R₁₃, C_3-7Cycloalkyl, or (2-, 3- or 4-pyridyl ), Pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, pi Perazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl ), Quinolinyl, naphthyl and phenyl. Or place A substituted aryl or heteroaryl group;   R₁₂Is R₁₃, C_3-7Cycloalkyl, (2-, 3- or 4-pyridyl), Limidyl, pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazi Nil, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), Selected from quinolinyl, naphthyl or phenyl;   R₈Is hydrogen or R₉Is;   R₉Is a C which may be substituted by 1 to 3 fluorines_1-4Alkyl;   R_TenIs OR₈Or R₁₁Is;   R₁₁Is hydrogen or C which may be substituted by 1 to 3 fluorines_1-4Archi Or R_TenAnd R₁₁Is -NR_TenR₁₁Are nitrogen and Together carbon or carbon and at least one selected from O, N or S Forming a 5- to 7-membered ring consisting of another heteroatom;   R₁₃Is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazo Ryl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, iso Selected from the group consisting of xazolyl, oxadiazolyl or thiadiazolyl An unsubstituted or substituted heteroaryl group;₁₃Is R₁₂Or R₁₃Replaced by Each ring is connected via a carbon atom to form a second R₁₃The rings are each substituted Or the methyl may be substituted with one or three fluoro atoms. One or two C_1-2Substituted with alkyl;   R₁₄Is hydrogen or R₇Or R₈And R₁₄Is NR₈R₁₄Place like If they are, together with nitrogen, selected from carbon or carbon and O, N or S. Forming a 5- to 7-membered ring having one or more other heteroatoms;   R_FifteenIs C (O) R₁₄, C (O) NR_FourR₁₄, S (O)_TwoR₇Or S (O)_TwoNR_FourR₁₄so is there;   However,   f) R₇Is C which may be substituted by 1 to 3 fluorines_1-4Other than alkyl Is the base) Or a pharmaceutically acceptable salt thereof.   2. R₁Is -CH_Two-Cyclopropyl, -CH_Two-C_5-6With cycloalkyl, OH -C substituted or unsubstituted_4-6Cycloalkyl, tetrahydrofuran- 3-yl, (3- or 4-cyclopentenyl), with one or more fluorines Substituted or unsubstituted benzyl or -C_1-2Alkyl or-(CH_Two )_2-4OH; R_TwoIs methyl or fluoro-substituted alkyl; W is ethini Or 1,3-butadiynyl; R_ThreeIs R₇(Where R₇Is unsubstituted or replaced X is YR_TwoAnd Z is CR₈R₈ OR_FifteenOr CR₈R₈NR_TenR₁₄The compound according to claim 1, which is   3. R₁Is -CH_Two-Cyclopropyl, cyclopentyl, 3-hydroxycyclo Pentyl, methyl or CF_TwoH is; X is YR_TwoY is oxygen; X_Two Is oxygen; X_ThreeIs hydrogen; R_TwoIs CF_TwoH or methyl; W is ethyl Rl or 1,3-butadiynyl;_ThreeIs a substituted or unsubstituted pyrimidinyl ring The compound according to claim 2, which is   4.   Cis- [3- (3-cyclopentyloxy-4-methoxyphenyl) -3- ( 4-pyridylethynyl) -1- (hydroxymethyl) cyclohexane], or   Cis- [3- (3-cyclopentyloxy-4-methoxyphenyl) -3- ( 4-pyridylethynyl) -1- (aminomethyl) cyclohexane] The compound according to claim 2, which is   5. It does not contain the compound of formula (I) of claim 1 and a pharmaceutically acceptable excipient. Pharmaceutical compositions.