4-azetidinyl-1-phenyl-cyclohexane antagonists of ccr2

Abstract

The present invention comprises compounds of Formula (I): wherein: X, R 1 , R 2 , R 3 , and R 4 are as defined in the specification. The invention also comprises a method of preventing, treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is type II diabetes, obesity and asthma. The invention also comprises a method of inhibiting CCR2 activity in a mammal by administration of a therapeutically effective amount of at least one compound of Formula (I).

1 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein:
 X is NH 2 , F, H, SH, S(O)CH 3 , SCH 3 , SO 2 CH 3 , or OH; 
 R 1  is phenyl optionally substituted with one or two substituents, one of which is selected from the group consisting of: OC (1-4) alkyl, SC (1-4) alkyl, SOC (1-4) alkyl, SO 2 C (1-4) alkyl, —OSO 2 NH 2 , —SO 2 NHC (1-4) alkyl, —OSO 2 NH 2 , —SO 2 NH 2 , N(C (1-4) alkyl) 2 , NH 2 , NHC 1-4) alkyl, NHSO 2 C (1-4) alkyl, N(SO 2 CH 3 ) 2 , OH, OC (1-4) alkylCO 2 C (1-4) alkyl, OC (1-4) alkylCO 2 H, OCH 2 CH 2 N(C (1-4) alkyl) 2 , F, Cl, CH 2 CN, CN, C (1-4) alkyl, NHCO 2 H, NHCO 2 C (1-4) alkyl, NHCOC (1-4) alkyl, —C≡CH, CONH 2 , NHCONH 2 , NHCONHC (1-4) alkyl, CONHC (1-4) alkyl, CH 2 CONHC (1-4) alkyl, C (1-4) alkylCONH 2 , C (1-4) alkylCO 2 C (1-4) alkyl, C (1-4) alkylCO 2 H, CO 2 H, CH 2 C(NH)NH 2 , CO 2 C (1-4) alkyl, CF 3 , OCHF 2 , CHF 2 , OCF 3 , OCH 2 CF 3 , cycloalkyl, heterocyclyl, phenoxy, phenyl, CH 2 phenyl, CH 2 heteroaryl, and heteroaryl; and the second substituent, if present, is selected from the group consisting of F, C (2-4) alkyl and OCH 3 , or said phenyl may be substituted on two adjacent carbon atoms to form a fused bicyclic system, selected from the group consisting of benzothiazolyl, benzooxazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, 3H-benzothiazol-2-onyl, 3H-benzooxazol-2-onyl, 1,3-dihydro-benzoimidazol-2-onyl, 1-methyl-1H-benzoimidazolyl, benzo[1,3]dioxolyl, 2,3-dihydro-benzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, wherein said 3H-benzooxazol-2-onyl, 1,3-dihydro-benzoimidazol-2-onyl, and 1-methyl-1H-benzoimidazolyl, are optionally substituted on any nitrogen atom with C (1-4) alkyl; 
 R 2  is H, C (1-4) alkyl, NH 2 , NO 2 , NHCH 2 CH 2 OH, N(C (1-4) alkyl) 2 , N(SO 2 CH 3 ) 2 , NHCONHC (1-4) alkyl, CN, F, Cl, Br, CF 3 , cycloalkyl, heterocyclyl, OCF 3 , OCF 2 H, CF 2 H, or OC (1-4) alkyl; 
 R 3  is F, Cl, CF 3 , or OC (1-4) alkyl; alternatively, R 2  and R 3  may be taken together with their attached phenyl to form a benzo[1,3]dioxolyl, 2,3-dihydro-benzofuranyl, or 2,3-dihydro-benzo[1,4]dioxinyl group; 
 R 4  is H, OC (1-4) alkyl, or F; 
 
       and solvates, hydrates, tautomers, prodrugs, and pharmaceutically acceptable salts thereof. 
     
     
         2 . A compound of  claim 1  wherein:
 X is NH 2 , F, H, or OH;   R 1  is phenyl optionally substituted with one or two substituents, one of which is selected from the group consisting of: OC (1-4) alkyl, SC (1-4) alkyl, SOC (1-4) alkyl, SO 2 C (1-4) alkyl, —OSO 2 NH 2 , —SO 2 NHC (1-4) alkyl, —OSO 2 NH 2 , —SO 2 NH 2 , N(C (1-4) alkyl) 2 , NH 2 , NHC (1-4) alkyl, NHSO 2 C (1-4) alkyl, N(SO 2 CH 3 ) 2 , OH, OCH 2 CO 2 C (1-4) alkyl, OCH 2 CO 2 H, OCH 2 CH 2 N(CH 3 ) 2 , F, Cl, CH 2 CN, CN, C (1-4) alkyl, NHCO 2 H, NHCO 2 C (1-4) alkyl, NHCOC (1-4) alkyl, —C≡CH, CONH 2 , NHCONH 2 , NHCONHC (1-4) alkyl, CONHC (1-4) alkyl, CH 2 CONHC (1-4) alkyl, CH 2 CONH 2 , CH 2 CO 2 C (1-4) alkyl, CH 2 CO 2 H, CO 2 H, CH 2 C(NH)NH 2 , CO 2 C (1-4) alkyl, CF 3 , OCHF 2 , CHF 2 , OCF 3 , cyclopentyl, cyclohexyl, morpholinyl, piperazinyl, piperidinyl, phenoxy, CH 2 phenyl, phenyl, CH 2 pyridyl, pyridyl, pyrrolidinyl, CH 2 tetrazolyl, and tetrazolyl; and the second substituent, if present, is selected from the group consisting of F, CH 2 CH 3  and OCH 3 , or said phenyl may be substituted on two adjacent carbon atoms to form a fused bicyclic system, selected from the group consisting of 3H-benzothiazol-2-onyl, 3H-benzooxazol-2-onyl, 1,3-dihydro-benzoimidazol-2-onyl, 1-methyl-1H-benzoimidazolyl, benzo[1,3]dioxolyl, 2,3-dihydro-benzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, wherein said 3H-benzooxazol-2-onyl, 1,3-dihydro-benzoimidazol-2-onyl, and 1-methyl-1H-benzoimidazolyl, are optionally substituted on any nitrogen atom with C (1-4) alkyl;   R 2  is H, C (1-4) alkyl, NH 2 , NO 2 , NHCH 2 CH 2 OH, N(C (1-4) alkyl) 2 , N(SO 2 CH 3 ) 2 , NHCONHC (1-4) alkyl, CN, F, Cl, Br, CF 3 , pyridinyl, pyrrolidinyl, OCF 3 , OCF 2 H, CF 2 H, or OC (1-4) alkyl;   R 3  is F, Cl, CF 3 , or OC (1-4) alkyl; alternatively, R 2  and R 3  may be taken together with their attached phenyl to form a benzo[1,3]dioxolyl group;   R 4  is H, OCH 3 , or F;   
       and solvates, hydrates, tautomers, prodrugs, and pharmaceutically acceptable salts thereof. 
     
     
         3 . A compound  claim 2  wherein:
 R 1  is phenyl optionally substituted with one or two substituents, one of which is selected from the group consisting of: OC (1-4) alkyl, SC (1-4) alkyl, SO 2 CH 3 , N(C (1-4) alkyl) 2 , NH 2 , NHSO 2 C (1-4) alkyl, N(SO 2 CH 3 ) 2 , OH, F, Cl, CH 2 CN, CN, C (1-4) alkyl, NHCO 2 C(CH 3 ) 3 , OCH 2 CO 2 C (1-4) alkyl, OCH 2 CO 2 H, OCH 2 CH 2 N(CH 3 ) 2 , —C≡CH, CONH 2 , CO 2 H, CO 2 C (1-4) alkyl, CH 2 CO 2 H, CH 2 CO 2 C (1-4) alkyl, CH 2 C(NH)NH 2 , CH 2 CONH 2 , pyrrolidinyl, CH 2 tetrazolyl, and tetrazolyl; and the second substituent, if present, is selected from the group consisting of F, CH 2 CH 3  and OCH 3 , or said phenyl may be substituted on two adjacent carbon atoms to form a fused bicyclic system, selected from the group consisting of 3H-benzooxazol-2-onyl, 1,3-dihydro-benzoimidazol-2-onyl, 1-methyl-1H-benzoimidazolyl, benzo[1,3]dioxolyl, 2,3-dihydro-benzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, wherein said 3H-benzothiazol-2-onyl, 3H-benzooxazol-2-onyl, 1,3-dihydro-benzoimidazol-2-onyl, and 1-methyl-1H-benzoimidazolyl, are optionally substituted on any nitrogen atom with C (1-4) alkyl;   R 2  is H, NH 2 , NO 2 , NHCH 2 CH 2 OH, N(CH 3 ) 2 , N(SO 2 CH 3 ) 2 , NHCONHC (1-4) alkyl, CN, F, Cl, Br, CF 3 , pyridinyl, pyrrolidinyl, or OCH 3 ;   R 3  is F, Cl, CF 3 , or OCH 3 ; alternatively, R 2  and R 3  may be taken together with their attached phenyl to form a benzo[1,3]dioxolyl group;   R 4  is H, or F;   
       and solvates, hydrates, tautomers, prodrugs, and pharmaceutically acceptable salts thereof. 
     
     
         4 . A compound  claim 3  wherein:
 R 1  is phenyl optionally substituted with one substituent selected from the group consisting of: OC (1-4) alkyl, SC (1-4) alkyl, SO 2 CH 3 , N(C (1-4) alkyl) 2 , NH 2 , NHSO 2 C (1-4) alkyl, N(SO 2 CH 3 ) 2 , OH, F, Cl, CH 2 CN, CN, C (1-4) alkyl, NHCO 2 C(CH 3 ) 3 , OCH 2 CO 2 C (1-4) alkyl, OCH 2 CO 2 H, OCH 2 CH 2 N(CH 3 ) 2 , —C≡CH, CONH 2 , CO 2 H, CO 2 C (1-4) alkyl, CH 2 CO 2 H, CH 2 CO 2 C (1-4) alkyl, CH 2 C(NH)NH 2 , CH 2 CONH 2 , pyrrolidinyl, CH 2 tetrazolyl, and tetrazolyl; or said phenyl may be substituted with one OCH 3  group and one F, or said phenyl may be substituted on two adjacent carbon atoms to form a fused bicyclic system, selected from the group consisting of 3H-benzothiazol-2-onyl, 3H-benzooxazol-2-onyl, 1,3-dihydro-benzoimidazol-2-onyl, 1-methyl-1H-benzoimidazolyl, benzo[1,3]dioxolyl, 2,3-dihydro-benzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, wherein said 3H-benzooxazol-2-onyl, 1,3-dihydro-benzoimidazol-2-onyl, and 1-methyl-1H-benzoimidazolyl, are optionally substituted on any nitrogen atom with C (1-4) alkyl. and solvates, hydrates, tautomers, prodrugs, and pharmaceutically acceptable salts thereof.   
     
     
         5 . A compound  claim 4  wherein:
 R 1  is phenyl,   
       
         
           
           
               
               
           
         
         wherein said phenyl is optionally substituted with one substituent selected from the group consisting of: OCH 3 , SCH 3 , SO 2 CH 3 , N(CH 3 ) 2 , NH 2 , NHSO 2 CH 3 , N(SO 2 CH 3 ) 2 , OH, F, Cl, CH 2 CN, CN, CH 3 , NHCO 2 C(CH 3 ) 3 , OCH 2 CO 2 CH 3 , OCH 2 CO 2 H, OCH 2 CH 2 N(CH 3 ) 2 , —C≡CH, CH 2 CH 3 , CONH 2 , CO 2 H, CO 2 CH 3 , CO 2 CH 2 CH 3 , CH 2 CO 2 H, CH 2 CO 2 CH 2 CH 3 , CH 2 C(NH)NH 2 , CH 2 CONH 2 , pyrrolidinyl, CH 2 tetrazolyl and tetrazolyl; or said phenyl may be substituted with one OCH 3  group and one F; 
         R 2  is H, F, Br, CF 3 , NO 2 , NH 2 , NHCH 2 CH 2 OH, N(CH 3 ) 2 , N(SO 2 CH 3 ) 2 , NHCONHC (1-4) alkyl, pyrrolidinyl, pyridinyl, OCH 3 ; 
         R 3  is CF 3 ; 
         R 4  is H; 
       
       and solvates, hydrates, tautomers, prodrugs, and pharmaceutically acceptable salts thereof. 
     
     
         6 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and solvates, hydrates, tautomers, prodrugs, and pharmaceutically acceptable salts thereof. 
     
     
         7 . A compound of  claim 6  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and solvates, hydrates, tautomers, prodrugs, and pharmaceutically acceptable salts thereof. 
     
     
         8 . A compound of  claim 7 , which is 
       
         
           
           
               
               
           
         
       
       and solvates, hydrates, tautomers, prodrugs, and pharmaceutically acceptable salts thereof. 
     
     
         9 . A pharmaceutical composition, comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         10 . A pharmaceutical composition made by mixing a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         11 . A process for making a pharmaceutical composition comprising mixing a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         12 . A process for the preparation of a compound of Formula (I) of  claim 1 , comprising reacting a compound of Formula (V) 
       
         
           
           
               
               
           
         
       
       with a compound of Formula (VI) 
       
         
           
           
               
               
           
         
       
       in the presence of a reducing agent to provide the compound of Formula (I). 
     
     
         13 . A product made by the process of  claim 12 . 
     
     
         14 . A process for the preparation of a compound of Formula (I) of  claim 1 , comprising reacting a compound of Formula (XIII) 
       
         
           
           
               
               
           
         
       
       where R a  is OH or Cl, with 
       
         
           
           
               
               
           
         
       
       in the presence of HOBt/EDCI or Et 3 N to provide the compound of Formula (I). 
     
     
         15 . A product made by the process of  claim 14 . 
     
     
         16 . A method for preventing, treating or ameliorating a CCR2 mediated syndrome, disorder or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         17 . A method for preventing, treating or ameliorating a CCR2 mediated inflammatory syndrome, disorder or disease wherein the syndrome, disorder or disease is associated with elevated MCP-1 expression or MCP-1 overexpression, or is an inflammatory condition that accompanies syndromes, disorders or diseases associated with elevated MCP-1 expression or MCP-1 overexpression comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 . 
     
     
         18 . A method of preventing, treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is selected from the group consisting of: Chronic Obstructive Pulmonary Disease (COPD), ophthalmic disorders, uveitis, atherosclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, multiple sclerosis, Crohn's Disease, ulcerative colitis, nephritis, organ allograft rejection, fibroid lung, renal insufficiency, type-I diabetes, type II diabetes and diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, overweight, obesity, obesity-associated insulin resistance, tuberculosis, chronic obstructive pulmonary disease, sarcoidosis, invasive staphyloccocia, inflammation after cataract surgery, allergic rhinitis, allergic conjunctivitis, chronic urticaria, asthma, allergic asthma, periodontal diseases, periodonitis, gingivitis, gum disease, diastolic cardiomyopathies, cardiac infarction, myocarditis, chronic heart failure, angiostenosis, restenosis, reperfusion disorders, glomerulonephritis, solid tumors and cancers, chronic lymphocytic leukemia, chronic myelocytic leukemia, multiple myeloma, malignant myeloma, Hodgkin's disease, and carcinomas of the bladder, breast, cervix, colon, lung, prostate, or stomach comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 . 
     
     
         19 . A method of preventing, treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is selected from the group consisting of: type II diabetes and diabetic complications, diabetic nephropathy, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, obesity, asthma, and allergic asthma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         20 . A method of treating a disorder selected from the group consisting of type II diabetes, obesity and asthma comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         21 . A compound of  claim 1 , which is the less polar isomer of any of Examples #1-88. 
     
     
         22 . A compound of  claim 1 , which is the less polar isomer of Example #30.