(12) United States Patent (10) Patent No.: US 7,183.293 B2 Marfat Et Al

US007 183293B2

(12) United States Patent (10) Patent No.: US 7,183.293 B2 Marfat et al. (45) Date of Patent: *Feb. 27, 2007

(54) ETHER DERIVATIVES USEFUL AS WO WO9918793 4f1999 INHIBITORS OF PDE4 ISOZYMES WO WO9920280 4f1999 WO WO992O625 4f1999 (75) Inventors: Anthony Marfat, Mystic, CT (US); WO WO O157O25 8, 2001 Robert J. Chambers, Msytic, CT (US); WO WO O157.036 8, 2001 Thomas V. Magee, Mystic, CT (US) OTHER PUBLICATIONS Trophy, Theodore J. et al., “Phosphodiesterase IV Inhibitors as (73) Assignees: Pfizer Inc., New York, NY (US); Pfizer Therapy for Eosinophil-induced Lung Injury in Asthma, Environ Products Inc., Groton, CT (US) mental Health Perspectives, vol. 102 Suppl. 10, Dec. 1994, pp. 79-84. (*) Notice: Subject to any disclaimer, the term of this (Continued) patent is extended or adjusted under 35 U.S.C. 154(b) by 97 days. Primary Examiner Rita Desai (74) Attorney, Agent, or Firm—Robert T. Ronau; Rosanne This patent is Subject to a terminal dis Goodman; Charles W. Ashbrook claimer. (21) Appl. No.: 10/918,820 (57) ABSTRACT (22) Filed: Aug. 13, 2004 This application is directed to compounds of the formula

(65) Prior Publication Data US 2005/00492.58 A1 Mar. 3, 2005 Related U.S. Application Data (62) Division of application No. 10/066,503, filed on Jan. 31, 2002, now Pat. No. 6,828,333. (60) Provisional application No. 60/265,304, filed on Jan. 31, 2001. (51) Int. Cl. whereinj is 1; k is 0 or 1; m is 1, 2 or 3; n is 1 or 2; W and CO7D 405/2 (2006.01) Ware independently —O— or S(=O), , where t is 0, A6 IK 3/44 (2006.01) 1, or 2: Y is =C(R') , where R is a member selected from the group consisting of H; F: Cl; CN: NO; —(C-C) (52) U.S. Cl...... 514/338; 546/284.1:546/270.1; alkyl; —(C-C)alkynyl; fluorinated-(C-C)alkyl; fluori 546/281.1 nated-(C-C)alkoxy; —OR'; and –C(=O)NR'R'',: (58) Field of Classification Search ...... 546/284.1 Rn, and R, are defined as set forth in the specification; 546/270. 1, 281. 1: 514/338 —R and Rare each a member independently selected from See application file for complete search history. the group consisting of H; F, CF; —(C-C)alkyl; (56) References Cited —(C-C)cycloalkyl, phenyl; and benzyl; wherein said cycloalkyl, phenyl, and benzyl moieties are each indepen U.S. PATENT DOCUMENTS dently substituted with 0 to 3 substituents R', which is 4,270,946 A 6/1981 Gutman ...... T1.94 defined as set forth in the specification; R'' and R'' are 4,692, 185 A 9/1987 Michaely ...... defined as set forth in the specification; R and RP have 4,861,891 A 8, 1989 Saccomano et al...... 546,194 the same meaning as defined above for RandR except that 5,552,438 A 9, 1996 Christensen, IV ...... 514,520 one of them must be —H, and they are selected indepen 5,602,157 A 2, 1997 Christensen, IV ...... 514,362 dently of each other and of R and R. R. and Rare each 5,614,540 A 3/1997 Christensen, IV ...... 514,362 a member independently selected from the group consisting 5,863,926 A 1/1999 Christensen, IV et al. .. 514/277 of H; F: Cl; CN: NO; —(C-C)alkyl; —(C-C)alkynyl: 5,922,557 A 7, 1999 Pon ...... 435/21 fluorinated-(C-C)alkyl: OR'; and C(=O)NR'R'',: 6,380,218 B1 4/2002 Marfat et al...... 514/326 -R is H;-(C-C)alkyl; phenyl; benzyl: or OR: R. R. 6,828,333 B2 * 12/2004 Marfat et al...... 514,338 and Rare defined as set forth in the specification: J' and J’ FOREIGN PATENT DOCUMENTS are each independently a moiety comprising a saturated or unsaturated six-membered monocyclic carbon ring; and Dis EP O550900 12/1992 a member independently selected from the group consisting EP O773024 5, 1997 EP OSOO989 12/1998 of partial Formulas (1.1.1) through (1.1.5) as set forth in the FR 214O772 1, 1973 specification; a pharmaceutically acceptable salt thereof. GB 2327675 2, 1999 which are useful as inhibitors of PDE4 in the treatment of JP 7304775 11, 1995 diseases regulated by the activation and degranulation of WO WO95OO139 1, 1995 eosinophils, especially asthma, chronic bronchitis, and WO WO 98.18796 5, 1998 chronic obstructuive pulmonary disease. WO WO9845268 10, 1998 WO WO9845628 10, 1998 3 Claims, No Drawings US 7,183.293 B2 Page 2

OTHER PUBLICATIONS Pascal.Y., et. al., “Synthesis and Structure.-activity Relationships of 4-oxo-1 pheyl-3,4,5,7-Tetrahydro-14Diazepino.6.7.1- Duplantier, Allen J., et al., “Biarylcarboxylic Acids and -amides: HIIndolines: Novel PDE4 Inhibitors,” 215 ACS, MEDI, 50, 1998. Inhibition of PhosphodiesteraseType IV versus HIRolipram Bind Burnouf, C., et. al., “Pharmacology of the Novel Phosphodiesterase ing Activity and Their Relationship to Emetic Behavior in the Type 4 Inhibitor, CI-1018, 215th ACS, MEDL 008, 1998. Ferret, Journal of Medicinal Chemistry.” 1996, vol. 39, No. 1, pp. 120-125. Mueller, George W., et. al., N-Phthaloyl-B-Aryl-B-Amino Deriva Schneider, Herbert H. et al., “Discriminative Stimulus Properties of tives Potent TNF-O. And PDE4 Inhibitors, MEDI, 299, 1999. the Stereoisomers of the Phosphodiesterase Inhibitor Rolipram.” Mueller, George W., et. al., “Thalidomide Analogs and PDE4 Pharmacology Biochemistry and Behavior, vol. 50, No. 2, 1995, pp. Inhibition.” Bioorganic & Medicinal Chemistry Letters, 8, 1998, pp. 211-217. 2669-2674. Banner, Katherine H., et. al., “Acute versus chronic administration Takayama, K., “Synthetic Studies on Selective Type IV of phosphodiesterase inhibitors on allergen-induced pulmonary cell Phosphodiesterase (PDE IV) Inhibitors,” MEDI 245, 1997. influx in sensitized guinea-pigs, British Journal of Pharmacology, Gordon, T., et. al., “Anti-Inflammatory Effects of a PDE4 Inhibitor 114, 1995, pp. 93-98. in a Rat Model of Chronic Bronchitis.” Am. J. Respir. Crit. Care Barnette, Mary S., et. al., “The Ability of Phosphodiesterase IV Med., 159, A33, 1999. Inhibitors to Suppress Superoxide Production in Guinea Pig Perrier, Helene, et. al., “Substituted Furans as Inhibitors of the Eosinophils Is Correlated with Inhibition of Phosphodiesterase IV PDE4 Enzyme.” Bioorganic & Medicinal Chemistry Letters 9, Catalytic Activity.” The Journal of Pharmacology and Experimental 1999, pp. 323-326. Therapeutics, 273, 1995 pp. 674-679. Groneberg, Robert D., et al., “Dual Inhibition of Phosphodiesterase Wright, Kathryn, F., et al., “Differential in vivo and in vitro 4 and Matrix Metalloproteinases by an (Arylsulfonyl)hydroxamic bronchorelaxant activities of CP-80,633, a selective Acid Template.” Journal of Medicinal Chemistry, 1999, vol. 42, No. phosphodiesterase 4 inhibitor.”Can. J. Physiol. Pharmacol. 75. 4, pp. 541-544. 1997, pp. 1001-1008. Fujimura, Masaki, et. al. Bronchoprotective Effects of KF-19514 Manabe, Haruhiko, “Anti-Inflammatory and Bronchodilator Prop and Cilostazol in Guinea Pigs In Vivo, European Journal of Phar erties of KF19514, a Phosphodiesterase 4 and 1 Inhibitor.” Euro macology, 327, 1997, pp. 57-63. pean Journal of Pharmacology, 332, 1997, pp. 97-107. Manabe, Haruhiko, et. al., “KF19514, a Phosphodiesterase 4 and 1 Ukita, Tatsuzo, et. al., Novel, Potent, and Selective Inhibitor, Inhibits PAF-Induced Lung Inflammatory Responses by Phosphodiesterase-4 Inhibitors as Antiasthmatic Agents: Synthesis Inhaled Administration in Guinea Pigs.” International Archives of and Biological Activities of a Series of 1-Pyridylnaphthalene Allergy-Immunology, 1997. 114, pp. 389-399. Derivatives, J. Med. Chem, 48, 1999, pp. 1088-1099. Suzuki, Fumio, et. al., “New Bronchodilators, 3. Imidazo4.5- Compton, CH, et. al., The Efficacy of ArifloTM (SB 207499. A c1.8 naphthyridin-4(5H)-ones,” Journal of Medicinal Chemistry, Second Generation, Oral PDE4 Inhibitor, In Patients with COPD, 1992, vol. 35, No. 26, pp. 4866-4874. Am. J. Respir, Crit. Care Med., 159, 1999, Leeman, Marc M.D., et. al., “Reduction in Pulmonary Hypertension Matsuura, Akihiro, et. al., "Substituted 1.8-Naphthyridin-2(1H)- and in Airway Resistances by Enoximone (MDL 17,043) in ones as Selective Phosphodiesterase IV Inhibitors.” Biol. Pharm. Decompensated COPD*,” Chest, 91, 1987, pp. 662-666. Bull. vol. 17(4), 1994, pp. 498-503. Rabe, K.F., et. al., “Identification of PDE Isozymes in Human Manabe, Haruhiko, et. al., “Pharmacological properties of a New Pulmonary Artery and Effect of Selective PDE Inhibitors.” Am. J. Bronchodilator, KF17625.” Jpn. J. Pharmacol., 58 (Suppl 1)., 1992 Physiol, 266 (LCMP 10), 1994, pp. L536-L543. pp. 238. Hughes, Bernadette, et. al., PDE 4 inhibitors: the use of molecular Montana, John G., et. al., “PDE4 Inhibitors: New Xanthine Ana cloning in the design and development of novel drugs, Drug logues.” Bioorganic & Medicinal Chemistry Letters 8, 1998, pp. Discovery Today, Science Direct, 2(3), 1997, pp. 89-101. 2925-2930. Banner, K.H., et al., “The Effect of Selective Phosphodiesterase Merz, Karl-Heinz, et. al., “Synthesis of 7-Benzylamino-6-chloro Inhibitors in Comparison with other Anti-asthma Drugs on Aller 2-piperazino-4-pyrrolidinopteridine and Novel Derivatives Free of gen-induced Eosinophilia in Guinea-pig Airways.” Pulmonary Positional Isomers. Potent Inhibitors of cAMP-Specific Pharmacology, 8, 1995, pp. 37-42. Phosphodiesterase and of Malignant Tumor Cell Growth.” Journal Raebum, David, et al., “Anti-inflammatory and bronchodilator of Medicinal Chemistry, vol. 41, No. 24, 1998, pp. 4733–4743. properties of RP 73401, a novel and selective phosphodiesterase Danhaive, P. et al., “UCB29936, A Selective Phosphodiesterase typed IV inhibitor.” Br, J. Pharmacol., 113, 1994, pp. 1423-1431. Type IV Inhibitor; Therapeutic Potential In Endotoxic Shock.” Am. Karlsson, J.A., et. al., “Anti-Inflammatory Effects of the Novel J. Respir, Crit. Care Med., 159, A611, 1999. Phosphodiesterase IV Inhibitor RP 73401.” Int. Arch Allergy Tian, Gaochao, et. al., “Dual Inhibition of Human Type 4 Immunol. 107, 1995, pp. 425-426. Phosphodiesterase Isostates by (R,R)-(+)-Methyl 3-Acetyl-4-3- Escott, K.J., et. al., Pharmacological Profiling of Phosphodiesterase, (cyclopentyloxy)-4-methoxyphenyl-3-methyl-1-pyr 4 (PDE4) Inhibitors and Analysis of the Therapeutic Ratio in Rats rolindinecarboxylate.” Biochemistry, 37(19), 1998 pp. 6894-6904. and Dogs, Br, J. Pharmacol. 123 (Proc suppl.) 1998 40P. Norman, Peter, “PDE4 Inhibitors 1999.” Exp. Opin. Ther. Patents Landells, L.J., et. al., “Oral Administration of the Phosphodiesterase 9(8) 1999, pp. 1101-1118. (PDE) 4 Inhibitor, V11294A Inhibits Ex-Vivo Agonist-induced Cell Activation.” Eur, Resp. J., 12 (Suppl. 28), 362s, 1998, P2393. Dyke, Hazel J. & Montana, John G., “The Therapeutic Potential of Gale, D.D., et. al., “Pharmacodynamic-Pharmacokinetic (PD/PK) PDE4 Inhibitors.” Expert Opinion on Investigational Drugs, 8(9), Profile of the Phosphodiesterase (PDE)4. Inhibitor, V11294A, in 1999, pp. 1301-1325. Human Volunteers.” Am. J. Respir. Crit Care Med., 159, A611, XP-002066969, Vinivk, Fredric J., et. al., “Nicotinamide Ethers: 1999, pp. A108. Novel Inhibitors of Calcium-Independent Phosphodiesterase and Montana, J., et. al., “Activity of D4418. A Novel Phosphodiesterase 3H]Rolipram Binding.” Journal of Medicinal Chemistry, vol. 34. 4 (PDE4) Inhibitor, Effects in Cellular and Animal Models of No. 1, 1991, pp. 86-89. Asthma and Early Clinical Studies,” Am. J. Respir. Crit., Care Med., Pruniaux, M.P., et. al., “The novel phosphodiesterase 4 inhibitor 159, A108, 1999, pp. A624. CI-1018 inhibits antigen-induced lung eosinophilia in sensitized Cavalla, D., et. al., “Activity of V11294A, A Novel brown-norway rats—comparison with rollipram.' Mediators of Phosphodiesterase 4 (PDE4) Inhibitor. In Cellular and Animal Inflammation, vol. 8, Supplement 1, 1999, S-04-6, pp. S10. Models of Asthma.” Am. J. Respir. Crit. Care Med. 155, 1997, pp. A660. * cited by examiner US 7,183,293 B2 1. 2 ETHER DERVATIVES USEFUL AS recent years, and beneficial pharmacological effects result INHIBITORS OF PDE4 ISOZYMES ing from that inhibition have been shown in a variety of disease models. See, e.g., Torphy et al., Environ. Health CROSS REFERENCE TO RELATED Perspect. 102 Suppl. 10, 79–84, 1994; Duplantier et al., J. APPLICATIONS Med. Chem. 39 120–125, 1996: Schneider et al., Pharmacol. Biochem. Behav. 50 211–217, 1995; Banner and Page, Br. J. This application is a division of U.S. application Ser. No. Pharmacol. 11493–98, 1995; Barnette et al., J. Pharmacol. 10/066,503, filed Jan. 31, 2002, now U.S. Pat. No. 6,828,333 Exp. Ther. 273 674–679, 1995; Wright et al., “Differential in which claims the benefit of U.S. Provisional Application No. vivo and in vitro bronchorelaxant activities of CP-80633, a 60/265,304, filed Jan. 31, 2001. 10 selective phosphodiesterase 4 inhibitor.” Can. J. Physiol. Pharmacol. 75 1001–1008, 1997: Manabe et al., “Anti 1.O REFERENCE TO RELATED APPLICATIONS inflammatory and bronchodilator properties of KF19514, a phosphodiesterase 4 and 1 inhibitor.' Eur: J. Pharmacol. 332 Reference is made to International application and US 97–107, 1997; and Ukita et al. “Novel, potent, and selective application based thereon, Ser. No. PCT/IB98/00315, both 15 phosphodiesterase-4 inhibitors as antiasthmatic agents: Syn filed Mar. 10, 1998, and published as WO 98/.45268 on Oct. thesis and biological activities of a series of 1-pyridylnaph 15, 1998; claiming priority from application Ser. No. thalene derivatives,” J. Med. Chem. 42 1088–1099, 1999. 60/043,403 filed Apr. 4, 1997, now abandoned; which dis Accordingly, there continues to be considerable interest in closes nicotinamide derivatives having biological activity as the art with regard to the discovery of further selective inhibitors of PDE4 isozymes, and thus being useful in the inhibitors of PDE4S. treatment of inflammatory, respiratory and allergic diseases The present invention is also concerned with the use of and conditions. Nothing that is disclosed in the above selective PDE4 inhibitors for the improved therapeutic treat mentioned applications would teach the person of ordinary ment of a number of inflammatory, respiratory and allergic skill in the pertinent art the novel compounds of the present diseases and conditions, but especially for the treatment of invention or their unexpectedly high level of inhibitory 25 asthma; chronic obstructive pulmonary disease (COPD) selectivity for PDE 4 isozymes. including chronic bronchitis, emphysema, and bronchiecta Reference is also made to copending application Ser. No. sis; chronic rhinitis; and chronic sinusitis. Heretofore in the 09/345,185 filed Jun. 30, 1999; claiming priority from art, however, the first-line therapy for treatment of asthma application Ser. No. 60/105,120 filed Oct. 21, 1998, which and other obstructive airway diseases has been the nonse discloses compounds and processes for preparing N-Substi 30 lective PDE inhibitor theophylline, as well as pentoxifylline tuted nicotinamide derivatives. However, the disclosed com and IBMX, which may be represented by Formulas (0.0.1), pounds and processes are not the same as those of the (0.0.2), and (0.0.3), respectively: present invention. Reference is further made to copending applications filed (0.0.1) of even date with the instant application, Ser. Nos. 60/265, 35 531; 60/265,250; 60/265,491; 60/265,486; 60/265,240; and 60/265,492, which involve other classes of nicotinamide derivatives useful as inhibitors of PDE4 isozymes. The disclosures of all of said copending applications are incor 40 Dr. porated herein by reference in their entireties. es ^ CH 2.O. BACKGROUND OF THE INVENTION Theophylline The 3',5'-cyclic nucleotide phosphodiesterases (PDEs) comprise a large class of enzymes divided into at least 45 (0.0.2) eleven different families which are structurally, biochemi O O cally and pharmacologically distinct from one another. The CH3 enzymes within each family are commonly referred to as isoenzymes, or isozymes. A total of more than fifteen gene HC --~~ N \X products is included within this class, and further diversity 50 results from differential splicing and post-translational pro 1. N cessing of those gene products. The present invention relates to the four gene products of the fourth family of PDEs, i.e., CH3 PDE4A, PDE4B, PDE4C, and PDE4D, and their inhibition, Pentoxifylline including selective inhibition of PDE4D. These enzymes are 55 (0.0.3) collectively referred to as being isoforms or subtypes of the PDE4 isozyme family. Further below will be found a more detailed discussion of the genomic organization, molecular structure and enzymatic activity, differential splicing, tran Scriptional regulation and phosphorylation, distribution and 60 es r 2 expression, and selective inhibition of the PDE4 isozyme Subtypes. The PDE4s are characterized by selective, high affinity hydrolytic degradation of the second messenger cyclic CH3 nucleotide, adenosine 3',5'-cyclic monophosphate (cAMP), 65 and by sensitivity to inhibition by rolipram. A number of IBMX selective inhibitors of the PDE4s have been discovered in US 7,183,293 B2 3 Theophylline, which has the PDEs as one of its biochemi cal targets, in addition to its well characterized bronchod -continued ilatory activity, affects the vasculature of patients with (0.0.6) increased pulmonary artery pressure, Suppresses inflamma HC-O O-CH tory cell responses, and induces apoptosis of eosinophils. Theophylline's adverse events, most commonly cardiac dysrhythmias and nausea, are also mediated by PDE inhi bition, however, leading to the search for more selective inhibitors of PDEs that are able to suppress both immune 10 cell functions in vitro and allergic pulmonary inflammation N-CH in vivo, while at the same time having improved side-effect profiles. Within the airways of patients suffering from Benafeintrine asthma and other obstructive airway diseases, PDE4 is the most important of the PDE isozymes as a target for drug 15 However, benafentrine results in bronchodilation only discovery because of its distribution in airway smooth when administered by inhalation, and Zardaverine produces muscle and inflammatory cells. Several PDE4 inhibitors only a modest and short-lived bronchodilation. Milrinone, a introduced to the art thus far have been designed to have an cardiotonic agent, induces short-lived bronchodilation and a improved therapeutic index concerning the cardiovascular, slight degree of protection against induced bronchoconstric gastrointestinal, and central nervous system side effects of tion, but has marked adverse events, e.g., tachycardia and the above-mentioned nonselective Xanthines. hypotension. Unsatisfactory results have also been obtained Airflow obstruction and airway inflammation are features with a weakly selective PDE4 inhibitor, tibenelast, and a of asthma as well as COPD. While bronchial asthma is selective PDE5 inhibitor, Zaprinast, which may be repre predominantly characterized by an eosinophilic inflamma 25 sented by Formulas (0.0.7) and (0.0.8): tion, neutrophils appear to play a major role in the patho genesis of COPD. Thus, PDEs that are involved in smooth (0.0.7) muscle relaxation and are also found in eosinophils as well as neutrophils probably constitute an essential element of the 30 C OH progress of both diseases. The PDEs involved include He1 No O PDE3s as well as PDE4s, and bronchodilating inhibitors Tibenelast have been discovered which are selective PDE3 inhibitors O (0.0.8) and dual PDE3/4 selective inhibitors. Examples of these are H milrinone, a selective PDE3 inhibitor, as well as Zardaverine 35 N and benafentrine, both dual PDE3/4 selective inhibitors, which may be represented by Formulas (0.0.4), (0.0.5), and \ N (0.0.6), respectively: O | 40 H3 1)N-1 N-N Zaprinast (0.0.4) CH3 H More relative success has been obtained in the art with the N \ o discovery and development of selective PDE4 inhibitors. O N 45 In vivo, PDE4 inhibitors reduce the influx of eosinophils / \ / to the lungs of allergen-challenged animals while also reduc ing the bronchoconstriction and elevated bronchial respon NC siveness occurring after allergen challenge. PDE4 inhibitors Millrinone also suppress the activity of immune cells, including CD4" 50 T-lymphocytes, monocytes, mast cells, and basophils; reduce pulmonary edema; inhibit excitatory nonadrenergic noncholinergic neurotransmission (eNANC); potentiate inhibitory nonadrenergic noncholinergic neurotransmission 55 (iNANC); reduce airway Smooth muscle mitogenesis; and induce bronchodilation. PDE4 inhibitors also suppress the (0.0.5) activity of a number of inflammatory cells associated with FHC the pathophysiology of COPD, including monocytes/mac O rophages, CD8" T-lymphocytes, and neutrophils. PDE4 60 inhibitors also reduce vascular Smooth muscle mitogenesis and, and potentially interfere with the ability of airway N epithelial cells to generate pro-inflammatory mediators. O 2YNE Through the release of neutral proteases and acid hydrolases CH3 N from their granules, and the generation of reactive oxygen O 65 species, neutrophils contribute to the tissue destruction Zardaverine associated with chronic inflammation, and are further impli cated in the pathology of conditions such as emphysema. US 7,183,293 B2 5 6 Selective PDE4 inhibitors which have been discovered enoXimone and motapizone may be represented by Formulas thus far that provide therapeutic advantages include SB-207, (0.0.10) and (0.0.11), respectively: 499, identified as ARIFLOR), which may be represented by Formula (0.1.9): (0.0.10) O H (0.1.9) N H3C V O COOH 10 HC O ) O NC Ns HC3 N O Enoximone (0.0.11) SB-207,499 15 HC H SB-207,499, administered orally at dosages of 5, 10, and 15 mg b.i.d., has produced significant increases in trough FEV1 O X-( N -N S (forced expiratory volume in 1 second) from placebo at H week 2 of a study involving a large number of patients. Motapizone Another potent, selective PDE4 inhibitor, CDP840, has shown Suppression of late reactions to inhaled allergen after The effects of PDE4 inhibitors on various inflammatory 9.5 days of oral administration at doses of 15 and 30 mg in cell responses can be used as a basis for profiling and a group of patients with bronchial asthma. CDP840 may be 25 represented by Formula (0.0.9): selecting inhibitors for further study. These effects include elevation of cAMP and inhibition of superoxide production, degranulation, chemotaxis, and tumor necrosis factor alpha

(0.0.9 (TNFC) release in eosinophils, neutrophils and monocytes. 30 PDE4 inhibitors may induce emesis, i.e., nausea and Vom iting, which, as expected, is an adverse effect. The emesis adverse effect became apparent when PDE4 inhibitors were first investigated for CNS indications such as depression, when rolipram and denbufylline were used in clinical trials. 35 Rolipram and denbufylline may be represented by Formulas (0.0.12) and (0.0.13), respectively: CDP840 (0.0.12) PDEs have also been investigated as potential therapy for 40 obstructive lung disease, including COPD. In a large study O of SB-207,499 in patients with COPD, the group of patients O)- receiving 15 mg b.i.d. has experienced a progressive O M NH improvement in trough FEV, reaching a maximum mean 45 HC difference compared with placebo of 160 mL at week 6, Rolipram which represents an 11% improvement. See Compton et al., “The efficacy of Ariflo (SB207499), a second generation, oral PDE4 inhibitor, in patients with COPD, Am. J. Respir: Crit. Care Med. 159, 1999. Patients with severe COPD have (0.0.13) been observed to have pulmonary hypertension, and decreases in mean pulmonary artery pressure under clinical conditions have been achieved by oral administration of the selective PDE3 inhibitors milrinone and enoximone. Enoxi 55 mone has also been shown to reduce airway resistance in patients hospitalized with decompensated COPD. See Lee man et al., Chest 91 662–6, 1987. Using selective PDE3 Denbufylline inhibition by motapizone and selective PDE5 inhibition by Zaprinast, it has been shown that combined inhibition of 60 The mechanism(s) by which PDE4 inhibitors may poten PDE 3 and 5 exerts a relaxation of pulmonary artery rings tially induce emesis is/are uncertain, but a study of the PDE4 which corresponds broadly to the pattern of PDE isozymes inhibitor Ro-20-1724 Suggests that nausea and vomiting are found in the pulmonary artery smooth muscle. See Rabe et at least partially mediated by the emesis centers in the brain. al., Am. J. Physiol. 266 (LCMP 10): L536-L543, 1994. The 65 Gastrointestinal adverse events may be caused by local structures of milrinone and Zaprinast are shown above as effects, e.g., rolipram is a very potent stimulator of acid Formulas (0.0.4) and (0.0.8), respectively. The structures of secretion from gastric parietal cells, and the resulting excess US 7,183,293 B2 7 8 acid, by producing local irritation, may exacerbate gas It has been known for some time that rolipram had the trointestinal disturbances. Ro-20-1724 may be represented ability to interact with a high-affinity binding site on brain by Formula (0.0.14): membranes, and it was later established in the art that this high-affinity rolipram binding site (S), which is distinct from the catalytic site (S), exists in a truncated recombinant (0.0.14) PDE4A and a full-length recombinant PDE4B. More recently, S, has been identified on all four PDE4 subtypes. NH See Hughes et al., Drug Discovery Today 203) 89-101, 1997. 10 The presence of S. appears to have a profound effect on the O)- ability of certain inhibitors such as rolipram and RS-25.344 to inhibit the catalytic activity of PDE4 isozymes. The impact of residues on inhibitor binding is also sig RO-20-1724 nificant. A single amino acid substitution (alanine for aspar 15 tate) in the catalytic region of PDE4B has been shown to be critical for inhibition by rolipram, and this appears to be a class effect because related inhibitors RP-73,401 and Ro-20 Efforts to minimize or eliminate the above-mentioned 1724 also lose potency on the mutant enzyme. However, the adverse events sometimes associated with PDE4 inhibitors have included creating inhibitors which do not penetrate the role of binding of inhibitors to the S or to the S., in terms central nervous system, and administering PDE4 inhibitors of elevation of cAMP and inhibition of cell responses, is not by inhalation rather than orally. fully understood at the present time. With regard to the PDE4 subtypes, A, B, C, and D, it has RP-73,401, in guinea-pig studies, has been found to be been found that PDE4C is usually less sensitive to all active in (1) the inhibition of antigen-induced lung eosino inhibitors; whereas, with respect to the subtypes A, B, and 25 philia and eosinophil peroxidase (EPO), Banner, K. H., “The D, there is as yet no clear evidence of inhibitor specificity, effect of selective phosphodiesterase inhibitors in compari which is defined as a 10-fold difference in ICs values. While son with other anti-asthma drugs on allergen-induced eosi most inhibitors, especially RS-25,344, are more potent nophilia in guinea-pig airways.” Pulm. Pharmacol. 837-42, against PDE4D, this does not amount to selectivity. RS-25, 30 1995; (2) antigen-induced bronchoalveolar lavage (BAL) 344 may be represented by Formula (0.0.15): eosinophilia, Raeburn et al., “Anti-inflammatory and bron chodilator properties of RP73401, a novel and selective (0.0.15) phosphodiesterase Type IV inhibitor. Br. J. Pharmacol. 113 O 1423–1431, 1994; (3) antigen-induced airway eosinophilia 35 and platelet activating factor-(PAF)- and ozone-induced N N N airway hyper-responsiveness (AHR), Karlsson et al., “Anti inflammatory effects of the novel phosphodiesterase IV N 21 O1. N N2 inhibitor RP73401.” Int. Arch. Allergy Immunol. 107 40 425-426, 1995; and (4) IL-5 induced pleural eosinophila. Development of RP-73,401, piclamilast, has been discon tinued. Piclamilast may be represented by Formula (0.0.17): NO RS-25,344 45 (0.0.17) C

On the other hand, there is a stereoselective effect on the O-R H )- elevation of cAMP in a range of cell types, which has been N \ / O demonstrated with the results of an investigation of 50 M CDP840, shown above as Formula (0.0.9), and its less active HC O Cl enantiomer CT-1731, which is represented by Formula (0.0.16): Piclamilast (RP-73.401) 55 A related series of compounds is represented by RPR (0.0.16) 132294 and RPR-132703, which have been demonstrated in O rat studies to have activity in the inhibition of antigen (r \ / induced bronchospasm; Escott et al., “Pharmacological pro O 60 filing of phosphodiesterase 4 (PDE4) inhibitors and analysis of the therapeutic ratio in rats and dogs.” Br. J. Pharmacol. 123(Proc. Suppl.) 40P, 1998; and Thurairatnam et al., “Bio l, ) logical activity and side effect profile of RPR-132294 and CT-1731 65 RPR-132703 novel PDE4 inhibitors, XV' EFMC Int. Symp. Med. Chem., 1998. The structure of RPR-132294 may be represented by Formula (0.0.18): US 7,183,293 B2 10

-continued (0.0.18) (0.1.12) H3C

O)- NH / O O leN / H3C O H3C 10 RPR-132294

Another compound whose development has been discon 15 Cipamfylline (BRL-61,063) tinued is WAY-PDA-641, filaminast, which in studies in the dog, has been found to be active in the inhibition of seratonin-induced bronchoconstriction. Filaminast may be Another compound which is in development is LAS represented by Formula (0.0.19): 31025, arofylline, which in guinea-pig studies, has been found to be active in the inhibition of antigen-induced bronchoconstriction; Beleta, B. J., “Characterization of LAS31025: a new selective PDE IV inhibitor for bronchial (0.0.19) asthma.” Third Int. Conf. On Cyclic Nucleotide Phosphodi esterase. From Genes to Therapies, Glasgow, UK, 1996, N-O 25 Abstract 73. LAS-31025, arofylline, may be represented by / W X-Nil, Formula (0.0.21): CH, O (0.0.21) Filaminast (WAY-PDA-641) 30 H N It has been suggested in the art that PDE4 inhibitors that have a high affinity at the S can be correlated with emesis and increased gastric acid secretion. RS-23.544, RP-73,401, es and CP-80,633 elicit emesis and have a high affinity at the 35 S. CDP840 and SB-207,499 have a comparatively low affinity at the S, but CDP840 has a significantly higher potency at the S than does SB-207,499. CDP840 has been demonstrated to provide significant inhibition of late-phase 40 response in the treatment of asthma without any adverse C events of nausea or headache. Another PDE4 inhibitor that Arofylline (LAS-31025) has been shown to have adverse events of nausea and vomiting is BRL-61,063, also referred to as cipamfylline, 45 A number of PDE4 inhibitors have been advanced in which is described further below. The development of development. For example, the effects of V-11294A on CDP840 has been discontinued, while CP-80,633, atizoram, LPS-stimulated ex vivo TNF release and PHA induced has been advanced into clinical studies. CP-80,633 and lymphocyte proliferation have been determined in a ran BRL-61,063 may be represented by Formulas (0.0.20) and domized, double-blind placebo-controlled study which has (0.1.12), respectively: 50 found that an oral dose of 300 mg is effective in reducing TNF levels and lymphocyte proliferation; Landells et al., “Oral administration of the phosphodiesterase (PDE) 4 (0.0.20) inhibitor, V11294A inhibits ex-vivo agonist-induced cell activation.” Eur: Resp.J. 12(Suppl. 28) 362s, 1998; and Gale 55 et al., “Pharmacodynamic-pharmacokinetic (PD/PK) profile of the phosphodiesterase (PDE) 4 inhibitor, V11294A, in human volunteers. Am. J. Respir: Crit Care Med. 159 A611, 1999. The compound D4418 has been administered to healthy 60 Volunteers in a single escalating dose, randomized, placebo controlled Phase I study; Montana et al., “Activity of D4418. a novel phosphodiesterase 4 (PDE4) inhibitor, effects in cellular and animal models of asthma and early clinical studies.” Am. J. Respir: Crit. Care Med 159 A108, 1999. 65 D4418 is a moderately potent PDE4 inhibitor with an ICso Atizoram (CP-80,633) of 200 nM. It has good oral absorption; a 200 mg dose provides a plasma C of 1.4 g/ml. D4418 has been US 7,183,293 B2 11 12 discontinued from development due to its moderate potency, The above-mentioned compounds have also been evalu and has been replaced by the preclinical development can ated in animal models which demonstrate their PDE4 inhi didate D4396. bition activity. For example, V-11294A, in guinea-pig stud V-11294A and D4418 may be represented by Formulas ies, has been found to be active in the inhibition of antigen (0.0.22) and (0.0.23), respectively: induced bronchoconstriction: Cavalla et al., “Activity of V11294A, a novel phosphodiesterase 4 (PDE4) inhibitor, in cellular and animal models of asthma.” Amer. J. Respir: Crit. (0.0.22) Care Med, 155 A660, 1997. D4418, in guinea-pig studies, HN1 Nchi, 10 has been found to be active in the inhibition of antigen induced early and late phase bronchoconstriction and BAL N N CH3 eosinophilia; Montana, et al., Ibid. C1-1018, in rat studies, X-( has been found to be active in the inhibition of antigen Nls N CH induced eosinophilia; Burnouf, et al., “Pharmacology of the 15 novel phosphodiesterase Type 4 inhibitor, C1-1018, 215' O ACS Nat. Meeting, MEDI 008, 1998. Other compounds which have been advanced in devel OCH opment include CDC-3052, D-22888, YM-58997, and rof lumilast, which may be represented by Formulas (0.0.27), W-11294A (0.0.28), (0,0.29), and (0.0.30), respectively: (0.0.23) N

H3CO 21 C 25 (0.0.27) O-CH N

O C 2N O O 30 V CH3 D4418 N O

Another compound, C1-1018, has been evaluated in 54 O-CH Subjects and no adverse events were reported at doses up to 35 400 mg. Pruniaux et al., “The novel phosphodiesterase CDC-3052 inhibitor C1-1018 inhibits antigen-induced lung eosinophilia in sensitized brown-norway rats—comparison with rollip ram.” Inflammation S-04-6, 1999. C1-1018 has been dem 40 onstrated to have good oral bioavailability (57% in the rat) (0.0.28) and good oral potency of with an EDso of 5 mg/kg in that CH same species. C1-1018 is a relatively weak PDE4 inhibitor with an ICs of 1.1 uM in U937 cells. C1-1018 has also been identified as, or associated with as closely related in struc 45 ture to, PD-168787, which in rat studies has been demon N O strated to have activity in the inhibition of antigen-induced eosinophilia; Pascal et al., “Synthesis and structure-activity H3C r 2 relationships of 4-oxo-1-phenyl-3,4,6,7-tetrahydro-1,4-di No N N1 N-CH azepino 6,7,1-hi indolines: novel PDE4 inhibitors,” 215" 50 sN ACS, Dallas, USA, MEDI 50, 1998. Inferred structures for HC C1-1018 and PD-168787 belong to a diazepinone class whose nucleus may be represented by Formula (0.0.24): D-22888 (0.0.29) 55 (0.0.24) rt HC N N O

21s 21 60

65 Br YM-58977 US 7,183,293 B2 13 14 -continued (0.0.30) autoimmune diseases. Thalidomide may be represented by -->F Formula (0.0.33): (0.0.33) Auo O

N O 10 N H O NH O O. Thalidomide

15 N CDC-801 has also been studied for the treatment of Crohn's N r disease, a chronic granulomatous inflammatory disease of Roflumilast unknown etiology commonly involving the terminal ileum, with scarring and thickening of the bowel wall which CDC-3052 has been discontinued from development, but frequently leads to intestinal obstruction and fistula and has been succeeded by very potent inhibitors of PDE4 such abscess formation. Crohn's disease has a high rate of recur as the compound represented by Formula (0.0.31), and by rence after treatment. the anti-inflammatory compound CDC-801 represented by YM-58997 has an ICs value of 1.2 nM against PDE4; 25 Takayama et al., “Synthetic studies on selective Type IV Formula (0.0.32), respectively: phosphodiesterase (PDE IV) inhibitors,” 214" American Chemical Society, Las Vegas, USA, MEDI 245, 1997. (0.0.31) YM-58997 has a 1.8-naphthyridin-2-one structure, as does YM-976. 30 O-CH Roflumilast has been studied for the treatment of both /- CH3 COPD and asthma, and has an ICso value of 3.5 nM in O O standard in vitro guinea-pig models of asthma. The use of roflumilast and a surfactant for the treatment of adult res 35 N O piratory distress syndrome (ARDS) has also been described. AWD-12,281, which is now designated as loteprednol, has been shown to be active in a rat model of allergic O NH rhinitis, as described further below in a section which deals HO 40 with allergic rhinitis and the use of PDE4 inhibitors to treat CDC-801 it. AWD-12,281 may be represented by Formula (0.0.34): (0.0.32) O-CH (0.0.34) HO 45 O O C N21 O F O 50 S N N N H C.O NH2 C O Loteprednol (AWD-12,281)

The compound of Formula (0.0.32) is reported to have 55 IC values of 42 pM and 130 nM as an inhibitor of PDE4 and Compounds related in structure to CDP840, shown fur TNF production, respectively; Muller et al., “N-Phthaloyl ther above as Formula (0.0.9), include L-826,141, which has beta-aryl-beta-amino derivatives: Potent TNF-alpha and been reported to have activity in a rat model of bronchitis; PDE4 inhibitors,” 217' American Chemical Society, 60 Gordon et al., “Anti-inflammatory effects of a PDE4 inhibi Annheim, Germany, MEDI 200, 1999; and Muller et al., tor in a rat model of chronic bronchitis. Am. J. Respir: Crit. “Thalidomide analogs and PDE4 inhibition, Bioorg. Med. Care Med. 159 A33, 1999. Another such compound is Chem. Letts. 82669-2674, 1998. related in structure to those reported in Perrier et al., CDC-801 is from a series of compounds based on thali 65 “Substituted furans as inhibitors of the PDE4 enzyme.” domide and has been developed primarily to improve the Bioorg. Med. Chem. Letts. 9 323-326, 1999, and is repre TNF-C. inhibitory activity of thalidomide for the treatment of sented by Formula (0.0.35): US 7,183,293 B2 15 16 Compounds have been created which combine PDE4 and (0.0.9) matrix metalloproteinase (MMP) inhibitory activity in a single molecule; Groneberg et al., “Dual inhibition of phos phodiesterase 4 and matrix metalloproteinases by an (aryl sulfonyl)hydroxamic acid template.” J. Med. Chem. 42(4) 541–544, 1999. Two examples of such compounds are represented by Formulas (0.0.39) and (0.0.40):

10 CDP840 (0.0.39) (0.0.35)

15 YoH s Sa O O O \ - no HC No O Other compounds which been found to be very potent YCH, PDE4 inhibitors are those represented by Formulas (0.0.36), (0.0.37), and (0.038): 25 (0.0.36) N (0.0.4.0) S is CH 30 N YOH HN On S so N21 35 H3C No O N w O

O 40 The respective ICs values for the compounds of Formulas CH (0.1.36) and (0.1.37) using a guinea-pig macrophage PDE4 (0.0.37) assay were 1 nM and 30 nM. The compounds identified as KF19514 and KF17625

45 have been shown in guinea-pig studies to have activity in the inhibition of the following: histamine-induced and antigen induced bronchoconstriction; PAF-induced lung eosino philia and antigen-induced BAL eosinophilia; acetylcholine (ACh)-induced AHR; PAF-induced BAL eosinophilia and 50 neutrophilia, and AHR; antigen-induced bronchospasm; and anaphylactic bronchoconstriction; Fujimura et al., “Bron choprotective effects of KF-19514 and cilostazol in guinea pigs in vivo.” Eur: J. Pharmacol. 32757–63, 1997: Manabe 55 et al., Ibid.; Manabe et al., “KF19514, a phosphodiesterase (0,0.38) 4 and 1 inhibitor, inhibits PAF-induced lung inflammatory responses by inhaled administration in guinea-pigs.” Int. Arch. Allergy Immunol. 114389–399, 1997: Suzuki et al., CH3 “New bronchodilators. 3. Imidazo[4,5-c.1.8naphthyridin O 60 4(5H)-ones,” J. Med. Chem. 354866–4874, 1992; Matsuura et al., “Substituted 1,8-naphthyridin-2(1H)-ones as selective phosphodiesterase IV inhibitors. Biol. Pharm. Bull. 17(4) H3C No O O O 498–503, 1994; and Manabe et al., “Pharmacological prop erties of a new bronchodilator, KF 17625, Jpn. J. Pharma O YCH, CH3 65 col. 58(Suppl. 1) 238P, 1992. KF19514 and KF17625 may be represented by Formulas (0.0.41) and (0.0.42): US 7,183,293 B2 17 18 covery of T-2585, one of the most potent PDE4 inhibitors described to date with an ICs value of 0.13 nM against (0.0.41) guinea-pig lung PDE4. T-440 and T-2585 may be repre sented by Formulas (0.0.45) and (0.0.46): / N N=\ S N (0.0.45) N N H3C O 2 N1 O OH N N O 10 He1 No OH 21

15 KF19514 O N (0.0.42) Ne N- O NCH, N S-\ T-440 (0.0.46) HC O CN N O N1 OH OH 25 He1 No

21 O KF17625 N 30 The reported potency and lack of emesis in a series of N indandiones suggests that the hypothesis that has related NS side-effects such as emesis to the ratio of affinity for the PDE4 enzyme relative to that for the high affinity rolipram 21 binding site (HARBS) is erroneous. Such indandiones may 35 be represented by Formulas (0.0.43) and (0.0.44): N-N T-2585 R 40 Another class of PDE4 inhibitors consists of benzofurans and benzothiophenes. In particular, furan and chroman rings have been utilized as surrogates for the cyclopentylether of the rolipram pharmacophore. An example of Such a com O-o 45 pound is one that is apparently related in structure to BAY O O 19–8004, and which may be represented by Formula (0.0.47): N -CH 50 (0.0.47) 2 O N R = benzyloxy (0.0.43) ls R = 1,4-piperidinyl-1'-carbonyloxy (0.0.44) HN NH2

55 O The PDE4 inhibitors that have been created heretofore fall into a significant number of different classes in terms of their chemical structures. Such classes have been as diverse as HC O)O phenanthridines and naphthyridines. One class of PDE4 inhibitors are lignans such as T-440, which has been dem 60 c-( ) onstrated to have activity in the inhibition of the following: early phase bronchoconstriction induced by antigen, hista mine, LTD4, U-46619, Ach, neurokinin A, and endothelin-1, allergen-induced early phase and late phase bronchocon striction and BAL eosinophilia; and ozone-induced AHR 65 Another benzofuran-type compound has been reported to and airway epithelial injury. Optimization of the PDE4 have an ICs value of 2.5 nM, and may be represented by inhibitory potency of Such compounds has led to the dis Formula (0.0.48): US 7,183,293 B2 19 20 Purines, xanthines, and pteridines represent yet further classes of chemical compounds to which PDE4 inhibitors

(0.0.48) described heretofore in the art belong. The compound V-11294A described further above and represented by For mula (0.0.22), is a purine. A PDE4 inhibitor which is a Xanthine compound, the class of compounds to which theo phylline belongs, has been described in the art; Montana et al., “PDE4 inhibitors, new xanthine analogues.” Bioorg. 10 Med. Chem. Letts. 8. 2925-2930, 1998. The xanthine com pound may be represented by Formula (0.0.54): A compound with a related Structure, which is not, however, a benzofuran, is characterized by a fused dioxicin ring and is reported to produce almost complete inhibition of 15 canine tracheal PDE4 at 100 nM. This compound may be (0.0.54) represented by Formula (0.0.49): (0.0.49) or) CH C 25

O o N -- (O) /

30 A potent PDE4 inhibitor belonging to the pteridine class Quinolines and quinolones are a further class of PDE4 of compounds has been demonstrated to have an ICs value inhibitor structures, and they serve as Surrogates for the of 16 nM against a PDE4 derived from tumor cells and to catechol moiety of rolipram. This compound and two com inhibit the growth of tumor cells at micromolar concentra pounds of similar structure may be represented by Formulas 35 tions; Merz et al., “Synthesis of 7-Benzylamino-6-chloro (0.0.50), (0,0.51), and (0.0.52): 2-piperazino-4-pyrrolidinopteridine and novel derivatives free of positional isomers. Potent inhibitors of cAMP (0.0.50) specific phosphodiesterase and of malignant tumor cell O O 40 growth,” J. Med. Chem. 41(24) 4733–4743, 1998. The pteridine PDE4 inhibitor may be represented by Formula FC N1 NN (0.0.55): H C N 45 (0.0.55) - C (0.0.51) O O 50 FC N H ul) -N 55 HN - (0.0.52) O O Triazines represent a still further class of chemical com 60 pounds to which PDE4 inhibitors belong that have been described in the artheretofore. Two such triazines have been described which display bronchodilator activity and are potent relaxant agents in a guinea-pig trachea model. These 65 compounds, which may be represented by Formulas (0.0.56) and (0.0.57) below, are also moderately potent PDE4 inhibi tors with ICs values of 150 and 140 nM, respectively: US 7,183,293 B2 21 22 -continued (0.0.56) 2 (0.0.59) 2

N N1 N n

10 2N21

(0.0.57) 15 O Another nicotinamide compound has been described in the art which may be useful in the treatment of CNS diseases such as multiple sclerosis; GB-2327675; and a rolipram derivative has been described in the art which is a PDE4 inhibitor which binds with equal affinity to both the catalytic and the HARB sites on human PDE4B2B: Tian et al., “Dual inhibition of human Type 4 phosphodiesterase isostates by D-N (R,R)-(+/-)-methyl-3-acetyl-4-3-(cyclopentyloxy)-4-meth 25 oxyphenyl-3-methyl-1-pyrrolidine carboxylate.” Biochem istry 37(19) 6894–6904, 1998. The nicotinamide derivative and the rolipram derivative may be represented by Formulas (0.0.60) and (0.0.61), respectively: A triazine having a structure assumed to be closely related to that of the compounds of Formulas (0.0.56) and (0.0.57) 30 is UCB-29936, which has been demonstrated to have activ (0.0.60) ity in a murine model of septic shock; Danhaive et al., “UCB29936, a selective phosphodiesterase Type IV inhibi N tor: therapeutic potential in endotoxic shock. Am. J. Respir: N 35 Crit. Care. Med. 159 A611, 1999. 2 N Efforts have also been made in the art to improve the selectivity of PDE4 inhibitors with respect to the A through D subtypes described further above. There are presently four known isoforms (subtypes) of the PDE4 isozyme, encom 40 passing seven splice variants, also described further above. (0.0.61)

The PDE4D isoform mRNA is expressed in inflammatory cells such as neutrophils and eosinophils, and it has been suggested in the art that D-selective inhibitors of PDE4 will provide good clinical efficacy with reduced side-effects. A 45 nicotinamide derivative displaying selectivity for inhibition of the PDE4D isoform has been described; WO98/.45268; as well as a naphthyridine derivative reported to be a PDE4D selective inhibitor; WO 98/18796. These compounds may be 50 represented by Formulas (0.0.58) and (0.0.59), respectively: Further background information concerning selective (0.0.58) PDE4 isozymes may be found in publications available in 55 the art, e.g., Norman, “PDE4 inhibitors 1999, Exp. Opin. Ther. Patents 9(8) 1101–1118, 1999 (Ashley Publications Ltd.); and Dyke and Montana, “The therapeutic potential of PDE4 inhibitors.” Exp. Opin. Invest. Drugs 8(9) 1301–1325, 60 1999 (Ashley Publications Ltd.). 3.O DESCRIPTION OF THE STATE OF THE ART WO 98/45268 (Marfat et al.), published Oct. 15, 1998, 65 discloses nicotinamide derivatives having activity as selec tive inhibitors of PDE4D isozyme. These selective inhibitors are represented by Formula (0.1.1): US 7,183,293 B2 24

(0.1.1) (0.1.4) O R4 RI Xs N N C 2 H x N (R), (O), 10 R2 U.S. Pat. No. 4,861,891 (Saccomano et al.), issued Aug. where n is 0–3; R is selected from numerous groups, but is 29, 1989, discloses nicotinamide compounds which function usually H, 6-CH, or 5-Cl; R is alkyl, alkenyl, alkynyl, as calcium independent C-AMP phosphodiesterase inhibi cycloalkyl, aryl or aralkyl; R1 and R2 is halo, CN, NO, tors useful as antidepressants, of Formula (0.1.2): 15 alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalky lthio, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, or arylthio; and R is alkyl. (0.1.2) O EP 500 989 (Mollner et al.) discloses ACE inhibitors of Formula (0.1.5): RI N N1 H (0.1.5) 2 (R3)n R2 N 25 (s R2 C 4S,-HCONH-C-CON H The nicotinamide nucleus of a typical compound disclosed COR in this patent is bonded directly to the R' group, which is 30 defined as 1-piperidyl, 1-(3-indolyl)ethyl, C-C alkyl, phe where n is 0–3; R is OH, SH, COOH, NH, halo, OR, SR, nyl, 1-(1-phenylethyl), or benzyl optionally mono-Substi COOR, NHR or N(R), where R is lower alkyl, option tuted by methyl, methoxy, chloro or fluoro. The R° substitu ally substituted aryl, or acyl: R is OH, lower alkoxy, ent is bicyclo[2.2.1]hept-2-yl or optionally substituted aryl lower alkoxy, aryloxy, or disub stituted amino; R is lower alkyl or amino lower alkyl, and 35 R1 and R2 is halo, NO, lower alkyl, halo lower alkyl, aryl lower alkyl, or aryl. Specific embodiments disclosed include compounds such as that of Formula (0.1.6):

40 (0.1.6) O CH where Y is H. F or Cl; and X is H. F. C1, OCH, CF, CN, N COOH, -C(=O)(C-C)alkoxy, NH(CH)C(=O)-(meth N sy CH ylcarbamoyl) or N(CH),C(=O)-(dimethylcarbamoyl). 45 2 O /S 3 U.S. Pat. No. 4,692,185 (Michaely et al.) discloses her N O O bicides such as those of Formula (0.1.3):

(0.1.3) 50

N FR2.140.772 (Aries) discloses compounds asserted to have utility as analgesics, tranquilizers, antipyretics, anti 2 55 inflammatories, and antirheumatics, of Formula (0.1.7): (0.1.7) O RI 60 N N SAS CF i | II 4. O 21 - * where R is (C-C)alkyl, (C-C)haloalkyl, or halo. 65 EP550 900 (Jeschke et al.) discloses herbicides and plant i-R nematicides of Formula (0.1.4): C US 7,183,293 B2 25 where R is 1 or 2 substituents chosen from lower alkyl, trihalomethyl, alkoxy, and halo; R is H or alkyl; and R" is (0.1.10.1) hydrogen or alkyl. JP 07304775 (Otsuka et al.) discloses naphthyridine and pyridopyrazine derivatives which have anti-inflammatory, X immunomodulating, analgesic, antipyretic, antiallergic, and antidepressive action. Also disclosed are intermediates of where Xs=H; s=0; R and RFCN; and Z=C(O)OR where Formula (0.1.8): RH. The disclosures of U.S. Pat. Nos. 5,602,157 and 10 5,614,540 differ from that of U.S. Pat. No. 5,552,438 and each other as to the definition of the R group, which in the (0.1.8) case of the ARIFLOR) compound, is CN. A preferred salt form of the ARIFLOR) compound is disclosed to be the tris(hydroxymethyl)ammonium methane salt. 15 U.S. Pat. No. 5,863,926 (Christensen et al.) discloses analogs of the ARIFLOR) compound, e.g., that of Formula (0.1.11):

(0.1.11) where X may be CH, and R and R' are each lower alkyl. With regard to the disclosures of the above-identified O COOH patents and published patent applications, it will be appre ciated that only the disclosure of WO 98/.45268 (Marfat et al.) concerns the inhibition of PDE4 isozymes. The state of 25 the art also contains information regarding compounds wholly dissimilar in chemical structure to those of Formula (1.0.0) of the present invention, but which, on the other WO 99/18793 (Webb et al.) discloses a process of making hand, possess biological activity similar to that of the the ARIFLOR) and related compounds. WO95/00139 (Bar compounds of Formula (1.0.0). Representative patents and nette et al., claims a compound which has an ICso ratio of published patent applications disclosing said information are about 0.1 or greater as regards the ICs for the PDE IV illustrated further below. catalytic form which binds rolipram with a high affinity, U.S. Pat. Nos. 5,552,438: 5,602,157; and 5,614,540 (all to divided by the ICs for the form which binds rolipram with Christensen), which all share the same Apr. 2, 1992 priority 35 a low affinity; but in a dependent claim restricts the scope thereof to a compound which was not known to be a PDE4 date, relate to a therapeutic agent identified as ARIFLOR), inhibitor prior to Jun. 21, 1993. which is a compound of Formula (0.1.9) and named as WO99/20625 (Eggleston) discloses crystalline polymor indicated below: phic forms of cipamfylline for treatment of PDE and TNF 40 mediated diseases, of Formula (0.1.12): (0.1.12) (0.1.9) H3C O V O COOH H N N NC 45 O Dr. N2- NH2 ARIFLOOR) cis-4-cyano-4-(3-cyclopentyl-oxy-4- methoxyphenyl)cyclo-hexane-1-carboxylic acid 50

The compound of Formula (0.1.9) falls within the scope Cipamfylline of U.S. Pat. No. 5,552,438 which discloses a genus of compounds of Formula (0.1.10): 55 WO 99/20280 (Griswold et al.) discloses a method of treating pruritis by administering an effective amount of a (0.1.10) PDE4 inhibitor, e.g., a compound of Formula (0.1.13): RX2 N X4 (0.1.13) O 60 eX R H X X3 'NN N

O1. N R3 where R= -(CRRs).R. where r–0 and RFC 65 cycloalkyl; X=YR where Y-O and R= -CH: X-O; R2 X=H; and X a moiety of partial Formula (0.1.10.1) US 7,183,293 B2 27 U.S. Pat. No. 5,922,557 (Pon) discloses a CHO-K1 cell line which stably expresses high levels of a full length -continued low-Km cAMP specific PDE4A enzyme, which has, in turn, been used to examine potent PDE4 enzyme inhibitors and Leukotriene (GE) compare the rank order of their potencies in elevating cAMP in a whole-cell preparation with their ability to inhibit phosphodiesterase activity in a broken-cell preparation. It is further said to be found that the soluble enzyme inhibition Receptor assay described in the prior art does not reflect behavior of the inhibitors acting in vivo. An improved soluble enzyme 10 whole-cell assay is then disclosed which is said to reflect the Accordingly, agents which are able to intervene in any of behavior of inhibitors acting in vivo. It is further disclosed the steps of the 5-lipoxygenase pathway afford an opportu that there exist at least four distinct PDE4 isoforms or nity for therapeutic treatment. An example of one such agent is the 5-lipoxygenase inhibitor, Zileuton, a therapeutic agent Subtypes, and that each Subtype has been shown to give rise 15 to a number of splice variants, which in themselves can identified as ZYFLOR) which may be represented by For exhibit different cellular localization and affinities for inhibi mula (0.1.14): tOrS. With regard to the disclosures of the above-identified (0.1.14) patents and published patent applications, it will be appre S CH ciated that the compounds involved possess the same bio logical activity as the compounds of Formula (1.0.0). At the / O same time, however, the artisan will observe that the chemi WN-( cal structures of said compounds disclosed in the prior art HO NH2 25 are not only diverse from each other but dissimilar to that of ZYFLOR) the novel compounds of the present invention as well. The Zileuton state of the art contains still further information regarding compounds which are dissimilar in chemical structure to those of Formula (1.0.0), and which, moreover, do not Another such agent is the LTD receptor antagonist possess PDE4 inhibitory activity similar to that of the 30 Zafirlukast, a therapeutic agent identified as ACCOLATER compounds of Formula (1.0.0). Such compounds disclosed which may be represented by Formula (0.1.15): in the prior art do, nevertheless, often have therapeutic utility similar to that possessed by the compounds of For (0.1.15) mula (1.0.0), i.e., in the treatment of inflammatory, respira 35 tory and allergic diseases and conditions. In particular this is pH, applicable to certain inhibitors of enzymes and antagonists of receptors in the so-called leukotriene pathway. This is especially the case with regard to the leukotrienes LTB and Clu-O- 40 -----K LTD. Accordingly, representative patents and published H3C patent applications disclosing further information of this type are described below. H3CO O S C Aw Arachidonic acid is metabolized by cyclooxygenase-1 ACCOLATER) O 4. Y, and by 5-lipoxygenase. The 5-lipoxygenase pathway leads Zafirlukast to the production of leukotrienes (LTs) which contribute to 45 the inflammatory response through their effect on neutrophil aggregation, degranulation and chemotaxis; vascular perme A further such LTD receptor antagonist is montelukast, a ability; Smooth muscle contractility; and on lymphocytes. therapeutic agent identified as SINGULAIR(R) which may be The cysteinyl leukotrienes, LTC LTD, and LTE, play an represented by Formula (0.1.16): important role in the pathogenesis of asthma. The compo 50 nents of the leukotriene pathway which afford targets for therapeutic intervention are illustrated in the following dia (0.1.16) gram: 55

Enzyme 5-lipoxygenase

ARACHIDONIC ACID 60 Enzyme LTA Hydrolase LTC Synthase 5-Lipoxygenase Activating Protein SINGULAIRR) (FLAP) 65 Montelukast US 7,183,293 B2 29 30 Another type of the above-mentioned therapeutic targets wherein is the LTB receptor, and an example of an antagonist for j is 0 or 1; provided that when j is 0, n must be 2: said receptor is BIIL-260, a therapeutic agent which may be represented by Formula (0.1.17): k is 0 or 1 (0.1.17) 5 m is 1, 2, or 3: n is 1 or 2; W' and W are independently —O ; S(=O), , where HO o-C- t is 0, 1, or 2; or N(R)— where R has the same 10 meaning as defined below: O NH Y is =C(R')—, where R', has the same meaning as H3C(H, defined below; or —NP(O), where k is 0 or 1: BIL-260 where Another example of a therapeutic agent which is an LTB receptor antagonist is CGS-25019c which may be repre 15 R", is a member selected from the group consisting of H; F; —Cl; —CN; —NO; —(C-C)alkyl; —(C-C) sented by Formula (0.1.18): alkynyl; fluorinated-(C-C)alkyl; fluorinated-(C-C) (0.1.18) alkoxy; OR'; and C(=O)NR'R'',: CH, O NH where OCH R’, and R', are each independently —H; —CH: H3C NH2 —CHCH: —CHCHCH: —CH2(CH), —CHCHCHCH, -CH(CH)CHCH. —CHCH HC CH o1-1N1\o (CH), —C(CH), cyclopropyl, cyclobutyl, or cyclo CGS-25O19C 25 pentyl: R" and Rare each a member independently selected from the group consisting of —H; —F. —CF, -(C-C) Nothing in the above-described state of the art discloses or would suggest to the artisan the novel compounds of the alkyl; —(C-C)cycloalkyl; phenyl; and benzyl, wherein present invention or their PDE4 inhibitory activity and the 30 said cycloalkyl, phenyl, and benzyl moieties are each resulting significant improvement in therapeutic utility and independently substituted with 0 to 3 substituents R': therapeutic index in the treatment of inflammatory, respira where tory and allergic diseases and conditions. R" is a member selected from the group consisting of 4.O SUMMARY OF THE INVENTION phenyl; pyridyl; —F: —Cl; CF; oxo (=O); —OR': 35 NO, CN; C(=O)CR; O C(=O)R'; The present invention is concerned with novel compounds C(=O)NR'R'7: O C(=O)NR'R'7; NR'R'7; which have biological activity as inhibitors of the phos NRC(=O)R'7; NRC(=O)CR'7; NR'S phodiesterase so-called “Type IV” isoenzyme (“PDE4 isozyme'). Embodiments of the novel compounds of the (=O).R'7; and—S(=O)NR'R'': where said phenyl or present invention are active as non-selective inhibitors of the 40 pyridyl is substituted by 0 to 3 R': PDE4 isozyme. Other embodiments of said novel com where pounds have PDE4 isozyme substrate specificity, especially R'' is —F; —Cl; CF; —CN; NO; OH: —(C-C) for the D Subtype. Said novel compounds having non alkoxy; —(C-C) alkyl; or - NR'R''. selective or D-selective PDE4 inhibitor activity are gener and ally useful in the therapeutic treatment of various inflam 45 matory, allergic, and respiratory diseases and conditions, and R'' and R'' are each a member independently selected from they afford in particular a significant improvement in the the group consisting of —H; —(C-C) alkyl; —(C-C) therapeutic treatment of obstructive respiratory diseases, alkenyl: —(C-C)cycloalkyl; phenyl; benzyl; and especially asthma and chronic obstructive pulmonary dis pyridyll; wherein said alkyl, alkenyl, cycloalkyl, phenyl, ease (COPD). 50 benzyl, or pyridyl is substituted by 0 to 3 substituents The present invention relates to a compound of Formula selected from the group consisting of —F. —Cl. —CF, (1.0.0): —CN, and —(C-C)alkyl; O 55

(1.0.0) R" and R are taken together, but only in the case where m is 1, to form a Spiro moiety of Formula (1.2.0):

60 (1.2.0)

(H2C) (CH2) 65 US 7,183,293 B2 31 32 where parathiazinyl; indolyl; indolinyl; benzobfuranyl: 2,3- rands are independently 0 to 4 provided that the sum of r-s dihydrobenzofuranyl: 2-H-chromenyl: chromanyl; ben is at least 1 but not greater than 5: Zothienyl: 1-H-indazolyl; benzimidazolyl; benzoxazolyl: and benzisoxazolyl; benzthiazolyl; quinolinyl; isoquinolinyl: X is selected from —CH2—, —CH(R') , or C(R') , where each R' is selected independently of the other and phthalazinyl; quinazolinyl; quinoxalinyl; and purinyl: each has the same meaning as defined above; —NR' , wherein said aryl and heterocyclyl moieties are each where R' has the same meaning as defined below: independently substituted with 0 to 2 substituents R' —O—; and —S(=O), , where t is 0, 1, or 2: where and 10 R'' is a member selected from the group consisting of said spiro moiety of partial Formula (1.2.0) is substituted as —(C-C) alkyl; —(C-C) cycloalkyl, phenyl; benzyl, to any one or more carbon atoms thereof, other than that defining X', by 0 to 3 substituents R'', where R' has the pyridyl; and quinolinyl; where said alkyl, cycloalkyl, same meaning as defined below; as to a nitrogen atom phenyl, benzyl, pyridyl, or quinolinyl is substituted by 0. thereof by 0 or 1 substituent R', where R' has the same 15 1, or 2 substituents —F. —Cl, —CH, —OR NO, meaning as defined below; and as to a Sulfur atom thereof —CN, or—NR'R'': and said R'' group further consists by 0 or 2 oxygen atoms; of-F:-Cl:—CF; oxo (=O); OR':-NO; –CN: R and R' have the same meaning as defined above for R' C(=O)CR: O C(=O)R'; C(=O)NR'R'7; and R except that one of them must be —H, and they are O C(=O)NR'R'7; NR'R'7; NRC(=O)R7; selected independently of each other and of R and R' NRC(=O)CR'7; NRS(=O).R'7; or S(=O), R" and R may individually or together appear on any ring NR'R'': where R'' and R7 have the same meanings as or rings comprising a meaning of the moiety ** as defined defined above; below; and R' and Rare each a member independently and further where Selected from the group consisting of —H; —F. —Cl; —CN; —NO; —(C-C)alkyl; —(C-C)alkynyl; flu 25 R" is a member independently selected from the group orinated-(C-C)alkyl; —OR'; and C(=O) consisting of H; NR'R'': C(=O)R': OR; NR'R'': where R', R’, and R, have the same —(C-C) alkyl-OR': C(=O)CR':-(C-C) alkyl meanings as defined above; C(=O)CR': C(=O)NR'R'7: -(C-C) alkyl; —R is —H; —(C-C)alkyl; phenyl; benzyl: or —OR', —(C-C) alkenyl; —(CH2)—(C-C) cycloalkyl where R' has the same meaning as defined above; 30 where u is 0, 1 or 2; phenyl; benzyl; pyridyl; and R, R and R may individually or together appear on any quinolinyl; wherein said alkyl, alkenyl, alkoxy, ring or rings comprising a meaning of the moiety * as cycloalkyl, phenyl, benzyl, pyridyl or quinolinyl is sub defined below; and R, R and R are each a member stituted with 0 to 3 substituents R'; where R'' and R'7 independently selected from the group consisting of have the same meanings as defined above; and the following: 35 where (a) —H; —F; Cl; —(C-C) alkynyl; R'; —OR'; R" is a member independently selected from the group S(=O).R.: C(=OR: C(=O)CR; OC consisting of —F; –Cl; COR'; OR'': –CN: (=O)R'; CN; NO: C(=O)NR'R'7: OC C(=O)NR'R'': NR'R'': NRC(=O)R’; (=O)NR'R'7; NR2C(=O)NR'R'7; NRPC 40 NRC(=O)CR'; NR's(=O).R', S(=O), (=NR'2)NR'R'7; NRC(=NCN)NR'R'7; NR'R'', where p is 1 or 2: —(C-C) alkyl; and NR’C(=N NO)NR'R'7; C(=NR’) —(C-C) alkoxy in the case where R' has the meaning NR'R'7: CHC(=NR2)NR'R'7; OC(=NR2) of —OR'' above and R' is defined as —(C-C) alkyl: wherein said alkyl and alkoxy are each independently 45 substituted with 0 to 3 substituents independently selected from —F. —Cl; —(C-C) alkoxycarbonyl: —(C-C) alkylcarbonyl: and —(C-C) alkylcarbonyloxy; where R has the same meaning as defined above; and p is 0, 1, or 2; and R’. R', and R'7 have the same where meanings as defined above; 50 (b) —(C-C) alkyl; and —(C-C) alkoxy in the case R" and R'' are independently selected from the group where one or more of R. R. or R has the meaning of consisting of —H; —(C-C) alkyl; and phenyl; where OR" under (a) above and R is defined as —(C-C) said alkyl or phenyl is substituted by 0–3 of —F; or —Cl; alkyl; wherein said alkyl and alkoxy are each indepen or in the case where) * is phenyl dently substituted with 0 to 3 substituents —For —Cl; or 55 0 or 1 substituent (C-C) alkoxycarbonyl-, (C-C) (d) Rand Rare taken together to form a moiety which is alkylcarbonyl-, or (C-C) alkylcarbonyloxy a member selected from the group consisting of partial and Formulas (1.3.1) through (1.3.15): (c) an aryl or heterocyclyl moiety selected from the group consisting of phenyl; benzyl; furanyl; tetrahydrofuranyl: 60 oxetanyl; thienyl; tetrahydrothienyl; pyrrolyl; pyrrolidi (1.3.1) nyl; oxazolyl, oxazolidinyl; isoxazolyl; isoxazolidinyl: thiazolyl; thiazolidinyl: isothiazolyl; isothiazolidinyl: pyrazolyl; pyrazolidinyl, oxadiazolyl; thiadiazolyl; imi O dazolyl; imidazolidinyl; pyridinyl; pyrazinyl; pyrimidi 65 nyl; pyridazinyl; piperidinyl; piperazinyl; triazolyl; triazi R20 nyl; tetrazolyl; pyranyl; azetidinyl; morpholinyl, US 7,183,293 B2 33 34

-continued -continued (1.3.2) (1.3.12) w R23 W /N1 ..", R2 -S A R24 (1.3.13) (1.3.3.) 10

N=N-- R24 Yes R20 -. 15 (1.3.14) (1.34) W. w N1 R23 N A R24 O 13. (1.3.15) (1.3.5)

--R20 (1.3.6) wherein 30 R” and R' are each a member independently selected from the group consisting of —H; —F. —Cl; —CH; —CHF: R21 O —CHF: —CF; —OCH; and —OCF; R° and Rare each independently —H; —CH: —OCH: R2 —CH2CH; —OCHCH; —CH2CHCH, -CH (1.3.7) 35 (CH), —CH2CH2CHCH; —CH(CH)CHCH: O —CH-CH(CH), —C(CH), or absent, in which case the dashed line - - - - represents a double bond; R *" is a moiety comprising a Saturated or unsaturated carbon 40 HO 2HO ring system that is a 3- to 7-membered monocyclic, or that R20 is a 7- to 12-membered, fused polycyclic; provided that (1.3.8) *" is not a discontinuous or restricted biaryl moiety; and wherein optionally one carbon atom of said carbon ring 45 system may be replaced by a heteroatom selected from N. O, and S.; where optionally a second carbon atom thereof, 1.HO R20 and further optionally a third carbon atom thereof may be (1.3.9) replaced by N: wherein 50 said moiety defining * is substituted on any ring or rings thereof by R. R and R, which have the same meaning as defined above; O R20 (1.3.10) * f is a moiety comprising a saturated or unsaturated carbon 55 ring system that is a 3- to 7-membered monocyclic, or that OH is a 7- to 12-membered, fused polycyclic; provided that * is not a discontinuous or restricted biaryl moiety; and R21 wherein optionally one carbon atom of said carbon ring system may be replaced by a heteroatom selected from N. O R20 60 O, and S.; where optionally a second carbon atom thereof, (1.3.11) and further optionally a third carbon atom thereof may be 23 Sae) R replaced by N: wherein 65 said moiety defining * is substituted on any ring or rings R thereof by R' and R, which have the same meaning as defined above; US 7,183,293 B2 35 36 D is a member independently selected from the group (1) —H; consisting of (2) —(C-C) alkyl; —(C-C) alkenyl: or —(C-C) alky the following nyl; where said alkyl, alkenyl or alkynyl is substituted by (a) the group consisting of partial Formulas (1.1.1) through 0 to 3 substituents R', where R' has the same meaning (1.1.9): 5 as defined above; (3) —(CH), (C-C) cycloalkyl where u is 0, 1 or 2; and further where said (C-C) cycloalkyl is substituted by 0 (1.1.1) to 3 substituents R' where R' has the same meaning as O defined above; 10 and : --- R7 (4) phenyl or benzyl, where said phenyl or benzyl is inde (1.1.2) pendently substituted by 0 to 3 substituents R' where R' O O has the same meaning as defined above: — R is a member independently selected from the group ls - 15 consisting of : 1, o1 the following: R9 (1) phenyl; tetrazol-5-yl: 1,2,4-triazol-3-yl: 1,2,4-triazol-3- (1.1.3) on-5-yl: 1,2,3-triazol-5-yl; imidazol-2-yl; imidazol-4-yl: imidazolidin-2-on-4-yl: 1,3,4-oxadiazolyl: 1,3,4-oxadia Zol-2-on-5-yl: 1,2,4-oxadiazol-3-yl: 1,2,4-oxadiazol-5- on-3-yl: 1,2,4-oxadiazol-5-yl: 1,2,4-oxadiazol-3-on-5-yl; 1,2,5-thiadiazolyl: 1,3,4-thiadiazolyl; morpholinyl; par athiazinyl: oxazolyl; isoxazolyl; thiazolyl; isothiazolyl, (1.1.4) pyrrolyl; pyrazolyl; Succinimidyll; glutarimidyl; pyrroli 25 donyl: 2-piperidonyl: 2-pyridonyl, 4-pyridonyl: pyridazin-3-onyl; pyridyl, pyrimidinyl, pyrazinyl: pyridazinyl: and (2) indolyl; indolinyl: isoindolinyl; benzobfuranyl; 2.3- (1.1.5) 30 dihydrobenzofuranyl: 1,3-dihydroisobenzofuranyl; 2H-1- benzopyranyl: 2-H-chromenyl; chromanyl; benzothienyl: 1H-indazolyl; benzimidazolyl; benzoxazolyl; benzisox azolyl; benzothiazolyl; benzotriazolyl; benzotriazinyl: phthalazinyl: 1.8-naphthyridinyl; quinolinyl; isoquinoli 35 nyl; quinazolinyl; quinoxalinyl; pyrazolo 3,4-dipyrimidi (1.1.6) nyl; pyrimido4.5-dpyrimidinyl, imidazol-2-alpyridi nyl; pyridopyridinyl; pteridinyl; and 1H-purinyl: where (1.1.7) any moiety recited in (1) or (2) above is optionally substi 40 tuted with respect to (i) any one or more carbon atoms thereof optionally by a substituent R' where R' has the same meaning as defined above; (ii) any one or more nitrogen atoms thereof that is not a point of attachment of (1.1.8) said moiety, optionally by a substituent R' where R' has 45 the same meaning as defined above, and all tautomer forms thereof; and (iii) any sulfur atom thereof that is not a point of attachment of said moiety, by 0, 1, or 2 oxygen atoms; (1.1.9) R is a member selected from the group consisting of H; —(C-C) alkyl: —(C-C2) cycloalkyl, phenyl; benzyl: 50 pyridyl: C(=O)CR': C(=O)R'; OR; —(C-C) alkyl-OR'; and —(C-C) alkyl-C(=O) OR'; where R' has the same meaning as defined above: wherein and D is further selected from G: (b) a moiety comprising a member selected from the group indicates the point of attachment of each partial Formula 55 consisting of —O—P(=O)(OH) (phosphoric); —PH (1.1.1) through (1.1.9) to the remaining portion of For (=O)CH (phosphinic); —P(=O)(OH), (phosphonic); mula (1.0.0); —P(=O)(OH)—O(C-C) alkyl (alkylphosphono); q is 1, 2, or 3, provided that where q is 2 or 3, R has the —P(=O)(OH)—O(C-C) alkyl) (alkylphosphinyl); meaning of —H in at least one instance, or two instances, —P(=O)(OH)NH. (phosphoramido), -P(=O)(OH)NH respectively; 60 (C-C) alkyl and - P(=O)(OH)NHR' (substituted v 0 or 1; phosphoramido); -O S(=O),OH (sulfuric): —S(=O).OH (sulfonic); S(=O)NHR or - NHS W is —O ; N(R) , where R has the same meaning (=O)R’ (sulfonamido) where R is —CH, -CF, or as defined below; or —OC(=O)—; o-toluyl; and acylsulfonamido selected from the group R’ is a member independently selected from the group 65 consisting of C(=O)NHS(=O)R’: C(=O)NHS consisting of (=O)NH; C(=O)NHS(=O)(C-C) alkyl; the following: C(=O)NHS(=O)NH(C-C) alkyl: C(=O)NHS US 7,183,293 B2 37 38

-continued NH(C-C) (1.1.17)

where R’ is —H: —(C-C) alkyl; phenyl: or -OR where R' 10 imidazolidin-2-on-4-yl has the same meaning as defined above; (1.1.18) O O a pharmaceutically acceptable salt thereof. y) 15 N-N The present invention is concerned in particular with a 1,3,4-oxadiazolyl compound of Formula (1.0.0) as above-recited wherein the (1.1.19) moiety D comprises as a preferred meaning of R". phenyl, benzyl, or cyclohexyl illustrated in partial Formulas (1.1.45) through (1.1.47) below; or the moiety D comprises R of V partial Formula (1.1.4) where V is 0 or 1, comprising a R 15 member selected from the group consisting of partial For 1,3,4-oxadiazol-2-on-5-yl mulas (1.1.11) through (1.1.44) illustrated below: (1.1.20) 25 (1.1.11) : N () a N 1,2,4-oxadiazol-3-yl // (1.1.21) N-N R 15 A 30 R 15 tetrazol-5-yl (1.1.12) : N YY Yy 35 1,2,4-oxadiazol-5-on-3-yl N-N (1.1.22) A : N R 15 1,2,4-triazol-3-yl ne i O-N (1.1.13) 40 : N O 1,2,4-oxadiazol-5-yl (1.1.23) N Y : N N- N Ney RI 5 Y. 5 45 O-N 1,2,4-triazol-3-on-5-yl Yis (1.1.14) : 1,2,4-oxadiazol-3-on-5-yl (1.1.24) Y.// : N N-N 50 a Ns A / R 15 FN 1,2,3-triazol-5-yl 1,2,5-thiadiazol-2-yl (1.1.15) (1.1.25) S 55 (1. N-N R 15 1,3,4-thiadiazolyl imidazol-2-yl (1.1.26) (1.1.16) 60 CCl : V 15 65 R15 imidazol-4-yl morpholin-3-yl US 7,183,293 B2 39 40

-continued -continued (1.1.27) (1.1.36) R 15 N rO ClR15 pyrrollidonyl parathiazin-3-yl 10 (1.1.37)

(1.1.28)

oxazolyl (1.1.38)

(1.1.29) :

2-pyridonyl isoxazolyl 25 (1.1.39) (1.1.30) R15 N 30 -

(1.1.31) : O 4-pyridonyl x^, 35 (1.1.40) -N isothiazolyl (1.1.32) R 15 40 N pyridazin-3-onyl (1.1.41) N (1.1.33) 45 rN pyridyl (1.1.42) 50 r N ) (1.1.34) N-N pyrimidinyl Sky 55 (1.1.43) lsr (1.1.35) N 60 pyrazinyl (1.1.44) 4N

65 su glutarimidyl pyridazinyl US 7,183,293 B2 41 42

-continued -continued (1.1.45) (1.1.15) :

phenyl R 15 (1.1.46) imidazol-2-yl : 10 (1.1.16)

benzyl V 15 (1.1.47) : 15 imidazol-4-yl (1.1.17)

cyclohexyl wherein “” indicates the point of attachment of each partial Formula (1.1.11) through (1.1.47) to the remaining portion imidazolidin-2-on-4-yl of Formula (1.0.0); and wherein each carbon atom of partial 25 (1.1.19) Formulas (1.1.11) through (1.1.44) is optionally substituted : O O by a substituent R'': where R'' and R' have the same NY meaning as defined above; and all tautomer forms, and N-N optionally N-oxide forms, thereof; and further wherein each Y is carbon atom of partial Formulas (1.1.45) through (1.1.47) is 30 1,3,4-oxadiazol-2-on-5-yl optionally substituted by a substituent R'; where R' has (1.1.21) the same meaning as defined above. R 15 The present invention is further concerned more particu larly with a compound of Formula (1.0.0) as above-recited 35 wherein the moiety D is especially the below-indicated member selected from the above-recited group consisting of YY partial Formulas (1.1.11) through (1.1.47): 1,2,4-oxadiazol-5-on-3-yl (1.1.23) : N O 40 N (1.1.11) ne Y O-N 2 N. Yis N A 1,2,4-oxadiazol-3-on-5-yl 45 R 15 (1.1.33) tetrazol-5-yl R15 (1.1.12) : YyN 50 - N-N A pyrazolyl R 15 (1.1.34) 1,2,4-triazol-3-yl (1.1.13) : N N YO 55 Sky N- N RI 5 Y. 5 1,2,4-triazol-3-on-5-yl (1.1.35) 60 (1.1.14) : Y).// N-N A R 15 65 1,2,3-triazol-5-yl glutarimidyl US 7,183,293 B2 43 44

-continued -continued (1.1.38) (1.4.2) R15 R 15 5 M ... ?? N O Ny 21 2N. indolinyl 2-pyridonyl 1.4.3) (1.1.39) ' : (1.4. R 15 A\ : 1. N-R

15 isolindolinyl (1.44) O O 4-pyridonyl X

(1.1.40) 20 ŽS. benzobfuranyl (14.5) OX 25 ŽQ : 2,3-dihydrobenzo-furanyl (1.1.41) (1.4.6) : 30 \\ O

(1.1.42) 1,3-dihydroisobenzo-furanyl; phthalanyl (14.7) 35 N : pyrimidinyl 2 (1.1.45) 2H-1-benzopyranyl : O 40 O (1.4.8) N : phenyl (1.1.47) : 45 chromanyl O S (14.9) cyclohexyl CC. 50 benzothienyl The present invention is further concerned in particular (1.4.10) with a compound of Formula (1.0.0) as above-recited wherein the moiety D comprises R of partial Formula N (1.1.4) where v is 0 or 1, and R of said partial Formula 55 Y. (1.1.4) is a member selected from the group consisting of f/ partial Formulas (1.4.1) through (1.4.28): : 1H-indazolyl (14.1) 60 (1.4.11) R15 A N N OCA : 65 X- : indolyl benzimidazolyl US 7,183,293 B2 45 46

-continued -continued (1.4.12) (1.4.22) OX N benzoxazolyl quinoxalinyl (1.4.13) (1.4.23) N 10 R15 N A A N : Na2 / benzisoxazolyl 15 (1.4.14) S 1H-pyrazolo 3,4-d-pyrimidinyl (1.4.24) X N benzothiazolyl Srs (1.4.15) se 2N 15 pyrimidoS,4-d-pyrimidinyl (1.4.25) C 25 21 NN-11N s * 2H-1,2-benzothiazinyl N1SN (1.4.16) imidazo-1,2-a-pyridinyl (1.4.26) 30 N 21 N re

35 pyridopyridinyl (1.4.17) (1.4.27) N N

: 2 N 40 N C2 quinolinyl pteridinyl (1.4.18) (1.4.28) n N R 15 M exd 45 : X isoquinolinyl CC---. (1.4.19) 1H-purinyl N N 21 y 50 : S where indicates the point of attachment to the remaining portion of Formula (1.0.0); and where each carbon atom is 1,8-naphthyridinyl optionally substituted by a substituent R'; and where R'' and R' have the same meaning as defined above; and all (1.4.20) 55 tautomer forms, and optionally N-oxide forms, thereof. s : The present invention is further concerned with a com 2N pound of Formula (1.0.0) wherein k comprises especially phthalazinyl a member selected from the group consisting of phenyl: 60 pyrrolyl; pyrrolidinyl; furanyl; thienyl; pyridyl, pyrimidinyl: (1.4.21) piperidinyl; piperazinyl; imidazolyl; imidazolidinyl: oxazolyl; isoxazolyl; morpholinyl; thiazolyl; indolyl; quino s : linyl; isoquinolinyl; benzimidazolyl; benzoxazolyl; quinu 2N clidinyl; and azabicyclo3.3.0 octanyl; a monocyclic 65 —(C-C2) cycloalkyl moiety; a monocyclic —(Cs-C7) quinazolinyl cycloalkenyl moiety that is a member selected from the group consisting of cyclopentenyl, cyclohexenyl, and cyclo US 7,183,293 B2 47 48 heptenyl; and a bicyclic —(C7-Co) cycloalkyl or —(C7-Co) cycloalkenyl moiety that is a member selected -continued (2.0.7) from the group consisting of norbornanyl, norbornenyl, : bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.0 octanyl, bicyclo[2.2.2]oct-5-enyl, bicyclo[2.2.2]oct-7-enyl, bicyclo3.3.1 nonanyl, cyclodecanyl, and adamantanyl. CH3 The present invention is still further concerned especially YCH, with a compound of Formula (1.0.0) wherein particularly k" 10 C,O and the substituents R. R. and R are selected in such a way that the left-hand terminus of said compound of For (2.0.8) mula (1.0.0) is represented by the following partial Formulas : (2.0.1) through (2.0.72): 15

: (2.0.1) F

(2.0.9) :

25 F : (2.0.2) F 3C (2.0.10) 30 :

F (2.0.3) 35 C. CF (2.0.11) :

40 NC

F : (2.0.4) O 45 C.O (2.0.12) :

C 50 (2.0.5) O C.O 55 (2.0.13) ON : (2.0.6)

O F C, 65 CH3 C CH US 7,183,293 B2 49 50

-continued -continued (2.0.14) (2.0.21)

y 10 N-O (2.0.22)

(2.0.15) 15

N-4 (2.0.23)

(2.0.16) : N 25 e N S (2.0.24) o S. M

30 (2.0.17)

S S. M (2.0.25) N 35 Sr.22 (2.0.18) :

40 (2.0.26)

Z Ny I 45 (2.0.19) (2.0.27)

N (2.0.28) W 55 N H (2.0.20)

CH3 60 (2.0.29)

N C.N 65 V CH US 7,183,293 B2 51 52

-continued -continued (2.0.30) (2.0.38)

10 (2.0.39) (2.0.31)

15 (2.0.4.0)

(2.0.32) (2.0.41) 25 2.

(2.0.42) 30 A

(2.0.33) o (2.0.43) 35

(2.0.34) (2.0.44) 40 c)

(2.0.35) 45 C (2.0.45)

50 (2.0.36) o (2.0.46)

55 (2.0.37) (2.0.47)

60 O (2.0.48) CH 65 O US 7,183,293 B2 53 54

-continued -continued (2.0.49) : (2.0.60) 2 '. 5

(2.0.50) 10 O 27 : (2.0.61)

: (2.0.51) 15 C. - CH". : : (2.0.62) 2O

(2.0.52)

25 OH (2.0.63) : (2.0.53) : 30 /

S (2.0.54) N : 35 : N (2.0.64) n 21 (2.0.55) 40 F F : (2.0.65) NN (2.0.56) 45 21

NO CH (2.0.66) 3 50 : ? (2.0.57) N

OC)N : (2.0.67) 55 H O : (2.0.58) - \ O O N 60 NCH, CH3 (2.0.59) : (2.0.68) : O

n-1 "3 FC US 7,183,293 B2 55 56

-continued -continued (2.0.69) (2.5.2) :

10 :F (2.5.3) (2.0.70) F

15 FC (2.0.71) (2.5.4)

OH (2.0.72)

25 (2.5.5) NO CH3 2

The present invention is further concerned with a com (2.5.6) pound of Formula (1.0.0) wherein k comprises especially CH3 a member selected from the group consisting of phenyl: 35 pyrrolyl; pyrrolidinyl; furanyl; thienyl; pyridyl, pyrimidinyl: piperidinyl: piperazinyl: imidazolyl, imidazolidinyl: oxazolyl; isoxazolyl; thiazolyl; indolyl; quinolinyl; iso quinolinyl; benzimidazolyl; benzoxazolyl; morpholinyl: 40 C quinuclidinyl; and azabicyclo3.3.0 octanyl; a monocyclic (2.5.7) —(C-C) cycloalkyl moiety; a monocyclic —(Cs-C-7) CF3 cycloalkenyl moiety that is a member selected from the group consisting of cyclopentenyl, cyclohexenyl, and cyclo heptenyl: and a bicyclic —(C7-Co) cycloalkyl or 45 —(C7-Co) cycloalkenyl moiety that is a member selected from the group consisting of norbornanyl, norbornenyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.0 (2.5.8) octanyl, bicyclo[2.2.2]oct-5-enyl, bicyclo[2.2.2]oct-7-enyl, bicyclo3.3.1 nonanyl, cyclodecanyl, and adamantanyl. 50 The present invention is also further concerned especially with a compound of Formula (1.0.0) wherein particularly k? : e (2.5.9) and the substituents R' and Rare selected in such a way that this portion of the right-hand terminus of said compound of 55 21 Formula (1.0.0) is represented by the following partial Formulas (2.5.1) through (2.5.50) set out below.

: (2.5.1) 60 (2.5.10) N H

65 : US 7,183,293 B2 57 58

-continued -continued (2.5.11) : S : : : (2.5.21) y 1 5 NC (2.5.12) (2.5.22) a S : :

o 10 (2.5.23)

: (2.5.13) 21 NN 15 N W : N (2.5.14) (2.5.24) : : F Ol 2O C (2.5.15) (2.5.25) CH : 25 : NN Ol 2 CH 30 : (2.5.26)

H3C CH3 (2.5.16) Ol :

: 35 (2.5.27) r : Nals : O : : (2.5.17) 4C (2.5.28) is, \= ( 45

(2.5.29) (2.5.18) CH : : 50 2 NH

N o :

: 55 (2.5.30) : (2.5.19)

6C (2.5.20) (2.5.31)

: US 7,183,293 B2 59 60

-continued -continued (2.5.32) : (2.5.42) : : n N 2

(2.5.33) : : 10 (2.5.43) 1SN (2.5.34) H3

(2.5.44) :: /: (2.5.35) t O 25 (2.5.45) (2.5.36) :

ntN-1s-1NN21N21 : 30 (2.5.37) (2.5.46) O: 1s 35

(2.5.38) (2.5.47) CHF 40 : Ol C (2.5.48) (2.5.39) 45 CF : or : F (2.5.49) C 50 (2.5.40) C O

55 CHF (2.5.50) o1 2

(2.5.41) 60 CH3 :

65 The present invention is still further concerned with a C compound of Formula (1.0.0) characterized as to the right hand side thereof, where m is 1, by partial Formula (1.0.5): US 7,183,293 B2 61 62

-continued (1.0.5) RA (1.5.7) : O n D R1 R2 RP O OH

O where 66: is a symbol representing the point of attachment 10 of the group of partial Formula (1.0.5) to the remaining portion of a compound of Formula (1.0.0) where R and R' (1.5.8) are both —H, or one is —H and the other is —CH, or both are —CH, or both are taken together to form spiro-cyclo propyl or spiro-cyclobutyl; R is H. —OCH, or 2'-F: R 15 is —H; and the moieties k and D are selected such that, said group of partial Formula (1.0.5) is a member selected from the group consisting of partial Formulas (1.5.1) through (1.5.54), as set out below. Where the moiety k is (1.5.9) phenyl, the 2'-position thereof is located as indicated in partial Formula (1.5.1):

25 (1.5.1)

(1.5.10)

H3C 30 ÖH, O (15.2) (1.5.11) 35

O (1.5.3) F O (1.5.12) 40 F : O OH HC ( : O NH2 ÖH, O (1.5.4) 45 (1.5.13)

N & S. 50 -()- N (1.5.5) F HC {N (1.5.14) F : O OH 55

: O N HC N (1.5.6) CH / H3C {N O 60 (1.5.15)

: O OH

65 US 7,183,293 B2 63 64

-continued -continued (1.5.25) (1.5.16) N E / N N y-g s N s e N C H3 N 10 (1.5.26) (1.5.17)

: O H O 15 O H s F-KYY-F (1.5.27) i H3 (1.5.18) : OON : OO OO os O (1.5.28) i H3 25 (1.5.19) O n1N.On 1 CN H3H : O (1.5.29) - NH 30 -(S)-F-Y-F H i O (1.5.20) CNH3H (1.5.30) 35 H3 o O O O H O H H3 s (1.5.21) 40 : r o (1.5.31) O N s 45 / S N (1.5.22) (1.5.32)

: O H 50 -O-) K O s CH (1.5.33) O H (1.5.23) 55 n1N.Osa - COH3H 60 ar (1.5.24) (1.5.34) O H OH O -(S)-y 65 US 7,183,293 B2 65 66

-continued -continued

(1.5.35) (1.5.44)

(1.5.36)

(1.5.45) H3C O

: (1.5.37) 2 O

O OH (1.5.46)

: H3C O (1.5.38)

(1.5.39) (1.5.47)

(1.5.40)

HC O (1.5.41) N (1.5.48) n

21 O

NH2 H3C O (1.5.42) (1.5.49)

H3C O (1.5.43) F

: O CH CH HC 65 OH US 7,183,293 B2 67 68 above which is useful in treating or preventing one or -continued members selected from the groups of diseases, disorders, (1.5.50) and conditions consisting of asthma of whatever type, etiology, or pathogenesis; or CH3 asthma that is a member selected from the group consisting of atopic asthma; non-atopic asthma, aller gic asthma; atopic, bronchial, IgE-mediated asthma, bronchial asthma, essential asthma; true asthma; intrin sic asthma caused by pathophysiologic disturbances; 10 extrinsic asthma caused by environmental factors; (1.5.51) essential asthma of unknown or inapparent cause; non atopic asthma; bronchitic asthma, emphysematous asthma, exercise-induced asthma, occupational asthma; infective asthma caused by bacterial, fungal, 15 protozoal, or viral infection; non-allergic asthma, incipient asthma, wheezy infant syndrome; chronic or acute bronchoconstriction; chronic bronchitis; Small airways obstruction; and emphysema; obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis; or an obstructive or (1.5.52) inflammatory airways disease that is a member selected from the group consisting of asthma; pneumoconiosis: chronic eosinophilic pneumonia; chronic obstructive 25 pulmonary disease (COPD); COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated therewith: COPD that is characterized by irreversible, progressive airways obstruction; adult res piratory distress syndrome (ARDS), and exacerbation 30 of airways hyper-reactivity consequent to other drug therapy; (1.5.53) pneumoconiosis of whatever type, etiology, or pathogen esis; or pneumoconiosis that is a member selected from the group consisting of aluminosis or bauxite workers’ CH3 35 disease; anthracosis or miners asthma, asbestosis or steam-fitters asthma, chalicosis or flint disease; ptilo sis caused by inhaling the dust from ostrich feathers; siderosis caused by the inhalation of iron particles; silicosis or grinders disease; byssinosis or cotton-dust 40 (1.5.54) asthma, and talc pneumoconiosis; O bronchitis of whatever type, etiology, or pathogenesis; or H O N bronchitis that is a member selected from the group consisting of acute bronchitis; acute laryngotracheal bronchitis; arachidic bronchitis; catarrhal bronchitis; O CH3 N-Ny 45 croupus bronchitis; dry bronchitis; infectious asthmatic bronchitis; productive bronchitis; Staphylococcus or streptococcal bronchitis; and vesicular bronchitis; wherein bronchiectasis of whatever type, etiology, or pathogen esis; or bronchiectasis that is a member selected from 66: indicates the point of attachment of each said group of 50 the group consisting of cylindric bronchiectasis; sac partial Formula (1.0.5) represented by partial Formulas culated bronchiectasis; fusiform bronchiectasis; capil (1.5.1) through (1.5.54) to the remaining portion of For lary bronchiectasis; cystic bronchiectasis; dry bron mula (1.0.0). chiectasis; and follicular bronchiectasis; The present invention is further concerned with a method 55 seasonal allergic rhinitis; or perennial allergic rhinitis; or of treating a Subject Suffering from a disease or condition sinusitis of whatever type, etiology, or pathogenesis; or mediated by the PDE4 isozyme in its role of regulating the sinusitis that is a member selected from the group activation and degranulation of human eosinophils, com consisting of purulent or nonpurulent sinusitis; acute or prising administering to said Subject in need of said treat chronic sinusitis; and ethmoid, frontal, maxillary, or ment a therapeutically effective amount of a compound of 60 sphenoid sinusitis; Formula (1.0.0) as described above. Similarly, the present rheumatoid arthritis of whatever type, etiology, or patho invention is also concerned with a pharmaceutical compo genesis; or rheumatoid arthritis that is a member sition for use in Such a therapeutic treatment, comprising a Selected from the group consisting of acute arthritis; compound of Formula (1.0.0) as described above together acute gouty arthritis; chronic inflammatory arthritis; with a pharmaceutically acceptable carrier. 65 degenerative arthritis; infectious arthritis; Lyme arthri The present invention relates to PDE4 isozyme inhibitors tis; proliferative arthritis; psoriatic arthritis; and verte comprising a compound of Formula (1.0.0) as described bral arthritis; US 7,183,293 B2 69 70 gout, and fever and pain associated with inflammation; benign familial pemphigus; pemphigus erythematosus; an eosinophil-related disorder of whatever type, etiology, pemphigus foliaceus; and pemphigus Vulgaris; or pathogenesis; or an eosinophil-related disorder that prevention of allogeneic graft rejection following organ is a member selected from the group consisting of transplantation; eosinophilia; pulmonary infiltration eosinophilia; Lof 5 inflammatory bowel disease (IBD) of whatever type, fler's syndrome; chronic eosinophilic pneumonia; etiology, or pathogenesis; or inflammatory bowel dis tropical pulmonary eosinophilia; bronchopneumonic ease that is a member selected from the group consist aspergillosis; aspergilloma; granulomas containing ing of ulcerative colitis (UC); collagenous colitis; coli eosinophils; allergic granulomatous angiitis or Churg tis polyposa; transmural colitis; and Crohn's disease Strauss syndrome; polyarteritis nodosa (PAN); and 10 (CD). systemic necrotizing vasculitis; septic shock of whatever type, etiology, or pathogenesis; atopic dermatitis; or allergic dermatitis; or allergic or or septic shock that is a member selected from the atopic eczema: group consisting of renal failure; acute renal failure; urticaria of whatever type, etiology, or pathogenesis; or cachexia; malarial cachexia; hypophysial cachexia; urticaria that is a member selected from the group 15 uremic cachexia; cardiac cachexia; cachexia Suprarena consisting of immune-mediated urticaria; complement lis or Addison's disease; cancerous cachexia; and mediated urticaria; urticariogenic material-induced cachexia as a consequence of infection by the human urticaria; physical agent-induced urticaria; stress-in immunodeficiency virus (HIV); duced urticaria; idiopathic urticaria; acute urticaria; liver injury; chronic urticaria; angioedema; cholinergic urticaria; pulmonary hypertension; and hypoxia-induced pulmo cold urticaria in the autosomal dominant form or in the nary hypertension; acquired form; contact urticaria; giant urticaria; and bone loss diseases; primary osteoporosis; and secondary papular urticaria; osteoporosis: conjunctivitis of whatever type, etiology, or pathogenesis; central nervous system disorders of whatever type, etiol or conjunctivitis that is a member selected from the 25 ogy, or pathogenesis; or a central nervous system group consisting of actinic conjunctivitis; acute disorder that is a member selected from the group catarrhal conjunctivitis; acute contagious conjunctivi consisting of depression; Parkinson's disease; learning tis; allergic conjunctivitis; atopic conjunctivitis; and memory impairment; tardive dyskinesia; drug chronic catarrhal conjunctivitis; purulent conjunctivi dependence; arteriosclerotic dementia; and dementias tis; and Vernal conjunctivitis 30 that accompany Huntington's chorea, Wilson's disease, uveitis of whatever type, etiology, or pathogenesis; or paralysis agitans, and thalamic atrophies; uveitis that is a member selected from the group infection, especially infection by viruses wherein such consisting of inflammation of all or part of the uvea; viruses increase the production of TNF-C. in their host, anterior uveitis; iritis; cyclitis; iridocyclitis; granulo or wherein Such viruses are sensitive to upregulation of matous uveitis; nongranulomatous uveitis; phacoanti 35 TNF-C. in their host so that their replication or other genic uveitis; posterior uveitis; choroiditis; and chori vital activities are adversely impacted, including a virus oretinitis; which is a member selected from the group consisting psoriasis; of HIV-1, HIV-2, and HIV-3; cytomegalovirus, CMV: multiple Sclerosis of whatever type, etiology, or patho influenza; adenoviruses; and Herpes viruses, including genesis; or multiple Sclerosis that is a member selected 40 Herpes Zoster and Herpes simplex: from the group consisting of primary progressive mul yeast and fungus infections wherein said yeast and fungi tiple Sclerosis; and relapsing remitting multiple Sclero are sensitive to upregulation by TNF-C. or elicit TNF-C. sis; production in their host, e.g., fungal meningitis; par autoimmune/inflammatory diseases of whatever type, eti ticularly when administered in conjunction with other ology, or pathogenesis; or an autoimmune/inflamma 45 drugs of choice for the treatment of systemic yeast and tory disease that is a member selected from the group fungus infections, including but are not limited to, consisting of autoimmune hematological disorders; polymixins, e.g., Polymycin B; imidazoles, e.g., clot hemolytic anemia; aplastic anemia; pure red cell ane rimazole, econazole, miconazole, and ketoconazole; mia; idiopathic thrombocytopenic purpura; systemic triazoles, e.g., fluconazole and itranazole; and ampho lupus erythematosus; polychondritis; Scleroderma; 50 tericins, e.g., Amphotericin B and liposomal Amphot Wegner's granulomatosis; dermatomyositis; chronic ericin B. active hepatitis; myasthenia gravis; Stevens-Johnson ischemia-reperfusion injury; autoimmune diabetes; reti syndrome; idiopathic sprue; autoimmune inflammatory nal autoimmunity; chronic lymphocytic leukemia; HIV bowel diseases; ulcerative colitis; Crohn's disease; infections; lupus erythematosus; kidney and ureter dis endocrin opthamopathy; Grave's disease; sarcoidosis: 55 ease; urogenital and gastrointestinal disorders; and alveolitis; chronic hypersensitivity pneumonitis; pri prostate diseases. mary biliary cirrhosis; juvenile diabetes or diabetes In particular, the compounds of Formula (1.0.0) are useful mellitus type I: anterior uveitis; granulomatous or pos in the treatment of (1) inflammatory diseases and conditions terior uveitis; keratoconjunctivitis sicca, epidemic comprising: joint inflammation, rheumatoid arthritis, rheu keratoconjunctivitis; diffuse interstitial pulmonary 60 matoid spondylitis, osteoarthritis, inflammatory bowel dis fibrosis or interstitial lung fibrosis; idiopathic pulmo ease, ulcerative colitis, chronic glomerulonephritis, derma nary fibrosis; cystic fibrosis; psoriatic arthritis; glom titis, and Crohn's disease; (2) respiratory diseases and erulonephritis with and without nephrotic syndrome; conditions comprising: asthma, acute respiratory distress acute glomerulonephritis; idiopathic nephrotic Syn syndrome, chronic pulmonary inflammatory disease, bron drome; minimal change nephropathy; inflammatory/ 65 chitis, chronic obstructive airway disease, and silicosis; (3) hyperproliferative skin diseases; psoriasis; atopic der infectious diseases and conditions comprising: sepsis, septic matitis; contact dermatitis; allergic contact dermatitis; shock, endotoxic shock, gram negative sepsis, toxic shock US 7,183,293 B2 71 72 syndrome, fever and myalgias due to bacterial, viral or factor type I (IGF-1) mimetics; (r) ciclesonide: (s) inhaled fungal infection, and influenza; (4) immune diseases and glucocorticoids with reduced systemic side effects, includ conditions comprising: autoimmune diabetes, systemic ing prednisone, prednisolone, flunisolide, triamcinolone lupus erythematosis, graft vs. host reaction, allograft rejec acetonide, beclomethasone dipropionate, budesonide, fluti tions, multiple Sclerosis, psoriasis, and allergic rhinitis; and 5 casone propionate, and mometaSone furoate; (t) tryptase (5) other diseases and conditions comprising: bone resorp inhibitors; (u) platelet activating factor (PAF) antagonists; tion diseases; reperfusion injury: cachexia secondary to (v) monoclonal antibodies active against endogenous infection or malignancy; cachexia secondary to human inflammatory entities; (w) IPL 576; (x) anti-tumor necrosis acquired immune deficiency syndrome (AIDS), human factor (TNFC.) agents including Etanercept, Infliximab, and immunodeficiency virus (HIV) infection, or AIDS related 10 complex (ARC), keloid formation; Scar tissue formation; D2E7: (y) DMARDs including Leflunomide: (Z) TCR pep type 1 diabetes mellitus; and leukemia. tides: (aa) interleukin converting enzyme (ICE) inhibitors: The present invention still further relates to the combi (bb) IMPDH inhibitors; (cc) adhesion molecule inhibitors nation of a compound of Formula (1.0.0) together with one including VLA-4 antagonists; (dd) cathepsins; (ee) MAP or more members selected from the group consisting of the 15 kinase inhibitors, (f) glucose-6 phosphate dehydrogenase following: (a) leukotriene biosynthesis inhibitors: 5-lipoxy inhibitors; (gg) kinin-B- and B-receptor antagonists; (hh) genase (5-LO) inhibitors and 5-lipoxygenase activating pro gold in the form of an aurothio group together with various tein (FLAP) antagonists selected from the group consisting hydrophilic groups; (ii) immunosuppressive agents, e.g., of zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175: cyclosporine, azathioprine, and methotrexate; (ii) anti-gout Abbott-85761; N-(5-substituted)-thiophene-2-alkylsulfona agents, e.g., colchicine; (kk) Xanthine oxidase inhibitors, mides of Formula (5.2.8); 2,6-di-tert-butylphenol hydra e.g., allopurinol; (Il) uricosuric agents, e.g., probenecid, Zones of Formula (5.2.10); the class of methoxytetrahydro Sulfinpyrazone, and benzbromarone; (mm) antineoplastic pyrans which includes Zeneca ZD-2138 of Formula agents, especially antimitotic drugs including the Vinca (5.2.11); the compound SB-210661 of Formula (5.2.12) and alkaloids Such as vinblastine and Vincristine; (nn) growth the class to which it belongs; the class of pyridinyl-substi 25 hormone secretagogues; (oo) inhibitors of matrix metallo tuted 2-cyanonaphthalene compounds to which L-739,010 proteases (MMPs), i.e., the stromelysins, the collagenases, belongs; the class of 2-cyanoquinoline compounds to which and the gelatinases, as well as aggrecanase; especially L-746,530 belongs; the classes of indole and quinoline collagenase-1 (MMP-1), collagenase-2 (MMP-8), collage compounds to which MK-591, MK-886, and BAY x 1005 nase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 belong; (b) receptor antagonists for leukotrienes LTB, 30 (MMP-10), and stromelysin-3 (MMP-11); (pp) transforming LTC LTD, and LTE selected from the group consisting of the phenothiazin-3-one class of compounds to which L-651, growth factor (TGFB); (qq) platelet-derived growth factor 392 belongs; the class of amidino compounds to which (PDGF); (rr) fibroblast growth factor, e.g., basic fibroblast CGS-25019c belongs; the class of benzoxaolamines to growth factor (bFGF), (SS) granulocyte macrophage colony which ontaZolast belongs; the class of benzenecarboximi 35 stimulating factor (GM-CSF); (tt) capsaicin cream; (uu) damides to which BIIL 284/260 belongs; and the classes of Tachykinin NK and NK receptor antagonists selected from compounds to which Zafirlukast, ablukast, montelukast, the group consisting of NKP-608C; SB-233412 (talnetant); pranlukast, verlukast (MK-679), RG-12525, Ro-245913, and D-4418; and (VV) elastase inhibitors selected from the iralukast (CGP 45715A), and BAYX 7195 belong; (c) PDE4 group consisting of UT-77 and ZD-0892. inhibitors including inhibitors of the isoform PDE4D; (d) 40 5-Lipoxygenase (5-LO) inhibitors; or 5-lipoxygenase acti DETAILED DESCRIPTION OF THE vating protein (FLAP) antagonists; (e) dual inhibitors of INVENTION 5-lipoxygenase (5-LO) and antagonists of platelet activating factor (PAF): (f) leukotriene antagonists (LTRAs) including 5.0 Compounds antagonists of LTB, LTC LTD, and LTE, (g) antihista 45 minic H receptor antagonists including cetirizine, lorata The present invention is concerned with novel compounds dine, desloratadine, fexofenadine, astemizole, azelastine, which may be represented by Formula (1.0.0) as follows: and chlorpheniramine; (h) gastroprotective H2 receptor antagonists: (i) C. - and C-adrenoceptor agonist vasocon strictor sympathomimetic agents administered orally or topi 50 (1.0.0) cally for decongestant use, including propylhexedrine, phe nylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, Xylometazoline hydrochlo ride, and ethylnorepinephrine hydrochloride; () C- and 55 C-adrenoceptor agonists in combination with inhibitors of 5-lipoxygenase (5-LO); (k) anticholinergic agents including ipratropium bromide, tiotropium bromide; oxitropium bro mide: pirenzepine; and telenzepine; (1) B- to B-adrenocep toragonists including metaproterenol, isoproterenol, isopre 60 naline, albuterol, Salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pir buterol; (m) methylxanthanines including theophylline and The broadest scope of the compounds of the present aminophylline, (n) sodium cromoglycate; (o) muscarinic invention is circumscribed above under Section 4.0 relating receptor (M1, M2, and M3) antagonists; (p) COX-1 inhibi 65 to the Summary of the Invention. A further description of tors (NSAIDs); COX-2 selective inhibitors including rofe said compounds is provided hereafter in terms of a range of coxib; and nitric oxide NSAIDs; (q) insulin-like growth different types and groups of embodiments, as well as US 7,183,293 B2 73 74 specific embodiments which characterize and exemplify the 1-phenylnaphthalene; diphenylmethane, 1-phenylpipera compounds of Formula (1.0.0). Preferred and more pre dine, 1-phenylpiperazine; bibenzyl; aZulene; 4,4'-diphenyl ferred embodiments of said compounds are also set forth, 2,2'-dipyridyl: 1-(diphenylmethyl) azetidine; 4,5-dipheny but it will be understood that the recital of such preferences loxazole; 2,5-diphenyloxazole; diphenyl-2-pyridylmethane is in no way intended to, and does not limit the scope of the and diphenyl-4-pyridylmethane; 3,6-diphenyl-1,2,4,5-tetra present invention with regard to said compounds. Zine, 1-benzylpiperazine; 1-benzylpiperidine: 2-benzylpyri As used herein, the expressions —(C-C) alkyl. dine, 3-benzylpyridine and 4-benzylpyridine; 4,5-diphe "—(C-C) alkyl, and “—(C-C) alkyl, as well as nylimidazole; phenothiazine; phenoxazine; phenazine; equivalent variations of the same, are intended to include 10 1-phenyl-3,4-dihydronaphthalene: 2-phenylindene: 2-phe branched as well as straight chain conformations of these nylindole, 4-phenylmorpholine: 2-phenylbenzothiazole; aliphatic groups. Thus, the above-quoted expressions 2-phenylbenzoxazole; and 2-phenylbenzimidazole. include, in addition to the straight chain entities methyl, ethyl, n-propyl. n-butyl, n-pentyl, and n-hexyl, the branched The above-recited types of biaryl and discontinuous ring chain entities iso-propyl, iso-butyl, sec-butyl, tert-butyl, 15 systems may, on the other hand, comprise a meaning of *'. iso-pentane (2-methylbutane), 2-methylpentane, 3-methyl As a further illustration, it will be understood that, e.g., a pentane, 1-ethylpropane, and 1-ethylbutane. The meanings naphthyl moiety is biaryl as defined herein, since it is a fused of the above-quoted expressions are also intended to apply bicyclic with a bond between the bridgehead carbon atoms, to said expressions whether or not they are substituted. Thus, and there are no heteroatoms present. A quinolinyl moiety, the expression “fluorinated-(C-C) alkyl is intended to on the other hand, while also a fused bicyclic with a bond encompass the various fluorinated species of the n-propyl between the bridgehead carbon atoms, is not biaryl as and iso-propyl aliphatic groups. defined herein, since a nitrogen heteroatom is also present, As used herein, the expression “saturated or unsaturated and the definition of “biary1' requires that in such a case the carbon ring system that is 3- to 7-membered monocyclic' is 25 fused ring system be tricyclic or higher polycyclic. The intended to include Such saturated monocyclic carbon ring biphenyl moiety is an example of a discontinuous ring systems as cyclopropane, cyclobutane, cyclopentane, cyclo system that, accordingly, may be a meaning of *', but may hexane, and cycloheptane. The above-quoted expression is also intended to include Such mono-unsaturated monocyclic not be a meaning of **. carbon ring systems as cyclopentene, cyclohexene, and 30 As used herein, the expression “saturated or unsaturated cycloheptene; as well as Such aromatic monocyclic carbon carbon ring system that is . . . 7- to 12-membered, fused or ring systems as phenylene. discontinuous, polycyclic” is intended to include such satu As used herein, the expressions “fused or discontinuous, rated fused bi- and tricyclic carbon ring systems as norbor polycyclic” and “fused polycyclic' are intended to mean nane, bicyclo2.2.2]octanyl, bicyclo3.2.1]octanyl, bicyclo first, a carbon ring system having two or more rings, 35 3.3.0 octanyl, bicyclo3.3.1 nonanyl, cyclodecanyl, and especially bicyclic and tricyclic, more especially bicyclic, in adamantanyl. The above-quoted expression is also intended which the rings are fused, i.e., there is at least one pair of to include Such mono-unsaturated bi- and tricyclic carbon bridgehead carbon atoms present. These polycyclic ring ring systems as norbornenyl, bicyclo2.2.2]oct-5-enyl, and systems may be saturated or unsaturated. Second, the above 40 bicyclo2.2.2]oct-7-enyl; as well as such aromatic bi- and quoted expression is intended to mean a carbon ring system tricyclic carbon ring systems as naphthylene and biphe having two or more rings in which said rings are discon nylene. The above-quoted expression is further intended to tinuous, i.e., they are attached to each other by a single or include Such aromatic disontinuous bicyclic carbon ring double covalent bond and there are no bridgehead carbon systems as biphenylene. atoms present. These polycyclic ring systems may also be 45 The carbon ring systems included within the scope of the saturated or unsaturated. above-quoted expression and described above also include The moiety k" may be discontinuous, while the moiety moieties wherein optionally one carbonatom thereof may be : may not be discontinuous. It is also provided herein that replaced by a heteroatom selected from N, O, or S, and ** may not have the meaning of a moiety which is biaryl or 50 where N is selected, optionally a second carbon atom thereof discontinuous. The expression “biaryl as used herein is may be replaced by a heteroatom selected from N, O, and S. intended to mean a fused polycyclic ring system as defined The resulting moieties include pyrrolyl; pyrrolidinyl; fura immediately above in which (1) bridgehead carbon atoms nyl; thienyl; pyridyl; pyrimidinyl; piperidinyl; piperazinyl: are joined by a bond, i.e., there are no additional carbon imidazolyl; imidazolidinyl; oxazolyl; isoxazolyl; thiazolyl, atoms present between said bridgehead carbon atoms; and 55 indolyl; quinolinyl; isoquinolinyl; benzimidazolyl; benzox (2)heteroatoms, if present, are contained only in a tricyclic azolyl; morpholinyl; quinuclidinyl; and azabicyclo[3.3.0 or higher polycyclic fused ring system. Further, as already octanyl. mentioned, * * may not be discontinuous, as that expression As used herein with respect to compounds of Formula is defined immediately above. 60 (1.0.0), as well as other formulas and partial formulas Consequently, the types of biaryl and discontinuous ring relating thereto, where one or more nitrogen atom compo nents thereof is or are represented as “N-(O), it or they systems that may comprise a meaning of of k", but that may comprise(s) an optional nitrogen oxide form of said nitrogen not comprise a meaning of * include, inter alia, the atom(s). Where there is more than one Such nitrogen oxide following: biphenyl; biphenylene; fluorene; 9H-carbazole; 65 form, they are selected independently of each other. Further, phenanthridine; phenanthrene, 2,2'-bipyridine, iminodiben it will be appreciated that said nitrogen oxide form(s) may Zyl. 2,2'-biquinoline; naphthalene; 2-phenylnaphthalene; also be represented as “NP(O),” where u is 0 or 1. US 7,183,293 B2 75 A portion of the core nucleus of the compounds of Formula (1.0.0) is that of a nicotinamide of Formula (1.0.1):

(1.0.2a) RA (1.0.1) 5 D

R5 R6

15 derived from nicotinic acid. This portion of the core nucleus is then elaborated by defining the Y moiety as being =C(R')—, or—Ne(O), where k is 0 or 1, and where (1.0.2b) the symbol P(O) indicates a nitrogen heteroatom in the form of its N-oxide when k is 1. It should be noted that in the N-containing heterocyclyl moieties which define R, it is RA provided that optionally one or more of the N-heteroatoms comprising said heterocyclyl moieties may be in the form of D the N-oxide of said N-heteroatoms. Accordingly, the con 25 RB siderations concerning N-oxides just described also apply to Such N-oxide-containing moieties defining R. Where Y has the meaning of —NP(O), the com pounds of the present invention are pyrimidines. The pyri midine group of compounds of Formula (1.0.0) is a signifi 30 cant part of the scope of the present invention. It is preferred, nevertheless, that the compounds of Formula (1.0.0) have In such embodiments of the present invention, the 5-po the Y moiety defined as =C(R)— where the substituent sition (R') and 2'-position (R') substituents serve the same R1 is selected independently from the other substituents that 35 function of modulating the properties of the overall com form the compounds of Formula (1.0.0). pound of Formula (1.0.0) with respect to its pharmacological In addition to H. R', of the =C(R')— moiety is and pharmacokinetic properties such as potency, Substrate defined as a member selected from the group consisting of specificity (selectivity), and physico-chemical properties. In preferred embodiments of the compounds of the present F: —Cl; —CN; —NO; —(C-C) alkyl; —(C-C) 40 alkynyl; fluorinated-(C-C) alkyl, fluorinated-(C-C) invention of this type, both the R' and R', substituents will alkoxy; —OR'; and –C(=O)NR'R'': where R', are have the same meaning, which will be —H or —F. each independently —H. —CH; —CH2CH: 5.1.0 Terminal Moiety D Is a Moiety of Partial Formulas —CH2CH2CH; —CH2(CH), —CH2CH2CHCH; —CH (1.1.1)–(1.1.9) (CH)CHCH; —CHCH(CH), —C(CH), cyclopropyl; 45 D is a member selected from the group of moieties defined cyclobutyl; or cyclopentyl: by partial Formulas (1.1.1) through (1.1.9) illustrated further above. The moieties of partial Formulas (1.1.1) through However, it is preferred that the R', substituent of the (1.1.5) which define the D group are typically but not =C(R') moiety have the meaning of H; —F; Cl; necessarily acids, amides, and heterocyclyl groups that act —CH; —OCH, or —(C-C) alkynyl; more preferably 50 as acid and amide mimetics, but they are not limited to these R1 is —For —H. types of functional groups. The moieties of partial Formulas It will be noted that R', has several substituent definitions, (1.1.6) through (1.1.9) which define the D group are typi especially —F, in common with those for the R' and R' cally but not necessarily tertiary alcohols and their mimetics, especially analogous acyl and nitrile moieties, but they are substituents on the k moiety. In the embodiments of the 55 not limited to these types of functional groups. Other moi compounds of Formula (1.0.0) where Y is =C(R')—, and eties as described herein may be employed at the right-hand both the *k' moiety and the k moiety have the preferred side of the compounds of Formula (1.0.0). These moieties meaning of phenyl, the Substituents at the 5-position of the are bioisostereic in that they permit the compounds of nicotinamide core nucleus and at the 2'-position, of the Formula (1.0.0) containing them to achieve PDE4 inhibition benzyl group attached to the amide portion thereof, are 60 essentially equivalent to that achieved by other moieties, selected from the same group of definitions, although on an especially acid, amide, and alcohol moieties. independent basis. The embodiments of the present inven 5.1.1 DIs a Moiety of Partial Formulas (1.1.1). (1.1.2), or tion wherein such substituents are involved, and where j is (1.1.3) 1, k is 0, n is 1, both R and RP are -H, and Y is 65 Embodiments of the present invention wherein the defi =C(R') , may be illustrated by generic Formula (1.0.2a) nition of the D group is illustrated by partial Formulas and sub-generic Formula (1.0.2b) as follows: (1.1.1); (1.1.2); and (1.1.3), are as follows: US 7,183,293 B2 77 78

-continued (1.1.1) (3.5.2) O : --- CH (1.1.2) (3.5.3)

(1.1.3) H3C CH3 (3.5.4) O 15 : o1 Nchi, One of a number of preferred moieties for defining the D (3.5.5) group is that of partial Formula (1.1.1) where R7 has the O t meaning of —H, which is a preferred meaning of this substituent. Where R7 is hydrogen and m is 1, 2, or 3 in : 1N1 Yeh, Formula (1.0.0), a simple carboxylic acid —COOH results, (3.5.6) and the group becomes a lower alkanoic acid. Benzoic acid O as a meaning of the D group, however, is a less preferred 25 us CH embodiment of the present invention. : r R' is an optional substituent of the moieties that define OH R", and there may be up to three such substituents when (3.5.7) present. The meaning of the R' substituent includes phenyl O or pyridyl where said phenyl or pyridyl is in turn optionally 30 substituted by up to 3 substituents R' where R' is —F, Cl, -CN, -NO, -OH, -(C-C) alkoxy, -(C-C) alkyl, or NR''. In preferred embodiments that include such R' substitution, there will be 1 or 2 substituents R' that have the meaning of —F. —Cl, —CH —OCH, 35 —OH, —CN, or N(CH). Preferably, there is 0 or 1 such R' substituent and when present it is - F or - C1. The meaning of the R' substituent further includes —F. —Cl, (3.5.8) CF, oxo(=O), OR, NO, CN, C(=O)CR', O C(=O)R', C(=O)NR'R'7, O C(=O) 40 NR'R'7, NR'R'7, NRC(=O)R 7, NRC(=O) OR'7, NRS(=O).R'7, or S(=O)NR'R'7. The sub-substituents R'' and R7 comprise —H: —(C-C) alkyl, preferably —CH; —(C-C) alkenyl: —(C-C) cycloalkyl, preferably cyclopropyl; phenyl; ben 45 Zyl; or pyridyl. Said alkyl, alkenyl, cycloalkyl, phenyl, benzyl, or pyridyl groups are in turn optionally substituted by up to 3 substituents —F. —Cl, or —CN. Among the (3.5.9) above-recited additional meanings of R", it is preferred that the R' substituent when present be pyridyl optionally sub 50 stituted by —F. —Cl, —OCH —CN, NO, or -NR'R'" where R'' and R'' are independently —H or —CH; or that the R' substituent when present be —F, C1, CF, CN, NO, C(=O)CR', or NR'R'7 where R'' and R7 are independently —H or —CH. 55 These and other preferred embodiments of the compounds of Formula (1.0.0) comprising the moieties of partial For (3.5.10) mula (1.1.1) based on the preferred meanings of R7 and R' as described above, include, interalia, the following groups illustrated by partial Formulas (3.5.1) through (3.5.15): 60

(3.5.1)

65 -- CH3 US 7,183,293 B2 79 80

-continued -continued (3.5.11) O (4.1.3) O O --, : ul 1s, CH CH (4.1.4) 10 O O (3.5.12) : ---,

O 15 (4.1.5) OD CH3 O O CH : ---, (3.5.13) O O CH ul O HC1

25 Those embodiments wherein the definition of D is that of rt NH2 an amide group, are illustrated by partial Formula (1.1.3): (3.5.14) O

(1.1.3) us CF 30

(3.5.15) 35 O These and other preferred embodiments of the compounds of Formula (1.0.0) comprising moieties of partial Formula : us (1.1.3), based on the meanings of R and R described 40 above, include, interalia, the following groups illustrated by HC ul ch partial Formulas (4.5.1) through (4.5.20): CH3

The D group is represented by partial Formula (1.1.2) in (4.5.1) which the nitrogen atom is substituted by R where R has 45 the meaning of —H; —(C-C) alkyl; —(C-C,) cycloalkyl; phenyl; benzyl; –C(=O)CR'': C(=O)R': —OR':-(C-C) alkyl-OR'; or -(C-C) alkyl-C(=O) (4.5.2) OR'': where R' is - H or -(C-C) alkyl. R' is prefer O ably —H or —CH. 50 Accordingly, embodiments of the present invention where : --- CH 3 the D group is represented by partial Formula (1.1.2) may be H illustrated as follows by partial Formulas (4.1.1) through (4.5.3) (4.1.5): O 55 : -- (4.1.1) O O N. (4.5.4) H 60 (4.1.2) O O

---. 65 CH US 7,183,293 B2 81 82

-continued -continued (45.5) (4.5.15) : ---,O ON : u-CN H (4.5.16) (4.5.6) O 10 : ---, F H : N F (45.7) (45.17) 15 C O

: : us, N H (4.5.8) C (4.5.18) O

: usH 25 O (4.5.9) NCH, (4.5.19)

30 : ---,O ICl. O H CH (4.5.10) (4.5.20) 35

40 5.1.2 D Is a Moiety of Partial Formula (1.1.4) (4.5.11) Preferred embodiments of the present invention also comprise those compounds of Formula (1.0.0) wherein terminal moiety D falls within the scope of partial Formula 45 (1.1.4), i.e., embodiments of this type are encompassed within the scope of the D moiety when it has the meaning of partial Formula (1.1.4): (4.5.12)

50 (1.1.4)

N (4.5.13) 55 F O wherein R is a monocyclic or bicyclic heterocyclyl which H is a member selected from the group consisting of tetrazol 60 5-yl: 1,2,4-triazol-3-yl: 1,2,4-triazol-3-on-5-yl: 1,2,3-tria u-CF Zol-5-yl; imidazol-2-yl, imidazol-4-yl; imidazolidin-2-on-4- (4.5.14) yl: 1,2,4-oxadiazol-3-yl: 1,2,4-oxadiazol-5-on-3-yl: 1,2,4- O 21 oxadiazol-5-yl: 1,2,4-oxadiazol-3-on-5-yl; 1,3,4- oxadiazolyl, 1,3,4-oxadiazol-2-on-5-yl; oxazolyl, 65 isoxazolyl; pyrrolyl; pyrazolyl; Succinimidyll; glutarimidyl; pyrrolidonyl: 2-piperidonyl: 2-pyridonyl: 4-pyridonyl: pyridazin-3-onyl; pyridazin-3-onyl; thiazolyl; isothiazolyl, US 7,183,293 B2 83 84 thiadiazolyl; morpholinyl; parathiazinyl; pyridyl; pyrimidi pyridyl and quinolinyl groups thus included are optionally nyl; pyrazinyl; pyridazinyl; indolyl; indolinyl: isoindolinyl: substituted with up to 2 substituents R''. benzobfuranyl: 2,3-dihydrobenzofuranyl: 1,3-dihy The sub-substituent R' comprises —F: —Cl; COR': droisobenzofuranyl: 2H-1-benzopyranyl: 2-H-chromenyl: OR; CN; C(=O)NR'R'': NR'R'': NRC chromanyl; benzothienyl: 1H-indazolyl; benzimidazolyl: 5 benzoxazolyl; benzisoxazolyl; benzothiazolyl; benzotriaz (=OR'; NR'C(=O)CR'; NRS(=O).R'; olyl; benzotriazinyl; phthalazinyl: 1.8-naphthyridinyl: —S(=O)NR'R'', where p is 1 or 2, preferably 2: quinolinyl; isoquinolinyl; quinazolinyl; quinoxalinyl; pyra —(C-C) alkyl, preferably —CH; and —(C-C) alkoxy, Zolo3,4-dipyrimidinyl; pyrimido-4,5-dipyrimidinyl; imi where R' has the meaning of OR'' above and R' is dazol-2-alpyridinyl; pyridopyridinyl: pteridinyl; and 10 defined as —(C-C) alkyl, and preferably R' is —OCH: 1H-purinyl. where said alkyl and alkoxy are in turn optionally Substi Partial Formulas (1.1.3) and (1.1.4) are similar and the tuted with up to 3 Substituents —F. —Cl; —(C-C) alkoxy distinction between them should be noted. Partial Formulas carbonyl: —(C-C) alkylcarbonyl; and —(C-C) alkyl (1.1.3) and (1.1.4) are as follows: carbonyloxy. The RandR'substituents are independently 15 selected from —H; —(C-C) alkyl, preferably —CH, or phenyl; and are optionally substituted with up to 3—F; or (1.1.3) —Cl. O No R substituents are shown in partial Formulas (1.1.11) R7 through (1.1.34) above, as well as further below, because the : --- R substituent is attached only to a nitrogen atom that does R9 not form an integral, component part of an attached hetero (1.1.4) cyclic moiety. The R substituent is optional in character in O that “ H” is included as a definition of the R substituent, R8 and in many of the embodiments of the compounds of 25 Formula (1.0.0) this is the preferred meaning of R. Another : N preferred meaning of R is —CHs. R9 There is also pointed out the distinction between the substituents R and R', both of which are attached only to Where v is 0, R is linked in a direct fashion to the 30 nitrogen atoms in any of the meanings of the moiety D. The remaining portion of a compound of Formula (1.0.0) and it substituent R' is attached only to a nitrogen atom that is an is, accordingly, readily distinguishable from a moiety of integral, component part of any heterocyclic moiety that partial Formula (1.1.3) in which R" is linked to the remain may be defined via the R substituent of partial Formula ing portion of a compound of Formula (1.0.0) through the (1.1.4) and in particular with reference to the more specific amide bridging moiety —C(=O)NR -. Where v is 1, on 35 heterocyclic moieties of partial Formulas (1.1.11) through the other hand, both the Rand the R moieties are linked to (1.1.34), shown above as well as further below. The R the remaining portion of a compound of Formula (1.0.0) Substituent, on the other hand, is attached only to a nitrogen through the amide bridging moiety —C(=O)NR -. In this atom that in turn is attached to, but is not an integral, instance, the distinction between the moieties of partial component part of any of the heterocyclic moieties that is Formulas (1.1.3) and (1.1.4) comprises the difference 40 defined by partial Formulas (1.1.2), (1.1.3), and (1.1.5). The between the meanings of the R and the R moieties. This R" substituent may be attached to one or more nitrogen difference has already been described above in detail. atoms and said nitrogen atoms may be present in any In order to facilitate the following description, the mono moieties falling within the scope of partial Formula (1.1.4) cyclic heterocyclyl moieties and the bicyclic heterocyclyl 45 that can be characterized as containing or comprising a moieties are first treated together and thereafter are dis nitrogen-containing heterocyclic moiety. cussed as separate groups. As an illustration of preferred subgeneric embodiments of Any one or more of the carbon atoms of the phenyl, the present invention wherein the D group has the meaning benzyl, or heterocyclyl moiety is substituted by 0 to 3 of a moiety that falls within the scope of partial Formula substituents R' where R' has the meanings and preferred 50 (1.1.4), there is set out below the groups of partial Formulas meanings already described above with regard to partial (1.1.11) through (1.1.44): Formulas (1.1.1), (1.1.2), and (1.1.3). Any one or more of the nitrogen atoms, which it will be appreciated occur only in the case of the heterocyclyl moieties, and which are not (1.1.11) N a point of attachment of said heterocyclyl moiety, are 55 a N optionally substituted by up to 3 substituents R'. Any sulfur // atom which happens to occur in a heterocyclyl moiety, that N -N A is not a point of attachment of said heterocyclyl moiety, is R 15 Substituted by 0, 1, or 2 oxygen atoms. tetrazol-5-yl The optional nitrogen heterocyclyl substituent R' com 60 (1.1.12) prises H; NR'R'7: C(=O)R'; OR', preferably : N –OCH: —(C-C) alkyl-OR'; C(=O)CR': Yy —(C-C) alkyl-C(=O)CR': C(=O)NR'R'7; N-N —(C-C) alkyl, preferably —CH; —(C-C) alkenyl: A —(CH), (C-C) cycloalkyl where u is 0, 1 or 2, pref 65 R 15 erably cyclopropyl; phenyl; benzyl, pyridyl, or quinolinyl. 1,2,4-triazol-3-yl The alkyl, alkenyl, alkoxy, cycloalkyl, phenyl, benzyl,

US 7,183,293 B2 87 88

-continued -continued (1.1.33) (1.1.41)

KSNA (1.1.42) N 10 (1.1.34) r1

pyrimidinyl (1.1.43) SY 15 N (1.1.35) sO pyrazinyl (1.1.44)

: 4N glutarimidyl su 25 pyridazinyl (1.1.36) R15 In order to provide another demonstration of preferred N O embodiments of the compounds of Formula (1.0.0) with reference to the D group where it is a moiety of partial 30 Formula (1.1.4) and v is 0 or 1, and R is a monocyclic pyrrollidonyl heterocyclic group, there is set out below the groups con sisting of partial Formulas (4.8.1) through (4.8.80) from (1.1.37) which the D moiety is selected in such preferred embodi ments: 35

(4.8.1) : a N N 40 // N-N (1.1.38) H N (4.8.2) N YN/ 45 N-N M HC 2-pyridonyl (4.8.3) : N (1.1.39) R 15 Yy 50 N-N N H N (4.84) - : N-"CH 55 N-N O H (4.8.5) 4-pyridonyl

(1.1.40) ne f CF N-N 60 H (4.8.6) : Y).N pyridazin-3-onyl 65 N-N US 7,183,293 B2 89 90

-continued -continued (4.8.7) (4.8.18) Na : N N f- O Scyr N-N H (4.8.19) (4.8.8) : N Ney 10 N-N H. H. (4.8.9) (4.8.20) : N NY" 15 N-N M H

(4.8.10) (4.8.21) 2O

(48.22) (4.8.11 25

30 (4.8.23)

(4.8.12)

35 (4.8.24)

(4.8.13) 40

(4.8.25)

(4.8.14) (4.8.26) 50

(4.8.15)

55 (4.8.1.6) (48.27)

(4.8.17)

65 US 7,183,293 B2 91 92

-continued -continued (4.8.28) (48.38) : cy

10 C : (48.39) (4.8.29) : ne Ny O-N 15 H H (4.8.40) : N O (48.30) O ne y -( CH3 V N CH3 S. M (4.8.41) : N CH3 : N O (48.31) ne y 25 N | N le (48.32) (4.842) 30 N2 O O

35 (48.33) C (4.843) : N 2 (48.34) 0 NY"

45 (48.35) (4.8.44)

50 (4.845)

O N (48.36) X HO O : : 55 (4.846) )- t N M O O 60 (48.37) y (4.8.47) 65 CF US 7,183,293 B2 93 94

-continued -continued (4.8.48) (48.58) : O O /

: N

10 O (4.8.59) H (48.49) N H O N O

15 CF : ulO (48.60) : N 21 (4.8.50) H : N Cl O (48.61) N H (48.51) 25 O S : -Cl O (4.8.6.2) N : 30 2YNEN (48.52) N O

: : O 35 (48.63) (48.53) H C O 3 V N O H \ 40 : O

(48.54) : : Hafn 33 (48.64) O 45 H N 4.N M (48.55) : M

50 :3 - ) O H (48.65) : N (4.8.56) N H : 55 N H O O NN (48.66) (48.57) 60 / (48.67)

65 US 7,183,293 B2 95 96 Preferred embodiments of the present invention where the -continued group D is a moiety of partial Formula (1.1.4) and V is 0 or (48.68) 1, also include those wherein the moiety R is a bicyclic heterocyclic group selected from the group consisting of indolyl; indolinyl: isoindolinyl; benzobfuranyl: 2,3-dihy drobenzofuranyl: 1,3-dihydroisobenzofuranyl; 2H-1-ben Zopyranyl: 2-H-chromenyl; chromanyl; benzothienyl: (48.69) 1H-indazolyl; benzimidazolyl; benzoxazolyl; benzisox azolyl; benzothiazolyl; benzotriazolyl; benzotriazinyl: 10 phthalazinyl: 1.8-naphthyridinyl; quinolinyl; isoquinolinyl: quinazolinyl; quinoxalinyl; pyrazolo 3,4-dipyrimidinyl: (4.8.70) pyrimidoA,5-dipyrimidinyl; imidazol-2-alpyridinyl; pyri dopyridinyl: pteridinyl; and 1H-purinyl. 15 In order to provide a still further demonstration of pre ferred embodiments of the compounds of Formula (1.0.0) with reference to the D group where it is a moiety of partial (4.8.71) : Formula (1.1.4), V is 0 or 1, and R is a bicyclic heterocyclic group, there is set out below the groups consisting of partial Formulas (5.0.1) through (5.0.28) from which the D moiety N is selected in such preferred embodiments: HCDO (4.8.72) (5.0.1) R 15 25 M N (4.8.73) X ŽS : indolyl 30 (5.0.2) R 15 (4.8.74) yM 35 >S : indolinyl (4.8.75) (5.0.3) :

40 \\ R15 (4.8.76) isolindolinyl (5.0.4) O 45 X (4.8.77) ŽS. benzobfuranyl (5.0.5) 50 OX (4.8.78) ŽS. 2,3-dihydrobenzo-furanyl (5.0.6) 55 :

(4.8.79) O

60 1,3-dihydroisobenzo-furanyl; phthalanyl (5.0.7) O (4.8.80) N : 2 65 2H-1-benzopyranyl US 7,183,293 B2 97 98

-continued -continued (5.0.8) (5.0.18) O NN N :

chromanyl (5.0.9) (5.0.19) OC. 10 benzothienyl (5.0.10) 1,8-naphthyridinyl 15 (5.0.20) s : 2 N phthalazinyl (5.0.21) 1H-indazolyl N (5.0.11) R 15 s : A N 2N 25 X quinazolinyl N (5.0.22) benzimidazolyl (5.0.12) O 30

X quinoxalinyl N benzoxazolyl (5.0.23) R15 5.0.13 O ( 35 N N N /

40 benzisoxazolyl 1H-pyrazolo 3,4-d-pyrimidinyl (5.0.14) (5.0.24) S N X - N Srs 45 benzothiazolyl se 2N (5.0.15) pyrimidoS,4-d-pyrimidinyl 15 (5.0.25) -N1 * 50 re, CC : N1SN 2H-1,2-benzothiazinyl imidazo-1,2-a-pyridinyl (5.0.16) (5.0.26) N 55 21 n

N-- :

benzotriazolyl 60 pyridopyridinyl (5.0.27) (5.0.17) N N

s : : 2 N 21 N 2 65 DC quinolinyl pteridinyl US 7,183,293 B2 99 100

-continued -continued (5.0.28) R 15 O (6.0.6) M N1-S-N : --~ O r H CO O 1H-purinyl 10 5.1.4 D is Other than a Carboxylic Acid where 66: indicates the point of attachment to the remaining Embodiments of the compounds of Formula (1.0.0) portion of Formula (1.0.0); and where each carbon atom is include those wherein the D moiety is other than a carboxy optionally substituted by a substituent R'; and where R'' lic acid and is, instead, a phosphorus or Sulfur acid or a and R' have the same meaning as defined above; and all 15 derivative thereof. There are a significant number of such tautomer forms, and optionally N-oxide forms, thereof. derivatives from which the D moiety may be selected, and 5.1.3 D is a Moiety of Partial Formula (1.1.5) they include the following: —O P(=O)(OH), (phospho There are further embodiments of the compounds of ric); – PH(=O)CH (phosphinic); - P(=O)(OH), (phos Formula (1.0.0) in which the D moiety comprises a group phonic); —P(=O)(OH) O(C-C)alkyl (alky falling within the scope of partial Formula (1.1.5): lphosphono); —P(=O)(OH)–O(C-C)alkyl) (alkylphosphinyl); - P(=O)(OH)NH (phosphoramido); (1.1.5) - P(=O)(OH)NH(C-C)alkyl and P(=O)(OH)NHR'. O f (substituted phosphoramido); —O S(=O)CH (sulfuric); 25 S(=O).OH (sulfonic); S(=O)NHR' or NHS : uso1 (C) Yws (=O)R’ (sulfonamido) where R is —CH, -CF, or H o-toluyl; and acylsulfonamido selected from the group con R7 sisting of C(=O)NHS(=O)R’: C(=O)NHS(=O), NH: C(=O)NHS(=O), (C-C)alkyl: C(=O)NHS 30 (=O)NH(C-C)alkyl: C(=O)NHS(=O)N(C-C) wherein q is 1, 2, or 3, provided that where q is 2 or 3, R alkyl); S(=O)NHC(=O)(C-C)alkyl; —S(=O) has the meaning of —H in at least one instance, or two instances, respectively; W is —O ; N(R)-; or —OC NHC(=O)NH; S(=O)NHC(=O)NH(C-C)alkyl: (=O)— where R has the same meaning as defined above; —S(=O)NHC(=O)N(C-C)alkyl); S(=O)NHC and R has the same meaning as defined above. 35 (=S)NH(C-C)alkyl: S(=O)NHCN; S(=O)NHC In preferred embodiments of the compounds of partial (=S)NH; —S(=O)NHC(=S)NH(C-C)alkyl: Formula (1.1.5), q is 1 or 2, R is -H, or —CH; W is —S(=O)NHC(=S)N(C-C)alkyl); and - S(=O) O , —O(C=O) , or -NH , and R is one of the NHS(=O)R’; where R is -H, -(C-C)alkyl; phenyl: preferred moieties already described above. or —OR', where R' has the same meaning as defined Representative embodiments of the compounds of For 40 above. mula (1.0.0) in which the D moiety falls within the scope of Preferred embodiments of the compounds of Formula partial Formula (1.1.5) are those illustrated by partial For (1.0.0) wherein D is a phosphorus or sulfur acid or a mulas (6.0.1) through (6.0.6): derivative thereof, are those wherein D is - P(=O)(OH) NHR' (substituted phosphoramido); -S(=O)NHR' or 45 NHS(=O)R’ (sulfonamido); or C(=O)NHS(=O), (6.0.1) R (acylsulfonamido); where R and R has the same O O meaning as defined above. Some of these preferred embodi ments may be illustrated by partial Formulas (6.5.1) through : -----, 50 (6.5.9): (6.0.2) O

O (6.5.1) : us1N1 NCH, O (6.0.3) O th 55 : -Nil, N OH : 1N1 YCH, (6.5.2) (6.0.4) CH O --N1 60 | H NH2 OH --~ (6.5.3) O CH- O (6.0.5) O 3 | : -s-s-s 65 US 7,183,293 B2 101 102 wherein said alkyl, alkenyl, cycloalkyl, phenyl, benzyl, or -continued pyridyl is substituted by 0 to 3 substituents selected from the (6.5.4) group consisting of F. —Cl, —CF, —CN, and —(C-C) alkyl. CH : -N1 3 The keto groups of partial Formulas (1.1.6) and (1.1.9) are H the same with respect to the carbonyl linking entity, but differ with respect to the attached group, R or R: (6.5.5) O \ 10 (1.1.6) : C-N| S -CH, H O (6.5.6) O O

: C-N-S 15 (1.1.9) H || O (6.5.7) O s-N-S-CH R’ in the moiety of partial Formula (1.1.6) has the same O meaning as defined further above, but in preferred embodi (6.5.8) O ments of the compounds of Formula (1.0.0) R' has espe cially the meaning of —H; —(C-C)alkyl, preferably -N--CF, 25 methyl, ethyl, iso-propyl, or tert-butyl; —(C-C)alkenyl, O preferably 2-propenyl; —(C-C)alkynyl, preferably ethy (6.5.9) nyl. Each of these meanings of R is optionally substituted H3C by up to 3 substituents R". The meaning of R' is the same O as defined above, but is preferably phenyl or pyridyl option | 30 ally substituted by up to 3 R' where R'' is preferably - F. : N —CF, —CN, —CH, or —OCH. R'' also preferably has | the meaning of F, CF, -OR, CN; –C(=O) O OR', C(=O)NR'R'7, NR'R'7; or NRS(=O), R'7, where R'' and R7 are preferably -H, methyl, ethyl, 35 cyclopropyl, phenyl, benzyl, or pyridyl optionally Substi 5.1.5 D is a Moiety of Partial Formulas (1.1.6) through tuted by up to 3 of —F, or 1 of CF, —CN, or —CH. (1.1.9) R" also has the meaning of-(CH2), (C-C,)cycloalkyl There are further embodiments of the compounds of where u is preferably 0 or 1 and where (C-C)cycloalkyl is Formula (1.0.0) in which the D moiety comprises a group preferably cyclopropyl, cyclopentyl, or cyclohexyl option falling within the scope of partial Formulas (1.1.6) through 40 ally substituted by up to 3 substituents R' where R' has the (1.1.9): same preferred meanings as defined in the paragraph imme diately above. R7 also has the meaning of phenyl or benzyl, where said (1.1.6) phenyl or benzyl optionally substituted by up to 3 substitu 45 ents R' where R' has the same preferred meanings as defined in the paragraph immediately above. R in the moiety of partial Formula (1.1.9) has the same (1.1.7) meaning as defined further above, but in preferred embodi 50 ments of the compounds of Formula (1.0.0) R has espe cially the meaning of tetrazol-5-yl: 1,2,4-triazol-3-yl: 1,2,3- triazol-5-yl: imidazol-2-yl; imidazol-4-yl; 1,3,4- (1.1.8) oxadiazolyl: 1,2,4-oxadiazol-3-yl: 1,2,4-oxadiazol-5-yl: 1.2, 5-thiadiazolyl: 1,3,4-thiadiazolyl; morpholinyl: oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; pyrrolyl; pyrazolyl, 55 pyridyll; indolyl; benzobfuranyl: 2,3-dihydrobenzofuranyl: 1H-indazolyl; benzimidazolyl; benzoxazolyl; benzisox (1.1.9) azolyl; benzothiazolyl; benzotriazolyl; quinolinyl; isoquino linyl; quinazolinyl; or quinoxalinyl. 60 Any of the above-recited especially preferred meanings of R is optionally substituted on a carbon atom by R'' where R" has the same meaning as defined above; and on a nitrogen atom by R' where R' has the same meaning as where R. R. R', and R7 have the same meaning as defined above. Especially included in the case of such defined above. For example, R'' and R7 are each indepen 65 nitrogen atom Substituents, are all tautomer forms of the dently selected from —H; —(C-C)alkyl; —(C-C)alk moieties of partial Formula (1.1.9). Sulfur atoms of said enyl; —(C-C)cycloalkyl; phenyl; benzyl, and pyridyl; moieties are optionally Substituted by 1 or 2 oxygen atoms. US 7,183,293 B2 103 104 In order to illustrate further meanings of D that fall within the scope of partial Formulas (1.1.6), (1.1.7), (1.1.8), and -continued (1.1.9), there are depicted below moieties of partial Formu (3.3.12) las (3.3.1) through (3.3.15) that represent different meanings CH that fall within the scope partial Formula (1.1.7): N OH CF (1.1.7) (3.3.13) CF3 10 N OH (3.3.1) CF (3.3.14) " 15 OH (3.3.2) N CF : (3.3.15)

H3C OH (3.3.3) CH OH : 25 Further meanings of Dare those that fall within the scope H3C OH (3.34) of partial Formula (1.1.8), in which a nitrile group, —CEN. C, CH3 serves as a bioisosteric replacement for the hydroxyl group of partial Formula (1.1.7). Accordingly, there are depicted 30 below moieties of partial Formulas (3.8.1) through (3.8.10) that represent different meanings that fall within the scope (3.3.5) partial Formula (1.1.8): :

35 (1.1.8) H3C OH CH3 (3.3.6) CH -X- : 40 (3.8.1) : CH3 H CH (3.3.7) H3C S CH3 N : (3.8.2) 45 CH

: H3C OH CH (3.3.8) : H3C S.S. N." 50 (3.8.3) CH

(3.3.9) : CH 55 HC S n N (3.8.4) (3.3.10) CH : OH : CH3 . CH 60 H3C CH3 (3.8.5) (3.3.11)

65 US 7,183,293 B2 105 106

-continued -continued (3.8.6) (3.9.4) : CHF O Š (3.8.7) (H3 10 N N (3.9.5) CF O (3.8.8) N-s,CF3 15 CF (3.8.9) ,NO (3.9.6) O CF CH3 (3.8.10) 25 : H3C F CH3 (3.9.7)

30 H In order to illustrate additional meanings of D that fall uo. within the scope of partial Formulas (1.1.6), (1.1.7), (1.1.8), 35 (3.9.8) and (1.1.9), there are depicted below moieties of partial O Formulas (3.9.1) through (3.9.9) that represent different meanings that fall within the scope partial Formulas (1.1.6) and (1.1.9): 40 - O (3.9.9) (1.1.6) O O

--, 45 (1.1.9) O ) (3.9.10) -- O (3.9.1) 50 N : \ f 1. N

1. CH 55 (3.9.11) O (3.9.2) O N -> YNy N 60 H (3.9.12) O (3.9.3) O 65 re ---, H US 7,183,293 B2 107 108

-continued -continued (3.9.13) (3.9.24) O

(3.9.14) 10 (3.9.25) O : \ d OO (3.9.15) 15 - : N (3.9.26)

(3.9.16) n N e 2 25 (3.9.27) O d (3.9.17)

S d 30 (3.9.18) 3. (3.9.28)

e Ns 35

(3.9.19)

40 (3.9.29) N (3.9.20) 45

(3.9.30) (3.9.21) 50

n 2 N H

55 (3.9.22)

(3.9.31)

60 : (3.9.23) N

65 US 7,183,293 B2 109 110

-continued -continued (3.9.32) (3.9.39)

10 e 5.2 Linkage W' and (R* , R , and R)-Substituted Moi ety sk' (3.9.33) O 15 The nicotinamide core nucleus is further elaborated by allowing the 2-carbon atom in the pyridyl or pyrimidinyl n N ring of said nucleus to form a linkage to a ring comprising the moiety k". In preferred embodiments, the moiety k" has the meaning of a phenyl ring which is para-Substituted by a moiety R', meta-substituted by a moiety R, or substituted on any of the remaining positions by a moiety R', resulting in a moiety of partial Formula (1.0.3): (3.9.34) O 25

(1.0.3) :

(3.9.35) 35 O

40 where W has the meaning —O : —S(=O), , where t is 0, 1, or 2; or N(R)— where R is —H; —(C-C)alkyl: phenyl; benzyl; or —OR'; and is preferably Hor—CH. (3.9.36) O e In other embodiments of the present invention, W' has the 45 meaning —S(=O), , where t is 0, 1, or 2; and preferably a NNo has the meaning —S - whereby a thioether linkage is formed. Where the sulfur atom of the thioether linkage is oxygenated, a Sulfinyl or a Sulfonyl linkage results. In still 50 further embodiments, where W has the meaning of - N(R)—, an amino linkage is formed, which preferably (3.9.37) will be —NH-. Nevertheless, the nitrogen atom may be O substituted and where this is the case, it is preferred that said substituent be —CH. 21 N 55 The meanings of the R, R and R substituents are selected from the same set of definitions, but it will be understood that said meanings are selected on an indepen dent basis from each other. R and R may also be —H. 60 (3.9.38) Accordingly, where the moiety k" has the meaning of a O phenyl ring, the para-(R), meta-(R), or ortho-(R)-position N of the phenyl ring may be substituted, or all three positions 21 may be substituted, or any combination of said positions 65 may be substituted. It is preferred, however, in the com Nan pounds of Formula (1.0.0) that the para- and/or meta positions be substituted, rather than the ortho-position. US 7,183,293 B2 111 112 Where the moiety k" has the preferred meaning of a phenyl ring, Rand R may also be taken together to form -continued a member selected from a group of partial formulas (1.3.2) described in more detail further below. Some of these meanings of R and R taken together also constitute pre ferred embodiments of the compounds of Formula (1.0.0) \, R2 RandR may be H. In addition to H. RandR may, inter alia, be —F; Cl; CN: NO: C(=O)R': (1.3.3.) OR: C(=O)CR'; or NR'R'7. Where R is H 10 and R is F, preferred embodiments of the present inven tion result. In a further preferred embodiment of the present invention, R and R may also be -OR', where R' is hydrogen; (C-C)alkyl, or (C-C)cycloalkyl, wherein said R20 15 1. alkyl and cycloalkyl are substituted by 0 to 3 substituents selected from the group consisting of —F and —Cl. Other (1.34) preferred embodiments are those wherein R' is methyl: difluoromethyl ethyl; or cyclopentyl. The medicinal chemist will appreciate that the choice of substituents from those described above will be influenced by the effect which such substituents have in turn on the 13. physico-chemical properties of the overall molecules which (1.3.5) result. The present state of the art provides the capability of quickly and facilely synthesizing a very large number of 25 chemically very similar compounds based on the Substituent choices outlined above, and of thereafter testing the relative effectiveness of the resulting molecules in rapid in vitro R20 testing methods. Combinatorial chemistry synthesis and (1.3.6) testing procedures currently available in the art have even 30 more considerably expanded the number of substituent combinations which can be rapidly evaluated. The informa R21 O tion which has thereby been produced through use of these R2 techniques permits a reasonable prediction herein of certain 35 preferences which exist as to various embodiments of the (1.3.7) present invention. Such preferred embodiments are O described in detail herein. Preferred embodiments of the present invention further R 40 include those wherein both R and Rare both —F; wherein HO 2HO R is -H and R is —F; and wherein R is – H and R is R20 —F. -OR', e.g., OCH, OCHF, —OCHF, or (1.3.8) OCF, CN; COOH: COOCH: CONH; —OCOCH or NH. The most preferred embodiments are those wherein R is - Hand R is —F; R is –CN and R' 45 is H; and R is NO, NH, —CN, OCH, or 1.HO R20 —C(=O)CH, and R is H. R and R may also be selected from substituents com (1.3.9) prising —(C-C)alkyl and —(C-C)alkoxy wherein said alkyl and alkoxy are substituted with 0 to 3 substituents —F 50 or —Cl; or 0 or 1 substituent (C-C)alkoxycarbonyl-: (C-C)alkylcarbonyl-, or (C-C)alkylcarbonyloxy-. 5.3.0 k' is Phenyl and R and Rare Taken Together O R20 (1.3.10) Where the moiety k" has the preferred meaning of a 55 phenyl ring, Rand R may also be taken together to form OH a moiety which is a member selected from the group consisting of partial Formulas (1.3.1) through (1.3.15): R21

60 O R20 (1.3.1) (1.3.11) 23 SN1 R

65 y US 7,183,293 B2 113 114

-continued -continued (1.3.12) (2.1.2) \ 8 SN1 R23 / N-S A. ty R24 (1.3.13) (2.1.3) 10

N=N-- R24 Yes (1.3.14) 15 (2.1.4) 4. Y R23 N A. R24 O (2.1.5) (1.3.15)

25 (O) R23 (2.1.6) wherein R' and R'' are each a member independently selected from the group consisting of —H; —F. —Cl; 30 CH; —CHF: —CHF: —CF; —OCH; and —OCF: (2.1.7) and R and R are each independently —H; —CH: —OCH; —CH2CH; —OCHCH; CHCH2CH: —CH (CH); —CHCHCHCH; —CH(CH)CHCH: 35 —CH-CH(CH), —C(CH); or absent, in which case the dashed line - - - - represents a double bond. For the moiety (2.1.8) of partial Formula (1.3.13) the nitrogen atom components thereof are represented as —N(OO)— and thus comprise optional nitrogen oxide forms of said nitrogen atoms, 40 selected independently of each other. It will be appreciated that said nitrogen oxide form may also be represented as (2.1.9) N(O), where j is 0 or 1, as in Formula (1.0.0). Where the moiety k" has the preferred meaning of a phenyl ring, and where R and Rare taken together to form 45 the moiety of partial Formula (1.3.1), and R' and R' are both hydrogen, there is formed together with the phenyl group to which it is attached, a 1,3-benzodioxole group. (2.1.10) Analogously, the structure of partial Formula (1.3.4) forms 50 a 1,4-benzodioxan group. Where the moiety k" has the preferred meaning of a phenyl ring, and where R and Rare taken together to form the moieties of partial Formulas (1.3.1) through (1.3.15), and Rand Rare as defined, benzofurazan, benzothiazan, 55 (2.1.11) triazole, and other analogous groups, as well as Substituted derivatives thereof are formed, including, inter alia, the following moieties of partial Formulas: (2.1.1) through N-O H (2.1.20): 60 (2.1.12) CH3 (2.1.1) -\ N1 N 65 H is,? O N-O US 7,183,293 B2 115 116 related by the shift of a hydrogen and one or more L-bonds, -continued and whenever necessary, the skilled artisan will be able to (2.1.13) readily discern or determine which tautomeric form is C present or is the most stable. t 1. Still more preferred embodiments of the type comprising the moieties of partial Formulas (2.1.1) through (2.1.20) MN illustrated above are those wherein R and R are taken H3C O (2.1.14) together to form a moiety which is a member selected from 10 the group consisting of partial Formulas (2.1.1), (2.1.4) t through (2.1.6), (2.1.11), and (2.1.16) through (2.1.20): N M HC O (2.1.1) (2.1.15) 15 \ S./ N-O (2.1.4) (2.1.16) s N-S (2.1.5) 25

(2.1.17)

30 (2.1.6)

(2.1.18) 35 (2.1.11)

N-O H 40 (2.1.19) (2.1.16) CH3 -\ /N1 N-S N 45 M (O) CH3 HC (2.1.20) 's- (2.1.17) r\, , 50

(O) -N O-CH (2.1.18) wherein the dashed line - - - - in partial Formulas (2.1.18), 55 (2.1.19), and (2.1.20) represents a double bond where no oxygenatom is attached to the corresponding nitrogen atom, and represents a single bond where an oxygen atom is attached to said corresponding nitrogen atom. The artisan of ordinary skill in the preparation of organic 60 molecules will appreciate that the compounds of Formula (2.1.19) (1.0.0) wherein R and R are taken together to form moi eties of the above-illustrated partial Formulas (2.1.2). (2.1.3), (2.1.7), (2.1.8), (2.1.10), (2.1.12), and (2.1.14) exist in tautomeric form, and each moiety of said partial Formulas 65 (2.1.2), (2.1.3), (2.1.7), (2.1.8), (2.1.10), (2.1.12), and (2.1.14) has a tautomer counterpart. These tautomers are US 7,183,293 B2 117 118

-continued -continued (2.1.20) (1.0.16) r\,'s- , N >, (O) -N O-CH

10 wherein the dashed line - - - - in partial Formulas (2.1.18), (2.1.19), and (2.1.20) represents a double bond where no oxygenatom is attached to the corresponding nitrogen atom, and represents a single bond where an oxygen atom is 15 attached to said corresponding nitrogen atom. (1.0.17) Preferred embodiments of the present invention result directly from the definition of Rand Ras taken together to form a moiety which is a member selected from the group consisting of partial Formulas (1.3.1), (1.3.11), (1.3.12), and (1.3.15):

(1.3.1) 25

O G,N-S (1.0.18) R20 O (1.3.11) 30 W R23 -\ SN1 / l 2 H N-O N W \ A. R24 35 (1.3.12) \ 8 SN1 R23 / N N -S 40 ? R24 V (1.3.15) R23

45 where R is H or —CH; and W has the meaning of —O : —S(=O), where t is 0, 1, or 2; or - N(R) where R is as defined herein and is preferably —H or —CH. In preferred compounds of Formula (1.0.0), W has the meaning of—O— whereby an ether linkage is created to attach the 50 benzo-fused, bicyclic heterocycle to the nicotinamide core Accordingly, there further results moieties of partial For nucleus. mulas (1.0.15) through (1.0.18): In preferred embodiments of the compounds of Formula (1.0.0), R and Rare both absent, except in compounds of (1.0.15) the type illustrated by partial Formula (1.3.11), where only 55 one of R or R* may be absent. It will be recognized that where R and R are both absent, and the dashed lines: - - - accordingly represent double bonds, that the phenyl portion of the resulting benzo-fused bicyclic hetero cycles depicted cannot have all of the double bonds depicted 60 in said partial Formulas, since the result would be prohibited pentavalent carbon atoms in said phenyl portion. Accordingly, where R and R'' are both absent, the resulting compounds are characterized by Such structures as those shown in partial Formulas (1.0.16) and (1.0.17) above. 65 In other embodiments of the compounds of Formula (1.0.0) the substituents R* and R' on the benzo-fused, C, bicyclic heterocycles represented by partial Formula (1.3.1) US 7,183,293 B2 119 120 are —H. —F. —Cl, —CH, —CHF, —CHF, or —CF. Preferably, R' and R are both -H or –F, in which case -continued the resulting compounds are characterized by the structure (1.8.2) shown in partial Formula (1.0.15) above, or its correspond ing difluoro analog (not shown). The substituents R* and 5 R on the benzo-fused, bicyclic heterocycles represented by the moieties of partial Formulas (1.3.9) through (1.3.13) are each independently —H; —CH; —OCH; or absent in F which case the dashed line - - - - represents a double bond. 10 It will be understood, of course, that where R and Rare absent; there are no pentavalent carbon atoms in the phenyl (1.8.3) portion of said benzo-fused, bicyclic heterocyles. The result :C. ing benzo-fused, bicyclic heterocyclic structures are shown in partial Formulas (1.0.16) through (1.0.18) above. 15 5.3.1 k" is Other than Phenyl In addition to those embodiments of the present invention where k" has the preferrred meaning of phenyl, the present invention has also been defined above as being concerned (1.8.4) with a compound of Formula (1.0.0) wherein k" has the C meaning defined above as a moiety comprising a saturated or unsaturated carbon ring system that is 3- to 7-membered monocyclic, or that is 7- to 12-membered, fused or discon 25 tinuous, polycyclic; wherein optionally one carbon atom thereof may be replaced by a heteroatom selected from N, O, (1.8.5) or S, and where N is selected, optionally a second carbon :Nafne atom thereof may be replaced by a heteroatom selected from 30 N, O, or S. The present invention is further concerned with a compound of Formula (1.0.0) wherein k comprises especially a member selected from the group consisting of phenyl; pyrrolyl; pyrrolidinyl; furanyl; thienyl; pyridyl; ON pyrimidinyl; piperidinyl; piperazinyl; imidazolyl; imidazo 35 (1.8.6) lidinyl, oxazolyl; isoxazolyl; morpholinyl; thiazolyl; indolyl; quinolinyl; isoquinolinyl; benzimidazolyl; benzox azolyl; quinuclidinyl; and azabicyclo3.3.0 octanyl; a mono cyclic —(C-C)cycloalkyl moiety; a monocyclic 40 —(Cs-C7)cycloalkenyl moiety that is a member selected from the group consisting of cyclopentenyl, cyclohexenyl, C.C and cycloheptenyl; and a bicyclic —(C7-Co)cycloalkyl or (1.8.7) —(C7-Co)cycloalkenyl moiety that is a member selected : from the group consisting of norbornanyl, norbornenyl, 45 bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.0 octanyl, bicyclo[2.2.2]oct-5-enyl, bicyclo[2.2.2]oct-7-enyl, C bicyclo3.3.1 nonanyl, cyclodecanyl, and adamantanyl. The present invention is still further concerned especially 50 TC H3 with a compound of Formula (1.0.0) wherein particularly k" O and the substituents R. R. and R are selected in such a (1.8.8) way that the left-hand terminus of said compound of For : mula (1.0.0) is represented by the following partial Formulas (1.8.1) through (1.8.72): 55

(1.8.1) 60 C. (1.8.9)

65 F F 3 ul US 7,183,293 B2 121 122

-continued -continued (1.8.17) (1.8.10) : : N e S N / S. NN O 2 10 CF (1.8.18) (1.8.11) : 15

N Z

O y C.O -/ O (1.8.12) (1.8.19) 25

30 N N

-H (1.8.13)

35 (1.8.20)

CH3 O 40 N 'sCH3 \ 3 C. V (1.8.14) CH 45 (1.8.21)

N 50 / -O (1.8.22) (1.8.15)

60 \- (1.8.23) (1.8.1.6) : 2N S 65 S. M US 7,183,293 B2 123 124

-continued -continued (1.8.24) (1.8.32)

(1.8.25) (1.8.33)

2O (1.8.26) (1.8.34)

(1.8.35)

(1.8.27) 30

(1.8.36) 35 (1.8.28)

(1.8.37) 40

(1.8.29) 45

50 (1.8.38) (1.8.30)

(1.8.31) (1.8.39)

(1.8.40)

65 US 7,183,293 B2 125 126

-continued -continued (1.8.41) (1.8.52)

(1.8.42) A (1.8.53) 10 o (1.8.43) 15 (1.8.54)

(1.8.44) c) (1.8.55)

(1.8.56) 25 O (1.8.45)

O 30 (1.8.46) (1.8.57)

(1.8.47) (1.8.58)

40 O (1.8.48) (1.8.59) 45 O (1.8.60) (1.8.49)

A. (1.8.61) (1.8.50) 55

60 27 (1.8.6.2) (1.8.51) A. 65 US 7,183,293 B2 127 128 which forms the left-hand-side of the compound of Formula -continued (1.0.0), has been discussed above. The right-hand-side of the (1.8.63) compound of Formula (1.0.0) comprises, in preferred : H N embodiments where k’ has the preferrred meaning of phe nyl, a benzyl group which is substituted by substituents R' and R''. Preferably, only a single substituent, R' or R is present, the single substituent R' or R is in the 2'-position, and the benzyl group is substituted in the 4-position by the Š moiety containing the substituents R', R, and D. This (1.8.64) 10 preferred right-hand-side of the compound of Formula : N n (1.0.0) may be represented by Formula (1.0.4):

(1.0.4) 15 CF F (1.8.65) NN 2

NO (1.8.66)

25 5.4.0 s is Phenyl Substituted by R' and R' : N -" The R' and R substituents are each a member indepen dently selected from the group consisting of H; —F. —Cl; X (C-C)alkyl; fluorinated- and/or chlorinated-(C-C)alkyl; N fluorinated- and/or chlorinated-(C-C)alkoxy, (C-C) : (1.8.67) 30 alkynyl:—CN:-NO: OR'; and –C(=O)NH. Where H O R" and/or R is H there will be no substituent at any position, especially the 2-position of the phenyl group, - attached to the remainder of the left-hand side of the \ O molecule of Formula (1.0.0). Such embodiments are not as preferred as those compounds of the present invention which K 35 have a substituent, especially one at the 2-position of the CH3 phenyl group. Thus, in Some preferred embodiments of the : (1.8.68) compounds of the present invention, the meaning of R' and O R’ is defined as —H; —Cl; —F; chlorinated- and/or fluori X 40 nated-(C-C)alkyl, chlorinated- and/or fluorinated FC N (C-C)alkoxy; or (C-C)alkynyl. (1.8.69) Where a 6-membered carbon ring system is involved, e.g., as in the case of cyclohexyl, phenyl, or pyridyl, it is F preferred in particular that such a moiety defining * * be 45 attached at its 1- and 4-positions, i.e., that the points of attachment of said moiety be in para relationship to each O other. However, other configurations of such a 6-membered : (1.8.70) carbon ring system defining k are within the scope of the O compounds of Formula (1.0.0), e.g., where the points of 50 attachment are at the 1- and 2-positions, or at the 1- and X 3-positions of said 6-membered carbon ring system. FC N It is preferred to have a halogen group at the point of the (1.8.71) molecule occupied by the R' or R substituent, since it usually results in improved performance. It is contemplated 55 to be within the scope of the present invention that R' or R is a small lipophilic group comprising —Cl or —F; chlori Ol OH nated- and/or fluorinated-(C-C)alkyl, or chlorinated- and/ (1.8.72) or fluorinated-(C-C)alkoxy. Thus, the meaning of the R' or R substituent, as well as of any other substituent of a 60 compound of Formula (1.0.0) that includes the definitions —C1 or —F; chlorinated- and/or fluorinated-(C-C)alkyl: or chlorinated- and/or fluorinated-(C-C)alkoxy, is selected from the group consisting of the following: 65 - F - CHF —CHF, CF – CH, CHF The character of the nicotinamide nucleus with an ether, CHCHCF, -CHCF, -CHFCHF CHFCHF, thioether or Sulfonyl linkage to a Substituted phenyl group, CHFCF, US 7,183,293 B2 129 130 —CFCFCF - O CHF - O CHF - O CF —O CHCHF -continued —O CHCHF - O CHCF - O CHFCHF (3.0.3) –O CHFCHF, O CHFCF, F —O CFCHF - O CFCHF - O CFCF The selectivity of the overall molecule which is achieved by utilizing a moiety of this type as the R' and R substituent may be due to the conformational alignment of the lipophilic moiety with a corresponding lipophilic Zone in the PDE4 or Cl PDE4D enzyme substrate, or it may be due to the change in 10 (3.0.4) the lipophilicity of the overall molecule which results. Whatever the actual mechanism by which such selectivity is achieved, all Such embodiments are contemplated to be within the scope of the present invention. 5.4.1 * * is Other than Phenyl 15 The present invention has also been defined above as 6. being concerned with a compound of Formula (1.0.0) (3.0.5) wherein k has the meaning defined above as a moiety NO comprising a saturated or unsaturated carbon ring system that is 3- to 7-membered monocyclic, or that is 7- to 12-membered, fused or discontinuous, polycyclic; wherein optionally one carbon atom thereof may be replaced by a heteroatom selected from N, O, or S, and where N is selected, optionally a second carbon atom thereof may be CH (3.0.6) replaced by a heteroatom selected from N, O, or S. The 25 present invention is further concerned with a compound of Formula (1.0.0) wherein k comprises especially a member selected from the group consisting of phenyl; pyrrolyl, pyrrolidinyl; furanyl; thienyl; pyridyl; pyrimidinyl; piperidi 30 nyl; piperazinyl; imidazolyl; imidazolidinyl, oxazolyl; isox S. azolyl; thiazolyl; indolyl; quinolinyl; isoquinolinyl; benz (3.0.7) imidazolyl; benzoxazolyl; morpholinyl; quinuclidinyl; and CF aZabicyclo3.3.0 octanyl; a monocyclic —(C-C)cy cloalkyl moiety; a monocyclic —(Cs C7)cycloalkenyl moi 35 ety that is a member selected from the group consisting of cyclopentenyl, cyclohexenyl, and cycloheptenyl; and a bicy clic —(C7-Co)cycloalkyl or —(C7-Co)cycloalkenyl moi ety that is a member selected from the group consisting of : (3.0.8) norbornanyl, norbornenyl, bicyclo2.2.2]octanyl, bicyclo 40 3.2.1]octanyl, bicyclo[3.3.0 octanyl, bicyclo[2.2.2]oct-5- enyl, bicyclo[2.2.2]oct-7-enyl, bicyclo[3.3.1 nonanyl, HC cyclodecanyl, and adamantanyl. 3 NN N The present invention is also further concerned especially with a compound of Formula (1.0.0) wherein particularly sk 45 and the substituents R' and Rare selected in such a way that this portion of the right-hand terminus of said compound of : (3.0.9) Formula (1.0.0) is represented by the following partial Formulas (3.0.1) through (3.0.47) set out below. 50 4. No (3.0.1)

55 (3.0.10) NO

(3.0.2) 4 No 60

: (3.0.11) : S 65 \ fo US 7,183,293 B2 131 132

-continued -continued : (3.0.12) : (3.0.22)

: (3.0.23) (3.0.13) :

N- : : (3.0.24) (3.0.14) : * a 15

3.0.15 N-1sCH ( 20 Ayr (3.0.25) 21 CH 25 :

: : (3.0.26) (3.0.16) H3C CH3 30 Sl : Nals --> (3.0.27) N : 35 : (3.0.17) CH 1. (3.0.28) HN N 40 or \- NH : (3.0.29) (3.0.18) CH3 45 N : N Y.2 : (3.0.30) NF CH

: 50 :

N (3.0.19)

: -C)O : 55 : H : (3.0.31) (3.0.20) N CF3 N /

: - S : 60 : (3.0.21) (3.0.32) : : N n

65 2 : : US 7,183,293 B2 133 134

-continued -continued (3.0.33) (3.0.41) OH

(3.0.42) 10 1). (3.0.34)

15 Ol (3.0.43) (3.0.44) (3.0.35)

25 (3.0.45)

(3.0.36) 30 C O N

(3.0.46) CHF 35

(3.0.37)

40 S. (3.0.47)

(3,0.38) 45 5.5 The R and R. Substituents The group of partial Formula (1.0.4) above is substituted in the 4-position by a moiety containing the Substituents D. 50 R", and R', which may be represented by partial Formula (1.1.8): (3.0.39)

(1.1.8) 55 RA : D C RP)

60 (3.0.40) where m is 1, 2, or 3. In the more preferred embodiments of the compounds of the present invention, m has the meaning of 0 or 1. When m is 1 the moiety —R C R is 65 present, and R' and R are preferably each a member independently selected from the group consisting of —H and (C-C)alkyl; more preferably —H and —CH. US 7,183,293 B2 135 136 In other preferred embodiments of the present invention R and R may be taken together, but only in the case where -continued (1.2.7) m is 1, to form a spiro moiety of Formula (1.2.0): :

(1.2.0) N X NR 15 (1.2.8) : : (H2C) (CH2) 10 R 14 N ls where rands are independently 0 to 4 provided that the sum 15 (1.2.9) of r+s is at least 1, but not greater than 5: X is —CH, : —CHR'', or - C(R') where each R'' is selected inde pendently of the other and each R' has the same meaning R 14 as defined herein; NR' where R' has the same mean ing as defined herein; —O ; or S(=O), where t is 0, 1, X (1.2.10) or 2; and said spiro moiety is Substituted as to any one or : : more carbon atoms thereof by 0 to 3 substituents R', as to a nitrogen atom thereof by 0 or 1 substituent R', and as to a Sulfur atom thereof by 0 or 2 oxygen atoms. Accordingly, 25 there results, inter alia, the moieties illustrated by partial 4 R1 r)N R1 Formulas (1.2.1) through (1.2.12): R15 (1.2.11) : : (1.2.1) 30 : : R13 R1 4

(1.2.2) 35 i (O) (1.2.12) : :

X. 40 (1.2.3) R15-N

{ -R 14 45 where t is 0, 1, or 2; and R'' and R' have the same meaning : : (1.2.4) as defined herein. Preferred meanings of the R'' substituent include —F; C1; =O; OH: CH: OCH: C(=O)CH: 50 C(=O)NH; NH; NHCH(CH); NHC(=O) R CH, -NHC(=O)CCHCH, -NHS(=O)CH; and —S(=O)NH2, resulting in moieties Such as those of partial N-X. Formulas (3.1.1) through (3.1.34): : : (1.2.5) 55 (3.1.1) R14--N R 14 (1.2.6) 60 (3.1.2)

14 14 65 N / HO US 7,183,293 B2 137 138

-continued -continued (3.1.3) (3.1.12) : :

CH3 (3.1.4) : : H3CO OCH 10 (3.1.13)

: : (3.1.5) 15 (3.1.14)

O (3.1.6) : : a & 25 (3.1.15) (3.1.7) : : 30

(3.1.16)

OH 35 (3.1.8) : :

(3.1.17) <- 40 (3.1.9) : :

45 (3.1.18)

F F 3.1.10 : : ( so

(3.1.19)

O (3.1.11) : : 60 (3.1.20)

65 O US 7,183,293 B2 139 140

-continued -continued (3.1.21) (3.1.30) : : : :

HC1 X CH 3 O (3.1.22) H NCH, : : 10 O

(3.1.31) : :

O 15 (3.1.23) : :

N O -3S ( (3.1.32) (3.1.24) : : : :

N H O tHO CH (3.1.25) 30 : : (3.1.33) : : HC O

35 HO HO (3.1.26) : : (3.1.34) : :

O 40

N H O (3.1.27) : : 45 CCH

5.6 The R and RP Substituents

*H 50 As already described, R and RP have the same meaning (3.1.28) as defined above for RandR, except that one of them must : : be —H, and they are selected independently of each other and of R and R. Accordingly, all of the particular and preferred embodiments of the compounds of Formula (1.0.0) 55 detailed above with regard to the R' and R substituents, are N H for the most part also particular and preferred embodiments HO of the compounds of Formula (1.0.0) with regard to the R O and RP substituents. (3.1.29) 60 : : 5.7 The Moiety N(R )- The subscript has the meaning of 0 or 1. Where has the meaning of 1, which is the preferred meaning, the moiety - N(R) is present and the compounds of Formula (1.0.0) 65 are essentially nicotinamides in structure with respect to the ClH left-hand side of the core nucleus. The nitrogen atom sub stituent R is preferably selected from H; —(C-C)alkyl; US 7,183,293 B2 141 142 and —(C-C)alkoxy; and is more preferably —H; —CH: (1.3.12), or (1.3.15) where Rand Rare absent or are or —OCH. In the most preferred embodiments of the —H, or —CH; 0 k is phenyl, norbornanyl, furanyl, compounds of Formula (1.0.0), R has the meaning of H. thienyl, pyrimidinyl, or cyclohexyl; 0 and D is Where k and k both have the prefered meaning of s —C(=O)CR where R is -H or -CH: –C(=O) phenyl; and j has the meaning of 0, which is a less preferred NH; or tetrazol-5-yl: meaning than where j is 1, the moiety —N(R) is absent and the compounds of Formula (1.0.0) are essentially nicotinoyl (ii) A compound according to paragraph (i) wherein R' moieties, i.e., ketones in structure with respect to the left and Rare both —CH, or one is —CH and the other hand side of the core nucleus. Such a ketone structure in the 10 is —CH(CH) or —C(CH), or one is —H and the left-hand side of the core nucleus, together with benzyl as a other is —CH or CF, or both taken together are preferred meaning of the k moiety, is represented by For spiro cyclopropyl or spiro cyclobutyl; 0 one of R and mula (1.0.7): Ris-Hand the other is -H or -CH; W is -O- 15 0 Y is =C(R) where R is -H, F, or Cl; 0 R' and Rare H, F, or Cl; 0 R is H; 0 R is H:

(1.0.7) 0 R and R are taken together to form a moiety of partial Formula (1.3.1) or (1.3.11) where R and R' are both absent; 0 ** is phenyl, thienyl, or cyclohexyl: 0 and D is C(=O)CR7 where R7 is -H or -CH: —C(=O)NH; or tetrazol-5-yl: (iii) A compound according to paragraph (ii) wherein R' and Rare both —CH, or both taken together are spiro 25 cyclopropyl; 0 one of R and RP is – H and the other is - Hor—CH; 0 Y is =C(R) - where R', is -H, - F, or - Cl; 0 R' and Rare H, F, or Cl; 0 R is H; 0 R is H; 0 Rand Rare taken together to 30 form a moiety of partial Formula (1.3.11) where R' and R are both absent: 0 * is phenyl; 0 and D is where all of the substituents and components thereof, i.e., D; C(=O)CR where R is H or CH: C(=O) W: Y: k, m, and n: R', R. R. R., and R; and R,R,R, NH; or tetrazol-5-yl: and R', have, for the most part, the same particular and (iv) A compound according to paragraph (iii) wherein R' preferred meanings described in detail herein as in the case 35 and Rare both CH; 0 R and RP are both H; 0 where j is 1 and the left-hand side of the core nucleus of the Yis =C(R)—where R', is-H; 0 and one of R and compounds is a nicotinamide in structure. R’ is —H and the other is —F: 5.8 Preferred Subgenus and Species Embodiments of For (v) A compound according to paragraph (iii) wherein Y is 40 =C(R) - where Ris-F; 0 and R' and Rare both mula (1.0.0) —H; In the above description various preferred aspects of the (vi) A compound according to paragraph (ii) wherein R' compounds of Formula (1.0.0) have been set forth. As a and Rare both —CH, or both taken together are spiro further demonstration of the scope and the content of the cyclopropyl; 0 one of R and RP is – H and the other present invention, Subgeneric embodiments of the com 45 is - Hor—CH; 0 Y is =C(R) - where R', is -H, pounds of Formula (1.0.0) are presented. Such preferred - F, or - Cl; 0 R and R are H, F, or Cl; 0 R embodiments include, but are not limited to, those recited in is H; 0 R is -H; R and R are taken together to the following paragraphs (i) through (viii): form a moiety of partial Formula (1.3.1) where R'' and (i) A compound according to Formula (1.0.0) wherein R’ are both - H; 0 k is phenyl; 0 and Dis–C(=O) where m is 1 or 2, and n is 1: 0 R and R are -H, 50 OR7 where R is -H or -CH: C(=O)NH; or —CF, or —(C-C)alkyl substituted by 0 or 1 of F, tetrazol-5-yl; C1, CF, CN, NH, or—C(=O)NH, or both (vii) A compound according to paragraph (vi) wherein R' taken together are spiro —(C-C)cycloalkyl-substi and Rare both CH; 0 R and RP are both H; 0 tuted by 0 or 1 of F. - C1, CF, or—CN; 0 one 55 Yis =C(R)—where R', is-H; 0 and one of R and of R and R' is -H, and the other is -H, -(C-C) R’ is —H and the other is —F; and alkyl, or phenyl, each substituted by 0 or 1 of F. —Cl, (viii) A compound according to paragraph (vii) wherein Y or CN: 0 W' is - O - or S ; 0 W is O. : 0 is =C(R')— where R', is —F; 0 and R' and Rare Y is =C(R) - where R', is -H, - F - C1, —CN, both - H. —CH, or —OCH; 0 R and R are -H, -F, - C1, 60 The above description various preferred aspects of the CN, NO, -OH, -CH, OCH, OCHF, or compounds of Formula (1.0.0) have been set forth. As a further demonstration of the scope and the content of the OCF; 0 R is H or CH; 0 R are H, F, present invention, specific compounds comprising embodi —CN, NO, -OH, -CH, or - OCH; 0 k' is ments of the compounds of Formula (1.0.0) are presented. phenyl; 0 R and R are taken together to form a 65 Such species of Formula (1.0.0) include, but are not limited moiety of partial Formula (1.3.1) where RandR are to the following compounds of Formulas (5.5.1) through —H or —CH; or a moiety of partial Formula (1.3.11), (5.5.106):

US 7,183,293 B2 161 162

-continued

NOMENCLATURE STRUCTURAL FORMULA

O pyridine-3-carbonyl-amino-methyl)-cyclohex-3- enyloxy)-propionic acid of Formula (5.5.3.7); N N H 2

O "CH, OH Y./

O pyridine-3-carbonyl-amino-methyl)-cyclohex-3- enyloxy)-propionic acid of Formula (5.5.38); N N H 2

O '' 'CH, OH Y./

O pyridine-3-carbonyl-amino-methyl)-cyclohex-3- enyloxy)-propionic acid of Formula (5.5.39); N N H 2

(R)-2-[4-(2-(4-Fluoro-phenoxy)-pyridine-3- O carbonyl-amino-methyl)-cyclohex-3-enyloxy propionic acid of Formula (5.5.40); N N H 2

O '', 'CH OH

US 7,183,293 B2 169 170

-continued

NOMENCLATURE STRUCTURAL FORMULA

O yloxy)-pyridine-3-carbonyl-amino-methyl)- cyclohexyloxy)-propionic acid of Formula (5.5.53); N N H 2

O : CH OH Y.W

(R)-2-[4-(2-(Benzo[2,1,3thiadiazol-5-yloxy)- O pyridine-3-carbonyl-amino-methyl)- cyclohexyloxy)-propionic acid of Formula (5.5.54); N N H 2

O '', CH OH Y.W

O pyridine-3-carbonyl-amino-methyl)- cyclohexyloxy)-propionic acid of Formula (5.5 55); N N H 2

O '' 'CH, OH Y./

O pyridine-3-carbonyl-amino-methyl)- cyclohexyloxy)-propionic acid of Formula (5.5.56); N N H 2 N O