USOO7084156B2

(12) United States Patent (10) Patent No.: US 7,084,156 B2 DeVita et al. (45) Date of Patent: Aug. 1, 2006

(54) 2-AMINOQUINOLINE COMPOUNDS 2004/0106645 A1 6/2004 Blackburn et al. (75) Inventors: Robert J. DeVita, Westfield, NJ (US); FOREIGN PATENT DOCUMENTS Lehua Chang, Ramsey, NJ (US); EP O 252 503 11, 1992 Danny Chaung, Clark, NJ (US); MyLe JP 2001-226269 8, 2001 Hoang, Colonia, NJ (US); JinLong JP 371,059 12/2002 Jiang, Scotch Plains, NJ (US); Peter WO WO 96,284.46 9, 1996 Lin, Edison, NJ (US); Andreas W. WO WO 98.27815 7, 1998 Sailer, Edison, NJ (US); Jonathan R. WO WO99, 19326 4f1999 WO WO 99,42464 8, 1999 (73) Assignee: Merck & Co., Inc., Rahway, NJ (US) WO WO 99,48492 * 9, 1999 (*) Notice: Subject to any disclaimer, the term of this (Continued) patent is extended or adjusted under 35 U.S.C. 154(b) by 5 days. OTHER PUBLICATIONS Antelman et al., Chem. Abstract, 91:68543, Current Medical (21) Appl. No.: 10/496,615 Research and Opinion (1979), vol. 6, pp. 73-82, “ The (22) PCT Filed: Nov. 22, 2002 importance of stress in assessing the effects of e Afaf 9 drugs'. (86). PCT No.: PCT/USO2/37.556 (Continued) S 371 (c)(1), (2), (4) Date: May 25, 2004 Primary Examiner D. Margaret Seaman s 9 (74) Attorney, Agent, or Firm—Catherine D. Fitch; Melvin (87) PCT Pub. No.: WO03/045313 Winokur PCT Pub. Date: Jun. 5, 2003 (57) ABSTRACT (65) Prior Publication Data The present invention is concerned with compounds of the US 2005/OO26915 A1 Feb. 3, 2005 general Formula I: Related U.S. Application Data (60) Provisional application No. 60/333,581, filed on Nov. R4 27, 2001. R R 6 N1 N. 3 (51) Int. Cl. CO7D 215/38 (2006.01) 44 2 -R2 CO7D 215/16 (2006.01) Rs N N A6 IK 3/47 (2006.01) l (52) U.S. Cl...... 514/312: 514/313; 514/314: 546/159:546/162:546/178 (58) Field of Classification Search ...... 546/159, and pharmaceutically acceptable salts thereof, which are 54.6/162,s 178:u. Y-s 514/312.s 314,- u is 313 usefulful as melan1nlani COncentrat1ngingh hormone receptOrp antago9. See application file for complete search history. nists, particularly MCH-1R antagonists. As such, com pounds of the present invention are useful for the treatment (56) References Cited or prevention of obesity or eating disorders associated with excessive food intake and complications thereof, osteoar U.S. PATENT DOCUMENTS thritis, certain cancers, AIDS wasting, cachexia, frailty (par ticularly in elderly), mental disorders stress, cognitive dis 4,013,665 A 3, 1977 Crenshaw et al. orders, sexual function, reproductive function, kidney 4,701.459 A 10, 1987 Meanwell et al. 5,942.520 A 8, 1999 Pamukcu et al. function, locomotor disorders, attention deficit disorder 6,221,613 B1 4/2001 Salon et al. (ADD), Substance abuse disorders and dyskinesias, Hun 6,410,561 B1* 6/2002 Shinkai et al...... 514/313 tington's disease, epilepsy, memory function, and spinal 6,569,861 B1 5/2003 Bakthavatchalam et al. muscular atrophy. Compounds of formula I may therefore be 6,720,324 B1 4/2004 Marzabadie et al. used in the treatment of these conditions, and in the manu 6,727,264 B1 4/2004 Marzabadi et al. facture of a medicament useful in treating these conditions. 2003, OO23085 A1 1/2003 Chen et al. Pharmaceutical formulations comprising one of the com 2003/0105094 A1 6, 2003 Clader et al. pounds of formula (I) as an active ingredient are disclosed, 2003. O144261 A1 7/2003 Palani et al. as are processes for preparing these compounds. 2003/019 1136 A1 10, 2003 Bakthavatchalam et al. 2003/0229119 A1 12/2003 Kym et al. 2004.0006370 A1 1/2004 Cheng et al. 18 Claims, No Drawings US 7,084,156 B2 Page 2

FOREIGN PATENT DOCUMENTS WO WO O3,087.045 10, 2003 WO WO O3,O87046 10, 2003 WO WO 99,53924 10, 1999 WO WO O3,O97047 11/2003 WO WOOOf 1874O 4/2000 WO WO 2004/002987 1, 2004 WO WOOO,35919 6, 2000 WO WOOOf 64877 11 2000 OTHER PUBLICATIONS WO WO O1,21169 3, 2001 WO WO O1/21577 3, 2001 Kato et al., Chem. Abstract, 134:266 103, “Preparation of WO WO O1/32646 5, 2001 N-tetrahydronaphthalenyl carboxamides of melanin concen WO WO O1 (40218 6, 2001 trating hormone antagonists'. W W 8 ... 658 Mueller et al., Chem. Abstract, 138:4532, “Preparation of WO WO O1/727.58 10, 2001 quinolines as ligands for the neuropeptide Y receptor useful WO WO O1/82925 11 2001 against arthritis, cardiovascular diseases, diabetes, renal WO WO O1/87834 11 2001 failure, eating disorders and obesity'. WO WO O2/OO654 1, 2002 Shinkai et al., J. Med. Chem., vol. 43 (2000), pp. 4667-4677, WO WO O2,04433 1, 2002 “4-Aminoquinolines: Novel nociceptin antagonist with anal WO WO O2,06245 1, 2002 ----- WO WO O2/O42458 5, 2002 ges1c activity”. WO WO O2/O51809 T 2002 Lanza et al., J. Med. Chem. Vol. 35 (1992), pp. 252-258, WO WO O2/O70522 9, 2002 “Substituted 4,6-diaminoquinolines as inhibitors of C5a WO WO O2/O76929 10, 2002 receptor binding”. WO WO O2/O76947 10, 2002 Ganoub. Heterocyclic Communications, vol. 7(2) (2001), WO WO O2/O83134 10, 2002 pp. 143-148, “A facile approach to N-heterocycles. The WO WO O2/O89729 11 2002 99 WO WO O2/O94799 11 2002 reactions of ylide phosphoranes with hydrazones WO WO O3,004O27 1, 2003 Kowalski et al., Expert Opin. Investig. Drugs, vol. 13(9) WO WO O3,O13574 2, 2003 (2004), pp. 1113-1122. “Therapeutic potential of melanin WO WO O3,O15769 2, 2003 concentrating hormone- 1 receptor antagonists for the treat WO WO O3,O27239 4/2003 ment of obesity”. WO WO O3,O27240 4/2003 Clarket al., J. Med. Chem., vol. 47 (2004), pp. 3962-3971, WO WO 03/028641 4/2003 “A virtual screening approach to finding novel and potent WO WO 03/033476 4/2003 WO WO 03/033480 4/2003 antagonists at the melanin-concentrating hormone 1 recep WO WO O3,O35055 5, 2003 tor'. WO WO O3,035624 5, 2003 Arienzo et al., Bioorg. & Medicinal Chem. Letters, vol. 14 WO WO 03/045918 6, 2003 (2004), pp. 4099-4102, "Structure-activity relationships of a WO WO 03/045920 6, 2003 novel series of melanin-concentrating hormone (MCH) WO WO O3,059289 T 2003 receptor antagonists'. WO WO O3,O70244 8, 2003 WO WO O3,087.044 10, 2003 * cited by examiner US 7,084, 156 B2 1. 2 2-AMINOQUINOLINE COMPOUNDS MCH deficient mice are lean, hypophagic and have increased metabolic rate. (Shimada, et al., 1998. Nature 396, CROSS-REFERENCE TO RELATED 670–673.) APPLICATIONS MCH action is not limited to modulation of food intake as 5 This application is a U.S. National Phase application effects on the hypothalamic-pituitary-axis have been under 35 U.S.C. S 371 of U.S. Application No. PCT/US02/ reported. (Nahon, 1994. Critical Rev. in Neurobiol. 8, 37556, filed Nov. 22, 2002, which claims priority under 35 221-262.) MCH may be involved in the body response to U.S.C. S 119 from U.S. Provisional Application No. 60/333, stress as MCH can modulate the stress-induced release of 581, filed Nov. 27, 2001. 10 CRF from the hypothalamus and ACTH from the pituitary. In addition, MCH neuronal systems may be involved in BACKGROUND OF THE INVENTION reproductive or maternal function. MCH transcripts and Obesity, defined as excess adiposity for a given body size, MCH peptide were found within germ cells in testes of adult results from a chronic imbalance between energy intake and 15 rats, suggesting that MCH may participate in stem cell energy expenditure. Body mass index (BMI, kg/m) is an renewal and/or differentiation of early spermatocytes accepted clinical estimate of being overweight (BMI 25 to (Hervieu et al., 1996). MCH injected directly into the medial 30) and of obesity (BMI>30). A BMI above 30 kg/m preoptic area (MPOA) or ventromedial nucleus (V) stimu significantly increases the risk of diabetes, hypertension, lated sexual activity in female rats (Gonzalez et al., 1996). dyslipidemias and cardiovascular disease, gallstones, In ovariectomized rats primed with estradiol, MCH stimu osteoarthritis and certain forms of cancer and reduces life expectancy. lated luteinizing hormone (LH) release while anti-MCH In the vast majority of obese individuals, the cause of the antiserum inhibited LH release (Gonzalez et al., 1997). The excess adiposity is not immediately apparent. A currently Zona incerta, which contains a large population of MCH cell accepted working hypothesis is that obesity is the result of 25 bodies, has previously been identified as a regulatory site for a maladaptation of the innate metabolic response to envi the pre-ovulatory LH surge (MacKenzie et al., 1984). There ronmental challenges such as unlimited availability of low fore modulators of MCH receptors may be useful in the cost/energy dense foods and sedentariness (Hill et al., Sci prevention and treatment of reproductive function. MCH has ence 1998; 28.0:1371). The study of energy intake in free been reported to influence release of pituitary hormones living humans has met with only limited Success and defini 30 including ACTH and oxytocin. Therefore, modulators of tive experimental evidence that hyperphagia causes most MCH receptors may be useful in the prevention and treat forms of human obesity is lacking. Following the discovery ment of obesity, Cushing's disease, sexual function, appetite of leptin, the interest in the neurohorminonal regulation of and eating disorders, obesity, diabetes, cardiovascular dis food intake has regained momentum. However, while much ease, hypertension, dyslipidemia, myocardial infarction, gall knowledge has been gained on the regulation of food intake 35 in rodents and other animal species, the understanding of the stones, osteoarthritis, certain cancers, AIDS wasting, neurophysiology of feeding behavior in humans remains cachexia, frailty (particularly in the elderly), binge eating extremely limited. disorders including bulimia, anorexia, kidney function, Neuropeptides present in the hypothalamus play a major diuresis, reproductive function and sexual function. role in mediating the control of body weight. (Flier, et al., 40 Two receptor subtypes have been identified in humans, 1998. Cell, 92, 437–440.) Melaninoncentrating hormone MCH-1R and MCH-2R. Both receptors, as well as the gene (MCH) is a cyclic 19-amino acid neuropeptide synthesized for the MCH peptide, have been mapped to regions previ as part of a larger pre-prohormone precursor in the hypo ously reported to contain a Susceptibility gene for psychi thalamus which also encodes neuropeptides NEI and NGE. atric disorders. In particular, MCH-1R was mapped to (Nahon, et al., 1990. Mol. Endocrinol. 4, 632–637.) MCH 45 chromosome 22d 13.2 (Kolakowski et al. 1996). The possi was first identified in salmon pituitary, and in fish MCH bility of linkage for schizophrenia susceptibility locus in this affects melanin aggregation thus affecting skin pigmenta area was suggested by independent studies from 2 groups tion. In trout and in eels MCH has also been shown to be (Pulver et al. 1994, Coon et al. 1994). In addition, a more involved in stress induced or CRF-stimulated ACTH release. recent study (Stoeber et al. 2000) of samples from patients (Kawauchi, et al., 1983. Nature 305, 321-323.) 50 with periodic catatonia, a clinical Subtype of unsystematic In humans two genes encoding MCH have been identified Schizophrenia Suggested possible linkage of the region that are expressed in the brain. (Breton, et al., 1993. Mol. around 22d 13. Human genetics implicates these loci not Brain Res. 18, 297-310.) In mammals MCH has been only for schizophrenia but also for bipolar disorder. The localized primarily to neuronal cell bodies of the hypothala second MCH receptor (MCH-2R) has been mapped to mus which are implicated in the control of food intake, 55 including perikarya of the lateral hypothalamus and Zona chromosome 6q16.2–16.3 (Sailer et al., 2001). Cao et al. inertia. (Knigge, et al., 1996. Peptides 17, 1063–1073.) (1997) were the first to report evidence of a schizophrenia Pharmacological and genetic evidence Suggest that the susceptibility locus in that area. This initial report was primary mode of MCH action is to promote feeding (orexi confirmed and extended by other reports (Martinez et al. genic). MCH mRNA is up-regulated in fasted mice and rats, 60 1999, Kaufmann et al. 1998, Levinson et al. 2000). Schizo in the ob?ob mouse and in mice with targeted disruption in phrenia has been recognized as a disorder with profound the gene for neuropeptide Y (NPY). (Qu, et al., 1996. Nature deficits in information-processing and attentional abnor 380, 243-247, and Erickson, et al., 1996. Nature 381, malities. One of the few possible paradigms available to 415-418.) Injection of MCH centrally intracelebroventricu assess these types of deficits in information processing is lar (ICV) stimulates food intake and MCH antagonizes the 65 sensory gating, a filtering process which can be demon hypophagic effects seen with C. melanocyte stimulating strated by using a paired auditory stimulus. Miller et al. hormone (CMSH). (Qu, et al., 1996. Nature 380, 243–247.) (1993) examined the effects of ICV administered MCH on US 7,084, 156 B2 3 4 the decrease in amplitude of the second of two tone-evoked in Some families. In view of the functional and neuroana CNS potentials that can be measured when pairs of identical tomical patterns of the MCH neural system in the rat and tones are presented 500 ms apart. They found that MCH human brains, the MCH gene may represent a good candi application decreased sensory gating in this paradigm. date for SCA2 or Darier's disease. Therefore, modulators of Based on pathogenesis and pathophysiology (reviewed in MCH receptors may be useful in the treatment of mental Lewis and Liebermann (2000)) several brain areas have disorders including manic depression, depression, Schizo been implicated in schizophrenia, all of which show high phrenia, mood disorders, delirium, dementia, severe mental expression for MCH receptors: thalamus, midbrain, nucleus retardation, anxiety, stress, cognitive disorders, and dyski accumbens, temporolimbic, and prefrontal cortices. These 10 nesias including Parkinson's disease, Tourette's syndrome, studies and findings support the use of MCH receptor Huntington's disease, cerebellar ataxia, and seizures. modulators in the treatment and prevention of Schizophre Further, the gene responsible for chronic or acute forms of 18. spinal muscular atrophies has been assigned to chromosome Kelsoe et al. (2001) recently reported on a genome survey 5q12–13 using genetic linkage analysis (Melki et al., 1990; indicating a possible Susceptibility locus for bipolar disorder 15 Westbrook et al., 1992). Therefore, modulators of MCH identified on 22q (Kelsoe et al. 2001). The MCH gene which receptors may be useful in treating muscular dystrophy and encodes the MCH pro-peptide was mapped to chromosome dyskinesias, including Parkinson's disease, Tourette’s Syn 12q23.1. This area has been identified by Morissette et al. drome, Huntington's disease, cerebellar ataxia, seizures, (1999) in a genome wide scan for susceptibility loci for locomotor disorders, attention deficit disorder (ADD) and bipolar disorder in families in the Province of Quebec. In Substance abuse disorders. addition, Ewald et al. (1998) showed significant linkage to Still further, modulators of MCH receptor binding may chromosome 12q23.1 (maximum lod score 3.37) in Danish also be useful in treating epilepsy. In the PTZ seizure model, families suffering from bipolar affective disorder. In addi injection of MCH prior to seizure induction prevented tion, Presse et al. (1997) have shown that lithium, the “gold 25 seizure activity in both rats and guinea pigs, suggesting that standard” and most appropriate initial treatment for the MCH-containing neurons may participate in the neural depressive phase of bipolar disorder, can alter MCH mRNA circuitry underlying PTZ-induced seizure (Knigge and Wag levels in NGF-treated PC12 cells by increasing mRNA ner, 1997). MCH has also been observed to affect behavioral stability. These studies and findings support the use of MCH 30 correlates of cognitive functions. MCH treatment hastened receptor modulators in the treatment and prevention of extinction of the passive avoidance response in rats bipolar disorder and depression. (McBride et al., 1994), raising the possibility that MCH Philippe and colleagues (1999) performed a genome-wide receptor antagonists may be beneficial for memory storage screen for a autism Susceptibility gene and found suggestive and/or retention. linkage for the region of chromosome 6q 16.2–16.3 (maxi 35 A role for MCH in the modulation or perception of pain mum lod score 2.23). This finding supports the use of MCH is supported by the dense innervation of the periaqueductal receptor modulators in the treatment of autism. grey (PAG) by MCH-positive fibers. MCH receptor modu In all species studied to date, a major portion of the lators may be useful as antinociceptives or as analgesics, neurons of the MCH cell group occupies a rather constant 40 particularly for the treatment of neuropathic pain. location in those areas of the lateral hypothalamus and Finally, MCH may participate in the regulation of fluid subthalamus where they lie and may be a part of some of the intake. ICV infusion of MCH in conscious sheep produced so-called “extrapyramidal' motor circuits. These involve , natriuretic, and kaliuretic changes in response to Substantial striato- and pallidofugal pathways involving the increased plasma volume (Parkes, 1996). Together with thalamus and cerebral cortex, hypothalamic areas, and recip 45 anatomical data reporting the presence of MCH in fluid rocal connections to subthalamic nucleus, Substantia nigra, regulatory areas of the brain, the results indicate that MCH and mid-brain centers (Bittencourt et al., 1992). In their may be an important peptide involved in the central control location, the MCH cell group may offer a bridge or mecha of fluid homeostasis in mammals. Therefore, modulators of nism for expressing hypothalamic visceral activity with MCH receptors may be useful in kidney function and appropriate and coordinated motor activity. Thus, modula 50 diuresis. tors of MCH receptor function may be useful in the treat ment and prevention of movement disorders, such as Par PCT publication WO 01/21169 to Takeda discloses MCH kinson's disease, Parkinson-like syndromes and antagonists of the structural formula shown below: Huntingdon's Chorea in which extrapyramidal circuits are known to be involved. 55 (0); Human genetic linkage studies have located authentic hMCH loci on chromosome 12 (12q23–24) and the variant hMCH loci on chromosome 5 (5q12–13) (Pedeutour et al., 1994). Locus 12q23–24 coincides with a locus to which 60 autosomal dominant cerebellar ataxia type II (SCA2) has been mapped (Auburger et al., 1992; Twells et al., 1992). This disease comprises neurodegenerative disorders, includ ing an olivopontocerebellaratrophy. Furtherminore, the gene for Darier's disease, has been mapped to locus 12q23–24 65 (Craddock et al., 1993). Dariers disease is characterized by and PCT publication WO 01/21577 discloses MCH antago abnormalities in keratinocyte adhesion and mental illnesses nists of the structural formula below: US 7,084, 156 B2 6

R R O 2 An R3 it u Y R4 x1 10 Rs U.S. Pat. No. 4,701,459 and EP 0 252 503 disclose 2,3-dihydro-2-oxo-1H-imidazo[4,5-biquinolinyl amine The compounds of the present invention are modulators derivatives of structural formula: of the MCH-1R receptor and are useful in the treatment, 15 prevention and Suppression of diseases mediated by the MCH-1R receptor. The invention is concerned with the use H R21 N N N of these novel compounds to selectively antagonize the MCH-1R receptor. As such, compounds of the present RsNN- X=0 invention are useful for the treatment or prevention of 21 2 N 2O R4 obesity, diabetes, appetite and eating disorders, cardiovas R cular disease, hypertension, dyslipidemia, myocardial inf arction, gall stones, osteoarthritis, certain cancers, AIDS wasting, cachexia, frailty (particularly in elderly), binge as useful in inhibiting blood platelet aggregation. U.S. Pat. No. 4,013,665 claims antiviral, substituted 1,3-dimethyl- 25 eating disorders including bulimina, anorexia, mental dis 1H-pyrazolo3.4biquinolines of structural formula below: orders including manic depression, depression, Schizophre nia, mood disorders, delirium, dementia, severe mental retardation, anxiety, stress, cognitive disorders, sexual func NH(CH)3 N(R)(R). tion, reproductive function, kidney function, diuresis, loco E CH 30 motor disorders, attention deficit disorder (ADD), substance abuse disorders and dyskinesias including Parkinson's dis N ease, Parkinson-like syndromes, Tourette's syndrome, Hun tington's disease, epilepsy, improving memory function, and 2 Y. G N 35 spinal muscular atrophy.

CH3 SUMMARY OF THE INVENTION

PCT publication WO99/48492 discloses nociceptin antago The present invention is concerned with compounds of nists of the formula below: the general Formula I: "y. Ne Ni-co (CH)-E-(CH2)-G-(Rs). N

50 PCT publication WO99/53924 discloses analgesic agent of the formula below: R4 y1Y sy, 55 R6 N N R3 R R% 2 4 N1 R2 R2 O Xns R10: 5 R (CH)-- 3 - 2 Su R k R R9 60 2 R4 x1 Rs and pharmaceutically acceptable salts thereof, which are Rs useful as melanin concentrating hormone (MCH)receptor antagonists. 65 As melanin concentrating hormone receptor antagonists, and PCT publication WO99/19326 discloses compounds of the compounds of the present invention are useful in the the formula below: treatment, prevention and Suppression of diseases mediated US 7,084, 156 B2 7 8 by the MCH receptor. In particular, certain compounds of In yet another subclass of this invention, R' is selected the present invention are selective antagonists of the MCH from: 1R Subtype receptor. As such, compounds of the present (1) hydrogen, and invention are useful for the treatment or prevention of (2) methyl. obesity, diabetes, appetite and eating disorders, cardiovas 5 In one embodiment of the present invention, R is selected cular disease, hypertension, dyslipidemia, myocardial inf from: arction, gall stones, osteoarthritis, certain cancers, AIDS (1) hydrogen, wasting, cachexia, frailty (particularly in elderly), binge (2) C- alkyl, eating disorders including bulimina, anorexia, mental dis (3) Calkenyl, orders including manic depression, depression, Schizophre 10 (4) C2-alkynyl, nia, mood disorders, delirium, dementia, severe mental (5) cycloalkyl-Co. alkyl, retardation, anxiety, stress, cognitive disorders, sexual func (6) heterocycloalkyl-Colo alkyl, tion, reproductive function, kidney function, diuresis, loco (7) aryl-Colo alkyl, and motor disorders, attention deficit disorder (ADD), substance (8) heteroaryl-Colo alkyl; abuse disorders and dyskinesias including Parkinson's dis 15 wherein alkyl, alkenyl, and alkynyl, moieties above are ease, Parkinson-like syndromes, Tourette's syndrome, Hun optionally substituted with one to four substituents indepen tington's disease, epilepsy, improving memory function, and dently selected from R', and cycloalkyl, heterocycloalkyl spinal muscular atrophy. aryland heteroaryl moieties above are optionally substituted In one embodiment of the present invention, R is selected with one to four substituents independently selected from from: R’; and wherein sulfur-containing heterocyclic rings may be (1) hydrogen, mono- or di-oxidized on the Sulfur atom. (2) C- alkyl, In one class of this embodiment of the present invention, (3) Calkenyl, R’ is selected from: (4) C2-alkynyl, (1) hydrogen, (5) cycloalkyl-Co. alkyl, 25 (2) C alkyl, (6) heterocycloalkyl-Colo alkyl, (3) Coalkenyl, (7) aryl-Co alkyl, and (4) cycloalkyl-Co. alkyl, (8) heteroaryl-Colo alkyl; (5) heterocycloalkyl-Co. alkyl, wherein alkyl, alkenyl, and alkynyl, moieties above are (6) aryl-Co. alkyl, and optionally substituted with one to four substituents indepen 30 (7) heteroaryl-Colo alkyl; dently selected from R', and cycloalkyl, heterocycloalkyl aryland heteroaryl moieties above are optionally substituted wherein alkyl and alkenyl moieties above are optionally with one to four substituents independently selected from substituted with one to three substituents independently R’; and wherein sulfur-containing heterocyclic rings may be selected from R', and cycloalkyl, heterocycloalkyl, aryland 35 heteroaryl moieties above are optionally substituted with mono- or di-oxidized on the Sulfur atom. one to three substituents independently selected from R. In one class of this embodiment of the present invention, In one subclass of this class, R is selected from: R" is selected from: (1) hydrogen, (1) hydrogen, (2) C- alkyl, (2) C- alkyl, 40 (3) cycloalkyl-Co. alkyl, (3) Calkenyl, (4) heterocycloalkyl-Co. alkyl, (4) cycloalkyl-Co. alkyl, (5) aryl-Co. alkyl, and (5) heterocycloalkyl-Co. alkyl, (6) heteroaryl-Colo alkyl; (6) aryl-Co. alkyl, and (7) heteroaryl-Colo alkyl; 45 wherein alkyl moieties above are optionally substituted with one to three substituents independently selected from R. wherein alkyl and alkenyl moieties above are optionally and cycloalkyl, heterocycloalkyl, aryl and heteroaryl moi substituted with one to three substituents independently eties above are optionally substituted with one to three selected from R', and cycloalkyl, heterocycloalkyl, aryland substituents independently selected from R. heteroaryl moieties above are optionally substituted with In another subclass of this class, R is selected from: one to three substituents independently selected from R. 50 (1) hydrogen, In one subclass of this class of the invention, R is (2) C alkyl, hydrogen, or C. alkyl, optionally substituted with one to (3) cycloalkyl-Co. alkyl, three substituents independently selected from R. (4) heterocycloalkyl-Co. alkyl, and (5) aryl-Co. alkyl, In another subclass of this class, R' is selected from: 55 (1) hydrogen, wherein alkyl moieties above are optionally substituted with (2) methyl, one to three substituents independently selected from R. (3) ethyl, and and cycloalkyl, heterocycloalkyl, aryl and heteroaryl moi (4) propyl. eties above are optionally substituted with one to three optionally substituted with one to three substituents inde 60 substituents independently selected from R. pendently selected from R. In yet another subclass of this class, R is selected from: In another subclass of this invention, R is selected from: (1) methyl, (1) hydrogen, and (2) ethyl, (2) methyl: (3) n-propyl. 65 (4) isopropyl. optionally substituted with one to three substituents inde (5) t-butyl, pendently selected from R. (6) n-butyl, US 7,084, 156 B2 10 (7) cyclopropyl. (12) aryl-C alkyl, (8) cyclobutyl, (13) heteroaryl, (9) cyclopentyl, (14) heteraryl-C- alkyl, (10) cyclohexyl, (15) - OR', (11) heterocycloalkyl-Coe alkyl, wherein the heterocy (16) NR7R7, cloalkyl moiety is selected from azetidinyl, pyrrolidinyl, (17) COR7, and pyridyl and (18) cyano, and (12) phenyl-Coe alkyl, (19) C(O)NR'R''. wherein alkyl moieties above are optionally substituted with wherein alkyl, alkenyl and alkynyl, moieties above are one to three substituents independently selected from R. 10 optionally substituted with one to four substituents indepen and cycloalkyl, heterocycloalkyl, and aryl moieties above dently selected from R', and cycloalkyl, heterocycloalkyl, are optionally substituted with one to three substituents aryland heteroaryl moieties above are optionally substituted independently selected from R. with one to four substituents independently selected from In another embodiment of the present invention, when R' R’; and wherein sulfur-containing heterocyclic rings may be is hydrogen or 2-hydroxyethyl, R is other than 4-meth 15 mono- or di-oxidized on the Sulfur atom. anSulfonamidophenethyl. In one class of this embodiment of the present invention, In another embodiment of the present invention, R" and R is selected from: R together with the nitrogen atom to which they are (1) hydrogen, attached, form a 4- to 11-membered bridged or unbridged or (2) halogen, spirocyclic heterocyclic ring, optionally containing one or (3) Cls alkyl, two additional heteroatoms selected from N. S., and O, (4) trifluoromethyl, optionally having one or more degrees of unsaturation, (5) Calkenyl, optionally fused to a 6-membered heteroaromatic or aro (6) cycloalkyl, matic ring, either unsubstituted or substituted with one to (7) cycloalkyl-C alkyl, four substituents independently selected from R”; and 25 (8) cycloheteroalkyl, wherein Sulfur-containing heterocyclic rings may be mono (9) cycloheteroalkyl-C alkyl, or di-oxidized on the sulfur atom. In one class of this (10) aryl, embodiment of the invention, R' and R together with the (11) aryl-C alkyl, nitrogen atom to which they are attached, form a 4- to (12) heteroaryl, 11-membered bridged or unbridged or spirocyclic heterocy 30 (13) heteroaryl-C alkyl, clic ring, optionally containing one additional heteroatom (14) —OR". selected from N. S., and O, optionally having one or more (15) NR7R7, degrees of unsaturation, optionally fused to a 6-membered (16) - CO.R. and heteroaromatic or aromatic ring, either unsubstituted or (17) C(O)NR'R''. substituted with an R substituent. In one subclass of this 35 class, R' and R together with the nitrogen atom to which wherein alkyl and alkenyl moieties above are optionally they are attached, form a 4- to 11-membered bridged or substituted with one to three substituents independently unbridged or spirocyclic heterocyclic ring, optionally con selected from R', and cycloalkyl, heterocycloalkyl, aryland taining one additional heteroatom selected from N. S. and 0. heteroaryl moieties above are optionally substituted with an either unsubstituted or substituted with an R substituent. In 40 R” substituent. another subclass of this class, R' and R together with the In one subclass of this class, R is selected from: nitrogen atom to which they are attached, form a 4- to (1) hydrogen, 11-membered bridged or unbridged or spirocyclic heterocy (2) halogen, clic ring, selected from: aZetidinyl, pyrrolidinyl, piperidinyl, (3) Cls alkyl, morpholinyl, 1-thia-4-azacyclohexyl, 2,5-diazabicyclo 45 (4) trifluoromethyl, 2.2.2]octanyl, azacycloheptyl, 2-oxa-5-azabicyclo[2.2.1 heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1 (6) —OCH, heptyl, 7-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2 (7) —NH2, octyl, 2-azabicyclo[2.2.2]octyl, and 3-azabicyclo3.2.2 (8) —COR', and nonyl, 2.7-diazaspiro4.4nonyl, 2.7-diazaspiro4.5decyl 50 (9) - C(O)NH; 2,7-diazaspiro4.6 undecyl, 1.7-diazaspiro4.4nonyl, 2.6- wherein alkyl moieties above are optionally substituted with diZaospiro4.5 decyl. 2,6-diazaspiro4.6-undecyl, either one to two substituents independently selected from R. unsubstituted or substituted with an R substituent. In another subclass of this class, R is selected from: In yet another embodiment of the present invention, R is (1) hydrogen, selected from: 55 (2) halogen, (1) hydrogen, (3) Cls alkyl, and (2) halogen, (4) trifluoromethyl, (3) Cls alkyl, wherein alkyl moieties above are optionally substituted with (4) perfluoro Ce alkyl, 60 one to two substituents independently selected from R. (5) Calkenyl, In yet another subclass of this class, R is selected from: (6) C. alkynyl, (1) hydrogen, (7) cycloalkyl, (2) halogen, (8) cycloalkyl-C alkyl, (3) methyl, (9) cycloheteroalkyl, 65 (4) ethyl, (10) cycloheteroalkyl-C alkyl, (5) propyl, and (11) aryl, (6) trifluoromethyl, US 7,084, 156 B2 11 12 wherein alkyl moieties above are optionally substituted with (12) —NH2, one to two substituents independently selected from R: (13) - COR7, and In still another embodiment of the present invention, R (14) - C(O)NH: is selected from: wherein alkyl moieties above are optionally substituted with (1) hydrogen, one to four substituents independently selected from R', and (2) halogen, cycloalkyl, heterocycloalkyl, aryl and heteroaryl moieties (3) Cls alkyl, above are optionally substituted with an R substituent. (4) perfluoro Ce alkyl, In another subclass of this class of the invention, R is (5) Calkenyl, selected from: (6) C- alkynyl, 10 (1) hydrogen, (7) cycloalkyl, (2) Cls alkyl, (8) cycloalkyl-C alkyl, (3) trifluoromethyl, (9) cycloheteroalkyl, (4) cycloalkyl, (10) cycloheteroalkyl-C alkyl, (5) cycloheteroalkyl, (11) aryl, 15 (12) aryl-C alkyl, (6) aryl, (13) heteroaryl, (7) heteroaryl, (14) heteroaryl-C alkyl, (8) —NH2, (15) - OR7, (9) -COH, (16) NR'R'', (10) —COCH and (17) - COR7, and (11) —COCHCH: (18) C(O)NR'R''. wherein alkyl moieties above are optionally substituted with wherein alkyl, alkenyl and alkynyl, moieties above are one to two substituents independently selected from R', and optionally substituted with one to four substituents indepen cycloalkyl, heterocycloalkyl, aryl and heteroaryl moieties dently selected from R', and cycloalkyl, heterocycloalkyl, 25 above are optionally substituted with an R substituent. aryland heteroaryl moieties above are optionally substituted In yet another subclass of this class of the invention, R with one to four substituents independently selected from is selected from: R”; and wherein sulfur-containing heterocyclic rings may be (1) hydrogen, mono- or di-oxidized on the Sulfur atom. (2) methyl, In one class of this embodiment of the present invention, 30 (3) ethyl, R" is selected from: (4) propyl. (1) hydrogen, (5) trifluoromethyl, (2) halogen, (6) —COH, (3) Cls alkyl, (7) —COCH and (4) trifluoromethyl, 35 (8) - COCHCH: (5) Calkenyl, wherein alkyl moieties above are optionally substituted with (6) cycloalkyl, one to three substituents independently selected from R. (7) cycloalkyl-C alkyl, In still another subclass of this class of the invention, R (8) cycloheteroalkyl, is selected from: (9) cycloheteroalkyl-C alkyl, 40 (1) Hydrogen, (10) aryl, (2) methyl, (11) aryl-C alkyl, (3) ethyl, (12) heteroaryl, (4) —COH, and (13) heteroaryl-C alkyl, 45 (5) – COCH. (14) —OR7, In another embodiment of the present invention, R and (15) NR7R7, R together with the ring carbon atoms to which they are (16) - CO.R. and attached, form a 5- to 7-membered heterocycloalkyl or (17) C(O)NR'R''. cycloalkyl ring, either unsubstituted or substituted with one wherein alkyl and alkenyl moieties above are optionally 50 to four substituents independently selected from R. In one substituted with one to three substituents independently class of this embodiment of the present invention, Rand R' selected from R', and cycloalkyl, heterocycloalkyl, aryland together with the ring carbon atoms to which they are heteroaryl moieties above are optionally substituted with an attached, form a 5- to 7-membered heterocycloalkyl or R” substituent. cycloalkyl ring, either unsubstituted or substituted with an In one subclass of this class of the invention, R is 55 R substituent. In one subclass of this class, R and R' selected from: together with the ring carbon atoms to which they are (1) hydrogen, attached, form cyclohexyl ring, either unsubstituted or Sub (2) halogen, stituted with an R' substituent. In another subclass of this (3) Cls alkyl, class, R and R together with the ring carbon atoms to (4) trifluoromethyl, 60 which they are attached, form a cyclohexyl ring, either (5) cycloalkyl, unsubstituted or substituted with oxo or hydroxy. (6) cycloheteroalkyl, In one embodiment of the present invention, R is selected (7) aryl, from: (8) aryl-C alkyl, (1) hydrogen, (9) heteroaryl, 65 (2) halogen, (10) -OH, (3)C alkyl, (11) –OCH, (4) perfluoro Ce alkyl, US 7,084, 156 B2 13 14 (5) –OR", and (6)–(CH), NRC(O)R’, (6) NR7R7. (7)-(CH.)NR7C(O)(CH), SR 7 In one class of this embodiment of the present invention, (8) —(CH), NRC(O)N(R), R is selected from: (9) —(CH),NHSOR". (1) hydrogen, (10) —(CH), N(R), and (2) halogen, (11) -(CH)NR'SON(R), (3) methyl, wherein one or two of the hydrogen atoms in (CH), may be (4) trifluoromethyl, Substituted with R. (5) hydroxy, In one subclass of this class, R is selected from: (6) methoxy, 10 (1) R7, (7) phenoxy, (2)-heteroaryl-R7. (8) —NH, (9) - NH(CH), and (3) - CON(R)(CH), (10) - N(CH). (4) -CHCONHR'. In one class of this embodiment of the invention, R is 15 (5) - CHCON(R)(CH), selected from: (6) - CH-NHC(O)R’, (1) hydrogen, (2) halogen, (8) —(CH),NHC(O)(CH),SR", (3) methyl, (4) trifluoromethyl, (5) hydroxy, (11) -(CH),NHSOR", (6) methoxy, (12) - NH(R7), (7) phenoxy, (13) - N(COCH)(R7), (8) —NH, (14) —(CH),NH(R), and (9) - NH(CH), and 25 (15) -(CH)N(COCH)(R), (10) - N(CH). wherein one or two of the hydrogen atoms in (CH), may be In one subclass of this class, R is selected from: Substituted with R. (1) hydrogen, In yet another embodiment of the present invention, R7 is (2) halogen, independently selected at each occurrence from: (3) methyl, 30 (1) hydrogen, (4) trifluoromethyl, (2) C- alkyl, (5) hydroxy, and (3) aryl, (6) methoxy. (4) heteroaryl, In another subclass of this class, R is hydrogen. (5) cycloalkyl, In another embodiment of the present invention, R is 35 (6) heterocycloalkyl, selected from: (7) aryl C. alkyl, (1) —CH2), R. (8) heteroaryl C. alkyl, (2) -(CH2)-aryl-R". (9) cycloalkyl C. alkyl, (3) —(CH)-heteroaryl-R". (10) heterocycloalkyl C alkyl, (4) —(CH)-heterocycloalkyl-R7. 40 (11) aryl C- alkenyl, (5) —(CH2)C=N. (12) heteroaryl C- alkenyl, (6)–(CH),CON(R7)2, (13) cycloalkyl C- alkenyl, and (7) —(CH),CO.R. (14) heterocycloalkyl C- alkenyl, (8) —(CH),COR". (9)-(CH)NR7C(O)R7, 45 wherein the alkyl and alkenyl moieties are optionally sub (10) -(CH), NRC(O)(CH), SR 7 stituted with one to four substituents selected from R', and (11)–(CH)NR'COR7. wherein the aryl, heteroaryl, cycloalkyl and heterocy (12) —(CH), NRC(O)N(R), cloalkyl moieties are independently substituted with one to (13)-(CH.)NR'SOR7, four substituents selected from R', and wherein sulfur (14) —(CH),S(O).R. 50 containing heterocyclic rings may be mono- or di-oxidized (15) -(CH), SON(R), on the Sulfur atom. (16) -(CH), OR7, In one class of this embodiment of the invention, the alkyl (17) -(CH), OC(O)R’, and alkenyl moieties in R7 are optionally substituted with (18) —(CH)OC(O)CR7, one to three substituents selected from R', and wherein the (19) —(CH), OC(O)N(R), 55 aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties in R7 are independently substituted with one to three substitu (20) —(CH2)N(R), and ents selected from R”; and wherein sulfur-containing het (21) -(CH)NR'SON(R7), erocyclic rings may be mono- or di-oxidized on the Sulfur wherein one or two of the hydrogenatoms in (CH), may be atOm. Substituted with R". 60 In another class of this embodiment of the invention, R7 In one class of this embodiment of the present invention, is independently selected at each occurrence from: R is selected from: (1) hydrogen, (1) —(CH2), R. (2) C alkyl, (2) -(CH2)-aryl-R". (3) aryl, selected from: phenyl, naphthyl, indanyl, indenyl, (3) —(CH)-heteroaryl-R7. 65 indolyl, quinazolinyl, quinolinyl, benzthiazolyl, benzoX (4) —(CH)-heterocycloalkyl-R7. azolyl, dihydroindanyl, benzisodiazolyl, spirocyclohexy (5) –(CH),CON(R), lindolinyl, spiro-(dihydrobenzothiophenyl)piperidinyl, US 7,084, 156 B2 15 16 spiro-indolinylpiperidinyl, indolinyl, tetrahydroisoquino dihydroindanyl, benzisodiazolyl, Spirocyclohexylindoli linyl, isoindolinyl, benzothiadiazolyl, benzotriazolyl, 1,3- nyl, spiro-(dihydrobenzothiophenyl)piperidinyl, spiro-in dihydro-2-benzofuranyl, benzothiophenyl, benzodiox dolinylpiperidinyl, indolinyl, tetrahydroisoquinolinyl, olyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, isoindolinyl, benzothiadiazolyl, benzotriazolyl, 1,3-dihy dihydrobenzopyranyl, and 1,4-benzodioxanyl. dro-2-benzofuranyl, benzothiophenyl, benzodioxolyl, tet (4) heteroaryl, selected from: pyrrolyl, isoxazolyl, isothiaz rahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydroben olyl pyrazolyl pyridyl, oxazolyl, oxadiazolyl, thiadiaz Zopyranyl, and 1,4-benzodioxanyl, olyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, (12) heteroaryl C- alkenyl, wherein the heteroaryl moiety triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, ben is selected from: pyrrolyl, isoxazolyl, isothiazolyl pyra Zoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, 10 Zolyl pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiaz benzothiophenyl, furo2,3-bipyridyl, quinolyl, indolyl, olyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, isoquinolyl, quinazolinyl, benzisodiazolyl, triazolopyrim thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, idinyl, 5,6,7,8-tetrahydroquinolinyl, 2,1,3-benzothiadiaz benzothiazolyl, benzimidazolyl, benzofuranyl, ben olyl, and thienopyridinyl, Zothiophenyl, furo2,3-bipyridyl, quinolyl, indolyl, iso (5) cycloalkyl, selected from: cyclopropyl, cyclobutyl, 15 quinolyl, quinazolinyl, benzisodiazolyl, triazolopyrimidi cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, nyl, 5,6,7,8-tetrahydroquinolinyl, 2,13 decahydronaphthyl, indanyl, bicyclo2.2.2]octanyl, tet benzothiadiazolyl, and thienopyridinyl, rahydronaphthyl, and dihydroindanyl. (13) cycloalkyl C- alkenyl, wherein the cycloalkyl moiety (6) heterocycloalkyl, selected from: aZetidinyl, pyridyl, pyr is selected from: cyclopropyl, cyclobutyl, cyclopentyl, rolidinyl, piperidinyl, piperazinyl, imidazolidinyl, mor cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahy pholinyl, 1-thia-4-aza-cyclohexane, 2,5-diazabicyclo dronaphthyl, indanyl, bicyclo2.2.2]octanyl, tetrahy 2.2.2]octanyl, 2,3-dihydrofuroI2,3-bipyridyl, dronaphthyl, and dihydroindanyl, and benzoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinoli (14) heterocycloalkyl C- alkenyl, wherein the heterocy nyl, dihydroindolyl, indolyl, indolinyl, isoindolinyl, 1,3- cloalkyl moiety is selected from: aZetidinyl, pyridyl, dihydro-2-benzofuranyl, benzodioxolyl, hexahy 25 pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, drothienopyridinyl, thienopyridinyl, azacycloheptyl, 4.4- morpholinyl, 1-thia-4-aza-cyclohexane, 2,5-diazabicyclo spiro[2,3-dihydrobenzothiophen-33-ylpiperidinyl, and 2.2.2]octanyl, 2,3-dihydrofuroI2,3-bipyridyl, benzoxazi 4.4-spiro indoli-3.3-yl)piperidinyl, nyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihy (7) aryl C alkyl, wherein the aryl moiety is selected from: droindolyl, indolyl, indolinyl, isoindolinyl, 1,3-dihydro phenyl, naphthyl, indanyl, indenyl, indolyl, quinazolinyl, 30 2-benzofuranyl, benzodioxolyl, quinolinyl, benzthiazolyl, benzoxazolyl, dihydroindanyl, hexahydrothienopyridinyl, thienopyridinyl, azacyclohep benzisodiazolyl, spirocyclohexylindolinyl, spiro-(dihy tyl, 4.4-spiro2,3-dihydrobenzothiophen-3.3-ylpiperidi drobenzothiophenyl)piperidinyl, Spiro-indolinylpiperidi nyl, and 4.4-Spiro indoli-3.3-yl)piperidinyl: nyl, indolinyl, tetrahydroisoquinolinyl, isolindolinyl, ben Zothiadiazolyl, benzotriazolyl, 1,3-dihydro-2- 35 wherein the alkyl moieties are optionally substituted with benzofuranyl, benzothiophenyl, benzodioxolyl, one to three substituents selected from R', and wherein the tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihy aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties drobenzopyranyl, and 1,4-benzodioxanyl. are independently substituted with one to three substituents (8) heteroaryl C alkyl, wherein the heteroaryl moiety is selected from R', and wherein sulfur-containing heterocy Selected: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, 40 clic rings may be mono- or di-oxidized on the Sulfur atom. pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, In another embodiment of the present invention, R is imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, independently selected from: pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, ben (1) OR, Zothiazolyl, benzimidazolyl, benzofuranyl, benzothiophe (2) NRS(O), R, nyl, furo 2.3-bipyridyl, quinolyl, indolyl, isoquinolyl, 45 (3) —NO, quinazolinyl, benzisodiazolyl, triazolopyrimidinyl, 5.6.7. (4) halogen, 8-tetrahydroquinolinyl, 2,1,3-benzothiadiazolyl, and (5) –S(O).R", thienopyridinyl, (6) - SR", (9) cycloalkyl C alkyl, wherein the cycloalkyl moiety is (7) S(O),OR, Selected from: cyclopropyl, cyclobutyl, cyclopentyl, 50 cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahy (8) —S(O)N(R'), dronaphthyl, indanyl, bicyclo2.2.2]octanyl, tetrahy (9) - N(R), dronaphthyl, and dihydroindanyl. (10) - O(CRR)N(R), (10) heterocycloalkyl C alkyl, wherein the heterocy (11) - C(O)R’, cloalkyl moiety is selected from: aZetidinyl, pyridyl, 55 (12) -COR", pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, (13) CO,(CRR),CON(R), morpholinyl, 1-thia-4-aza-cyclohexane, 2,5-diazabicyclo (14) - OC(O)R’, 2.2.2]octanyl, 2,3-dihydrofuro 2,3-bipyridyl, benzoxazi (15) - CN, nyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihy (16) –C(O)N(R'), droindolyl, indolyl, indolinyl, isoindolinyl, 1,3-dihydro 60 2-benzofuranyl, benzodioxolyl, (17) NRC(O)R’, hexahydrothienopyridinyl, thienopyridinyl, azacyclohep (18) - OC(O)N(R), tyl, 4.4-spiro[2,3-dihydrobenzothiophen-3.3-yl)piperidi (19) NRC(O)OR, nyl, and 4.4-Spiro indoli-3.3-yl)piperidinyl, (20) - NRC(O)N(R), (11) aryl C- alkenyl, wherein the aryl moiety is selected 65 (21) CR(N OR), from: phenyl, naphthyl, indanyl, indenyl, indolyl, (22) —CF, quinazolinyl, quinolinyl, benzthiazolyl, benzoxazolyl, (23) cycloalkyl, US 7,084, 156 B2 17 18 (24) cycloheteroalkyl, and (5) heteroaryl, (25) oxo; (6) aryl, and at each occurrence. (7) aryl-Co alkyl; In one class of this embodiment of the present invention, wherein alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, het each R" is independently selected from: eroaryl, and aryl moieties in R* and R are optionally (1) OR, substituted with one to four substituents independently (2) - NHSOCH, selected from R. (3) —NO, (4) halogen, In yet another embodiment of the present invention, each 10 R is independently selected from: (5) —S(O)CH, (1) halogen, (6) —SCH, (7) –SCF, (2) amino, (8) S(O).OR, (3) carboxy, (9) —S(O)N(R'), (4) C. alkyl, (10) - N(CH), 15 (5) Calkoxy, (11) - NH (6) aryl, (12) - O(CRR)N(R), (7) aryl C alkyl, (13) - C(O)R’, (8) hydroxy, (14) —COH, (9) —CF, (15) - COCH, (16) t-butyloxycarbonyl, (10) —OC(O)C alkyl, (17) CO,(CRR),CON(R), (11) —OC(O)N(R), and (18) - OC(O)R’, (12) aryloxy. (19) - CN, In still another embodiment of the present invention, R (20) - C(O)N(R), 25 is independently selected from hydrogen, Ce alkyl, C (21) NRC(O)R, alkenyl: C. alkynyl, cycloalkyl, cycloalkyl-C alkyl; (22) OC(O)N(R), cycloheteroalkyl, cycloheteroalkyl-C alkyl, aryl; het (23) NRC(O)OR, eroaryl; aryl-C alkyl; and heteroaryl-C alkyl, wherein (24) - NRC(O)N(R), the alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, (25) CR(N OR), 30 heteroaryl, and aryl in Rare optionally substituted with one (26) —CF, to four substituents independently selected from R. In one (27) cycloalkyl, class of this embodiment of the present invention, the alkyl, (28) cycloheteroalkyl, and alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, heteroaryl, (29) oxo. and aryl in R are optionally substituted with one to two In another embodiment of the present invention, each R' 35 substituents independently selected from a R. is independently selected from: In another embodiment of the present invention, each R (1) R', is selected from halo, methyl, methoxy, trifluoromethyl, (2) —Sn(CH), trifluoromethoxy, and hydroxy. (3) Coalkyl, In still another embodiment of the present invention, each (4) Coalkenyl, 40 m is independently selected from 1 and 2. In one class of this (5) Clo alkynyl, embodiment, m is 1. In another class of this embodiment m (6) heteroaryl, is 2. (7) aryl, and In yet another embodiment of the present invention, n is (8) aryl-Co alkyl: 45 independently elected from 0, 1, 2, 3, 4, and 5 at each wherein alkyl, alkenyl, alkynyl, cycloalkyl, cyclohet occurrence. In one class of this embodiment, each n is eroalkyl, heteroaryl, and aryl are optionally substituted independently selected from 0, 1, 2, 3, and 4. In one subclass with one to four R substituents. of this class, n is selected from 0, 1, 2, and 3. In another In one class of this embodiment of the present invention, subclass of this class, n is selected from 0, 1, and 2. In still each R is independently selected from: 50 another Subclass of this class, n is 0. (1) R', In still another embodiment of the present invention, each (2) —Sn(CH), (3) Coalkyl, p is independently selected from 0, 1, and 2. In one class of (4) Coalkenyl, this embodiment, p is 0. In another class of this embodiment, (5) heteroaryl, p is 1. In still another class of this embodiment, p is 2. 55 As MCH-1R antagonists, the compounds of the present (6) aryl, and invention may be useful in treating the following conditions: (7) aryl-Co alkyl, obesity, diabetes, appetite and eating disorders, cardiovas wherein alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, het cular disease, hypertension, dyslipidemia, myocardial inf eroaryl, and aryl are optionally substituted with one to arction, gall stones, osteoarthritis, certain cancers, AIDS four Substituents selected from a group independently 60 wasting, cachexia, frailty (particularly in elderly), binge selected from R. eating disorders including bulimina, anorexia, mental dis In one subclass of this class, each R is independently orders including manic depression, depression, Schizophre selected from: nia, mood disorders, delirium, dementia, severe mental (1) R', retardation, anxiety, stress, cognitive disorders, sexual func (2) —Sn(CH), 65 tion, reproductive function, kidney function, diuresis, loco (3)C alkyl, motor disorders, attention deficit disorder (ADD), substance (4) C2-alkenyl, abuse disorders and dyskinesias including Parkinson's dis US 7,084, 156 B2 19 20 ease, Parkinson-like syndromes, Tourette's syndrome, Hun pyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tet tington's disease, epilepsy, improving memory function, and rahydronaphthyl, decahydronaphthyl, indanyl, bicyclo spinal muscular atrophy. 2.2.2]octanyl, tetrahydronaphthyl, dihydroindanyl, 3.3- The present invention is also concerned with treatment of spirohexylindoline, 5,6,7,8-tetrahydroquinoline, and the these conditions, and the use of compounds of the present like. invention for manufacture of a medicament useful in treating "Aryl means mono- or bicyclic aromatic rings containing these conditions. only carbon atoms. The term also includes aryl group fused The invention is also concerned with pharmaceutical to a monocyclic cycloalkyl or monocyclic heterocycloalkyl formulations comprising one of the compounds as an active group in which the point of attachment is on the aromatic ingredient. 10 portion. Examples of aryl include phenyl, naphthyl, indanyl. The invention is further concerned with processes for indenyl, indolyl, quinazolinyl, quinolinyl, benzthiazolyl, preparing the compounds of this invention. benzoxazolyl, dihydroindanyl, benzisodiazolyl, spirocyclo hexylindolinyl, spiro-(dihydrobenzothiophenyl)piperidinyl, DETAILED DESCRIPTION OF THE spiro-indolinylpiperidinyl, indolinyl, tetrahydroisoquinoli INVENTION 15 nyl, isoindolinyl, benzothiadiazolyl, benzotriazolyl, 1,3-di hydro-2-benzofuranyl, benzothiophenyl, benzodioxolyl, tet The compounds of this invention are represented by the rahydronaphthyl, 2,3-dihydrobenzofuranyl, compound of structural formula I: dihydrobenzopyranyl, 1,4-benzodioxanyl, and the like. “Heteroaryl' means a mono- or bicyclic aromatic ring containing at least one heteroatom selected from N, O and R4 S, with each ring containing 5- to 6 atoms. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyra R6 N N R3 Zolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, Y4 4. N1 R2 25 pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothia 5 Zolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo R 2,3-bipyridyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, benzisodiazolyl, triazolopyrimidinyl, 5,6,7,8-tetrahydro quinolinyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, and the and pharmaceutically acceptable salts thereof. 30 like. “Alkyl, as well as other groups having the prefix 'alk’, “Heterocycloalkyl” means mono- or bicyclic saturated Such as alkoxy, alkanoyl, means carbon chains which may be rings containing at least one heteroatom selected from N. S linear or branched or combinations thereof. Examples of and O, each of said ring having from 3 to 14 atoms in which alkyl groups include methyl, ethyl, n-propyl, isopropyl. the point of attachment may be carbon or nitrogen. The term n-butyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, n-pen 35 also refers to bridged rings, includes monocyclic hetero tyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dim cycles fused to an aryl or heteroaryl group in which the point ethylpropyl, 1,1-dimethylpropyl. 2.2-dimethylpropyl. of attachment is on the non-aromatic portion, and also n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, includes spirocyclic rings in which the point of attachment 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, is via a heterocyclic ring. Examples of "heterocycloalkyl 1,1-dimethyl butyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 40 include azetidinyl, pyridyl, pyrrolidinyl, piperidinyl, piper 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3.3-dimethyl butyl, azinyl, imidazolidinyl, morpholinyl, 1-thia-4-aza-cyclohex n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, ane, 2,5-diazabicyclo[2.2.2]octanyl, 2,3-dihydrofuro2,3-b 4-methylhexyl, 5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, pyridyl, benzoxazinyl, tetrahydroquinolinyl, 3-ethylpentyl, 4-ethylpentyl, 1-propylbutyl, 2-propylbutyl, tetrahydroisoquinolinyl, dihydroindolyl, indolyl, indolinyl, 3-propylbutyl, 1,1-dimethylpentyl, 1,2-dimethylpentyl, 1,3- 45 isoindolinyl, 1,3-dihydro-2-benzofuranyl, benzodioxolyl, dimethylpentyl, 1,4-dimethylpentyl, 2,2-dimethylpentyl, hexahydrothienopyridinyl, thienopyridinyl, azacycloheptyl, 2,3-dimethylpentyl. 2,4-dimethylpentyl, 3.3-dimethylpen 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1 tyl, 3,4-dimethylpenty1, 4,4-dimethylpentyl, 1-methyl-1- heptyl, 2-azabiclyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1.hep ethylbutyl, 1-methyl-2-ethylbutyl, 2-methyl-2-ethylbutyl, tyl, 2,4-dizaobicyclo2.2.2]octyl, 2-azabicyclo2.2.2]octyl, 1-ethyl-2-methylbutyl, 1-ethyl-3-methylbutyl, 1,1-diethyl 50 3-azabicyclo[3.2.2]nonyl, 2H-pyrrolyl, 4.4-spiro[2,3-dihy propyl. n-octyl, n-nonyl, and the like. drobenzothiophen-3.3-yl)piperidinyl, 4.4-spiro indoli-3.3- “Alkenyl' means carbon chains which contain at least one ylpiperidinyl, 2,7-diazaspiro4.4nonyl, 2.7-diazaspiro4.5 carbon-carbon double bond, and which may be linear or decyl. 2,7-diazaspiro4.6 undecyl, 1.7-diazaspiro4.4nonyl, branched or combinations thereof. Examples of alkenyl 55 2,6-dizaospiro4.5decyl. 2,6-diazaspiro4.6-undecyl and include vinyl, allyl, isopropenyl, pentenyl, hexenyl, hepte the like. The term also includes partially unsaturated mono nyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. cyclic rings that are not aromatic, such as 2- or 4-pyridones “Alkynyl' means carbon chains which contain at least one attached through the nitrogen or N-substituted-(1H.3H)- carbon-carbon triple bond, and which may be linear or pyrimidine-2,4-diones (N-substituted uracils). branched or combinations thereof. Examples of alkynyl 60 "Halogen includes , chlorine, bromine and include ethynyl, propargyll, 3-methyl-1-pentynyl, 2-heptynyl iodine. and the like. Compounds of Formula I contain one or more asymmetric “Cycloalkyl means mono- or bicyclic saturated carbocy centers and can thus occur as racemates and racemic mix clic rings, each of which having from 3 to 10 carbon atoms. tures, single enantiomers, diastereomeric mixtures and indi The term also includes monocyclic rings fused to an aryl 65 vidual diastereomers. The present invention is meant to group in which the point of attachment is on the non comprehend all Such isomeric forms of the compounds of aromatic portion. Examples of cycloalkyl include cyclopro Formula I. US 7,084, 156 B2 21 22 Some of the compounds described herein contain olefinic demia, myocardial infarction, gall stones, osteoarthritis, double bonds, and unless specified otherwise, are meant to certain cancers, AIDS wasting, cachexia, frailty (particularly include both E and Z geometric isomers. in elderly), binge eating disorders including bulimina, anor Some of the compounds described herein may exist with exia, mental disorders including manic depression, depres different points of attachment of hydrogen, referred to as Sion, Schizophrenia, mood disorders, delirium, dementia, tautomers. Such an example may be a ketone and its enol severe mental retardation, anxiety, stress, cognitive disor form known as keto-enol tautomers. The individual tau ders, sexual function, reproductive function, kidney func tomers as well as mixtures thereof are encompassed with tion, diuresis, locomotor disorders, attention deficit disorder compounds of Formula I. (ADD), Substance abuse disorders and dyskinesias including Compounds of the Formula I may be separated into 10 Parkinson's disease, Parkinson-like syndromes, Tourette's diastereoisomeric pairs of enantiomers by, for example, syndrome, Huntington's disease, epilepsy, improving fractional crystallization from a suitable solvent, for memory function, and spinal muscular atrophy. example MeOH or ethyl acetate or a mixture thereof. The The utilities of the present compounds in these diseases or pair of enantiomers thus obtained may be separated into disorders may be demonstrated in animal disease models individual stereoisomers by conventional means, for 15 that have been reported in the literature. The following are example by the use of an optically active amine as a examples of Such animal disease models: a) Suppression of resolving agent or on a chiral HPLC column. Alternatively, food intake and resultant in rats (Life Sciences any enantiomer of a compound of the general Formula I may 1998, 63, 113–117); b) reduction of Sweet food intake in be obtained by Stereospecific synthesis using optically pure marmosets (Behavioural Pharm. 1998, 9, 179–181); c) starting materials or reagents of known configuration. reduction of Sucrose and ethanol intake in mice (Psychop The term “pharmaceutically acceptable salts' refers to harm. 1997, 132, 104-106); d) increased motor activity and salts prepared from pharmaceutically acceptable non-toxic place conditioning in rats (Psychopharm. 1998, 135, bases or acids including inorganic or organic bases and 324–332: Psychopharmacol. 2000, 151: 25–30); e) sponta inorganic or organic acids. Salts derived from inorganic neous locomotor activity in mice (J. Pharm. Exp. Ther. 1996, bases include aluminum, ammonium, , copper, fer 25 277, 586–594). ric, ferrous, lithium, magnesium, manganic salts, manga The magnitude of prophylactic or therapeutic dose of a nous, potassium, Sodium, zinc, and the like. Particularly compound of Formula I will, of course, vary with the nature preferred are the ammonium, calcium, magnesium, potas of the severity of the condition to be treated and with the sium, and Sodium salts. Salts derived from pharmaceutically particular compound of Formula I and its route of admin acceptable organic non-toxic bases include salts of primary, 30 istration. It will also vary according to the age, weight and secondary, and tertiary amines, Substituted amines including response of the individual patient. In general, the daily dose naturally occurring substituted amines, cyclic amines, and range lie within the range of from about 0.001 mg to about basic ion exchange resins. Such as arginine, betaine, , 100 mg per kg body weight of a mammal, preferably 0.01 , N,N'-dibenzylethylenediamine, diethylamine, 2-di mg to about 50 mg per kg, and most preferably 0.1 to 10 mg ethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, 35 per kg, in single or divided doses. On the other hand, it may ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, be necessary to use dosages outside these limits in some glucamine, , histidine, hydrabamine, isopropy CaSCS. lamine, , methylglucamine, morpholine, , For use where a composition for intravenous administra , polyamine resins, procaine, purines, theobro tion is employed, a Suitable dosage range is from about mine, triethylamine, trimethylamine, tripropylamine, 40 0.001 mg to about 25 mg (preferably from 0.01 mg to about tromethamine, and the like. 1 mg) of a compound of Formula I per kg of body weight per When the compound of the present invention is basic, day and for cytoprotective use from about 0.1 mg to about salts may be prepared from pharmaceutically acceptable 100 mg (preferably from about 1 mg to about 100 mg and non-toxic acids, including inorganic and organic acids. Such more preferably from about 1 mg to about 10 mg) of a acids include acetic, benzenesulfonic, benzoic, camphorsul 45 compound of Formula I per kg of body weight per day. fonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, In the case where an oral composition is employed, a hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, Suitable dosage range is, e.g. from about 0.01 mg to about mandelic, methanesulfonic, mucic, nitric, pamoic, pan 100 mg of a compound of Formula I per day, preferably from tothenic, phosphoric, Succinic, Sulfuric, tartaric, p- about 0.1 mg to about 10 mg per day. For oral administra sulfonic acid, and the like. Particularly preferred are citric, 50 tion, the compositions are preferably provided in the form of hydrobromic, hydrochloric, maleic, phosphoric, Sulfuric, tablets containing from 0.01 to 1,000 mg, preferably 0.01, and tartaric acids. 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 40.0, It will be understood that, as used herein, references to the 50.0 or 1000.0 milligrams of the active ingredient for the compounds of Formula I are meant to also include the symptomatic adjustment of the dosage to the patient to be pharmaceutically acceptable salts. 55 treated. Compounds of this invention are antagonists of the MCH Another aspect of the present invention provides pharma receptor and as such are useful for the prevention and ceutical compositions which comprises a compound of treatment of disorders or diseases associated with the MCH Formula I and a pharmaceutically acceptable carrier. The receptor. Accordingly, another aspect of the present inven term “composition', as in pharmaceutical composition, is tion provides a method for the treatment (including preven 60 intended to encompass a product comprising the active tion, alleviation, amelioration or Suppression) of diseases or ingredient(s), and the inert ingredient(s) (pharmaceutically disorders or symptoms mediated by MCH receptor binding acceptable excipients) that make up the carrier, as well as and Subsequent cell activation, which comprises adminis any product which results, directly or indirectly, from com tering to a mammal an effective amount of a compound of bination, complexation or aggregation of any two or more of Formula I Such diseases, disorders, conditions or symptoms 65 the ingredients, or from dissociation of one or more of the are, for example, obesity, diabetes, appetite and eating ingredients, or from other types of reactions or interactions disorders, cardiovascular disease, hypertension, dyslipi of one or more of the ingredients. Accordingly, the pharma US 7,084, 156 B2 23 24 ceutical compositions of the present invention encompass In addition to the common dosage forms set out above, the any composition made by admixing a compound of Formula compounds of Formula I may also be administered by I, additional active ingredient(s), and pharmaceutically controlled release means and/or delivery devices such as acceptable excipients. those described in U.S. Pat. Nos. 3,845,770; 3,916,899; Any suitable route of administration may be employed for 3,536,809; 3,598,123; 3,630,200 and 4,008,719. providing a mammal, especially a human with an effective Pharmaceutical compositions of the present invention dosage of a compound of the present invention. For Suitable for oral administration may be presented as discrete example, oral, rectal, topical, parenteral, ocular, pulmonary, units such as capsules, cachets or tablets each containing a nasal, and the like may be employed. Dosage forms include predetermined amount of the active ingredient, as a powder tablets, troches, dispersions, Suspensions, Solutions, cap 10 Sules, creams, ointments, aerosols, and the like. or granules or as a solution or a suspension in an aqueous The pharmaceutical compositions of the present invention liquid, a non-aqueous liquid, an oil-in-water emulsion or a comprise a compound of Formula I as an active ingredient water-in-oil liquid emulsion. Such compositions may be or a pharmaceutically acceptable Salt thereof, and may also prepared by any of the methods of pharmacy but all methods contain a pharmaceutically acceptable carrier and optionally 15 include the step of bringing into association the active other therapeutic ingredients. The term “pharmaceutically ingredient with the carrier which constitutes one or more acceptable salts' refers to salts prepared from pharmaceu necessary ingredients. In general, the compositions are pre tically acceptable non-toxic bases or acids including inor pared by uniformly and intimately admixing the active ganic bases or acids and organic bases or acids. ingredient with liquid carriers or finely divided solid carriers The compositions include compositions Suitable for oral, or both, and then, if necessary, shaping the product into the rectal, topical, parenteral (including Subcutaneous, intra desired presentation. For example, a tablet may be prepared muscular, and intravenous), ocular (ophthalmic), pulmonary by compression or molding, optionally with one or more (aerosol inhalation), or nasal administration, although the accessory ingredients. Compressed tablets may be prepared most Suitable route in any given case will depend on the by compressing in a Suitable machine, the active ingredient nature and severity of the conditions being treated and on the 25 in a free-flowing form such as powder or granules, option nature of the active ingredient. They may be conveniently ally mixed with a binder, lubricant, inert diluent, surface presented in unit dosage form and prepared by any of the active or dispersing agent. Molded tablets may be made by methods well-known in the art of pharmacy. molding in a Suitable machine, a mixture of the powdered For administration by inhalation, the compounds of the compound moistened with an inert liquid diluent. Desirably, present invention are conveniently delivered in the form of 30 each tablet contains from about 1 mg to about 500 mg of the an aerosol spray presentation from pressurized packs or active ingredient and each cachet or capsule contains from nebulizers. The compounds may also be delivered as pow about 1 to about 500 mg of the active ingredient. ders which may be formulated and the powder composition The following are examples of representative pharmaceu may be inhaled with the aid of an insufflation powder inhaler 35 tical dosage forms for the compounds of Formula I: device. The preferred delivery systems for inhalation are metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or Solution of a compound of Formula I in suitable propellants, such as fluorocarbons or Injectable Suspension (I.M.) mg/mL hydrocarbons and dry powder inhalation (DPI) aerosol, 40 Compound of Formula I 10 which may be formulated as a dry powder of a compound of Methylcellulose S.O Formula I with or without additional excipients. Tween 80 O.S Benzyl 9.0 Suitable topical formulations of a compound of formula I Benzalkonium chloride 1.O include transdermal devices, aerosols, creams, ointments, Water for injection to a total volume of 1 mL lotions, dusting powders, and the like. 45 In practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharma ceutical compounding techniques. The carrier may take a Tablet mg tablet wide variety of forms depending on the form of preparation 50 Compound of Formula I 25 desired for administration, e.g., oral or parenteral (including Microcrystalline Cellulose 415 intravenous). In preparing the compositions for oral dosage Povidone 14.0 form, any of the usual pharmaceutical media may be Pregelatinized Starch 43.5 employed, such as, for example, water, glycols, oils, alco Magnesium Stearate 2.5 hols, flavoring agents, preservatives, coloring agents and the 55 like in the case of oral liquid preparations, such as, for 500 example, Suspensions, elixirs and solutions; or carriers such as starches, Sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral Solid preparations such as, for 60 example, powders, capsules and tablets, with the solid oral Capsule mg capsule preparations being preferred over the liquid preparations. Compound of Formula I 25 Because of their ease of administration, tablets and capsules Lactose Powder 573.5 represent the most advantageous oral dosage unit form in Magnesium Stearate 1.5 which case solid pharmaceutical carriers are obviously 65 600 employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. US 7,084, 156 B2 26 include: , fluvoxamine, paroxetine and Sertraline, and pharmaceutically acceptable salts thereof. The present invention also provides a method for the Aerosol Per canister treatment or prevention of obesity, which method comprises Compound of Formula I 24 mg administration to a patient in need of Such treatment an , NF Liq. Conc. 1.2 mg amount of a compound of the present invention and an Trichlorofluoromethane, NF 4.025 g amount of growth hormone secretagogues such as those Dichlorodifluoromethane, NF 12.15g disclosed and specifically described in U.S. Pat. No. 5,536, 716; agonists such as Melanotan II; B-3 ago Compounds of Formula I may be used in combination 10 nists Such as those disclosed and specifically described in with other drugs that are used in the treatment/prevention/ patent publications WO94/18161, WO95/29159, WO97/ Suppression or amelioration of the diseases or conditions for 46556, WO98/04526 and WO98/32753: 5HT-2 agonists: which compounds of Formula I are useful. Such other drugs orexin antagonists; melanin concentrating hormone antago may be administered, by a route and in an amount com nists; galanin antagonists; CCK agonists; GLP-1 agonists; monly used therefor, contemporaneously or sequentially 15 corticotropin-releasing hormone agonists; NPY-5 antago with a compound of Formula I. When a compound of nists: CB1 modulators, such as N-(1-piperidinyl)-5-(4-chlo Formula I is used contemporaneously with one or more rophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-car other drugs, a pharmaceutical composition containing Such boxamide (SR141716A), and those described in U.S. Pat. other drugs in addition to the compound of Formula I is No. 5,624,941 and U.S. Pat. No. 6,028,084, PCT Applica preferred. Accordingly, the pharmaceutical compositions of tion Nos. WO98/43636, WO98/31227, WO98/41519, the present invention include those that also contain one or WO98/37061, WO00/10967, WO00/10968, WO97/29079, more other active ingredients, in addition to a compound of WO99/02499 and WO98/43635, and EPO Application No. Formula I. It will be appreciated that for the treatment or EP-658546; and Y1 antagonists, such that together they give prevention of eating disorders, including obesity, bulimia effective relief. nervosa and compulsive eating disorders, a compound of the 25 As used herein “obesity refers to a condition whereby a present invention may be used in conjunction with other mammal has a Body Mass Index (BMI), which is calculated anorectic agents. as weight per height squared (kg/m), of at least 25.9. The present invention also provides a method for the Conventionally, those persons with normal weight, have a treatment or prevention of eating disorders, which method BMI of 19.9 to less than 25.9. comprises administration to a patient in need of Such treat 30 It will be appreciated that for the treatment or prevention ment an amount of a compound of the present invention and of obesity, the compounds of the present invention may also an amount of an anorectic agent, such that together they give be used in combination with histamine receptor-3 (H3) effective relief. modulators, CB1 cannabinoid receptor antagonists or Suitable anorectic agents of use in combination with a inverse agonists, and/or phosphodiesterase-3B (PDE3B) compound of the present invention include, but are not 35 inhibitors. limited to, , amphechloral, , benz The obesity described herein may be due to any cause, phetamine, , , , clomi whether genetic or environmental. Examples of disorders norex, clortemine, cyclexedrine, , dextro that may result in obesity or be the cause of obesity include amphetamine, diethylpropion, diphemethoxidine, overeating and bulimia, polycystic ovarian disease, cran N-ethylamphetamine, , , , 40 iopharyngioma, the Prader-Willi Syndrome. Frohlich's syn , , , furfurylmethylamphet drome, Type II diabetes, GH-deficient subjects, normal amine, levamfetamine, , , variant short stature, Turner's syndrome, and other patho , , , norpseu logical conditions showing reduced metabolic activity or a doephedrine, , , , decrease in resting energy expenditure as a percentage of , , and Sibutra 45 total fat-free mass, e.g., children with acute lymphoblastic mine; and pharmaceutically acceptable salts thereof. leukemia. A particularly Suitable class of anorectic agent are the “Treatment” (of obesity) refers to reducing the BMI of the halogenated amphetamine derivatives, including chlorphen mammal to less than about 25.9, and maintaining that weight termine, cloforex, , dexfenfluramine, fenflu for at least 6 months. The treatment suitably results in a ramine, picilorex and ; and pharmaceutically 50 reduction in food or calorie intake by the mammal. acceptable salts thereof. “Prevention' (of obesity) refers to preventing obesity Particularly preferred halogenated amphetamine deriva from occurring if the treatment is administered prior to the tives of use in combination with a compound of the present onset of the obese condition. Moreover, if treatment is invention include: fenfluramine and dexfenfluramine, and commenced in already obese subjects. Such treatment is pharmaceutically acceptable salts thereof. 55 expected to prevent, or to prevent the progression of the It will be appreciated that for the treatment or prevention medical sequelae of obesity, Such as, e.g., arteriosclerosis, of obesity, the compounds of the present invention may also Type II diabetes, polycystic ovarian disease, cardiovascular be used in combination with a selective reuptake diseases, osteoarthritis, dermatological disorders, hyperten inhibitor (SSRI). Sion, insulin resistance, hypercholesterolemia, hypertriglyc The present invention also provides a method for the 60 eridemia, and cholelithiasis. treatment or prevention of obesity, which method comprises Excessive weight is a contributing factor to different administration to a patient in need of Such treatment an diseases including hypertension, diabetes, dyslipidemias, amount of a compound of the present invention and an cardiovascular disease, gall stones, osteoarthritis and certain amount of an SSRI, such that together they give effective forms of cancers. Bringing about a weight loss can be used, relief. 65 for example, to reduce the likelihood of such diseases and as Suitable selective serotonin reuptake inhibitors of use in part of a treatment for Such diseases. Weight reduction can combination with a compound of the present invention be achieved by antagonizing MCH-1R receptor activity to US 7,084, 156 B2 27 28 obtain, for example, one or more of the following effects: 5,712,303, U.S. Pat. No. 5,968,944, U.S. Pat. No. 5,958,948, reducing appetite, increasing metabolic rate, reducing fat U.S. Pat. No. 6,103,900 and U.S. Pat. No. 6,005,109; the intake or reducing carbohydrate craving. tetrahydropteridine derivatives disclosed in U.S. Pat. No. Other compounds that may be combined with a com 6,083,948; the benzoperimidine carboxylic acid derivatives pound of Formula I, either administered separately or in the 5 disclosed in U.S. Pat. No. 5,861,398; the substituted 4-phe same pharmaceutical compositions, for the treatment of nylaminothiazol derivatives disclosed in U.S. Pat. No. diabetes and other sequelae of excessive weight include, but 5,880,135; the cyclic CRF analogs disclosed in U.S. Pat. No. are not limited to: 5,493,006, U.S. Pat. No. 5,663,292 and U.S. Pat. No. (a) insulin sensitizers including (i) PPARY agonists such 5,874.227; and the compounds disclosed in U.S. Pat. No. as the glitaZones (e.g. troglitaZone, pioglitaZone, englita- 10 5,063,245, U.S. Pat. No. 5,245,009, U.S. Pat. No. 5,510,458 Zone, MCC-555, BRL49653 and the like), and compounds and U.S. Pat. No. 5,109,111; as well as compounds disclosed in WO97/27857, 97/28115, 97/28137 and described in International Patent Specification Nos. WO 97/27847; (ii) biguanides such as and phen 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and formin; WO 94/13677. (b) insulin or insulin mimetics; 15 As used herein, the term "substance abuse disorders' (c) sulfonylureas, Such as tolbutamide and glipizide; includes substance dependence or abuse with or without (d) C-glucosidase inhibitors (such as acarbose), physiological dependence. The Substances associated with (e) cholesterol lowering agents such as (i) HMG-CoA reduc these disorders are: alcohol, (or amphet tase inhibitors (lovastatin, simvastatin, pravastatin, fluvas amine-like Substances), caffeine, cannabis, , halluci tatin, atorvastatin, and other statins), (ii) sequestrants nogens, inhalants, , opioids, (or phen (cholestyramine, colestipol and a dialkylaminoalkyl deriva cyclidine-like compounds), sedative-hypnotics or tives of a cross-linked dextran), (ii) nicotinyl alcohol nico benzodiazepines, and other (or unknown) Substances and tinic acid or a salt thereof, (iii) proliferator-activator receptor combinations of all of the above. a agonists such as fenofibric acid derivatives (gemfibrozil, In particular, the term “substance abuse disorders' clofibrate, fenofibrate and benzafibrate), (iv) inhibitors of 25 includes drug withdrawal disorders such as alcohol with cholesterol absorption for example beta-sitosterol and (acyl drawal with or without perceptual disturbances; alcohol CoA:cholesterol acyltransferase) inhibitors for example withdrawal delirium; amphetamine withdrawal; cocaine melinamide, (v) probucol, (vi) E, and (vii) thyro withdrawal; nicotine withdrawal; opioid withdrawal; seda mimetics; tive, hypnotic or anxiolytic withdrawal with or without (f) PPARö agonists, such as those disclosed in WO97/ 30 perceptual disturbances; sedative, hypnotic or anxiolytic 28149: withdrawal delirium; and withdrawal symptoms due to other (g) antiobesity compounds, such as fenfluramine, dexfen substances. It will be appreciated that reference to treatment fluramine, phentermine, Sibutramine, , or 3 adrener of nicotine withdrawal includes the treatment of symptoms gic receptor agonists; associated with Smoking cessation. 35 Other “substance abuse disorders' include substance (h) feeding behavior modifying agents, such as neuropep induced anxiety disorder with onset during withdrawal: tide Y antagonists (e.g. neuropeptide Y5) Such as those Substance-induced mood disorder with onset during with disclosed in WO 97/19682, WO 97/20820, WO 97/20821, drawal; and Substance-induced sleep disorder with onset WO 97/20822 and WO 97/20823; during withdrawal. (i) PPARC agonists such as described in WO 97/36579 by 40 Similarly, compound of Formula I, will be useful as a Glaxo: partial or complete Substitute for conventional pain relievers (1) PPARY antagonists as described in WO97/10813; in preparations wherein they are presently co-administered (k) serotonin reuptake inhibitors such as fluoxetine and with other agents or ingredients. Thus in further aspects, the Sertraline; invention encompasses pharmaceutical compositions for (1) growth hormone secretagogues such as MK-0677. 45 modulating the perception of pain comprising a non-toxic It will be appreciated that for the treatment or prevention therapeutically effective amount of the compound of For of stress, a compound of the present invention may be used mula I as defined above and one or more ingredients such as in conjunction with other anti-stress agents, such as anti another pain reliever including acetaminophen or phenace anxiety agents. Suitable classes of anti-anxiety agents tin, or a cyclooxygenase-2 (COX-2) inhibitor, a potentiator include benzodiazepines and 5-HT agonists or antago- 50 including caffeine; a including misoprostol, nists, especially 5-HT, partial agonists, and corticotropin enprostil, rioprostil, ornoprostol or rosaprostol: a diuretic; a releasing factor (CRF) antagonists. sedating or non-sedating . Examples of Suitable benzodiazepines include: alprazolam, chlordiaz cyclooxygenase-2 selective inhibitors include rofecoxib epoxide, clonazepam, chloraZepate, diazepam, halazepam, (VIOXX(R), see U.S. Pat. No. 5,474,995), etoricoxib (AR lorazepam, oxazepam and prazepam, and pharmaceutically 55 COXIATM see U.S. Pat. No. 5,861.419), celecoxib (CELE acceptable salts thereof. BREXR, see U.S. Pat. No. 5,466,823), Valdecoxib (see U.S. Suitable 5-HT, receptor agonists or antagonists include, Pat. No. 6,633,272), parecoxib (see U.S. Pat. No. 5,932, in particular, the 5-HT, receptor partial agonists , 598), COX-189 (Novartis), BMS347070 (Bristol Myers , and , and pharmaceutically Squibb), tiracoxib (JTE522, Japan Tobacco), ABT963 (Ab acceptable salts thereof. 60 bott), CS502 (Sankyo) and GW406381 (GlaxoSmithKline). Suitable CRF antagonists include the 4-tetrahydropy Other examples of cyclooxygenase-2 inhibitors compounds ridylpyrimidine derivatives disclosed in U.S. Pat. No. 6,187. are disclosed in U.S. Pat. No. 6,020,343. In addition the 781; the aryloxy and arylthio-fused pyridine and pyrimidine invention encompasses a method of treating pain compris derivatives disclosed in U.S. Pat. No. 6,124.300; the ary ing: administration to a patient in need of Such treatment a lamino-fused pyrimidine derivatives disclosed in U.S. Pat. 65 non-toxic therapeutically effective amount of the compound No. 6,107.300; the pyrazole and pyrazolopyrimidine deriva of Formula I, optionally co-administered with one or more tives disclosed in U.S. Pat. No. 5,705,646, U.S. Pat. No. of Such ingredients as listed immediately above. US 7,084, 156 B2 29 30 Suitable agents of use in combination with Suitable reversible inhibitors of monoamine oxidase a compound of the present invention for the treatment of include: moclobemide, and pharmaceutically acceptable Schizophrenia include the , , het salts thereof. erocyclic dibenzazepine, butyrophenone, diphenylbutylpip Suitable serotonin and noradrenaline reuptake inhibitors eridine and indolone classes of antipsychotic agent. Suitable 5 examples of include , of use in the present invention include: , and , , , , pharmaceutically acceptable salts thereof. and . Suitable examples of Suitable CRF antagonists include those described here include and thiothixene. Suit inabove able examples of dibenzazepines include and 10 Suitable atypical anti-depressants include: , . An example of a butyrophenone is . lithium, , and , and pharma An example of a diphenylbutylpiperidine is . An ceutically acceptable salts thereof. example of an indolone is molindolone. Other antipsychotic The neurokinin-1 may be peptidal or agents include , and . It will be non-peptidal in nature, however, the use of a non-peptidal appreciated that the antipsychotic agents when used in 15 neurokinin-1 receptor antagonist is preferred. In a preferred combination with a CB1 may be in the embodiment, the neurokinin-1 receptor antagonist is a CNS form of a pharmaceutically acceptable salt, for example, penetrant neurokinin-1 receptor antagonist. In addition, for chlorpromazine hydrochloride, mesoridazine besylate, thior convenience the use of an orally active neurokinin-1 recep idazine hydrochloride, acetophenazine maleate, fluiphena tor antagonist is preferred. To facilitate dosing, it is also Zine hydrochloride, flurphenazine enathate, fluiphenazine preferred that the neurokinin-1 receptor antagonist is a long decanoate, trifluoperazine hydrochloride, thiothixene hydro acting neurokinin-1 receptor antagonist. An especially pre chloride, , loxapine Succinate and ferred class of neurokinin-1 receptor antagonists of use in hydrochloride. Perphenazine, chlorprothixene, the present invention are those compounds which are orally clozapine, olanzapine, haloperidol, pimozide and risperi active and long acting. done are commonly used in a non-salt form. 25 Other classes of antipsychotic agent of use in combination Neurokinin-1 receptor antagonists of use in the present with a compound of the present invention include invention are fully described, for example, in U.S. Pat. Nos. receptor antagonists, especially D2, D3 and D4 dopamine 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, receptor antagonists, and muscarinic M1 receptor agonists. 5,459.270, 5,494,926, 5,496,833, 5,637,699: European An example of a D3 antagonist is the 30 Patent Publication Nos. EPO 360 390, O 394989, O428 434, compound PNU-99.194A. An example of a D4 dopamine 0.429 366, 0430 771, 0436 334,0443 132,0482 539, 0 receptor antagonist is PNU-101387. An example of a mus 498 069,0499313,0512901, 0 512 902, 0.514 273,0514 carinic M1 receptor agonist is Xanomeline. 274,0514275,0514276,0515 681 0517589,0520555, Another class of antipsychotic agent of use in combina 0.522 808, 0.528495, 0532 456, 0.533. 280,0536 817, 0 35 545 478, 0.558 156,0577 394,0585913,0590 152,0599 tion with a CB1 receptor modulator is the -HT, receptor 538, 0 610793,0634 402,0686 629,0693489, 0 694 535, antagonists, examples of which include MDL100907 and 0 699 655, 0699 674, 0 707 006, 0708 101, O 709375, 0 . Also of use in combination with a compound of 709 376, 0 714 891, 0 723 959, 0 733632 and 0 776893; the present invention are the serotonin dopamine antagonists PCT International Patent Publication Nos. WO 90/05525, (SDAs) which are believed to combine 5-HT, and dopam 40 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, ine receptor antagonist activity, examples of which include 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, olanzapine and Ziperasidone. 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, It will be appreciated that for the treatment of depression 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, or anxiety, a compound of the present invention may be used 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, in conjunction with other anti-depressant or anti-anxiety 45 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, agents. 94/O1402, 94/02461, 94/02595, 94/03429, 94/03445, Suitable classes of anti-depressant agents include norepi 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, nephrine reuptake inhibitors, selective serotonin reuptake 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, reversible inhibitors of monoamine oxidase (RIMAs), sero 50 94/19323, 94/20500, 94/26735, 94/26740, 94/293.09, tonin and noradrenaline reuptake inhibitors (SNRIs), corti 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, cotropin releasing factor (CRF) antagonists, C.-adrenorecep 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, tor antagonists neurokinin-1 antagonists and atypical anti 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, depressants. 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, Suitable reuptake inhibitors include ter 55 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, tiary amine tricyclics and secondary amine tricyclics. Suit 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, able examples of tertiary amine tricyclics include: amitrip 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, tyline, clornipramine, , and 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, , and pharmaceutically acceptable salts thereof. 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, Suitable examples of secondary amine tricyclics include: 60 97/14671, 97/17362, 97/18206, 97/19084, 97/19942, , , , and pro 97/21702, and 97/49710; and in British Patent Publication triptyline, and pharmaceutically acceptable salts thereof. Nos. 2266 529, 2268.931, 2269 170,2269 590,2271 774, Suitable selective serotonin reuptake inhibitors include 2 292 144, 2 293 168, 2 293 169, and 2 302 689. those described Supra. Specific neurokinin-1 receptor antagonists of use in the Suitable monoamine oxidase inhibitors include: isocar 65 present invention include: boxazid, phenelzine, and , and (+)-(2R3R,2S3S)-N-(2-cyclopropoxy-5-(trifluo pharmaceutically acceptable salts thereof. romethoxy)-phenyl)methyl)-2-phenylpiperidin-3-amine; US 7,084, 156 B2 31 32 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluo For the treatment of epilepsy, the compounds of the rophenyl)-4-(3-(5-oxo-1H4H-1,2,4-triazolo)methyl)mor present invention may be used together with anticonvulsants pholine; Such as penytoin, phenobarbital, primidone, carbamazepine, 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4- trimethadione, clonazepam, Valproate and ethoSuximide In (3-(5-oxo-1H4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-mor 5 one embodiment of a combination for the treatment of male pholine; or female sexual dysfunction, the second ingredient to be 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo combined with a compound of Formula I can be a type V 1H4H-1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine; cyclic-GMP-specific phosphodiesterase (PDE-V) inhibitor, 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- Such as and IC-351 or a pharmaceutically accept (S)-(4-fluorophenyl)-4-(3-(5-oxo-1H4H-1,2,4-triazolo)me 10 able salt thereof an alpha- receptor antagonist, thyl)morpholine; Such as and or a pharmaceutically 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4- acceptable salt thereof, or a dopamine receptor agonist, Such (5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl as or a pharmaceutically acceptable salt 3-(S)-phenylmorpholine: thereof. “Male sexual dysfunction' includes impotence, loss 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4- 15 of , and . “Erectile dysfunction' is (5-(N,N-dimethylamino)methyl-1,2,3-triazol-4-yl)methyl a disorder involving the failure of a male mammal to achieve 3-(S)-(4-fluorophenyl)morpholine; erection, ejaculation, or both. Symptoms of erectile dysfunc (3S,5R,6S)-3-2-cyclopropoxy-5-(trifluoromethoxy)phe tion include an inability to achieve or maintain an erection, nyl-6-phenyl-1-Oxa-7-aza-spiro4.5 decane; ejaculatory failure, , or inability to (3R,5R,6S)-3-2-cyclopropoxy-5-(trifluoromethoxy)phe achieve an orgasm. An increase in erectile dysfunction and nyl-6-phenyl-1-Oxa-7-aza-spiro4.5 decane; sexual dysfunction can have numerous underlying causes, 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxy including but not limited to (1) aging, (b) an underlying ethoxy)-3-(S)-(4-fluorophenyl)-4-(1,2,4-triazol-3-yl)meth physical dysfunction, Such as trauma, Surgery, and periph ylmorpholine; eral vascular disease, and (3) side-effects resulting from drug 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- 25 treatment, depression, and other CNS disorders. “Female (S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5-oxo-1H-1, sexual dysfunction' can be seen as resulting from multiple 2,4-triazolo)methyl)morpholine; components including dysfunction in desire, sexual arousal, 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- sexual receptivity, and orgasm related to disturbances in the (S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-1H-1, clitoris, vagina, periurethral glans, and other trigger points 2,4-triazolo)methyl)morpholine; 30 of sexual function. In particular, anatomic and functional 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- modification of Such trigger points may diminish the orgas (S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5-oxo-1H-1, mic potential in breast cancer and gynecologic cancer 2,4-triazolo)methyl)morpholine; patients. Treatment of female sexual dysfunction with an 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- MC-4 receptor agonist can result in improved blood flow, 35 improved lubrication, improved sensation, facilitation of (S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl-1H-1,2,4-tria reaching orgasm, reduction in the refractory period between Zolo)methyl)morpholine; orgasms, and improvements in arousal and desire. In a 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- broader sense, “female sexual dysfunction” also incorpo (S)-(4-fluorophenyl)-4-(3-(1-monophosphoryl-5-oxo-4H-1, rates sexual pain, premature labor, and dysmenorrhea. 2,4-triazolo)methyl)morpholine; 40 For the treatment of male and female sexual dysfunction, 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4- the compounds of the present invention may be employed in (4-N,N-dimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl) combination with a compound selected from a type V morpholine; cyclic-GMP-specific phosphodiesterase (PDE-V) inhibitor, or a pharmaceutically acceptable salt thereof. Such as sildenafil and IC-351 or a pharmaceutically accept 45 able salt thereof an alpha- antagonist, Suitable classes of anti-anxiety agents include benzodi Such as phentolamine and yohimbine or a pharmaceutically azepines and 5-HT agonists or antagonists, especially acceptable salt thereof, or a dopamine receptor agonist, Such 5-HT, partial agonists, and corticotropin releasing factor as apomorphine or a pharmaceutically acceptable salt (CRF) antagonists. thereof. Suitable benzodiazepines include those previously 50 MCH-1R antagonist compounds can be provided in kit. described herein. Such a kit typically contains an active compound in dosage Suitable receptor agonists or antagonists include, in par forms for administration. A dosage form contains a Sufficient ticular, those described Supra. amount of active compound Such that a beneficial effect can For the treatment of autism, the compounds of the present be obtained when administered to a patient during regular invention may be used in combination with butyrophenones. 55 intervals, such as 1 to 6 times a day, during the course of 1 For the treatment of Parkinson's disease and Parkinson or more days. Preferably, a kit contains instructions indicat like syndromes, the compounds of the present invention may ing the use of the dosage form for weight reduction (e.g., to be used in combination with levodopa, carbidopa/levodopa, treat obesity or overweight) or stress reduction, and the , bromocryptine and other ergot , anti amount of dosage form to be taken over a specified time cholinergic such as benztropine, trihex 60 period. yphenidyl, such as and The method of treatment of this invention comprises a orphenadrine, mild sedatives, tricyclic such method of treating melanin concentrating hormone receptor as amitriptiline and others described Supra, and propanolol. mediated diseases by administering to a patient in need of For the treatment of Huntingdon's Chorea, the com Such treatment a non-toxic therapeutically effective amount pounds of the present invention may be used in combination 65 of a compound of this invention that selectively antagonizes with phenothiazine, chlorpromazine, and butyrophenone the MCH receptor in preference to the other G-protein neuroleptics such as haloperidol or . coupled receptors. In particular, the present invention com US 7,084, 156 B2 33 34 prises a method of treating MCR-1R receptor subtype medi carbon in a protic solvent such as methanol or ethanol. In ated diseases by administering to a patient in need of Such cases where catalytic hydrogenation is contraindicated due treatment a non-toxic therapeutically effective amount of a to the presence of other potentially reactive functionalities, compound of this invention that selectively antagonizes the removal of CBZ groups can also be achieved by treatment MCH-1R receptor. The weight ratio of the compound of the Formula I to the with a solution of hydrogen bromide in acetic acid or by second active ingredient may be varied and will depend treatment with a mixture of trifluoroacetic acid (TFA) and upon the effective dose of each ingredient. Generally, an dimethylsulfide. Removal of BOC protecting groups is effective dose of each will be used. Thus, for example, when carried out with a strong acid, Such as trifluoroacetic acid, a compound of the Formula I is combined with a B-3 agonist 10 hydrochloric acid, or hydrogen chloride gas, in a solvent the weight ratio of the compound of the Formula I to the B-3 Such as methylene chloride, methanol, or ethyl acetate. agonist will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combina tions of a compound of the Formula I and other active Abbreviations Used in the Description of the ingredients will generally also be within the aforementioned 15 Preparation of the Compounds of the range, but in each case, an effective dose of each active Present Invention and Biological Assays: ingredient should be used. BOC (boc) -butyloxycarbonyl The compounds of Formula I of the present invention can BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium be prepared according to the procedures of the following hexafluorophosphate Schemes and Examples, using appropriate materials and are BSA Bovine serum albumin further exemplified by the following specific examples. Bu butyl calc. calculated Moreover, by utilizing the procedures described with the CBZ (Cbz) benzyloxycarbonyl disclosure contained herein, one of ordinary skill in the art DCC ,3-dicyclohexylcarbodiimide can readily prepare additional compounds of the present DIEA diisopropylethylamine invention claimed herein. The compounds illustrated in the 25 DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide examples are not, however, to be construed as forming the ECB buffer Extra cellular buffer: 140 nM NaCl, 20 nM KC1, 20 mM only genus that is considered as the invention. The Examples HEPES-NaOH pH 7.4, 5 mM glucose, 1 mM MgCl2, 1 mM further illustrate details for the preparation of the com CaCl2, 0.1 mg/mL BSA pounds of the present invention. Those skilled in the art will EDC -(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl 30 EDTA Ethylenediaminetetraacetic acid readily understand that known variations of the conditions eq. equivalent(s) and processes of the following preparative procedures can ES-MS electron spray ion-mass spectroscopy be used to prepare these compounds. The instant compounds E ethyl are generally isolated in the form of their pharmaceutically EtOAC ethyl acetate HEPES 4-(2-hydroxyethyl)piperazine-1-ethane Sulfonic acid acceptable salts, such as those described previously herein HOAC acetic acid above. The free amine bases corresponding to the isolated 35 HOBt 1-hydroxybenzotriazole hydrate salts can be generated by neutralization with a suitable base, HPLC high performance liquid chromatography Such as aqueous sodium hydrogen carbonate, sodium car l hour bonate, sodium hydroxide, and potassium hydroxide, and Me methyl MF molecular formula extraction of the liberated amine free base into an organic MS mass spectrum solvent followed by evaporation. The amine free base iso 40 MS methanesulfonyl lated in this manner can be further converted into another POCl, phosphorous oxychloride pharmaceutically acceptable salt by dissolution in an organic Ph phenyl solvent followed by addition of the appropriate acid and Pr propyl Subsequent evaporation, precipitation, or crystallization. All prep. preparative rt. room temperature temperatures are degrees Celsius unless otherwise noted. 45 TEA triethylamine Mass spectra (MS) were measured by electron-spray. TFA trifluoroacetic acid The phrase “standard peptide coupling reaction condi THF tetrahydrofuran tions' means coupling a carboxylic acid with an amine using TLC thin-layer chromatography. an acid activating agent such as 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide HCl (EDC), 1,3-dicyclohexylcarbodi 50 imide (DCC), and benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (BOP) in an inert General Preparation of Solvent such as dichloromethane in the presence of a catalyst N-2-(aminoquinolin-6-yl)carboxamide Compounds such as 4-dimethylaminopyridine (DMAP) or 1-hydroxy 8 benzotriazole hydrate (HOBT). The use of protecting groups 55 for the amine, carboxylic acid or other functionalities to facilitate the desired reaction and minimize undesired reac tions is well documented. Conditions required to remove Scheme A protecting groups are found in standard textbooks Such as R4 Greene, T. and Wuts, P. G. M., Protective Groups in Organic 60 R Synthesis, John Wiley & Sons, Inc., New York, N.Y., 1991. 21 3 aq. HNO3 Benzyloxycarbonyl (CBZ) and t-butyloxycarbonyl (BOC) --- aC. H2SO4 protecting groups are commonly used protecting groups in SAS organic synthesis, and conditions for their removal are N O Rs H known to those skilled in the art. For example, CBZ may be 65 removed by catalytic hydrogenation in the presence of a noble metal or its oxide such as palladium on activated US 7,084, 156 B2 36 These intermediates 2 may be converted to the substituted -continued quinoline intermediates 3, which possess a leaving group R4 Such as halogen, mesylate or triflate at the 2-position by a DDQ, variety of methods known to those skilled in the art. For ON R3 POCl3 --- example, treatment of 3,4-dihydroquinolin-2(1H)-ones 2 benzene For example, with phosphorous oxychloride and 2,3-dichloro-5,6-dicy S. S4 N O ano-1,4-benzoquinone in refluxing benzene provides the OCCRs H intermediate 3 with X=Cl. Heating intermediates 3 with a 2 variety of amine intermediates 4, neat or with excess amine 10 in an alcoholic solvent provides the 2-amino-6-nitroquino line intermediates 5. Alternatively, the 2-substituted-6-nit R4 RIn N1 R roquinoline intermediates 3 may be reacted with an amine or amine salt 4 in the presence of excess amine, a tertiary amine 4 15 base or inorganic base Such as Sodium bicarbonate to pro He vide the intermediates 5. If the amine reagent 4 is volatile the o R3 (XCESSH 44 n.4N O reaction may be performed in a sealed tube or other appa Rs in presence of base ratus known to those skilled in the art. The 6-nitroquinoline 3 intermediates 5 may be reduced to the substituted quinoline X = F, Cl, Br, l, 2,6-diamine intermediates 6 using a variety of methods OMs, OTf, etc. known to those skilled in the art. For example, the reduction may be achieved by catalytic hydrogenation in the presence of a noble metal or its oxide Such as palladium on activated carbon in a protic solvent Such as methanol or ethanol. 25 Alternatively, the nitro group may be reduced by a variety of R4 chemical methods known to those skilled in the art Such as, ON R3 catalytic iron (IEI) chloride hexahydrate with carbon and N N 6-nitro hydrazine system or tin (II) chloride-hydrate in an alcoholic group Solvent. Reaction of the quinoline-2,6-diamine intermedi A. 2 4. N -R2 Hessreduction 30 ates 6 with a variety of carboxylic acid chloride intermedi Rs ates 7 in acetic acid solvent or in an inert Solvent Such as 5 R methylene chloride in the presence of a tertiary amine base provides the desired compounds 8 of the present invention. Alternatively, the carboxamide compounds 8 may be pro 35 duced by reaction of 2.6-quinolin-2,6-diamine intermediates 6 and a variety of carboxylic acid intermediates 9 using standard peptide coupling conditions such as 1-(3-dimethy R4 laminopropyl)3-ethylcarbodiimide HCl (EDC) and 4-dim RCOCI HN R3 HOAc 40 ethylaminopyridine (DMAP) in an inert solvent such as methylene chloride. 2 R2 (7) Treatment of carboxylic acid intermediates 9 with oxalyl O)A-4N N1 R-CO2H,O chloride with a catalytic amount of N,N-dimethylformamide Rs EDC, DMAP (DMF) in an inert solvent such as methylene chloride under 6 R (9) 45 an inert atmosphere provides the corresponding acid chlo ride intermediates 7 (Scheme B). Similarly, treatment of the carboxylic acid intermediates 9 with thionyl chloride in toluene at reflux provides acid chloride intermediates 7. Carboxylic acid intermediates 9 are available from a wide Rs R4 50 range of commercial sources. Alternatively, carboxylic acid derivatives 9 may be prepared by a variety of methods S-1s-1 known to those skilled in the art such as, but not limited to, oxidation of other functional groups, carbonylation reac o Y-4S4 55 tions, Saponification of ester intermediates, or deprotection Rs of protected carboxylic acids. Homologated carboxylic acids 8 R may be prepared from carboxylic acids 9 by conversion to the corresponding carboxaldehyde intermediates (or directly from available carboxaldehydes) followed by homologation There are many known preparation of quinolines avail 60 utilizing stabilized Wittig or Horner-Emmons reagents to able to those skilled in the art. Scheme A illustrates the provide unsaturated acid or ester intermediates. These inter preparation of substituted quinolines utilized for the present mediates may be converted directly to carboxylic acid invention and follows closely to published procedures derivatives 9. Alternatively, the resulting olefin may be reported by Lee et al. Heterocycles 1998, 48 (12), pp functionalized or reduced to the saturated derivative by a 2637-2641. Treatment of substituted 3,4-dihydroquinolin-2 65 variety of conditions known to those skilled in the art such (1H)-ones 1, with aq. nitric acid in aq. Sulfuric acid provides as by catalytic hydrogenation in the presence of a noble the 6-nitro-3,4-dihydroquinolin-2(1H)-one intermediates 2. metal catalyst Such as palladium on carbon or platinum US 7,084, 156 B2 37 38 oxide. These saturated intermediates may in turn be con Treatment of quinolin-2,6-diamine intermediates 6 with verted to carboxylic acid derivatives 9. isocyanate intermediates 10 in an inert solvent provides the substituted N,N'-(2-aminoquinolin-6-yl)urea compounds 11. Alternatively, treatment of an amine intermediate 12 with Scheme B phosgene or equivalent reagent in the presence of a tertiary O O amine base such as triethylamine provides isocyanate or uls oxalylcatalytic chloride DMF carbamoyl chloride intermediates which in turn may be R OH O R C reacted with intermediates 6 to provide N,N'-(2-amino 7 SOCl. 8 10 quinolin-6-yl)urea compounds 11. Similarly, treatment of toluene reflux quinolin-2,6-diamine intermediates 6 with phosgene or equivalent reagent in the presence of a tertiary amine base Such triethylamine provides isocyanate or carbamoyl chlo ride intermediates, which in turn may be reacted with amine 15 homologation9. R9 R10 acidformation chloride intermediates 12 to provide N,N'-(2-aminoquinolin-6-yl) V / urea compounds 11. 1C OH R-1 in General Preparation of O 2-aminoquinolin-6-carboxamide and Related Derivatives

Amine intermediates 4 are available from commercial Sources or alternatively may be prepared from a variety of Scheme D intermediates known to those skilled in the art. For example, 25 amines may be prepared by those skilled in the art by R4 reduction of other functional groups such as carboxamides, R3 lactams, nitrites and nitro-containing compounds. Alterna 21 12, AgSO4 tively, amines may be prepared from compounds containing 30 leaving groups by reaction with amines, amine Surrogates Rs>S N O such as azides or carbamates followed by reduction or deprotection. Furthermore, primary amines may be reacted 1 with carboxaldehydes or carboxylic acids or derivatives R4 thereof followed by reduction with a variety of reagents such 35 R Pod-cat. as sodium cyanoborohydride, sodium borohydride, lithium 21 - 99 - ROH, TEA aluminium hydride or borane reagents to produce amine S/S DMF intermediates 4. Many other methods to produce amine N O intermediates are know in the literature and may be utilized Rs H by those skilled in the art for their preparation. 40 13 R4 General Preparation of N,N'-(2-aminoquinolin-6-yl)urea Compounds 11 ROC 21 R3 POCl, 45 Sa DDQ Her Sa. N O benzene Rs H reflux Scheme C 14 for example R8 R4 RNCO R4 Rin -R2 N HN R3 10 50 ROsC R3 H N1 N. g N1 N. 4 phosgene. --- 2 R phosgene, (XCESS A 4N N1 TEA A. 2 N 2 X O Rs In presence 5 l RRoNH of base (12) 55 6 15 R4 X = F, Cl, Br, l, OMs, OTf, etc. N N R3 R-1 r N1 N. 60 ROC O A-4N 2 N1 R N1 N. Rs Saponification R 4N4 1. -- orRs 11 65 16 US 7,084, 156 B2 39 40 General Preparation of Homologated -continued 2-aminoquinolin-6-carboxamide and Related R4 Derivatives RRoNH, HOC N1 N. R3 (12) 5 Scheme E. EDC, DMAP R4 A 2 4. * ROC N N R3 Homologation 17 R 10 A. 21 N2 N - R2 O R4 Rs R RN S-1s-1 16 R9 R10 R4 R9 4N4S-R A N r N N R3 1. PG removal 18 R 2. Amide O A. 2 2 -R2 formation Compounds of the present invention containing carboxa- 2O Rs N mides at the quinoline 6-position may be prepared as out- R lined in Scheme D. Reaction of 3,4-dihydroquinolinone intermediates 1 with iodine and silver sulfate affords the 19 6-iodo intermediates 13. Carbonylation of the iodide under R9 R10 R4 a variety of procedures known to those skilled in the art, 25 R8RN C N N R3 Such as use of a Pd-catalyst in the presence of carbon monoxide (CO) and an alcohol, provides the 2-oxo-1,2,3,4- O A. 2 2 -R2 tetrahydroquinoline-6-carboxylate ester intermediates 14. Rs N N 2-Chloroquinoline formation using procedures described above in Scheme A affords the 2-chloroquinoline-6-car- 30 Homologated carboxamide analogs may be prepard by boxylatey ester intermediates 15 (X=Cl). Displacementp reac- homologation o f the carboxylic acid intermediates 16 or tions of the 2-chloro group with amine intermediates 4 under other intermedates derived thereof using method known to those skilled in the art such as, but not limited to, the conditions described in Scheme A provides the 2-amino- Arndt-Eistert homologation, or by the sequence of conver quinoline-6-carboxylate intermediates 16. Hydrolysis or 35 sion of the acid to the alcohol, leaving group formation, Saponification of the carboxylate intermediates 16 under cyanide displacement followed by hydrolysis to the homolo acidic or basic conditions produces the carboxylic acid gated carboxylic acid intermediates 19. Similarly, the car intermediates 17. Similarly, removal of other carboxylate boxylic acid intermediates 16 may be converted to the protecting group not removed by hydrolysis or for interme- carboxaldehyde intermediate followed by Wittig or Homer diates containing other functional groups incompatible with " Emmons homologation and Subsequent functional group the above mentioned hydrolysis conditions may be achieved manipulation aS described earlier. These homologated car boxylic acid intermediates 19 may be converted by standard using conditions known to those skilled in the art. For peptide coupling techniques such as those described in example, tert-butyl esters may be cleaved by treatment with Scheme D, with a variety of amines to homologated car trifluoroacetic acid. Alternatively, benzyl esters may be 45 boxamide derivatives 20. Alternatively, the homologated cleaved by catalytic hydrogenation over a noble metal carboxylic acid intermediates 19 may be prepared from catalysts such as palladium on activated carbon. Treatment 3,4-dihydro-quinolin-2-one intermediates that possess a of the resulting carboxylic acid intermediates 17 with amine homologated carboxylic acid functional group using the intermediates 12 understandard peptide coupling conditions reaction sequence outlined in Scheme A. such as EDC and DMAP in an inert solvent such as General Preparation of 4-amino-6-heterocycle methylene chloride provides the desired quinoline-6-car- Substituted Quinoline Derivatives and Related boxamides 18. Analogs Scheme F eq. 1 Rio R4 O R. Rio R4 R7O "N-NC R3 1N1ul OH O. "N." O y- % -- — - ) - A4 4 -*. 5 EDC, DMAP R Rs R Heat R 19 22 Nile formation US 7,084, 156 B2 41 42 -continued eq. 2 R9 R10 R9 R10 R4

x R3 N Y4 R3 NC in N1 N 1. NH-OHHCI o1 Y- N1 N. NaHCO3, FN A-4N 2 N1 R He-aq. ROH A-4N 2 N1 R Rs 2. R-CO2H R Rs R EDC, DMAP R Heat 23 24

Quinoline derivatives containing heterocycle groups at Preparation of 6-substituted quinolin-2.6-diamine the 6-position in place a 6-carboxamide or related analogs 15 Derivatives may be prepared as outlined in Scheme F from 2-amino quinoline-6-carboxylic acid derivatives 19 or related homologs 1,2,4-Oxadiazolyl or related heterocyclic deriva tives are known to be useful replacements for carboxamide, Scheme G urea, Sulfonamide and other hydrogen bond donating func R4 tional groups. Removal of these hydrogen bonding groups R N R3 may change water Solubility, remove waters of hydration or N N reducing vary other physical chemical properties that may improve O R agent pharmacokinetic parameters such as oral absorption, oral 25 A-4N 2 N1 —- or metabolic disposition of these compounds. Rs These heterocycle substituted quinoline derivatives may R be prepared by a variety of methods known to those skilled 8 in the art. For example, treatment of quinolin-6-carboxylic 30 acid intermediates 19 with EDC and DMAP in the presence of an amidoxime derivative 21 followed by heating at reflux in an inert Solvent such 1,4-dioxane or 1,2-dimethoxyethane Rs R4 provides 6-(3-Substituted-1,2,4-oxadiazol-yl)guinolin-2- 35 amine derivatives 22. Similarly, homologated (2-amino Rin-N N N R3 quinolin-6-yl)carboxylic acid intermediates 19 provide the related homologated 6-(3-substituted-1,2,4-oxadiazol-5-yl A 21 N2 N -R2 Rs quinolin-2-amine analogs 22. Amidoxime intermediates 21 40 may be commercially available or may be prepared from R nitrile intermediates by treatment with hydroxylamine 25 hydrochloride in the presence of an inorganic base such as Sodium bicarbonate in an alcoholic solvent. 45 Isomeric (5-substituted-1,2,4-oxadiazol-3-yl)guinolin-2- amines 24 may be prepared in a similar fashion from R9 R10 R4 2-aminoquinoline-6-nitrile intermediates 23 or related R8RN C R3 homologs. 2-Aminoquinoline-6-nitrile intermediates 23 N N reducing O R agent may be prepared as outlined in Scheme A directly from 50 2 -- nitrile substituted 3,4-dihydroquinolin-2-one intermediates. A-4N N1 Alternatively, quinoline-6-carboxylic acid derivatives 19 Rs may be converted to quinoline-6-carboxamide derivatives as R described earlier followed by dehydration using a variety of 2O methods known to those skilled in the art. Reaction of the 55 nitrile intermediates 23 with hydroxylamine as described above affords the corresponding amidoxime intermediates. Coupling of the amidoxime intermediates with a carboxylic R9 R10 acid derivatives 7 in the presence of EDC and DMAP 60 Ren C R3 followed by heating in an inert solvent provides the isomeric R1 N N 6-(5-substituted-1,2,4-oxadiazol-3-yl)guinolin-2-amine analogs 24. Similarly, homologated 2-aminoquinolin-6-yl) A. 2 N 2 N - R2 carboxylic acid intermediates 19 may be converted to Rs homologated nitrile intermediates 23 then, by analogy, to 65 R related 6-(5-substituted-1,2,4-oxadiazol-3-yl)guinolin-4- 26 amine homologs 24. US 7,084, 156 B2 43 44

-continued -continued eq. 3 eq. 2 R9 R10 R4 R9 R10 R4 RO C R3 R C R N1 N 1. Curti N1 N. 3 US O R Rearrangement -- O A. 21 2 - R2 RRsNH A. 2 4. N1 2 2. PG removal R N N reducing agent Rs 5 R R 19 30 R8 R9 R10 R4 15 R1 N C N1 N1 N. R3 R9 R10 R4 H R R A. 21 N2 N - N2 R7 NN c N N R3 Rs R Rs 2 R2 A-4N N1 31 Rs R Similarly, quinoline diamine derivatives 28 may be con 27 verted to other quinoline-diamine derivatives 29 by reduc 25 tive amination with a carboxaldehyde or ketone derivative Preparation of further 6-substituted-quinolin-2,6-diamine (Scheme H, eq. 1) or by first, carboxamide formation, followed by reduction of the carboxamide intermediate to derivatives is outlined in Scheme G. Simple chemical reduc the quinoline diamine derivatives 29. Alternatively, (2-ami tion of the carboxamide group of N-(2-aminoquinolin-6-yl) noquinolin-6-yl) derived carboxaldehyde intermediates 30 carboxamide intermediates 8 (eq. 1) by a variety of reducing 30 (R = H, eq. 2) or related ketone intermediates 30 agents known to those skilled in the art, such as borane (R-alkyl, aryl, cycloalkyl, eq. 2) may be converted to derivatives or lithium aluminium hydride, affords the 6-sub quinoline diamine derivatives 31 by reductive amination stituted-quinolin-2,6-diamine derivatives 25 respectively. with a variety of amines under a variety of conditions known Alternatively, carboxylic acid intermediates 19 may be con 35 to those skilled in the art such as sodium cyanoborohydride verted to amine derivatives 25 by rearrangement reactions in the presence of a drying agent and acid buffer in an appropriate solvent such as methanol. (2-Aminoquinoline Such as the Curtius reaction or related rearrangement reac 6-carboxaldehyde intermediates 30 or related homologated tions known to those skilled in the art. Hydrolysis of amine intermediates may be prepared by a variety of methods intermediates or removal of protecting groups resulting from known to those skilled in the art. For example, oxidation of the rearrangement reaction products may provide the desired 40 related alcohol derivatives or reduction of carboxylic acid or diaminoquinoline derivatives 27. related carboxamide, ester or nitrile derivatives may provide the desired (2-aminoquinoline-6-carboxaldehyde intermedi ates 30 or related homologs. Similarly, (2-aminoquinolin-6- Scheme H 45 yl)ketone intermediates 30 or related homologs may be eq. 1 prepared from above intermediates by many methods known to those skilled in the art. Alternatively, quinoline carbox R9 R10 R4 aldehyde or ketone intermediates 30 may be reduced to the H c R3 corresponding alcohol intermediates, Subsequent leaving n N in N1 N. RCHO or 50 group formation then displacement with a suitable amine or R7COR11 Surrogate amine nucleophile. Further functional group R8 A. 2 4. -- reducing agent manipulation or protecting group removal may provide --- Rs O quinoline diamine derivatives 31. R 1. Amide formation 2. Reduction 28 55 Scheme I eq. 1 y R9 R10 R4 R9 R10 R4 C R3 -2N1 is N1 N. 60 H n N e N N R3 H various Rs 2 R2 R8 A. 21 2 -R2 electrophilic A-4N N1 R N N reagents Rs 5 He R 65 R 29 32 US 7,084, 156 B2 45 46 (3.5g, 15.6 mmol) in 50 mL benzene was added dropwise -continued by addition funnel to phosphorous oxychloride (7.1 mL, 78 R9 R10 R4 mmol). The resulting reaction mixture was heated at reflux C R for 5 hat which time it was cooled in an ice bath. To the 's N N 3 cooled mixture was carefully added water (50 mL). The resulting mixture was neutralized with 5N aq. Sodium Rs 2 2 -R2 hydroxide (-60 mL) then filtered. The filtrate was extracted x-r with ether (3x200 mL). The ether extracts were combined, R 10 dried over sodium sulfate, filtered and the solvent removed 33 under vacuum to afford the product, MS: m/z. 208 (MH), which was used directly in the next step. Further derivatives of quinoline diamine intermediates 32 Step C: Preparation of 6-nitro-2-piperidin-1-ylquinoline may be prepared by reaction of the amine with a variety of electrophiles such as carboxylic acids or their acid chlorides, isocyanates, carbamoyl chlorides, ketenes, chloroformates, The product (208 mg, 1.0 mmol) from Step B and sulfonic acids or their sulfonyl chloride to provide further piperidine (0.5 mL, 5 mmol) were mixed in absolute ethanol derivatives of the present invention of the general structure (3 mL) and then heated at reflux for 4 h. The reaction 33 (Scheme I). mixture was cooled to r.t., and the solvent removed under The following Examples are provided to illustrate the vacuum. The solids were taken up in EtOAc (125 mL). The invention and are not to be construed as limiting the scope mixture was transferred to a separatory funnel and washed of the invention in any manner. with water (3x15 mL). The organic layer was dried over sodium sulfate, filtered and the solvent removed under EXAMPLE 1. 25 vacuum to afford the product as a yellow solid, MS: m/z 258 (MH) which was used without further purification. Step D: Preparation of 2-piperidin-1-ylquinolin-6-amine C The product (204 mg. 0.8 mmol) of Step C and palladium a N hydroxide on carbon (100 mg) was Suspended in methanol. The resulting mixture was degassed then stirred under O 2 N N hydrogen atmosphere (balloon) until all the yellow solids 35 had dissolved. The reaction mixture was filtered through filter aid and the solvent removed under vacuum to afford the product as a brown solid, MS: m/Z 228 (MH), which was used without further purification

(2E)-3-(4-chlorophenyl)-N-2-(piperidin-1-yl)guino 40 Step E: Preparation of (2E)-3-(4-chlorophenyl)prop-2-enoyl lin-6-yl)-prop-2-enamide hydrochloride chloride

Step A: Preparation of 6-nitro-3,4-dihydrogiuinolin-2(1H)- To a solution of (2E)-3-(4-chlorophenyl)prop-2-enoic O acid (2.0 g, 11 mmol) in 50 mL methylene chloride was 45 added oxalyl chloride (1.05 mL, 12.1 mmol) and N.N- In a 500 mL round bottom flask equipped with a stir bar was placed 3,4-dihydroquinolin-2(1H)-one (5 g, 34 mol). To dimethylformamide (0.05 mL, 0.6 mmol). The resulting the Solid was added with stirring, concentrated Sulfuric acid mixture was stirred at r,t. for 6 h. The solvent was removed (100 mL). After complete dissolution of the solids, the under vacuum. The resulting solid was diluted with hexanes reaction mixture was cooled in an ice/methanol bath. To the 50 and the Solvent removed under vacuum to provide an resulting solution was added water (25 mL) followed by off-white solid which was used without further purification. dropwise addition by addition funnel of 61% aq. nitric acid (4.6 mL, 34 mmol; 2.1 mL 70% nitric acid diluted with 2.5 Step F: Preparation of (2E)-3-(4-chlorophenyl)-N-(2-piperi mL water). The resulting deep red reaction mixture was din-1-ylquinolin-6-yl)prop-2-enamide hydrochloride stirred for 0.25 h with cooling in the ice/methanol bath. The 55 reaction mixture was carefully poured onto ice (250 g) with To a solution of the product of Step D (91 mg, 0.4 mmol) stirring and external cooling. After the ice melted, the in 2 mL HOAc was added the product of Step E (64 mg. 0.32 resulting solids were filtered, washed with excess water mmol). The resulting mixture was stirred at r.t. for 3 h then (2x25 mL) followed by ether (2x25 mL). Resulting solids 60 diluted with 3 mL ether. The resulting mixture was filtered were air dried to provide the product as an off-white solid, and the resulting solids were washed with ether. The solids MS: m/z 193 (MH"), which was used without further were dried under vacuum to afford the product, MS: m/z 392 purification in the Subsequent reaction. (MH), as an off-white solid. Using the appropriate starting Step B: Preparation of 2-chloro-6-nitroquinoline materials and following procedures similar to those 65 described above for Example 1, the following compounds To a mixture of the crude product (3.0 g, 15.6 mmol) from were prepared from the corresponding quinoline-2,6-di Step A, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone amine intermediates: US 7,084, 156 B2 47 48

R. N N

O 2 N R

Parent Ion Ex. ii R = NR, R (MH)m/z o 426 352

386

352

386

C 366

400

10 C O 366 11 FC O 452 12 C O 418 US 7,084, 156 B2 50

-continued R. N. N

CON R

Parent Ion Ex. ii R = NR, R2 (MH)m/z

13 404 O N al

14 F3 C 438 O N l 15 N 394 O OO 16 F C N 428 3 N

O

17 440 F3 C N1a h CF

18 N O 407 N O CrN H 19 441 F3 C N O NCr

F3 C N 440

C DO 21 N

O C DO 22 426 F3 C N O

23 F3 C N 471 M-56 O O CH3 SkCH O CH3

US 7,084, 156 B2 54

-continued R. N N

O 2 N R

Parent Ion Ex. ii R = NR, R2 (MH")m/z 35 442

36 FC 412

37 FC 398

38 440

39 400

40 FC 466

41 468

42 438

43 442

44 FC 490

45 428

US 7,084, 156 B2 58

-continued

R N

O 2 N R

Parent Ion Ex. ii (MH")m/z

57 CH 416

> lchCH3 3 H

58 FC 414

59 FC 418

60 FC 400

61 430

62 436

63 428

64 416

65 CH3 416 N CH

66 FC 360

US 7,084, 156 B2 64

-continued R. N. N

CON R

Parent Ion Ex. ii (MH)m/z

87 FC CH3 430

88 430

89 418

90 N CH

91 416

92 430

93 FC 464

94 FC 478

95 FC 492

96 FC 442 US 7,084, 156 B2 65 66

-continued

Parent Ion Ex. ii (MH)m/z 97 Clus Oro 518 98 428

CH3 99 FC CH 474 N N O CH CH O

1OO N CH 430

CH3 CH3

101 FC CH3 444 > CH3 CH 102 CH3 431 N CH

CH

103 416 N NS. 1Net, 104 444 N N 1N1 CH s 105 FC 456 > CH3

106 470

N N

CH US 7,084, 156 B2 67 68

-continued R. N N

O 2 N R

Parent Ion Ex. ii (MH)m/z

107 FC 450

CH3

108 FC CH 416

NN CH CH

109 458 N OH

110 FC 432

111 FC

112 FC 417

N CH

113 414

N CH3

114 C 380 O N CH

115 F3 C 479

116 FC 479

CH3 2 US 7,084, 156 B2

-continued

R N

O OlN R

Parent Ion Ex. ii R7 R = NR, R2 (MH)m/z 117 FC CH 474 NN O CH CH3 H O 118 FC O 488

S-X-M H HC CH

EXAMPLE 119 Step C: Preparation of tert-butyl 3-6-(trifluoromethyl)pyri 25 din-3-ylprop-2-enoate To a solution of 6-(trifluoromethyl)pyridin-3-yl)metha nol (9.6 g. 54 mmol) in methylene chloride (200 mL) under nitrogen atmosphere was added ten-butyl (triphenylphos F3CN4 phoranylidene)acetate (24.6 g. 65 mmol) and MnO (47.3 g, 30 N 544 mmol). The resulting mixture was stirred at r,t. for 24 h. then filtered through a pad of silica gel. The pad was eluted / with hexanes/EtOAc (7:1) and the solvent removed under S. O CO% N vacuum to afford the product as a white solid, MS: m/z, 274 (MH). 35 N-2-(2-azabicyclo[2.2.2]oct-2-yl)cquinolin-6-yl)-3- Step D: Preparation of tert-butyl 3-6-(trifluoromethyl)py 6-(trifluoromethyl)pyridin-3-yl)propanamide ridin-3-ylpropanoate The product of Step C (2.2 g, 8.1 mmol) in 40 mL methanol and 5% palladium on carbon (0.25 g) was stirred Step A: Preparation of 2-(2-azabicyclo[2.2.2]oct-2-yl)-6- 40 under hydrogen atmosphere (balloon) for 1 h. The reaction nitroquinoline mixture was filtered through filter aid and the solvent A mixture of 2-chloro-6-nitroquinoline (5.0 g, 24 mmol. removed under vacuum to afford the product as a solid, MS: Example 1, Step B), 2-azabicyclo2.2.2]octane p-toluene m/z 276 (MH"). sulfonic acid salt (10.2g, 36 mmol) and sodium bicarbonate Step E: Preparation of 3-6-(trifluoromethyl)pyridin-3-yl (5.1 g, 60 mmol) were mixed in absolute ethanol (100 mL) 45 and then heated at reflux for 24 h. The reaction mixture was propanoic acid: To a solution of the product Step D (580 mg, 2.1 mmol) cooled to r,t., and the solvent removed under vacuum. The in 2 mL methylene chloride was added anisole (2 drops) and solids were taken up in EtOAc (750 mL). The mixture was trifluoroacetic acid (1 mL). The mixture was heated at 40° transferred to a separatory funnel washed with water (3x100 C. for several hours and the solvent removed under vacuum. mL) then brine (100 mL). The organic layer was dried over 50 sodium sulfate, filtered and the solvent removed under The resulting oil was dried in a vacuum oven at 40° C. vacuum to afford the product as a yellow solid, MS: m/z 284 overnight to afford the product as a semi-solid, MS: m/z 220 (MH) which was used without further purification. (MH"). Step B: Preparation of 2-(2-azabicyclo[2.2.2]oct-2-yl) Step F: Preparation of N-2-(2-azabicyclo[2.2.2]oct-2-yl) quinolin-6-amine 55 quinolin-6-yl)-3-6-(trifluoromethyl)pyridin-3-ylpropana The product of Step A and palladium hydroxide on carbon mide (1.3 g 20% by wt) was suspended in methanol (100 mL) and To a solution of the product of Step B (307 mg, 1.2 ethyl acetate (100 mL). The resulting mixture was degassed mmol), the product of Step E (404 mg, 1.2 mmol) and then stirred under hydrogen atmosphere (balloon) for 6 h. triethylamine (0.17 mL, 1.2 mmol) in 10 mL methylene The reaction mixture was filtered through filter aid and the 60 chloride was added 4-dimethylaminopyridine (222 mg, 1.8 Solvent removed under vacuum. The resulting oil was dis mmol) followed by 1-(3-dimethylaminopropyl)3-ethylcar solved in ethyl acetate and the solvent removed under bodiimide HCl (349 mg, 1.82 mmol). The resulting mixture vacuum. The resulting oil was suspended in ether and was stirred at r.t. for 3 days. The solvent was removed under triturated until crystallization occurred. The solids were vacuum and residue was purified by preparative thin layer filtered and washed with ice-cold ether then dried under 65 chromatography eluting with hexane/ethyl acetate/triethy vacuum to afford the product as a brown solid, MS: m/z 254 lamine (1:7:0.1) to afford the product, MS: m/z 455 (MH"), (MH), which was used without further purification as an off-white solid. US 7,084, 156 B2 71 72 Using the appropriate starting materials and following procedures similar to those described above for Example 119 or Example 1, the following compounds were prepared:

R N

O 2 N R

Parent Ion Ex. ii R7 R = NR, R2 (MH") m/z

120 O 442 H3CN O 4, 21

121 O 444 H3C O Out N /4,

122 466 Co. N 4. 123 FC OcOc N 4, 502 124 Clus 454 N

125 FC 441

H O N N /4. , 126 "Olus 412 21 N N4, 127 FC Or 4, 440 US 7,084, 156 B2 73 74

-continued

H s / O

Parent Ion (MH) m/z 386

414

414

131 427

132 414

133 400 N.A

134 452

135 CF 452

136 479

137 HC1 416 US 7,084, 156 B2

-continued

R 7 N

O 2 N R

Parent Ion Ex. ii R7 R = NR, R2 (MH") m/z 138 CH3 429 - N /

139 CH3 430 c1 21 N /

140 415 HC 21 Nan N / N

141 O 464

N / 142 C 456 N 21

143 NN 424 KCN N /

144 C 432

N /

145 444 --> N / 146 O 454

N / US 7,084, 156 B2 77

-continued

R 7 N

N R

Parent Ion Ex. ii R7 R = NR, R2 (MH) m/z 147 443

S

N--> 4, 148 O 441 N O 4,

149 S 430 HC1 O21 n 4 150 H3C 456 N N- N Ol 4,

151 / 424 O 4,

152 445

O

N e s1\ 4,

153 446 u0)X-ra 4, 154 S 425

ic-Ce 1N 45 155 HC 404 N 4, US 7,084, 156 B2 79 80

-continued

H s N O 2 N R

Parent Ion Ex. ii R7 R = NR, R2 (MH) m/z 1S6 s 390 N1 N n1N / N

157 ON 389 HC * \ 2 N / N

158 Hics/ 450

N / O- N/

159 429

160 HCN4O 1NH3 426 OM N CH3 CH3

161 CH3 40S

N CH3 N --> CH

EXAMPLE 162 Step A: Preparation of N-2-(2-azabicyclo[2.2.2]oct-2-yl) quinolin-6-yl)-N'-[4-(methylthio)phenylurea To a solution of 2-(2-azabicyclo[2.2.2]oct-2-yl)guinolin 6-amine (21 mg 0.08 mmol. Example 119, Step B), triethy H H lamine (0.013 mL, 0.09 mmol) in 1 mL methylene chloride N r N n was added 4-(methylthio)phenylisocyanate (15 mg, 0.09 O /1 60 mmol). The resulting mixture was stirred at r.t. for 2 h. The HCN, % N Solvent was removed under vacuum and the residue was purified by preparative thin layer chromatography eluting with hexane/ethyl acetate (1:1) to afford the product, MS: m/z. 419 (MH), as an off-white solid. 65. Using the appropriate starting materials and following N-2-(2-azabicyclo[2.2.2]oct-2-yl)cquinolin-6-yl)-N'- procedures similar to those described above for Example 4-(methylthio)phenylurea 162, the following compounds were prepared:

US 7,084, 156 B2 83

-continued R. N N

ON R

Parent Ion Ex. ii R7 (MH) m/z

172 373 N N /

173 441 N / FC N

174 442 21 N

Sa / FC N N

175 388 N

N / HN

176 403 N H3C No N

177 435 N HC / i N O

178 451 N V N / HC1 S\

179 455

N /

18O 421

N /

US 7,084, 156 B2 87

-continued

R

O 2 OlN R

Parent Ion Ex. ii R7 R = NR,R, (MH) m/z

189 449 O-O-, N44, 190 H 387 NS N.4 HC N

191 H 413 Crs n 44,

H 192 OrrN 456 FC N N / N

193 H 415 Nan H3C N / N

O

194 H 424 21 N N Sa N.4 N N

195 H 417 NS HC N / N

OH

196 H 374 21 N N NS n 4f >

197 415 UC n 44,

US 7,084, 156 B2 91

-continued

R 7 N

O OlN R

Parent Ion Ex. ii R7 R = NR, R2 (MH") m/z

HC N N / N N

208 398

O N N / NC

209 416

HC3 O N N / N

CH

210 CH 4O1

N / N HC Ors 211 455 V

212 1. 427

N /

213 427

214 430

1. N / 215 N 391 N /

US 7,084, 156 B2 95 96

-continued

H s / O

Parent Ion Ex. ii (MH) m/z 225 40S

226 443

227 428

228

CH3

229 389

230 417

231 470

232 486

233 443

US 7,084, 156 B2 103 104

-continued R. N N

ON R

Parent Ion Ex. ii R7 (MH) m/z

262 430 S N N / {ON 263 H 415

264 456

N /

O . 461 N ? / N N ( \

266 H 439 o NS FC N O N /

267 H 430 He-KS NN N N

268 430 N N / (S N

269 400 N N ( / N H N

270 416 / N N S 2 N /

US 7,084, 156 B2 107 108

-continued

R 7 N

O 2 N R

Parent Ion Ex. ii R7 R = NR, R2 (MH) m/z 28O H3C 440 / N HC N N M H3C

281 O 464

EXAMPLE 282 30 chloroform, the extracts were combined, dried, filtered and the solvent removed under vacuum to afford the product, MS: m/Z 224 (MH"), which was used directly in the next step. C 35 CH Step B: Preparation of N-ethyl-3-methyl-6-nitroquinolin-2- amine

O 2 The product (1 g, 4.5 mmol) from Step A and a solution N N1ch, of 2N ethylamine in methanol (5 mL, 25 mmol) were used 40 to prepare the product according to the procedure of Example 1, Step C.

(2E)-3-(4-Chlorophenyl)-N-2-(ethylamino)-3-meth Step C. Preparation of N-ethyl-3-methylquinoline-2,6-di ylquinolin-6-ylprop-2-enamide hydrochloride 45 amine The product (0.8 g) of Step B and platinum oxide on carbon (~80 mg) was suspended in methanol. The resulting mixture was hydrogenated at 50 PSI for 1 h. The reaction Step A: Preparation of 2-chloro-3-methyl-6-nitroquinoline mixture was filtered through filter aid and the solvent 50 removed under vacuum to afford the product, which was To a solution of 4-nitroaniline (10 g, 72 mmol) in chlo used without further purification. roform at 0° was added propionyl chloride (7 mL, 80 mol) followed by triethylamine (11.1 mL). The resulting solution Step D: Preparation of (2E)-3-(4-Chlorophenyl)-N-2-(ethy was stirred for 2 hat r,t. at which time the reaction mixture 55 lamino)-3-methylduinolin-6-ylprop-2-enamide hydrochlo was washed with aq. 2N HC1. The organic layer was dried ride filtered and the solvent removed under vacuum to provide a According to the procedure for Example 1, Step F, the solid. A solution of phosphorous oxychloride (25 mL) and product of Step C (35 mg, 0.17 mmol) and (2E)-3-(4- N,N-dimethylformamide (4.5 mL) was stirred at 0° for 0.15 60 chlorophenyl)prop-2-enoyl chloride. Example 1, Step E (38 h then the above solid was added. The resulting reaction mg, 0.19 mmol) were utilized to afford the product, MS: m/z. mixture was heated at 75° for 12 h at which time the 367 (MH), as an off-white solid. volatiles were removed under vacuum. The residue was Using the appropriate starting materials and following cooled in an ice bath. To the cooled mixture was carefully 65 procedures similar to those described above, the following added water (50 mL). The resulting solids were filtered and compounds were prepared from the corresponding quino then washed with water. The solids were extracted with line-2,6-diamine intermediates: US 7,084, 156 B2

H R N N CH

O 2 N R

Ex. ii R7 R = NR, R2 Parent Ion (MH+) m/z 283 FC n-CH3 400

21 CH

284 C n-CH3 366

21 CH3

285 FC N -CH3 4O2

CH3

286 C- 466 NA y 287 Cl- 432 NA , 288 Clus 468 N 289 FC Sr. 442 O- N O 290 FC Clus Sr.Null 444 291 389 N N-CH CH FC

292 NH N 431 N N-l FC 293 FC O 454

US 7,084, 156 B2 113 114

-continued s N-C's

O CCN R

Ex. ii R7 R = NR, R2 Parent Ion (MH+) m/z

305 FC 21 CH 431 Nin N CH3 CH3 306 FC 455 21 N N

307 FC 469 21

al N N

3O8 S16

FC ( ) ( ) N 4, 309 N 449

NA , 310 C 480

N

EXAMPLE 311 45 resulting solution rose to approximately 50°. The reaction mixture was heated at reflux for 1 h, cooled to rt and carefully poured onto ice. The resulting precipitate was filtered, washed with ice cold water and ether, then dried FC under vacuum to provide a solid. A mixture of the solid (8.5 CH3 50 g) and phosphorous oxychloride (40 mL) was heated at 100° for 0.45 hat which time the volatiles were removed under 21 N vacuum. The residue was cooled in an ice bath. To the O 2 CH3 cooled mixture was carefully added water (50 mL). The N N1 resulting solids were filtered then washed with water and 55 ether and then dried under vacuum to afford the product, CH MS: m/z 224 (MH), which was used directly in the next step. Step B: Preparation of N.N.4-trimethyl-6-nitroquinolin-2- (2E)-N-2-(Dimethylamino)-4-methylduinolin-6-yl)- amine 3-4-(trifluoromethyl)phenylprop-2-enamide hydro 60 The product was obtained from the product of Step A and chloride a solution of 2N dimethylamine in methanol (5 mL, 25 mmol) according to the procedure of Example 1, Step C. Step A: Preparation of 2-chloro-4-methyl-6-nitroquinoline Step C. Preparation of N.N.4-trimethylquinoline-2,6-di To a solution of 4-methylduinolin-2(1H)-one (11 g. 69 65 amine mmol) in concentrated sulfuric acid (100 mL) was added The product was obtained from the product of Step B fuming nitric acid (2.7 mL, 80 mol). The temperature of the according to the procedure of Example 282, Step C. US 7,084, 156 B2 115 116 Step D: Preparation of (2E)-N-2-(dimethylamino)-4-meth then extracted with excess chloroform. The combined ylquinolin-6-yl)-3-4-(trifluoromethyl)phenylprop-2-ena organic extracts were washed with Saturated sodium bicar mide hydrochloride bonate, dried over sodium sulfate, filtered and the solvent The product was obtained from the product of Step D (35 mg, 0.17 mmol) and (2E)-3-((4-trifluoromethyl)phenyl) 5 removed under vacuum to provide a solid. prop-2-enoyl chloride according to the procedure for Step B: Preparation of 2-chloro-4-ethyl-6-nitroquinoline Example 1, Step F, MS: m/z 400 (MH"). Using the appropriate starting materials and following The product was obtained from 4-ethylduinolin-2(1H)- procedures similar to those described above, the following one (Step A) according to the procedure for Example 311, compounds were prepared from the corresponding quino- 10 Step A, MS: m/Z 237 (MH"), which was used directly in the line-2,6-diamine intermediates: next step.

R4

R.7 N r N O 2 N R Ex. ii R7 R R = NR, R2 Parent Ion (MH+) m/z 312 FC —CH n-CH3 Clus NCH3 466 313 O- —CH 21 N 4, 468 314 Clus —CH A f , N

EXAMPLE 315 40 Step C. Preparation of 4-ethyl-N,N-dimethyl-6-nitro quinolin-2-amine The product was obtained from the product of Step B and a solution of 2N dimethyl-amine in methanol (5 mL, 25 F. C 45 mmol) according to the procedure of Example 1, Step C. Step D: Preparation of 4-ethyl-N,N-dimethylquinoline 2.6-diamine OYXY. Y. Y. Yi Y The product was obtained from the product of Step C 50 according to the procedure of Example 282, Step C. Step E: 3-(4-Trifluoromethyl)phenylpropanoyl chloride The product was obtained from 3-(4-trifluoromethyl) phenylpropanoic acid and oxalyl chloride according to the N-2-(Dimethylamino)-4-ethylduinolin-6-yl)-3-4- procedure for Example 1, Step E. (trifluoromethyl)phenylpropanamide hydrochloride 55 Step F Preparation of N-2-(dimethylamino)-4-ethylduino lin-6-yl)-3-4-(trifluoromethyl)phenylpropanamide hydro Step A: Preparation of 4-ethylduinolin-2(1H)-one chloride To a suspension of 4-methylduinolin-2(1H)-one (5 g, 31 mmol) in anhydrous tetrahydrofuran (100 mL) under a 60 The product was obtained from the product of Step D (35 nitrogen atmosphere cooled in an acetone/dry ice bath was mg, 0.17 mmol) and 3-((4-trifluoromethyl)phenyl)pro added dropwise by syringe a 1.6N solution of n-butyl panoyl chloride according to the procedure for Example 1, lithium in hexanes (49 mL, 78 mol). The resulting solution Step F, MS: m/z 417 (MH). was warmed to r,t. for 2 hat which time iodomethane (3 mL, Using the appropriate starting materials and following 47 mmol) was added by Syringe. The reaction mixture was 65 procedures similar to those described above, the following stirred at r,t. for 0.5 h then cooled in an ice bath. The reaction compounds were prepared from the corresponding quino mixture was quenched by the addition of aq. 2N HCl and line-2,6-diamine intermediates: US 7,084, 156 B2 117 118

R4

R.7 N. r N O 2 N R Ex. ii R7 R R = NR, R2 Parent Ion (MH+) m/z 316 FC —CH2CH3 n O) 440

317 FC —CH2CHs n O) 442

318 —CH2CH3 N -CH3 N N

FC Or .

35 EXAMPLE 319 Step B: Preparation of methyl 2-chloro-6-nitroquinoline-4- carboxylate The product was obtained from methyl 2-oxo-1,2-dihyd 40 roquinoline-4-carboxylate (Step A) according to the proce FC O OCH dure for Example 311, Step A, MS: m/z 267 (MH), which was used directly in the next step. Step C: Preparation of methyl 2-(2-azabicyclo[2.2.1]hept 2-yl)-6-nitroquinoline-4-carboxylate O N2 27 45 N N The product was obtained from methyl 2-chloro-6-nitro quinoline-4-carboxylate (Step B) and 2-azabicyclo[2.2.1 heptane according to the procedure for Example 1, Step C. Methyl 2-(2-azabicyclo[2.2.1]hept-2-yl)-6-({3-4- Step D: Preparation of methyl 6-amino-2-(2-azabicyclo (trifluoromethyl)phenylpropanoyl)amino)quinoline 2.2.1]hept-2-yl)guinoline-4-carboxylate 4-carboxylate The product was obtained from methyl 2-(2-azabicyclo 2.2.1]hept-2-yl)-6-nitro-quinoline-4-carboxylate (Step C) according to the procedure for Example 282, Step C. Step A: Preparation of methyl 2-oxo-1,2-dihydroquinoline Step E: Preparation of methyl 2-(2-azabicyclo[2.2.1]hept-2- 4-carboxylate 55 yl)-6-(3-4-(trifluoromethyl)phenylpropanoyl)amino) In a heavy-walled PYREX tube was placed 2-iodoaniline quinoline-4-carboxylate (2.84 g, 13 mmol), dimethylmaleate (2.44 g. 17 mmol), The product was obtained from methyl 6-amino-2-(2- triethylamine (1.4 mL, 10 mmol), palladium diacetate (31 aZabicyclo[2.2.1]hept-2-yl)guinoline-4-carboxylate (Step mg, 0.14 mmol) and 6 mL acetonitrile. The tube was flushed 60 D) (35 mg, 0.17 mmol) and 3-(4-trifluoromethyl)phenyl propanoyl chloride (Example 315, Step E) according to the with nitrogen and sealed. The sealed tube was heated at 100° procedure for Example 1, Step F, MS: m/z 498 (MH"). for 3.5 h then cooled to rt. The tube was opened and the Using the appropriate starting materials and following resulting solids filtered and washed with acetonitrile. The procedures similar to those described above, the following solids were dissolved in chloroform and the solvent removed 65 compounds were prepared from the corresponding quino under vacuum to provide a solid. line-2,6-diamine intermediates: US 7,084, 156 B2 119 120

R4 R 7 r N O 2 N R Ex. ii R7 R R = NR, R2 Parent Ion (MH+) m/z 32O —COCH 485 N N FC

EXAMPLE 321 Step E) according to the procedure for Example 1, Step F, MS: m/z 529 (MH). 2O FC Step D: Preparation of N-2-(3-aminopyrrolidin-1-yl)guino lin-6-yl)-3-4-(trifluoromethyl)phenylpropanamide bis trif O a H 25 OO CH3 luoroacetic acid salt N O)-st O To a solution of tert-butyl 1-6-({3-4-(trifluoromethyl) 30 phenylpropanoyl)amino)quinolin-2-ylpyrrolidin-3-yl car bamate hydrochloride (800 mg, 1.42 mmol; Step C) in methylene chloride (5 mL) was added anisole (0.77 mL, 7.1 N-2-3-(Acetylamino)pyrrolidin-1-ylquinolin-6- mmol) and trifluoroacetic acid (5 mL). The resulting solu tion was stirred at r,t. for several hours and then the solvent yl)-3-4-(trifluoromethyl)phenylpropanamide 35 hydrochloride was removed under vacuum. The resulting oil was left at r,t overnight. The residue was triturated with ethyl acetate and the resulting solids filtered, washed with ice cold ethyl acetate and dried under vacuum to afford the product, MS: 40 m/Z 429 (MH), as an off-white solid. Step A: Preparation of tert-butyl 1-(6-nitroquinolin-2-yl) pyrrolidin-3-ylcarbamate Step E: N-2-3-(Acetylamino)pyrrolidin-1-ylquinolin-6- yl)-3-4-(trifluoromethyl)phenylpropanamide hydrochlo The product was obtained from 2-chloro-6-nitroquinoline ride (Example 1, Step B) and tert-butyl pyrrolidin-3-ylcarbamate 45 according to the procedure of Example 119, Step A, MS: m/z. To a suspension of N-2-(3-aminopyrrolidin-1-yl)guino 359 (MH"). lin-6-yl)-3-4-(trifluoro-methyl)phenylpropanamide bis tri fluoroacetic acid salt (100 mg, 0.15 mmol; Step D) in 50 methylene chloride (1 mL) at r.t. under nitrogen atmosphere Step B: Preparation of tert-butyl 1-(6-aminoquinolin-2-yl) was added by syringe triethylamine (0.07 mL, 0.5 mmol). To pyrrolidin-3-ylcarbamate the resulting solution was added by Syringe acetyl chloride (0.012 mL, 0.16 mol). The resulting mixture was stirred at The product was obtained from tert-butyl 1-(6-nitroquino rt for several hours, during which time a precipitate formed. lin-2-yl)pyrrolidin-3-ylcarbamate (Step A) according to the 55 The solids were filtered and washed with minimal amount of procedure for Example 1, Step D, MS: m/z 329 (MH"), solvent. The solids were taken up in methanol and treated which was used directly in the next step. with a solution of 2N HCl in ethanol (0.2 mL). The solvent was removed under vacuum to provide an oil which was crystallized by trituration with ethyl acetate. The solvent was Step C. tert-Butyl 1-6-({3-4-(trifluoromethyl)phenyl 60 removed under vacuum to provide the product, MS: m/z. 471 propanoyl)amino)quinolin-2-ylpyrrolidin-3-ylcarbamate (MH), as an off-white solid. hydrochloride Using the appropriate starting materials and reagents and The product was obtained from tert-butyl 1-(6-amino 65 following procedures similar to those described above, the quinolin-2-yl)pyrrolidin-3-yl carbamate (Step B) and 3-(4- following compounds were prepared from the correspond trifluoromethyl)phenylpropanoyl chloride (Example 319, ing intermediates:

US 7,084, 156 B2 127 128

-continued R r N

O OlN R

Parent Ion Ex. ii R7 R = NR, R2 (MH+) m/z 353 CH3 456 F O N N l DX N YCH, O 354 FC Me 483 N

355 FC 7– 559 N

356 FC H 469 M SSC)N

EXAMPLE 357

S- N CH3 H FC N CH ro CH O

2,2-Dimethyl-N-(1-6-(5-2-4-(trifluoromethyl) 55 triturated with ether. The solids were collected on a fritted phenylethyl-1,2,4-oxadiazol-3-yl)guinolin-2-yl) funnel and dried under vacuum. This provided the title pyrrolidin-3-yl)propanamide compound. Step B: 2-Oxo-1,2,3,4-tetrahydroquinoline-6-carbonitrile Step A: 6-Iodo-3,4-dihydroquinolin-2(1H)-one 6-Iodo-3,4-dihydroquinolin-2(1H)-one (1.50 g; 5.50 3,4-Dihydroquinolin-2(1H)-one (7.5 g. 51 mmol) and " mmol), sodium cyanide (0.54 g; 11.0 mmol), copper (I) silver (I) sulfate (17.5 g; 56.1 mmol) were suspended in iodide (0.105 g; 0.5 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.32 g; 0.3 mmol) were combined in a flask ethanol (250 mL). A solution of iodine in ethanol (250 mL) equipped with a reflux condenser. The flask was subjected to was added slowly to the reaction over 1 hour. After 6 hours, several evacuation-nitrogen purge cycles followed by the the reaction was filtered through CELITE diatomaceous addition of acetonitrile (25 mL). The reaction was heated to earth and washed copiously with methanol. The volatiles reflux for 5 hours. After cooling, the reaction was diluted were removed under vacuum and the crude residue was with ethyl acetate (200 mL), filtered through CELITE diato US 7,084, 156 B2 129 130 maceous earth and rinsed with copious amounts of ethyl C. for 6 h. The mixture was diluted with dichloromethane, acetate. The organic solution was washed twice with brine washed twice with brine, dried over sodium sulfate, filtered (50 mL), dried over sodium sulfate, filtered through a fritted through a fritted funnel and the volatiles were removed funnel, and the volatiles were removed under vacuum. The under vacuum. This provided the product, MS: m/z. 356, crude residue was crystallized from methanol, which which was used in the next step without further purification. afforded the title compound. Step C: 2-Chloroquinoline-6-carbonitrile Step F: 2,2-Dimethyl-N-1-6-(5-2-4-(trifluoromethyl) The crude product was prepared from the product of Step phenylethyl-1,2,4-oxadiazol-3-yl)guinolin-2-ylpyrroli B according to the procedure for Example 1, Step B. This din-3-yl)propanamide furnished the title compound. 10 To a mixture of the product of Step E, (66 mg) in anhydrous diglyme (2 mL) was added 4-trifluoromethylphe Step D: N-1-(6-cyanoquinolin-2-yl)pyrrolidin-3-yl)-2.2- nylpropionic acid (1.1 eq.) and EDC (2 eq.). The reaction dimethylpropanamide mixture was heated to 50° C. overnight. After approximately The product was prepared from the product of Step C and 18 h, the mixture was heated at 110° C. for 2 hr. The mixture 2,2-dimethyl-N-pyrrolidin-3-ylpropanamide according to 15 was cooled to r.t., quenched with water and extracted with the procedure for Example 119, Step A. This furnished the excess EtOAc. The combined extracts were dried over a title compound MS: m/z, 323. drying agent filtered and the solvent removed under vacuum. Step EN-(1-6-(Hydroxyamino)(imino)methylquinolin-2- The residue was purified by preparative TLC eluting with ylpyrrolidin-3-yl)-2,2-dimethylpropanamide EtOAc to afford the product, MS: m/z 538. A mixture of the product of Step D (60 mg; 0.1863 mmol), Using the appropriate starting materials and following hydroxyl amine hydrochloride (3 eq.), sodium carbonate (4 procedures similar to those described above, the following eq.) in 1.5 mL water and 2.5 mL ethanol was heated to 90° compounds were prepared:

R6 N

2 N R

Parention Ex. ii R (MH+) m/z 358 O-N 510

N y Crys O

FC

359 O-N Me 524 N >

^ -->O

360 O-N H 554 \ N N O Me NN > N Me O Me

FC 361 O-N\ N NH2 454 N N

FC

362 510 US 7,084, 156 B2 131 132 Biological Assays ICso calculations were performed using Prism 3.0 (Graph Pad Software, San Diego, Calif.). MCH-1R and MCH-2R Radioligand Binding Assays Functional Assay for MCH-1R and MCH-2R The aequorin bioluminescence assay is a reliable test for Membrane binding assays were performed on transiently identifying G-protein-coupled receptors which couple transfected COS-7 cells expressing human MCH-2R from through the G protein subunit family consisting of G, and G, the plasmid vector pCI-neo (Promega, Madison, Wis.), on a which leads to the activation of phospholipase C, mobiliza Chinese hamster ovary (CHO) cell line stably expressing the tion of intracellular calcium, and activation of protein kinase MCH-2R from the plasmid vector pEF1/V5-HisB (Invitro C. Stable cell lines expressing either the MCH-1R or the gen, Carlsbad, Calif.), or a CHO cell line stably expressing 10 MCH-2R and the aequorin reporter protein were used. The human MCH-1R from pcDNA3.1. For transient expression, assay was performed using a Luminoskan RT luminometer COS-7 cells were cultured in Dulbecco's modified Eagle (Labsystems Inc., Gaithersburg, Md.) controlled by custom medium (Gibco BRL, Rockville, Md.) with 10% heat inac Software written for a Macintosh PowerPC 6100. tivated fetal calf serum. A suspension of 7x10°COS-7 cells 293AEQ17/MCH-1R(or MCH-2R) cells were cultured for were transfected with 20 g of pCI-neo/MCH-2R plasmid 15 72 h and the apo-aequorin in the cells was charged for 1 h by electroporation and cells were harvested after 60–72 with coelenterazine (10 uM) under reducing conditions (300 hours. Membranes were prepared from transient and stable M reduced glutathione) in ECB buffer (140 mM. NaCl, 20 transfectants by hypotonic lysis, frozen in liquid nitrogen, mM KC1, 20 mM HEPES-NaOH, pH 7.4, 5 mM glucose, 1 and stored at -80° C. A scintillation proximity assay (SPA) mM MgCl2, 1 mM CaCl2, 0.1 mg/mL bovine serum albu was developed to measure the specific binding of ''Il min). The cells were harvested, washed once in ECB Phe'Tyr-hMCH. SPA were carried out using wheat medium, and resuspended to 500,000 cells/mL. 100 uL of germ agglutinin-polyvinyltoluene beads (Amersham Corp., cell suspension (corresponding to 5x10" cells) was then Arlington Heights, Ill.), in 96-well OptiPlates (Packard, injected into the test plate containing the test ligands, and the Meriden, Conn.). Each well contained 0.25 mg of SPA 25 integrated light emission was recorded over 30s, in 0.5-S beads, 1-10 ug of membrane protein, and 200 uL binding units. 20 uL of lysis buffer (0.1% final Triton X-100 con centration) was then injected and the integrated light emis buffer (50 mM Tris pH 7.4, 10 mM MgCl, 2 mM EDTA, sion recorded over 10s, in 0.5-S units. To detect antagonists, 12% glycerol, 0.1% BSA). Binding buffer contained 50 mM test ligands were pre-incubated for ~10 minutes at varying Tris pH 7.4, 8 mM MgCl2, 12% glycerol, 0.1% BSA (Sigma, concentrations prior to injection on the test plate St. Louis, Mo.) and protease inhibitors: 4 Lig/mL of leupeptin 30 containing MCH agonists. The “fractional response' values (Sigma, St. Louis, Mo.), 40 ug/ML of Bacitracin (Sigma, St. for each well were calculated by taking the ratio of the Louis, Mo.), 5 lug/mL of Aprotinin (Roche Molecular Bio integrated response to the initial challenge to the total chem. Indianapolis, Ind.), 0.05MAEBSF (Roche Molecular integrated luminescence including the Triton X-100 lysis Biochem., Indianapolis, Ind.), and 5 mM Phosphoramidon response. The functional ECso values were measured in (Boeringer Mannheim). Assays were optimized with respect 35 three separate assays. to membrane preparations: for CHO/MCH-1R membranes, Selective MCH-1R antagonist compounds of the present 1 Jug of membranes per well yielded a >6x specific binding invention have ICs affinities for the MCH-1R receptor window and for COS or CHOMCH-2R membranes, 8 ug of between 0.1 and 10000 nM, are at least 20x selective for the membrane protein yielded a window of about 3.x. Specific MCH-1R receptor over the MCH-2R receptor, and are binding is defined as the difference between total binding 40 and non-specific binding conducted in the presence of 500 functional antagonists lacking agonist activity at the MCH nM unlabeled hMCH. Beads were coated with membranes 1R receptor. for 20 minutes and dispensed to the 96 wells, various REFERENCES concentrations of test compounds in DMSO were added (final DMSO concentration 1%–2%), then 25 nGi of ''I- 45 Phe'Tyr-hMCH (-2000 Ci/mmol; NEN Life Sciences, MCH-1R (Human) Boston, Mass.) was added to the wells. After equilibrating at Lakaye et al., “Cloning of the rat brain cDNA encoding rt. for 3 hours, the plates were read in a TopCount (Packard, for the SLC-1 G protein-coupled receptor reveals the pres Meriden, Conn.). ICso calculations were performed using ence of an intron in the gene. Biochim. Biophys Acta; Prism 3.0 (GraphPad Software, San Diego, Calif.). The ICso 50 1401(2):216-20 (1998). values were measured in three different experiments. A Saito et al., “Molecular characterization of the melanin filter-based assay was also used for MCH-2R in 96-well concentrating-hormone receptor, Nature; 400(6741):265-9 plates. Total volume per binding assay point was 200 uL. (1999). Binding conditions were 50 mM Tris pH 7.4, 10 mM MgCl, Chambers et al., “Melanin-concentrating hormone is the 2 mM EDTA 200 g/mL bacitracin, 1 uM phosphoramidon, 55 cognate ligand for the orphan G-protein-coupled receptor 2.5 to 5ug protein, with and without 10 uMMCH unlabeled SLC-1, Nature: 400(6741): 261–5 (1999). peptide as a competitor. Dose response curves were from 10 MCH-2R (human): uM in 5 fold or 3-fold dilution series for 11 points. The Sailer et al., “Identification and characterization of a mixture was shaken for 5 minutes on a platform shaker, and second melanin-concentrating hormone receptor, MCH incubated at r.t. for 1 hour. Filter plates were presoaked in 60 1% PEI. The binding reaction was harvested onto filters 2R, Proc. Natl. Acad. Sci. USA:98(13):7564-9 (2001). using Packard Filternate harvester (Meriden, Conn.). The In Vivo Food Intake Models. filters were then washed in 50 mM Tris pH 7.4, 10 mM 1) Overnight food intake. Sprague Dawley rats are MgCl, 2 mM EDTA, 0.04% Tween 20, 6–8 times per plate. injected intracerebroventricularly with a test compound in The plates were dried for 20 minutes at 55° C. or overnight 65 400 mL of 50% propylene glycol/artificial cerebrospinal fluid at r.t. 30 uL microscintillant was added per well and counted one hour prior to onset of dark cycle (12 hours). Food intake for 1.5–3 minutes in inverted format on Packard TopCount. is determined using a computerized system in which each US 7,084, 156 B2 133 134 rats food is placed on a computer monitored balance. from N. S., and O, optionally having one or more Cumulative food intake for 16 hours post compound admin degrees of unsaturation, optionally fused to a 6-mem istration is measured. bered heteroaromatic or aromatic ring, either unsubsti 2) Food intake in diet induced obese mice. Male C57/ tuted or substituted with one to four substituents inde B16J mice maintained on a high fat diet (60% fat calories) pendently selected from R', and wherein sulfur for 6.5 months from 4 weeks of age are dosed intraperito containing heterocyclic rings may be mono- or neally with test compound. Food intake and body weight are di-oxidized on the sulfur atom; measured over an eight day period. Biochemical parameters R and R are independently selected from the group relating to obesity, including leptin, insulin, triglyceride, free consisting of: fatty acid, cholesterol and serum glucose levels are deter 10 (1) hydrogen, mined. (2) halogen, While the invention has been described and illustrated in (3) Cls alkyl, reference to certain preferred embodiments thereof, those (4) perfluoro Ce alkyl, skilled in the art will appreciate that various changes, (5) Calkenyl, modifications and substitutions can be made therein without 15 (6) C- alkynyl, departing from the spirit and scope of the invention. For (7) cycloalkyl, example, effective dosages other than the preferred doses as (8) cycloalkyl-C alkyl, set forth hereinabove may be applicable as a consequence of (9) cycloheteroalkyl, variations in the responsiveness of the mammal being (10) cycloheteroalkyl-C alkyl, treated for obesity, diabetes, or for other indications for the (11) aryl, compounds of the invention indicated above. Likewise, the (12) aryl-C alkyl, specific pharmacological responses observed may vary (13) heteroaryl, according to and depending upon the particular active com (14) heteroaryl-C alkyl, pound selected or whether there are present pharmaceutical (15) - OR7, carriers, as well as the type of formulation and mode of 25 (16) NR'R'', administration employed, and Such expected variations or (17) COR7, differences in the results are contemplated in accordance (18) cyano, and with the objects and practices of the present invention. It is (19) C(O)NR'R7; intended, therefore, that the invention be limited only by the wherein alkyl, alkenyl and alkynyl, moieties above are scope of the claims that follow and that such claims be 30 optionally substituted with one to four substituents interpreted as broadly as is reasonable. independently selected from R'; and wherein What is claimed is: cycloalkyl, heterocycloalkyl, aryl and heteroaryl moi 1. A compound of structural formula (I): eties above are optionally substituted with one to four substituents independently selected from R', and 35 wherein Sulfur-containing heterocyclic rings may be R4 mono- or di-oxidized on the Sulfur atom; R is R6 N N R3 hydrogen (6): A-4N 2n 1- R.. 40 R is selected from the group consisting of: Rs (1)–(CH2)-heteroaryl-R". R (2) —(CH), NRC(O)R’, and (3) —(CH), N(R), and wherein one or two of the hydrogen atoms in (CH), may wherein: 45 be substituted with R: R" and R are independently selected from the group R’ is independently selected at each occurrence from the consisting of: group consisting of (1) hydrogen, (1) hydrogen, (2) C- alkyl, (2) Co. alkyl, (3) Calkenyl, 50 (4) C2-alkynyl, (3) aryl, (5) cycloalkyl-Co. alkyl, (4) heteroaryl, (6) heterocycloalkyl-Colo alkyl, (5) cycloalkyl, (7) aryl-Colo alkyl, and (6) heterocycloalkyl, (8) heteroaryl-Colo alkyl; 55 (7) aryl C alkyl, wherein alkyl, alkenyl, and alkynyl, moieties above are (8) heteroaryl C alkyl, optionally substituted with one to four substituents (9) cycloalkyl C. alkyl, independently selected from R'; and wherein (10) heterocycloalkyl C alkyl, cycloalkyl, heterocycloalkyl aryl and heteroaryl moi (11) aryl C- alkenyl, eties above are optionally substituted with one to four 60 (12) heteroaryl C- alkenyl, substituents independently selected from R', and (13) cycloalkyl C- alkenyl, and wherein Sulfur-containing heterocyclic rings may be (14) heterocycloalkyl C- alkenyl, mono- or di-oxidized on the Sulfur atom; wherein the alkyl and alkenyl moieties are optionally or, R' and R together with the nitrogen atom to which Substituted with one to four substituents selected from they are attached, form a 4- to 11-membered bridged or 65 R"; and wherein the aryl, heteroaryl, cycloalkyl and unbridged or spirocyclic heterocyclic ring, optionally heterocycloalkyl moieties are independently substi containing one or two additional heteroatoms selected tuted with one to four substituents selected from R': US 7,084, 156 B2 135 136 and wherein Sulfur-containing heterocyclic rings may m is selected from 1 and 2: be mono- or di-oxidized on the sulfur atom; n is selected from: 0, 1, 2, 3, 4, and 5; each R" is independently selected from: p is selected from 0, 1, and 2: (1) OR, and pharmaceutically acceptable salts thereof. (2) - NRS(O).R., 2. The compound according to claim 1, wherein: (3) —NO, R" and R are independently selected from the group (4) halogen, consisting of: (5) –S(O).R", (1) hydrogen, (6) SR, (2) C alkyl, (7) S(O),OR, 10 (3) Coalkenyl, (4) cycloalkyl-Co. alkyl, (9)(8) - S(O)N(R').N(R), (5) heterocycloalkyl-Co. alkyl, (10) - O(CRR)N(R), (6) aryl-Co. alkyl, and (11) - C(O)R, (7) heteroaryl-Colo alkyl: (12) -COR", 15 wherein alkyl and alkenyl moieties above are optionally (13) - CO(CRR),CON(R), substituted with one to three substituents independently (14) - OC(O)R’, selected from R'; wherein cycloalkyl, heterocy (15) - CN, cloalkyl, aryland heteroaryl moieties above are option ally substituted with one to three substituents indepen (16) –C(O)N(R'), dently selected from R': (17) NRC(O)R’, or, R' and R together with the nitrogen atom to which (18) - OC(O)N(R), they are attached, form a 4- to 11-membered bridged or (19) NRC(O)OR, unbridged or spirocyclic heterocyclic ring, optionally (20) - NRC(O)N(R), containing one additional heteroatom selected from N. (21) CR(N OR), 25 S, and O, optionally having one or more degrees of (22) —CF, unsaturation, optionally fused to a 6-membered het (23) cycloalkyl, eroaromatic or aromatic ring, either unsubstituted or (24) cycloheteroalkyl, and substituted with an R substituent; (25) oxo; R and R are independently selected from the group each R" is independently selected from: 30 consisting of: (1) R', (1) hydrogen, (2) —Sn(CH), (2) halogen, (3) Co alkyl, (3) Cls alkyl, (4) Coalkenyl, (4) trifluoromethyl, (5) Clo alkynyl, 35 (5) Calkenyl, (6) heteroaryl, (6) cycloalkyl, (7) aryl, and (7) cycloalkyl-C alkyl, (8) aryl-Co alkyl; (8) cycloheteroalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cyclo (9) cycloheteroalkyl-C alkyl, heteroalkyl, heteroaryl, and aryl are optionally 40 (10) aryl, Substituted with one to four substituents selected (11) aryl-C alkyl, from a group independently selected from R: (12) heteroaryl, each R is independently selected from: (13) heteroaryl-C alkyl, (1) halogen, (14) —OR7, (2) amino, 45 (15) NR7R7, (3) carboxy, (16) - CO.R. and (4) C. alkyl, (17) C(O)NR'R7; (5) Calkoxy, wherein alkyl and alkenyl moieties above are optionally (6) aryl, substituted with one to four substituents independently 50 selected from R'; and wherein cycloalkyl, heterocy (7) aryl C alkyl, cloalkyl, aryland heteroaryl moieties above are option (8) hydroxy, ally substituted with an R' substituent; (9) —CF, R is (10) —OC(O)C alkyl, hydrogen (11) —OC(O)N(R), and 55 (10); (12) aryloxy; R is selected from the group consisting of: R" is independently selected from hydrogen, C. alkyl, (1)–(CH2)-heteroaryl-R". Calkenyl: C, alkynyl, cycloalkyl, cycloalkyl-C, (2) —(CH), NRC(O)R’, and alkyl, cycloheteroalkyl, cycloheteroalkyl-C alkyl; (3) —(CH2)N(R), aryl; heteroaryl; aryl-C alkyl, and heteroaryl-C 60 wherein one or two of the hydrogen atoms in (CH), may alkyl: be substituted with R: wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cyclohet R’ is independently selected at each occurrence from the eroalkyl, heteroaryl, and aryl in Rare optionally sub group consisting of stituted with one to four substituents independently (1) hydrogen, selected from R: 65 (2) Co. alkyl, each R is selected from halo, methyl, methoxy, trifluo (3) aryl, romethyl, trifluoromethoxy, and hydroxy: (4) heteroaryl, US 7,084, 156 B2 137 138 (5) cycloalkyl, each R" is independently selected from hydrogen, C. (6) heterocycloalkyl, alkyl, C- alkenyl: C- alkynyl; cycloalkyl: (7) aryl C. alkyl, cycloalkyl-C, alkyl, cycloheteroalkyl, cyclohet (8) heteroaryl C. alkyl, eroalkyl-C, alkyl: aryl; heteroaryl: aryl-C-alkyl; and (9) cycloalkyl C. alkyl, heteroaryl-C alkyl; (10) heterocycloalkyl C alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cyclohet (11) aryl C- alkenyl, eroalkyl, heteroaryl, and aryl in Rare optionally sub (12) heteroaryl C- alkenyl, stituted with one to two substituents independently (13) cycloalkyl C- alkenyl, and selected from a R: (14) heterocycloalkyl C- alkenyl, 10 each R is selected from halo, methyl, methoxy, trifluo wherein the alkyl and alkenyl moieties are optionally romethyl, trifluoromethoxy, and hydroxy: Substituted with one to four substituents selected from m is selected from 1 and 2: R"; and wherein the aryl, heteroaryl, cycloalkyl and n is selected from: 0, 1, 2, 3, 4, and 5; heterocycloalkyl moieties are independently Substi p is selected from 0, 1, and 2: tuted with one to four substituents selected from R': 15 and pharmaceutically acceptable salts thereof. and wherein Sulfur-containing heterocyclic rings may 3. The compound according to claim 2, wherein: be mono- or di-oxidized on the sulfur atom; R" is selected from the group consisting of: each R" is independently selected from: (1) hydrogen, and (1 ) OR, (2) C alkyl, optionally substituted with one to three (2) - NRS(O),R, substituents independently selected from R': (3) - NO, R is selected from the group consisting of: (4) halogen, (1) hydrogen, (5) –S(O).R. (2) C alkyl, (6) - SR", (3) cycloalkyl-Co. alkyl, (7) S(O),OR, 25 (4) heterocycloalkyl-Co. alkyl, (5) aryl-Co. alkyl, and (8)(9) - S(O)N(R').N(R'), (6) heteroaryl-Colo alkyl, (10) - O(CRR)N(R), wherein alkyl moieties above are optionally substituted (11) - C(O)R’, with one to three substituents independently selected (12) - COR, 30 from R'; and wherein cycloalkyl, heterocycloalkyl, (13) - CO(CRR),CON(R), aryland heteroaryl moieties above are optionally sub (14) OC(O)R", stituted with one to three substituents independently (15) - CN, selected from R: (16) –C(O)N(R'), or, R' and R together with the nitrogen atom to which (17) NRC(O)R’, 35 they are attached, form a 4- to 11-membered bridged or (18) - OC(O)N(R), unbridged or spirocyclic heterocyclic ring, optionally (19) NRC(O)OR, containing one additional heteroatom selected from N. (20) - NRC(O)N(R), S, and O, either unsubstituted or substituted with an R' (21) CR(N OR), Substituent; (22) —CF, 40 R is selected from the group consisting of: (23) cycloalkyl, (1) hydrogen, (24) cycloheteroalkyl, and (2) halogen, (25) oxo; (3) Cls alkyl, each R" is independently selected from: (4) trifluoromethyl, (1) R', 45 (2) —Sn(CH), (6) —OCH, (3) Co alkyl, (7) - NH, (4) Coalkenyl, (8) —CO.R.", and (5) heteroaryl, (9) –C(O)NH: (6) aryl, and 50 wherein alkyl moieties above are optionally substituted (7) aryl-Co alkyl, with one to two substituents independently selected wherein alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, from R': heteroaryl, and aryl are optionally substituted with R" is selected from the group consisting of: one to four R substituents; (1) hydrogen, each R is independently selected from: 55 (2) halogen, (1) halogen, (3) Cls alkyl, (2) amino, (4) trifluoromethyl, (3) carboxy, (5) cycloalkyl, (4) C. alkyl, (6) cycloheteroalkyl, (5) Calkoxy, 60 (7) aryl, (6) aryl, (8) aryl-C alkyl, (7) aryl C alkyl, (9) heteroaryl, (8) hydroxy, (10) -OH, (9) —CF, (11) –OCH, (10) —OC(O)C alkyl, 65 (12) —NH2, (11) –OC(O)N(R), and (13) - COR7, and (12) aryloxy; (14) - C(O)NH; US 7,084, 156 B2 139 140 wherein alkyl moieties above are optionally substituted (4) Calkenyl, with one to four substituents independently selected (5) heteroaryl, from R'; and wherein cycloalkyl, heterocycloalkyl, (6) aryl, and aryland heteroaryl moieties above are optionally sub (7) aryl-Co alkyl, stituted with an R substituent; 5 wherein alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, het R is eroaryl, and aryl moieties in R and R are optionally hydrogen Substituted with one to four R. Substituents; (10); each R is independently selected from: R is selected from the group consisting of: (1) halogen, (1)–(CH2)-heteroaryl-R". 10 (2) amino, (2) —(CH), NRC(O)R’, and (3) carboxy, (3) —(CH2)N(R), (4) C. alkyl, wherein one or two of the hydrogen atoms in (CH), may (5) Calkoxy, be substituted with R: (6) aryl, R’ is independently selected at each occurrence from the 15 (7) aryl C alkyl, group consisting of (8) hydroxy, (1) hydrogen, (9) —CF, (2) C- alkyl, (10) —OC(O)C alkyl, (3) aryl, (11) –OC(O)N(R), and (4) heteroaryl, (12) aryloxy; (5) cycloalkyl, R" is independently selected from hydrogen, C, alkyl, (6) heterocycloalkyl, C. alkenyl: C, alkynyl, cycloalkyl, cycloalkyl-C1s (7) aryl C alkyl, alkyl, cycloheteroalkyl, cycloheteroalkyl-C alkyl: (8) heteroaryl C. alkyl, aryl; heteroaryl; aryl-C alkyl; and heteroaryl-C (9) cycloalkyl C. alkyl, 25 alkyl: (10) heterocycloalkyl C alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cyclohet (11) aryl C- alkenyl, eroalkyl, heteroaryl, and aryl in Rare optionally sub (12) heteroaryl C- alkenyl, stituted with one to two substituents independently (13) cycloalkyl C- alkenyl, and selected from a R: (14) heterocycloalkyl C- alkenyl, 30 each R is selected from halo, methyl, methoxy, trifluo wherein the alkyl and alkenyl moieties are optionally romethyl, trifluoromethoxy, and hydroxy: Substituted with one to three substituents selected from m is selected from 1 and 2: R"; and wherein the aryl, heteroaryl, cycloalkyl and n is selected from: 0, 1, 2, 3, and 4: heterocycloalkyl moieties are independently Substi p is selected from 0, 1, and 2: tuted with one to three substituents selected from R: 35 and pharmaceutically acceptable salts thereof. and wherein Sulfur-containing heterocyclic rings may 4. The compound according to claim 3, wherein: be mono- or di-oxidized on the sulfur atom; R" is selected from the group consisting of: each R" is independently selected from: (1) hydrogen, (1) OR, (2) methyl, (2) NRS(O), R, 40 (3) ethyl, and (3) —NO, (4) propyl. (4) halogen, optionally substituted with one to three substituents inde (5) –S(O).R", pendently selected from R': (6) - SR", R is selected from the group consisting of: (7) S(O),OR, 45 (1) hydrogen, (8) S(O)N(R'). (2) C alkyl, (9) - N(R), (3) cycloalkyl-Co. alkyl, (10) - O(CRR)N(R), (4) heterocycloalkyl-Co. alkyl, and (11) - C(O)R, (5) aryl-Co. alkyl, (12) -COR", 50 (13) - CO(CRR),CON(R), wherein alkyl moieties above are optionally substituted (14) - OC(O)R’, with one to three substituents independently selected (15) - CN, from R'; and wherein cycloalkyl, heterocycloalkyl, (16) –C(O)N(R), aryland heteroaryl moieties above are optionally sub (17) NRC(O)R, 55 stituted with one to three substituents independently (18) - OC(O)N(R), selected from R: (19) NRC(O)OR, or, R' and R together with the nitrogen atom to which (20) - NRC(O)N(R), they are attached, form a 4- to 11-membered bridged or (21) CR(N OR), unbridged or spirocyclic heterocyclic ring, optionally (22) —CF, 60 containing one additional heteroatom selected from N. (23) cycloalkyl, S, and O, either unsubstituted or substituted with an R' (24) cycloheteroalkyl, and Substituent; (25) oxo; R is selected from the group consisting of: each R" is independently selected from: (1) hydrogen, (1) R', 65 (2) halogen, (2) —Sn(CH), (3) Cls alkyl, and (3) Co alkyl, (4) trifluoromethyl, US 7,084, 156 B2 141 142 wherein alkyl moieties above are optionally substituted (15) - CN, with one to two substituents independently selected (16) –C(O)N(R), from R': (17) NRC(O)R’, R" is selected from the group consisting of: (18) - OC(O)N(R), (1) hydrogen, (19) NRC(O)OR, (2) Cls alkyl, (20) - NRC(O)N(R), (3) trifluoromethyl, (21) CR(N OR), (4) cycloalkyl, (22) —CF, (5) cycloheteroalkyl, (23) cycloalkyl, (6) aryl, 10 (24) cycloheteroalkyl, and (7) heteroaryl, (25) oxo; (8) —NH2, each R is independently selected from: (9) -COH, (1) R', (10) - COCH, and (2) —Sn(CH), (11) —COCHCH: 15 (3)C alkyl, wherein alkyl moieties above are optionally substituted (4) Coalkenyl, with one to two substituents independently selected (5) heteroaryl, from R'; and wherein cycloalkyl, heterocycloalkyl, (6) aryl, and aryland heteroaryl moieties above are optionally sub (7) aryl-Co alkyl, stituted with an R' substituent; wherein alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, het R is eroaryl, and aryl moieties in R* and R are optionally hydrogen Substituted with one to four R substituents; (6): each R is independently selected from: R is selected from the group consisting of: (1) halogen, (1)–(CH2)-heteroaryl-R". 25 (2) amino, (2) —(CH), NRC(O)R’, and (3) carboxy, (3) —(CH),N(R), (4) C. alkyl, wherein one or two of the hydrogen atoms in (CH), may (5) Calkoxy, be substituted with R"; (6) aryl, R’ is independently selected at each occurrence from the 30 (7) aryl C alkyl, group consisting of (8) hydroxy, (1) hydrogen, (9) —CF, (2) C alkyl, (10) —OC(O)C alkyl, (3) aryl, (11) —OC(O)N(R), and (4) heteroaryl, 35 (12) aryloxy; (5) cycloalkyl, R" is independently selected from hydrogen, C. alkyl, (6) heterocycloalkyl, C. alkenyl: C, alkynyl, cycloalkyl, cycloalkyl-C1s (7) aryl C. alkyl, alkyl, cycloheteroalkyl, cycloheteroalkyl-C alkyl, (8) heteroaryl C. alkyl, aryl; heteroaryl; aryl-C alkyl; and heteroaryl-C (9) cycloalkyl C alkyl, 40 alkyl: (10) heterocycloalkyl C alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cyclohet (11) aryl C- alkenyl, eroalkyl, heteroaryl, and aryl in Rare optionally sub (12) heteroaryl C- alkenyl, stituted with one to two substituents independently (13) cycloalkyl C- alkenyl, and selected from a R: (14) heterocycloalkyl C- alkenyl, 45 each R is selected from halogen, methyl, methoxy, trif wherein the alkyl and alkenyl moieties are optionally luoromethyl, trifluoromethoxy, and hydroxy: Substituted with one to three substituents selected from m is selected from 1 and 2: R"; and wherein the aryl, heteroaryl, cycloalkyl and n is selected from: 0, 1, 2, 3, and 4: heterocycloalkyl moieties are independently Substi p is selected from 0, 1, and 2: tuted with one to three substituents selected from R': 50 and pharmaceutically acceptable salts thereof. and wherein Sulfur-containing heterocyclic rings may 5. The compound according to claim 4, wherein: be mono- or di-oxidized on the sulfur atom; R" is selected from the group consisting of: each R" is independently selected from: (1) hydrogen, and (1 ) OR, (2) methyl: (2) - NHSOCH, 55 optionally substituted with one to three substituents inde (3) - NO, pendently selected from R: (4) halogen, R is selected from the group consisting of: (5) —S(O)CH, (1) methyl, (6) - SR", (2) ethyl, (7) S(O),OR, 60 (3) n-propyl. (4) isopropyl. (9)(8) - S(O)N(R'),N(R'), (5) t-butyl, (10) - O(CRR)N(R), (6) n-butyl, (11) - C(O)R’, (7) cyclopropyl. (12) -COR", 65 (8) cyclobutyl, (13) - CO(CRR),CON(R), (9) cyclopentyl, (14) - OC(O)R’, (10) cyclohexyl, US 7,084, 156 B2 143 144 (11) heterocycloalkyl-Co. alkyl, wherein the heterocy (4) heteroaryl, selected from: pyrrolyl, isoxazolyl, cloalkyl moiety is selected from aZetidinyl, pyrro isothiazolyl pyrazolyl pyridyl, oxazolyl, oxadiaz lidinyl, and pyridyl and olyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, (12) phenyl-Coe alkyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, wherein alkyl moieties above are optionally substituted 5 pyridazinyl, pyrazinyl, benzoxazolyl, benzothiaz with one to three substituents independently selected olyl, benzimidazolyl, benzofuranyl, benzothiophe from R'; and wherein cycloalkyl, heterocycloalkyl, and nyl, furo2.3-bipyridyl, quinolyl, indolyl, iso aryl moieties above are optionally substituted with one quinolyl, quinazolinyl, benzisodiazolyl, to three substituents independently selected from R: triazolopyrimidinyl, 5,6,7,8-tetrahydroquinolinyl, or, R' and R together with the nitrogen atom to which 10 2,1,3-benzothiadiazolyl, and thienopyridinyl, they are attached, form a 4- to 11-membered hetero (5) cycloalkyl, selected from: cyclopropyl, cyclobutyl, cyclic ring, selected from: aZetidinyl, pyrrolidinyl, pip cyclopentyl, cyclohexyl, cycloheptyl, tetrahy eridinyl, morpholinyl, 1-thia-4-azacyclohexyl, 2,5-di dronaphthyl, decahydronaphthyl, indanyl, bicyclo aZabicyclo[2.2.2]octanyl, azacycloheptyl, 2-oxa-5- 2.2.2]octanyl, tetrahydronaphthyl, and dihydroinda azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 15 nyl, 2-azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl, (6) heterocycloalkyl, selected from: azetidinyl, pyridyl, 2,5-diazabicyclo2.2.2]octyl, 2-azabicyclo2.2.2]octyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidi and 3-azabicyclo3.2.2]nonyl, 2.7-diazaspiro4.4 nyl, morpholinyl, 1-thia-4-aza-cyclohexane, 2,5-di nonyl, 2.7-diazaspiro4.5decyl. 2,7-diazaspiro4.6 un azabicyclo[2.2.2]octanyl, 2,3-dihydrofuro2,3-bpy decyl, 1.7-diazaspiro4.4nonyl, 2,6-dizaospiro4.5de ridyl, benzoxazinyl, tetrahydroquinolinyl, cyl, 2,6-diazaspiro4.6-undecyl, either unsubstituted tetrahydroisoquinolinyl, dihydroindolyl, indolyl, or substituted with an R substituent; indolinyl, isoindolinyl, 1,3-dihydro-2-benzofuranyl, R is selected from the group consisting of: benzodioxolyl, hexahydrothienopyridinyl, thienopy (1) hydrogen, ridinyl, azacycloheptyl, 4.4-spiro2,3-dihydroben (2) halogen, 25 Zothiophen-3.3-yl)piperidinyl, and 4.4-spiro indoli (3) methyl, 3.3-yl)piperidinyl, (4) ethyl, (7) aryl C alkyl, wherein the aryl moiety is selected (5) propyl, and from: phenyl, naphthyl, indanyl, indenyl, indolyl, (6) trifluoromethyl, quinazolinyl, quinolinyl, benzthiazolyl, benzox wherein alkyl moieties above are optionally substituted 30 azolyl, dihydroindanyl, benzisodiazolyl. Spirocyclo with one to two substituents independently selected hexylindolinyl, spiro-(dihydrobenzothiophenyl)pip from R: eridinyl, spiro-indolinylpiperidinyl, indolinyl, R" is selected from the group consisting of: tetrahydroisoquinolinyl, isoindolinyl, benzothiadia (1) hydrogen, Zolyl, benzotriazolyl, 1,3-dihydro-2-benzofuranyl, (2) methyl, 35 benzothiophenyl, benzodioxolyl, tetrahydronaph (3) ethyl, thyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyra (4) propyl. nyl, and 1,4-benzodioxanyl. (5) trifluoromethyl, (8) heteroaryl C alkyl, wherein the heteroaryl moiety (6) —COH, is selected: pyrrolyl, isoxazolyl, isothiazolyl pyra (7) —COCH and 40 Zolyl pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, (8) - COCHCH: thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl. wherein alkyl moieties above are optionally substituted triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, with one to three substituents independently selected benzoxazolyl, benzothiazolyl, benzimidazolyl, ben from R: Zofuranyl, benzothiophenyl, furo2,3-bipyridyl, 45 quinolyl, indolyl, isoquinolyl, quinazolinyl, benziso R is hydrogen; diazolyl, triazolopyrimidinyl, 5,6,7,8-tetrahydro R is selected from the group consisting of: quinolinyl, 2,1,3-benzothiadiazolyl, and thienopy (1)-heteroaryl-R7. ridinyl, (2) - NHC(O)R’, (9) cycloalkyl C alkyl, wherein the cycloalkyl moi (3) - NH(R), and 50 ety is selected from: cyclopropyl, cyclobutyl, cyclo (4)–(CH),NH(R), pentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, wherein one or two of the hydrogen atoms in (CH), may decahydronaphthyl, indanyl, bicyclo[2.2.2]octanyl. be substituted with R: tetrahydronaphthyl, and dihydroindanyl. R’ is independently selected at each occurrence from the (10) heterocycloalkyl C alkyl, wherein the heterocy group consisting of 55 cloalkyl moiety is selected from: aZetidinyl, pyridyl, (1) hydrogen, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidi (2) C- alkyl, nyl, morpholinyl, 1-thia-4-aza-cyclohexane, 2,5-di (3) aryl, selected from: phenyl, naphthyl, indanyl, inde azabicyclo[2.2.2]octanyl, 2,3-dihydrofuro2,3-bpy nyl, indolyl, quinazolinyl, quinolinyl, benzthiazolyl, ridyl, benzoxazinyl, tetrahydroquinolinyl, benzoxazolyl, dihydroindanyl, benzisodiazolyl, spi 60 tetrahydroisoquinolinyl, dihydroindolyl, indolyl, rocyclohexylindolinyl, spiro-(dihydrobenzothiophe indolinyl, isoindolinyl, 1,3-dihydro-2-benzofuranyl, nyl)piperidinyl, spiro-indolinylpiperidinyl, indoli benzodioxolyl, hexahydrothienopyridinyl, thienopy nyl, tetrahydroisoquinolinyl, isoindolinyl, ridinyl, azacycloheptyl, 4.4-spiro2,3-dihydroben benzothiadiazolyl, benzotriazolyl, 1,3-dihydro-2- Zothiophen-3.3-yl)piperidinyl, and 4.4-spiro indoli benzofuranyl, benzothiophenyl, benzodioxolyl, tet 65 3.3-yl)piperidinyl, rahydronaphthyl, 2,3-dihydrobenzofuranyl, dihy (11) aryl C- alkenyl, wherein the aryl moiety is drobenzopyranyl, and 1,4-benzodioxanyl, selected from: phenyl, naphthyl, indanyl, indenyl, US 7,084, 156 B2 145 146 indolyl, quinazolinyl, quinolinyl, benzthiazolylben (22) OC(O)N(R), Zoxazolyl, dihydroindanyl, benzisodiazolyl, spirocy clohexylindolinyl, spiro-(dihydrobenzothiophenyl) (23) NRC(O)OR, piperidinyl, Spiro-indolinylpiperidinyl, indolinyl, (24) - NRC(O)N(R), tetrahydroisoquinolinyl, isoindolinyl, benzothiadia (25) CR(N OR), Zolyl, benzotriazolyl, 1,3-dihydro-2-benzofuranyl, (26) —CF, benzothiophenyl, benzodioxolyl, tetrahydronaph (27) cycloalkyl, thyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyra nyl, and 1,4-benzodioxanyl. (28) cycloheteroalkyl, and (12) heteroaryl C- alkenyl, wherein the heteroaryl 10 (29) oxo; moiety is selected from: pyrrolyl, isoxazolyl, isothia each R is independently selected from: Zolyl pyrazolyl pyridyl, oxazolyl, oxadiazolyl, thia diazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, (1) R', furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, (2) —Sn(CH), pyrazinyl, benzoxazolyl, benzothiazolyl, benzimida 15 (3)C alkyl, Zolyl, benzofuranyl, benzothiophenyl, furoI2,3-b (4) Coalkenyl, pyridyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, (5) heteroaryl, benzisodiazolyl, triazolopyrimidinyl, 5,6,7,8-tet rahydroquinolinyl, 2,1,3-benzothiadiazolyl, and (6) aryl, and thienopyridinyl, (7) aryl-Co alkyl; (13) cycloalkyl C- alkenyl, wherein the cycloalkyl wherein alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, het moiety is selected from: cyclopropyl, cyclobutyl, eroaryl, and aryl moieties in R and R are optionally cyclopentyl, cyclohexyl, cycloheptyl, tetrahy Substituted with one to four R substituents; dronaphthyl, decahydronaphthyl, indanyl, bicyclo each R is independently selected from: 2.2.2]octanyl, tetrahydronaphthyl, and dihydroinda 25 nyl, and (1) halogen, (14) heterocycloalkyl C- alkenyl, wherein the hetero (2) amino, cycloalkyl moiety is selected from: aZetidinyl, (3) carboxy, pyridyl, pyrrolidinyl, piperidinyl, piperazinyl, imi (4) C alkyl, dazolidinyl, morpholinyl, 1-thia-4-aza-cyclohexane, 30 2,5-diazabicyclo[2.2.2]octanyl, 2,3-dihydrofuro2,3- (5) Calkoxy, bipyridyl, benzoxazinyl, tetrahydroquinolinyl, tet (6) aryl, rahydroisoquinolinyl, dihydroindolyl, indolyl, (7) aryl C alkyl, indolinyl, isoindolinyl, 1,3-dihydro-2-benzofuranyl, (8) hydroxy, benzodioxolyl, hexahydrothienopyridinyl, thienopy 35 ridinyl, azacycloheptyl, 4.4-spiro2,3-dihydroben (9) —CF, Zothiophen-3.3-yl)piperidinyl, and 4.4-spiro indoli (10) —OC(O)C alkyl, 3.3-yl)piperidinyl: (11) –OC(O)N(R), and wherein the alkyl moieties are optionally substituted with (12) aryloxy; one to three substituents selected from R'; and wherein 40 the aryl, heteroaryl, cycloalkyl and heterocycloalkyl R" is independently selected from hydrogen, C. alkyl, moieties are independently substituted with one to three substituents selected from R', and wherein sulfur aryl;is "E.R.E.E.S."heteroaryl; aryl-C alkyl; and heteroaryl-C ii. containing heterocyclic rings may be mono- or di alkyl: oxidized on the sulfur atom; 45 each R" is independently selected from: wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cyclohet (1 ) OR, eroalkyl, heteroaryl, and aryl in Rare optionally sub (2) - NHSOCH, stituted with one to two substituents independently (3) - NO, selected from a R: (4) halogen, 50 each R is selected from halogen, methyl, methoxy, trif (5) —S(O)CH, luoromethyl, trifluoromethoxy, and hydroxy: (6) —SCH, m is selected from 1 and 2: (7) - SCF, n is selected from: 0, 1, 2, 3, and 4: (8) S(O).OR, p is selected from 0, 1, and 2: (9) —S(O)N(R'), 55 (10) - N(CH), and pharmaceutically acceptable salts thereof. (11) —NH2, 6. The compound according to claim 1 of structural (12) - O(CRR)N(R), formula: (13) - C(O)R’, (14) —COH, 60 (15) - COCH, R. (16) t-butyloxycarbonyl, N (17) CO,(CRR),CON(R), O 2 (18) - OC(O)R’, N R (19) - CN, 65 (20) - C(O)N(R), (21) NRC(O)R, wherein: R and R are as illustrated in the table below: US 7,084, 156 B2 147 148

Ex. ii O O C O O C O O C

C O 10 O 11 O 12 C O US 7,084, 156 B2 149 150

-continued

Ex. ii

13

14

15

16

17

18

19

23

24 FC US 7,084, 156 B2 151 152

-continued

Ex. ii

25

26

27

28

29

30

31

32

33

34

35

36 US 7,084, 156 B2 153 154

-continued

Ex. ii

37

38

39

40

41

42

\

43

44

45

46

47

\/ 48 US 7,084, 156 B2 155 156

-continued

Ex. ii 49 FC

50

51 FC

52 FC

53

S4

55 FC CH N CH3

56 CH3 N CH

57

58 FC

59 FC

60 FC

US 7,084, 156 B2 163 164

-continued

Ex. ii

94 FC

CH 95 N CH3

96

CH D

97 98 st CH

99 FC CH3 > --- CH CH O

1OO CH Sr. 3 CH, CH

101 CH N ~sCH CH

102 CH N- CH3 CH3 103 N1)-cit,

ls CH 104 n-n-CH Null US 7,084, 156 B2 165 166

-continued

Ex. ii

105 FC

106 FC O

107

108

109 N OH

110

111

112 FC

113 FC

114 C O US 7,084, 156 B2 167 168

-continued

Ex. ii R7 R = NR'R'' 115 FC > N CH3 2N

116 FC N

CH3 2 N

117 FC CH Clus N--r)- CH H O 118 FC ul Clus HDrxso CH3 HC CH

119 FC 21

N N

120 O

HC 3 No N 21

121 O

HC 3 ou N 122 Co. 123 O 124

N US 7,084, 156 B2 169 170

-continued

Ex. ii

125

126

127

128

129

130

131

132

133

134

135 US 7,084, 156 B2 171 172

-continued

Ex. ii

136

137

138

139

140

141

143 US 7,084, 156 B2 173 174

-continued

Ex. ii US 7,084, 156 B2 175 176

-continued

Ex. ii

155

N

157

N

158

N

159 . N

160

N N u CH3

161

N N J CH

162

N

163

164

N US 7,084, 156 B2 177 178

-continued

Ex. ii

16S II III IN

N

166

N

167 N FC No N

168 21 N

H3C S. s N N CH3

169

N H

170 N

N ON

171 N

HC N

CH

172 N

N

173 N

N FC

174 21 N

N N

US 7,084, 156 B2 183 184

-continued

Ex. ii

194

195

196

197

198

199

2OO

2O1

CH

2O2

2O3 US 7,084, 156 B2 185 186

-continued

Ex. ii US 7,084, 156 B2 187 188

-continued

Ex. ii R7

214 CH O N es N H

215

N

216 21 N

N N H3C N

217

1s, N H

218 21 N HC N No N

219 N FCN N 220 N

HN

O

221 N

1. H3 C NN

222

N

223 N N US 7,084, 156 B2 189 190

-continued Ex. ii R7 R = NR'R2

224

N

225

N

226

N

227

N N

228

N HC Sn

CH

229

230

HO N

231

232

N

233 N N US 7,084, 156 B2 191 192

-continued

Ex. ii

2 34 H N N H3C OSa N No N

235

N N FC CrsN

236

HCin ls N Os N H H

237 O 21 N HC *s-( S. N UN 'N 238

N

239

240

N

241

N

242

N

243

N HO US 7,084, 156 B2 193 194

-continued Ex. ii R = NR'R2 244 F. C

C N N HOR7 N 245

246 N CH 247 NNoN-o

248 N C H3 /Nean-/\/ \N

249

N N

250

N N

251

252

N

253 1.

N N N/NN1O N US 7,084, 156 B2 195 196

-continued

Ex. ii R7

255 H

COrsO N ^ N N N N H

257

N

258

N

259

N

260 MO N FCN O

261 21 OS

N H3C N

262 H {S NS N

263

264 NNN

N