US 20070203209A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0203209 A1 Bartolini et al. (43) Pub. Date: Aug. 30, 2007
(54) USEFUL INDOLE COMPOUNDS Related U.S. Application Data (76) Inventors: Wilmin Bartolini, Amesbury, MA (60) Provisional application No. 60/709,958, filed on Aug. (US); Brian M. Cali, Arlington, MA 18, 2005. Provisional application No. 60/751,443, (US); Barbara Chen, Northbrook, IL filed on Dec. 16, 2005. (US); Yueh-Tyng Chien, Newton, MA (US); Mark G. Currie, Sterling, MA Publication Classification (US); G. Todd Milne, Brookline, MA (US); James Philip Pearson, (51) Int. Cl. Cambridge, MA (US); John Jeffrey A6II 3/428 (2006.01) Talley, Somerville, MA (US); Jing Jing A6II 3/405 (2006.01) Yang, Boxborough, MA (US); Craig C07D 417/02 (2006.01) Zimmerman, Topsfield, MA (US); Alex C07D 209/20 (2006.01) W. Monreal, Boston, MA (US) (52) U.S. Cl...... 514/367: 514/419: 548/498: 548/159 Correspondence Address: FSH & RICHARDSON PC P.O. BOX 1022 (57) ABSTRACT MINNEAPOLIS, MN 55440-1022 (US) Indoles having various activities, including indoles that are (21) Appl. No.: 11/507,099 CRTH2 are described. The compounds are useful for treat ing asthma, neuropathic pain, allegic rhinitis and other (22) Filed: Aug. 18, 2006 disorders.
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DAO Activity Assay DAO IC50 Row %. Inhibition at 10uM (uM)
254 5,7-dichloro-8-hydroxyquinolin-2(1H)-one a. 255 5-(4-fluorophenyl)sulfonyl)amino-2-methyl-1-benzofuran-3- carboxylic acid <
256 5-butyl-1H-indole-2-carboxylic acid < 257 5-chloro-1H-indole-2-carboxylic acid 50-100
258 5-chloro-3-phenyl-l-benzofuran-2(3H)-one 10-50 10-50 259 5-ethyl-1H-indole-2-carboxylic acid 260 5-ethyl-3-phenyl-l-benzofuran-2(3H)-one 10-50 261 5-fluoro-1-benzothiophene-2-carboxylic acid k 62 5-fluoro-lh-indole-2-carboxylic acid 50-100 263 5-fluoro-2-methyl-1H-indole-3-carbaldehyde <1 5-hydroxy-1-(4-methoxyphenyl)-2-methyl-1H-indole-3-carboxylic acid 10-50 265 5-hydroxy-1H-indole-2-carboxylic acid 50-100 266 5-hydroxy-1H-indole-3-carboxylic acid 50-00 267 5-hydroxy-2-methylnaphtho1,2-bfuran-3-carboxylic acid 50-100
2685-isopropyl-1H-indole-2-carboxylic- acid K 269 5-methoxy-1H-indole-2-carboxylic acid <1 270 5-methoxy-2-methyl-l-benzofuran-3-carboxylic acid
27 5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid K1 2725-methylthiophene-2-carboxylic acid 50-00 73 5-oxo-L-proline <1 274 5-phenyl-2-furoic acid <1 275 5-sec-butyl-1H-indole-2-carboxylic acid g 2765-tert-butyl-1H-indole-2-carboxylic acid <1
Patent Application Publication Aug. 30, 2007 Sheet 74 of 75 US 2007/0203209 A1 Figure 6
UPAC Name DAO Activity Assay DAO IC50 %. Inhibition at 10uM (uM)
propyl (5-hydroxy-2-methyl-1H-indol-3-yl)acetate 50-100 1-10 propyl (1-(4-chlorobenzoyl)-5-hydroxy-2-methyl-1H-indol-3- <1 llacetate propyl (1-(4-chlorobenzoyl)-6-fluoro-5-hydroxy-2-methyl-1H-indol-3 k
llacetate 327 pyridine-2-carboxylic acid <1 328 quinoline-2,8-diol 10-50 S0-100 sec-butyl (1-(4-chlorobenzoyl)-6-fluoro-5-hydroxy-2-methyl-1H indol-3-yllacetate sec-butyl 6-chloro-1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H 330 indol-3-yllacetate sec-butyl {6-chloro-1-(4-(difluoromethoxy)benzoyl)-5-methoxy-2- methyl-1H-indol-3-yl acetate sodium (5E)-5-[(aminocarbonyl)hydrazono-1-methyl-6-oxo-2,3,5,6- 332 tetrahydro-1H-indole-2-sulfonate trihydrate
333 sodium 6-methoxy-1,3-benzothiazole-2-carboxylate Patent Application Publication Aug. 30, 2007 Sheet 75 of 75 US 2007/0203209 A1
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USEFUL INDOLE COMPOUNDS FAAH Inhibitors 0001 Under 35 U.S.C. S 119 (e)(1), this application 0007 Many fatty acid amides are known to have anal claims the benefit of U.S. Provisional Applications 60/709, gesic activity. A number of fatty acid amides (e.g., arachi 958, filed Aug. 18, 2005 and 60/751,443, filed Dec. 16, donyl amino acids and anandamide) induce analgesia in 2005, both of which are incorporated in their entirety. animal models of pain (see, for example, Walker et al. 1999 Proc Natl Acad Sci 96:12198. Fride and Mechoulam 1993 BACKGROUND Eurj Pharmacol 231:313). Anandamide and certain other fatty acid amides (e.g., N-palmitoyl ethanolamine, N-oleoyl 0002 Cox Inhibitors ethanolamide, oleamide, 2-arachidonoylglycerol) are 0003 Cyclooxygenases play an essential role in prostag cleaved and inactivated by fatty acid amide hydrolase landin synthesis. Cyclooxygenase-1 (COX-1) is constitutive (FAAH) (Deutsch et al. 2003 Prostaglandins Leukot Essent and relatively long-lived, whereas cyclooxygenase-2 (COX Fatty Acids 66:201; and Cravatt and Lichtman 2003 Current 2) is inducible and relatively short-lived. COX-1 is thought Opinion in Chemical Biology 7:469). to be responsible for maintaining basal level prostaglandin 0008 Inhibition of FAAH is expected to lead to an production, which is important for normal gastrointestinal increase in the level of anandamide and other fatty acid and renal function. COX-2 is induced by certain inflamma amides. This increase in fatty acid amides may lead to an tory agents, hormones, growth factors, cytokines, and other increase in the nociceptive threshold. Thus, inhibitors of agents. COX-2 plays a significant role in prostaglandin FAAH are useful in the treatment of pain. Such inhibitors synthesis within inflammatory cells Such as macrophages might also be useful in the treatment of other disorders that and monocytes, and prostaglandin production associated can be treated using fatty acid amides or modulators of with COX-2 induction can have a deleterious effect on the cannabinoid receptors (e.g., anxiety, eating disorders, and body. Thus, to reduce unwanted inflammation and to treat cardiovascular disorders). NPAA (N-palmitoylethanolamine certain other conditions, it can be desirable to inhibit COX-2 acid anhydrolase) is a hydrolase that breaks down N-palmi activity without significantly inhibiting COX-1 activity. toyl ethanolamine (PEA), a fatty acid amide. PEA is a naturally occurring Substrate for the cannabinoid receptor 2 0004 Many non-steroidal anti-inflammatory drugs (CB2 receptor). Inhibition of NPAA may lead to increased (NSAIDs) inhibit both COX-1 and COX-2. These non PEA levels. Accordingly, NPAA inhibitors may be useful in selective inhibitors include indomethacin (Shen et al. 1963 the treatment of inflammation and nociceptive pain control. J Am Chem Soc 85:4881: 4-chlorobenzoyl-5-methoxy-2- Monoacylglycerol lipase (MAGL, MGL) is a hydrolase methyl-1H-indole-3-acetic acid). It is desirable to identify which degrades the endocannabinoid ligand, 2-arachi NSAIDs that inhibit COX-2 activity, but do not significantly donoylglycerol (2-AG). Although FAAH can also degrade inhibit COX-1 activity at physiological levels where COX-2 2-AG, MAGL is believed to be the main enzyme responsible activity is significantly inhibited. Such selective inhibitors for 2-AG metabolism in the brain. Thus, 2-AG inhibitors are expected to have the desirable anti-inflammatory, anti may be useful in the treatment of cannabinoid receptor pyretic, and analgesic properties associated with NSAIDs, related therapies including anxiety, eating disorders, and while having reduced or no gastrointestinal or renal toxicity. cardiovascular disorders. 0005 Subsequent to indomethacin administration, the 0009. In addition, there is evidence (see, e.g., Weber et al. unchanged parent compound, the desmethyl metabolite 2004 J. Lipid Res. 45:757) that when FAAH activity is (O-desmethylindomethacin: (1-(4-chlorobenzoyl)-5-hy reduced or absent, one of its Substrates, anandamide, acts as a substrate for COX-2 that can be converted to a prostamide. droxy-2-methyl-1H-indol-3-yl)acetic acid), the desbenzoyl Thus, certain prostamides may be elevated in the presence of metabolite (N-deschlorobenzoylindomethacin; (5-methoxy an FAAH inhibitor. Given that certain prostamides are 2-methyl-1H-indol-3-yl)acetic acid) and the desmethy-des associated with reduced intraocular pressure and ocular benzoyl metabolite (O-desmethy-N-deschlorobenzoylin hypotensivity, FAAH inhibitors may be useful agents for domethacin: (5-hydroxy-2-methyl-1H-indol-3-yl)acetic treating glaucoma. acid) can be found in plasma in significant amounts (Stra chman et al. 1964J Am Chem Soc 8: 799: Helleberg 1981 CRTH2 Modulators Clin Pharmacokinet 6:245), all in an unconjugated form 0010 CRTH2 is a G protein-coupled receptor that is (Harman et al. 1964J Pharmocol Exp. Therap 143:215). It thought to be involved in both mediating PGD-induced has been reported that all three metabolites are devoid of chemoattraction and in activation of specific cell types anti-inflammatory activity (Helleberg 1981 Clin Pharma involved in allergic inflammation. It has been reported that cokine. 6:245 and Duggan et al. 1972 Pharmacol and Exp CRTH2 is expressed by Th2 cells, eosinophils and baso Ther 181:562), although it has also been reported that the phils, but not by Th1 cells, B cells or NK cells. (Nagata et desmethyl metabolite has some ability to inhibit prostaglan al. 1999 FEBS Letters 459:195-199). din synthesis (Shen et al. 1977 Adv. Drug Res 12:90). 0011 PGD is produced by allergen-activated mast cells 0006 Indomethacin derivatives in which the benzoyl and has been implicated in various allergic diseases as a group has been replaced by a 4-bromobenzyl group or the pro-inflammatory mediator, although it may have anti-in acetic acid side chain has been extended exhibit greater flammatory activity in certain situations (Ajuebor et al. 2000 selectivity for inhibition of COX-2 relative to COX-1 (Black Am J Physiol Gastrointest Liver Physiol 279:G238-44). et al. 1996 Bioorganic & Medicinal Chem Lett 6:725 and CRTH2 receptor is a high affinity receptor for PGD, as is Black et al. 1997 Advances in Experimental Medicine and DP-1, a G protein-coupled receptor. Biology 407:73). In addition, synthesis methodology has 0012 CRTH2 agonists activate eosinophils, basophils been demonstrated for the preparation of indomethacin and Th2 cells in vitro, resulting in induction of actin analogues, some of which do not inhibit cyclooxygenases polymerization, calcium influx, CD11b expression and (Touhey et al. 2002 Eur J Cancer 38:1661). chemotaxis (Monneret et al 2003 J Pharmacol Exp. Ther US 2007/0203209 A1 Aug. 30, 2007
304:349-55). An in vivo study has demonstrated that injec Drug Metabol Drug Interact. 11:153-60). DAO degrades tion of a CRTH2 agonist can elicit transient recruitment of D-serine and other D-amino acids. D-glutamate and eosinophils from bone marrow into the blood (Shichijo 2003 D-serine are thought to be agonists of N-methyl-D-aspartate J Pharmacol Exp. Ther 307:518-525). A genetic study of (NMDA)-glutamate receptors that mediate a wide variety of African American and Chinese cohorts found that polymor phisms in CRTH2 were tightly associated with asthma brain activities, including the synaptic plasticity that is susceptibility (Huang et al. 2004 Hum Mol. Genet 2791). It associated with certain types of memory and learning has been suggested that modulators of CRTH2 may be (US20030162825). Thus, it is thought that inhibition of useful in the prevention and/or treatment of allergic asthma DAO will lead to increased D-serine levels and improved and other allergic disorders (US 2002/0022218 A1 and WO cognitive function. 03/066047). Recruitment and/or activation of eosinophils, basophils and Th2 cells is a prominent feature of the changes SUMMARY that occur in the asthmatic lung. Similar activation of these cell types, or subsets thereof, are believed to play an 0.015 Described herein are various inhibitors of CRTH2 important role in the etiology of other diseases, including pharmaceutically acceptable salts thereof, pharmaceutical eosinophilic esophagitis and atopic dermatitis (Arora and compositions comprising Such compounds and methods for Yamakazi 2004 Clin Gastroenterol Hepatol 2:523-30; Kiehl treating a patient by administering such pharmaceutical et al. 2001 BrJ Dermatol 145:720-729). This fact, combined with the fact that CRTH2 mediates PGD-induced chemo compositions alone or in combination with one or more taxis, Suggests that compounds that alter chemotaxis by other therapeutic agents. The compounds can be used to treat modulating CRTH2 activity could be useful in controlling various disorders, including neuropathic pain, asthma, chronic airway inflammation, atopic dermatitis, chronic including modest o severse asthma and allergic rhinitis, obstructive pulmonary disease (COPD), and/or eosinophilic including both seasonal or perennial rhinitis. esophagitis. Compounds that alter chemotaxis by modulat ing CRTH2 activity could also be useful in controlling 0016 Described herein a compound having Formula I allergic rhinitis. Allergic rhinitis is classified as either sea sonal (SAR) or perennial (PAR) depending upon the type of trigger and duration of symptoms. SAR symptoms occur in Formula I the spring, Summer and/or early fall and can be triggered by outdoor allergens Such as airborne tree, grass and weed pollens while PAR is usually persistent and chronic with symptoms occurring year-round and is commonly associ ated with indoor allergens such as dust mites, animal dander and/or mold spores. Symptoms of allergic rhinitis may include runny nose, nasal itching, Sneezing, watery eyes and nasal congestion. CRTH2 modulators may be useful for treating SAR and/or PAR. CRTH2 antagonists that reduce the ability of Th2 cells and eosinophils to respond to mast-cell derived PGD, could be useful for preventing and/or treating allergic disorders such as allergic rhinitis and asthma. (R) 0013. It is often found that agonists induce desensitiza tion of the cell system by promoting internalization and down regulation of the cell surface receptor (Int Immunol 0017 wherein: 15:29-38, 2003). Therefore, certain CRTH2 agonists may be therapeutically useful because they can cause the desensiti 0018) R' is H or a halogen: zation of PGD-responsive cells. It has been shown that certain CRTH2 agonists can induce desensitization of 0.019 R is H, OH, a halogen, —CH, wherein any PGD-responsive cells to subsequent activation by a CRTH2 carbon can be optionally, independently substituted with one agonist (see, e.g., Yoshimura-Uchiyama et al. 2004 Clin Exp or more halogen; or —OCH3, wherein any carbon can be Allergy 34:1283-1290). Importantly, CRTH2 agonists may optionally, independently substituted with one or more halo also cause cross-desensitization. Cross-desensitization, gen, which can occur in many cell-signaling systems, refers to a phenomena whereby an agonist for one receptor can reduce 0020 R is H, a halogen or -CH: or eliminate sensitivity of a cell type to an unrelated agonist/ receptor signaling system. For example, it is known that 0021 R is H or Cl; treatment with the CRTH2 agonist indomethacin reduces expression of CCR3, the receptor for the chemoattractant, eotaxin (Stubbs et al. 2002, J Biol Chem 277:26012-26020). DAO Inhibitors S 0014. It has been suggested that certain inhibitors of D-amino acid oxidase (DAO), including certain heterocylic N N is AO O 2-carboxylic acids, might be useful for improving memory, s (R6) learning and cognition in patients suffering from neurode generative disorders (US2003.0162825). Indomethacin has (R', 4 also been shown to be an inhibitor of DAO (Chenet. al 1994 US 2007/0203209 A1 Aug. 30, 2007
0030) further provided that when -continued
s’ / (R') is s 0022 Ris independently selected from F, Cl, Br, —CH, R" is H, R is H, R is C1, and R is H, and R is —CH, CF, OCH, OCFH, OCFH –OCF, CN, —SCF, -SCH, -CFH, or -SCFH: 0023) m is 0, 1, 2, or 3. 0024 R is H, a halogen, —CHCH or —CH: 0025 n=1, 2, or 3: 0026 R is CH or H, wherein when n=2 or 3, R is independently —CH or H: is not —CHC(O)CCH: 0027) and A is -OH, - OCH, –OCHCH 0031 further provided that when –OCHCHCH, or - OCHCHCHCH: 0028) provided that when
A R5
(R) is s is —CHC(O)CCH, R" is H, R is F. R is H, R is H, and R is CH, A R5
(R) is s
is not —CHC(O)CH: R is H, R is OCH R is C1, and R is H, R is not Br 0032 further provided that when R3 is halogen, R9 is or H: CH3, R1 is H, R is OCH3, R8 is H, 0029 further provided that when
(R) is s
R" is H. Riis H, R is CH, Riis H, and R is —CH, is —CHC(O)OH,
(R)-O" (R) & ) is not CHC(O)OCH or -CHC(O)OH. IN certain embodiment one or more or all of the following provisos m is 1, then R6 is not C1 in the para position or —OCF in apply: the para position; US 2007/0203209 A1 Aug. 30, 2007
0033 further provided that that when R is C1, R is 0035 further provided that when OH, —CH R is H, R is OCH or -OH, R is H,
in O -O" & ) (R) (R) is —CHC(O)CH, m is 0, R is H, R is H, R is Br, R is H, R is —CH, then
A R5 -O is -x\ / s O (R) (R) is not —CHC(O)CCHCH m is 1, then R is OCF in the para position, then 0.036 further provided that when
A R5
O o is -O -xV / s (R) (R) is not CHC(O)OH: 0034) further provided that further provided that that m is 0, R is H, R is OCH R is C1, R is H, R is Br, when R is F. R. is CH, R is F. R is OCH or -OH, then R is H,
is not —(CH),C(O)OCHCH is CHC(O)OH 0037 further provided that when 2 s
-O" & ) o (R) (R) x / (R) is (R6),1\\x / s m is 1, then R is Br in the para position, then m is 0, R is H, R is H, R is F. R is H. R9 is H, then
is not CHC(O)OH: is not -(CH),C(O)OCHCH: US 2007/0203209 A1 Aug. 30, 2007
0038 further provided that when 0041 further provided that when
(R) is C s (R) is (R6-Š / s m is 0, R is H, R is OCH R3 is C1, R8 is H. R9 is H, m is 1, R is —Br in the para position, R is F. R is OH or then –OCH R is F. R is H, R is —CH, then
A A R5 RS O ... O is not —CH2C(O)OH: is not CHC(O)OH: 0039 further provided that when 0.042 further provided that when m is 0; R', R, R and Rare H, R is CH, then
(R) ( ) is (Rs.1&M / O mis 0, R is H, R2 is H, R is C1, R8 is H, R is CH, then is not CH3C(OOH: 0.043 further provided that when
R5
O (R) -O is (R6-83. / s is not CHC(O)OH 0040 further provided that when m is 1, R is OCF in the para position R' is H, R is OH, R is C1, R is H, R is —CH, then A R
o O
(R) -O is (R6)1V3. s is not —CHC(O)CH: m is 1, R is OCF in the para position, R is H. R. is OH, 0044 further provided that when R is C1, R is H, R is —CH, then
R5
A (R) is (R6 & 3./ s is not CHC(O)OH: m is 0, R is H, R is OCH R is C1, R is H, R is H, then US 2007/0203209 A1 Aug. 30, 2007
0051). In other embodiments: wherein R is -CH3, CHCH, or a halogen; R9 is a halogen; R is —CH or Cl; R’ is CH: R is Cl; R is H, F, C1, OCH or CH: R is —OCH or -CH: R is —OCH: R is —CH: R is —OCH, singly or independently multiply substituted with is not —CH2C(O)OH: one or more halogen or —CH singly or independently multiply substituted with one or more halogen; R is —OH: 0045 further provided that when R is a halogen; R is F, Cl, or Br; R is Cl; R is Br; R is F; R is H; 0.052. In other embodiments: (R) -O is Sd s m is 0, R is OCH in the meta position R is F. R is OH or —OCH3, R is H, R is H, R is CH, then A (R)o is (R')nC s RS m=1, 2, or 3 and R is independently a halogen, -SCFs, —SCH. —CF, OCF or —OCH. 0053) In certain cases: R is - SCF. R is - SCH: R is not CHC(O)OH or - CHCHC(O)OH. is CF; R is OCF. R is —OCH: R is a halogen; R 0046) In some embodiments: is Cl; R is F: 0054) In other embodiments: (R) -O is O 0047. In other embodiments: (R) is R6
A In some cases: m is 1. In other cases m is 2. RS 0055) 0056) In other embodiments: O is O V 0.048 - CHCHC(O)OH, CHC(O)OH, (R) is (Rs)& / —CHCHC(O)CCH —CHC(O)OCH, —CHCHC(O)OCHCH —CHC(O)OCHCH —CHCHC(O)CCHCHCH O m is 2 or 3 and at least one R is in the meta position. —CHC(O)OCHCHCH 0057. In other embodiments: 0049. In other embodiments:
A R5
O is
(R) is 2 0050 CH(CH)C(O)OH, -CH(CH)C(O)CCH, CH(CH)CHC(O)CH, CH(CH)CHC(O)OCH, US 2007/0203209 A1 Aug. 30, 2007
0058. In other embodiments:
A R5
O is O M (R) is . 0.064 CHCHC(O)OH, CHC(O)OH, - CHCHC(O)OCH, —CHC(O)OCH, - CHCHC(O)OCHCH —CHC(O)OCHCH m is 1 and R is in the ortho or para position. —CHCHC(O)CCHCHCH, CHC(O)CCHCHCH: 0059. In other embodiments: R' and Rare H. A is 0060. In other embodiments: R5 (X1, O
0065 –CH(CH)C(O)OH, -CH(CH)C(O)OCH, CH(CH)CHC(O)CH, CH(CH)CHC(O)OCH, —CH(CH)C(O)OCHCH O is CHC(O)OH. CH(CH2)CHC(O)OCHCH: R is -CH3, -CHCH or a halogen; R is a halogen; R is CH or Cl; R is —CH: R 0061. In other embodiments: is Cl; R is H. F. C1, OCH or -CH: R is —OCH or —CH: R is OCH: R is —CH: R' and Rare both H: R" and Rare not both not H; R is a halogen; R is Cl: R is F. 0066. In some cases: R in at in the meta position and R3 is a halogen; R is the metaposition is OCF; R is Cl; R is —CH; R is —OCH or —CH, either optionally sub stituted with one or more halogen; R' is H; R is H; m is 2: the two R differ and are both in the meta position; the two is CHCHC(O)OH. Rare the same and are both in the meta position; or n is 1. 0062). Other compounds described have the formula: 0067. Also disclosed are compounds having the formula:
0063) In some cases: R is: —CH, —CF, —OCH, –OCF. H. —OCFH - OCF, CN, SCF, -SCH, 0068 wherein: —CFH, or - SCFH: R is: —OCH, OCFH, 0069) R' is H or a halogen; –OCFH, OCF, CN, -SCF, -SCH, -CFH, or —SCFH: R is: —OCH, OCF.H. OCFH, or 0070 R is H, -OH, a halogen, —CH; or - OCH3, —OCF. R is H. F. Cl, —CH, optionally, independently wherein any carbon can be optionally, independently Sub Substituted with one or more halogen, or —OCH option stituted with one or more halogen; ally, independently Substituted with one or more halogen; 0.071) R' is a halogen or -CH: US 2007/0203209 A1 Aug. 30, 2007
0072 R is H or Cl; 0081. Also described is a method for treating asthma 0073 R is CH, CF, OCH, OCFH, comprising administering any of the compounds described –OCFH, OCF, CN, -SCF, -SCH, -CFH, or above with the provisos. SCFH: 0082 Also described is a method for treating neuropathic 0074 R is H, a halogen, —CHCH or —CH: pain comprising administering any of the compounds 0075) n=1, 2, or 3: described above with the provisos. 0076 R is CH or H, wherein when n=2 or 3, R is 0083. Also described is a method for treating allergic independently —CH or H: rhinitis comprising administering any of the compounds described above with the provisos. 0077 and A is -OH, - OCH, –OCHCH –OCHCHCH, or - OCHCHCHCH. 0084. Also described is a method for treating asthma 0078. In other embodiments: R is a halogen; comprising administering any of the compounds described above without the provisos. A is R5 0085 Also described is a method for treating neuropathic ( pain comprising administering any of the compounds O described above without the provisos. 0086 Also described is a method for treating allergic 0079 –CHCHC(O)OH, CHC(O)OH, rhinitis comprising administering any of the compounds —CHCHC(O)OCH, —CHC(O)OCH, described above without the provisos. —CHCHC(O)CCHCH —CHC(O)OCHCH —CHCHC(O)OCHCHCH 0087 Compounds described include those having For CHC(O)OCHCHCH;in mula I
A is Formula I R5 ( O
0080) -CH(CH)C(O)OH, -CH(CH)C(O)OCH, CH(CH)CHC(O)CH, CH(CH)CHC(O)OCH, —CH(CH)C(O)OCHCH O CH(CH2)CHC(O)CCHCH: R is CH3, CHCH or a halogen; R is a halogen; R is CH or Cl; R is —CH: R’ is Cl; R is H, F, C1, OCH or CH: R is OCH (R) or —CH; R is OCH R is —CH: R is —OCH, singly or independently multiply substituted with one or more halogen or —CH singly or independently multiply substi tuted with one or more halogen; R is OH: R is —OCF; 0088 For compounds having Formula I R is F, C1 or Br; R is Cl; R is Br; R is F: R is H; R and Rare both H: 0089) R' is: H or a halogen; 0090 R is: H, a halogen, —CN, C to C alkyl, R'S - or RPO - wherein 0091) R' is selected from: 0092 (a) H: 0093 (b) C to C alkyl or a C to Calkenyl that is optionally independently substituted with one or more is CHC(O)OH: of a halogen, OH, -NH, or —C(O)OH: A R5 ( (c) O is CHCHC(O)OH. US 2007/0203209 A1 Aug. 30, 2007
-continued (g) Y 0094) wherein each R’ is independently: H, a C to C alkyl, a C to Calkenyl, a C to C alkynyl, a C to Co aryl, wherein the carbonyl carbon is bonded to the N of the a C to Co cycloalkyl, or a C, to Carylalkyl optionally 1. dol e independently substituted with one or more halogen, —OH, s —C(O)OH, or - NH: (h) 0.095 R is H, a halogen, —CH, -CF, CFH, –OCFH, OCF, -SCFH, -SCF, or—CN: 0096) Z is selected from: (a) wherein the carbonyl carbon is bonded to the N of the indole,
(b) (i)
CFS,
(c)
wherein the carbonyl carbon is bonded to the N of the indole, or 0.098 () a bond; 0099 A is selected from: wherein the carbonyl carbon is bonded to the N of the indole, 0100 (a) - XR, 0101 (b) - X, opo (d) O E S E O, (c) ty.X 0097 (e) C to C alkyl,
(f) 0102 (d) a C to C alkyl or alkenyl, independently Substituted with one or more halogen, X 0103) (e) –C(O)CX wherein X is H or a C to C. alkyl or alkenyl, independently substituted with one or ) more halogen; and 0104 (f) –C(O)NH; and 0105 wherein: wherein the the carbonyl carbon is bonded to the N of the 0106 X" is indole and q is 1, 2, 3, or 4, - N(H)S(O)–: US 2007/0203209 A1 Aug. 30, 2007 10
01.07) R' is H. -OH, a C, to Coalkoxy, a C, to Co represents: a C to C Saturated carbocycle; a Caryl, Cs to alkyl, a C to Coalkenyl; a C to Co alkynyl; a C to C non-saturated, non-aromatic carbocycle; a 6-membered Cs cycloalkyl, a C to Ca hydroxyalkyl; a hydroxyl heteroaryl having 1, 2, 3, 4 or 5 heteroatoms independently Substituted C to C aryl; a primary, secondary or selected from O, S, S(O), N, S(O) and N(R); a 3- to tertiary C to C alkylamino; primary, secondary or 7-membered saturated or non-Saturated heterocycle having tertiary C to Carylamino; C to C alkylcarboxylic 1, 2, 3, 4 or 5 heteroatoms independently selected from O, acid; a C to C alkylester; a C to Co aryl; a C to Co S, S(O), N, S(O) and N(R); a 6, 5-fused heteroaromatic arylcarboxylic acid; a C to Co arylester; a C to Co ring system having 1, 2, 3 or 4 heteroatoms independently aryl substituted C to C alkyl; a 4 to 8 membered selected from N, O and S; a 6, 6-fused heteroaromatic ring unsaturated or saturated heterocycle or a 4 to 8 mem system having 1, 2, 3 or 4 heteroatoms independently bered heteroaryl wherein the heteroatoms are selected from O, S, S(O), N, and S(O); an alkyl-substituted or selected from N, O and S; a napthyl group: aryl-substituted 4 to 8 membered or saturated hetero 0.124 each R is independently: H, -OH, a halogen, a cycle or 4 to 8 membered heteroaryl wherein the C-C alkyl, -CN, OCH, -SCH, OCHCH, heteroatoms are selected from O, S, S(O), N, and —SCHCH. —CHCH. —SOCH, —C(O)OCH, S(O), wherein one or more H within R* can be replaced —C(O)CHa C-C alkoxy, a C to C saturated carbocycle, by a halogen, —OH, -C(O)OH, or —NH; a Caryl, C-C non-Saturated, non-aromatic carbocycle, a 6-membered heteroaryl having 1, 2, 3, 4 or 5 heteroatoms 0108) X is: independently selected from O, S, S(O), N. S(O) and 0.109 (a) a benzyl group: N(R), a 3- to 7-membered saturated or non-saturated het 0110 (b) a 6-membered unsaturated heterocycle hav erocycle having 1, 2, 3, 4 or 5 heteroatoms independently ing 1, 2, 3 or 4 heteroatoms independently selected selected from O, S, S(O), N, S(O) and N(R) wherein one from N, O, and S: or more H within R can be replaced by a halogen; 0.111 (c) a 5-membered unsaturated heterocycle hav 0.125 m=1, 2, 3, 4, or 5: ing 1, 2, 3 or 4 heteroatoms independently selected 0126) R' is: H, a halogen, —CH, —CN, OCH, from N, O and S; —SCH-SCHCH —OCHCH, CHCH or a C-C, 0112 (d) a 5, 5 or 6, 5 unsaturated or aromatic fused alkoxy wherein one or more H can be replaced by a halogen; ring having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S.: 0127 R is: H, a halogen or —CH, wherein one or more H can be replaced by a halogen; and 0113 (e) C(O)OH, 0128 R is C1, a C to C alkyl, wherein one or more H 0114 (f) a C-C alkyl, can be replaced by a halogen. 0115 (g) a C-C alkoxyl, and 0129. Also described are compounds having Formula II 0116 (h) a C-C thioalkoxy,
0117 wherein X can be independently singly or multiply Formula II substituted at any substitutable position with OH, -CN. lower alkyl, lower alkoxy, halogen, and —CH, -SCH, RI —OCH, —CHCH —OCHCH, or —SCHCH Z C." wherein one or more H can be replaced by a halogen. R2 0118 Y is C or N: Y-R 0119 Q is O or S; R3 N 0120 X and X’ are independently selected from H, R8 —C(O)H, —COH, a C to C alkyl, a benzyl, a 6-mem R5 bered unsaturated or aromatic heterocycle having 1, 2, or 3 A heteroatoms independently selected from N, O, and S, and O a 5-membered unsaturated or aromatic heterocycle having 1. 2, or 3 heteroatoms independently selected from N, O and S; 0121 provided that when Y is N, X is absent: 0.130 For compounds having Formula II 0122) n is 1, 2, 3, 4 or 5: 0131) R' is: H or a halogen: 0123) Each R is independently: H, -OH, halogen, or an 0132 R is: H, a halogen, —CN, C to C alkyl, R'S - optionally substituted C to C alkyl, wherein the substitu or RPO - wherein ents are independently selected from a halogen and —OH: 0.133 R’ is selected from: 0134 (a) H: O 0135 (b) C to C alkyl or a C to C alkenyl that is optionally independently substituted with one or more of a halogen, —OH, -NH2 or —C(O)OH: US 2007/0203209 A1 Aug. 30, 2007 11
wherein the the carbonyl carbon is bonded to the N of the (c) indole and q is 1, 2, 3, or 4,
R2A O (g) R2 sO R2A. O R2
O wherein the carbonyl carbon is bonded to the N of the R2A indole, wherein each R is independently: H, a C to C alkyl, a (h) C. to Calkenyl, a C to C alkynyl, a C to Co aryl, a C to Co cycloalkyl, or a C7 to Co arylalkyl option ally independently substituted with one or more halo gen, OH, C(O)OH, or NH; 0136 R is H, a halogen, CH, —CF, CF.H. –OCF. H. —OCF, -SCFH, -SCF, or –CN: 0137 Z is selected from: wherein the carbonyl carbon is bonded to the N of the (a) indole, (i)
(b)
sC E S, 4. wherein the carbonyl carbon is bonded to the N of the (c) indole, or 0139 () a bond O 0140) A is selected from: \ 0141 (a) - XR, 0.142 (b) - X, wherein the carbonyl carbon is bonded to the N of the indole, X3 (c) opo (d) N-Y O E S O, Kys
0.143 (d) a C to C alkyl or alkenyl, independently 0138 (e) C to C alkyl, Substituted with one or more halogen, (f) 0144 (e) - C(O)OX wherein X is H or a C to C alkyl or alkenyl, independently substituted with one or more halogen; and
t HN 0145 and () ) 0146 (f) –C(O)NH; and 0147 wherein: s 0148 X" is -O-, - S -, - N(H)– or - N(H)S(O)–: US 2007/0203209 A1 Aug. 30, 2007 12
0149) R' is H. -OH, a C, to Coalkoxy, a C, to Co heteroaryl having 1, 2, 3, 4 or 5 heteroatoms independently alkyl, a C to Coalkenyl; a C to Co alkynyl; a C to selected from O, S, S(O), N, S(O) and N(R); a 3- to Cs cycloalkyl, a C to Ca hydroxyalkyl; a hydroxyl 7-membered saturated or non-Saturated heterocycle having Substituted C to Cs aryl; a primary, secondary or 1, 2, 3, 4 or 5 heteroatoms independently selected from O, tertiary C to C alkylamino; primary, secondary or S, S(O), N, S(O) and N(R); a 6, 5-fused heteroaromatic tertiary C to Cs arylamino; C to C alkylcarboxylic ring system having 1, 2, 3 or 4 heteroatoms independently acid; a C to C alkylester; a C to Co aryl; a C to Co selected from N, O and S; a 6, 6-fused heteroaromatic ring arylcarboxylic acid; a C to Co arylester; a C to Co system having 1, 2, 3 or 4 heteroatoms independently aryl substituted C to C alkyl; a 4 to 8 membered unsaturated or saturated heterocycle or a 4 to 8 mem selected from N, O and S; a napthyl group: bered heteroaryl wherein the heteroatoms are selected 0166 each R is independently: H, -OH, a halogen, a from O, S, S(O), N, and S(O); an alkyl-substituted or C-C alkyl, -CN, OCHs. SCH, OCHCHs. aryl-substituted 4 to 8 membered or saturated hetero - SCHCH. —CHCH. —SOCH, —C(O)OCH, cycle or 4 to 8 membered heteroaryl wherein the —C(O)OH, a C-C alkoxy, a C to C Saturated carbocycle, heteroatoms are selected from O, S, S(O), N, and a Caryl, C-C non-Saturated, non-aromatic carbocycle, a S(O), wherein one or more H within R' can be replaced 6-membered heteroaryl having 1, 2, 3, 4 or 5 heteroatoms by a halogen, —OH, -C(O)OH, or —NH; independently selected from O, S, S(O), N. S(O) and N(R), a 3- to 7-membered saturated or non-saturated het O150 X is: erocycle having 1, 2, 3, 4 or 5 heteroatoms independently 0151 (a) a benzyl group: selected from O, S, S(O), N, S(O) and N(R) wherein one or more H within R' can be replaced by a halogen; 0152 (b) a 6-membered unsaturated heterocycle hav ing 1, 2, 3 or 4 heteroatoms independently selected 0167 m=1, 2, 3, 4, or 5: from N, O, and S: 0168 R is: H, a halogen, —CH, —CN, OCH, 0.153 (c) a 5-membered unsaturated heterocycle hav —SCH. —SCHCH. —OCHCH, —CHCH or a C-C, ing 1, 2, 3 or 4 heteroatoms independently selected alkoxy wherein one or more H can be replaced by a halogen; from N, O and S; 0169 R is: H, a halogen or —CH, wherein one or more 0154 (d) a 5, 5 or 6, 5 unsaturated or aromatic fused H can be replaced by a halogen; and ring having 1, 2, 3 or 4 heteroatoms independently 0170 R is C1, a C to C alkyl, wherein one or more H selected from N, O and S.: can be replaced by a halogen. O155 (e) - C(O)CH, 0171 Also disclosed are compounds having Formula III 0156 (f) a C-C alkyl, 0157 (g) a C-C alkoxyl, and Formula III 0158 (h) a C-C thioalkoxy; 0159) wherein X can be independently singly or multi ply substituted at any substitutable position with OH, - CN, R12 lower alkyl, lower alkoxy, halogen, and —CH, -SCH, —OCH, —CHCH —OCHCH, or —SCHCH wherein one or more H can be replaced by a halogen. 0160 Y is C or N: 0172 wherein 0161 Q is O or S; 0173 R' is selected from: H, CH, F, Cl, Br. -OH, 0162 X and X’ are independently selected from H, —CF, —CF.H. —OCH, OCF. H. —OCF. —SCH, —C(O)H, —COH, a C to C alkyl, a benzyl, a 6-mem SCFH, -SCF, CN, NO, -SOCH, -SOCH, bered unsaturated or aromatic heterocycle having 1, 2, or 3 —SONH: heteroatoms independently selected from N, O, and S, and 0174) R' is selected from: H, F, Cl, Br, —CH, OCH, a 5-membered unsaturated or aromatic heterocycle having 1. —CF, CFH, OCFH, OCF, -SCH, -SCFH, 2, or 3 heteroatoms independently selected from N, O and S; —SCF, —CN, —SOCH - SOCH —SONH; and 0163 provided that when Y is N, X is absent: O175 a) R 3. is C O OH: R 14 is H; and R 15 is H;
0164 n is 1, 2, 3, 4 or 5: 3. 14 15 0165) Each R is independently: H, -OH, halogen, or an O176 b R is H; R is C(O OH: and R is H; optionally substituted C to C alkyl, wherein the substitu 0.177 C 1S 1S , an 1S — ents are independently selected from a halogen and —OH: 0.178 (d) R' is H; R is C(O)CH; and R' is C(O)CH: 0179 (e) R' is C(O)OH: R'' is H; and R' is O - C(O)OH; or 0180 (d) R' is selected from: H, C-C alkyl, represents: a C to C Saturated carbocycle; a Caryl, Cs to —C(O)CH, and –PO(OH): R'' is selected from H, Ce non-saturated, non-aromatic carbocycle; a 6-membered C-C alkyl, -C(O)OH, and –PO(OH); and R' is US 2007/0203209 A1 Aug. 30, 2007
selected from —CH2PO(OH), —CHCHPO(OH), H, CH, -CHCOH, -CHCHCO.H. -continued (b) 0181 Also disclosed are compounds having Formula IV:
Formula IV 4.CFS, (c)
wherein the carbonyl carbon is bonded to the N of the indole, (R) (d) 0182. Wherein opo 0183) R' is: H or a halogen: O E S E O, 0184 R is: H, a halogen, —CN, C to C alkyl, RS– or RO– wherein 0.185) R' is selected from: 0191 (e) C to C alkyl, 0186 (a)H: 0187 (b) C to C alkyl or a C to C alkenyl that is (f) optionally independently substituted with one or more of a halogen, OH, -NH, or —C(O)OH:
(c) O O O R2A V R’s s 2A s N ; or O R R2/ O wherein the the carbonyl carbon is bonded to the N of the indole and q is 1, 2, 3, or 4, R2A-O-P-
O (g) R2A
0188 wherein each R’ is independently: H, a C to C alkyl, a C to Calkenyl, a C to C alkynyl, a C to Co aryl, a C to Co cycloalkyl, or a C7 to Cao arylalkyl optionally independently substituted with one or more halogen, —OH, —C(O)OH, or - NH: wherein the carbonyl carbon is bonded to the N of the 0189 R is H, a halogen, CH, -CF, indole, –OCFH, OCF, -SCFH, -SCF, or—CN: 0190. Z is selected from: (h)
(a)
* . s 4. US 2007/0203209 A1 Aug. 30, 2007
wherein the carbonyl carbon is bonded to the N of the 0206 (c) a 5-membered unsaturated heterocycle hav indole, ing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; 0207 (d) a 5, 5 or 6, 5 unsaturated or aromatic fused ring having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S.: 0208 (e) - C(O)OH, 0209 (f) a C-C alkyl, 0210 (g) a C-C alkoxyl, and wherein the carbonyl carbon is bonded to the N of the 0211 (h) a C-C thioalkoxy; indole, or 0212 wherein X can be independently singly or multi ply substituted at any substitutable position with OH, -CN. 0.192 (i) a bond lower alkyl, lower alkoxy, halogen, and —CH, -SCH, 0193 A is selected from: —OCH, —CHCH —OCHCH, or —SCHCH 0194 (a) - XR, wherein one or more H can be replaced by a halogen. 0.195 (b) X, 0213 Y is C or N: (c) 0214) Q is O or S: X3 M 0215 X and X’ are independently selected from H, N-Y —C(O)H, —COH, a C to C alkyl, a benzyl, a 6-mem bered unsaturated or aromatic heterocycle having 1, 2, or 3 f > heteroatoms independently selected from N, O, and S, and Q X4, a 5-membered unsaturated or aromatic heterocycle having 1. 2, or 3 heteroatoms independently selected from N, O and S; 0196) (d) a C to C alkyl or alkenyl, independently 0216) provided that when Y is N, X is absent: Substituted with one or more halogen, 0217 n is 1, 2, 3, 4 or 5: 0197) (e) –C(O)CX wherein X is H or a C to C 0218. Each R is independently: H, -OH, halogen, or an alkyl or alkenyl, independently substituted with one or optionally substituted C to C alkyl, wherein the substitu more halogen; and ents are independently selected from a halogen and —OH: 0198 and 0199 (f) = C(O)NH; and 0200 wherein: O 0201 X is - N(H)S(O)–: represents: a C to C. Saturated carbocycle; a Caryl, C. to 0202) R' is H. -OH, a C, to Coalkoxy, a C, to Co Ce non-saturated, non-aromatic carbocycle; a 6-membered alkyl, a C to Coalkenyl; a C to Co alkynyl; a C to heteroaryl having 1, 2, 3, 4 or 5 heteroatoms independently Cs cycloalkyl, a C to Ca hydroxyalkyl; a hydroxyl selected from O, S, S(O), N, S(O) and N(R7); a 3- to Substituted C to C aryl; a primary, secondary or 7-membered saturated or non-Saturated heterocycle having tertiary C to C alkylamino; primary, secondary or 1, 2, 3, 4 or 5 heteroatoms independently selected from O, tertiary C to Carylamino; C to C alkylcarboxylic S, S(O), N, S(O) and N(R); a 6, 5-fused heteroaromatic acid; a C to C alkylester; a C to Co aryl; a C to Co ring system having 1, 2, 3 or 4 heteroatoms independently arylcarboxylic acid; a C to Co arylester; a C to Co selected from N, O and S; a 6, 6-fused heteroaromatic ring aryl substituted C to C alkyl; a 4 to 8 membered system having 1, 2, 3 or 4 heteroatoms independently unsaturated or saturated heterocycle or a 4 to 8 mem selected from N, O and S; a napthyl group: bered heteroaryl wherein the heteroatoms are selected from O, S, S(O), N, and S(O); an alkyl-substituted or 0219) each R is independently: H, -OH, a halogen, a aryl-substituted 4 to 8 membered or saturated hetero C-C alkyl, -CN, OCH, -SCH, OCHCHs. cycle or 4 to 8 membered heteroaryl wherein the —SCHCH. —CHCH. —SOCH, —C(O)OCH, heteroatoms are selected from O, S, S(O), N, and —C(O)CH, a C-C alkoxy, a C to C. Saturated carbocycle, S(O), wherein one or more H within R* can be replaced a Caryl, C-C non-Saturated, non-aromatic carbocycle, a by a halogen, —OH, -C(O)OH, or —NH; 6-membered heteroaryl having 1, 2, 3, 4 or 5 heteroatoms independently selected from O, S, S(O), N. S(O) and 0203 X is: N(R), a 3- to 7-membered saturated or non-saturated het 0204 (a) a benzyl group: erocycle having 1, 2, 3, 4 or 5 heteroatoms independently 0205 (b) a 6-membered unsaturated heterocycle hav selected from O, S, S(O), N, S(O) and N(R) wherein one ing 1, 2, 3 or 4 heteroatoms independently selected or more H within R can be replaced by a halogen; from N, O, and S: 0220 m=1, 2, 3, 4, or 5: US 2007/0203209 A1 Aug. 30, 2007 15
0221) R' is: H, a halogen, —CH, —CN, OCH, thiazole, oxazole, and imidazole —SCH. —SCHCH. —OCHCH, —CHCH or a C-C, alkoxy wherein one or more H can be replaced by a halogen; 0222 R is: H, a halogen or —CH, wherein one or more H can be replaced by a halogen; and N2 N2 N2 can0223 be replacedR is C1, by a aC halogen. to C alkyl, wherein one or more H ls/ l/ l/ 0224 Disclosed herein are: a pharmaceutical composi- (R) (R) (R) tion comprising any of the forgoing compounds and a pharmaceutically acceptable carrier; a method for treating Na N2 Na inflammationprising any of comprising the forgoing administering compounds; aa composition method for treat-com- us s/s us s/s us s / ing anxiety comprising administering any of the forgoing (R) (R) (R) compounds; a method for treating a sleep disorder compris- 6 6 6 ing administering any of the forgoing compounds; and a (R) (R) (R) method for treating a respiratory disorder (e.g., asthma) salv sely sely comprising administering any of the forgoing compounds. S O NR; 0225. A method for inhibiting COX-2 activity in a S. S. S. patient, the method comprising administering any of the forgoing compounds, e.g., a compound of Formula I wherein A is X'R' and wherein X is O and R is H is disclosed. 0226. Also disclosed is a method for inhibiting FAAH activity in a patient, the method comprising administering any of the forgoing compounds (e.g., a compound of For- N N N mula I wherein Ais-X'R' and X is O and R is other than 2- \ 2- \ 2 \, H or A is X or A is: s S s O s NR (R) (R) (R) X3 N N N-Y 2 \, 2 \, 2 \, () > SS/ S ss/O ss/NR Q X4 (R)6 (R)6 (R)6 (R) (R) (R) AaN AeN AsN 0227. A method for modulating CRTH2 activity on a \s Yo YR: patient is disclosed, the method comprising administering S. S. S. any of the compounds described herein. 0228. For any of the compounds decribed herein where 1,2,3-triazole O NaN NaN is a 5-membered ring heterocycle, suitable 5-membered ring S. NR S. NR; heterocycles include: thiophene, fiuran, and pyrrole -Sk R6 R6
e e e 1,2,4-triazole US 2007/0203209 A1 Aug. 30, 2007 16 tetrazole 1,2,4-thiadiazole
eN NR, NSSN / -( -k R6 J. J. 1.2.3-oxadiazole 1,2,5-thiadiazole
1,2,4-oxadiazole 1,3,4-thiadiazole
N1 N R6 3. R6 S)—is
1,2,5-oxadiazole 1,2,3,4-thiadiazole Y-8. NNNO / 0229. For any of the compounds decribed herein where 1,3,4-oxadiazole
-N O
X is a 5 or 6-membered ring saturated heterocycle, suitable 5 or 6-membered ring Saturated heterocycles include: 1,2,3,4-oxatriazole 0230 Piperidine and substituted piperidine
N R7 n. C (R) U1s (R) 1,2,3-thiadiazole
N R6 N R1 Nrs. N- (R) C.- (R) / R6 s/ S US 2007/0203209 A1 Aug. 30, 2007 17
0231 Pyyrolidine and substituted pyrrolidine 0235. Thiomorpholine and substituted thiomorpholine and their sulfoxide and sulfone derivatives
( R-N N N -/- (R) -1-(R) C - - e. t - -(e. 8, 8, -/- (R) O)n 2 N R N -- H(R6) 0232 AZetidine and substituted azetidine
0236. Thioethers, substituted thioethers, their sulfoxides and Sulfones
cy "is) N R.) R 0237 Ethers and substituted ethers
0233 Piperazine and substituted piperazine x1 (R) (Aso
N N C G- (R) G- (R) 0238 1,4-Thioether-ethers and 1,4-dioxane derivatives N N l l (O)0-2 (O)0-2
0234 Morpholine and substituted morpholine C - C Crs Cec Cir. 0239 1,4-bis-Thioethers, their sulfoxides and sulfones
Ge.S US 2007/0203209 A1 Aug. 30, 2007
0240 Also included are tetrahydrofuran, dihydrofuran, 0246 1,2,3-triazine tetrahydrothiophene, dihydrothiophene, piperidine, dihyro pyrrole, 1,3-dithiolane, 1,2-dithiolane, isoxazolidine, isothiazolidine, pyrazolidine, tetrahydro-2H-pyran, tetrahy dro-2H-thiopyran, 3,6-dihydro-2H-thiopyran, 3,4-dihydro 2H-thiopyran, piperidine, 1.2.3,6-tetrahydropyridine, 1.2.3, 4-tetrahydropyridine, morpholine, thiomorpholine, piperazine, thiomorpholine 1-oxide, thiomorpholine 1,1- dioxide, and the like. 0241 For any of the compounds decribed herein where 0247 1,2,4-triazine O is a 6-membered ring hetereocycle, suitable 6-membered Nin 2 ring heteroaryls include: N 0242 pyridine 0248 1,3,5-triazine
N Y n -ie NS-2N
0249 1,2,3,4-tetrazine R6 rs N n? N:
0250) 1,2,3,5-tetrazine Y Ns R6; N na N
0251) 1,2,4,5-tetrazine - H(R6) Y NSN NelsNN R6; 0245 pyridazine 0252 pentazine
NseN N US 2007/0203209 A1 Aug. 30, 2007 19
0253) Suitable carbocycles for 0260 cyclobutenyl and substituted cyclobutenyl O include: &R6), YR6) 0254 cyclohexyl and substituted cyclohexyl 0261) Where O represents a 6, 5-fused heteroaromatic ring system having 1. 2, 3 or 4 heteroatoms independently selected from N, O and 0255 cyclopentyl and substituted cyclopentyl S, the heteroaromatic ring is attached to the indole core nitrogen via the 5-membered ring or via the 6-membered ring. Suitable 6, 5-fused heteroaromatic ring systems include: 0262) 1,3-benzoxazole-2-yl, 1,3-benzoxazole-4-yl, 1,3- (, ,- benzoxazole-5-yl, 1,3-benzoxazole-6-yl, 1,3-benzoxazole 0256 cyclobutyl and substituted cyclobutyl 3-cr) CO) 0257 cyclopropyl and substituted cyclopropyl y O
0263. 1,3-benzothiazole-2-yl, 1,3-benzothiazole-4-yl, 1,3-benzothiazole-5-yl, 1,3-benzothiazole-6-yl, 1,3-ben 0258 cyclohexenyl and substituted cyclohexenyl Zothiazole-7-yl
21 - H(R6) - H(R6) - H(R6) N 3-coX-C) 0259 cyclopentenyl and substituted cyclopentenyl S) OC)S Ny S 21 6 6 f(R6) - (R) - (R); and