Fused tricyclic heterocycles useful for treating hyper-proliferative disorders Number:7,144,885 from the United States Patent and Trademark Office (PTO) owispatent This invention relates to a novel fused tricyclic heterocycle of the formula (Ia, Ib) and its use for the treatment of hyper-proliferative disorders ##STR00001##<H proliferative, heterocycles, Fused, tricyclic, 7144885.html, Patent, pto, 7144885

Title: Fused tricyclic heterocycles useful for treating hyper-proliferative disorders

Abstract: This invention relates to a novel fused tricyclic heterocycle of the formula (Ia, Ib) and its use for the treatment of hyper-proliferative disorders ##STR00001##

Patent Number: 7,144,885 Issued on 12/05/2006 to Zhang, et al.

Inventors: Zhang; Chengzhi (Orange, CT), Burke; Michael (New Haven, CT), Chen; Zhi (Hamden, CT), Dumas; Jacques (Bethany, CT), Fan; Dongping (North Haven, CT), Jones; Benjamin D. (Hamden, CT), Ladouceur; Gaetan (Guilford, CT), Lee; Wendy (Hamden, CT), Phillips; Barton (New Haven, CT), Wilhelm; Scott M. (Orange, CT), Zhao; Qian (Wallingford, CT)
Assignee: Bayer Pharmaceuticals Corporation (West Haven, CT)

Appl. No.: 10/501,690

Filed: February 21, 2003

PCT Filed: February 21, 2003

PCT No.: PCT/US03/05395

371(c)(1),(2),(4) Date: July 17, 2004

PCT Pub. No.: WO03/072566

PCT Pub. Date: September 04, 2003

Current U.S. Class: 514/255.05 ; 514/291; 514/337; 514/365; 514/374; 514/443; 514/450; 514/454; 514/463; 514/468; 544/405; 546/284.1; 546/83; 548/200; 548/236; 549/350; 549/387; 549/43; 549/433; 549/436; 549/458; 549/57

Current International Class: A61K 31/497 (20060101); A61K 31/427 (20060101); A61K 31/4355 (20060101); A61K 31/443 (20060101); A61K 31/4436 (20060101)

Field of Search: 549/43,57,350,387,433,436,458 548/200,236 544/405 546/83,284.1

References Cited [Referenced By]

U.S. Patent Documents


5466810	November 1995	Godfrey
5504213	April 1996	Fischer
5565488	October 1996	Braunlich
5622989	April 1997	Braunlich
5691359	November 1997	Fischer
5922740	July 1999	Braunlich

Foreign Patent Documents


0551662	Jul., 1993	EP
0731099	Sep., 1996	EP
0885893	Dec., 1998	EP
9802440	Jan., 1998	WO
0069841	Nov., 2000	WO
0069842	Nov., 2000	WO
0069843	Nov., 2000	WO
0069844	Nov., 2000	WO

Other References

Patent Abstracts of Japan, vol. 009, No. 205 (C-299), Aug. 22, 1985 and JP 60 072880 A (Kaken Seiyaku KK), Apr. 24, 1985. cited by other .
Hayakawa, et al., "4-Hydroxy-3-Methyl-6-Phenylbenzofuran-2-Carboxylic Acid Ethyl Ester Derivatives as Potent Anti-Tumor Agents," Bioorg. Med. Chem. Lett., 14, 455-458 (2004). cited by other .
Hayakawa, et al., "A Library Synthesis of 4-Hydroxy-3-Methyl-6-Phenylbenzofuran-2-Carboxylic Acid Ethyl Ester Derivatives as Anti-Tumor Agents," Bioorg. Med. Chem. Lett., 14, 4383-4387 (2004). cited by other .
Hayakawa, et al., "Thienopyridine and Benzofuran Derivatives as Potent Anti-Tumor Agents Possessing Different Structure-Activity Relationships," Bioorg. Med. Chem. Lett., 14, 3411-3414 (2004). cited by other.

Primary Examiner: Saeed; Kamal A.
Assistant Examiner: Nolan; Jason M.

Claims

What is claimed is:

1. A compound selected from Formula Ia and Formula Ib ##STR00536## where X is O or S; R.sup.1 is in each instance independently selected from H, C.sub.1 C.sub.6 alkyl, benzoyl, and C(O)R.sup.A; R.sup.A is in each instance independently H, (C.sub.1 C.sub.6)alkoxy, NR.sup.BR.sup.B, or (C.sub.1 C.sub.6)alkyl, said alkyl being optionally substituted with OH, .dbd.O, (C.sub.1 C.sub.3)alkoxy, C(O)R.sup.B, halo or NR.sup.BR.sup.B; R.sup.B is in each instance independently H, (C.sub.3 C.sub.6)cycloalkyl, or (C.sub.1 C.sub.6)alkyl, said alkyl being optionally substituted with OH, .dbd.O, halo, (C.sub.1 C.sub.6)alkoxy, NH(C.sub.1 C.sub.3)alkyl, N[(C.sub.1 C.sub.3)alkyl].sub.2, NC(O)(C.sub.1 C.sub.3)alkyl or phenyl, and where R.sup.B, when it is attached to a N atom, is in each instance (C.sub.1 C.sub.4)alkyl, then the 2 (C.sub.1 C.sub.4)alkyl groups, taken together with the N atom to which they are attached, may be joined together to form a saturated ring, and where R.sup.B and R.sup.B together with the N to which they are attached may form a morpholinyl ring or a piperazinyl ring optionally substituted on the available N atom with (C.sub.1 C.sub.6)alkyl, said alkyl being optionally substituted with OH, .dbd.O, NH.sub.2, NH(C.sub.1 C.sub.3)alkyl, N[(C.sub.1 C.sub.3)alkyl].sub.2, or (C.sub.1 C.sub.6)alkoxy, and with the proviso that when R.sup.B is attached to S(O) or to S(O).sub.2, it cannot be H; R.sup.2 is selected from phenyl and naphthyl, each optionally substituted with 1, 2, or 3 substitutents each independently selected from OH, CN, NO.sub.2, (C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkoxy, (C.sub.3 C.sub.6)cycloalkyl, halo, halo(C.sub.1 C.sub.6)alkyl, halo(C.sub.1 C.sub.6)alkoxy, C(O)R.sup.A, C(O)NR.sup.BR.sup.B, NR.sup.BR.sup.B, NH[(C.sub.1 C.sub.6)alkyl].sub.0-1S(O).sub.2R.sup.B, NH[(C.sub.1 C.sub.6)alkyl].sub.0-1C(O)R.sup.A, and NH[(C.sub.1 C.sub.6)alkyl].sub.0-1C(O)OR.sup.B, a heterocycle selected from a six membered heterocycle, a five membered heterocycle and a fused bicyclic heterocycle, each heterocycle being optionally substituted with 1, 2 or 3 substitutents each independently selected from OH, CN, NO.sub.2, (C.sub.1 C.sub.6)alkyl, (C.sub.3 C.sub.6)cycloalkyl, (C.sub.1 C.sub.6)alkoxy, halo, halo(C.sub.1 C.sub.6)alkyl, halo(C.sub.1 C.sub.6)alkoxy, C(O)R.sup.A, C(O)NR.sup.BR.sup.B, NR.sup.BR.sup.B, NH[(C.sub.1 C.sub.6)alkyl].sub.0-1S(O).sub.2R.sup.B, NH[(C.sub.1 C.sub.6)alkyl].sub.0-1C(O)R.sup.A, and NH[(C.sub.1 C.sub.6)alkyl].sub.0-1C(O)OR.sup.B, R.sup.3 and R.sup.4 are each independently selected from H, halo, OH, CN, (C.sub.1 C.sub.3)alkoxy, (C.sub.1 C.sub.3)alkyl, halo(C.sub.1 C.sub.3)alkoxy and halo(C.sub.1 C.sub.3)alkyl with the proviso that when X in Formula Ib is S, then R.sup.4 cannot be (C.sub.1 C.sub.3)alkyl; B is a 5 or 6 membered cyclic moiety being optionally substituted with 1 or 2 subsituents each independently selected from .dbd.O, OH, N oxide, halo, halo(C.sub.1 C.sub.6)alkyl, halo(C.sub.1 C.sub.6)alkoxy, (C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.3)alkylphenyl, (C.sub.1 C.sub.6)alkoxy, C(O)R.sup.A, C(O)OR.sup.B, C(O)NR.sup.BR.sup.B, NR.sup.BR.sup.B, NH[(C.sub.1 C.sub.6)alkyl].sub.0-1S(O).sub.2R.sup.B, and NH[(C.sub.1 C.sub.6)alkyl].sub.0-1C(O)R.sup.A; or a pharmaceutically acceptable salt or ester thereof.

2. A compound of claim 1 comprising a compound of Formula Ia.

3. A compound of claim 1 comprising a compound of Formula Ib.

4. A compound of claim 2 where R.sup.2 is selected from phenyl, a six membered heterocycle and a 5 membered heterocycle, each being optionally substituted.

5. A compound of claim 2 where at least one R.sup.1 is H.

6. A compound of claim 2 where B is selected from a ring having all C atoms and a ring having one heteroatom, each being optionally substituted.

7. A compound of claim 2 where R.sup.2 is selected from phenyl, a six membered heterocycle and a 5 membered heterocycle, each being optionally substituted, and B is selected from a ring having all C atoms and a ring having one heteroatom, each being optionally substituted.

8. A compound of claim 6 where R.sup.2 is optionally substituted with 1 or 2 substituents and R.sup.3 and R.sup.4 are each independently selected from H, OH, Cl, F, CN, CH.sub.3, OCH.sub.3, CF.sub.3 and OCF.sub.3.

9. A compound of claim 7 where optionally substituted B, contains no unsaturation other than the shared double bond which is part of the phenyl ring from which B is fused to.

10. A compound of claim 9 where B is substituted with .dbd.O, OH, Cl, F, (C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkoxy, NR.sup.BR.sup.B, CF.sub.3 or OCF.sub.3.

11. A compound of claim 3 where R.sup.2 is selected from phenyl, a six membered heterocycle and a 5 membered heterocycle, each being optionally substituted.

12. A compound of claim 3 where at least one R.sup.1 is H.

13. A compound of claim 3 where B is selected from a ring having all C atoms and a ring having one heteroatom, each being optionally substituted.

14. A compound of claim 3 where R.sup.2 is selected from phenyl, a six membered heterocycle and a 5 membered heterocycle, each being optionally substituted, and B is selected from a ring having all C atoms and a ring having one heteroatom, each being optionally substituted.

15. A compound of claim 13 where R.sup.2 is optionally substituted with 1 or 2 substituents and R.sup.3 and R.sup.4 are each independently selected from H, OH, Cl, F, CN, CH.sub.3, OCH.sub.3, CF.sub.3 and OCF.sub.3.

16. A compound of claim 14 where optionally substituted B, contains no unsaturation other than the shared double bond which is part of the phenyl ring from which B is fused to.

17. A compound of claim 16 where B is substituted with .dbd.O, OH, Cl, F, (C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkoxy, NR.sup.BR.sup.B, CF.sub.3 or OCF.sub.3.

18. A composition comprising a compound of Formula Ia or Formula Ib.

19. A composition of claim 18 comprising a compound of Formula Ia.

20. A composition of claim 18 comprising a compound of Formula Ib.

21. A composition of claim 19 where R.sup.2 is selected from phenyl, a six membered heterocycle and a 5 membered heterocycle, each being optionally substituted.

22. A composition of claim 21 where at least one R.sup.1 is H.

23. A composition of claim 21 where B is selected from a ring having all C atoms and a ring having one heteroatom, each being optionally substituted.

24. A composition of claim 20 where R.sup.2 is selected from phenyl, a six membered heterocycle and a 5 membered heterocycle, each being optionally substituted.

25. A composition of claim 24 where at least one R.sup.1 is H.

26. A composition of claim 24 where B is selected from a ring having all C atoms and a ring having one heteroatom, each being optionally substituted.

Description

FIELD OF THE INVENTION

This invention relates to novel fused tricyclic heterocyclic compounds, pharmaceutical compositions containing such compounds, and the use of those compounds and/or compositions for treating hyper-proliferative disorders.

DESCRIPTION OF THE INVENTION

Compounds of the Invention

One embodiment of this invention relates to a compound selected from Formula Ia and Formula Ib

##STR00002## where X is O or S; R.sup.1 is in each instance independently selected from H, C.sub.1 C.sub.6 alkyl, benzoyl, and C(O)R.sup.A; R.sup.A is in each instance independently H, (C.sub.1 C.sub.6)alkoxy, NR.sup.BR.sup.B, or (C.sub.1 C.sub.6)alkyl, said alkyl being optionally substituted with OH, .dbd.O, (C.sub.1 C.sub.3)alkoxy, C(O)R.sup.B, halo and NR.sup.BR.sup.B; R.sup.B is in each instance independently H, (C.sub.3 C.sub.6)cycloalkyl, and (C.sub.1 C.sub.6)alkyl, said alkyl being optionally substituted with OH, .dbd.O, halo, (C.sub.1 C.sub.6)alkoxy, NH(C.sub.1 C.sub.3)alkyl, N[(C.sub.1 C.sub.3)alkyl].sub.2, NC(O)(C.sub.1 C.sub.3)alkyl and phenyl, and where R.sup.B, when it is attached to a N atom, is in each instance (C.sub.1 C.sub.4)alkyl, then the 2 (C.sub.1 C.sub.4)alkyl groups, taken together with the N atom to which they are attached, may be joined together to form a saturated ring, and where R.sup.B and R.sup.B together with the N to which they are attached may form a morpholinyl ring or a piperazinyl ring optionally substituted on the available N atom with (C.sub.1 C.sub.6)alkyl, said alkyl being optionally substituted with OH, .dbd.O, NH.sub.2, NH(C.sub.1 C.sub.3)alkyl, N[(C.sub.1 C.sub.3)alkyl].sub.2, and (C.sub.1 C.sub.6)alkoxy, and with the proviso that when R.sup.B is attached to S(O) or to S(O).sub.2, it cannot be H; R.sup.2 is selected from phenyl and naphthyl, each optionally substituted with 1, 2, or 3 substituents each independently selected from OH, CN, NO.sub.2, (C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.6)alkoxy, (C.sub.3 C.sub.6)cycloalkyl, halo, halo(C.sub.1 C.sub.6)alkyl, halo(C.sub.1 C.sub.6)alkoxy, C(O)R.sup.A, C(O)NR.sup.BR.sup.B, NR.sup.BR.sup.B, NH[(C.sub.1 C.sub.6)alkyl].sub.0-1S(O).sub.2R.sup.B, NH[(C.sub.1 C.sub.6)alkyl].sub.0-1C(O)R.sup.A, and NH[(C.sub.1 C.sub.6)alkyl].sub.0-1C(O)OR.sup.B, a heterocycle selected from a six membered heterocycle, a five membered heterocycle and a fused bicyclic heterocycle, each heterocycle being optionally substituted with 1, 2 or 3 substituents each independently selected from OH, CN, NO.sub.2, (C.sub.1 C.sub.6)alkyl, (C.sub.3 C.sub.6)cycloalkyl, (C.sub.1 C.sub.6)alkoxy, halo, halo(C.sub.1 C.sub.6)alkyl, halo(C.sub.1 C.sub.6)alkoxy, C(O)R.sup.A, C(O)NR.sup.BR.sup.B, NR.sup.BR.sup.B, NH[(C.sub.1 C.sub.6)alkyl].sub.0-1S(O).sub.2R.sup.B, NH[(C.sub.1 C.sub.6)alkyl].sub.0-1C(O)R.sup.A, and NH[(C.sub.1 C.sub.6)alkyl].sub.0-1C(O)OR.sup.B, R.sup.3 and R.sup.4 are each independently selected from H, halo, OH, CN, (C.sub.1 C.sub.3)alkoxy, (C.sub.1 C.sub.3)alkyl, halo(C.sub.1 C.sub.3)alkoxy and halo(C.sub.1 C.sub.3)alkyl with the proviso that when X in Formula Ib is S, then R.sup.4 cannot be (C.sub.1 C.sub.3)alkyl; B is a 5 or 6 membered cyclic moiety being optionally substituted with 1 or 2 substituents each independently selected from .dbd.O, OH, N oxide, halo, halo(C.sub.1 C.sub.6)alkyl, halo(C.sub.1 C.sub.6)alkoxy, (C.sub.1 C.sub.6)alkyl, (C.sub.1 C.sub.3)alkylphenyl, (C.sub.1 C.sub.6)alkoxy, C(O)R.sup.A, C(O)OR.sup.B, C(O)NR.sup.BR.sup.B, NR.sup.BR.sup.B, NH[(C.sub.1 C.sub.6)alkyl].sub.0-1 S(O).sub.2R.sup.B, and NH[(C.sub.1C.sub.6)alkyl].sub.0-1C(O)R.sup.A; or a pharmaceutically acceptable salt or ester thereof.

The terms identified above have the following meaning throughout:

The term "optionally substituted" means that the moiety so modified may have from none to up to about the highest number of substituents indicated. When there are two or more substituents on any moiety, each substituent is defined independently of any other substituent and can, accordingly, be the same or different.

The term "(C.sub.1 C.sub.6)alkyl, said alkyl being optionally substituted" means an alkyl group as defined below wherein each C atom is bonded to 0, 1, 2 or 3H atoms, as appropriate, and any up to all H atoms may be replaced with a recited substituent, with the proviso that combinations of recited substituents result in a chemically stable compound.

The terms "(C.sub.1 C.sub.6)alkyl", "(C.sub.1 C.sub.4)alkyl", and "(C.sub.1 C.sub.3)alkyl" mean linear or branched saturated carbon groups having from about 1 to about 3, 4, or 6 C atoms respectively. Such groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.

The terms "(C.sub.1 C.sub.6)alkoxy" and "(C.sub.1 C.sub.3)alkoxy" mean a linear or branched saturated carbon group having from about 1 to about 6 or 3 C atoms, respectively, said carbon group being attached to an O atom. The O atom is the point of attachment of the alkoxy substituent. Such groups include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

The term "C.sub.3 C.sub.6 cycloalkyl" means a saturated monocyclic alkyl group of from 3 to about 6 carbon atoms and includes such groups as cyclopropyl, cyclopentyl, cyclohexyl, and the like.

The term "halo" means an atom selected from Cl, Br, F and I, where Cl, Br and F are preferred and Cl and F are most preferred.

The terms "halo(C.sub.1 C.sub.6)alkyl" and "halo(C.sub.1 C.sub.3)alkyl" mean a linear or branched saturated carbon group having from about 1 to about 6 or 3 C atoms respectively that is substituted with at least 1 and up to perhalo (that is, up to 3 per C atom, as appropriate) Cl or F atoms selected in each instance independently from any other Cl or F atom. Such groups include but are not limited to trifluoromethyl, trichloromethyl, pentafluoroethyl, fluorobutyl, 6-chlorohexyl, and the like.

The terms "halo(C.sub.1 C.sub.6)alkoxy" and "halo(C.sub.1 C.sub.3)alkoxy" mean a linear or branched saturated carbon group having from about 1 to about 6 or 3 C atoms, respectively, said carbon group being attached to an O atom and being substituted with at least 1 and up to perhalo (that is, up to 3 per C atom, as appropriate) Cl or F atoms selected in each instance independently from any other Cl or F atom. Such groups include but are not limited to trifluoromethoxy, trichloromethoxy, pentafluoroethoxy, fluorobutoxy, 6-chlorohexoxy, and the like.

The term "six membered heterocycle" means an aromatic ring made of 6 atoms, 1, 2, or 3 of which are N atoms, the rest being C, where the heterocycle is attached to the core molecule at any available C atom and is optionally substituted at any available C atom with the recited substituents. Such groups include pyridine, pyrimidine, pyridazine and triazine in all their possible isomeric forms.

The term "five membered heterocycle" means an aromatic ring made of 5 atoms and having 1, 2 or 3 heteroatom(s) each selected independently from O, N, and S, the rest being C atoms, with the proviso that there can be no more than 2 O atoms in the heterocycle and when there are 2 O atoms they must be nonadjacent. This heterocycle is attached to the core molecule at any available C atom and is optionally substituted at any available C or N atom with the recited substituents. Such groups include pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, oxadiazole, thiadiazole, and tetrazole in all their possible isomeric forms.

The term "fused bicyclic heterocycle" means a group having from 9 to 12 atoms divided into 2 rings that are fused together through adjacent C atoms where 1, 2, or 3 of the remaining atoms are heteroatoms each independently selected from N, O, and S. The heteroatoms may be located at any available position on the fused bicyclic moiety with the proviso that there can be no more than 2 O atoms in any fused bicyclic heterocycle, and when 2 O atoms are present, they must not be adjacent. At least one of the two fused rings must be aromatic. The other ring, if it were not fused to the aromatic ring, may be aromatic, partially saturated or unsaturated. An aromatic ring is always attached to the core molecule through any available C atom. The fused bicyclic heterocycle is optionally substituted at any available C atom with the recited substituents. Such groups include 5-5, 5-6, and 6-6 fused bicycles, where one of the rings is one of the heterocycles described above and the second ring is either benzene or another heterocycle including, but not limited to, chroman, chromene, benzofuran, benzthiophene, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, purine, indole, indazole, isoindole, indolizine, cinnoline, pteridine, isoindole, thienofuran, imidazothiazole, dithianaphthalene, benzoxazine, piperonyl, and the like.

The term "B is a 5 or 6 membered cyclic moiety" means a partially unsaturated or an aromatic ring having about 5 or 6 atoms respectively, said ring having all C atoms or having 1 or 2 heteroatoms selected from O, N and S, with the proviso that there can be no more than 2 O atoms in any heterocyclic moiety and when there are 2 O atoms, they must be non-adjacent. The term "partially unsaturated" used in relation to B includes a ring as described above, that, if it stood alone and was not fused to the core molecule, could be saturated. That is, the ring may be, by itself, a saturated ring but, when fused to the core molecule, becomes partially saturated. The cyclic moiety is fused to the core molecule through any 2 adjacent C atoms and is optionally substituted at any available C or N atom with the recited substituents. Such cyclic moieties include but are not limited to cyclopentyl, cyclohexyl, include pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, oxazine, isothiazole, pyridine, pyrimidine, pyridazine, pyrazoline, piperidine, piperazine, pyrrolidine, imidazolidine, imidazoline, and the like, in all their possible isomeric forms.

The term "N-oxide" means that for heterocycles containing an otherwise unsubstituted sp.sup.2 N atom, the N atom may bear a covalently bound O atom, i.e., --N(->O). Examples of such N-oxide substituted heterocycles include pyridyl N-oxides, pyrimidyl N-oxides, pyrazinyl N-oxides and pyrazolyl N-oxides.

The term "Formula I" means, severally and collectively, Formula Ia and Formula Ib.

Representative compounds of Formula Ia and Formula Ib are disclosed later herein.

The compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration or (R,S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Substituents on a ring may also be present in either cis or trans form, and a substituent on a double bond may be present in either Z or E form. It is intended that all such configurations (including enantiomers and diastereomers) are included within the scope of the present invention. Preferred compounds are those with the absolute configuration of the compound of this invention which produces the more desirable biological activity. Separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention.

The use of pharmaceutically acceptable salts of the compounds of this invention are also within the scope of this invention. The term "pharmaceutically acceptable salt" refers to either inorganic or organic acid or base salts of a compound of the present invention that have properties acceptable for the therapeutic use intended. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1 19.

Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts that are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate. The term acid addition salts also comprises the hydrates and the solvent addition forms which the compounds of this invention are able to form. Examples of such forms are, for example, hydrates, alcoholates and the like.

Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides including benzyl and phenethyl bromides, and others.

The esters of appropriate compounds of this invention are pharmaceutically acceptable esters such as alkyl esters, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters, and the like. Additional esters such as phenyl-(C.sub.1 C.sub.5)alkyl may be used, although methyl ester is preferred.

Unless the context clearly indicates to the contrary, whenever the term "compounds of this invention," "compounds of the present invention", and the like, are used herein, they are intended to include the chemically feasible pharmaceutically acceptable salts and/or esters as well as all stereoisomeric forms of the referenced compounds.

Method of Making the Compounds of the Present Invention

Proton (.sup.1H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me.sub.4Si (.delta. 0.00) or residual protonated solvent (CHCl.sub.3 .delta. 7.26; MeOH .delta. 3.30; DMSO .delta. 2.49) as standard. Carbon (.sup.13C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDCl.sub.3 .delta. 77.0; d.sub.3-MeOD; .delta. 49.0; d.sub.6-DMSO .delta. 39.5) as standard.

Chiral separations were performed using a commercially available Chiracel.RTM. AD HPLC column, eluting with a gradient of isopropanol in hexane (from 1% to 15%) with addition of 0.1% trifluoroacetic acid.

DEFINITIONS

When the following abbreviations are used herein, they have the following meaning: ADDP 1,1'-(azodicarbonyl)-dipiperidine DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DMF N,N-dimethylformamide DMSO Dimethylsulfoxide EA Elemental analysis ES Electrospray Et Ethyl Et.sub.2O Diethyl ether EtOAc Ethyl acetate GC-MS Gas chromatography-mass spectroscopy HEX Hexanes LC-MS Liquid Chromatography/Mass Spectroscopy Me Methyl MeCN Acetonitrile MeOH Methanol MPLC Medium Pressure Liquid Chromatograph NCS N-chlorosuccinimide NMR Nuclear Magnetic Resonance Spectroscopy Ph Phenyl PyBOP Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate RT (RT) Retention time (HPLC) Rf TLC Retention Factor rt Room temperature THF Tetrahydrofuran TLC Thin layer chromatography

In general, the compounds of this invention may be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by processes disclosed below, using starting materials which are either commercially available, producible according to routine, conventional chemical methods or the synthesis of which is described herein. The particular process to be utilized in the preparation of a compound of this invention depends upon the specific compound desired. Such factors as whether the amine is substituted or not, the selection of the specific substituents possible at various locations on the molecule, and the like, each play a role in the path to be followed. Those factors are readily recognized by one of ordinary skill in the art.

The general method used to prepare the compounds in this invention is illustrated in Reaction Scheme 1 below. The amino benzofuran or benzothiophene compounds of formula (Ia) or (Ib) may be synthesized by the condensation of haloketone of formula (IIa) or (IIb) and a properly substituted 2-cyanophenol (X=O) or thiophenol (X=S), and 1-aryl-2-halo-ethanone (III). The reaction conditions may be carried out under basic conditions (such as cesium carbonate, potassium carbonate, sodium carbonate, DBU), in a solvent such as DMF and MeCN, and at temperatures between room temperature to 100.degree. C. The components IIa, IIb, and III, can be prepared but not limited to the methods described below. The various means that used to prepare components (III) were summarized in method I, to prepare components IIa and IIb were summarized in method II, the synthesis of benzofuran core were summarized in method III, and the synthesis of benzothiophene core were summarized in method IV.

##STR00003##

It is to be understood that sensitive or reactive substituents attached to intermediates or to compounds of Formula (Ia) and (Ib) may need to be protected and deprotected during the preparations described above. Protecting groups in general may be added and removed by conventional methods well known in the art (see, e.g., T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis; Wiley: New York, (1999)).

Variations of the compounds of the invention can be readily prepared using the processes described above and referenced below, or by other standard chemical processes known in the art, by employing appropriate starting materials or intermediate compounds that are readily available and/or are described herein.

Generally, a desired salt of a compound of this invention can be prepared in situ during the final isolation and purification of a compound by means well known in the art. For example, a desired salt can be prepared by separately reacting the purified compound in its free base or free acid form with a suitable organic or inorganic acid, or suitable organic or inorganic base, respectively, and isolating the salt thus formed. In the case of basic compounds, for example, the free base is treated with anhydrous HCl in a suitable solvent such as THF, and the salt isolated as a hydrochloride salt. In the case of acidic compounds, the salts may be obtained, for example, by treatment of the free acid with anhydrous ammonia in a suitable solvent such as ether and subsequent isolation of the ammonium salt. These methods are conventional and would be readily apparent to one skilled in the art.

The compounds of this invention may be esterified by a variety of conventional procedures including reacting the appropriate anhydride, carboxylic acid or acid chloride with the alcohol group of a compound of this invention. The appropriate anhydride is reacted with the alcohol in the presence of a base to facilitate acylation such as 1,8-bis[dimethylamino]naphthalene or N,N-dimethylaminopyridine. Or, an appropriate carboxylic acid can be reacted with the alcohol in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide or other water soluble dehydrating agents which are used to drive the reaction by the removal of water, and, optionally, an acylation catalyst. Esterification can also be effected using the appropriate carboxylic acid in the presence of trifluoroacetic anhydride and, optionally, pyridine, or in the presence of N,N-carbonyldiimidazole with pyridine. Reaction of an acid chloride with the alcohol can be carried out with an acylation catalyst such as 4-DMAP or pyridine.

One skilled in the art would readily know how to successfully carry out these as well as other known methods of esterification of alcohols.

The purification of isomers and the separation of isomeric mixtures of a compound of Formula (Ia) and (Ib) may be accomplished by standard techniques known in the art.

The following examples are provided to further illustrate the compounds of the invention and their preparation but should not be construed to be limiting in any way.

PREPARATIVE EXAMPLES OF THE INVENTION

Proton (.sup.1H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me.sub.4Si (.delta. 0.00) or residual protonated solvent (CHCl.sub.3 .delta. 7.26; MeOH .delta. 3.30; DMSO .delta. 2.49) as standard. Carbon (.sup.13C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDCl.sub.3 .delta. 77.0; d.sub.3-MeOD; .delta. 49.0; d.sub.6-DMSO .delta. 39.5) as standard.

Chiral separations were performed using a commercially available Chiracel.RTM. AD HPLC column, eluting with a gradient of isopropanol in hexane (from 1% to 15%) with addition of 0.1% trifluoroacetic acid.

General Method I: Preparation of Intermediate 1-aryl-2-halo-ethanones (III)

The starting ketones of formula (III) are prepared by the methods exemplified below.

Example 1

Method I-1

Preparation 2-bromo-1-(2,4,6-trichlorophenyl)ethanone

##STR00004##

A mixture of 1,3,5-trichlorobenzene (10.0 g, 55.1 mmol), 2-bromoacetyl bromide (5.0 mL, 57.8 mmol, 1.05 eq), and aluminum chloride (7.7 g, 57.8 mmol, 1.05 eq) was heated neat at 80.degree. C. under argon for 17 h until a black precipitate is formed. The reaction was cooled to room temperature, and the resultant black mass was dissolved in ethyl acetate (500 mL). Water (200 mL) was added slowly at 0.degree. C. to quench the reaction, and the biphasic layers were separated. The organic layer was then washed with water (2.times.150 mL) and brine (1.times.150 mL), dried (MgSO.sub.4), filtered, and evaporated in vacuo. Recrystallization from hexane gave 11.5 g (69.3%) of 2-bromo-1-(2,4,6-trichlorophenyl)ethanone as a fluffy white solid. .sup.1H-NMR (DMSO-d.sub.6) .delta. 7.86 (s, 2H), 4.78 (s, 2H); R.sub.f=0.28, 2% ethyl acetate-hexane.

Example 2

Method I-2

Preparation of 2-bromo-1-(2,5-dichlorophenyl)ethanone

##STR00005##

To 2,5-dichloroacetophenone (5.0 g, 26.45 mmol) in anhydrous tetrahydrofuran (53 mL) under argon was added phenyltrimethylammonium tribromide (9.94 g, 26.45 mmol, 1.0 eq) at 0.degree. C. The reaction mixture was stirred at ambient temperature for 16 h, concentrated, and re-dissolved in ethyl acetate. The organic layer was washed with water (2.times.250 mL) and brine (1.times.150 mL), dried (MgSO.sub.4), filtered, and evaporated in vacuo. Purification using MPLC chromatography (Biotage) gave 3.47 g (52.5%) of 2-bromo-1-(2,5-dichlorophenyl)ethanone as a clear oil. .sup.1H-NMR (DMSO-d.sub.6) .delta. 7.93 (dd, J=2.1 Hz, 0.9 Hz, 1H), 7.61 to 7.60 (m, 2H), 4.86 (s, 2H);

Many 2-bromo-1-arylethanones were prepared using this method. A few examples are listed below:

Example 3

Preparation of Starting Material 1-[2,4-bis(trifluoromethyl)phenyl]-2-bromoethanone

##STR00006##

This compound was prepared from 1-[2,4-bis(trifluoromethyl)phenyl]ethanone (5.0 g, 19.52 mmol) in the manner described for 2-bromo-1-(2,5-dichlorophenyl)ethanone, affording 4.12 g (63%) of a white solid. .sup.1H-NMR (DMSO-d.sub.6) .delta. 8.28 to 8.16 (m, 3H), 4.98 (s, 2H);

Example 4

Preparation of intermediate 2-Bromo-1-(2-bromo-phenyl)-ethanone

##STR00007##

This compound was prepared from 1-(2-bromo-phenyl)-ethanone (2.5 g, 12.6 mmol) in the manner described for 2-bromo-1-(2,5-dichlorophenyl)ethanone (Method I-2), affording 1.98 g (57%) of 2-bromo-1-(2-bromo-phenyl)-ethanone as a clear oil. .sup.1H-NMR (CD.sub.2Cl.sub.2) .delta. 8.13 (t, J=2 Hz, 1H), 7.92 (dm, J=8 Hz, 1H), 7.78 (dm, J=8 Hz, 1H), 7.42 (t, J=8 Hz, 1H), 4.49 (s, 2H); TLC Rf=0.38, 15%, ethyl acetate-hexanes.

Example 5

Preparation of 2-Bromo-1-(2-bromo-4-fluoro-phenyl)-ethanone

##STR00008##

This compound was prepared from 1-(2-bromo-4-fluoro-phenyl)-ethanone (2.5 g, 11.52 mmol) in the manner described for 2-bromo-1-(2,5-dichlorophenyl)-ethanone (Method I-2), affording 2.14 g (63%) of 2-bromo-1-(2-bromo-4-fluoro-phenyl)-ethanone as a clear oil. .sup.1H-NMR (CD.sub.2Cl.sub.2) .delta. 7.57 (dd, J=9, 6 Hz, 1H), 7.44 (dd, J=8, 2 Hz, 1H), 7.21 ((m, 7.21 7.14, 1H), 4.51 (s, 2H); TLC Rf=0.38, 15% ethyl acetate-hexanes.

Example 6

Method I-3

Preparation of 2-chloro-1-(4-methyl-3-pyridinyl)ethanone

##STR00009## Step 1: Preparation of 1-(4-methyl-3-pyridinyl)ethanone

##STR00010##

A solution of 3-acetylpyridine (100 g, 0.82 mmol), dimethyl sulfide (400 mL, 5.4 mmol) and copper (I) iodide (7.94 g, 0.041 mmol) in anhydrous THF (2 L) was stirred at room temperature under an argon atmosphere. Phenyl chloroformate (0.4 mL, 0.82 mmol) was then added, producing a dark brown precipitate. After 30 min, the mixture was cooled below -21.degree. C. and methyl magnesium bromide (1.4 M in 3:1 toluene-THF, 586 mL, 0.82 mmol) was added over 50 min, keeping the reaction temperature below -15.degree. C. The color lightened as the mixture became a solution; a lime green precipitate formed near the end of the addition, but re-dissolved upon completion. The mixture was stirred and allowed to warm slowly; after 2 h it had warmed to 8.8.degree. C. Saturated aqueous ammonium chloride solution (500 mL) was added; after stirring 10 min, the mixture was poured into a separatory funnel with water (500 mL). The organic phase was separated, washed with brine (500 mL), dried (Na.sub.2SO.sub.4), filtered and then concentrated in vacuo. The residue was purified by silica gel chromatography using a hexane-EtOAc gradient to afford 134.3 g (63.7%) of the intermediate dihydropyridine.

A solution of the intermediate dihydropyridine (0.52 mmol) in dichloromethane (100 mL) was added to a stirred suspension of sulfur (16.67 g, 0.52 mmol) in decalin and slowly heated to reflux under an argon sweep. After refluxing 1 h, the mixture was allowed to cool to room temperature, then filtered through a pad of silica gel. After eluting the decalin with hexane, elution with a hexane-diethyl ether gradient afforded 49.4 g (70.3%) the desired 1-(4-methyl-3-pyridinyl)ethanone as a reddish-brown oil: TLC Rf 0.19 (diethyl ether); TLC Rf 0.14 (1:1 hexane-EtOAc); .sup.1H NMR (CD.sub.2Cl.sub.2) .delta. 8.9 (s, 1H), 8.5(d, 1H), 7.2 (dd, 1H), 2.6 (s, 3H), 2.51 (s, 3H); MS GC-MS (MH.sup.+135).

Step 2: Preparation of 2-chloro-1-(4-methyl-3-pyridinyl)ethanone Hydrochloride

##STR00011##

In a 500 mL round bottom flask was placed 1-(4-methyl-3-pyridinyl)ethanone (10.0 g, 74.1 mmol) in 90 mL of Et.sub.2O. To this solution was added 88.9 mL of 1M HCl/Et.sub.2O (1.2 eq, 88.9 mmol) with stirring and the solution allowed to stir for 1 h at room temperature, at which point, the precipitate was filtered and washed with Et.sub.2O. The solid was then dried in vacuo at about 60.degree. C. This HCl salt (12. g, 70.0 mmol) was then dissolved in 70.0 mL of 1M HCl/acetic acid where 9.34 g (1 eq, 70.0 mmol) of N-chlorosuccinimide (NCS) was added and the reaction allowed to stir under Argon at room temperature overnight. At this point, 300 mL of Et.sub.2O was added resulting in an off-white precipitate. This was allowed to stir for 1 h at which point the solid was filtered and rinsed with Et.sub.2O to provide 12.0 g (83%) of the desired 2-chloro-1-(4-methyl-3-pyridinyl)ethanone hydrochloride. .sup.1H-NMR (DMSO-d.sub.6) .delta. 2.51 (s, 3H), 5.15 (s, 2H), 7.68 (d, 1H), 8.68 (d, 1H), 9.06 (s, 1H); MS GC-MS [MH].sup.+169.

Example 7

Method I-4

Preparation of 2-chloro-1-[4-(trifluoromethyl)-3-pyridinyl]ethanone Hydrochloride

##STR00012##

Step 1: In a 250 mL round bottom flask was placed 3.0 g of 4-trifluoronicotinic acid (15.7 mmol, 1 eq) in 100 mL of THF. To this was added 5.3 mL (3.8 g, 37.7 mmol, 2.4 eq) of triethylamine and 9.8 g (18.8 mmol, 1.2 eq) of PyBOP. This was allowed to stir for 10 min at room temperature where 2.7 g of Meldrum's acid (18.8 mmol, 1.2 eq) was added and the reaction allowed stirring at room temperature overnight. (18 h).

At this point, 30 mL of 1M HCl (aq) was added and the reaction turned immediately from orange to purple. This was then heated at for 18 h gradually turning from purple to yellow.

The reaction was then basified with saturated NaHCO.sub.3 and extracted with EtOAc (3.times.200 mL). The combined organic layers were dried, filtered, and evaporated. The residue was purified via BIOTAGE (35% EtOAc/Hex) to provide methyl 4-trifluoromethylnicotinate 1.84 g (62%) of the desired product as a colorless oil. TLC R.sub.f=0.57 (50% EtOAc:Hex).

Step 2: In a 100 mL flask was placed 1.84 g (9.7 mmol, 1 eq) of methyl 4-trifluoromethylnicotinate in 25 mL of 1 M HCl in CH.sub.3COOH. To this was then added 1.3 g of NCS (9.7 mmol, 1 eq) and the reaction allowed stirring overnight (18 h).

The mixture was then transferred to a 500 mL Erlenmeyer flask and to this was added 300 mL of 2 M HCl in Et.sub.2O with stirring. This resulted in a white precipitate which was then filtered to provide 1.2 g (49%) of the desired 2-chloro-1-[4-(trifluoromethyl)-3-pyridinyl]ethanone hydrochloride as a white solid. .sup.1H-NMR (DMSO-d.sub.6) .delta. 9.21 (s, 1H), 9.02 (d, 1H), 7.94 (d, 1H), 5.19 (s, 2H).

Example 8

Method I-5

Preparation of 2-bromo-1-(3-ethyl-pyrazin-2-yl)-ethanone

##STR00013##

To a solution of 2-acetyl-3-ethylpyrazine (1.0 g, 6.66 mmol) in chloroform (15 mL) was added Br2 (0.38 mL, 7.32 mmol, 1.1 eq) dropwise at 0.degree. C. The reaction mixture was stirred at 40.degree. C. for 4 h. The reddish solution turned to dark brown. The reaction mixture was concentrated in vacuo and used in the step 2 without further purification. MS LC-MS (MH.sup.+=231).

Example 9

Method I-6

Preparation of 2-chloro-1-(2,5-dichloro-3-pyridinyl)-ethanone

##STR00014##

Step 1: In a 100 mL round bottom flask was placed magnesium chloride (316.7 mg, 3.33 mmol, 0.7 eq in 20 mL of toluene. To this suspension was added dimethyl malonate (653 mg, 4.94 mmol, 1.04 eq) and triethylamine (1.63 mL, 11.69 mmol, 2.46 eq). The resulted mixture was stirred for 1 h at room temperature then a solution of 2,5-dichloropyridine-3-carbonyl chloride (1.0 g, 4.75 mmol, 1.0 eq) in 10 mL of toluene was added slowly and the reaction was allowed stirring at room temperature overnight (18 h).

At this point, 30 mL of water and 1.0 mL of concentrated HCl was added and extracted with ethyl ether (3.times.50 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to provide 2.0 g of reddish crude oil. This oil was dissolved in 4.4 mL of DMSO and 0.16 mL of water and was allowed to heat at 135.degree. C. overnight (18 h).

The reaction solution was cooled down and 30 mL of water was added and extracted with ethyl ether (3.times.50 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to provide 1-(2,5-dichloro-3-pyridinyl)ethanone, 2.0 g of brownish oil which will be used in next step reaction without purification.

Step 2: In a 50 mL flask was placed 1-(2,5-dichloro-3-pyridinyl)ethanone (505 mg, 2.66 mmol, 1 eq) in 2.7 mL of 1 M HCl in CH3COOH. To this was then added NCS (355.2 mg, 2.66 mmol, 1 eq) and the reaction allowed stirring overnight. (18 h).

The mixture was basified with solution of 40% NaOH to pH about 8 at 0.degree. C. then extracted with EtOAc (3.times.50 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to provide a crude residue, which was chromatographed with Hexane/EtOAc=3/1 to provide 339.3 mg of desired 2-chloro-1-(2,5-dichloro-3-pyridinyl)ethanone as a yellow semi-solid (56.8%). 1H-NMR (DMSO-d6) .delta. 8.66 (s, 1H), 8.46 (s, 1H), 5.11 (s, 2H).

Example 10

Method I-7

Preparation of 1-Benzo[1,3]dioxol-4-yl-2-bromo-ethanone

##STR00015## Step 1: Preparation of Starting Material 1-Benzo[1,3]dioxol-4-yl-ethanone

##STR00016##

To a solution of MeMgBr in THF (1 M, 50 mL, 50 mmol, 1.5 eq) was diluted with 50 mL THF and cooled to -10.degree. C. A solution of benzo[1,3]dioxole-4-carbaldehyde (5.0 g, 33.3 mmol) in 50 mL THF was slowly added, and the reaction left to stir for 1 h. The reaction mixture was then quenched by poured into 500 mL of ice cold sat. ammonium chloride and the mixture was extracted with ether. The organic layers were dried over sodium sulfate and filtered through a plug of silica gel before concentrating in vacuo, providing 4.9 g of a white solid. A mixture of this solid (2.0 g, 12.0 mmol) and MnO.sub.2 (10.5 g, 120.4 mmol, 10.0 eq) in 75 mL diethyl ether was stirred vigorously for 48 h. The reaction mixture was then filtered first through a plug of silica gel, then through a 0.46 .mu.m frit before concentrating in vacuo to provide 2.1 g of an off-white solid. Purification by MPLC (Biotage) using a hexane-ethyl acetate gradient provided 1.47 g (74%) of 1-benzo[1,3]dioxol-4-yl-ethanone as an off-white solid. .sup.1H-NMR (CDCl.sub.3) .delta. 7.35 (d, J=8 Hz, 1H), 6.97 (dm, J=8 Hz, 1H), 6.87 (dd, J=8 Hz, 1H), 6.08 (s, 2H), 2.59 (s, 3H); TLC Rf=0.18, 25% ethyl acetate-hexanes.

Step 2: Preparation of Intermediate 1-Benzo[1,3]dioxol-4-yl-2-bromo-ethanone

##STR00017##

This compound was prepared from 1-benzo[1,3]dioxol-4-yl-ethanone (2.15 g, 13.1 mmol) in the manner described for 2-bromo-1-(2,5-dichlorophenyl)ethanone (Method I-2), affording 1.54 g (48%) of 1-benzo[1,3]dioxol-4-yl-2-bromo-ethanone as an off-white solid.

.sup.1H-NMR (CD.sub.2Cl.sub.2) .delta. 7.41 (dd, J=8, 1 Hz, 1H), 7.05 (dd, J=8, 1 Hz, 1H), 6.94 (dd, J=8, 8 Hz, 1H), 6.13 (s, 2H), 4.55 (s, 2H). TLC Rf=0.28, 15%, ethyl acetate-hexanes.

General Method II: Preparation of substituted 2-cyanophenols (IIa and IIb)

Example 11

Method II-1

Preparation of of 5,6,7,8-tetrahydro-3-cyano-2-naphthol and of 5,6,7,8-tetrahydro-1-cyano-2-naphthol as a mixture

##STR00018##

To a stirred mixture of 5,6,7,8-tetrahydro-2-naphthol (10.0 g, 67.47 mmol) in anhydrous dichloroethane (45 mL) was added, at 0.degree. C., 1.0 M boron trichloride in dichloromethane (74.2 mL, 74.2 mmol, 1.1 eq,) followed by methyl thiocyanate (5.1 mL, 74.2 mmol, 1.1 eq) and aluminum chloride (9.0 g, 67.47 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 2 days and then cooled to 0.degree. C. To the dark brown reaction mixture was added 50% aqueous sodium hydroxide solution (150 mL) until pH reached above 12. The resulting yellow biphasic layers were stirred at reflux for 1 h and then cooled to room temperature. The biphasic layers were separated, and the aqueous layer was adjusted to pH 1 with 50% aqueous hydrogen chloride solution (.about.200 mL) at 0.degree. C. The acidified aqueous mixture was extracted with ethyl acetate (3.times.400 mL), and the combined organic layers were dried (MgSO.sub.4), filtered, and concentrated under reduced pressure. The crude cyanophenols were purified through a pad of silica eluted with 25% ethyl acetate-hexane to give a 2:1 mixture of 5,6,7,8-tetrahydro-3-cyano-2-naphthol and of 5,6,7,8-tetrahydro-1-cyano-2-naphthol, respectively, as a white solid (6.64 g, 56.8%). For 5,6,7,8-tetrahydro-3-cyano-2-naphthol:

.sup.1H-NMR (DMSO-d.sub.6) .delta. 10.55 (s, 1H), 7.23 (s, 1H), 6.65 (s, 1H), 2.73 to 2.49 (m, 8H); MS GC-MS (MH.sup.+=174).

For 5,6,7,8-tetrahydro-1-cyano-2-naphthol:

.sup.1H-NMR (DMSO-d.sub.6) .delta. 10.63 (s, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 1.75 to 1.58 (m, 8H); MS GC-MS (MH.sup.+=174).

The mixture prepared according to the above-described procedure gave a range of 2:1 to 1:1 ratio of the two regioisomers in favor of 5,6,7,8-tetrahydro-3-cyano-2-naphthol. They were used as such to prepare the benzofuran derivatives that can be separated by convention chromatographic purification means.

An improved procedure as described in method II-2, however, gave 5,6,7,8-tetrahydro-3-cyano-2-naphthol exclusively.

Example 12

Method II-2

Preparation of 5,6,7,8-tetrahydro-3-cyano-2-naphthol

##STR00019##

In a 1000 mL round-bottom flask was placed 5,6,7,8-tetrahydro-2-naphthalenol (13.4 g, 90.9 mmol, 1 eq) in 60 mL of dry dichloroethane under argon. This was cooled to 0.degree. C. where boron trichloride (100 mL, 1M in CH.sub.2Cl.sub.2, 100 mmol, 1.1 eq) was added via cannula over 10 min. At this point, methyl thiocyanate (7.3 g, 100 mmol, 1.1 eq) was added followed by aluminum trichloride (12.1 g, 90.9 mmol, 1 eq). The reaction was allowed to warm up to rt slowly overnight (18 h) and then allowed to stir further 72 h.

At this point, 200 mL of 50% w/w NaOH was added, together with 150 mL of water, resulting in a thick paste. The flask was equipped with a large volume condenser and then heated at 100.degree. C. for 3 h. The mixture was transferred to an Erlenmeyer flask and acidified to pH.about.1 with conc. HCl. This solution was then extracted in portions with EtOAc and the combined organic layers were dried over NaSO.sub.4, filtered and evaporated. The residue was suspended in CH.sub.2Cl.sub.2 and filtered. The filtrate was concentrated and the suspension procedure was repeated until no further solid precipitated. The combined solids were found to be nearly pure product with minor contaminants. The contaminants were removed with silica gel plug filtration to provide 10.7 g (68%) of the desired product as an off-white solid.

.sup.1H-NMR (CD.sub.3CN) .delta. 7.77 (s, 1H, OH), 7.25 (s, 1H), 6.70 (s, 1H), 2.76 (m, 2H), 2.69 (m, 2H), 1.77 (m, 4H). LC/MS RT=2.86; [M+H+MeCN].sup.+=215.4.

Example 13

Preparation of 6-hydroxy-indan-5-carbonitrile

##STR00020##

To a stirred solution of Indan-5-ol (5.0 g, 32.3 mmol) in anhydrous dichloroethane (21.5 mL) was added, at 0.degree. C., 1.0 M boron trichloride in dichloromethane (41.0 mL, 41.0 mmol, 1.2 eq), followed by methyl thiocyanate (2.43 mL, 35.5 mmol, 1.1 eq) and aluminum chloride (4.30 g, 2.3 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 2 d and then cooled to 0.degree. C. To the dark brown reaction mixture was added 50% aqueous sodium hydroxide solution (100 mL) until pH=11. The resulting yellow biphasic layers were stirred at reflux for 3 h. The biphasic layers were separated, and the aqueous layer was adjusted to pH=1 with 50% aqueous hydrogen chloride solution at 0.degree. C. The acidified aqueous mixture was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate and concentrated at reduced pressure. Crystallization from ether-hexane afforded the cyanophenol as a white solid (3.02 g, 50.9%). .sup.1H-NMR (DMSO-d.sub.6) .delta. 10.67 (s, 1H), 7.36 (s, 1H), 6.84 (s, 1H), 2.81 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 1.99 to 1.93 (m, 2H); R.sub.f=0.23, 25% ethyl acetate-hexane.

This one-step cyanation was widely used in this invention to prepare the substituted 2-cyanophenols needed for many examples. In case the desired substituted phenol is not commercially available, it was synthesized by conventional methods. Some examples are shown below (but not limited to these examples):

Example 14

Preparation of 8-methyl-5,6,7,8-tetraydro-napthalen-2-ol

##STR00021## Step 1: Preparation of 7-methoxy-1-methyl-1,2,3,4-tetrahdro-napthalen-1-ol

##STR00022##

To a round-bottomed flask which had been purged of air and back-filled with argon was added methylmagnesium bromide (16.9 g, 142 mmol). This was cooled to -78.degree. C. To this was added anhydrous THF (125 mL) via canula. Once this had cooled back to -78.degree. C., a solution of 7-methoxy-1-tetralone (10 g, 57 mmol) in anhydrous THF (100 mL) was added slowly by canula. After this addition was complete, the cold bath was removed and the flask was allowed to return to rt. This solution was then poured into saturated ammonium carbonate (500 mL) which had been pre-chilled to 0.degree. C. Ethyl acetate (200 mL) was added and the mixture was poured into a separatory funnel. The organic layer was washed once with water (2.times.200 mL) and once with a mixture of water and brine. The organic layer was collected and dried overnight using magnesium sulfate. This solution was filtered through a pad of celite and concentrated in vacuo to yield 10.75 g (93.6%) of 7-methoxy-1-methyl-1,2,3,4-tetrahdro-napthalen-1-ol. .sup.1HNMR (DMSO-d.sub.6) .delta. 7.04 (d, J=2.3 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 6.67 (dd, J=8.0, 2.3 Hz, 1H), 4.83 (s, 1H), 3.68 (s, 3H), 2.59 (m, 2H), 1.82 (m, 1H), 1.75 (m, 2H), 1.65 (m, 1H), 1.34 (s, 3H), GC/MS RT=10.2 min, (M.sup.+=192), TLC Rf=0.55 (30% ethyl acetate-hexanes).

Step 2: Preparation of 7-methoxy-1-methyl-1,2,3,4-tetrahydro-napthalene

##STR00023##

To a round-bottomed flask which had been purged of air and back-filled with argon was added palladium (II) hydroxide (2.1 g, 15 mmol). Ethanol (220 mL) was added via canula, and a solution of 7-methoxy-1-methyl-1,2,3,4-tetrahdro-napthalen-1-ol in ethanol (220 mL) was then added in the same manner. While stirring vigorously, the flask was purged of argon under vacuum and backfilled with hydrogen gas; this process was repeated 3 times. The solution was allowed to stir under 1 atm hydrogen for 6 h at rt. The solution was then filtered through a pad of celite once followed by a 0.45 .mu.m syringe filter. The filtrate was concentrated in vacuo to yield 8.67 g (91.3%) of 7-methoxy-1-methyl-1,2,3,4-tetrahydro-napthalene as a greenish oil. .sup.1HNMR (DMSO-d.sub.6) .delta. 6.83 (d, J=8.8 Hz, 1H), 6.68 (d, J=2.50 Hz, 1H), 6.56 (dd, J=8.5, 2.8 Hz, 1H), 3.65 (s, 3H), 2.76 (m, 1H), 2.57 (m, 2H), 1.86 1.52 (m, 3H), 1.39 (m, 1H), 1.18 (d, J=7.3, 3H), GC/MS RT=9.57 min (M.sup.+=176), TLC Rf=0.9 (30% ethyl acetate-hexane).

Step 3: Preparation of 8-methyl-5,6,7,8-tetraydro-napthalen-2-ol

##STR00024##

To a solution of 7-methoxy-1-methyl-1,2,3,4-tetrahydro-napthalene (230 mg, 1.30 mmol) in dichloromethane (2.5 mL) at 0.degree. C. was added aluminum chloride (870 mg, 6.52 mmol). This was allowed to stir for 5 min. Ethane thiol (405 mg, 6.52 mmol) was added and the solution was allowed to stir 1 h at 0.degree. C. followed by 2 h at rt. The reaction was then cooled back down to 0.degree. C. and quenched with water (10 mL). The product was then extracted using methylene chloride (3.times.10 mL). The organic was dried with sodium sulfate and concentrated in vacuo to yield 208 mg (98.1%) of 8-methyl-5,6,7,8-tetraydro-napthalen-2-ol. .sup.1HNMR (CD.sub.2Cl.sub.2) .delta. 6.91 (d, J=8.5 Hz, 1H), 6.68 (d, J=1 Hz, 1H), 6.61 (dd, J=8.5, 2.8, 1H) 4.64 (s, 1H), 2.84 (m, 1H), 2.66 (m, 2H), 1.95 1.76 (m, 2H), 1.75 1.60 (m, 1H), 1.56 1.42 (m, 1H), 1.25 (d, J=5.1 Hz, 3H), GC-MS RT=11.20 min, (M.sup.+=162), TLC Rf=0.75 (10% ethyl acetate-hexane).

Example 15

Method II-3

Preparation of starting material 7-Hydroxy-chroman-6-carbonitrile

##STR00025## Step 1: Preparation of 4-(3-Hydroxy-propyl)-benzene-1,3-diol

##STR00026##

To a stirred solution of 7-hydroxycoumarin (7.0 g, 43.2 mmol) in anhydrous THF (200 mL) at rt under argon was added Lithium borohydride (2M, 65.8 mL, 129.6 mmol, 3.0 eq) solution in THF dropwise. Anhydrous methanol (1.0 mL) was added as catalyst to the reaction mixture. The mixture was heated at 65.degree. C. for 17 h. The reaction mixture was then cooled to ambient temperature. Saturated ammonium chloride solution (40 mL) was added dropwise to the solution, followed by 1N HCl solution (40 mL). The mixture was extracted with ethyl acetate (2.times.100 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4), filtered, and evaporated in vacuo. The residue was purified on silica gel (flash column chromatography) eluting with 30% ethyl acetate-hexane to provide the desired product as white solid (3.05 g, 42%). .sup.1H-NMR (CD.sub.3CN) .delta. 6.91 (d, 1H), 6.29 (s, 1H), 6.28 (d, 1H), 3.51 (t, 2H), 2.56 (t, 2H), 1.73 (m, 2H). MS GC-MS (M.sup.+=168).

Step 2: Preparation of Chroman-7-ol

##STR00027##

To a stirred solution of 4-(3-Hydroxy-propyl)-benzene-1,3-diol (3.05 g, 18.1 mmol, from Step 1) in anhydrous THF (50 mL) were added Ph.sub.3P (7.13 g, 27.2 mmol, 1.5 eq) and ADDP (6.86 g, 27.2 mmol, 1.5 eq) under argon. The mixture was stirred at rt for 17 h. The white solid was filtered off and the solvent was removed from the filtrate. The residue was purified on silica gel (flash column chromatography) eluting with 5% ethyl acetate-hexane followed by 20% ethyl acetate-hexane to provide the desired product as white solid (1.80 g, 60.5%). .sup.1H-NMR (CD.sub.3CN) .delta. 6.87 (d, 1H), 6.70 (broad, s, 1H, OH), 6.31 (dd, J=2.4, 8.2 Hz, 1H), 6.20 (d, 1H), 4.12 (t, 2H), 2.69 (t, 2H), 1.95 (m, 2H).

Step 3: Preparation of starting material 7-Hydroxy-chroman-6-carbonitrile

##STR00028##

In a 250 mL round-bottom flask was placed Chroman-7-ol (1.8 g, 12.0 mmol, from Step 3-1-2) in dry dichloroethane (30 mL) under argon. The solution was cooled to 0.degree. C. where boron trichloride (13.2 mL, 1M in CH.sub.2Cl.sub.2, 13.2 mmol, 1.1 eq) was added dropwise. At this point, methyl thiocyanate (0.97 g, 13.2 mmol, 1.1 eq) was added followed by aluminum trichloride (1.6 g, 12.0 mmol, 1 eq). The reaction was allowed to warm up to rt and stirred for 17 h. The reaction mixture was cooled down to 0.degree. C. and 10 mL of 50% w/w NaOH was added to adjust the solution to PH.about.14, followed by 40 mL of water. The solution was then refluxed at 65.degree. C. for 2 h. The solution was allowed to cool to ambient temperature. The aqueous layer was washed with dichloromethane (20 mL). The aqueous solution was then transferred to an Erlenmeyer flask and acidified to pH.about.1 with conc. HCl (aq.). This solution was extracted with EtOAc (3.times.20 mL) and the combined organic layers were dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was suspended in cold CH.sub.2Cl.sub.2 and filtered. The filtrate was concentrated and the suspension procedure was repeated until no further solid precipitated. The combined solids were found to be nearly pure product with minor contaminants. The desired product was white solid (1.20 g, 54.3%). .sup.1H-NMR (CD.sub.3CN) .delta. 7.87 (s, 1H, OH), 7.25 (s, 1H), 6.35 (s, 1H), 4.21 (t, 2H), 2.70 (t, 2H), 1.98 m, 2H).

Example 16

Method II-4

Preparation of 7-Hydroxy-2,2-dimethyl-chroman-6-carbonitrile

##STR00029## Step 1: Preparation of 7-Methoxy-2,2-dimethyl-chroman

##STR00030##

A solution of precocene I (5.0 g, 26.3 mmol) in EtOH (200 mL) was hydrogenated by using 10% Pd/C (0.5 g) as catalyst. The catalyst was filtered of and EtOH was removed under reduced pressure. The crude material was then washed with dichloromethane (2.times.50 mL) to afford the desired product as white solid (4.55 g, 90%). .sup.1H-NMR (CD.sub.3CN) .delta. 6.97 (d, J=8.0 Hz, 1H), 6.42 (d, J=8.0 Hz, 1H), 6.27 (s, 1H), 3.74 (s, 3 H), 2.72 (t, 2 H), 1.80 (t, 2 H), 1.32 (s, 6 H); MS LC-MS (MH.sup.+=193).

Step 2: Preparation of 2,2-Dimethyl-chroman-7-ol

##STR00031##

To a stirred solution of 7-Methoxy-2,2-dimethyl-chroman (4.55 g, 23.7 mmol, from step 1) in anhydrous dichloromethane (50 mL) was added 1M BBr.sub.3 (72.86 mL, 47.4 mmol, 2.0 eq) via cannula over 10 min. The resulting dark brown solution was stirred at rt for 17 h. Saturated solution of NaHCO.sub.3 (50 mL) was added and extracted with CH.sub.2Cl.sub.2 (3.times.50 mL. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified on silica gel (flash column chromatography) eluting with 5% ethyl acetate-hexane followed by 20% ethyl acetate-hexane to provide the desired product as white solid (1.76 g, 42%). .sup.1H-NMR (CD.sub.3CN) .delta. 6.89 (d, J=8.5 Hz, 1H), 6.68 (broad, s, 1H, OH), 6.31 (dd, J=2.4, 8.5 Hz, 1H), 6.15 (d, J=2.4 Hz, 1H), 2.69 (t, 2H), 1.79 (t, 2H), 1.31