Indian Patents. 263525:DIARYL-PURINE, AZAPURINES AND DEAZAPURINES AS NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS FOR TREATMENT OF HIV

Title of Invention	DIARYL-PURINE, AZAPURINES AND DEAZAPURINES AS NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS FOR TREATMENT OF HIV
Abstract	This application concerns certain 2-phenylamino-6-aryl amino-, 6-aryloxy-, and 6- arylthio- purines, -azapurines and -deazapurines. These compounds are non-nucleoside reverse transcriptase inhibitors and have potential as anti-HIV treatment.

Full Text	DIARYL-PURINES, -AZAPURINES AND -DEAZAPURINES AS NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS FOR TREATMENT OF HIV Cross-reference to Related Applications This application claims priority to U.S. Provisional Application Ser. No. 60/678,667, filed May 5,2005, the entirety of which is incorporated herein by reference. Field of the Invention This application concerns certain 2-phenylamino-6-aryl amino-, 6-aryloxy-, and 6-arrythio- purines, -azapurines and -deazapurines. These compounds are non-nucleoside reverse transcriptase inhibitors and have potential as anti-HIV treatment. Background of the Invention Human Immunodeficiency Virus (HIV) presents a public-health and social catastrophe too well known to require documentation. One therapeutic approach to HIV has been inhibition of the viral RNA-dependent RNA polymerase; this enzyme is frequently referred to as "reverse transcriptase," abbreviated "RT." The first RT inhibitors were nucleoside analogs such as AZT and ddl. Although such nucleoside RT inhibitors were frequently effective against the wild-type virus, any single-drug treatment has been hobbled by the virus's ability to readily produce drug-resistant mutants. This has led to an intense -search for non-nucleoside RT inhibitors ("NNRTIs") which are both effective and capable of retaining their effectiveness despite drug-resistance mutations. A recent review of NNRTIs can be found Balzami, J., 2004, Cur. Top. Med Chem. 4,921-44 (Erratum ibid. 4,1825). Four leading NNRTI are: 1) Efavirenz (4S)-6-chloro-4-(cyclopropylethynyl)-l,4-dihydro-4-(trifluoromethyl)-2H-3,l-ben20xazin-2-one; 2) Capravirine: lH-Imidazole-2-methanol, 5-((3,5-dichlorophenyl)thio)-4-(l-methylethyl)-l-(4-pyridinylmethyl)-carbamate (ester); 3) Etravirine(TMC 125):4-((6-amino-5-bromo-2-((4-cyanophenyl)amino)-4-pyrimidinyl)oxy)-3,5-dimethy-benzonitrile; and 4) Rilpivirine (TMC-278): 4-([4-[(4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl)amino]-2-pyrimidinyl)amino]ben2onitrile. Rilpivirine and Etravirine belong to a subclass of NNRTIs called diarylpyrmidines ("DAPY"). For a review of these DAPY NNRTIs see Ludovici, D.W., et al, 2002, Bioorg, Med. Chem Lett. 11,2235-9. An extensive patent literature also exists for DAPY. U.S. Patent No. 6,197,779; WO 00/27850; WO 2003/016306; and WO 2004/069812, all assigned to Janssen Phannaceuticals. Diaryl compounds similar to Etravirine and Rilpivirine where the pyrimidine moiety is replaced by a purine are described in WO 2005/028479, which also is assigned to Janssen. Brief Description of the Invention The invention provides a compound of formula I where the dashed line represents a double bond that may be located either between A and B or between B and D, where A is -N-, N(Z) or C(Z); B is CH or =Ns D is CW or=N-,or N(W); T is NH,O or S ; Z is H, F, CI, Br, CH3, CH2CH3, cyclopropyl, or benzyl, in which the phenyl moiety of the benzyl group is optionally substituted with methyl or methoxy, provided that Z is not F or CI when A is NZ; W is H, F, CI, Br, methyl, ethyl, cyclopropyl, allyl, CH2CF3, cyanomethyl, cyanoethyl, CH=CHCN, or benzyl, in which the phenyl moiety of the benzyl group is optionally substituted with one or two groups selected independently from melhoxy and methyl, provided that W is not F or C1 when D is NW; V is F, CI, CN, SO2CH3, SO2NH2, SO2NHCH3, C=CCH3, or CH=CHCN; provided that when D is CW, A is not CZ and further provided that when neither A nor D is CZ or CW, then B is CH; and Ar is selected from (a), (b), (c), and (d) below: wherein each Rp is selected from among methyl, ethyl, propyl, isopropyl, cyclopropylmethyl, or C3-C6 cycloalkyl, cyano, CH=CHCN, CI, Br, I, acetyl and alkylamino; R4, R5 and each R6 are independently selected from among H, F, CI, Br, CH3, CF3.CH2F, CHF2, isopropyl, cyclopropyl, OCH3, OH, OCF3, NH2 and NHCH3, or R6 and Rp on adjacent ring atoms, together with the ring atoms to which they are attached, form an additional fused five-membered ring; Q and Q' are independently selected from N and CH; R7 is CI, Br, I, CH3, CF3, OCH3, isopropyl, cyclopropyl, t-butyl, or cyclobutyl; and R8 -R11 are, independently, H or CH3. Compounds of formula I have inhibitory activity against both wild-lype and mutated Forms of human immunodeficiency virus type 1 (HIV-l). Detailed Description of the Invention In one embodiment this invention provides a compound of formula lA, in which the 6-linker T of formula I is P, which may be 0 or S. When T of formula I or T of formula lA is O, the invention excludes 1) compounds where both Rp and V are CH=CHCN or cyano unless at least one of A or D is neither —N= nor -NH" and 2) compounds where a) R is CH=CHCN5 cyano, or melhyl; b) V is cyano or CH=CHCN; and c) A and D are both one of -N=; N-benzyl or N-(substituted benzyl). In one subgeneric embodiment, the invention provides a compoimd of formula lA where Ar is selected from 4-cyclopropyI phenyl; 4-cyclopropylmethyl phenyl; 4-bromophenyl; 4-cyclopropyl-naphth-l-yl; 2,6-dimethyl-4-cyanophenyl; 2,6-dimethoxy-4-cyanophenyl; 2,6-dimethyl-4-(2-cyanoethenyl) phenyl; 2,6-dimethoxy-4-(2-cyanoethenyI) phenyl; 2-methyl-4-cyclopropyl phenyl; 2,6-dimethyl-4-cyclopropyl phenyl; 2,6-di-trifluoromethyl"4-cyclopropyl phenyl; 2,4,6-trimethyl phenyl; and 2,6-dime1hyl-4-ace1yl phenyl. In another subgeneric embodiment, the invention contemplates a compound of formula lA where Ar is selected from the following: 5-cyclopropyl-8-quinolyl; 5-isopropyl-8-quinolyl; 5-cyano-8-quinolyl; 5-cyclopropyl-7-trifluoromethy]-8-quinolyl; 5-ace1yl-8-quinolyl; 5-cyano-7-methoxy-8-quinolyl; 5-cyano-7-methyl-8-quinolyl; 5-cyclopropyl-7-trifluoromethoxy-8-isoquinolyl; 5-cyano-84soquinolyl; 5-cyano-7-methoxy-8-isoquinolyl; 5-cyano-7-methyl-8-isoquinolyl; 5-cyclobutyl-7"-difluoromethyl-8-isoquinolyl;5,7-dimethyl-8-cinnolyl; 5-cyclopropyl-7-methyl-8-cinnolyl; and 5-(2-cyanoethenyl)-7-methyl-8-cinnolyl. In another subgeneric embodiment, the invention provides a compound of formula IA-1 where Ar, V, W, and Z are defined as for formula I. In another subgeneric embodiment, the invention provides a compound of formula IA-2 where Ar, V, W, and Z are defined as for formula I. In another subgeneric embodiment, the invention provides a compound of formula IA-3 where Ar, V, W, and Z are defined as for formula I. In another subgeneric embodiment, this invention provides a compound of formula lA-4 where Ax, V, W, and Z are defined as for formula L In another subgeneric embodiment, this invention provides a compound of formula lAo where Ar, V, W, and Z are defined as for formula L In another subgeneric embodiment, this invention provides a compound of formula IA-6 where Ar, V, W, and Z are defined as for formula L In another subgeneric embodiment, this invention provides a compound of formula IA-7 where Ar, V, W, and Z are defined as for formula I. In another subgeneric embodiment, this invention provides a compound of formula IA-8 where Ar, V, W, and Z are defined as for formula I. In another subgeneric embodiment, this invention provides a compound of formula IA-9 where At, V, W, and Z are defined as for formula I. In another subgeneric embodiment, this invention provides a compound of formula IA-10 where Ar, V, W, and Z are defined as for formula I. In another embodiment, this invention provides a compound of formula IB where all substituents are as described above, except that when Ar is (c), this invention excludes compounds in which V is either cyano or CH=CHCN, unless A or D is CZ or CW. In one subgeneric embodiment, the invention provides a compound of formula IB where At is (c), subject to the exclusion in the immediately preceding paragraph. In a more specific subgeneric embodiment, the invention provides a compound of formula IB where Ar is where R^p is CN, CH=CHCN, or cyclopropyl; where R6 and R7 are either both methyl or both methoxy; and subject to the exclusion described above for fonnula IB. In another subgeneric embodiment, this invention provides a compound of formula IB-1. In another subgeneric embodiment, this invention provides a compound of formula IB-2, where Ar, V, W, and Z are as described above for fonnula IB, In another subgeneric embodiment, the invention provides a compound of formula IB-3. where Ar, W, and Z are as described above for formula IB, In another subgeneric embodiment, the invention provides a compound of formula IB-4. where Ar, V, and Z are as described above for formula IB, In more specific embodiments, the invention provides compounds of any of IA-1, lA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, lA-10, IB-1, IB-2, IB-3,and IB-4, where Ar is (a). In additional more specific embodiments, the invention provides compoimds of any of IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, IA-10, IB-l, IB-2, IB-3,and IB-4, where Ar is (b). In additional more specific embodiments, the invention provides compounds of any of IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, IA-10, B-l, IB-2, IB-3,and IB-4, where Ar is (c). In additional more specific embodiments, the invention provides compounds of any of IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, IA-10, IB-1, IB-2, 16-3, and IB-4, where Ar is (d). In a more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-7, IA-8, IA-9, or IA-10, where Ar is 4-cyclopropyl-, 4-ace1yl-, 4-methyl-, 4-bromo-, or 4-cyano-2,6-di-substituted phenyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula lA-l, IA-2, IA-3, or IA-4, where Ar is 4-cyclopropyl-, 4-acetyl-, 4-methyl-, 4-bromo-, or 4-cyano-2,6-di-substituted phenyl. In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-5 or IA-6, where Ar is 4-cyclopropyl-, 4-acetyl-, 4-methyl-, 4-bromo-or 4-cyano-2,6-di-Subsituted phenyl. Synthetic procedures Compounds of this invention which are of the 7-deaza-8-azapurine type can be prepared according to Scheme 1. Compound (1), 2-meroapto-6-hydroxy-7-dea2;a-8-aza-purine, can be synthesized by published procedures known to those skilled in the art. Youssif, S., et al, 2003, Bull Kor, Chem. Soc, 24,1429-32; Bontems, RJ., et aL, 1990, J, Med Chem. 33,2174-8; Badger, G.M., & Rao, R.P„ 1965,Aust J, Chem, 18,1267-71. Alternatively, the 7-deaza-8-azapurines can be synthesized according to Scheme 2, where "PMBCl" is;7-methoxy benzyl chloride. The starting material is prepared by published procedures known to those skilled in the art. Seek, F., 1999, Helv. Chim. Act. 82,105-124; Taylor, E., 1992, Tetrahedron 48, 8089-100; Seela, F., 1986, Helv. Chim. Act 69,16024613. The 8-aza-9-deazapurines of this invention can be synthesized according to Scheme 3. The synthesis of the starting material was described by Lewis, A.F., & Townsend, L-B., 1982, J. Am. Chem. Soc. 104,1073-78. - The 9-deazapurines of this invention can be synthesized by Scheme 4. The synthesis of the starting material is described by Kielich, Klaus, ed., "Synthetic Communications" 2002 vol. 32, pp-3797-3802. Scheme 4 The 7-deazapurines of this invention are prepared by the procedure of Scheme 5. The starting material can be synthesized by the condensation of 2,6-diamino-l,2-dihydro[3H]pyrimidin-4-one with chloroacetaldehyde followed by treatment with phosphorus oxychloride, as indicated in Examples 1 and 3. The purine compounds of this invention can be synthesized by strategies similar to those provided above, using N7-ben2yl-2,6-dichloropurine as the startmg material. This procedure is illustrated in WO 2005/028479. 2-Amino-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one. To a mixture of 2,4-diamino-6-hydroxypyrimidine (20.0 g, 159 mmol) and NaOAc (26.0 g, 317 namol) in H2O (300 mL) at 65oC was added a solution of chloroacetaldehyde (22.0 mL, 50% in H2O,173 mmol) in H2O (22 mL) dropwise for 90 min. The mixture was stirred at 65oC for an additional 2 h and cooled to room temperature. The reaction noixture was concentrated in vacuo to one third of its original volume and stored at 4 °C for 16 h. The light pink precipitates were filtered, washed with an ice cold H2O (5 mL), and dried under high vacuum for 16 h. The precipitates were placed in Soxhlet exctractor and refluxed with methanol (200 mL) for 24 h. The methanol was concentrated to give 13.3 g (56%) of 2-amino-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as a light pink solid. 4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine. To a solution of 2-amino-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (5.00 g, 33.3 mmol), dimethylaniline (4.22 mL, 41.0 mmol) and benzyltriediylammonium chloride (15.2 g, 66.6 mmol) in acetonitrile (25 mL) at room temperature under argon was added POCl3 (18.6 mL, 200 mmol) dropwise for 30 min. The mixture was refluxed at 85oC for 3 h and cooled to room temperature. The reaction was concentrated in vacuo to brown oil and to the oil was added an ice cold H2O (10 mL). The pH of the solution was adjusted to 5 by the addition of an aqueous NH4OH solution. Silica gel chromatography (CH2Cl2;MeOH = 95: 5) yielded 2.53 g (45%) of 4.chloro-7H-pyrrolo[2,3-d]pyrinudin-2-ylamine as a light yellow solid. The product was then benzylated using standard techniques. 7-benzyl-4-(2,4,6-trimefhyl-phenoxy)-7H-pyrrolo[2,3-dlpyrimidin-ylamine. To a solution of 2,4,6-trimethylphenol (161 mg, 1.16 mmol) in l-methyl-2-pyrridone (2 mL) in a sealed tube was added NaH (46 mg, 1.16 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (100 mg, 0.39 mmol) in l-methyl'-2-pyrridone (1 mL) was added to the mixture. The mixture was heated at 150 oC for 16 h and cooled to room temperature. The reaction mixture was poured into ice water and extracted with EtOAc (2 x 20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and mmol) in a polyethylene flask at -50 °C under argon was added 60% HF in pyridine (12 mL). To the resulting solution tert-butylnitrite (0.052 mL, 0.44 nmiol) was added dropwise for 5 min. The reaction was warmed to -40 °C and stirred for 30 min at the temperature. The reaction mixture was diluted with CHCl3 (100 mL) and poured into K2CO3 (3 g) in a beaker. Ice water (50 mL) was carefully added to the mixture. The CHCI3 layer was separated, washed with aqueous NaHCOs solution (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 75:25) yielded 72 mg (68%) of 7-beii2yl-2-fluoro-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidine as a light yellow solid. pyrridone (1 mL) was added NaH (34 mg, 0.86 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-ben2yl-2-fluoro-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidine (62 mg, 0.17 mmol) in l-methyl-2-pyrridone (1 mL) was added to the mixture. The mixture was stirred at room temperature for 1 h, poured into ice water, and extracted with EtOAc (2 x 20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc - 75:25) yielded 64 mg (82%) of 4-[7-benzyl-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile Step F: To a solution of 4-[7-benzyl-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile (38 mg, 0.083 mmol) in 1,2-dichlorobenzene (1 mL) was added aluminium chloride (55 mg, 0.42 mmol). The reaction mixture was stirred at 160 °C for 4 h and cooled to room temperature. The mixture was poured into ice water and extracted with CH2CI2 (2 X 10 mL). The combined organic solution was washed with brine (10 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 50:50) yielded 15 mg (49%) of 4-[4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile as a tan solid, 7--benzyl-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine. To a solution of 2,4,6-trimethylbenzene-l-thiol (231 mg, 1.52 mmol) in l-methyl-2-pyrridone (2 mL) was added NaH (58 mg, 1.52 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (131 mg, 0.51 mmol) in l-methyl-2-pyrridone (2 mL) was added to the mixture. The mixture was heated at 60oC for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with EtOAc (2 x 20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 75:25) yielded 180 mg (94%) of 7-benzyl-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[23-d]pyrimidin-2-ylamine. Step B: 7-benzyl-4(2,4,6-trirnethyl-phenylsulfanyl)-7H-pyn:olo[2,3-dJpyrimidin-2-ylamine (155 mg, 0.41 mmol) in a polyethylene flask at -50 °C under argon was added 60% HF in pyridine (12 mL). To the solution was added tert-butylnitrite (0.074 mL, 0.62 mmol) dropwise for 5 min. The reaction was wanned to -40 °C and stirred for 30 min at the temperature. The reaction was diluted with CHCl3 (100 mL) and poured into K2CO3 (3 g) in a beaker. To the mixture was carefully added ice water (50 mL). The CHCl3 layer was separated, washed with aqueous NaHCO3 solution (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 75:25) yielded 118 mg (77%) of 7-benzyl-2-fluoro-4-(2,4,6-trimethyl--phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid. benzonitrile. To a solution of 4-aminobenzonitrile (184 mg, 1.56 mmol) in l-methyl-2-pyrridone (2 mL) was added NaH (62 mg, 1.56 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-2-fluoro-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine (118 mg, 0.31 mmol) in l-methyl-2-pyrridone (2 mL) was added to the mixture. The mixture was stirred at room temperature for 4 h, then poured into ice water and extracted with EtOAc (2 x 20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc - 75:25) yielded 123 mg (83%) of 4-[7-benzyl-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[23-d]pyrimidin-2-ylamino]- benzonitrile. benzonitrile. To a solution of 4-[7-benzyl-4-(2,4,6-trnnethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile (103 mg, 0.21 mmol) in 1,2-dichlorobetizene (2 mL) was added aluminum chloride (87 mg, 0.65 mmol). The reaction mixture was stirred at 160 oC for 1.5 h and cooled to room temperature. The mixture was poured into ice water and extracted with CH2Cl2 (2 x10 mL). The combined organic solution was washed with brine (10 mL), dried with Na2SO45 and concentrated to dryness. Silica gel chromatography (HexanesrEtOAc = 50:50) yielded 28 mg (34%) of 4-[4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile a as a tan solid. pyrridone (5 mL) in a sealed tube was added NaH (441 mg, 11.0 xnmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (950 mg, 3.67 mmol) in l-methyl-2-pyrridone (5 mL) was added to the mixture. The mixture was heated at 150 oC for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with EtOAc (2 x 50 mL). The combined organic solution was washed with H2O (50 mL) and brine (50 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanesr EtOAc = 75:25) (Hexanes:EtOAc = 50:50) yielded 6 mg (27%) of 4-[2-(4-cyano-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-3,5-dimethyl-ben2onitrile as a tan solid. suspension of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (200 mg, 0.78 nunol) and 2,4,6-trimethylaniline (0.44 mL, 3.08 mmol) in 2,2,2-trifluoroethanol (4 mL) was added trifluoroacetic acid (0.48 mL, 6.24 mmol). The resulting solution was heated at 100 oC for 2 days and cooled to room temperature. The reaction was concentrated to brown oil and diluted with CH2Cl2 (30 mL). The organic solution was washed with aqueous NaHCO3 solution (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (CH2Cl2:MeOH = 95:5) yielded 251 mg (90%) of 7-benzyl-N4-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine. 7-benzyl-N4-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[23-d]pyrimidine-2,4-diamine(251 mg, 0.70 mmol) in a polyethylene flask at -50 oC under argon was added 60% HF in pyridine (24 mL). To the solution was added tert-butylnitrite (0.42 mL, 3.5 mmol) dropwise for 10 min. The reaction was warmed to -40 oC and stirred for 30 min at the temperature. The reaction was diluted with CHCl3 (200 mL) and poured into K2CO3 (6 g) in a beaker. To the mixture was carefully added ice water (100 mL). The CHCI3 layer was separated, washed with aqueous NaHCO3 solution (40 mL) and brine (40 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 75:25) yielded 56 mg (22%) of (7-ben2yl-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-(2,4,6-trimethyl-phenyl)-amine. benzonitrile. To a suspension of (7-ben2yl-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-(2,4,6-trime1hyl-phenyl)-amine (42 mg, 0.12 mmol) and 4-aminoben2onitrile (55 mg, 0.47 mmol) in 2,2,2-trifluoroethanol (4 mL) was added trifluoroacetic acid (0.072 mL, 0.94 mmol). The resulting solution was heated at 90 oC C for 16 h, then cooled to room temperature. The reaction was concentrated to produce a brown oil and diluted with CH2Cl2 (30 mL). The organic solution was washed with H2O (20mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 75:25) yielded 34 mg (64%) of 4-[7-benzyl-4-(2,4,6-trimethyl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile. benzonitrile. To a solution of 4-[7-benzyl-4-(2,4,6-trimethyl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile (34 mg, 0.074 mmol) in 1,2-dichlorobenzene (1 mL) was added aluminum chloride (50 mg, 0.37 mmol). The reaction mixture was stirred at 160 °C for 2 h and cooled to room temperature. The mixture was poured into ice water and extracted with CHCI3 (2x10 mL). The combined organic solution was washed with brine (10 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (CH2Cl2: Acetone = 90:10) yielded 5 mg (19%) of 4-[4-(2,4,6-trimethyl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile as a tan solid. benzonitrile. To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (1.62 mg, 11.0 mmol) in l-methyl-2-pyrridone (5 mL) in a sealed tube was added NaH (441 mg, 11.0 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (950 mg, 3,67 mmol) in l-methyl-2-pyrridone (5 mL) was added to the mixture. The mixture was heated at 150 oC C for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with EK)Ac (2 x 50 mL). The combined organic solution was washed with H2O (50 mL) and brine (50 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatograhy (Hexanes:EtOAc = 75:25) yielded 1.12 mg (83%) of 4-(2-amino-7-benzyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile. 4-(7-benzyl-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile. To 4-(2-amino-7-benzyl-7H-pyrrolo[23-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile (70 mg, 0.19 mmol) in a polyethylene flask at -50 °C under argon was added 60% HF m pyridine (12 mL). To the solution was added tert-butylnitrite (0.068 mL, 0.57 mmol) dropwise for 5 min. The reaction was warmed to -40 °C and stirred for 30 min at the temperature. The reaction was then diluted with CHCl3 (100 mL) and poured into K2CO3 (3 g) in a beaker. Ice water (50 mL) was carefully added. The CHCl3 layer was separated, washed with aqueous NaHCO3 solution (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 75:25) yielded 36 mg (51%) of 4-(7-benzyl-2-fluoro-7H-pyrrolo[2,3-4]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile. stirred at room temperature for 15 min and a solution of 4-(7-benzyl-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitri]e (34 mg, 0.091 mmol) in l-methyl-2-pyrridone (1 mL) was added to the mixture. The mixture was stirred at room temperature for 1 h, poured into ice water and extracted with EtOAc (2 x 20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc - 75:25) yielded 28 mg (65%)of 4-[7-benzyl-2-(4-cyano-phenylamino)-7H-pyn-olo[2,3-d]pyrimidin-4-yloxy]-3,5-, dimethyl-benzonitrile. (1 mL) was added aluminum chloride (40 mg, 0.30 mmol). The reaction mixture was stirred at 160 oC for 45 min and cooled to room temperature. The mixture was poured into ice water and extracted with CH2Cl2 (2x10 mL). The combined organic solution was washed with brine (10 mL), dried with Na2O4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 50:50) yielded 6 mg (27%) of 4-[2-(4-cyano-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-3,5-dimeihyl-benzonitrile as a tan solid. tert-butyldimethylsflane (668 mg, 2.12 mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0.11 mmol) in THF (20 mL) was added cyclopropyl zinc chloride (28.0 mL, 11.2 mmol). The mixture was heated at 80°C for 24 h and cooled to room temperature. The reaction was passed through a short pad of SiO2 to remove the catalyst and the solution was concentrated to oil. The resulting oil was diluted in EtOAc (100 mL), washed with brine (100 mL), dried with Na2SO45 and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 90:10) yielded 370 mg (63%) of tert-butyl(4-cyclopropyl-2,6-dimethylphenoxy)dimeihylsilane. To tert-butyl(4-cyclopropyl-2,6- dimethylphenoxy)dimethylsilane (320 mg, 1.16 mmol) in TEIF (10 mL) was added a solution of tetrabutylammonium fluoride (5.0 mL, 1 M in THF, 5.0 mmol) and acetic acid (0.40 mL). The reaction was stirred at room temperature for 3 h and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 85:15) yielded 175 mg (93%) of 4-cyclopropyl-2,6-dimethylphenol as a light yellow oil. 2-chloro-6-(4'-cyclopropyl-2,6-dimethylphenoxy)-9H-purine. To a solution of 4-cyclopropyl-2,6-dimethylphenol (263 mg, 1.62 mmol) in l-methyl-2-pyrridone (3 roL) at -0oC was added NaH (65 mg, 1.62 mmol). The reaction mixture was stirred at room temperature for 30 min and a solution of 2,6-dichloropurine (102 mg, 0.54 mmol) in l-methyl-2-pyrridone (2 mL) was added to the mixture. The mixture was heated at 100°C for 16 h and then cooled to room temperature. The reaction was poured into ice water and extracted with CHCI3 (3 x 20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (MeOH:CHCl3 = 5:95) yielded 114 mg (67%) of 2-chloro-6-(4-cyclopropyl-2,6-dimethylphenoxy)-9H-purine. 4-(6-(4-cyclopropyl-2,6-dimethyiphenoxy)-9H-purm-2--ylammo)beiizonitriIe. To a suspension of 2-chloro-6-(4-cyclopropyl-2,6-dimethylphenoxy)-9H-purine (28 mg, 0.088 mmol) and 4-aminobenzonitrile (42 mg, 0.35 mmol) in 2,2,2-trifluoroethanol (3 mL) in a sealed tube was added trifluoroacetic acid (0.056 mL, 0.70 mmol). The resulting solution was heated at 90oC for 3 days. The reaction was cooled to room temperature and concentrated to dryness. Silica gel chromatography (CH2Cl2:Acetone = 80:20) yielded 7 mg (20%) of 4-(6-(4-cyclopropyl-2,6-dimethylphenoxy)-9H-purin-2-ylamino)ben2onitrile as a light yellow solid. d]pyrimidiii-2-ylamme (500 mg, 2.97 mmol) in 1,2-dichloroethane (40 mL) at -10oC under argon was added antimony chloride (750 mg, 3.29 mmol). After stirring for 5 min, tert-butylnitrite (2.50 mL, 20.8 mmol) was added to fhe solution. The reaction was stirred at -10oC for 3 h. The reaction was diluted with CHCl3 (100 mL) and poured into ice water (50 mL). The CHCl3 layer was separated, washed with brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 50:50) yielded 239 mg (43%) of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine as a tan solid. solution of 4-cyclopropyl-2,6-dimethylphenol (259 mg, 1.60 mmol) in THF (3 mL) at 0oC was added NaH (64 mg, 1.60 mmol). The reacticm mixture was stirred at room temperature for 30 min and a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.53 mmol) in THF (2 mL) was added to the mixture. The mixture was heated at 80°C for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with CHCl3 (3 X 20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (HexanesrEtOAc = 75:25) yielded 79 mg (48%) of 2-chloro-4-(4-cyclopropyl-2,6-dimethylphenoxy)-7H-pyrrolo[2,3-d]pyrimidine as a tan solid. mmol) in 2,2,2-trifluoroethanol (4 mL) in a sealed tube was added trifluoroacetic acid (0.15 mL, 1.92 mmol). The resulting solution was heated at 90°C for 3 days. The reaction was diluted with EtOAc (50 mL), washed with NaHCO3 (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (CH2Cl2:Acetone = 90:10) yielded 15 mg (16%) of 4-(4-(4-cyclopropyl-2,6-dimethylphenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzonitrile as a tan solid. to afford the corresponding 2-(dimethylamino)methyleneimino derivative. It was then benzylated to produce 3-benzyl-2-[(dimethylamino)methyleneimino]-5-nitro-6-methylpyrimidin-4-one by treating with benzyl bromide and converted to benzylated-2,6-bis-dimethylaminomethylene derivative with DMF-DMA. Reductive cyclization with sodium hydrosulfite followed by de-protection with 3M NaOH and de-benzylation with Pd/C and NH4CO2H afforded 9-deazaguanine. Scheme 2 illustrates the 3 different pathways which provide the various substituted 9-deazapuiines. Other products are synthesized by analogous methods, which a person skilled in the art could formulate, based on the reaction sequences given above. In certain cases, the person skilled in the art would see that protecting groups might be necessary. The synthetic schemee can be summarized as follows. Benzylation of 9-deazaguanine followed by chlorination with POCl3 gives the chlorinated 9-deazapurine product. This chlorinated intermediate can either be coupled with R2 (pathway 1) followed by diazotization with t-butyl nitrite; displaced with F; coupled with R3 and de-benzylated to give the product; or it can undergo pathway 2, which is diazotization with t-butyI nitrite in the presence of antimony chloride followed by coupling with R2 and E3, followed by de-benzylation to afford the final product. Alternatively, pathway 3 provides for de-benzylation of the dichloro-9-deazapurine followed by the coupling with R2 and R3 respectively to provide the various substituted 9-deazapurine. H2SO4 at 0 oC was added 40 mL of HNO3 with an additional funnel. After being stirred at room temperature for 3 h, the reaction mixture was slowly poured into 3.6 L of diethyl ether and stirred for 15 min. Decant the ether solution and added 1.0L of ethyl acetate to the solid and stirred for 10 h. The solid (54.8 g, 81% yield) was filtered and used for next step without any further purification. in CH2CI2 (461 mL) was added DMF-dimethylacetal (103.1 mL, 0.77 mol) and stirred at room temperature for 1.5 h. The reaction mixture was filtered, washed with CH2CI2, and used for the next step without further purification (31.9 g, 44% yield). dihydropyrimidin-2-yl)formimidamide (53,4 g, 0.24 mmol) in DMF (690 mL) was added DBU (44.6 mL, 0.30 mol) and benzyl bromide (44.4 mL, 0.29 mol) and stirred at room temperature for 1 h. The excess of DBU was neutralized with HCl, and the mixture was concentrated in vacuo. The residue was dissolved in methylene chloride and extracted twice with 2M HCl and water, then dried over Na2SO4 and concentrated. Trituration with ethanol afforded the crystalline product which was washed with ethanol to give the product (64,7 g, 86% yield) and used in the next step without further purification. N,N-draiethylformimidamide (64.7 g, 0.2 mol) in DMF (254 mL) was added DMF-dimethylacetal (54.5 mL, 0.41 mol). The reaction mixture was stirred for 3 h at 65oC, cooled, and the solvent was removed under reduced pressure. The residue was triturated with ethanol, and the solid was collected by vacuum filtration (69.2 g, 91%) and used in the next step without further purification. dihydropyrimidin-2-yl)-N,N-dimethylformimidamide (43.0 g, 0.12 mol) in THF (151 mL) was added an aqueous saturated solution of Na2S2O4 and stirred at room temperature overnight Upon completion of the reaction, the solid was filtered and washed with THF to afford the product (21.2 g, 62% yield) which was used m the next step without further purification. yl)-N,N-dimethyIfonnimidamide (21.2 g, 0.07 mol) in MeOH (382 mL) was added 3M NaOH (276 mL) and heated at 100 °C for 5 h. After completion of the reaction, the reaction mixture was cooled to 0 °C. The solid was filtered (15.8 g, 91%) and used in the next step without further purification. mol) in MeOH (334 mL) was added 10% Pd/C (2 g), ammonium formate (13.2 g, 0.21 mmol) and heated at 75oC for 4 h. After completion of the reaction, the reaction mixture was cooled and filtered through a pad of Celite with hot 1:1 DMF/MeOH. The filtrate was concentrated in vacuo to provide the product as an off-white solid (6.2 g, 99%). mmol) in CH2CI2 (14.3 mL) was added benzyl bromide (0.26 mL, 2.2 mmol) and TBABr (644 mg, 2.0 mmol). The reaction mixture was cooled to 0 °C, and to it was added 50% NaOH (1.7 mL). The resulting mixture was stirred for 2 h as it warmed from 0oCC to room temperature. Water was then added, and the solution was washed with CHCI3. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated m vacuo. Purification by column chromatography, eluting with CH2Cl2/Acetone (5:1-1:1), afforded the product as a tan solid (423 mg, 82%) A mixture of 2-amino-5-benzyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-One (1.1 g, 7.4 mmol) and POCl3 (7 mL, 74 mmol) was heated at 116 °C for 3 L Upon completion of the reaction, the reaction mixture was poured into ice and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography, eluting with CHaCh/Acetone (3:1), afforded the product as a white solid (490 mg, 40%). To a stirred suspension of NaH (56 mg, 2.33 mmol) in dry NMP (2 mL) was added 2,4,6-trimethyl phenol (317 mg, 2.33 mmol). The mixture was stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-4-chloro-5H-pyn:olo[3,2-d]pyrimidin-2-amine (200 mg, 0.78 mmol) in dry NMP (1.5 mL) and the resulting solution was heated at 90 oCfor 16 h. After completion of the reaction, the reaction mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, and brine and dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by colunm chromatography, eluting with hexanes/ethyl acetate (3:1) to give the product as a white solid (140 mg, 50%). A solution of 5-benzyl-4-(mesityloxy)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (139.9 mg, 0.39 mmol) in pyridine (1.6 mL) was cooled to -50oC and HF-pyr (8 mL) and t-butyl nitrite (0.19 mL, 1.56 mmol) was added dropwise. The reaction mixture was stirred at 50 °C to -30 oCfor 1.5 h. Upon completion of the reaction, the reaction mixture was poured into K2CO3 (5 g), slowly added water and washed with CHCI3 x 3. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes/ethyl acetate (2:1) to give the product as a white solid (116 mg, 82%). A stirred suspension of NaH (63.8 mg, 2.66 mmol) in dry NMP (1.5 mL) was added 4-aminobenzylnitrile (188 mg, 2.66 mmol) and stirred at room temperature for 30 min imder argon. The reaction mixture was added to a solution of 5-benzyl-2-fluoro-4-(mesityloxy)-5H-pyrrolo[3,2-d]pyrimidine (115 mg, 0.32 mmol) in dry NMP (1.7 mL) and stirred at room temperature for 2 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc 3 times. The combined organic layers were washed with water, NH4Cl, water x 2, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with 1% MeOH:CH2Cl2, which afforded the product as a tan solid (120 mg, 80%). ylamino)benzomtrile (150 mg, 0.33 mmol) in 1,2-dichlorobenzene (13 mL) was added AlCl3 (436 mg, 3,27 mmol). The reaction mixture was heated at 160oC for 1.5 h during which the reaction mixture became dark and homogeneous. Upon completion of the reaction, the reaction mixture was cooled and washed with NH4Cl. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with Hexanes:Ethyl acetate (5:1-1:1) provided the product as a tan solid (27.8 mg, 23%). 4-hydroxy-3,5-dimethylbenzonitrile (570 mg, 3.88 mmol), and the mixture was stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (400 mg, 1.55 mmol) in dry NMP (4 mL) and heated at 160oC for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (2:1-1:4) to give the product as a light yellow solid (342 mg, 60%). dimethylbenzonitrile (319.4 mg, 0.87 mmol) in pyridme (3 mL) was cooled to -50 °C and HF-pyr (15 mL) and t-butul nitrite (0.42 mL, 3.46 xninol) were added dropwise. The reaction mixture was stirred at -50oC to -20 °C for 1,5 h. Upon completion of the reaction, the mixture was poured into K2CO3 (8 g), diluted with water and washed with CHCl3 x 3. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes/ethyl acetate (2:1-1:1) which same the product as a light yellow solid (314 mg, 97%), To a stirred suspension of NaH (101 mg, 4.21 mmol) in dry NMP (4 mL) was added 4-aminobenzylnitrile (299 mg, 2.53 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 4-(5-benzyl-2-fluoro-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzomtrile (314 mg, 0.84 mmol) in dry NMP (4.4 mL) and stirred at room temperature for 2 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc x 3. The combined organic layers were washed with water, NH4CI, water x 2, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with 1% MeOH:CH2Cl2, producing the product as a tan solid (320 mg, 80%), over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC TLC, eluting with 5 % Acetone/CH2Cl2 to give the product as a light yellow solid (10.5 mg, 45%). 2,4,6-trimethyl phenol (30.2 mg, 0.22 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 2,4-dichloro-5-methyl-5-H-pyrrolo[3,2-d]pyrimidine (44.6 mg, 0.22 mmol) in dry NMP (1.0 mL) and heated at 90oC for 16 h. After completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (5:1-2:1), to give the product as a light yellow solid (52.7 mg, 80%). d]pyrimidine (52.7 mg, 0.18 nunol), 4-aminobenzonitrile (83 mg, 0.70 mmol), TFE (1.0 mL) and TFA (0.11 mL, 1.44 mmol). The reaction mixture was stirred at 90oC for 48 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with NaHCO3, brine, dried over Na2SO45 filtered, and concentrated in vacuo. The crude product was purified by preparative TLC, eluting with hexanes:ethyl acetate (5:1-2:1), to give the product as a light yellow solid To a stirred solution of NaH (42.1 mg, 1.05 mmol) in dry NMP (2.5 mL) was added 4-hydroxy-3,5-dimethylbenzomtrile (154.7 mg, 1.05 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 2,4-dichloro-5- methyl-5H-pyrrolo[3,2-d]pyrimidine (211.3 mg, 1.05 mmol) in dry NMP (2.7 mL) and heated at 160 °C for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (3:1-1:1), to give the product as a light yellow solid (294 mg, 85%). yloxy)-3,5-dimethylbenzonitrile (294 mg, 0.94 mmol), 4-aminobenzonitrile (455 mg, 3.77 mmol), TFE (3.1 mL) and TFA (0.58 mL, 7.52 mmol). The reaction mixture was stirred at 90 °C for 48 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC, eluting with hexanes:ethyl acetate (4:1-1:2), to give the product as an off-white solid (133 mg, 40%). To a stirred solution of NaH (31 mg, 0.78 mmol) in dry NMP (2 mL) was added l-(4-hydroxy-3,5-dimethylphenyl)ethanone (127 mg, 0.78 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-2,4-dichloro-5Hpyrrolo[3,2-d]pyrimidine (216 mg, 0.78 mmol) in dry NMP (2.4 mL) and heated at 160 °C for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1-2:1), to give the product as a light yellow solid (111 mg, 35%). yloxy)-3,5-dimethylphenyl)ethanone (111 mg, 0.27 mmol), 4-aminobenzontrile (129 mg, 1.1 mmol), TFE (1.7 mL) and TFA (0.2 mL, 2.16 mmol). The reaction mixture was stirred at 90 °C for 16 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water, and washed with EtOAc. The combined organic layers were washed with NaHCO3 and brine; dried over Na2SO4; filtered; and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes:ethyl acetate (9:1-100 % EtOAc), to give the product as an off-white solid (68 mg, 51%). d]pyrimidin-2-ylamino)benzonitrile (65 mg, 0.13 mmol) in 1,2-dichlorobenzene (5.3 xnL) . was added AICI3 (178 mg, 1.3 mmol). The reaction mixture was heated at 160 oC for 1.5 h, after which time the reaction mixture became dark and homogeneous. Upon completion of the reaction, the reaction mixture was cooled, CHCl3 was added, and the mixture was washed with NH4Cl. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel colunm chromatography, eluting with hexanes:ethyl acetate (3:1), to give the product as a brown solid (41 mg, 77%). Example 14 ((dimethylamino)methyl)-2,6-dimethylphenol (216.4 mg, 1.0 mmol) and the mixture was stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-ben2yl-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (216 mg, 0.78 mmol) in dry NMP (2.6 mL) and heated at 120 °C for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed twice with water, washed with, brine, dried over Na2SO45 filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with MeOH/CH2Cl2 (10%-30%), to give the product as a tan solid (71 mg, 17%). (78.9 mg, 0.67 mmol), TFE (1.1 mL) and TFA (0.1 mL, 1.3 mmol). The reaction mixture was stirred at 90oC for 16 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water, and washed with EtOAc. The combined organic layers were washed with NaHCO3 solution and with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with MeOH/CH2Cl2 (20%-40%), to give the product as a tan solid (17 mg, 20%). The benzyl group was removed according to the same procedure as described for example 13. To a stirred solution of NaH (61.9 mg, 2.6 mmol) in diy NMP (4,7 mL) was added 2,6-dimethyl-4-nitrophenol (258.9 mg, 1.55 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (431 mg, 1.55 mmol) in dry NMP (4 mL) and heated at 90 °C for 16 h. After completion of the reaction, fee resulting mixture was diluted with water and washed wife EtOAc. The combined organic layers were washed twice wife water, washed wife brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting wife hexanes;efeyl acetate (3:1-1:1), to give fee product as a white solid (598 mg, 94%). I TFE (9.1 mL) and TFA (1.97 mL, 11.7 mmol). The reaction mixture was stirred at 90 °C for 16 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with NaHCO3, brine, f dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes:ethyl acetate (3:1-1:1), to give the product (442 mg, 60%). ylamino)benzonitrile (13 mg, 0.03 mmol) in CH2Cl2 (1 mL) was added NCS (4.4 mg, 0.03 mmol) and the mixture refluxed for 16 h. After the completion of the reaction, the solvent was concentrated and purified by preparative TLC eluting with hexanes:ethyl acetate (2:1) to give the product (4.2 mg, 30%). ylamino)benzomtrile (10 mg, 0.02 mmol) in CH2CI2 (5 mL) was added NCS (2.8 mg, 0.02 mmol) and the resolution mixture refluxed for 16 h. After the completion of the reaction, the solvent was concentrated and purified by preparative TLC, eluting with hexanes:ethyl acetate (3:1), to give the product (8.8 mg, 88%). Example 18 ylamino)benzonitrile (22.7 mg, 0.06 mmol) in CH2Cl2 (10 mL) was added NBS (10.5 mg, 0.06 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by reversed phase HPLC to give the product as a white solid (6.4 mg, 23%). Example 19 ylamino)benzonitrile (17.3 mg, 0.05 mmol) in CH2Cl2 (5 mt) was added NCS (6.03 mg, 0.05 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by preparative TLC, eluting with hexanes:ethyl acetate (3:1), to give the product as an off-white solid (3.4 mg, 6%). yloxy)-3,5-dimethylbenzonitrile (21.5 mg, 0.06 mmol) in CH2Cl2 (3 mL) was added NCS (73 mg, 0.06 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by preparative TLC, eluting with Hexanes:Ethyl acetate (3:1), to give the product as a light yellow solid (13.2 mg, 56%). Example 21 yloxy)-3,5-dimethylbenzonitrile (58 mg, 0.15 mmol) in CH2Cl2 (8 mL) was added NBS (29 mg, 0.16 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by preparative TLC, eluting with hexanes:ethyl acetate (2:1), to give the product as a yellow solid (40 mg, 57%). 3,5-dimethylben2onitrile (28.1 mg, 0.07 mmol) in CH2Cl2 (4 mL) was added NCS (9.9 mg, 0.07 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by preparative TLC eluting with hexanesrethyl acetate (2:1), to give the product as a pink solid (20 mg, 65%). Table 3 Contemplated Compounds of Formula IA-3 Table 4 Contemplated Compounds of Formula IA-4 Additional contemplated and prophetic examples, which are not exhaustive but merely-representative of this invention, are shown below: Claims What is claimed is 1. A compound of formula where the dashed line represents a double bond between either A and B or B and D, where T is O or S; A is-N=, NZ or =CZ; B is =CH or =N-; D is =CW or ==N-, or NW, provided that at least one of A and D is -N= or NZ or NW, and further provided that when both A and D are nitrogen, then B is CH; Z is H, F, CI, Br, CH3, CH2CH3, cyclopropyl, or benzyl, in which the phenyl moiety of the benzyl group is optionally substituted with methyl or methoxy, provided that Z is not F or C1 when A is NZ; Z is H, F, CI, Br, CH3, CH2CH3, cyclopropyl, or benzyl, the phenyl moiety of said benzyl optionally substituted with one or two groups selected independently from methyl and methoxy, provided that when A is NZ, Z is neither F nor CI; W is H, F, CI, Br, methyl, ethyl, cyclopropyl, allyl, CH2CF3, cyanomethyl, CH2CH2CN, CH=CHCN, or benzyl, the phenyl moiely of said benzyl optionally substituted with one or two groups selected independently from methyl and methoxy, provided that when D is NW, W is neither F or CI; V is F, CI, CN, SO2CH3, SO2NH2, SO2NHCH3, C=CCH3, or CH=CHCN; and AT is one of (a), (b), (c), and (d) below where the dashed lines in (a) represent optional double bonds; where Rp is C1, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropyhnelhyl, C3-C6 cycloalkyl, CH=CHCN, acetyl, or NH-C1-C6 alkyl, said alkyl and cycloalkyl groups optionally substituted with methyl, methoxy, halogen, or cyano; R4, R5, and R6 are, independently, H, F, CI, Br, CH3, CH2F, CHF2, CF3. isopropyl, cyclopropyl, OCH3, OH, OCF3, NH2 and NHCH3, or R6 and RP on adjacent ring atoms, together with the ring atoms to which they are attached, form an additional fused five-membered ring; Q and Q' are, independently, N or CH; R7 is CI, Br, I, CH3, CF3, OCH3, isopropyl, cyclopropyl, t-butyl, or cyclobutyl; and R87 - R11 are, independently, H or CH3, with the proviso that when Ar is (c), and the A,B ,D ring is imidazolo, Rp and V are not both one of CH3, CN, and CH=CHCN. 2. The compound of claim 1, wherein Ar is (a) or (c). 3. The compound of claim 2, where R6 either is H or is in the 2-position 4. The compound of claim 3, wherein Ar is selected from 4-cyclopropyl phenyl; 4-cyclopropylmethyl phenyl; 4-bromophenyl; 2-chloro-4-bromophenyl; 4-bromo-l-naphthyl; 4-cyclopropyl-1-naphthyl; 2,6-dimethyl-4-cyanophenyl; 2,6-dimethoxy-4-cyanophenyl; 2,6-dimethyl-4-(2-cyanoethenyl) phenyl; 2,6-dimethoxy-4-(2-cyanoethenyl) phenyl; 2-methyl-4-cyclopropyl phenyl; 2,6-dimethyl-4-cyclopropyl phenyl; 2,6-di-trifluoromethyl-4-cyclopropyl phenyl; 2,4,6-trimethyl phenyl; and 2,6-dimethyl-4-acetyl phenyl. 5. The compound of claim 1, which is a compound of formula IA-1 6. The compound of claim 1, which is a compound of formula IA-2 7. The compound of claim 1, which is a compound of formula IA-3 8. The compound of claim 1, which is a compound of formula IA-4 9. The compound of any of claims 5-8, where Ar is 4-cyclopropyl-, 4-acetyl-, 4-methyl-, 4- bromo-, or 4-cyano-2,6-di-substituted phenyl. 10. The compound of claim 9, where V is CN, and where W and Z are, independently, H, methyl, halo, or benzyl. where the dashed line represents a double bond between either A and B or B and D; where A is -N=, NZ or CZ; B is CHor-N- D is CW or=N-,or NW; Z is H, F, CI, Br, CH3, CH2CH3, cyclopropyl, or benzyl, the phenyl moiety of said benzyl optionally substituted with methyl or methoxy, provided that when A is NZ, Z is neither F nor CI; W is H, F, CI, Br, methyl, ethyl, cyclopropyl, allyl, CH2CF3, CH2CN, CH2CH2CN, CH==CHCN, or benzyl, the phenyl moiety of said benzyl optionally substituted with methyl or methoxy, provided that when D is NW, W is neither F nor CI; V is F, CI, CN, SO2CH3, SO2NH2, SO2NHCH3, C=CHs, or CH=CHCN; provided that at least one of A and D is "-N= or NZ or NW, and further provided that when both A and D are nitrogen, then B is CH and V is other than CN or CH=CHCN; wherein Rp is CI, Br, I, CN, CH=CHCN, methyl, ethyl, n-propyl, isopropyl, cyclopropyhnethyl, C3-C6 cycloalkyl, acetyl, and NH-C3-C6 alkyl; R6 is H, F, CI, Br, CH3, CH2F, CHF2, CF3, isopropyl, cyclopropyl, OCH3, OH, OCF3, NH2 and NHCH3; R7 is C1, Br, I, CH3, CF3, OCH3, isopropyl, cyclopropyl, f-butyl, or cyclobutyl. 17. The compound of claim 16, where V is CN or CH=CHCN, R6 is 2-methyl, 2-methoxy, or 2-chloro and R7 is H, 6-methyl, or 6-methoxy. 18. The compound of claim 17, where Rp is CN, cyclopropyl, methyl, Br, CI, CH=CHCN, or acetyl. 19. The compound of claim l, where one of A and D is =N- and the other is NZ or NW. 20. The compound of claim 5 which is a compound of formula IA-1 selected from compounds in Table 1: Claims What is claimed is 1. A compound of formula where the dashed line represents a double bond between either A and B or B and D, where T is O or S; A is-N=, NZ or =CZ; B is =CH or =N-; D is =CW or ==N-, or NW, provided that at least one of A and D is -N= or NZ or NW, and further provided that when both A and D are nitrogen, then B is CH; Z is H, F, CI, Br, CH3, CH2CH3, cyclopropyl, or benzyl, in which the phenyl moiety of the benzyl group is optionally substituted with methyl or methoxy, provided that Z is not F or C1 when A is NZ; Z is H, F, CI, Br, CH3, CH2CH3, cyclopropyl, or benzyl, the phenyl moiety of said benzyl optionally substituted with one or two groups selected independently from methyl and methoxy, provided that when A is NZ, Z is neither F nor CI; W is H, F, CI, Br, methyl, ethyl, cyclopropyl, allyl, CH2CF3, cyanomethyl, CH2CH2CN, CH=CHCN, or benzyl, the phenyl moiely of said benzyl optionally substituted with one or two groups selected independently from methyl and methoxy, provided that when D is NW, W is neither F or CI; V is F, CI, CN, SO2CH3, SO2NH2, SO2NHCH3, C=CCH3, or CH=CHCN; and AT is one of (a), (b), (c), and (d) below where the dashed lines in (a) represent optional double bonds; where Rp is C1, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropyhnelhyl, C3-C6 cycloalkyl, CH=CHCN, acetyl, or NH-C1-C6 alkyl, said alkyl and cycloalkyl groups optionally substituted with methyl, methoxy, halogen, or cyano; R4, R5, and R6 are, independently, H, F, CI, Br, CH3, CH2F, CHF2, CF3. isopropyl, cyclopropyl, OCH3, OH, OCF3, NH2 and NHCH3, or R6 and RP on adjacent ring atoms, together with the ring atoms to which they are attached, form an additional fused five-membered ring; Q and Q' are, independently, N or CH; R7 is CI, Br, I, CH3, CF3, OCH3, isopropyl, cyclopropyl, t-butyl, or cyclobutyl; and R87 - R11 are, independently, H or CH3, with the proviso that when Ar is (c), and the A,B ,D ring is imidazolo, Rp and V are not both one of CH3, CN, and CH=CHCN. 2. The compound of claim 1, wherein Ar is (a) or (c). 3. The compound of claim 2, where R6 either is H or is in the 2-position 4. The compound of claim 3, wherein Ar is selected from 4-cyclopropyl phenyl; 4-cyclopropylmethyl phenyl; 4-bromophenyl; 2-chloro-4-bromophenyl; 4-bromo-l-naphthyl; 4-cyclopropyl-1-naphthyl; 2,6-dimethyl-4-cyanophenyl; 2,6-dimethoxy-4-cyanophenyl; 2,6-dimethyl-4-(2-cyanoethenyl) phenyl; 2,6-dimethoxy-4-(2-cyanoethenyl) phenyl; 2-methyl-4-cyclopropyl phenyl; 2,6-dimethyl-4-cyclopropyl phenyl; 2,6-di-trifluoromethyl-4-cyclopropyl phenyl; 2,4,6-trimethyl phenyl; and 2,6-dimethyl-4-acetyl phenyl. 5. The compound of claim 1, which is a compound of formula IA-1 6. The compound of claim 1, which is a compound of formula IA-2 7. The compound of claim 1, which is a compound of formula IA-3 8. The compound of claim 1, which is a compound of formula IA-4 9. The compound of any of claims 5-8, where Ar is 4-cyclopropyl-, 4-acetyl-, 4-methyl-, 4- bromo-, or 4-cyano-2,6-di-substituted phenyl. 10. The compound of claim 9, where V is CN, and where W and Z are, independently, H, methyl, halo, or benzyl. where the dashed line represents a double bond between either A and B or B and D; where A is -N=, NZ or CZ; B is CHor-N- D is CW or=N-,or NW; Z is H, F, CI, Br, CH3, CH2CH3, cyclopropyl, or benzyl, the phenyl moiety of said benzyl optionally substituted with methyl or methoxy, provided that when A is NZ, Z is neither F nor CI; W is H, F, CI, Br, methyl, ethyl, cyclopropyl, allyl, CH2CF3, CH2CN, CH2CH2CN, CH==CHCN, or benzyl, the phenyl moiety of said benzyl optionally substituted with methyl or methoxy, provided that when D is NW, W is neither F nor CI; V is F, CI, CN, SO2CH3, SO2NH2, SO2NHCH3, C=CHs, or CH=CHCN; provided that at least one of A and D is "-N= or NZ or NW, and further provided that when both A and D are nitrogen, then B is CH and V is other than CN or CH=CHCN; wherein Rp is CI, Br, I, CN, CH=CHCN, methyl, ethyl, n-propyl, isopropyl, cyclopropyhnethyl, C3-C6 cycloalkyl, acetyl, and NH-C3-C6 alkyl; R6 is H, F, CI, Br, CH3, CH2F, CHF2, CF3, isopropyl, cyclopropyl, OCH3, OH, OCF3, NH2 and NHCH3; R7 is C1, Br, I, CH3, CF3, OCH3, isopropyl, cyclopropyl, f-butyl, or cyclobutyl. 17. The compound of claim 16, where V is CN or CH=CHCN, R6 is 2-methyl, 2-methoxy, or 2-chloro and R7 is H, 6-methyl, or 6-methoxy. 18. The compound of claim 17, where Rp is CN, cyclopropyl, methyl, Br, CI, CH=CHCN, or acetyl. 19. The compound of claim l, where one of A and D is =N- and the other is NZ or NW. 20. The compound of claim 5 which is a compound of formula IA-1 selected from compounds in Table 1:

Full Text

DIARYL-PURINES, -AZAPURINES AND -DEAZAPURINES AS NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
FOR TREATMENT OF HIV
Cross-reference to Related Applications
This application claims priority to U.S. Provisional Application Ser. No. 60/678,667, filed May 5,2005, the entirety of which is incorporated herein by reference.
Field of the Invention
This application concerns certain 2-phenylamino-6-aryl amino-, 6-aryloxy-, and 6-arrythio- purines, -azapurines and -deazapurines. These compounds are non-nucleoside reverse transcriptase inhibitors and have potential as anti-HIV treatment.
Background of the Invention
Human Immunodeficiency Virus (HIV) presents a public-health and social catastrophe too well known to require documentation. One therapeutic approach to HIV has been inhibition of the viral RNA-dependent RNA polymerase; this enzyme is frequently referred to as "reverse transcriptase," abbreviated "RT." The first RT inhibitors were nucleoside analogs such as AZT and ddl. Although such nucleoside RT inhibitors were frequently effective against the wild-type virus, any single-drug treatment has been hobbled by the virus's ability to readily produce drug-resistant mutants. This has led to an intense -search for non-nucleoside RT inhibitors ("NNRTIs") which are both effective and capable of retaining their effectiveness despite drug-resistance mutations. A recent review of NNRTIs can be found Balzami, J., 2004, Cur. Top. Med Chem. 4,921-44 (Erratum ibid. 4,1825).
Four leading NNRTI are: 1) Efavirenz (4S)-6-chloro-4-(cyclopropylethynyl)-l,4-dihydro-4-(trifluoromethyl)-2H-3,l-ben20xazin-2-one; 2) Capravirine: lH-Imidazole-2-methanol, 5-((3,5-dichlorophenyl)thio)-4-(l-methylethyl)-l-(4-pyridinylmethyl)-carbamate (ester); 3) Etravirine(TMC 125):4-((6-amino-5-bromo-2-((4-cyanophenyl)amino)-4-pyrimidinyl)oxy)-3,5-dimethy-benzonitrile; and 4) Rilpivirine (TMC-278): 4-([4-[(4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl)amino]-2-pyrimidinyl)amino]ben2onitrile. Rilpivirine and Etravirine belong to a subclass of NNRTIs called diarylpyrmidines ("DAPY"). For a review of these DAPY NNRTIs see Ludovici, D.W., et al, 2002, Bioorg, Med. Chem Lett.

11,2235-9. An extensive patent literature also exists for DAPY. U.S. Patent No. 6,197,779; WO 00/27850; WO 2003/016306; and WO 2004/069812, all assigned to Janssen
Phannaceuticals.
Diaryl compounds similar to Etravirine and Rilpivirine where the pyrimidine moiety is replaced by a purine are described in WO 2005/028479, which also is assigned to Janssen.
Brief Description of the Invention
The invention provides a compound of formula I

where the dashed line represents a double bond that may be located either between A and B
or between B and D,
where A is -N-, N(Z) or C(Z);
B is CH or =Ns
D is CW or=N-,or N(W);
T is NH,O or S ;
Z is H, F, CI, Br, CH3, CH2CH3, cyclopropyl, or benzyl, in which the phenyl moiety of the
benzyl group is optionally substituted with methyl or methoxy, provided that Z is not F or CI
when A is NZ;
W is H, F, CI, Br, methyl, ethyl, cyclopropyl, allyl, CH2CF3, cyanomethyl, cyanoethyl,
CH=CHCN, or benzyl, in which the phenyl moiety of the benzyl group is optionally
substituted with one or two groups selected independently from melhoxy and methyl,
provided that W is not F or C1 when D is NW;
V is F, CI, CN, SO2CH3, SO2NH2, SO2NHCH3, C=CCH3, or CH=CHCN;
provided that when D is CW, A is not CZ and further provided that when neither A nor D is
CZ or CW, then B is CH; and
Ar is selected from (a), (b), (c), and (d) below:

wherein each Rp is selected from among methyl, ethyl, propyl, isopropyl, cyclopropylmethyl,
or C3-C6 cycloalkyl, cyano, CH=CHCN, CI, Br, I, acetyl and alkylamino; R4, R5 and each R6 are independently selected from among H, F, CI, Br, CH3, CF3.CH2F, CHF2, isopropyl, cyclopropyl, OCH3, OH, OCF3, NH2 and NHCH3, or R6 and Rp on adjacent ring atoms, together with the ring atoms to which they are attached, form an additional fused five-membered ring; Q and Q' are independently selected from N and CH; R7 is CI, Br, I, CH3, CF3, OCH3, isopropyl, cyclopropyl, t-butyl, or cyclobutyl; and R8 -R11 are, independently, H or CH3.
Compounds of formula I have inhibitory activity against both wild-lype and mutated Forms of human immunodeficiency virus type 1 (HIV-l).

Detailed Description of the Invention
In one embodiment this invention provides a compound of formula lA, in which the 6-linker T of formula I is P, which may be 0 or S.

When T of formula I or T of formula lA is O, the invention excludes 1) compounds where both Rp and V are CH=CHCN or cyano unless at least one of A or D is neither —N= nor -NH" and 2) compounds where a) R is CH=CHCN5 cyano, or melhyl; b) V is cyano or CH=CHCN; and c) A and D are both one of -N=; N-benzyl or N-(substituted benzyl).
In one subgeneric embodiment, the invention provides a compoimd of formula lA where Ar is selected from 4-cyclopropyI phenyl; 4-cyclopropylmethyl phenyl; 4-bromophenyl; 4-cyclopropyl-naphth-l-yl; 2,6-dimethyl-4-cyanophenyl; 2,6-dimethoxy-4-cyanophenyl; 2,6-dimethyl-4-(2-cyanoethenyl) phenyl; 2,6-dimethoxy-4-(2-cyanoethenyI) phenyl; 2-methyl-4-cyclopropyl phenyl; 2,6-dimethyl-4-cyclopropyl phenyl; 2,6-di-trifluoromethyl"4-cyclopropyl phenyl; 2,4,6-trimethyl phenyl; and 2,6-dime1hyl-4-ace1yl phenyl.
In another subgeneric embodiment, the invention contemplates a compound of formula lA where Ar is selected from the following: 5-cyclopropyl-8-quinolyl; 5-isopropyl-8-quinolyl; 5-cyano-8-quinolyl; 5-cyclopropyl-7-trifluoromethy]-8-quinolyl; 5-ace1yl-8-quinolyl; 5-cyano-7-methoxy-8-quinolyl; 5-cyano-7-methyl-8-quinolyl; 5-cyclopropyl-7-trifluoromethoxy-8-isoquinolyl; 5-cyano-84soquinolyl; 5-cyano-7-methoxy-8-isoquinolyl; 5-cyano-7-methyl-8-isoquinolyl; 5-cyclobutyl-7"-difluoromethyl-8-isoquinolyl;5,7-dimethyl-8-cinnolyl; 5-cyclopropyl-7-methyl-8-cinnolyl; and 5-(2-cyanoethenyl)-7-methyl-8-cinnolyl.
In another subgeneric embodiment, the invention provides a compound of formula
IA-1

where Ar, V, W, and Z are defined as for formula I.
In another subgeneric embodiment, the invention provides a compound of formula IA-2

where Ar, V, W, and Z are defined as for formula I.
In another subgeneric embodiment, the invention provides a compound of formula IA-3

where Ar, V, W, and Z are defined as for formula I.
In another subgeneric embodiment, this invention provides a compound of formula lA-4

where Ax, V, W, and Z are defined as for formula L
In another subgeneric embodiment, this invention provides a compound of formula lAo

where Ar, V, W, and Z are defined as for formula L
In another subgeneric embodiment, this invention provides a compound of formula IA-6

where Ar, V, W, and Z are defined as for formula L
In another subgeneric embodiment, this invention provides a compound of formula
IA-7
where Ar, V, W, and Z are defined as for formula I.
In another subgeneric embodiment, this invention provides a compound of formula IA-8

where Ar, V, W, and Z are defined as for formula I.
In another subgeneric embodiment, this invention provides a compound of formula IA-9
where At, V, W, and Z are defined as for formula I.
In another subgeneric embodiment, this invention provides a compound of formula IA-10
where Ar, V, W, and Z are defined as for formula I.
In another embodiment, this invention provides a compound of formula IB

where all substituents are as described above, except that when Ar is (c), this invention excludes compounds in which V is either cyano or CH=CHCN, unless A or D is CZ or CW.

In one subgeneric embodiment, the invention provides a compound of formula IB where At is (c), subject to the exclusion in the immediately preceding paragraph.
In a more specific subgeneric embodiment, the invention provides a compound of formula IB where Ar is

where R^p is CN, CH=CHCN, or cyclopropyl; where R6 and R7 are either both methyl or both methoxy; and subject to the exclusion described above for fonnula IB.
In another subgeneric embodiment, this invention provides a compound of formula IB-1.

In another subgeneric embodiment, this invention provides a compound of formula IB-2,

where Ar, V, W, and Z are as described above for fonnula IB,
In another subgeneric embodiment, the invention provides a compound of formula IB-3.

where Ar, W, and Z are as described above for formula IB,
In another subgeneric embodiment, the invention provides a compound of formula IB-4.

where Ar, V, and Z are as described above for formula IB,
In more specific embodiments, the invention provides compounds of any of IA-1, lA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, lA-10, IB-1, IB-2, IB-3,and IB-4, where Ar is (a).
In additional more specific embodiments, the invention provides compoimds of any of IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, IA-10, IB-l, IB-2, IB-3,and IB-4, where Ar is (b).
In additional more specific embodiments, the invention provides compounds of any of IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, IA-10, B-l, IB-2, IB-3,and IB-4, where Ar is (c).
In additional more specific embodiments, the invention provides compounds of any of IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, IA-10, IB-1, IB-2, 16-3, and IB-4, where Ar is (d).
In a more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-7, IA-8, IA-9, or IA-10, where Ar is 4-cyclopropyl-, 4-ace1yl-, 4-methyl-, 4-bromo-, or 4-cyano-2,6-di-substituted phenyl.

In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula lA-l, IA-2, IA-3, or IA-4, where Ar is 4-cyclopropyl-, 4-acetyl-, 4-methyl-, 4-bromo-, or 4-cyano-2,6-di-substituted phenyl.
In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-5 or IA-6, where Ar is 4-cyclopropyl-, 4-acetyl-, 4-methyl-, 4-bromo-or 4-cyano-2,6-di-Subsituted phenyl.
Synthetic procedures
Compounds of this invention which are of the 7-deaza-8-azapurine type can be prepared according to Scheme 1.

Compound (1), 2-meroapto-6-hydroxy-7-dea2;a-8-aza-purine, can be synthesized by published procedures known to those skilled in the art. Youssif, S., et al, 2003, Bull Kor, Chem. Soc, 24,1429-32; Bontems, RJ., et aL, 1990, J, Med Chem. 33,2174-8; Badger, G.M., & Rao, R.P„ 1965,Aust J, Chem, 18,1267-71.
Alternatively, the 7-deaza-8-azapurines can be synthesized according to Scheme 2, where "PMBCl" is;7-methoxy benzyl chloride. The starting material is prepared by published procedures known to those skilled in the art. Seek, F., 1999, Helv. Chim. Act. 82,105-124; Taylor, E., 1992, Tetrahedron 48, 8089-100; Seela, F., 1986, Helv. Chim. Act 69,16024613.

The 8-aza-9-deazapurines of this invention can be synthesized according to Scheme 3. The synthesis of the starting material was described by Lewis, A.F., & Townsend, L-B., 1982, J. Am. Chem. Soc. 104,1073-78.

- The 9-deazapurines of this invention can be synthesized by Scheme 4. The synthesis of the starting material is described by Kielich, Klaus, ed., "Synthetic Communications" 2002 vol. 32, pp-3797-3802.
Scheme 4

The 7-deazapurines of this invention are prepared by the procedure of Scheme 5. The starting material can be synthesized by the condensation of 2,6-diamino-l,2-dihydro[3H]pyrimidin-4-one with chloroacetaldehyde followed by treatment with phosphorus oxychloride, as indicated in Examples 1 and 3.

The purine compounds of this invention can be synthesized by strategies similar to those provided above, using N7-ben2yl-2,6-dichloropurine as the startmg material. This procedure is illustrated in WO 2005/028479.

2-Amino-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one. To a mixture of 2,4-diamino-6-hydroxypyrimidine (20.0 g, 159 mmol) and NaOAc (26.0 g, 317 namol) in H2O (300 mL) at 65oC was added a solution of chloroacetaldehyde (22.0 mL, 50% in H2O,173 mmol) in H2O (22 mL) dropwise for 90 min. The mixture was stirred at 65oC for an additional 2 h and cooled to room temperature. The reaction noixture was concentrated in vacuo to one third of its original volume and stored at 4 °C for 16 h. The light pink precipitates were filtered, washed with an ice cold H2O (5 mL), and dried under high vacuum for 16 h. The precipitates were placed in Soxhlet exctractor and refluxed with methanol (200 mL) for 24 h. The methanol was concentrated to give 13.3 g (56%) of 2-amino-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as a light pink solid.

4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine. To a solution of 2-amino-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (5.00 g, 33.3 mmol), dimethylaniline (4.22 mL, 41.0 mmol) and benzyltriediylammonium chloride (15.2 g, 66.6 mmol) in acetonitrile (25 mL) at room temperature under argon was added POCl3 (18.6 mL, 200 mmol) dropwise for 30 min. The mixture was refluxed at 85oC for 3 h and cooled to room temperature. The reaction was concentrated in vacuo to brown oil and to the oil was added an ice cold H2O (10 mL). The pH of the solution was adjusted to 5 by the addition of an aqueous NH4OH solution. Silica gel chromatography (CH2Cl2;MeOH = 95: 5) yielded 2.53 g (45%) of 4.chloro-7H-pyrrolo[2,3-d]pyrinudin-2-ylamine as a light yellow solid. The product was then benzylated using standard techniques.

7-benzyl-4-(2,4,6-trimefhyl-phenoxy)-7H-pyrrolo[2,3-dlpyrimidin-ylamine. To a
solution of 2,4,6-trimethylphenol (161 mg, 1.16 mmol) in l-methyl-2-pyrridone (2 mL) in a sealed tube was added NaH (46 mg, 1.16 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (100 mg, 0.39 mmol) in l-methyl'-2-pyrridone (1 mL) was added to the mixture. The mixture was heated at 150 oC for 16 h and cooled to room temperature. The reaction mixture was poured into ice water and extracted with EtOAc (2 x 20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and

mmol) in a polyethylene flask at -50 °C under argon was added 60% HF in pyridine (12 mL). To the resulting solution tert-butylnitrite (0.052 mL, 0.44 nmiol) was added dropwise for 5 min. The reaction was warmed to -40 °C and stirred for 30 min at the temperature. The reaction mixture was diluted with CHCl3 (100 mL) and poured into K2CO3 (3 g) in a beaker. Ice water (50 mL) was carefully added to the mixture. The CHCI3 layer was separated, washed with aqueous NaHCOs solution (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 75:25) yielded 72 mg (68%) of 7-beii2yl-2-fluoro-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidine as a light yellow solid.

pyrridone (1 mL) was added NaH (34 mg, 0.86 mmol). The reaction mixture was stirred at

room temperature for 15 min and a solution of 7-ben2yl-2-fluoro-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidine (62 mg, 0.17 mmol) in l-methyl-2-pyrridone (1 mL) was added to the mixture. The mixture was stirred at room temperature for 1 h, poured into ice water, and extracted with EtOAc (2 x 20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc - 75:25) yielded 64 mg (82%) of 4-[7-benzyl-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile
Step F:

To a solution of 4-[7-benzyl-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile (38 mg, 0.083 mmol) in 1,2-dichlorobenzene (1 mL) was added aluminium chloride (55 mg, 0.42 mmol). The reaction mixture was stirred at 160 °C for 4 h and cooled to room temperature. The mixture was poured into ice water and extracted with CH2CI2 (2 X 10 mL). The combined organic solution was washed with brine (10 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 50:50) yielded 15 mg (49%) of 4-[4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile as a tan solid,

7--benzyl-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine. To
a solution of 2,4,6-trimethylbenzene-l-thiol (231 mg, 1.52 mmol) in l-methyl-2-pyrridone (2 mL) was added NaH (58 mg, 1.52 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (131 mg, 0.51 mmol) in l-methyl-2-pyrridone (2 mL) was added to the mixture. The mixture was heated at 60oC for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with EtOAc (2 x 20 mL). The combined organic solution

was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 75:25) yielded 180 mg (94%) of 7-benzyl-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[23-d]pyrimidin-2-ylamine.
Step B:

7-benzyl-4(2,4,6-trirnethyl-phenylsulfanyl)-7H-pyn:olo[2,3-dJpyrimidin-2-ylamine (155 mg,
0.41 mmol) in a polyethylene flask at -50 °C under argon was added 60% HF in pyridine (12 mL). To the solution was added tert-butylnitrite (0.074 mL, 0.62 mmol) dropwise for 5 min. The reaction was wanned to -40 °C and stirred for 30 min at the temperature. The reaction was diluted with CHCl3 (100 mL) and poured into K2CO3 (3 g) in a beaker. To the mixture was carefully added ice water (50 mL). The CHCl3 layer was separated, washed with aqueous NaHCO3 solution (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 75:25) yielded 118 mg (77%) of 7-benzyl-2-fluoro-4-(2,4,6-trimethyl--phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine as a yellow solid.

benzonitrile. To a solution of 4-aminobenzonitrile (184 mg, 1.56 mmol) in l-methyl-2-pyrridone (2 mL) was added NaH (62 mg, 1.56 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-2-fluoro-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine (118 mg, 0.31 mmol) in l-methyl-2-pyrridone (2 mL) was added to the mixture. The mixture was stirred at room temperature for 4 h, then

poured into ice water and extracted with EtOAc (2 x 20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc - 75:25) yielded 123 mg (83%) of 4-[7-benzyl-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[23-d]pyrimidin-2-ylamino]-
benzonitrile.

benzonitrile. To a solution of 4-[7-benzyl-4-(2,4,6-trnnethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile (103 mg, 0.21 mmol) in 1,2-dichlorobetizene (2 mL) was added aluminum chloride (87 mg, 0.65 mmol). The reaction mixture was stirred at 160 oC for 1.5 h and cooled to room temperature. The mixture was poured into ice water and extracted with CH2Cl2 (2 x10 mL). The combined organic solution was washed with brine (10 mL), dried with Na2SO45 and concentrated to dryness. Silica gel chromatography (HexanesrEtOAc = 50:50) yielded 28 mg (34%) of 4-[4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile a as a tan solid.

pyrridone (5 mL) in a sealed tube was added NaH (441 mg, 11.0 xnmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (950 mg, 3.67 mmol) in l-methyl-2-pyrridone (5 mL) was added to the mixture. The mixture was heated at 150 oC for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with EtOAc (2 x 50 mL). The combined organic solution was washed with H2O (50 mL) and brine (50 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanesr EtOAc = 75:25)

(Hexanes:EtOAc = 50:50) yielded 6 mg (27%) of 4-[2-(4-cyano-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-3,5-dimethyl-ben2onitrile as a tan solid.

suspension of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (200 mg, 0.78 nunol) and 2,4,6-trimethylaniline (0.44 mL, 3.08 mmol) in 2,2,2-trifluoroethanol (4 mL) was added trifluoroacetic acid (0.48 mL, 6.24 mmol). The resulting solution was heated at 100 oC for 2 days and cooled to room temperature. The reaction was concentrated to brown oil and diluted with CH2Cl2 (30 mL). The organic solution was washed with aqueous NaHCO3

solution (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (CH2Cl2:MeOH = 95:5) yielded 251 mg (90%) of 7-benzyl-N4-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine.

7-benzyl-N4-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[23-d]pyrimidine-2,4-diamine(251 mg, 0.70 mmol) in a polyethylene flask at -50 oC under argon was added 60% HF in pyridine (24 mL). To the solution was added tert-butylnitrite (0.42 mL, 3.5 mmol) dropwise for 10 min. The reaction was warmed to -40 oC and stirred for 30 min at the temperature. The reaction was diluted with CHCl3 (200 mL) and poured into K2CO3 (6 g) in a beaker. To the mixture was carefully added ice water (100 mL). The CHCI3 layer was separated, washed with aqueous NaHCO3 solution (40 mL) and brine (40 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 75:25) yielded 56 mg (22%) of (7-ben2yl-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-(2,4,6-trimethyl-phenyl)-amine.

benzonitrile. To a suspension of (7-ben2yl-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-(2,4,6-trime1hyl-phenyl)-amine (42 mg, 0.12 mmol) and 4-aminoben2onitrile (55 mg, 0.47 mmol) in 2,2,2-trifluoroethanol (4 mL) was added trifluoroacetic acid (0.072 mL, 0.94 mmol). The resulting solution was heated at 90 oC C for 16 h, then cooled to room temperature.

The reaction was concentrated to produce a brown oil and diluted with CH2Cl2 (30 mL). The organic solution was washed with H2O (20mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 75:25) yielded 34 mg (64%) of 4-[7-benzyl-4-(2,4,6-trimethyl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile.

benzonitrile. To a solution of 4-[7-benzyl-4-(2,4,6-trimethyl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile (34 mg, 0.074 mmol) in 1,2-dichlorobenzene (1 mL) was added aluminum chloride (50 mg, 0.37 mmol). The reaction mixture was stirred at 160 °C for 2 h and cooled to room temperature. The mixture was poured into ice water and extracted with CHCI3 (2x10 mL). The combined organic solution was washed with brine (10 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (CH2Cl2: Acetone = 90:10) yielded 5 mg (19%) of 4-[4-(2,4,6-trimethyl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile as a tan solid.

benzonitrile. To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (1.62 mg, 11.0 mmol) in l-methyl-2-pyrridone (5 mL) in a sealed tube was added NaH (441 mg, 11.0 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (950 mg, 3,67 mmol) in l-methyl-2-pyrridone (5 mL) was added to the mixture. The mixture was heated at 150 oC C for 16 h and cooled to

room temperature. The reaction was poured into ice water and extracted with EK)Ac (2 x 50 mL). The combined organic solution was washed with H2O (50 mL) and brine (50 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatograhy (Hexanes:EtOAc = 75:25) yielded 1.12 mg (83%) of 4-(2-amino-7-benzyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile.

4-(7-benzyl-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile. To
4-(2-amino-7-benzyl-7H-pyrrolo[23-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile (70 mg, 0.19 mmol) in a polyethylene flask at -50 °C under argon was added 60% HF m pyridine (12 mL). To the solution was added tert-butylnitrite (0.068 mL, 0.57 mmol) dropwise for 5 min. The reaction was warmed to -40 °C and stirred for 30 min at the temperature. The reaction was then diluted with CHCl3 (100 mL) and poured into K2CO3 (3 g) in a beaker. Ice water (50 mL) was carefully added. The CHCl3 layer was separated, washed with aqueous NaHCO3 solution (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 75:25) yielded 36 mg (51%) of 4-(7-benzyl-2-fluoro-7H-pyrrolo[2,3-4]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile.

stirred at room temperature for 15 min and a solution of 4-(7-benzyl-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitri]e (34 mg, 0.091 mmol) in l-methyl-2-pyrridone (1 mL) was added to the mixture. The mixture was stirred at room temperature for 1 h, poured into ice water and extracted with EtOAc (2 x 20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc - 75:25) yielded 28 mg (65%)of 4-[7-benzyl-2-(4-cyano-phenylamino)-7H-pyn-olo[2,3-d]pyrimidin-4-yloxy]-3,5-, dimethyl-benzonitrile.

(1 mL) was added aluminum chloride (40 mg, 0.30 mmol). The reaction mixture was stirred at 160 oC for 45 min and cooled to room temperature. The mixture was poured into ice water and extracted with CH2Cl2 (2x10 mL). The combined organic solution was washed with brine (10 mL), dried with Na2O4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 50:50) yielded 6 mg (27%) of 4-[2-(4-cyano-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-3,5-dimeihyl-benzonitrile as a tan solid.

tert-butyldimethylsflane (668 mg, 2.12 mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0.11 mmol) in THF (20 mL) was added cyclopropyl zinc chloride (28.0 mL, 11.2 mmol). The mixture was heated at 80°C for 24 h and cooled to room temperature. The reaction was passed through a short pad of SiO2 to remove the catalyst and the solution was concentrated to oil. The resulting oil was diluted in EtOAc (100 mL), washed with brine (100 mL), dried with Na2SO45 and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 90:10) yielded 370 mg (63%) of tert-butyl(4-cyclopropyl-2,6-dimethylphenoxy)dimeihylsilane. To tert-butyl(4-cyclopropyl-2,6-
dimethylphenoxy)dimethylsilane (320 mg, 1.16 mmol) in TEIF (10 mL) was added a solution of tetrabutylammonium fluoride (5.0 mL, 1 M in THF, 5.0 mmol) and acetic acid (0.40 mL). The reaction was stirred at room temperature for 3 h and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 85:15) yielded 175 mg (93%) of 4-cyclopropyl-2,6-dimethylphenol as a light yellow oil.

2-chloro-6-(4'-cyclopropyl-2,6-dimethylphenoxy)-9H-purine. To a solution of 4-cyclopropyl-2,6-dimethylphenol (263 mg, 1.62 mmol) in l-methyl-2-pyrridone (3 roL) at -0oC was added NaH (65 mg, 1.62 mmol). The reaction mixture was stirred at room temperature for 30 min and a solution of 2,6-dichloropurine (102 mg, 0.54 mmol) in l-methyl-2-pyrridone (2 mL) was added to the mixture. The mixture was heated at 100°C for 16 h and then cooled to room temperature. The reaction was poured into ice water and extracted with CHCI3 (3 x 20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (MeOH:CHCl3 = 5:95) yielded 114 mg (67%) of 2-chloro-6-(4-cyclopropyl-2,6-dimethylphenoxy)-9H-purine.

4-(6-(4-cyclopropyl-2,6-dimethyiphenoxy)-9H-purm-2--ylammo)beiizonitriIe. To a suspension of 2-chloro-6-(4-cyclopropyl-2,6-dimethylphenoxy)-9H-purine (28 mg, 0.088 mmol) and 4-aminobenzonitrile (42 mg, 0.35 mmol) in 2,2,2-trifluoroethanol (3 mL) in a sealed tube was added trifluoroacetic acid (0.056 mL, 0.70 mmol). The resulting solution was heated at 90oC for 3 days. The reaction was cooled to room temperature and concentrated to dryness. Silica gel chromatography (CH2Cl2:Acetone = 80:20) yielded 7 mg (20%) of 4-(6-(4-cyclopropyl-2,6-dimethylphenoxy)-9H-purin-2-ylamino)ben2onitrile as a light yellow solid.

d]pyrimidiii-2-ylamme (500 mg, 2.97 mmol) in 1,2-dichloroethane (40 mL) at -10oC under argon was added antimony chloride (750 mg, 3.29 mmol). After stirring for 5 min, tert-butylnitrite (2.50 mL, 20.8 mmol) was added to fhe solution. The reaction was stirred at -10oC for 3 h. The reaction was diluted with CHCl3 (100 mL) and poured into ice water (50 mL). The CHCl3 layer was separated, washed with brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc = 50:50) yielded 239 mg (43%) of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine as a tan solid.

solution of 4-cyclopropyl-2,6-dimethylphenol (259 mg, 1.60 mmol) in THF (3 mL) at 0oC was added NaH (64 mg, 1.60 mmol). The reacticm mixture was stirred at room temperature for 30 min and a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.53 mmol) in THF (2 mL) was added to the mixture. The mixture was heated at 80°C for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with CHCl3 (3 X 20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (HexanesrEtOAc = 75:25) yielded 79 mg (48%) of 2-chloro-4-(4-cyclopropyl-2,6-dimethylphenoxy)-7H-pyrrolo[2,3-d]pyrimidine as a tan solid.

mmol) in 2,2,2-trifluoroethanol (4 mL) in a sealed tube was added trifluoroacetic acid (0.15 mL, 1.92 mmol). The resulting solution was heated at 90°C for 3 days. The reaction was diluted with EtOAc (50 mL), washed with NaHCO3 (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (CH2Cl2:Acetone = 90:10) yielded 15 mg (16%) of 4-(4-(4-cyclopropyl-2,6-dimethylphenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzonitrile as a tan solid.

to afford the corresponding 2-(dimethylamino)methyleneimino derivative. It was then benzylated to produce 3-benzyl-2-[(dimethylamino)methyleneimino]-5-nitro-6-methylpyrimidin-4-one by treating with benzyl bromide and converted to benzylated-2,6-bis-dimethylaminomethylene derivative with DMF-DMA. Reductive cyclization with sodium

hydrosulfite followed by de-protection with 3M NaOH and de-benzylation with Pd/C and NH4CO2H afforded 9-deazaguanine.

Scheme 2 illustrates the 3 different pathways which provide the various substituted 9-deazapuiines. Other products are synthesized by analogous methods, which a person skilled in the art could formulate, based on the reaction sequences given above. In certain cases, the person skilled in the art would see that protecting groups might be necessary. The synthetic schemee can be summarized as follows.
Benzylation of 9-deazaguanine followed by chlorination with POCl3 gives the chlorinated 9-deazapurine product. This chlorinated intermediate can either be coupled with R2 (pathway 1) followed by diazotization with t-butyl nitrite; displaced with F; coupled with R3 and de-benzylated to give the product; or it can undergo pathway 2, which is diazotization

with t-butyI nitrite in the presence of antimony chloride followed by coupling with R2 and E3, followed by de-benzylation to afford the final product. Alternatively, pathway 3 provides for de-benzylation of the dichloro-9-deazapurine followed by the coupling with R2 and R3 respectively to provide the various substituted 9-deazapurine.

H2SO4 at 0 oC was added 40 mL of HNO3 with an additional funnel. After being stirred at room temperature for 3 h, the reaction mixture was slowly poured into 3.6 L of diethyl ether and stirred for 15 min. Decant the ether solution and added 1.0L of ethyl acetate to the solid and stirred for 10 h. The solid (54.8 g, 81% yield) was filtered and used for next step without any further purification.

in CH2CI2 (461 mL) was added DMF-dimethylacetal (103.1 mL, 0.77 mol) and stirred at room temperature for 1.5 h. The reaction mixture was filtered, washed with CH2CI2, and used for the next step without further purification (31.9 g, 44% yield).

dihydropyrimidin-2-yl)formimidamide (53,4 g, 0.24 mmol) in DMF (690 mL) was added DBU (44.6 mL, 0.30 mol) and benzyl bromide (44.4 mL, 0.29 mol) and stirred at room

temperature for 1 h. The excess of DBU was neutralized with HCl, and the mixture was concentrated in vacuo. The residue was dissolved in methylene chloride and extracted twice with 2M HCl and water, then dried over Na2SO4 and concentrated. Trituration with ethanol afforded the crystalline product which was washed with ethanol to give the product (64,7 g, 86% yield) and used in the next step without further purification.

N,N-draiethylformimidamide (64.7 g, 0.2 mol) in DMF (254 mL) was added DMF-dimethylacetal (54.5 mL, 0.41 mol). The reaction mixture was stirred for 3 h at 65oC, cooled, and the solvent was removed under reduced pressure. The residue was triturated with ethanol, and the solid was collected by vacuum filtration (69.2 g, 91%) and used in the next step without further purification.

dihydropyrimidin-2-yl)-N,N-dimethylformimidamide (43.0 g, 0.12 mol) in THF (151 mL) was added an aqueous saturated solution of Na2S2O4 and stirred at room temperature overnight Upon completion of the reaction, the solid was filtered and washed with THF to afford the product (21.2 g, 62% yield) which was used m the next step without further purification.

yl)-N,N-dimethyIfonnimidamide (21.2 g, 0.07 mol) in MeOH (382 mL) was added 3M NaOH (276 mL) and heated at 100 °C for 5 h. After completion of the reaction, the reaction mixture was cooled to 0 °C. The solid was filtered (15.8 g, 91%) and used in the next step without further purification.

mol) in MeOH (334 mL) was added 10% Pd/C (2 g), ammonium formate (13.2 g, 0.21 mmol) and heated at 75oC for 4 h. After completion of the reaction, the reaction mixture was cooled and filtered through a pad of Celite with hot 1:1 DMF/MeOH. The filtrate was concentrated in vacuo to provide the product as an off-white solid (6.2 g, 99%).

mmol) in CH2CI2 (14.3 mL) was added benzyl bromide (0.26 mL, 2.2 mmol) and TBABr (644 mg, 2.0 mmol). The reaction mixture was cooled to 0 °C, and to it was added 50% NaOH (1.7 mL). The resulting mixture was stirred for 2 h as it warmed from 0oCC to room temperature. Water was then added, and the solution was washed with CHCI3. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated m vacuo. Purification by column chromatography, eluting with CH2Cl2/Acetone (5:1-1:1), afforded the product as a tan solid (423 mg, 82%)

A mixture of 2-amino-5-benzyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-One (1.1 g, 7.4 mmol) and POCl3 (7 mL, 74 mmol) was heated at 116 °C for 3 L Upon completion of the reaction, the reaction mixture was poured into ice and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography, eluting with CHaCh/Acetone (3:1), afforded the product as a white solid (490 mg, 40%).

To a stirred suspension of NaH (56 mg, 2.33 mmol) in dry NMP (2 mL) was added 2,4,6-trimethyl phenol (317 mg, 2.33 mmol). The mixture was stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-4-chloro-5H-pyn:olo[3,2-d]pyrimidin-2-amine (200 mg, 0.78 mmol) in dry NMP (1.5 mL) and the resulting solution was heated at 90 oCfor 16 h. After completion of the reaction, the reaction mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, and brine and dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by colunm chromatography, eluting with hexanes/ethyl acetate (3:1) to give the product as a white solid (140 mg, 50%).

A solution of 5-benzyl-4-(mesityloxy)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (139.9
mg, 0.39 mmol) in pyridine (1.6 mL) was cooled to -50oC and HF-pyr (8 mL) and t-butyl nitrite (0.19 mL, 1.56 mmol) was added dropwise. The reaction mixture was stirred at 50 °C to -30 oCfor 1.5 h. Upon completion of the reaction, the reaction mixture was poured into K2CO3 (5 g), slowly added water and washed with CHCI3 x 3. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes/ethyl acetate (2:1) to give the product as a white solid (116 mg, 82%).

A stirred suspension of NaH (63.8 mg, 2.66 mmol) in dry NMP (1.5 mL) was added 4-aminobenzylnitrile (188 mg, 2.66 mmol) and stirred at room temperature for 30 min imder argon. The reaction mixture was added to a solution of 5-benzyl-2-fluoro-4-(mesityloxy)-5H-pyrrolo[3,2-d]pyrimidine (115 mg, 0.32 mmol) in dry NMP (1.7 mL) and stirred at room temperature for 2 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc 3 times. The combined organic layers were washed with water, NH4Cl, water x 2, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with 1% MeOH:CH2Cl2, which afforded the product as a tan solid (120 mg, 80%).

ylamino)benzomtrile (150 mg, 0.33 mmol) in 1,2-dichlorobenzene (13 mL) was added AlCl3 (436 mg, 3,27 mmol). The reaction mixture was heated at 160oC for 1.5 h during which the

reaction mixture became dark and homogeneous. Upon completion of the reaction, the reaction mixture was cooled and washed with NH4Cl. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with Hexanes:Ethyl acetate (5:1-1:1) provided the product as a tan solid (27.8 mg, 23%).

4-hydroxy-3,5-dimethylbenzonitrile (570 mg, 3.88 mmol), and the mixture was stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (400 mg, 1.55 mmol) in dry NMP (4 mL) and heated at 160oC for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (2:1-1:4) to give the product as a light yellow solid (342 mg, 60%).

dimethylbenzonitrile (319.4 mg, 0.87 mmol) in pyridme (3 mL) was cooled to -50 °C and

HF-pyr (15 mL) and t-butul nitrite (0.42 mL, 3.46 xninol) were added dropwise. The reaction mixture was stirred at -50oC to -20 °C for 1,5 h. Upon completion of the reaction, the mixture was poured into K2CO3 (8 g), diluted with water and washed with CHCl3 x 3. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes/ethyl acetate (2:1-1:1) which same the product as a light yellow solid (314 mg, 97%),

To a stirred suspension of NaH (101 mg, 4.21 mmol) in dry NMP (4 mL) was added 4-aminobenzylnitrile (299 mg, 2.53 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 4-(5-benzyl-2-fluoro-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzomtrile (314 mg, 0.84 mmol) in dry NMP (4.4 mL) and stirred at room temperature for 2 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc x 3. The combined organic layers were washed with water, NH4CI, water x 2, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with 1% MeOH:CH2Cl2, producing the product as a tan solid (320 mg, 80%),

over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC TLC, eluting with 5 % Acetone/CH2Cl2 to give the product as a light yellow solid (10.5 mg, 45%).

2,4,6-trimethyl phenol (30.2 mg, 0.22 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 2,4-dichloro-5-methyl-5-H-pyrrolo[3,2-d]pyrimidine (44.6 mg, 0.22 mmol) in dry NMP (1.0 mL) and heated at 90oC for 16 h. After completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (5:1-2:1), to give the product as a light yellow solid (52.7 mg, 80%).

d]pyrimidine (52.7 mg, 0.18 nunol), 4-aminobenzonitrile (83 mg, 0.70 mmol), TFE (1.0 mL) and TFA (0.11 mL, 1.44 mmol). The reaction mixture was stirred at 90oC for 48 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water and washed

with EtOAc. The combined organic layers were washed with NaHCO3, brine, dried over Na2SO45 filtered, and concentrated in vacuo. The crude product was purified by preparative TLC, eluting with hexanes:ethyl acetate (5:1-2:1), to give the product as a light yellow solid

To a stirred solution of NaH (42.1 mg, 1.05 mmol) in dry NMP (2.5 mL) was added 4-hydroxy-3,5-dimethylbenzomtrile (154.7 mg, 1.05 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 2,4-dichloro-5-
methyl-5H-pyrrolo[3,2-d]pyrimidine (211.3 mg, 1.05 mmol) in dry NMP (2.7 mL) and heated at 160 °C for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (3:1-1:1), to give the product as a light yellow solid (294 mg, 85%).

yloxy)-3,5-dimethylbenzonitrile (294 mg, 0.94 mmol), 4-aminobenzonitrile (455 mg, 3.77 mmol), TFE (3.1 mL) and TFA (0.58 mL, 7.52 mmol). The reaction mixture was stirred at 90 °C for 48 h. Upon completion of the reaction, the resulting mixture was cooled, diluted

with water and washed with EtOAc. The combined organic layers were washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC, eluting with hexanes:ethyl acetate (4:1-1:2), to give the product as an off-white solid (133 mg, 40%).

To a stirred solution of NaH (31 mg, 0.78 mmol) in dry NMP (2 mL) was added l-(4-hydroxy-3,5-dimethylphenyl)ethanone (127 mg, 0.78 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-2,4-dichloro-5Hpyrrolo[3,2-d]pyrimidine (216 mg, 0.78 mmol) in dry NMP (2.4 mL) and heated at 160 °C for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1-2:1), to give the product as a light yellow solid (111 mg, 35%).

yloxy)-3,5-dimethylphenyl)ethanone (111 mg, 0.27 mmol), 4-aminobenzontrile (129 mg, 1.1 mmol), TFE (1.7 mL) and TFA (0.2 mL, 2.16 mmol). The reaction mixture was stirred at 90 °C for 16 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water, and washed with EtOAc. The combined organic layers were washed with NaHCO3 and brine; dried over Na2SO4; filtered; and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes:ethyl acetate (9:1-100 % EtOAc), to give the product as an off-white solid (68 mg, 51%).

d]pyrimidin-2-ylamino)benzonitrile (65 mg, 0.13 mmol) in 1,2-dichlorobenzene (5.3 xnL) . was added AICI3 (178 mg, 1.3 mmol). The reaction mixture was heated at 160 oC for 1.5 h, after which time the reaction mixture became dark and homogeneous. Upon completion of the reaction, the reaction mixture was cooled, CHCl3 was added, and the mixture was washed with NH4Cl. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel colunm chromatography, eluting with hexanes:ethyl acetate (3:1), to give the product as a brown solid (41 mg, 77%).
Example 14

((dimethylamino)methyl)-2,6-dimethylphenol (216.4 mg, 1.0 mmol) and the mixture was stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-ben2yl-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (216 mg, 0.78 mmol) in dry NMP (2.6 mL) and heated at 120 °C for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed twice with water, washed with, brine, dried over Na2SO45 filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with MeOH/CH2Cl2 (10%-30%), to give the product as a tan solid (71 mg, 17%).

(78.9 mg, 0.67 mmol), TFE (1.1 mL) and TFA (0.1 mL, 1.3 mmol). The reaction mixture was stirred at 90oC for 16 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water, and washed with EtOAc. The combined organic layers were washed with NaHCO3 solution and with brine, dried over Na2SO4, filtered, and concentrated

in vacuo. The crude product was purified by silica gel column chromatography, eluting with MeOH/CH2Cl2 (20%-40%), to give the product as a tan solid (17 mg, 20%).

The benzyl group was removed according to the same procedure as described for example 13.

To a stirred solution of NaH (61.9 mg, 2.6 mmol) in diy NMP (4,7 mL) was added 2,6-dimethyl-4-nitrophenol (258.9 mg, 1.55 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (431 mg, 1.55 mmol) in dry NMP (4 mL) and heated at 90 °C for 16 h. After completion of the reaction, fee resulting mixture was diluted with water and washed wife EtOAc. The combined organic layers were washed twice wife water, washed wife brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting wife hexanes;efeyl acetate (3:1-1:1), to give fee product as a white solid (598 mg, 94%).

I
TFE (9.1 mL) and TFA (1.97 mL, 11.7 mmol). The reaction mixture was stirred at 90 °C for 16 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water
and washed with EtOAc. The combined organic layers were washed with NaHCO3, brine,
f
dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes:ethyl acetate (3:1-1:1), to give the product (442 mg, 60%).

ylamino)benzonitrile (13 mg, 0.03 mmol) in CH2Cl2 (1 mL) was added NCS (4.4 mg, 0.03 mmol) and the mixture refluxed for 16 h. After the completion of the reaction, the solvent was concentrated and purified by preparative TLC eluting with hexanes:ethyl acetate (2:1) to give the product (4.2 mg, 30%).

ylamino)benzomtrile (10 mg, 0.02 mmol) in CH2CI2 (5 mL) was added NCS (2.8 mg, 0.02 mmol) and the resolution mixture refluxed for 16 h. After the completion of the reaction, the solvent was concentrated and purified by preparative TLC, eluting with hexanes:ethyl acetate (3:1), to give the product (8.8 mg, 88%).
Example 18

ylamino)benzonitrile (22.7 mg, 0.06 mmol) in CH2Cl2 (10 mL) was added NBS (10.5 mg, 0.06 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by reversed phase HPLC to give the product as a white solid (6.4 mg, 23%).
Example 19

ylamino)benzonitrile (17.3 mg, 0.05 mmol) in CH2Cl2 (5 mt) was added NCS (6.03 mg, 0.05 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by preparative TLC, eluting with hexanes:ethyl acetate (3:1), to give the product as an off-white solid (3.4 mg, 6%).

yloxy)-3,5-dimethylbenzonitrile (21.5 mg, 0.06 mmol) in CH2Cl2 (3 mL) was added NCS (73 mg, 0.06 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by preparative TLC, eluting with Hexanes:Ethyl acetate (3:1), to give the product as a light yellow solid (13.2 mg, 56%).
Example 21

yloxy)-3,5-dimethylbenzonitrile (58 mg, 0.15 mmol) in CH2Cl2 (8 mL) was added NBS (29 mg, 0.16 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by preparative TLC, eluting with hexanes:ethyl acetate (2:1), to give the product as a yellow solid (40 mg, 57%).

3,5-dimethylben2onitrile (28.1 mg, 0.07 mmol) in CH2Cl2 (4 mL) was added NCS (9.9 mg, 0.07 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by preparative TLC eluting with hexanesrethyl acetate (2:1), to give the product as a pink solid (20 mg, 65%).

Table 3 Contemplated Compounds of Formula IA-3

Table 4 Contemplated Compounds of Formula IA-4

Additional contemplated and prophetic examples, which are not exhaustive but merely-representative of this invention, are shown below:

Claims
What is claimed is
1. A compound of formula

where the dashed line represents a double bond between either A and B or B and D, where T is O or S; A is-N=, NZ or =CZ;
B is =CH or =N-; D is =CW or ==N-, or NW, provided that at least one of A and D is -N= or NZ or NW, and further provided that when both A and D are nitrogen, then B is CH; Z is H, F, CI, Br, CH3, CH2CH3, cyclopropyl, or benzyl, in which the phenyl moiety of the benzyl group is optionally substituted with methyl or methoxy, provided that Z is not F or C1 when A is NZ;
Z is H, F, CI, Br, CH3, CH2CH3, cyclopropyl, or benzyl, the phenyl moiety of said benzyl optionally substituted with one or two groups selected independently from methyl and methoxy, provided that when A is NZ, Z is neither F nor CI; W is H, F, CI, Br, methyl, ethyl, cyclopropyl, allyl, CH2CF3, cyanomethyl, CH2CH2CN, CH=CHCN, or benzyl, the phenyl moiely of said benzyl optionally substituted with one or two groups selected independently from methyl and methoxy, provided that when D is NW, W is neither F or CI; V is F, CI, CN, SO2CH3, SO2NH2, SO2NHCH3, C=CCH3, or CH=CHCN;
and AT is one of (a), (b), (c), and (d) below

where the dashed lines in (a) represent optional double bonds; where Rp is C1, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropyhnelhyl, C3-C6 cycloalkyl, CH=CHCN, acetyl, or NH-C1-C6 alkyl, said alkyl and cycloalkyl groups optionally substituted with methyl, methoxy, halogen, or cyano; R4, R5, and R6 are, independently, H, F, CI, Br, CH3, CH2F, CHF2, CF3. isopropyl, cyclopropyl, OCH3, OH, OCF3, NH2 and NHCH3, or R6 and RP on adjacent ring atoms, together with the ring atoms to which they are attached, form an additional fused five-membered ring; Q and Q' are, independently, N or CH; R7 is CI, Br, I, CH3, CF3, OCH3, isopropyl, cyclopropyl, t-butyl, or cyclobutyl; and R87 - R11 are, independently, H or CH3,
with the proviso that when Ar is (c), and the A,B ,D ring is imidazolo, Rp and V are not both one of CH3, CN, and CH=CHCN.
2. The compound of claim 1, wherein Ar is (a) or (c).
3. The compound of claim 2, where R6 either is H or is in the 2-position

4. The compound of claim 3, wherein Ar is selected from 4-cyclopropyl phenyl; 4-cyclopropylmethyl phenyl; 4-bromophenyl; 2-chloro-4-bromophenyl; 4-bromo-l-naphthyl; 4-cyclopropyl-1-naphthyl; 2,6-dimethyl-4-cyanophenyl; 2,6-dimethoxy-4-cyanophenyl; 2,6-dimethyl-4-(2-cyanoethenyl) phenyl; 2,6-dimethoxy-4-(2-cyanoethenyl) phenyl; 2-methyl-4-cyclopropyl phenyl; 2,6-dimethyl-4-cyclopropyl phenyl; 2,6-di-trifluoromethyl-4-cyclopropyl phenyl; 2,4,6-trimethyl phenyl; and 2,6-dimethyl-4-acetyl phenyl.
5. The compound of claim 1, which is a compound of formula IA-1

6. The compound of claim 1, which is a compound of formula IA-2

7. The compound of claim 1, which is a compound of formula IA-3

8. The compound of claim 1, which is a compound of formula IA-4

9. The compound of any of claims 5-8, where Ar is 4-cyclopropyl-, 4-acetyl-, 4-methyl-, 4-
bromo-, or 4-cyano-2,6-di-substituted phenyl.
10. The compound of claim 9, where V is CN, and where W and Z are, independently, H,
methyl, halo, or benzyl.

where the dashed line represents a double bond between either A and B or B and D;
where A is -N=, NZ or CZ;
B is CHor-N-
D is CW or=N-,or NW;
Z is H, F, CI, Br, CH3, CH2CH3, cyclopropyl, or benzyl, the phenyl moiety of said benzyl
optionally substituted with methyl or methoxy, provided that when A is NZ, Z is neither F
nor CI;
W is H, F, CI, Br, methyl, ethyl, cyclopropyl, allyl, CH2CF3, CH2CN, CH2CH2CN,
CH==CHCN, or benzyl, the phenyl moiety of said benzyl optionally substituted with methyl or
methoxy, provided that when D is NW, W is neither F nor CI;
V is F, CI, CN, SO2CH3, SO2NH2, SO2NHCH3, C=CHs, or CH=CHCN;
provided that at least one of A and D is "-N= or NZ or NW, and further provided that when
both A and D are nitrogen, then B is CH and V is other than CN or CH=CHCN;
wherein Rp is CI, Br, I, CN, CH=CHCN, methyl, ethyl, n-propyl, isopropyl, cyclopropyhnethyl, C3-C6 cycloalkyl, acetyl, and NH-C3-C6 alkyl; R6 is H, F, CI, Br, CH3, CH2F, CHF2, CF3, isopropyl, cyclopropyl, OCH3, OH, OCF3, NH2 and NHCH3; R7 is C1, Br, I, CH3, CF3, OCH3, isopropyl, cyclopropyl, f-butyl, or cyclobutyl.
17. The compound of claim 16, where V is CN or CH=CHCN, R6 is 2-methyl, 2-methoxy, or 2-chloro and R7 is H, 6-methyl, or 6-methoxy.
18. The compound of claim 17, where Rp is CN, cyclopropyl, methyl, Br, CI, CH=CHCN, or acetyl.
19. The compound of claim l, where one of A and D is =N- and the other is NZ or NW.
20. The compound of claim 5 which is a compound of formula IA-1 selected from compounds in Table 1:

Claims
What is claimed is
1. A compound of formula

where the dashed line represents a double bond between either A and B or B and D, where T is O or S; A is-N=, NZ or =CZ;
B is =CH or =N-; D is =CW or ==N-, or NW, provided that at least one of A and D is -N= or NZ or NW, and further provided that when both A and D are nitrogen, then B is CH; Z is H, F, CI, Br, CH3, CH2CH3, cyclopropyl, or benzyl, in which the phenyl moiety of the benzyl group is optionally substituted with methyl or methoxy, provided that Z is not F or C1 when A is NZ;
Z is H, F, CI, Br, CH3, CH2CH3, cyclopropyl, or benzyl, the phenyl moiety of said benzyl optionally substituted with one or two groups selected independently from methyl and methoxy, provided that when A is NZ, Z is neither F nor CI; W is H, F, CI, Br, methyl, ethyl, cyclopropyl, allyl, CH2CF3, cyanomethyl, CH2CH2CN, CH=CHCN, or benzyl, the phenyl moiely of said benzyl optionally substituted with one or two groups selected independently from methyl and methoxy, provided that when D is NW, W is neither F or CI; V is F, CI, CN, SO2CH3, SO2NH2, SO2NHCH3, C=CCH3, or CH=CHCN;
and AT is one of (a), (b), (c), and (d) below

where the dashed lines in (a) represent optional double bonds; where Rp is C1, Br, I, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropyhnelhyl, C3-C6 cycloalkyl, CH=CHCN, acetyl, or NH-C1-C6 alkyl, said alkyl and cycloalkyl groups optionally substituted with methyl, methoxy, halogen, or cyano; R4, R5, and R6 are, independently, H, F, CI, Br, CH3, CH2F, CHF2, CF3. isopropyl, cyclopropyl, OCH3, OH, OCF3, NH2 and NHCH3, or R6 and RP on adjacent ring atoms, together with the ring atoms to which they are attached, form an additional fused five-membered ring; Q and Q' are, independently, N or CH; R7 is CI, Br, I, CH3, CF3, OCH3, isopropyl, cyclopropyl, t-butyl, or cyclobutyl; and R87 - R11 are, independently, H or CH3,
with the proviso that when Ar is (c), and the A,B ,D ring is imidazolo, Rp and V are not both one of CH3, CN, and CH=CHCN.
2. The compound of claim 1, wherein Ar is (a) or (c).
3. The compound of claim 2, where R6 either is H or is in the 2-position

4. The compound of claim 3, wherein Ar is selected from 4-cyclopropyl phenyl; 4-cyclopropylmethyl phenyl; 4-bromophenyl; 2-chloro-4-bromophenyl; 4-bromo-l-naphthyl; 4-cyclopropyl-1-naphthyl; 2,6-dimethyl-4-cyanophenyl; 2,6-dimethoxy-4-cyanophenyl; 2,6-dimethyl-4-(2-cyanoethenyl) phenyl; 2,6-dimethoxy-4-(2-cyanoethenyl) phenyl; 2-methyl-4-cyclopropyl phenyl; 2,6-dimethyl-4-cyclopropyl phenyl; 2,6-di-trifluoromethyl-4-cyclopropyl phenyl; 2,4,6-trimethyl phenyl; and 2,6-dimethyl-4-acetyl phenyl.
5. The compound of claim 1, which is a compound of formula IA-1

6. The compound of claim 1, which is a compound of formula IA-2

7. The compound of claim 1, which is a compound of formula IA-3

8. The compound of claim 1, which is a compound of formula IA-4

9. The compound of any of claims 5-8, where Ar is 4-cyclopropyl-, 4-acetyl-, 4-methyl-, 4-
bromo-, or 4-cyano-2,6-di-substituted phenyl.
10. The compound of claim 9, where V is CN, and where W and Z are, independently, H,
methyl, halo, or benzyl.

where the dashed line represents a double bond between either A and B or B and D;
where A is -N=, NZ or CZ;
B is CHor-N-
D is CW or=N-,or NW;
Z is H, F, CI, Br, CH3, CH2CH3, cyclopropyl, or benzyl, the phenyl moiety of said benzyl
optionally substituted with methyl or methoxy, provided that when A is NZ, Z is neither F
nor CI;
W is H, F, CI, Br, methyl, ethyl, cyclopropyl, allyl, CH2CF3, CH2CN, CH2CH2CN,
CH==CHCN, or benzyl, the phenyl moiety of said benzyl optionally substituted with methyl or
methoxy, provided that when D is NW, W is neither F nor CI;
V is F, CI, CN, SO2CH3, SO2NH2, SO2NHCH3, C=CHs, or CH=CHCN;
provided that at least one of A and D is "-N= or NZ or NW, and further provided that when
both A and D are nitrogen, then B is CH and V is other than CN or CH=CHCN;
wherein Rp is CI, Br, I, CN, CH=CHCN, methyl, ethyl, n-propyl, isopropyl, cyclopropyhnethyl, C3-C6 cycloalkyl, acetyl, and NH-C3-C6 alkyl; R6 is H, F, CI, Br, CH3, CH2F, CHF2, CF3, isopropyl, cyclopropyl, OCH3, OH, OCF3, NH2 and NHCH3; R7 is C1, Br, I, CH3, CF3, OCH3, isopropyl, cyclopropyl, f-butyl, or cyclobutyl.
17. The compound of claim 16, where V is CN or CH=CHCN, R6 is 2-methyl, 2-methoxy, or 2-chloro and R7 is H, 6-methyl, or 6-methoxy.
18. The compound of claim 17, where Rp is CN, cyclopropyl, methyl, Br, CI, CH=CHCN, or acetyl.
19. The compound of claim l, where one of A and D is =N- and the other is NZ or NW.
20. The compound of claim 5 which is a compound of formula IA-1 selected from compounds in Table 1:

Documents:

5588-CHENP-2007 CORRESPONDENCE OTHERS 05-12-2011.pdf

5588-CHENP-2007 FORM-1 05-12-2011.pdf

5588-CHENP-2007 FORM-13 05-12-2011.pdf

5588-CHENP-2007 FORM-2 05-12-2011.pdf

5588-CHENP-2007 AMENDED CLAIMS 15-10-2014.pdf

5588-CHENP-2007 AMENDED PAGES OF SPECIFICATION 15-10-2014.pdf

5588-CHENP-2007 CORRESPONDENCE OTHERS 23-01-2014.pdf

5588-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 15-10-2014.pdf

5588-CHENP-2007 FORM-1 15-10-2014.pdf

5588-CHENP-2007 FORM-13 15-03-2010.pdf

5588-CHENP-2007 POWER OF ATTORNEY 15-10-2014.pdf

5588-chenp-2007 correspondance others.pdf

5588-chenp-2007 form-18.pdf

5588-chenp-2007-abstract.pdf

5588-chenp-2007-claims.pdf

5588-chenp-2007-correspondnece-others.pdf

5588-chenp-2007-description(complete).pdf

5588-chenp-2007-form 1.pdf

5588-chenp-2007-form 3.pdf

5588-chenp-2007-form 5.pdf

5588-chenp-2007-pct.pdf

Form 3.pdf

Petition for Annexure.pdf

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Patent Number

263525

Indian Patent Application Number

5588/CHENP/2007

PG Journal Number

44/2014

Publication Date

31-Oct-2014

Grant Date

31-Oct-2014

Date of Filing

05-Dec-2007

Name of Patentee

ARDEA BIOSCIENCES, INC

Applicant Address

4939 DIRECTORS PLACE SAN DIEGO CA 92121

Inventors:

#	Inventor's Name	Inventor's Address
1	GIRARDET, JEAN-LUC	17 OPEN VIEW LANE ALISO VIEJO CA 92656
2	KOH, YUNG-HYO	22 OAKHURST ROAD IRVINE, CA 92620
3	SHAW, STEPHANIE	55 PEPPERDALE DRIVE ROWLAND HEIGHTS CA 91748
4	KIM, HONG, WOO	400 SANTA MARIA DRIVE IRVINE, CA 92606

PCT International Classification Number

A61K 31/551

PCT International Application Number

PCT/US06/17677

PCT International Filing date

2006-05-05

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/678,667	2005-05-05	U.S.A.