Substituted purine derivative

Abstract

The present invention relates to a substituted purine derivative of formula (1) wherein R.sup.1 is alkoxy or the like, R.sup.2 is alkyl or the like, Ring Q.sup.1 is aryl or the like, W.sup.1 is alkylene or the like, Ring Q.sup.2 is aromatic carbocyclyl or the like, n is 1-4, R.sup.3 is hydrogen atom or the like, X.sup.1 is single bond or the like, W.sup.2 is alkylene or the like, and R.sup.4 is hydrogen atom or the like, or a pharmaceutically acceptable salt thereof, which has a potent inhibitory effect against TLR7, and thereby is useful for treating autoimmune disease. ##STR00001##

Claims

1. A compound of formula (1): ##STR00736## or a pharmaceutically acceptable salt thereof wherein R.sup.1 is optionally-substituted C.sub.1-6 alkoxy, optionally-substituted C.sub.3-7 cycloalkoxy, optionally-substituted 4- to 10-membered saturated heterocyclyloxy, optionally-substituted C.sub.1-6 alkyl, optionally-substituted C.sub.3-7 cycloalkyl, optionally-substituted C.sub.1-6 alkylthio, optionally-substituted 4- to 10-membered saturated heterocyclyl, optionally-substituted amino, halogen atom, or hydroxy; R.sup.2 is optionally-substituted C.sub.1-6 alkyl, optionally-substituted C.sub.3-7 cycloalkyl, or optionally-substituted amino; W.sup.1 is single bond, or optionally-substituted C.sub.1-4 alkylene; Ring Q.sup.1 is (1) pyridyl which may be substituted with 1-5 the same or different substituents selected from the group consisting of (a) halogen atom, (b) cyano, (c) C.sub.1-6 alkyl which may be substituted with 1-3 the same or different halogen atoms, and (d) C.sub.1-6 alkoxy which may be substituted with 1-3 the same or different halogen atoms, or (2) pyrimidinyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of (a)-(d) in the above (1), Ring Q.sup.2 is C.sub.6-10 aromatic carbocyclyl, or 5- to 10-membered aromatic heterocyclyl; n is 1, 2, 3, or 4; R.sup.3 is, independently if there are plural R.sup.3, hydrogen atom, halogen atom, cyano, hydroxy, optionally-substituted C.sub.1-6 alkyl, optionally-substituted C.sub.1-6 alkoxy, optionally-substituted C.sub.3-7 cycloalkyl, optionally-substituted C.sub.3-7 cycloalkoxy, or optionally-substituted amino; Q.sup.2-X.sup.1 is Q.sup.2-(single bond)-, Q.sup.2-(CH.sub.2).sub.mO, Q.sup.2-(CH.sub.2).sub.mS, Q.sup.2-(CH.sub.2).sub.mS(O).sub.2, Q.sup.2-(CH.sub.2).sub.mNR.sup.aS(O).sub.2, Q.sup.2-(CH.sub.2).sub.mS(O).sub.2NR.sup.a, Q.sup.2-(CH.sub.2).sub.mC(O), Q.sup.2-(CH.sub.2).sub.mNR.sup.a, Q.sup.2-(CH.sub.2).sub.mNR.sup.aC(O), or Q.sup.2-(CH.sub.2).sub.mC(O)NR.sup.a, wherein R.sup.a is hydrogen atom or C.sub.1-6 alkyl; m is 0, 1, or 2; W.sup.2 is single bond, or optionally-substituted C.sub.1-8 alkylene; and R.sup.4 is hydrogen atom, OR.sup.b (wherein R.sup.b is hydrogen atom, optionally-substituted C.sub.1-6 alkyl, optionally-substituted C.sub.1-6 alkylcarbonyl, optionally-substituted aminocarbonyl, or optionally-substituted C.sub.1-6 alkylsulfonyl), NR.sup.cR.sup.d (wherein R.sup.c is hydrogen atom or optionally-substituted C.sub.1-6 alkyl; and R.sup.d is hydrogen atom, optionally-substituted C.sub.1-6 alkyl, optionally-substituted C.sub.1-6 alkylcarbonyl, optionally-substituted C.sub.1-6 alkoxycarbonyl, or optionally-substituted C.sub.1-6 alkylsulfonyl), optionally-substituted 4- to 10-membered saturated heterocyclyl, or optionally-substituted 5- to 10-membered heteroaryl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is (1) C.sub.1-6 alkoxy which may be substituted with 1-3 the same or different substituents selected from the group consisting of (a) halogen atom, (b) hydroxy, (c) C.sub.1-6 alkoxy which may be substituted with 1-3 the same or different halogen atoms, (d) C.sub.3-7 cycloalkyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, (e) C.sub.3-7 cycloalkoxy which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, (f) phenyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, (g) 5- or 6-membered heteroaryl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, and (h) 4- to 7-membered saturated heterocyclyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, (2) C.sub.3-7 cycloalkoxy which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, (3) 4- to 10-membered saturated heterocyclyloxy which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, (4) C.sub.1-6 alkyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy, (5) C.sub.3-7 cycloalkyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, (6) C.sub.1-6 alkylthio which may be substituted with 1-3 the same or different halogen atoms, (7) 4- to 10-membered saturated heterocyclyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, (8) amino which may be substituted with 1-2 the same or different C.sub.1-6 alkyl which may be substituted with 1-3 the same or different halogen atoms, (9) halogen atom, or (10) hydroxy; R.sup.2 is C.sub.1-6 alkyl (which may be substituted with 1-3 the same or different halogen atoms), C.sub.3-7 cycloalkyl, or amino (which may be substituted with 1-2 the same or different C.sub.1-6 alkyl); Ring Q.sup.1 is (1) pyridyl which may be substituted with 1-5 the same or different substituents selected from the group consisting of (a) halogen atom, (b) cyano, (c) C.sub.1-6 alkyl which may be substituted with 1-3 the same or different halogen atom, and (d) C.sub.1-6 alkoxy which may be substituted with 1-3 the same or different halogen atoms, or (2) pyrimidinyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of (a)-(d) in the above (1); W.sup.1 is single bond, or C.sub.1-4 alkylene which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy, Ring Q.sup.2 is C.sub.6-10 aromatic carbocyclyl, or 5- to 10-membered aromatic heterocyclyl; n is 1, 2, 3, or 4; R.sup.3 is, independently if there are plural R.sup.3, (1) hydrogen atom, (2) halogen atom, (3) cyano, (4) hydroxy, (5) C.sub.1-6 alkyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy, (6) C.sub.1-6 alkoxy which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy, (7) C.sub.3-7 cycloalkyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, (8) C.sub.3-7 cycloalkoxy which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, or (9) amino which may be substituted with 1-2 the same or different C.sub.1-6 alkyl which may be substituted with 1-3 the same or different halogen atoms; Q.sup.2-X.sup.1 is Q.sup.2-(single bond)-, Q.sup.2-(CH.sub.2).sub.mO, Q.sup.2-(CH.sub.2).sub.mS, Q.sup.2-(CH.sub.2).sub.mS(O).sub.2, Q.sup.2-(CH.sub.2).sub.mNR.sup.aS(O).sub.2, Q.sup.2-(CH.sub.2).sub.mS(O).sub.2NR.sup.a, Q.sup.2-(CH.sub.2).sub.mC(O), Q.sup.2-(CH.sub.2).sub.mNR.sup.a, Q.sup.2-(CH.sub.2).sub.mNR.sup.aC(O), or Q.sup.2-(CH.sub.2).sub.mC(O)NR.sup.a, wherein R.sup.a is hydrogen atom or C.sub.1-6 alkyl; m is 0, 1, or 2; W.sup.2 is single bond, or C.sub.1-8 alkylene which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy; and R.sup.4 is (1) hydrogen atom, (2) OR.sup.b wherein R.sup.b is hydrogen atom, C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, mono- or di-C.sub.1-6 alkyl-aminocarbonyl, or C.sub.1-6 alkylsulfonyl, (3) NR.sup.cR.sup.d wherein R.sup.c is hydrogen atom or C.sub.1-6 alkyl which may be substituted with 1-3 the same or different halogen atoms; and R.sup.d is hydrogen atom, C.sub.1-6 alkyl (which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, amino (which may be substituted with 1-2 the same or different C.sub.1-6 alkyl), and C.sub.1-6 alkoxy), C.sub.1-6 alkylcarbonyl (which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, amino (which may be substituted with 1-2 the same or different C.sub.1-6 alkyl), and C.sub.1-6 alkoxy), C.sub.1-6 alkoxycarbonyl, or C.sub.1-6 alkylsulfonyl, (4) 4- to 10-membered saturated heterocyclyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of (a) halogen atom, (b) hydroxy, (c) cyano, (d) C.sub.1-6 alkyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy, (e) C.sub.1-6 alkoxy which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy, (f) C.sub.3-7 cycloalkyl, (g) C.sub.1-6 alkylcarbonyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, amino (which may be substituted with 1-2 the same or different C.sub.1-6 alkyl), and C.sub.1-6 alkoxy, (h) C.sub.1-6 alkoxycarbonyl, (i) 4- to 7-membered saturated heterocyclyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, (j) phenyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, (k) 5- or 6-membered heteroaryl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, and (1) oxo, or (5) 5- to 10-membered heteroaryl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is C.sub.1-6 alkoxy (which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C.sub.1-6 alkoxy, C.sub.3-7 cycloalkyl and 4- to 7-membered saturated heterocyclyl), 4- to 10-membered saturated heterocyclyloxy (which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, and C.sub.1-6 alkyl), C.sub.1-6 alkyl (which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy), 4- to 10-membered saturated heterocyclyl (which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), amino (which may be substituted with 1-2 the same or different C.sub.1-6 alkyl), halogen atom, or hydroxy.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is C.sub.1-6 alkoxy (which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy), or halogen atom.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is C.sub.1-6 alkyl or amino.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W.sup.1 is methylene.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring Q.sup.2 is benzene ring group, or 5- or 6-membered aromatic heterocyclyl.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring Q.sup.2 is pyridine ring group, pyrazole ring group, isoxazole ring group, or benzene ring group.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is hydrogen atom, halogen atom, cyano, hydroxy, C.sub.1-6 alkyl (which may be substituted with 1-3 the same or different halogen atoms), or C.sub.1-6 alkoxy (which may be substituted with 1-3 the same or different halogen atoms).

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q.sup.2-X.sup.1 is Q.sup.2-(single bond)-, Q.sup.2-(CH.sub.2).sub.mO, Q.sup.2-(CH.sub.2).sub.mC(O), Q.sup.2-(CH.sub.2).sub.mNR.sup.a, or Q.sup.2-(CH.sub.2).sub.mC(O)NR.sup.a, wherein R.sup.a is hydrogen atom or C.sub.1-6 alkyl; m is 0, 1, or 2.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X.sup.1 is single bond or O.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W.sup.2 is single bond or C.sub.1-3 alkylene.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W.sup.2 is single bond or methylene.

14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is (1) hydrogen atom, (2) OR.sup.b wherein R.sup.b is hydrogen atom, C.sub.1-6 alkyl, or C.sub.1-6 alkylsulfonyl, (3) NR.sup.cR.sup.d wherein R.sup.c and R.sup.d are independently hydrogen atom or C.sub.1-6 alkyl which may be substituted with 1-3 the same or different halogen atoms, (4) 4- to 10-membered saturated heterocyclyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of (a) halogen atom, (b) hydroxy, (c) cyano, (d) C.sub.1-6 alkyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy, (e) C.sub.1-6 alkoxy which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy, (f) C.sub.3-7 cycloalkyl, (g) C.sub.1-6 alkylcarbonyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, amino (which may be substituted with 1-2 the same or different C.sub.1-6 alkyl), and C.sub.1-6 alkoxy, (h) C.sub.1-6 alkoxycarbonyl, (i) 4- to 7-membered saturated heterocyclyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, and (j) oxo, or (5) 5- to 10-membered heteroaryl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is (1) NR.sup.cR.sup.d wherein R.sup.c and R.sup.d are independently hydrogen atom or C.sub.1-6 alkyl which may be substituted with 1-3 the same or different halogen atoms, or (2) 4- to 10-membered saturated nitrogen-containing heterocyclyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of (a) halogen atom, (b) hydroxy, (c) cyano, (d) C.sub.1-6 alkyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy, (e) C.sub.1-6 alkoxy which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy, (f) C.sub.3-7 cycloalkyl, (g) C.sub.1-6 alkylcarbonyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, amino (which may be substituted with 1-2 the same or different C.sub.1-6 alkyl), and C.sub.1-6 alkoxy, and (h) 4- to 7-membered saturated heterocyclyl.

16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein formula (1) is represented as formula (1a): ##STR00737## wherein R.sup.11 is C.sub.1-6 alkoxy (which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C.sub.1-6 alkoxy, C.sub.3-7 cycloalkyl and 4- to 7-membered saturated heterocyclyl), 4- to 10-membered saturated heterocyclyloxy (which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, and C.sub.1-6 alkyl), C.sub.1-6 alkyl (which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy), 4- to 10-membered saturated heterocyclyl (which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy), amino (which may be substituted with 1-2 the same or different C.sub.1-6 alkyl), halogen atom, or hydroxy; R.sup.12 is C.sub.1-6 alkyl or amino; Ring Q.sup.11 is (1) pyridyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of (a) halogen atom, (b) cyano, (c) C.sub.1-6 alkyl which may be substituted with 1-3 the same or different halogen atoms, and (d) C.sub.1-6 alkoxy which may be substituted with 1-3 the same or different halogen atoms, or (2) pyrimidinyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of (a)-(d) in the above (1); Ring Q.sup.12 is benzene ring group, or 5- or 6-membered aromatic heterocyclyl; R.sup.13 is hydrogen atom, halogen atom, hydroxy, C.sub.1-6 alkyl (which may be substituted with 1-3 the same or different halogen atoms), or C.sub.1-6 alkoxy (which may be substituted with 1-3 the same or different halogen atoms); Q.sup.2-X.sup.11 is Q.sup.12-(single bond)-, Q.sup.12-(CH.sub.2).sub.mO, Q.sup.12-(CH.sub.2).sub.mC(O), Q.sup.12-(CH.sub.2).sub.mNR.sup.a, or Q.sup.12-(CH.sub.2).sub.mC(O)NR.sup.a, wherein R.sup.a is hydrogen atom or C.sub.1-6 alkyl; m is 0, 1, or 2; W.sup.12 is single bond or C.sub.1-3 alkylene; and R.sup.14 is (1) hydrogen atom, (2) OR.sup.b wherein R.sup.b is hydrogen atom, C.sub.1-6 alkyl, or C.sub.1-6 alkylsulfonyl, (3) NR.sup.cR.sup.d wherein R.sup.c and R.sup.d are independently hydrogen atom, or C.sub.1-6 alkyl which may be substituted with 1-3 the same or different halogen atoms, (4) 4- to 10-membered saturated heterocyclyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of (a) halogen atom, (b) hydroxy, (d) C.sub.1-6 alkyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy, (e) C.sub.1-6 alkoxy which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy, (f) C.sub.3-7 cycloalkyl, (g) C.sub.1-6 alkylcarbonyl which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, amino (which may be substituted with 1-2 the same or different C.sub.1-6 alkyl), and C.sub.1-6 alkoxy, (h) C.sub.1-6 alkoxycarbonyl, (i) 4- to 7-membered saturated heterocyclyl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy, and (j) oxo, or (5) 5- to 10-membered heteroaryl which may be substituted with 1-4 the same or different substituents selected from the group consisting of halogen atom, C.sub.1-6 alkyl, and C.sub.1-6 alkoxy.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein R.sup.12 is C.sub.1-4 alkyl.

18. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein R.sup.13 is hydrogen atom or halogen atom.

19. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein Ring Q.sup.11 is 5-fluoropyridin-3-yl, 5-cyanopyridin-3-yl, pyridin-3-yl, or pyrimidinyl.

20. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein Ring Q.sup.12 is pyridine ring group, pyrazole ring group, isoxazole ring group, or benzene ring group.

21. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein R.sup.14 is the following formula (2), (3), (4), (5), (6), (8), (9), (10), (11), (12), (13), (14), (15), or (16): ##STR00738## ##STR00739## wherein R.sup.15 is halogen, hydroxy, C.sub.1-6 alkyl (which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy), C.sub.3-7 cycloalkyl, C.sub.1-6 alkylcarbonyl (which may be substituted with one amino which may be substituted with 1-2 the same or different C.sub.1-6 alkyl), or 4- to 7-membered saturated heterocyclyl.

22. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein R.sup.14 is the following formula (2), (3), (4), (5), (6), (8), (9), or (10): ##STR00740## ##STR00741## wherein R.sup.15 is halogen, hydroxy, C.sub.1-6 alkyl (which may be substituted with 1-3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, and C.sub.1-6 alkoxy), C.sub.3-7 cycloalkyl, C.sub.1-6 alkylcarbonyl (which may be substituted with one amino which may be substituted with 1-2 the same or different C.sub.1-6 alkyl), or 4- to 7-membered saturated heterocyclyl.

23. The compound of claim 1 which is selected from the following compounds, or a pharmaceutically acceptable salt thereof: 9-({6-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridin-3-yl}methyl)-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-({6-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridin-3-yl}methyl)-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine, 8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9-(4-{[(1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)-9H-purine, 2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9-(4-{[(1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)-9H-purine, 2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9-(4-{[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)-9H-purine, 2-ethoxy-9-(4-{[(1 S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine, 9-(4-{[(1 S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9-(4-{[(1 S,4S)-5-propyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)-9H-purine, 9-{4-[(5R)-1,4-diazabicyclo[3.2.1]oct-4-ylmethyl]benzyl}-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine, 9-{4-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]benzyl}-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9-{4-[(4-methylpiperazine-1-yl)methyl]benzyl}-9H-purin, 9-[4-(1-azabicyclo[2.2.2]oct-3-yl)-2-methoxybenzyl]-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine, 2-(1-azabicyclo[2.2.2]oct-3-yl)-5-{[2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purin-9-yl]methyl}benzonitrile, 9-{[1-(1-azabicyclo[2.2.2]oct-3-ylmethyl)-1H-pyrazol-4-yl]methyl}-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine, 2-(1-azabicyclo[2.2.2]oct-3-yl)-5-{[8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purin-9-yl]methyl}benzonitrile, 9-[2-fluoro-4-[(1-methylpiperidin-4-yl)methyl]benzyl}-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-[2-fluoro-4-[(1-methylazetidin-3-yl)methoxy]benzyl]-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 5-f 9-[4-(1-ethylpiperidin-4-yl)-2-fluorobenzyl]-2-methoxy-6-methyl-9H-purin-8-yl)pyridine-3-carbonitrile, 9-[2-fluoro-4-(1-methylpyrrolidin-3-yl)benzyl]-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-[4-(1-ethylpyrrolidin-3-yl)-2-fluorobenzyl]-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-[2-fluoro-4-(1-methylpiperidin-4-yl)benzyl]-2-methoxy-6-methyl-8-(pyridin-3-yl)-9H-purine, 9-[4-(1-ethylpiperidin-4-yl)-2-fluorobenzyl]-2-methoxy-6-methyl-8-(pyridin-3-yl)-9H-purine, 9-(2-fluoro-4-{[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}benzyl)-2-methoxy-6-methyl-8-(pyridin-3-yl)-9H-purine, 9-{4-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]-2-fluorobenzyl}-2-methoxy-6-methyl-8-(pyrimidin-5-yl)-9H-purine, 9-[4-(1-azabicyclo[2.2.2]oct-3-yl)-3-fluorobenzyl]-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-[3-(1-azabicyclo[2.2.2]oct-3-yl)benzyl]-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-{[6-(1-azabicyclo[2.2.2]oct-3-yl)-2-methylpyridin-3-yl]methyl}-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine, 9-{4-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]-2-fluorobenzyl}-2-methoxy-6-methyl-8-(pyridin-3-yl)-9H-purine, 9-{2-fluoro-4-[(1-methylpiperidin-4-yl)oxy]benzyl}-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-(2-fluoro-4-{[(3S)-1-methylpyrrolidin-3-yl]oxy}benzyl)-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-(2-fluoro-4-{[(3R)-1-methylpyrrolidin-3-yl]oxy}benzyl)-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-{2-fluoro-4-[(1-methylazetidin-3-yl)oxy]benzyl}-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 1-(3-fluoro-4-{[8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purin-9-yl]methyl}phenyl)-N,N-dimethylmethanamine, 9-[4-(azetidin-1-ylmethyl)-2-fluorobenzyl]-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-(2-fluoro-4-{[(1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-[2-fluoro-4-(1-methylpiperidin-4-yl)benzyl]-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-[4-(1-ethylpiperidin-4-yl)-2-fluorobenzyl]-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-(2-fluoro-4-{[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}benzyl)-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-(2-fluoro-4-{[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}benzyl)-2-methoxy-6-methyl-8-(pyrimidin-5-yl)-9H-purine, 5-[9-(2-fluoro-4-{[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}benzyl}-2-methoxy-6-methyl-9H-purin-8-yl]pyridine-3-carbonitrile, 5-[9-(4-{[(3-endo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}-2-fluorobenzyl)-2-methoxy-6-methyl-9H-purin-8-yl]pyridine-3-carbonitrile, 9-[4-(1-azabicyclo[2.2.2]oct-3-yl)-2-fluorobenzyl]-2-methoxy-6-methyl-8-(pyridin-3-yl)-9H-purine, 9-[4-(1-azabicyclo[2.2.2]oct-3-yl)-2-fluorobenzyl]-2-methoxy-6-methyl-8-(4-methylpyridin-3-yl)-9H-purine, 9-[4-(1-azabicyclo[2.2.2]oct-3-yl)-2-fluorobenzyl]-2-methoxy-6-methyl-8-(5-methylpyridin-3-yl)-9H-purine, 5-[9-(2-fluoro-4-{[(1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)-2-methoxy-6-methyl-9H-purin-8-yl]pyridine-3-carbonitrile, 5-[9-(4-{[(1 S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}-2-fluorobenzyl)-2-methoxy-6-methyl-9H-purin-8-yl]pyridine-3-carbonitrile, 9-(2-fluoro-4-{[(1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)-2-methoxy-6-methyl-8-(pyridin-3-yl)-9H-purine, 5-[2-ethoxy-9-(2-fluoro-4-{[(1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)-6-methyl-9H-purin-8-yl]pyridine-3-carbonitrile, 2-ethoxy-9-(2-fluoro-4-{[(1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)-6-methyl-8-(pyrimidin-5-yl)-9H-purine, 2-ethoxy-9-(2-fluoro-4-{[(1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine, 5-(9-{4-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]-2-fluorobenzyl}-2-methoxy-6-methyl-9H-purin-8-yl)pyridine-3-carbonitrile, 9-{[6-(1-azabicyclo[2.2.2]oct-3-yl)pyridin-3-yl]methyl}-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine, 9-[4-(1-azabicyclo[2.2.2]oct-3-yl)-2-fluorobenzyl]-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 5-{9-[4-(1-azabicyclo[2.2.2]oct-3-yl)-2-fluorobenzyl]-2-methoxy-6-methyl-9H-purin-8-yl}pyridine-3-carbonitrile, 9-{4-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]-2-fluorobenzyl}-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-{4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]-2-fluorobenzyl}-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-(2-fluoro-4-{[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}benzyl)-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, and 9-[5-(1-azabicyclo[2.2.2]oct-3-yl)-2-fluorobenzyl]-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine.

24. The compound of claim 1 which is selected from the following compounds, or a pharmaceutically acceptable salt thereof: 1-(3-fluoro-4-{[8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purin-9-yl]methyl}phenyl)-N,N-dimethylmethanamine, 9-[4-(azetidin-1-ylmethyl)-2-fluorobenzyl]-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-(2-fluoro-4-[(1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-[2-fluoro-4-(1-methylpiperidin-4-yl)benzyl]-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-[4-(1-ethylpiperidin-4-yl)-2-fluorobenzyl]-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-(2-fluoro-4-{[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}benzyl)-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-(2-fluoro-4-{[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}benzyl)-2-methoxy-6-methyl-8-(pyrimidin-5-yl)-9H-purine, 5-[9-(2-fluoro-4-{[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}benzyl}-2-methoxy-6-methyl-9H-purin-8-yl]pyridine-3-carbonitrile, 5-[9-(4-{[(3-endo)-8-ethyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}-2-fluorobenzyl)-2-methoxy-6-methyl-9H-purin-8-yl]pyridine-3-carbonitrile, 9-[4-(1-azabicyclo[2.2.2]oct-3-yl)-2-fluorobenzyl]-2-methoxy-6-methyl-8-(pyridin-3-yl)-9H-purine, 9-[4-(1-azabicyclo[2.2.2]oct-3-yl)-2-fluorobenzyl]-2-methoxy-6-methyl-8-(4-methylpyridin-3-yl)-9H-purine, 9-[4-(1-azabicyclo[2.2.2]oct-3-yl)-2-fluorobenzyl]-2-methoxy-6-methyl-8-(5-methylpyridin-3-yl)-9H-purine, 5-[9-(2-fluoro-4-{[(1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl}-2-methoxy-6-methyl-9H-purin-8-yl]pyridine-3-carbonitrile, 5-({[(1 S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}-2-fluorobenzyl)-2-methoxy-6-methyl-9H-purin-8-yl]pyridine-3-carbonitrile, 9-(2-fluoro-4-{[(1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)-2-methoxy-6-methyl-8-(pyridin-3-yl)-9H-purine, 5-[2-ethoxy-9-(2-fluoro-4-{[(1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)-6-methyl-9H-purin-8-yl]pyridine-3-carbonitrile, 2-ethoxy-9-(2-fluoro-4-{[(1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl)-6-methyl-8-(pyrimidin-5-yl)-9H-purine, 2-ethoxy-9-(2-fluoro-4-{[(1 S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}benzyl}-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine, 5-(9-{4-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]-2-fluorobenzyl}-2-methoxy-6-methyl-9H-purin-8-yl)pyridine-3-carbonitrile, 9-{[6-(1-azabicyclo[2.2.2]oct-3-yl)pyridin-3-yl]methyl}-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine, 9-[4-(1-azabicyclo[2.2.2]oct-3-yl)-2-fluorobenzyl]-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 5-f 9-[4-(1-azabicyclo[2.2.2]oct-3-yl)-2-fluorobenzyl]-2-methoxy-6-methyl-9H-purin-8-yl)pyridine-3-carbonitrile, 9-{4-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]-2-fluorobenzyl}-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-f 4-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]-2-fluorobenzyl}-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine, 9-(2-fluoro-4-1f[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}benzyl)-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purin, and 9-[5-(1-azabicyclo[2.2.2]oct-3-yl)-2-fluorobenzyl]-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine.

25. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a carrier.

26. A method for treating autoimmune disease, comprising administering a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a mammal.

27. A method for treating systemic lupus erythematosus, lupus nephritis, Sjogren's syndrome, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, polymyositis, dermatomyositis, Behcet's disease, multiple sclerosis, or pemphigus, comprising administering a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a mammal.

Description

EXAMPLES

(1) The present invention is explained in more detail in the following by referring to Examples, Reference examples, and Tests; however, the technical scope of the present invention is not limited thereto. The compound names used in Examples and Reference examples are not always based on IUPAC nomenclature system.

(2) In the present specification, the abbreviations shown below may be sometimes used. (Boc).sub.2O: di-tert-butyl dicarbonate Tf: trifluoromethanesulfonyl DMAP: N,N-dimethyl-4-aminopyridine EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EDCI.Math.HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBt: 1-hydroxybenzotriazole HOBt.Math.H.sub.2O: 1-hydroxybenzotriazole monohydrate Boc: tert-butoxycarbonyl Me: methyl Et: ethyl Tf: trifluoromethanesulfonyl Rt: retention time

(3) In the following Examples and Reference examples, the reaction device shown below was used as appropriate. Microwave reactor: Biotage AB Initiator

(4) The physicochemical data of each compound in Examples and Reference examples were obtained with the instrument shown below.

(5) .sup.1H-NMR: JEOL JNM-AL400; Brucker AVANCE 400 Spectrometer

(6) The LC/MS data of each compound in Examples and Reference examples were obtained with the instrument shown below. Detector: ACQUITY SQ deteceter (Waters) HPLC: ACUITY UPLC SYSTEM Column: Waters ACQUITY UPLC BEH C18 (1.7 m, 2.1 mm30 mm)

(7) The analytical conditions are as follows.

(8) TABLE-US-00001 Method Solvent Gradient condition Method A A: 0.05% formic acid/ 0.0-1.3 min Linear water gradient from B 2% to B: acetonitrile 96% Method B A: 0.05% formic acid 0.0-1.3 min Linear water gradient from B 1% to B: acetonitrile 95% Method C A: 0.05% formic acid/ 0.0-1.3 min Linear water gradient from B 10% B: acetonitrile to 95% Method D A: 0.06% formic acid/ 0.0-1.3 min Linear water gradient from B 2% to B: 0.06% formic acid/ 96% acetonitrile
Flow rate: 0.8 mL/min; Detection UV: 220 nm and 254 nm; Temperature: 40 C.

(9) The compound names in Examples and Reference examples were determined with ACD/Name (ACD/Labs 12.0, Advanced Chemistry Development Inc.).

Example 1

9-Benzyl-2-butoxy-8-(5-fluoropyridin-3-yl)-9H-purine-6-amine

(10) ##STR00043##

(11) To a solution of 9-benzyl-8-bromo-2-butoxy-9H-purine-6-amine (70.1 mg) in a mixture of 1,4-dioxane (3 mL)/water (1 mL) were added 3-fluoropyridine-5-boronic acid pinacol ester (46.4 mg), potassium carbonate (77.6 g), and tetrakis(triphenylphosphine)palladium (0.021 g), and the mixture was stirred at 120 C. under microwave irradiation for one hour. The reaction mixture was cooled to room temperature, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (22.6 mg).

(12) LC-MS [M+H].sup.+/Rt (min): 393.0/0.988 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.67 (1H, t, J=1.8 Hz), 8.67 (1H, d, J=7.9 Hz), 7.98-7.95 (1H, m), 7.47 (2H, brs), 7.28-7.19 (3H, m), 6.99-6.96 (2H, m), 5.47 (2H, s), 4.22 (2H, t, J=6.4 Hz), 1.64 (2H, tt, C=6.4, 7.9 Hz), 1.38 (2H, qt, J=7.3, 7.9 Hz), 0.90 (3H, t, J=7.3 Hz).

Examples 2-46

(13) According to the method of Example 1, Examples 2-46 were prepared by using the corresponding material compounds. As appropriate, some reactions were carried out under reflux or under microwave irradiation.

(14) TABLE-US-00002 Example Chemical Structure Instrumental analysis data 2 LC-MS [M + H].sup.+/Rt (min): 375.0/0.899 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.81 (1H, d, J = 1.8 Hz), 8.63 (1H, dd, J = 1.2, 4.9 Hz), 8.02 (1H, dt, J = 1.8, 7.9 Hz), 7.48 (1H, dd, J = 4.9, 7.9 Hz), 7.42 (2H, brs), 7.27-7.19 (3H, m), 6.97 (2H, d, J = 6.7 Hz), 5.43 (2H, s), 4.21 (2H, t, J = 6.7 Hz), 1.64 (2H, tt, J = 6.7, 7.9 Hz), 1.38 (2H, qt, J = 7.3, 7.9 Hz), 0.90 (3H, t, J = 7.3 Hz). 3 LC-MS [M + H].sup.+/Rt (min): 376.1/0.643 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.83 (1H, d, J = 1.2 Hz), 8.65 (1H, dd, J = 1.2, 4.9 Hz), 8.41 (1H, dd, J = 1.8, 4.9 Hz), 8.27 (1H, d, J = 1.2 Hz), 8.04 (1H, ddd, J = 1.8, 1.8 7.9 Hz), 7.51 (1H, dd, J = 4.9, 7.9 Hz), 7.49 (2H, brs), 7.35-7.34 (1H, m), 7.26 (1H, dd, J = 4.9, 7.9), 5.46 (2H, s), 4.21 (2H, t, J = 6.7 Hz), 1.64 (2H, tt, J = 6.7, 7.9 Hz), 1.38 (2H, qt, J = 7.3, 7.9 Hz), 0.90 (3H, t, J = 7.3 Hz). 4 LC-MS [M + H].sup.+/Rt (min): 375.1/0.891 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.64 (2H, dd, J = 1.8, 4.3 Hz), 7.64 (2H, dd, J = 1.8, 4.3 Hz), 7.49 (2H, brs), 7.28-7.19 (3H, m), 7.00 (2H, d, J = 6.7 Hz), 5.50 (2H, s), 4.21 (2H, t, J = 6.7 Hz), 1.63 (2H, tt, J = 6.7, 7.9 Hz), 1.38 (2H, qt, J = 7.3, 7.9 Hz), 0.89 (3H, t, J = 7.3 Hz). 5 LC-MS [M + H].sup.+/Rt (min): 376.1/0.891 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 9.23 (1H, s), 9.03 (1H, s), 9.02 (1H, s), 7.50 (2H, brs), 7.28-7.19 (3H, m), 6.99 (2H, d, J = 6.7 Hz), 5.49 (2H, s), 4.23 (2H, t, J = 6.7 Hz), 1.64 (2H, tt, J = 6.7, 7.9 Hz), 1.39 (2H, qt, J = 7.3, 7.9 Hz), 0.90 (3H, t, J = 7.3 Hz). 6 LC-MS [M + H].sup.+/Rt (min): 391.1/0.833 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.40 (2H, s), 7.35-7.21 (5H, m), 7.07 (2H, s), 7.01 (2H, d, J = 6.7 Hz), 5.38 (2H, s), 4.19 (2H, t, J = 6.7 Hz), 1.63 (2H, tt, J = 6.7, 7.9 Hz), 1.37 (2H, qt, J = 7.3, 7.9 Hz), 0.89 (3H, t, J = 7.3 Hz). 7 LC-MS [M + H].sup.+/Rt (min): 364.1/1.008 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.05 (1H, s), 7.77 (1H, dd, J = 1.2, 1.8 Hz), 7.32-7.20 (5H, m), 7.05 (2H, d, J = 7.3 Hz), 6.85 (1H, d, J = 1.8 Hz), 5.46 (2H, s), 4.19 (2H, t, J = 6.7 Hz), 1.63 (2H, tt, J = 6.7, 7.9 Hz), 1.37 (2H, qt, J = 7.3, 7.9 Hz), 0.89 (3H, t, J = 7.3 Hz). 8 0 .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 8.11 (1H, s), 7.76 (1H, s), 7.33-7.21 (5H, m), 5.46 (2H, s), 4.19 (2H, t, J = 6.5 Hz), 3.86 (3H, s), 1.63 (2H, tt, J = 6.5, 7.9 Hz), 1.38 (2H, qt, J = 7.3, 7.9 Hz), 0.90 (3H, t, J = 7.3 Hz). 9 .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 8.43-8.41 (1H, m),8.27- 8.26 (1H, m), 7.67-7.48 (5H, m), 7.45-7.34 (3H, m),7.30- 7.26 (1H, m), 5.44 (2H, s), 4.21 (2H, t, J = 6.6 Hz), 1.65 (2H, tt, J = 6.6, 7.9 Hz), 1.38 (2H, qt, J = 7.3, 7.9 Hz), 0.91 (3H, t, J = 7.3 Hz). 10 .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 8.41 (1H, d, J = 1.7 Hz), 8.36 (1H, d, J = 2.8 Hz), 7.53- 7.37 (3H, m), 7.32-7.20 (3H, m), 7.03-7.00 (2H, m), 5.45 (2H, s), 4.22 (2H, t, J = 6.6 Hz), 1.66 (2H, tt, J = 6.6, 7.9 Hz), 1.39 (2H, qt, J = 7.3, 7.9 Hz), 0.91 (3H, t, J = 7.3 Hz). 11 LC-MS: [M + H].sup.+/Rt (min): 374.1/1.078 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 7.65-7.61 (2H, m), 7.47- 7.43 (3H, m), 7.33 (2H, brs), 7.28-7.19 (3H, m), 6.97 (2H, d, J = 6.7 Hz), 5.38 (2H, s), 4.20 (2H, t, J = 6.7 Hz), 1.63 (2H, tt, J = 6.7, 7.9 Hz), 1.37 (2H, qt, J = 7.3, 7.9 Hz), 0.89 (3H, t, J = 7.3 Hz). 12 LC-MS: [M + H].sup.+/Rt (min): 404.2/1.091 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 7.39-7.31 (3H, m), 7.30- 7.19 (4H, m), 7.11-7.09 (1H, m), 7.04-6.98 (3H, m), 5.38 (2H, s), 4.19 (2H, t, J = 6.7 Hz), 3.66 (3H, s), 1.63 (2H, tt, J = 6.7, 7.9 Hz), 1.36 (2H, qt, J = 7.3, 7.9 Hz), 0.89 (3H, t, J = 7.3 Hz). 13 LC-MS: [M + H].sup.+/Rt (min): 408.1/1.162 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 7.68-7.66 (1H, m), 7.61- 7.57 (1H, m), 7.59-7.50 (1H, m), 7.49 (2H, dd, J = 7.3, 7.9 Hz), 7.40 (2H, brs), 7.29-7.20 (3H, m), 6.99 (2H, d, J = 7.3 Hz), 5.41 (2H, s), 4.20 (2H, t, J = 6.7 Hz), 1.64 (2H, tt, J = 6.7, 7.9 Hz), 1.37 (2H, qt, J = 7.3, 7.9 Hz), 0.89 (3H, t, J = 7.3 Hz). 14 .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 7.65 (2H, d, J = 8.1 Hz), 7.45 (2H, d, J = 8.1 Hz), 7.41 (2H, brs), 7.35-7.26 (3H, m), 7.06-7.03 (2H, m), 5.46 (2H, s), 4.27 (2H, t, J = 6.6 Hz), 3.66-3.62 (4H, m), 3.56 (2H, m), 2.44-2.38 (4H, m), 1.70 (2H, tt, J = 6.6, 7.9 Hz), 1.44 (2H, qt, J = 7.3, 7.9 Hz), 0.97 (3H, t, J = 7.3 Hz). 15 .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 7.56 (2H, d, J = 8.8 Hz), 7.55-7.20 (5H, m), 7.03-6.98 (4H, m), 5.38 (2H, s), 4.19 (2H, t, J = 6.6 Hz), 4.04 (2H, t, J = 6.4 Hz), 3.59-3.55 (4H, m), 2.41 (2H, t, J = 7.1 Hz), 2.38-2.33 (4H, m), 1.88 (2H, tt, J = 6.4, 7.1 Hz), 1.64 (2H, tt, J = 6.6, 7.9 Hz), 1.38 (2H, qt, J = 7.3, 7.9 Hz), 0.90 (3H, t, J = 7.3 Hz). 16 .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 7.58-7.51 (2H, m), 7.43-7.34 (4H, m), 7.18-7.20 (3H, m), 6.99 (2H, d, J = 6.8 Hz), 5.38 (2H, s), 4.21 (2H, t, J = 6.6 Hz), 3.56-3.49 (4H, m), 3.43 (2H, s), 2.31-2.24 (4H, m), 1.65 (2H, tt, J = 6.6, 7.9 Hz), 1.38 (2H, qt, J = 7.3, 7.9 Hz), 0.91 (3H, t, J = 7.3 Hz). 17 LC-MS: [M + H].sup.+/Rt (min): 409.1/1.048 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.75 (1H, d, J = 1.8 Hz), 8.69 (1H, d, J = 2.4 Hz), 8.15- 8.13 (1H, m), 7.47 (2H, brs), 7.29-7.19 (3H, m), 7.01-6.98 (2H, m), 5.47 (2H, s), 4.22 (2H, t, J = 6.7 Hz), 1.64 (2H, tt, J = 6.7, 7.9 Hz), 1.38 (2H, qt, J = 7.3, 7.9 Hz), 0.90 (3H, t, J = 7.3 Hz). 18 0 LC-MS: [M + H].sup.+/Rt (min): 389.3/0.940 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.60 (1H, d J = 1.8 Hz), 8.47 (1H, d, J = 1.2 Hz), 7.84- 7.83 (1H, m), 7.40 (2H, brs), 7.29-7.20 (3H, m), 7.01-6.98 (2H, m), 5.42 (2H, s), 4.21 (2H, t, J = 6.7 Hz), 2.30 (3H, s), 1.64 (2H, tt, J = 6.7, 7.9 Hz), 1.38 (2H, qt, J = 7.3, 7.9 Hz), 0.90 (3H, t, J = 7.3 Hz). 19 LC-MS [M + H].sup.+/Rt (min): 419.6/0.939 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.60 (1H, d J = 1.8 Hz), 8.47 (1H, d, J = 1.2 Hz), 7.84- 7.83 (1H, m), 7.40 (2H, brs), 7.29-7.20 (3H, m), 7.01-6.98 (2H, m), 5.42 (2H, s), 4.21 (2H, t, J = 6.7 Hz), 2.30 (3H, s), 1.64 (2H, tt, J = 6.7, 7.9 Hz), 1.38 (2H, qt, J = 7.3, 7.9 Hz), 0.90 (3H, t, J = 7.3 Hz). 20 LC-MS: [M + H].sup.+/Rt (min): 405.1/0.824 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.67 (1H, d, J = 2.4 Hz), 8.56 (1H, d, J = 1.8 Hz), 8.02- 7.99 (1H, m), 7.42 (2H, brs), 7.28-7.19 (3H, m), 7.00 (2H, d, J = 6.7 Hz), 5.44 (2H, s), 5.39 (1H, t, J = 5.5 Hz), 4.55 (2H, d, J = 5.5 Hz), 4.21 (2H, t, J = 6.7 Hz), 1.64 (2H, tt, J = 6.7, 7.9 Hz), 1.38 (2H, qt, J = 7.3, 7.9), 0.90 (3H, t, J = 7.3 Hz). 21 LC-MS [M + H].sup.+/Rt (min): 365.5/0.845 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.71-8.69 (1H, m), 8.67 (1H, d, J = 2.8 Hz), 8.00-7.96 (1H, m), 7.50 (2H, brs), 7.29- 7.20 (3H, m), 6.99 (2H, d, J = 6.8 Hz), 5.48 (2H, s), 4.27 (2H, q, J = 7.1 Hz), 1.28 (3H, t, J = 7.1 Hz). 22 LC-MS [M + H].sup.+/Rt (min): 366.4/0.587 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6 : 8.71-8.68 (2H, m), 8.41 (1H, dd, J = 1.2, 4.9 Hz), 8.29 (1H, d, J = 1.8 Hz), 8.04-8.00 (1H, m), 7.48 (2H, brs), 7.38- 7.35 (1H, m), 7.27 (1H, dd, J = 4.9, 7.9 Hz), 5.50 (2H, s), 4.26 (2H, q, J = 7.3 Hz), 1.27 (3H, t, J = 7.3 Hz). 23 .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 8.60 (1H, d, J = 1.8 Hz), 8.47 (1H, d, J = 1.2 Hz), 7.85- 7.82 (1H, m), 7.44 (2H, brs), 7.31-7.19 (3H, m), 7.01-6.98 (2H, m), 5.42 (2H, s), 4.33 (2H, t, J = 4.9 Hz), 3.60 (2H, t, J = 4.9 Hz), 3.27 (3H, s), 2.30 (3H, s). 24 LC-MS [M + H].sup.+/Rt (min): 407.1/0.773 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.40 (1H, d, J = 1.8 Hz), 8.35 (1H, d, J = 3.1 Hz), 7.51 (1H, dd, J = 1.8, 2.4 Hz), 7.46 (2H, brs), 7.31-7.21 (3H, m), 7.03-6.98 (2H, m), 5.43 (2H, s), 4.33 (2H, t, J = 4.9 Hz), 3.76 (3H, s), 3.60 (2H, t, J = 4.9 Hz), 3.27 (3H, s). 25 LC-MS: [M + H].sup.+/Rt (min): 395.6/0.799 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.69 (1H, d, J = 1.8 Hz), 8.66 (1H, d, J = 3.1 Hz), 7.98- 7.94 (1H, m), 7.50 (2H, brs), 7.28-7.19 (3H, m), 6.99-6.96 (2H, m), 5.47 (2H, s), 4.34 (2H, t, J = 4.9 Hz), 3.61 (2H, t, J = 4.9 Hz), 3.27 (3H, s). 26 LC-MS: [M + H].sup.+/Rt (min): (404.2/0.813 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.38 (1H, d, J = 1.2 Hz), 8.30 (1H, d, J = 2.4 Hz), 7.46- 7.44 (1H, m), 7.30-7.19 (3H, m), 7.03 (2H, d, J = 7.3 Hz), 6.87 (2H, brs), 6.42-6.37 (1H, m), 5.37 (2H, s), 3.74 (3H, s), 3.22 (2H, dt, J = 6.4, 6.7 Hz), 1.47 (2H, tt, J = 6.7, 7.3 Hz), 1.28 (2H, qt, J = 7.3, 7.3 Hz), 0.85 (3H, t, J = 7.3 Hz). 27 LC-MS: [M + H].sup.+/Rt (min): 403.2/0.861 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.41 (1H, d, J = 1.2 Hz), 8.36 (1H, d, J = 3.1 Hz), 7.53- 7.51 (1H, m), 7.31 (2H, brs), 7.29-7.20 (3H, m), 6.97 (2H, d, J = 6.7 Hz), 5.50 (2H, s), 3.75 (3H, s), 2.65 (2H, t, J = 7.3 Hz), 1.71 (2H, tt, J = 6.7, 7.3 Hz), 1.32-1.23 (4H, m), 0.83 (3H, t, J = 6.7 Hz). 28 0 .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 8.71-8.68 (2H, m), 8.02- 7.99 (1H, m), 7.39 (2H, brs), 7.28-7.19 (3H, m), 6.98-6.95 (2H, m), 2.67 (2H, t, J = 7.4 Hz), 1.77-1.69 (2H, m), 1.34- 1.23 (4H, m), 0. 85 (3H, t, J = 6.8 Hz). 29 .sup.1H-NMR (400 MHz, DMSO- d.sub.6) : 8.75-8.74 (1H, m), 8.59- 8.58 (1H, s), 7.98 (1H, s), 7.45 (2H, brs), 7.30-7.21 (3H, m), 7.02-7.00 (2H, m), 5.45 (2H, s), 4.47 (2H, s), 4.23 (2H, t, J = 6.6 Hz), 3.28 (3H, s), 1.66 (2H, tt, J = 6.6, 7.9 Hz), 1.39 (2H, qt, J = 7.3, 7.9 Hz), 0.91 (3H, t, J = 7.3 Hz). 30 LC-MS: [M + H].sup.+/Rt (min): 397.1/0.877 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.96 (1H, s), 8.82 (1H, s), 8.23 (1H, s), 7.48 (2H, brs), 7.28-7.19 (3H, m), 7.17 (1H, t, J = 54.9 Hz), 7.00 (2H, d, J = 7.3 Hz), 5.48 (2H, s), 4.27 (2H, q, J = 7.3 Hz), 1.27 (3H, t, J = 7.3 Hz). 31 LC-MS [M + H].sup.+/Rt (min): 459.1/0.497 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 9.06 (1H, d, J = 1.8 Hz), 9.04 (1H, d, J = 2.4 Hz), 8.50 (1H, dd, J = 1.8, 2.4 Hz), 7.52 (2H, brs), 7.13 (1H, d, J = 7.9 Hz), 6.91 (1H, d, J = 7.9 Hz), 5.47 (2H, s), 4.35 (2H, t, J = 4.9 Hz), 3.61 (2H, t, J = 4.9 Hz), 3.31 (3H, s), 3.27 (2H, s), 2.07 (6H, s). 32 LC-MS [M + H].sup.+/Rt (min): 484.2/0.566 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 9.18 (1H, d, J = 2.4 Hz), 8.58 (1H, d, J = 1.8 Hz), 8.03 (1H, d, J = 8.5 Hz), 7.93 (1H, d, J = 7.9 Hz), 7.84-7.79 (1H, m), 7.68-7.64 (1H, m), 7.50 (2H, brs), 7.13 (2H, d, J = 7.9 Hz), 6.97 (2H, d, J = 7.9 Hz), 5.55 (2H, s), 4.36 (2H, t, J = 4.9 Hz), 3.62 (2H, t, J = 4.9 Hz), 3.28 (3H, s), 3.25 (2H, s), 2.01 (6H, s). 33 LC-MS: [M + H].sup.+/Rt (min): 418.5/0.538 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.58 (1H, d, J = 1.8 Hz), 8.46 (1H, d, J = 1.8 Hz), 7.80- 7.79 (1H, m), 7.39 (2H, brs), 7.16 (1H, d, J = 7.9 Hz), 6.93 (2H, d, J = 7.9 Hz), 5.40 (2H, s), 4.26 (2H, q, J = 7.3 Hz), 3.28 (2H, s), 2.28 (3H, s), 2.05 (6H, s), 1.27 (3H, t, J = 7.3 Hz). 34 LC-MS: [M + H].sup.+/Rt (min): 448.2/0.537 (Method A); .sup.1H- NMR (400 MHz, DMSO-d.sub.6) : 8.73 (1H, d, J = 1.8 Hz), 8.56 (1H, d, J = 2.4 Hz), 7.95- 7.93 (1H, m), 7.42 (2H, brs), 7.16 (2H, d, J = 7.9 Hz), 6.94 (2H, d, J = 7.9 Hz), 5.41 (2H, s), 4.44 (2H, s), 4.26 (2H, q, J = 7.3 Hz), 3.28 (2H, s), 3.26 (3H, s), 2.06 (6H, s), 1.27 (3H, t, J = 7.3 Hz). 35 LC-MS [M + H].sup.+/Rt (min): 375.4/1.070 (Method C); .sup.1H- NMR (CDCl.sub.3) : 8.64 (1H, d, J = 4.9 Hz), 8.17 (1H, d, J = 7.9 Hz), 7.76 (1H, td, J = 1.6, 7.9 Hz), 7.31-7.24 (3H, m), 7.21-7.16 (3H, m), 6.06 (2H, s), 5.59 (2H, br s), 4.37 (2H, t, J = 6.7 Hz), 1.83-1.76 (2H, m), 1.56-1.47 (2H, m), 0.97 (3H, t, J = 7.3 Hz). 36 LC-MS [M + H].sup.+/Rt (min): 434.5/0.590 (Method B); .sup.1H- NMR (CDCl.sub.3) : 8.43 (1H, s), 8.38-8.37 (1H, m), 7.32-7.32 (1H, m), 7.22 (2H, d, J = 7.9 Hz), 7.05 (2H, d, J = 7.9 Hz), 5.52 (2H, s), 5.40 (2H, s), 4.40 (2H, q, J = 7.2 Hz), 3.75 3H, s), 3.36 (2H, s), 2.19 (6H, s), 1.41 (3H, t, J = 7.2 Hz). 37 LC-MS [M + H].sup.+/Rt (min): 369.0/0.535 (Method C); .sup.1H- NMR (CDCl.sub.3) : 8.43 (1H, s), 8.38-8.37 (1H, m), 7.32-7.32 1H, m), 7.22 (2H, d, J = 7.9 Hz), 7.05 (2H, d, J = 7.9 Hz), 5.52 (2H, s), 5.40 (2H,s), 4.40 (2H, q, J = 7.2 Hz), 3.75 (3H, s), 3.36 (2H, s), 2.19 (6H, s), 1.41 (3H, t, J = 7.2 Hz). 38 0 LC-MS [M + H].sup.+/Rt (min): 465.3/0.545 (Method D); .sup.1H- NMR (CDCl.sub.3) : 8.63 (1H, br s), 8.59 (1H, br s), 7.86 (1H, s), 7.65 (1H, dd, J = 1.5, 8.9 Hz), 7.35 (1H, d, J = 8.5 Hz), 6.65 (1H, d, J = 8.5 Hz), 5.55 (2H, br s), 5.37-5.34 (3H, m), 4.41 (2H, q, J = 7.0 Hz), 2.87- 2.78 (2H, m), 2.70-2.67 (1H, m), 2.37-2.29 (5H, m), 1.95- 1.90 (1H, m), 1.43 (3H, t, J = 7.0 Hz). 39 LC-MS [M + H].sup.+/Rt (min): 465.3/0.514 (Method D); .sup.1H- NMR (CDCl.sub.3) : 8.68 (1H, br s), 8.59 (1H, d, J = 2.4 Hz), 7.86 (1H, s), 7.66 (1H, d, J = 9.2 Hz), 7.34 (1H, d, J = 8.5 Hz), 6.66 (1H, d, J = 8.5 Hz), 5.52 (2H, s), 5.37-5.34 (3H, m), 4.41 (2H, q, J = 7.1 Hz), 2.87-2.78 (2H, m), 2.71-2.67 (1H, m), 2.37-2.32 (5H, m), 1.92 (1H, br s), 1.43 (3H, t, J = 7.3 Hz). 40 LC-MS [M + H].sup.+/Rt (min): 491.4/0.661 (Method C); .sup.1H- NMR (CDCl.sub.3) : 8.68 (1H, br s), 8.59 (1H, d, J = 2.4 Hz), 7.86 (1H, d, J = 1.8 Hz), 7.68- 7.65 (1H, m), 7.36 (1H, dd, J = 2.4, 8.5 Hz), 6.64 (1H, d, J = 8.5 Hz), 5.55 (2H, s), 5.35 (2H, s), 4.97-4.94 (1H, m), 4.42 (2H, q, J = 7.1 Hz), 3.34- 3.27 (1H, m), 2.94-2.71 (5H, m), 2.13-2.09 (1H, m), 1.97- 1.88 (1H, m), 1.74-1.66 (1H, m), 1.63-1.54 (1H, m), 1.44- 1.34 (4H, m). 41 LC-MS [M + H].sup.+/Rt (min): 491.4/0.652 (Method C); .sup.1H- NMR (CDCl.sub.3) : 8.68 (1H, br s), 8.59 (1H, d, J = 2.4 Hz), 7.86 (1H, d, J = 1.8 Hz), 7.68- 7.65 (1H m), 7.36 (1H, dd, J = 2.4, 8.5 Hz), 6.64 (1H, d, J = 8.5 Hz), 5.54 (2H, s), 5.35 (2H, s), 4.97-4.93 (1H, m), 4.42 (2H, q, J = 7.1 Hz), 3.34- 3.27 (1H, m), 2.98-2.70 (5H, m), 2.12-2.09 (1H, m), 1.97- 1.88 (1H, m), 1.74-1.65 (1H, m), 1.63-1.58 (1H, m), 1.44- 1.34 (4H, m). 42 LC-MS: [M + H].sup.+/Rt (min): 467.0/0.465 (Method C); .sup.1H- NMR (CDCl.sub.3) : 8.68 (1H, s), 8.59 (1H, d, J = 2.4 Hz), 7.88 (1H, s), 7.67-7.65 (1H, m), 7.37-7.34 (1H, m), 6.63 (1H, d, J = 8.5 Hz), 5.54 (2H, s), 5.35 (2H, s), 4.42 (2H, q, J = 7.1 Hz), 4.28 (2H, t, J = 6.7 Hz), 2.40 (2H, t, J = 7.3 Hz), 2.23 (6H, s), 1.94-1.87 (2H, m), 1.43 (3H, t, J = 7.6 Hz). 43 LC-MS [M + H].sup.+/Rt (min): 413.0/0.787 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 8.64-8.61 (1H, m), 8.54 (1H, d, J = 2.4 Hz), 7.66-7.59 (1H, m), 6.96 (1H, dd, J = 9.2, 9.2 Hz), 6.77-6.70 (1H, m), 6.50 (1H, dd, J = 5.5, 3.1 Hz), 5.61 (2H, s), 5.42 (2H, s), 4.38 (2H, q, J = 7.1 Hz), 3.64 (3H, s), 1.39 (3H, t, J = 7.1 Hz). 44 LC-MS [M + H].sup.+/Rt (min): 383.0/0.785 (Method C); .sup.1H- NMR (CDCl.sub.3) : 8.63-8.59 (1H, m), 8.54 (1H, d, J = 3.1 Hz), 7.64-7.59 (1H, m), 7.06- 6.98 (2H, m), 6.98-6.93 (1H, m), 5.63 (2H, s), 5.47 (2H, s), 4.37 (2H, q, J = 7.1 Hz), 1.38 (3H, t, J = 7.1 Hz). 45 LC-MS [M + H].sup.+/Rt (min): 460.4/0.805 (method C); .sup.1H- NMR (CDCl.sub.3) : 8.68-8.65 (1H, m), 8.64-8.61 (1H, m), 8.56 (1H, d, J = 2.4 Hz), 8.46 (1H, d, J = 2.4 Hz), 7.70-7.66 (1H, m), 7.57-7.50 (3H, m), 7.22 (2H, d, J = 8.5 Hz), 5.64 (2H, s), 5.50 (2H, s), 4.41 (2H, q, J = 7.3 Hz), 1.42 (3H, t, J = 7.3 Hz). 46 LC-MS[M + H].sup.+/Rt (min): 474.5/0.519 (Method C); .sup.1H- NMR (400 MHz, (CDCl.sub.3) : 8.68-8.65 (1H, m), 8.56 (1H, d, J = 3.1 Hz), 7.67-7.60 (1H, m), 7.21 (2H, d, J = 7.9 Hz), 7.08 (2H, d, J = 7.9 Hz), 5.64 (2H, s), 5.43 (2H, s), 4.42 (2H, q, J = 7.0 Hz), 3.40-3.31 (1H, m), 3.13-3.05 (1H, m), 3.05-2.84 (5H, m), 1.95-1.91 (1H, m), 1.81-1.75 (2H, m), 1.69-1.58 (1H, m), 1.43 (3H, t, J = 7.0 Hz), 1.41-1.35 (1H, m).

Example 47

2-Ethoxy-8-(5-fluoropyridin-3-yl)-9-{4-[2-(pyrrolidin-1-yl)ethoxy]benzyl}-9H-purine-6-amine

(15) ##STR00089##

(16) To a solution of the compound of Example 208 (44.0 mg) in N,N-dimethylformamide (2.5 mL) were added 1-(2-chloroethyl)pyrrolidine hydrochloride (35.8 mg), potassium carbonate (80.0 mg), and potassium iodide (11.5 mg), and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added water, and the mixture was extracted with chloroform/methanol. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (5.4 mg).

(17) LC-MS [M+H].sup.+/Rt (min): 478.51/0.574 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.69-8.67 (1H, m), 8.56 (1H, d, J=3.1 Hz), 7.64-7.61 (1H, m), 7.01 (2H, d, J=9.2 Hz), 6.83 (2H, d, J=9.2 Hz), 5.63 (2H, s), 5.37 (2H, s), 4.42 (2H, q, J=7.3 Hz), 4.07 (2H, t, J=6.1 Hz), 2.89 (2H, t, J=6.1 Hz), 2.64-2.61 (4H, m), 1.83-1.80 (4H, m), 1.43 (3H, t, J=7.3 Hz).

Examples 48-56

(18) According to the method of Example 47, Examples 48-56 were prepared by using the corresponding material compounds.

(19) TABLE-US-00003 Example Chemical Structure Instrumental analysis data 48 0 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.72-8.63 (1H, m), 8.56 (1H, d, J = 2.4 Hz), 7.71-7.53 (1H, m), 7.01 (2H, d, J = 9.2 Hz), 6.83 (2H, d, J = 9.2 Hz), 5.66 (2H, s), 5.37 (2H, s), 4.42 (2H, q, J = 7.1 Hz), 4.02 (2H, t, J = 5.8 Hz), 2.71 (2H, t, J = 5.8 Hz), 2.33 (6H, s), 1.43 (3H, t, J = 7.1 Hz). 49 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.68-8.66 (1H, m), 8.56 (1H, d, J = 2.4 Hz), 7.67-7.60 (1H, m), 7.01 (2H, d, J = 8.5 Hz), 6.81 (2H, d, J = 8.5 Hz), 5.63 (2H, s), 5.36 (2H, s), 4.42 (2H, q, J = 6.9 Hz), 4.06 (2H, t, J = 5.8 Hz), 2.80 (2H, t, J = 5.8 Hz), 2.74- 2.34 (8H, m), 2.30 (3H, s), 1.43 (3H, t, J = 6.9 Hz). 50 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.69-8.65 (1H, m), 8.56-8.50 (1H, m), 7.63 (1H, d, J = 9.2 Hz), 7.22 (1H, dd, J = 7.9, 8.0 Hz), 6.82 (1H, d, J = 7.9 Hz), 6.68-6.62 (2H, m), 5.64 (2H, s), 5.40 (2H, s), 4.41 (2H, q, J = 7.3 Hz), 3.98 (2H, t, J = 5.8 Hz), 2.68 (2H, t, J = 5.8 Hz), 2.31 (6H, s), 1.42 (3H, t, J = 7.3 Hz). 51 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.67 (1H, s), 8.54 (1H, d, J = 2.4 Hz), 7.65-7.60 (1H, m), 7.21 (1H, dd, J = 8.2, 8.0 Hz), 6.82 (1H, d, J = 9.2 Hz), 6.68-6.62 (2H, m), 5.77 (2H, s), 5.39 (2H, s), 4.40 (2H, q, J = 7.3 Hz), 4.03 (2H, t, J = 5.8 Hz), 2.88 (2H, t, J = 5.8 Hz), 2.68-2.58 (4H, m), 1.87-1.77 (4H, m), 1.41 (3H, t, J = 7.3 Hz). 52 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.70-8.65 (1H, m), 8.55 (1H, d, J = 3.1 Hz), 7.65-7.59 (1H, m), 7.00 (2H, d, J = 8.5 Hz), 6.80 (2H, d, J = 8.5 Hz), 5.75 (2H, s), 5.36 (2H, s), 4.42 (3H, q, J = 7.0 Hz), 3.97 (2H, t, J = 6.8 Hz), 2.44 (2H, t, J = 6.8 Hz), 2.25 (6H, s), 1.97-1.90 (2H, m), 1.43 (3H, t, J = 7.0 Hz). 53 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.69-8.65 (1H, m), 8.56-8.51 (1H, m), 7.63 (1H, d, J = 8.4 Hz), 7.20 (1H, dd, J = 6.8, 8.4 Hz), 6.80 (1H, d, J = 7.9 Hz), 6.66-6.61 (2H, m), 5.78 (2H, s), 5.39 (2H, s), 4.41 (2H, q, J = 7.3 Hz), 3.93 (2H, t, J = 6.4 Hz), 2.46 (2H, t, J = 7.3 Hz), 2.28 (6H, s), 1.99-1.88 (2H, m), 1.42 (3H, t, J = 7.3 Hz). 54 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.69-8.65 (1H, m), 8.57 (1H, d, J = 2.4 Hz), 7.68-7.62 (1H, m), 6.99 (1H, dd, J = 8.2, 10.7 Hz), 6.80 (1H, dd, J = 2.1, 7.6 Hz), 6.64-6.58 (1H, m), 5.60 (2H, s), 5.37 (2H, s), 4.42 (2H, q, J = 7.1 Hz), 4.02 (2H, t, J = 5.8 Hz), 2.73 (2H, t, J = 5.8 Hz), 2.33 (6H, s), 1.44 (4H, t, J = 7.1 Hz). 55 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.69-8.64 (1H, m), 8.57 (1H, d, J = 2.4 Hz), 7.67-7.61 (1H, m), 6.99 (1H, dd, J = 8.5, 11.0 Hz), 6.79 (1H, dd, J = 2.4, 7.6 Hz), 6.63-6.57 (1H, m), 5.71 (2H, s), 5.37 (2H, s), 4.42 (2H, q, J = 7.1 Hz), 4.05 (2H, t, J = 6.1 Hz), 2.89 (2H, t, J = 6.1 Hz), 2.66- 2.53 (4H, m), 1.85-1.76 (4H, m), 1.43 (3H, t, J = 7.1 Hz). 56 LC-MS [M + H].sup.+/Rt (min): 453.4/0.602 (Method C); .sup.1H- NMR (CDCl.sub.3) : 8.90 (1H, br s), 8.54 (1H, d, J = 3.1 Hz), 8.26 (1H, d, J = 2.4 Hz), 8.10-8.06 (1H, m), 7.27-7.25 (1H, m), 7.17 (1H, dd, J = 3.1, 8.5 Hz), 5.57 (2H, s), 5.43 (2H, s), 4.38 (2H, q, J = 7.1 Hz), 4.08 (2H, t, J = 5.6 Hz), 2.72 (2H, t, J = 5.6 Hz), 2.33 (6H, s), 1.40 (3H, t, J = 7.1 Hz).

Example 57

9-({2-[2-(Dimethylamino)ethoxy]pyridin-4-yl)methyl}-2-ethoxy-8-(5-fluoropyridin-3-yl)-9H-purine-6-amine

(20) ##STR00099##

(21) To a solution of N,N-dimethylethanolamine (111 mg) in 1,4-dioxane (1.5 mL) was added sodium hydride (27.3 mg), and the mixture was stirred at room temperature for 10 minutes. Then, the compound of Example 191 (50.0 mg) was added thereto. The reaction solution was heated to 80 C. and stirred with heating for 6 hours. To the reaction mixture was added 35% hydrochloric acid (54 l), and the mixture was extracted with chloroform/methanol solution. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (11.8 mg).

(22) .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.64-8.60 (1H, m), 8.55 (1H, d, J=2.4 Hz), 8.10 (1H, d, J=4.9 Hz), 7.70-7.64 (1H, m), 6.64 (1H, d, J=4.9 Hz), 6.44-6.40 (1H, m), 5.72 (2H, s), 5.37 (2H, s), 4.38 (2H, d, J=7.0 Hz), 4.36 (2H, t, J=5.5 Hz), 2.67 (2H, t, J=5.5 Hz), 2.30 (6H, s), 1.40 (3H, t, J=7.0 Hz).

Examples 58-63

(23) According to the method of Example 57, Examples 58-63 were prepared by using the corresponding material compounds.

(24) TABLE-US-00004 Example Chemical Structure Instrumental analysis data 58 00 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.71-8.66 (1H, m), 8.60 (1H, d, J = 3.1 Hz), 7.89 (1H, s), 7.69- 7.63 (1H, m), 7.39-7.34 (1H, m), 6.71 (1H, dd, J = 3.1, 8.5 Hz), 5.67 (2H, s), 5.36 (2H, s), 4.43 (2H, q, J = 7.1 Hz), 4.36 (2H, t, J = 5.5 Hz), 2.69 (2H, t, J = 5.5 Hz), 2.31 (6H, s), 1.43 (3H, t, J = 7.1 Hz). 59 01 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.69-8.67 (1H, m), 8.59 (1H, d, J = 2.4 Hz), 7.89 (1H, d, J = 2.4 Hz), 7.69-7.63 (1H, m), 7.36 (1H, dd, J = 2.4, 8.5 Hz), 6.67 (1H, d, J = 8.5 Hz), 5.75 (2H, s) 5.35 (2H, s), 4.43 (2H, t, J = 5.8 Hz), 4.40 (2H, q, J = 7.0 Hz), 2.77 (2H, t, J = 5.8 Hz), 2.71-2.31 (8H, m), 2.29 (3H, s), 1.43 (3H, t, J = 7.0 Hz). 60 02 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.71-8.67 (1H, m), 8.60 (1H, d, J = 2.4 Hz), 7.87 (1H, d, J = 2.4 Hz), 7.70-7.64 (1H, m), 7.37 (2H, dd, J = 2.4, 8.5 Hz), 6.63 (1H, d, J = 8.5 Hz), 5.69 (2H, s), 5.35 (2H, s), 5.04-4.97 (1H, m), 4.42 (2H, q, J = 7.1 Hz), 2.77-2.64 (2H, m), 2.31 (3H, s), 2.33-2.24 (2H, m), 2.09-1.94 (2H, m), 1.85-1.73 (2H, m), 1.44 (3H, t, J = 7.1 Hz). 61 03 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.70-8.67 (1H, m), 8.60 (1H, d, J = 2.4 Hz), 7.89 (1H, d, J = 2.1 Hz), 7.69-7.63 (1H, m), 7.37 (1H, dd, J = 2.1, 8.5 Hz), 6.70 (1H, d, J = 8.5 Hz), 5.72 (2H, s), 5.36 (2H, s), 4.43 (2H, t, J = 5.8 Hz), 4.40 (2H, q, J = 7.0 Hz), 2.86 (2H, t, J = 5.8 Hz), 2.63-2.55 (4H, m), 1.82- 1.76 (4H, m), 1.44 (3H, t, J = 7.0 Hz). 62 04 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.98-8.92 (1H, m), 8.58-8.50 (1H, m), 8.18-8.09 (1H, m), 7.53 (1H, d, J = 13.4 Hz), 6.91 (1H, d, J = 6.1 Hz), 6.73-6.65 (1H, m), 5.74 (2H, s), 5.40 (2H, s), 4.38 (2H, q, J = 6.7 Hz), 4.24 (2H, t, J = 5.8 Hz), 2.60 (2H, t, J = 5.8 Hz), 2.27 (6H, s), 1.40 (3H, t, J = 6.7 Hz). 63 05 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.87-8.81 (1H, m), 8.54 (1H, d, J = 1.2 Hz), 8.39 (1H, d, J = 5.5 Hz), 8.01 (1H, dd, J = 1.2, 9.5 Hz), 6.81-6.71 (2H, m), 5.76 (2H, s), 5.45 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 4.05 (2H, t, J = 5.2 Hz), 2.70 (2H, t, J = 5.2 Hz), 2.31 (6H, s), 1.40 (3H, t, J = 7.1 Hz).

Example 64

N-(5-{[6-Amino-2-ethoxy-8-(5-fluoropyridin-3-yl)-9H-purin-9-yl]methyl}pyridin-2-yl)-N,N,N-trimethylethane-1,2-diamine

(25) ##STR00106##

(26) A suspension of the compound of Example 189 (70 mg) and N,N,N-trimethylethylenediamine (683 L) was stirred at 120 C. for 6 hours. The reaction mixture was cooled to room temperature, and then water was added thereto. The mixture was extracted with ethyl acetate, and the organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (34 mg).

(27) LC-MS [M+H].sup.+/Rt (min): 466.6/0.559 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.71 (1H, s), 8.58 (1H, d, J=3.1 Hz), 7.88 (1H, d, J=2.4 Hz), 7.69-7.66 (1H, m), 7.22 (1H, dd, J=2.4, 8.5 Hz), 6.37 (1H, d, J=8.5 Hz), 5.56 (2H, s), 5.28 (2H, s), 4.43 (2H, q, J=7.1 Hz), 3.61 (2H, t, J=7.0 Hz), 3.01 (3H, s), 2.45 (2H, t, J=7.0 Hz), 2.27 (6H, s), 1.44 (3H, t, J=7.1 Hz).

Example 65

(28) According to the method of Example 64, Example 65 was prepared by using the corresponding material compound.

(29) TABLE-US-00005 Example Chemical Structure Instrumental analysis data 65 07 LC-MS [M + H].sup.+/Rt (min): 464.5/0.543 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.70 (1H, s), 8.59-8.58 (1H, m), 7.94 (1H, s), 7.68 (1H, d, J = 8.5 Hz), 7.27-7.26 (1H, m), 6.55-6.52 (1H, m), 5.55 (2H, s), 5.30 (2H, s), 4.46-4.39 (2H, m), 3.53 (4H, br s), 2.49 (4H, br s), 2.33 (3H, br s), 1.46-1.41 (3H, m).

Example 66

9-{4-[(3S)-1-Azabicyclo[2.2.2]oct-3-yloxy]benzyl}-2-ethoxy-8-(5-fluoropyridin-3-yl)-9H-purine-6-amine

(30) ##STR00108##

(31) To an ice-cooled solution of the compound of Reference example 121 (602 mg) in tetrahydrofuran (13.8 mL) were added (R)-3-quinuclidinol (703 mg), triphenyiphosphine (1.45 g), and diisopropyl azodicarboxylate (1.09 mL), and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added water, and the mixture was extracted with chloroform/methanol. The organic layer was washed with brine, dried over sodium sulfate, filtrated, and then concentrated in vacuo. To a solution of the obtained residue methanol (13.8 mL) was added 28% ammonia (13.8 mL), and the mixture was stirred at 60 C. for 2.5 hours. To the reaction mixture was added water, and the mixture was extracted with chloroform/methanol. The organic layer was washed with brine, dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (248 mg).

(32) LC-MS [M+H].sup.+/Rt (min): 490.5/0.659 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.67 (1H, br s), 8.55 (1H, d, J=2.7 Hz), 7.65-7.61 (1H, m), 7.00 (2H, d, J=8.4 Hz), 6.75 (2H, d, J=8.4 Hz), 5.57 (2H, s), 5.35 (2H, s), 4.41 (2H, q, J=6.8 Hz), 4.32-4.30 (1H, m), 3.24 (1H, dd, J=8.0, 13.9 Hz), 3.00-2.75 (5H, m), 2.10 (1H, br s), 1.99-1.92 (1H, m), 1.76-1.49 (2H, m), 1.46-1.33 (4H, m).

Example 67

(33) According to the method of Example 66, Example 67 was prepared by using the corresponding material compound.

(34) TABLE-US-00006 Example Chemical Structure Instrumental analysis data 67 09 LC-MS [M + H].sup.+/Rt (min): 490.3/0.641 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.66 (1H, br s), 8.55 (1H, d, J = 3.1 Hz), 7.65-7.61 (1H, m), 7.01 (2H, d, J = 8.5 Hz), 6.75 (2H, d, J = 8.5 Hz), 5.57 (2H, br s), 5.35 (2H, s), 4.44-4.35 (3H, m), 3.32-3.27 (1H, m), 3.06-2.84 (5H, m), 2.17 (1H, br s), 2.04-2.01 (1H, m), 1.81-1.59 (2H, m), 1.48-1.40 (4H, m).

Example 68

2-Ethoxy-8-(5-fluoropyridin-3-yl)-9-[4-(4-methylpiperazin-1-yl)benzyl]-9H-purine-6-amine

(35) ##STR00110##

(36) To a solution of the compound of Reference example 123 (11.3 mg) in methanol was added 28% ammonia (0.8 mL) at room temperature. The reaction mixture was stirred at 60 C. for 4 hours, and then extracted with chloroform/methanol. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (7.1 mg).

(37) LC-MS [M+H].sup.+/Rt (min): 463.4/0.495 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.72-8.67 (1H, m), 8.56 (1H, d, J=3.1 Hz), 7.68-7.62 (1H, m), 7.01 (2H, d, J=8.5 Hz), 6.83 (2H, d, J=8.5 Hz), 5.62 (2H, s), 5.35 (2H, s), 4.43 (2H, q, J=7.1 Hz), 3.32-3.19 (4H, m), 2.77-2.53 (4H, m), 2.40 (3H, s), 1.44 (3H, t, J=7.1 Hz).

Example 69

9-({6-[(3S)-1-Azabicyclo[2.2.2]oct-3-yloxy]pyridin-3-yl}methyl)-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine

(38) ##STR00111##

(39) To an ice-cooled solution of (S)-(+)-3-quinuclidinol (135 mg) in tetrahydrofuran (1.0 mL) was added potassium tert-butoxide (119 mg), and the mixture was stirred for 15 minutes. A solution of the compound of Example 204 (150 mg) in tetrahydrofuran (3 mL) was added thereto, and the mixture was stirred in ice bath for 1.5 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtrated, and then concentrated in vacuo. The obtained residue was purified by amino silica gel column chromatography (chloroform/methanol), and then purified by silica gel column chromatography (chloroform/methanol) to give the title compound (91 mg).

(40) LC-MS [M+H].sup.+/Rt (min): 476.4/0.557 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.71 (1H, br s), 8.63 (1H, d, J=2.4 Hz), 7.85 (1H, d, J=2.4 Hz), 7.75-7.72 (1H, m), 7.34 (1H, dd, J=2.4, 8.5 Hz), 6.64 (1H, d, J=8.5 Hz), 5.40 (2H, s), 4.96-4.93 (1H, m), 4.08 (3H, s), 3.33-3.27 (1H, m), 2.97-2.70 (8H, m), 2.11-2.09 (1H, m), 1.96-1.87 (1H, m), 1.74-1.66 (1H, m), 1.62-1.58 (1H, m), 1.42-1.34 (1H, m).

Examples 70-76

(41) According to the method of Example 69, Examples 70-76 were prepared by using the corresponding material compounds.

(42) TABLE-US-00007 Example Chemical Structure Instrumental analysis data 70 LC-MS [M + H].sup.+/Rt (min): 476.4/0.529 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.72-8.71 (1H, m), 8.63 (1H, d, J = 2.4 Hz), 7.85 (1H, d, J = 2.4 Hz), 7.75-7.71 (1H, m), 7.34 (1H, dd, J = 8.4, 2.7 Hz), 6.64 (1H, d, J = 8.4 Hz), 5.40 (2H, s), 4.96- 4.93 (1H, m), 4.08 (3H, s), 3.33- 3.27 (1H, m), 2.97-2.70 (8H, m), 2.11-2.08 (1H, m), 1.96-1.87 (1H, m), 1.70-1.65 (1H, m), 1.62-1.54 (1H, m), 1.41-1.33 (1H, m). 71 LC-MS [M + H].sup.+/Rt (min): 490.4/0.684 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.71-8.70 (1H, m), 8.63 (1H, d, J = 2.4 Hz), 7.84 (1H, d, J = 2.4 Hz), 7.74-7.71 (1H, m), 7.33 (1H, dd, J = 8.5, 2.4 Hz), 6.64 (1H, d, J = 8.5 Hz), 5.39 (2H, s), 4.97- 4.93 (1H, m), 4.49 (2H, q, J = 7.1 Hz), 3.33-3.27 (1H, m), 2.97-2.71 (8H, m), 2.12-2.09 (1H, m), 1.96- 1.88 (1H, m), 1.74-1.66 (1H, m), 1.63-1.55 (1H, m), 1.47 (3H, t, J = 7.1 Hz), 1.42-1.34 (1H, m). 72 LC-MS [M + H].sup.+/Rt (min): 490.4/0.690 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.71-8.71 (1H, m), 8.63 (1H, d, J = 3.1 Hz), 7.84 (1H, d, J = 2.4 Hz), 7.75-7.71 (1H, m), 7.33 (1H, dd, J = 2.4, 8.5 Hz), 6.64 (1H, d, J = 8.5 Hz), 5.40 (2H, s), 4.97- 4.93 (1H, m), 4.49 (2H, q, J = 7.1 Hz), 3.34-3.28 (1H, m), 2.98-2.71 (8H, m), 2.13-2.09 (1H, m), 1.97- 1.88 (1H, m), 1.75-1.55 (2H, m), 1.47 (3H, t, J = 7.0 Hz), 1.43-1.35 (1H, m). 73 LC-MS [M + H].sup.+/Rt (min): 504.4/0.0597 (Method D); .sup.1H-NMR (CDCl.sub.3) : 8.71 (1H, br s), 8.63 (1H, d, J = 3.1 Hz), 7.88 (1H, d, J = 1.8 Hz), 7.75-7.72 (1H, m), 7.34 (1H, dd, J = 3.1, 8.5 Hz), 6.63 (1H, d, J = 8.5 Hz), 5.41 (2H, s), 4.50 (2H, q, J = 6.9 Hz), 4.21 (2H, d, J = 7.9 Hz), 3.11-3.05 (1H, m), 2.88-2.79 (7H, m), 2.49-2.44 (1H, m), 2.15-2.07 (1H, m), 1.87-1.85 (1H, m), 1.75- 1.53 (3H, m), 1.48 (3H, t, J = 7.0 Hz), 1.44-1.36 (1H, m). 74 LC-MS [M + H].sup.+/Rt (min): 450.3/0.554 (Method D); .sup.1H-NMR (CDCl.sub.3) : 8.69 (1H, t, J = 1.5 Hz), 8.62 (1H, d, J = 2.4 Hz), 7.84 (1H, d, J = 2.4 Hz), 7.73-7.70 (1H, m), 7.34 (1H, dd, J = 2.4, 8.5 Hz), 6.65 (1H, d, J = 8.5 Hz), 5.39 (2H, s), 5.17-5.11 (1H, m), 4.49 (2H, q, J = 7.1 Hz), 3.77-3.74 (2H, m), 3.09- 3.05 (2H, m), 2.81 (3H, s), 2.38 (3H, s), 1.47 (3H, t, J = 7.1 Hz). 75 LC-MS [M + H].sup.+/Rt (min): 504.2/0.603 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.71 (1H, br s), 8.63 (1H, d, J = 2.4 Hz), 7.84 (1H, d, J = 2.4 Hz), 7.74-7.71 (1H, m), 7.33 (1H, dd, J = 2.4, 8.5 Hz), 6.64 (1H, d, J = 8.5 Hz), 5.40 (2H, s), 4.97- 4.93 (1H, m), 4.39 (2H, t, J = 6.7 Hz), 3.33-3.27 (1H, m), 2.97-2.71 (8H, m), 2.11-2.09 (1H, m), 1.93- 1.86 (3H, m), 1.74-1.54 (2H, m), 1.41-1.34 (1H, m), 1.08 (3H, t, J = 7.6 Hz). 76 LC-MS [M + H].sup.+/Rt (min): 500.1/0.580 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67 (1H, d, J = 1.8 Hz), 8.59 (1H, d, J = 2.0 Hz), 7.84 (1H, d, J = 2.4 Hz), 7.77 (1H, br s), 7.34 (1H, dd, J = 2.4, 8.5 Hz), 6.63 (1H, d, J = 8.5 Hz), 5.36 (2H, s), 4.97- 4.93 (1H, m), 4.38 (2H, t, J = 6.7 Hz), 3.34-3.29 (1H, m), 2.94-2.71 (8H, m), 2.41 (3H, s), 2.11-2.10 (1H, m), 1.96-1.84 (3H, m), 1.74- 1.55 (2H, m), 1.42-1.35 (1H, m), 1.08 (3H, t, J = 7.6 Hz).

Example 77

(4-{[6-Amino-2-ethoxy-8-(5-fluoropyridin-3-yl)-9H-purin-9-yl]methyl}phenyl)methanol

(43) ##STR00119##

(44) To an ice-cooled solution of the compound of Example 182 (385 mg) in tetrahydrofuran (50 mL) was added diisobutylaluminum hydride (1.02 mol/L hexane solution, 8.2 mL), and the mixture was stirred for 2.5 hours. To the reaction mixture were added ethyl acetate (5 mL) and aqueous saturated potassium sodium tartrate, and the mixture was stirred at room temperature overnight. The mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (220 mg).

(45) LC-MS ([M+H].sup.+/Rt (min.)): 395.4/0.671 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.70 (1H, dd, J=1.2, 1.8 Hz), 8.66 (1H, d, J=3.1 Hz), 8.01-7.96 (1H, m), 7.46 (2H, brs), 7.19 (2H, d, J=7.9 Hz), 6.94 (2H, d, J=7.9 Hz), 5.45 (2H, s), 5.12 (1H, t, J=5.5 Hz), 4.40 (2H, d, J=5.5 Hz), 4.26 (2H, q, J=6.7 Hz), 1.27 (3H, t, J=6.7 Hz).

Examples 78-79

(46) According to the method of Example 77, Examples 78-79 were prepared by using the corresponding material compounds.

(47) TABLE-US-00008 Example Chemical Structure Instrumental analysis data 78 0 LC-MS [M + H].sup.+/Rt (min): 394.4/0.760 (Method A) 79 LC-MS [M + H].sup.+/Rt (min): 422.1/0.892 (Method A)

Example 80

9-{4-[(Dimethylamino)methyl]benzyl}-2-ethoxy-8-(5-fluoropyridin-3-yl)-9H-purine-6-amine

(48) ##STR00122##

(49) To a solution of the compound of Example 187 (69.8 mg) in tetrahydrofuran (10 ml) were added dimethylamine (2.0 mol/L tetrahydrofuran solution, 0.5 mL) and triacetoxysodium borohydride (95.1 mg), and the mixture was stirred at room temperature for 3 days. To the reaction mixture in ice bath was added aqueous saturated sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated, and then concentrated vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) give the title compound (64.5 mg).

(50) LC-MS [M+H].sup.+/Rt (min): 422.5/0.542; .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.68-8.67 (2H, m), 8.64 (1H, d, J=2.4 Hz), 7.95-7.92 (1H, m), 7.46 (2H, brs), 7.14 (d, J=7.9 Hz), 6.91 (2H, d, J=7.9 Hz), 5.45 (2H, s), 4.27 (2H, q, J=7.3 Hz), 3.27 (2H, s), 2.05 (6H, s), 1.27 (3H, t, J=7.3 Hz).

Examples 81-122

(51) According to the method of Example 80, Examples 81-122 were prepared by using the corresponding material compounds.

(52) TABLE-US-00009 Example Chemical Structure Instrumental analysis data 81 LC-MS [M + H].sup.+/Rt (min): 477.4/0.539; .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.68-8.67 (1H, m), 8.64 (1H, d, J = 3.0 Hz), 7.95-7.92 (1H, m), 7.46 (2H, brs), 7.15 (2H, d, J = 7.9 Hz), 6.91 (2H, d, J = 7.9 Hz), 5.44 (2H, s), 4.27 (2H, q, J = 7.3 Hz), 3.34 (2H, s), 2.40-2.12 (8H, m), 2.11 (3H, s), 1.27 (3H, t, J = 7.3 Hz). 82 LC-MS [M + H].sup.+/Rt (min): 450.2/0.637 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.67 (1H, dd, J = 1.2, 1.8 Hz), 8.64 (1H, d, J = 3.1 Hz), 7.96-7.91 (1H, m), 7.46 (2H, brs), 7.14 (2H, d, J = 7.9 Hz), 6.91 (2H, d, J = 7.9 Hz), 5.45 (2H, s), 4.22 (2H, t, J = 6.4 Hz), 3.27 (2H, s), 2.05 (6H, s), 1.64 (2H, tt, J = 6.4, 7.9 Hz), 1.38 (2H, qt, J = 7.3, 7.9 Hz), 0.90 (3H, t, J = 7.3 Hz). 83 LC-MS [M + H].sup.+/Rt (min): 492.2/0.647 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.68- 8.66 (1H, m), 8.64 (1H, d, J = 3.1 Hz), 7.96-7.91 (1H, m), 7.46 (2H, brs), 7.16 (2H, d, J = 7.9 Hz), 6.92 (2H, d, J = 7.9 Hz), 5.45 (2H, s), 4.22 (2H, t, J = 6.7 Hz), 3.53-3.49 (4H, m), 3.35 (2H, s), 2.26-2.23 (4H, m), 1.64 (2H, tt, J = 6.7, 7.9 Hz), 1.38 (2H, qt, J = 7.3, 7.9 Hz, 0.90 (3H, t, J = 7.3 Hz). 84 LC-MS [M + H].sup.+/Rt (min): 450.2/0.648 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.67 (1H, dd, J = 1.2, 1.8 Hz), 8.63 (1H, J = 2.4 Hz), 7.96-7.91 (1H, m), 7.46 (2H, brs), 7.18 (1H, dd, J = 7.3, 7.9 Hz), 7.09 (1H, d, J = 7.3 Hz), 6.92- 6.90 (1H, m), 6.83 (1H, d J = 7.9 Hz), 5.47 (2H, s), 4.23 (2H, t, J = 6.7 Hz), 3.23 (2H, s), 2.00 (3H, s), 1.65 (2H, tt, J = 6.7, 7.9 Hz), 1.38 (2H, qt, J = 7.3, 7.9 Hz), 0.90 (3H, t, J = 7.3 Hz). 85 LC-MS [M + H].sup.+/Rt (min): 446.2/0.643 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.59 (1H, d, J = 1.8 Hz) 8.45 (1H, d, J = 1.3 Hz), 7.83-7.81 (1H, m), 7.40 (2H, brs), 7.19 (1H, dd, J = 7.3, 7.9 Hz), 7.10 (1H, d, J = 7.3 Hz) 6.94-6.92 (1H, m), 6.85 (1H, d J = 7.9 Hz), 5.42 (2H, s), 4.22 (2H, t, J = 6.7 Hz), 3.24 (2H, s), 2.29 (3H, s), 2.01 (6H, s), 1.65 (2H, tt, J = 6.7, 7.9 Hz), 1.38 (2H, qt, J = 7.3, 7.9 Hz), 0.90 (3H, t, J = 7.3 Hz). 86 LC-MS [M + H].sup.+/Rt (min): 492.2/0.635 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.69-8.66 (1H, m), 8.64 (1H, d, J = 2.4 Hz), 7.98-7.93 (1H, m), 7.47 (2H, brs), 7.19 (1H, dd, J = 7.3, 7.9 Hz), 7.11 (1H, d, J = 7.3 Hz), 6.93-6.90 (1H, m), 6.86 (1H, d J = 7.9 Hz), 5.48 (2H, s), 4.23 (2H, t, J = 6.7 Hz), 3.50-3.45 (4H, m), 3.31 (2H, s), 2.25-2.15 (4H, m), 1.65 (2H, tt, J = 6.7, 7.9 Hz), 1.39 (2H, qt, J = 7.3, 7.9 Hz), 0.90 (3H, t, J = 7.3 Hz). 87 LC-MS [M + H].sup.+/Rt (min): 452.2/0.516 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sup.6) : 8.67 (1H, dd, J = 1.2, 1.8 Hz), 8.65 (1H, d, J = 3.1 Hz), 7.96-7.92 (1H, m), 7.50 (2H, brs), 7.15 (2H, d, J = 7.9 Hz), 6.91 (2H, d, J = 7.9 Hz), 5.45 (2H, s), 4.34 (2H, t, J = 4.9 Hz), 3.61 (2H, t, J = 4.9 Hz), 3.32 (3H, s), 3.27 (2H, s), 2.05 (6H, s). 88 0 LC-MS [M + H].sup.+/Rt (min): 494.2/0.511 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.68-8.66 (1H, m), 8.65 (1H, d, J = 2.4 Hz), 7.96-7.92 (1H, m), 7.50 (2H, brs), 7.17 (2H, d, J = 7.9 Hz), 6.92 (2H, d, J = 7.9 Hz), 5.45 (2H, s), 4.34 (2H, t, J = 4.9 Hz), 3.61 (2H, t, J = 4.9 Hz), 3.53-3.49 (4H, m), 3.35 (3H, s), 3.27 (2H, s), 2.26-2.23 (4H, m). 89 LC-MS [M + H].sup.+/Rt (min): 452.1/0.524 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.68-8.66 (1H, m), 8.64 (1H, d, J = 2.4 Hz), 7.97-7.92 (1H, m), 7.50 (2H, brs), 7.19 (1H, dd, J = 7.3, 7.9 Hz), 7.10 (1H, d, J = 7.3 Hz), 6.91-6.90 (1H, m), 6.84 (1H, d, J = 7.9 Hz), 5.48 (2H, s), 4.35 (2H, t, J = 4.9 Hz), 3.61 (2H, t, J = 4.9 Hz), 3.27 (3H, s), 3.24 (2H, s), 2.00 (6H, s). 90 LC-MS [M + H].sup.+/Rt (min): 494.1/0.533 (Method A); .sup.1H-NMR (400 MHz DMSO-d.sub.6) : 8.68-8.66 (1H, m), 8.65 (1H, d, J = 2.4 Hz), 7.98-7.94 (1H, m), 7.52 (2H, brs), 7.20 (1H, dd, J = 7.3, 7.9 Hz), 7.11 (1H, d, J = 7.3 Hz), 6.91-6.89 (1H, m), 6.86 (1H, d, J = 7.9 Hz), 5.48 (2H, s), 4.34 (2H, t, J = 4.9 Hz), 3.61 (2H, t, J = 4.9 Hz), 3.51-3.45 (4H, m), 3.31 (2H, s), 3.27 (3H, s), 2.22-2.16 (4H, m). 91 LC-MS [M + H].sup.+/Rt (min): 492.5/0.559 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.69-8.67 (1H, m), 8.65 (1H, d, J = 2.7 Hz), 7.96-7.92 (1H, m), 7.49 (2H, brs), 7.14 (2H, d, J = 8.2 Hz), 6.91 (2H, d, J = 8.2 Hz), 5.45 (2H, s), 4.34 (2H, t, J = 4.8 Hz), 3.61 (2H, t, J = 4.8 Hz), 3.30 (2H, s), 3.27 (3H, s), 2.26-2.16 (4H, m), 1.46-1.38 (4H, m), 1.37-1.30 (2H, m). 92 LC-MS [M + H].sup.+/Rt (min): 528.5/0.584 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.68-8.67 (1H, m), 8.65 (1H, d, J = 2.7 Hz), 7.96-7.93 (1H, m), 7.49 (2H, brs), 7.17 (2H, d, J = 8.2 Hz), 6.93 (2H, d, J = 8.2 Hz), 5.45 (2H, s), 4.34 (2H, t, J = 4.6 Hz), 3.61 (2H, t, J = 4.6 Hz), 3.44 (2H, s), 3.27 (3H, s), 2.42-2.35 (4H, m), 1.95-1.83 (4H, m). 93 LC-MS [M + H].sup.+/Rt (min): 491.5/0.581 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.67-8.66 (1H, m), 8.64 (1H, d, J = 3.1 Hz), 7.96-7.92 (1H, m), 7.47 (2H, brs), 7.18 (2H, d, J = 7.9 Hz), 6.94 (2H, d, J = 7.9 Hz), 5.46 (2H, s), 4.26 (2H, q, J = 7.3 Hz), 3.43 (2H, s), 3.19 (2H, t, J = 5.5 Hz), 2.86 (2H, s), 2.77 (3H, s), 2.52 (2H, t, J = 5.5 Hz), 1.27 (3H, t, J = 7.3 Hz). 94 LC-MS [M + H].sup.+/Rt (min): 489.2/0.508 (Method A); .sup.1H-NMR (400 MHz DMSO-d.sub.6) : 8.68-8.67 (1H, m), 8.65 (1H, d, J = 2.4 Hz), 7.97-7.93 (1H, m), 7.47 (2H, brs), 7.19 (2H, d, J = 7.9 Hz), 6.91 (2H, d, J = 7.9 Hz), 5.44 (2H, s), 4.26 (2H, q, J = 7.3 Hz), 3.37-3.24 (4H, m), 3.17 (1H, brs), 2.84-2.75 (1H, m), 2.59-2.53 (2H, m), 2.33 (2H, s), 1.27 (3H, t, J = 7.3 Hz). 95 LC-MS [M + H].sup.+/Rt (min): 503.5/0.553 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 3.69-8.68 (1H, m), 8.65 (1H, d, J = 2.4 Hz), 7.96-7.92 (1H, m), 7.46 (2H, brs), 7.21 (2H, d, J = 7.9 Hz), 6.91 (2H, d, J = 7.9 Hz), 5.44 (2H, s), 4.27 (2H, q, J = 7.3 Hz), 3.36 (2H, s), 2.93-3.88 (2H, m), 2.46-2.40 (2H, m), 2.10-2.04 (5H, m), 1.83-1.76 (2H, m), 1.67-1.61 (2H, m), 1.27 (3H, t, J = 7.3 Hz). 96 LC-MS [M + H].sup.+/Rt (min): 476.5/0.530 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.68-8.67 (1H, m), 8.65 (1H, d, J = 3.0 Hz), 7.97-7.93 (1H, m), 7.46 (2H, brs), 7.19 (2H, d, J = 7.9 Hz), 6.91 (2H, d, J = 7.9 Hz), 5.44 (2H, s), 4.30- 4.29 (1H, m), 4.28 (2H, q, J = 7.3 Hz), 3.84 (1H, d, J = 7.3 Hz), 3.63 (1H, d, J = 13.4 Hz), 3.58 (1H, d, J = 13.4 Hz), 3.46 (1H, dd, J = 1.8, 7.3 Hz), 3.34-3.30 (1H, m), 2.52 (1H, dd, J = 1.8, 9.4 Hz), 1.72 (1H, dd, J = 1.8, 9.4), 1.55-1.51 (1H, m), 1.27 (3H, t, J = 7.3 Hz). 97 LC-MS [M + H].sup.+/Rt (min): 464.4/0.528 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.68-8.67 (1H, m), 8.64 (1H, d J = 2.4 Hz), 7.95-7.92 (1H, m), 7.46 (2H, brs), 7.17 (2H, d, J = 7.9 Hz), 6.92 (2H, d, J = 7.9 Hz), 5.45 (2H, s), 4.27 (2H, q, J = 7.3 Hz) 3.52-3.50 (4H, m), 3.35 (2H, s), 2.28-2.22 (4H, m), 1.27 (3H, t, J = 7.3 Hz). 98 0 LC-MS [M + H].sup.+/Rt (min): 462.3/0.583 (Method A); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.59-8.58 (1H, m), 8.46 (1H, d, J = 3.1 Hz), 7.55-7.51 (1H, m), 7.16 (2H, d, J = 7.9 Hz), 6.94 (2H, d, J = 7.9 Hz), 5.51 (2H, brs), 5.34 (2H, s), 4.33 (2H, q, J = 7.3 Hz), 3.34 (2H, s), 2.28-2.20 (4H, m), 1.51-1.44 (4H, m), 1.38-1.30 (2H, m), 1.34 (3H, t, J = 7.3 Hz). 99 LC-MS [M + H].sup.+/Rt (min): 498.3/0.603 (Method A); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.63-8.62 (1H, m), 8.51 (1H, d, J = 2.4 Hz), 7.61-7.57 (1H, m), 7.21 (2H, d, J = 7.9 Hz) 7.01 (2H, d, J = 7.9 Hz), 5.56 (2H, brs), 5.39 (2H, s), 4.38 (2H, q, J = 7.3 Hz), 3.47 (2H, s), 2.50-2.44 (4H, m), 2.01-1.89 (4H, m), 1.39 (3H, t, J = 7.3 Hz). 100 LC-MS [M + H].sup.+/Rt (min): 434.3/0.545 (Method A); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.58-8.57 (1H, m), 8.45 (1H, d, J = 3.1 Hz), 7.54-7.50 (1H, m), 7.12 (2H, d, J = 7.9 Hz), 6.94 (2H, d, J = 7.9 Hz), 5.52 (2H, brs), 5.33 (2H, s), 4.32 (2H, J = 7.3 Hz), 3.44 (2H, s), 3.11 (4H, t, J = 6.7 Hz), 2.00 (2H, quin, J = 6.7 Hz), 1.34 (3H, t, J = 7.3 Hz). 101 LC-MS [M + H].sup.+/Rt (min): 470.3/0.632 (Method A); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.62-8.61 (1H, m), 8.51 (1H, d, J = 2.4 Hz), 7.60-7.57 (1H, m), 7.19 (2H, d, J = 8.5 Hz), 7.02 (2H, d, J = 8.5 Hz), 5.56 (2H, brs), 5.39 (2H, s), 4.37 (2H, q, J = 7.3 Hz), 3.67 (2H, s), 3.62-3.50 (5H, m), 1.39 (3H, t, J = 7.3 Hz). 102 LC-MS [M + H].sup.+/Rt (min): 472.1/0.647 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.66 (1H, dd, J = 1.8, 1.8 Hz), 8.64 (1H, d, J = 2.4 Hz), 7.95-7.91 (1H, m), 7.46 (2H, brs), 7.17 (2H, d J = 7.9 Hz), 6.93 (2H, d, J = 7.9 Hz), 6.06 (1H, tt, J = 4.2, 47.6 Hz), 5.45 (2H, s), 4.27 (2H, q, J = 7.3 Hz), 3.51 (2H, s), 2.68 (2H, dt, J = 4.2, 11.0 Hz), 2.15 (3H, s), 1.27 (3H, t, J = 7.3 Hz). 103 LC-MS [M + H].sup.+/Rt (min): 459.1/0.556 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.67-8.65 (2H, m), 7.97-7.92 (1H, m), 7.46 (2H, brs), 7.13 (2H, d, J = 7.3 Hz), 6.92 (2H, d, J = 7.3 Hz), 5.44 (2H, s), 4.26 (2H, q, J = 7.3 Hz), 3.47 (2H, s), 3.45-3.38 (1H, m), 3.35 (2H, t, J = 6.1 Hz), 3.18 (2H, t, J = 6.1 Hz), 1.27 (3H, t, J = 7.3 Hz). 104 LC-MS [M + H].sup.+/Rt (min): 448.5/0.561 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.68 (1H, d, J = 1.8 Hz), 8.65 (1H, d, J = 2.4 Hz), 7.97-7.92 (1H, m), 7.46 (2H, brs), 7.16 (2H, d, J = 7.3 Hz), 6.91 (2H, d, J = 7.3 Hz), 5.45 (2H, s), 4.27 (2H, q, J = 7.3 Hz), 3.46 (2H, s), 2.38-2.35 (4H, m), 1.63-1.59 (4H, m), 1.27 (3H, t, J = 7.3 Hz). 105 LC-MS [M + H].sup.+/Rt (min): 484.5/0.605 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.68-8.66 (1H, m), 8.65 (1H, d, J = 2.7 Hz), 7.96-7.92 (1H, m), 7.45 (2H, brs), 7.13 (2H, d, J = 8.2 Hz), 6.91 (2H, d, J = 8.2 Hz), 6.18 (1H, dt, J = 5.2, 56.9 Hz), 5.43 (2H, s), 4.26 (2H, q, J = 7.3 Hz), 3.45 (2H, s), 3.19 (2H, t, J = 7.7 Hz), 3.00 (2H, t, J = 7.7 Hz), 2.88-2.74 (1H, m), 1.27 (3H, t, J = 7.3 Hz). 106 LC-MS [M + H].sup.+/Rt (min): 464.1/0.540 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.68-8.67 (1H, m), 8.66 (1H, d, J = 2.4 Hz), 7.97-7.93 (1H, m), 7.47 (2H, brs), 7.12 (2H, d, J = 7.9 Hz), 6.90 (2H, d, J = 7.9 Hz), 5.43 (2H, s), 5.10 (1H, s), 4.26 (2H, q, J = 7.3 Hz), 3.46 (2H, s), 3.06 (2H, d, J = 7.3 Hz), 2.78 (2H, d, J = 7.3 Hz), 1.30 (3H, s), 1.27 (3H, t, J = 7.3 Hz). 107 LC-MS [M + H].sup.+/Rt (min): 474.4/0.525 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.73-8.72 (2H, m), 8.06-8.02 (1H, m), 7.17 (2H, d, J = 6.7 Hz), 6.91 (2H, d, J = 6.7 Hz), 5.54 (2H, s), 3.95 (3H, s), 3.57 (1H, d, J = 13.4 Hz), 3.50 (1H, d, J = 13.4 Hz), 3.07 (2H, d, J = 9.8 Hz), 2.71 (3H, s), 2.61 (1H, d, J = 9.8 Hz), 2.46-2.40 (2H, m), 2.21 (3H, s), 1.53 (3H, s). 108 0 LC-MS [M + H].sup.+/Rt (min): 421.4/0.587 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.73-8.70 (2H, m), 8.05-8.00 (1H, m), 7.14 (2H, d, J = 7.9 Hz), 6.92 (2H, d, J = 7.9 Hz), 5.53 (2H, s), 4.38 (2H, q, J = 7.3 Hz), 3.27 (2H, s), 2.70 (3H, s), 2.04 (6H, s), 1.33 (3H, t, J = 7.3 Hz). 109 LC-MS [M + H].sup.+/Rt (min): 488.5/0.573 (Method A); .sup.1H-NMR (400 MHz DMSO-d.sub.6) : 8.73-8.71 (2H, m), 8.05-8.01 (1H, m), 7.18 (1H, d, J = 7.9 Hz), 6.91 (2H, d, J = 7.9 Hz), 5.52 (2H, s), 4.38 (2H, q, J = 7.3 Hz), 3.58 (1H, d, J = 13.4 Hz), 3.51 (1H, d, J = 13.4 Hz), 3.31 (2H, s), 3.17 (1H, s), 3.13 (1H, s) 2.70 (3H, s), 2.54-2.44 (4H, m), 2.28 (3H, s), 1.59 (2H, s), 1.33 (3H, t, J = 7.3 Hz). 110 LC-MS [M + H].sup.+/Rt (min): 488.5/0.596 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.73-8.71 (2H, m), 8.05-8.01 (1H, m), 7.18 (1H, d, J = 7.9 Hz), 6.91 (2H, d, J = 7.9 Hz), 5.52 (2H, s), 4.38 (2H, q, J = 7.3 Hz), 3.57 (1H, d, J = 13.4 Hz), 3.50 (1H, d, J = 13.4 Hz), 3.31 (2H, s), 3.10 (2H, s), 2.70 (3H, s), 2.63 (1H, d, J = 9.2 Hz), 2.51-2.42 (3H, m), 2.23 (3H, s), 1.55 (2H, s), 1.33 (3H, t, J = 7.3 Hz). 111 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.74-8.72 (2H, m), 8.05-8.01 (1H, m), 7.15 (1H, d, J = 8.1 Hz), 6.93 (2H, d, J = 8.1 Hz), 5.55 (2H, s), 4.35 (2H, t, J = 6.6 Hz), 2.71 (3H, s), 2.05 (6H, s), 1.73 (2H, tt, J = 6.6, 7.9 Hz), 1.42 (2H, qt, J = 7.3, 7.9), 0.93 (3H, t, J = 7.3 Hz). 112 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.73-8.72 (2H, m), 8.05-8.01 (1H, m), 7.24 (1H, d, J = 8.1 Hz), 6.94 (2H, d, J = 8.1 Hz), 5.55 (2H, s), 4.35 (2H, t, J = 6.6 Hz), 2.71 (3H, s), 2.28-2.22 (4H, s), 1.72 (2H, tt, J = 6.6, 7.9 Hz), 1.42 (2H, qt, J = 7.3, 7.9), 0.93 (3H, t, J = 7.3 Hz). 113 LC-MS [M + H].sup.+/Rt (min): 451.2/0.537 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.73-8.71 (2H, m), 8.05-8.01 (1H, m), 7.14 (2H, d, J = 7.9 Hz), 6.92 (2H, d, J = 7.9 Hz), 5.54 (2H, s), 4.46 (2H, t, J = 4.9 Hz), 3.67 (2H, t, J = 4.9 Hz), 3.31 (3H, s), 3.27 (2H, s), 2.71 (3H, s), 2.04 (6H, s). 114 LC-MS [M + H].sup.+/Rt (min): 493.1/0.562 (Method A) 115 LC-MS [M + H].sup.+/Rt (min): 506.2/0.578 (Method A) 116 LC-MS [M + H].sup.+/Rt (min): 458.5/0.611 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.73 (1H, d, J = 3.1 Hz) 8.71-8.70 (1H, m), 8.05-8.02 (1H, m), 7.12 (2H, d, J = 7.9 Hz), 6.92 (2H, d, J = 7.9 Hz), 5.52 (2H, s), 4.38 (2H, q, J = 7.3 Hz), 3.46 (2H, s), 3.45-3.38 (1H, m), 3.34 (2H, t, J = 6.7 Hz), 3.18 (2H, t, J = 6.7 Hz), 2.70 (3H, s), 1.33 (3H, t, J = 7.3 Hz). 117 LC-MS [M + H].sup.+/Rt (min): 421.4/0.473 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.68 (1H, s), 8.58 (1H, d, J = 2.4 Hz), 7.89- 7.86 (1H, m), 7.15 (2H, d, J = 7.9 Hz), 6.93 (2H, d, J = 7.9 Hz), 6.93 (2H, brs), 6.44 (1H, t, J = 5.5 Hz), 5.40 (2H, s), 3.31-3.23 (4H, m), 2.05 (6H, s), 1.08 (3H, t, J = 7.3 Hz). 118 0 LC-MS [M + H].sup.+/Rt (min): 412.3/0.396 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.66 (1H, s), 8.58-8.56 (1H, m), 7.61-7.58 (1H, m), 7.27- 7.24 (2H, m), 6.98 (2H, d, J = 8.5 Hz), 6.10-5.92 (2H, m), 5.47 (2H, s), 3.40 (2H, s), 2.21 (6H, s). 119 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.70-8.67 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 7.71-7.64 (1H, m), 7.25 (3H, d, J = 7.9 Hz), 7.01 (2H, d, J = 7.9 Hz), 5.47 (2H, s), 4.49 (2H, q, J = 7.1 Hz), 3.36 (2H, dd, J = 13.4, 19.5 Hz), 3.15-3.10 (1H, m), 3.06-2.94 (2H, m), 2.84 (3H, s), 2.83-2.74 (1H, m), 2.64 (1H, dd, J = 4.0, 13.4 Hz), 2.58-2.51 (1H, m), 2.48 (1H, dd, J = 4.6, 11.9 Hz), 2.32-2.23 (1H, m), 2.05-1.95 (1H, m), 1.47 (3H, t, J = 7.1 Hz). 120 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.69-8.61 (1H, m), 8.56-8.49 (1H, m), 7.60 (1H, d, J = 8.5 Hz), 7.24 (2H, d, J = 6.1 Hz), 7.02 (2H, d, J = 6.1 Hz), 5.83 (2H, s), 5.41 (2H, s), 4.39 (2H, q, J = 7.0 Hz), 3.33 (2H, dd, J = 13.4, 17.1 Hz), 3.11- 3.03 (1H, m), 3.02-2.82 (3H, m), 2.79-2.67 (1H, m), 2.62-2.52 (1H, m), 2.52-2.36 (2H, m), 2.02-1.88 (1H, m), 1.41 (3H, t, J = 7.0 Hz). 121 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.80-8.77 (1H, m), 8.63 (1H, d, J = 2.4 Hz), 7.83-7.77 (1H, m), 6.20 (1H, s), 5.57 (2H, s), 4.41 (2H, q, J = 7.1 Hz), 2.24 (6H, s), 1.44 (3H, t, J = 7.1 Hz). 122 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.91-8.88 (1H, m), 8.56 (1H, d, J = 3.1 Hz), 8.47 (1H, d, J = 1.8 Hz), 8.13-8.08 (1H, m), 7.66 (1H, dd, J = 1.8, 7.9 Hz), 7.25-7.22 (1H, m), 5.50 (2H, s), 4.42 (2H, q, J = 7.1 Hz), 3.86-3.79 (2H, m), 3.67 (1H, d, J = 13.4 Hz), 3.44-3.37 (1H, m), 3.19-3.07 (1H, m), 3.07- 2.91 (2H, m), 2.90-2.81 (1H, m), 2.80 (3H, s), 2.70 (1H, d, J = 9.2 Hz), 2.05-1.93 (2H, m), 1.42 (3H, t, J = 7.1 Hz), 1.33 (3H, t, J = 7.2 Hz).

Example 123

9-{4-[(1S,4S)-2,5-Diazabicyclo[2.2.1]hept-2-ylmethyl]benzyl}-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine

(53) ##STR00165##

(54) To the compound of Example 225 (138 mg) was added trifluoroacetic acid (1.5 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with toluene, and then concentrated in vacuo. To the reaction mixture in ice bath was added aqueous saturated sodium bicarbonate, and the mixture was extracted with chloroform-methanol (20:1). The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by amino silica gel column chromatography (chloroform/methanol) to give the title compound (105 mg).

(55) LC-MS [M+H].sup.+/Rt (min): 474.5/0.531 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.72-8.71 (1H, m), 8.31-8.30 (1H, m), 8.05-8.01 (1H, m), 7.18 (1H, d, J=7.3 Hz), 6.90 (2H, d, J=7.3 Hz), 5.52 (2H, s), 4.42-4.35 (2H, m), 3.14-3.13 (1H, m), 2.92 (1H, d, J=9.8 Hz), 2.70 (3H, s), 2.65-2.50 (3H, m), 2.19 (1H, d, J=9.2 Hz), 1.58 (1H, d, J=9.2 Hz), 1.35-1.31 (4H, m).

Examples 124-125

(56) According to the method of Example 123, Examples 124-125 were prepared by using the corresponding material compounds.

(57) TABLE-US-00010 Example Chemical Structure Instrumental analysis data 124 LC-MS [M + H].sup.+/Rt (min): 475.5/0.518 (Method A); .sup.1H-NMR (DMSO-d.sub.6) : 8.68-8.67 (1H, m), 8.65 (1H, d, J = 3.1 Hz), 7.97-7.92 (1H, m), 7.46 (2H, brs), 7.18 (1H, d, J = 7.9 Hz), 6.90 (2H, d, J = 7.9 Hz), 5.43 (2H, s), 4.26 (2H, q, J = 7.3 Hz), 3.58 (1H, d, J = 13.4 Hz), 3.52 (1H, d, J = 13.4 Hz), 3.15 (1H, brs), 2.93 (1H, d, J = 9.8 Hz), 2.64-4.48 (2H, m), 2.20 (1H, d, J = 9.2 Hz), 1.59 (1H, d, J = 8.5 Hz), 1.34 (1H, d, J = 9.2 Hz), 1.27 (3H, t, J = 7.3 Hz). 125 LC-MS [M + H].sup.+/Rt (min): 460.5/0.555 (Method A); .sup.1H-NMR (400 MHz DMSO-d.sub.6) : 8.73- 8.72 (2H, m), 8.06-8.01 (1H, m), 7.16 (1H, d, J = 7.9 Hz), 6.90 (2H, d, J = 7.9 Hz), 5.33 (2H, s), 3.95 (3H, s), 3.58 (1H, d, J = 13.4 Hz), 3.51 (1H, d, J = 13.4 Hz), 3.14 (1H, brs), 2.92 (1H, d, J = 9.8 Hz), 2.70 (3H, s), 2.64- 2.54 (2H, m), 2.19 (1H, d, J = 9.2 Hz), 1.58 (1H, d, J = 9.2 Hz), 1.33 (1H, d, J = 9.2 Hz).

Example 126

1-[(1S,4S)-5-(4-{[6-Amino-2-ethoxy-8-(5-fluoropyridin-3-yl)-9H-purin-9-yl]methyl}benzyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethanone

(58) ##STR00168##

(59) To an ice-cooled solution of the compound of Example 124 (40.2 mg) in pyridine (5.0 mL) was added acetic anhydride (0.050 ml). The reaction mixture was stirred at room temperature for 4.5 hours, and then concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (38.2 mg).

(60) LC-MS [M+H].sup.+/Rt (min): 517.5/0.517 (Method A)

Example 127

2-Ethoxy-8-(5-fluoropyridin-3-yl)-9-[4-(1-methylpiperidin-4-yl)benzyl]-9H-purine-6-amine

(61) ##STR00169##

(62) To an ice-cooled solution of the compound of Example 194 (145 mg) in chloroform (3 mL) was added triflucroacetic acid (0.409 ml). The reaction mixture was warmed to room temperature, stirred for 2 days, and then concentrated. The obtained residue was dissolved in tetrahydrofuran (3 ml). To the solution were added sodium acetate (65.3 mg), 37% formaldehyde solution (0.041 ml) and triacetoxysodium borohydride (112 mg) under ice temperature. Then, the mixture was warmed to room temperature, and stirred for one hour. To the reaction mixture in ice bath was added aqueous saturated sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (72 mg).

(63) LC-MS ([M+H].sup.+/Rt (min)): 462.5/0.461 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.71-8.62 (1H, m), 8.55 (1H, d, J=3.1 Hz), 7.67-7.58 (1H, m), 7.15 (2H, d, J=7.9 Hz), 7.03 (2H, d, J=7.9 Hz), 5.80 (2H, s), 5.40 (2H, s), 4.41 (2H, q, J=7.1 Hz), 2.98 (2H, d, J=11.6 Hz), 2.51-2.38 (1H, m), 2.33 (3H, s), 2.13-2.00 (2H, m), 1.86-1.72 (4H, m), 1.41 (3H, t, J=7.1 Hz).

Examples 128-139

(64) According to the methods of Examples 80 and 127, Examples 128-139 were prepared by using the corresponding material compounds.

(65) TABLE-US-00011 Example Chemical Structure Instrumental analysis data 128 0 LC-MS [M + H].sup.+/Rt (min): 503.5/0.536 (Method A); .sup.1H-NMR (DMSO-d.sub.6) : 8.68-8.67 (1H, m), 8.65 (1H, d, J = 3.1 Hz), 7.96- 7.93 (1H, m), 7.46 (2H, brs), 7.18 (2H, d, J = 7.9 Hz), 6.90 (2H, d, J = 7.9 Hz), 5.43 (2H, br s), 4.26 (2H, q, J = 7.3 Hz), 3.58 (1H, d, J = 14.0 Hz), 3.50 (1H, d, J = 14.0 Hz), 3.22 (1H, s), 3.11 (1H, s), 2.58 (1H, d, J = 9.8 Hz), 2.54-2.34 (3H, m), 1.53 (2H, q, J = 7.3 Hz), 1.27 (3H, t, J = 7.3 Hz), 0.93 (3H, t, J = 7.3 Hz). 129 LC-MS [M + H].sup.+/Rt (min): 531.6/0.552 (Method A); .sup.1H-NMR (DMSO-d.sub.6) : 8.68-8.67 (1H, m), 8.65 (1H, d, J = 3.1 Hz), 7.96- 7.92 (1H, m), 7.46 (2H, brs), 7.19 (2H, d, J = 8.5 Hz), 6.90 (2H, d, J = 8.5 Hz), 5.43 (2H, s), 4.54 (1H, t, J = 6.7 Hz), 4.49 (1H, t, J = 6.7 Hz), 4.36 (1H, t, J = 5.5 Hz), 4.33-4.24 (3H, m), 3.83-3.77 (1H, m), 3.59 (1H, d, J = 14.0 Hz), 3.50 (1H, d, J = 14.0 Hz), 3.15 (2H, s), 2.72 (1H, d, J = 9.2 Hz), 2.47-2.35 (3H, m), 1.55 (1H, d, J = 9.7 Hz), 1.49 (1H, d, J = 9.7 Hz), 1.27 (3H, t, J = 7.3 Hz). 130 LC-MS [M + H].sup.+/Rt (min): 515.6/0.584 (Method A); .sup.1H-NMR (DMSO-d.sub.6) : 8.68-8.67 (1H, m), 8.65 (1H, d, J = 2.4 Hz), 7.96- 7.92 (1H, m), 7.46 (2H, brs), 7.19 (2H, d, J = 8.5 Hz), 5.43 (2H, s), 4.27 (2H, q, J = 7.3 Hz), 3.59 (1H, d, J = 14.0 Hz), 3.52 (1H, d, J = 14.0 Hz), 3.22 (1H, m), 3.13 (1H, m), 2.62 (1H, dd, J = 2.4, 9.2 Hz), 2.75 (1H, d, J = 9.2 Hz), 2.55 (1H, d, J = 9.2 Hz), 2.50-2.43 (3H, m), 1.95-1.90 (1H, m), 1.56 (1H, d, J = 9.2 Hz), 1.51 (1H, d, J = 9.2 Hz), 1.27 (3H, t, J = 7.3 Hz), 0.36-0.28 (2H, m), 0.25- 0.21 (2H, m). 131 LC-MS [M + H].sup.+/Rt (min): 502.2/0.628 (Method A); .sup.1H-NMR (DMSO-d.sub.6)8.73-8.71 (2H, m), 8.05-8.01 (1H, m), 7.18 (2H, d, J = 7.9 Hz), 6.91 (2H, d, J = 7.9 Hz), 5.52 (2H, s), 4.38 (2H, q, J = 7.3 Hz), 3.58 (1H, d, J = 14.0 Hz), 3.50 (1H, d, J = 14.0 Hz), 3.11 (1H, s), 2.70 (3H, s), 2.55-2.34 (3H m), 1.60-1.48 (2H, m), 1.33 (3H, t, J = 7.3 Hz), 0.93 (3H, t, J = 7.3 Hz). 132 LC-MS [M + H].sup.+/Rt (min): 488.5/0.611 (Method A); .sup.1H-NMR (DMSO-d.sub.6) : 8.73-8.71 (2H, m), 8.06-8.01 (1H, m), 7.18 (2H, d, J = 7.7 Hz), 6.91 (2H, d, J = 7.7 Hz), 5.54 (2H, s), 3.95 (3H, s), 3.58 (1H, d, J = 14.2 Hz), 3.51 (1H, d, J = 14.2 Hz), 3.13 (1H, s), 2.71 (3H, s), 2.70-2.38 (5H m), 1.62-1.51 (2H, m), 0.95 (3H, t, J = 7.3 Hz). 133 LC-MS [M + H].sup.+/Rt (min): 502.5/0.775 (Method A); .sup.1H-NMR (DMSO-d.sub.6) : 8.73-8.72 (2H, m), 8.05-8.02 (1H, m), 7.17 (2H, d, J = 7.3 Hz), 6.90 (2H, d, J = 7.3 Hz), 5.53 (2H, br s), 3.95 (3H, s), 3.57 (1H, d, J = 14.0 Hz), 3.50 (1H, d, J = 14.0 Hz), 3.17 (1H, s), 3.08 (1H, s), 2.71 (3H, s), 2.56-2.47 (2H, m), 2.44-2.38 (2H, m), 2.33- 2.23 (1H, m), 1.55-1.47 (2H, m), 1.36-1.27 (2H, m), 0.82 (3H, t, J = 7.9 Hz). 134 LC-MS [M + H].sup.+/Rt (min): 489.5/0.526 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.66-8.65 (1H, m), 8.54 (1H, d, J = 3.1 Hz), 7.63- 7.59 (1H, m), 7.28-7.26 (2H, m), 7.02 (2H, d, J = 8.0 Hz), 5.61 (2H, br s), 5.41 (2H, s), 3.98 (3H, s), 3.71 (1H, d, J = 13.2 Hz), 3.62 (1H, d, J = 13.2 Hz), 3.42 (1H, s), 3.24 (1H, s), 2.80-2.53 (5H, m), 1.76- 1.74 (3H, m), 1.10 (3H, t, J = 7.0 Hz). 135 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.67- 8.63 (1H, m), 8.55 (1H, d, J = 1.8 Hz), 7.67-7.60 (1H, m), 7.16 (2H, d, J = 7.9 Hz), 7.03 (2H, d, J = 7.9 Hz), 5.73 (2H, s), 5.41 (2H, s), 4.72-4.62 (4H, m), 4.41 (2H, q, J = 6.9 Hz), 3.51 (1H, dd, J = 6.0, 6.2 Hz), 2.91-2.81 (2H, m), 2.56- 2.43 (1H, m), 1.99-1.71 (6H, m), 1.42 (3H, t, J = 6.9 Hz). 136 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.69- 8.63 (1H, m), 8.56 (1H, d, J = 2.4 Hz), 7.67-7.61 (1H, m), 7.21 (2H, d, J = 7.9 Hz), 7.03 (2H, d, J = 7.9 Hz), 5.69 (2H, s), 5.41 (2H, s), 4.41 (2H, q, J = 7.0 Hz), 3.45-3.31 (1H, m), 3.09-3.00 (1H, m), 2.91-2.78 (1H, m), 2.77-2.63 (1H, m), 2.60-2.48 (1H, m), 2.45 (3H, s), 2.40-2.27 (1H, m), 1.93- 1.79 (1H, m), 1.42 (3H, t, J = 7.0 Hz). 137 LC-MS: [M + H].sup.+/Rt (min): 420.4/0.388 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3): : 8.67-8.65 (1H, m), 8.55 (1H, d, J = 3.1 Hz), 7.65-7.58 (1H, m), 7.12 (1H, d, J = 8.5 Hz), 6.92-6.91 (2H, m), 5.93 (2H, s), 5.41 (2H, s), 4.41 (2H, q, J = 7.1 Hz), 3.91 (2H, s), 3.86 (2H, s), 2.58 (3H, s), 1.42 (3H, t, J = 7.0 Hz). 138 0 LC-MS [M + H].sup.+/Rt (min): 447.3/0.663 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.73-8.65 (1H, m), 8.59 (1H, d, J = 2.4 Hz), 7.73-7.67 (1H, m), 7.20 (2H, d, J = 7.9 Hz), 7.00 (2H, d, J = 7.9 Hz), 5.45 (2H, s), 4.49 (2H, q, J = 7.1 Hz), 3.41- 3.27 (1H, m), 2.98 (1H, dd, J = 8.5, 8.5 Hz), 2.84 (3H, s), 2.81-2.73 (1H, m), 2.69-2.60 (1H, m), 2.46 (1H, dd, J = 8.0, 8.5 Hz), 2.41 (3H, s), 2.38- 2.27 (1H, m), 1.89-1.77 (1H, m), 1.47 (3H, t, J = 7.1 Hz). 139 LC-MS [M + H].sup.+/Rt (min): 434.3/0.539 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.72-8.68 (1H, m), 8.60 (1H, d, J = 2.4 Hz), 7.74-7.67 (1H, m), 7.20 (2H, d, J = 7.9 Hz), 7.00 (2H, d, J = 7.9 Hz), 5.46 (2H, s), 4.08 (3H, s), 3.40-3.29 (1H, m), 2.96 (1H, dd, J = 8.8, 9.2 Hz), 2.85 (3H, s), 2.80-2.72 (1H, m), 2.69-2.58 (1H, m), 2.48-2.42 (1H, m), 2.40 (3H, s), 2.37-2.26 (1H, m), 1.87- 1.76 (1H, m).

Example 140

9-(4-{[2-(Dimethylamino)ethoxy]methyl}benzyl)-2-ethoxy-8-(5-fluoropyridin-3-yl)-9H-purine-6-amine

(66) ##STR00182##

(67) To an ice-cooled solution of sodium hydride (13.9 mg, purity: 55%) tetrahydrofuran (0.5 mL) was added N,N-dimethylethanolamine (0.032 mL), and the mixture was stirred for 10 minutes. Then, a solution of the compound of Example 232 (50 mg) tetrahydrofuran (0.56 mL) was added thereto, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtrated, and then concentrated in vacuo. The obtained residue was purified by amino silica gel column chromatography (chloroform/ethyl acetate/methanol), and then the residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (4.0 mg).

(68) LC-MS [M+H].sup.+/Rt (min): 466.1/0.479 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67 (1H, br s), 8.55 (1H, d, J=2.7), 7.65-7.61 (1H, m), 7.00 (2H, d, J=8.4 Hz), 6.75 (2H, d, J=8.4 Hz), 5.57 (2H, s), 5.35 (2H, s), 4.41 (2H, q, J=6.8 Hz), 4.32-4.30 (1H, m), 3.24 (1H, dd, J=13.9, 8.0 Hz), 3.00-2.75 (5H, m), 2.10 (1H, br s), 1.99-1.92 (1H, m), 1.76-1.49 (2H, m), 1.46-1.33 (4H, m).

Example 141

9-Benzyl-2-butoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine

(69) ##STR00183##

(70) To an ice-cooled solution of sodium hydride (13.9 mg, purity: 55%) in tetrahydrofuran (0.5 mL) was added N,N-dimethylethanolamine (0.032 mL), and the mixture was stirred for 10 minutes. Then, a solution of the compound of Reference example 135 (50.0 mg) in tetrahydrofuran (0.56 mL) was added thereto, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtrated, and then concentrated in vacuo. The obtained residue was purified by amino silica gel column chromatography (chloroform/ethyl acetate/methanol), and then the residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (4.0 mg).

(71) LC-MS [M+H].sup.+/Rt (min): 466.1/0.479 (Method C); .sup.1H-NMR (DMSO-d.sub.6) : 8.67 (1H, br s), 8.55 (1H, d, J=2.7 Hz), 7.65-7.61 (1H, m), 7.00 (2H, d, J=8.4 Hz), 6.75 (2H, d, J=8.4 Hz), 5.57 (2H, s), 5.35 (2H, s), 4.41 (2H, q, J=6.8 Hz), 4.32-4.30 (1H, m), 3.24 (1H, dd, J=13.9, 8.0 Hz), 3.00-2.75 (5H, m), 2.10 (1H, br s), 1.99-1.92 (1H, m), 1.76-1.49 (2H, m), 1.46-1.33 (4H, m).

Example 142

(72) According to the method of Example 141, Example 142 was prepared by using the corresponding material compound.

(73) TABLE-US-00012 Example ChemicalStructure Instrumental analysis data 142 LC-MS [M + H].sup.+/Rt (min): 404.0/1.056 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.45-8.41 (2H, m), 7.56 (1H, dd, J = 1.8, 2.4), 7.30-7.20 (3H, m), 7.02- 6.99 (2H, m), 5.52 (2H, s), 4.32 (2H, t, J = 6.4 Hz), 3.78 (3H, s), 2.70 (3H, s), 1.70 (2H, tt, J = 6.4, 7.9 Hz), 1.41 (2H, qt, J = 7.3, 7.9 Hz), 0.91 (3H, t, J = 7.3 Hz).

Example 143

(4-{[6-Amino-2-ethoxy-8-(5-fluoropyridin-3-yl)-9H-purin-9-yl]methyl}phenyl) (4-methylpiperazin-1-yl)methanone

(74) ##STR00185##

(75) To a solution of the compound of Example 235 (66.3 mg) in dimethylformamide (5 mL) were added EDCI.Math.HCl (63.3 mg), HOBT (21.7 mg), 1-methylpiperazine (0.027 mL), and diisopropylethylamine (0.056 mL), and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added aqueous saturated sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (60.5 mg).

(76) LC-MS ([M+H].sup.+/Rt (min.)): 491.4/0.507; .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.68-8.67 (1H, m), 8.65 (1H, d, J=3.1 Hz), 7.98-7.94 (1H, m), 7.48 (2H, brs), 7.25 (2H, d, J=7.9 Hz), 7.03 (2H, d, J=7.9 Hz), 5.50 (2H, s), 4.26 (2H, t, J=4.9 Hz), 3.64-3.46 (2H, m), 3.24-3.10 (2H, m), 2.35-2.14 (4H, m), 2.16 (3H, s), 1.27 (3H, t, J=6.7 Hz).

Examples 144-147

(77) According to the method of Example 143, Examples 144-147 were prepared by using the corresponding material compounds.

(78) TABLE-US-00013 Example Chemical Structure Instrumental analysis data 144 LC-MS [M + H].sup.+/Rt (min): 490.5/0.891 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.68-8.67 (1H, m), 8.65 (1H, d, J = 2.4 Hz), 7.98-7.94 (1H, m), 7.48 (2H, brs), 7.23 (2H, d, J = 7.9 Hz), 7.02 (2H, d, J = 7.9 Hz), 5.50 (2H, s), 4.43-4.31 (1H, m), 4.27 (2H, q, J = 6.7 Hz), 3.40-3.27 (2H, m), 2.98-2.84 (1H, m), 2.76- 2.62 (1H, m), 1.70-1.45 (2H, m), 1.27 (3H, t, J = 6.7 Hz), 1.08- 0.93 (2H, m), 0.88 (3H, d, J = 6.1 Hz). 145 LC-MS [M + H].sup.+/Rt (min): 479.5/0.541 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.69-8.68 (1H, m), 8.66 (1H, d, J = 2.4 Hz), 8.30 (1H, t, J = 5.5 Hz), 7.99-7.95 (1H, m), 7.70 (2H, d, J = 7.9 Hz), 7.48 (2H, brs), 7.06 (2H, d, J = 7.9 Hz), 5.52 (2H, s), 4.26 (2H, q, J = 7.3 Hz), 3.31-3.27 (2H, m), 2.34 (2H, t, J = 6.7 Hz), 2.13 (6H, s), 1.26 (3H, t, J = 7.3 Hz). 146 LC-MS [M + H].sup.+/Rt (min): 505.1/0.569 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.69-8.68 (1H, m), 8.66 (1H, d, J = 2.4 Hz), 8.36 (1H, t, J = 5.5 Hz), 8.00-7.96 (1H, m), 7.70 (2H, d, J = 7.9 Hz), 7.49 (2H, brs), 7.06 (2H, d, J = 7.9 Hz), 5.52 (2H, s), 4.25 (2H, q, J = 7.3 Hz), 2.54-2.40 (8H, m), 1.68-1.61 (4H, m), 1.26 (3H, t, J = 7.3 Hz). 147 LC-MS [M + H].sup.+/Rt (min): 519.2/0.621 (Method A): .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.68-8.67 (1H, m), 8.65 (1H, d, J = 2.4 Hz), 8.00-7.95 (1H, m), 7.50 (2H, brs), 7.33 (1H, dd, J = 7.3, 7.9 Hz), 7.21 (1H, d, J = 7.3 Hz), 7.06 (1H, d, J = 7.9 Hz), 6.94 (1H, s), 5.52 (2H, s), 4.22 (2H, t, J = 6.7 Hz), 3.60-3.46 (2H, m), 3.15-3.02 (2H, m), 2.34-2.20 (2H, m), 2.16 (3H, s), 2.14-2.02 (2H, m), 1.65 (2H, tt, J = 6.7, 7.9 Hz), 1.38 (2H, qt, J = 7.3, 7.9 Hz), 0.90 (3H, t, J = 7.3 Hz).

Example 148

1-[4-(4-{[6-Amino-2-ethoxy-8-(5-fluoropyridin-3-yl)-9H-purin-9-yl]methyl}phenyl)piperidin-1-yl]-2-(dimethylamino)ethanone

(79) ##STR00190##

(80) To a solution of the compound of Example 227 (68 mg) in N,N-dimethylformamide (4 mL) were added N,N-dimethylglycine hydrochloride (27.7 mg), N,N-diisopropylethylamine (0.070 mL), and HATU (64.5 mg) at room temperature. The reaction mixture was stirred for 16 hours, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (40.7 mg).

(81) LC-MS [M+H].sup.+/Rt (min): 533.5/0.498 (Method C)

Example 149

(82) According to the method of Example 148, Example 149 was prepared by using the corresponding material compound.

(83) TABLE-US-00014 Example Chemical Structure Instrumental analysis data 149 .sup.1H-NMR (400 MHz, CDCl.sub.3) (mixture of rotamers, 1:1) : 8.66-8.63 (1H, m), 8.57-8.54 (1H, m), 7.66 (1H, ddd, J = 2.0, 6.8, 8.8 Hz), 7.22 (1H, dd, J = 23.8, 7.9 Hz), 7.09-6.92 (2H, m), 5.75 (2H, s), 5.45 (2H, s), 4.88 (1H, s), 4.84 (1H, s), 4.79 (1H, s), 4.75 (1H, s), 4.41 (2H, q, J = 7.1 Hz), 3.22 (1H, s), 3.20 (1H, s), 2.40 (3H, s), 2.38 (3H, s), 1.42 (3H, t, J = 7.1 Hz).

Example 150

9-{4-[(Dimethylamino)methyl]benzyl}-8-(5-fluoropyridin-3-yl-2-methoxy-9H-purine-6-amine

(84) ##STR00192##

(85) To a solution of the compound of Example 118 (70 mg) in 1,4-dioxane (1.9 mL) was added sodium methoxide (46 mg), and the mixture was stirred at 100 C. for 3 hours. To the reaction mixture was added water under ice temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol). The obtained solid was triturated with diethyl ether to give the title compound (20 mg).

(86) LC-MS [M+H].sup.+/Rt (min): 408.5/0.498 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.65 (1H, br s), 8.53 d, J=2.4 Hz), 7.62-7.59 (1H, m), 7.26-7.24 (2H, m), 7.05 (2H, d, J=8.5 Hz), 5.58 (2H, br s), 5.43 (2H, s), 3.97 (3H, s), 3.45 (2H, s), 2.25 (6H, brs).

Examples 151-155

(87) According to the method of Example 150, Examples 151-155 were prepared by using the corresponding material compounds.

(88) TABLE-US-00015 Example Chemical Structure Instrumental analysis data 151 LC-MS [M + H].sup.+/Rt (min): 478.5/0.544 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.65 (1H, br s), 8.53 (1H, d, J = 3.1 Hz), 7.60- 7.58 (1H, m), 7.23 (2H, d, J = 7.9 Hz), 7.02 (2H, d, J = 7.9 Hz), 5.70 (2H, s), 5.40 (2H, s), 5.22-5.16 (1H, m), 4.03- 3.98 (2H, m), 3.61-3.55 (2H, m), 3.41 (2H, s), 2.22 (6H, s), 2.08-2.04 (2H, m), 1.90-1.82 (2H, m). 152 LC-MS [M + H].sup.+/Rt (min): 492.6/0.582 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.64 (1H, s), 8.53 (1H, d, J = 2.4 Hz), 7.61-7.57 (1H, m), 7.26-7.24 (2H, m), 7.04 (2H, d, J = 7.9 Hz), 5.67 (2H, s), 5.42 (2H, s), 4.19 (2H, d, J = 6.7 Hz), 4.00 (2H, dd, J = 3.1, 11.6 Hz), 3.49- 3.38 (4H, m), 2.28 (6H, s), 2.13-2.04 (2H, m), 1.79-1.76 (1H, m), 1.49-1.41 (2H, m). 153 LC-MS [M + H].sup.+/Rt (min): 433.5/0.501 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.63 (1H, br s), 8.47 (1H, d, J = 3.1 Hz), 7.59- 7.55 (1H, m), 7.21 (2H, d, J = 7.9 Hz), 7.05 (2H, d, J = 7.9 Hz), 5.55 (2H, s), 5.35 (2H, s), 4.14-4.09 (4H, m), 3.37 (2H, s), 2.35-2.20 (2H, m), 2.20 (6H, s). 154 LC-MS [M + H].sup.+/Rt (min): 449.5/0.551 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.63 (1H, br s), 8.48 (1H, d, J = 2.7 Hz), 7.59- 7.56 (1H, m), 7.22 (2H, d, J = 7.8 Hz), 7.06 (2H, d, J = 7.8 Hz), 5.45 (2H, s), 5.34 (2H, s), 4.91-4.89 (1H, m) 3.43- 3.38 (4H, m), 2.21 (6H, s), 1.60-1.53 (2H, m), 1.43-1.34 (2H, m), 0.92 (3H, t, J = 7.3 Hz). 155 LC-MS [M + H].sup.+/Rt (min): 463.5/0.653 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.64 (1H, br s), 8.47 (1H, d, J = 3.1 Hz), 7.61- 7.58 (1H, m), 7.23 (2H, d, J = 8.4 Hz), 7.09 (2H, d, J = 8.4 Hz), 5.34 (2H, s), 5.29 (2H, s), 3.62 (2H, t, J = 7.3 Hz), 3.39 (2H, s), 3.13 (3H, s), 2.22 (6H, s), 1.61-1.54 (2H, m), 1.34-1.25 (2H, m), 0.90 (3H, t, J = 7.3 Hz).

Example 156

9-{4-[(Dimethylamino)methyl]benzyl}-8-(5-fluoropyridin-3-yl)-2-methyl-9H-purine-6-amine

(89) ##STR00198##

(90) To a solution of the compound of Example 118 (30 mg) in tetrahydrofuran (0.728 mL) were added his (tri-tert-butylphosphine)palladium (7.4 mg) and methyltin chloride (2.0 mol/L a tetrahydrofuran solution, 0.182 mL), and the mixture was stirred at 60 C. for 4 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo. The residue was purified by amino silica gel column chromatography (chloroform/ethyl acetate). The obtained residue was purified by reverse-phase column chromatography (water/acetonitrile) to give the title compound (11.2 mg).

(91) LC-MS [M+H].sup.+/Rt (min): 392.4/0.411 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.65 (1H, br s), 8.53 (1H, d, J=2.7 Hz), 7.61-7.58 (1H, m), 7.22 (2H, d, J=8.2 Hz), 6.98 (2H, d, J=8.2 Hz), 5.77 (2H, s), 5.48 (2H, s), 3.38 (2H, s), 2.62 (3H, s), 2.20 (6H, s).

Example 157

(92) According to the method of Example 156, Example 157 was prepared by using the corresponding material compound.

(93) TABLE-US-00016 Example Chemical Structure Instrumental analysis data 157 LC-MS [M + H].sup.+/Rt (min): 406.4/0.466 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.66 (1H, br s), 8.54 (1H, d, J = 2.4 Hz), 7.62-7.59 (1H, m), 7.23 (2H, d, J = 8.2 Hz), 7.02 (2H, d, J = 8.2 Hz), 5.66 (2H, s), 5.49 (2H, s), 3.39 (2H, s), 2.87 (2H, q, J = 7.7 Hz), 2.22 (6H, s), 1.36 (3H, t, J = 7.7 Hz).

Example 158

9-{4-[(Dimethylamino)methyl]benzyl}-8-(5-fluoropyridin-3-yl)-2-[(1-methoxypropan-2-yl)oxy]-9H-purine-6-amine

(94) ##STR00200##

(95) To a solution of the compound of Reference example 136 (105 mg) in N-methyl-2-pyrrolidone (1.42 mL) were added 3-bromo-5-fluoropyridine (0.058 mL), copper(I) iodide (162 mg), cesium carbonate (231 mg), and palladium(II) acetate 6.4 mg), and the mixture was stirred at 160 C. under microwave irradiation for 2 hours. The reaction mixture was filtrated through Celite. The filtrate was diluted with 28% ammonia, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol), and then purified by reverse-phase column chromatography (water/acetonitrile) to give the title compound (16.4 mg).

(96) LC-MS [M+H].sup.+/Rt (min): 466.5/0.578 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.65-8.63 (1H, m), 8.52 (1H, d, J=2.4 Hz), 7.61-7.57 (1H, m), 7.23 (2H, d, J=7.9 Hz), 7.02 (2H, d, J=7.9 Hz), 5.69 (2H, br s), 5.40-5.35 (3H, m), 3.67-3.63 (1H, m), 3.50-3.46 (1H, m), 3.39-3.38 (5H, m), 2.21 (6H, s), 1.35 (3H, d, J=6.7 Hz).

Examples 159-162

(97) According to the method of Example 158, Examples 159-162 were prepared by using the corresponding material compounds. As appropriate, microwave irradiation was used.

(98) TABLE-US-00017 Example Chemical Structure Instrumental analysis data 159 01 LC-MS [M + H].sup.+/Rt (min): 458.4/0.589 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.65 (1H, br s), 8.55 (1H, d, J = 3.1 Hz), 7.62-7.59 (1H, m), 7.26-7.24 (2H, m), 7.01 (2H, d, J = 7.9 Hz), 6.12 (1H, tt, J = 4.3, 55.5 Hz), 5.72 (2H, br s), 5.42 (2H, s), 4.56 (2H, td, J = 4.5, 13.3 Hz), 3.42 (2H, s), 2.23 (6H, s). 160 02 LC-MS [M + H].sup.+/Rt (min): 448.4/0.613 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.64 (1H, br s), 8.52 (1H, d, J = 2.4 Hz), 7.60-7.57 (1H, m), 7.23 (2H, d, J = 7.9 Hz), 7.02 (2H, d, J = 7.9 Hz), 5.68 (2H, s), 5.41 (2H, s), 4.17 (2H, d, J = 7.3 Hz), 3.39 (2H, s), 2.21 (6H, s), 1.34-1.25 (1H, m), 0.61- 0.56 (2H, m), 0.37-0.33 (2H, m). 161 03 LC-MS [M + H].sup.+/Rt (min): 475.4/0.562 (Method B); .sup.1H-NMR (CDCl.sub.3) : 8.66 (1H, br s), 8.54 (1H, d, J = 2.7 Hz), 7.62-7.59 (1H, m), 7.30-7.26 (2H, m), 7.02 (2H, d, J = 8.2 Hz), 5.58 (2H, s), 5.41 (2H, s), 3.98 (3H, s), 3.70 (1H, d, J = 13.4 Hz), 3.63 (1H, d, J = 13.4 Hz), 3.24 (2H, s), 2.88 (1H, br s), 2.74-2.61 (3H, m), 2.41 (3H, s), 1.73 (2H, br s). 162 04 LC-MS [M + H].sup.+/Rt (min): 436.4/0.724 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.66 (1H, br s), 8.54 (1H, d, J = 2.7 Hz), 7.62-7.59 (1H, m), 7.30-7.26 (2H, m), 7.02 (2H, d, J = 8.2 Hz), 5.58 (2H, s), 5.41 (2H, s), 3.98 (3H, s), 3.70 (1H, d, J = 13.4 Hz), 3.63 (1H, d, J = 13.4 Hz), 3.24 (2H, s), 2.88 (1H, br s), 2.74-2.61 (3H, m), 2.41 (3H, s), 1.73 (2H, br s).

Example 163

9-{[1-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-1H-pyrazol-4-yl]methyl}-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine

(99) ##STR00205##

(100) To a solution of the compound of Example 207 (50 mg) in tetrahydrofuran (0.70 mL) were added 1-azabicyclo[2,2,2]oct-3-ylmethanol (24 mg) and (cyanomethylene)tributylphosphorane (0.056 mL), and the mixture was stirred at 80 C. for 3 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo. The obtained residue was purified by amino silica gel column chromatography (chloroform/methanol), and then purified by purified by reverse-phase silica gel column chromatography (acetonitrile/water) to give the title compound. (24 mg).

(101) LC-MS [M+H].sup.+/Rt (min): 477.1/0.467 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.78 (1H, s), 8.62 (1H, d, J=3.1 Hz), 7.79-7.76 (1H, m), 7.32 (1H, s), 7.22 (1H, s), 5.31 (2H, s), 4.51 (2H, q, J=7.1 Hz), 4.00 (2H, d, J=7.9 Hz), 2.98-2.93 (1H, m), 2.87-2.71 (7H, m), 2.38-2.33 (1H, m), 2.19-2.13 (1H, m), 1.68-1.55 (2H, m), 1.49-1.40 (6H, m).

Example 164

(102) According to the method of Example 163, Example 164 was prepared by using the corresponding material compound.

(103) TABLE-US-00018 Example Chemical Structure Instrumental analysis data 164 06 LC-MS [M + H].sup.+/Rt (min): 437.1/0.455 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.79 (1H, t, J = 1.5 Hz), 8.63 (1H, d, J = 3.1 Hz), 7.80-7.77 (1H, m), 7.45 (1H, s), 7.31 (1H, s), 5.30 (2H, s), 4.81- 4.74 (1H, m), 4.52 (2H, q, J = 7.1 Hz), 2.89-2.73 (6H, m), 2.48- 2.36 (5H, m), 2.07-1.98 (1H, m), 1.49 (3H, t, J = 7.1 Hz).

Example 165

9-[4-(1-Azabicyclo[2.2.2]oct-3-yl)benzyl]-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine

(104) ##STR00207##

(105) To a solution of the compound of Reference example 107 (299 mg) in 2-propanol (4 mL) were added 5-fluoronicotinaldehyde (159 mg) and ferric(III) chloride (549 mg) at room temperature, and the mixture was refluxed with heating. The reaction mixture was stirred for 2 hours. To the reaction mixture was added water, and the mixture was extracted with chloroform/methanol. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (231 mg).

(106) LC-MS [M+H].sup.+/Rt (min): 459.1/0.488 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.69-8.65 (1H, m), 8.57 (1H, d, J=3.1 Hz), 7.70-7.66 (1H, m), 7.18 (2H, d, J=7.9 Hz), 7.02 (2H, d, J=7.9 Hz), 5.46 (2H, s), 4.06 (3H, s), 3.33-3.24 (1H, m), 3.04-2.96 (1H, m), 2.96-2.77 (8H, m), 1.88-1.82 (1H, m), 1.75-1.67 (2H, m), 1.59-1.50 (1H, m), 1.39-1.26 (1H, m).

Examples 1.66-172

(107) According to the method of Example 165, Examples 166-172 were prepared by using the corresponding material compounds.

(108) TABLE-US-00019 Example Chemical Structure Instrumental analysis data 166 08 LC-MS [M + H].sup.+/Rt (min): 451.1/0.471 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.78-8.78 (1H, m), 8.63 (1H, d, J = 3.1 Hz), 7.80- 7.76 (1H, m), 7.33 (1H, s), 7.30 (1H, s), 5.31 (2H, s), 4.52 (2H, q, J = 7.1 Hz), 4.07- 4.00 (1H, m), 2.96-2.93 (2H, m), 2.80 (3H, s), 2.31 (3H, s), 2.17-1.85 (6H, m), 1.49 (3H, t, J = 7.1 Hz). 167 09 LC-MS [M + H].sup.+/Rt (min): 463.0/0.504 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.80 (1H, br s), 8.64 (1H, d, J = 2.4 Hz), 7.82- 7.79 (1H, m), 7.38 (1H, s), 7.36 (1H, s), 5.34 (2H, s), 4.53 (2H, q, J = 7.1 Hz), 4.29- 4.26 (1H, m), 3.51-3.46 (1H, m), 3.34-3.28 (1H, m), 3.06- 2.81 (7H, m), 2.04-2.02 (1H, m), 1.79-1.77 (6H, m), 1.41- 1.34 (1H, m). 168 0 LC-MS [M + H].sup.+/Rt (min): 365.2/0.685 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.69-8.66 (1H, m), 8.61 (1H, d, J = 2.7 Hz), 8.55-8.52 (1H, m), 8.41 (1H, d, J = 1.8 Hz), 7.73-7.68 (1H, m), 7.41-7.36 (1H, m), 7.22 (1H, dd, J = 4.8, 8.0 Hz), 5.50 (2H, s), 4.47 (2H, q, J = 7.2 Hz), 2.82 (3H, s), 1.45 (3H, t, J = 7.2 Hz). 169 .sup.1H-NMR (CDCl.sub.3) : 7.99-7.96 (1H, m), 7.87 (1H, d, J = 2.4 Hz), 7.00-6.96 (1H, m), 6.48 (2H, d, J = 7.9 Hz), 6.31 (2H, d, J = 7.9 Hz), 4.75 (2H, s), 3.77 (2H, q, J = 7.1 Hz), 2.63-2.55 (1H, m), 2.35-2.27 (1H, m), 2.26-2.08 (8H, m), 1.19-1.14 (1H, m), 1.04-0.98 (2H, m), 0.94-0.82 (1H, m), 0.74 (3H, t, J = 7.1 Hz), 0.67-0.58 (1H, m). 170 LC-MS [M + H].sup.+/Rt (min): 447.3/0.581 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.69-8.65 (1H, m), 8.56 (1H, d, J = 2.4 Hz), 7.67- 7.62 (1H, m), 7.24 (2H, d, J = 7.9 Hz), 6.99 (2H, d, J = 7.9 Hz), 5.44 (2H, s), 4.47 (2H, q, J = 7.1 Hz), 3.22-3.16 (1H, m), 2.97 (1H, dd, J = 9.2, 9.2 Hz), 2.82 (3H, s), 2.24 (1H, dd, J = 9.2, 17.6 Hz), 2.17-2.06 (4H, m), 1.98-1.82 (1H, m), 1.82- 1.71 (1H, m), 1.71-1.62 (1H, m), 1.44 (3H, t, J = 7.1 Hz). 171 .sup.1H-NMR (CDCl.sub.3) : 8.69-8.66 (1H, m), 8.60 (1H, d, J = 3.1 Hz), 8.33 (1H, d, J = 2.4 Hz), 7.74- 7.69 (1H, m), 7.32 (1H, dd, J = 7.9, 2.4 Hz), 7.10 (1H, d, J = 7.9 Hz), 5.46 (2H, s), 4.47 (2H, q, J = 7.1 Hz), 3.46-3.37 (1H, m), 3.22-3.13 (1H, m), 3.04-2.82 (4H, m), 2.81 (3H, s), 2.79-2.73 (1H, m), 2.00- 1.95 (1H, m), 1.74-1.68 (2H, m), 1.59-1.47 (1H, m), 1.45 (3H, t, J = 7.1 Hz), 1.32-1.22 (1H, m). 172 .sup.1H-NMR (CDCl.sub.3) : 8.67-8.63 (1H, m), 8.57 (1H, d, J = 2.4 Hz), 7.73-7.65 (1H, m), 6.98-6.85 (3H, m), 5.49 (2H, s), 4.45 (2H, q, J = 7.1 Hz), 3.32-3.23 (1H, m), 2.99-2.79 (6H, m), 2.81 (3H, s), 1.91-1.82 (1H, m), 1.73-1.66 (2H, m), 1.60- 1.48 (1H, m), 1.43 (3H, t, J = 7.1 Hz), 1.39-1.27 (1H, m).

Examples 173, 174

9-{4-[(5S)-1,4-Diazabicyclo[3.2.1]oct-4-ylmethyl]benzyl}-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine; 9-{4-[(5R)-1,4-diazabicyclo[3.2.1]oct-4-ylmethyl]benzyl}-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine

(109) ##STR00215##

(110) The compound of Example 119 (180 mg) was optically separated in the following conditions to obtain the title compounds (Example 173: 75.4 mg-first peak: 33.0 min, Example 174: 70.2 mg-second peak: 43.1 min).

(111) Column: CHIRALPAK AD-H; Solvent: Solution A: hexane, Solution B: ethanol/2-propanol/diethylamine=2/1/0.3%; Mobile phase condition: A/B=70/30; Flow rate: 10 mL/min; Detection UV: 220 nm; Column temperature: 40 C.

(112) TABLE-US-00020 Example Instrumental analysis data 173 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.70-8.67 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 7.71-7.64 (1H, m), 7.25 (3H, d, J = 7.9 Hz), 7.01 (2H, d, J = 7.9 Hz), 5.47 (2H, s), 4.49 (2H, q, J = 7.1 Hz), 3.36 (2H, dd, J = 13.4, 19.5 Hz), 3.15-3.10 (1H, m), 3.06-2.94 (2H, m), 2.84 (3H, s), 2.83-2.74 (1H, m), 2.64 (1H, dd, J = 4.0, 13.4 Hz), 2.58-2.51 (1H, m), 2.48 (1H, dd, J = 4.6, 11.9 Hz), 2.32-2.23 (1H, m), 2.05-1.95 (1H, m), 1.47 (3H, t, J = 7.1 Hz). 174 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.70-8.67 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 7.71-7.64 (1H, m), 7.25 (3H, d, J = 7.9 Hz), 7.01 (2H, d, J = 7.9 Hz), 5.47 (2H, s), 4.49 (2H, q, J = 7.1 Hz), 3.36 (2H, dd, J = 13.4, 19.5 Hz), 3.15-3.10 (1H, m), 3.06-2.94 (2H, m), 2.84 (3H, s), 2.83-2.74 (1H, m), 2.64 (1H, dd, J = 4.0, 13.4 Hz), 2.58-2.51 (1H, m), 2.48 (1H, dd, J = 4.6, 11.9 Hz), 2.32-2.23 (1H, m), 2.05-1.95 (1H, m), 1.47 (3H, t, J = 7.1 Hz).

Examples 175, 176

9-{4-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]benzyl}-2-ethoxy-8-(5-fluoropyridin-3-yl)-9H-purine-6-amine; 9-{4-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]benzyl}-2-ethoxy-8-(5-fluoropyridin-3-yl)-9H-purine-6-amine

(113) ##STR00216##

(114) The compound of Example 46 (13.0 mg) was optically separated in the following conditions to obtain the title compounds (Example 175: 6.1 mg-first peak: 61.4 min, Example 176: 6.1 mg-second peak: 78.8 min).

(115) Column: CHIRALPAK AS-H; Solvent: Solution A: hexane, Solution B: ethanol/2-propanol/diethylamine=2/1/0.3%; Mobile phase condition: A/B=93/7; Flow rate: 10 mL/min; Detection UV: 220 nm; Column temperature: 40 C.

(116) TABLE-US-00021 Example Instrumental analysis data 175 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.63-8.65 (1H, m), 8.56 (1H, d, J = 3.1 Hz), 7.67-7.60 (1H, m), 7.21 (2H, d, J = 7.9 Hz), 7.08 (2H, d, J = 7.9 Hz), 5.64 (2H, s), 5.43 (2H, s), 4.42 (2H, q, J = 7.0 Hz), 3.40-3.31 (1H, m), 3.13-3.05 (1H, m), 3.05-2.84 (5H, m), 1.95-1.91 (1H, m), 1.81-1.75 (2H, m), 1.69-1.58 (1H, m), 1.43 (3H, t, J = 7.0 Hz), 1.41-1.35 (1H, m). 176 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.68-8.65 (1H, m), 8.56 (1H, d, J = 3.1 Hz), 7.67-7.60 (1H, m), 7.21 (2H, d, J = 7.9 Hz), 7.08 (2H, d, J = 7.9 Hz), 5.64 (2H, s), 5.43 (2H, s), 4.42 (2H, q, J = 7.0 Hz), 3.40-3.31 (1H, m), 3.13-3.05 (1H, m), 3.05-2.84 (5H, m), 1.95-1.91 (1H, m), 1.81-1.75 (2H, m), 1.69-1.58 (1H, m), 1.43 (3H, t, J = 7.0 Hz), 1.41-1.35 (1H, m).

Examples 177 and 178

9-{4-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]benzyl}-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine; 9-{4-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]benzyl}-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine

(117) ##STR00217##

(118) The compound of Example 165 (30.0 mg) was optically separated in the following conditions to obtain the title compounds (Example 177: 8.6 mg-first peak: 24.1 min, Example 178: 6.6 mg-second peak: 34.5 min).

(119) Column: CHIRALPAK AS-H; Solvent: Solution A: hexane, Solution B: ethanol/2-propanol/diethylamine/methanol=2/1/0.3/2%; Mobile phase condition: A/B=93/7; Flow rate: 10 mL/min; Detection UV: 220 nm; Column temperature: 40 C.

(120) TABLE-US-00022 Example Instrumental analysis data 177 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.69-9.65 (1H, m), 8.57 (1H, d, J = 3.1 Hz), 7.70-7.66 (1H, m), 7.18 (2H, d, J = 7.9 Hz), 7.02 (2H, d, J = 7.9 Hz), 5.46 (2H, s), 4.06 (3H, s), 3.33-3.24 (1H, m), 3.04-2.96 (1H, m), 2.96-2.77 (8H, m), 1.88-1.82 (1H, m), 1.75-1.67 (2H, m), 1.59-1.50 (1H, m), 1.39-1.26 (1H, m). 178 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.69-9.65 (1H, m), 8.57 (1H, d, J = 3.1 Hz), 7.70-7.66 (1H, m), 7.18 (2H, d, J = 7.9 Hz), 7.02 (2H, d, J = 7.9 Hz), 5.46 (2H, s), 4.06 (3H, s), 3.33-3.24 (1H, m), 3.04-2.96 (1H, m), 2.96-2.77 (8H, m), 1.88-1.82 (1H, m), 1.75-1.67 (2H, m), 1.59-1.50 (1H, m), 1.39-1.26 (1H, m).

Examples 179-199

(121) According to the method of Example 1, Examples 179-199 were prepared by using the corresponding material compounds. As appropriate, microwave irradiation was used.

(122) TABLE-US-00023 Example Chemical Structure Instrumental analysis data 179 LC-MS [M + H].sup.+/Rt (min): 417.3/1.105 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 7.48- 7.44 (2H, m), 7.31-7.20 (5H, s), 7.02 (2H, d, J = 6.7 Hz), 5.36 (2H, s), 4.17 (2H, t, J = 6.7 Hz), 2.93 (6H, s), 1.61 (2H, tt, J = 6.7, 7.9 Hz), 1.36 (2H, qt, J = 7.3, 7.9 Hz), 0.88 (3H, t, J = 7.3 Hz). 181 LC-MS: [M + H].sup.+/Rt (min): 428.2/0.621 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.68- 8.66 (2H, m), 8.52-8.50 (2H, m), 7.99-7.95 (1H, m), 7.59 (2H, brs), 7.37 (2H, d J = 6.1 Hz), 7.22-7.18 (3H, m), 6.93- 6.90 (2H, m), 5.46 (2H, s), 5.40 (2H, s). 181 0 LC-MS: [M + H].sup.+/Rt (min): 512.3/0.486 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.10- 9.08 (2H, m), 8.54-8.53 (1H, m), 7.58 (2H, brs), 7.17 (2H, d, J = 7.9 Hz), 6.98 (2H, d, J = 7.9 Hz), 5.50 (2H, s), 4.35 (2H, t, J = 4.8 Hz), 3.61 (2H, t, J = 4.8 Hz), 3.28 (3H, s), 3.26 (2H, s), 2.06 (6H, s). 182 LC-MS [M + H].sup.+/Rt (min): 423.5/0.844 (Method A) 183 LC-MS [M + H].sup.+/Rt (min): 453.1/0.778 (Method A) 184 LC-MS [M + H].sup.+/Rt (min): 409.4/0.813 (Method A) 185 LC-MS [M + H].sup.+/Rt (min): 422.4/0.721 (Method A) 186 LC-MS [M + H].sup.+/Rt (min): 423.3/0.714 (Method A) 187 LC-MS [M + H].sup.+/Rt (min): 393.3/0.775 (Method A) 188 .sup.1H-NMR (CDCl.sub.3) : 8.63-8.58 (2H, m), 7.98 (2H, d, J = 8.2 Hz), 7.62-7.59 (1H, m), 7.11 (2H, d, J = 8.2 Hz), 5.91 (2H, br s), 5.54 (2H, s), 3.90 (3H, s). 189 .sup.1H-NMR (CDCl.sub.3) : 8.65-8.60 (2H, m), 8.21 (1H, d, J = 2.7 Hz), 7.70-7.63 (1H, m), 7.43 (1H, dd, J = 2.7, 8.2 Hz), 7.27-7.25 (1H, m), 5.64 (2H, br s), 5.42 (2H, s), 4.39 (2H, q, J = 7.2 Hz), 1.42 (3H, t, J = 7.2 Hz). 190 .sup.1H-NMR (DMSO-D.sub.6) : 8.81-8.80 (1H, m), 8.66 (1H, d, J = 3.1 Hz), 8.46 (1H, d, J = 3.1 Hz), 8.18-8.15 (1H, m), 7.80 (1H, dd, J = 2.4, 8.5 Hz), 7.50- 7.44 (3H, m), 5.55 (2H, s), 4.23 (2H, q, J = 7.1 Hz), 3.42 (3H, s), 1.24 (3H, t, J = 7.1 Hz). 191 0 LC-MS [M + H].sup.+/Rt (min): 400.3/0.664 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.59-8.55 (2H, m), 8.35 (1H, d, J = 5.2 Hz), 7.69-7.64 (1H, m), 7.06 (1H, s), 6.94 (1H, dd, J = 5.2, 1.5 Hz), 5.71 (2H, s), 5.41 (2H, S), 4.37 (2H, q, J = 7.1 Hz), 1.40 (3H, t, J = 7.1 Hz). 192 LC-MS [M + H].sup.+/Rt (min): 400.4/0.664 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.81 (1H, s), 8.59-8.55 (1H, m), 8.04- 7.98 (1H, m), 7.62 (1H, dd, J = 7.6, 7.9 Hz), 7.29-7.26 (1H, m), 7.15 (1H, d, J = 7.9 Hz), 5.61 (2H, s), 5.45 (2H, s), 4.36 (2H, q, J = 6.9 Hz), 1.39 (3H, t, J = 6.9 Hz) 193 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.90-8.86 (1H, m), 8.57 (1H, d, J = 3.1 Hz), 8.46 (1H, d, J = 5.5 Hz), 8.08-8.04 (1H, m), 7.39 (1H, d, J = 1.2 Hz), 7.25-7.23 (1H, m), 5.60 (2H, s), 5.46 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 1.41 (3H, t, J = 7.1 Hz). 194 LC-MS [M + H].sup.+/Rt (min): 548.5/1.105 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.65-8.63 (1H, m), 8.54 (1H, d, J = 2.7 Hz), 7.62 (1H, ddd, J = 2.0, 2.7, 9.2 Hz), 7.12 (2H, d, J = 8.2 Hz), 7.02 (2H, d, J = 8.2 Hz), 5.63 (2H, s), 5.39 (2H, s), 4.40 (2H, q, J = 7.1 Hz), 4.30-4.13 (2H, m), 2.83-2.72 (2H, m), 2.66-2.54 (1H, m), 1.82-1.72 (2H, m), 1.61-1.49 (2H, m), 1.47 (9H, s), 1.41 (3H, t, J = 7.1 Hz). 195 LC-MS [M + H].sup.+/Rt (min): 534.5/0.997 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.66-8.61 (1H, m), 8.56 (1H, d, J = 2.4 Hz), 7.68-7.59 (1H, m), 7.17 (2H, d, J = 7.9 Hz), 7.04 (2H, d, J = 7.9 Hz), 6.06 (2H, br s), 5.41 (2H, s), 4.42 (3H, q, J = 7.1 Hz), 3.85-3.69 (1H, m), 3.66-3.46 (1H, m), 3.44- 3.19 (2H, m), 2.26-2.19 (1H, m), 1.98-1.87 (2H, m), 1.47 (9H, s), 1.42 (3H, t, J = 7.1 Hz). 196 LC-MS [M + H].sup.+/Rt (min): 506.5/0.942 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.63 (1H, s), 8.56-8.51 (1H, m), 7.62 (1H, d, J = 9.2 Hz), 7.17 (1H, dd, J = 23.8, 7.9 Hz), 7.02- 6.88 (2H, m), 5.71 (2H, s), 5.42 (2H, s), 4.67-4.53 (4H, m), 4.39 (2H, q, J = 7.0 Hz), 1.49 (9H, s), 1.40 (3H, t, J = 7.0 Hz). 197 LC-MS [M + H].sup.+/Rt (min): 428.4/0.709 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.78-8.72 (1H, m), 8.63 (1H, d, J = 1.8 Hz), 7.84-7.75 (1H, m), 6.60 (1H, s), 5.64 (2H, s), 5.54 (2H, s), 4.49-4.31 (4H, m), 1.46-1.33 (6H, m). 198 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.70-8.66 (1H, m), 8.66-8.62 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 8.48 (1H, d, J = 2.4 Hz), 7.70 (1H, ddd, J = 2.0, 2.4, 4.8 Hz), 7.59-7.53 (1H, m), 7.53 (2H, d, J = 7.9 Hz), 7.24 (2H, d, J = 7.9 Hz), 5.65 (2H, s), 5.51 (2H, s), 4.43 (2H, q, J = 7.3 Hz), 1.43 (3H, t, J = 7.3 Hz). 199 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.66-8.62 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 7.68-7.62 (1H, m), 7.24 (2H, d, J = 9.2 Hz), 7.18 (2H, d, J = 9.2 Hz), 5.62 (2H, s), 5.45 (2H, s), 4.41 (2H, q, J = 7.1 Hz), 3.14 (3H, s), 1.43 (3H, t, J = 7.0 Hz).

Reference Examples 200-207

(123) According to the method of Example 165, Examples 200-207 were prepared by using the corresponding material compounds.

(124) TABLE-US-00024 Example Chemical Structure Instrumental analysis data 200 LC-MS [M + H].sup.+/Rt (min): 533.5/1.12 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.69-8.66 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 7.73-7.67 (1H, m), 7.15 (2H, d, J = 7.9 Hz), 7.01 (2H, d, J = 7.9 Hz), 5.45 (2H, s), 4.47 (2H, q, J = 7.1 Hz), 3.82- 3.70 (1H, m), 3.64-3.48 (1H, m), 3.43-3.16 (3H, m), 2.82 (3H, s), 2.26-2.17 (1H, m), 1.97-1.85 (1H, m), 1.50-1.41 (12H, m). 201 0 LC-MS [M + H].sup.+/Rt (min): 519.4/1.048 (Method D); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.69-8.66 (1H, m), 8.60-8.56 (1H, m), 7.80-7.73 (1H, m), 7.15 (2H, d, J = 7.9 Hz), 7.02 (2H, d, J = 7.9 Hz), 5.46 (2H, s), 4.06 (3H, s), 3.85-3.70 (1H, m), 3.64-3.48 (1H, m), 3.42-3.17 (3H, m), 2.84 (3H, s), 2.26- 2.17 (1H, m), 1.97-1.85 (1H, m), 1.46 (9H, s). 202 LC-MS [M + H].sup.+/Rt (min): 423.3/0.892 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 9.12 (1H, d, J = 1.8 Hz), 8.88-8.85 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 8.27 (1H, dd, J = 2.4, 8.5 Hz), 8.08-8.03 (1H, m), 7.37 (1H, d, J = 8.5 Hz), 5.59 (2H, s), 4.42 (2H, q, J = 7.1 Hz), 3.94 (3H, s), 2.82 (3H, s), 1.42 (3H, t, J = 7.1 Hz). 203 .sup.1H-NMR (CDCl.sub.3) : 8.68-8.64 (2H, m), 8.02 (1H, d, J = 2.4 Hz), 7.75-7.72 (1H, m), 7.58-7.53 (1H, m), 6.87 (1H, dd, J = 8.5, 3.1 Hz), 5.48 (2H, s), 4.48 (2H, q, J = 6.9 Hz), 2.82 (3H, s), 1.46 (3H, q, J = 6.9 Hz). 204 .sup.1H-NMR (CDCl.sub.3) : 8.69 (1H, br s), 8.65 (1H, d, J = 2.4 Hz), 8.02-8.01 (1H, m), 7.75-7.73 (1H, m), 7.59-7.55 (1H, m), 6.89-6.86 (1H, m), 5.49 (2H, s), 4.08 (3H, s), 2.83 (3H, s). 205 .sup.1H-NMR (CDCl.sub.3) : 8.68 (1H, br s), 8.64 (1H, d, J = 3.1 Hz), 8.02-8.01 (1H, m), 7.75-7.71 (1H, m), 7.58-7.53 (1H, m), 6.87 (1H, dd, J = 3.1, 8.5 Hz), 5.49 (2H, s), 4.37 (2H, t, J = 6.7 Hz), 2.82 (3H, s), 1.92- 1.83 (2H, m), 1.07 (3H, t, J = 7.3 Hz). 206 LC-MS [M + H].sup.+/Rt (min): 393.0/0.769 (Method C) 207 LC-MS [M + H].sup.+/Rt (min): 354.0/0.561 (Method C)

Example 208

4-{[6-Amino-2-ethoxy-8-(5-fluoropyridin-3-yl)-9H-purin-9-yl]methyl}phenol

(125) ##STR00247##

(126) To an ice-cooled solution of the compound of Example 199 (53.9 mg) in acetonitrile (4 mL) was added potassium trimethylsilanolate (272 mg). The reaction mixture was warmed to room temperature, and then stirred for 24 hours. To the reaction mixture were added acetic acid (0.121 mL) and water, and the mixture was extracted with chloroform/methanol. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (36.2 mg).

(127) LC-MS [M+H].sup.+/Rt (min): 381.36/0.608 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.68-8.64 (1H, m), 8.56 (1H, d, J=3.1 Hz), 7.71-7.66 (1H, m), 6.94 (2H, d, J=8.5 Hz), 6.71 (2H, d, J=8.5 Hz), 5.68 (2H, s), 5.36 (2H, s), 4.42 (2H, q, J=7.1 Hz), 1.42 (4H, t, J=7.1 Hz).

Example 209

(128) According to the method of Example 208, Example 209 was prepared by using, the corresponding material compound.

(129) TABLE-US-00025 Example Chemical Structure Instrumental analysis data 209 LC-MS [M + H].sup.+/Rt (min): 382.3/0.690 (Method C)

Examples 210-215

(130) According to the method of Example 77, Examples 210-215 were prepared by using the corresponding material compounds.

(131) TABLE-US-00026 Example Chemical Structure Instrumental analysis data 210 LC-MS [M + H].sup.+/Rt (min): 425.1/0.640 (Method A) 211 0 LC-MS [M + H].sup.+/Rt (min): 394.4/0.602 (Methog A) 212 .sup.1H-NMR (DMSO-D.sub.6) : 8.71-8.70 (2H, m), 8.03-7.99 (3H, m), 7.20 (2H, d, J = 7.9 Hz), 6.92 (2H, d, J = 7.9 Hz), 5.49 (2H, s), 5.13 (1H, t, J = 5.5 Hz), 4.41 (2H, d, J = 6.1 Hz). 213 .sup.1H-NMR (DMSO-D.sub.6) : 8.23 (1H, s), 7.76 (2H, s), 7.28-7.22 (4H, m), 5.29 (2H, s), 5.14 (1H, t, J = 5.7 Hz), 4.44 (2H, d, J = 5.5 Hz). 214 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.74- 8.71 (1H, m), 8.59 (1H, d, J = 2.4 Hz), 7.82-7.77 (1H, m), 6.27 (1H, s), 5.90 (2H, s), 5.46 (2H, s), 4.69 (2H, s), 4.37 (2H, q, J = 7.1 Hz), 1.39 (3H, t, J = 7.1 Hz). 215 LC-MS [M + H].sup.+/Rt (min): 395.3/0.715 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.90-8.86 (1H, m), 8.56 (1H, d, J = 1.8 Hz), 8.51-8.47 (1H, m), 8.13- 8.05 (1H, m), 7.69 (1H, d, J = 7.9 Hz), 7.30-7.26 (1H, m), 5.53 (2H, s), 4.71 (2H, s), 4.42 (2H, q, J = 7.0 Hz), 2.81 (3H, s), 1.42 (3H, t, J = 7.0 Hz).

Example 216

4-{[2-Ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purin-9-yl]methyl}benzaldehyde

(132) ##STR00255##

(133) To a solution of the compound of Example 78 (826 mg) in tetrahydrofuran (30 mL) was added manganese dioxide (3.22 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was filtrated through Celite, and the filtrate was concentrated in vacuo. The residue was tied by silica gel column chromatography (chloroform/methanol) give the title compound (719 mg).

(134) LC-MS ([M+H].sup.+/Rt (m 392.4/0.858 (Method A)

Examples 217-223

(135) According to the method of Example 216, Examples 217-223 were prepared by using the corresponding material compounds.

(136) TABLE-US-00027 Example Chemical Structure Instrumental analysis data 217 LC-MS: [M + H].sup.+/Rt (min): 392.4/0.666 (Method A) 218 LC-MS [M + H].sup.+/Rt (min): 423.3/0.714 (Method A) 219 LC-MS [M + H].sup.+/Rt (min): 378.6/0.774 (Method A) 220 LC-MS [M + H].sup.+/Rt (min): 383.3/0.672 (Method C) 221 0 .sup.1H-NMR (DMSO-D.sub.6) : 9.97 (1H, s), 8.28 (1H, s), 7.89-7.82 (4H, m), 7.43 (2H, d, J = 7.9 Hz), 5.45 (2H, s). 222 LC-MS: [M + H].sup.+/Rt (min): 386.4/0.479 (Method C) 223 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 10.08 (1H, s), 8.98 (1H, d, J = 1.8 Hz), 8.87-8.85 (1H, m), 8.58 (1H, d, J = 3.1 Hz), 8.16 (1H, dd, J = 7.9, 2.4 Hz), 8.07-8.01 (1H, m), 7.47 (1H, d, J = 7.9 Hz), 5.61 (2H, s), 4.41 (3H, q, J = 7.1 Hz), 2.82 (3H, s), 1.41 (3H, t, J = 7.1 Hz).

Examples 224-226

(137) According to the method of Example 80, Examples 224-226 were prepared by using the corresponding material compounds.

(138) TABLE-US-00028 Example Chemical Structure Instrumental analysis data 224 LC-MS [M + H].sup.+/Rt (min): 575.6/0.681 (Method A) 225 LC-MS [M + H].sup.+/Rt (min): 574.5/0.731 (Method A) 226 LC-MS [M + H].sup.+/Rt (min): 560.4/0.703 (Method A)

Example 227

2-Ethoxy-8-(5-fluoropyridin-3-yl)-9-[4-(piperidin-4-yl)benzyl]-9H-purine-6-amine trifluoroacetate

(139) ##STR00266##

(140) To an ice-cooled solution of the compound of Example 194 (219 mg) in chloroform (3 mL) was added trifluoroacetic acid (0.308 mL). The reaction mixture was warmed to room temperature, and stirred for 18 hours. The reaction mixture was concentrated to give the title compound (240 mg).

(141) .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.69-8.58 (2H, m), 7.70 (1H, d, J=7.9 Hz), 7.21 (2H, d, J=7.9 Hz), 7.04 (2H, d, J=7.9 Hz), 5.44 (2H, s), 4.58 (2H, q, J=7.3 Hz), 3.64-3.47 (2H, m), 3.11-2.95 (2H, m), 2.84-2.71 (1H, m), 2.16-1.86 (4H, m), 1.47 (3H, q, J=7.3 Hz).

Examples 228-231

(142) According to the methods of Example 123 and Example 227, Examples 228-231 were prepared using the corresponding material compounds.

(143) TABLE-US-00029 Example Chemical Structure Instrumental analysis data 228 .sup.1H-NMR (CDCl.sub.3) : 8.65 (1H, s), 8.53 (1H, d, J = 2.4 Hz), 7.62- 7.60 (1H, m), 7.27-7.26 (2H, m), 7.02 (2H, d, J = 8.8 Hz), 5.61 (2H, s), 5.41 (2H, s), 3.98 (3H, s), 3.71-3.62 (2H, m), 3.54 (1H, s), 3.31 (1H, s), 3.19-3.16 (1H, m), 2.87-2.80 (2H, m), 2.41 (1H, d, J = 9.2 Hz), 1.80 (1H, d, J = 9.2 Hz), 1.57-1.55 (2H, m). 229 LC-MS [M + H].sup.+/Rt (min): 406.4/0.346 (Method C); .sup.1H-NMR (CD.sub.3OD) : 8.64-8.61 (1H, m), 8.59 (1H, d, J = 2.4 Hz), 7.95- 7.90 (1H, m), 7.36 (1H, d, J = 7.9 Hz), 7.17-7.11 (2H, m), 5.59 (2H, s), 4.56 (2H, s), 4.52 (2H, s), 4.47 (2H, q, J = 7.0 Hz), 1.40 (3H, t, J = 7.0 Hz). 230 LC-MS [M + H].sup.+/Rt (min): 433.4/0.601 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.69-8.66 (1H, m), 8.57 (1H, d, J = 1.2 Hz), 7.71- 7.66 (1H, m), 7.15 (2H, d, J = 7.3 Hz), 6.99 (2H, d, J = 7.3 Hz), 5.44 (2H, s), 4.47 (2H, q, J = 7.1 Hz), 3.37-3.29 (1H, m), 3.23-3.03 (3H, m), 2.86-2.75 (4H, m), 2.26-2.16 (1H, m), 1.84-1.73 (1H, m), 1.45 (3H, t, J = 7.1 Hz), 1.24 (1H, s). 231 0 LC-MS [M + H].sup.+/Rt (min): 419.3/0.586 (Method D); .sup.1H-NMR (CDCl.sub.3) : 8.69-8.65 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 7.72- 7.67 (1H, m), 7.15 (2H, d, J = 7.9 Hz), 6.99 (2H, d, J = 7.9 Hz), 5.45 (2H, s), 4.06 (3H, s), 3.32 (1H, dd, J = 10.7, 7.6 Hz), 3.21-3.02 (3H, m), 2.82 (3H, s), 2.78 (1H, dd, J = 10.7, 8.2 Hz), 2.24-2.15 (1H, m), 1.82-1.72 (1H, m).

Example 232

4-{[6-Amino-8-(5-fluoropyridin-3-yl)-9H-purin-9-yl]methyl}benzyl methanesulfonate

(144) ##STR00271##

(145) To an ice-cooled suspension of the compound of Example 77 (400 mg) in tetrahydrofuran (3.4 mL) were added triethylamine (0.424 mL) and methanesulfonyl chloride (0.118 mL), and the mixture was stirred in ice bath for 2 hours. To the reaction mixture was added water, and the mixture was extracted with chloroform/methanol. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo to give the title compound (465 mg).

(146) .sup.1H-NMR (CDCl.sub.3) : 8.62-8.61 (1H, m), 8.54 (1H, d, J=2.4 Hz), 7.64-7.61 (1H, m), 7.36 (2H, d, J=8.5 Hz), 7.13 (2H, d, J=8.5 Hz), 5.62 (2H, s), 5.45 (2H, s), 5.20 (2H, s), 4.39 (2H, q, J=7.1 Hz), 2.92 (3H, s), 1.40 (3H, t, J=7.1 Hz).

Examples 233-234

(147) According to the method of Example 141, Examples 233-234 were prepared by using the corresponding material compounds.

(148) TABLE-US-00030 Example Chemical Structure Instrumental analysis data 233 LC-MS [M + H].sup.+/Rt (min): 422.4/0.930 (Method A) 234 LC-MS [M + H].sup.+/Rt (min): 408.3/0.890 (Method A)

Example 235

4-{[6-Amino-2-ethoxy-8-(5-fluoropyridin-3-yl)-9H-purin-9-yl]methyl}benzoic acid

(149) ##STR00274##

(150) To a solution of the compound of Example 182 (302 mg) in a mixture of tetrahydrofuran (5 mL) and methanol (9 mL) was added 1 mol/L aqueous sodium hydroxide (4 mL), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo. To the residue was added 1 mol/L hydrochloric acid under ice temperature. The precipitated solid was collected on a filter, washed with water and methyl tert-butyl ether, and then dried in vacuo to give the title compound (244 mg).

(151) LC-MS ([M+H].sup.+/Rt (min)): 409.3/0.679 (Method A)

Example 236

(152) According to the method of Example 158, Example 236 was prepared by using the corresponding material compound. As appropriate, microwave irradiation was used.

(153) TABLE-US-00031 Example Chemical Structure Instrumental analysis data 236 LC-MS [M + H].sup.+/Rt (min): 561.5/0.668 (Method B)

Example 237-241

(154) According to the method of Example 1, Examples 237-241 were prepared by using the corresponding material compounds. As appropriate, some reactions were carried out under reflux or under microwave irradiation.

(155) TABLE-US-00032 Example Chemical Structure Instrumental analysis data 237 LC-MS [M + H].sup.+/Rt (min): 389.97/0.706 (method C); .sup.1H-NMR (CDCl.sub.3) : 8.61- 8.58 (2H, m), 7.68-7.64 (1H, m), 7.60 (1H, d, J = 7.9 Hz), 7.49-7.40 (2H, m), 7.34 (1H, d, J = 7.9 Hz), 5.72 (2H, s), 5.47 (2H, s), 4.40 (2H, q, J = 7.1 Hz), 1.42 (3H, t, J = 7.1 Hz). 238 .sup.1H-NMR (CDCl.sub.3) : 8.72-8.47 (2H, m), 7.63 (1H, d, J = 8.5 Hz), 7.35-7.29 (1H, m), 7.17-7.08 (2H, m), 6.92 (1H, d, J = 7.3 Hz), 6.54 (1H, t, J = 73.4 Hz), 5.76 (2H, s), 5.51 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 1.41 (3H, t, J = 7.1 Hz). 239 LC-MS [M + H].sup.+/Rt (min): 390.0/0.709 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.55 (1H, d, J = 3.1 Hz), 8.53-8.50 (1H, m), 7.69 (1H, dd, J = 7.9, 1.2 Hz), 7.65-7.60 (1H, m), 7.53-7.48 (1H, m), 7.40 (1H, dd, J = 7.3, 7.3 Hz), 6.99 (1H, d, J = 7.3 Hz), 5.66 (2H, s), 5.63 (2H, s), 4.33 (2H, q, J = 7.1 Hz), 1.36 (3H, t, J = 7.1 Hz). 240 LC-MS [M + H].sup.+/Rt (min): 401.0/0.789 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.62- 8.59 (1H, m), 8.56 (1H, d, J = 3.1 Hz), 7.68-7.61 (1H, m), 7.06-6.98 (1H, m), 6.98-6.90 (1H, m), 6.75- 6.67 (1H, m), 5.65 (2H, s), 5.43 (2H, s), 4.38 (2H, q, J = 7.1 Hz), 1.40 (3H, t, J = 7.3 Hz). 241 0 .sup.1H-NMR (DMSO-D.sub.6) : 8.74-8.71 (2H, m), 8.10-8.05 (1H, m), 7.86-7.81 (1H, m), 7.69 (1H, dd, J = 6.9, 2.3 Hz), 7.39 (1H, dd, J = 10.1, 8.7 Hz), 5.49 (2H, s), 4.25 (2H, q, J = 7.0 Hz), 1.26 (3H, t, J = 7.0 Hz).

Example 242

2-Ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9-[(1-methyl-1H-pyrazol-4-yl)methyl]-9H-purine

(156) ##STR00281##

(157) To a solution of the compound of Example 207 (120 mg) in N,N-dimethylformamide (6 mL) were added methyl iodide (72.1 mg) and potassium carbonate (93.7 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was extracted with chloroform/methanol. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (51.8 mg).

(158) LC-MS [M+H].sup.+/Rt (min): 468.2/0.695 (Method A); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.84-8.82 (1H, m), 8.67 (1H, d, J=2.5 Hz), 7.86-7.82 (1H, m), 7.36 (1H, brs), 7.28-7.27 (1H, m), 5.34 (2H, s), 4.55 (2H, q, J=7.0 Hz), 3.85 (3H, s), 2.83 (3H, s), 1.52 (3H, t, J=7.0 Hz).

Examples 243-257

(159) According to the method of Example 242, Examples 243-257 were prepared by using the corresponding material compounds.

(160) TABLE-US-00033 Example Chemical Structure Instrumental analysis data 243 LC-MS [M + H].sup.+/Rt (min): 354.3/0.630 (Method A); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.84-8.82 (1H, m), 8.67 (1H, d, J = 3.0 Hz), 7.86-7.82 (1H, m), 7.36 (1H, brs), 7.30 (1H, brs), 5.34 (2H, s), 4.13 (3H, s), 3.85 (3H, s), 2.84 (3H, s). 244 LC-MS [M + H].sup.+/Rt (min): 425.3/0.528 (Method A); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.84-8.81 (1H, m), 8.66 (1H, d, J = 2.8 Hz), 7.86-7.79 (1H, m), 7.50 (2H, s), 5.38 (2H, s), 4.54 (2H, q, J = 7.2 Hz), 4.15 (2H, t, J = 6.4 Hz), 2.83 (3H, s), 2.70 (2H, t, J = 6.4 Hz), 2.25 (6H, s), 1.52 (3H, t, J = 7.2 Hz). 245 LC-MS [M + H].sup.+/Rt (min): 439.3/0.549 (Method A); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.84-8.81 (1H, m), 8.66 (1H, d, J = 3.0 Hz), 7.86-7.79 (1H, m), 7.37 (1H, s), 7.32 (1H, s), 5.34 (2H, s) 4.54 (2H, q, J = 7.0 Hz), 4.11 (2H, t, J = 7.0 Hz), 2.82 (3H, s), 2.22-2.13 (8H, m), 1.99-1.94 (2H, m), 1.51 (3H, t, J = 7.0 Hz). 246 LC-MS [M + H].sup.+/Rt (min): 451.3/0.540 (Method A); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.84-8.81 (1H, m), 8.66 (1H, d, J = 2.8 Hz), 7.86-7.79 (1H, m), 7.41-7.35 (2H, m), 5.34 (2H, s), 4.54 (2H, q, J = 7.2 Hz), 4.21 (2H, t, J = 6.8 Hz), 2.94-2.86 (2H, m), 2.83 (3H, s), 2.56-2.47 (4H, m), 1.52 (3H, t, J = 7.2 Hz). 247 LC-MS [M + H].sup.+/Rt (min): 465.3/0.563 (Method A); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.84-8.81 (1H, m), 8.66 (1H, d, J = 2.5 Hz), 7.86-7.81 (1H, m), 7.37 (1H, s), 7.32 (1H, s), 5.34 (2H, s) 4.54 (2H, q, J = 7.0 Hz), 4.13 (2H, t, J = 7.0 Hz), 2.83 (3H, s), 2.49-2.41 (4H, m), 2.37 (2H, t, J = 7.0 Hz), 2.05-1.96 (2H, m), 1.74-1.82 (4H, m), 1.51 (3H, t, J = 7.5 Hz). 248 LC-MS [M + H].sup.+/Rt (min): 467.3/0.525 (Method A); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.84-8.81 (1H, m), 8.66 (1H, d, J = 3.0 Hz), 7.86-7.81 (1H, m), 7.39 (1H, s), 7.37 (1H, s), 5.34 (2H, s), 4.54 (2H, q, J = 7.0 Hz), 4.16 (2H, t, J = 6.5 Hz), 3.68-3.60 (4H, m), 2.83 (3H, s), 2.74 (2H, t, J = 6.5 Hz), 2.47-2.40 (4H, m), 1.51 (3H, t, J = 7.0 Hz). 249 LC-MS [M + H].sup.+/Rt (min): 481.3/0.547 (Method A); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.84-8.81 (1H, m), 8.66 (1H, d, J = 2.5 Hz), 7.86-7.79 (1H, m), 7.37 (1H, s), 7.30 (1H, s), 5.34 (2H, s) 4.54 (2H, q, J = 7.0 Hz), 4.12 (2H, t, J = 7.0 Hz), 3.67 (4H, t, J = 5.0 Hz), 2.83 (3H, s), 2.40- 2.32 (4H, m), 2.24 (2H, t, J = 7.0 Hz), 2.03-1.92 (2H, m), 1.51 (3H, t, J = 7.0 Hz). 250 LC-MS [M + H].sup.+/Rt (min): 411.3/0.455 (Method A); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.84-8.81 (1H, m), 8.66 (1H, d, J = 2.0 Hz), 7.86-7.79 (1H, m), 7.40 (1H, s), 7.37 (1H, s), 5.34 (2H, s), 4.18-4.08 (5H, m), 2.83 (3H, s), 2.68 (2H, t, J = 6.5 Hz), 2.23 (6H, s). 251 0 LC-MS [M + H].sup.+/Rt (min): 425.3/0.497 (Method A); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.84-8.81 (1H, m), 8.66 (1H, d, J = 2.8 Hz), 7.86-7.79 (1H, m), 7.39-7.31 (2H, m), 5.35 (2H, s), 4.22-4.02 (5H, m), 2.84 (3H, s), 2.26-2.10 (8H, m), 2.08-1.87 (2H, m). 252 LC-MS [M + H].sup.+/Rt (min): 494.4/0.508 (Method A); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.84-8.81 (1H, m), 8.66 (1H, d, J = 2.5 Hz), 7.86-7.79 (1H, m), 7.36 (1H, s), 7.29 (1H, s), 5.34 (2H, s) 4.53 (2H, q, J = 7.0 Hz), 4.10 (2H, t, J = 7.0 Hz), 2.83 (3H, s), 2.57-2.30 (6H, m), 2.28 (3H, s), 2.24 (2H, t, J = 7.0 Hz), 2.00- 1.92 (2H, m), 1.82-1.76 (2H, m), 1.51 (3H, t, J = 7.0 Hz). 253 LC-MS [M + H].sup.+/Rt (min): 552.40/0.985 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.81 (1H, s), 8.65 (1H, d, J = 3.1 Hz), 7.84-7.79 (1H, m), 7.37 (1H, s), 7.23 (1H, s), 5.34 (2H, s), 4.54 (2H, q, J = 7.1 Hz), 4.17-4.03 (2H, m), 3.89 (2H, d, J = 7.3 Hz), 2.83 (3H, s), 2.73-2.58 (2H, m), 2.03-1.96 (1H, m), 1.55- 1.39 (14H, m), 1.16-1.03 (2H, m). 254 LC-MS [M + H].sup.+/Rt (min): 551.3/0.895 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.79- 8.76 (1H, m), 8.62 (1H, d, J = 3.1 Hz), 7.81-7.76 (1H, m), 7.33 (1H, s), 7.23 (1H, s), 5.35-5.26 (2H, m), 4.52 (2H, q, J = 7.2 Hz), 3.96- 3.82 (2H, m), 3.78-3.64 (2H, m), 2.93-2.86 (1H, m), 2.81 (3H, s), 2.68-2.62 (1H, m), 2.03-1.96 (1H, m), 1.76-1.52 (3H, m), 1.48 (3H, t, J = 7.2 Hz), 1.38 (9H, brs), 1.16- 1.04 (1H, m) 255 LC-MS [M + H].sup.+/Rt (min): 551.3/0.893 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.79- 8.76 (1H, m), 8.62 (1H, d, J = 2.4 Hz), 7.81-7.76 (1H, m), 7.33 (1H, s), 7.25-7.23 (1H, m), 5.35-5.26 (2H, m), 4.53 (2H, q, J = 7.2 Hz), 3.96-3.82 (2H, m), 3.76-3.64 (2H, m), 2.94-2.86 (1H, m), 2.83 (3H, s), 2.69-2.61 (1H, m), 2.04-1.96 (1H, m), 1.76-1.52 (3H, m), 1.48 (3H, t, J = 7.2 Hz), 1.38 (9H, brs), 1.16-1.04 (1H, m) 256 LC-MS [M + H].sup.+/Rt (min): 537.4/0.845 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.77 (1H, s), 8.63 (1H, d, J = 2.4 Hz), 7.82-7.76 (1H, m), 7.33 (1H, s), 7.26-7.22 (1H, m), 5.31 (2H, s), 4.52 (2H, q, J = 7.0 Hz), 4.05-3.95 (2H, m), 3.47-3.34 (2H, m), 3.32- 3.22 (1H, m), 3.04-2.95 (1H, m), 2.81 (3H, s), 2.70-2.61 (1H, m), 1.90-1.82 (1H, m), 1.72-1.52 (1H, m), 1.48 (3H, t, J = 7.0 Hz), 1.42 (9H, s) 257 LC-MS [M + H].sup.+/Rt (min): 537.4/0.847 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.77 (1H, s), 8.63 (1H, d, J = 3.1 Hz), 7.82-7.76 (1H, m), 7.33 (1H, s), 7.26-7.22 (1H, m), 5.31 (2H, s), 4.51 (2H, q, J = 7.0 Hz), 4.05-3.95 (2H, m), 3.45-3.34 (2H, m), 3.32- 3.22 (1H, m), 3.04-2.95 (1H, m), 2.81 (3H, s), 2.70-2.60 (1H, m), 1.90-1.82 (1H, m), 1.67-1.52 (1H, m), 1.48 (3H, t, J = 7.0 Hz), 1.42 (9H, s)

Example 258

(161) According to the method of Example 77, Example 258 was prepared by using the corresponding material compound.

(162) TABLE-US-00034 Example Chemical Structure Instrumental analysis data 258 LC-MS [M + H].sup.+/Rt (min): 398.4/0.713 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.77-8.74 (2H, m), 8.16-8.11 (1H, m), 7.04-6.95 (3H, m), 5.56 (2H, s), 5.26 (1H, t, J = 5.5 Hz), 4.40 (2H, d, J = 5.5 Hz), 3.94 (3H, s), 2.69 (3H, s).

Examples 259-266

(163) According to the method of Example 80, Examples 259-266 were prepared by using the corresponding material compounds.

(164) TABLE-US-00035 Example Chemical Structure Instrumental analysis data 259 LC-MS [M + H].sup.+/Rt (min): 425.4/0.569 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.74-8.71 (2H, m), 8.12-8.07 (1H, m), 7.00-6.90 (3H, m), 5.57 (2H, s), 3.94 (3H, s), 3.28 (2H, s), 2.69 (3H, s), 2.04 (6H, s). 260 LC-MS [M + H].sup.+/Rt (min): 437.4/0.574 (Method A); .sup.1H-NMR(400 MHz, DMSO-d.sub.6) : 8.74 (1H, d, J = 3.1 Hz), 8.73-8.71 (1H, m), 8.13-8.08 (1H, m), 6.97-6.88 (3H, m), 5.55 (2H, s), 3.93 (3H, s), 3.40 (2H, s), 3.02 (4H, t, J = 6.7 Hz), 2.69 (3H, s), 1.92 (2H, quin, J = 6.7 Hz). 261 00 LC-MS [M + H].sup.+/Rt (min): 481.5/0.608 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.75 (1H, d, J = 3.1 Hz), 8.71-8.69 (1H, m), 8.16-8.12 (1H, m), 7.29-7.26 (1H, m), 7.18-7.15 (1H, m), 7.11-7.07 (1H, m), 5.62 (2H, s), 4.37 (2H, s), 3.95 (3H, s), 3.11-3.04 (5H, m), 2.70 (3H, s), 1.25-1.19 (9H, m). 262 01 LC-MS [M + H].sup.+/Rt (min): 476.4/0.593 (Method A); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.66 (1H, dd, J = 1.2, 1.8 Hz), 8.55 (1H, d, J = 3.1 Hz), 7.66-7.62 (1H, m), 7.21 (2H, d, J = 7.9 Hz), 5.44 (2H, s), 4.45 (2H, q, J = 7.3 Hz), 3.43 (2H, s), 2.81 (3H, s), 2.50-2.30 (6H, m), 2.28 (3H, s), 1.66-1.54 (2H, m), 1.43 (3H, t, J = 7.3 Hz). 263 02 LC-MS [M + H].sup.+/Rt (min): 447.3/0.605 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.74-8.73 (2H, m), 7.97-7.92 (1H, m), 7.18 (2H, d, J = 7.9 Hz), 6.93 (2H, d, J = 7.9 Hz), 5.54 (2H, s), 4.39 (2H, q, J = 7.3 Hz), 3.50 (2H, s), 2.71 (3H, s), 2.43-2.30 (4H, m), 1.68-1.60 (4H, m), 1.34 (3H, t, J = 7.3 Hz). 264 03 LC-MS [M + H].sup.+/Rt (min): 461.3/0.625 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.76-8.70 (2H, m), 8.05-8.01 (1H, m), 7.15 (2H, d, J = 7.9 Hz), 6.93 (2H, d, J = 7.9 Hz), 5.54 (2H, s), 4.39 (2H, q, J = 7.3 Hz), 3.36- 3.29 (4H, m), 2.71 (3H, s), 2.28-2.14 (4H, m), 1.48-1.39 (4H, m), 1.34 (3H, t, J = 7.3 Hz). 265 04 LC-MS [M + H].sup.+/Rt (min): 502.4/0.611 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.74-8.72 (2H, m), 8.06-8.02 (1H, m), 7.22 (2H, d, J = 7.9 Hz), 6.93 (2H, d, J = 7.9 Hz), 5.54 (2H, s), 4.39 (2H, q, J = 7.3 Hz), 3.37 (2H, s), 2.95-2.89 (2H, m), 2.71 (3H, s), 2.48-2.41 (2H, m), 2.09 (3H, s), 1.84-1.76 (2H, m), 1.68-1.62 (2H, m), 1.34 (3H, t, J = 7.3 Hz). 266 05 LC-MS [M + H].sup.+/Rt (min): 449.3/0.620 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.74-8.72 (2H, m), 8.06-8.01 (1H, m), 7.18 (2H, d, J = 7.9 Hz), 6.62 (2H, d, J = 7.9 Hz), 5.54 (2H, s), 4.39 (2H, q, J = 7.3 Hz), 3.42 (2H, s), 2.71 (3H, s), 2.36 (4H, q, J = 7.3 Hz), 1.34 (3H, t, J = 7.3 Hz), 0.91 (3H, t, J = 7.3 Hz).

Examples 267-271

(165) According to the method of Example 123, Examples 267-271 were prepared by using the corresponding material compounds.

(166) TABLE-US-00036 Example Chemical Structure Instrumental analaysis data 267 06 LC-MS [M + 2H].sup.+2/2/Rt (min): 250.8/0.547 (Method C) 250.8/0.547 (Method C); .sup.1H-NMR (CD.sub.3OD) : 9.06 (2H, dd, J = 3.7, 2.4 Hz), 8.46 (1H, t, J = 1.8 Hz), 7.03 (1H, t, J = 8.9 Hz), 6.59-6.52 (2H, m), 5.56 (2H, s), 4.56-4.55 (1H, m), 4.08 (3H, s), 3.54-3.44 (2H, m), 2.77 (3H, s), 2.14-2.03 (3H, m), 1.93-1.75 (5H, m). 268 07 LC-MS [M + 2H].sup.+2/2/Rt (min): 226.1/0.471 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.79-8.76 (1H, m), 8.62 (1H, d, J = 2.7 Hz), 7.80- 7.76 (1H, m), 7.31 (1H, s), 7.21 (1H, s), 5.30 (2H, s), 4.50 (2H, q, J = 7.1 Hz), 3.96-3.84 (2H, m), 3.00-2.94 (1H, m), 2.88-2.81 (1H, m), 2.79 (3H, s), 2.59-2.52 (1H, m), 2.34-2.27 (1H, m), 2.08-1.99 (1H, m), 1.96-1.75 (1H, m), 1.68-1.58 (2H, m), 1.53-1.43 (1H, m), 1.47 (3H, t, J = 7.1 Hz), 1.12-1.01 (1H, m) 269 08 LC-MS [M + 2H].sup.+2/2/Rt (min): 226.2/0.468 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.79-8.76 (1H, m), 8.62 (1H, d, J = 2.7 Hz), 7.80- 7.76 (1H, m), 7.31 (1H, s), 7.21 (1H, s), 5.30 (2H, s), 4.50 (2H, q, J = 7.1 Hz), 3.96-3.84 (2H, m), 3.00-2.94 (1H, m), 2.88-2.81 (1H, m), 2.79 (3H, s), 2.59-2.52 (1H, m), 2.34-2.27 (1H, m), 2.08-1.99 (1H, m), 1.96-1.75 (1H, m), 1.68-1.58 (2H, m), 1.53-1.43 (1H, m), 1.47 (3H, t, J = 7.1 Hz), 1.12-1.01 (1H, m) 270 09 LC-MS [M + 2H].sup.+2/2/Rt (min): 219.2/0.456 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.77 (1H, s), 8.62 (1H, d, J = 3.1 Hz), 7.81-7.76 (1H, m), 7.32 (1H, s), 7.27 (1H, s), 5.30 (2H, s), 4.50 (2H, q, J = 7.2 Hz), 3.99 (2H, d, J = 7.3 Hz), 3.04-2.90 (3H, m), 2.79 (3H, s), 2.66-2.58 (2H, m), 2.07-1.80 (2H, m), 1.50-1.38 (1H, m), 1.47 (3H, t, J = 7.2 Hz) 271 0 LC-MS [M + 2H].sup.+2/2/Rt (min): 219.1/0.454 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.78-8.76 (1H, m), 8.62 (1H, d, J = 3.1 Hz), 7.81- 7.76 (1H, m), 7.32 (1H, s), 7.27 (1H, s), 5.30 (2H, s), 4.50 (2H, q, J = 7.2 Hz), 3.99 (2H, d, J = 6.7 Hz), 3.04-2.89 (3H, m), 2.79 (3H, s), 2.66-2.57 (2H, m), 2.07-1.80 (2H, m), 1.50-1.37 (1H, m), 1.47 (3H, t, J = 7.2 Hz)

Examples 272-298

(167) According to the method of Example 127, Examples 272-298 were prepared by using the corresponding material compounds.

(168) TABLE-US-00037 Example Chemical Structure Instrumental analysis data 272 LC-MS [M + H].sup.+/Rt (min): 467.3/0.574 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.81-8.78 (2H, m), 8.13-8.09 (1H, m), 7.43 (1H, s), 7.17 (1H, s), 5.37 (2H, s), 4.42 (2H, q, J = 7.3 Hz), 4.04-3.97 (2H, m), 3.71-3.68 (1H, m), 3.64-3.58 (1H, m), 3.40-3.33 (1H, m), 3.31-3.28 (1H, m), 2.67 (3H, s), 2.53-2.42 (1H, m), 2.09 (3H, s), 1.89-1.82 (1H, m), 1.55 (1H, dd, J = 10.4, 11.0 Hz), 1.36 (3H, t, J = 7.3 Hz). 273 LC-MS [M + H].sup.+/Rt (min): 467.3/0.576 (Method A); .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.81-8.78 (2H, m), 8.13-8.09 (1H, m), 7.43 (1H, s), 7.17 (1H, s), 5.37 (2H, s), 4.42 (2H, q, J = 7.3 Hz), 4.05-3.96 (2H, m), 3.71-3.66 (1H, m), 3.65-3.58 (1H, m), 3.40-3.33 (1H, m), 3.31-3.28 (1H, m), 2.67 (3H, s), 2.52-2.43 (1H, m), 2.09 (3H, s), 1.89-1.82 (1H, m), 1.55 (1H, dd, J = 10.4, 11.0 Hz), 1.36 (3H, t, J = 7.3 Hz). 274 LC-MS [M + H].sup.+/Rt (min): 467.3/0.571 (Method A) 275 LC-MS [M + H].sup.+/Rt (min): 466.4/0.566 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.19 (1H, d, J = 1.4 Hz), 8.02 (1H, d, J = 2.7 Hz), 7.20-7.15 (1H, m), 6.72 (1H, s), 6.60 (1H, s), 4.71 (2H, s), 3.91 (2H, q, J = 7.2 Hz), 3.26 (2H, d, J = 6.9 Hz), 2.22-2.16 (5H, m), 1.62 (3H, s), 1.28-1.11 (3H, m), 0.88 (3H, t, J = 7.2 Hz), 0.85-0.81 (2H, m), 0.70-0.56 (2H, m). 276 LC-MS [M + 2H].sup.+2/2/Rt (min): 233.2/0.459 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.78-8.76 (1H, m), 8.61 (1H, d, J = 2.7 Hz), 7.80- 7.76 (1H, m), 7.31 (1H, s), 7.26-7.24 (1H, m), 5.32-5.28 (2H, m), 4.50 (2H, q, J = 7.2 Hz), 3.96-3.92 (2H, m), 2.81- 2.50 (2H, m), 2.79 (3H, s), 2.35-1.94 (5H, m), 1.91-1.51 (4H, m), 1.47 (3H, t, J = 7.2 Hz), 1.01-0.83 (1H, m). 277 LC-MS [M + 2H].sup.+2/2/Rt (min): 233.2/0.466 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.79-8.76 (1H, m), 8.61 (1H, d, J = 2.7 Hz), 7.80- 7.76 (1H, m), 7.31 (1H, s), 7.26-7.24 (1H, m), 5.35-5.26 (2H, m), 4.50 (2H, q, J = 7.1 Hz), 4.01-3.88 (2H, m), 2.86- 2.51 (2H, m), 2.79 (3H, s), 2.35-1.94 (5H, m), 1.91-1.51 (4H, m), 1.47 (3H, t, J = 7.1 Hz), 1.01-0.83 (1H, m). 278 LC-MS [M + 2H].sup.+2/2/Rt (min): 226.1/0.453 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.78-8.76 (1H, m), 8.62 (1H, d, J = 2.7 Hz), 7.79- 7.76 (1H, m), 7.31 (1H, s), 7.28 (1H, s), 5.30 (2H, s), 4.50 (2H, q, J = 7.0 Hz), 4.09-3.96 (2H, m), 2.83-2.67 (2H, m), 2.79 (3H, s), 2.60-2.48 (2H, m), 2.47-2.33 (1H, m), 2.38 (3H, s), 2.02-1.91 (1H, m), 1.57-1.45 (1H, m), 1.47 (3H, t, J = 7.1 Hz). 279 LC-MS [M + H].sup.+/Rt (min): 451.3/0.440 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.78-8.76 (1H, m), 8.62 (1H, d, J = 2.7 Hz), 7.79- 7.76 (1H, m), 7.31 (1H, s), 7.27 (1H, s), 5.30 (2H, s), 4.50 (2H, q, J = 7.0 Hz), 4.09-3.96 (2H, m), 2.81-2.62 (2H, m), 2.79 (3H, s), 2.55-2.46 (2H, m), 2.43-2.34 (1H, m), 2.36 (3H, s), 2.02-1.91 (1H, m), 1.56-1.44 (1H, m), 1.47 (3H, t, J = 7.1 Hz). 280 LC-MS [M + H].sup.+/Rt (min): 492.5/0.578 (Method A); .sup.1H-NMR (DMSO-d.sub.6) : 8.74-8.72 (2H, m), 8.12-8.08 (1H, m), 7.03-6.89 (3H, m), 5.55 (2H, s), 3.94 (3H, s), 3.57 (1H, d, J = 14.0 Hz), 3.50 (1H, d, J = 14.0 Hz), 3.09- 3.06 (2H, m), 2.69 (3H, s), 2.59 (1H, d, J = 11.0), 2.52-2.48 (1H m), 2.48-2.41 (2H, m), 2.21 (3H, s), 1.54 (2H, brs). 281 0 LC-MS [M + 2H].sup.+2/2/Rt (min): 253.6/0.394 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.72-8.70 (1H, m), 8.58 (1H, d, J = 3.0 Hz), 8.12 (1H, s), 7.76-7.71 (1H, m), 6.50 (1H, s), 5.41 (2H, s), 4.43 (2H, q, J = 7.1 Hz), 3.65 (3H, s), 2.87-2.80 (2H, m), 2.77 (3H, s), 2.59 (2H, d, J = 7.1 Hz), 2.26 (3H, s), 1.99-1.63 (3H, m), 1.59-1.52 (2H, m), 1.45-1.32 (2H, m), 1.42 (3H, t, J = 7.1 Hz). 282 LC-MS [M + H].sup.+/Rt (min): 465.4/0.477 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.66-8.62 (1H, m), 8.57 (1H, d, J = 3.1 Hz), 7.72- 7.66 (1H, m), 6.93-6.83 (3H, m), 5.47 (2H, s), 4.02 (3H, s), 3.21-3.06 (2H, m), 2.81 (3H, s), 2.57-2.38 (4H, m), 2.34-2.16 (2H, m), 2.05-1.77 (4H, m). 283 LC-MS [M + 2H].sup.+2/2/Rt (min): 240.3/ 0.546 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.65-8.63 (1H, m), 8.56 (1H, d, J = 2.4 Hz), 7.70-7.64 (1H, m), 6.87-6.74 (3H, m), 5.47 (2H, s), 4.03 (3H, s), 3.00-2.86 (2H, m), 2.81 (3H, s), 2.47 (2H, d, J = 6.1 Hz), 2.33 (3H, s), 2.07- 1.93 (2H, m), 1.62-1.53 (2H, m), 1.51-1.33 (3H, m). 284 LC-MS [M + 2H].sup.+2/2/Rt (min): 240.3/ 0.497 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.65-8.62 (1H, m), 8.57 (1H, d, J = 2.4 Hz), 7.71-7.65 (1H, m), 6.93-6.82 (3H, m), 5.47 (2H, s), 4.02 (3H, s), 3.35-3.03 (2H, m), 2.81 (3H, s), 2.69-2.39 (3H, m), 2.26-1.49 (6H, m), 1.28-1.08 (3H, m). 285 LC-MS [M + 2H].sup.+2/2/Rt (min): 254.3/ 0.542 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.66-8.64 (1H, m), 8.58 (1H, d, J = 3.1 Hz), 7.72-7.67 (1H, m), 6.94-6.88 (1H, m), 6.50-6.42 (2H, m), 5.43 (2H, s), 4.51-4.42 (1H, m), 4.04 (3H, s), 3.40-3.19 (2H, m), 2.80 (3H, s), 2.60-1.87 (11H, m). 286 LC-MS [M + 2H].sup.+2/2/Rt (min): 234.3/ 0.491 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.68-8.64 (1H, m), 8.58 (1H, d, J = 3.0 Hz), 7.72-7.65 (1H, m), 6.96-6.85 (1H, m), 6.62-6.49 (2H, m), 5.43 (2H, s), 4.04 (3H, s), 4.01 (2H, d, J = 6.7 Hz), 3.40-3.33 (2H, m), 3.10-3.02 (2H, m), 2.85-2.76 (1H, m), 2.80 (3H, s), 2.30 (3H, s). 287 LC-MS [M + 2H].sup.+2/2/Rt (min): 241.4/ 0.538 (Method C) 288 LC-MS [M + 2H].sup.+2/2/Rt (min): 236.8/ 0.481 (Method C); .sup.1H-NMR (CDCl.sub.3) : 9.01 (1H, d, J = 1.8 Hz), 8.94 (1H, d, J = 1.8 Hz), 8.20- 8.17 (1H, m), 6.98-6.87 (3H, m), 5.46 (2H, s), 4.04 (3H, s), 3.16-3.02 (2H, m), 2.81 (3H, s), 2.55-2.35 (4H, m), 2.29-2.09 (2H, m), 2.00-1.75 (4H, m). 289 LC-MS [M + 2H].sup.+2/2/Rt (min): 243.8/ 0.498 (Method C); .sup.1H-NMR (CDCl.sub.3) : 9.01 (1H, d, J = 2.4 Hz), 8.94 (1H, d, J = 2.4 Hz), 8.20- 8.16 (1H, m), 6.97-6.85 (3H, m), 5.46 (2H, s), 4.04 (3H, s), 3.31-3.06 (2H, m), 2.81 (3H, s), 2.70-2.43 (3H, m), 2.27-1.69 (5H, m), 1.36-1.07 (4H, m). 290 LC-MS [M + 2H].sup.+2/2/Rt (min): 226.2/ 0.478 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.66-8.63 (1H, m), 8.57 (1H, d, J = 2.4 Hz), 7.73-7.66 (1H, m), 6.99-6.81 (3H, m), 5.47 (2H, s), 4.03 (3H, s), 3.35-3.24 (1H, m), 2.94-2.85 (1H, m), 2.81 (3H, s), 2.75-2.58 (2H, m), 2.48-2.40 (1H, m), 2.37 (3H, s), 2.34-2.24 (1H, m), 1.81-1.68 (1H, m). 291 0 LC-MS [M + 2H].sup.+2/2/Rt (min): 233.3/ 0.496 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67-8.63 (1H, m), 8.57 (1H, d, J = 2.4 Hz), 7.72-7.66 (1H, m), 6.99-6.82 (3H, m), 5.47 (2H, s), 4.03 (3H, s), 3.33-3.23 (1H, m), 3.00-2.93 (1H, m), 2.81 (3H, s), 2.79-2.73 (1H, m), 2.65-2.37 (4H, m), 2.32-2.21 (1H, m), 1.80-1.70 (1H, m), 1.10 (3H, t, J = 7.0 Hz). 292 LC-MS [M + 2H].sup.+2/2/Rt (min): 224.3/ 0.439 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.83-8.81 (1H, m), 8.72-8.69 (1H, m), 7.95-7.91 (1H, m), 7.41-7.37 (1H, m), 6.91-6.82 (3H, m), 5.45 (2H, s), 4.02 (3H, s), 3.17-3.02 (2H, m), 2.81 (3H, s), 2.53-2.36 (4H, m), 2.29-2.14 (2H, m), 1.98-1.75 (4H, m). 293 LC-MS [M + H].sup.+/Rt (min): 461.5/0.441 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.84-8.82 (1H, m), 8.72-8.68 (1H, m), 7.95-7.90 (1H, m), 7.41-7.35 (1H, m), 6.90-6.80 (3H, m), 5.45 (2H, s), 4.01 (3H, s), 3.16-3.02 (2H, m), 2.80 (3H, s), 2.55-2.38 (3H, m), 2.12-1.96 (2H, m), 1.87-1.69 (4H, m), 1.18-1.06 (3H, m). 294 LC-MS [M + 2H].sup.+2/2/Rt (min): 245.7/0.465 (Method C); .sup.1H-MMR (CDCl.sub.3) : 9.30 (1H, s), 8.98 (2H, s), 6.95-6.89 (1H, m), 6.50-6.43 (2H, m), 5.43 (2H, s), 4.51-4.45 (1H, m), 4.05 (3H, s), 3.42-3.27 (2H, m), 2.81 (3H, s), 2.59-2.39 (2H, m), 2.45 (3H, s), 2.18-2.04 (4H, m), 1.99-1.91 (2H, m). 295 LC-MS [M + 2H].sup.2+/2/Rt min): 257.8/0.560 (Method C); .sup.1H-NMR (CD.sub.3OD) : 9.05 (2H, dd, J = 6.1, 1.8 Hz), 8.46 (1H, t, J = 1.8 Hz), 7.02 (1H, t, J = 8.9 Hz), 6.58-6.50 (2H, m), 5.54 (2H, s), 4.50-4.44 (1H, m), 4.07 (3H, s), 3.19-3.07 (2H, m), 2.75 (3H, s), 2.28 (3H, s), 2.13-1.95 (8H, m). 296 LC-MS [M + 2H].sup.2+/2/Rt (min): 264.82/0.578 (Method C); .sup.1H-NMR (CD.sub.3OD) : 9.79-9.79 (2H, m), 9.25-9.23 (1H, m), 7.81-7.78 (1H, m), 7.49-7.38 (2H, m), 5.35 (2H, s), 4.53-4.34 (1H, m), 3.99 (3H, s), 3.48-3.44 (2H, m), 2.87 (3H, s), 2.51 (3H, q, J = 6.4 Hz), 2.06-2.01 (2H, m), 2.01- 1.93 (4H, m), 1.92-1.89 (2H, m), 1.65 (3H, t, J = 10.0 Hz). 297 LC-MS [M + 2H].sup.2+/2/Rt (min): 245.31/0.506 (Method C); .sup.1H-NMR (CD.sub.3OD) : 8.82 (1H, d, J = 1.2 Hz), 8.70 (1H, dd, J = 4.9, 1.2 Hz), 8.13 (1H, dt, J = 7.9, 1.8 Hz), 7.59 (1H, dd, J = 7.9, 4.9 Hz), 6.98 (1H, t, J = 8.9 Hz), 6.57-6.49 (2H, m), 5.52 (2H, s), 4.46 (1H, t, J = 4.9 Hz), 4.05 (3H, s), 3.17-3.09 (2H, m), 2.75 (3H, s), 2.28 (3H, s), 2.14-2.05 (2H, m), 2.05-1.95 (4H, m), 1.88-1.79 (2H, m). 298 LC-MS [M + 2H].sup.2+/2/Rt (min): 252.2/0.523 (Method C); .sup.1H-NMR (CD.sub.3OD) : 8.81 (1H, d, J = 1.8 Hz), 8.70 (1H, dd, J = 5.2, 1.5 Hz), 8.13 (1H, dt, J = 7.9, 1.8 Hz), 7.58 (1H, dd, J = 7.9, 4.9 Hz), 6.97 (1H, t, J = 8.9 Hz), 6.55-6.53 (1H, m), 6.53-6.50 (1H, m), 5.52 (2H, s), 4.52-4.45 (1H, m), 4.05 (3H, s), 3.29-3.22 (2H, m), 2.75 (3H, s), 2.48 (2H, q, J = 7.1 Hz), 2.15-2.04 (2H, m), 2.04-1.88 (4H, m), 1.87-1.76 (2H, m), 1.10 (3H, t, J = 7.3 Hz).

Example 299

(169) test-Butyl (1S,4S)-5-(3-fluoro-4-{[8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purin-9-yl]methyl}benzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

(170) ##STR00338##

(171) To an ice-cooled solution of the compound of Example 438 (40.1 mg) in N,N-dimethylformamide (5 mL) were added tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (41.8 mg), potassium carbonate (43.1 mg), and potassium iodide (17.9 mg). The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added aqueous saturated sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (40.1 mg).

(172) LC-MS [M+H].sup.+/Rt (min): 578.5/0.704 (Method A)

Example 300

(173) According to the method of Example 163, Example 300 was prepared by using the corresponding material compound.

(174) TABLE-US-00038 Example Chemical Structure Instrumental analysis data 300 LC-MS [M + H].sup.+/Rt (min): 480.4/0.538 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.84-8.81 (1H, m), 8.66 (1H, d, J = 2.4 Hz), 7.86- 7.79 (1H, m), 7.37 (2H, d, J = 5.2 Hz), 5.34 (2H, s), 4.54 (2H, q, J = 7.2 Hz), 4.16 (2H, t, J = 6.8 Hz), 2.83 (3H, s), 2.75 (2H, t, J = 6.4 Hz), 2.57-2.37 (8H, m), 2.31 (3H, s), 1.51 (3H, t, J = 7.2 Hz).

Example 301

9-[4-(1-Azabicyclo[2.2.2]oct-3-yl)-2-fluorobenzyl]-2-methoxy-6-methyl-8-(pyrazin-2-yl)-9H-purine

(175) ##STR00340##

(176) To a solution of the compound of Reference example 223 (187 mg) in chloroform (10 mL) were added pyrazine-2-carboxylic acid (187 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (290 mg), 1-hydroxybenzotriazole (204 mg), and N,N-diisopropylethylamine (0.514 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 50% aqueous potassium carbonate, and the mixture was extracted with chloroform/ethanol (3/1). The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. To the obtained residue (904 mg) was added N,O-bis(trimethylsilyl)acetamide (4 mL), and the mixture was stirred at 55 C. for 2 hours. The reaction mixture was cooled to room temperature. 50% aqueous potassium carbonate was added thereto, and the mixture was extracted with chloroform/ethanol (3/1). The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The obtained residue was purified by amino silica gel column chromatography (chloroform/methanol) to give the title compound (119 mg).

(177) LC-MS [M+H].sup.+/Rt (min): 459.2/0.488 (Method C); .sup.1H-NMR (CDCl.sub.3) : 9.55 (1H, d, J=1.2 Hz), 8.58 (1H, d, J=2.4 Hz), 0.54-8.53 (1H, m), 6.90-6.78 (3H, m), 6.06 (2H, s), 4.04 (3H, s), 3.40-3.26 (1H, m), 3.08-2.81 (6H, m), 2.83 (3H, s), 1.94-1.88 (1H, m), 1.82-1.69 (2H, m), 1.65-1.52 (1H, m), 1.46-1.33 (1H, m).

Examples 302-348

(178) According to the method of Example 165 or Example 301, Examples 302-348 were prepared by the corresponding material compounds.

(179) TABLE-US-00039 Example Chemical Structure Instrumental analysis data 302 LC-MS [M + 2H].sup.2+/2/Rt (min): 245.4/0.523 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.36-8.35 (2H, m), 7.39-7.37 (1H, m), 6.90-6.81 (3H, m), 5.44 (2H, s), 3.98 (3H, s), 3.77 (3H, s), 3.28- 3.20 (1H, m), 2.94-2.78 (6H, m), 2.77 (3H, s), 1.86-1.73 (1H, m), 1.70-1.62 (2H, m), 1.54-1.44 (1H, m), 1.36-1.26 (1H, m). 303 LC-MS [M + 2H].sup.2+/2/Rt (min): 230.4/0.478 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.79-8.78 (1H, m), 8.66 (1H, dd, J = 1.2, 3.7 Hz), 7.92-7.90 (1H, m), 7.35 (1H, dd, J = 3.1, 4.9 Hz), 6.88-6.84 (3H, m), 5.42 (2H, s), 3.98 (3H, s), 3.29-3.22 (1H, m), 2.96-2.78 (6H, m), 2.77 (3H, s), 1.86-1.82 (1H, m), 1.75- 1.46 (3H, m), 1.36-1.27 (1H, m). 304 .sup.1H-NMR (CDCl.sub.3) : 8.56 (1H, d, J = 4.9 Hz), 8.42 (1H, s), 7.20 (1H, d, J = 5.5 Hz), 6.94-6.89 (1H, m), 6.86-6.83 (1H, m), 6.81-6.78 (1H, m), 5.26 (2H, s), 4.05 (3H, s), 3.32-3.24 (1H, m), 2.97-2.82 (6H, m), 2.78 (3H, s), 2.09 (3H, s), 1.88-1.82 (1H, m), 1.78-1.64 (2H, m), 1.56-1.46 (1H, m), 1.40-1.31 (1H, m). 305 LC-MS [M + 2H].sup.2+/2/Et (min): 237.3/0.521 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.55 (1H, d, J = 1.8 Hz), 8.49 (1H, d, J = 1.8 Hz), 7.73-7.71 (1H, m), 6.89-6.85 (3H, m), 5.42 (2H, s), 3.98 (3H, s), 3.29-3.21 (1H, m), 2.96-2.77 (6H, m), 2.77 (3H, s), 2.32 (3H, s), 1.86-1.81 (1H, m), 1.78-1.63 (2H, m), 1.57-1.45 (1H, m), 1.37-1.26 (1H, m). 306 LC-MS [M + 2H].sup.2+/2/Rt (min): 237.4/0.498 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.65-8.64 (1H, m), 7.81 (1H, dd, J = 2.4, 5.5 Hz), 7.21-7.19 (1H, m), 6.90-6.79 (3H, m), 5.41 (2H, s), 3.96 (3H, s), 3.29-3.21 (1H, m), 2.95-2.78 (6H, m), 2.76 (3H, s), 2.56 (3H, s), 1.86-1.81 (1H, m), 1.72-1.61 (2H, m), 1.56-1.45 (1H, m), 1.36-1.26 (1H, m). 307 LC-MS [M + H].sup.+/Rt (min): 481.5/0.655 (Method A); 308 LC-MS [M + H].sup.+/Rt (min): 499.5/0.558 (Method A); 499.5/0.558 (Method A); .sup.1H-NMR (DMSO-d.sub.6) : 9.19 (1H, d, J = 1.8 Hz), 9.15 (1H, d, J = 1.8 Hz), 8.71-8.69 (1H, m), 7.06- 6.95 (3H, m), 5.60 (2H, s), 3.98 (3H, s), 3.69-3.50 (2H, m), 3.12-3.09 (2H, m), 2.73 (3H, s), 2.64-2.61 (1H, m), 2.53-2.43 (2H, m), 1.57 (2H, brs), 1.46-1.32 (1H, m). 309 LC-MS [M + H].sup.+/Rt (min): 513.5/0.578 (Method A); 310 LC-MS [M + H].sup.+/Rt (min): 474.5/0.533 (Method A); 311 0 LC-MS [M + H].sup.+/Rt (min): 513.5/0.625 (Method A); 513.5/0.625 (Method A); .sup.1H-NMR (DMSO-d.sub.6) : 9.15 (1H, d, J = 1.8 Hz), 9.11 (1H, d, J = 1.8 Hz), 8.66-8.64 (1H, m), 7.03- 6.91 (3H, m), 5.55 (2H, s), 4.38 (2H, q, J = 7.3 Hz), 3.57 (1H, d, J = 14.0 Hz), 3.50 (1H, d, J = 14.0 Hz), 3.08-3.07 (2H, m), 2.68 (3H, s), 2.61-2.59 (1H, m), 2.54-2.40 (2H, m), 2.22 (3H, s), 1.54 (2H, brs), 1.44-1.28 (1H, m), 1.32 (3H, t, J 7.3 Hz). 312 LC-MS [M + H].sup.+/Rt (min): 489.5/0.549 (Method A); 489.5/0.549 (Method A); .sup.1H-NMR (DMSO-d.sub.6) : 9.31 (1H, s), 9.12 (2H, s), 7.04-6.93 (3H, m), 5.55 (2H, s), 4.37 (2H, q, J = 7.3 Hz), 3.57 (1H, d, J = 14.0 Hz), 3.50 (1H, d, J = 14.0 Hz), 3.10-3.06 (2H, m), 2.68 (3H, s), 2.59 (1H, d, J = 11.0), 2.50-2.42 (2H, m), 2.21 (3H, s), 1.54 (2H, brs), 1.42-1.34 (1H, m), 1.32 (3H, t, J 7.3 Hz). 313 LC-MS [M + H].sup.+/Rt (min): .sup.1H-NMR (DMSO-d.sub.6) : 8.75- 8.73 (2H, m), 8.12-8.09 (1H, m), 7.05-6.97 (2H, m), 6.93- 6.89 (1H, m), 5.55 (2H, s), 4.38 (2H, q, J = 7.3 Hz), 3.59 (1H, d, J = 14.0 Hz), 3.52 (1H, d, J = 14.0 Hz), 3.38- 3.35 (1H, m), 3.10-3.07 (2H, m), 2.69 (3H, s), 2.60 (1H, d, J = 11.0), 2.47-2.41 (2H, m), 2.23 (3H, m), 1.55 (2H, brs), 1.44-1.30 (1H, m), 1.33 (3H, t, J 7.3 Hz). 314 LC-MS [M + H].sup.+/Rt (min): 477.1/0.494 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.70-8.67 (1H, m), 8.61 (1H, d, J = 2.4 Hz), 7.75- 7.70 (1H, m), 6.99-6.91 (3H, m), 5.53 (2H, s), 4.08 (3H, s), 3.36-3.26 (1H, m), 3.01-2.80 (9H, m), 1.93-1.85 (1H, m), 1.77-1.65 (2H, m), 1.59-1.50 (1H, m), 1.42-1.30 (1H, m). 315 LC-MS [M + H].sup.+/Rt (min): 488.44/0.626 (Method A); .sup.1H-NMR (CDCl.sub.3) : 6.62 (1H, s), 8.59 (1H, d, J = 3.0 Hz), 7.74-7.69 (1H, m), 6.92 (1H, d, J = 7.9 Hz), 6.84 (1H, d, J = 7.9 Hz), 5.46 (2H, s), 4.45 (2H, q, J = 7.1 Hz), 3.50-3.43 (1H, m), 3.24-3.16 (1H, m), 3.07-2.97 (2H, m), 2.96-2.88 (2H, m), 2.87 (3H, s), 2.85-2.77 (1H, m), 2.51 (3H, s), 2.02-1.97 (1H, m), 1.75-1.68 (2H, m), 1.66-1.57 (1H, m), 1.44 (3H, t, J = 7.1 Hz), 1.35-1.26 (1H, m). 316 LC-MS [M + H].sup.+/Rt (min): 498.4/0.665 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.68-8.60 (2H, m), 7.78-7.73 (1H, m), 7.50 (1H, d, J = 7.9 Hz), 7.40 (1H, d, J = 1.8 Hz), 7.32-7.29 (1H, m), 5.50 (2H, s), 4.50 (2H, q, J = 7.1 Hz), 3.44-3.38 (1H, m), 3.38-3.30 (1H, m), 3.10-3.00 (1H, m), 3.00-2.87 (4H, m), 2.86 (3H, s), 1.92-1.82 (2H, m), 1.79-1.73 (1H, m), 1.54- 1.44 (4H, m), 1.42-1.33 (1H, m). 317 LC-MS [M + H].sup.+/Rt (min): 521.40/0.703 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.72 (1H, s), 8.62 (1H, d, J = 3.0 Hz), 7.75-7.70 (1H, m), 6.98 (1H, d, J = 11.0 Hz), 6.55 (1H, d, J = 6.1 Hz), 5.50 (2H, s), 4.51 (2H, q, J = 7.1 Hz), 3.59 (3H, s), 3.42- 3.32 (1H, m), 3.27-3.20 (1H, m), 3.03-2.91 (3H, m), 2.91- 2.75 (5H, m), 1.80-1.62 (4H, m), 1.51-1.37 (4H, m). 318 LC-MS [M + H].sup.+/Rt (min): 484.38/0.680 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.65-8.62 (2H, m), 7.79-7.75 (1H, m), 7.50 (1H, d, J = 7.9 Hz), 7.41 (1H, d, J = 1.8 Hz), 7.33-7.29 (1H, m), 5.51 (2H, s), 4.09 (3H, s), 3.47-3.39 (1H, m), 3.39-3.32 (1H, m), 3.12-3.03 (1H, m), 3.02-2.89 (4H, m), 2.87 (3H, s), 1.94-1.90 (1H, m), 1.80- 1.71 (1H, m), 1.56-1.45 (1H, m), 1.44-1.34 (1H, m), 1.34- 1.25 (1H, m). 319 LC-MS [M + H].sup.+/Rt (min): 445.17/1.044 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.93-8.91 (1H, m), 8.63-8.59 (2H, m), 8.13-8.09 (1H, m), 7.82 (1H, dd, J = 8.2, 2.1 Hz), 7.26 (1H, d, J = 3.2 Hz), 5.50 (2H, s), 4.45 (2H, q, J = 7.1 Hz), 2.84 (3H, s), 1.45 (3H, t, J = 7.0 Hz). 320 LC-MS [M + H].sup.+/Rt (min): 431.2/0.968 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.95-8.93 (1H, m), 8.63-8.60 (2H, m), 8.15-8.11 (1H, m), 7.82 (1H, dd, J = 8.5, 2.4 Hz), 7.29 (1H, d, J = 8.5 Hz), 5.50 (2H, s), 4.04 (3H, s), 2.84 (3H, s). 321 0 LC-MS [M + H].sup.+/Rt (min): 522.2/0.925 (Method A) 322 LC-MS [M + 2H].sup.2+/2/Rt (min): 250.67/0.538 (Method C); .sup.1H-NMR (CD.sub.3OD) : 9.06 (2H, s), 8.46 (1H, t, J = 2.1 Hz), 7.04 (1H, t, J = 8.9 Hz), 6.66-6.56 (2H, m), 5.55 (2H, s), 4.50-4.41 (1H, m), 4.08 (3H, s), 3.29- 3.22 (1H, m), 2.93-2.66 (5H, m), 2.76 (3H, s), 2.12-2.05 (1H, m), 1.98-1.87 (1H, m), 1.83-1.72 (1H, m), 1.71-1.57 (1H, m), 1.52-1.41 (1H, m). 323 LC-MS [M + 2H].sup.2+/2/Rt (min): 238.6/0.467 (Method C); .sup.1H-NMR (CD.sub.3OD) : 9.29 (1H, s), 9.08 (2H, s), 7.06 (1H, t, J = 8.9 Hz), 6.66-6.56 (2H, m), 5.56 (2H, s), 4.48-4.41 (1H, m), 4.06 (3H, s), 3.30-3.22 (1H, m), 2.92-2.77 (4H, m), 2.75 (3H, s), 2.72-2.66 (1H, m), 2.10-2.04 (1H, m), 1.97-1.85 (1H, m), 1.82-1.71 (1H, m), 1.69-1.57 (1H, m), 1.51-1.38 (1H, m). 324 LC-MS [M + 2H].sup.2+/2/Rt (min): 238.7/0.455 (Method C) 325 LC-MS [M + H].sup.+/Rt (min): 472.1/0.992 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67-8.65 (1H, m), 8.56 (1H, d, J = 2.7 Hz), 7.73- 7.68 (1H, m), 6.98-6.93 (2H, m), 6.72 (1H, d, J = 8.2 Hz), 5.39 (2H, s), 4.43 (2H, q, J = 7.0 Hz), 3.71 (3H, s), 2.81 (3H, s), 1.42 (3H, t, J = 7.0 Hz). 326 LC-MS [M + H].sup.+/Rt (min): 446.3/0.949 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.65-8.63 (1H, m), 8.60 (1H, d, J = 3.0 Hz), 7.40- 7.35 (1H, m), 7.17 (1H, dd, J = 2.4, 4.3), 6.93 (1H, dd, J = 9.1, 9.1 Hz), 5.46 (2H, s), 4.05 (3H, s), 2.82 (3H, s). 327 LC-MS [M + 2H].sup.2+/2/Rt (min): 252.7/0.588 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67-8.66 (1H, m), 8.57 (1H, d, J = 3.0 Hz), 7.77- 7.73 (1H, m), 7.09 (1H, d, J = 7.3 Hz), 6.63 (1H, d, J = 7.3 Hz), 5.39 (2H, s), 4.43 (2H, q, J = 7.0 Hz), 3.85 (3H, s), 3.60-3.51 (1H, m), 3.21-3.04 (2H, m), 3.03-2.82 (4H, m), 2.80 (3H, s), 1.98-1.94 (1H, m), 1.79-1.65 (3H, m), 1.42 (3H, t, J = 7.0 Hz), 1.39-1.29 (1H, m). 328 LC-MS [M + H].sup.+/Rt (min): 454.5/1.016 (Method A) 329 LC-MS: [M + 2H].sup.2+/2/Rt (min): 245.6/0.507 (Method C); .sup.1H-NMR (CD.sub.3OD) : 8.95 (2H, s), 7.04 (1H, t, J = 8.5 Hz), 6.65-6.58 (2H, m), 5.54 (2H, s), 4.48- 4.42 (1H, m), 4.06 (3H, s), 3.30-3.21 (1H, m), 2.91-2.79 (2H, m), 2.77 (3H, s), 2.76 (3H, s), 2.74-2.65 (2H, m), 2.11-2.04 (1H, m), 1.97-1.86 (1H, m), 1.82-1.71 (1H, m), 1.68-1.58 (1H, m), 1.49-1.39 (1H, m). 330 LC-MS [M + 2H].sup.2+/2/Rt (min): 244.7/0.507 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.60-8.58 (1H, m), 8.55 (1H, d, J = 3.0 Hz), 7.83 (1H, s), 7.71-7.66 (1H, m), 6.96 (1H, s), 5.51-5.39 (2H, m), 4.42 (2H, q, J = 7.0 Hz), 3.43-3.36 (1H, m), 3.17-3.10 (1H, m), 2.97-2.70 (5H, m), 2.81 (3H, s), 2.18 (3H, s), 1.98-1.94 (1H, m), 1.73-1.46 (3H, m), 1.41 (3H, t, J = 7.0 Hz), 1.30-1.21 (1H, m). 331 0 LC-MS [M + H].sup.+/Rt (min): 429.2/0.731 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.71-8.70 (1H, m), 8.61 (1H, d, J = 3.0 Hz), 8.02 (1H, s), 7.78-7.74 (1H, m), 6.74 (1H, s), 5.40 (2H, s), 4.43 (2H, q, J = 7.0 Hz), 3.69 (3H, s), 2.79 (3H, s), 1.43 (3H, t, J = 7.0 Hz). 332 LC-MS [M + H].sup.+/Rt (min): 446.1/0.901 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.64-8.63 (1H, m), 8.59 (1H, d, J = 3.0 Hz), 7.74- 7.69 (1H, m), 7.50-7.44 (1H, m), 6.88-6.83 (1H, m), 6.75- 6.70 (1H, m), 5.42 (2H, s), 4.04 (3H, s), 2.82 (3H, s). 333 LC-MS [M + H].sup.+/Rt (min): 432.0/0.632 (Method C); .sup.1H-NMR (DMSO-D.sub.6) : 12.12 (1H, br s), 8.73 (1H, d, J = 2.4 Hz), 8.66- 8.62 (1H, m), 8.02-7.96 (1H, m), 7.64-7.57 (1H, m), 7.13- 7.08 (1H, m), 6.84-6.79 (1H, m), 5.32 (2H, s), 2.56 (3H, s). 334 LC-MS [M + H].sup.+/Rt (min): 461.2/0.875 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.85-8.83 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 8.31- 8.29 (1H, m), 8.01-7.96 (1H, m), 7.63-7.58 (1H, m), 5.54- 5.52 (2H, m), 4.37 (2H, q, J = 7.0 Hz), 2.79 (3H, s), 1.39 (3H, t, J = 7.0 Hz). 335 LC-MS [M + H].sup.+/Rt (min): 467.2/0.933 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.59 (1H, d, J = 2.4 Hz), 8.53-8.51 (1H, m), 7.70- 7.65 (1H, m), 7.41 (1H, d, J = 8.2 Hz), 7.13 (1H, d, J = 8.2 Hz), 5.65 (2H, s), 4.38 (2H, q, J = 7.0 Hz), 2.84 (3H, s), 1.39 (3H, t, J = 7.0 Hz). 336 LC-MS [M + H].sup.+/Rt (min): 424.3/0.801 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.65 (1H, d, J = 2.4 Hz), 8.57-8.54 (1H, m), 7.77- 7.73 (1H, m), 7.47-7.39 (2H, m), 5.65 (2H, s), 4.40 (2H, q, J = 7.0 Hz), 2.81 (3H, s), 1.42 (3H, t, J = 7.0 Hz). 337 LC-MS [M + H].sup.+/Rt (min): 446.2/0.902 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.65-8.62 (1H, m), 8.59 (1H, d, J = 3.0 Hz), 7.73- 7.68 (1H, m), 7.25-7.20 (1H, m), 7.18-7.15 (1H, m), 6.89- 6.83 (1H, m), 5.45 (2H, s), 4.02 (3H, s), 2.81 (3H, s). 338 LC-MS [M + H].sup.+/Rt (min): 417.3/0.820 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.66-8.62 (2H, m), 8.00 (1H, d, J = 1.8 Hz), 7.76- 7.71 (1H, m), 7.29-7.25 (1H, m), 5.47 (2H, s), 4.46 (2H, q, J = 7.0 Hz), 2.81 (3H, s), 1.45 (3H, t, J = 7.0 Hz). 339 LC-MS [M + H].sup.+/Rt (min): 467.3/0.889 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.61 (1H, d, J = 3.1 Hz), 8.53-8.52 (1H, m), 7.82 (1H, d, J = 2.0 Hz), 7.74-7.70 (1H, m), 7.61 (1H, dd, J = 8.0, 2.0 Hz), 6.85 (1H, d, J = 8.0 Hz), 5.60 (2H, s), 4.40 (2H, q, J = 7.0 Hz), 2.82 (3H, s), 1.41 (3H, t, J = 7.0 Hz). 340 LC-MS [M + H].sup.+/Rt (min): 484.3/0.465 (Method C); .sup.1H-NMR (CDCl.sub.3) : 9.03-9.01 (1H, m), 8.95-8.94 (1H, m), 8.21-8.19 (1H, m), 7.02-6.89 (3H, m), 5.48 (2H, s), 4.05 (3H, s), 3.38-3.29 (1H, m), 3.04-2.83 (6H, m), 2.81 (3H, s), 1.96- 1.90 (1H, m), 1.81-1.72 (2H, m), 1.63-1.51 (1H, m), 1.47- 1.34 (1H, m). 341 0 LC-MS [M + H].sup.+/Rt (min): 428.2/0.879 (Method C) 342 LC-MS [M + H].sup.+/Rt (min): 462.3/0.728 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.65-8.63 (1H, m), 8.60 (1H, d, J = 3.0 Hz), 7.74- 7.70 (1H, m), 7.09-6.97 (3H, m), 5.51 (2H, s), 4.03 (3H, s), 3.14 (3H, s), 2.82 (3H, s). 343 LC-MS [M + 2H].sup.2+/2/Rt (min): 229.8/0.471 (Method C); .sup.1H-NMR (CDCl.sub.3) : 9.02-9.00 (1H, m), 8.95-8.93 (1H, m), 8.20-8.16 (1H, m), 6.99-6.85 (3H, m), 5.47 (2H, s), 4.05 (3H, s), 3.28-3.20 (2H, m), 2.81 (3H, s), 2.79-2.69 (2H, m), 2.64- 2.53 (1H, m), 2.41-2.04 (1H, m), 1.92-1.76 (2H, m), 1.73- 1.58 (2H, m). 344 LC-MS [M + 2H].sup.2+/2/Rt (min): 242.3/0.563 (Method C); .sup.1H-NMR (CDCl.sub.3) : 7.86-7.82 (2H, m), 7.77-7.73 (1H, m), 7.60-7.55 (1H, m), 6.99-6.89 (3H, m), 5.45 (2H, s), 4.04 (3H, s), 3.44-3.33 (1H, m), 3.13-2.87 (6H, m), 2.81 (3H, s), 2.00- 1.93 (1H, m), 1.87-1.74 (2H, m), 1.68-1.55 (1H, m), 1.52- 1.41 (1H, m). 345 LC-MS [M + 2H].sup.2+/2/Rt (min): 217.2/0.440 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.84-8.80 (1H, m), 8.74-8.69 (1H, m), 7.96-7.91 (1H, m), 7.41-7.35 (1H, m), 6.90-6.79 (3H, m), 5.45 (2H, s), 4.02 (3H, s), 3.25-3.17 (2H, m), 2.81 (3H, s), 2.77- 2.67 (2H, m), 2.61-2.51 (1H, m), 2.39-2.12 (1H, m), 1.83- 1.74 (2H, m), 1.68-1.54 (2H, m). 346 LC-MS [M + H].sup.+/Rt (min): 460.3/0.408 (Method C); .sup.1H-NMR (CDCl.sub.3) : 9.29 (1H, s), 8.98 (2H, s), 6.98-6.88 (3H, m), 5.49 (2H, s), 4.04 (3H, s), 3.52-3.32 (1H, m), 3.19-2.88 (6H, m), 2.82 (3H, s), 2.01- 1.95 (1H, m), 1.90-1.76 (2H, m), 1.71-1.57 (1H, m), 1.55- 1.41 (1H, m). 347 LC-MS [M + 2H].sup.2+/2/Rt (min): 230.3/0.446 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.73-8.69 (2H, m), 7.56-7.51 (2H, m), 7.00-6.82 (3H, m), 5.51 (2H, s), 4.02 (3H, s), 3.37-3.28 (1H, m), 3.05-2.78 (6H, m), 2.82 (3H, s), 1.94-1.88 (1H, m), 1.80- 1.69 (2H, m), 1.63-1.52 (1H, m), 1.45-1.33 (1H, m). 348 LC-MS [M + 2H].sup.2+/2/Rt (min): 237.7/0.444 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.87 (2H, s), 6.97- 6.88 (3H, m), 5.47 (2H, s), 4.02 (3H, s), 3.38-3.30 (1H, m), 3.05-2.84 (6H, m), 2.81 (3H, s), 2.79 (3H, s), 1.97- 1.89 (1H, m), 1.82-1.71 (2H, m), 1.66-1.52 (1H, m), 1.47- 1.35 (1H, m). 349 LC-MS [M + H].sup.+/Rt (min): 391.3/0.646 (Method C)

Example 350

5-Bromo-2-{[2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purin-9-yl]methyl}phenol

(180) ##STR00389##

(181) To the compound of Example 325 (236 mg) was added a solution of boron tribromide in dichloromethane (1 mol/L, 5 mL), and the mixture was stirred at room temperature for 5 days. To the reaction mixture was added methanol, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=>chloroform/methanol) and amino silica gel chromatography (chloroform/methanol) to give the title compound (60 mg).

(182) LC-MS [M+H].sup.+/Rt (min): 458.1/0.851 (Method C); .sup.1H-NMR (DMSO-d.sub.6) : 10.26 (1H, br s), 8.75-8.71 (2H, m), 8.10-8.05 (1H, m), 6.88 (1H, d, J=1.8 Hz), 6.82 (1H, dd, J=7.9, 1.8 Hz), 6.71 (1H, d, J=7.9 Hz), 5.36 (2H, s), 4.35 (2H, q, J=7.0 Hz), 2.67 (3H, s), 1.31 (3H, t, J=7.0 Hz).

Example 351

9-(4-Bromo-2-ethoxybenzyl)-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine

(183) ##STR00390##

(184) To a solution compound of Example 350 (55 mg) in N,N-dimethylformamide (6 mL) were added potassium carbonate (50 mg) and iodoethane (0.015 mL), and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine twice, dried over sodium sulfate, filtrated, and then concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (54 mg).

(185) LC-MS [M+H].sup.+/Rt (min): 486.1/1.060 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67-8.64 (1H, m), 8.54 (1H, d, J=3.0 Hz), 7.72-7.67 (1H, m), 6.96 (1H, d, J=1.8 Hz), 6.91 (1H, dd, J=8.2, 1.8 Hz), 6.62 (1H, d, J=8.2 Hz), 5.41 (2H, s), 4.43 (2H, q, J=7.2 Hz), 3.97 (2H, q, J=6.8 Hz), 2.80 (3H, d, J=10.4 Hz), 1.42 (3H, t, J=7.2 Hz), 1.28 (3H, t, J=6.8 Hz).

Example 352

9-{[5-(1-Azabicyclo[2.2.2]oct-2-en-3-yl)pyridin-2-yl]methyl}-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine

(186) ##STR00391##

(187) To a solution of the compound of Example 319 (113 mg) in 1,4-dioxane (2 mL) were added bis(pinacolato)diboron (114 mg), potassium acetate (86 mg), 1,1-bis(diphenylphosphino)ferrocene palladium chloride (22 mg), and 1,1-bis(diphenylphosphino)ferrocene (7.5 mg), and the mixture was stirred at 95 C. for 2 hours. To the reaction mixture were added the compound of Reference example 25 (150 mg), potassium carbonate (94 mg), 1,1-bis(diphenylphosphino)ferrocene palladium chloride (22 mg), and water (0.5 ml), and the mixture was stirred at 95 C. for 2 hours. The reaction mixture was cooled to room temperature. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (122 mg).

(188) LC-MS [M+H].sup.+/Rt (min): 472.38/0.678 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.94 (1H, s), 8.63-8.59 (2H, m), 8.21-8.16 (1H, m), 7.68 (1H, dd, J=8.2, 2.1 Hz), 7.31 (1H, d, J=8.2 Hz), 6.90 (1H, d, J=1.8 Hz), 5.55 (2H, s), 4.46 (2H, q, J=7.1 Hz), 3.15-3.10 (1H, m), 3.10-3.00 (2H, m), 2.84 (3H, s), 2.73-2.61 (2H, m), 1.83-1.77 (2H, m), 1.63-1.53 (2H, m), 1.46 (3H, t, J=7.1 Hz).

Examples 353-364

(189) According to the method of Example 352, Example 353-364 were prepared by using the correspond compounds.

(190) TABLE-US-00040 Example Chemical Structure Instrumental analysis data 353 LC-MS [M + H].sup.+/Rt (min): 458.4/0.645 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.96 (1H, s), 8.64- 8.58 (2H, m), 8.23-8.17 (1H, m), 7.68 (1H, dd, J = 8.2, 2.1 Hz), 7.33 (1H, d, J = 8.2 Hz), 6.89 (1H, d, J = 1.8 Hz), 5.55 (2H, s), 4.05 (3H, s), 3.14-3.10 (1H, m), 3.08-3.00 (2H, m), 2.84 (3H, s), 2.71-2.61 (2H, m), 1.82-1.76 (2H, m), 1.63-1.52 (2H, m). 354 LC-MS [M + 2H].sup.2+/2/Rt (min): 251.2/0.591 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.70-8.67 (1H, m), 8.54 (1H, d, J = 2.4 Hz), 7.75- 7.71 (1H, m), 6.86-6.79 (4H, m), 5.46 (2H, s), 4.43 (2H, q, J = 7.2 Hz), 3.76 (3H, s), 3.17-2.98 (3H, m), 2.81 (3H, s), 2.75-2.63 (2H, m), 1.84-1.74 (2H, m), 1.61-1.52 (2H, m), 1.42 (3H, t, J = 7.2 Hz). 355 LC-MS [M + 2H].sup.2+/2/Rt (min): 251.6/0.518 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.72-8.69 (1H, m), 8.59 (1H, d, J = 3.0 Hz), 8.11 (1H, s), 7.79-7.74 (1H, m), 7.14-7.13 (1H, m), 6.88 (1H, s), 5.45 (2H, s), 4.43 (2H, q, J = 7.0 Hz), 3.74 (3H, s), 3.59-3.54 (1H, m), 3.12-3.03 (2H, m), 2.78 (3H, s), 2.75-2.65 (2H, m), 1.83-1.74 (2H, m), 1.59-1.49 (2H, m), 1.42 (3H, t, J = 7.0 Hz). 356 LC-MS [M + 2H).sup.2+/2/Rt (min): 258.2/0.641 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.68-8.66 (1H, m), 8.52 (1H, d, J = 3.0 Hz), 7.74-7.68 (1H, m), 6.85 (1H, d, J = 1.2 Hz), 6.82-6.78 (2H, m), 6.72 (1H, d, J = 7.9 Hz), 5.48 (2H, s), 4.43 (2H, q, J = 7.0 Hz), 4.03 (2H, q, J = 7.0 Hz), 3.14-2.99 (3H, m), 2.82 (3H, s), 2.73-2.63 (2H, m), 1.83-1.73 (2H, m), 1.61-1.50 (2H, m), 1.41 (3H, t, J = 7.0 Hz), 1.30 (3H, t, J = 7.0 Hz). 357 LC-MS [M + 2H].sup.2+/2/Rt (min): 238.1/0.525 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67-8.64 (1H, m), 8.59 (1H, d, J = 2.4 Hz), 7.76-7.71 (1H, m), 7.21 (1H, t, J = 7.9 Hz), 6.83-6.75 (3H, m), 5.45 (2H, s), 4.04 (3H, s), 3.07-2.98 (3H, m), 2.83 (3H, s), 2.72-2.63 (2H, m), 1.79-1.70 (2H, m), 1.66-1.56 (2H, m). 358 LC-MS [M + H].sup.+/Rt (min): 461.3/0.361 (Method C); .sup.1H-NMR (DMSO-D.sub.6) : 12.12 (1H, br s), 8.74 (1H, d, J = 3.0 Hz), 8.68- 8.67 (1H, m), 8.04-7.99 (1H, m), 7.32-7.27 (1H, m), 6.97-6.90 (1H, m), 6.85-6.81 (1H, m), 6,68-6.64 (1H, m), 5.34 (2H, s), 2.95-2.82 (3H, m), 2.56 (3H, s), 2.48-2.38 (2H, m), 1.71-1.61 (2H, m), 1.50-1.39 (2H, m). 359 LC-MS [M + 2H].sup.2+/2/Rt (min): 245.6/0.532 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.89-8.85 (1H, m), 8.57 (1H, d, J = 3.0 Hz), 8.30-8.27 (1H, m), 8.07-8.02 (1H, m), 7.38 (1H, dd, J = 10.4, 1.8 Hz), 6.88 (1H, d, J = 1.8 Hz), 5.57 (2H, s), 4.38 (2H, q, J = 7.0 Hz), 3.07- 2.97 (3H, m), 2.79 (3H, s), 2.68- 2.57 (2H, m), 1.82-1.73 (2H, m), 1.58-1.47 (2H, m), 1.39 (3H, t, J = 7.0 Hz). 360 LC-MS [M + 2H].sup.2+/2/Rt (min): 270.7/0.644 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.57 (1H, d, J = 2.4 Hz), 8.54-8.52 (1H, m), 7.73-7.69 (1H, m), 7.52 (1H, d, J = 8.5 Hz), 7.27 (1H, s), 7.07 (1H, d, J = 8.5 Hz), 5.67 (2H, s), 4.39 (2H, q, J = 7.2 Hz), 3.70-3.63 (1H, m), 3.12-3.01 (2H, m), 2.84 (3H, s), 2.73-2.61 (2H, m), 1.85-1.75 (2H, m), 1.61-1.50 (2H, m), 1.39 (3H, t, J = 7.2 Hz). 361 00 LC-MS [M + 2H].sup.2+/2/Rt (min): 249.3/0.535 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.62 (1H, d, J = 2.4 Hz), 8.56-8.52 (1H, m), 7.79-7.73 (1H, m), 7.59 (1H, d, J = 8.5 Hz), 7.35 (1H, d, J = 8.5 Hz), 7.27 (1H, s), 5.67 (2H, s), 4.41 (2H, q, J = 7.2 Hz), 3.76-3.68 (1H, m), 3.19-3.06 (2H, m), 2.82 (3H, s), 2.78-2.64 (2H, m), 1.90-1.79 (2H, m), 1.63-1.51 (2H, m), 1.41 (3H, t, J = 7.2 (Hz). 362 01 LC-MS [M + 2H].sup.2+/2/Rt (min): 245.8/0.514 (Method C) 363 02 LC-MS [M + 2H].sup.2+/2/Rt (min): 248.8/0.529 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.59 (1H, d, J = 3.1 Hz), 8.55-8.53 (1H, m), 7.76-7.72 (1H, m), 7.69 (1H, d, J = 1.8 Hz), 7.51-7.48 (1H, m), 6.93 (1H, d, J = 8.5 Hz), 6.88 (1H, d, J = 1.8 Hz), 5.65 (2H, s), 4.41 (2H, q, J = 7.0 Hz), 3.12- 3.00 (3H, m), 2.83 (3H, s), 2.70-2.60 (2H, m), 1.86-1.78 (2H, m), 1.60-1.50 (2H, m), 1.41 (3H, t, J = 7.0 Hz). 364 03 LC-MS [M + 2H].sup.2+/2/Rt (min): 229.3/0.513 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.69-8.68 (1H, m), 8.57 (1H, d, J = 3.0 Hz), 7.70-7.65 (1H, m), 7.31-7.22 (2H, m), 7.13 (1H, s), 6.91 (1H, d, J = 7.3 Hz), 6.70 (1H, d, J = 1.2 Hz), 5.46 (2H, s), 4.05 (3H, s), 3.03-2.94 (3H, m), 2.82 (3H, s), 2.66-2.57 (2H, m), 1.80-1.69 (2H, m), 1.57-1.45 (2H, m).

Example 365

test-Butyl 4-(3-fluoro-4-{[8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purin-9-yl]methyl}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

(191) ##STR00404##

(192) To a solution of the compound of Example 337 (89 mg) in 1,2-dimethoxyethane (4 mL) were added 1-N-tert-butoxycarbonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (74 mg), dichlorobis(tri-o-tolylphosphine)palladium (II) (7.9 mg), potassium carbonate (83 mg), and water (1 mL), and the mixture was stirred at 100 C. for 4.5 hours. The reaction mixture was cooled to room temperature. Aqueous saturated sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (121 mg).

(193) LC-MS [M+H].sup.+/Rt (min): 549.4/1.061 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67-8.62 (1H, m), 8.57 (1H, d, J=3.0 Hz), 7.73-7.67 (1H, m), 7.07-6.98 (2H, m), 6.9-6.86 (1H, m), 6.06-5.93 (1H, m), 5.49 (2H, s), 4.05-4.01 (2H, m), 4.03 (3H, s), 3.63-3.53 (2H, m), 2.81 (3H, s), 2.45-2.35 (2H, m), 1.45 (9H, s).

Examples 366-367

(194) According to the method of Example 365, Examples 366-367 were prepared by using the corresponding material compounds.

(195) TABLE-US-00041 Example Chemical Structure Instrumental analysis data 366 05 LC-MS [M + 2H].sup.2+/2/Rt (min): 245.7/0.463 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.72-8.70 (1H, m), 8.57 (1H, d, J = 3.0 Hz), 8.09 (1H, s), 7.77-7.72 (1H, m), 6.77 (1H, s), 6.54-6.51 (1H, m), 5.43 (2H, s), 4.42 (2H, q, J = 7.1 Hz), 3.69 (3H, s), 3.21-3.13 (2H, m), 2.77 (3H, s), 2.71-2.59 (4H, m), 2.40 (3H, s), 1.41 (3H, t, J = 7.1 Hz). 367 06 LC-MS [M + H].sup.+/Rt (min): 535.4/1.005 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.66-8.64 (1H, m), 8.59 (1H, d, J = 2.4 Hz), 7.74-7.68 (1H, m), 7.07-6.89 (3H, m), 6.17-6.09 (1H, m), 5.51 (2H, s), 4.44-4.22 (4H, m), 4.04 (3H, s), 2.84 (3H, s), 1.50-1.45 (9H, m).

Example 368

tert-Butyl 4-(3-fluoro-4-{[8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purin-9-yl]methyl}benzyl)piperazine-1-carboxylate

(196) ##STR00407##

(197) To a solution 1-tert-butoxycarbonyl-4-methylenepiperidine (178 mg) in tetrahydrofuran (3 mL) was added 9-borabicyclo[3.3.1]nonane (0.5 mol/L, tetrahydrofuran solution, 1.8 mL) at room temperature, and the mixture was stirred at 75 C. for 3 hours and 20 minutes. The reaction mixture was cooled to room temperature. The compound of Example 337 (134 mg), potassium carbonate (124 mg), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (25 mg), 1,2-dimethoxyethane (3 mL), and water (2 mL) were added thereto, and the mixture was stirred at 75 C. for 3 hours and 40 minutes. The reaction mixture was cooled to room temperature. Aqueous saturated sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The obtained residue was purified by amino silica gel chromatography (hexane/ethyl acetate) and silica gel column chromatography (chloroform/methanol) to give the title compound (146 mg).

(198) LC-MS [M+H].sup.+/Rt (min): 565.4/1.123 (Method. C); .sup.1H-NMR (CDCl.sub.3) : 8.66-8.63 (1H, m), 8.57 (1H, d, J=3.0 Hz), 7.70-7.64 (1H, m), 6.88-6.74 (3H, m), 5.48 (2H, s), 4.12-3.96 (2H, m), 4.03 (3H, s), 2.81 (3H, s), 2.68-2.53 (2H, m), 2.50-2.41 (2H, m), 1.64-1.47 (3H, m), 1.42 (9H, s), 1.15-1.01 (2H, m).

Example 369

(199) According to the method of Example 368, Example 369 was prepared by using the corresponding material compound.

(200) TABLE-US-00042 Example Chemical Structure Instrumental analysis data 369 08 LC-MS [M + H].sup.+/Rt (min): 592.4/0.670 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.72-8.67 (1H, m), 8.59 (1H, d, J = 3.0 Hz), 8.12 (1H, s), 7.78-7.72 (1H, m), 6.52 (1H, s), 5.42 (2H, s), 4.43 (2H, q, J = 7.1 Hz), 4.11-3.94 (2H, m), 3.67 (3H, br s), 2.78 (3H, s), 2.69-2.51 (4H, m), 1.93-1.83 (1H, m), 1.63-1.47 (1H, m), 1.46-1.38 (12H, m), 1.31-1.21 (1H, m), 1.18-1.06 (2H, m).

Example 370

9-{[5-(1-Azabicyclo[2.2.2]oct-3-yl)pyridin-2-yl]methyl}-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine

(201) ##STR00409##

(202) To a solution the compound of Example 352 (104 mg) in ethyl acetate (2 mL) was added 20% palladium carbon (31 mg). The reaction mixture was stirred at room temperature under hydrogen atmosphere for 6 hours, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (85 mg).

(203) LC-MS [M+H].sup.+/Rt (min): 474.4/0.706 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.95 (1H, s), 8.60 (1H, d, J=3.0 Hz), 8.47 (1H, d, J=2.4 Hz), 8.18-8.13 (1H, m), 7.58 (1H, dd, J=8.2, 2.4 Hz), 7.29 (1H, d, J=8.2 Hz), 5.54 (2H, s), 4.46 (2H, q, J=7.1 Hz), 3.43-3.31 (1H, m), 3.07-2.86 (6H, m), 2.84 (3H, s), 1.92-1.35 (1H, m), 1.81-1.74 (2H, m), 1.65-1.54 (1H, m), 1.49-1.37 (4H, m).

Examples 371-387

(204) According to the method of Example 370, Examples 371-387 were prepared by using the corresponding material compounds.

(205) TABLE-US-00043 Example Chemical Structure Instrumental analysis data 371 0 .sup.1H-NMR (CDCl.sub.3) : 8.96 (1H, s), 8.60 (1H, d, J = 3.0 Hz), 8.47 (1H, d, J = 2.4 Hz), 8.19-8.15 (1H, m), 7.59 (1H, dd, J = 8.5, 3.0 Hz), 7.32 (1H, d, J = 8.5 Hz), 5.54 (2H, s), 4.05 (3H, s), 3.42-3.34 (1H, m), 3.09-2.87 (6H, m), 2.85 (3H, s), 1.98-1.91 (1H, m), 1.83-1.76 (2H, m), 1.66-1.56 (1H, m), 1.50-1.39 (1H, m). 372 LC-MS [M + 2H].sup.2+/2/Rt (min): 252.2/0.590 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.68-8.66 (1H, m), 8.53 (1H, d, J = 2.4 Hz), 7.73-7.68 (1H, m), 6.81 (1H, d, J = 7.9 Hz), 6.73-6.67 (2H, m), 5.44 (2H, s), 4.44 (2H, q, J = 7.0 Hz), 3.72 (3H, s), 3.40-3.25 (1H, m), 3.12-2.83 (6H, m), 2.80 (3H, s), 2.17-1.55 (4H, m), 1.47-1.32 (1H, m), 1.42 (3H, t, J = 7.0 Hz). 373 LC-MS [M + H].sup.+/Rt (min): 394.2/0.878 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.69-8.67 (1H, m), 8.53 (1H, d, J = 3.0 Hz), 7.71-7.66 (1H, m), 7.25-7.20 (1H, m), 6.85- 6.77 (3H, m), 5.47 (2H, s), 4.43 (2H, q, J = 7.2 Hz), 3.72 (3H, s), 2.81 (3H, s), 1.42 (3H, t, J = 7.2 Hz). 374 LC-MS [M + 2H].sup.2+/2/Rt (min): 252.6/0.510 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.66-8.64 (1H, m), 8.53 (1H, d, J = 3.0 Hz), 8.05 (1H, s), 7.74-7.69 (1H, m), 6.54 (1H, s), 5.43-5.33 (2H, m), 4.39 (2H, q, J = 7.0 Hz), 3.64 (3H, s), 3.54-3.46 (1H, m), 3.16-3.07 (1H, m), 3.03-2.82 (4H, m), 2.81-2.70 (1H, m), 2.74 (3H, s), 1.98-1.93 (1H, m), 1.75-1.62 (2H, m), 1.60-1.48 (1H, m), 1.38 (3H, t, J = 7.0 Hz), 1.31-1.17 (1H, m). 375 LC-MS [M + 2H].sup.2+/2/Rt (min): 246.6/0.436 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.71-8.67 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 8.11-8.07 (1H, m), 7.78-7.72 (1H, m), 6.64-6.60 (1H, m), 5.44-5.39 (2H, m), 4.43 (2H, q, J = 7.0 Hz), 3.71-3.64 (3H, m), 3.17-3.04 (1H, m), 2.78 (3H, s), 2.75-2.55 (1H, m), 2.48-1.51 (10H, m), 1.42 (3H, t, J = 7.0 Hz). 376 LC-MS [M + 2H].sup.2+/2/Rt (min): 259.2/0.636 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67-8.65 (1H, m), 8.50 (1H, d, J = 2.4 Hz), 7.69- 7.64 (1H, m), 6.72-6.65 (3H, m), 5.46 (2H, s), 4.43 (2H, q, J = 7.0 Hz), 3.97 (2H, q, J = 7.0 Hz), 3.34-3.24 (1H, m), 3.07-2.83 (6H, m), 2.81 (3H, s), 2.07-1.85 (1H, m), 1.77-1.68 (2H, m), 1.65-1.54 (1H, m), 1.44-1.31 (1H, m), 1.41 (3H, t, J = 7.0 Hz), 1.25 (3H, t, J = 7.0 Hz). 377 LC-MS [M + 2H].sup.2+/2/Rt (min): 239.1/0.528 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.66-8.64 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 7.73-7.69 (1H, m), 7.28-7.23 (1H, m), 6.83- 6.74 (2H, m), 5.44 (2H, s), 4.05 (3H, s), 3.34-3.17 (2H, m), 2.99- 2.79 (5H, m), 2.82 (3H, s), 1.92- 1.65 (3H, m), 1.63-1.53 (1H, m), 1.43-1.33 (1H, m). 378 LC-MS [M + H].sup.+/Rt (min): 463.3/0.360 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.65-8.62 (1H, m), 8.58 (1H, d, J = 3.0 Hz), 7.69- 7.64 (1H, m), 7.28-7.23 (1H, m), 6.86-6.74 (2H, m), 5.36 (2H, s), 3.38-3.21 (2H, m), 3.07-2.84 (5H, m), 2.82 (3H, s), 1.95-1.88 (1H, m), 1.86-1.68 (2H, m), 1.67- 1.54 (1H, m), 1.48-1.36 (1H, m). 379 LC-MS [M + 2H].sup.2+/2/Rt (min): 246.7/0.515 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.87-8.84 (1H, m), 8.55 (1H, d, J = 2.4 Hz), 8.15-8.12 (1H, m), 8.04-7.99 (1H, m), 7.32- 7.26 (1H, m), 5.57-5.55 (2H, m), 4.38 (2H, q, J = 7.0 Hz), 3.42-3.31 (1H, m), 3.05-2.85 (6H, m), 2.79 (3H, s), 1.95-1.89 (1H, m), 1.81- 1.72 (2H, m), 1.60-1.41 (2H, m), 1.38 (3H, t, J = 7.0 Hz). 380 LC-MS [M + 2H].sup.2+/2/Rt (min): 230.2/0.475 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.85-8.83 (1H, m), 8.73- 8.70 (1H, m), 7.96-7.91 (1H, m), 7.42-7.37 (1H, m), 7.27-7.21 (1H, m), 6.83-6.73 (2H, m), 5.40 (2H, s), 4.04 (3H, s), 3.31-3.14 (2H, m), 2.98-2.75 (5H, m), 2.81 (3H, s) 1.87-1.83 (1H, m), 1.77- 1.63 (2H, m), 1.60-1.52 (1H, m), 1.40-1.29 (1H, m). 381 0 LC-MS [M + H].sup.+/Rt (min): 542.2/0.635 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.56 (1H, d, J = 3.0 Hz), 8.54-8.51 (1H, m), 7.72-7.66 (1H, m), 7.27-7.20 (1H, m), 7.07- 7.01 (1H, m), 5.72-5.61 (2H, m), 4.39 (2H, q, J = 7.0 Hz), 3.62-3.47 (1H, m), 3.31-2.77 (6H, m), 2.84 (3H, s), 2.02-1.54 (4H, m), 1.42- 1.28 (1H, m), 1.38 (3H, t, J = 7.0 Hz). 382 LC-MS [M + 2H].sup.2+/2/Rt (min): 250.3/0.521 (Method C); .sup.1H-NMR (DMSO-D.sub.6) : 8.78-8.74 (2H, m), 8.18-8.13 (1H, m), 7.57 (1H, d, J = 8.2 Hz), 7.51 (1H, d, J = 8.2 Hz), 5.70 (2H, s), 4.28 (2H, q, J = 7.0 Hz), 3.27-3.16 (1H, m), 3.07-2.95 (2H, m), 2.80-2.58 (4H, m), 2.67 (3H, s), 1.90-1.86 (1H, m), 1.69- 1.53 (2H, m), 1.27-1.14 (2H, m), 1.25 (3H, t, J = 7.0 Hz). 383 LC-MS [M + 2H].sup.2+/2/Rt (min): 246.8/0.536 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67-8.64 (1H, m), 8.62 (1H, d, J = 2.4 Hz), 8.15-8.12 (1H, m), 7.76-7.71 (1H, m), 7.12- 7.06 (1H, m), 5.47 (2H, s), 4.46 (2H, q, J = 7.0 Hz), 3.70-3.60 (1H, m), 3.38-3.26 (1H, m), 3.15-3.01 (2H, m), 3.01-2.87 (2H, m), 2.86-2.72 (1H, m), 2.81 (3H, s), 2.00-1.63 (3H, m), 1.59-1.48 (1H, m), 1.44 (3H, t, J = 7.0 Hz), 1.33-1.20 (1H, m). 384 LC-MS [M + 2H].sup.2+/2/Rt (min): 249.9/0.530 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.58 (1H, d, J = 2.4 Hz), 8.55-8.53 (1H, m), 7.75-7.69 (1H, m), 7.56 (1H, d, J = 1.8 Hz), 7.40-7.33 (1H, m), 6.91 (1H, d, J = 7.9 Hz), 5.64 (2H, s), 4.41 (2H, q, J = 7.0 Hz), 3.39-3.29 (1H, m), 3.04-2.79 (6H, m), 2.82 (3H, s), 1.94-1.74 (3H, m), 1.58-1.45 (1H, m), 1.45-1.35 (1H, m), 1.40 (3H, t, J = 7.0 Hz). 385 LC-MS [M + H].sup.+/Rt (min): 551.5/1.061 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.65-8.62 (1H, m), 8.57 (1H, d, J = 2.4 Hz), 7.71-7.66 (1H, m), 6.90-6.81 (3H, m), 5.47 (2H, s), 4.30-4.13 (2H, m), 4.03 (3H, s), 2.82 (3H, s), 2.80-2.67 (2H, m), 2.63-2.52 (1H, m), 1.79-1.70 (2H, m), 1.64-1.47 (2H, m), 1.45 (9H, s). 386 LC-MS [M + H].sup.+/Rt (min): 459.4/0.492 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.68-8.66 (1H, m), 8.56 (1H, d, J = 2.4 Hz), 7.72-7.62 (1H, m), 7.28-7.21 (1H, m), 7.16 (1H, d, J = 7.9 Hz), 7.06-6.92 (1H, m), 6.88 (1H, d, J = 7.9 Hz), 5.48 (2H, s), 4.04 (3H, s), 3.44-3.23 (1H, m), 3.18-2.85 (6H, m), 2.82 (3H, s), 1.93-1.67 (3H, m), 1.65- 1.48 (1H, m), 1.46-1.30 (1H, m). 387 LC-MS [M + H].sup.+/Rt (min): 537.5/0.988 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.66-8.62 (1H, m), 8.57 (1H, d, J = 3.1 Hz), 7.74-7.67 (1H, m), 6.94-6.85 (3H, m), 5.48 (2H, s), 4.02 (3H, s), 3.83-3.66 (1H, m), 3,63-3.44 (1H, m), 3.41- 3.10 (3H, m), 2.81 (3H, s), 2.25- 2.14 (1H, m), 1.93-1.81 (1H, m), 1.44 (9H, s).

Example 388

9-[4-(1-Azabicyclo[2.2.2]oct-3-yl)benzyl]-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purin-2-ol

(206) ##STR00427##

(207) To a solution of the compound of Example 165 (88 mg) in ethyl acetate (2 mL) and methanol (0.2 mL) was added a solution of hydrochloric acid in ethyl acetate (4 mol/L, 0.055 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated in vacuo, and the residue was purified by amino silica gel column chromatography (chloroform/methanol) to give the title compound (15 mg).

(208) LC-MS [M+H].sup.+/Rt (min): 445.4/0.346 (Method C); .sup.1H-NMR (DMSO-D.sub.6) : 8.69 (1H, d, J=3.0 Hz), 8.67-8.64 (1H, m), 7.99-7.94 (1H, m), 7.18 (2H, d, J=8.2 Hz), 6.94 (2H, d, J=8.2 Hz), 5.32 (2H, s), 3.69-3.00 (3H, m), 2.88-2.59 (5H, m), 2.54 (3H, s), 1.73-1.68 (1H, m), 1.66-1.52 (2H, m), 1.44-1.33 (1H, m), 1.26-1.13 (1H, m).

Example 389

(209) According to the method of Example 388, Example 389 was prepared by using the corresponding material compound.

(210) TABLE-US-00044 Instru- Ex- mental am- analysis ple Chemical Structure data 389 LC-MS [M + H].sup.+/ Rt (min): 4.63.4/ 0.361 (Method C)

Examples 390, 391

9-({6-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]pyridin-3-yl}methyl)-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine; 9-{[6-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]pyridin-3-yl}methyl)-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine

(211) ##STR00429##

(212) The compound of Example 171 (25.9 mg) was optically separated in the following conditions to obtain the title compounds (Example 390: 12.0 mg-first peak: 18.2 min, Example 391: 8.9 mg-second peak: 31.4 min).

(213) Column: CHIRALPAK AS-H; Solvent: Solution A: hexane/diethylamine=1/0.1%, solution B: ethanol/2-propanol/diethylamine/methanol=3/2/0.1/1%; Mobile phase condition: A/B=85/15; Flow rate: 10 mL/min; Detection UV: 220 nm; Column temperature: 40 C.

(214) TABLE-US-00045 Example Instrumental analysis data 390 .sup.1H-NMR (400 MHz, CDCl.sub.3): 8.69-8.66 (1H, m), 8.60 (1H, d, J = 3.1 Hz), 8.33 (1H, d, J = 2.4 Hz), 7.74-7.69 (1H, m), 7.32 (1H, dd, J = 7.9, 2.4 Hz), 7.10 (1H, d, J = 7.9 Hz), 5.46 (2H, s), 4.47 (2H, q, J = 7.1 Hz), 3.46-3.37 (1H, m), 3.22-3.13 (1H, m), 3.04-2.82 (4H, m), 2.81 (3H, s), 2.79-2.73 (1H, m), 2.00-1.95 (1H, m), 1.74-1.68 (2H, m), 1.59-1.47 (1H, m), 1.45 (3H, t, J = 7.1 Hz), 1.32-1.22 (1H, m). 391 .sup.1H-NMR (400 MHz, CDCl.sub.3): 8.69-8.66 (1H, m), 8.60 (1H, d, J = 3.1 Hz), 8.33 (1H, d, J = 2.4 Hz), 7.74-7.69 (1H, m), 7.32 (1H, dd, J = 7.9, 2.4 Hz), 7.10 (1H, d, J = 7.9 Hz), 5.46 (2H, s), 4.47 (2H, q, J = 7.1 Hz), 3.46-3.37 (1H, m), 3.22-3.13 (1H, m), 3.04-2.82 (4H, m), 2.81 (3H, s), 2.79-2.73 (1H, m), 2.00-1.95 (1H, m), 1.74-1.68 (2H, m), 1.59-1.47 (1H, m), 1.45 (3H, t, J = 7.1 Hz), 1.32-1.22 (1H, m).

Examples 392, 393

9-{4-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-2-fluorobenzyl}-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine; 9-{4-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2-fluorobenzyl}-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine

(215) ##STR00430##

(216) The compound of Example 314 (30.3 mg) was optically separated in the following conditions to obtain the title compounds (Example 392: 12.2 mg-first peak: 19.4 min, Example 393: 11.3 mg-second peak: 36.7 min).

(217) Column: CHIRALPAK AD-H; Solvent: Solution A: hexane, Solution B: ethanol/2-propanol=1/2; Mobile phase condition: A/B/diethylamine=70/30/0.2%; Flow rate: 10 mL/min; Detection UV: 220 nm; Column temperature: 40 C.

(218) TABLE-US-00046 Example Instrumental analysis data 392 .sup.1H-NMR CDCl.sub.3) : 8.70-8.67 (1H, m), 8.61 (1H, d, J = 2.4 Hz), 7.75-7.70 (1H, m), 6.99-6.91 (3H, m), 5.53 (2H, s), 4.08 (3H, s), 3.36-3.26 (1H, m), 3.01-2.80 (9H, m), 1.93-1.85 (1H, m), 1.77-1.65 (2H, m), 1.59-1.50 (1H, m), 1.42-1.30 (1H, m). 393 .sup.1H-NMR (CDCl.sub.3) : 8.70-8.67 (1H, m), 8.61 (1H, d, J = 2.4 Hz), 7.75-7.70 (1H, m), 6.99-6.91 (3H, m), 5.53 (2H, s), 4.08 (3H, s), 3.36-3.26 (1H, m), 3.01-2.80 (9H, m), 1.93-1.85 (1H, m), 1.77-1.65 (2H, m), 1.59-1.50 (1H, m), 1.42-1.30 (1H, m).

Examples 394, 395

2-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purin-9-yl]methyl}benzonitrile; 2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-{[2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purin-9-yl]methyl}benzonitrile

(219) ##STR00431##

(220) The compound of Example 316 (29.5 mg) was optically separated in the following conditions to obtain the title compounds (Example 394: 14.6 mg-first peak: 10.8 min, Example 395: 15.0 mg-second peak: 26.9 min).

(221) Column: CHIRALPAK AD-H; Solvent: Solution A: hexane, Solution B: ethanol/2-propanol/methanol=6/3/1; Mobile phase condition: A/B/diethylamine=70/30/0.2%; Flow rate: 10 mL/min; Detection UV: 220 nm; Column temperature: 40 C.

(222) TABLE-US-00047 Example Instrumental analysis data 394 .sup.1H-NMR (CDCl.sub.3) : 8.68-8.60 (2H, m), 7.78-7.73 (1H, m), 7.50 (1H, d, J = 7.9 Hz), 7.40 (1H, d, J = 1.8 Hz), 7.32-7.29 (1H, m), 5.50 (2H, s), 4.50 (2H, q, J = 7.1 Hz), 3.44-3.38 (1H, m), 3.38-3.30 (1H, m), 3.10-3.00 (1H, m), 3.00-2.87 (4H, m), 2.86 (3H, s), 1.92-1.82 (2H, m), 1.79-1.73 (1H, m), 1.54-1.44 (4H, m), 1.42-1.33 (1H, m). 395 .sup.1H-NMR (CDCl.sub.3) : 8.68-8.60 (2H, m), 7.78-7.73 (1H, m), 7.50 (1H, d, J = 7.9 Hz), 7.40 (1H, d, J = 1.8 Hz), 7.32-7.29 (1H, m), 5.50 (2H, s), 4.50 (2H, q, J = 7.1 Hz), 3.44-3.38 (1H, m), 3.38-3.30 (1H, m), 3.10-3.00 (1H, m), 3.00-2.87 (4H, m), 2.86 (3H, s), 1.92-1.82 (2H, m), 1.79-1.73 (1H, m), 1.54-1.44 (4H, m), 1.42-1.33 (1H, m).

Examples 396, 397

9-({6-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-2-methylpyridin-3-yl}methyl)-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine; 9-({6-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methylpyridin-3-yl}methyl)-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine

(223) ##STR00432##

(224) The compound of Example 315 (30.0 mg) was optically separated in the following conditions to obtain the title compounds (Example 396: 14.6 mg-first peak: 11.4 min, Example 397: 15.0 mg-second peak: 16.1 min).

(225) Column: CHIRALPAK AD-H; Solvent: Solution A: hexane, Solution B: ethanol/2-propanol/methanol=1/1/1; Mobile phase condition: A/B/diethylamine=80/20/0.2%; Flow rate: 5 mL/min; Detection UV: 220 nm; Column temperature: 40 C.

(226) TABLE-US-00048 Example Instrumental analysis data 396 .sup.1H-NMR (CDCl.sub.3) : 8.62 (1H, s), 8.59 (1H, d, J = 3.0 Hz), 7.74-7.69 (1H, m), 6.92 (1H, d, J = 7.9 Hz), 6.84 (1H, d, J = 7.9 Hz), 5.46 (2H, s), 4.45 (2H, q, J = 7.1 Hz), 3.50-3.43 (1H, m), 3.24-3.16 (1H, m), 3.07-2.97 (2H, m), 2.96-2.88 (2H, m), 2.87 (3H, s), 2.85-2.77 (1H, m), 2.51 (3H, s), 2.02-1.97 (1H, m), 1.75-1.68 (2H, m), 1.66-1.57 (1H, m), 1.44 (3H, t, J = 7.1 H2), 1.35-1.26 (1H, m). 397 .sup.1H-NMR (CDCl.sub.3) : 8.62 (1H, s), 8.59 (1H, d, J = 3.0 Hz), 7.74-7.69 (1H, m), 6.92 (1H, d, J = 7.9 Hz), 6.84 (1H, d, J = 7.9 Hz), 5.46 (2H, s), 4.45 (2H, q, J = 7.1 Hz), 3.50-3.43 (1H, m), 3.24-3.16 (1H, m), 3.07-2.97 (2H, m), 2.96-2.88 (2H, m), 2.87 (3H, s), 2.85-2.77 (1H, m), 2.51 (3H, s), 2.02-1.97 (1H, m), 1.75-1.68 (2H, m), 1.66-1.57 (1H, m), 1.44 (3H, t, J = 7.1 Hz), 1.35-1.26 (1H, m),

Examples 398, 399

9-({1-[(3S)-1-Azabicyclo[2.2.2]oct-3-ylmethyl]-1H-pyrazol-4-yl}methyl)-2-ethoxy-8-(3-fluoropyridin-3-yl)-6-methyl-9H-purine; 9-({1-[(3R)-1-azabicyclo[2.2.2]oct-3-ylmethyl]-1H-pyrazol-4-yl}methyl)-2-ethoxy-8-(5-fluoropyridin-3-yl)-6-methyl-9H-purine

(227) ##STR00433##

(228) The compound of Example 163 (33.0 mg) was optically separated in the following conditions to obtain the title compounds (Example 398: 16.0 mg-first peak: 28.1 min, Example 399: 16.3 mg-second peak: 38.0 min).

(229) Column: CHIRALPAK AS-H; Solvent: Solution A: hexane/diethylamine=1/0.2%, Solution B: ethanol/2-propanol/diethylamine=2/1/0.2%; Mobile phase condition: A/B=90/10; Flow rate: 10 mL/min; Detection UV: 220 nm; Column temperature: 40 C.

(230) TABLE-US-00049 Example Instrumental analysis data 398 .sup.1H-NMR (CDCl.sub.3) : 8.78 (1H, s), 8.62 (1H, d, J = 3.1 Hz), 7.79-7.76 (1H, m), 7.32 (1H, s), 7.22 (1H, s), 5.31 (2H, s), 4.51 (2H, q, J = 7.1 Hz), 4.00 (2H, d, J = 7.9 Hz), 2.98-2.93 (1H, m), 2.87-2.71 (7H, m), 2.38-2.33 (1H, m), 2.19-2.13 (1H, m), 1.68-1.55 (2H, m), 1.49-1.40 (6H, m). 399 .sup.1H-NMR (CDCl.sub.3) : 8.78 (1H, s), 8.62 (1H, d, J = 3.1 Hz), 7.79-7.76 (1H, m), 7.32 (1H, s), 7.22 (1H, s), 5.31 (2H, s), 4.51 (2H, q, J = 7.1 Hz), 4.00 (2H, d, J = 7.9 Hz), 2.98-2.93 (1H, m), 2.87-2.71 (7H, m), 2.38-2.33 (1H, m), 2.19-2.13 (1H, m), 1.68-1.55 (2H, m), 1.49-1.40 (6H, m).

Examples 400, 401

2-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-5-{[8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purin-9-yl]methyl}benzonitrile; 2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-{[8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purin-9-yl]methyl}benzonitrile

(231) ##STR00434##

(232) The compound of Example 318 (40.0 mg) was optically separated in the following conditions to obtain the title compounds (Example 400: 21.2 mg-first peak: 11.9 min, Example 401: 18.2 mg-second peak: 26.9 min).

(233) Column: CHIRALPAK AD-H; Solvent: Solution A: hexane/diethylamine=1/0.2%, Solution B: ethanol/2-propanol/methanol/diethylamine=6/3/1/0.2%; Mobile phase condition: A/B=70/30; Flow rate: 10 mL/min; Detection UV: 220 nm; Column temperature: 40 C.

(234) TABLE-US-00050 Example Instrumental analysis data 400 LC-MS [M + 2H].sup.+2/2/Rt (min): 242.9/0.495 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.61-8.58 (2H, m), 7.75-7.70 (1H, m), 7.46 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 1.8 Hz), 7.27 (1H, dd, J = 8.5, 1.8 Hz), 5.47 (2H, s), 4.04 (3H, s), 3.43-3.27 (2H, m), 3.08-2.84 (5H, m), 2.83 (3H, s), 2.04-1.78 (2H, m), 1.78-1.66 (1H, m), 1.53-1.30 (2H, m). 401 LC-MS [M + H].sup.+2/2/Rt (min): 242.8/0.500 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.62-8.56 (2H, m), 7.77-7.71 (1H, m), 7.53-7.31 (3H, m), 5.48 (2H, s), 4.05 (3H, s), 3.64-3.54 (1H, m), 3.51-3.41 (1H, m), 3.39-2.98 (5H, m), 2.84 (3H, s), 2.15-1.83 (3H, m), 1.69-1.48 (2H, m).

Examples 402, 403

5-(9-{4-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-2-fluorobenzyl}-2-methoxy-6-methyl-9H-purin-8-yl)pyridine-3-carbonitrile; 5-(9-{4-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2-fluorobenzyl}-2-methoxy-6-methyl-9H-purin-8-yl)pyridine-3-carbonitrile

(235) ##STR00435##

(236) The compound of Example 344 (40.0 mg) was optically separated in the following conditions to obtain the title compounds (Example 402: 21.0 mg-first peak: 7.47 min, Example 403: 23.0 mg second peak: 13.6 min).

(237) Column: CHIRALPAK AD-H; Solvent: Solution A: hexane/diethylamine=1/0.2%, Solution B: 2-propanol/diethylamine=1/0.1%; Mobile phase condition: A/B=60/40; Flow rate: 10 mL/min; Detection UV: 220 nm; Column temperature: 40 C.

(238) TABLE-US-00051 Example Instrumental analysis data 402 LC-MS [M + 2H].sup.+2/2/Rt (min): 242.7/0.492 (Method C); .sup.1H-NMR CDCl.sub.3) : 9.02 (1H, d, J = 2.4 Hz), 8.95 (1H, d, J = 1.8 Hz), 8.21-8.19 (1H, m), 7.02-6.91 (3H, m), 5.48 (2H, s), 4.05 (3H, s), 3.41-3.32 (1H, m), 3.07-2.84 (6H, m), 2.81 (3H, s), 1.97-1.92 (1H, m), 1.81-1.74 (2H, m), 1.64-1.53 (1H, m), 1.49-1.36 (1H, m). 403 LC-MS [M + 2H].sup.+2/2/Rt (min): 242.8/0.491 (Method C); .sup.1H-NMR (CDCl.sub.3) : 9.03 (1H, d, J = 1.8 Hz), 8.95 (1H, d, J = 1.8 Hz), 8.22-8.20 (1H, m), 7.00-6.90 (3H, m), 5.48 (2H, s), 4.05 (3H, s), 3.31-3.23 (1H, m), 2.98-2.79 (6H, m), 2.81 (3H, s), 1.88-1.83 (1H, m), 1.73-1.61 (2H, m), 1.57-1.46 (1H, m), 1.40-1.29 (1H, m).

Examples 404, 405

3-Fluoro-4-{[8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purin-9-yl]methyl}phenol; 9-(2-fluoro-4-methoxybenzyl)-8-(5-fluoropyridin-3-yl)-2-methoxy-6-methyl-9H-purine

(239) ##STR00436##

(240) To an ice-cooled solution of the compound of Example 342 (103 mg) in methanol (2 mL)/tetrahydrofuran (2 mL) was added 1 mol/L aqueous potassium hydroxide (0.223 mL), and the mixture was stirred in ice bath for 10 hours. To the reaction mixture was added 50% aqueous potassium carbonate, and the mixture was extracted with chloroform/ethanol (3/1). The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The obtained residue was purified by amino silica gel column chromatography (chloroform/methanol) and amino silica gel column chromatography (hexane/ethyl acetate) to give the compound of Example 404 (57.0 mg) and the compound of Example 405 (10.0 mg).

(241) Compound of Example 404: LC-MS [M+H].sup.+/Rt. (min): 384.2/0.650 (Method C); .sup.1H-NMR (DMSO-D.sub.6) : 9.95 (1H, br s), 8.75 (1H, d, J=2.4 Hz), 8.74-8.71 (1H, m), 8.14-8.08 (1H, m), 6.86-6.78 (1H, m), 6.45-6.38 (2H, m), 5.44 (2H, s), 3.95 (3H, s), 2.68 (38, s).

(242) Compound of Example 405: LC-MS [M+H].sup.+/Rt (min): 398.3/0.801 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67-8.66 (1H, m), 8.58 (1H, d, J=3.0 Hz), 7.70-7.66 (1H, m), 6.92 (1H, t, J=8.5 Hz), 6.57-6.52 (2H, m), 5.43 (2H, s), 4.04 (3H, s), 3.73 (3H, s), 2.80 (3H, s).

Examples 406-407

(243) According to the method of Example 405, Examples 405-406 were prepared by using the corresponding material compounds.

(244) TABLE-US-00052 Ex- Instrumental am- analysis ple Chemical Structure data 406 LC-MS [M + H].sup.+/Rt (min): 446.2/0.740 (Method C) 407 LC-MS [M + H].sup.+/Rt (min): 3.662/0.575 (Method C)

Example 408

tert-Butyl (3-endo)-3-(4-{[8-(5-cyanopyridin-3-yl)-2-methoxy-6-methyl-9H-purin-9-yl]methyl}-3-fluorophenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate

(245) ##STR00439##

(246) To an ice-cooled solution of the compound of Example 349 (25.0 mg) in chloroform (0.4 mL) were added tert-butyl (1R,3S,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (29.0 mg), triphenylphosphine (34.0 mg), and diisopropyl azodicarboxylate (0.025 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the obtained residue was purified by amino silica gel column chromatography (hexane/ethyl acetate) to give the title compound (29.0 mg).

(247) .sup.1H-NMR (CDCl.sub.3) : 9.07-9.04 (1H, m), 8.99-8.95 (1H, m), 8.24-8.18 (1H, m), 7.00 (1H, t, J=8.9 Hz), 6.60-6.45 (2H, m), 5.44 (2H, s), 4.55-4.48 (1H, m), 4.07 (3H, s), 3.75 (2H, s), 2.82 (3H, s), 1.99-1.91 (2H, m), 1.91-1.84 (2H, m), 1.48-1.46 (4H, m), 1.26 (9H, s).

Examples 409-421

(248) According to the methods of Example 66 and Example 408, Examples 409-421 were prepared by using the corresponding material compounds.

(249) TABLE-US-00053 Example Chemical Structure Instrumental analysis data 409 0 LC-MS [M + 2H].sup.2+/2/Rt (min): 278.3/0.581 (Method C) 410 LC-MS [M + 2H].sup.2+/2/Rt (min): 238.68/1.075 (Method C); .sup.1H-NMR (CD.sub.3OD) : 8.84-8.81 (1H, m), 8.70 (1H, dd, J = 4.9, 1.2 Hz), 8.12 (1H, dt, J = 7.9, 1.8 Hz), 7.57 (1H, dt, J = 7.9, 3.1 Hz), 6.97 (1H, t, J = 8.5 Hz), 6.60-6.54 (2H, m), 5.50 (2H, s), 4.45-4.37 (1H, m), 4.03 (3H, s), 3.26-3.21 (1H, m), 2.91-2.74 (3H, m), 2.72 (3H, s), 2.71-2.63 (1H, m), 2.09-2.00 (1H, m), 1.95-1.83 (1H, m), 1.79-1.68 (1H, m), 1.66-1.54 (1H, m), 1.48-1.35 (1H, m), 1.31- 1.18 (H, m). 411 LC-MS [M + 2H].sup.2+/2/Rt (min): 241.3/0.520 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67-8.64 (1H, m), 8.58 (1H, d, J = 3.1 Hz), 7.72-7.66 (1H, m), 6.94-6.86 (1H, m), 6.59- 6.50 (2H, m), 5.43 (2H, s), 4.35- 4.23 (1H, m), 4.04 (3H, s), 2.80 (3H, s), 2.78-2.69 (2H, m), 2.59- 2.30 (2H, m), 2.38 (3H, s), 2.16- 2.02 (2H, m), 1.91-1.79 (2H, m). 412 LC-MS [M + 2H].sup.2+/2/Rt (min): 247.4/0.517 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67-8.64 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 7.72- 7.67 (1H, m), 6.94-6.88 (1H, m), 6.53-6.47 (2H, m), 5.43 (2H, s), 4.45-4.25 (1H, m), 4.04 (3H, s), 3.44-3.18 (1H, m), 3.05-2.77 (5H, m), 2.80 (3H, s), 2.51-1.37 (5H, m) . 413 LC-MS [M + 2H].sup.2+/2/Rt (min): 247.3/0.525 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67-8.64 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 7.72- 7.66 (1H, m), 6.95-6.88 (1H, m), 6.53-6.47 (2H, m), 5.43 (2H, s), 4.40-4.29 (1H, m), 4.04 (3H, s), 3.39-3.24 (1H, m), 3.08-2.82 (5H, m), 2.80 (3H, s), 2.49-1.38 (5H, m). 414 LC-MS [M + 2H].sup.2+/2/Rt (min): 234.3/0.499 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.66-8.64 (1H, m), 8.58 (1H, d, J = 3.0 Hz), 7.71- 7.65 (1H, m), 6.93-6.87 (1H, m), 6.53-6.47 (2H, m), 5.43 (2H, s), 4.79-4.72 (1H, m), 4.04 (3H, s), 3.12-2.60 (4H, m), 2.80 (3H, s), 2.48 (3H, s), 2.37-2.26 (1H, m), 2.04-1.94 (1H, m). 415 LC-MS [M + 2H].sup.2+/2/Rt (min): 234.3/0.479 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.66-8.64 (1H, m), 8.58 (1H, d, J = 3.0 Hz), 7.71- 7.66 (1H, m), 6.93-6.86 (1H, m), 6.52-6.46 (2H, m), 5.42 (2H, s), 4.78-4.71 (1H, m), 4.04 (3H, s), 3.05-2.75 (3H, m), 2.80 (3H, s), 2.70-2.55 (1H, m), 2.45 (3H, s), 2.36-2.25 (1H, m), 2.03-1.92 (1H, m). 416 LC-MS [M + 2H].sup.2+/2/Rt (min): 227.2/0.473 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.65-8.64 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 7.71- 7.65 (1H, m), 6.94-6.87 (1H, m), 6.45-6.37 (2H, m), 5.42 (2H, s), 4.72-4.65 (1H, m), 4.03 (3H, s), 3.93-3.86 (2H, m), 3.19-3.13 (2H, m), 2.80 (3H, s), 2.45 (3H, s). 417 LC-MS [M + H].sup.+/Rt (min): 5.93.5/1.126 (Method C) 418 LC-MS [M + 2H].sup.2+/2/Rt (min): 254.3/0.519 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.66-8.64 (1H, m), 8.58 (1H, d, J = 3.1 Hz), 7.71- 7.66 (1H, m), 6.93-6.86 (1H, m), 6.55-6.49 (2H, m), 5.42 (2H, s), 4.48-4.37 (1H, m), 4.04 (3H, s), 3.50-3.34 (2H, m), 2.80 (3H, s), 2.47 (3H, s), 2.30-1.92 (6H, m), 1.78-1.66 (2H, m). 419 0 LC-MS [M + H].sup.+/Rt (min): 553.4/0.969 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67-8.65 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 7.71-7.66 (1H, m), 6.95-6.88 (1H, m), 6.58- 6.51 (2H, m), 5.44 (2H, s), 4.07- 3.97 (4H, m), 4.04 (3H, s), 3.75-3.70 (2H, m), 2.97-2.85 (1H, m), 2.80 (3H, s), 1.41 (9H, s). 420 LC-MS [M + 2H].sup.2+/2/Rt (min): 228.3/0.463 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67-8.64 (1H, m), 8.58 (1H, d, J = 3.0 Hz), 7.71-7.66 (1H, m), 6.95-6.88 (1H, m), 6.61- 6.54 (2H, m), 5.44 (2H, s), 4.24- 4.11 (2H, m), 4.04 (3H, s), 3.03- 2.89 (2H, m), 2.80 (3H, s), 2.53 (6H, br s). 421 LC-MS [M + 2H].sup.2+/2/Rt (min): 235.2/0.496 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.68-8.64 (1H, m), 8.58 (1H, d, J = 3.1 Hz), 7.71-7.65 (1H, m), 6.93-6.86 (1H, m), 6.57- 6.50 (2H, m), 5.43 (2H, s), 4.04 (3H, s), 3.95 (2H, t, J = 6.1 Hz), 2.80 (3H, s), 2.71-2.61 (2H, m), 2.42 (6H, br s), 2.12-2.01 (2H, m).

Example 422

5-(9-{4-[(3S)-1-Azabicyclo[2.2.2]oct-3-yloxy]-2-fluorobenzyl}-2-methoxy-6-methyl-9H-purin-8-yl)pyridine-3-carbonitrile

(250) ##STR00453##

(251) To a solution of the compound of Example 409 (50.0 mg) in N,N-dimethylformamide (1.5 mL) were added tetrakis(triphenylphosphine)palladium (10.4 mg) and zinc cyanide (12.7 mg), and the reaction solution was heated to 85 C. and stirred with heating for 2 hours. The reaction solution was filtrated, and the filtrate was purified by reversed-phase column chromatography (water/acetonitrile/trifluoruacetic acid) to give the title compound (12.2 mg).

(252) LC-MS [M+2H].sup.2+/2//Rt (min): 250.67/0.538; .sup.1H-NMR (CD.sub.3OD) : 9.06 (2H, s), 8.46 (1H, t, J=2.1 Hz), 7.04 (1H, t, J=8.9 Hz), 6.64-6.58 (2H, m), 5.55 (2H, s), 4.52-4.40 (1H, m), 4.08 (3H, s), 3.38-3.22 (1H, m), 2.94-2.79 (3H, m), 2.79-2.67 (2H, m), 2.76 (3H, s), 2.12-2.04 (1H, m), 1.98-1.88 (1H, m), 1.84-1.72 (1H, m), 1.70-1.58 (1H, m), 1.52-1.40 (1H, m).

Example 423

(253) According to the method of Example 216, Example 423 was prepared by using the corresponding material compound.

(254) TABLE-US-00054 Ex- Instrumental am- analysis ple Chemical Structure data 423 LC-MS [M + H].sup.+/Rt (min): 396.4/0.800 (Method A)

Examples 424-437

(255) According to the methods of Example 123 and Example 227, Examples 424-237 were prepared by using the corresponding material compounds.

(256) TABLE-US-00055 Example Chemical Structure Instrumental analysis data 424 LC-MS [M + H].sup.+/Rt (min): 453.3/0.569 (Method A); 425 LC-MS [M + H].sup.+/Rt (min): 453.3/0.572 (Method A); 426 LC-MS [M + H].sup.+/Rt (min): 453.3/0.564 (Method A); 427 LC-MS [M + H].sup.+/Rt (min): 453.3/0.565 (Method A); 428 LC-MS [M + H].sup.+/Rt (min): 451.3/0.589 (Method A); 429 0 LC-MS [M + H].sup.+/Rt (min): 478.5/0.561 (Method A); 430 LC-MS [M + 2H].sup.2+/2/Rt (min): 246.8/0.393 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.72-8.69 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 8.12 (1H, s), 7.77-7.72 (1H, m), 6.50 (1H, s), 5.41 (2H, s), 4.43 (2H, q, J = 7.0 Hz), 3.65 (3H, s), 3.07-3.01 (2H, m), 2.77 (3H, s), 2.61-2.51 (4H, m), 1.91-1.69 (2H, m), 1.59-1.52 (2H, m), 1.42 (3H, t, J = 7.0 Hz), 1.29-1.14 (2H, m). 431 LC-MS [M + 2H].sup.2+/2/Rt (min): 226.1/0.489 (Method C) ; .sup.1H-NMR (CDCl.sub.3) : 8.66-8.62 (1H, m), 8.57 (1H, d, J = 2.4 Hz), 7.72-7.65 (1H, m), 6.91-6.84 (3H, m), 5.47 (2H, s), 4.03 (3H, s), 3.25-3.16 (2H, m), 2.81 (3H, s), 2.77-2.67 (2H, m), 2.62-2.50 (1H, m), 2.04- 1.83 (1H, m), 1.83-1.74 (2H, m), 1.68-1.54 (2H, m). 432 LC-MS [M + 2H].sup.2+/2/Rt (min): 233.3/0.554 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.65-8.63 (1H, m), 8.56 (1H, d, J = 3.1 Hz), 7.71-7.64 (1H, m), 6.88-6.73 (3H, m), 5.47 (2H, s), 4.03 (3H, s), 3.13-3.04 (2H, m), 2.81 (3H, s), 2.59-2.50 (2H, m), 2.49-2.42 (2H, m), 2.31-2.06 (1H, m), 1.67-1.49 (3H, m), 1.27-1.12 (2H, m). 433 LC-MS [M + 2H].sup.2+/2/Rt (min): 247.3/0.534 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.67-8.64 (1H, m), 8.58 (1H, d, J = 3.1 Hz), 7.72-7.66 (1H, m), 6.94-6.88 (1H, m), 6.49-6.42 (2H, m), 5.42 (2H, s), 4.50-4.41 (1H, m), 4.04 (3H, s), 3.63-3.53 (2H, m), 2.80 (3H, s), 2.31-1.75 (7H, m), 1.30-1.19 (2H, m). 434 LC-MS [M + 2H].sup.2+/2/Rt (min): 227.2/0.482 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.66-8.63 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 7.72-7.66 (1H, m), 6.96-6.86 (1H, m), 6.65- 6.49 (2H, m), 5.44 (2H, s), 4.32- 3.90 (5H, m), 4.04 (3H, s), 3.86- 3.67 (2H, m), 3.25-3.09 (1H, m), 2.80 (3H, s). 435 LC-MS [M + 2H].sup.2+/2/Rt (min): 219.2/0.466 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.66-8.62 (1H, m), 8.57 (1H, d, J = 3.0 Hz), 7.74-7.67 (1H, m), 6.94-6.85 (3H, m), 5.48 (2H, s), 4.03 (3H, s), 3.43-3.35 (1H, m), 3.26-3.07 (3H, m), 2.87- 2.80 (1H, m), 2.81 (3H, s), 2.47- 2.15 (2H, m), 1.86-1.74 (1H, m). 436 LC-MS [M + 2H].sup.2+/2/Rt (min): 250.9/0.522 (Method C); .sup.1H-NMR (CDCl.sub.3) : 9.06 (2H, dd, J = 3.7, 2.4 Hz), 8.46 (1H, t, J = 1.8 Hz), 703 (1H, t, J = 8.9 Hz), 6.59-6.52 (2H, m), 5.56 (2H, s), 4.56-4.55 (1H, m), 4.08 (3H, s), 3.54-3.44 (2H, m), 2.77 (3H, s), 2.14-2.03 (3H, m), 1.93-1.75 (5H, m). 437 LC-MS [M + 2H].sup.2+/2/Rt (min): 238.34/0.511 (Method C)

Example 438

(257) According to the method of Example 232, Example 438 was prepared by using the corresponding material compound.

(258) TABLE-US-00056 Example Chemical Structure Instrumental analysis data 438 LC-MS: [M + H].sup.+/Rt (min): 476.4/0.810 (Method A)

Examples 439-441

(259) According to the method of Example 165 or Example 301, Examples 439-441 were prepared by using the corresponding material compounds.

(260) TABLE-US-00057 Example Chemical Structure Instrumental analysis data 439 0 LC-MS: [M + 2H].sup.2+/2/Rt (min): 259.7/0.477 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.82-8.76 (1H, m), 8.23 (1H, d, J = 7.3 Hz), 8.03 (1H, dd, J = 2.4, 7.9 Hz), 6.85 (1H, t, J = 8.5 Hz), 6.46-6.39 (2H, m), 5.38 (2H, s), 4.23-4.17 (1H, m), 4.00 (3H, s), 3.20-3.12 (1H, m), 2.93- 2.77 (2H, m), 2.77 (3H, s), 2.75- 2.63 (2H, m), 2.05-1.99 (1H, m), 1.92-1.78 (1H, m), 1.71-1.62 (1H, m), 1.51-1.41 (1H, m), 1.36-1.25 (1H, m). 440 LC-MS: [M + 2H].sup.2+/2/Rt (min): 263.3/0.559 (Method C); .sup.1H-NMR (CD.sub.3OD) : 8.99-8.95 (1H, m), 8.45- 8.41 (1H, m), 8.27 (1H, d, J = 1.8 Hz), 8.15 (1H, d, J = 9.2 Hz), 8.04 (1H, dd, J = 2.1, 8.9 Hz), 7.65 (1H, dd, J = 4.3, 7.9 Hz), 6.98- 6.91 (1H, m), 6.55-6.47 (2H, m), 5.60 (2H, s), 4.41-4.35 (1H, m), 4.07 (3H, s), 3.25-3.17 (1H, m), 2.85-2.79 (2H, m), 2.77 (3H, s), 2.67-2.62 (2H, m), 2.00-1.95 (1H, m), 1.91-1.81 (1H, m), 1.79-1.69 (1H, m), 1.64-1.53 (1H, m), 1.46- 1.35 (1H, m). 441 LC-MS [M + 2H].sup.2+/2/Rt (min): 238.6/ 0.540; .sup.1H-NMR (CD.sub.3OD) : 9.26 (1H, dd, J = 4.9, 1.8 Hz), 8.51-8.50 (1H, m), 7.90-7.87 (1H, m), 7.03 (1H, t, J = 8.5 Hz), 6.60-6.55 (2H, m), 6.11 (2H, s), 4.46-4.39 (1H, m), 4.07 (3H, s), 3.29-3.20 (1H, m), 2.91- 2.81 (2H, m), 2.78 (3H, m), 2.77- 2.65 (2H, m), 2.10-2.03 (1H, m), 1.98-1.87 (1H, m), 1.81-1.70 (1H, m), 1.67-1.57 (1H, m), 1.49-1.37 (1H, m).

Example 442

(261) According to the method of Example 352, Example 442 was prepared by using the corresponding material compound.

(262) TABLE-US-00058 Example Chemical Structure Instrumental analysis data 442 LC-MS: [M + H].sup.+/Rt (min): 475.5/0.639 (Method A)

Example 443

(263) According to the method of Example 370, Example 443 was prepared by using the corresponding material compound.

(264) TABLE-US-00059 Example Chemical Structure Instrumental analysis data 443 LC-MS (M + 2H].sup.2+/2/Rt (min): 239.2/0.514 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.65-8.64 (1H, m), 8.58 (1H, d, J = 2.4 Hz), 7.73-7.70 (1H, m), 7.17-7.10 (1H, m), 7.05-6.98 (1H, m), 6.95-6.90 (1H, m), 5.51 (2H, s), 4.03 (3H, s), 3.39-3.29 (1H, m), 3.12-2.88 (6H, m), 2.82 (3H, s), 1.85-1.74 (3H, m), 1.58- 1.47 (1H, m), 1.45-1.34 (1H, m).

Examples 444, 445

9-{4-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-2-fluorobenzyl}-2-methoxy-6-methyl-8-(pyrimidin-5-yl)-9H-purine; 9-{4-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2-fluorobenzyl}-2-methoxy-6-methyl-8-(pyrimidin-5-yl)-9H-purine

(265) ##STR00475##

(266) The compound of Example 346 (190 mg) was optically separated in the following conditions to obtain the title compounds (Example 444: 88.0 mg-first peak: 7.19 min, Example 445: 88.0 mg-second peak: 16.6 min.).

(267) Column: CHIRALPAK AD-H; Solvent: Solution A: hexane/diethylamine=1/0.1%, Solution B: 2-propanol/diethylamine=1/0.1%; Mobile phase condition: A/B=60/40; Flow rate: 10 mL/min; Detection UV: 220 nm; Column temperature: 40 C.

(268) TABLE-US-00060 Example Instrumental analysis data 444 LC-MS [M + 2H].sup.2+/2/Rt (min): 230.7/0.425 (Method C); .sup.1H-NMR (CDCl.sub.3) : 9.29 (1H, s), 8.98 (2H, s), 6.98-6.89 (3H, m), 5.49 (2H, s), 4.04 (3H, s), 3.47-3.29 (1H, m), 3.14-2.87 (6H, m), 2.82 (3H, s), 1.99-1.92 (1H, m), 1.87-1.72 (2H, m), 1.68-1.55 (1H, m), 1.51-1.38 (1H, m). 445 LC-MS [M + 2H].sup.2+/2/Rt (min): 230.7/0.428 (Method C); .sup.1H-NMR (CDCl.sub.3) : 9.29 (1H, s), 8.98 (2H, s), 6.98-6.89 (3H, m), 5.49 (2H, s), 4.04 (3H, s), 3.45-3.30 (1H, m), 3.14-2.86 (6H, m), 2.82 (3H, s), 1.98-1.91 (1H, m), 1.86-1.72 (2H, m), 1.67-1.53 (1H, m), 1.50-1.37 (1H, m).

Reference Example 1

6-{[(Methylsulfonyl)oxy]methyl}pyridin-3-yl methanesulfonate

(269) ##STR00476##

(270) To an ice-cooled solution of 6-(hydroxymethyl)pyridin-3-ol (946 mg) in tetrahydrofuran (25 mL) were added triethylamine (2.4 mL) and methanesulfonyl chloride (1.3 mL), and the mixture was stirred in ice bath for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate, dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (842 mg).

(271) .sup.1H-NMR (CDCl.sub.3) : 8.56 (1H, d, J=2.6 Hz), 7.73 (1H, dd, J=2.6, 8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 5.34 (2H, s), 3.24 (3H, s), 3.12 (3H, s).

Reference Example 2

Methyl 4-[(6-amino-2-ethoxy-9H-purin-9-yl)methyl]benzoate

(272) ##STR00477##

(273) To an ice-cooled solution of 2-ethoxy-9H-purine-6-amine trifluoroacetate (2.00 g) in N,N-dimethylformamide (30 mL) were added potassium carbonate (3.01 g) and methyl 4-(bromomethyl)benzoate (2.00 g). The reaction mixture was stirred at room temperature for 28 hours. To the reaction mixture was added aqueous saturated sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.57 g).

(274) LC-MS [M+H].sup.+/Rt (min): 328.3/0.745 (Method A)

Reference Examples 3-22

(275) According to the method of Reference example 2, Reference examples 3-22 were prepared by using the corresponding material compounds.

(276) TABLE-US-00061 Reference example Chemical Structure Instrumental analysis data 3 LC-MS: [M + H].sup.+/Rt (min): 356.1/0.858 (Method A) 4 LC-MS: [M + H].sup.+/Rt (min): 358.2/0.604 (Method A) 5 0 LC-MS: [M + H].sup.+/Rt (min): 327.3/0.652 (Method A) 6 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 9.97 (1H, s), 8.09 (1H, s), 7.89 (2H, d, J = 8.2 Hz), 7.48 (2H, d, J = 8.2 Hz), 7.30 (2H, brs), 5.38 (2H, s), 4.30 (2H, t, J = 4.7 Hz), 3.58 (2H, t, J = 4.7 Hz), 3.26 (3H, s). 7 LC-MS: [M + H].sup.+/Rt (min): 298.3/0.650 (Method A) 8 .sup.1H-NMR (CDCl.sub.3) : 8.45 (1H, d, J = 2.4 Hz), 7.62-7.59 (2H, m), 7.30 (1H, d, J = 7.9 Hz), 5.61 (2H, br s), 5.27 (2H, s), 4.37 (2H, q, J = 7.1 Hz), 1.41 (3H, t, J = 7.1 Hz). 9 .sup.1H-NMR (CDCl.sub.3) : 8.36 (1H, d, J = 1.8 Hz), 7.88-7.83 (1H, m), 6.92-6.89 (1H, m), 5.44 (2H, s), 5.30 (2H, s), 4.39 (2H, q, J = 7.2 Hz), 1.42 (3H, t, J = 7.2 Hz). 10 .sup.1H-NMR (DMSO-D.sub.6) : 8.26 (1H, s), 7.94-7.91 (2H, m), 7.81 (2H, br s), 7.35 (2H, d, J = 8.5 Hz), 5.43 (2H, s), 3.82 (3H, s). 11 LC-MS [M + H].sup.+/Rt (min): 365.2/0.667 (Method C) 12 .sup.1H-NMR (CDCl.sub.3) : 7.59 (1H, s), 7.51 (1H, s), 7.40 (1H, s), 5.47 (2H, s), 5.14 (2H, s), 4.41 (2H, q, J = 7.1 Hz), 3.87 (3H, s), 1.45- 1.40 (3H, m). 13 LC-MS: [M + H].sup.+/Rt (min): 305.3/0.536 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 8.34 (1H, d, J = 5.5 Hz), 7.62 (1H, s), 7.17 (1H, s), 7.05 (1H, d, J = 5.5 Hz), 5.72 (2H, s), 5.27 (2H, s), 4.34 (2H, q, J = 7.1 Hz), 1.38 (3H, t, J = 7.0 Hz). 14 LC-MS: [M + 1].sup.+/Rt (min): 305.3/0.584 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 7.79 (1H, s), 7.59 (1H, dd, J = 7.9, 7.9 Hz), 7.25 (1H, d, J = 7.9 Hz), 7.09 (1H, d, J = 7.9 Hz), 5.71 (2H, s), 5.36 (2H, s), 4.35 (2H, q, J = 7.0 Hz), 1.38 (3H, t, J = 7.0 Hz). 15 0 LC-MS: [M + H].sup.+/Rt (min): 305.3/0.573 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 8.46 (1H, d, J = 6.1 Hz), 7.78 (1H, s), 7.24-7.23 (2H, m), 5.56 (2H, s), 5.37 (2H, s), 4.37 (2H, q, J = 7.1 Hz), 1.40 (3H, t, J = 7.1 Hz). 16 LC-MS: [M + H].sup.+/Rt (min): 411.4/0.848 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 7.58 (1H, d, J = 2.4 Hz), 7.25-7.10 (3H, m), 5.57 (2H, s), 5.26 (2H, s), 4.69-4.57 (4H, m), 4.39 (2H, q, J = 7.1 Hz), 1.50 (9H, s), 1.41 (3H, t, J = 7.1 Hz). 17 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.74 (1H, s), 6.63 (1H, s), 5.62 (2H, s), 5.45 (2H, s), 4.47-4.35 (4H, m), 1.46- 1.37 (6H, m). 18 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.58 (1H, s), 7.47 (2H, d, J = 8.5 Hz), 7.17 (2H, d, J = 8.5 Hz), 5.62 (2H, s), 5.22 (2H, s), 4.38 (2H, q, J = 7.1 Hz), 1.41 (3H, t, J = 7.1 Hz). 19 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.62 (1H, s), 7.37 (2H, d, J = 8.5 Hz), 7.27 (2H, d, J = 8.5 Hz), 5.63 (2H, s), 5.29 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 3.14 (3H, s), 1.41 (3H, t, J = 7.1 Hz). 20 LC-MS [M + H].sup.+/Rt (min): 318.0/0.676 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 7.66 (1H, s), 7.03-6.98 (1H, m), 6.84 (1H, dd, J = 3.1, 6.1 Hz), 6.82-6.76 (1H, m), 5.67 (2H, s), 5.27 (2H, s), 4.40 (2H, q, J = 7.1 Hz), 3.71 (3H, s), 1.41 (3H, t, J = 7.0 Hz). 21 LC-MS [M + H].sup.+/Rt (min): 288.0/0.658 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 7.67 (1H, s), 7.35-7.25 (2H, m), 7.13-7.04 (2H, m), 5.56 (2H, s), 5.32 (2H, s), 4.40 (2H, q, J = 7.1 Hz), 1.41 (3H, t, J = 7.1 Hz). 22 LC-MS [M + H].sup.+/Rt (min): 295.0/0.551 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 7.78 (1H, s), 7.71 (1H, d, J = 7.9 Hz), 7.58-7.52 (1H, m), 7.46-7.40 (2H, m), 5.56 (2H, s), 5.50 (2H, s), 4.38 (2H, q, J = 7.1 Hz), 1.40 (3H, t, J = 7.1 Hz).

Reference Example 23

tert-Butyl 4-{4-[(6-amino-2-ethoxy-9H-purin-9-yl)methyl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate

(277) ##STR00498##

(278) To a solution of the compound of Reference example 18 (700 mg) in a mixture of dimethylformamide (10 mL)/water (1.7 mL) were added N-Boc-1,2,5,6-tetrahydropyridine-4-(pinacolato)boronate (715 mg), potassium carbonate (834 mg), and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (221 mg), and the mixture was stirred at 80 C. for 2 hours. The reaction mixture was cooled to room temperature. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (820 mg).

(279) LC-MS [M+H].sup.+/Rt (min): 451.5/0.963 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.58 (1H, s), 7.34 (2H, d, J=7.9 Hz), 7.26 (2H, d, J=7.9 Hz), 6.05-5.97 (1H, m), 5.54 (2H, s), 5.25 (2H, s), 4.39 (2H, q, J=7.1 Hz), 4.09-4.03 (2H, m), 3.65-3.59 (2H, m), 2.52-2.43 (2H, m), 1.48 (9H, s), 1.41 (3H, t, J=7.1 Hz).

Reference Example 24

(280) According to the method of Reference example 23, Reference example 24 was prepared by using the corresponding material compound.

(281) TABLE-US-00062 Reference example Chemical Structure Instrumental analysis data 24 LC-MS [M + H].sup.+/Rt (min): 437.4/0.912 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 7.61 (1H, s), 7.35 (2H, d, J = 7.8 Hz), 7.27 (2H, d, J = 7.8 Hz), 6.20-6.06 (1H, m), 5.72 (2H, s), 5.26 (2H, s), 4.56- 4.20 (6H, m), 1.50 (9H, s), 1.41 (3H, t, J = 6.9 Hz).

Reference Example 25

1-Azabicyclo[2.2.2]oct-2-en-3-yl trifluoromethanesulfonate

(282) ##STR00500##

(283) To a solution of quinuclidin-3-one (5.34 g) in tetrahydrofuran (220 mL) was added lithium bis(trimethylsilyl)amide (1.3 mol/1, 58.4 ml) at 78 C. The mixture was stirred for 30 minutes, and then N-phenyl(trifluoromethane)sulfonamide (14.15 g) was added thereto. The mixture was stirred at 78 C. for one hour, and warmed to room temperature, followed by stirring for 2 hours. The reaction mixture was cooled to 0 C. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (6.15 g).

(284) LC-MS [M+H].sup.+/Rt (min): 258.1/0.374 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 6.47 (1H, d, J=2.3 Hz), 3.01-2.91 (2H, m), 2.87-2.82 (1H, m), 2.69-2.59 m), 1.90-1.73 (4H, m).

Reference Example 26

9-[4-(1-Azabicyclo[2.2.2]oct-2-en-3-yl)benzyl]-2-ethoxy-9H-purine-6-amine

(285) ##STR00501##

(286) To a solution of the compound of Reference example 25 (515 mg) in 1,4-dioxane (10 mL) were added bis(pinacolato)diboron (610 mg), potassium acetate (432 mg), 1,1-bis(diphenylphosphino)ferrocene palladium chloride (131 mg), and 1,1-bis(diphenylphosphino)ferrocene (44.4 mg), and the mixture was stirred at 90 C. for 2 hours.

(287) To the reaction mixture were added the compound of Reference example 18 (581 mg), potassium carbonate (461 mg), 1,1-bis(diphenylphosphino)ferrocene palladium chloride (98 mg), and water (0.3 ml), and the mixture was stirred at 80 C. for 2 hours. The reaction mixture was cooled to room temperature. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (403 mg).

(288) .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.59 (1H, s), 7.39 (2H, d, J=7.9 Hz), 7.29 (2H, d, J=7.9 Hz), 6.81 (1H, d, J=1.2 Hz), 5.59 (2H, s), 5.26 (2H, s), 4.39 (2H, q, J=7.0 Hz), 3.16-3.11 (1H, m), 3.06-2.96 (2H, 2.69-2.59 (2H, m), 1.81-1.72 (2H, m), 1.61-1.49 (2H, m), 1.41 (3H, t, J=7.0 Hz).

Reference Examples 27-29

(289) According to the method of Reference example 26, Reference examples 27-29 were prepared by using the corresponding material compounds.

(290) TABLE-US-00063 Reference example Chemical Structure Instrumental analysis data 27 02 LC-MS [M + H].sup.+/Rt (min): 258.2/0.615 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.01 (2H, d, J = 8.5 Hz), 7.46 (2H, d, J = 8.5 Hz), 6.91 (1H, d, J = 1.2 Hz), 4.38 (2H, q, J = 7.1 Hz), 3.22-3.14 (1H, m), 3.07-2.93 (2H, m), 2.73-2.57 (2H, m), 1.85- 1.68 (2H, m), 1.64-1.50 (2H, m), 1.40 (3H, t, J = 7.0 Hz). 28 03 LC-MS [M + H].sup.+/Rt (min): 244.9/0.330 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 9.18 (1H, d, J = 2.4 Hz), 8.23 (1H, dd, J = 2.4, 9.2 Hz), 7.54 (1H, d, J = 9.2 Hz), 7.32 (1H, d, J = 1.8 Hz), 3.95 (3H, s), 3.63-3.57 (1H, m), 3.09-2.99 (2H, m), 2.72- 2.59 (2H, m), 1.85-1.74 (2H, m), 1.62-1.49 (2H, m). 29 04 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.94-7.88 (1H, m), 7.26-7.22 (1H, m), 7.16 (1H, dd, J = 12.2, 1.8 Hz), 6.95 (1H, d, J = 1.8 Hz), 3.93 (3H, s), 3.15-3.11 (1H, m), 3.06-2.98 (2H, m), 2.68-2.58 (2H, m), 1.83-1.74 (2H, m), 1.60-1.50 (2H, m).

Reference Example 30

9-[4-(1-Azabicyclo[2.2.2]oct-3-yl)benzyl]-2-ethoxy-9H-purine-6-amine

(291) ##STR00505##

(292) To a solution of the compound of Reference example 26 (260 mg) in ethanol (2 mL)/tetrahydrofuran (0.1 ml) were added acetic acid (0.237 ml) and 5% palladium carbon (294 mg). The reaction mixture was stirred at room temperature under hydrogen atmosphere for 10 hours, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (149 mg).

(293) .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.59 (1H, s), 7.27 (2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.5 Hz), 5.55 (2H, s), 5.24 (2H, s), 4.40 (2H, q, J=7.1 Hz), 3.37-3.24 (1H, m), 3.10-3.02 (1H, m), 3.01-2.79 (5H, m), 1.93-1.88 (1H, m), 1.79-1.69 (2H, m), 1.68-1.57 (1H, m), 1.41 (3H, t, J=7.1 Hz), 1.39-1.31 (1H, m).

Reference Examples 31-35

(294) According to the method of Reference example 30, Reference examples 31-35 were prepared by using the corresponding material compounds.

(295) TABLE-US-00064 Reference example Chemical Structure Instrumental analysis data 31 06 LC-MS: [M + H].sup.+/Rt (min): 453.5/1.01 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.58 (1H, s), 7.24 (2H, d, J = 7.9 Hz), 7.17 (2H, d, J = 7.9 Hz), 5.59 (2H, s), 5.23 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 4.30-4.12 (2H, m), 2.86-2.69 (2H, m), 2.68-2.57 (1H, m), 1.82-1.73 (2H, m), 1.65-1.53 (2H, m), 1.47 (9H, s), 1.41 (3H, t, J = 7.1 Hz). 32 07 LC-MS: [M + H].sup.+/Rt (min): 439.4/0.902 (Method C) 33 08 LC-MS [M + H].sup.+/Rt (min): 260.3/0.629 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 8.01 (2H, d, J = 7.9 Hz), 7.34 (2H, d, J = 7.9 Hz), 4.37 (2H, q, J = 7.1 Hz), 3.41- 3.28 (1H, m), 3.16-2.78 (6H, m), 1.98-1.90 (1H, m), 1.78- 1.58 (3H, m), 1.39 (3H, t, J = 7.1 Hz), 1.38-1.32 (1H, m). 34 09 LC-MS [M + H].sup.+/Rt (min): 247.0/0.315 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 9.18 (1H, d, J = 2.1 Hz), 8.21 (1H, dd, J = 8.2, 2.1 Hz), 7.28 (1H, d, J = 8.2 Hz), 3.94 (3H, s), 3.61-3.51 (1H, m), 3.30-3.20 (1H, m), 3.18- 3.11 (1H, m), 3.11-2.99 (1H, m), 2.99-2.88 (2H, m), 2.88- 2.77 (1H, m), 2.11-2.04 (1H, m), 1.81-1.66 (2H, m), 1.66- 1.54 (1H, m), 1.41-1.26 (1H, m). 35 0 LC-MS [M + H].sup.+/Rt (min): 263.9/0.368 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 7.90 (1H, dd, J = 7.9, 12.8 Hz), 7.10 (1H, d, J = 7.9 Hz), 7.05 (1H, d, J = 12.8 Hz), 3.92 (3H, s), 3.39-3.27 (1H, m), 3.08-2.79 (6H, m), 1.99- 1.93 (1H, m), 1.78-1.69 (2H, m), 1.66-1.55 (1H, m), 1.44- 1.33 (1H, m).

Reference Example 36

Methyl 4-[(6-amino-8-bromo-2-ethoxy-9H-purin-9-yl)methyl]benzoate

(296) ##STR00511##

(297) To an ice-cooled solution of the compound of Reference example 2 (1.57 g) in a mixture of chloroform (15 mL)/methanol (3 mL) were added sodium acetate (0.786 g), and then a solution of bromine (0.358 ml) in chloroform (5 mL) dropwise. The reaction mixture was stirred in ice bath for 3 hours. To the reaction mixture were added aqueous saturated sodium thiosulfate and aqueous saturated sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.77 g).

(298) LC-MS [M+H].sup.+/Rt (min): 406.3/0.876 (Method A)

Reference Examples 37-58

(299) According to the method of Reference example 36, Reference examples 37-58 were prepared by using the corresponding material compounds.

(300) TABLE-US-00065 Reference example Chemical Structure Instrumental analysis data 37 LC-MS: [M + H].sup.+/Rt (min): 436.2/0.811 (Method A) 38 LC-MS: [M + H].sup.+/Rt (min): 405.3/0.759 (Method A) 39 LC-MS [M + H].sup.+/Rt (min): 406.0/0.731 (Method A) 40 LC-MS: [M + H].sup.+/Rt (min): 376.3/0.792 (Method A) 41 .sup.1H-NMR (CDCl.sub.3) : 8.01 (2H, d, J = 8.5 Hz), 7.34 (2H, d, J = 8.5 Hz), 5.74 (2H, br s), 5.41 (2H, s), 3.91 (3H, s). 42 .sup.1H-NMR (CDCl.sub.3) : 8.52 (1H, d, J = 2.4 Hz), 7.68 (1H, dd, J = 2.4, 8.0 Hz), 7.29 (1H, d, J = 8.0 Hz), 5.53 (2H, br s), 5.29 (2H, s), 4.38 (2H, q, J = 7.1 Hz), 1.41 (3H, t, J = 7.1 Hz). 43 .sup.1H-NMR (CDCl.sub.3) : 8.36 (1H, d, J = 1.8 Hz), 7.88-7.83 (1H, m), 6.92-6.89 (1H, m), 5.44 (2H, s), 5.30 (2H, s), 4.39 (2H, q, J = 7.2 Hz), 1.42 (3H, t, J = 7.2 Hz). 44 .sup.1H-NMR (DMSO-D.sub.6) : 8.50 (1H, d, J = 2.8 Hz), 7.84 (1H, dd, J = 2.8, 8.6 Hz), 7.42 (1H, d, J = 8.6 Hz), 5.39 (2H, s), 4.19 (2H, q, J = 7.1 Hz), 3.45 (3H, s), 1.21 (3H, t, J = 7.1 Hz). 45 0 .sup.1H-NMR (CDCl.sub.3) : 7.57 (1H, s), 7.44 (1H, s), 5.41 (2H, s), 5.16 (2H, s), 4.41 (2H, q, J = 7.1 Hz), 3.84 (3H, s), 1.43 (3H, t, J = 7.3 Hz). 46 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.35 (1H, d, J = 5.5 Hz), 7.21 (1H, d, J = 1.2 Hz), 7.09 (1H, dd, J = 1.2, 5.5 Hz), 5.56 (2H, s), 5.28 (2H, s), 4.36 (2H, q, J = 7.0 Hz), 1.40 (3H, t, J = 7.0 Hz). 47 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.57 (1H, dd, J = 7.3, 7.6 Hz), 7.24 (1H, d, J = 7.6 Hz), 6.80 (1H, d, J = 7.3 Hz), 5.55 (2H, s), 5.42 (2H, s), 4.32 (2H, q, J = 7.1 Hz), 1.36 (3H, t ,J = 7.1 Hz). 48 LC-MS: [M + H].sup.+/Rt (min): 385.2/0.727 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 8.45 (1H, d, J = 5.5 Hz), 7.23 (1H, dd, J = 5.5, 1.8 Hz), 7.05 (1H, d, J = 1.8 Hz), 5.58 (2H, s), 5.42 (2H, s), 4.34 (2H, q, J = 7.1 Hz), 1.37 (3H, t, J = 7.1 Hz). 49 LC-MS: [M + H].sup.+/Rt (min): 533.4/1.094 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 7.30 (2H, d, J = 7.9 Hz), 7.14 (2H, d, J = 7.9 Hz), 5.49 (2H, s), 5.26 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 4.28-4.13 (2H, m), 2.83- 2.70 (2H, m), 2.66-2.56 (1H, m), 1.82-1.73 (2H, m), 1.60-1.50 (2H, m), 1.47 (9H, s), 1.41 (3H, t, J = 7.1 Hz). 50 LC-MS: [M + H].sup.+/Rt (min): 519.4/1.054 (Method C) 51 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.34 (2H, d, J = 8.5 Hz), 7.22 (2H, d, J = 8.5 Hz), 5.48 (2H, s), 5.28 (2H, s), 4.39 (2H, q, J = 6.9 Hz), 3.38-3.30 (1H, m), 3.13- 3.04 (1H, m), 3.04-2.82 (5H, m), 2.00-1.90 (1H, m), 1.81-1.71 (2H, m), 1.70- 1.60 (1H, m), 1.45-1.33 (4H, m). 52 LC-MS: [M + H].sup.+/Rt (min): 491.35/0.987 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.30-7.19 (2H, m), 7.16 (1H, d, J = 11.0 Hz), 5.52 (2H, s), 5.29 (2H, s), 4.64 (2H, s), 4.60 (2H, s), 4.38 (2H, q, J = 7.1 Hz), 1.50 (9H, s), 1.41 (3H, t, J = 7.1 Hz). 53 LC-MS: [M + H].sup.+/Rt (min): 413.3/0.763 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 6.56 (1H, s), 5.57 (2H, s), 5.47 (2H, s), 4.49-4.32 (4H, m), 1.45-1.35 (6H, m). 54 LC-MS: [M + H].sup.+/Rt (min): 428.2/0.956 (Method C): .sup.1H- NMR (400 MHz, CD.sub.3OD) : 7.48 (2H, d, J = 8.5 Hz), 7.22 (2H, d, J = 8.5 Hz), 5.29 (2H, s), 4.36 (2H, q, J = 7.1 Hz), 1.35 (3H, t, J = 7.1 Hz). 55 0 LC-MS [M + H].sup.+/Rt (min): 444.2/0.731 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 7.43 (2H, d, J = 8.5 Hz), 7.31 (2H, d, J = 8.5 Hz), 5.37 (2H, s), 4.38 (2H, q, J = 6.7 Hz), 3.19 (3H, s), 1.37 (3H, t, J = 6.7 Hz). 56 LC-MS [M + H].sup.+/Rt (min): 397.9/0.849 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 7.04-6.97 (1H, m), 6.80- 6.73 (1H, m), 6.57 (1H, dd, J = 6.1, 3.1 Hz), 5.66 (2H, s), 5.33 (2H, s), 4.36 (2H, q, J = 7.1 Hz), 3.67 (3H, s), 1.38 (3H, t, J = 7.1 Hz). 57 LC-MS [M + H].sup.+/Rt (min): 367.8/0.834 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 7.31-7.24 (1H, m), 7.12- 7.01 (3H, m), 5.76 (2H, s), 5.38 (2H, s), 4.35 (2H, q, J = 6.9 Hz), 1.38 (3H, t, J = 6.9 Hz). 58 LC-MS [M + H].sup.+/Rt (min): 374.8/0.740 (Method C); .sup.1H- NMR (400 MHz, CDCl.sub.3) : 7.72 (1H, dd, J = 7.9, 1.2 Hz), 7.53-7.48 (1H, m), 7.44-7.38 (1H, m), 7.02 (1H, d, J = 7.9 Hz), 5.58 (2H, s), 5.55 (2H, s), 4.34 (2H, q, J = 7.1 Hz), 1.37 (3H, t, J = 7.1 Hz).

Reference Example 59

2-Chloro-6-methyl-5-nitropyrimidine-4-amine

(301) ##STR00534##

(302) To a solution of 2,4-dichloro-6-methyl-5-nitropyrimidine (20 g) in tetrahydrofuran (321 mL) were added dropwise N,N-diisopropylethylamine (24.5 mL) and ammonia (7.0 mol/L methanol solution, 20.6 mL) at 10 C., and the mixture was stirred at 10 C. for 2.5 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtrated, and then concentrated in vacuo to give the title compound (17.5 g).

(303) LC-MS [M+H].sup.+/Rt (min): 188.8/0.503 (Method C)

Reference Example 60

tert-Butyl 3-(4-{[(2-chloro-6-methyl-5-nitropyrimidin-4-yl)amino]methyl}phenyl)pyrrolidine-1-carboxylate

(304) ##STR00535##

(305) To an ice-cooled solution of 2,4-dichloro-6-methyl-5-nitropyrimidine (502 mg) in tetrahydrofuran (10 mL) were added N,N-diisopropylethylamine (0.506 ml), and a solution of tert-butyl 3-(4-(aminomethyl)phenyl)pyrrolidine-1-carboxylate (714 mg) in tetrahydrofuran (15 mL). The reaction mixture was warmed to room temperature, and then stirred for 30 minutes. To the mixture in ice bath was water, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.06 g).

(306) .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.40 (1H, t, J=5.5 Hz), 7.31 (2H, d, J=7.9 Hz), 7.24 (2H, d, J=7.9 Hz), 4.76 (2H, d, J=5.5 Hz), 3.87-3.72 (1H, m), 3.66-3.52 (1H, m), 3.45-3.22 (3H, m), 2.73 (3H, s), 2.32-2.21 (1H, m), 2.02-1.93 (1H, m), 1.47 (9H, s).

Reference Example 61

(307) tert-Butyl 3-(4-{[(2-ethoxy-6-methyl-5-nitropyrimidin-4-yl)amino]methyl}phenyl)pyrrolidine-1-carboxylate

(308) ##STR00536##

(309) To an ice-cooled solution of the compound of Reference example 60 (479 mg) in ethanol (6 mL) was added 20% sodium ethoxide solution (1.09 mL). The reaction mixture was warmed to room temperature, and then stirred for one hour. To the reaction mixture was added aqueous saturated ammonium chloride, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (291 mg).

(310) LC-MS [M+H].sup.+/Rt (min): 459.4/1.220 (Method D); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.80 (1H, t, J=5.5 Hz), 7.29 (2H, d, J=7.9 Hz), 7.23 (2H, d, J=7.9 Hz), 4.76 (2H, d, J=5.5 Hz), 4.40 (2H, q, J=7.0 Hz), 3.87-3.72 m), 3.69-3.50 (1H, m), 3.45-3.20 (3H, m), 2.74 (3H, s), 2.31-2.19 (1H, m), 2.07-1.90 (1H, m), 1.47 (9H, s), 1.39 (3H, t, J=7.0 Hz).

Reference Examples 62-65

(311) According to the method of Reference example 61, Reference examples 62-65 were prepared by using the corresponding material compounds.

(312) TABLE-US-00066 Reference example Chemical Structure Instrumental analysis data 62 LC-MS [M + H].sup.+/Rt (min): 445.3/1.166 (Method D): .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.79 (1H, t, J = 5.5 Hz), 7.29 (2H, d, J = 7.9 Hz), 7.23 (2H, d, J = 7.9 Hz), 4.77 (2H, d, J = 5.5 Hz), 3.98 (3H, s), 3.88-3.72 (1H, m), 3.68-3.50 (1H, m), 3.46-3.21 (3H, m), 2.74 (3H, s), 2.29-2.22 (1H, m), 2.01-1.91 (1H, m), 1.47 (9H, s). 63 LC-MS [M + H].sup.+/Rt (min): 184.7/0.554 (Method D) 64 .sup.1H-NMR (CDCl.sub.3) : 7.89 (1H, br s), 5.89 (1H, br s), 4.43-4.37 (2H, m), 2.75 (3H, s), 1.45-1.38 (3H, m). 65 0 LC-MS ([M + ].sup.+/Rt (min)): 212.9/0.779 (Method A)

Reference Example 66

tert-Butyl (2-ethoxy-6-methyl-5-nitropyrimidin-4-yl)carboxylate

(313) ##STR00541##

(314) To an ice-cooled solution of the compound of Reference example 64 (1.8 g) in tetrahydrofuran (30 mL) were added dimethylaminopyridine (110 mg) and di-tert-butyl dicarbonate (3.71 g). The reaction mixture was warmed to room temperature and then stirred for 4 hours. To the reaction mixture was added 20% sodium ethoxide solution (6.2 mL), and the mixture was stirred for one more hour. To the reaction mixture was added aqueous saturated ammonium chloride, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.54 g).

(315) LC-MS [M+H].sup.+/Rt (min): 299.2/1.035 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 9.26 (1H, s), 4.51 (2H, q, J=7.1 Hz), 2.70 (3H, s), 1.53 (9H, s), 1.43 (3H, t, J=7.1 Hz).

Reference Examples 67-68

(316) According to the method of Reference example 66, Reference examples 67-68 were prepared by using the corresponding material compounds.

(317) TABLE-US-00067 Reference example Chemical Structure Instrumental analysis data 67 .sup.1H-NMR (CDCl.sub.3) : 9.22 (1H, brs), 4.08 (3H, s), 2.71 (3H, s), 1.46 (9H, s). 68 LC-MS [M + H].sup.+/Rt (min): 313.5/1.096 (Method A)

Reference Example 69

tert-Butyl (2-ethoxy-6-methyl-5-nitropyrimidin-4-yl)[(6-fluoropyridin-3-yl)methyl]carboxylate

(318) ##STR00544##

(319) To an ice-cooled solution of the compound of Reference example 66 (0.8 g) in N,N-dimethylformamide (13 mL) were added potassium carbonate (0.56 g), tetrabutylammonium iodide (50 mg), and 5-(chloromethyl)-2-fluoropyridine (0.59 g), and the mixture was stirred at room temperature for 28 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtrated, and then concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.96 g).

(320) .sup.1H-NMR (CDCl.sub.3) : 8.23 (1H, d, J=2.4 Hz), 7.97-7.93 (1H, m), 6.92-6.89 (1H, m), 5.15 (2H, s), 4.42 (2H, q, J=7.1 Hz), 2.61 (3H, s), 1.44-1.38 (12H, m).

Reference Examples 70-73

(321) According to the method of Reference example 69, Reference examples 70-73 were prepared by using the corresponding material compounds.

(322) TABLE-US-00068 Reference example Chemical Structure Instrumental analysis data 70 .sup.1H-NMR (CDCl.sub.3) : 8.23 (1H, d, J = 2.4 Hz), 7.98-7.93 (1H, m), 6.92- 6.89 (1H, m), 5.15 (2H, s), 4.02 (3H, s), 2.62 (3H, s), 1.40 (9H, s). 71 .sup.1H-NMR (CDCl.sub.3) : 8.22 (1H, s), 7.97-7.93 (1H, m), 6.92-6.90 (1H, m), 5.15 (2H, s), 4.30 (2H, t, J = 6.7 Hz), 2.61 (3H, s), 1.84- 1.80 (2H, m), 1.40 (9H, s), 1.03 (3H, t, J = 7.3 Hz). 72 LC-MS [M + H].sup.+/Rt (min): 390.3/0.959 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.64-8.61 (1H, m), 8.51 (1H, dd, J = 4.6, 1.5 Hz), 7.83-7.78 (1H, m), 7.27 (3H, dd, J = 4.6, 7.6 Hz), 5.17 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 2.61 (3H, s), 1.44-1.35 (12H, m). 73 LC-MS [M + H].sup.+/Rt (min): 448.3/1.158 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 9.12 (1H, d, J = 3.1 Hz), 8.27 (1H, dd, J = 2.1, 7.9 Hz), 7.51 (1H, d, J = 7.9 Hz), 5.33 (2H, s), 4.22 (2H, q, J = 6.9 Hz), 3.94 (3H, s), 2.64 (3H, s), 1.37 (9H, s), 1.29 (3H, t, J = 6.9 Hz).

Reference Example 74

[1-(1-Methylpiperidin-4-yl)-1H-pyrazol-4-yl]methanol

(323) ##STR00549##

(324) To a solution of 4-(4-bromo-1H-pyrazol-1-yl)-1-methylpiperidine (389 mg) in tetrahydrofuran (5.3 mL) was added N-butyllithium (1.14 mL, 1.54 mol/L hexane solution) at 78 C., and the mixture was stirred for 15 minutes. Subsequently, a solution of N,N-dimethylformamide (0.185 mL) in tetrahydrofuran (0.5 mL) was added dropwise thereto, and the mixture was warmed to room temperature and stirred for one hour. To the reaction mixture was added water, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo.

(325) The obtained crude product (308 mg) was dissolved in methanol (12.5 mL). Sodium borohydride (121 mg) was slowly added to the solution in ice bath, and the mixture was stirred at 0 C. for 30 minutes. To the reaction mixture were added aqueous saturated ammonium chloride and then aqueous saturated sodium bicarbonate, and the mixture was extracted with chloroform/methanol. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by amino silica gel column chromatography (chloroform/methanol) to give the title compound (132 mg).

(326) .sup.1H-NMR (CDCl.sub.3) : 7.49 (1H, s), 7.45 (1H, s), 4.59 (2H, s), 4.13-4.05 (1H, m), 2.97-2.94 (2H, m), 2.32 (3H, s), 2.15-2.09 (4H, m), 2.02-1.99 (2H, m), 1.63 (1H, br s).

Reference Example 75

Methyl 5-(hydroxymethyl)pyridine-2-carboxylate

(327) ##STR00550##

(328) To a solution of 6-(methoxycarbonyl)nicotinic acid (2.03 g) in tetrahydrofuran (50 ml) were added ethyl chloroformate (1.14 ml) and triethylamine (1.75 ml) at 0 C., and the mixture was stirred for one hour. Then, the reaction mixture was filtrated, and the filtrate was added to a solution of sodium borohydride (0.892 mg) in water (3 ml) at 0 C. The reaction mixture was stirred for 30 minutes. To the reaction mixture was added aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (990 mg).

(329) .sup.1H-NMR (400 MHz, CDCl.sub.3) : 9.16 (1H, d, J=1.2 Hz), 8.29 (1H, dd, J=7.3, 1.2 Hz), 7.36 (1H, d, J=7.3 Hz), 4.83 (2H, d, J=4.9 Hz), 3.96 (3H, s), 3.63 (1H, t, J=4.9 Hz).

Reference Example 76

(330) According to the method of Reference example 75, Reference example 76 was prepared by using the corresponding material compound.

(331) TABLE-US-00069 Reference example Chemical Structure Instrumental analysis data 76 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.29 (2H, d, J = 7.3 Hz), 7.15 (2H, d, J = 7.3 Hz), 4.78 (1H, br s), 4.66 (2H, s), 3.69-3.44 (2H, m), 2.36- 2.22 (1H, m), 1.96-1.60 (4H, m), 1.19 (9H, s).

Reference Example 77

[4-(1-Azabicyclo[2.2.2]oct-3-yl)phenyl]methanol

(332) ##STR00552##

(333) To a solution of lithium aluminum hydride (121 mg) in tetrahydrofuran (4 mL) was added a solution of the compound of Reference example 33 (332 mg) in tetrahydrofuran (4 mL) at 0 C. The mixture was stirred in ice bath for 1.5 hours, and water (0.121 ml), 15% aqueous sodium hydroxide (0.121 ml), and then water (0.363 ml) were added thereto at 0 C. The reaction mixture was stirred for one hour, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (196 mg).

(334) LC-MS [M+H].sup.+/Rt (min): 218.2/0.442 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.33 (2H, d, J=7.9 Hz), 7.24 (2H, d, J=7.9 Hz), 4.65 (2H, s), 3.28-3.19 (1H, m), 2.99-2.74 (6H, m), 1.93-1.88 (1H, m), 1.75-1.68 (2H, m), 1.67-1.58 (1H, 1.38-1.26 (1H m).

Reference Examples 78-79

(335) According to the method of Reference example 77, Reference examples 78-79 were prepared by using the corresponding material compounds.

(336) TABLE-US-00070 Reference example Chemical Structure Instrumental analysis data 78 LC-MS [M + H].sup.+/Rt (min): 219.0/0.151 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.55 (1H, d, J = 2.4 Hz), 7.66 (1H, dd, J = 7.9, 2.4 Hz), 7.18 (1H, d, J = 7.9 Hz), 4.68 (2H, s), 3.37 (1H, ddd, J = 1.8, 6.7, 13.4 Hz), 3.20-3.11 (1H, m), 3.09-3.02 (1H, m), 2.97-2.82 (3H, m), 2.80-2.71 (1H, m), 2.07- 2.02 (1H, m), 1.80-1.58 (3H, m), 1.35-1.25 (1H, m). 79 LC-MS [M + H].sup.+/Rt (min): 235.9/0.207 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.37 (1H, dd, J = 7.9, 11.6 Hz), 7.04 (1H, dd, J = 1.5, 7.9 Hz), 6.96 (1H, dd, J = 1.5, 11.6 Hz), 4.72 (2H, s), 3.33- 3.23 (1H, m), 3.00-2.76 (6H, m), 1.95-1.90 (1H, m), 1.76-1.68 (2H, m), 1.68-1.56 (1H, m), 1.41-1.31 (1H, m).

Reference Example 80

[4-(1-Methylpyrrolidin-2-yl)phenyl]methanol

(337) ##STR00555##

(338) To a solution of lithium aluminum hydride (166 mg) in tetrahydrofuran (5 mL) was added a solution of tert-butyl 2-(4-(hydroxymethyl)phenyl)pyrrolidine-1-carboxylate (304 mg) in tetrahydrofuran (5 mL) at 0 C. The reaction solution was heated, and then stirred under reflux for one hour. The reaction solution was cooled to 0 C., and water (0.166), 15% aqueous sodium hydroxide (0.166 mL), and then water (0.332 mL) were added thereto at 0 C. The reaction mixture was stirred for one hour, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (214 mg).

(339) LC-MS [M+H].sup.+/Rt (min): 191.9/0.182 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.39-7.28 (4H, m), 4.67 (2H, d, J=6.7 Hz), 3.30-3.17 (1H, m), 3.09-2.96 (1H, m), 2.27 (1H, t, J=6.7 Hz), 2.21-2.08 (4H, m), 2.01-1.86 (1H, m), 1.86-1.66 (3H, m).

Reference Example 81

Ethyl 1-(1-azabicyclo[2.2.2]oct-3-yl)-1H-pyrazole-4-carboxylate

(340) ##STR00556##

(341) To an ice-cooled solution of ethyl 1H-pyrazole-4-carboxylate (1.0 g) in tetrahydrofuran (23.8 mL) were added 3-quinuclidinol (1.36 g) and cyanomethylenetributylphosphorane (2.8 mL), and the mixture was stirred at 80 C. for 4 hours. To the reaction mixture was added water, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.63 g).

(342) .sup.1H-NMR (CDCl.sub.3) : 7.99 (1H, s), 7.93 (1H, s), 4.39-4.27 (3H, m), 3.54-3.48 (1H, m), 3.43-3.36 (1H, m), 3.11-3.03 (1H, m), 2.96-2.81 (3H, m), 2.22-2.18 (1H, m), 1.82-1.61 (3H, m), 1.47-1.33 (4H, m).

Reference Example 82

[1-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]methanol

(343) ##STR00557##

(344) To an ice-cooled solution of the compound of Reference example 81 (1.63 g) in tetrahydrofuran (32.7 mL) was added diisobutylaluminum hydride (19.2 mL, 1.02 mol/L hexane solution), and the mixture was stirred at 0 C. for 2 hours. To the reaction mixture in ice bath was added aqueous saturated potassium sodium tartrate, and the mixture was extracted with chloroform/methanol. The organic layer was washed with brine, dried over sodium sulfate, filtrated, and concentrated in vacuo to give the title compound (0.41 g).

(345) .sup.1H-NMR (CDCl.sub.3) : 7.53 (1H, s), 7.50 (1H, s), 4.59 (2H, s), 4.35-4.30 (1H, m), 3.53-3.48 (1H, m), 3.38-3.32 (1H, m), 3.10-3.02 (1H, m), 2.94-2.79 (3H, m), 2.18-2.14 (1H, m), 1.93 (1H, br s), 1.80-1.65 (3H, m), 1.44-1.36 (1H, m).

Reference Example 83

tert-Butyl {[1-(1-azabicyclo[2.2.2]oct-3-yl)-1H-pyrazol-4-yl]methyl}(2-ethoxy-6-methyl-5-nitropyrimidin-4-yl)carboxylate

(346) ##STR00558##

(347) To ice-cooled solution of the compound of Reference example 66 (1.14 g) in tetrahydrofuran (12.7 mL) were added (1-quinuclidin-3-yl)-1H-pyrazol-4-yl)methanol (950 mg), triphenylphosphine (1.50 g), and diisopropyl azodicarboxylate (1.12 mL), and the mixture was stirred at room temperature for 12 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate/methanol. The organic layer was washed with brine, dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.21 g).

(348) .sup.1H-NMR (CDCl.sub.3) : 7.61 (1H, s), 7.53 (1H, s), 5.01 (2H, s), 4.46 (2H, q, J=7.1 Hz), 4.34-4.29 (1H, m), 3.53-3.48 (1H, m), 3.38-3.32 (1H, m), 3.08-3.00 (1H, m), 2.94-2.80 (3H, m), 2.60 (3H, s), 2.13-2.11 (1H, m), 1.79-1.66 (2H, m), 1.63-1.50 (1H, m), 1.50-1.33 (13H, m).

Reference Examples 84-90

(349) According to the method of Reference example 83, Reference examples 84-90 were prepared by using the corresponding material compounds.

(350) TABLE-US-00071 Reference example Chemical Structure Instrumental analysis data 84 .sup.1H-NMR (CDCl.sub.3) : 8.14 (1H, s), 7.79 (1H, s), 5.00 (2H, s), 4.45 (2H, q, J = 7.1 Hz), 2.61 (3H, s), 1.63 (9H, s), 1.44 (9H, s), 1.26 (3H, t, J = 7.1 Hz). 85 0 .sup.1H-NMR (CDCl.sub.3) : 7.53 (1H, s), 7.50 (1H, s), 4.99 (2H, s), 4.46 (2H, q, J = 7.0 Hz), 4.10- 4.03 (1H, m), 2.96-2.93 (2H, m), 2.60 (3H, s), 2.31 (3H, s), 2.15-2.12 (4H, m), 2.03-1.96 (2H, m), 1.46-1.42 (12H, m). 86 LC-MS [M + H].sup.+/Rt (min): 484.2/0.752 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.35 (2H, d, J = 7.9 Hz), 7.20 (2H, d, J = 7.9 Hz), 5.16 (2H, s), 3.96 (3H, s), 3.32-3.23 (1H, m), 3.08-3.00 (1H, m), 2.97-2.78 (5H, m), 2.60 (3H, s), 1.89- 1.84 (1H, m), 1.74-1.66 (2H, m), 1.65-1.56 (1H, m), 1.39- 1.29 (10H, m). 87 LC-MS [M + H].sup.+/Rt (min): 493.5/0.9331 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.35 (2H, d, J = 8.2 Hz), 7.21 (2H, d, J = 8.2 Hz) 5.16 (2H, s), 4.36 (2H, q, J = 7.2 Hz), 3.34-3.24 (1H, m), 3.09-2.99 (1H, m), 2.98-2.77 (5H, m), 2.60 (3H, s), 1.91-1.85 (1H, m), 1.75- 1.68 (2H, m), 1.68-1.57 (1H, m), 1.42-1.32 (13H, m). 88 LC-MS [M + H].sup.+/Rt (min): 472.2/0.700 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.33 (2H, d, J = 7.3 Hz) 7.27 (2H, d, J = 7.3 Hz), 5.15 (2H, s), 4.35 (2H, q, J = 7.3 Hz), 3.26-3.18 (1H, m), 3.03-2.96 (1H, m), 2.61 (3H, s), 2.26 (1H, dd, J = 9.0, 18.0 Hz), 2.19-2.08 (4H, m), 2.01-1.84 (1H, m), 1.84-1.65 (2H, m), 1.41-1.30 (12H, m). 89 LC-MS [M + H].sup.+/Rt (min): 499.1/0.759 (Method C): .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.56 (1H, d, J = 2.4 Hz), 7.74 (1H, dd, J = 7.9, 2.4 Hz), 7.18 (1H, d, J = 7.9 Hz), 5.16 (2H, s), 4.40 (2H, q, J = 7.1 Hz), 3.51-3.42 (1H, m), 3.27-3.17 (1H, m), 3.10-2.85 (4H, m), 2.85-2.75 (1H, m), 2.61 (3H, s), 2.06-2.00 (1H, m), 1.81- 1.67 (2H, m), 1,62-1.53 (1H, m), 1.47-1.35 (13H, m). 90 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.42 (1H, dd, J = 7.9, 11.6 Hz), 7.00 (1H, dd, J = 1.2, 7.9 Hz), 6.93 (1H, dd, J = 1.2, 11.6 Hz), 5.22 (2H, s), 4.36 (2H, q, J = 7.1 Hz), 3.37-3.26 (1H, m), 3.06-2.77 (6H, m), 2.62 (3H, s), 1.93-1.87 (1H, m), 1.76- 1.67 (2H, m), 1.61-1.55 (1H, m), 1.42-1.31 (13H, m).

Reference Example 91

2-Ethoxy-N-[(6-fluoropyridin-3-yl)methyl]-6-methyl-5-nitropyrimidine-4-amine

(351) ##STR00566##

(352) To an ice-cooled solution of the compound of Reference example 69 (930 in dichloromethane (7.6 mL) was added trifluoroacetic acid (1.8 mL), and the mixture was stirred at 40 C. for 3 hours. The reaction mixture was poured to 28% ammonia in ice bath, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (680 mg).

(353) .sup.1H-NMR (CDCl.sub.3) : 8.85 (1H, br s), 8.23 (1H, s), 7.79-7.75 (1H, m), 6.94 (1H, dd, J=8.5, 3.0 Hz), 4.79 (2H, d, J=5.9 Hz), 4.38 (2H, q, J=7.2 Hz), 2.75 (3H, d, J=1.8 Hz), 1.39 (3H, t, J=7.2 Hz).

Reference Examples 92-105

(354) According to the method of Reference example 91, Reference examples 92-105 were prepared by using the corresponding material compounds.

(355) TABLE-US-00072 Reference example Chemical Structure Instrumental analysis data 92 .sup.1H-NMR (CDCl.sub.3) : 8.84 (1H, s), 8.24 (1H, d, J = 2.4 Hz), 7.80-7.76 (1H, m) 6.95-6.92 (1H, m), 4.79 (2H, d, J = 6.1 Hz), 3.97 (3H, s), 2.75 (3H, s). 93 .sup.1H-NMR (CDCl.sub.3) : 8.85 (1H, s), 8.23 (1H, s), 7.79-7.75 (1H, m), 6.95-6.92 (1H, m), 4.79 (2H, d, J = 6.1 Hz), 4.27 (2H, t, J = 6.7 Hz), 2.75 (3H, s), 1.83-1.74 (2H, m), 1.01 (3H, t, J = 7.3 Hz). 94 LC-MS [M + H].sup.+/Rt (min): 279.0/0.624 (Method C) 95 0 LC-MS [M + H].sup.+/Rt (min): 376.0/0.495 (Method C) 96 LC-MS [M + H].sup.+/Rt (min): 388.3/0.575 (Method D) 97 .sup.1H-NMR (CDCl.sub.3) : 7.60 (2H, s), 5.43 (2H, br s), 4.56 (2H, d, J = 5.5 Hz), 4.33 (2H, q, J = 7.1 Hz), 2.47 (2H, s), 2.28 (3H, s), 1.39 (3H, t, J = 7.1 Hz). 98 LC-MS [M + H].sup.+/Rt (min): 346.0/0.190 Method D) 99 LC-MS [M + H].sup.+/Rt (min): 290.2/0.582 (Method C); .sup.1H-NMR (400 MHz, CD.sub.3OD) : 8.99-8.97 (1H, m), 8.84 (1H, d, J = 6.1 Hz), 8.73-8.71 (1H, m), 8.12 (1H, dd, J = 6.1, 7.9 Hz), 5.13 (2H, s), 4.52 (2H, q, J = 7.1 Hz), 2.75 (3H, s), 1.37 (3H, t, J = 7.1 Hz). 100 LC-MS [M + H].sup.+/Rt (min): 348.24/0.911 (Method C); .sup.1H-NMR (400 MHz, CD.sub.3OD) : 9.27 (1H, s), 8.95 (1H, d, J = 7.9 Hz), 8.17 (1H, d, J = 7.9 Hz), 5.35 (2H, s), 4.43 (2H, q, J = 6.9 Hz), 4.02 (3H, s), 2.79 (3H, s), 1.32 (3H, t, J = 6.9 Hz). 101 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.78 (1H, br s), 7.30 (2H, d, J = 7.9 Hz), 7.26 (2H, d, J = 7.9 Hz), 4.76 (2H, d, J = 5.5 Hz), 3.93 (3H, s), 3.35-3.26 (1H, m), 3.09-3.01 (1H, m), 2.99- 2.80 (5H, m), 2.73 (3H, s), 1.93-1.86 (1H, m), 1.76-1.69 (2H, m), 1.67-1.59 (1H, m), 1.40-1.28 (1H, m). 102 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.80 (1H, s), 7.30 (2H, d, J = 8.5 Hz), 7.26 (2H, d, J = 8.5 Hz), 4.76 (2H, d, J = 5.5 Hz), 4.40 (2H, q, J = 7.1 Hz), 3.38-3.26 (1H, m), 3.13-3.02 (1H, m), 3.02-2.80 (5H, m), 2.74 (3H, s), 1.95-1.89 (1H, m), 1.80- 1.70 (2H, m), 1.70-1.60 (1H, m), 1.38 (3H, t, J = 7.1 Hz), 1.37-1.31 (1H, m). 103 LC-MS [M + H].sup.+/Rt (min): 372.04/0.535 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.80 (1H, t, J = 5.5 Hz), 7.33 (2H, d, J = 7.9 Hz), 7.27 (2H, d, J = 7.9 Hz), 4.76 (2H, d, J = 5.5 Hz), 4.40 (2H, q, J = 7.1 Hz), 3.26-3.20 (1H, m), 3.03 (1H, dd, J = 8.2, 9.0 Hz), 2.74 (3H, s), 2.28 (1H, dd, J = 9.0, 18.0 Hz), 2.20-2.12 (4H, m), 1.99-1.88 (1H, m), 1.85- 1.67 (2H, m), 1.38 (3H, t, J = 7.1 Hz). 104 LC-MS [M + H].sup.+/Rt (min): 399.0/0.505 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.83 (1H, t, J = 5.5 Hz), 8.58 (1H, d, J = 2.4 Hz), 7.58 (1H, dd, J = 2.4, 7.9 Hz), 7.20 (1H, d, J = 7.9 Hz), 4.78 (2H, d, J = 5.5 Hz), 4.40 (2H, q, J = 7.1 Hz), 3.53-3.45 (1H, m), 3.28- 3.20 (1H, m), 3.10-2.90 (4H, m), 2.86-2.77 (1H, m), 2.74 (3H, s) ( 2.07-2.02 (1H, m), 1.81-1.68 (2H, m), 1.44-1.30 (5H, m). 105 0 LC-MS [M + H].sup.+/Rt (min): 416.36/0.678 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.81 (1H, s), 7.29 (1H, d, J = 7.9 Hz), 7.05-6.98 (2H, m), 4.81 (2H, d, J = 5.5 Hz), 4.42 (2H, q, J = 7.1 Hz), 3.37-3.29 (1H, m), 3.06-2.84 (6H, m), 2.73 (3H, s), 1.94-1.90 (1H, m), 1.77- 1.70 (2H, m), 1.64-1.58 (1H, m), 1.43-1.34 (4H, m).

Reference Example 106

tert-Butyl 3-(4-{[(5-amino-2-ethoxy-6-methylpyrimidin-4-yl)amino]methyl}phenyl)pyrrolidine-1-carboxylate

(356) ##STR00581##

(357) To a solution of the compound of Reference example 61 (209 mg) in tetrahydrofuran (1 ml)/water (1 mL) were added ammonium chloride (244 mg) and zinc (149 mg) at room temperature. The reaction mixture was stirred under reflux for 2 hours, cooled to room temperature, filtrated, and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (165 mg).

(358) LC-MS ([M+H].sup.+/Rt (min)): 428.4/0.797 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.30 (2H, d, J=7.9 Hz), 7.20 (2H, d, J=7.9 Hz), 5.58 (1H, t, J=5.5 Hz), 4.63 (2H, d, J=5.5 Hz), 4.29 (2H, q, J=7.1 Hz), 3.87-3.68 (1H, m), 3.67-3.52 (1H, m), 3.44-3.21 (3H, m), 2.28 (3H, s), 2.26-2.20 (1H, m), 2.03-1.90 (1H, m), 1.47 (9H, s), 1.35 (3H, t, J=7.1 Hz).

Reference Example 107

N.SUP.4.-[4-(1-Azabicyclo[2.2.2]oct-3-yl)benzyl]-2-methoxy-6-methylpyrimidine-4,5-diamine

(359) ##STR00582##

(360) To a solution of the compound of Reference example 101 (319 mg) in methanol (8 ml) was added tin(II) chloride (789 mg) at room temperature. The reaction mixture was stirred under reflux for 3 hours, and cooled to room temperature. Aqueous ammonia was added thereto, and the mixture was stirred. The reaction solution was filtrated, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (300 mg).

(361) .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.31 (2H, d, J=7.9 Hz), 7.22 (2H, d, J=7.9 Hz), 5.57 (1H, br s), 4.62 (2H, d, J=6.1 Hz), 3.88 (3H, s), 3.34-3.26 (1H, m), 3.09-2.99 (1H, m), 2.99-2.79 (5H, m), 2.43 (2H, s), 2.28 (3H, s), 1.92-1.87 (1H, m), 1.77-1.69 (3H, m), 1.39-1.28 (1H, m).

Reference Examples 108-120

(362) According to the methods of Reference example 106 and Reference example 107, Reference examples 108-120 were prepared by using the corresponding material compounds.

(363) TABLE-US-00073 Reference example Chemical Structure Instrumental analysis data 108 .sup.1H-NMR (CDCl.sub.3) : 8.13 (1H, s), 7.81-7.77 (1H, m), 6.89-6.86 (1H, m), 5.79 (1H, s), 4.66 (2H, d, J = 6.1 Hz), 3.86 (3H, s), 2.53 (2H, br s), 2.30 (3H, s). 109 .sup.1H-NMR (CDCl.sub.3) : 8.20 (1H, d, J = 1.8 Hz), 7.83-7.79 (1H, m), 6.89 (1H, dd, J = 8.5, 3.0 Hz), 6.04 (1H, s), 4.67 (2H, d, J = 5.9 Hz), 4.28 (2H, q, J = 7.2 Hz), 2.30 (3H, s), 1.76 (2H, br s), 1.35 (3H, t, J = 7.2 Hz). 110 .sup.1H-NMR (CDCl.sub.3) : 8.85 (1H, s), 8.23 (1H, s) 7.79-7.75 (1H, m), 6.95-6.92 (1H, m), 4.79 (2H, d, J = 6.1 Hz), 4.27 (2H, t, J = 6.7 Hz), 2.75 (3H, s), 1.83-1.74 (2H, m), 1.01 (3H, t, J = 7.3 Hz). 111 LC-MS [M + H].sup.+/Rt (min): 358.3/0.361 (Method D) 112 .sup.1H-NMR (CDCl.sub.3) : 7.60 (2H, s), 5.43 (2H, br s), 4.56 (2H, d, J = 5.5 Hz), 4.33 (2H, q, J = 7.1 Hz), 2.47 (2H, s), 2.28 (3H, s), 1.39 (3H, t, J = 7.1 Hz). 113 LC-MS [M + H].sup.+/Rt (min): 346.0/0.190 (Method D) 114 LC-MS ([M + H].sup.+/Rt (min)): 519.42/1.048 (Method D); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.31 (2H, d, J = 7.9 Hz), 7.20 (2H, d, J = 7.9 Hz) 5.64 (1H, t, J = 5.5 Hz), 4.63 (2H, d, J = 5.5 Hz), 3.89 (3H, m), 3.87-3.69 (1H, m), 3.66-3.51 (1H, m), 3.43- 3.23 (3H, m), 2.30 (3H, s), 2.26-2.20 (1H, m), 2.02-1.91 (1H, m), 1.47 (9H, s). 115 0 LC-MS [M + H].sup.+/Rt (min): 260.2/0.409 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.60-8.58 (1H, m), 8.50 (1H, dd, J = 4.9, 1.2 Hz), 7.68-7.63 (1H, m), 7.24 (1H, dd, J = 7.9, 4.9 Hz), 5.77 (1H, t, J = 6.1 Hz), 4.67 (2H, d, J = 6.1 Hz), 4.27 (2H, q, J = 7.1 Hz), 2.53 (2H, s), 2.29 (3H, s), 1.34 (3H, t, J = 7.1 Hz). 116 LC-MS [M + H].sup.+/Rt (min): 318.25/0.501 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 9.17 (1H, s), 8.24 (1H, d, J = 8.5 Hz), 7.37 (1H, d, J = 7.9 Hz), 6.42 (1H, t, J = 5.5 Hz), 4.83 (2H, d, J = 5.5 Hz), 4.25 (2H, q, J = 7.1 Hz), 3.95 (3H, s), 2.30 (3H, s), 1.34 (3H, t, J = 7.1 Hz). 117 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.31 (2H, d, J = 7.9 Hz), 7.24 (2H, d, J = 7.9 Hz), 5.58 (1H, t, J = 5.5 Hz) 4.63 (2H, d, J = 5.5 Hz), 4.30 (2H, q, J = 7.1 Hz), 3.36-3.26 (1H, m), 3.10-3.02 (1H, m), 3.00-2.82 (5H, m), 2.28 (3H, s), 1.92-1.88 (1H, m), 1.76-1.69 (2H, m), 1.69- 1.61 (1H, m), 1.39-1.31 (4H, m). 118 .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.28 (2H, d, J = 8.5 Hz), 7.25 (2H, d, J = 8.5 Hz), 4.59 (2H, s), 4.27 (2H, q, J = 7.1 Hz), 3.26- 3.19 (1H, m), 3.00 (1H, dd, J = 8.2, 9.0 Hz), 2.26 (1H, dd, J = 9.0, 17.2 Hz), 2.19-2.10 (7H, m), 2.00-1.88 (1H, m), 1.84- 1.70 (2H, m), 1.35 (3H, t, J = 7.1 Hz). 119 LC-MS [M + H].sup.+/Rt (min): 369.1/0.138 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.56 (IH, d, J = 1.8 Hz), 7.61 (1H, dd, J = 1.8, 7.9 Hz), 7.16 (1H, d, J = 7.9 Hz), 5.67 (1H, t, J = 6.1 Hz), 4.65 (2H, d, J = 6.1 Hz), 4.29 (2H, q, J = 7.1 Hz), 3.51-3.44 (1H, m), 3.27-3.19 (1H, m), 3.09-2.86 (4H, m), 2.86-2.76 (1H, m), 2.48 (2H, s), 2.29 (3H, s), 2.07-2.02 (1H, m), 1.81-1.58 (3H, m), 1.39-1.26 (4H, m). 120 LC-MS [M + H].sup.+/Rt (min): 386.4/0.418 (Method C); .sup.1H-NMR (400 MHz, CDCl.sub.3) : 7.33 (1H, dd, J = 8.2, 8.6 Hz), 7.02- 6.95 (2H, m), 5.64 (1H, t, J = 5.5 Hz), 4.69 (2H, d, J = 5.5 Hz), 4.31 (2H, q, J = 7.1 Hz), 3.35-3.27 (1H, m), 3.05-2.79 (6H, m), 2.48 (2H, s), 2.28 (3H, s), 1.93-1.88 (1H, m), 1.76-1.68 (2H, m), 1.64-1.57 (1H, m), 1.41-1.30 (4H, m).

Reference Example 121

N-[2-Ethoxy-8-(5-fluoropyridin-3-yl)-9-(4-hydroxybenzyl)-9H-purin-6-yl]-N,N-dimethylimidoformamide

(364) ##STR00596##

(365) To a solution of the compound of Example 208 (570 mg) in N,N-dimethylformamide (5.0 mL) was added N,N-dimethylformamide dimethyl acetal (0.602 mL), and the mixture was stirred at 60 C. for one hour. To the reaction mixture was added water, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, filtrated, and then concentrated in vacuo to give the title compound (602 mg).

(366) LC-MS [M+H].sup.+/Rt (min): 436.4/0.658 (Method B)

Reference Example 122

(367) According to the method of Reference example 121, Reference example 122 was prepared by using the corresponding material compound.

(368) TABLE-US-00074 Reference example Chemical Structure Instrumental analysis data 122 LC-MS ([M + H].sup.+/Rt (min)): 500.3/0.776 (Method C); .sup.1H-NMR (400 MHz, CD.sub.3OD) : 8.95 (1H, s), 8.64 (1H, s), 8.59 (1H, d, J = 2.4 Hz), 7.92-7.88 (1H, m), 7.43 (2H, d, J = 8.5 Hz), 6.97 (2H, d, J = 8.5 Hz), 5.49 (2H, m), 4.43 (2H, q, J = 7.3 Hz), 3.24 (6H, s), 1.39 (3H, t, J = 7.3 Hz).

Reference Example 123

(369) N-{2-Ethoxy-8-(5-fluoropyridin-3-yl)-9-[4-(4-methylpiperazin-1-yl)benzyl]-9H-purin-6-yl}-N,N-dimethylimidoformamide

(370) ##STR00598##

(371) To a solution of the compound of Reference example 122 (80.9 mg) in 1,4-dioxane (2 mL) were added 1-methylpiperazine (0.045 mL), lithium bis(trimethylsilyl)amide (1.3 mol/0.25 mL), tris(dibenzylideneacetone)dipalladium (14.9 mg), and 2-(dicyclohexylphosphino)-2-(N,N-dimethylamino)biphenyl (6.4 mg), and the mixture was stirred at 35 C. for 4 hours. The reaction mixture was cooled to room temperature. Water was added thereto, and the mixture was extracted with chloroform/methanol. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (14.0 mg).

(372) .sup.1H-NMR (400 MHz, CDCl.sub.3) : 8.97 (1H, s), 8.73 (1H, s), 8.50 (1H, d, J=3.1 Hz), 7.77-7.72 (1H, m), 6.95 (2H, d, J=8.5 Hz), 6.79 (2H, d, J=8.5 Hz), 5.61 (2H, s), 5.38 (2H, s), 4.46 (2H, q, J=6.5 Hz), 3.19-3.14 (4H, m), 2.61-2.52 (4H, m), 2.38-2.32 (9H, m), 1.44 (3H, t, J=6.5 Hz).

Reference Examples 124-128

(373) According to the method of Example 69, Reference examples 124-128 were prepared by using the corresponding material compounds.

(374) TABLE-US-00075 Reference example Chemical Structure Instrumental analysis data 124 .sup.1H-NMR (CDCl.sub.3) : 8.24 (1H, d, J = 2.4 Hz), 7.63 (1H, dd, J = 2.4, 8.5 Hz), 6.59 (1H, d, J = 8.5 Hz), 5.41 (3H, br s), 5.21 (2H, s), 4.40 (2H, q, J = 7.0 Hz), 2.88-2.79 (2H, m), 2.73- 2.69 (1H, m), 2.37-2.30 (5H, m), 1.99-1.90 (1H, m), 1.43 (3H, t, J = 7.0 Hz). 125 00 .sup.1H-NMR (CDCl.sub.3) : 8.24 (1H, d, J = 2.4 Hz), 7.63 (1H, dd, J = 2.4, 8.9 Hz), 5.69 (1H, d, J = 8.9 Hz), 5.42-5.38 (3H, m), 5.21 (2H, s), 4.40 (2H, q, J = 7.1 Hz), 2.87-2.79 (2H, m), 2.73-2.69 (1H, m), 2.37-2.32 (5H, m), 1.98-1.92 (1H, m), 1.43 (3H, t, J = 7.3 Hz). 126 01 .sup.1H-NMR (CDCl.sub.3) : 8.23 (1H, d, J = 3.1 Hz), 7.67-7.64 (1H, m), 6.68 (1H, d, J = 8.5 Hz), 5.41 (2H, s), 5.21 (2H, s), 5.01- 4.97 (1H, m), 4.40 (2H, q, J = 7.1 Hz), 3.36-3.30 (1H, m), 2.98-2.73 (5H, m), 2.14-2.10 (1H, m), 1.98-1.89 (1H, m), 1.75-1.55 (2H, m), 1.45-1.34 (4H, m). 127 02 .sup.1H-NMR (CDCl.sub.3) : 8.23 (1H, d, J = 1.8 Hz), 7.65 (1H, dd, J = 2.4, 8.5 Hz), 6.68 (1H, d, J = 8.5 Hz), 5.48 (2H, br s), 5.21 (2H, s), 5.01-4.97 (1H, m), 4.40 (2H, q, J = 7.1 Hz), 3.36- 3.30 (1H, 2.98-2.73 (5H, m), 2.14-2.10 (1H, m), 1.98- 1.89 (1H, m), 1.75-1.56 (2H, m), 1.44-1.34 (4H, m). 128 03 .sup.1H-NMR (CDCl.sub.3) : 8.26 (1H, d, J = 2.4 Hz), 7,64 (1H, dd, J = 2.4, 8.5 Hz), 6.67 (1H, d, J = 8.5 Hz), 5.43 (2H, s), 5.21 (2H, s), 4.40 (2H, q, J = 7.0 Hz), 4.31 (2H, t, J = 6.4 Hz), 2.40 (2H, t, J = 7.3 Hz), 2.23 (6H, br s), 1.96-1.89 (2H, m), 1.43 (3H, t, J = 7.0 Hz).

Reference Examples 129-132

(375) According to the method of Example 80, Reference examples 129-132 were prepared by using the corresponding material compounds.

(376) TABLE-US-00076 Reference example Chemical Structure Instrumental analysis data 129 04 LC-MS [M].sup.+/Rt (min) 405.3/0.531 (Method A) 130 05 .sup.1H-NMR (CDCl.sub.3) : 7.70 (1H, s), 7.32 (2H, d, J = 7.9 Hz), 7.26-7.24 (2H, m), 5.84 (2H, br s), 5.31 (2H, s), 3.43 (2H, s), 2.24 (6H, s). 131 06 .sup.1H-NMR (DMSO-D.sub.6) : 8.23 (1H, s), 7.76 (2H, br s), 7.28 (2H, d, J = 7.9 Hz), 7.19 (2H, d, J = 7.9 Hz), 5.29 (2H, s), 3.59 (2H, q, J = 13.6 Hz), 3.15 (1H, s), 3.07 (1H, s), 2 64 (1H, d, J = 9.2 Hz) , 2.55-2.44 (3H, m), 2.22 (3H, s), 1.56 (2H, s). 132 07 LC-MS [M + H].sup.+/Rt (min): 470.4/0.600 (Method B)

Reference Example 133

Methyl 4-{[6-chloro-2-ethoxy-8-(5-fluoropyridin-3-yl)-9H-purin-9-yl]methyl}benzoate

(377) ##STR00608##

(378) To a solution of the compound of Example 182 (1.93 g) in dichloromethane (30 mL) were added benzyltriethylammonium chloride (2.08 g), chlorotrimethylsilane (5.79 mL), and tert-butyl nitrite (3.00 mL), and the mixture was stirred under reflux for 3 hours. To the reaction mixture in ice bath was added aqueous saturated sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.57 g).

(379) LC-MS [M+H].sup.+/Rt (min): 442.4/1.029 (Method A)

Reference Examples 134-135

(380) According to the method of Reference example 133, Reference examples 134-135 were prepared by using the corresponding material compounds.

(381) TABLE-US-00077 Reference example Chemical Structure Instrumental analysis data 134 09 LC-MS [M + H].sup.+/Rt (min): 428.3/0.972 (Method A) 135 0 .sup.1H-NMR (400 MHz, DMSO-d.sub.6) : 8.77 (1H, d, J = 2.7 Hz), 8.75-8.74 (1H, m), 8.10-8.06 (1H, m), 7.29-7.23 (2H, m), 7.06-7.03 (2H, m), 5.60 (2H s) , 4.38 (2H, t, J = 6.6 Hz), 1.71 (2H, tt, J = 6.6, 7.9 Hz), 1.40 (2H, qt, J = 7.3, 7.9 Hz), 0.93 (3H, t, J = 7.3 Hz).

Reference Examples 136-141

(382) According to the method of Example 150, Reference examples 136-141 were prepared by using the corresponding material compounds. As appropriate, microwave irradiation was used.

(383) TABLE-US-00078 Reference example Chemical Structure Instrumental analysis data 136 LC-MS [M + H].sup.+/Rt (min): 371.3/0.507 (Method B) 137 .sup.1H-NMR (CDCl.sub.3) : 7.64 (1H, s), 7.33 (2H, d, J = 7.9 Hz), 7.26-7.24 (2H, m), 6.13 (1H, tt, J = 55.8, 4.3 Hz), 5.57 (2H, br s), 5.26 (2H, s), 4.55 (2H, td, J = 13.1, 4.3 Hz), 3.47 (2H, s), 2.27 (6H, s). 138 .sup.1H-NMR (CDCl.sub.3) : 7.58 (1H, s), 7.30 (2H, d, J = 7.9 Hz), 7.26-7.24 (2H, m), 5.47 (2H, br s), 5.25 (2H, s), 4.16 (2H, d, J = 6.7 Hz), 3.44 (2H, s), 2.25 (6H, s), 1.35-1.28 (1H, m), 0.61-0.57 (2H, m), 0.38-0.34 (2H, m). 139 .sup.1H-NMR (CDCl.sub.3) : 7.58 (1H, s), 7.29-7.24 (4H, m), 5.47 (2H, s), 5.25 (2H, s), 4.29 (2H, t, J = 6.7 Hz), 3.40 (2H, s), 2.22 (6H, s), 1.87-1.78 (2H, m), 1.04 (3H, t, J = 7.2 Hz). 140 .sup.1H-NMR (CDCl.sub.3) : 7.59 (1H, s), 7.32 (2H, d, J = 7.9 Hz), 7.26-7.23 (2H, m), 5.51 (2H, s), 5.25 (2H, s), 3.97 (3H, s), 3.74- 3.64 (2H, m), 3.25-3.20 (2H, m), 2.87 (1H, d, J = 9.8 Hz), 2.73-2.57 (3H, m), 2.39 (3H, s), 1.72 (2H, s). 141 LC-MS [M + H].sup.+/Rt (min): 466.5/0.581 (Method B)

Reference Examples 142-145

(384) According to the method of Reference example 2, Reference examples 142-145 were prepared by using the corresponding material compounds.

(385) TABLE-US-00079 Reference example Chemical Structure Instrumental analysis data 142 LC-MS [M + H].sup.+/Rt (min): 294.96/0.590 (Method C); .sup.1H- NMR (CDCl.sub.3) : 7.65-7.59 (3H, m), 7.56-7.51 (1H, m), 7.50- 7.45 (1H, m), 5.63 (2H, s), 5.32 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 1.42 (3H, t, J = 7.1 Hz). 143 LC-MS [M + H].sup.+/Rt (min): 337.2/0.845 (Method A); .sup.1H- NMR (CDCl.sub.3) : 7.69 (1H, s), 7.39-7.30 (2H, m), 7.21-7.11 (2H, m), 5.63 (2H, s), 6.62 (1H, t, J = 73.4 Hz), 5.35 (2H, s), 4.40 (2H, q, J = 7.1 Hz), 1.42 (3H, t, J = 7.1 Hz). 144 LC-MS [M + H].sup.+/Rt (min): 305.9/0.673 (method C); .sup.1H- NMR (CDCl.sub.3) : 7.68 (1H, s), 7.10-6.94 (3H, m), 5.54 (2H, s), 5.29 (2H, s), 4.40 (2H, q, J = 7.1 Hz), 1.42 (3H, t, J = 7.1 Hz). 145 0 LC-MS [M + H].sup.+/Rt (min): 313.5/0.688 (method A); .sup.1H- NMR (CDCl.sub.3) : 7.69-7.66 (2H, m), 7.66-7.61 (1H, m), 7.22 (1H, dd, J = 8.8, 8.8 Hz), 5.60 (2H, s), 5.34 (2H, s), 4.39 (2H, q, J = 7.0 Hz), 1.42 (3H, t, J = 7.0 Hz).

Reference Examples 146-147

(386) According to the method of Reference example 26, Reference examples 146-147 were prepared by using the corresponding material compounds.

(387) TABLE-US-00080 Reference Instrumental example Chemical Structure analysis data 146 LC-MS [M + H].sup.+/ Rt (min): 275.1/0.389 (Method C) 147 LC-MS [M + H].sup.+/ Rt (min): 259.1/0.394 (Method C)

Reference Examples 143-149

(388) According to the method of Reference example 30, Reference examples 148-149 were prepared by using the corresponding material compounds.

(389) TABLE-US-00081 Reference Instrumental example Chemical Structure analysis data 148 LC-MS [M + H].sup.+/ Rt (min): 277.1/0.377 (Method C) 149 LC-MS [M + H].sup.+/ Rt (min): 261.1/0.409 (Method C)

Reference Examples 150-153

(390) According to the method of Reference example 36, Reference examples 150-153 were prepared by using the corresponding material compounds.

(391) TABLE-US-00082 Reference example Chemical Structure Instrumental analysis data 150 .sup.1H-NMR (CDCl.sub.3) : 7.66 (1H, s), 7.64-7.58 (2H, m), 7.50- 7.44 (1H, m), 5.70 (2H, s), 5.33 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 1.43 (3H, t, J = 7.1 Hz). 151 LC-MS [M + H].sup.+/Rt (min): 416.16/0.985 (Method A); .sup.1H- NMR (CDCl.sub.3) : 7.35-7.30 (1H, m), 7.20-7.11 (2H, m), 6.92 (1H, d, J = 7.9 Hz), 6.66 (1H, t, J = 73.4 Hz), 5.58 (2H, s), 5,42 (2H, s), 4.35 (2H, q, J = 7.1 Hz), 1.39 (3H, t, J = 7.1 Hz). 152 LC-MS [M + H].sup.+/Rt (min): 385.8/0.310 (method A); .sup.1H-NMR (CDCl.sub.3) : 7.09-7.02 (1H, m), 7.00-6.92 (1H, m), 6.80-6.74 (1H, m), 5.72 (2H, s), 5.34 (2H, s), 4.36 (2H, q, J = 7.1 Hz), 1.39 (3H, t, J = 7.1 Hz). 153 LC-MS [M + H].sup.+/Rt (min): 393.1/0.834 (method A); .sup.1H-NMR (CDCl.sub.3) : 7.65-7.60 (1H, m), 7.42 (1H, d, J = 5.9 Hz), 7.25-7.19 (1H, m), 5.58 (2H, s), 5.38 (2H, s), 4.35 (2H, q, J = 6.9 Hz), 1.40 (3H, t, J = 6.9 Hz).

Reference Examples 154-164

(392) According to the method of Reference example 69, Reference examples 154-161 were prepared by using the corresponding material compounds.

(393) TABLE-US-00083 Reference example Chemical Structure Instrumental analysis data 154 LC-MS [M + H].sup.+/Rt (min): 497.2/1.296 (Method C); .sup.1H-NMR (CDCl.sub.3) : 7.20 (1H, d, J = 8.2 Hz), 7.02 (1H, dd, J = 8.2, 1.8 Hz), 6.94 (1H, d, J = 1.8 Hz), 5.08 (2H, s), 4.32 (2H, q, J = 7.0 Hz), 3.70 (3H, s), 2.60 (3H, s), 1.36 (9H, s), 1.34 (3H, t, J = 7.3 Hz). 155 0 LC-MS ([M + H].sup.+/Rt (min)): 451.4/1.212 (Method A) 156 LC-MS ([M + H].sup.+/Rt (min)): 421.4/1.130 (Method A) 157 LC-MS [M + H].sup.+/Rt (min): 435.4/1.186 (Method A) 158 LC-MS [M + H].sup.+/Rt (min): 471.3/1.284 (Method A) 159 LC-MS [M + H].sup.+/Rt (min): 471.1/1.245 (Method C) 160 LC-MS [M + H].sup.+/Rt (min): 449.2/1.161 (Method C) 161 LC-MS [M + H].sup.+/Rt (min): 471.3/1.259 (Method C) 162 LC-MS [M + H].sup.+/Rt (min): 442.3/1.182 (Method C) 163 LC-MS [M + H].sup.+/Rt (min): 492.3/1.246 (Method C) 164 LC-MS [M + H].sup.+/Rt (min): 453.2/1.235 (Method C)

Reference Examples 165-166

(394) According to the method of Reference example 77, Reference examples 165-166 were prepared by using the corresponding material compounds.

(395) TABLE-US-00084 Ref- erence example Chemical Structure Instrumental analysis data 165 0 LC-MS [M + H].sup.+/Rt (min): 249.1/0.305 (Method C); (CDCl.sub.3) : 7.47 (1H, d, J = 7.3 Hz), 6.73 (1H, d, J = 7.3 Hz), 4.60 (2H, s), 3.98 (3H, s), 3.61-3.52 (1H, m), 3.20-3.05 (2H, m), 3.02-2.80 (4H, m), 2.00-1.95 (1H, m), 1.86-1.65 (3H, m), 1.37-1.27 (1H, m). 166 LC-MS [M + H].sup.+/Rt (min): 233.1/0.148 (Method C)

Reference Example 167

Ethyl 2-fluoro-4-(oxiran-2-yl)benzoate

(396) ##STR00642##

(397) To an ice-cooled solution of ethyl 2-fluoro-4-vinylbenzoate (1.30 g) in dichloromethane (50 mL) was added 3-chloroperbenzoic acid (2.66 and the mixture was stirred at room temperature overnight. To the reaction mixture were added aqueous sodium bicarbonate and aqueous saturated sodium thiosulfate, and the mixture was extracted with chloroform. The organic layer was washed with aqueous saturated sodium bicarbonate, dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.36 g).

(398) .sup.1H-NMR (CDCl.sub.3) : 7.89 (1H, dd, J=7.9 Hz), 7.11 (1H, dd, J=1.8, 7.9 Hz), 7.02 (1H, dd, J=1.8, 11.3 Hz), 4.37 (2H, q, J=7.1 Hz), 3.86 (1H, dd, J=2.4, 4.0 Hz), 3.16 (1H, dd, J=4.0, 5.5 Hz), 2.73 (1H, dd, J=2.4, 5.5 Hz), 1.37 (3H, t, J=7.1).

Reference Example 168

Ethyl 2-fluoro-4-{1-hydroxy-2-[(2-hydroxyethyl)amino]ethyl}benzoate

(399) ##STR00643##

(400) To a solution of the compound of Reference example 167 (1.36 g) in tetrahydrofuran (50 mL) was added 2-aminoethanol (3.9 mL), and the mixture was stirred at room temperature for one day, and then at 60 C. for 12 hours. To the reaction mixture was aqueous sodium bicarbonate, and the mixture was extracted with a mixture of chloroform and ethanol. The organic layer was washed with aqueous saturated sodium bicarbonate, dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.36 g).

(401) LC-MS [M+H].sup.+/Rt (min): 272.2/0.486 (Method A)

Reference Example 169

Ethyl 4-(2-{[(benzyloxy)carbonyl](2-hydroxyethyl)amino}-1-hydroxyethyl)-2-fluorobenzoate

(402) ##STR00644##

(403) To a solution of the compound of Reference example 168 (1.15 g) in a mixture of tetrahydrofuran (20 mL) and water (10 mL) were added sodium bicarbonate (0.535 mg) and benzyl chloroformate (0.893 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added aqueous saturated sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (913 mg).

(404) LC-MS [M+H].sup.+/Rt. (min): 406.3/0.887 (Method A)

Reference Example 170

Benzyl 2-[4-(ethoxycarbonyl)-3-fluorophenyl]morpholine-4-carboxylate

(405) ##STR00645##

(406) To a solution of the compound of Reference example 169 (910 mg) in toluene (45 mL) were added triphenylphosphine (913 mg) and diisopropyl azodicarboxylate (0.665 mL), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo, and then the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (583 mg).

(407) LC-MS [M+H].sup.+/Rt (min): 388.2/1.145 (Method A)

Reference Example 171

[2-Fluoro-4-(4-methylmorpholin-2-yl)phenyl]methanol

(408) ##STR00646##

(409) To an ice-cooled solution of the compound of Reference example 170 (581 mg) in tetrahydrofuran (45 mL) was added diisobutylaluminum hydride (1.02 mol/L hexane solution, 3.38 mL), and the mixture was stirred for one hour. Further, diisobutylaluminum hydride (1.02 mol/L hexane solution, 9.0 mL) was added thereto, and the mixture was stirred in ice bath for 5 hours. To the reaction mixture in ice bath were slowly added water (0.47 mL), aqueous sodium hydroxide (4 mol/L, 0.47 mL), and water (1.41 mL), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was filtrated and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (177 mg).

(410) LC-MS [M+H].sup.+/Rt (min): 226.1/0.346 (Method A)

Reference Examples 172-185

(411) According to the method of Reference example 83, Reference examples 172-185 were prepared by using the corresponding material compounds.

(412) TABLE-US-00085 Reference example Chemical Structure Instrumental analysis data 172 .sup.1H-NMR (CDCl.sub.3) : 7.44 (1H, dd, J = 11.6, 7.9 Hz), 7.02 (1H, d, J = 7.9 Hz), 6.95 (1H, d, J = 11.6 Hz), 5.25 (2H, s), 3.98 (3H, s), 3.37-3.28 (1H, m), 3.07-2.98 (1H, m), 2.98-2.81 (5H, m), 2.63 (3H, s), 1.93- 1.87 (1H, m), 1.76-1.66 (2H, m), 1.65-1.57 (1H, m), 1.44- 1.31 (10H, m). 173 LC-MS [M + H].sup.+/Rt (min): 513.4/0.908 (Method A); .sup.1H-NMR (CDCl.sub.3) : 7.62 (1H, d, J = 7.9 Hz), 7.03 (1H, d, J = 7.9 Hz), 5.18 (2H, s), 4.33 (2H, q, J = 7.1 Hz), 3.51-3.44 (1H, m), 3.27-3.17 (1H, m), 3.09-2.98 (2H, m), 2.98-2.89 (2H, m), 2.89-2.75 (1H, m), 2.64 (3H, s), 2.59 (3H, s), 2.05-1.99 (1H, m), 1.71-1.59 (3H, m), 1.42-1.24 (13H, m). 174 .sup.1H-NMR (CDCl.sub.3) : 7.72-7.56 (1H, m), 7.55-7.51 (1H, m), 5.17 (2H, s), 4.42 (2H, q, J = 7.1 Hz), 3.47-3.40 (1H, m), 3.40-3.30 (1H, m), 3.17-3.06 (1H, m), 3.06-2.86 (4H, m), 2.65 (3H, s), 1.94-1.83 (2H, m), 1.79-1.68 (1H, m), 1.61- 1.50 (1H, m), 1.46-1.34 (13H, m). 175 0 LC-MS [M + H].sup.+/Rt (min): 546.5/0.941 (Method A); .sup.1H-NMR (CDCl.sub.3) : 7.06 (1H, d, J = 6.7 Hz), 6.97 (1H, d, J = 11.6 Hz), 5.29 (2H, s), 4.41 (2H, q, J = 7.1 Hz), 3.77 (3H, s), 3.37-3.28 (1H, m), 3.28-3.23 (1H, m), 3.00-2.89 (3H, m), 2.88-2.77 (2H, m), 2.63 (3H, s), 1.91-1.85 (1H, m), 1.75-1.62 (3H, m), 1.45 (9H, s), 1.43-1.35 (4H, m). 176 .sup.1H-NMR (CDCl.sub.3) : 7.73 (1H, s), 7.57-7.46 (2H, m), 5.18 (2H, s), 4.02 (3H, s), 3.48-3.41 (1H, m), 3.39-3.31 (1H, m), 3.15- 3.08 (1H, m), 3.07-2.89 (4H, m), 2.66 (3H, s), 1.90-1.84 (2H, m), 1.80-1.71 (1H, m), 1.61-1.50 (1H, m), 1.46-1.35 (10H, m). 177 LC-MS [M + H].sup.+/Rt (min): 468.3/1.324 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.59 (1H, d, J = 2.4 Hz), 7.81 (1H, dd, J = 8.5, 2.4 Hz), 7.37 (1H, d, J = 8.5 Hz), 5.26 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 2.65 (3H, s), 1.41 (9H, s), 1.34 (3H, t, J = 7.1 Hz). 178 LC-MS [M + H].sup.+/Rt (min): 456.2/1.288 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.59 (1H, d, J = 2.4 Hz), 7.81 (1H, dd, J = 8.5, 2.4 Hz), 7.37 (1H, d, J = 8.5 Hz), 5.27 (2H, s), 3.90 (3H, s), 2.66 (3H, s), 1.41 (9H, s). 179 LC-MS [M + H].sup.+/Rt (min): 529.4/0.873 (Method C) 180 LC-MS ([M + H].sup.+/Rt (min)): 506.3/0.866 (Method A) 181 LC-MS [M + H].sup.+/Rt (min): 513.4/0.787 (Method C) 182 LC-MS [M + H].sup.+/Rt (min): 454.2/1.082 (Method C) 183 LC-MS [M + H].sup.+/Rt (min): 486.2/1.207 (Method C); .sup.1H-NMR (CDCl.sub.3) 8.37- 8.34 (1H, m), 7.58-7.53 (1H, m), 5.23-5.21 (2H, m), 4.14 (2H, q, J = 7.2 Hz), 2.60 (3H, s), 1.40 (9H s), 1.25 (3H, t, J = 7.2 Hz). 184 LC-MS [M + H].sup.+/Rt (min): 492.3/1.275 (Method C) 185 0 LC-MS [M + H].sup.+/Rt (min): 487.3/1.065 (Method C)

Reference Examples 186-187

(413) According to the methods Examples 352 and 365, Reference examples 186-187 were prepared by using the corresponding material compounds.

(414) TABLE-US-00086 Reference example Chemical Structure Instrumental analysis data 186 LC-MS [M + H].sup.+/Rt (min): 500.4/0.708 (Method C) 187 LC-MS [M + H].sup.+/Rt (min): 444.4/0.721 (Method C)

Reference Examples 188-189

(415) According to the method of Example 80, Reference examples 188-189 were prepared by using the corresponding material compounds.

(416) TABLE-US-00087 Reference example Chemical Structure Instrumental analysis data 188 LC-MS ([M + H].sup.+/Rt (min)): 603.5/0.880 (Method A) 189 LC-MS ([M + H].sup.+/Rt (min)): 617.5/0.0932 (Method A)

Reference Example 190, Reference Example 191

N-(4-Bromo-2-fluorobenzyl)-2-methoxy-6-methyl-5-nitropyrimidine-4-amine; 4-[(4-bromo-2-fluorobenzyl)amino]-6-methyl-5-nitropyrimidin-2-ol

(417) ##STR00665##

(418) To an ice-cooled solution of the compound of Reference example 161 (4.6 g) in ethyl acetate (10 mL) was added a solution of hydrochloric acid in ethyl acetate (4 mol/L, 49 mL), and the mixture was stirred at room temperature for 2 hours, and at 50 C. for 2 hours. The reaction mixture was cooled to room temperature, and then the solvent was removed under reduced pressure to give the two title compounds (4.7 g) as a mixture.

(419) Reference example 190: LC-MS [M+H].sup.+/Rt (min): 370.9/1.008

(420) Reference example 191: LC-MS [M+H].sup.+/Rt (min): 357.0/0.709

Reference Examples 192-218

(421) According to the method of Reference example 91, Reference examples 192-218 were prepared by using the corresponding material compounds.

(422) TABLE-US-00088 Reference example Chemical Structure Instrumental analysis data 192 LC-MS [M + H].sup.+/Rt (min): 402.0/0.514 (Method C); .sup.1H-NMR (CDCl.sub.3) : 8.83- 8.81 (1H, br m), 7.34-7.28 (1H, m), 7.06-6.39 (2H, m), 4.84 (2H, d, J = 5.5 Hz), 4.03 (3H, s), 3.41-3.31 (1H, m), 3.09-2.84 (6H, m), 2.75 (3H, s), 2.02-1.90 (1H, m), 1.80-1.71 (2H, m), 1.69- 1.61 (1H, m), 1.45-1.33 (1H, m). 193 LC-MS [M + H].sup.+/Rt (min): 413.4/0.659 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.74- 8.68 (1H, m), 7.48 (1H, d, J = 7.9 Hz), 7.05 (1H, d, J = 7.9 Hz), 4.77 (2H, d, J = 5.5 Hz), 4.41 (2H, q, J = 7.1 Hz), 3.52-3.46 (1H), m), 3.27-3.19 (1H, m), 3.10-2.99 (2H, m), 2.99- 2.89 (2H, m), 2.88-2.78 (1H, m), 2.77 (3H, s), 2.60 (3H, s), 2.07-2.01 (1H, m), 1.77-1.63 (3H, m), 1.40 (3H, t, J = 7.1 Hz), 1.37- 1.22 (1H, m). 194 LC-MS [M + H].sup.+/Rt (min): 423.4/0.700 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.88 1H, t, J = 5.5 Hz), 7.69-7.61 (1H, m), 7.61-7.51 (2H, m), 4.81 (2H, d, J = 5.5 Hz), 4.39 (2H, q, J = 7.1 Hz), 3.50-3.43 (1H, m), 3.43- 3.31 (1H, m), 3.19-3.09 (1H, m), 3.09-2.89 (4H, m), 2.77 (3H, s), 1.98- 1.87 (2H, m), 1.83-1.73 (1H, m), 1.63-1.51 (1H, m), 1.47-1.34 (4H, m). 195 LC-MS [M + H].sup.+/Rt (min): 446.4/0.785 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.80 (1H, t, J = 5.5 Hz), 7.05 (1H, d, J = 11.0 Hz), 6.81 (1H, d, J = 6.1 Hz), 4.81 (2H, d, J = 5.5 Hz), 4.46 (2H, q, J = 7.1 Hz), 3.79 (3H, s), 3.41-3.33 (1H, m), 3.30-3.24 (1H, m), 3.02- 2.80 (5H, m), 2.75 (3H, s), 1.93-1.89 (1H, m), 1.82- 1.65 (3H, m), 1.47-1.34 (4H, m). 196 0 LC-MS [M + H].sup.+/Rt (min): 409.4/0.712 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.86 (6H, t, J = 6.1 Hz), 7.65 (1H, s), 7.60-7.52 (2H, m), 4.82 (2H, d, J = 6.1 Hz), 3.97 (3H, s), 3.49-3.43 (1H, m), 3.41-3.32 (1H, m), 3.16-3.08 (1H, m), 3.08-2.88 (4H, m), 2.78 (3H, s), 1.96-1.85 (2H, m), 1.81-1.72 (1H, m), 1.61-1.52 (1H, m), 1.43- 1.36 (1H, m). 197 LC-MS [M + H].sup.+/Rt (min): 370.2/1.100 (Method A); .sup.1H-NMR (CDCl.sub.3) : 9.35 (1H, t, J = 5.5 Hz), 8.69 (1H, d, J = 2.4 Hz), 7.83 (1H, dd, J = 7.9, 2.4 Hz), 7.21 (1H, d, J = 8.5 Hz), 4.86 (2H, d, J = 5.5 Hz), 4.40 (2H, q, J = 7.1 Hz), 2.77 (3H, s), 1.40 (4H, t, J = 7.1 Hz). 198 LC-MS [M + H].sup.+/Rt (min): 356.1/1.018 (Method A); .sup.1H-NMR (CDCl.sub.3) : 9.35 (1H, t, J = 4.9 Hz), 8.69 (1H, d, J = 2.4 Hz), 7.83 (1H, dd, J = 8.5, 2.4 Hz), 7.22 (1H, d, J = 8.5 Hz), 4.87 (3H, d, J = 4.9 Hz), 3.98 (3H, s), 2.77 (3H, s). 199 LC-MS [M + H].sup.+/Rt (min): 397.1/1.130 (Method C) 200 LC-MS [M + 2H].sup.2+/2/Rt (min): 215.1/0.671 (Method C); .sup.1H-NMR (CDCl.sub.3) : 9.04-8.95 (1H, m), 7.42 (1H), d, J = 7.3 Hz), 6.69 (1H, d, J = 7.3 Hz), 4.68 (2H, d, J = 5.5 Hz), 4.40 (2H, q, J = 7.0 Hz), 4.00 (3H, s), 3.55-3.47 (1H, m), 3.17-3.02 (2H, m), 2.98- 2.77 (4H, m), 2.69 (3H, s), 1.97-1.93 (1H, m), 1.83-1.62 (3H, m), 1.38 (3H, t, J = 7.0 Hz), 1.34- 1.21 (1H, m). 201 LC-MS [M + H].sup.+/Rt (min): 406.5/0.729 (Method A) 202 LC-MS [M + H].sup.+/Rt (min): 350.9/0.984 (Method A) 203 LC-MS [M + H].sup.+/Rt (min): 403.4/0.523 (Method A) 204 LC-MS [M + H].sup.+/Rt (min): 417.4/0.592 (Method A) 205 LC-MS [M + H].sup.+/Rt (min): 371.2/1.074 (Method A) 206 0 LC-MS [M + 2H].sup.2+/2/Rt (min): 207.0/0.561 (Method C) 207 LC-MS [M + H].sup.+/Rt (min): 354.1/0.856 (Method C) 208 LC-MS [M + H].sup.+/Rt (min): 370.9/1.008 (Method C) 209 LC-MS [M + H].sup.+/Rt (min): 357.1/0.709 (Method C) 210 LC-MS [M + H].sup.+/Rt (min): 386.0/1.005 (Method C) 211 LC-MS [M + H].sup.+/Rt (min): 392.1/1.038 (Method C) 212 LC-MS [M + H].sup.+/Rt (min): 349.2/0.903 (Method C) 213 LC-MS [M + H].sup.+/Rt (min): 371.2/1.036 (Method C) 214 LC-MS [M + H].sup.+/Rt (min): 342.2/0.904 (Method C) 215 LC-MS [M + H].sup.+/Rt (min): 392.2/1.006 (Method C) 216 0 LC-MS [M + H].sup.+/Rt (min): 400.2/0.554 (Method C) 217 LC-MS [M + H].sup.+/Rt (min): 353.1/0.998 (Method C) 218 LC-MS [M + H].sup.+/Rt (min): 387.2/0.832 (Method C)

Reference Examples 219-222

(423) According to the method of Example 127, Reference examples 219-222 were prepared by using the corresponding material compounds.

(424) TABLE-US-00089 Reference example Chemical Structure Instrumental analysis data 219 LC-MS [M + H].sup.+/Rt (min): 417.4/0.581 (Method A) 220 LC-MS [M + H].sup.+/Rt (min): 431.45/0.596 (Method A) 221 LC-MS [M + H].sup.+/Rt (min): 431.4/0.651 (Method A)

Reference Example 222

4-{[(5-Amino-2-methoxy-6-methylpyrimidin-4-yl)amino]methyl}-3-fluorophenylmethanesulfonate

(425) ##STR00696##

(426) To a solution of the compound of Reference example 218 (7.38 g) in ethanol (100 mL) was added 5% palladium carbon (1.13 g) at room temperature. The reaction mixture was stirred at room temperature under ambient-pressure hydrogen atmosphere for 3 hours, and then filtrated through Celite. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (4.22 g).

(427) LC-MS [M+H].sup.+/Rt (min): 357.2/0.441 (Method C)

Reference Examples 223-249

(428) According to the methods of Reference example 106, Reference example 107, and Reference example 222, Reference examples 223-249 were prepared by using the corresponding material compounds.

(429) TABLE-US-00090 Reference example Chemical Structure Instrumental analysis data 223 LC-MS [M + 2H].sup.2+/2/Rt (min): 186.6/0.252 (Method C); .sup.1H-NMR (CDCl.sub.3) : 7.39-7.33 (1H, m), 7.04-6.96 (2H, m), 5.68 (1H, t, J = 6.1 Hz), 4.71 (2H, d, J = 6.1 Hz), 3.91 (3H, s), 3.37-3.29 (1H, m), 3.07-2.81 (6H, m), 2.50 (2H, s), 2.31 (3H, s), 1.94-1.90 (1H, m), 1.78-1.69 (2H, m), 1.69-1.64 (1H, m), 1.44-1.32 (1H, m). 224 .sup.1H-NMR (CDCl.sub.3) : 7.50 (1H, d, J = 7.9 Hz), 7.03 (1H, d, J = 7.9 Hz), 5.53 (1H, t, J = 5.5 Hz), 4.64 (2H, d, J = 5.5 Hz), 4.30 (2H, q, J = 6.9 Hz), 3.51- 3.42 (1H, m), 3.29-3.18 (1H, m), 3.09-2.99 (2H, m), 2.99- 2.89 (2H, m), 2.89-2.77 (1H, m), 2.58 (3H, s), 2.51 (2H, s), 2.32 (3H, s), 2.07-2.00 (1H, m), 1-77-1.62 (3H, m), 1.37 (3H, t, J = 6.9 Hz), 1.34-1.27 (1H, m). 225 .sup.1H-NMR (CDCl.sub.3) : 7.64 (1H, d, J = 1.2 Hz), 7.57 (1H, dd, J = 7.9, 1.2 Hz), 7.50 (1H, d, J = 7.9 Hz), 5.79 (1H, t, J = 6.1 Hz), 4.69 (2H, d, J = 6.1 Hz), 4.28 (2H, q, J = 6.9 Hz), 3.47- 3.40 (1H, m), 3.38-3.30 (1H, m), 3.15-3.07 (1H, m), 3.03- 2.87 (4H, m), 2.53 (2H, s), 2.32 (3H, s), 1.94-1.83 (2H, m), 1.80-1.73 (1H, m), 1.60-1.52 (1H, m), 1.43-1.32 (4H, m). 226 00 LC-MS [M + H].sup.+/Rt (min): 416.4/0.485 (Method A); .sup.1H-NMR (CDCl.sub.3) : 7.02 (1H, d, J = 11.6 Hz), 6.92 (1H, d, J = 6.1 Hz), 5.66 (1H, t, J = 5.5 Hz), 4.69 (2H, d, J = 5.5 Hz), 4.34 (2H, q, J = 7.1 Hz), 3.78 (3H s), 3.43-3.32 (1H, m), 3.31-3.25 (1H, m), 3.04- 2.92 (3H, m), 2.92-2.82 (2H, m), 2.50 (2H, s), 2.30 (3H, s), 1.97-1.90 (1H, m), 1.83-1.68 (3H, m), 1.48-1.34 (4H, m). 227 01 .sup.1H-NMR (CDCl.sub.3) : 7.65 (1H, d, J = 1.8 Hz), 7.59 (1H, dd, J = 7.9, 1.8 Hz), 7.50 (1H, d, J = 7.9 Hz), 5.82 (1H, t, J = 5.5 Hz), 4.70 (2H, d, J = 5.5 Hz), 3.87 (3H, s), 3.51-3.44 (1H, m), 3.41-3.33 (1H, m), 3.19- 3.12 (1H, m), 3.08-2.92 (4H, m), 2.54 (2H, s), 2.34 (3H, s), 1.99-1.87 (2H, m), 1.82- 1.74 (1H, m), 1.65-1.55 (1H, m), 1.46-1.36 (1H, m). 228 02 LC-MS [M + H].sup.+/Rt (min): 340.1/0.649 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.64 (1H, d, J = 1.8 Hz), 7.78 (1H, dd, J = 7.9, 1.8 Hz), 7.24 (1H, d, J = 7.9 Hz), 6.40 (1H, t, J = 5.5 Hz), 4.74 (2H, d, J = 5.5 Hz), 4.29 (2H, q, J = 7.1 Hz), 2.32 (3H, s), 1.36 (3H, t, J = 7.1 Hz). 229 03 LC-MS [M + H].sup.+/Rt (min): 326.1/0.585 (Method A); .sup.1H-NMR (CDCl.sub.3) : 8.63 (1H, d, J = 2.4 Hz), 7.78 (1H, dd, J = 8.5, 2.4 Hz), 7.24 (1H, d, J = 8.5 Hz), 6.37 (1H, t, J = 5.5 Hz), 4.74 (2H, d, J = 5.5 Hz), 3.87 (3H, s), 2.32 (3H, s). 230 04 LC-MS [M + H].sup.+/Rt (min): 367.0/0.654 (Method C); .sup.1H-NMR (CDCl.sub.3) : 7.15 (1H, d, J = 8.2 Hz), 7.02-6.98 (2H, m), 6.14 (1H, br s), 4.59 (2H, d, J = 5.9 Hz), 4.29 (2H, q, J = 7.2 Hz), 3.84 (3H, s), 2.27 (3H, s), 1.33 (3H, t, J = 7.2 Hz). 231 05 LC-MS [M + 2H].sup.2+/2/Rt (min): 200.1/0.392 (Method C); .sup.1H-NMR (CDCl.sub.3) : 7.48 (1H, d, J = 7.3 Hz), 6.68 (1H, d, J = 7.3 Hz), 5.78 (1H, t, J = 6.0 Hz), 4.57 (2H, d, J = 6.0 Hz), 4.27 (2H, q, J = 7.0 Hz), 3.98 (3H, s), 3.68-3.55 (1H, m), 3.24-3.09 (2H, m), 3.05-2.82 (4H, m), 2.53-2.42 (2H, m), 2.25 (3H, s), 2.03-1.95 (1H, m), 1.90-1.67 (3H, m), 1.40- 1.29 (1H, m), 1.34 (3H, t, J = 7.0 Hz). 232 06 LC-MS ([M + H].sup.+/Rt (min)): 376.5/0.457 (Method A) 233 07 LC-MS ([M + H].sup.+/Rt (min)): 321.3/0.598 (Method A) 234 08 LC-MS [M + H].sup.+/Rt (min): 387.4/0.348 (Method A) 235 09 LC-MS [M + H].sup.+/Rt (min): 401.4/0361 (Method A) 236 0 LC-MS ([M + H].sup.+/Rt (min)): 401.4/0.389 (Method A) 237 LC-MS [M + H].sup.+/Rt (min): 341.2/0.630 (Method A) 238 LC-MS [M + 2H].sup.2+/Rt (min): 192.1/0.287 (Method C) 239 LC-MS [M + H].sup.+/Rt (min): 324.1/0.453 (Method C) 240 LC-MS [M + H].sup.+/Rt (min): 341.0/0.578 (Method C) 241 LC-MS [M + H].sup.+/Rt (min): 327.0/0.456 (Method C) 242 LC-MS [M + H].sup.+/Rt (min): 356.0/0.512 (Method C) 243 LC-MS [M + H].sup.+/Rt (min): 362.1/0.601 (Method C) 244 LC-MS [M + H].sup.+/Rt (min): 319.2/0.498 (Method C) 245 LC-MS [M + H].sup.+/Rt (min): 341.1/0.585 (Method C) 246 0 LC-MS [M + H].sup.+/Rt (min): 312.2/0.489 (Method C) 247 LC-MS [M + H].sup.+/Rt (min): 362.2/0.592 (Method C) 248 LC-MS [M + H].sup.+/Rt (min): 323.2/0.552 (Method C) 249 LC-MS [M + H].sup.+/Rt (min): 446.4/0.721 (Method C)

Reference Example 250

4-{[(5-Amino-2-methoxy-6-methylpyrimidin-4-yl)amino]methyl}-3-fluorophenol

(430) ##STR00724##

(431) To an ice-cooled solution of the compound of Reference example 222 (1.70 g) in methanol (20 mL)/tetrahydrofuran (20 mL) was added 5 mol/L aqueous sodium hydroxide (4.77 mL), and the mixture was stirred in ice bath for 15 hours. To the reaction mixture was added 50% aqueous potassium carbonate, and the mixture was extracted with chloroform/ethanol (3/1). The organic layer was dried over sodium sulfate, filtrated, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.914 q).

(432) LC-MS [M+H].sup.+/Rt (min): 279.2/0.390 (Method C)

Reference Examples 251-252

(433) According to the method of Reference example 106, Reference example 107, and Reference example 222, Reference examples 251-252 were prepared by using the corresponding material compounds.

(434) TABLE-US-00091 Reference example Chemical Structure Instrumental analysis data 251 LC-MS [M + 2H].sup.2+/2/Rt (min): 195.0/0.248 Method C) 252 LC-MS [M + H].sup.+/Rt (min): 488.4/0.755 (Method C)

Reference Example 253

(435) According to the method of Reference example 2, Reference example 253 was prepared by using the corresponding material compound.

(436) TABLE-US-00092 Reference example Chemical Structure Instrumental analysis data 253 .sup.1H-NMR (DMSO-d.sub.6) : 9.97 (1H, s), 8.08 (1H, s), 7.86-7.84 (2H, m), 7.69-7.66 (1H, m), 7.62-7.57 (1H, m), 7.24 (2H, brs), 5.37 (2H, s), 4.19 (2H, t, J = 6.4 Hz), 1.62 (2H, tt, J = 6.4, 7.9 Hz), 1.39 (2H, qt, J = 7.3, 7.9 Hz), 0.90 (3H, t, J = 7.3 Hz).

Reference Examples 254-255

(437) According to the method of Reference example 36, Reference examples 254-255 were prepared by using the corresponding material compounds.

(438) TABLE-US-00093 Reference example Chemical Structure Instrumental analysis data 254 .sup.1H-NMR (DMSO-d.sub.6) : 10.0 (1H, s), 7.88-7.85 (1H, m), 7.76 (1H, brs), 7.62-7.56 (2H, m), 7.48 (2H, brs), 5.36 (2H, s), 4.33 (2H, t, J = 4.7 Hz), 3.60 (2H, t, J = 4.7 Hz), 3.27 (3H, s). 255 .sup.1H-NMR (DMSO-d.sub.6) : 9.98 (1H, s), 7.90 (2H, d, J = 7.9 Hz), 7.45 (2H, brs), 7.41 (2H, d, J = 7.9 Hz), 5.37 (2H, s), 4.19 (2H, t, J = 6.4 Hz), 1.64 (2H, tt, J = 6.4, 7.9 Hz), 1.37 (2H, qt, J = 7.3, 7.9 Hz), 0.90 (3H, t, J = 7.3 Hz).

Reference Examples 256-261

(439) According to the method of Example 80, Reference examples 256-261 were prepared by using the corresponding material compounds.

(440) TABLE-US-00094 Reference example Chemical Structure Instrumental analysis data 256 0 .sup.1H-NMR (DMSO-d.sub.6) : 7.46 (2H, brs), 7.31-7.27 (1H, m), 7.25-7.18 (2H, m), 7.11-7.09 (1H, m), 5.25 (2H, s), 4.34 (2H, t, J = 4.7 Hz), 3.61 (2H, t, J = 4.7 Hz), 3.33 (2H, s), 3.28 (3H s), 2.10 (6H, s). 257 .sup.1H-NMR (DMSO-d.sub.6) : 7.48 (2H, brs), 7.32-7.27 (1H, m), 7.23-7.19 (2H, m), 7.13-7.10 (1H, m), 5.25 (2H, s), 4.32 (2H, t, J = 4.7 Hz), 3.61 (2H, t, J = 4.7 Hz), 3.55-3.49 (4H, m), 3.45-3.33 (5H, m), 3.27 (3H, s). 258 .sup.1H-NMR (DMSO-d.sub.6) : 7.45 (2H, brs), 7.26 (2H, d, J = 7.9 Hz), 7.19 (2H, d, J = 7.9 Hz), 5.23 (2H, s), 4.33 (2H, t, J = 4.7 Hz), 3.61 (2H, t, J = 4.7 Hz), 3.33 (2H, s), 3.28 (3H, s), 2.10 (6H, s). 259 .sup.1H-NMR (DMSO-d.sub.6) : 7.46 (2H, brs), 7.27 (2H, d, J = 7.9 Hz), 7.20 (2H, d, J = 7.9 Hz), 5.23 (2H, s), 4.32 (2H, t, J = 4.7 Hz), 3.61 (2H, t, J = 4.7 Hz), 3.55-3.52 (4H, m), 3.38 (2H, s), 3.27 (3H, s), 2.34- 2.28 (4H, m). 260 .sup.1H-NMR (DMSO-d.sub.6) : 7.41 (2H, brs), 7.31-7.27 (1H, m), 7.23-7.18 (2H, m), 7.12-7.09 (1H, m), 5.25 (2H, s), 4.22 (2H, t, J = 6.4 Hz), 3.31 (2H, s), 2.10 (6H, s), 1.66 (2H, tt, J = 6.4, 7.9 Hz), 1.39 (2H, qt, J = 7.3, 7.9 Hz), 0.91 (3H, t, J = 7.3 Hz). 261 .sup.1H-NMR (DMSO-d.sub.6) : 7.42 (2H, brs), 7.32-7.27 (1H, m), 7.24-7.20 (2H, m), 7.14-7.11 (1H, m), 5.24 (2H, s), 4.21 (2H, t, J = 6.4 Hz), 3.58-3.48 (4H, m), 3.42 (2H, s), 2.32-2.26 (4H, m), 1.65 (2H, tt, J = 6.4, 7.9 Hz), 1.39 (2H, qt, J = 7.3, 7.9 Hz), 0.91 (3H, t, J = 7.3 Hz).

(441) Next, the pharmacological activities of the typical compounds of the present invention are explained in more detail with the following Tests.

Test 1: Test for Evaluating the Inhibition of the Activation of Human TLR7

(442) As human TLR7 expressing cell line, HEK293 cell line was bought from IMGENEX Corporation (TLR7/NF-B/SEAPorter HEK293 cell), which is human embryonic kidney cell line and stably expresses full-length human TLR7 gene and secreted alkaline phosphatase (SEAP) reporter gene under the transcriptional control of an NE-B response element. The TLR7/NF-B/SEAPorter HEK293 cell was cultivated with DMEM containing 10% fetal bovine serum (FBS) and 10 g/mL blasticidin S at 37 C. in the presence of 5% CO.sub.2. The TLR7/NF-B/SEAPorter HEK293 cell was seeded into 96-well microtiter plate at 510.sup.4 cell/90 L/well, and the place was cultivated at 37 C. in a CO.sub.2 incubator overnight. Each test compound that was diluted with the medium was added to the wells (10 L/well), wherein each final concentration was adjusted to 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, and 10 mol/L, or 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, and 100 mol/L. After 0.5 hour, R-848 that is TLR7/8 ligand was added to each well (10 L/well), wherein each final concentration was adjusted to 200 nmol/L. The total volume was adjusted to 110 L/well, the test samples were incubated in CO.sub.2 incubator for 201 hours, and then the SEAP activity was measured as activation of TLR7. The SEAP activity was evaluated as follows: p-nitro-phenyl phosphate (pNPP) (Invitrogen) was added to the incubated sample (50 L/well); after 15 minutes, 4 mol/L sodium hydroxide solution (nacalai tesque) was added thereto (50 L/well) to quench the reaction; and the absorbance of each sample was measured at 405 nm with microplate reader Elx808 (BioTek). The 50% inhibitory concentration (IC.sub.50 value) of each sample compound was calculated based on 100% of the SEAP activity wherein the test sample comprises no sample compound.

(443) Each compound prepared in the Examples was evaluated by Test 1. Each concentration of each test compound shown in the table below denotes the concentration to inhibit the cell growth by 50% (IC.sub.50 value; mol/L).

(444) TABLE-US-00095 TLR7 IC.sub.50 Example (mol/L) 1 2.3 2 5.5 3 9.2 4 7.8 5 1.4 6 9.6 7 7.8 8 9.3 9 12.8 10 0.80 11 10.9 12 9.2 13 9.3 14 8.2 15 4.1 16 13.9 17 1.1 18 2.7 19 1.4 20 22.5 21 0.70 22 2.0 23 9.1 24 13.7 25 3.5 26 18.7 27 1.4 28 9.5 29 1.0 30 2.8 31 7.7 32 8.6 33 0.82 34 1.7 35 18.1 36 2.9 37 2.7 38 0.52 39 0.82 40 0.12 41 0.14 42 0.55 43 2.0 44 0.75 45 0.95 46 0.025 47 0.030 48 0.099 49 0.067 50 0.077 51 0.059 52 0.089 53 0.060 54 0.42 55 0.62 56 0.66 57 1.8 58 0.81 59 0.28 60 0.23 61 0.62 62 1.43 63 5.8 64 0.68 65 0.55 66 0.021 67 0.051 68 0.18 69 0.13 70 0.11 71 0.058 72 0.081 73 0.16 74 1.4 75 0.20 76 0.40 77 2.4 78 1.3 79 3.5 80 0.54 81 0.060 82 0.40 83 1.3 84 0.50 85 0.80 86 0.30 87 2.5 88 0.90 89 1.4 90 4.2 91 0.25 92 0.37 93 0.29 94 0.020 95 0.050 96 0.080 97 0.10 98 0.071 99 0.146 100 0.096 101 0.056 102 0.81 103 1.6 104 0.76 105 0.059 106 0.062 107 0.027 108 0.16 109 0.010 110 0.005 111 0.20 112 0.10 113 1.0 114 0.30 115 0.10 116 0.16 117 7.0 118 0.95 119 0.028 120 0.051 121 1.3 122 0.23 123 0.033 124 0.22 125 0.085 126 0.15 127 0.053 128 0.019 129 0.071 130 0.043 131 0.007 132 0.019 133 0.013 134 0.17 135 0.085 136 0.020 137 0.84 138 0.049 139 0.084 140 0.12 141 3.3 142 6.6 143 1.57 144 2.6 145 2.1 146 1.7 147 3.5 148 0.016 149 0.46 150 0.50 151 16.6 152 2.9 153 5.8 154 13.6 155 8.1 156 5.0 157 8.9 158 13.7 159 0.93 160 1.3 161 0.028 162 0.21 163 0.010 164 0.17 165 0.016 166 0.050 167 0.11 168 1.4 169 0.007 170 0.082 171 0.018 172 0.003 173 0.063 174 0.026 175 0.094 176 0.011 177 0.010 178 0.003 179 16.2 181 19.7 237 2.02 238 2.17 240 0.357 242 2.68 243 2.66 244 0.445 245 0.198 246 0.3 247 0.085 248 0.248 249 0.1 250 0.2 251 0.18 252 0.028 258 0.169 259 0.028 260 0.018 261 1.16 262 0.027 263 0.102 264 0.063 265 0.057 266 0.029 268 0.027 269 0.019 270 0.272 271 0.099 272 0.261 273 0.2 274 0.1 275 0.033 276 0.024 277 0.023 278 0.072 279 0.040 280 0.003 281 0.142 282 0.008 283 0.021 284 0.003 285 0.002 286 0.026 287 0.029 288 0.062 289 0.030 290 0.022 291 0.017 292 0.039 293 0.018 294 0.019 295 0.013 296 0.021 297 0.050 300 0.028 301 0.043 302 0.067 303 0.007 304 0.004 305 0.005 306 0.040 307 0.057 308 0.027 309 0.020 310 0.028 311 0.011 312 0.025 313 0.008 314 0.008 315 0.053 316 0.007 317 1.61 318 0.007 322 0.013 323 0.070 325 1.52 326 0.389 327 0.023 329 0.120 330 0.213 332 6.48 337 1.34 338 0.667 339 0.160 340 0.026 342 0.816 343 0.067 344 0.012 345 0.036 346 0.019 347 0.035 348 0.092 352 0.505 353 0.504 354 0.036 355 1.60 356 0.463 357 0.062 358 0.018 359 0.855 360 1.72 361 0.582 363 0.592 364 0.011 365 0.291 366 1.13 368 0.355 369 1.69 370 0.117 371 0.264 372 0.011 373 0.209 374 1.63 375 0.199 376 0.084 377 0.007 379 0.506 380 0.225 381 1.39 382 0.575 383 0.083 384 0.270 385 0.094 386 0.013 388 1.35 389 2.04 390 0.31 391 0.038 392 0.013 393 0.001 394 0.114 395 0.005 396 0.061 397 0.031 398 0.021 399 0.039 400 0.263 401 0.006 402 0.132 403 0.021 404 0.846 405 3.41 410 0.070 411 0.026 412 0.005 413 0.009 414 0.016 415 0.016 416 0.050 418 0.019 419 0.712 420 0.139 421 0.073 424 0.1 425 0.093 426 0.2 427 0.028 428 0.210 430 0.549 431 0.008 432 0.062 433 0.009 434 0.09 435 0.018 436 0.037 437 0.016 439 0.134 440 0.084 441 0.176 443 0.017 444 0.098 445 0.021

(445) The compounds of the present invention exhibited potent inhibitory effect against TLR7 in the test for evaluating inhibition of the activation of TLR7. In particular, the compounds of Examples 46, 47, 48, 49, 50, 51, 52, 53, 66, 67, 69, 70, 71, 72, 81, 94, 95, 96, 98, 100, 101, 105, 106, 107, 109, 110, 119, 123, 125, 127, 128, 129, 130, 131, 132, 133, 135, 136, 138, 139, 148, 161, 163, 165, 166, 169, 171, 172, 173, 174, 175, 176, 177, 178, 252, 259, 260, 262, 264, 265, 266, 275, 276, 277, 278, 279, 280, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 318, 322, 323, 327, 340, 343, 344, 345, 346, 347, 348, 372, 376, 377, 383, 386, 391, 392, 393, 395, 396, 397, 398, 399, 401, 403, 410, 411, 412, 413, 414, 415, 416, 418, 421, 431, 432, 433, 436, 437, 443, and 445 exhibited potent inhibitory effect against TLR7.

Test 2: Test for Evaluating the Inhibition of the Activation of Human TLR8

(446) As human TLR8 expressing cell line, HEK293 cell line was bought from IMGENEX Corporation (TLR8/NF-B/SEAPorter HEK293 cell), which is human embryonic kidney cell line and stably expresses full-length human TLR8 gene and secreted alkaline phosphatase (SEAP) reporter gene under the transcriptional control of an NF-B response element. The TLR8/NF-B/SEAPorter HEK293 cell was cultivated with DMEM containing 10% fetal bovine serum (FBS) and 10 g/mL blasticidin S at 37 C. in the presence of 5% CO.sub.2. The TLR8/NF-B/SEAPorter HEK293 cell was seeded into 96-well microtiter plate at 510.sup.4 cell/90 L/well, and the place was cultivated at 37 C. in a CO.sub.2 incubator overnight. Each test compound that was diluted with the medium was added to the wells (10 L/well), wherein each final concentration was adjusted to 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, and 100 mol/L. After 0.5 hour, R-848 that is TLR7/8 ligand was added to each well (10 L/well), wherein each final concentration was adjusted to 30 mol/L. The total volume was adjusted to 110 L/well, the test samples were incubated in CO.sub.2 incubator for 201 hours, and then the SEAP activity was measured as activation of TLR8. The SEAP activity was evaluated as follows: p-nitro-phenyl phosphate (pNPP, Invitrogen) was added to the incubated sample (50 L/well); after 15 minutes, 4 mol/L sodium hydroxide solution (nacalai tesque) was added thereto (50 L/well) to quench the reaction; and the absorbance of each sample was measured at 405 nm with microplate reader Elx808 (BioTek). The 50% inhibitory concentration (IC.sub.50 value) of each sample compound was calculated based on 100% of the SEAP activity wherein the test sample comprises no sample compound.

Test 3: Test for Evaluating the Inhibition of the Activation of Human TLR9

(447) As human TLR9 expressing cell line, HEK293 cell line was bought from IMGENEX Corporation (TLR9/NF-B/SEAPorter HEK293 cell), which is human embryonic kidney cell line and stably expresses full-length human TLR9 gene and the secreted alkaline phosphatase (SEAP) reporter gene under the transcriptional control of an NF-B response element. The TLR9/NE-B/SEAPorter HEK293 cell was cultivated with DMEM containing 10% fetal bovine serum (FBS) and 10 g/mL blasticidin S at 37 C. in the presence of 5% CO.sub.2. The TLR9/NF-B/SEAPorter HEK293 cell was suede into 96-well microtiter plate at 510.sup.4 cell/90 L/well, and the place was cultivated at 37 C. in a CO.sub.2 incubator overnight. Each test compound that was diluted with the medium was added to the wells (10 L/well), wherein each concentration was adjusted to 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, and 100 mol/L. After 0.5 hour, CpG-B DNA (CpG2006, Hokkaido System Science Co., Ltd.) that is TLR9 ligand was added to each well (10 L/well), wherein each final concentration was adjusted to 500 nmol/L. The total volume was adjusted to 110 L/well, that test samples were incubated in CO.sub.2 incubator for 201 hours, and then the SEAP activity was measured as activation TLR9. The SEAP activity was evaluated as follows: p-nitro-phenyl phosphate (pNPP) (Invitrogen) was added to the incubated sample (50 L/well); after 15 minutes, 4 mol/L sodium hydroxide solution (nacalai tesque) was added thereto (50 L/well) to quench the reaction; and the absorbance of each sample was measured at 405 nm with microplate reader Elx808 (BioTek). The 50% inhibitory concentration (IC.sub.50 value) of each sample compound was calculated based on 100% of the SEAP activity wherein the test sample comprises no sample compound.

Test 4: Pharmacokinetic Study with Mice

(448) For the evaluation of pharmacokinetic study of each sample, 11-week-old mouse (Jcl: ICR, male, CLEA Japan, Inc.) was used. In order to implement the single-dose oral administration to a mouse herein, each compound suspended in 0.5% methylcellulose solution was administered at 10, 30, or 100 mg/kg. As for tail vein injection, each compound dissolved in saline was administered at 1 mg/kg. The blood collection was once with a heparinized syringe, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours after the oral administration; and 5 minutes, 15 minutes, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours after the tail vein injection. Each collected blood was centrifuged to give its plasma. The plasma was diluted with methanol, wherein the final concentration of methanol was adjusted to 80%, centrifuged, and then filtrated to deproteinize the plasma. The obtained filtrate was analyzed with an LC-MS/MS (API4000, 5500Qtrap, 6500Qtrap, AB SCIEX) to detect and assay the test compound. For the assay, the calibration curve was prepared from mouse plasma comprising known amount of the compound, and phenytoin was used as an internal standard.

Test 5: Test for Evaluating the Inhibition of the Activation of Mouse TLR7

(449) As mouse TLR7 expressing cell line, mouse TLR7 gene-stably-expressing HEK293 cell line which is human embryonic kidney cell line was bought from InvivoGen (293XL-mTLR7 cell). The 293XL-mTLR7 cell was cultivated with DMEM containing 10% fetal bovine serum (FBS) and 10 g/mL blasticidin S at 37 C. in the presence of 5% CO.sub.2. The 293XL-mTLR7 cell was seeded into 6-well plate (collagen-coated) at 310.sup.5 cell/2 mL/well, and the place was cultivated an 37 C. in a CO.sub.2 incubator overnight. pNF-B-Luc plasmid (Agilent Technologies) that was diluted with FuGENER 6 Transfection Reagent (Promega) and the medium was added to the 293XL-mTLR7 cell-cultivating plate (1 g/100 L/well), the plate was cultivated at 37 C. in a CO.sub.2 incubator overnight. The pNF-B-Luc plasmid-transfected 293XL-mTLR7 cell was seeded into 96-well plate for fluorescence/luminescence assay at 210.sup.4 cell/90 L/well. Each test compound that was diluted with the medium was added to the wells (10 L/well), wherein each final concentration was adjusted to 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 mol/L, or 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100 mol/L. After 0.5 hour, R-848 that is TLR7/8 ligand was added to each well (10 L/well), wherein each final concentration was adjusted to 200 nmol/L. The total volume was adjusted to 110 L/well, the test samples were incubated in CO.sub.2 incubator for 6 hours, and then the luciferase activity was measured as activation of TLR7. The luciferase activity was evaluated as follows: Bright-Glo Luciferase Assay System (Promega) was added to the incubated sample (100 L/well); after 2 minutes, the luminescence intensity of each sample was measured with a luminometer (Envision). The 50% inhibitory concentration (IC.sub.50 value) of each sample compound was calculated based on 100% of the luciferase activity wherein the test sample comprises no sample compound.

Test 6: Test for Evaluating the Inhibition of the Activation of Mouse TLR9

(450) As mouse TLR9 expressing cell line, mouse TLR9 gene-stably-expressing HEK293 cell line which is human embryonic kidney cell line was bought from InvivoGen (293-mTLR9 cell). The 293-mTLR9 cell was cultivated with DMEM containing 10% fetal bovine serum (FBS) and 10 g/mL blasticidin S at 37 C. in the presence of 5% CO.sub.2. The 293-mTLR9 cell was seeded into 6-well plate (collagen-coated) at 310.sup.5 cell/2 mL/well, and the place was cultivated at 37 C. in a CO.sub.2 incubator overnight to prepare 293-mTLR9 (pNF-B-Luc) cell. The 293-mTLR9 (pNF-B-Luc) cell was seeded into 96-well plate for fluorescence/luminescence assay at 210.sup.4 cell/90 L/well. Each test compound that was diluted with the medium was added to the wells (10 L/well), wherein each final concentration was adjusted to 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100 mol/L. After 0.5 hour, CpG-B DNA (CpG1826, Hokkaido System Science Co., Ltd.) that is TLR9 ligand was added to each well (10 L/well), wherein each final concentration was adjusted to 100 nM. The total volume was adjusted to 110 L/well, the test samples were incubated in CO.sub.2 incubator for 6 hours, and then the luciferase activity was measured as activation of TLR9. The luciferase activity was evaluated as follows: Bright-Glo Luciferase Assay System (Promega) was added to the incubated sample (100 L/well); after 2 minutes, the luminescence intensity of each sample was measured with a luminometer (Envision). The 50% inhibitory concentration (IC.sub.50 value) of each sample compound was calculated based on 100% of the luciferase activity wherein the test sample comprises no sample compound.

Test 7: Test for Evaluating the Inhibition of Blood Cytokine Production in Mouse Treated with Oral Single Administration

(451) 6 to 17-week-old mice (ICR, male, CHARLES RIVER LABORATORIES JAPAN, INC.; or BALB/c, female, Japan SLC, Inc.) were used in the present test. Each example compound dissolved or suspended in 0.5% methylcellulose solution was orally administered to the mouse. Three or six hours later, R848 which is a TLR7 agonist was subcutaneously administered to the back of the mouse at 15 g/200 L/head. 1.5 hours after the administration of R848, the blood was collected with a heparinized syringe, and the induced IL-6 in the plasma was assayed with a commercially available ELISA kit (Quantikine Mouse IL-6 ELISA; R&D system (# M6000B).

Test 8: Test for Evaluating Drug in Case of Prophylactic Administration with NZBW F1 Mouse

(452) NZBW F1 mice (Japan SLC, Inc., female) used herein were consumed when they were 22 weeks old. The urinary albumin/creatinine ratio (UACR) of the mice when they were 24 weeks old was measured, and the mice were grouped based on their weight and UACR (vehicle control group (0.5% methylcellulose), Example compound group, and prednisolone group). Mice whose creatinine concentration was over 100 mg/g when they were 24 weeks old were excluded as onset individual. The test mice received daily oral administration (once a day) for 13 weeks since they were 25 weeks old. The urine was collected from all the mice with a metabolism cage once in one or two weeks. 14 weeks after the start of the administration (38-week-old), the blood was collected and the kidney was extirpated from all the mice. The UACR was measured with an autoanalyzer. The blood dsDNA antibody titer was assayed with a Mouse Anti-dsDNA ELISA KIT (Shibayagi Corporation). The extirpated kidney was tested about histopathological work-up.

(453) The compounds of the present invention exhibited potent pharmacological effect in a dose-dependent manner at the drug efficiency evaluation with NZBW F1 mice receiving prophylactic administration.

Test 9: Test for Evaluating Drug in case of Therapeutic Administration with NZBW F1 Mouse

(454) NZBW F1 mice (Japan SLC, inc., female) used herein were consumed when they were 22 weeks old. The mice whose urinary albumin/creatinine ratio (UACR) was 300-4000 (mg/g creatinine) were chosen, which were grouped (vehicle control group (0.5% methylcellulose), and Example compound group). The administration was sequentially started after onset of each individual, and the oral administration was continued every day for 4 weeks. The urine was collected from all the mice with a metabolism cage once a week, and the UACR was measured with an autoanalyzer. Four weeks after the start of the administration, the blood was collected and the kidney was extirpated from all the alive mice. The extirpated kidney was tested about histopathological work-up.

(455) The compounds of the present invention exhibited potent pharmacological effect in an administration-frequency-dependent manner at the drug efficiency evaluation with NZBW F1 mice receiving therapeutic administration.

Test 10: Test for Evaluating Drug in Case of Prophylactic Administration with NZWBXSB F1 Mouse

(456) NZWBXSB F1 mice (Japan SLC, Inc., female) used herein were consumed when they were 4 weeks old. The blood of the 6-week-old NZWBXSB F1 mice was partially collected from their neck at 100 L/head, which was treated with EDTA, and the mice were grouped based on the platelet count in blood and the body weight (vehicle control group (0.5% methylcellulose), Example compound group, and prednisolone group). The platelet count was measured with a Sysmex XT-1800I. From the next day of the grouping, the test mice received daily oral administration (once a day) for 12 weeks. Every 3 weeks after the start of the administration, the blood was partially collected from the neck, which was treated with EDTA. The effect that the test drug can inhibit the platelet depletion was studied by monitoring the platelet count with time. From the mice which received the last administration, the urine was collected with a metabolism cage, and the urinary albumin/creatinine ratio (UACR) was measured with an autoanalyzer. The weights of kidney and spleen were measured.

(457) The compounds of the present invention exhibited potent pharmacological effect in a dose-dependent manner at the drug efficiency evaluation with NZBW F1 mice receiving prophylactic administration.

INDUSTRIAL APPLICABILITY

(458) Thus, the compounds of the present invention have inhibitory effect to TLR, which are useful for preventing and/or treating autoimmune disease.