CROSSLINKED OPTICALLY ACTIVE SECONDARY AMINE DERIVATIVE

Abstract

The present invention relates to the compound of formula (1a) wherein p is 1 or 2, R.sup.1-R.sup.4 are hydrogen atom or the like, Ring A is cycloalkylene or the like, L is single bond or the like, and R is methyl or the like, or a pharmaceutically acceptable salt thereof, which has an anticancer effect by inhibiting the binding between a MLL fusion protein that is fused with AF4, AF9, or the like, which is a representative fusion partner gene causing MLL leukemia, and menin.

##STR00001##

Claims

1. A compound of formula (1a): ##STR00144## or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each independently hydrogen atom, halogen, —OR.sup.7, or —M—Q; or R.sup.1 and R.sup.2 and/or R.sup.3 and R.sup.4 may be Combined together to form each independently ═O or ═CR.sup.12AR.sup.13A; M is, each independently if there are plural, C.sub.1-6 alkylene (which may be substituted with 1 to 5 the same or different substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, —CONR.sup.36AR.sup.37A, —NR.sup.36AR.sup.37A, —NR.sup.36ACOR.sup.35A, NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano) , C.sub.2-6 alkenylene, C.sub.2-6 alkynylene, C.sub.3-10 cycloalkylene, 3- to 10-membered saturated heterocyclyl, C.sub.6-10 arylene, or 5- to 12-membered heteroarylene, wherein the alkenylene, the alkynylene, the cycloalkylene, the saturated heterocyclyl, the arylene, and the heteroarylene may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, C.sub.1-3 alkyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, —CONR.sup.36AR.sup.37A, —CONR.sup.36AR.sup.37A, —NR.sup.36ACOR.sup.35A, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano; Q is, each independently if there are plural, hydrogen atom, C.sub.3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C.sub.6-10 aryl, or 5- to 12-membered heteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, C.sub.1-3 alkyl , C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, —CONR.sup.36AR.sup.37A, —NR.sup.36AR.sup.37A, —NR.sup.36ACOR.sup.35A, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano; R.sup.7 is, each independently if there are plural, hydrogen atom, C.sub.1-6 alkyl (which may be substituted with 1 to 5 the same or different substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, phenyl, 5- to 6-membered heteroaryl, C.sub.2-4 alkynyl, C.sub.3-7 cycloalkyl, 3- to 7-membered saturated heterocyclyl, C.sub.1-3 alkoxy, —CONR.sup.36AR.sup.37A, —NR.sup.36AR.sup.37A, —NR.sup.36ACOR.sup.35A, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano) , C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C.sub.6-10 aryl, or 5- to 12-membered heteroaryl, wherein the alkenyl, the alkynyl, the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, C.sub.1-3 alkyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, —CONR.sup.36AR.sup.37A, —NR.sup.36AR.sup.37A, NR.sup.36ACOR.sup.35A, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano; R.sup.12A and R.sup.13A are each independently hydrogen atom, halogen, C.sub.1-6 alkyl (which may be substituted with 1 to 5 the same or different substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, —CONR.sup.36AR.sup.37A, —NR.sup.36AR.sup.37A, —NR.sup.36ACOR.sup.35A, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano), C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C.sub.6-10 aryl, or 5- to 12-membered heteroaryl, wherein the alkenyl, the alkynyl, the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, C.sub.1-3 alkyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, —CONR.sup.36AR.sup.37A, —NR.sup.36AR.sup.37A, —NR.sup.36ACOR.sup.35A, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano, and if there are plural R.sup.12A or R.sup.13A, each R.sup.12A or R.sup.13A may be the same or different, or when R.sup.12A and R.sup.13A are both C.sub.1-6 alkyl, they may be combined with the carbon atom to which they are attached to form 3- to 8-membered saturated carbocycle; R.sup.35A is, each independently if there are plural, C.sub.1-6 alkyl; R.sup.36A and R.sup.37A are each independently hydrogen atom or C.sub.1-6 alkyl, and if there are plural R.sup.36A or R.sup.37A, each R.sup.36A or R.sup.37A may be the same or different, or when R.sup.36A and R.sup.37A are both C.sub.1-6 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 6-membered nitrogen-containing saturated heterocycle; Ring A is (A-1), (A-2), (A-3), or (A-4): ##STR00145## wherein * is a bonding site to L, ** is a bonding site to the carbonyl group, and the dot-line in the ring means that there may be optionally a unsaturated bond in the ring; R.sup.A1 and R.sup.A2 are each independently hydrogen atom or C.sub.1-3 alkyl, or R.sup.A1 and R.sup.A2 may be combined with each carbon atom to which they are attached to form a bridged structure with C.sub.1-3 alkylene; a, b, c, and d are each independently 1, 2, or 3; L is single bond or —CH.sub.2—; and R is methyl or isopropyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein M is, each independently if there are plural, C.sub.1-6 alkylene which may be substituted with 1 to 5 the same or different substituents selected from the group consisting of fluorine atom, hydroxy, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, CONR.sup.36AR.sup.37A, —NR.sup.36AR.sup.37A, —NR.sup.36ACOR.sup.35A, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano.

3. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Q is, each independently if there are plural, C.sub.3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C.sub.6-10 aryl, or 5- to 12-membered heteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, C.sub.1-3 alkyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, —CONR.sup.36AR.sup.37A, —NR.sup.36AR.sup.37A, —NR.sup.36ACOR.sup.35A, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano.

4. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R.sup.7 is, each independently if there are plural, hydrogen atom, C.sub.1-6 alkyl (which may be substituted with 1 to 5 the same or different substituents selected from the group consisting of fluorine atom, phenyl, C.sub.3-7 cycloalkyl, and 3- to 7-membered saturated heterocyclyl), C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl (wherein the cycloalkyl and the saturated heterocyclyl may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of fluorine atom and C.sub.1-3 alkyl) , C.sub.6-10 aryl, or 5- to 12-membered heteroaryl, wherein the aryl and the heteroaryl may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, and C.sub.1-3 alkyl.

5. The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R.sup.7 is, each independently if there are plural, hydrogen atom, C.sub.1-6 alkyl (which may be substituted with one phenyl), or C.sub.2-6 alkenyl.

6. The compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R.sup.12A and R.sup.13A are each independently hydrogen atom, C.sub.1-6, alkyl (which may be substituted with 1 to 5 the same or different substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, —CONR.sup.36AR.sup.37A, —NR.sup.36AR.sup.37A, —NR.sup.36ACOR.sup.35A, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano), C.sub.3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C.sub.6-10 aryl, or 5- to 12-membered heteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 5 the same or different substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, C.sub.1-3 alkyl , C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, —CONR.sup.36AR.sup.37A, —NR.sup.36AR.sup.37A, —NR.sup.36ACOR.sup.35A, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A and cyano, and if there are plural R.sup.12A or R.sup.13A, each R.sup.12A or R.sup.13A may be the same or different, or when R.sup.12A and R.sup.13A are both C.sub.1-6 alkyl, they may be combined with the carbon atom to which they are each attached to form 3- to 8-membered saturated carbocycle.

7. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each independently hydrogen atom, halogen, —OR.sup.7, or —M—Q; or R.sup.1 and R.sup.2 and/or R.sup.3 and R.sup.4 may be combined together to form each independently ═O or ═CR.sup.12AR.sup.13A; M is, each independently if there are plural, C.sub.1-6 alkylene which may be substituted with 1 to 3 the same or different substituents selected from the group consisting of fluorine atom, hydroxy, C.sub.2-4 alkynyl, C.sub.2-3 alkoxy, —CONR.sup.36AR.sup.37A, —NR.sup.36AR.sup.37A, —NR.sup.36ACOR.sup.35A, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2R.sup.35A, SO.sub.2NR.sup.36AR.sup.37A, and cyano; Q is, each independently if there are plural, C.sub.3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C.sub.6-10 aryl, or 5- to 12-membered heteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 3 the same or different substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, C.sub.1-3 alkyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, —CONR.sup.36AR.sup.37A, —NR.sup.36AR.sup.37A, —NR.sup.36ACOR.sup.35A, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano; R.sup.7 is, each independently if there arc plural, hydrogen atom, C.sub.1-6 alkyl (which may be substituted with one phenyl), or C.sub.2-6 alkenyl; R.sup.12A and R.sup.13A are each independently hydrogen atom, C.sub.1-6 alkyl (which may be substituted with 1 to 3 the same or different substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, —CONR.sup.36AR.sup.37A, —NR.sup.36AR.sup.37A, —NR.sup.36ACOR.sup.35A, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano), C.sub.3-10 cycloalkyl, 3- to 10-membered saturated heterocyclyl, C.sub.6-10, aryl, or 5- to 12-membered heteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, the aryl, and the heteroaryl may be each independently substituted with 1 to 3 the same or different substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, hydroxy, C.sub.1-3 alkyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, —CONR.sup.36AR.sup.37A, —NR.sup.36AR.sup.37A, —NR.sup.36ACOR.sup.37A, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2R.sup.35A, —SO.sub.2NR.sup.37AR.sup.37A, and cyano, and if there are plural R.sup.12A or R.sup.13A, each R.sup.12A or R.sup.13A may be the same or different, or when R.sup.12A and R.sup.13A are both C.sub.1-6 alkyl, they may be combined with the carbon atom to which they are attached to form 3- to 8-membered saturated carbocycle; R.sup.35Ais, each independently if there are plural, C.sub.1-6 alkyl; R.sup.36A and R.sup.37A are each independently hydrogen atom or C.sub.1-6 alkyl, and if there are plural R.sup.36A or R.sup.37A, each R.sup.36A or R.sup.37A may be the same or different, or when R.sup.36A and R.sup.37A are both C.sub.1-6 alkyl, they may be combined with the nitrogen atom to which they are attached to form 3- to 6-membered nitrogen-containing saturated heterocycle; Ring A is (A-1) , (A-2) , or (A-3); a, b, c, and d are independently 1, 2, or 3; L is single bond or —CH.sub.2—; and R is methyl or isopropyl.

8. The compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each independently hydrogen atom, fluorine atom, or —M—Q; or R.sup.1 and R.sup.2 and/or R.sup.3 and R.sup.4 may be combined together to form each independently ═O or ═CR.sup.12AR.sup.13A.

9. The compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein M is, each independently if there are plural, C.sub.1-3 alkylene which may be substituted with 1 to 3 the same or different substituents selected from the group consisting of fluorine atom, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, —NR.sup.36AR.sup.37A, and cyano.

10. The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein M is, each independently if there are plural, C.sub.1-3 alkylene.

11. The compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein Q is, each independently if there are plural, C.sub.3-6 cycloalkyl, 3- to 6-membered saturated heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, the phenyl, and the heteroaryl may be each independently substituted with 1 to 3 the same or different substituents selected from the group consisting of fluorine atom, chlorine atom, bromine atom, C.sub.1-3 alkyl, C.sub.2-4 alkynyl, C.sub.1-3 alkoxy, —CONR.sup.36AR.sup.37A, —NR.sup.36AR.sup.37A, —NR.sup.36ACOR.sup.35A, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano.

12. The compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein Q is, each independently if there are plural, C.sub.3-6 cycloalkyl, 3- to 6-membered saturated heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the cycloalkyl, the saturated heterocyclyl, the phenyl, and the heteroaryl may be each independently substituted with 1 to 3 the same or different substituents selected from the group consisting of fluorine atom, C.sub.1-3 alkyl, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano.

13. The compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein Q is, each independently if there are plural, C.sub.3-6 cycloalkyl which may be substituted with 1 to 3 the same or different substituents selected from the group consisting of fluorine atom, C.sub.1-3 alkyl, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano.

14. The compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R.sup.12A and R.sup.13A are each independently hydrogen atom, C.sub.1-6 alkyl (which may be substituted with 1 to 3 the same or different substituents selected from the group consisting of fluorine atom, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano), C.sub.3-10 cycloalkyl (which may be substituted with 1 to 3 the same or different substituents selected from the group consisting of fluorine atom, C.sub.1-3 alkyl, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano) , and if there are plural R.sup.12A or R.sup.13A, each R.sup.12A or R.sup.13A, may be the same or different, or when R.sup.12A and R.sup.13A are both C.sub.1-3 alkyl, they may be combined with the carbon atom to which they are attached to form 3- to 6-membered saturated carbocycle.

15. The compound of any one claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R.sup.12A and R.sup.13A are each independently hydrogen atom, or C.sub.3-6 cycloalkyl which may be substituted with 1 to 3 the same or different substituents selected from the group consisting of fluorine atom, C.sub.1-3 alkyl, —NR.sup.36ASO.sub.2R.sup.35A, —SO.sub.2NR.sup.36AR.sup.37A, and cyano, and if there are plural R.sup.12A and R.sup.13A, each R.sup.12A and R.sup.13A may be the same or different.

16. The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein Ring A is (A-1) or (A-3).

17. The compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein L is single bond.

18. The compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein L is methylene.

19. The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein Ring A is (A-1), and L is single bond.

20. The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein Ring A is (A-1), and L is methylene.

21. The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein Ring A is (A-3), and L is single bond.

22. The compound of any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each independently hydrogen atom, fluorine atom, or —M—Q; or R.sup.1 and R.sup.2 and/or R.sup.3 and R.sup.4 may be combined together to form each independently ═CR.sup.12AR.sup.13A.

23. The compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, wherein M is methylene.

24. The compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein Q is, each independently if there are plural, cycloalkyl which may be substituted with 1 to 3 the same or different substituents selected from the group consisting of fluorine atom and C.sub.1-3 alkyl.

25. The compound of any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, wherein Q is, each independently if there are plural, C.sub.3-6 cycloalkyl.

26. The compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, wherein R.sup.12A and R.sup.13A are hydrogen atom.

27. The compound of any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each independently hydrogen atom, fluorine atom, or —M—Q; or R.sup.1 and R.sup.2 and/or R.sup.3 and R.sup.4 may be combined together to form ═CH.sub.2; M is, each independently if there are plural, methylene; and Q is, each independently if there are plural, C.sub.3-6 cycloalkyl.

28. The compound of any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, wherein R.sup.1 and R.sup.2 are hydrogen atom; and R.sup.3 and R.sup.4 are each independently hydrogen atom or fluorine atom; provided that both R.sup.3 and R.sup.4 are not simultaneously hydrogen atom.

29. The compound of any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, wherein R.sup.1 and R.sup.2 are each independently hydrogen atom or —M—Q; and R.sup.3 and R.sup.4 are each independently hydrogen atom or fluorine atom; provided that both R.sup.1 and R.sup.2 are not simultaneously hydrogen atom.

30. The compound of any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is —M—Q, R.sup.2 is hydrogen atom, R.sup.3 is hydrogen atom or fluorine atom, and R.sup.4 is hydrogen atom.

31. The compound of any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each independently hydrogen atom; or R.sup.1 and R.sup.2 and/or R.sup.3 and R.sup.4 may be combined together to form ═CH.sub.2; provided that all of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are not simultaneously hydrogen atom.

32. The compound of any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, wherein R.sup.1 and R.sup.2 are hydrogen atom; and R.sup.3 and R.sup.4 are combined together to form ═CH.sub.2.

33. The compound of any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, wherein the sum of a and b is 2.

34. The compound of any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, wherein the sum of a and b is 3.

35. The compound of any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, wherein the sum of a and b is 4.

36. The compound of any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, wherein the sum of a and b is 5.

37. The compound of any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, wherein the sum of a and b is 6.

38. The compound of any one of claims 1 to 37 or a pharmaceutically acceptable salt thereof, wherein p is 1.

39. The compound of any one of claims 1 to 37 or a pharmaceutically acceptable salt thereof, wherein p is 2.

40. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from: 2-(3-{1-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]piperidin-4-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-di(propan-2-yl)benzamide, 2-(3-{1-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-methyl-N-(propan-2-yl)benzamide, 2-(3-{1-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-di(propan-2-yl)benzamide, 2-(3-{1-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]piperidin-4-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-methyl-N-(propan-2-yl)benzamide, 5-fluoro-2-(3-{1-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]piperidin-4-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-N,N-di(propan-2-yl)benzamide, 2-(3-{1-[(1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]piperidin-4-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-di(propan-2-yl)benzamide, 2-(3-{1-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]pyrrolidin-3-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-methyl-N-(propan-2-yl)benzamide, 2-(3-{1-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]pyrrolidin-3-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-di(propan-2-yl)benzamide, 2-(3-{1-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]piperidin-3-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-methyl-N-(propan-2-yl)benzamide, 2-(3-{1-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]azepan-4-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-methyl-N-(propan-2-yl)benzamide, 2-(3-({1-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]azepan-4-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-methyl-N-(propan-2-yl)benzamide, 5-fluoro-2-(3-{1-[(1S,3S,4S,5S)-5-fluoro-2-azabicyclo[2.2.2]octane-3-carbonyl]azepan-4-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-methyl-N-(propan-2-yl)benzamide, 5-fluoro-N-methyl-2-(3-{1-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carbonyl]azepan-4-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-(propan-2-yl)benzamide, 2-(3-{1-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]-1,2,3,4,7,8-hexahydroazocin-5-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-di(propan-2-yl)benzamide, 2-(3-{1-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]azocan-5-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-methyl-N-(propan-2-yl)benzamide, 5-fluoro-N-methyl-2-(3-{1-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]azocan-5-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-(propan-2-yl)benzamide, 2-(3-{1-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]azocan-5-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-di(propan-2-yl)benzamide, 5-fluoro-2-(3-{1-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]azocan-5-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-N,N-di(propan-2-yl)benzamide, 2-(3-{8-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]-8-azabicyclo[3.2.1]oct-2-en-3-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-di(propan-2-yl)benzamide, 2-(3-{8-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]-8-azabicyclo[3.2.1]oct-2-en-3-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-di(propan-2-yl)benzamide, 2-(3-{8-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]-8-azabicyclo[3.2.1]octan-3-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-methyl-N-(propan-2-yl)benzamide, 5-fluoro-N-methyl-2-(3-{8-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-8-azabicyclo[3.2.1]octan-3-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-(propan-2-yl)benzamide, 2-(3-{8-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]-8-azabicyclo[3.2.1]octan-3-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-di(propan-2-yl)benzamide, 5-fluoro-2-(3-{8-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-8-azabicyclo[3.2.1]octan-3-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-N,N-di(propan-2-yl)benzamide, 2-(3-{2-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2-azaspiro[3.4]octan-6-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N-methyl-N-(propan-2-yl)benzamide, 2-[3-({1-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]pyrrolidin-3-yl}methyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]-5-fluoro-N-methyl-N-(propan-2-yl)benzamide, 2-[3-({1-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]azetidin-3-yl}methyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]-5-fluoro-N-methyl-N-(propan-2-yl)benzamide, 2-[3-({1-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]piperidin-4-yl}methyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]-5-fluoro-N-methyl-N-(propan-2-yl)benzamide, 2-[3-({4-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]piperazin-1-yl}methyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]-5-fluoro-N-methyl-N-(propan-2-yl)benzamide, 2-[3-({4-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]-1,4-diazepan-1-yl}methyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]-5-fluoro-N-methyl-N-(propan-2-yl)benzamide, and (3S)-N-[(1S)-3-(1-{4-fluoro-2-[methyl(propan-2-yl)carbamoyl]phenyl}-1H-pyrrolo[2,3-c]pyridin-3-yl)cyclohexyl]-2-azabicyclo[2.2.2]octane-3-carboxamide.

41. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from: 5-fluoro-2-(3-{1-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]piperidin-4-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-N,N-di(propan-2-yl)benzamide, 2-(3-{1-[(1S,3S,4R,65)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carbonyl]piperidin-4-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-di(propan-2-yl)benzamide, 5-fluoro-N-methyl-2-(3-{1-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carbonyl]azepan-4-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-(propan-2-yl)benzamide, and 2-[3-({1-[(3S)-2-azabicyclo[2.2.2]octane-3-carbonyl]pyrrolidin-3-yl}methyl)-1H-pyrrolo[2,3-c]pyridin-1-yl]-5-fluoro-N-methyl-N-(propan-2-yl)benzamide.

42. A medicament comprising the compound of any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof as an active ingredient.

43. An antitumor medicament comprising the compound of any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof as an active ingredient.

44. The antitumor medicament of claim 43, wherein the tumor is acute leukemia (including MLL acute leukemia, MLL partial tandem duplicate acute leukemia, NPM mutated acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, and CALM acute leukemia), chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), brain tumor, cancer of the head and neck, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, gastric cancer, gallbladder and bile duct cancer, liver cancer, hepatocellular cancer, pancreatic cancer, colon cancer, rectal cancer, anal cancer, chorionepithelioma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, renal cancer, renal cell cancer, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer.

45. The antitumor medicament of claim 43 or 44, wherein the tumor is acute leukemia (including MLL acute leukemia, MLL partial tandem duplicate acute leukemia, NPM mutated acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, and CALM acute leukemia), chronic myeloid leukemia, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), brain tumor, prostate cancer, breast cancer, neuroblastoma, Ewing's sarcoma, or liver cancer.

46. The antitumor medicament of any one of claims 43 to 45, wherein the tumor is MLL acute leukemia, MLL partial tandem duplicate acute leukemia, NPM mutated acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, chronic myeloid leukemia, B-cell lymphoma, multiple myeloma, neuroblastoma, or prostate cancer.

47. The antitumor medicament of any one of claims 43 to 46, wherein the tumor is MLL acute leukemia, MLL partial tandem duplicate acute leukemia, NPM mutated acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, chronic myeloid leukemia, B-cell lymphoma, or multiple myeloma.

48. The antitumor medicament of any one of claims 43 to 47, wherein the tumor is MLL acute leukemia, or NPM mutated acute leukemia.

49. The antitumor medicament of any one of claims 43 to 48, wherein the tumor is accompanied by high expression of HOXa gene cluster, or MEIS gene cluster.

50. The antitumor medicament of any one of claims 43 to 49, wherein the tumor is accompanied by p53 gain-of-function mutation.

51. A method for treating a tumor comprising administrating the compound of any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

52. The method of claim 51, wherein the tumor is involved in Menin-MLL.

53. Use of the compound of any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof in the manufacture of an antitumor medicament.

54. The compound of any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof for use in the treatment of a tumor.

55. A pharmaceutical composition comprising the compound of any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof in combination with at least one different agent, wherein the different agent is at least one agent selected from the group consisting of an antitumor alkylating agent, an antitumor antimetabolite, an antitumor antibiotic, a plant-derived antitumor medicament, an antitumor platinum complex compound, an antitumor camptothecin derivative, an antitumor tyrosine kinase inhibitor, an antitumor serine/threonine kinase inhibitor, an antitumor phospholipid kinase inhibitor, an antitumor monoclonal antibody, interferon, an biological response modifier, a hormone preparation, an angiogenic inhibitor, an immune checkpoint inhibitor, an epigenetics-associated molecular inhibitor, a protein post-translational modification inhibitor, a proteasome inhibitor, and other antitumor medicaments.

56. The compound of any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof for treating a tumor, which is used in combination with at least one different agent, wherein the different agent is at least one agent selected from an antitumor alkylating agent, an antitumor antimetabolite, an antitumor antibiotic, a plant-derived antitumor medicament, an antitumor platinum complex compound, an antitumor camptothecin derivative, an antitumor tyrosine kinase inhibitor, an antitumor serine/threonine kinase inhibitor, an antitumor phospholipid kinase inhibitor, an antitumor monoclonal antibody, interferon, a biological response modifier, a hormone preparation, an angiogenic inhibitor, an immune checkpoint inhibitor, an epigenetics-associated molecular inhibitor, a protein post-translational modification inhibitor, a proteasome inhibitor, and other antitumor medicaments.

Description

EXAMPLES

[0753] The present invention is explained in more detail in the following by referring to Reference examples, Examples, and Tests; however, the technical scope of the present invention should not be limited thereto.

[0754] In the present specification, the abbreviations shown below may be used. [0755] THF: tetrahydrofuran [0756] TFA: trifluoroacetic acid [0757] DMF: N,N-dimethylformamide [0758] DMSO: dimethylsulfoxide [0759] MeCN: acetonitrile [0760] Me: methyl [0761] Et: ethyl [0762] Ph: phenyl [0763] Bn: benzyl [0764] Boc: tert-butoxycarbonyl [0765] BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl [0766] Pd.sub.2(dba).sub.3: tris(dibenzylideneacetone)dipalladium(0) [0767] Ac: acetyl [0768] dppf: 1,1′-bis(diphenylphosphino)ferrocene [0769] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene [0770] Dess-Martin reagent: Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one) [0771] Petasis reagent: bis(cyclopentadienyl)dimethyltitanium Bredereck reagent: tert-butoxy-bis(dimethylamino)methane [0772] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate [0773] WSCI-HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [0774] HOBt: 1-hydroxybenzotriazole [0775] p-: para- [0776] tert-: tertiary-

[0777] NMR (Nuclear Magnetic Resonance) data used for identification of compounds were obtained with a JNM-ECS400 type nuclear magnetic resonance instrument (400 MHz) from JEOL Ltd.

[0778] The symbols used in NMR are defined as follows, s: singlet, d: doublet, dd: doublet of doublet, t: triplet, td: triplet of doublet, q: quartet, m: multiplet, br: broad, brs: broad singlet, brm: broad multiplet, and J: coupling constant.

[0779] Analytical conditions of LC/MS (Liquid Chromatography-Mass Spectrometry) used for identification of compounds are shown below. In observed mass spectrometry values [MS(m/z)], monoisotopic mass (exact mass consisting of only main isotope) is shown in [M+H].sup.+, [M−H].sup.−, or [M+2H].sup.2+, etc., and retention time is shown as Rt (min). [0780] The analytical conditions of LC/MS:

Analytical Condition A

[0781] Detection apparatus: ACQUITY™ SQ detector (Waters Corporation) [0782] HPLC: ACQUITY™ UPLC system [0783] Column: Waters ACQUITY™ UPLC BEH C18 (1.7 μm, 2.1 mm×30 mm) [0784] Solvent: A: 0.06% formic acid/H.sub.2O, B: 0.06% formic acid/MeCN [0785] Gradient condition: 0.0 to 1.3 minutes Linear gradient from [0786] B 2% to B 96% [0787] Flow rate: 0.8 mL/min [0788] UV: 220 nm and 254 nm [0789] Column temperature: 40° C.
Analytical condition B [0790] Detection apparatus: LCMS-2020 (Shimadzu Corporation) [0791] HPLC: Nexera X2 [0792] Column: Phenomenex Kinetex™ 1.7 μm C18 (50 mm×2.1 mm) [0793] Solvent: A: 0.05% TFA/H.sub.2O, B: MeCN [0794] Gradient condition: 0.0 to 1.7 minutes Linear gradient from [0795] B 10% to B 99% [0796] Flow rate: 0.5 mL/min [0797] UV: 220 nm and 254 nm [0798] Column temperature: 40° C.

Reference Example 1

tert-Butyl 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

Reference Example 2

tert-Butyl 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylate

[0799] ##STR00035##

a) Preparation of tert-butyl 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0800] To a solution of 6-azaindole (3.9 g) and 1-(tert-butoxycarbonyl)-4-piperidone (6.6 g) in ethylene glycol (40 mL) was added potassium hydroxide (3.7 g), and the mixture was stirred at 100° C. for 10 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield the title compound (10.2 g).

[0801] .sup.1H-NMR (CDCl.sub.3) δ: 8.90 (1H, s) , 8.21 (1H, d, J=5.5 Hz), 7.79 (1H, d, J=5.5 Hz), 7.46 (1H, s), 6.13 (1H, s), 4.17-4.08 (2H, m), 3.71-3.62 (2H, m), 2.58-2.50 (2H, m), 2.07 (1H, s). [0802] b) Preparation of tert-butyl 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylate

[0803] To a solution of tert-butyl 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (10.2 g) in methanol (100 mL) was added 10% palladium hydroxide/carbon (4.8 g), and the mixture was stirred at room temperature under ambient-pressured hydrogen atmosphere for 12 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to yield the title compound (9.5 g). LC-MS; [M+H].sup.+ 302.29/Rt (min) 0.652 (Analytical condition A)

Reference examples 3-10

[0804] The following Reference examples 3 to 10 were prepared according to similar methods to Reference examples 1 and 2 by using each corresponding starting compound.

TABLE-US-00001 LC-MS; [M + H].sup.+ Reference Rt (min) example Structure Analytical condition 3 [00036] 288.1/0.606/Analytical condition A 4 [00037] 302.0/0.723/Analytical condition A 5 [00038] 316.0/656/Analytical condition A 6 [00039] 328.17/0.687/Analytical condition A 7 [00040] 330.17/0.792/Analytical condition A 8 [00041] 326.17/0.705/Analytical condition A 9 [00042] 327.9/0.895/Analytical condition A 10 [00043] 328.0/0.885/Analytical condition A

Reference Example 11

tert-Butyl 3-[(1H-pyrrolo[2,3-c]pyridin-3-yl)methyl]pyrrolidine-1-carboxylate

[0805] ##STR00044##

a) Preparation of tert-butyl 3-[methoxy(1H-pyrrolo[2,3-c]pyridin-3-yl)methyl]pyrrolidine-1-carboxylate

[0806] 6-Azaindole (2.00 g) was suspended in methanol (50.0 mL), and tert-butyl 3-formyl-pyrrolidine-1-carboxylate (6.75 g), 28% sodium methoxide in methanol (13.1 g) were added to the suspension at 0° C. The mixture was stirred at 80° C. for 18 hours. The reaction solution was left to stand until cool and then concentrated under reduced pressure. The residue was quenched with brine. The obtained aqueous solution was extracted with chloroform twice. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield the title compound (5.00 g). [0807] LC-MS; [M+H].sup.+ 299.97/Rt (min) 0.808 (Analytical condition A)

b) Preparation of tert-butyl 3-[(1H-pyrrolo[2,3-c]pyridin-3-yl)methyl]pyrrolidine-1-carboxylate

[0808] tert-Butyl 3-[methoxy(1H-pyrrolo[2,3-c]pyridin-3-yl)methyl]pyrrolidine-1-carboxylate (5.00 g) was dissolved in chloroform (50.0 mL), and triethylsilane (24.0 mL) and trifluoroacetic acid (12.0 mL) were added to the solution at 0° C. The mixture was stirred at 40° C. for 5 hours. The reaction solution was left to stand until cool and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and water (100 mL), and potassium carbonate (6.26 g) and di-tert-butyl dicarbonate (16.5 g) were added to the solution at 0° C. The mixture was stirred at room temperature for 5 hours. The reaction solution was quenched with brine. The obtained aqueous solution was extracted with ethyl acetate twice. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by amino silica gel column chromatography (chloroform/methanol) to yield the title compound (1.49 g). LC-MS; [M+H].sup.+ 301.97/Rt (min) 0.781 (Analytical condition A)

Reference Examples 12-13

[0809] The following Reference examples 12 and 13 were prepared according to a similar method to Reference example 11 by using each corresponding starting compound.

TABLE-US-00002 LC-MS; [M + H].sup.+ Reference Rt (min) example Structure Analytical condition 12 [00045] 287.97/0.614/Analytical condition A 13 [00046] 316.3/0.642/Analytical condition A

Reference Example 14

tert-Butyl 4-[(1H-pyrrolo[2,3-c]pyridin-3-yl)methyl]piperazine-1-carboxylate

[0810] ##STR00047##

[0811] 1H-Pyrrolo[2,3-c]pyridine-3-carbaldehyde (500 mg) was dissolved in methylene chloride (15.0 mL), and tert-butyl 1-piperazine-carboxylate (1.59 g) and sodium triacetoxyborohydride (1.81 g) were added to the solution at 0° C. The mixture was stirred at room temperature for 5 hours. The reaction solution was quenched with saturated aqueous sodium bicarbonate. The obtained aqueous solution was extracted with chloroform twice. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield the title compound (500 mg). [0812] LC-MS; [M+H].sup.+ 317.02/Rt (min) 0.567 (Analytical condition A)

Reference Example 15

[0813] The following Reference example 15 was prepared according to a similar method to Reference example 14 by using the corresponding starting compound.

TABLE-US-00003 LC-MS; [M + H].sup.+ Reference Rt (min) example Structure Analytical condition 15 [00048] 331.0/0.362/Analytical condition A

Reference example 16

tert-Butyl [(1S)-3-(1H-pyrrolo[2,3-c]pyridin-3-yl)cyclohexyl]carbamate

[0814] ##STR00049##

[0815] 6-Azaindole (2.00 g) and (3S)-N-Boc-aminocyclohexanone (3.97 g) were dissolved in ethylene glycol (5.00 mL), and potassium hydroxide (1.90 q) was added to the solution at 0° C. The mixture was stirred at 100° C. for 10 hours. The reaction solution was left to stand until cool and then quenched with brine. The obtained aqueous solution was extracted with chloroform twice. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered, and the solvent of the filtrate was removed under reduced pressure. The obtained redisue was dissolved in methanol (50.0 mL), and ammonium formate (10.6 g) and 10% palladium/carbon (1.01 g) were added to the solution. The mixture was heated under reflux for 3 hours. The reaction solution was left to stand until cool and then cooled to room temperature. The cooled reaction mixture was filtered with Celite, and brine was added to the filtrate. The obtained aqueous solution was extracted with chloroform twice. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield the title compound (2.00 g). LC-MS; [M+H]' 316.16/Rt (min) 0.667 (Analytical condition A)

Reference Example 17

5-Fluoro-2-[3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl]-N,N-di(propan-2-yl)benzamide

[0816] ##STR00050##

a) Preparation of 2-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1H-pyrrolo[2,3-c]pyridin-1-yl}-5-fluorobenzoic acid

[0817] A solution of tert-butyl 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylate (500 mg), 5-fluoro-2-iodobenzoic acid (662 mg), copper(I) iodide (95 mg), and 1,10-phenanthroline (90 mg) in DMF (100 mL) was stirred at 70° C. for 24 hours, and concentrated under reduced pressure to give the title compound as a crude product. [0818] LC-MS; [M+H].sup.+ 440.4/Rt (min) 0.652 (Analytical condition A)

b) Preparation of tert-butyl 4-(1-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenyl}-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylate

[0819] 2-{3-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-1H-pyrrolo[2,3-c]pyridin-1-yl}-5-fluorobenzoic acid which was prepared in the above Spte a) as a crude product was suspended in chloroform (10 mL). To the suspension were added HATU (1.89 g), N,N-diisopropylamine (839 mg), and triethylamine (2.3 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added saturated aqueous sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield the title compound.

[0820] LC-MS; [M+H].sup.+ 523.5/Rt (min) 0.807 (Analytical condition A)

c) Preparation of 5-fluoro-2-{3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl}-N,N-di(propan-2-yl)benzamide

[0821] To a solution of tert-butyl 4-(1-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenyl}-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carboxylate prepared in the above Step b) in methylene chloride (10 mL) was added trifluoroacetic acid (1.3 mL). The mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was purified by amine silica gel column chromatography (chloroform/methanol) to yield the title compound (500 mg). [0822] LC-MS; [M+2H].sup.2+ 212.2/Rt (min) 0.547 (Analytical condition A)

Reference Examples 18-37

[0823] The following Reference examples 18 to 37 were prepared according to similar methods to Reference examples 1 and 2 by using each corresponding starting compound.

TABLE-US-00004 [00051] LC-MS; [M + H].sup.+ or [M + 2H].sup.2+ Reference Rt (min) example A B Analytical condition 18 Me [00052] 197.2/0.392/Analytical condition A 19 i-Pr [00053] 211.26/0.481/Analytical condition A 20 Me [00054] 198.15/0.383/Analytical condition A 21 Me [00055] 381.3/0.334/Analytical condition A 22 i-Pr [00056] 205.5/0.504/Analytical condition A 23 Me [00057] 198.13/0.424/Analytical condition A 24 Me [00058] 409.0/0.339/Analytical condition A 25 i-Pr [00059] 449.5/0.577/Analytical condition A 26 Me [00060] 212.16/0.522/Analytical condition A 27 i-Pr [00061] 226.2/0.600/Analytical condition A 28 i-Pr [00062] 447.4/0.556/Analytical condition A 29 Me [00063] 211.71/0.351/Analytical condition A 30 i-Pr [00064] 225.32/0.537/Analytical condition A 31 Me [00065] 421.3/0.368/Analytical condition A 32 Me [00066] 395.1/0.452/Analytical condition A 33 Me [00067] 191.1/0.376/Analytical condition A 34 Me [00068] 205.13/0.390/Analytical condition A 35 Me [00069] 205.88/0.351/Analytical condition A 36 Me [00070] 212.2/0.349/Analytical condition A 37 Me [00071] 205.25/0.406/Analytical condition A

Reference Example 38

(1S,3S,4S,5R)-2-(tert-Butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid

[0824] ##STR00072##

a) Preparation of ethyl (2E)-{[(1R)-1-phenylethyl]imino}acetate

[0825] To (R)-1-phenylethylamine (63 mL) was added ethyl oxoacetate (100 mL), and the mixture was stirred at room temperature for an hour. The mixture was concentrated under reduced pressure to yield the title compound as a crude product. The obtained product was used in the next step without purification.

b) Preparation of ethyl (1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate

[0826] To a solution of ethyl (2E)-{[(1R)-1-phenylethyl]imino}acetate which was prepared in the above Spte a) as a crude product in dichloromethane (475 mL) was added molecular sieve 4A (powder, 10 g), and the reaction mixture was cooled to −70° C. To the reaction mixture were added dropwise trifluoroacetic acid (32 mL) and boron trifluoride diethyl ether complex (53 mL), and the mixture was stirred for 15 hours. Then 1,3-cyclohexadiene (42 mL) was added dropwise to the reaction mixture. The reaction mixture was warmed to room temperature and stirred overnight. To the reaction solution was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield the title compound (59.4 g). LC-MS; [M+H].sup.+ 286.2/Rt (min) 0.53 (Analytical condition A)

c) Preparation of ethyl (1S,3S,4S,5R)-5-hydroxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.2]octane-3-carboxylate

[0827] To a solution of ethyl (1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate (85.5 g) in THF (500 mL) was added dropwise 1.0 mol/L borane-THF complex (300 mL) at 0 to 5° C., and the mixture was stirred at room temperature overnight. To the reaction solution were added 3 mol/L aqueous sodium hydroxide (62 mL) and 30% aqueous hydrogen peroxide (62 mL) at ice temperature, and the reaction mixture was stirred for 30 minutes. Then, aqueous sodium thiosulfate was added to the reaction mixture, and the mixture was stirred for an hour. To the reaction solution was added ethyl acetate/chloroform, and the mixture was extracted. The organic layer was washed with brine. The organic layer was dried over sodium sulfate and filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield the title compound (51.7 g) as a crude product. [0828] LC-MS; [M+H].sup.+ 304.2/Rt (min) 0.53 (Analytical condition A)

d) Preparation of ethyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate

[0829] To a solution of the crude product (51.7 g) prepared in the above Step c) in ethanol (500 mL) was added 10% palladium hydroxide (10.2 g), and the mixture was stirred at room temperature for 6 hours under pressured hydrogen atmosphere (0.3 to 0.4 MPa). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield the title compound, ethyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate (19.0 g). LC-MS; [M+H].sup.+ 200.2/Rt (min) 0.27 (Analytical condition A) e) Preparation of (1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid

Reference Example 38

[0830] To a solution of ethyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylate (10.48 g) in 1,4-dioxane (153 mL) was added 1 mol/L aqueous sodium hydroxide (238 mL), and the mixture was stirred at room temperature for an hour. Then, the reaction solution was cooled to 0° C., and di-tert-butyl dicarbonate (11.48 g) was added to the reaction solution. The reaction solution was stirred for an hour, and then acidified with 1 mol/L aqueous hydrochloric acid. Brine was added to the acidified solution, and the mixture was extracted with a mixture of 10% ethanol/chloroform. The organic layer was dried over sodium sulfate and filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was washed with diisopropyl ether, collected on a filter, dried to yield the title compound (8.40 g).

[0831] .sup.1H-NMR (DMSO-D.sub.6) δ: 12.55 (1H, br s), 4.86 (1H, br s), 3.96-3.81 (3H, m), 2.09-1.69 (4H, m), 1.59-1.49 (1H, m), 1.36 (3H, s), 1.31 (6H, s), 1.29-1.17 (2H, m).

Reference Example 39

(1S,3S,4S,5R)-2-(tert-Butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid

[0832] ##STR00073##

a) Preparation of ethyl (1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate

[0833] The title compound (10.8 g) was prepared from ethyl (2E)-{[(1R)-1-phenylethyl]imino}acetate (12.0 g) and cyclopentadiene (4.92 mL) according to a similar method to Step b) in Reference example 38. [0834] LC-MS; [M+H].sup.+ 272.2/Rt (min) 0.54 (Analytical condition A)

b) Preparation of ethyl (1S,3S,4S,5R)-5-hydroxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate

[0835] The title compound (7.49 g) was prepared from ethyl (1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (10.8 g) according to a similar method to Step c in Reference example 38.

[0836] LC-MS; [M+H].sup.+ 290.2/Rt (min) 0.46 (Analytical condition A)

Preparation of ethyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylate

[0837] The title compound (2.89 g) was prepared from ethyl (1S,3S,4S,5R)-5-hydroxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (7.49 g) according to a similar method to Step d) in Reference example 38. [0838] LC-MS; [M+H].sup.+ 186.1/Rt (min) 0.27 (Analytical condition A)

d) Preparation of (1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (Reference Example 39)

[0839] The title compound (980 mg) was prepared from ethyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylate (2.88 g) according to a similar method to Step e in Reference example 38.

[0840] .sup.1H-NMR (DMSO-D.sub.6) δ: 4.99 (1H, br s), 4.11-3.95 (1H, m), 3.95-3.82 (1H, m), 3.48-3.40 (1H, m), 2.41-2.31 (1H, m), 1.90-1.75 (1H, m), 1.69-1.49 (2H, m), 1.45-1.19 (10H, m).

Reference Example 40

3-Benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

[0841] ##STR00074##

a) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

[0842] To a solution of (1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid (28.0 g) and potassium carbonate (28.5 g) in acetonitrile (300 mL) was added benzyl bromide (12.3 mL) at room temperature, and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure. To the obtained residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield the title compound (33.1 g).

[0843] LC-MS; [M+H].sup.+ 362.3/Rt (min) 0.95 (Analytical condition A)

b) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (Reference example 40)

[0844] To a solution of 3-benzyl 2-tert-butyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (33.0 g) in dichloromethane (400 mL) was added Dess-Martin reagent (46.5 g) at room temperature, and the mixture was stirred at room temperature overnight. To the reaction solution were added aqueous sodium thiosulfate and aqueous sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield the title compound (33.8 g) as a crude product. [0845] LC-MS; [M+H].sup.+ 360.2/Rt (min) 1.02 (Analytical condition A)

[0846] .sup.1H-NMR (CDCl.sub.3) δ: 7.38-7.28 (5H, m), 5.33-5.05 (2H, m), 4.66-4.42 (2H, m), 2.80-2.69 (1H, m), 2.59-2.45 (1H, m), 2.36-2.16 (2H, m), 1.82-1.62 (3H, m), 1.45 (2.5H, s), 1.31 (6.5H, s).

Reference Example 41

3-Benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate

[0847] ##STR00075##

a) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate

[0848] The title compound (1.73 g) was prepared from (1S,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.5 g) according to a similar method to Step a) in Reference example 40. [0849] LC-MS; [M+H].sup.+ 348.2/Rt (min) 0.92 (Analytical condition A)

b) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (Reference example 41)

[0850] The title compound (1.40 g) was prepared from 3-benzyl 2-tert-butyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.73 g) according to a similar method to Step b) in Reference example 40. [0851] LC-MS; [M+H].sup.+ 346.2/Rt (min) 1.01 (Analytical condition A)

Reference example 42:

(1S,3S,4R)-2-(tert-Butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carboxylic acid

[0852] ##STR00076##

a) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

[0853] To a solution of 3-benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (3.0 g) in THF (30 mL) was added Petasis reagent (5% THF/toluene solution, 35 g) at room temperature, and the mixture was stirred at 95° C. for 5 hours. The reaction mixture was cooled to room temperature, and Petasis reagent (5% THF/toluene solution, 10 g) was further added to the reaction mixture. The mixture was stirred under reflux at 130° C. The reaction mixture was left to stand until cool, and then diethyl ether was added to the reaction mixture. The precipitated orange solid was removed with filter, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield the title compound (1.9 g).

[0854] LC-MS; [M+H].sup.+ 358.0/Rt (min) 1.21 (Analytical condition A) b) Preparation of (1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carboxylic acid (Reference example 42)

[0855] To a solution of 3-benzyl 2-tert-butyl (1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (1.9 g) in methanol (60 mL) was added 5 mol/L aqueous sodium hydroxide (5.1 mL), and the mixture was stirred at 50° C. for 5 hours. The reaction solution was cooled to room temperature, then neutralized with 1 mol/L hydrochloric acid, and extracted with chloroform. The organic layer was dried over sodium sulfate, and filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield the title compound (0.99 g). [0856] LC-MS; [M+H].sup.+ 268.0/Rt (min) 0.83 (Analytical condition A) Reference example 43:

(1S,3S,4R)-2-(tert-Butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carboxylic acid

[0857] ##STR00077##

a) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate

[0858] The title compound (1.10 g) was prepared from 3-benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.40 g) according to a similar method to Step a) in Reference example 42. [0859] LC-MS; [M+H]' 344.2/Rt (min) 1.18 (Analytical condition A)

b) Preparation of (1S,3S,4R)-2-(tert-butoxycarbonyl)-5-methylidene-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (Reference example 43)

[0860] The title compound (0.69 g) was prepared from 3-benzyl 2-tert-butyl (1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.10 g) according to a similar method to Step b) in Reference example 42. [0861] LC-MS; [M+H].sup.+ 254.3/Rt (min) 0.82 (Analytical condition A)

Reference example 44

3-Benzyl 2-tert-butyl (1S,3S,4S,6E)-6-(cyclopropylmethylidene)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

[0862] ##STR00078##

a) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S,6E)-6-[(dimethylamino)methylidene]-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

[0863] To a solution of 3-benzyl 2-tert-butyl (1S,3S,4S)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (33.8 g) in N,N-dimethylformamide (180 mL) was added Bredereck reagent (32.8 g), and the mixture was stirred at 100° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield the title compound (39.0 g) as a crude product. [0864] LC-MS; [M+H].sup.+ 415.4/Rt (min) 0.95 (Analytical condition A)

b) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S,6E)-6-(cyclopropylmethylidene)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (Reference example 44)

[0865] A solution of 3-benzyl 2-tert-butyl (1S,3S,4S,6E)-6-[(dimethylamino)methylidene]-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (39.0 g) in tetrahydrofuran (300 mL) was cooled to 0° C., and cyclopropylmagnesium bromide (0.5 moL/L tetrahydrofuran solution, 245 mL) was added dropwise to the solution. The mixture was stirred at room temperature for 6 hours. Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield the title compound (32.3 g). [0866] LC-MS; [M+H].sup.+ 412.4/Rt (min) 1.16 (Analytical condition A)

[0867] .sup.1H-NMR (CDCl.sub.3) 7.39-7.27 (5H, m), 5.91 (1H, t, J=11.0 Hz), 5.38-5.04 (3H, m), 4.50-4.36 (1H, m), 2.90-2.76 (1H, m), 2.37-2.22 (1H, m), 1.82-1.59 (4H, m), 1.44 (3H, s), 1.31 (6H, s), 1.09-0.95 (2H, m), 0.73-0.58 (2H, m).

Reference Example 45

[0868] 3-Benzyl 2-tert-butyl (1S,3S,4S,5R)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

##STR00079##

a) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S)-6-(cyclopropylmethyl)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

[0869] To a solution of 3-benzyl 2-tert-butyl (1S,3S,4S,6E)-6-(cyclopropylmethylidene)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (32.3 g) in tetrahydrofuran (300 mL) was added triphenylphosphine-copper(I) hydride hexamer (38.5 g), and the mixture was stirred at room temperature for 12 hours. The reaction solution was filtered with Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield the title compound (23.2 g) as a mixture of stereoisomers. [0870] LC-MS; [M+H].sup.+ 414.1/Rt (min) 1.22 (Analytical condition A)

b) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S,5R)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (Reference example 45)

[0871] A solution of 3-benzyl 2-tert-butyl (1S,3S,4S)-6-(cyclopropylmethyl)-5-oxo-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (23.2 g) in methanol (200 mL) was cooled to 0° C., and sodium borohydride (2.12 g) was added to the solution. The mixture was stirred for an hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield the title compound (10.2 g). [0872] LC-MS; [M+H].sup.+ 416.1/Rt (min) 1.01 (Analytical condition A)

Reference Example 46

(1S,3S,4R,6S)-2-(tert-Butoxycarbonyl)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid

[0873] ##STR00080##

a) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

[0874] A solution of 3-benzyl 2-tert-butyl (1S,3S,4S,5R)-6-(cyclopropylmethyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (7.3 g) in acetonitrile (50 mL) was cooled to 0° C., and 4-(dimethylamino)pyridine (8.6 g) and phenyl chlorothionoformate (4.74 mL) were added to the solution. The mixture was stirred at 50° C. for 12 hours. The reaction solution was cooled to room temperature, and then brine was added to the cooled reaction solution. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 3-benzyl 2-tert-butyl (1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (1.80 g). [0875] LC-MS; [M+H].sup.+ 552.2/Rt (min) 1.42 (Analytical condition A) b) Preparation of 3-benzyl 2-tert-butyl (1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate

[0876] A solution of 3-benzyl 2-tert-butyl (1S,3S,4S,5R,6R)-6-(cyclopropylmethyl)-5-[(phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (1.80 g) in toluene (50 mL) was cooled to 0° C., and tris(trimethylsilyl)silane (5.03 mL) and 2,2′-azobis(2-methylpropionitrile) (0.11 g) were added to the solution. The mixture was stirred at 50° C. for 5 hours. The reaction solution was cooled to room temperature, and then brine was added to the cooled reaction solution. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield the title compound (0.80 g). LC-MS; [M+H].sup.+ 400.2/Rt (min)1.38 (Analytical condition A)

c) Preparation of (1S,3S,4R,6S)-2-(tert-butoxycarbonyl)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (Reference example 46)

[0877] The title compound (3.90 g) was prepared from 3-benzyl 2-tert-butyl (1S,3S,4R,6S)-6-(cyclopropylmethyl)-2-azabicyclo[2.2.2]octane-2,3-dicarboxylate (5.50 g) according to a similar method to Step b) in Reference example 42. [0878] LC-MS; [M+H].sup.+ 310.2/Rt (min) 1.02 (Analytical condition A)

Reference Example 47

tert-Butyl (3S)-3-[4-(1-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenyl}-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carbonyl]-2-azabicyclo[2.2.2]octane-2-carboxylate

[0879] ##STR00081##

[0880] To a solution of 5-fluoro-2-[3-(piperidin-4-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl]-N,N-di(propan-2-yl)benzamide (150 mg) which was prepared in Reference example 17 in methylene chloride (5.00 mL) were added commercially-available (1S,3S,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (109 mg), HATU (270 mg), and triethylamine (0.25 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield the title compound (245 mg). [0881] LC-MS; [M+H].sup.+ 660.55/Rt (min) 0.970 (Analytical condition A)

Reference Examples 48-72

[0882] The following Reference examples 48 to 76 were prepared according to a similar method to Reference example 47 by using each corresponding starting compound.

TABLE-US-00005 [00082] LC-MS; [M + H].sup.+ or [M + 2H].sup.2+ Reference Rt (min) example A B Analytical condition 48 Me [00083] 630.49/0.829/Analytical condition A 49 i-Pr [00084] 658.55/0.816/Analytical condition A 50 Me [00085] 632.6/0.822/Analytical condition A 51 i-Pr [00086] 672.5/0.922/Analytical condition A 52 i-Pr [00087] 714.8/1.088/Analytical condition A 53 Me [00088] 618.49/0.831/Analytical condition A 54 i-Pr [00089] 646.60/0.993/Analytical condition A 55 Me [00090] 646.7/0.856/Analytical condition A 56 Me [00091] 632.6/0.794/Analytical condition A 57 Me [00092] 646.8/0.787/Analytical condition A 58 Me [00093] 664.8/0.738/Analytical condition A 59 Me [00094] 644.5/0.768/Analytical condition A 60 i-Pr [00095] 686.7/0.951/Analytical condition A 61 Me [00096] 660.55/1.032/Analytical condition A 62 Me [00097] 672.7/0.982/Analytical condition A 63 i-Pr [00098] 688.7/0.871/Analytical condition A 64 i-Pr [00099] 700.67/1.163/Analytical condition A 65 i-Pr [00100] 684.7/0.877/Analytical condition A 66 Me [00101] 658.6/0.863/Analytical condition A 67 Me [00102] 671.61/0.786/Analytical condition A 68 i-Pr [00103] 686.60/1.013/Analytical condition A 69 i-Pr [00104] 698.72/0.843/Analytical condition A 70 Me [00105] 644.8/0.735/Analytical condition A 71 Me [00106] 632.40/0.753/Analytical condition A 72 Me [00107] 618.7/0.707/Analytical condition A 73 Me [00108] 645.9/0.878/Analytical condition A 74 Me [00109] 647.2/0.626/Analytical condition A 75 Me [00110] 331.4/0.942/Analytical condition A 76 Me [00111] 646.7/0.856/Analytical condition A

Example 1

2-(3-{1-[(3S)-2-Azabicyclo[2.2.2]octane-3-carbonyl]piperidin-4-yl}-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-di(propan-2-yl)benzamide

[0883] ##STR00112##

[0884] To a solution of tert-butyl (3S)-3-[4-(1-{2-[di(propan-2-yl)carbamoyl]-4-fluorophenyl}-1H-pyrrolo[2,3-c]pyridin-3-yl)piperidine-1-carbonyl]-2-azabicyclo[2.2.2]octane-2-carboxylate (245 mg) which was prepared in Reference example 47 in dichloromethane (5.00 mL) was added TFA (2.00 mL) at room temperature, and the mixture was stirred at room temperature for an hour. The solvent was removed from the reaction mixture under reduced pressure, and the residue was purified by amine silica gel column chromatography (ethyl acetate/methanol) to yield the title compound (171 mg). [0885] LC-MS; [M+H].sup.+ 560/Rt (min) 1.443 (Analytical condition B)

[0886] .sup.1H-NMR (DMSO-D6) δ: 8.64 (1H, s), 8.23 (1H, d, J=5.5 Hz), 7.75-7.68 (2H, m), 7.52-7.41 (2H, m), 7.38 (1H, d, J=4.3 Hz), 4.61 (1H, d, J=11.6 Hz), 3.98-3.88 (2H, m), 3.51-3.11 (3H, m), 2.88-2.80 (2H, m), 2.18-1.99 (2H, m), 1.88-1.27 (15H, m), 1.01-0.92 (6H, m), 0.22 (3H, d, J=4.3 Hz).

Examples 2-30

[0887] The following Examples 2 to 30 were prepared according to a similar method to Example 1 by using each corresponding starting compound.

TABLE-US-00006 [00113] LC-MS; [M + H].sup.+ or [M + 2H].sup.2+ Rt (min) Analytical condition Example A B .sup.1H-NMR 2 Me [00114] 266.14/0.494/Analytical condition A 3 i-Pr [00115] 558/1.460/Analytical condition B .sup.1H-NMR (DMSO-D6) δ: 8.64 (1H, s) , 8.27 (1H, d, J = 5.5 Hz), 7.95-7.88 (1H, m), 7.79-7.72 (1H, m), 7.69-7.62 (1H, m), 7.54-7.40 (2H, m), 6.39-6.26 (1H, m), 4.35-4.08 (2H, m), 3.95 (1H, d, J = 16.5 Hz), 3.71-3.58 (2H, m), 3.51-3.16 (3H, m), 2.84 (1H, s), 2.63-2.41 (2H, m), 1.90-1.38 (8H, m), 1.36 (3H, d, J = 6.1 Hz), 0.96 (3H, d, J = 6.7 Hz), 0.92-0.77 (3H, m), 0.27- 0.09 (3H, m). 4 Me [00116] 266.69/0.530/Analytical condition A .sup.1H-NMR (DMSO-D6) δ: 8.65- 8.51 (1H, m), 8.24-8.18 (1H, m), 7.78-7.65 (2H, m), 7.54- 7.44 (2H, m), 7.38-7.31 (1H, m), 4.65-4.49 (1H, m), 3.98- 3.83 (2H, m), 3.51-3.09 (2H, m), 2.89-2.76 (2H, m), 2.58-2.33 (3H, m), 2.13- 1.95 (2H, m), 1.87-1.33 (12H, m), 1.03-0.89 (3H, m), 0.58-0.08 (3H, m). 5 i-Pr [00117] 286.8/0.599/Analytical condition A .sup.1H-NMR (DMSO-D6) δ: 8.64- 8.58 (1H, m), 8.25-8.16 (1H, m), 7.74-7.65 (2H, m), 7.50- 7.32 (3H, m), 5.00-4.53 (3H, m), 3.93 (1H, s), 3.87-3.73 (1H, m), 3.53-3.09 (5H, m), 3.05 (1H, s), 2.89-2.74 (1H, m), 2.44-2.23 (2H, m), 2.23-1.94 (2H, m), 1.81-1.39 (6H, m), 1.36 (3H, d, J = 6.7 Hz), 1.01-0.85 (6H, m), 0.31- 0.14 (3H, m). 6 i-Pr [00118] 614/1.555/Analytical condition B .sup.1H-NMR (DMSO-D6) δ: 8.62 (1H, s), 8.21 (1H, d, J = 5.5 Hz), 7.70 (2H, dd, J = 26.3, 13.1 Hz) , 7.49-7.39 (2H, m), 7.35 (1H, d, J = 8.6 Hz), 4.65-4.53 (1H, m), 3.98-3.84 (2H, m), 3.49-3.08 (3H, m), 2.85-2.74 (1H, m), 2.71 (1H, s), 2.17-1.95 (4H, m), 1.76-1.21 (12H, m), 1.19-1.02 (2H, m), 1.00- 0.85 (6H, m), 0.75-0.63 (1H, m), 0.45-0.36 (2H, m), 0.25-0.15 (3H, m), 0.10--0.03 (2H, m). 7 Me [00119] 260.19/0.533/Analytical condition A 8 i-Pr [00120] 240.08/0.813/Analytical condition A 9 Me [00121] 266.63/0.524/Analytical condition A 10 Me [00122] 532.4/0.477/Analytical condition A .sup.1H-NMR (CDC1.sub.3) δ: 8.71- 8.62 (1H, m), 8.34-8.26 (1H, m), 7.57-7.45 (2H, m), 7.33-7.15 (3H, m), 4.69-4.05 (1H, m), 3.88- 3.57 (4H, m), 3.51-2.93 (3H, m), 2.71-2.53 (2H, m), 2.37-2.21 (2H, m), 2.20-1.52 (10H, m), 1.42- 1.33 (1H, m), 1.09-0.88 (2H, m), 0.63--0.04 (3H, m). 11 Me [00123] 273.8/0.480/Analytical condition A 12 Me [00124] 282.8/0.479/Analytical condition A 13 Me [00125] 272.8/0.482/Analytical condition A .sup.1H-NMR (CDC1.sub.3) δ: 8.70- 8.60 (1H, m), 8.34-8.20 (1H, m), 7.56-7.43 (2H, m), 7.35-7.14 (3H, m), 5.19-5.08 (1H, m), 4.94- 4.86 (1H, m), 4.67-4.50 (1H, m), 4.19-3.91 (2H, m), 3.81-3.35 (3H, m), 3.11-2.84 (4H, m), 2.70- 2.61 (2H, m), 2.41-1.49 (10H, m), 1.09-0.86 (3H, m), 0.60-0.07 (3H, m). 14 i-Pr [00126] 586.35/1.4 4 5/Analytical condition B 15 Me [00127] 560/1.50/Analytical condition B 16 Me [00128] 572/1.408/Analytical condition B 17 i-Pr [00129] 588/1.50/Analytical condition B 18 i-Pr [00130] 600/1.496/Analytical condition B 19a i-Pr [00131] 584.35/1.446/Analytical condition B .sup.1H-NMR (CDC1.sub.3) δ: 8.67 (1H, m), 8.34 (1H, m), 7.84-7.64 (1H, m), 7.62- 7.41 (2H, m), 7.23 (1H, m), 7.13 (1H, m), 6.58 and 6.46 (total 1H, each m), 5.21 and 4.86 (total 1H, each br s), 4.41 (1H, m), 4.00 (1H, m), 3.64 (0.7H, m), 3.38 (1H, m), 3.28-2.89 (total 3.3H, br m), 2.57-1.34 (total 12H, m), 1.31-1.02 (total 7H, each m), 0.93 (3H, m), 0.05 (3H, m). 19b i-Pr [00132] 584.35/1.436/Analytical condition B 20 Me [00133] 279.8/0.614/Analytical condition A .sup.1H-NMR (DMSO-D6) δ: 8.66- 8.51 (1H, m), 8.25-8.17 (1H, m), 7.78-7.57 (2H, m), 7.55-7.27 (3H, m), 4.81-4.50 (1H, m), 4.42- 4.21 (1H, m), 3.88-3.74 (1H, m), 3.56-3.36 (2H, m), 2.88-2.78 (1H, m), 2.58-2.53 (2H, m), 2.41- 2.31 (2H, m), 2.11-1.34 (16H, m), 1.07-0.89 (3H, m), 0.57-0.10 (3H, m). 21 Me [00134] 286.5/0.532/Analytical condition A 22 i-Pr [00135] 586/1.51/Analytical condition B 23 i-Pr [00136] 300.54/0.638/Analytical condition A 24 Me [00137] 272.84/0.486/Analytical condition A .sup.1H-NMR (CDC1.sub.3) δ: 8.63- 8.58 (1H, m), 8.27-8.20 (1H, m), 7.51-7.40 (2H, m), 7.25-7.09 (3H, m), 4.65-3.82 (4H, m), 3.74 (1H, s), 3.50-3.21 (2H, m), 2.65-2.57 (2H, m), 2.54-2.45 (1H, m), 2.42- 2.29 (1H, m), 2.26-2.11 (3H, m), 2.11-1.84 (4H, m), 1.84-1.39 (5H, m), 1.34-1.25 (1H, m), 1.07- 0.81 (3H, m), 0.61--0.05 (3H, m). 25 Me [00138] 267.60/0.424/Analytical condition A .sup.1H-NMR (DMSO-D6) δ: 8.50- 8.36 (1H, m), 8.10-8.02 (1H, m), 7.61-7.47 (2H, m), 7.40-7.19 (3H, m), 3.61-3.39 (3H, m), 3.39- 3.20 (4H, m), 2.80-2.55 (3H, m), 2.50-2.36 (2H, m), 2.24-2.15 (1H, m), 1.90-1.13 (11H, m), 0.88- 0.68 (3H, m), 0.42--0.08 (3H, m). 26 Me [00139] 259.5/0.836/Analytical condition A 27 Me [00140] 273.6/0.623/Analytical condition A 28 Me [00141] 274.1/0.487/Analytical condition A 29 Me [00142] 281.1/0.687/Analytical condition A 30 Me [00143] 273.7/0.549/Analytical condition A

Tests

Test 1: Test for Evaluating the Inhibition of Cell Proliferation

[0888] MV4; 11 cells were obtained from American Type Culture Collection (ATCC). The cells were cultured at 37° C. in the presence of 5% CO.sub.2 in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin/streptomycin.

[0889] The cells were plated to a 96-well plate in 2000 cells/well, each test compound was added thereto to adjust the final concentration of DMSO to 0.1% of DMSO, and the cells were cultured for 7 days. After the cultivation, the cell viability was calculated with PrestoBlue™ Cell Viability Reagent (Invitrogen, A13261). The IC.sub.50 value was calculated from a survival curve that corresponds to the concentration of the test compound at which the cell proliferation inhibition rate is 50%.

[0890] The results of the evaluation in Test 1 are shown in the following table.

TABLE-US-00007 Example MV4; 11 IC.sub.50 (μM)  1 0.26  2 0.53  3 0.036  4 0.073  5 0.035  6 <0.0030  7 0.052  8 0.024  9 1.7 10 0.089 11 <0.030 12 <0.030 13 0.13 14 2.2 15 0.42 16 0.24 17 0.83 18 0.73 19a <0.030 19b 0.14 20 0.085 21 0.43 22 0.064 23 0.28 24 0.058 25 0.029 26 1.7 27 0.78 28 3.2 29 2.9 30 0.55

[0891] The compounds of Examples 3, 4, 5, 6, 7, 8, 10, 11, 12, 19, 20, 22, 24, and 25 showed the potent cell proliferation inhibition activity as shown in the above table.

Test 2: Test for the hERG Inhibition

[0892] To a cultured CHO cell strain which stably expresses hERG (human Ether-a-go-go Related Gene) was added each test compound to adjust the final concentration to 0.0135 to 0.5% of DMSO. The hERG current was measured with QPatch HT (Sophion Inc.), and the concentration at which 50% of the hERG current was inhibited by each test compound (IC.sub.50 value; μM) was calculated.

[0893] The compounds of Examples were tested according to Test example 2. And, the hERG/MV4; 11 was calculated by dividing the compound concentration obtained in Test example 2, at which 50% of the hERG current is inhibited, by the compound concentration obtained in Test example 1, at which 50% of the proliferation of MV4; 11 cells is inhibited. The results are shown in the following table.

TABLE-US-00008 Example hERG IC.sub.50 (μM) hERG/MV4; 11  1 30 114  2 54 102  3 18 489  4 >100 >1370  5 21 589  6 <2.7 —  7 40 775  8 9.7 404  9 37 22 10 55 621 11 39 >1287 12 32 >1050 13 26 198 14 3.2 1.5 15 17 40 16 — — 17 3.0 3.6 18 — — 19a 6.0 >200 19b 4.5 32 20 32 373 21 — — 22 5.8 91 23 — — 24 67 1157 25 9.7 334 26 >100 >59 27 >100 >128 28 >100 >31 29 >100 >34 30 7.3 13

[0894] As shown in the above table, there is a more than 100-fold gap between the concentration at which 50% of the proliferation of MV4; 11 cells was inhibited and the concentration at which 50% of the hERG current was inhibited in the compounds of Examples 1, 2, 3, 4, 5, 7, 8, 10, 11, 12, 13, 19, 20, 24, 25, and 27. Especially, it is proved that there is a more than 1000-fold excellent gap between the concentration at which 50% of the proliferation of RS4; 11 cells was inhibited and the concentration at which 50% of the hERG current was inhibited in the compounds of Examples 4, 11, 12, and 24.

INDUSTRIAL APPLICABILITY

[0895] The compounds of the present invention can inhibit the binding of a MLL fusion protein and menin to provide the antitumor effect.