ARYL OR HETEROARYL DERIVATIVE
20230167073 · 2023-06-01
Assignee
Inventors
- Sakae SUGIYAMA (Tokyo, JP)
- Takuya Yokosaka (Tokyo, JP)
- Kunio Minamizono (Tokyo, JP)
- Asahi KAWANA (Tokyo, JP)
- Toshiyuki KANEKO (Tokyo, JP)
- Akinobu Maruyama (Tokyo, JP)
- Kosuke Sasaki (Tokyo, JP)
- Shinnosuke HOSODA (Tokyo, JP)
- Masaki KOSHIMIZU (Tokyo, JP)
- Susumu Takeuchi (Tokyo, JP)
- Kenta Kato (Tokyo, JP)
- Nagasree Chakka (Lexington, MA)
- Brett M. JOHNSON (S. Weymouth, MA, US)
- Ryan D. White (Somerville, MA)
- WEI ZHAO (WESTFORD, MA, US)
Cpc classification
C07D409/12
CHEMISTRY; METALLURGY
C07D491/107
CHEMISTRY; METALLURGY
C07D491/052
CHEMISTRY; METALLURGY
C07D413/04
CHEMISTRY; METALLURGY
C07D409/04
CHEMISTRY; METALLURGY
A61P43/00
HUMAN NECESSITIES
A61P9/04
HUMAN NECESSITIES
C07D403/10
CHEMISTRY; METALLURGY
C07D231/20
CHEMISTRY; METALLURGY
C07D417/10
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
C07D405/12
CHEMISTRY; METALLURGY
C07D239/47
CHEMISTRY; METALLURGY
C07D403/12
CHEMISTRY; METALLURGY
C07D487/12
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
C07D405/04
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
C07D401/10
CHEMISTRY; METALLURGY
C07D403/04
CHEMISTRY; METALLURGY
C07D413/12
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
C07D417/04
CHEMISTRY; METALLURGY
International classification
C07D491/107
CHEMISTRY; METALLURGY
C07D487/12
CHEMISTRY; METALLURGY
C07D239/47
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
C07D417/04
CHEMISTRY; METALLURGY
C07D413/04
CHEMISTRY; METALLURGY
C07D409/04
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
C07D409/12
CHEMISTRY; METALLURGY
C07D405/12
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
C07D403/12
CHEMISTRY; METALLURGY
C07D403/04
CHEMISTRY; METALLURGY
C07D231/20
CHEMISTRY; METALLURGY
C07D405/04
CHEMISTRY; METALLURGY
C07D413/12
CHEMISTRY; METALLURGY
Abstract
A compound indicated by formula (I) or a pharmacologically acceptable salt thereof is provided as a compound that can be a therapeutic or prophylactic drug for TRPC6-related diseases, such as nephrotic syndrome, membranous nephropathy, acute renal failure, septicemia, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung injury, heart failure, malignant tumor, and muscular dystrophy. (In the formula, Ar.sup.1, Ar.sup.2, X.sup.1-X.sup.3, R.sup.1, R.sup.3, R.sup.7, R.sup.8, L.sup.1, and L.sup.2 are as defined in the specifications.)
##STR00001##
Claims
1. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. ##STR01503## [wherein, X.sup.1, X.sup.2, and X.sup.3 are independently CH, N, or CY; At least one of X.sup.1, X.sup.2, and X.sup.3 is CH or CY; Y is a halogen atom, or a C.sub.1-3 alkyl group optionally substituted with 1 to 3 halogen atoms; R.sup.1 is a cyano group, a fluorine atom, or a chlorine atom; L.sup.1 is —O—, —S—, —SO—, —CH(R.sup.11)—, —C(═CH.sub.2)—, —CO—, 1,1-cyclopropylidene group, or —NR.sup.12—; R.sup.11 is a hydrogen atom, a hydroxy group, a C.sub.1-3 alkyl group optionally substituted with 1 to 3 halogen atoms, or a C.sub.1-3 alkoxy group optionally substituted with 1 to 2 cyano groups; R.sup.12 is a hydrogen atom, or a C.sub.1-3 alkyl group optionally substituted with 1 to 3 halogen atoms; Ar.sup.1 is a nitrogen-containing heteroaryl ring optionally substituted with 1 to 3 R.sup.2; R.sup.2 is independently a halogen atom, a cyano group, or a C.sub.1-4 alkyl group optionally substituted with 1 to 3 halogen atoms; R.sup.3 is a hydrogen atom, a halogen atom, an amino group, a cyano group, a carboxy group, a (C.sub.1-3 alkylcarbonyl)amino group, a (C.sub.1-6 alkylamino)carbonyl group, a di(C.sub.1-3 alkyl)aminocarbonyl group, a (C.sub.1-3 alkoxy)carbonyl group, a (C.sub.3-8 cycloalkyl)amino group, a (C.sub.3-8 heterocycloalkyl)amino group, a C.sub.3-8 cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, a C.sub.3-8 cycloalkyloxy group optionally substituted with 1 to 6 R.sup.31, a C.sub.1-6 alkyl group optionally substituted with 1 to 6 R.sup.31, a C.sub.1-6 alkoxy group optionally substituted with 1 to 6 R.sup.31, a di(C.sub.1-6 alkyl)amino group optionally substituted with 1 to 6 R.sup.31, a (C.sub.1-6 alkyl)amino group optionally substituted with 1 to 6 R.sup.31, a 3- to 8-membered heterocycloalkyl group optionally substituted with 1 to 4 R.sup.32, an aryl group optionally substituted with 1 to 4 R.sup.32, or a heteroaryl group optionally substituted with 1 to 4 R.sup.32; R.sup.31 is independently a halogen atom, a hydroxy group, a cyclopropylidene group, a C.sub.3-8 cycloalkyl group optionally substituted with 1 to 3 halogen atoms, a 3- to 8-membered heterocycloalkyl group, an oxetanylidene group, a C.sub.1-4 alkoxy group, or a 3- to 8-membered cycloalkyloxy group; R.sup.32 is independently a halogen atom, a hydroxy group, an acetylamino group, a C.sub.1-3 alkyl group optionally substituted with 1 to 3 halogen atoms, a C.sub.1-3 alkoxy group optionally substituted with 1 to 3 halogen atoms, an oxo group, a cyano group, a carboxy group, a (C.sub.1-3 alkoxy)carbonyl group, a (C.sub.1-3 alkyl)sulfonyl group, a carboxamide group, or a benzyloxy group; when R.sup.2 and R.sup.3 are bonded to atoms adjacent to each other on Ar.sup.1, R.sup.2 and R.sup.3 may be bonded via a single bond or —O— to form a 5- to 7-membered ring together with the atoms of Ar.sup.1 to which they are bonded; Ar.sup.2 is an aryl ring optionally substituted with 1 to 4 R.sup.4, or a heteroaryl ring optionally substituted with 1 to 4 R.sup.4; R.sup.4 is independently a halogen atom, a hydroxy group, a carboxy group, a cyano group, a cyanomethyl group, an amino group, a di(C.sub.1-3 alkyl)amino group, a C.sub.1-3 alkyl group optionally substituted with 1 to 3 halogen atoms, or C.sub.1-3 alkoxy group; L.sup.2 is a single bond, a C.sub.1-6 alkylene group optionally substituted with 1 to 3 R.sup.21, a C.sub.3-8 cycloalkylene group optionally substituted with 1 to 3 R.sup.21, or a 4- to 8-membered heterocycloalkylene group optionally substituted with 1 to 3 R.sup.21; L.sup.2 may be bonded at any position to Ar.sup.2 or —NR.sup.7R.sup.8 which is located at either end thereof, One sp.sup.3 carbon atom at any position of L.sup.2 may be replaced by a structure of —O— or —NR.sup.22—; R.sup.21 is independently a halogen atom, a hydroxy group, an oxo group, a cyano group, a 1,1-cyclopropylidene group, an oxetanylidene group, a carboxy group, a carboxamide group, a C.sub.1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, a C.sub.3-8 cycloalkyl group, a C.sub.1-6 alkoxy group, a (C.sub.1-3 alkoxy)C.sub.1-3 alkyl group, a (C.sub.1-3 alkoxy) C.sub.1-3 alkoxy group, a (hydroxy) C.sub.1-6 alkyl group, a (carboxy)C.sub.1-3 alkyl group, a (carboxy)C.sub.1-3 alkoxy group, a (C.sub.1-3 alkoxy)carbonyl group, a (C.sub.1-3 alkoxycarbonyl)C.sub.1-3 alkyl group, a (C.sub.1-6 alkylamino)carbonyl group, a di(C.sub.1-3 alkyl) aminocarbonyl group, a phenyl group optionally substituted with 1 to 3 halogen atoms, a heteroaryl group optionally substituted with 1 to 3 halogen atoms, or a phenoxy group optionally substituted with 1 to 3 halogen atoms; R.sup.22 is a hydrogen atom or a C.sub.1-3 alkyl group; L.sup.2 and R.sup.7 may be bonded via a single bond, —O—, —S(═O).sub.n—, or —NR.sup.23—, to form a 4- to 8-membered ring containing a nitrogen atom to which L.sup.2 and R.sup.7 are bonded, and the ring is optionally substituted with 1 to 3 halogen atoms or 1 to 2 hydroxy groups; n represents an integer from 0 to 2; R.sup.23 is a hydrogen atom or a C.sub.1-3 alkyl group; when L.sup.2 and R.sup.4 are bonded to atoms adjacent to each other on Ar.sup.2, they may be bonded via a single-bond or —O— to form a 5- to 8-membered ring together with the atoms of Ar.sup.2 to which they are bonded; R.sup.7 is a hydrogen atom, or C.sub.1-3 alkyl group; R.sup.7 and an atom of Ar.sup.2 may be bonded via a single bond to form a 5- to 8-membered ring; R.sup.8 is a hydrogen atom, a C.sub.1-6 alkyl group, an adamantyl group, a C.sub.1-6 cycloalkyl group, a cyanomethyl group, an oxetanyl group, a (C.sub.1-3 alkylamino)carbonylmethyl group, a di(C.sub.1-3 alkyl)aminocarbonylmethyl group, a (C.sub.1-3 alkylamino)C.sub.1-8 alkyl group, a di(C.sub.1-3 alkyl)aminoC.sub.1-8 alkyl group, a (hydroxy)C.sub.1-8 alkyl group, a (carboxy)C.sub.1-3 alkyl group, a (C.sub.1-3 alkoxycarbonyl)C.sub.1-3 alkyl group, or a (C.sub.1-3 alkoxy)C.sub.1-3 alkyl group; R.sup.7 and R.sup.8 may be bonded each other via a single bond, —O—, —S(═O).sub.m—, or —NR.sup.41 to form a 3- to 8-membered ring, and further, the ring is optionally substituted with an amino group, an oxo group, or a C.sub.1-3 alkyl group; m represents an integer from 0 to 2; R.sup.41 is a hydrogen atom or a C.sub.1-3 alkyl group.]
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X.sup.1, X.sup.2, and X.sup.3 are CH.
3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is a cyano group.
4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is a fluorine atom.
5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the nitrogen-containing heteroaryl ring of Ar.sup.1 is one of the following groups: ##STR01504##
6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L.sup.1 is —O—.
7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L.sup.1 is —CO—.
8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L.sup.1 is —CH.sub.2—.
9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is a methyl group.
10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is a C.sub.3-8 cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, a C.sub.3-8 cycloalkyloxy group optionally substituted with 1 to 6 R.sup.31, a C.sub.1-6 alkyl group optionally substituted with 1 to 6 R.sup.31, a C.sub.1-6 alkoxy group optionally substituted with 1 to 6 R.sup.31, a di(C.sub.1-6 alkyl)amino group optionally substituted with 1 to 6 R.sup.31, a (C.sub.1-6 alkyl)amino group optionally substituted with 1 to 6 R.sup.31, a 3- to 8-membered heterocycloalkyl group optionally substituted with 1 to 4 R.sup.32, an aryl group optionally substituted with 1 to 4 R.sup.32, or a heteroaryl group optionally substituted with 1 to 4 R.sup.3.
11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.31 is a halogen atom, a cyclopropylidene group, or a C.sub.1-4 alkoxy group.
12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.32 is a halogen atom, a C.sub.1-3 alkyl group optionally substituted with 1 to 3 halogen atoms, a C.sub.1-3 alkoxy group optionally substituted with 1 to 3 halogen atoms, an oxo group or a cyano group.
13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the heteroaryl ring of Ar.sup.2 is ##STR01505##
14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L.sup.2 is a C.sub.1-3 alkylene group optionally substituted with 1 to 2 R.sup.21.
15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L.sup.2 is —CH.sub.2—.
16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L.sup.2 is —CH.sub.2CH.sub.2—.
17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.7 is a hydrogen atom.
18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.8 is a hydrogen atom.
19. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) is selected from the following (1) to (150): (1) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile (2) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile (3) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile (4) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(5-methylpyridin-2-yl)pyrazol-3-yl]oxybenzonitrile (5) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(4-fluorophenyl)-2-methylpyrazol-3-yl]oxybenzonitrile (6) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(3-fluorophenyl)-2-methylpyrazol-3-yl]oxybenzonitrile (7) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile (8) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(2-methylpropyl)pyrazol-3-yl]oxybenzonitrile (9) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (10) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-propylpyrazol-3-yl)oxybenzonitrile (11) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(5-cyclobutyl-2-methylpyrazol-3-yl)oxybenzonitrile (12) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile (13) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-6-pyrrolidin-1-ylpyridin-4-yl)oxybenzonitrile (14) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-6-pyridin-2-ylpyridin-4-yl)oxybenzonitrile (15) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propylpyrazol-3-yl)oxybenzonitrile (16) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (17) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyrrolidin-1-ylpyridin-4-yl)oxybenzonitrile (18) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile (19) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-cyclobutyl-2-methylpyrazol-3-yl)oxybenzonitrile (20) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile (21) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-phenylpyrimidin-4-yl)oxybenzonitrile (22) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(6-phenylpyridazin-4-yl)oxybenzonitrile (23) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile (24) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile (25) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile (26) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile (27) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(2-cyanophenyl)-2-methylpyrimidin-4-yl]oxybenzonitrile (28) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2,5-dimethylpyrazol-3-yl)oxybenzonitrile (29) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile (30) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile (31) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-butyl-2-methylpyrazol-3-yl)oxybenzonitrile (32) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile (33) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile (34) 4-[5-(aminomethyl)pyridin-2-yl]-3-(5-ethyl-2-methylpyrazol-3-yl)oxybenzonitrile (35) 4-[5-(aminomethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile (36) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile (37) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile (38) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-propylpyrazol-3-yl)oxybenzonitrile (39) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (40) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-propylpyrazol-3-yl)oxybenzonitrile (41) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (42) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazol-3-yl)oxybenzonitrile (43) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyridin-2-ylpyridin-4-yl)oxybenzonitrile (44) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-methyl-5-(1,3-thiazol-2-yl)pyrazol-3-yl]oxybenzonitrile (45) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazol-2-yl)pyrazol-3-yl]oxybenzonitrile (46) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-cyclopentyl-2-methylpyrazol-3-yl)oxybenzonitrile (47) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile (48) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(3-fluorophenyl)-2-methylpyrazol-3-yl]oxybenzonitrile (49) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-[(2S)-2-(difluoromethyl)morpholin-4-yl]-6-methylpyridin-4-yl]oxybenzonitrile (50) 4-[5-(aminomethyl)pyridin-2-yl]-3-[2-methyl-5-(oxan-4-yl)pyrazol-3-yl]oxybenzonitrile (51) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-[(2R)-2-(difluoromethyl)morpholin-4-yl]-6-methylpyridin-4-yl]oxybenzonitrile (52) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridin-4-yl]oxybenzonitrile (53) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-piperidin-1-ylpyrimidin-4-yl)oxybenzonitrile (54) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyrrolidin-1-ylpyrimidin-4-yl)oxybenzonitrile (55) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-4-yl]oxybenzonitrile (56) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[2-[2-methoxyethyl(methyl)amino]-6-methylpyridin-4-yl]oxybenzonitrile (57) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(propan-2-ylamino)pyridin-4-yl]oxybenzonitrile (58) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(3R)-3-methylmorpholin-4-yl]pyridin-4-yl]oxybenzonitrile (59) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(3S)-3-methylmorpholin-4-yl]pyridin-4-yl]oxybenzonitrile (60) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazol-3-yl)oxybenzonitrile (61) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-(2-methyl-5-pyrrolidin-1-ylpyrazol-3-yl)oxybenzonitrile (62) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile (63) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazol-2-yl)pyrazol-3-yl]oxybenzonitrile (64) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-pyridin-2-ylpyrimidin-4-yl)oxybenzonitrile (65) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxybenzonitrile (66) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazol-3-yl)oxybenzonitrile (67) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-pyrrolidin-1-ylpyrazol-3-yl)oxybenzonitrile (68) 4-[5-(aminomethyl)pyridin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile (69) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(4-methylpyridin-2-yl)pyrazol-3-yl]oxybenzonitrile (70) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile (71) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile (72) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-6-pyrrolidin-1-ylpyrimidin-4-yl)oxybenzonitrile (73) 4-[5-(aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-pyrrolidin-1-ylpyrimidin-4-yl]oxybenzonitrile (74) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile (75) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile (76) 4-[5-(aminomethyl)pyridin-2-yl]-3-(6-piperidin-1-ylpyridazin-4-yl)oxybenzonitrile (77) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[(5-phenyl-1,3,4-thiadiazol-2-yl)oxy]benzonitrile (78) 4-[5-(2-aminoethyl)pyridin-2-yl]-3-[5-(diethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile (79) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(2-methylpropyl)amino]pyrazol-3-yl]oxybenzonitrile (80) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[cyclopropylmethyl(methyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (81) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(propyl)amino]pyrazol-3-yl]oxybenzonitrile (82) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazol-3-yl)oxybenzonitrile (83) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(propan-2-yl)amino]pyrazol-3-yl]oxybenzonitrile (84) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(methyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (85) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-[methyl(2,2,2-trifluoroethyl)amino]pyrazol-3-yl]oxybenzonitrile (86) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(2S)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]oxybenzonitrile (87) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile (88) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile (89) 4-[5-(aminomethyl)pyridin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile (90) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile (91) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile (92) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-methylpyridin-4-yl]oxybenzonitrile (93) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-methylpyridin-4-yl]oxybenzonitrile (94) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(3-methyl-1-pyridin-2-ylpyrazol-4-yl)oxybenzonitrile (95) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(3-methyl-1-pyridin-2-ylpyrazol-4-yl)oxybenzonitrile (96) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]oxybenzonitrile (97) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[ethyl(propan-2-yl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (98) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-(2-methylpropoxy)pyrimidin-4-yl]oxybenzonitrile (99) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[6-(diethylamino)-2-methylpyrimidin-4-yl]oxybenzonitrile (100) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[methyl(propan-2-yl)amino]pyrimidin-4-yl]oxybenzonitrile (101) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(2R)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]oxybenzonitrile (102) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-6-[(2S)-2-methylpyrrolidin-1-yl]pyrimidin-4-yl]oxybenzonitrile (103) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(3,3,4,5-tetrafluoropyrrolidin-1-yl)pyrazol-3-yl]oxybenzonitrile (104) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (105) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (106) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[2-methyl-5-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrazol-3-yl]oxybenzonitrile (107) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile (108) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(1-pyridin-2-ylpyrazol-4-yl)oxybenzonitrile (109) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[1-(2,2-dimethylpropyl)-3-methylpyrazol-4-yl]oxybenzonitrile (110) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(1,3-thiazol-4-yl)pyrazol-3-yl]oxybenzonitrile (111) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[3-ethyl-1-(2-methylpropyl)pyrazol-4-yl]oxybenzonitrile (112) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[1-(2-methylpropyl)-3-(trifluoromethyl)pyrazol-4-yl]oxybenzonitrile (113) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(4-methyl-1,3-thiazol-5-yl)pyrazol-3-yl]oxybenzonitrile (114) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(5-methyl-1,3-thiazol-4-yl)pyrazol-3-yl]oxybenzonitrile (115) 2-[2-[4-fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine (116) 5-[2-[5-(2-aminoethyl)pyrimidin-2-yl]-5-fluorophenoxy]-N,N-diethyl-1-methylpyrazole-3-amine (117) 2-[6-[4-fluoro-2-(2-methyl-5-morpholin-4-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethanamine (118) 2-[2-[4-fluoro-2-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethanamine (119) 2-[2-[4-fluoro-2-(2-methyl-5-pyrrolidin-1-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethanamine (120) 2-[6-[4-fluoro-2-(2-methyl-5-pyrrolidin-1-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethanamine (121) 5-[2-[5-(2-aminoethyl)pyrimidin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N,1-dimethylpyrazole-3-amine (122) 5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N,1-dimethylpyrazole-3-amine (123) 5-[2-[5-(2-aminoethyl)pyrimidin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N-ethyl-1-methylpyrazole-3-amine (124) 5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N-(2,2-difluoroethyl)-N-ethyl-1-methylpyrazole-3-amine (125) 5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N,N-diethyl-1-methylpyrazole-3-amine (126) 5-[2-[5-(2-aminoethyl)pyridin-2-yl]-5-fluorophenoxy]-N,N,1-trimethylpyrazole-3-amine (127) 2-[6-[4-fluoro-2-[2-methyl-5-(oxan-4-yl)pyrazol-3-yl]oxyphenyl]pyridin-3-yl]ethanamine (128) [2-[4-fluoro-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]methanamine (129) 2-[2-[4-fluoro-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethanamine (130) 2-[6-[4-fluoro-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]ethanamine (131) 2-[6-[2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxy-4-fluorophenyl]pyridin-3-yl]ethanamine (132) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazole-3-carbonyl)benzonitrile (133) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-ethyl-2-methylpyrazole-3-carbonyl)benzonitrile (134) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile (135) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile (136) 4-[5-(aminomethyl)pyridin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile (137) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile (138) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile (139) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile (140) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(1-pyridin-2-ylpyrazole-4-carbonyl)benzonitrile (141) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)benzonitrile (142) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile (143) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(dimethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile (144) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-(diethylamino)-2-methylpyrazole-3-carbonyl]benzonitrile (145) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazole-3-carbonyl)benzonitrile (146) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-piperidin-1-ylpyrazole-3-carbonyl)benzonitrile (147) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrrolidin-1-ylpyrazole-3-carbonyl)benzonitrile (148) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrrolidin-1-ylpyrazole-3-carbonyl)benzonitrile (149) 4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazole-3-carbonyl]benzonitrile (150) 4-[5-(aminomethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazole-3-carbonyl]benzonitrile.
20. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition having TRPC6 channel inhibitory activity, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
22. A therapeutic or prophylactic agent for nephrotic syndrome, membranous nephropathy, acute renal failure, sepsis, chronic renal failure, diabetic nephropathy, pulmonary hypertension, acute lung injury, heart failure, malignant tumor, or muscular dystrophy, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
Description
DESCRIPTION OF EMBODIMENTS
[0220] Terms used alone or in combination in the present description will be explained below. Unless otherwise stated, the explanation of each substituent shall be common to each site. In addition, combinations of substituents and variables are permissible only if such combinations result in chemically stable compounds. When the substituent itself is substituted with two or more groups, these many groups can exist on the same or different carbon atom as long as a stable structure is formed.
[0221] In the present invention, the number situated to the right of carbon atom indicates the number of carbon atoms. For example, “C.sub.1-6” represents having “1 to 6 carbon atoms.” For example, a “C.sub.1-4 alkyl group” means an alkyl group having 1 to 4 carbon atoms. The number of carbon atoms in other groups is handled in the same manner. Incidentally, for example, in an expression such as “(C.sub.1-3 alkyl)carbonyl group”, the number of carbon atoms of C.sub.1-3 represents the number of carbon atoms of the C.sub.1-3 alkyl in the parentheses, and the carbon in the carbonyl is not considered. The number of carbon atoms in a similar representation is calculated in the same manner. Unless otherwise specified, the method of naming a substituent shall be performed by naming from the terminal portion of the functional group and then naming the functional group adjacent to the binding point.
[0222] In the present invention, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
[0223] In the present invention, “alkyl group” means a saturated linear or branched aliphatic hydrocarbon group and includes, for example, a methyl group, a ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1-ethylpropyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a neopentyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl group, a 3,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, a 1-ethylbutyl group, a 2-ethylbutyl group and the like.
[0224] In the present invention, the “cycloalkyl group” means a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, and includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and the like.
[0225] In the present invention, a “heterocycloalkyl group” means a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon ring in which one or more carbon atoms are substituted with a hetero atom selected from O, S and N, and includes, for example, an aziridino group, an azetidino group, an oxetanyl group, a morpholino group, a thiomorpholino group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, an imidazolidinyl group, a pyrazoridinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group and the like.
[0226] In the present invention, the “alkoxy group”, “cycloalkyloxy group” and “heterocycloalkyloxy group” mean an oxy group substituted with an alkyl group, a cycloalkyl group or a heterocycloalkyl group.
[0227] In the present invention, “(alkoxy)alkoxy group” and “(carboxy)alkoxy group” mean an alkoxy group substituted with an alkoxy group or a carboxy group. For example, “(C.sub.1-3 alkoxy)C.sub.1-3 alkoxy group” means an alkoxy group having 1 to 3 carbon atoms substituted with an alkoxy group having 1 to 3 carbon atoms.
[0228] In the present invention, “(alkoxy)carbonyl group” means a carbonyl group substituted with an alkoxy group. For example, “(C.sub.1-3 alkoxy)carbonyl group” means a carbonyl group substituted with an alkoxy group having 1 to 3 carbon atoms.
[0229] In the present invention, “(alkyl) amino group”, “(cycloalkyl) amino group” and “(heterocycloalkyl) amino group” mean an amino group substituted with one alkyl group, cycloalkyl group and heterocycloalkyl group, respectively. For example, “(C.sub.3-8 heterocycloalkyl)amino group” means an amino group substituted with a 3- to 8-membered heterocycloalkyl group.
[0230] In the present invention, “di(alkyl)amino group” means an amino group substituted with two of the same or different alkyl groups. For example, “di(C.sub.1-6 alkyl)amino group” means an amino group substituted with two of the same or different alkyl groups having 1 to 6 carbon atoms.
[0231] In the present invention, “(alkylcarbonyl)amino group” means an amino group substituted with one alkylcarbonyl group. For example, “(C.sub.1-3 alkyl)carbonylamino group” means an amino group substituted with one (C.sub.1-3 alkyl)carbonyl group.
[0232] In the present invention, “(alkylamino)carbonyl group” means a carbonyl group substituted with an alkylamino group. Similarly, “di(alkyl)aminocarbonyl group” means a carbonyl group substituted with a di(alkyl)amino group.
[0233] In the present invention, “alkoxyalkyl group”, “alkoxycarbonylalkyl group”, “di(alkyl)aminoalkyl group”, “hydroxyalkyl group” and “carboxyalkyl group” mean an alkyl group substituted with an alkoxy group, an alkoxycarbonyl group, a di(alkyl)amino group, a hydroxy group and a carboxy group, respectively. Further, “di(alkyl) aminocarbonylmethyl group” means a methyl group substituted with a di(alkyl)aminocarbonyl group.
[0234] In the present invention, “alkylene group” means a divalent group derived by removing one hydrogen atom at an arbitrary position from the “alkyl group”, and includes, for example, a methylene group, an ethylene group, an n-propylene group, an isopropylene group, an n-butylene group, an isobutylene group, an n-pentylene group, an n-hexylene group and the like.
[0235] In the present invention, “cycloalkylene group” means a divalent group derived by removing one hydrogen atom at an arbitrary position from the “cycloalkyl group”, and includes, for example, a cyclopropylene group, a cyclobutylene group, a cyclohexylene group and the like.
[0236] In the present invention, “heterocycloalkylene group” means a divalent group derived by removing one hydrogen atom at an arbitrary position from the “heterocycloalkyl group”.
[0237] In the present invention, “optionally substituted C.sub.1-3 alkyl group” represents an alkyl group having 1 to 3 carbon atoms which may have one or more substituents at substitutable positions. When a plurality of substituents is present, each substituent may be the same or different. Similar expressions have the same meaning.
[0238] In the present invention, “aryl group” means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms, and includes, for example, a phenyl group, a naphthyl group, an indenyl group, an azulenyl group and the like. “Aryl ring” refers to the ring portion of an aryl group.
[0239] In the present invention, “heteroaryl group” means a 5- to 10-membered monocyclic or bicyclic aromatic heterocyclic group having 1 to 5 heteroatoms selected from O, S, and N. Heteroaryl group includes a pyridyl group, a pyrazil group, a pyrimidyl group, a pyridadyl group, a furyl group, a thienyl group, an isooxazolyl group, an isothiazolyl group, a benzofuranyl group, a benzothienyl group, a benzothiazolyl group, a benzoimidazolyl group, a benzoxazolyl group, a pyranyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a triazinyl group, a triazolyl group, a benzoxazolyl group, a benzoisoxazolyl group and the like. “Heteroaryl ring” refers to the ring portion of a heteroaryl group. “Nitrogen-containing heteroaryl ring” means a heteroaryl ring containing one or more Ns on the ring.
[0240] In the formula (I), X.sup.1, X.sup.2, and X.sup.3 are independently CH, N, or CY, and at least one of X.sup.1, X.sup.2, and X.sup.3 is CH or CY. Preferably, X.sup.1, X.sup.2, and X.sup.3 are CH.
[0241] Y is a halogen atom or a methyl group.
[0242] In the formula (I), R.sup.1 is a cyano group, a fluorine atom, or a chlorine atom, and preferably a cyano group or a fluorine atom.
[0243] In the formula (I), linker L.sup.1 is —O—, —S—, —SO—, —CH(R.sup.11)—, —C(═CH.sub.2)—, —CO—, a 1,1-cyclopropylidene group, or —NR.sup.12—, preferably, —O—, —S—, —CH(R.sup.11)—, —CO—, or —NR.sup.12—, and more preferably —O—, —CO—, or —CH.sub.2—.
[0244] R.sup.11 is a hydrogen atom, a hydroxy group, a C.sub.1-3 alkyl group optionally substituted with 1 to 3 halogen atoms, or a C.sub.1-3 alkoxy group optionally substituted with 1 to 2 cyano groups.
[0245] R.sup.12 is a hydrogen atom or a C.sub.1-3 alkyl group optionally substituted with 1 to 3 halogen atoms.
[0246] In the formula (I), Ar.sup.1 is a nitrogen-containing heteroaryl ring optionally substituted with 1 to 3 R.sup.2, and preferably has the following structures.
##STR00005##
[0247] R.sup.2 is independently a halogen atom, a cyano group, or a C.sub.1-4 alkyl group optionally substituted with 1 to 3 halogen atoms, preferably a C.sub.1-4 alkyl group optionally substituted with 1 to 3 halogen atoms, and more preferably a methyl group. When R.sup.2 and R.sup.3 are bonded to atoms adjacent to each other on Ar.sup.1, R.sup.2 and R.sup.3 may be bonded via a single bond or —O— to form a 5- to 7-membered ring together with the atoms on Ar.sup.1 to which they are bonded.
[0248] In the formula (I), R.sup.3 is a hydrogen atom, a halogen atom, an amino group, a cyano group, a carboxy group, a (C.sub.1-3 alkylcarbonyl)amino group, a (C.sub.1-6 alkylamino)carbonyl group, a di(C.sub.1-3 alkyl)aminocarbonyl group, a (C.sub.1-3 alkoxy)carbonyl group, a (C.sub.3-8 cycloalkyl)amino group, a (C.sub.3-8 heterocycloalkyl)amino group, a C.sub.3-8 cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, a C.sub.3-8 cycloalkyloxy group optionally substituted with 1 to 6 R.sup.31, a C.sub.1-6 alkyl group optionally substituted with 1 to 6 R.sup.31, a C.sub.1-6 alkoxy group optionally substituted with 1 to 6 R.sup.31, a di(C.sub.1-6 alkyl)amino group optionally substituted with 1 to 6 R.sup.31, a (C.sub.1-6 alkyl)amino group optionally substituted with 1 to 6 R.sup.31, a 3- to 8-membered heterocycloalkyl group optionally substituted with 1 to 4 R.sup.32, an aryl group optionally substituted with 1 to 4 R.sup.32, or a heteroaryl group optionally substituted with 1 to 4 R.sup.32.
[0249] R.sup.31 is independently a halogen atom, a hydroxy group, a cyclopropylidene group, a C.sub.3-8 cycloalkyl group optionally substituted with 1 to 3 halogen atoms, a 3- to 8-membered heterocycloalkyl group, an oxetanylidene group, a C.sub.1-4 alkoxy group, or a 3- to 8-membered cycloalkyloxy group.
[0250] R.sup.32 is independently a halogen atom, a hydroxy group, an acetylamino group, a C.sub.1-3 alkyl group optionally substituted with 1 to 3 halogen atoms, a C.sub.1-3 alkoxy group optionally substituted with 1 to 3 halogen atoms, an oxo group, a cyano group, a carboxy group, a (C.sub.1-3 alkoxy)carbonyl group, a (C.sub.1-3 alkyl)sulfonyl group, a carboxamide group, or a benzyloxy group.
[0251] In the formula (I), preferred R.sup.3 is a C.sub.3-8 cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, a C.sub.3-8 cycloalkyloxy group optionally substituted with 1 to 6 R.sup.31, a C.sub.1-6 alkyl group optionally substituted with 1 to 6 R.sup.31, a C.sub.1-6 alkoxy group optionally substituted with 1 to 6 R.sup.31, a di(C.sub.1-6 alkyl)amino group optionally substituted with 1 to 6 R.sup.31, a (C.sub.1-6 alkyl)amino group optionally substituted with 1 to 6 R.sup.31, a 3- to 8-membered heterocycloalkyl group optionally substituted with 1 to 4 R.sup.32, an aryl group optionally substituted with 1 to 4 R.sup.32 or a heteroaryl group optionally substituted with 1 to 4 R.sup.32.
[0252] Preferred R.sup.31 is a halogen atom, a cyclopropylidene group, or a C.sub.1-4 alkoxy group.
[0253] Preferred R.sup.32 is a halogen atom, a C.sub.1-3 alkyl group optionally substituted with 1 to 3 halogen atoms, a C.sub.1-3 alkoxy group optionally substituted with 1 to 3 halogen atoms, an oxo group, or a cyano group.
[0254] In the formula (I), Ar.sup.2 is an aryl ring optionally substituted with 1 to 4 R.sup.4, or a heteroaryl ring optionally substituted with 1 to 4 R.sup.4, preferably a heteroaryl ring optionally substituted with 1 to 4 R.sup.4, and more preferably a pyridine ring or a pyrimidine ring having a substitution pattern of the following structure.
##STR00006##
[0255] R.sup.4 is independently a halogen atom, a hydroxy group, a carboxy group, a cyano group, a cyanomethyl group, an amino group, a di(C.sub.1-3 alkyl)amino group, a C.sub.1-3 alkyl group optionally substituted with 1 to 3 halogen atoms, or a C.sub.1-3 alkoxy group.
[0256] In the formula (I), L.sup.2 is a single bond, a C.sub.1-6 alkylene group optionally substituted with 1 to 3 R.sup.21, a C.sub.3-8 cycloalkylene group optionally substituted with 1 to 3 R.sup.21, or a 4- to 8-membered heterocycloalkylene group optionally substituted with 1 to 3 R.sup.21. L.sup.2 may be bonded at any position to Ar.sup.2 or —NR.sup.7R.sup.8 which is located at either end of it. One sp.sup.3 carbon atom at any position of L.sup.2 may be replaced by a structure of —O— or —NR.sup.22—. Preferred L.sup.2 is a C.sub.1-3 alkylene group optionally substituted with 1 to 2 R.sup.21, and more preferably —CH.sub.2— or —CH.sub.2CH.sub.2—.
[0257] R.sup.21 is independently a halogen atom, a hydroxy group, an oxo group, a cyano group, a 1,1-cyclopropylidene group, an oxetanylidene group, a carboxy group, a carboxamide group, a C.sub.1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, a C.sub.3-8 cycloalkyl group, a C.sub.1-6 alkoxy group, a (C.sub.1-3 alkoxy)C.sub.1-3 alkyl group, a (C.sub.1-3 alkoxy)C.sub.1-3 alkoxy group, a (hydroxy) C.sub.1-6 alkyl group, a (carboxy)C.sub.1-3 alkyl group, a (carboxy)C.sub.1-3 alkoxy group, a (C.sub.1-3 alkoxy)carbonyl group, a (C.sub.1-3 alkoxycarbonyl)C.sub.1-3 alkyl group, a (C.sub.1-6 alkylamino)carbonyl group, a di(C.sub.1-3 alkyl) aminocarbonyl group, a phenyl group optionally substituted with 1 to 3 halogen atoms, a heteroaryl group optionally substituted with 1 to 3 halogen atoms, or a phenoxy group optionally substituted with 1 to 3 halogen atoms. Preferred R.sup.21 is a halogen atom, a hydroxy group, an oxo group, an oxetanylidene group, or a C.sub.1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and more preferred is a halogen atom or a hydroxy group.
[0258] R.sup.22 is a hydrogen atom or a C.sub.1-3 alkyl group.
[0259] L.sup.2 and R.sup.7 may be bonded via a single bond, —O—, —S(═O).sub.n—, or —NR.sup.23— to form a 4- to 8-membered ring containing a nitrogen atom to which L.sup.2 and R.sup.7 are bonded, and the ring is optionally substituted with 1 to 3 halogen atoms or 1 to 2 hydroxy groups, wherein n represents an integer from 0 to 2.
[0260] R.sup.23 is a hydrogen atom or a C.sub.1-3 alkyl group.
[0261] When L.sup.2 and R are bonded to atoms adjacent to each other on Ar.sup.2, they may be bonded via a single-bond or —O— to form a 5- to 8-membered ring together with the atoms of Ar.sup.2 to which they are bonded.
[0262] In the formula (I), R.sup.7 is a hydrogen atom or a C.sub.1-3 alkyl group, and more preferably a hydrogen atom. R.sup.7 and an atom of Ar.sup.2 may be bonded via a single bond to form a 5- to 8-membered ring.
[0263] In the formula (I), R.sup.8 is a hydrogen atom, a C.sub.1-6 alkyl group, an adamantyl group, a C.sub.1-6 cycloalkyl group, a cyanomethyl group, an oxetanyl group, a (C.sub.1-3 alkylamino)carbonylmethyl group, a di(C.sub.1-3 alkyl)aminocarbonylmethyl group, a (C.sub.1-3 alkylamino)C.sub.1-8 alkyl group, a di(C.sub.1-3 alkyl)aminoC.sub.1-8 alkyl group, a (hydroxy)C.sub.1-8 alkyl group, a (carboxy)C.sub.1-3 alkyl group, a (C.sub.1-3 alkoxycarbonyl)C.sub.1-3 alkyl group, or a (C.sub.1-3 alkoxy)C.sub.1-3 alkyl group. More preferred R.sup.8 is a hydrogen atom.
[0264] R.sup.7 and R.sup.8 may be bonded each other via a single bond, —O—, —S(═O).sub.m—, or —NR.sup.41— to form a 3- to 8-membered ring, and further, the ring is optionally substituted with an amino group, an oxo group, or a C.sub.1-3 alkyl group, wherein m represents an integer from 0 to 2.
[0265] R.sup.41 is a hydrogen atom or a C.sub.1-3 alkyl group.
[0266] Among the compounds of the present invention, preferable is the following compound group, that is, the compound group in the formula (I),
wherein,
[0267] X.sup.1, X.sup.2, and X.sup.3 are CH,
[0268] R.sup.1 is a cyano group or a fluorine atom,
[0269] linker L.sup.1 is —O—, —CO—, or —CH.sub.2—,
[0270] Ar.sup.1 has the following structure,
##STR00007##
[0271] R.sup.2 is a methyl group,
[0272] R.sup.3 is a C.sub.3-8 cycloalkyl group, a 3- to 8-membered heterocycloalkyloxy group, a C.sub.3-8 cycloalkyloxy group optionally substituted with 1 to 6 R.sup.31, a C.sub.1-6 alkyl group optionally substituted with 1 to 6 R.sup.31, a C.sub.1-6 alkoxy group optionally substituted with 1 to 6 R.sup.31, a di(C.sub.1-6 alkyl)amino group optionally substituted with 1 to 6 R.sup.31, a (C.sub.1-6 alkyl)amino group optionally substituted with 1 to 6 R.sup.31, a 3- to 8-membered heterocycloalkyl group optionally substituted with 1 to 4 R.sup.32, an aryl group optionally substituted with 1 to 4 R.sup.32 or a heteroaryl group optionally substituted with 1 to 4 R.sup.32.
[0273] R.sup.31 is a halogen atom, a cyclopropylidene group, or a C.sub.1-4 alkoxy group, and
[0274] R.sup.32 is a halogen atom, a C.sub.1-3 alkyl group optionally substituted with 1 to 3 halogen atoms, a C.sub.1-3 alkoxy group optionally substituted with 1 to 3 halogen atoms, an oxo group, or a cyano group.
[0275] Ar.sup.2 is a pyridine ring or a pyrimidine ring having a substitution pattern of the following structure.
##STR00008##
[0276] L.sup.2 is —CH.sub.2— or —CH.sub.2CH.sub.2—,
[0277] R.sup.7 is a hydrogen atom, and
[0278] R.sup.8 is a hydrogen atom.
[0279] Specific examples of the compound of the formula (I) include the compounds shown in the following Table 1.
TABLE-US-00001 TABLE 1 Compound number Structural formula Compound name 1
[0280] Among these, preferable compounds are those of compound number 2, 6, 7, 9, 11, 17, 21, 25, 26, 30, 32, 33, 46, 50, 62, 65, 66, 69, 70, 82, 93, 100, 101, 112, 113, 115, 120, 130, 133, 137, 138, 149, 150, 153, 157, 159-162, 164, 170-177, 179, 180, 182, 183, 185-187, 197-199, 202, 204-206, 211-213, 215, 225-233, 237, 238, 241, 246-250, 253, 254, 258, 260-262, 264, 266, 267, 272-278, 285, 287-289, 293-296, 299, 301, 306, 310, 312-315, 317-321, 324-329, 333-338, 341, 344, 346, 348, 360-367, 370-376, 378, 379, 381-384, 388, 390-394, 396, 398, 399, 401-407, 413, 426, 429, 430, 432, 434, 439-441, 444-448, 454, 458, 459, 461, 467, 469-471, 477, 482-485, 493, 496, 498-503, 505-510, 517, 521, 522, 525-527, 529-532, 536, 541-544, 550, 562, 575, 587, 592, 599, 604, 609, 610, 619, 621-629, 634, 637, 642, 644, 651, 652, 655-657, 668, 670-672, 691, 695-697, 701, 702, 704, 706, 708, 711, 714, 715, 718, 724, 734, 735, 737, 742, 743, 748, 754, 758-760, 765, 767-770, 772-775, 786, 787, 795, 799, 801-803, 808-812, 822, 823, 826-828, 832-835, 842, 848-850, 854, 856, 857, 859-861, 866, 872-878, 900, 903-910, 912-916, 932, 935, 937, 945, 948-953, 955, 957, 958, 963, 966, 968, 969, 972, 975, 977-980, 983, 985, 987-992, 996, 1000, 1001, 1010-1014, 1017, 1018, 1025-1033, 1035, 1037, 1042-1049, 1051, 1054, 1057-1063, 1065, 1066, 1071-1080, 1086, 1087, 1097, 1106, 1107, 1110, 1120, 1129-1131, 1135, 1137, 1143-1145, 1147-1156, 1167, 1173, 1184-1187, 1195, 1199, 1202, 1203, 1205-1208, 1210-1212, 1214, 1215, 1217-1219, 1233, 1234, 1237, 1239-1241, 1243, 1244, 1249, 1255, 1258, 1259, 1279, 1280, 1295, 1296, 1299-1302, 1304, 1306, 1312, 1316, 1317, 1322-1325, 1330, 1334, 1335, 1337-1340, 1346, 1348, 1350, 1354, 1357, 1360, 1361, 1366-1369, 1371, 1373, 1380, 1387, 1395, 1398 and 1404, more preferably those of compound number 173, 175, 176, 182, 185, 199, 202, 228-230, 237, 250, 254, 258, 260-262, 264, 272, 274, 275, 277, 285, 288, 289, 293, 295, 299, 310, 317, 319, 324-329, 361-364, 367, 371, 390, 391, 393, 394, 402, 439, 440, 444, 445, 447, 448, 454, 459, 461, 470, 471, 541-543, 592, 599, 609, 621-623, 652, 655-658, 671, 672, 697, 706, 754, 758, 769, 770, 773, 775, 786, 787, 795, 801, 802, 810, 811, 812, 826, 827, 832, 833, 835, 842, 849, 856, 857, 859, 860, 866, 874, 875, 877, 907, 912, 937, 948, 953, 955, 958, 963, 966, 972, 975, 977, 979, 980, 987-991, 1000, 1010, 1012-1014, 1018, 1025-1032, 1037, 1042, 1043, 1051, 1061-1063, 1071-1074.
<General Synthesis Method>
[0281] The compound represented by the formula (I) of the present invention and a pharmaceutically acceptable salt thereof (hereinafter, these are collectively referred to as the compound of the present invention) can be synthesized by a combination of known methods in the art including the synthesis methods described below. Reagents or solvents described as conditions in the chemical formula are merely examples as described in the description. Each substituent may be protected with a suitable protecting group, if necessary, and may be protected or deprotected at an appropriate step. As a suitable protecting group and a removal method of the protecting group, a protecting group for each substituent and a known method, widely used in this field, can be adopted, and are described, for example, in PROTECTIVE GROUPS in ORGANIC SYNTHESIS, THIRD EDITION, John Wiley&Sons, Inc. Further, the intermediate produced in the following synthesis method may be isolated and purified by a method such as column chromatography, recrystallization, or distillation, or may be used in the next step without isolation.
[0282] Typical synthesis methods of the compound of the present invention represented by the general formula (I) will be described below. The synthesis method of the compound of the present invention is not limited to these. The symbols in each formula are defined in the formula (I).
[0283] The compound of the present invention can be produced by several synthesis methods. Hereinafter, a typical synthesis method will be described for each structure of L.sup.1 of the formula (I).
[0284] When L.sup.1 in the formula (I) is —NR.sup.12— in the compound of the present invention, the synthesis can be performed by the method, for example as shown in the following reaction scheme, of constructing a biaryl structure with Ar.sup.2 ring and then bonding with Ar.sup.1 ring. That is, (A-I) is converted to a boronic acid ester (A-II), then converted to (A-III) by a Suzuki-Miyaura coupling reaction, and then (A-IV) is obtained by a Buchwald-Hartwig amination reaction. The target compound can be synthesized by deprotecting this compound. The target compound can be also synthesized by modifying the amino group after deprotection.
[0285] In the following reaction scheme, PG is a protecting group for the amino group (the same applies hereinafter).
##STR01414##
[0286] Step 1: Bis(pinacolato)diboron is preferable as the borylation reagent, and tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. As the base to be used, potassium acetate or the like is preferable. Here, the solvent is not particularly limited and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.
[0287] Step 2: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0288] Step 3: Tris(dibenzylideneacetone)dipalladium, palladium acetate or the like is preferable as the palladium catalyst. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl or the like is preferable as the ligand. The base includes inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like, potassium tert-butoxide, sodium tert-butoxide and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 150° C.
[0289] Step 4: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0290] Step 5: The reaction can be performed using an alkyl halide or the like as a reagent having a leaving group. The base includes organic bases such as triethylamine, N,N-diisopropylethylamine, and the like, and inorganic bases such as potassium carbonate, cesium carbonate, and the like. Tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 120° C., and particularly preferable from 0° C. to room temperature. When X.sup.1, X.sup.2 and X.sup.3 in the formula (I) are CH, the synthesis is performed in the above reaction scheme, while even the compound wherein at least one of X.sup.1, X.sup.2 and X.sup.3 is N or CY (wherein Y is a halogen atom or a methyl group) can be synthesized in the same method.
[0291] When L.sup.1 in the formula (I) is —NR.sup.12— in the compound of the present invention, synthesis can be performed by the method, for example as shown in the following reaction scheme, of reacting with Ar.sup.1 ring having an amino group and constructing the L.sup.1 linker moiety, and then forming a biaryl bond with Ar.sup.2 ring.
##STR01415##
[0292] Step 1: Tris(dibenzylideneacetone)dipalladium, palladium acetate or the like is preferable as the palladium catalyst. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl or the like is preferable as the ligand. The base includes inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like, potassium tert-butoxide, sodium tert-butoxide and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 150° C.
[0293] Step 2: Bis(pinacolato)diboron is preferable as the borylation reagent and tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. The base to be used include potassium acetate and the like. Here, the solvent is not particularly limited, and include, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.
[0294] Step 3: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0295] Step 4: A strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the reagent, and a solvent such as dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.
[0296] When L.sup.1 in the formula (I) is —O— in the compound of the present invention, synthesis can be performed by using the following synthesis methods.
[0297] For example, the synthesis can be performed by the method shown in the following reaction scheme. That is, by obtaining (C-II) bonding with Ar.sup.1 ring via an oxygen atom by nucleophilic aromatic substitution reaction, converting (C-II) into a boron compound, a tin compound, or the like, and by performing the cross-coupling reaction with the corresponding Ar.sup.2 ring compound, the biaryl form (C-IV) can be synthesized. After that, if the amino group is protected, the deprotection thereof can be performed, and if necessary, the target compound can be synthesized by modification of a free amino group. On the other hand, (C-II) can be directly used to perform cross-coupling reaction or the like with Ar.sup.2 ring compounds having suitable reactive substituents without an operation of step 2. Further, substituent R.sup.3 can be converted at an appropriate timing in the following reaction scheme by methods known to those skilled in the art, depending on a target structure.
##STR01416##
[0298] Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or the like is preferable as the base to be used. Preferred solvents include, for example, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from room temperature to 150° C.
[0299] Step 2: The borylation reagent to be used includes, for example, bis(pinacolato)diboron and the like, and the tin reagent includes, for example, hexamethylditin and the like. Tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis (diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. Potassium acetate or the like is preferable as the base for borylation. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.
[0300] Step 3: Tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0301] Step 4: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine or ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0302] Step 5: Alkyl halide or the like can be used for the reaction as a reaction reagent having a leaving group. The base includes, for example, organic bases such as triethylamine, N,N-diisopropylethylamine and the like, and inorganic bases such as potassium carbonate, cesium carbonate and the like. Tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 120° C.
[0303] When L.sup.1 in the formula (I) is —O— in the compound of the present invention, the target compound can be also synthesized using the intermediate pyrazole (D-I) as shown in the following reaction scheme. That is, after reacting (D-I) with a reagent having a leaving group and modifying the amino group to obtain (D-II), the target compound can be synthesized by the same method as described above.
##STR01417##
(Wherein, R.sup.D1 and R.sup.D2 are substituents that form —NR.sup.D1R.sup.D2 to satisfy R.sup.3 in the formula (I).)
[0304] Step 1: Reaction reagent having a leaving group includes, for example, alkyl halides and alkyl triflate and the like. Organic bases such as triethylamine and N,N-diisopropylethylamine, inorganic bases such as potassium carbonate and cesium carbonate or the like is preferable as the base. If necessary, an additive such as potassium iodide may be added. 1,4-Dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or the like is preferable as the solvent. The reaction temperature is preferably from room temperature to 150° C., and particularly preferably from 50° C. to 120° C.
[0305] Step 2: The borylation reagent includes, for example, bis(pinacolato)diboron and the like. Tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. Potassium acetate or the like is preferable as the base to be used. Here, the solvent is not particularly limited and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.
[0306] Step 3: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0307] Step 4: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0308] When L.sup.1 in the formula (I) is —O— in the compound of the present invention, the target compound can be also synthesized, as shown in the following reaction scheme, by constructing a biaryl bond with Ar.sup.2 ring, then converting the amino group in (E-III) to a bromine atom, and introducing R.sup.3 substituent by, for example, cross-coupling reaction.
##STR01418## ##STR01419##
[0309] Step 1: Bis(pinacolato)diboron is preferable as the borylation reagent, and tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. Potassium acetate or the like is preferable as the base to be used. Here, the solvent is not particularly limited and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.
[0310] Step 2: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0311] Step 3: Isoamyl nitrite is preferable as the reagent to be used, and copper bromide or the like is preferable as the bromination reagent. Preferred solvents include acetonitrile, toluene, and the like. The reaction temperature is preferably from 0° C. to 50° C.
[0312] Step 4: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0313] Step 5: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0314] When L.sup.1 in the formula (I) is —O— in the compound of the present invention, the target compound can be also synthesized, as shown in the following reaction scheme, by performing an aromatic nucleophilic substitution reaction using a raw material (F-I) having a nitro group, then converting the functional group of the nitro group, followed by a biaryl bond formation with Ar.sup.2 ring.
##STR01420## ##STR01421##
[0315] Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or the like is preferable as the base to be used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from room temperature to 100° C.
[0316] Step 2: Iron, zinc, or the like is preferable as the metal reagent to be used, and is preferably used in combination with a reagent such as ammonium chloride, acetic acid, or the like. Preferred solvents include organic solvents such as ethanol, methanol, tetrahydrofuran, and the like, mixed solvents obtained by adding water thereto, and the like. The reaction temperature is preferably from room temperature to 100° C.
[0317] Step 3: Isoamyl nitrite is preferable as the reagent to be used, and copper bromide or the like is preferable as the bromination reagent. Preferred solvents include acetonitrile, toluene, and the like. The reaction temperature is preferably from 0° C. to 50° C.
[0318] Step 4: Bis(pinacolato)diboron is preferable as the borylation reagent, and tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. Potassium acetate or the like is preferable as the base to be used. Here, the solvent is not particularly limited and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.
[0319] Step 5: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0320] Step 6: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0321] When L.sup.1 in the formula (I) is —O— in the compound of the present invention, the target compound can be also synthesized, using the intermediate pyrazole (G-IV) obtained through the cyclization reaction, as shown in the following reaction scheme. That is, after reacting a reagent having a leaving group with pyrazole (G-IV) obtained in three steps from the starting material (G-1) to introduce R.sup.3 substituent, the target compound can be synthesized by the same method as described above.
##STR01422## ##STR01423##
[0322] Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or the like is preferable as the base to be used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from room temperature to 100° C.
[0323] Step 2: This reaction is preferably performed without solvent. The reaction temperature is preferably from 50° C. to 100° C.
[0324] Step 3: The reaction is performed using hydrazine monohydrate as a reagent. Acetic acid or the like is preferable as the solvent. The reaction temperature is preferably from 70° C. to 120° C.
[0325] Step 4: The reaction reagent having a leaving group includes, for example, alkyl halides, aryl halides, and the like. Organic bases such as triethylamine and N,N-diisopropylethylamine, and the like, inorganic bases such as potassium carbonate and cesium carbonate, and the like are preferable as the base. Here, the solvent is not particularly limited and includes, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from room temperature to 150° C.
[0326] Step 5: Bis(pinacolato)diboron is preferable as the borylation reagent, and tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. Potassium acetate or the like is preferable as the base to be used. Here, the solvent is not particularly limited and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.
[0327] Step 6: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0328] Step 7: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0329] When L.sup.1 in the formula (I) is —O— in the compound of the present invention, an aromatic nucleophilic substitution reaction or the like can be also performed using a substrate having a leaving group in Ar.sup.1 ring as shown in the following reaction scheme. (H-IV) can be synthesized by reacting (H-II) directly with Ar.sup.2 ring compounds having suitable reactive substituents without an operation of step 2. Substituent R.sup.3 (e.g., a halogen atom) can be converted to a target structure at an appropriate timing in the following reaction scheme by a method known to those skilled in the art, depending on a target structure.
##STR01424##
[0330] Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or the like is preferable as the base to be used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from room temperature to 150° C.
[0331] Step 2: Bis(pinacolato)diboron is preferable as the borylation reagent, and tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. Potassium acetate or the like is preferable as the base to be used. Here, the solvent is not particularly limited and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, a mixed solvent thereof, and the like. The reaction temperature is preferably 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.
[0332] Step 3: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0333] Step 4: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0334] Step 5: The reaction reagent having a leaving group includes, for example, alkyl halides and aryl triflate, and the like. The base includes, for example, organic bases such as triethylamine, N,N-diisopropylethylamine and the like, and inorganic bases such as potassium carbonate, cesium carbonate and the like. Tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 120° C.
[0335] When L.sup.1 in the formula (I) is —O— in the compound of the present invention, the target compound can be synthesized by modifying the compound (I-I) having an alcohol as shown in the following reaction scheme.
##STR01425##
(Wherein, R.sup.1 is a substituent which forms —OR.sup.1 to satisfy R.sup.21 in the formula (I).)
[0336] Step 1: The reaction reagent having a leaving group includes, for example, alkyl halides and alkyl triflate and the like. Sodium hydride, potassium carbonate, cesium carbonate or the like is preferable as the base. Here, the solvent is not particularly limited and includes, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 120° C.
[0337] Step 2: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and a solvent such as dichloromethane, tetrahydrofuran, ethyl acetate and the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.
[0338] When L.sup.1 in the formula (I) is —O— in the compound of the present invention, after converting the alcohol in (J-I) to a leaving group to introduce an alkoxy group as shown in the following reaction scheme, the target compound can also be synthesized by the same method as described above.
##STR01426##
(Wherein,
[0339] Ms is a methanesulfonyl group;
R.sup.J is a substituent which forms —OR.sup.J to satisfy R.sup.21 in the formula (I).)
[0340] Step 1: As the mesylation reagent, methanesulfonyl chloride can be used to perform the reaction. Triethylamine, potassium carbonate, cesium carbonate or the like is preferable as the base. The solvent is not particularly limited in this reaction and includes, for example, organic solvents such as tetrahydrofuran, dichloromethane, and the like. This reaction is performed preferably at 0° C. to 60° C., and particularly preferably at 0° C. to room temperature.
[0341] Step 2: An alcohol (R.sup.J—OH) corresponding to the target compound can be used to perform the reaction. As preferred bases, inorganic bases such as sodium hydride, potassium carbonate, cesium carbonate, and the like can be used. The solvent in this reaction includes, for example, organic solvents such as tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and the like, or a mixed solvent thereof. This reaction is performed preferably at room temperature to 150° C., and particularly preferably at room temperature to 100° C.
[0342] Step 3: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and a solvent such as dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.
[0343] When L.sup.1 in the formula (I) is —O— in the compound of the present invention, after introducing the target substituent via tosylhydrazone (K-II) as described in the following reaction scheme, synthesis can be performed by the same method as described above.
##STR01427##
(Wherein,
[0344] Ts is a p-toluenesulfonyl group;
R.sup.K is a C.sub.1-3 alkoxy-C.sub.1-3 alkyl group, a hydroxy(C.sub.1-6 alkyl) group, a hydroxycarbonyl-(C.sub.1-3 alkyl) group, a (C.sub.1-3 alkoxy)carbonyl-(C.sub.1-3 alkyl) group, or a phenyl group optionally substituted with 1 to 3 halogen atoms.)
[0345] Step 1: Tosylhydrazine is used as a reagent in this reaction. Preferred solvents include toluene, methanol, ethanol, and the like. The reaction temperature is preferably from room temperature to 120° C., and particularly preferably from 50° C. to 120° C.
[0346] Step 2: Potassium carbonate, cesium carbonate, cesium fluoride or the like is preferable as the base to be used. Here, the solvent is not particularly limited and includes, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane and the like. The reaction temperature is preferably from room temperature to 150° C., and particularly preferably from 80° C. to 120° C.
[0347] Step 3: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and a solvent such as dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.
[0348] When L.sup.1 in the formula (I) is —O— in the compound of the present invention, synthesis can be performed also by a method described in the following reaction scheme. That is, the target compound can be synthesized by the following steps: the raw material (L-I) is reacted with paramethoxybenzyl alcohol to obtain compound (L-II); subsequently, the biaryl compound (L-IV) is obtained through functional group conversion of the bromine atom in (L-II), and then the PMB group is deprotected to lead to phenol (L-V); after linking this phenol (L-V) with Ar.sup.1 compound having a reactive substituent by an appropriate reaction, an amino group is deprotected.
##STR01428##
[0349] Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or the like is preferable as the base to be used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from room temperature to 100° C.
[0350] Step 2: Bis(pinacolato)diboron is preferable as the borylation reagent to be used, and tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. Potassium acetate or the like is preferable as the base to be used. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.
[0351] Step 3: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0352] Step 4: As a removal method of the paramethoxybenzyl group, a known method can be adopted. For example, strong acids include such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, and the like, and the solvent is not particularly limited and includes, for example, tetrahydrofuran, 1,4-dioxane, dichloromethane and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0353] Step 5: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or the like is preferable as the base to be used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from room temperature to 150° C.
[0354] Step 6: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0355] When L.sup.1 in the formula (I) is —O— in the compound of the present invention, synthesis can be performed also by a method described in the following reaction scheme. That is, the target compound can be synthesized by the following steps: 2,4-dihydroxy-6-methylpyridine is reacted with the raw material (M-I) to obtain compound (M-II); subsequently, (M-II) is triflated, and then the target R.sup.3 substituents is introduced thereto to give (M-IV); subsequently, the biaryl compound (M-VI) is obtained through functional group conversion of the bromine atom in (M-IV), and then the amino group is deprotected.
##STR01429## ##STR01430##
[0356] Step 1: Potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide or the like is preferable as the base to be used. Preferred solvents include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from room temperature to 160° C.
[0357] Step 2: The triflation agent to be used includes trifluoromethanesulfonic anhydride (Tf.sub.2O) and the like, and pyridine, triethylamine, N,N-diisopropylethylamine or the like is preferable as the base. Preferred solvents include tetrahydrofuran, dichloromethane, 1,2-dichloroethane and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0358] Step 3: As a method for introducing R.sup.3 substituent, a known method commonly used in the art can be adopted. For example, in the case of introducing R.sup.3 substituent using boronic acid derivatives, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0359] Further, for example, in the case of reacting with an alcohol or an amine corresponding to R.sup.3 substituent, preferred base includes, for example, organic bases such as triethylamine and N,N-diisopropylethylamine, an inorganic base such as potassium carbonate and cesium carbonate and the like. Here, the solvent is not particularly limited and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from room temperature to 150° C.
[0360] Step 4: Bis(pinacolato)diboron is preferable as the borylation reagent to be used, and tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. The base to be used includes potassium acetate and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.
[0361] Step 5: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0362] Step 6: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0363] When L.sup.1 in the formula (I) is —CO— in the compound of the present invention, the synthesis can be performed by using the following synthesis methods.
[0364] For example, the synthesis can be performed by the method shown in the following reaction scheme. That is, an Ar.sup.1 ring compound having an aldehyde is reacted with an anionic reagent prepared from the compound (N-I) to synthesize a corresponding alcohol (N-II), which is further oxidized to give a ketone (N-III). Subsequently, a biaryl bond can be formed to synthesize (N-V). Further, R.sup.3 substituent can be converted at an appropriate timing in the following reaction scheme by a method known to those skilled in the art, depending on a target structure.
##STR01431##
[0365] Step 1: The reagent for preparing an anion by reacting with (N-I) includes, for example, n-butyllithium, isopropylmagnesium chloride-lithium chloride complex solution, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like. The reaction temperature is preferably from −78° C. to 50° C., and particularly preferably from −40° C. to room temperature.
[0366] Step 2: Dess-Martin periodinane, 2-iodoxybenzoic acid, pyridinium chlorochromate or the like is preferable as the oxidizing agent to be used. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0367] Step 3: The borylation reagent to be used includes bis(pinacolato)diboron and the like, and the tin reagent includes hexamethylditin and the like. Tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. The base to be used for borylation includes potassium acetate and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.
[0368] Step 4: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0369] Step 5: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0370] When L.sup.1 in the formula (I) is —CO— in the compound of the present invention, the target compound can be synthesized also by utilizing the intermediate pyrazole (O-II) as shown in the following reaction scheme. That is, after the amino group in (O-II) obtained by reducing (O-I) was modified with a reagent having a leaving group to obtain (O-III), the target compound can be synthesized by the same method as described above.
##STR01432## ##STR01433##
(Wherein, R.sup.O1, R.sup.O2 are substituents that form —NR.sup.O1R.sup.O2 which may be included in R.sup.3 of formula (I).)
[0371] Step 1: Iron, zinc or the like is preferable as the metal reagent to be used, and the metal reagent is preferably used in combination with a reagent such as ammonium chloride and acetic acid. Preferred solvents include organic solvents such as ethanol, methanol, tetrahydrofuran and the like, mixed solvents obtained by adding water thereto, and the like. The reaction temperature is preferably from room temperature to 100° C.
[0372] Step 2: The reaction reagent having a leaving group includes, for example, alkyl halides, alkyl triflate and the like. Organic bases such as triethylamine, N,N-diisopropylethylamine, and the like and inorganic bases such as potassium carbonate, cesium carbonate and the like are preferable as the base. 1,4-Dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or the like is preferable as the solvent. The reaction temperature is preferably from room temperature to 150° C.
[0373] Step 3: The borylation reagent to be used includes bis(pinacolato)diboron, and the tin reagent includes hexamethylditin and the like. The preferred palladium catalyst includes, for example, tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride and the like. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. The base used for borylation includes, for example, potassium acetate and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.
[0374] Step 4: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0375] Step 5: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0376] When L.sup.1 in the formula (I) is —CO— in the compound of the present invention, as shown in the following reaction scheme, after reacting the anionic reagent prepared from Ar.sup.1 ring with aldehyde (P-I) to obtain a corresponding alcohol (P-II), the synthesis can be performed by the same method as described above.
##STR01434##
(Wherein, X.sup.P is H or a halogen atom.)
[0377] Step 1: The reagent for preparing an anion in the reaction system includes, for example, n-butyllithium, isopropylmagnesium chloride-lithium chloride complex solution and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like. The reaction temperature is preferably from −78° C. to 50° C., and particularly preferably from −40° C. to room temperature.
[0378] Step 2: Dess-Martin periodinane, 2-iodoxybenzoic acid, pyridinium chlorochromate or the like is preferable as the oxidizing agent to be used. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0379] Step 3: The borylation reagent to be used includes, for example, bis(pinacolato)diboron, and the tin reagent includes, for example, hexamethylditin, and the like. Tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the preferred palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. The base to be used for borylation includes, for example, potassium acetate and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.
[0380] Step 4: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0381] Step 5: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. The solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0382] When L.sup.1 in the formula (I) is —CO— in the compound of the present invention, after synthesizing the corresponding ketone (Q-II) using Ar.sup.1 ring having the Weinreb amide (Q-II) as shown in the following reaction scheme, the synthesis can be performed by the same method as described above.
##STR01435##
[0383] Step 1: The reagent for preparing an anion in the reaction system includes, for example, n-butyllithium, isopropylmagnesium chloride-lithium chloride complex solution, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like. The reaction temperature is preferably from −78° C. to 50° C., and particularly preferably from −40° C. to room temperature.
[0384] Step 2: The borylation reagent to be used includes, for example, bis(pinacolato)diboron, and the tin reagent includes, for example, hexamethylditin and the like. Tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. The base to be used for borylation includes, for example, potassium acetate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.
[0385] Step 3: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0386] Step 4: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0387] When L.sup.1 in the formula (I) is —CH.sub.2— in the compound of the present invention, synthesis can be performed by using the following synthesis methods.
[0388] For example, synthesis can be performed as shown in the following reaction scheme. That is, after bonding Ar.sup.1 ring compound (R-II) having a reactive substituent such as a boronic acid derivative with benzyl bromide (R-I) by a cross-coupling reaction, by converting (R-III) to a boron compound, tin compound, or the like, then performing the cross-coupling reaction with the corresponding Ar.sup.2 ring compounds, a biaryl bond can be formed to complete the synthesis. On the other hand, (R-III) can be directly used to perform cross-coupling reaction or the like with Ar.sup.2 ring compounds having suitable reactive substituents without an operation of step 2.
##STR01436##
[0389] Step 1: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0390] Step 2: The borylation reagent to be used includes, for example, bis(pinacolato)diboron, and the tin reagent includes, for example, hexamethylditin and the like. Tris(dibenzylideneacetone)dipalladium, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like is preferable as the palladium catalyst. If necessary, tricyclohexylphosphine, tricyclohexylphosphonium tetrafluoroborate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or the like is used as the ligand. The base to be used for borylation includes, for example, potassium acetate and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly from preferably 70° C. to 120° C.
[0391] Step 3: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0392] Step 4: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid is preferable, and when the protecting group is phthalimide, hydrazine or ethylenediamine is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0393] When L.sup.1 in the formula (I) is —CH.sub.2— in the compound of the present invention, as shown in the following reaction scheme, after obtaining (S-II) by bonding to Ar.sup.1 ring through an alkylation reaction using a nitrogen atom in the Ar.sup.1 ring, the synthesis can be performed by the same method as described above.
##STR01437##
[0394] Step 1: Triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate or the like is preferable as the base. Here, the solvent is not particularly limited and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from room temperature to 120° C., and particularly preferably from 40° C. to 100° C.
[0395] Step 2: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0396] Step 3: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0397] When L.sup.1 in the formula (I) is —CH.sub.2— in the compound of the present invention, as shown in the following reaction scheme, a target compound in which amino group or alkoxy group is introduced can be synthesized using the aldehyde of intermediate (T-I) as a foothold.
##STR01438##
(Wherein, R.sup.T1, R.sup.T2, R.sup.T3 are H atoms or C.sub.1-6 alkyl groups.)
[0398] Step 1: A reductive amination reaction is performed using an amine suitable for the target compound. The imine reducing agent includes, for example, sodium triacetoxyborohydride, sodium cyanoborohydride, and the like. Preferred solvents include, for example, toluene, dichloromethane, dichloroethane, and the like. The reaction temperature is preferably from room temperature to 80° C.
[0399] Step 2: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like, is preferable as the strong acid to be used, and dichloromethane, tetrahydrofuran, ethyl acetate or the like, is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.
[0400] Step 3: The reducing agent to be used includes, for example, sodium borohydride, lithium borohydride, and the like. Preferred solvents include tetrahydrofuran, methanol, a mixed solvent thereof, and the like. The reaction temperature is preferably from 0° C. to room temperature.
[0401] Step 4: Alkyl halide, alkyl triflate or the like is used as a reagent having a leaving group. The base includes, for example, sodium hydride, potassium carbonate, cesium carbonate. Tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 80° C.
[0402] Step 5: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.
[0403] When L.sup.1 in the formula (I) is —CH.sub.2— in the compound of the present invention, as shown in the following reaction scheme, a target compound having an amide group can be synthesized via functional group conversion of the ester group in intermediate (U-I).
##STR01439##
(Wherein, R.sup.U is a C.sub.1-6 alkyl group.)
[0404] Step 1: The base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and the like, metal alkoxides such as sodium ethoxide, sodium methoxide, and the like, a solution thereof diluted with water, and the like. Here, the solvent is not particularly limited, and includes, for example, tetrahydrofuran, methanol, ethanol, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 0° C. to 60° C.
[0405] Step 2: The condensing agent to be used includes, for example, HATU, HOBt, HOAt, EDCI, and the like. The reaction is performed in the presence of no base or a base such as triethylamine, N,N-diisopropylethylamine, and the like. Tetrahydrofuran, dichloromethane, N,N-dimethylformamide or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 100° C.
[0406] Step 3: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and a solvent such as dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.
[0407] When L in the formula (I) is —CH.sub.2— in the compound of the present invention, the synthesis can also be performed by the method shown in the following reaction scheme. That is, after obtaining triazole (V-IV) by reacting the acetylene compound (V-III) with the (V-II) into which an azide group is introduced, the synthesis can be performed by the same method as described above.
##STR01440##
[0408] Step 1: This reaction is a reaction of introducing an azido group using sodium azide. The solvent includes, for example, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from room temperature to 100° C.
[0409] Step 2: This reaction is a reaction of performing triazole ring synthesis using an alkyne compound corresponding to the target compound. Copper(I) iodide, copper(I) bromide or the like is preferable as the metal reagent, and if necessary, a ligand such as tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) is also added. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from room temperature to 80° C.
[0410] Step 3: Preferred palladium catalyst includes, for example, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, and the like, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0411] Step 4: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. The solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0412] When L.sup.1 in the formula (I) is —CH.sub.2— in the compound of the present invention, the synthesis can be performed also by the method shown in the following reaction scheme. That is, after obtaining (W-V) by a coupling reaction between boronic acid (W-I) and nitropyrazole ring (W-II), reducing a nitro group, and modifying an amino group, the target compound can be synthesized by the same method as described above.
##STR01441## ##STR01442##
(Wherein, R.sup.W1 and R.sup.W2 are substituents which form —NR.sup.W1R.sup.W2 which may be included in R.sup.3 of the formula (I).)
[0413] Step 1: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like is preferable as the palladium catalyst and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0414] Step 2: Iron, zinc, or the like is preferable as the metal reagent to be used, and is preferably used in combination with a reagent such as ammonium chloride, acetic acid, and the like. Preferred solvents include, for example, organic solvents such as ethanol, methanol and tetrahydrofuran, and mixed solvents obtained by adding water thereto, and the like. The reaction temperature is preferably from room temperature to 100° C.
[0415] Step 3: The reaction reagent having a leaving group includes, for example, alkyl halides, alkyl triflate, and the like. Organic bases such as triethylamine, N,N-diisopropylethylamine, or the like, or inorganic bases such as potassium carbonate, cesium carbonate, or the like is preferable as the base. 1,4-Dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or the like is preferable as the solvent. The reaction temperature is preferably from room temperature to 150° C.
[0416] Step 4: The borylation reagent includes, for example, bis(pinacolato)diboron, and the like. Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium acetate, XPhos-Pd-G2, or the like is preferable as the catalyst. If necessary, the ligand such as tricyclohexylphosphine, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, or the like can be used. Potassium acetate or the like is preferable as the base. Preferred solvents include, for example, 1,4-dioxane, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 70° C. to 120° C.
[0417] Step 5: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0418] Step 6: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0419] When L.sup.1 in the formula (I) is —CHMe-, —C(═CH.sub.2)—, or a 1,1-cyclopropropylidene group in the compound of the present invention, synthesis can be performed as shown in the following reaction scheme. That is, after reacting tosylhydrazone (X-III) with an Ar.sup.1 ring compound having a halogen atom to obtain an exoolefin (X-IV), the target compound can be synthesized by reducing or cyclopropanating the olefin, and then deprotecting. The compound represented by formula (I) in which L.sup.1 is —C(═CH.sub.2)— can be synthesized by deprotecting (X-IV).
##STR01443##
[0420] Step 1: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0421] Step 2: This reaction is a reaction of forming tosylhydrazone using tosylhydrazine as a reagent. Preferred solvents include toluene, methanol, ethanol, and the like. The reaction temperature is preferably from room temperature to 120° C.
[0422] Step 3: This reaction is a reaction of synthesizing an exoolefin by performing a coupling reaction between tosylhydrazone and aryl halide. Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium acetate, or the like is preferable as the catalyst. If necessary, a ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-(dicyclohexylphosphino)-2′,4′,6′-tri-isopropyl-1,1′-biphenyl, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, or the like can be used. Preferred bases include cesium carbonate, lithium tert-butoxide, tripotassium phosphate. Preferred solvents include 1,4-dioxane, toluene, fluorobenzene, and the like. The reaction temperature is preferably from 50° C. to 150° C.
[0423] Step 4: This reaction is a reaction of reducing an olefin by combining a metal reagent such as palladium carbon (Pd/C) and a hydrogen source such as hydrogen gas. Ethanol, methanol, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 100° C.
[0424] Step 5: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.
[0425] Step 6: This reaction is a reaction of converting an olefin to cyclopropane using trimethylsulfoxonium iodide. Preferred bases include, for example, sodium hydride, potassium tert-butoxide, and the like. Dimethyl sulfoxide, tetrahydrofuran or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 100° C.
[0426] Step 7: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and dichloromethane, tetrahydrofuran, ethyl acetate, or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.
[0427] When L in the formula (I) is —CH(R.sup.11)— in the compound of the present invention, synthesis can be performed by using the following methods.
[0428] For example, synthesis can be performed as shown in the following reaction scheme. That is, after reducing the ketone of (Y-I) prepared by the synthesis method described above, the target compound can be synthesized by deprotecting the amino group. It is also possible to modify the hydroxy group in intermediate (Y-II) by an alkylation reaction or the like.
##STR01444##
(Wherein, R.sup.Y is a substituent which forms —OR.sup.Y which satisfies R.sup.11 in the formula (I).)
[0429] Step 1: The reducing reagent includes, for example, sodium borohydride, lithium borohydride, and the like. Preferred solvents include, for example, tetrahydrofuran, methanol, ethanol, a mixed solvent thereof, and the like. The reaction temperature is preferably from 0° C. to 50° C.
[0430] Step 2: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0431] Step 3: Alkyl halide, alkyl triflate or the like is used as the reagent having a leaving group. The base includes, for example, sodium hydride, potassium carbonate, cesium carbonate, and the like. Tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 80° C.
[0432] Step 4: As a removal method of the protecting group, a known method widely used in this field can be adopted. For example, when the protecting group is a Boc group, a strong acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable, and when the protecting group is phthalimide, hydrazine, ethylenediamine or the like is preferable. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0433] When L.sup.1 in the formula (I) is —CH(R.sup.11)— in the compound of the present invention, the synthesis can be performed also as shown in the following reaction scheme. That is, after introducing an ethynyl group on the raw material aldehyde (Z-I), cyclization reaction is performed using (Z-IV) to obtain target isoxazole (Z-V) having R.sup.3 substituent. After modifying the hydroxy group of (Z-V) by an alkylation reaction or the like, the target compound can be synthesized by deprotecting the amino group.
##STR01445##
(Wherein, R.sup.Z is a substituent which forms —OR.sup.Z which satisfies R.sup.11 in the formula (I).)
[0434] Step 1: This reaction is an addition reaction of ethynylmagnesium bromide (Z-II) to aldehyde (Z-I). Tetrahydrofuran, dichloromethane, or the like is preferable as the solvent to be used. The reaction temperature is preferably from −78° C. to room temperature.
[0435] Step 2: This reaction is a reaction of constructing an isoxazole ring using an oxime reagent (Z-IV) corresponding to the target compound. Potassium carbonate, sodium carbonate, cesium carbonate, or the like is preferable as the base, and 1,4-dioxane, toluene, or the like is preferable as the solvent. The reaction temperature is preferably from 50° C. to 120° C.
[0436] Step 3: Alkyl halide, alkyl triflate or the like is used as the reagent having a leaving group. The base includes, for example, sodium hydride, potassium carbonate, cesium carbonate, and the like. Tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 80° C.
[0437] Step 4: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, a mixed solvent thereof, and the like. The reaction temperature is preferably from 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0438] Step 5: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.
[0439] When L.sup.1 in the formula (I) is —S— or —SO— in the compound of the present invention, the synthesis can be performed using the following methods.
[0440] For example, synthesis can be performed as shown in the following reaction scheme. That is, after converting the intermediate (A′-I) obtained by the above-mentioned synthesis method into triflate (A′-II), a thiol side chain is introduced by a coupling reaction, and this compound (A′-III) is treated with a suitable base and subjected to an aromatic nucleophilic substitution reaction to be bonded with Ar.sup.1 ring. If necessary, after this, the target compound can be synthesized by introducing the target side chain substituent using a halogen atom in Ar.sup.1 as a foothold. If the Ar.sup.1 compound used in step 3 has already been modified with R.sup.3, the operation in step 4 can be omitted.
##STR01446##
[0441] Step 1: The triflation agent to be used include trifluoromethanesulfonic anhydride (Tf.sub.2O), and the like and pyridine, triethylamine, N,N-diisopropylethylamine or the like is preferable as the base. Preferred solvents include, for example, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, and the like. The reaction temperature is preferably from −20° C. to 50° C.
[0442] Step 2: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium acetate, or the like is preferable as the catalyst. If necessary, the ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-(dicyclohexylphosphino)-2′,4′,6′-tri-isopropyl-1,1′-biphenyl and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, or the like can be used. Preferred bases include, for example, N,N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate, and the like. The solvent includes, for example, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, and the like. The reaction temperature is preferably from 50° C. to 150° C.
[0443] Step 3: Potassium carbonate, cesium carbonate, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) or the like is preferable as the base. Preferred solvents include, for example, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 150° C.
[0444] Step 4: For introduction of the R.sup.3 substituent, a known method commonly used in the art can be adopted. For example, when the R.sup.3 substituent is introduced using boronic acid derivatives, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride or the like is preferable as the palladium catalyst, and the base includes, for example, inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. Here, the solvent is not particularly limited, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water, mixed solvent thereof, and the like. The reaction temperature is preferably form 50° C. to 150° C., and particularly preferably from 80° C. to 120° C.
[0445] Further, for example, when an alcohol or an amine corresponding to the R.sup.3 substituent is reacted, preferred bases include, for example, organic bases such as triethylamine, N,N-diisopropylethylamine, and the like, and inorganic bases such as potassium carbonate, cesium carbonate, and the like. Here, the solvent is not particularly limited, and includes, for example, ethers such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, and the like, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from room temperature to 150° C.
[0446] Step 5: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably 0° C. to room temperature.
[0447] When L.sup.1 in the formula (I) is —S— in the compound of the present invention, synthesis can be performed also as shown in the following reaction scheme. That is, since an aromatic nucleophilic substitution reaction can be used as a method for bonding with an Ar.sup.2 ring such as pyrazole or the like, after the formation of a biaryl bond, the synthesis can be performed in the same manner as in the above scheme.
##STR01447##
[0448] Step 1: Triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate, or the like is preferable as the base to be used. Preferred solvents include, for example, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from room temperature to 150° C.
[0449] Step 2: Tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium, palladium acetate, or the like is preferable as the catalyst. If necessary, the ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-(dicyclohexylphosphino)-2′,4′,6′-tri-isopropyl-1,1′-biphenyl, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, or the like can be used. Preferred bases include N,N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate, and the like. The solvent includes, for example, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, and the like. The reaction temperature is preferably from 50° C. to 150° C.
[0450] Step 3: Potassium carbonate, cesium carbonate, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) or the like is preferable as the base. Preferred solvents include, for example, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 150° C.
[0451] Step 4: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and dichloromethane, tetrahydrofuran, ethyl acetate or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.
[0452] When L.sup.1 in the formula (I) is —SO— in the compound of the present invention, as shown in the following reaction scheme, the target compound can be synthesized by oxidizing sulfide (C′-I) to convert to sulfoxide (C′-II), and then performing deprotection.
##STR01448##
[0453] Step 1: The oxidizing agent to be used includes, for example, 3-chloroperbenzoic acid and the like. The solvent includes, for example, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and the like. The reaction temperature is preferably from 0° C. to 100° C.
[0454] Step 2: Trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like is preferable as the strong acid to be used, and dichloromethane, tetrahydrofuran, ethyl acetate, or the like is preferable as the solvent. The reaction temperature is preferably from 0° C. to 50° C., and particularly preferably from 0° C. to room temperature.
[0455] Pharmaceutically acceptable salts of the compounds represented by formula (I) are not particularly limited as long as they are pharmaceutically acceptable salts, and include, for example, salts with inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, and the like, salts with organic acids such as maleic acid, fumaric acid, citric acid, malic acid, tartaric acid, lactic acid, succinic acid, benzoic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, formic acid, and the like, salts with amino acids such as glycine, lysine, arginine, histidine, ornithine, glutamic acid, aspartic acid, and the like, salts with alkali metals such as sodium, potassium, lithium, and the like, salts with alkaline earth metals such as calcium, magnesium, and the like, salts with metals such as aluminum, zinc, iron, and the like, salts with organic oniums such as tetramethylammonium, choline, and the like, and salts with organic bases such as ammonia, propanediamine, pyrrolidine, piperidine, pyridine, ethanolamine, N,N-dimethylethanolamine, 4-hydroxypiperidine, t-octylamine, dibenzylamine, morpholine, glucosamine, phenylglycyl alkyl ester, ethylenediamine, N-methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, N-benzylphenylamine, piperazine, tris(hydroxymethyl)aminomethane, and the like.
[0456] Further, the compounds represented by formula (I) or pharmaceutically acceptable salts thereof include various hydrates and solvates. The solvents of the solvates include, though not particularly limited, for example, methanol, ethanol, 1-propanol, 2-propanol, butanol, t-butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, t-butylmethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, benzene, toluene, N,N-dimethylformamide, dimethyl sulfoxide, and the like.
[0457] The medically acceptable salts of the compound represented by the formula (I) may be appropriately produced based on conventional knowledge in the art.
[0458] The compounds represented by formula (I) or pharmaceutically acceptable salts thereof include stereoisomers, racemates and all possible optically active substances thereof.
[0459] The compound represented by formula (I) of the present invention or the pharmaceutically acceptable salt thereof can be used in any formulation such as solid preparation, semi-solid preparation and liquid preparation, or any application such as oral and non-oral preparations (injections, percutaneous absorption agents, eye drops, suppositories, transnasal absorption agents, inhalants, and the like).
[0460] The pharmaceutical composition containing a compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof is prepared using additives usually used for formulation. The additives for a solid preparation includes, for example, an excipient such as lactose, saccharose, glucose, corn starch, potatostarch, crystalline cellulose, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminometasilicate, calcium hydrogen phosphate, and the like, a binder such as crystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose sodium, polyvinyl pyrrolidone, and the like, a disintegrating agent such as starch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, croscarmellose sodium and sodium carboxy methyl starch, and the like, a lubricant such as talc, stearic acids, and the like, a coating agent such as hydroxymethylpropylcellulose, hydroxypropylmethylcellulose phthalate, ethylcellulose, and the like, and a coloring agent; the additives for a semisolid preparation include, for example, a substrate such as white petrolatum and the like; and the additives for a liquid preparation includes, for example, a solvent such as ethanol, and the like, a solubilizing agent such as ethanol, and the like, a preservative such as para-hydroxybenzoate, and the like, a isotonizing agent such as glucose, and the like, a buffer such as citric acid, and the like, an antioxidant such as L-ascorbic acid, and the like, a chelating agent such as EDTA, and the like, and a suspending agent and an emulsifying agent such as polysorbate 80 and the like.
[0461] The therapeutically effective amount of the active ingredient in the therapeutic agent or prophylactic agent in the present invention, which depends on the route of administration, the age and sex of the patient, and the severity of the disease, is usually of the order of 0.1 to 1000 mg/day, and the frequency of administration is usually one to three times/day to one to seven times/week. The preparation is preferably prepared so as to satisfy such conditions.
[0462] In the present invention, the term “prevention” means to prevent incidence or onset of diseases in an individual who is not affected by diseases or has not yet developed diseases and the term “treatment” means to cure, suppress, or remedy diseases or symptoms in an individual who has already been affected by diseases or has developed diseases.
EXAMPLES
[0463] Hereinafter, the present invention will be described in greater detail by way of working examples, but not limited thereto. Abbreviations in the present invention are as follows:
BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
DBU=1,8-diazabicyclo[5.4.0]-7-undecene
DMA=N,N-dimethylacetamide
DMF=N,N-dimethylformamide
[0464] DMSO=dimethyl sulfoxide
HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
NMP=1-methyl-2-pyrrolidone
TFA=trifluoroacetic acid
THF=tetrahydrofuran
[0465] The structure of the novel compound isolated was identified by .sup.1H-NMR and/or mass spectrometry using a single quadrupole instrumentation equipped with an electron spray source, or by other suitable analytical methods.
[0466] For the measurement of .sup.1H-NMR spectrum (400 MHz, DMSO-d.sub.6, CDCl.sub.3, or CD.sub.3OD), the chemical shift (δ: ppm) and coupling constant (J: Hz) are shown. As for the result of mass spectrometry, the measured value observed as M.sup.++H, that is, the value obtained by adding the mass of a proton (H.sup.+) to the molecular mass of a compound (M) is shown. The abbreviations used are as follows:
s=singlet, d=doublet, t=triplet, q=quartet, quin=quintet, brs=broad singlet, m=multiplet.
Reference Example 1
tert-Butyl (2-hydroxy-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)ethyl)carbamate
[0467] ##STR01449##
[0468] tert-Butyl (2-(4-bromophenyl)-2-hydroxyethyl)carbamate (503 mg, 1.59 mmol) was dissolved in 1,4-dioxane (10 mL), then to the solution, bis(pinacolato)diboron (404 mg, 1.59 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (61 mg, 0.084 mmol) and potassium acetate (469 mg, 4.78 mmol) were added, and the mixture was stirred at 90° C. for 15 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound (412 mg, 71%).
[0469] .sup.1H-NMR (CDCl.sub.3) δ: 7.81 (2H, d, J=7.8 Hz), 7.38 (2H, d, J=7.8 Hz), 4.90-4.86 (2H, m), 3.53-3.45 (1H, m)), 3.27-3.20 (1H, m), 1.45 (9H, s), 1.34 (12H, s).
Reference Example 2
tert-Butyl N-[3,3-difluoro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl]carbamate
[0470] ##STR01450##
Step 1: 1-Bromo-4-(1,1-difluoro-3-nitropropan-2-yl)benzene
[0471] 1-Bromo-4-[(E)-2-nitroethenyl]benzene (1 g) was dissolved in acetonitrile (4.4 mL), the solution was cooled to 0° C., then to the solution, (bromodifluoromethyl)trimethylsilane (1.03 mL), triphenylphosphine (1.38 g), and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.06 mL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to −20° C., then to the mixture, chlorotrimethylsilane (0.11 mL) and methanol (0.89 mL) were added, and the mixture was stirred at the same temperature for 15 minutes and then heated to room temperature. Water (4 mL) and pyridine (0.42 mL) were added to the reaction mixture, and the mixture was stirred at 80° C. for 1.5 hours, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (785 mg).
[0472] .sup.1H-NMR (CDCl.sub.3) δ: 7.54 (2H, d, J=9.0 Hz), 7.18 (2H, d, J=8.2 Hz), 6.01 (1H, td, J=55.3, 2.7 Hz), 4.94 (1H, dd, J=13.7, 5.5 Hz), 4.83 (1H, ddd, J=71.4, 13.7, 7.3 Hz), 4.06-3.93 (OH, m).
Step, 2: tert-Butyl N-[2-(4-bromophenyl)-3,3-difluoropropyl]carbamate
[0473] 1-Bromo-4-(1,1-difluoro-3-nitropropan-2-yl)benzene (785 mg) was suspended in a mixed solvent of ethanol (7 mL) and water (2 mL), then to the suspension, iron powder (470 mg) and ammonium chloride (450 mg) were added, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, the mother liquor was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. This crude product was dissolved in dichloromethane (14 mL), then to the solution, di-tert-butyl dicarbonate (612 mg) and N,N-diisopropylethylamine (0.39 mL) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (667 mg).
[0474] MS: m/z 294.1 (M-tBu+H).sup.+.
Step 3: tert-Butyl N-[3,3-difluoro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl]carbamate
[0475] tert-Butyl N-[2-(4-bromophenyl)-3,3-difluoropropyl]carbamate (667 mg) was dissolved in 1,4-dioxane (19 mL), then to the solution, bis (pinacolato)diboron (629 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (139 mg) and potassium acetate (561 mg) were added, and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure to obtain a crude product of the title compound.
Reference Example 3
tert-Butyl N-[2-(6-chloropyridin-3-yl)-2-hydroxyethyl]carbamate
[0476] ##STR01451##
Step 1: 1-(6-Chloropyridin-3-yl)-2-nitroethanol
[0477] Nitromethane (3 mL) and triethylamine (3 mL) were added to 6-chloropyridin-3-carbaldehyde (1 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.
Step 2: tert-Butyl N-[2-(6-chloropyridin-3-yl)-2-hydroxyethyl]carbamate
[0478] The crude product obtained in Step 1 was dissolved in THF (10 mL), then to the solution, zinc powder (2.31 g) and acetic acid (3 mL) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite and then concentrated under reduced pressure. This crude product was dissolved in dichloromethane (14 mL), then to the solution, di-tert-butyl dicarbonate (1.54 g) and N,N-diisopropylethylamine (2 mL) were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the title compound (651 mg).
[0479] MS: m/z 273.2 (M+H).sup.+.
Reference Example 4
tert-Butyl N-[2-(2-chloropyrimidin-5-yl)-2-hydroxyethyl]carbamate
[0480] ##STR01452##
Step 1: 1-(2-Chloropyrimidin-5-yl)-2-nitroethanol
[0481] Nitromethane (1 mL) and triethylamine (2 mL) were added to 2-chloropyrimidine-5-carbaldehyde (428 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.
Step 2: tert-Butyl N-[2-(2-chloropyrimidin-5-yl)-2-hydroxyethyl]carbamate
[0482] The crude product obtained in Step 1 was dissolved in THF (5 mL), then to the solution, zinc powder (981 mg) and acetic acid (0.86 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite and then concentrated under reduced pressure. This crude product was dissolved in dichloromethane (5 mL), then to the solution, di-tert-butyl dicarbonate (1.31 g) and N,N-diisopropylethylamine (1.6 mL) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound (208 mg).
[0483] MS: m/z 274.1 (M+H).sup.+.
[0484] .sup.1H-NMR (CDCl.sub.3) δ: 8.64 (2H, s), 4.96-4.94 (2H, m), 3.55-3.51 (1H, m), 3.34-3.27 (1H, m), 1.45 (9H, s).
Reference Example 5
tert-Butyl N-[2-(5-chloropyrazin-2-yl)-2-hydroxyethyl]carbamate
[0485] ##STR01453##
Step 1: 1-(5-Chloropyrazin-2-yl)-2-nitroethanol
[0486] Nitromethane (1 mL) and triethylamine (1 mL) were added to 5-chloropyrazine-2-carbaldehyde (826 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.
Step 2: tert-Butyl N-[2-(5-chloropyrazin-2-yl)-2-hydroxyethyl]carbamate
[0487] The crude product obtained in Step 1 was dissolved in THF (5 mL), the solution was cooled to 0° C., then to the solution, di-tert-butyl dicarbonate (1.06 g), zinc powder (792 mg) and acetic acid (0.7 mL) were added, and then the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound (57.5 mg).
[0488] MS: m/z 218.1 (M-tBu+H).sup.−.
Reference Example 6
tert-Butyl 3-(6-chloropyridin-3-yl)-3-fluoroazetidine-1-carboxylate
[0489] ##STR01454##
Step 1: tert-Butyl 3-(6-chloropyridin-3-yl)-3-hydroxyazetidine-1-carboxylate
[0490] 5-Bromo-2-chloropyridine (385 mg) was dissolved in THF (10 mL), the solution was cooled to −78° C., and to the solution, n-butyllithium (1.2 mL) was added dropwise. After stirring at the same temperature for 1 hour, then to the solution, a solution (2 mL) of 1-(tert-butoxycarbonyl)-3-azetidinone (342 mg) in THF was added, and the temperature of the solution was raised to room temperature over 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (209 mg).
[0491] MS: m/z 285.0 (M+H).sup.+.
Step 2: tert-Butyl 3-(6-chloropyridin-3-yl)-3-fluoroazetidine-1-carboxylate
[0492] tert-Butyl 3-(6-chloropyridin-3-yl)-3-hydroxyazetidine-1-carboxylate (100 mg) was dissolved in dichloromethane (1.8 mL), the solution was cool to −78° C., then to the solution bis(2-methoxyethyl)aminosulfur trifluoride (0.078 mL) was added, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was heated to room temperature, then to the solution, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solution was concentrated under reduced pressure to obtain a crude product of the title compound (40 mg).
[0493] MS: m/z 287.0 (M+H).sup.+.
Reference Example 7
N-[3-[(6-Chloropyridin-3-yl)methyl]oxetan-3-yl]-2-methylpropane-2-sulfinamide
[0494] ##STR01455##
[0495] 2-Chloro-5-iodopyridine (479 mg) was dissolved in THF (10 mL) and to the solution, isopropylmagnesium bromide (1 M solution in THF, 2.0 mL) was added dropwise at 0° C. After stirring the solution at the same temperature for 1 hour, then to the solution, copper(I) iodide (38.1 mg) was added, and the mixture was cooled to −30° C. A solution (2 mL) of 1-tert-butylsulfinyl-5-oxa-1-azaspiro[2.3]hexane (189 mg) in THF was added dropwise to the reaction mixture, the mixture was heated to room temperature, and the mixture was stirred for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound (108 mg).
[0496] MS: m/z 303.1 (M+H).sup.+.
[0497] .sup.1H-NMR (CDCl.sub.3) δ: 8.33 (1H, s), 7.71 (1H, d, J=7.3 Hz), 7.30 (1H, d, J=8.2 Hz), 4.83 (1H, d, J=6.4 Hz), 4.66-4.56 (3H, m), 3.59 (1H, s), 3.41 (2H, q, J=14.5 Hz), 1.22 (9H, s).
Reference Example 8
tert-Butyl N-[(2R)-2-(6-chloropyridin-3-yl)-2-fluoroethyl]carbamate
[0498] ##STR01456##
[0499] tert-Butyl N-[(2S)-2-(6-chloropyridin-3-yl)-2-hydroxyethyl]carbamate (164 mg) obtained by chiral separation of the racemic compound of Reference Example 3 was added to dichloromethane (3 mL), and to the mixture, bis(2-methoxyethyl)aminosulfur trifluoride (0.13 mL) was added dropwise at 0° C. After stirring the mixture at the same temperature for 1 hour, the reaction mixture was directly purified by silica gel column chromatography to obtain the title compound (37.5 mg).
[0500] MS: m/z 275.1 (M+H).sup.+.
Reference Example 9
tert-Butyl N-[(2R)-2-(2-chloropyrimidin-5-yl)-2-fluoroethyl]carbamate
[0501] ##STR01457##
[0502] tert-Butyl N-[(2S)-2-(2-chloropyrimidin-5-yl)-2-hydroxyethyl]carbamate (547 mg) obtained by chiral separation of the racemic compound of Example 4 was dissolved in dichloromethane (10 mL), and to the solution, bis(2-methoxyethyl)aminosulfur trifluoride (0.44 mL) was added dropwise at 0° C. After stirring the mixture at the same temperature for 1 hour, the reaction mixture was directly purified by silica gel column chromatography to obtain the title compound (83.3 mg).
[0503] MS: m/z 276.2 (M+H).sup.+.
Reference Example 10
2-[2-(6-Chloropyridin-3-yl)-2,2-difluoroethyl]isoindole-1,3-dione
[0504] ##STR01458##
Step 1: Ethyl 2-(6-chloropyridin-3-yl)-2,2-difluoroacetate
[0505] 2-Chloro-5-iodopyridine (2 g) was dissolved in DMSO (33 mL), then to the solution, ethyl bromodifluoroacetate (1.87 g) and copper powder (1.33 g) were added, and the mixture was stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, an aqueous disodium hydrogen phosphate solution was added to the solution, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (958 mg).
[0506] MS: m/z 236.1 (M+H).sup.+.
Step 2: 2-(6-Chloropyridin-3-yl)-2,2-difluoroethanol
[0507] Ethyl 2-(6-chloropyridin-3-yl)-2,2-difluoroacetate (958 mg) was dissolved in methanol (20 mL), the solution was cooled to 0° C., and to the solution, sodium borohydride (308 mg) was added. The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (493 mg).
[0508] MS: m/z 194.1 (M+H).sup.+.
Step 3: 2-[2-(6-Chloropyridin-3-yl)-2,2-difluoroethyl]isoindole-1,3-dione
[0509] 2-(6-Chloropyridin-3-yl)-2,2-difluoroethanol (493 mg), phthalimide (487 mg) and triphenylphosphine (1 g) were suspended in THF (5 mL), then to the suspension, diisopropyl azodicarboxylate (0.74 mL) was added dropwise, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound (395 mg).
[0510] MS: m/z 323.1 (M+H).sup.+.
Example 1
4-[4-(2-Aminoacetyl)phenyl]-3-[(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)amino]benzonitrile (Compound No. 4)
[0511] ##STR01459##
Step 1: 3-Amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzonitrile
[0512] 3-Amino-4-chlorobenzonitrile (700 mg, 4.59 mmol) was dissolved in 1,4-dioxane (23 mL), then to the solution, bis(pinacolato)diboron (1.28 g, 5.05 mmol), tris(dibenzylideneacetone)dipalladium (126 mg, 0.14 mmol), tricyclohexylphosphonium tetrafluoroborate (101 mg, 0.28 mmol) and potassium acetate (1.35 g, 13.8 mmol) were added, and the mixture was stirred at 100° C. for 15 hours. The reaction mixture was cooled to room temperature and filtered through Celite, then the mother liquor was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (541 mg, 48%).
[0513] .sup.1H-NMR (CDCl.sub.3) δ: 7.65 (1H, d, J=7.3 Hz), 6.89 (1H, d, J=7.8 Hz), 6.81 (1H, s), 4.93 (2H, brs), 1.35 (12H, s).
Step 2: tert-Butyl (2-(2′-amino-4′-cyano-[1,1′-biphenyl]-4-yl)-2-oxoethyl)carbamate
[0514] To a solution of 3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzonitrile (245 mg, 1.00 mmol) in toluene/water (=4/1, 5 mL), tert-butyl N-[2-(4-bromophenyl)-2-oxo-ethyl]carbamate (315 mg, 1.00 mmol), tetrakis(triphenylphosphine)palladium (57.9 mg, 0.050 mmol) and potassium carbonate (416 mg, 3.00 mmol) were added, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite. Water was added to the mother liquor, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (280 mg, 80%).
[0515] MS: m/z 296.1 (M-tBu+H).sup.+.
Step 3: tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxoethyl)carbamate
[0516] tert-Butyl (2-(2′-amino-4′-cyano-[1,1′-biphenyl]-4-yl)-2-oxoethyl)carbamate (50.8 mg, 0.145 mmol) was dissolved in toluene (2 mL), then to the solution, 4-(6-chloro-2-methylpyrimidin-4-yl)morpholine (30.9 mg, 0.145 mmol), tris(dibenzylideneacetone)dipalladium (6.6 mg, 0.072 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.4 mg, 0.015 mmol) and sodium tert-butoxide (27.8 mg, 0.289 mmol) were added, and the mixture was stirred at 150° C. under microwave irradiation for 1.5 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
Step 4: 4-[4-(2-Aminoacetyl)phenyl]-3-[(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)amino]benzonitrile
[0517] Dichloromethane (2 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 3, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (2.09 mg).
Exact MS: 428.2
[0518] Obs. MS (M+H)+: 429.4
Example 2
4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]benzonitrile (Compound No. 6)
[0519] ##STR01460##
Step 1: 4-Chloro-3-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]benzonitrile
[0520] 1,4-Dioxane (6.7 mL) was added to 3-bromo-4-chlorobenzonitrile (578 mg, 2.67 mmol) and N,2-dimethyl-5-phenylpyrazole-3-amine (500 mg, 2.67 mmol), and to the mixture, tris(dibenzylideneacetone)dipalladium (122 mg, 0.134 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (232 mg, 0.401 mmol), and cesium carbonate (2.18 g, 6.68 mmol) were added, and the mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature, and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (512 mg, 59%).
[0521] MS: m/z 323.1 (M+H).sup.+.
Step 2: 3-[Methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
[0522] 4-Chloro-3-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]benzonitrile (256 mg, 0.792 mmol) was dissolved in 1,4-dioxane (2.6 mL), then to the solution, bis(pinacolato)diboron (302 mg, 1.19 mmol), bis(tricyclohexylphosphine)palladium dichloride (58.5 mg, 0.0792 mmol), and potassium acetate (233 mg, 2.38 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, and filtered through Celite, and then the solution was concentrated under reduced pressure. The obtained crude product was used in the next reaction without further purification.
[0523] MS: m/z 415.0 (M+H).sup.+.
Step 3: tert-Butyl N-[2-[2-[4-cyano-2-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]phenyl]pyrimidin-5-yl]ethyl]carbamate
[0524] The crude product obtained in Step 2 was dissolved in 1,4-dioxane (2.6 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (50.0 mg, 0.194 mmol), tetrakis(triphenylphosphine)palladium (22.4 mg, 0.0194 mmol), potassium carbonate (80.4 mg, 0.582 mmol) and water (0.1 mL) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, ethyl acetate and water were added to the mixture, and the mixture was extracted. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0525] MS: m/z 510.0 (M+H).sup.+.
Step 4: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[methyl-(2-methyl-5-phenylpyrazol-3-yl)amino]benzonitrile
[0526] Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 3, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (48.3 mg).
[0527] Exact MS: 409.2
[0528] Obs. MS (M+H).sup.+: 410.4
Example 3
4-[4-(2-Aminoethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 7)
[0529] ##STR01461##
Step 1: 4-Bromo-3-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)benzonitrile
[0530] 4-Bromo-3-hydroxybenzonitrile (1.19 g, 6.0 mmol) was dissolved in DMF (10 mL), then to the solution, 4-(6-chloro-2-methylpyrimidin-4-yl)morpholine (1.28 g, 6.0 mmol) and potassium carbonate (2.49 g, 18 mmol) were added to the mixture, and the mixture was stirred at 150° C. for 23 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified on a silica gel column to obtain the target compound (1.23 g, 54%).
Step 2: tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yloxy)-[1,1′-biphenyl]-4-ylethyl)carbamate
[0531] 4-Bromo-3-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)benzonitrile (110 mg, 0.29 mmol) was dissolved in toluene/water (=4/1) mixed solution (2.5 mL), then to the solution, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenethylcarbamate (132 mg, 0.38 mmol), tetrakistriphenylphosphine palladium (16.9 mg, 0.015 mmol) and potassium carbonate (121 mg, 0.88 mmol) were added, and the mixture was stirred at 110° C. for 10 hours. The reaction mixture was cooled to room temperature, water was added to the solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (140 mg, 93%).
[0532] MS: m/z 516.3 (M+H).sup.+.
Step 3: 4-[4-(2-Aminoethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile
[0533] tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)ethyl)carbamate (140 mg, 0.27 mmol) was dissolved in 1,4-dioxane (2 mL), then to the solution, a 4 M (=mol/L) hydrochloric acid/1,4-dioxane solution (2 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the crude product was dissolved in a mixed solution of ethyl acetate (50 mL) and 2 M hydrochloric acid (20 mL), and the target compound was back-extracted into an aqueous layer. Then, methanol/dichloromethane (=1/4) mixed solution (50 mL) and a 2 M aqueous sodium hydroxide solution (22 mL) were added to the mixture and the target compound was extracted into an organic phase. The organic layer was dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (84.1 mg).
[0534] Exact MS: 415.2
[0535] Obs. MS (M+H).sup.+: 416.2
Example 4
4-[4-(2-Amino-1-methoxyethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 11)
[0536] ##STR01462##
Step 1: tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)-2-methoxyethyl)carbamate
[0537] tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)-2-hydroxyethyl)carbamate (29 mg, 0.055 mmol) synthesized by the same method as in Example 3 was dissolved in DMF (1 mL), then to the solution, sodium hydride (2.7 mg) was added, and the mixture was stirred at room temperature for 5 minutes. Iodomethane (4.2 μL, 0.066 mmol) was added to this reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, the mixture was stirred, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
Step 2: 4-[4-(2-Amino-1-methoxyethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile
[0538] The crude product obtained in Step 1 was dissolved in dichloromethane (2 mL), then to the solution, TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (8.7 mg).
[0539] Exact MS: 445.2
[0540] Obs. MS (M+H).sup.+: 446.2
Example 5
4-[4-(2-Amino-1-phenoxyethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 13)
[0541] ##STR01463##
Step 1: 2-((tert-Butoxycarbonyl)amino)-1-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)ethylmethanesulfonate
[0542] tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)-2-hydroxyethyl)carbamate (60.9 g, 0.115 mmol) synthesized by the same method as in Example 3 was dissolved in THF (2 mL), then to the solution, triethylamine (48 μL, 0.34 mmol) and methanesulfonyl chloride (11 μL, 0.14 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0543] MS: m/z 610.3 (M+H).sup.+.
Step 2: tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)-2-phenoxyethyl)carbamate
[0544] The crude product obtained in Step 1 was dissolved in DMF (2 mL), then to the solution, phenol (10.8 mg, 0.115 mmol) and potassium carbonate (47.5 mg, 0.34 mmol) were added, and the mixture was stirred at 100° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0545] MS: m/z 608.3 (M+H).sup.+.
Step 3: 4-[4-(2-Amino-1-phenoxyethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile
[0546] The crude product obtained in Step 2 was dissolved in dichloromethane (2 mL), then to the solution, TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (5.5 mg).
[0547] Exact MS: 507.2
[0548] Obs. MS (M+H).sup.+: 508.2
Example 6
4-[4-(2-Aminoethyl)phenyl]-3-(2-methyl-6-piperidin-1-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 17)
[0549] ##STR01464##
Step 1: tert-Butyl (2-(4′-cyano-2′-hydroxy-[1,1′-biphenyl]-4-yl)ethyl)carbamate
[0550] To a solution (50 mL) of 4-bromo-3-hydroxybenzonitrile (8.6 g, 43.4 mmol) in toluene/water (=9/1), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenethylcarbamate (22.7 g, 65.1 mmol), tetrakistriphenylphosphine palladium (5.0 g, 4.34 mmol), and potassium carbonate (11.9 g, 86.1 mmol) were added, and the mixture was stirred at 90° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite, the mother liquor was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (5.0 g, 35%).
Step 2: tert-Butyl (2-(2′-((6-chloro-2-methylpyrimidin-4-yl)oxy)-4′-cyano-[1,1′-biphenyl]-4-yl)ethyl)carbamate
[0551] To a solution of tert-butyl (2-(4′-cyano-2′-hydroxy-[1,1′-biphenyl]-4-yl)ethyl)carbamate (2.8 g, 8.3 mmol) in DMF (15 mL), 4,6-dichloro-2-methylpyrimidine (1.35 g, 8.28 mmol) and cesium carbonate (5.38 g, 16.6 mmol) were added, and the mixture was stirred overnight at room temperature. Water and ethyl acetate were added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.8 g, 46%).
[0552] MS: m/z 464.8 (M+H).sup.+.
Step 3: tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-(piperidin-1-ylpyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)ethyl)carbamate
[0553] tert-Butyl (2-(2′-((6-chloro-2-methylpyrimidin-4-yl)oxy)-4′-cyano-[1,1′-biphenyl]-4-yl)ethyl)carbamate (100 mg, 0.216 mmol) was dissolved in DMF (3 mL), then to the solution, piperidine (0.043 mL, 0.432 mmol) and cesium carbonate (140 mg, 0.431 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, the mixture was extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0554] MS: m/z 514.3 (M+H).sup.+.
Step 4: 4-[4-(2-Aminoethyl)phenyl]-3-(2-methyl-6-piperidin-1-ylpyrimidin-4-yl)oxybenzonitrile
[0555] TFA (0.5 mL) was added to a solution of the crude product obtained in Step 3 in dichloromethane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (57.2 mg).
[0556] Exact MS: 413.2
[0557] Obs. MS (M+H).sup.+: 414.0
[0558] .sup.1H-NMR (DMSO-d.sub.6) δ: 7.73 (1H, d, J=8.4 Hz), 7.68 (1H, s), 7.61 (1H, d, J=8.0 Hz), 7.35 (2H, d, J=7.6 Hz), 7.21 (2H, d, J=7.6 Hz), 6.03 (1H, s), 3.52 (4H, bs), 2.75-2.78 (2H, m), 2.64 (2H, s), 2.15 (3H, s), 1.59 (2H, s), 1.45 (4H, bs).
Example 7
4-[4-(2-Aminoethyl)phenyl]-3-[6-(2-cyanophenyl)-2-methylpyrimidin-4-yl]oxybenzonitrile (Compound No. 21)
[0559] ##STR01465##
Step 1: tert-Butyl (2-(4′-cyano-2′-((6-(2-cyanophenyl)-2-methylpyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)ethyl)carbamate
[0560] An intermediate of tert-butyl (2-(2′-((6-chloro-2-methylpyrimidin-4-yl)oxy)-4′-cyano-[1,1′-biphenyl]-4-yl)ethyl)carbamate (100 mg, 0.215 mmol) obtained in Example 6 was dissolved in 1,4-dioxane (2 mL), then to the solution, potassium carbonate (59 mg, 0.43 mmol), 2-cyanophenylboronic acid (47 mg, 0.32 mmol), and tetrakistriphenylphosphine palladium (20 mg, 0.017 mmol) were added, and the mixture was stirred overnight at 100° C. under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through Celite, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
Step 2: 4-[4-(2-Aminoethyl)phenyl]-3-[6-(2-cyanophenyl)-2-methylpyrimidin-4-yl]oxybenzonitrile
[0561] The crude product obtained in Step 1 was dissolved in dichloromethane (2 mL), then to the solution, TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (15.4 mg).
[0562] Exact MS: 431.2
[0563] Obs. MS (M+H).sup.+: 431.9
[0564] .sup.1H-NMR (DMSO-d.sub.6) δ: 8.01-7.99 (2H, m), 7.95-7.93 (1H, m), 7.89-7.82 (2H, m), 7.74-7.70 (2H, m), 7.44-7.39 (3H, m), 7.28-7.23 (2H, m), 3.23 (2H, s), 1.90 (3H, s), 1.23 (2H, s).
Example 8
4-[4-(2-Aminoethyl)phenyl]-3-[6-(2,2-dimethylpropoxy)-2-methylpyrimidin-4-yl]oxybenzonitrile (Compound No. 47)
[0565] ##STR01466##
Step 1: 4-Chloro-2-methyl-6-(neopentyloxy)pyrimidine
[0566] To a stirred mixture of sodium hydride (82 mg, 3.4 mmol) suspended in THF (4 mL), a solution of 2,2-dimethylpropan-1-ol (323 mg, 3.68 mmol) in THF (0.5 mL) was added dropwise at room temperature and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was cooled to 0° C., a solution of 4,6-dichloro-2-methylpyrimidine (400 mg, 2.45 mmol) in THF (0.5 mL) was added dropwise to the mixture, and the mixture was stirred at 0° C. for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The crude product was purified on a silica gel column to obtain the target compound (245 mg, 47%).
Step 2: tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-(neopentyloxy)pyrimidin-4-yloxy)-[1,1′-biphenyl]-4-yl)ethyl)carbamate
[0567] tert-Butyl (2-(4′-cyano-2′-hydroxy-[1,1′-biphenyl]-4-yl)ethyl)carbamate (50 mg, 0.148 mmol) was dissolved in DMF (1 mL), then to the solution, 4-chloro-2-methyl-6-(neopentyloxy)pyrimidine (63.5 mg, 0.296 mmol) and cesium carbonate (96.4 mg, 0.296 mmol) were added, and the mixture was stirred at 70° C. overnight. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0568] MS: m/z 517.0 (M+H).sup.+.
Step 3: 4-[4-(2-Aminoethyl)phenyl]-3-[6-(2,2-dimethylpropoxy)-2-methylpyrimidin-4-yl]oxybenzonitrile
[0569] Dichloromethane (2 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 2, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (21.4 mg).
[0570] Exact MS: 416.2
[0571] Obs. MS (M+H)+: 417.3
Example 9
4-[4-[2-(3-Hydroxypropylamino)ethyl]phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 58)
[0572] ##STR01467##
Step 1: 4-[4-[2-(3-Hydroxypropylamino)ethyl]phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile
[0573] 4-[4-(2-Aminoethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (54 mg, 0.13 mmol) obtained in Example 3 was dissolved in DMF (1 mL), then to the solution, 3-bromopropan-1-ol (0.014 ml, 0.16 mmol) and triethylamine (0.055 mL, 0.39 mmol) were added, and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by HPLC to obtain the target compound (11.3 mg).
[0574] Exact MS: 473.2
[0575] Obs. MS (M+H).sup.+: 474.5
Example 10
4-[4-(2-Amino-1-phenylethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 59)
[0576] ##STR01468##
Step 1: tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)-2-(2-tosylhydrazono)ethyl)carbamate
[0577] tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)-2-oxoethyl)carbamate (855.8 mg, 1.62 mmol) synthesized by the same method in Example 3 was dissolved in toluene (8 mL), then to the solution, p-toluenesulfonyl hydrazide (301 mg, 1.62 mmol) was added, and the mixture was stirred at 110° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.
[0578] MS: m/z 698.2 (M+H).sup.+.
Step 2: tert-Butyl (2-(4′-cyano-2′-((2-methyl-6-morpholinopyrimidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)-2-phenylethyl)carbamate
[0579] An aliquot (30 mg) of the crude product obtained in Step 1 was dissolved in 1,4-dioxane (1 mL), then to the solution, phenylboronic acid (11 mg, 0.086 mmol) and potassium carbonate (24 mg, 0.17 mmol) were added, and the mixture was stirred at 110° C. for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0580] MS: m/z 592.3 (M+H).sup.+.
Step 3: 4-[4-(2-Amino-1-phenylethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile
[0581] The crude product obtained in Step 2 was dissolved in dichloromethane (2 mL), then to the solution, TFA (0.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (3.1 mg).
[0582] Exact MS: 491.2
[0583] Obs. MS (M+H).sup.+: 492.5
Example 11
4-(2-Amino-1-oxo-2,3-dihydroinden-5-yl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 131)
[0584] ##STR01469##
Step 1: 3-(2-Methyl-6-morpholin-4-ylpyrimidin-4-yl)oxy-4-(1-oxo-2,3-dihydroinden-5-yl)benzonitrile
[0585] 4-Bromo-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (300 mg, 0.800 mmol) was dissolved in 1,4-dioxane (2 mL), then to the solution, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydroinden-1-one (289 mg, 1.12 mmol), tetrakis(triphenylphosphine)palladium (46.2 mg, 0.0400 mmol), potassium carbonate (332 mg, 2.40 mmol) and water (0.5 mL) were added, and the mixture was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (290 mg, 85%).
[0586] MS: m/z 427.2 (M+H).sup.+.
Step 2: 4-(2-Bromo-1-oxo-2,3-dihydroinden-5-yl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile
[0587] 3-(2-Methyl-6-morpholin-4-ylpyrimidin-4-yl)oxy-4-(1-oxo-2,3-dihydroinden-5-yl)benzonitrile (290 mg, 0.680 mmol) was dissolved in a mixed solvent (6 mL) of chloroform/ethyl acetate (=1/1), then to the solution, copper(II) bromide (304 mg, 1.36 mmol) was added, and the mixture was stirred at 90° C. for 7 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (26.0 mg, 8%).
[0588] MS: m/z 505.1 (M+H).sup.+.
Step 3: 4-[2-[(2,4-Dimethoxyphenyl)methylamino]-1-oxo-2,3-dihydroinden-5-yl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile
[0589] 4-(2-Bromo-1-oxo-2,3-dihydroinden-5-yl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (26.0 mg, 0.0514 mmol) was dissolved in DMF (I mL), then to the solution, 2,4-dimethoxybenzenemethanamine (12.9 mg, 0.0772 mmol) and triethylamine (0.022 mL, 0.154 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
Step 4: 4-(2-Amino-1-oxo-2,3-dihydroinden-5-yl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile
[0590] TFA (1 mL) was added to the crude product obtained in Step 3, and the mixture was stirred at 120° C. for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (6.00 mg).
[0591] Exact MS: 441.2
[0592] Obs. MS (M+H).sup.+: 442.2
Example 12
4-[4-(2-Amino-1-hydroxyethyl)-3-fluorophenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (Compound No. 149)
[0593] ##STR01470##
Step 1: 4-(3-fluoro-4-formylphenyl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile
[0594] 4-Bromo-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (188 mg, 0.500 mmol) was dissolved in 1,4-dioxane (4 mL), then to the solution, 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (250 mg, 1.00 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (36.6 mg, 0.0500 mmol), potassium carbonate (415 mg, 3.00 mmol) and water (1 mL) were added, and the mixture was stirred at 100° C. for 30 minutes. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (174 mg, 83%).
[0595] MS: m/z 419.2 (M+H).sup.+.
Step 2: 4-[3-Fluoro-4-(1-hydroxy-2-nitroethyl)phenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile
[0596] 4-(3-Fluoro-4-formylphenyl)-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile (174 mg, 0.416 mmol) was dissolved in THF (4 mL), then to the solution, nitromethane (0.5 mL) and triethylamine (1 mL) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.
[0597] MS: m/z 480.2 (M+H).sup.+.
Step 3: 4-[4-(2-Amino-1-hydroxyethyl)-3-fluorophenyl]-3-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)oxybenzonitrile
[0598] Zinc powder (500 mg, 7.64 mmol) and acetic acid (4 mL) were added to the crude product obtained in Step 2, and the mixture was stirred for 30 minutes. The reaction mixture was filtered through Celite and concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (15.7 mg).
[0599] Exact MS: 449.2
[0600] Obs. MS (M+H).sup.+: 450.2
Example 13
4-[4-[(1R)-2-Amino-1-hydroxyethyl]pyrazol-1-yl]-3-(2-methyl-6-phenylpyrimidin-4-yl)oxybenzonitrile (Compound No. 170)
[0601] ##STR01471##
Step 1: Ethyl 1-(4-cyano-2-methoxyphenyl)pyrazole-4-carboxylate
[0602] DMSO (120 mL) was added to 4-fluoro-3-methoxybenzonitrile (15.1 g, 100 mmol), ethyl 1H-pyrazole-4-carboxylate (15.4 g, 110 mmol), and potassium carbonate (27.6 g, 200 mmol), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was stirred. The precipitated solid was collected by filtration through a glass filter and dried to obtain the target compound (22.8 g, 84%).
[0603] MS: m/z 272.0 (M+H).sup.+.
Step 2: 1-(4-Cyano-2-methoxyphenyl)pyrazole-4-carboxylic acid
[0604] Ethyl 1-(4-cyano-2-methoxyphenyl)pyrazole-4-carboxylate (11.0 g, 40.5 mmol) was dissolved in a mixed solvent of THF (40 mL)/methanol (40 mL), then to the solution, a 2 M aqueous sodium hydroxide solution (40.5 mL, 81.1 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After adding 2M hydrochloric acid to the reaction mixture and stirring the mixture, water was further added to the solution to precipitate the target compound. The target compound was collected by filtration with a glass filter and dried to obtain the target compound (7.38 g, 75%).
[0605] MS: m/z 244.0 (M+H).sup.+.
Step 3: 3-Methoxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile
[0606] To 1-(4-cyano-2-methoxyphenyl)pyrazole-4-carboxylic acid (7.38 g, 30.3 mmol), DMF (40 mL) and 1,1′-carbonyldime (5.90 g, 36.4 mmol) were added and the mixture was stirred for 2 hours (reaction mixture A). Nitromethane (2.78 g, 45.5 mmol) and DMF (40 mL) were added to another reaction vessel, sodium hydride (1.59 g, 36.4 mmol) was further added, and the mixture was stirred for 2 hours to separately prepare another solution (reaction mixture B). The reaction mixture B was cooled to 0° C., the reaction mixture A was added dropwise to the reaction mixture B, and then the mixture was heated to 100° C. and stirred for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the target compound was precipitated. The precipitate was collected by filtration with a glass filter and dried to obtain the target compound (8.70 g, quant.).
[0607] MS: m/z 287.0 (M+H).sup.+.
Step 4: 3-Hydroxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile
[0608] 3-Methoxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile (4.50 g, 15.7 mmol) was dissolved in DMF (40 mL), then to the solution, lithium chloride (6.67 g, 157 mmol) was added, and the mixture was stirred at 150° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0609] MS: m/z 273.0 (M+H).sup.+.
Step 5: 3-(2-Methyl-6-phenylpyrimidin-4-yl)oxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile
[0610] The crude product obtained in Step 4 was dissolved in DMF (40 mL), then to the solution, 4-chloro-2-methyl-6-phenylpyrimidine (3.54 g, 17.3 mmol) and potassium carbonate (4.35 g, 31.4 mmol) were added, and the mixture was stirred at 100° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure to obtain the target compound (2.69 g, 39%).
[0611] MS: m/z 441.1 (M+H).sup.+.
Step 6: tert-Butyl N-[2-[1-[4-cyano-2-(2-methyl-6-phenylpyrimidin-4-yl)oxyphenyl]pyrazol-4-yl]-2-oxoethyl]carbamate
[0612] THF (40 mL) and acetic acid (1.83 g, 30.5 mmol) were added to 3-(2-methyl-6-phenylpyrimidin-4-yl)oxy-4-[4-(2-nitroacetyl)pyrazol-1-yl]benzonitrile (2.69 g, 6.11 mmol), di-tert-butyl dicarbonate (4.00 g, 18.3 mmol) and zinc powder (2.00 g, 30.5 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (540 mg, 17%).
[0613] MS: m/z 511.2 (M+H).sup.+.
Step 7: tert-Butyl N-[(2R)-2-[I-[4-cyano-2-(2-methyl-6-phenylpyrimidin-4-yl)oxyphenyl]pyrazol-4-yl]-2-hydroxyethyl]carbamate
[0614] tert-Butyl N-[2-[1-[4-cyano-2-(2-methyl-6-phenylpyrimidin-4-yl)oxyphenyl]pyrazol-4-yl]-2-oxoethyl]carbamate (106 mg, 0.208 mmol) and (S)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine (5.8 mg, 0.021 mmol) were dissolved in dichloromethane (1 mL) and the solution was cooled to 0° C. Dimethyl sulfide borane (47.3 mg, 0.633 mmol) was added to the reaction mixture, and the mixture was stirred at the same temperature for 10 hours. Methanol and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0615] MS: m/z 513.2 (M+H).sup.+.
Step 8: 4-[4-[(1R)-2-Amino-1-hydroxyethyl]pyrazol-1-yl]-3-(2-methyl-6-phenylpyrimidin-4-yl)oxybenzonitrile
[0616] The crude product obtained in Step 7 was dissolved in dichloromethane (1 mL), TFA (1 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (18.6 mg).
[0617] Exact MS: 412.2
[0618] Obs. MS (M+H).sup.+: 413.2
Example 14
3-(6-Cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-[4-(2-oxopiperazin-1-yl)pyrazol-1-yl]benzonitrile (Compound No. 208)
[0619] ##STR01472##
Step 1: 3-(6-Chloro-2-methylpyrimidin-4-yl)oxy-4-fluorobenzonitrile
[0620] 4-Fluoro-3-hydroxybenzonitrile (3.7 g, 27 mmol) was dissolved in DMF (90 mL), then to the solution, 4,6-dichloro-2-methylpyrimidine (6.6 g, 40 mmol) and potassium carbonate (7.5 g, 54 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified on a silica gel column to obtain the target compound (6.5 g).
[0621] MS: m/z 264.1 (M+H).sup.+.
[0622] .sup.1H-NMR (CDCl.sub.3) δ: 7.61 (1H, dq, J=8.7, 2.1 Hz), 7.56 (1H, dd, J=7.1, 2.2 Hz), 7.32 (1H, dd, J=9.5, 8.5 Hz), 6.90 (1H, s), 2.51 (3H, s).
Step 2: 3-(6-Cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-fluorobenzonitrile
[0623] THF (12.6 mL) was added to 3-(6-chloro-2-methylpyrimidin-4-yl)oxy-4-fluorobenzonitrile (1.0 g, 3.79 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (557 mg, 0.759 mmol), then to the mixture, cyclopentyl zinc bromide (1.22 g, 5.69 mmol) was added dropwise, and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified on a silica gel column to obtain the target compound (888 mg).
[0624] MS: m/z 298.1 (M+H).sup.+.
Step 3: 3-(6-Cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-(4-iodopyrazol-1-yl)benzonitrile
[0625] 3-(6-Cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-fluorobenzonitrile (100 mg, 0.336 mmol) was dissolved in DMSO (0.5 mL), then to the solution, 4-iodo-1H-pyrazole (65.2 mg, 0.336 mmol) and potassium carbonate (93.0 mg, 0.673 mmol) were added, and the mixture was stirred at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified on a silica gel column to obtain the target compound (78.9 mg).
[0626] MS: m/z 472.1 (M+H).sup.+.
Step 4: 3-(6-Cyclopentyl-2-methylpyrimidin-1-yloxy-4-(4-iodopyrazol-1-yl)benzonitrile
[0627] 3-(6-Cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-(4-iodopyrazol-1-yl)benzonitrile (34.2 mg, 0.0726 mmol) was added to 1,4-dioxane (0.4 mL), then to the solution, tert-butyl 3-oxopiperazine-1-carboxylate (16 mg, 0.080 mmol), copper(I) iodide (2.8 mg, 0.015 mmol), trans-1,2-cyclohexanediamine (1.7 mg, 0.015 mmol) and tripotassium phosphate (46.2 mg, 0.218 mmol) were added, and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
Step 5: 3-(6-Cyclopentyl-2-methylpyrimidin-4-yl)oxy-4-[4-(2-oxopiperazin-1-yl)pyrazol-1-yl]benzonitrile
[0628] Dichloromethane (1 mL) and TFA (1 mL) were added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (7.3 mg).
[0629] Exact MS: 443.2
[0630] Obs. MS (M+H).sup.+: 444.3
Example 15
3-(2-Methyl-5-phenylpyrazol-3-yl)oxy-4-[4-(7-oxo-1,4-diazepan-1-yl)pyrazol-1-yl]benzonitrile (Compound No. 219)
[0631] ##STR01473##
Step 1: 3-Fluoro-4-(4-iodopyrazol-1-yl)benzonitrile
[0632] DMF (8.6 mL) was added to 3,4-difluorobenzonitrile (430 mg, 3.09 mmol), 4-iodo-1H-pyrazole (500 mg, 2.58 mmol), and cesium carbonate (1.68 g, 5.16 mmol), and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (428 mg, 53%).
[0633] .sup.1H-NMR (CDCl.sub.3) δ: 8.18 (1H, d, J=2.7 Hz), 8.15 (1H, t, J=8.2 Hz), 7.79 (1H, s), 7.60-7.55 (2H, m).
Step 2: 4-(4-Iodopyrazol-1-yl)-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile
[0634] NMP (2.6 mL) was added to 3-fluoro-4-(4-iodopyrazol-1-yl)benzonitrile (201 mg, 0.642 mmol), 2-methyl-5-phenyl-4H-pyrazol-3-one (123 mg, 0.706 mmol), and potassium carbonate (177 mg, 1.28 mmol), and the mixture was stirred at 120° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (198 mg, 66%).
[0635] MS: m/z 468.1 (M+H).sup.+.
Step 3: tert-Butyl 4-[1-[4-cyano-2-(2-methyl-5-phenylpyrazol-3-yl)oxyphenyl]pyrazol-4-yl]-5-oxo-1,4-diazepane-1-carboxylate
[0636] tert-Butyl 5-oxo-1,4-diazepane-1-carboxylate (24 mg, 0.11 mmol), copper(I) iodide (3.7 mg, 0.020 mmol), trans-1,2-cyclohexanediamine (2.2 mg, 0.020 mmol) and tripotassium phosphate (62.7 mg, 0.295 mmol) were added to a solution (0.5 mL) of 4-(4-Iodopyrazol-1-yl)-3-(2-methyl-5-phenylpyrazol-3-yl)oxybenzonitrile (46 mg, 0.098 mmol) in 1,4-dioxane, and the mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
Step 4: 3-(2-Methyl-5-phenylpyrazol-3-yl)oxy-4-[4-(7-oxo-1,4-diazepan-1-yl)pyrazol-1-yl]benzonitrile
[0637] The crude product obtained in Step 3 was dissolved in dichloromethane (1 mL), TFA (1 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (15.7 mg).
[0638] Exact MS: 453.2
[0639] Obs. MS (M+H).sup.+: 454.3
Example 16
4-[5-(2-aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile (Compound No. 250)
[0640] ##STR01474##
Step 1: 4-Bromo-3-(2-hydroxy-6-methylpyridin-4-yl)oxybenzonitrile
[0641] NMP (400 mL) was added to 4-bromo-3-fluorobenzonitrile (40.0 g, 200 mmol), 6-methylpyridine-2,4-diol (30.0 g, 240 mmol), and sodium carbonate (53.0 g, 500 mmol), and the mixture was stirred at 160° C. for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. Ethyl acetate was added to the concentrated crude product to prepare a suspension, heptane was further added to the suspension, and the precipitated solid was collected by filtration through a glass filter. The solid was vacuum dried to obtain the target compound (20.3 g, 33%).
[0642] MS: m/z 305.0 (M+H).sup.+.
[0643] .sup.1H-NMR (DMSO-d.sub.6) δ: 11.47 (1H, s), 8.00 (1H, d, J=8.2 Hz), 7.92 (1H, d, J=1.8 Hz), 7.73 (1H, dd, J=8.2, 2.3 Hz), 5.89 (1H, d, J=1.8 Hz), 5.15 (l H, d, J=2.7 Hz), 2.15 (3H, s).
Step 2: [4-(2-Bromo-5-cyanophenoxy)-6-methylpyridin-2-yl]trifluoromethanesulfonate
[0644] Dichloromethane (22 mL) was added to 4-bromo-3-(2-hydroxy-6-methylpyridin-4-yl)oxybenzonitrile (2.7 g, 8.85 mmol), the mixture was cooled to 0° C., and then trifluoromethanesulfonic anhydride (3.25 g, 11.5 mmol) was added to the mixture. Pyridine (2.1 mL, 26.5 mmol) was added dropwise to this reaction mixture at the same temperature, then the temperature was raised to room temperature, and the mixture was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0645] MS: m/z 436.9 (M+H).sup.+.
Step 3: 4-Bromo-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile
[0646] The crude product obtained in Step 2 was dissolved in DMSO (18 mL), then to the solution, morpholine (1.16 g, 13.3 mmol) and N, N-diisopropylethylamine (4.73 mL, 26.5 mmol) were added, and the mixture was stirred at 70° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. Ethanol was added to the concentrated crude product and dried overnight. The precipitated target compound was collected by filtration through a glass filter and dried to obtain the target compound (1.87 g, 57%).
[0647] MS: m/z 374.0 (M+H).sup.+.
[0648] .sup.1H-NMR (CDCl.sub.3) δ: 7.77 (I H, d, J=8.2 Hz), 7.35 (1H, dd, J=8.2, 1.8 Hz), 7.29 (1H, d, J=1.8 Hz), 6.02 (1H, d, J=1.4 Hz), 6.00 (1H, d, J=1.4 Hz), 3.80 (4H, t, J=5.0 Hz), 3.48 (4H, t, J=4.8 Hz), 2.36 (3H, s).
Step 4: 3-(2-methyl-6-morpholin-4-ylpyridin-4-yloxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
[0649] 4-Bromo-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile (790 mg, 2.11 mmol) was dissolved in 1,4-dioxane (11 mL), then to the solution, bis(pinacolato)diboron (804 mg, 3.17 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (76.4 mg, 0.106 mmol), and potassium acetate (415 mg, 4.22 mmol) were added, and the mixture was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (567 mg).
[0650] MS: m/z 422.3 (M+H).sup.+.
Step 5: tert-Butyl N-[2-[2-[4-cyano-2-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxyphenyl]pyrimidin-5-yl]ethyl]carbamate
[0651] 3-(2-Methyl-6-morpholin-4-ylpyridin-4-yl)oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (222 mg, 0.527 mmol) was dissolved in 1,4-dioxane (1.8 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (90.5 mg, 0.351 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (12.8 mg, 0.0176 mmol), potassium carbonate (97.1 mg, 0.702 mmol), and water (0.4 mL) were added, and the mixture was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (71.9 mg, 40%).
[0652] MS: m/z 517.3 (M+H).sup.+.
[0653] .sup.1H-NMR (CDCl.sub.3) δ: 8.61 (2H, s), 8.05 (1H, d, J=8.2 Hz), 7.61 (11H, dd, J=8.2, 1.4 Hz), 7.44 (1H, d, J=1.4 Hz), 6.01 (1H, d, J=1.4 Hz), 5.94 (1H, d, J=1.8 Hz), 4.70 (1H, brs), 3.78 (4H, t, J=4.8 Hz), 3.41 (4H, t, J=4.8 Hz), 3.36 (2H, q, J=6.6 Hz), 2.82 (2H, t, J=6.6 Hz), 2.29 (3H, s), 1.43 (9H, s).
Step 6: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxybenzonitrile
[0654] tert-Butyl N-[2-[2-[4-cyano-2-(2-methyl-6-morpholin-4-ylpyridin-4-yl)oxyphenyl]pyrimidin-5-yl]ethyl]carbamate (71.9 mg, 0.139 mmol) was dissolved in dichloromethane (1 mL), then TFA (1 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (63.62 mg).
[0655] Exact MS: 416.2
[0656] Obs. MS (M+H).sup.+: 417.4
[0657] .sup.1H-NMR (CD.sub.3OD) δ: 8.79 (2H, s), 8.33 (1H, d, J=8.2 Hz), 7.90 (1H, dd, J=8.0, 1.6 Hz), 7.79 (l H, d, J=1.4 Hz), 6.46 (1H, d, J=1.8 Hz), 6.39 (1H, d, J=1.8 Hz), 3.79 (4H, t, J=5.0 Hz), 3.55 (4H, t, J=5.0 Hz), 3.25 (2H, t, J=7.8 Hz), 3.04 (2H, t, J=7.8 Hz), 2.50 (3H, s).
Example 17
4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (Compound No. 261)
[0658] ##STR01475##
Step 1: 4-Bromo-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile
[0659] 4-Bromo-3-fluorobenzonitrile (2.14 g, 10.7 mmol) and 2-methyl-5-propan-2-ylpyrazole-3-ol (1.50 g, 10.7 mmol) were dissolved in DMA (21 mL), then potassium carbonate (4.44 g, 32.1 mmol) was added to the solution, and the mixture was stirred at 130° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.06 g, 31%).
[0660] MS: m/z 322.1 (M+H).sup.+.
[0661] .sup.1H-NMR (CDCl.sub.3) δ: 7.77 (1H, d, J=8.2 Hz), 7.34-7.32 (2H, m), 5.52 (1H, s), 3.70 (3H, s), 2.94-2.87 (1H, m), 1.25 (6H, d, J=6.9 Hz).
Step 2: 3-(2-Methyl-5-propan-2-ylpyrazol-3-yloxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
[0662] 4-Bromo-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile (646 mg, 2.02 mmol) was dissolved in 1,4-dioxane (10 mL), then to the solution, bis(pinacolato)diboron (615 mg, 2.42 mmol), bis(triphenylphosphine)palladium dichloride (70.8 mg, 0.101 mmol) and potassium acetate (396 mg, 4.03 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0663] MS: m/z 368.2 (M+H).sup.+.
Step 3: tert-Butyl N-[2-[2-[4-cyano-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethyl]carbamate
[0664] To a solution (13.5 mL) of the crude product in 1,4-dioxane obtained in Step 2, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (520 mg, 2.02 mmol), tetrakis(triphenylphosphine)palladium (117 mg, 0.101 mmol), potassium carbonate (697 mg, 5.04 mmol) and water (3.4 mL) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (946 mg, containing impurities).
[0665] MS: m/z 463.2 (M+H).sup.+.
Step 4: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxybenzonitrile
[0666] tert-Butyl N-[2-[2-[4-cyano-2-(2-methyl-5-propan-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]ethyl]carbamate (946 mg, 1.23 mmol) was dissolved in 1,4-dioxane (5.1 mL), then to the solution, a 4 M hydrochloric acid/1,4-dioxane solution (5.1 mL) was added dropwise at 0° C., the temperature of the mixture was raised to room temperature, and the mixture was stirred for 5 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the concentrated crude product, and the mixture was concentrated under reduced pressure again. The mixture was vacuum dried to obtain the hydrochloride salt of the target compound (681 mg, 76%).
[0667] Exact MS: 362.2
[0668] Obs. MS (M+H).sup.+: 363.3
Example 18
4-[4-(2-Aminoethyl)pyrazol-1-yl]-3-(6-pyrrolidin-1-ylpyridazin-4-yl)oxybenzonitrile (Compound No. 284)
[0669] ##STR01476##
Step 1: tert-Butyl N-[2-[1-(4-cyano-2-phenylmethoxyphenyl)pyrazol-4-yl]ethyl]carbamate
[0670] DMA (2 mL) was added to 4-fluoro-3-phenylmethoxybenzonitrile (307 mg, 1.35 mmol), tert-butyl N-[2-(1H-pyrazol-4-yl)ethyl]carbamate (190 mg, 0.900 mmol), and potassium carbonate (373 mg, 2.70 mmol), and the mixture was stirred at 150° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (263 mg, 70%).
[0671] MS: m/z 419.2 (M+H).sup.+.
Step 2: tert-Butyl N-[2-[1-(4-cyano-2-hydroxyphenyl)pyrazol-4-yl]ethyl]carbamate
[0672] tert-Butyl N-[2-[1-(4-cyano-2-phenylmethoxyphenyl)pyrazol-4-yl]ethyl]carbamate (263 mg, 0.628 mmol) was dissolved in methanol (5 mL)/ethyl acetate (5 mL) and palladium-activated carbon (100 mg) was added to the solution under a nitrogen atmosphere. A hydrogen gas balloon was attached to the reaction vessel, and after the inside of the vessel was replaced with hydrogen gas, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (172 mg, 83%).
[0673] MS: m/z 273.0 (M-tBu+H).sup.+.
Step 3: tert-Butyl N-[2-[1-[2-(6-chloropyridazin-4-yl)oxy-4-cyanophenyl]pyrazol-4-yl]ethyl]carbamate
[0674] DMF (1.3 mL) was added to tert-butyl N-[2-[1-(4-cyano-2-hydroxyphenyl)pyrazol-4-yl]ethyl]carbamate (172 mg, 0.524 mmol), 3,5-dichloropyridazine (101 mg, 0.681 mmol), and potassium carbonate (217 mg, 1.57 mmol), and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (218 mg, 94%).
[0675] MS: m/z 385.0 (M-tBu+H).sup.+.
Step 4: tert-Butyl N-[2-[1-[4-cyano-2-(6-pyrrolidin-1-ylpyridazin-4-yl)oxyphenyl]pyrazol-4-yl]ethyl]carbamate
[0676] tert-Butyl N-[2-[1-[2-(6-chloropyridazin-4-yl)oxy-4-cyanophenyl]pyrazol-4-yl]ethyl]carbamate (70.0 mg, 0.159 mmol) was dissolved in toluene (0.8 mL), then to the solution, pyrrolidine (33.9 mg, 0.476 mmol), tris(dibenzylideneacetone)dipalladium (7.3 mg, 7.9 μmol), (±)-BINAP (9.9 mg, 16 μmol)), and cesium carbonate (220 mg, 2.25 mmol) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (51.0 mg, 68%).
Step 5: 4-[4-(2-Aminoethyl)pyrazol-1-yl]-3-(6-pyrrolidin-1-ylpyridazin-4-yl)oxybenzonitrile
[0677] tert-Butyl N-[2-[1-[4-cyano-2-(6-pyrrolidin-1-ylpyridazin-4-yl)oxyphenyl]pyrazol-4-yl]ethyl]carbamate (51.0 mg, 0.107 mmol) was dissolved in dichloromethane (2 mL), then TFA (0.5 mL) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (9.71 mg).
[0678] Exact MS: 375.2
[0679] Obs. MS (M+H).sup.+: 376.2
Example 19
4-[5-(1-Amino-2-morpholin-4-yl-2-oxoethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile (Compound No. 487)
[0680] ##STR01477##
Step 1: Methyl 2-[6-[4-cyano-2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetate
[0681] 3-(5-Cyclopropyl-2-methylpyrazol-3-yl)oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (881 mg, 2.41 mmol) synthesized in the same method as in Example 17 was dissolved in 1,4-dioxane (12 mL), then to the solution, methyl 2-(6-chloropyridin-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetate (725 mg, 2.41 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (176.5 mg, 0.241 mmol), potassium carbonate (1.00 g, 7.24 mmol) and water (3 mL) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (976 mg, 80%).
[0682] MS: m/z 504.4 (M+H).sup.+.
Step 2: 2-[6-[4-Cyano-2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid
[0683] Methyl 2-[6-[4-cyano-2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetate (976 mg, 1.94 mmol) was dissolved in methanol (10 mL), then a 2 M aqueous sodium hydroxide solution (2 mL) was added to the solution, and the mixture was stirred at room temperature for 15 minutes. After adding 1 M hydrochloric acid (4 mL) to the reaction mixture and stirring the mixture, the mixture was extracted by adding ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0684] MS: m/z 490.3 (M+H).sup.+.
Step 3: tert-Butyl N-[1-[6-[4-cyano-2-(5-cyclopropyl-2-methylpyrazol-3-yl)oxyphenyl]pyridin-3-yl]-2-morpholin-4-yl-2-oxoethyl]carbamate
[0685] An aliquot (160 mg, 0.320 mmol) of the crude product obtained in Step 2 was dissolved in DMF (1 mL), then to the solution, morpholine (0.041 mL, 0.48 mmol), HATU (160 mg, 0.420 mmol), and triethylamine (0.130 mL, 0.960 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0686] MS: m/z 559.4 (M+H).sup.+.
Step 4: 4-[5-(1-Amino-2-morpholin-4-yl-2-oxoethyl)pyridin-2-yl]-3-(5-cyclopropyl-2-methylpyrazol-3-yl)oxybenzonitrile
[0687] The crude product obtained in Step 3 was dissolved in dichloromethane (1 mL), then TFA (0.5 mL) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (39.7 mg).
[0688] Exact MS: 458.2
[0689] Obs. MS (M+H).sup.+: 459.3
Example 20
4-[5-[(3-Aminooxetan-3-yl)methyl]pyridin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile (Compound No. 670)
[0690] ##STR01478##
Step 1: 4-Bromo-3-(6-chloro-2-methylpyrimidin-4-yl)oxybenzonitrile
[0691] 4-Bromo-3-hydroxybenzonitrile (1.78 g, 9.00 mmol) was dissolved in DMSO (30 mL), then to the solution, 4,6-dichloro-2-methylpyrimidine (1.28 g, 6.0 mmol) and potassium carbonate (2.49 g, 18.0 mmol) were added, and the mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.16 g, 60%).
[0692] MS: m/z 324.0 (M+H).sup.+.
Step 2: 3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxy-4-bromobenzonitrile
[0693] 4-Bromo-3-(6-chloro-2-methylpyrimidin-4-yl)oxybenzonitrile (325 mg, 1.00 mmol) was dissolved in DMF (5 mL), then to the solution, 7-azabicyclo[2.2.1]heptane hydrochloride (200 mg, 1.50 mmol) and potassium carbonate (415 mg, 3.00 mmol) were added, and the mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with a mixed solution of ethyl acetate/heptane (=1/1). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (235 mg, 61%).
[0694] MS: m/z 385.1 (M+H).sup.+.
[0695] .sup.1H-NMR (CDCl.sub.3) δ: 7.73 (1H, d, J=8.2 Hz), 7.47 (1H, d, J=2.3 Hz), 7.36 (1H, dd, J=8.2, 1.8 Hz), 5.89 (1H, s), 4.51 (2H, brs), 2.36 (3H, s), 1.82-1.80 (4H, m), 1.57-1.50 (4H, m).
Step 3: 3-[6-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
[0696] 3-[6-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxy-4-bromobenzonitrile (231 mg, 0.600 mmol) was dissolved in 1,4-dioxane (3 mL), then to the solution, bis(pinacolato)diboron (305 mg, 1.20 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (43.9 mg, 0.0600 mmol), and potassium acetate (177 mg, 1.80 mmol) were added, and the mixture was stirred at 100° C. overnight. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The concentrated crude product was used in the next reaction without further purification.
Step 4: N-[3-[[6-[2-[6-(7-Azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxy-4-cyanophenyl]pyridin-3-yl]methyl]oxetan-3-yl]-2-methylpropane-2-sulfinamide
[0697] An aliquot (64.8 mg) of the crude product obtained in Step 3 was dissolved in 1,4-dioxane (1 mL), then to the solution, N-[3-[(6-chloropyridin-3-yl)methyl]oxetan-3-yl]-2-methylpropane-2-sulfinamide (30.3 mg, 0.100 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (7.3 mg, 0.010 mmol), potassium carbonate (41.5 mg, 0.300 mmol) and water (0.2 mL) were added, and the mixture was stirred at 100° C. overnight. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The concentrated crude product was used in the next reaction without further purification.
Step 5: 4-[5-[(3-Aminooxetan-3-yl)methyl]pyridin-2-yl]-3-[6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-methylpyrimidin-4-yl]oxybenzonitrile
[0698] The crude product obtained in Step 4 was dissolved in methanol (1 mL), then to the solution, a 4 M hydrochloric acid/1,4-dioxane solution (0.15 mL) was added at 0° C., and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate (5 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (8.2 mg).
[0699] Exact MS: 468.2
[0700] Obs. MS (M+H).sup.+: 469.2
Example 21
4-[5-(2-Aminoethyl)pyridin-2-yl]-3-[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]benzonitrile (Compound No. 712)
[0701] ##STR01479##
Step 1: 4-Bromo-3-[(4-methoxyphenyl)methoxy]benzonitrile
[0702] 4-Bromo-3-fluorobenzonitrile (6.00 g, 30.0 mmol) was added to a solution of 4-methoxybenzyl alcohol (4.97 g, 36.0 mmol) and potassium tert-butoxide (4.04 g, 36.0 mmol) in DMF (100 mL), and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, the mixture was stirred, and the precipitated solid was collected by filtration through a glass filter and vacuum dried to obtain the target compound (8.04 g, 84%).
[0703] .sup.1H-NMR (CDCl.sub.3) δ: 7.65 (1H, d, J=7.8 Hz), 7.37 (2H, d, J=8.7 Hz), 7.13 (2H, dd, J=9.8, 1.1 Hz), 6.93 (2H, d, J=8.2 Hz), 5.11 (2H, s), 3.83 (3H, s).
Step 2: 3-[(4-Methoxyphenyl]methoxyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylbenzonitrile
[0704] 4-Bromo-3-[(4-methoxyphenyl)methoxy]benzonitrile (1.0 g, 3.14 mmol) was dissolved in 1,4-dioxane (16 mL), then to the solution, bis(pinacolato)diboron (1.20 g, 4.71 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (115 mg, 0.157 mmol) and potassium acetate (617 mg, 6.29 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The concentrated crude product was used in the next reaction without further purification.
[0705] MS: m/z 433.2 (M+H).sup.+.
Step 3: tert-Butyl N-[2-[6-[4-cyano-2-[(4-methoxyphenyl)methoxy]phenyl]pyridin-3-yl]ethyl]carbamate
[0706] tert-Butyl N-[2-(6-chloropyridin-3-yl)ethyl]carbamate (807 mg, 3.14 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (231 mg, 0.314 mmol), potassium carbonate (2.05 g, 6.29 mmol) and water (1 mL) were added to a solution of the crude product in 1,4-dioxane (6 mL) obtained in Step 2, and the mixture was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.17 g, 81%).
[0707] MS: m/z 460.2 (M+H).sup.+.
Step 4: 4-[5-(2-Aminoethyl)pyridin-2-yl]-3-hydroxybenzonitrile
[0708] tert-Butyl N-[2-[6-[4-cyano-2-[(4-methoxyphenyl)methoxy]phenyl]pyridin-3-yl]ethyl]carbamate (1.05 g, 1.60 mmol) was dissolved in dichloromethane (10 mL), then TFA (2 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the concentrated crude product was used in the next reaction without further purification.
Step 5: tert-Butyl N-[2-[6-(4-cyano-2-hydroxyphenyl)pyridin-3-yl]ethyl]carbamate
[0709] The crude product obtained in Step 4 was dissolved in dichloromethane (5 mL), then to the solution, di-tert-butyl dicarbonate (698 mg, 3.20 mmol) and triethylamine (1.00 mL) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (526 mg, 97%).
[0710] MS: m/z 340.1 (M+H).sup.+.
Step 6: tert-Butyl N-[2-[6-[4-cyano-2-[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]phenyl]pyridin-3-yl]ethyl]carbamate
[0711] tert-Butyl N-[2-[6-(4-cyano-2-hydroxyphenyl)pyridin-3-yl]ethyl]carbamate (30 mg, 0.088 mmol) was dissolved in NMP (1 mL), then to the solution, 2-bromo-5-(trifluoromethyl)-1,3,4-thiadiazole (24.7 mg, 0.106 mmol) and potassium carbonate (36.7 mg, 0.265 mmol) were added, and the mixture was stirred at 80° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The obtained crude product was used in the next reaction without further purification.
[0712] MS: m/z 492.1 (M+H).sup.+.
Step 7: 4-[5-(2-Aminoethyl)pyridin-2-yl]-3-[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]benzonitrile
[0713] The crude product obtained in Step 6 was dissolved in dichloromethane (1 mL), TFA (0.5 mL) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (35.9 mg).
[0714] Exact MS: 391.1
[0715] Obs. MS (M+H).sup.+: 392.2
Example 22
4-[5-(Aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile (Compound No. 811)
[0716] ##STR01480##
Step 1: 3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxy-4-nitrobenzonitrile
[0717] 3-Fluoro-4-nitrobenzonitrile (664 mg, 4.00 mmol) and 2-methyl-5-(trifluoromethyl)-4H-pyrazol-3-one (731 mg, 4.40 mmol) were dissolved in DMF (6 mL), then potassium carbonate (663 mg, 4.80 mmol) was added to the solution, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The obtained solid was washed with a small amount of ethyl acetate to obtain the target compound (417 mg).
[0718] MS: m/z 313.1 (M+H).sup.+.
Step 2: 4-Amino-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile
[0719] Iron powder (224 mg, 4.01 mmol), ammonium chloride (214 mg, 4.01 mmol), ethanol (1.3 mL) and water (1.3 mL) were added to 3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxy-4-nitrobenzonitrile (417 mg, 1.34 mmol), and the mixture was stirred at 70° C. for 1.5 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then extracted by adding ethyl acetate and water to the mother liquor. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrated crude product was used in the next reaction without further purification.
[0720] MS: m/z 283.1 (M+H).sup.+.
Step 3: 4-Bromo-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile
[0721] The crude product obtained in Step 2 was dissolved in acetonitrile (6.5 mL), then isoamyl nitrite (224 mg, 1.92 mmol) and copper(II) bromide (341 mg, 1.53 mmol) were added to the solution, and the mixture was stirred at 65° C. for 16 hours. The reaction mixture was cooled to room temperature, 20% hydrochloric acid was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (389 mg).
[0722] MS: m/z 346.0 (M+H).sup.+.
Step 4: 3-[2-Methyl-5-(trifluoromethyl)pyrazol-3-yl]oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
[0723] 4-Bromo-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile (389 mg, 1.12 mmol) was dissolved in 1,4-dioxane (5.6 mL), then to the solution, bis(pinacolato)diboron (428 mg, 1.68 mmol), bis(triphenylphosphine)palladium dichloride (78.8 mg, 0.112 mmol) and potassium acetate (220 mg, 2.25 mmol) were added, and the mixture was stirred at 110° C. for 1 hour. The reaction solution was cooled to room temperature and used in the next reaction without further purification.
[0724] MS: m/z 394.2 (M+H).sup.+.
Step 5: tert-Butyl N-[[2-[4-cyano-2-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxyphenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate
[0725] tert-Butyl N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (107 mg, 0.31 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (21 mg, 0.028 mmol), potassium carbonate (120 mg, 0.840 mmol), and water (0.3 mL) were added to an aliquot (1.2 mL) of the reaction mixture obtained in Step 4, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The concentrated crude product was used in the next reaction without further purification.
Step 6: 4-[5-(Aminomethyl)pyrimidin-2-yl]-3-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]oxybenzonitrile
[0726] Dichloromethane (0.5 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 5, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (88.7 mg).
[0727] Exact MS: 374.1
[0728] Obs. MS (M+H).sup.+: 375.3
Example 23
4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (Compound No. 875)
[0729] ##STR01481##
Step 1: 3-(5-Amino-2-methylpyrazol-3-yl)oxy-4-bromobenzonitrile
[0730] 4-Bromo-3-fluorobenzonitrile (3.0 g, 15 mmol) and 5-amino-2-methyl-4H-pyrazol-3-one (1.7 g, 15 mmol) were dissolved in DMA (40 mL), and potassium carbonate (4.14 g, 30.0 mmol) was added to the solution, and the mixture was stirred at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (444 mg, 10%).
[0731] MS: m/z 292.9 (M+H).sup.+.
[0732] .sup.1H-NMR (CDCl.sub.3) δ: 7.76 (1H, d, J=8.2 Hz), 7.36 (1H, d, J=1.8 Hz), 7.32 (1H, dd, J=8.0, 1.6 Hz), 5.11 (1H, s), 3.63 (2H, brs), 3.57 (3H, s).
Step 2: 4-Bromo-3-[5-(2,2-difluoroethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile
[0733] 3-(5-Amino-2-methylpyrazol-3-yl)oxy-4-bromobenzonitrile (1.47 g, 5.00 mmol) was dissolved in DMA (10 mL), then to the solution, 1,1-difluoro-2-iodoethane (1.44 g, 7.50 mmol) and N,N-diisopropylethylamine (1.74 mL, 10.0 mmol) were added, and the mixture was stirred at 140° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.10 g, 62%).
[0734] MS: m/z 359.0 (M+H).sup.+.
Step 3: 4-Bromo-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile
[0735] 4-Bromo-3-[5-(2,2-difluoroethylamino)-2-methylpyrazol-3-yl]oxybenzonitrile (1.10 g, 3.09 mmol) was dissolved in DMA (10 mL), then to the solution, iodoethane (963 mg, 6.17 mmol) and N,N-diisopropylethylamine (1.08 mL, 6.17 mmol) were added, and the mixture was stirred at 120° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (766 mg, 64%).
[0736] MS: m/z 385.0 (M+H).sup.+.
Step 4: 3-[5-[2,2-Difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
[0737] 4-Bromo-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile (766 mg, 1.99 mmol) was dissolved in 1,4-dioxane (10 mL), then to the solution, bis(pinacolato)diboron (758 mg, 2.98 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (72.8 mg, 0.0995 mmol), and potassium acetate (391 mg, 3.98 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0738] MS: m/z 433.2 (M+H).sup.+.
Step 5: tert-Butyl N-[2-[2-[4-cyano-2-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxyphenyl]pyrimidin-5-yl]ethyl]carbamate
[0739] The crude product obtained in Step 4 was dissolved in 1,4-dioxane (10 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (462 mg, 1.79 mmol), tetrakis(triphenylphosphine)palladium (115 mg, 0.0995 mmol), potassium carbonate (550 mg, 3.98 mmol) and water (3 mL) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (648 mg, 62%).
[0740] MS: m/z 528.2 (M+H).sup.+.
Step 6: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxybenzonitrile
[0741] tert-Butyl N-[2-[2-[4-cyano-2-[5-[2,2-difluoroethyl(ethyl)amino]-2-methylpyrazol-3-yl]oxyphenyl]pyrimidin-5-yl]ethyl]carbamate (648 mg, 1.23 mmol) was dissolved in 1,4-dioxane (4 mL), then a 4 M hydrochloric acid/1,4-dioxane solution (2 mL) was added dropwise at 0° C. to the mixture, then the temperature of the mixture was raised to room temperature, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the solid obtained was vacuum dried to obtain a hydrochloride of the target compound (642 mg).
[0742] Exact MS: 427.2
[0743] Obs. MS (M+H).sup.+: 428.3
Example 24
4-[5-(Aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrazin-2-ylpyrazol-3-yl)oxybenzonitrile (Compound No. 931)
[0744] ##STR01482##
Step 1: 3-(5-Amino-2-methylpyrazol-3-yl)oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
[0745] The intermediate of 3-(5-amino-2-methylpyrazol-3-yl)oxy-4-bromobenzonitrile (879 mg, 3.00 mmol) obtained in Example 23 was dissolved in 1,4-dioxane (7.5 mL), then to the solution, bis(pinacolato)diboron (1.52 g, 6.00 mmol), bis(triphenylphosphine)palladium dichloride (211 mg, 0.300 mmol), and potassium acetate (589 mg, 6.00 mmol) were added, and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The concentrated crude product was used in the next reaction without further purification.
Step 2: tert-Butyl N-[[2-[2-(5-amino-2-methylpyrazol-3-yl)oxy-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate
[0746] To a solution of the crude product in 1,4-dioxane (15 mL) obtained in Step 1, tert-butyl N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (1.03 g, 3.00 mmol), [1,1′-bis (diphenylphosphino)ferrocene]palladium dichloride (220 mg, 0.300 mmol), potassium carbonate (1.24 g, 9.00 mmol), and water (3 mL) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.48 g, containing impurities).
[0747] MS: m/z 522.3 (M+H).sup.+.
Step 3: tert-Butyl N-[[2-[2-(5-bromo-2-methylpyrazol-3-yl)oxy-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate tert-Butyl N-[[2-[2-(5-amino-2-methylpyrazol-3-yl)oxy-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (1.48 g, 2.83 mmol) was dissolved in acetonitrile (28 mL), then isoamyl nitrite (488 mg, 4.17 mmol) and copper(I) bromide (476 mg, 3.32 mmol) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (289 mg).
[0748] MS: m/z 585.2 (M+H).sup.+.
Step 4: tert-Butyl N-[[2-[4-cyano-2-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-3-yl]oxyphenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate
[0749] tert-Butyl N-[[2-[2-(5-bromo-2-methylpyrazol-3-yl)oxy-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (40 mg, 0.068 mmol) was dissolved in 1,4-dioxane (0.2 mL), then to the solution, bis(pynacolato)diboron (26.0 mg, 0.102 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (5.0 mg, 6.8 μmol) and potassium acetate (20.1 mg, 0.205 mmol) were added, and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product obtained was used in the next reaction without further purification.
Step 5: tert-Butyl N-[[2-[4-cyano-2-(2-methyl-5-pyrazin-2-ylpyrazol-3-yl)oxyphenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate
[0750] An aliquot (24 mg) of the crude product obtained in Step 4 was dissolved in 1,4-dioxane (0.19 mL), then to the solution, 2-chloropyrazine (25.7 mg, 0.076 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (2.8 mg, 3.8 μmol), potassium carbonate (16 mg, 0.11 mmol) and water (0.038 mL) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
Step 6: 4-[5-(Aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-pyrazin-2-ylpyrazol-3-yl)oxybenzonitrile
[0751] TFA (0.5 mL) was added to the crude product obtained in Step 5, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (5.25 mg).
[0752] Exact MS: 384.1
[0753] Obs. MS (M+H).sup.+: 385.2
Example 25
2-[2-[4-Fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine (Compound No. 966) (Target compound) and 2-[2-[4-fluoro-2-[5-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine (Compound No. 967) (Regioisomer)
[0754] ##STR01483##
Step 1: 1-(2-Bromo-5-fluorophenoxy)propan-2-one
[0755] 2-Bromo-5-fluorophenol (2.29 g, 12.0 mmol) and 1-bromopropan-2-one (1.97 g, 14.4 mmol) were dissolved in DMF (20 mL), potassium carbonate (3.32 g, 24.0 mmol) was added to the solution, and the mixture was heated and stirred at 100° C. After completion of the reaction, the reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (2.51 g, 85%).
Step 2: 3-(2-Bromo-5-fluorophenoxy)-4-(dimethylamino)but-3-en-2-one
[0756] To 1-(2-bromo-5-fluorophenoxy)propan-2-one (2.73 g, 11.0 mmol), N,N-dimethylformamide dimethylacetal (1.58 g, 13.2 mmol) was added, the mixture was stirred at 80° C. overnight. After cooling the reaction mixture to room temperature, acetic acid (20 mL) and hydrazine monohydrate (826 mg, 16.5 mmol) were added to the mixture, and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (2.41 g, 81%).
[0757] MS: m/z 271.0 (M+H).sup.+.
Step 3: 4-(2-Bromo-5-fluorophenoxy)-3-methyl-1-(2-methylpropyl)pyrazole
[0758] To 4-(2-bromo-5-fluorophenoxy)-3-methyl-1H-pyrazole (270 mg, 1.0 mmol), DMSO (2 mL), 1-bromo-2-methylpropane (160 mg, 1.2 mmol), and potassium carbonate (280 mg, 2.0 mmol) were added, and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a mixture (185 mg) of the target compound and its regioisomer. Regioisomers were separated by HPLC purification after the last step.
[0759] MS: m/z 327.1 (M+H).sup.+.
[0760] .sup.1H-NMR (DMSO-d.sub.6) δ: 7.80 (1H, s), 7.72 (1H, dd, J=9.2, 2.8 Hz), 6.93-6.88 (I H, m), 6.60 (1H, dd, J=10.4, 2.8 Hz), 3.81 (1H, d, J=7.2 Hz), 2.14-2.07 (1H, m), 1.98 (3H, s), 0.85 (6H, d, J=6.8 Hz).
Step 4: 4-[5-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy]-3-methyl-1-(2-methylpropyl)pyrazole
[0761] The isomer mixture (185 mg, 0.565 mmol) obtained in Step 3 was dissolved in 1,4-dioxane (1.1 mL), then to the solution, bis(pinacolato)diboron (215 mg, 0.848 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (20.7 mg, 0.0283 mmol) and potassium acetate (111 mg, 1.13 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
Step 5: tert-Butyl N-[2-[2-[4-fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethyl]carbamate
[0762] An aliquot (106 mg) of the crude product obtained in Step 4 was dissolved in 1,4-dioxane (1 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (87.6 mg, 0.340 mmol), tetrakis(triphenylphosphine)palladium (16.4 mg, 0.0142 mmol), potassium carbonate (78.3 mg, 0.566 mmol), and water (0.3 mL) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
Step 6: 2-[2-[4-Fluoro-2-[3-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine (Target compound) and 2-[2-[4-fluoro-2-[5-methyl-1-(2-methylpropyl)pyrazol-4-yl]oxyphenyl]pyrimidin-5-yl]ethanamine (Regioisomer)
[0763] The crude product obtained in Step 5 was dissolved in dichloromethane (1 mL), TFA (0.5 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (11.82 mg) and its regioisomer (10.77 mg).
[0764] Exact MS: 369.2
[0765] Obs. MS (M+H).sup.+: 370.4 (Compound No. 966), 370.3 (Compound No. 967)
Example 26
4-[5-(Aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile (Compound No. 1028)
[0766] ##STR01484##
Step 1: 4-Chloro-3-[hydroxy-(2-methyl-5-nitropyrazol-3-yl)methyl]benzonitrile
[0767] 3-Bromo-4-chlorobenzonitrile (5.69 g, 26.3 mmol) was dissolved in THF (50 mL), then to the solution, isopropylmagnesium chloride lithium chloride complex (14% solution in THF, 20 mL, 26.27 mmol) was added dropwise at 0° C., and the mixture was stirred at the same temperature for 30 minutes. A solution (5 mL) of 2-methyl-5-nitropyrazole-3-carbaldehyde (3.13 g, 20.2 mmol) in THF was added dropwise to this reaction mixture, the temperature of the mixture was raised to room temperature, and the mixture was stirred for 1 hour. 1 M hydrochloric acid was added to the reaction mixture, the mixture was stirred, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (4.85 g, 82%).
[0768] MS: m/z 293.1 (M+H).sup.+.
[0769] .sup.1H-NMR (CDCl.sub.3) δ: 8.06 (1H, s), 7.67 (1H, dd, J=8.2, 1.8 Hz), 7.56 (1H, d, J=8.2 Hz), 6.39 (1H, s), 6.23 (1H, s), 4.10 (3H, s), 2.97 (1H, s).
Step 2: 4-Chloro-3-(2-methyl-5-nitropyrazole-3-carbonyl)benzonitrile
[0770] Dess-Martin reagent (7.73 g, 18.2 mmol) was added to a solution (83 mL) of 4-chloro-3-[hydroxy-(2-methyl-5-nitropyrazol-3-yl)methyl]benzonitrile (4.85 g, 16.6 mmol) in dichloromethane, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was stirred and then extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0771] MS: m/z 291.0 (M+H).sup.+.
[0772] .sup.1H-NMR (DMSO-d.sub.6) δ: 8.21 (1H, d, J=2.3 Hz), 8.11 (1H, dd, J=8.5, 2.1 Hz), 7.88 (1H, d, J=8.2 Hz), 7.58 (1H, s), 4.27 (3H, s).
Step 3: 3-(5-Amino-2-methylpyrazole-3-carbonyl)-4-chlorobenzonitrile
[0773] The crude product obtained in Step 2 was suspended in a mixed solvent (66 mL) of ethanol/water (=1/1), then to the suspension, iron powder (2.78 g, 49.7 mmol) and ammonium chloride (2.66 g, 49.74 mol) were added, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then most of the ethanol was evaporated under reduced pressure. The residue was extracted by adding ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (3.76 g, 87%).
[0774] MS: m/z 261.1 (M+H).sup.+.
[0775] .sup.1H-NMR (CDCl.sub.3) δ: 7.72-7.70 (2H, m), 7.60 (1H, d, J=9.1 Hz), 5.67 (1H, s), 4.11 (3H, s), 3.73 (2H, brs).
Step 4: 4-Chloro-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile
[0776] 3-(5-Amino-2-methylpyrazole-3-carbonyl)-4-chlorobenzonitrile (449 mg, 1.72 mmol) was dissolved in NMP (4.3 mL), then to the solution, bis(2-bromoethyl)ether (439 mg, 1.89 mmol) and potassium iodide (28.6 mg, 0.172 mmol) were added, and the mixture was stirred at 110° C. for 16 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added to the mixture, and the mixture was extracted. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (391 mg, 69%).
[0777] MS: m/z 331.1 (M+H).sup.+.
[0778] .sup.1H-NMR (CDCl.sub.3) δ: 7.73-7.71 (2H, m), 7.61 (1H, dd, J=7.5, 1.6 Hz), 5.68 (1H, s), 4.15 (3H, s), 3.80 (4H, t, J=4.8 Hz), 3.14 (4H, t, J=4.8 Hz).
Step 5: 3-(2-Methyl-5-morpholin-4-ylpyrazole-3-carbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
[0779] 4-Chloro-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile (391 mg, 1.18 mmol) was dissolved in 1,4-dioxane (4 mL), then to the solution, bis(pinacolato)diboron (451 mg, 1.78 mmol), bis(tricyclohexylphosphine)palladium dichloride (87.3 mg, 0.118 mmol) and potassium acetate (348 mg, 3.55 mmol) were added, and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0780] MS: m/z 423.2 (M+H).sup.+.
Step 6: tert-Butyl N-[[2-[4-cyano-2-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)phenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate
[0781] An aliquot (166 mg) of the crude product obtained in Step 5 was dissolved in 1,4-dioxane (1 mL), then to the solution, tert-butyl N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (50.0 mg, 0.145 mmol), tetrakis(triphenylphosphine)palladium (16.8 mg, 0.0145 mmol), potassium carbonate (60.3 mg, 0.436 mmol), and water (0.1 mL) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0782] MS: m/z 604.3 (M+H).sup.+.
[0783] .sup.1H-NMR (CDCl.sub.3) δ: 8.70 (2H, s), 8.51 (1H, d, J=8.2 Hz), 7.90 (1H, d, J=8.2 Hz), 7.79 (1H, s), 5.38 (1H, S), 4.73 (2H, s), 4.14 (3H, s), 3.72 (4H, t, J=4.8 Hz), 3.00 (4H, t, J=4.8 Hz), 1.48 (18H, s).
Step 7: 4-[5-(Aminomethyl)pyrimidin-2-yl]-3-(2-methyl-5-morpholin-4-ylpyrazole-3-carbonyl)benzonitrile
[0784] Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 6, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (34.2 mg).
[0785] Exact MS: 403.2
[0786] Obs. MS (M+H).sup.+: 404.3 .sup.1H-NMR (DMSO-d.sub.6) δ: 8.93 (2H, s), 8.49 (1H, d, J=7.8 Hz), 8.32 (3H, brs), 8.18 (1H, dd, J=8.2, 1.8 Hz), 8.10 (1H, d, J=1.8H), 5.72 (1H, S), 4.10 (2H, d, J=5.9 Hz), 4.02 (3H, S), 3.57 (4H, t, J=4.8 Hz), 2.92 (4H, t, J=4.6 Hz).
Example 27
4-[5-(Aminomethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile (Compound No. 1030)
[0787] ##STR01485##
Step 1: 3-[(5-tert-Butyl-2-methylpyrazol-3-yl)-hydroxymethyl]-4-chlorobenzonitrile
[0788] 3-Bromo-4-chlorobenzonitrile (3.28 g, 15.2 mmol) was dissolved in THF (50 mL), and isopropylmagnesium chloride lithium chloride complex (14% solution in THF, 13 mL, 16.7 mmol) was added dropwise to the solution at 0° C., and the mixture was stirred at the same temperature for 15 minutes. A solution (5 mL) of 5-tert-butyl-2-methylpyrazole-3-carbaldehyde (2.52 g, 15.2 mmol) in THF was added dropwise to the reaction solution, then the temperature of the mixture was raised to room temperature, and the mixture was stirred for 1.5 hours. 1 M Hydrochloric acid was added to the reaction mixture, the mixture was stirred, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. Ethanol was added to the crude product, the mixture was stirred, and then the precipitated solid was collected by filtration through a glass filter, and vacuum dried to obtain the target compound (2.22 g, 48%).
[0789] MS: m/z 304.2 (M+H).sup.+.
[0790] .sup.1H-NMR (CDCl.sub.3) δ: 8.02 (1H, d, J=1.8 Hz), 7.60 (1H, dd, J=8.2, 1.8 Hz), 7.49 (1H, d, J=8.2 Hz), 6.15 (1H, d, J=5.0 Hz), 5.62 (1H, s), 3.90 (3H, s), 2.49 (1H, d, J=5.0 Hz), 1.23 (9H, s).
Step 2: 3-(5-tert-Butyl-2-methylpyrazole-3-carbonyl)-4-chlorobenzonitrile
[0791] Dess-Martin reagent (768 mg, 1.81 mmol) was added to a solution (16 mL) of 3-[(5-tert-butyl-2-methylpyrazol-3-yl)-hydroxymethyl]-4-chlorobenzonitrile (500 mg, 1.65 mmol) in dichloromethane, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was stirred and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (440 mg, 89%).
[0792] MS: m/z 302.1 (M+H).sup.+.
Step 3: 3-(5-tert-Butyl-2-methylpyrazole-3-carbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
[0793] 3-(5-tert-Butyl-2-methylpyrazole-3-carbonyl)-4-chlorobenzonitrile (440 mg, 1.46 mmol) was dissolved in 1,4-dioxane (4.9 mL), then to the solution, bis(pinacolato)diboron (556 mg, 2.19 mmol), bis(tricyclohexylphosphine)palladium dichloride (53.9 mg, 0.073 mmol) and potassium acetate (430 mg, 4.38 mmol) were added, and the mixture was stirred at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0794] MS: m/z 394.3 (M+H).sup.+.
Step 4: tert-Butyl N-[[2-[2-(5-tert-butyl-2-methylpyrazole-3-carbonyl)-4-cyanophenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate
[0795] An aliquot (115 mg) of the crude product obtained in Step 3 was dissolved in 1,4-dioxane (1 mL), then to the solution, tert-butyl N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (50.0 mg, 0.145 mmol), tetrakis(triphenylphosphine)palladium (16.8 mg, 0.0145 mmol), potassium carbonate (60.3 mg, 0.436 mmol), and water (0.1 mL) was added, and the mixture was stirred at 100° C. for 1 hour. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0796] MS: m/z 575.4 (M+H).sup.+.
Step 5: 4-[5-(Aminomethyl)pyrimidin-2-yl]-3-(5-tert-butyl-2-methylpyrazole-3-carbonyl)benzonitrile
[0797] Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (9.7 mg).
[0798] Exact MS: 374.2
[0799] Obs. MS (M+H).sup.+: 375.4
Example 28
4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)benzonitrile (Compound No. 1042)
[0800] ##STR01486##
Step 1: N-Methoxy-N,2-dimethyl-6-morpholin-4-ylpyridine-4-carboxamide
[0801] 2-Methyl-6-morpholin-4-ylpyridine-4-carboxylic acid (235 mg, 1.43 mmol) was dissolved in DMF (5.3 mL), then to the solution, N,O-dimethylhydroxylamine hydrochloride (124 mg, 1.27 mmol), HATU (524 mg, 1.38 mmol) and triethylamine (0.45 mL, 3.18 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solution was concentrated under reduced pressure. Then, the crude product was purified by silica gel column chromatography to obtain the target compound (174 mg, 62%).
[0802] MS: m/z 266.1 (M+H).sup.+.
Step 2: 4-Chloro-3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)benzonitrile
[0803] 3-Bromo-4-chlorobenzonitrile (284 g, 1.31 mmol) was dissolved in THF (3.3 mL), and isopropylmagnesium chloride lithium chloride complex (14% solution in THF, 1.0 mL, 1.31 mmol) was added dropwise to the solution at 0° C., and the mixture was stirred at the same temperature for 30 minutes. A solution (1 mL) of N-methoxy-N,2-dimethyl-6-morpholin-4-ylpyridine-4-carboxamide (174 mg, 0.656 mmol) in THF was added dropwise to the reaction mixture, and then the temperature of the mixture was raised to room temperature, and the mixture was stirred for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was stirred, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (67.1 mg, 30%).
[0804] MS: m/z 342.1 (M+H).sup.+.
Step 3: 3-(2-Methyl-6-morpholin-4-ylpyridine-4-carbonyl)-4-trimethylstannylbenzonitrile
[0805] 4-Chloro-3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)benzonitrile (67.1 mg, 0.196 mmol) was dissolved in 1,4-dioxane (1 mL), then to the solution, hexamethylditin (96.5 mg, 0.294 mmol) and tetrakis(triphenylphosphine)palladium (22.7 mg, 0.0196 mmol) were added, and the mixture was stirred at 110° C. for 3 hours. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (21.3 mg, 23%).
[0806] MS: m/z 472.1 (M+H).sup.+.
Step 4: tert-Butyl N-[2-[2-[4-cyano-2-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)phenyl]pyrimidin-5-yl]ethyl]carbamate
[0807] 3-(2-Methyl-6-morpholin-4-ylpyridine-4-carbonyl)-4-trimethylstannylbenzonitrile (21.3 mg, 0.0453 mmol) was dissolved in 1,4-dioxane (1 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (30.0 mg, 0.116 mmol), tetrakis(triphenylphosphine)palladium (5.2 mg, 4.53 μmol), and copper(I) iodide (1.7 mg, 9.06 μmol) was added, and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0808] MS: m/z 529.3 (M+H).sup.+.
Step 5: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-(2-methyl-6-morpholin-4-ylpyridine-4-carbonyl)benzonitrile
[0809] Dichloromethane (1.0 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (5.0 mg, 26%).
[0810] Exact MS: 428.2
[0811] Obs. MS ((M+H).sup.+: 429.3
Example 29
4-[5-(Aminomethyl)pyrimidin-2-yl]-3-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)benzonitrile (Compound No. 1064)
[0812] ##STR01487##
Step 1: 4-Chloro-3-[hydroxy-(4-methyl-2-morpholin-4-yl-1,3-thiazol-5-yl)methyl]benzonitrile
[0813] 4-(4-Methyl-1,3-thiazol-2-yl)morpholine (1.25 g, 6.78 mmol) was dissolved in THF (34 mL), the solution was cooled to −78° C., then to the solution, an n-butyllithium hexane solution (2.76 M, 2.7 mL, 7.46 mmol) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, 4-chloro-3-formylbenzonitrile (1.24 g, 7.46 mmol) was added, and the mixture was stirred at −78° C. for 1 hour. Then, the temperature of the mixture was raised to room temperature, a saturated aqueous ammonium chloride solution was added to the mixture, the mixture was stirred, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.30 g, 55%).
[0814] MS: m/z 350.0 (M+H).sup.+.
Step 2: 4-Chloro-3-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)benzonitrile
[0815] 4-Chloro-3-[hydroxy-(4-methyl-2-morpholin-4-yl-1,3-thiazol-5-yl)methyl]benzonitrile (500 mg, 1.43 mmol) was dissolved in THF (15 mL), then to the solution, 2-iodoxybenzoic acid (801 mg, 2.86 mmol) was added, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, a saturated aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. Then, the crude product was purified by silica gel column chromatography to obtain the target compound (310 mg, 62%).
[0816] MS: m/z 348.0 (M+H).sup.+.
Step 3: 3-(4-Methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)-4-trimethylstannylbenzonitrile
[0817] 4-Chloro-3-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)benzonitrile (170 mg, 0.489 mmol) was dissolved in 1,4-dioxane (1.2 mL), then to the solution, hexamethylditin (240 mg, 0.733 mmol) and tetrakis(triphenylphosphine)palladium (56.5 mg, 0.0489 mmol) were added, and the mixture was stirred at 110° C. for 4 hours. The reaction mixture was cooled to room temperature and purified directly by silica gel column chromatography to obtain the target compound (138 mg, 59%).
[0818] MS: m/z 478.0 (M+H).sup.+.
Step 4: tert-Butyl N-[[2-[4-cyano-2-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)phenyl]pyrimidin-5-yl]methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate
[0819] 3-(4-Methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)-4-trimethylstannylbenzonitrile (46.0 mg, 0.0966 mmol) was dissolved in 1,4-dioxane (1 mL), then to the solution, tert-butyl N-[(2-chloropyrimidin-5-yl)methyl]-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (66.0 mg, 0.193 mmol), tetrakis(triphenylphosphine)palladium (11.2 mg, 9.66 μmol) and copper(I) iodide (3.68 mg, 0.0193 mmol) were added, and the mixture was stirred at 110° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.
Step 5: 4-[5-(Aminomethyl)pyrimidin-2-yl]-3-(4-methyl-2-morpholin-4-yl-1,3-thiazole-5-carbonyl)benzonitrile
[0820] Dichloromethane (0.5 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (10.8 mg).
[0821] Exact MS: 420.1
[0822] Obs. MS (M+H).sup.+: 421.2
Example 30
4-[5-(2-Aminoethyl)pyridin-2-yl]-3-[(4-phenylimidazol-1-yl)methyl]benzonitrile (Compound No. 1131)
[0823] ##STR01488##
Step 1: 3-[(4-Phenylimidazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
[0824] 3-(Bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (6.00 g, 18.6 mmol) was dissolved in DMF (80 mL), then to the solution, 4-phenyl-1H-imidazole (2.69 g, 18.6 mmol) and potassium carbonate (5.15 g, 37.3 mmol) were added, and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was used in the next reaction without further purification.
[0825] MS: m/z 386.2 (M+H).sup.+.
Step 2: tert-Butyl N-[2-[6-[4-cyano-2-[(4-phenylimidazol-1-yl)methyl]phenyl]pyridin-3-yl]ethyl]carbamate
[0826] The crude product obtained in Step 1 was dissolved in 1,4-dioxane (80 mL), then to the solution, tert-butyl N-[2-(6-chloropyridin-3-yl)ethyl]carbamate (3.87 g, 15.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (552 mg, 0.754 mmol), potassium carbonate (4.17 g, 30.2 mmol) and water (20 mL) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.41 g, 20%).
[0827] MS: m/z 480.2 (M+H).sup.+.
Step 3: 4-[5-(2-Aminoethyl(pyridin-2-yl]-3-[(4-phenylimidazol-1-yl)methyl]benzonitrile
[0828] 1,4-Dioxane (20 mL) was added to tert-butyl N-[2-[6-[4-cyano-2-[(4-phenylimidazol-1-yl)methyl]phenyl]pyridin-3-yl]ethyl]carbamate (1.19 g, 2.49 mmol), then to the mixture, a 4 M hydrochloric acid/dioxane solution (20 mL) was added dropwise at 0° C., the temperature of the mixture was raised to room temperature, and the mixture was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (678 mg, 72%).
[0829] Exact MS: 379.2
[0830] Obs. MS (M+H).sup.+: 380.3
Example 31
4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[[2-methyl-4-(piperidin-1-ylmethyl)imidazol-1-yl]methyl]benzonitrile (Compound No. 1179)
[0831] ##STR01489##
Step 1: 3-[(4-Formyl-2-methylimidazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
[0832] 3-(Bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (354 mg, 1.10 mmol) was dissolved in acetonitrile (5 mL), then to the solution, 2-methyl-1H-imidazole-4-carbaldehyde (110 mg, 1.00 mmol) and triethylamine (0.356 mL, 2.00 mmol) were added, and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product obtained was used in the next reaction without further purification.
Step 2: tert-Butyl N-[2-[2-[4-cyano-2-[(4-formyl-2-methylimidazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate
[0833] The crude product obtained in Step 1 was dissolved in 1,4-dioxane (5 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (283 mg, 1.10 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (73.4 mg, 0.100 mmol), potassium carbonate (415 mg, 3.00 mmol) and water (1 mL) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (446 mg, quant.).
[0834] MS: m/z 447.3 (M+H).sup.+.
Step 3: tert-Butyl N-[2-[2-[4-cyano-2-[[2-methyl-4-(piperidin-1-ylmethyl)imidazol-1-yl]methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate
[0835] tert-Butyl N-[2-[2-[4-cyano-2-[(4-formyl-2-methylimidazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate (31.0 mg, 0.070 mmol) was dissolved in dichloromethane (0.7 mL), then to the solution, piperidine (7.2 mg, 0.084 mmol) and sodium triacetoxyborohydride (37.0 mg, 0.180 mmol) were added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The obtained crude product was used in the next reaction without further purification.
Step 4: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[[2-methyl-4-(piperidin-1-ylmethyl)imidazol-1-yl]methyl]benzonitrile
[0836] Dichloromethane (0.5 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 3, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (12.2 mg).
[0837] Exact MS: 415.3
[0838] Obs. MS (M+H).sup.+: 416.4
Example 32
4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[(4-cyclopropyltriazol-1-yl)methyl]benzonitrile (Compound No. 1187)
[0839] ##STR01490##
Step 1: 3-(Azidomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
[0840] 3-(Bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (3.50 g, 10.9 mmol) was dissolved in DMSO (22 mL), then to the solution, sodium azide (777 mg, 12.0 mmol) was added, and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (2.80 g, 91%).
Step 2: 3-[(4-Cyclopropyltriazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
[0841] 3-(Azidomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.10 g, 3.87 mmol) was dissolve in DMSO (10 mL), then to the solution, ethynylcyclopropane (307 mg, 4.65 mmol), copper(I) iodide (36.9 mg, 0.194 mmol) and TBTA (103 mg, 0.194 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (416 mg, 31%).
Step 3: tert-Butyl N-[2-[2-[4-cyano-2-[(4-cyclopropyltriazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate
[0842] 3-[(4-Cyclopropyltriazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (208 mg, 0.594 mmol) was dissolved in 1,4-dioxane (3 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (168 mg, 0.653 mmol), tetrakis(triphenylphosphine)palladium (34 mg, 0.030 mmol), sodium carbonate (126 mg, 1.19 mmol) and water (1 mL) were added, and the mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (120 mg, 45%).
Step 4: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[(4-cyclopropyltriazol-1-yl)methyl]benzonitrile
[0843] Dichloromethane (1 mL) and TFA (0.5 mL) were added to tert-butyl N-[2-[2-[4-cyano-2-[(4-cyclopropyltriazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate (120 mg, 0.269 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (12.8 mg).
[0844] Exact MS: 345.2
[0845] Obs. MS (M+H).sup.+: 346.2
Example 33
4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[[I-(2-methylpropyl)pyrazol-4-yl]methyl]benzonitrile (Compound No. 1195)
[0846] ##STR01491##
Step 1: 1-(2-Methylpropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole
[0847] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.94 g, 10.0 mmol) was dissolved in DMF (10 mL), then to the solution, 1-bromo-2-methylpropane (1.64 g, 12.0 mmol) and potassium carbonate (4.14 g, 30.0 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The obtained crude product was used in the next reaction without further purification.
[0848] MS: m/z 251.2 (M+H).sup.+.
Step 2: 4-Chloro-3-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]benzonitrile
[0849] An aliquot (500 mg, 2.00 mmol) of the crude product obtained in Step 1 was dissolved in 1,4-dioxane (10 mL), then to the solution, 3-(bromomethyl)-4-chlorobenzonitrile (461 mg, 2.00 mmol), tetrakis(triphenylphosphine)palladium (162 mg, 0.140 mmol), cesium carbonate (1.95 g, 6.00 mmol) and water (2 mL) were added, and the mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (548 mg, containing impurities).
[0850] MS: m/z 274.1 (M+H).sup.+.
Step 3: 3-[[1-(2-Methylpropyl)pyrazol-4-yl]methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
[0851] 4-Chloro-3-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]benzonitrile (274 mg, 1.00 mmol) was dissolved in 1,4-dioxane (3.3 mL), then to the solution, bis(pinacolato)diboron (381 mg, 1.50 mmol), bis(tricyclohexylphosphine)palladium dichloride (73.8 mg, 0.100 mmol), and potassium acetate (294 mg, 3.00 mmol) were added, and the mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0852] MS: m/z 366.3 (M+H).sup.+.
Step 4: tert-Butyl N-[2-[2-[4-cyano-2-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate
[0853] An aliquot (37 mg) of the crude product obtained in Step 3 was dissolved in 1,4-dioxane (0.5 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (25.8 mg, 0.100 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (7.3 mg, 0.01 mmol), potassium carbonate (41.0 mg, 0.300 mmol), and water (0.1 mL) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate, the solution was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.
Step 5: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[[1-(2-methylpropyl)pyrazol-4-yl]methyl]benzonitrile
[0854] TFA (0.5 mL) was added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (26.0 mg).
[0855] Exact MS: 360.2
[0856] Obs. MS (M+H).sup.+: 361.0
Example 34
4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[(4-pyrrolidin-1-ylpyrazol-1-yl)methyl]benzonitrile (Compound No. 1198)
[0857] ##STR01492##
Step 1: 3-[(4-Nitropyrazol-1-yl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
[0858] 3-(bromomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (230 mg, 0.700 mmol) was dissolved in DMF (0.7 mL), then to the solution, 4-nitro-1H-pyrazole (95 mg, 0.84 mmol) and potassium carbonate (190 mg, 1.40 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the crude product was used in the next reaction without further purification.
[0859] MS: m/z 355.2 (M+H).sup.+.
Step 2: tert-Butyl N-[2-[2-[4-cyano-2-[(4-nitropyrazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate
[0860] The crude product obtained in Step 1 was dissolved in 1,4-dioxane (3.5 mL), then to the solution, tert-butyl N-[2-(2-chloropyrimidin-5-yl)ethyl]carbamate (180 mg, 0.700 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (51.2 mg, 0.0700 mmol), potassium carbonate (290 mg, 2.10 mmol), and water (0.7 mL) were added, and the mixture was stirred at 100° C. for 1 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (310 mg, 99%).
[0861] MS: m/z 450.2 (M+H).sup.+.
Step 3: tert-Butyl N-[2-[2-[2-[(4-aminopyrazol-1-yl)methyl]-4-cyanophenyl]pyrimidin-5-yl]ethyl]carbamate
[0862] tert-Butyl N-[2-[2-[4-cyano-2-[(4-nitropyrazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate (310 mg, 0.690 mmol) was dissolved in methanol (0.7 mL) and palladium-active carbon ethylenediamine complex (50 mg) was added to the mixture. A hydrogen gas balloon was attached to the reaction vessel, and after the inside of the vessel was replaced with hydrogen gas, the mixture was stirred at room temperature overnight. After filtering the reaction mixture with Celite, the solution was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.
[0863] MS: m/z 420.3 (M+H).sup.+.
Step 4: tert-Butyl N-[2-[2-[4-cyano-2-[(4-pyrrolidin-1-ylpyrazol-1-yl)methyl]phenyl]pyrimidin-5-yl]ethyl]carbamate
[0864] An aliquot (45.2 mg) of the crude product obtained in Step 3 was dissolved in DMA (0.5 mL), then to the solution, 1,4-dibromobutane (25.6 mg, 0.119 mmol) and N,N-diisopropylethylamine (0.054 mL, 0.323 mmol) were added, and the mixture was stirred at 110° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0865] MS: m/z 474.3 (M+H).sup.+.
Step 5: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[(4-pyrrolidin-1-ylpyrazol-1-yl)methyl]benzonitrile
[0866] TFA (0.5 mL) was added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (7.4 mg).
[0867] Exact MS: 373.2
[0868] Obs. MS (M+H).sup.+: 374.2
Example 35
4-[4-(2-Aminoethyl)phenyl]-3-[1-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)ethyl]benzonitrile (Compound No. 1226))
[0869] ##STR01493##
Step 1: tert-Butyl (2-(2′-acetyl-4′-cyano-[1,1′-biphenyl]-4-yl)ethyl)carbamate
[0870] To a mixed solution (5 mL) of 2-acetyl-4-cyanophenyltrifluoromethanesulfonate (250 mg, 0.85 mmol) in toluene/water (=4/1), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenethylcarbamate (355 mg, 1.02 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (62.4 mg, 0.085 mmol), and potassium carbonate (354 mg, 2.56 mmol) were added, and the mixture was stirred at 110° C. for 30 minutes. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added to the mixture. The mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (328 mg, quant.).
[0871] MS: m/z 309.1 (M+H-tBu).sup.+.
Step 2: tert-Butyl (2-(4′-cyano-2′-(1-(2-tosylhydrazono)ethyl)-[1,1′-biphenyl]-4-yl)ethyl)carbamate
[0872] p-Toluene sulfonyl hydrazide (167 mg, 0.899 mmol) was added to a solution (3 mL) of tert-butyl (2-(2′-acetyl-4′-cyano-[1,1′-biphenyl]-4-yl)ethyl)carbamate (328 mg, 0.899 mmol) in toluene, and the mixture was stirred at 110° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.
[0873] MS: m/z 477.2 (M+H-tBu).sup.+.
Step 3: tert-Butyl (2-(4′-cyano-2′-(1-(2-methyl-6-morpholinopyrimidin-4-yl)vinyl)-[1,1′-biphenyl]-4-ylethylcarbamate
[0874] The crude product obtained in Step 2 was dissolved in 1,4-dioxane (4.5 mL), then to the solution, 4-(6-chloro-2-methylpyrimidin-4-yl)morpholine (192 mg, 0.899 mmol), tris(dibenzylideneacetone)dipalladium (32.9 mg, 0.036 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (68.6 mg, 0.14 mmol) and lithium tert-butoxide (166 mg, 2.07 mmol) were added, and the mixture was stirred at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (96.1 mg, 20%).
[0875] MS: m/z 526.3 (M+H).sup.+.
Step 4: tert-Butyl (2-(4′-cyano-2′-(1-(2-methyl-6-morpholinopyrimidin-4-yl)ethyl)-[1,1′-biphenyl]-4-yl)ethyl carbamate
[0876] Ethyl acetate (4 mL) was added to tert-butyl (2-(4′-cyano-2′-(1-(2-methyl-6-morpholinopyrimidin-4-yl)vinyl)-[1,1′-biphenyl]-4-yl)ethyl)carbamate (79 mg, 0.15 mmol), and 10% palladium-activated carbon (20 mg) was added to the mixture under a nitrogen atmosphere. A hydrogen gas balloon was attached to the reaction vessel, the inside of the vessel was replaced with hydrogen gas, and the mixture was stirred at room temperature for 1 hour. After replacing the reaction system with nitrogen, the reaction mixture was filtered through Celite and concentrated under reduced pressure. The obtained crude product was used in the next reaction without further purification.
[0877] MS: m/z 528.3 (M+H).sup.+.
Step 5: 4-[4-(2-Aminoethyl)phenyl]-3-[1-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)ethyl]benzonitrile
[0878] The crude product obtained in Step 4 was dissolved in dichloromethane (1 mL), TFA (0.5 mL) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (30.8 mg).
[0879] Exact MS: 427.2
[0880] Obs. MS (M+H).sup.+: 428.5
Example 36
4-[4-(2-Aminoethyl)phenyl]-3-[1-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]benzonitrile (Compound No. 1227)
[0881] ##STR01494##
Step 1: tert-Butyl (2-(4′-cyano-2′-(1-(2-methyl-6-morpholinopyrimidin-4-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)ethyl)carbamate
[0882] DMSO (0.5 mL) and sodium hydride (1.3 mg) were added to trimethyl sulfoxonium iodide (7.1 mg, 0.032 mmol), the mixture was stirred at room temperature for 40 minutes, then to the mixture, a solution (0.5 mL) of tert-butyl (2-(4′-cyano-2′-(1-(2-methyl-6-morpholinopyrimidin-4-yl)vinyl)-[1,1′-biphenyl]-4-yl)ethyl)carbamate (16.9 mg, 0.032 mmol) in DMSO obtained in Example 35 was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0883] MS: m/z 540.3 (M+H).sup.+.
Step 2: 4-[4-(2-Aminoethyl)phenyl]-3-[1-(2-methyl-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]benzonitrile
[0884] The crude product obtained in Step 1 was dissolved in dichloromethane (1 mL), TFA (0.5 mL) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the target compound (11.6 mg).
[0885] Exact MS: 439.2
[0886] Obs. MS (M+H).sup.+: 440.5
Example 37
4-[4-(2-Aminoethyl)phenyl]-3-[methoxy-[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]methyl]benzonitrile (Compound No. 1232)
[0887] ##STR01495##
Step 1: 4-Bromo-3-(1-hydroxyprop-2-ynyl)benzonitrile
[0888] THF (40 mL) was added to 4-bromo-3-formylbenzonitrile (1.38 g, 6.57 mmol), then to the mixture, a 0.5 M ethynylmagnesium bromide solution (14.5 mL, 7.23 mmol) in THF was added dropwise at 0° C., and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, 2 M hydrochloric acid was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product obtained was used in the next reaction.
Step 2: 4-Bromo-3-[hydroxy-[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]methyl]benzonitrile
[0889] To an aliquot (283 mg) of the crude product obtained in Step 1, (2Z)—N-hydroxy-1,3-thiazole-2-carboximidoyl chloride (163 mg, 1.00 mmol), potassium carbonate (276 mg, 2.00 mmol) and toluene (1 mL) were added, and the mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (65.6 mg, 18%).
[0890] MS: m/z 362.0 (M+H).sup.+.
Step 3: 4-Bromo-3-[methoxy-[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]methyl]benzonitrile
[0891] 4-Bromo-3-[hydroxy-[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]methyl]benzonitrile (65.6 mg, 0.181 mmol) was dissolved in DMF (1 mL), then sodium hydride (9.5 mg, 0.217 mmol) was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. Iodomethane (38.8 mg, 0.272 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. After completion of the reaction, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product obtained was used in the next reaction.
[0892] MS: m/z 377.9 (M+H).sup.+.
Step 4: tert-Butyl N-[2-[4-[4-cyano-2-[methoxy-[3-(1,3-thiazol-2-yl-1,2-oxazol-5-yl]methyl]phenyl]phenyl]ethyl]carbamate
[0893] The crude product obtained in Step 3 was dissolved in 1,4-dioxane (0.8 mL), then to the solution, tert-butyl N-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate (75.4 mg, 0.217 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (6.6 mg, 9.0 μmol), potassium carbonate (50.0 mg, 0.362 mmol) and water (0.2 mL) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate, the solution was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.
[0894] MS: m/z 517.2 (M+H).sup.+.
Step 5: 4-[4-(2-aminoethyl)phenyl]-3-[methoxy-[3-(1,3-thiazol-2-yl)-1,2-oxazol-5-yl]methyl]benzonitrile
[0895] Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (48.3 mg).
[0896] Exact MS: 416.1
[0897] Obs. MS (M+H).sup.+: 417.2
Example 38
4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[(5-tert-butyl-2-methylpyrazol-3-yl)-(cyanomethoxy)methyl]benzonitrile (Compound No. 1237)
[0898] ##STR01496##
Step 1: tert-Butyl N-[2-[2-[2-[(5-tert-butyl-2-methylpyrazol-3-yl)-hydroxymethyl]-4-cyanophenyl]pyrimidin-5-yl]ethyl]carbamate
[0899] THF (7.8 mL) was added to tert-butyl N-[2-[2-[2-(5-tert-butyl-2-methylpyrazole-3-carbonyl)-4-cyanophenyl]pyrimidin-5-yl]ethyl]carbamate (379 mg, 0.776 mmol), which can be synthesized in the same method as in Example 27, and a 4 M lithium borohydride solution (0.776 mL, 2.33 mmol) in THF was added dropwise to the mixture. After stirring the mixture at room temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product obtained was used in the next reaction.
[0900] MS: m/z 491.3 (M+H).sup.+.
Step 2: tert-Butyl N-[2-[2-[2-[(5-tert-butyl-2-methylpyrazol-3-yl)-(cyanomethoxy)methyl]-4-cyanophenyl]pyrimidin-5-yl]ethyl]carbamate
[0901] An aliquot (127 mg) of the crude product obtained in Step 1 was dissolved in DMF (1 mL), then to the solution, chloroacetonitrile (23.4 mg, 0.310 mmol) and cesium carbonate (169 mg, 0.517 mmol) were added, and the mixture was stirred at 60° C. for 16 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The crude product obtained was used in the next reaction.
[0902] MS: m/z 530.3 (M+H).sup.+.
Step 3: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-[(5-tert-butyl-2-methylpyrazol-3-yl)-(cyanomethoxy)methyl]benzonitrile
[0903] Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 2, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (10.2 mg).
[0904] Exact MS: 429.2
[0905] Obs. MS (M+H).sup.+: 430.2
Example 39
4-[4-(2-Aminoethyl)phenyl]-3-(6-piperidin-1-ylpyridazin-4-yl)sulfanylbenzonitrile (Compound No. 1240)
[0906] ##STR01497##
Step 1: [5-Cyano-2-[5-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]pyridin-2-yl]phenyl]trifluoromethanesulfonate
[0907] Dichloromethane (5 mL), and pyridine (172 mg, 2.17 mmol) were added to the intermediate of tert-butyl N-[2-[4-(4-cyano-2-hydroxyphenyl)phenyl]ethyl]carbamate (245 mg, 0.724 mmol) obtained in Example 6, the mixture was cooled to 0° C., and trifluoromethanesulfonic anhydride (306 mg, 1.09 mmol) was added dropwise to the mixture. After stirring the mixture at the same temperature for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (301 mg, 88%).
[0908] MS: m/z 415.0 (M-tBu+H).sup.+.
Step 2: 2-Ethylhexyl 3-[5-cyano-2-[4-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]phenyl]phenyl]sulfanylpropanoate
[0909] [5-Cyano-2-[5-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]pyridin-2-yl]phenyl]trifluoromethanesulfonate (301 mg, 0.640 mmol) was dissolved in 1,4-dioxane (2.6 mL), then to the solution, 2-ethylhexyl 3-mercaptopropionate (168 mg, 0.768 mmol), tris(dibenzylideneacetone)dipalladium (29 mg, 0.032 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (37 mg, 0.064 mmol) and N,N-diisopropylethylamine (0.223 mL, 1.28 mmol) were added, and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (479 mg, containing impurities).
[0910] MS: m/z 439.2 (M-Boc+H).sup.+.
Step 3: tert-Butyl N-[2-[4-[2-(6-chloropyridazin-4-ylsulfanyl-4-cyanophenyl]phenyl]ethyl]carbamate
[0911] 2-Ethylhexyl 3-[5-cyano-2-[4-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]phenyl]phenyl]sulfanylpropanoate (479 mg) was dissolved in DMF (5 mL), then to the solution, 3,5-dichloropyridazine (265 mg, 1.78 mmol) and DBU (0.5 mL) were added, and the mixture was stirred at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (340 mg).
[0912] MS: m/z 411.0 (M-tBu+H).sup.+.
[0913] .sup.1H-NMR (CDCl.sub.3) δ: 8.58 (1H, d, J=2.3 Hz), 7.98 (1H, d, J=1.4 Hz), 7.86 (1H, dd, J=8.0, 1.6 Hz), 7.61 (1H, d, J=7.8 Hz), 7.22-7.17 (4H, m), 6.83 (1H, d, J=2.3 Hz), 4.65 (1H, brs), 3.36 (2H, q, J=6.6 Hz), 2.80 (2H, t, J=6.9 Hz), 1.45 (9H, s).
Step 4: tert-Butyl N-[2-[4-[4-cyano-2-(6-piperidin-1-ylpyridazin-4-yl)sulfanylphenyl]phenyl]ethyl]carbamate
[0914] DMF (1 mL) was added to tert-butyl N-[2-[4-[2-(6-chloropyridazin-4-yl)sulfanyl-4-cyanophenyl]phenyl]ethyl]carbamate (50.0 mg, 0.107 mmol), then to the solution, piperidine (27.4 mg, 0.321 mmol) and N,N-diisopropylethylamine (0.15 mL) were added, and the mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate, the solution was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.
Step 5: 4-[4-(2-Aminoethyl)phenyl]-3-(6-piperidin-1-ylpyridazin-4-yl)sulfanylbenzonitrile
[0915] Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (41.7 mg).
[0916] Exact MS: 415.2
[0917] Obs. MS (M+H).sup.+: 416.4
Example 40
4-[4-(2-Aminoethyl)pyrazol-1-yl]-3-(6-piperidin-1-ylpyridazin-4-yl)sulfanylbenzonitrile (Compound No. 1246)
[0918] ##STR01498##
Step 1: tert-Butyl N-[2-[1-(2-bromo-4-cyanophenyl)pyrazol-4-yl]ethyl]carbamate
[0919] DMF (15 mL) was added to 3-bromo-4-fluorobenzonitrile (1.80 g, 9.00 mmol), tert-butyl N-[2-(1H-pyrazol-4-yl)ethyl]carbamate (950 mg, 4.50 mmol) and potassium carbonate (1.87 g, 13.5 mmol), and the mixture was stirred at 150° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (1.86 g, containing impurities).
[0920] MS: m/z 391.0 (M+H).sup.+.
Step 2: 2-Ethylhexyl 3-[5-cyano-2-[4-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]pyrazol-1-yl]phenyl]sulfanylpropanoate
[0921] tert-Butyl N-[2-[1-(2-bromo-4-cyanophenyl)pyrazol-4-yl]ethyl]carbamate (500 mg, 1.28 mmol) was dissolved in 1,4-dioxane (5.11 mL), then to the solution, 2-ethylhexyl 3-mercaptopropionate (335 mg, 1.53 mmol), tris(dibenzylideneacetone)dipalladium (58.5 mg, 0.0639 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (73.9 mg, 0.128 mmol) and N,N-diisopropylethylamine (0.445 mL, 2.56 mmol) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (723 mg, 96%).
[0922] MS: m/z 529.3 (M+H).sup.+.
Step 3: tert-Butyl N-[2-[l-[2-(6-chloropyridazin-4-yl)sulfanyl-4-cyanophenyl]pyrazol-4-yl]ethyl]carbamate
[0923] 2-Ethylhexyl 3-[5-cyano-2-[4-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethyl]pyrazol-1-yl]phenyl]sulfanylpropanoate (723 mg, 1.37 mmol) was dissolved in DMF (2 mL), then to the solution, 3,5-dichloropyridazine (408 mg, 2.74 mmol) and DBU (0.5 mL) were added, and the mixture was stirred at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (543 mg, 87%).
[0924] MS: m/z 401.1 (M-tBu+H).sup.+.
[0925] .sup.1H-NMR (CDCl.sub.3) δ: 8.78 (1H, d, J=1.8 Hz), 7.95 (1H, d, J=1.8 Hz), 7.88 (1H, dd, J=8.5, 2.1 Hz), 7.77 (1H, d, J=8.2 Hz), 7.72 (1H, s), 7.52 (1H, s), 7.00 (1H, d, J=1.8 Hz), 4.61 (1H, brs), 3.29 (2H, q, J=6.6 Hz), 2.66 (2H, t, J=7.1 Hz), 1.44 (9H, s).
Step 4: tert-Butyl N-[2-[1-[4-cyano-2-(6-piperidin-1-ylpyridazin-4-yl)sulfanylphenyl]pyrazol-4-yl]ethyl]carbamate
[0926] DMF (1 mL) was added to tert-butyl N-[2-[1-[2-(6-chloropyridazin-4-yl)sulfanyl-4-cyanophenyl]pyrazol-4-yl]ethyl]carbamate (60 mg, 0.131 mmol), then to the mixture, piperidine (33.5 mg, 0.394 mmol) and N,N-diisopropylethylamine (0.15 mL) were added, and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was used in the next reaction without further purification.
Step 5: 4-[4-(2-Aminoethyl)pyrazol-1-yl]-3-(6-piperidin-1-ylpyridazin-4-yl)sulfanylbenzonitrile
[0927] Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 4, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (50.3 mg, 95%).
[0928] Exact MS: 405.2
[0929] Obs. MS (M+H).sup.+: 406.4
Example 41
4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-(6-piperidin-1-ylpyridazin-4-yl)sulfinylbenzonitrile (Compound No. 1276)
[0930] ##STR01499##
Step 1: tert-Butyl N-[2-[2-[2-(6-chloropyridazin-4-yl)sulfinyl-4-cyanophenyl]pyrimidin-5-yl]ethyl]carbamate
[0931] Dichloromethane (3.3 mL) was added to tert-butyl N-[2-[2-[2-(6-chloropyridazin-4-yl)sulfanyl-4-cyanophenyl]pyrimidin-5-yl]ethyl]carbamate (154 mg, 0.328 mmol), then to the mixture, 3-chloroperbenzoic acid (75.4 mg, 0.328 mmol) was added at 0° C., and then the reaction mixture was heated to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product obtained was used in the next reaction.
[0932] MS: m/z 485.1 (M+H).sup.+.
Step 2: tert-Butyl N-[2-[2-[4-cyano-2-(6-piperidin-1-ylpyridazin-4-yl)sulfinylphenyl]pyrimidin-5-yl]ethyl]carbamate
[0933] An aliquot (79.1 mg) of the crude product obtained in Step 1 was dissolved in 1,4-dioxane (1 mL), then to the solution, piperidine (27.8 mg, 0.326 mmol), tris(dibenzylideneacetone)dipalladium (14.9 mg, 0.0163 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (18.9 mg, 0.0326 mmol), and cesium carbonate (159 mg, 0.489 mmol) were added, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude was used in the next reaction.
[0934] MS: m/z 534.2 (M+H).sup.+.
Step 3: 4-[5-(2-Aminoethyl)pyrimidin-2-yl]-3-(6-piperidin-1-ylpyridazin-4-yl)sulfinylbenzonitrile
[0935] Dichloromethane (1 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 2, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (1.72 mg).
[0936] Exact MS: 433.2
[0937] Obs. MS (M+H).sup.+: 434.3
Example 42
5-[5-(2-Aminoethyl)pyridin-2-yl]-4-(2-methyl-5-phenylpyrazol-3-yl)oxypyridine-2-carbonitrile (Compound No. 1277)
[0938] ##STR01500##
Step 1: 5-Bromo-2-chloro-4-(2-methyl-5-phenylpyrazol-3-yl)oxypyridine
[0939] 5-Bromo-2,4-dichloropyridine (230 mug, 1.00 mmol) and 2-methyl-5-phenyl-4H-pyrazol-3-one (170 mg, 1.00 mmol) were dissolved in NMP (4 mL), then to the solution, potassium carbonate (280 mg, 2.00 mmol) was added, and the mixture was stirred at 130° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (279 mg, 77%).
[0940] MS: m/z 364.0 (M+H).sup.+.
Step 2: tert-Butyl N-[2-[6-[6-chloro-4-(2-methyl-5-phenylpyrazol-3-yl)oxypyridin-3-yl]pyridin-3-yl]ethyl]carbamate
[0941] tert-Butyl N-[2-(6-chloropyridin-3-yl)ethyl]carbamate (77 mg, 0.30 mmol) was dissolved in 1,4-dioxane (1.5 mL), then to the solution, hexamethylditin (128 mg, 0.390 mmol) and tetrakis(triphenylphosphine)palladium (34.7 mg, 0.030 mmol) were added, and the mixture was stirred at 130° C. for 1.5 hours. To the reaction mixture, 5-bromo-2-chloro-4-(2-methyl-5-phenylpyrazol-3-yl)oxypyridine (109 mg, 0.300 mmol) and copper(I) iodide (5.7 mg, 0.030 mmol) were added, and the mixture was stirred at 130° C. for 2 hours. The reaction solution was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (47.2 mg, 31%).
[0942] MS: m/z 506.2 (M+H).sup.+.
Step 3: tert-Butyl N-[2-[6-[6-cyano-4-(2-methyl-5-phenylpyrazol-3-yl)oxypyridin-3-yl]pyridin-3-yl]ethyl]carbamate
[0943] tert-Butyl N-[2-[6-[6-chloro-4-(2-methyl-5-phenylpyrazol-3-yl)oxypyridin-3-yl]pyridin-3-yl]ethyl]carbamate (32.2 mg, 0.0636 mmol) was dissolved in DMF (0.13 mL), then to the solution, zinc cyanide (4.5 mg, 0.038 mmol), zinc powder (0.4 mg, 6.4 μmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride-dichloromethane adduct (2.6 mg, 3.2 μmol) were added, and the mixture was stirred at 130° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
Step 4: 5-[5-(2-Aminoethyl)pyridin-2-yl]-4-(2-methyl-5-phenylpyrazol-3-yl)oxypyridine-2-carbonitrile
[0944] Dichloromethane (0.5 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 3, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (3.6 mg).
[0945] Exact MS: 396.2
[0946] Obs. MS (M+H).sup.+: 397.2
Example 43
5-[5-(2-Aminoethyl)pyridin-2-yl]-6-(2-methyl-5-phenylpyrazol-3-yl)oxypyridine-2-carbonitrile (Compound No. 1279)
[0947] ##STR01501##
Step 1: 3-Bromo-6-chloro-2-(2-methyl-5-phenylpyrazol-3-yl)oxypyridine
[0948] 3-Bromo-6-chloro-2-fluoropyridine (420 mg, 2.00 mmol) and 2-methyl-5-phenyl-4H-pyrazol-3-one (348 mg, 2.00 mmol) were dissolved in NMP (8 mL), then to the solution, potassium carbonate (552 mg, 3.99 mmol) was added, and the mixture was stirred at 130° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (495 mg, 68%).
[0949] MS: m/z 364.0 (M+H).sup.+.
Step 2: tert-Butyl N-[2-[6-[6-cyano-2-(2-methyl-5-phenylpyrazol-3-yl)oxypyridin-3-yl]pyridin-3-yl]ethyl]carbamate
[0950] tert-Butyl N-[2-(6-chloropyridin-3-yl)ethyl]carbamate (77 mg, 0.30 mmol) was dissolved in 1,4-dioxane (1.5 mL), then to the solution, hexamethylditin (128 mg, 0.390 mmol) and tetrakis(triphenylphosphine)palladium (34.7 mg, 0.030 mmol) were added, and the mixture was stirred at 130° C. for 1.5 hours. To the reaction mixture, 3-bromo-6-chloro-2-(2-methyl-5-phenylpyrazol-3-yl)oxypyridine (109 mg, 0.300 mmol) and copper(I) iodide (5.7 mg, 0.030 mmol) were added, and the mixture was stirred at 130° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (32.9 mg, 22%).
[0951] MS: m/z 506.2 (M+H).sup.+.
Step 3: tert-Butyl N-[2-[6-[6-cyano-2-(2-methyl-5-phenylpyrazol-3-yl)oxypyridin-3-yl]pyridin-3-yl]ethyl]carbamate
[0952] tert-Butyl N-[2-[6-[6-cyano-2-(2-methyl-5-phenylpyrazol-3-yl)oxypyridin-3-yl]pyridin-3-yl]ethyl]carbamate (20 mg, 0.0395 mmol) was dissolved in DMF (0.13 mL), then to the solution, zinc cyanide (2.8 mg, 0.024 mmol), zinc powder (0.3 mg, 4 μmol), and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride-dichloromethane adduct (1.6 mg, 2 μmol) were added, and the mixture was stirred at 130° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
[0953] MS: m/z 497.3 (M+H).sup.+.
Step 4: 5-[5-(2-Aminoethyl)pyridin-2-yl]-6-(2-methyl-5-phenylpyrazol-3-yl)oxypyridine-2-carbonitrile
[0954] Dichloromethane (0.5 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 3, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (8.6 mg).
[0955] Exact MS: 396.2
[0956] Obs. MS (M+H).sup.+: 397.4
Example 44
6-[5-(Aminomethyl)pyridin-2-yl]-5-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxypyridine-3-carbonitrile (Compound No. 1289)
[0957] ##STR01502##
Step 1: tert-Butyl N-[[6-(5-cyano-3-fluoropyridin-2-yl)pyridin-3-yl]methyl]carbamate
[0958] tert-Butyl N-[(6-chloropyridin-3-yl)methyl]carbamate (72.8 mg, 0.300 mmol) was dissolved in 1,4-dioxane (1.5 mL), then to the solution, hexamethylditin (128 mg, 0.390 mmol) and tetrakis(triphenylphosphine)palladium (34.7 mg, 0.030 mmol) were added, and the mixture was stirred at 130° C. for 1.5 hours. To the reaction mixture, 6-chloro-5-fluoropyridine-3-carbonitrile (51.7 mg, 0.330 mmol) and copper(I) iodide (5.7 mg, 0.030 mmol) were added, and the mixture was stirred at 130° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through Celite, and then the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound (77.9 mg, 79%).
[0959] MS: m/z 329.2 (M+H).sup.+.
Step, 2: tert-Butyl N-[[6-[5-cyano-3-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxypyridin-2-yl]pyridin-3-yl]methyl]carbamate
[0960] tert-Butyl N-[[6-(5-cyano-3-fluoropyridin-2-yl)pyridin-3-yl]methyl]carbamate (77.9 mg, 0.237 mmol) and 2-methyl-5-pyridin-2-yl-4H-pyrazol-3-one (41.6 mg, 0.237 mmol) were dissolved in NMP (0.95 mL), then to the solution, potassium carbonate (65.6 mg, 0.475 mmol) was added, and the mixture was stirred at 130° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The crude product was used in the next reaction without further purification.
Step 3: 6-[5-(Aminomethyl)pyridin-2-yl]-5-(2-methyl-5-pyridin-2-ylpyrazol-3-yl)oxypyridine-3-carbonitrile
[0961] Dichloromethane (0.5 mL) and TFA (0.5 mL) were added to the crude product obtained in Step 2, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain the target compound (6.9 mg).
[0962] Exact MS: 383.2
[0963] Obs. MS (M+H).sup.+: 384.2
Example 45
[0964] Compounds 1 to 1405 shown in Table 1 above were synthesized by protection, deprotection and the like as necessary according to the synthesis methods described in Examples 1 to 44. The MS data is shown in Table 2 below.
TABLE-US-00002 TABLE 2 Compound Exact Obs MS number MS (M + H).sup.+ 1 377.2 378.1 2 414.2 415.2 3 454.2 455.2 4 428.2 429.4 5 482.2 483.4 6 409.2 410.4 7 415.2 416.2 8 429.2 430.2 9 431.2 432.2 10 470.2 471.3 11 445.2 446.2 12 456.2 457.3 13 507.2 508.2 14 389.2 390.2 15 401.2 402.4 16 429.3 430.5 17 413.2 414.0 18 449.2 450.4 19 449.2 450.4 20 410.2 411.4 21 431.2 431.9 22 422.2 422.9 23 474.2 474.9 24 421.2 422.4 25 399.2 400.2 26 471.2 471.9 27 427.2 428.0 28 409.2 409.9 29 409.2 409.9 30 413.1 413.9 31 429.2 430.0 32 412.1 412.9 33 412.1 412.9 34 397.2 398.4 35 428.1 428.9 36 406.2 406.9 37 442.2 443.4 38 402.2 402.9 39 442.2 443.0 40 413.1 413.8 41 416.2 417.3 42 430.2 431.3 43 414.2 415.3 44 428.2 429.3 45 414.2 415.3 46 398.2 399.2 47 416.2 417.3 48 404.2 405.2 49 414.2 415.3 50 401.2 402.4 51 417.2 418.5 52 427.2 428.5 53 441.2 442.5 54 515.3 516.5 55 499.2 500.5 56 487.2 488.5 57 487.3 488.6 58 473.2 474.5 59 491.2 492.5 60 509.2 510.4 61 509.2 510.5 62 429.2 430.5 63 489.2 490.4 64 489.2 490.2 65 385.2 386.2 66 399.2 400.4 67 441.2 442.3 68 445.2 446.4 69 392.2 393.3 70 408.2 409.0 71 443.1 444.1 72 497.2 498.3 73 481.2 482.3 74 416.2 417.3 75 407.2 408.3 76 351.1 352.2 77 402.2 403.1 78 400.2 401.2 79 351.1 352.2 80 402.2 403.1 81 400.2 401.1 82 408.2 409.3 83 418.2 419.3 84 435.1 436.2 85 416.2 417.3 86 407.2 408.3 87 351.1 352.2 88 351.1 352.0 89 402.2 403.3 90 400.2 401.3 91 402.2 403.3 92 400.2 401.1 93 417.2 418.3 94 435.2 436.3 95 427.2 428.3 96 450.2 451.3 97 476.2 477.2 98 471.2 472.2 99 468.2 469.3 100 459.2 460.2 101 483.2 484.2 102 393.2 394.3 103 393.2 394.3 104 440.2 441.3 105 449.2 450.3 106 459.2 460.3 107 400.2 401.3 108 402.2 403.3 109 414.1 415.2 110 411.2 412.3 111 464.2 465.2 112 424.2 425.3 113 469.2 470.2 114 393.2 394.3 115 394.2 395.3 116 410.2 411.2 117 476.1 477.2 118 422.2 423.2 119 449.2 450.2 120 450.2 451.2 121 436.2 437.2 122 469.2 470.1 123 416.2 417.1 124 416.2 417.1 125 402.2 403.3 126 416.2 417.3 127 432.2 433.2 128 414.2 415.2 129 452.2 453.1 130 424.2 425.2 131 441.2 442.2 132 427.2 428.2 133 465.2 466.2 134 443.2 444.2 135 368.1 369.1 136 421.2 422.1 137 384.2 385.1 138 414.2 415.3 139 451.2 452.2 140 430.2 431.2 141 430.2 431.2 142 426.2 427.2 143 441.2 442.2 144 421.2 422.1 145 401.2 402.2 146 410.1 411.1 147 470.2 471.2 148 470.2 471.2 149 449.2 450.2 150 465.2 466.2 151 499.2 500.2 152 447.2 448.2 153 467.2 468.2 154 398.1 399.1 155 475.2 476.1 156 461.2 462.2 157 445.2 446.2 158 470.2 471.2 159 446.1 447.1 160 395.2 396.3 161 411.2 412.3 162 396.2 397.3 163 395.2 396.3 164 409.2 410.3 165 412.2 413.3 166 408.2 409.3 167 425.2 426.2 168 438.1 439.2 169 421.2 422.3 170 412.2 413.2 171 412.2 413.2 172 415.2 416.3 173 415.2 416.2 174 395.2 396.3 175 395.2 396.3 176 396.2 397.3 177 411.2 412.2 178 396.2 397.3 179 396.2 397.2 180 425.2 426.3 181 410.2 411.3 182 410.2 411.3 183 428.2 429.2 184 413.2 414.3 185 413.2 414.2 186 412.2 413.3 187 413.2 414.3 188 408.2 409.3 189 422.2 423.3 190 425.2 426.2 191 448.2 449.1 192 438.2 439.2 193 438.2 439.2 194 415.2 416.3 195 429.1 430.2 196 387.1 388.3 197 430.2 431.3 198 428.2 429.3 199 413.2 414.3 200 412.2 413.1 201 419.2 420.3 202 359.2 360.4 203 411.2 412.3 204 400.2 401.1 205 426.2 427.3 206 426.2 427.3 207 451.2 452.3 208 443.2 444.3 209 457.2 458.4 210 457.2 458.3 211 374.2 375.3 212 390.2 391.3 213 358.2 359.3 214 372.2 373.3 215 374.2 375.3 216 381.1 382.1 217 439.2 440.3 218 453.2 454.3 219 453.2 454.3 220 431.1 432.3 221 426.2 427.4 222 429.1 430.1 223 429.1 430.1 224 429.1 430.3 225 417.1 418.1 226 411.2 412.1 227 403.2 404.3 228 375.2 376.0 229 361.2 362.0 230 361.2 362.0 231 426.2 427.2 232 405.2 406.2 233 419.2 420.2 234 461.3 462.1 235 447.2 448.2 236 427.2 428.1 237 373.2 374.0 238 395.1 396.0 239 445.2 446.1 240 449.2 450.0 241 420.2 421.2 242 376.2 377.1 243 416.3 417.1 244 468.2 469.0 245 417.2 418.2 246 415.1 416.1 247 443.2 444.1 248 412.2 413.0 249 412.2 413.1 250 416.2 417.4 251 449.2 450.3 252 441.2 442.0 253 487.2 488.0 254 399.2 400.1 255 391.2 392.2 256 455.2 456.3 257 455.2 456.3 258 407.2 408.2 259 405.2 406.3 260 362.2 363.3 261 362.2 363.3 262 400.2 401.1 263 429.1 430.3 264 387.1 388.4 265 420.2 421.3 266 434.2 435.2 267 408.2 409.3 268 434.1 435.3 269 406.2 407.3 270 420.2 421.3 271 442.2 443.3 272 374.2 375.3 273 404.2 405.3 274 396.2 397.3 275 408.2 409.3 276 389.2 390.4 277 394.2 395.3 278 390.2 391.4 279 451.2 452.4 280 428.2 429.2 281 429.2 430.4 282 391.2 392.2 283 389.2 390.2 284 375.2 376.2 285 397.2 398.4 286 398.2 399.4 287 390.2 391.4 288 347.2 348.4 289 381.2 382.3 290 382.2 383.3 291 407.2 408.4 292 408.2 409.4 293 348.2 349.2 294 409.2 410.4 295 433.2 434.2 296 423.2 424.2 297 429.2 430.3 298 391.2 392.2 299 333.2 334.2 300 319.1 320.3 301 439.2 440.3 302 449.2 450.3 303 459.2 460.3 304 322.2 323.2 305 334.2 335.2 306 381.1 382.3 307 451.2 452.4 308 431.2 432.3 309 391.2 392.3 310 382.2 383.2 311 320.1 321.3 312 396.2 397.2 313 396.2 397.2 314 412.2 413.3 315 371.2 372.3 316 363.1 364.3 317 360.2 361.3 318 391.2 392.4 319 376.2 377.4 320 441.2 442.4 321 427.2 428.4 322 517.2 518.4 323 319.1 320.3 324 334.2 335.3 325 346.2 347.3 326 333.2 334.3 327 345.2 346.3 328 402.2 403.4 329 401.2 402.4 330 333.2 334.3 331 345.2 346.3 332 402.2 403.4 333 443.2 444.4 334 387.2 388.4 335 403.2 404.3 336 419.2 420.4 337 392.2 393.3 338 424.2 425.4 339 430.2 431.3 340 446.1 447.3 341 437.2 438.4 342 430.2 431.3 343 446.1 447.3 344 437.2 438.4 345 363.2 364.4 346 396.2 397.4 347 360.2 361.4 348 375.2 376.4 349 349.2 350.3 350 431.2 432.4 351 480.2 481.4 352 413.2 414.4 353 480.2 481.4 354 426.2 427.4 355 480.2 481.4 356 413.2 414.4 357 480.2 481.4 358 426.2 427.4 359 378.2 379.3 360 414.2 415.3 361 347.2 384.4 362 347.2 348.4 363 348.2 349.3 364 348.2 349.3 365 411.2 412.3 366 411.2 412.4 367 376.2 377.4 368 417.2 418.3 369 402.2 403.4 370 443.2 444.3 371 408.2 409.2 372 376.2 377.3 373 376.2 377.3 374 375.2 376.3 375 375.2 376.3 376 438.1 439.2 377 445.1 446.2 378 425.2 426.4 379 428.2 429.3 380 388.2 389.3 381 424.2 425.4 382 403.2 404.4 383 439.2 440.4 384 370.1 371.3 385 376.2 377.3 386 364.2 365.3 387 432.2 433.3 388 416.2 417.4 389 404.2 405.4 390 402.1 403.2 391 403.1 404.3 392 403.2 404.3 393 388.2 389.4 394 383.1 384.3 395 410.2 411.3 396 396.2 397.2 397 429.2 430.4 398 415.2 416.4 399 379.2 380.2 400 373.2 374.3 401 359.2 360.3 402 414.2 415.3 403 429.2 430.3 404 430.2 431.3 405 391.2 392.4 406 392.2 393.4 407 403.2 404.4 408 404.2 405.4 409 459.2 460.3 410 445.2 446.3 411 444.2 445.3 412 431.2 432.3 413 391.2 392.4 414 371.1 372.3 415 407.1 408.3 416 331.1 332.2 417 332.1 333.2 418 444.2 445.3 419 486.2 487.4 420 376.2 377.3 421 375.2 376.3 422 370.2 371.2 423 426.2 427.3 424 415.2 416.3 425 471.2 472.4 426 389.1 390.3 427 401.2 402.3 428 425.1 426.3 429 431.2 432.3 430 432.2 433.3 431 375.2 376.3 432 375.2 376.3 433 423.1 424.2 434 417.2 418.2 435 458.2 459.3 436 402.2 403.2 437 360.2 361.2 438 345.2 346.2 439 466.2 467.3 440 389.2 390.3 441 390.2 391.2 442 419.2 420.3 443 345.2 346.2 444 466.2 467.3 445 442.2 443.3 446 457.2 458.3 447 415.2 416.3 448 401.2 402.3 449 489.2 490.3 450 331.1 332.2 451 331.1 332.2 452 381.2 382.2 453 381.2 382.2 454 442.2 443.3 455 429.2 430.3 456 428.2 429.3 457 421.2 422.2 458 418.2 419.3 459 417.2 418.3 460 429.2 430.3 461 388.2 389.3 462 428.2 429.3 463 372.2 373.3 464 442.2 443.2 465 443.2 444.3 466 423.2 424.3 467 403.2 404.2 468 371.1 372.2 469 411.2 412.2 470 430.2 431.3 471 430.2 431.3 472 395.1 396.2 473 417.2 418.2 474 413.1 414.2 475 371.1 372.2 476 444.2 445.3 477 388.2 389.3 478 446.2 447.3 479 448.2 449.3 480 345.2 346.2 481 359.2 360.2 482 359.2 360.2 483 390.2 391.2 484 389.2 390.2 485 404.2 405.3 486 456.2 457.3 487 458.2 459.3 488 444.2 445.3 489 416.2 417.2 490 430.2 431.3 491 402.2 403.2 492 405.2 406.2 493 384.2 385.3 494 440.2 441.2 495 390.2 391.2 496 389.2 390.2 497 481.3 482.2 498 415.2 416.2 499 416.2 417.2 500 429.2 430.2 501 430.2 431.2 502 419.2 420.2 503 404.2 405.2 504 388.2 389.2 505 459.2 460.2 506 460.2 416.2 507 416.2 417.2 508 417.2 418.2 509 430.2 431.2 510 431.2 432.2 511 413.2 414.2 512 397.2 398.2 513 453.2 454.2 514 419.2 420.2 515 385.2 386.2 516 424.2 425.2 517 431.2 432.2 518 409.1 352.1 519 375.2 376.2 520 351.1 352.1 521 388.1 389.1 522 421.2 422.2 523 460.2 461.2 524 461.2 462.2 525 423.2 424.2 526 424.2 425.2 527 443.2 444.2 528 444.2 445.2 529 445.2 446.2 530 446.2 447.2 531 459.2 460.2 532 460.2 461.2 533 429.2 430.2 534 389.2 390.2 535 389.2 390.2 536 418.1 419.1 537 443.2 444.2 538 445.2 446.2 539 471.2 472.2 540 413.2 414.2 541 402.2 403.2 542 388.2 389.2 543 362.2 363.2 544 418.2 419.2 545 404.2 405.2 546 378.2 379.2 547 376.2 377.2 548 392.2 393.2 549 392.2 393.2 550 445.2 446.2 551 402.2 403.2 552 428.2 429.2 553 442.2 443.2 554 442.2 443.2 555 442.2 443.2 556 375.2 376.2 557 404.2 405.2 558 446.2 447.2 559 447.2 448.2 560 460.2 461.2 561 461.2 462.2 562 457.2 458.2 563 444.2 445.2 564 443.2 444.2 565 470.2 471.3 566 431.2 432.3 567 431.2 432.2 568 470.2 471.2 569 470.2 471.2 570 399.2 400.2 571 411.2 412.3 572 394.2 395.2 573 375.2 376.2 574 419.1 420.1 575 376.2 377.2 576 350.1 351.2 577 334.2 335.2 578 428.2 429.2 579 408.2 409.2 580 430.2 431.2 581 443.2 444.2 582 352.1 353.1 583 388.1 389.1 584 335.1 336.1 585 389.2 390.2 586 389.2 390.2 587 396.2 397.2 588 402.1 403.2 589 422.2 423.2 590 441.2 442.2 591 418.2 419.2 592 389.1 390.1 593 408.1 409.1 594 371.1 372.2 595 414.1 415.1 596 398.1 399.2 597 409.2 410.2 598 415.1 416.1 599 409.2 410.2 600 444.1 445.1 601 444.1 445.1 602 429.1 430.1 603 430.1 431.1 604 424.2 425.2 605 443.1 444.1 606 444.1 445.1 607 407.1 408.2 608 388.1 389.2 609 382.2 383.2 610 401.2 402.2 611 459.2 460.2 612 403.2 404.2 613 457.2 458.2 614 459.2 460.2 615 403.2 404.2 616 442.2 443.2 617 422.2 423.1 618 389.1 390.2 619 401.2 402.2 620 403.2 404.2 621 388.2 389.2 622 374.2 375.2 623 348.2 349.2 624 389.2 390.2 625 375.2 376.2 626 349.2 350.1 627 403.2 404.2 628 389.2 390.2 629 363.2 364.2 630 375.2 376.1 631 361.2 362.1 632 375.2 376.1 633 373.2 374.1 634 389.2 390.2 635 417.2 418.1 636 431.2 432.1 637 389.2 390.2 638 415.2 416.2 639 391.2 392.1 640 415.1 416.2 641 385.2 386.1 642 382.2 383.1 643 360.2 361.2 644 374.2 375.2 645 371.2 372.2 646 372.2 373.2 647 415.2 416.2 648 416.2 417.2 649 401.1 402.2 650 397.2 398.2 651 401.1 402.2 652 397.2 398.1 653 409.1 410.3 654 493.2 494.3 655 377.2 378.2 656 391.2 392.2 657 386.2 387.2 658 387.2 388.2 659 360.2 361.2 660 361.2 362.2 661 458.2 459.2 662 423.2 424.2 663 425.2 426.2 664 439.2 440.2 665 453.2 454.2 666 517.3 518.3 667 474.2 475.2 668 433.2 434.2 669 419.2 420.2 670 468.2 469.2 671 427.2 428.2 672 413.2 414.2 673 467.2 468.2 674 426.2 427.2 675 412.2 413.2 676 307.1 308.1 677 321.1 322.1 678 346.2 347.1 679 362.1 363.1 680 346.2 347.1 681 402.2 403.2 682 383.1 384.2 683 359.2 360.3 684 360.2 361.3 685 360.2 361.3 686 409.2 410.3 687 411.2 412.3 688 424.2 425.3 689 429.1 430.2 690 413.1 414.3 691 423.2 424.3 692 424.2 425.3 693 424.2 425.3 694 443.1 444.3 695 343.1 344.2 696 372.2 373.3 697 386.2 387.3 698 346.2 347.3 699 387.1 388.1 700 388.0 389.1 701 416.2 417.3 702 397.2 398.3 703 401.1 402.3 704 407.2 408.3 705 386.1 387.2 706 400.1 401.2 707 393.1 394.2 708 417.2 418.3 709 431.2 432.3 710 431.2 432.3 711 386.2 387.3 712 391.1 392.2 713 344.1 345.2 714 373.2 374.2 715 387.2 388.2 716 347.1 348.2 717 408.1 409.2 718 363.1 364.1 719 392.1 393.2 720 365.1 366.1 721 383.1 384.1 722 397.1 398.2 723 409.1 410.2 724 395.2 396.2 725 379.1 380.2 726 393.1 394.2 727 367.1 368.1 728 364.1 365.1 729 401.1 402.1 730 401.1 402.1 731 385.2 386.2 732 422.2 423.2 733 441.2 442.2 734 411.2 412.2 735 430.2 431.2 736 384.2 385.2 737 421.2 422.2 738 452.2 453.3 739 411.2 412.2 740 397.2 398.2 741 430.2 431.3 742 444.2 445.3 743 404.2 405.3 744 415.2 416.2 745 415.2 416.3 746 415.2 416.3 747 415.2 416.3 748 437.2 438.3 749 423.2 424.2 750 386.2 387.2 751 372.2 373.3 752 412.2 413.3 753 398.2 399.2 754 390.2 391.3 755 402.2 403.2 756 481.2 482.3 757 481.2 482.3 758 405.2 406.3 759 419.2 420.3 760 407.2 408.2 761 443.1 444.2 762 452.2 453.3 763 361.2 362.2 764 361.2 362.3 765 375.2 376.3 766 375.1 376.3 767 419.2 420.2 768 425.2 426.3 769 403.2 404.3 770 391.2 392.3 771 405.2 406.3 772 391.2 392.3 773 390.2 391.3 774 377.2 378.3 775 391.2 392.3 776 360.2 361.3 777 360.2 361.2 778 428.2 429.3 779 414.2 415.3 780 428.2 429.3 781 442.2 443.3 782 456.2 457.3 783 442.2 443.3 784 404.2 405.3 785 472.2 473.3 786 413.2 414.3 787 431.2 432.3 788 388.2 389.3 789 373.2 374.3 790 375.2 376.4 791 389.2 390.4 792 389.2 390.4 793 391.2 392.1 794 401.2 402.4 795 401.2 402.4 796 401.2 402.4 797 405.2 406.4 798 393.2 394.3 799 392.2 393.2 800 421.2 422.3 801 376.2 377.3 802 362.2 363.2 803 362.2 363.1 804 376.2 377.3 805 362.2 363.2 806 362.2 363.2 807 422.1 423.3 808 397.2 398.3 809 397.2 398.3 810 373.1 374.3 811 374.1 375.3 812 388.1 389.3 813 363.2 364.3 814 349.2 350.2 815 421.1 422.3 816 421.1 422.3 817 381.1 382.3 818 388.2 389.3 819 376.2 377.3 820 397.1 398.2 821 401.2 402.4 822 395.2 396.4 823 427.2 428.3 824 387.2 388.4 825 403.2 404.4 826 412.2 413.4 827 426.2 427.3 828 355.1 356.3 829 356.1 357.3 830 397.2 398.2 831 383.1 384.2 832 397.2 398.2 833 383.1 384.2 834 402.1 403.2 835 388.1 389.2 836 402.1 403.2 837 388.1 389.2 838 435.2 436.5 839 509.3 510.4 840 528.3 529.4 841 451.2 452.2 842 405.2 406.4 843 392.2 393.4 844 404.2 405.4 845 404.2 405.4 846 390.2 391.4 847 424.1 425.4 848 390.2 391.4 849 404.2 405.4 850 400.2 401.4 851 401.2 402.4 852 403.2 404.4 853 387.2 388.4 854 389.2 390.4 855 401.2 402.4 856 403.2 404.4 857 403.2 404.4 858 405.2 406.4 859 415.2 416.4 860 415.2 416.4 861 415.2 416.4 862 419.2 420.4 863 435.2 436.4 864 402.2 403.4 865 388.2 389.4 866 447.1 448.3 867 421.2 422.4 868 435.2 436.3 869 432.2 433.4 870 346.2 347.3 871 402.2 403.3 872 434.2 435.3 873 399.2 400.2 874 413.2 414.3 875 427.2 428.3 876 434.2 435.4 877 461.2 462.3 878 435.2 436.4 879 417.2 418.4 880 415.2 416.2 881 414.2 415.4 882 387.1 388.3 883 438.2 439.3 884 430.1 431.4 885 432.2 433.2 886 404.2 405.3 887 402.2 403.4 888 418.2 419.4 889 418.2 419.3 890 406.2 407.4 891 412.1 413.3 892 388.2 389.3 893 416.1 417.3 894 418.2 419.4 895 390.1 391.3 896 376.2 377.3 897 398.1 399.3 898 374.1 375.3 899 416.2 417.3 900 430.2 431.3 901 402.2 403.4 902 416.2 417.4 903 406.1 407.3 904 406.1 407.3 905 381.2 382.4 906 381.2 382.3 907 362.2 363.3 908 348.2 349.3 909 380.2 381.2 910 380.2 381.2 911 388.1 389.2 912 383.1 384.2 913 409.2 410.4 914 409.2 410.4 915 408.2 409.4 916 408.2 409.4 917 402.2 403.3 918 388.2 389.3 919 416.2 417.3 920 402.2 403.3 921 416.2 417.3 922 402.2 403.3 923 373.2 374.2 924 384.2 385.4 925 384.2 385.4 926 386.1 387.0 927 370.1 371.3 928 401.1 402.2 929 384.0 385.1 930 384.1 385.2 931 384.1 385.2 932 384.1 385.2 933 400.2 401.2 934 384.1 385.2 935 389.1 390.2 936 386.2 387.2 937 390.2 391.2 938 390.2 391.2 939 390.2 391.2 940 398.2 399.2 941 411.2 412.2 942 376.2 377.2 943 416.2 417.2 944 417.2 418.3 945 386.2 387.2 946 386.2 387.2 947 386.2 387.2 948 389.1 390.0 949 398.2 399.0 950 398.2 399.2 951 403.1 404.0 952 403.1 404.0 953 390.2 391.1 954 390.2 391.2 955 430.2 431.1 956 377.2 378.2 957 403.1 404.2 958 403.1 404.1 959 403.1 404.1 960 403.1 404.1 961 404.1 405.2 962 403.1 404.2 963 403.1 404.1 964 344.1 345.2 965 410.2 411.4 966 369.2 370.4 967 369.2 370.3 968 395.1 396.5 969 390.2 391.2 970 395.1 396.5 971 390.2 391.5 972 384.2 385.2 973 398.2 399.2 974 384.2 385.2 975 397.2 398.3 976 383.2 384.2 977 390.2 391.4 978 409.2 410.2 979 382.2 383.2 980 381.2 382.2 981 341.2 342.2 982 355.2 356.2 983 355.2 356.2 984 355.2 356.2 985 383.2 384.2 986 383.2 384.2 987 406.2 407.2 988 405.2 406.2 989 420.2 421.2 990 419.2 420.3 991 383.2 384.2 992 370.2 371.2 993 392.2 393.2 994 406.2 407.2 995 368.2 369.2 996 367.2 368.2 997 342.2 343.0 998 341.2 342.0 999 356.2 357.0 1000 355.2 356.0 1001 409.2 410.0 1002 396.2 397.0 1003 395.2 396.0 1004 376.1 377.0 1005 363.1 364.0 1006 395.2 396.0 1007 383.2 384.2 1008 382.2 383.2 1009 397.2 398.2 1010 396.2 397.1 1011 340.2 342.1 1012 341.2 341.1 1013 355.2 356.2 1014 354.2 355.2 1015 339.1 340.1 1016 338.2 339.1 1017 353.2 354.1 1018 352.2 353.1 1019 381.1 382.1 1020 357.1 358.2 1021 371.2 372.2 1022 379.1 380.1 1023 397.1 398.2 1024 392.1 393.2 1025 360.2 361.3 1026 346.2 347.3 1027 417.2 418.4 1028 403.2 404.3 1029 402.2 403.3 1030 374.2 375.4 1031 388.2 389.4 1032 403.2 404.4 1033 386.2 387.5 1034 386.2 387.5 1035 372.2 373.4 1036 372.2 373.4 1037 395.1 396.3 1038 381.1 382.2 1039 403.1 404.1 1040 429.2 430.2 1041 402.2 403.3 1042 428.2 429.3 1043 375.2 376.1 1044 360.2 361.2 1045 346.2 347.2 1046 372.2 373.2 1047 358.2 359.2 1048 401.1 402.1 1049 414.2 415.2 1050 387.1 388.1 1051 361.2 362.2 1052 396.1 397.0 1053 415.2 416.3 1054 360.2 361.2 1055 382.1 383.0 1056 388.2 389.2 1057 372.2 373.1 1058 358.2 359.1 1059 432.2 433.2 1060 374.2 375.2 1061 389.2 390.1 1062 415.2 416.2 1063 401.2 402.1 1064 420.1 421.2 1065 434.2 435.2 1066 419.1 420.1 1067 419.1 420.2 1068 433.2 434.2 1069 420.1 421.1 1070 434.2 435.1 1071 401.2 402.2 1072 387.2 388.2 1073 439.2 440.1 1074 425.2 426.1 1075 360.2 361.1 1076 433.2 434.1 1077 487.1 488.1 1078 488.1 489.1 1079 413.2 414.1 1080 473.1 474.0 1081 402.2 403.1 1082 390.1 391.1 1083 403.2 404.1 1084 404.2 405.1 1085 389.1 390.1 1086 403.2 404.1 1087 474.1 475.1 1088 419.1 420.1 1089 390.1 391.1 1090 391.1 392.1 1091 404.2 407.1 1092 405.2 406.1 1093 406.1 408.1 1094 420.1 421.1 1095 407.1 408.1 1096 421.1 422.1 1097 421.2 422.3 1098 375.1 376.2 1099 361.1 362.2 1100 325.1 326.1 1101 365.2 366.2 1102 353.2 354.2 1103 422.2 423.0 1104 408.2 409.2 1105 396.2 397.0 1106 409.2 410.0 1107 410.2 411.0 1108 365.2 366.2 1109 351.1 352.1 1110 364.2 365.2 1111 378.2 379.3 1112 378.2 379.3 1113 387.2 388.3 1114 401.2 402.3 1115 401.2 402.2 1116 346.2 347.1 1117 388.2 389.2 1118 346.2 347.3 1119 388.2 389.3 1120 392.2 393.2 1121 344.2 345.3 1122 369.2 370.3 1123 370.2 371.3 1124 446.2 447.2 1125 460.2 461.3 1126 388.2 389.2 1127 384.2 384.9 1128 398.2 399.1 1129 394.2 395.2 1130 408.2 409.2 1131 379.2 380.3 1132 379.2 380.3 1133 395.2 396.4 1134 380.2 381.3 1135 380.2 381.2 1136 395.2 396.4 1137 394.2 395.4 1138 395.2 396.4 1139 409.2 410.3 1140 375.2 376.4 1141 376.2 377.4 1142 390.2 391.4 1143 397.2 398.4 1144 413.1 414.3 1145 393.2 394.4 1146 393.2 394.4 1147 397.2 398.4 1148 393.2 394.4 1149 397.2 398.4 1150 393.2 394.4 1151 407.2 408.4 1152 411.2 412.4 1153 407.2 408.4 1154 411.2 412.4 1155 407.2 408.4 1156 411.2 412.4 1157 394.2 395.3 1158 393.2 394.3 1159 373.2 374.3 1160 380.2 381.3 1161 427.2 428.2 1162 428.2 429.2 1163 387.2 388.2 1164 388.2 389.2 1165 417.2 418.3 1166 418.2 419.2 1167 381.2 382.3 1168 367.2 368.2 1169 381.2 382.3 1170 367.2 368.2 1171 360.2 361.3 1172 346.2 347.3 1173 386.1 387.2 1174 372.1 373.2 1175 401.2 402.3 1176 368.2 369.2 1177 433.2 434.3 1178 375.2 376.4 1179 415.2 416.4 1180 483.2 484.4 1181 389.2 390.4 1182 380.2 381.3 1183 366.2 367.2 1184 361.2 362.3 1185 347.2 348.3 1186 387.2 388.3 1187 345.2 346.2 1188 347.2 348.3 1189 333.2 334.2 1190 373.2 374.3 1191 331.2 332.2 1192 399.2 400.2 1193 412.2 413.2 1194 413.2 414.3 1195 360.2 361.0 1196 346.2 347.0 1197 381.2 382.2 1198 373.2 374.2 1199 374.2 375.2 1200 389.2 390.2 1201 380.2 381.1 1202 395.2 396.2 1203 394.2 395.2 1204 414.2 415.3 1205 381.2 382.1 1206 375.2 376.2 1207 389.2 390.2 1208 388.2 389.2 1209 347.2 348.1 1210 373.2 374.2 1211 387.2 388.2 1212 386.2 387.2 1213 387.2 388.2 1214 395.2 396.3 1215 394.2 395.3 1216 361.2 363.3 1217 360.2 361.2 1218 401.2 402.4 1219 400.2 401.4 1220 374.2 375.0 1221 352.2 353.0 1222 353.2 354.1 1223 339.2 340.0 1224 367.2 368.3 1225 353.2 354.3 1226 427.2 428.5 1227 439.2 440.5 1228 425.2 426.2 1229 395.2 396.3 1230 425.2 426.3 1231 409.2 410.3 1232 416.1 417.2 1233 375.2 376.4 1234 376.2 377.2 1235 390.2 391.1 1236 404.2 405.2 1237 429.2 430.2 1238 433.2 434.1 1239 417.2 418.4 1240 415.2 416.4 1241 401.2 402.4 1242 418.2 419.4 1243 416.2 417.4 1244 402.2 403.4 1245 407.2 408.3 1246 405.2 406.4 1247 391.2 392.4 1248 432.2 433.2 1249 430.2 431.3 1250 416.2 417.4 1251 421.2 422.4 1252 419.2 420.3 1253 405.2 406.4 1254 433.2 434.3 1255 431.2 432.4 1256 417.2 418.4 1257 419.2 420.3 1258 417.2 418.3 1259 403.2 404.3 1260 432.2 433.2 1261 418.2 419.2 1262 403.2 404.2 1263 377.1 378.3 1264 388.1 389.2 1265 389.1 390.2 1266 362.1 363.2 1267 363.1 364.2 1268 403.2 404.2 1269 409.1 410.1 1270 423.1 424.2 1271 411.1 412.2 1272 377.1 378.2 1273 391.2 392.3 1274 440.1 441.3 1275 426.1 427.2 1276 433.2 434.3 1277 396.2 397.2 1278 382.2 383.2 1279 396.2 397.4 1280 397.2 398.3 1281 361.2 362.2 1282 400.2 401.5 1283 384.1 385.4 1284 416.2 417.4 1285 403.2 404.2 1286 395.1 396.2 1287 384.1 385.2 1288 382.2 383.3 1289 383.1 384.2 1290 405.1 406.3 1291 391.1 392.2 1292 405.1 406.2 1293 391.1 392.3
Example 46
[0965] Evaluation of TRPC6 Channel Inhibitory Activity (1) (Compound Nos. 1-1293)
[0966] In order to investigate TRPC6 channel inhibitory activity of the compounds, evaluation was conducted using FLIPR® Calcium 5 Assay Kit (Molecular Devices) in accordance with the following procedure. Human TRPC6 stably-expressing cells were seeded in a 384-well black clear bottom plate at a density of 5×10.sup.3/well and cultured in an incubator at 37° C. 5% CO.sub.2 for 24 hours. Thereafter, 25 μL of a Non Wash Dye Solution, prepared using Component A, 20 mM HEPES-HBSS and 250 mM probenecid, all of which are included in the kit, was added to each well, and the plate was incubated for 30 minutes. A volume of 12.5 μL of a compound solution was added into each well while the fluorescence was measured with FLIPR tetra. After 20 minutes, 12.5 μL of a 1-oleoyl-2-acetyl glycerol (OAG) solution was added at a final concentration of 30 μM. The difference between the minimum fluorescence intensity before the addition of the compound and the maximum fluorescence intensity after the addition of OAG was defined as a signal. An inhibition rate was calculated, assuming the average signal of wells without the compound as the inhibition rate of 0% and the average signal of wells without the compound and OAG as the inhibition rate of 100%. The calculated inhibition rate was analyzed by a four-parameter logistic regression to quantify the inhibition rate in the logarithm of the inverse of the effective concentration which gives a 50% inhibition rate (pIC.sub.50). The results are shown in the following Table 3. The intensity was expressed by the following symbols (+, ++, +++).
+: pIC.sub.50<6.0
++: 6.0≤pIC.sub.50<8.0
+++: 8.0≤pIC.sub.50
Example 47
[0967] Evaluation of TRPC6 Channel Inhibitory Activity (2) (Compound Nos. 1293 to 1405)
[0968] The activity of the TRPC6 inhibitor was measured by stimulating HEK293 cells, in which human TRPC6 was stably introduced, with OAG (1-Oleoyl-2-acetyl-sn-glycerol, Miliipore Sigma, 06754), using the FLIPR tetra system. The cells were proliferated in a humid environment at 37° C. 5% CO.sub.2 using a growth medium (DMEM (Dulbecco's Modified Eagle's Medium) high glucose containing 10% fetal bovine serum, 1×PSGlu (penicillin-streptomycin glutamine), 1×NEAA (Non-essential amino acid), sodium pyruvate and 200 μg/mL hyglomycin. For cell subculture, the cells were proliferated to 70-90% confluence, and gently washed twice with PBS (phosphate-buffered saline) free of calcium and magnesium after removing the medium. Then, the cells were incubated at 37° C. for 5 minutes after adding trypsin (3 mL), peeled off by tapping the flask at the base of the hand, 7 mL of growth medium was added to inactivate trypsin, and then the cells were resuspended. Usually, the cells were separated every 2-3 days to become a cell density of ⅕. The day before evaluation, the cells were seeded in a poly-D-lysine (PDL) coated 384-well plate using a multi-channel pipette or multidrop at a cell density of 1.0-1.5×10.sup.4 cells/25 μL/well. After culturing overnight in a PDL-coated 384 Blackwell plate, a fluorescent dye buffer was added first to the cells and the cells were cultured at room temperature for 90-120 minutes. For preparing 10 mL of fluorescent dye buffer, 9 mL of assay buffer, 1 mL of 10×PBX signal enhancer, and 10 μL of calcium indicator were mixed. Cells treated with the compounds of each level 25 minutes before the stimulation with OAG of TRPC6 agonist were incubated. OAG solution was prepared by adding OAG to assay buffer (Ca ringer solution base: 10 mM HEPES (4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid), 4 mM MgCl.sub.2, 120 mM NaCl, 5 mM KCl, pH=7.2 (25° C.)+0.1% BSA+2 mM CaCl.sub.2)) to give an OAG concentration of 0.2 mM/2% DMSO. The final concentration of OAG added to the cells is 50 μM/0.5% DMSO. A volume of 12.5 μL of OAG solution was added, and activation of TRPC6 channel was measured using the FLIPR tetra system assaying the change in intracellular calcium level as an index. The 180 seconds imaging frame was defined as the background signal, and the subtraction of the background signal from the raw data was used as the fluorescence peak signal. Each fluorescence peak signal is standardized using an OAG-induced signal and buffer-induced signal as 100% and 0%, respectively. The inhibition rate obtained by plotting the peak signal after the addition of the compounds of each level was analyzed by a four-parameter logistic regression to quantify the inhibition rate in the logarithm of the inverse of the effective concentration which gives a 50% inhibition rate (pIC.sub.50). The results are shown in the following Table 3. The intensity was expressed by the above-mentioned symbols (+, ++, +++).
TABLE-US-00003 TABLE 3 Compound Inhibitory number activity 1 ++ 2 +++ 3 ++ 4 + 5 + 6 +++ 7 +++ 8 + 9 +++ 10 + 11 +++ 12 + 13 ++ 14 + 15 ++ 16 ++ 17 +++ 18 ++ 19 ++ 20 ++ 21 +++ 22 ++ 23 ++ 24 ++ 25 +++ 26 +++ 27 ++ 28 ++ 29 ++ 30 +++ 31 ++ 32 +++ 33 +++ 34 ++ 35 ++ 36 ++ 37 + 38 + 39 + 40 + 41 + 42 + 43 ++ 44 + 45 ++ 46 +++ 47 ++ 48 ++ 49 ++ 50 +++ 51 + 52 ++ 53 ++ 54 + 55 + 56 + 57 + 58 ++ 59 ++ 60 ++ 61 + 62 +++ 63 + 64 + 65 +++ 66 +++ 67 ++ 68 ++ 69 +++ 70 +++ 71 ++ 72 ++ 73 ++ 74 ++ 75 ++ 76 + 77 + 78 ++ 79 + 80 + 81 + 82 +++ 83 + 84 ++ 85 ++ 86 ++ 87 + 88 + 89 + 90 ++ 91 + 92 + 93 +++ 94 + 95 + 96 + 97 + 98 + 99 + 100 +++ 101 +++ 102 ++ 103 ++ 104 + 105 + 106 + 107 ++ 108 ++ 109 + 110 + 111 ++ 112 +++ 113 +++ 114 ++ 115 +++ 116 ++ 117 ++ 118 ++ 119 + 120 +++ 121 + 122 ++ 123 ++ 124 ++ 125 ++ 126 + 127 + 128 + 129 + 130 +++ 131 + 132 ++ 133 +++ 134 ++ 135 + 136 ++ 137 +++ 138 +++ 139 ++ 140 ++ 141 ++ 142 ++ 143 + 144 ++ 145 ++ 146 + 147 ++ 148 ++ 149 +++ 150 +++ 151 ++ 152 ++ 153 +++ 154 ++ 155 ++ 156 ++ 157 +++ 158 ++ 159 +++ 160 +++ 161 +++ 162 +++ 163 ++ 164 +++ 165 ++ 166 ++ 167 ++ 168 ++ 169 + 170 +++ 171 +++ 172 +++ 173 +++ 174 +++ 175 +++ 176 +++ 177 +++ 178 ++ 179 +++ 180 +++ 181 ++ 182 +++ 183 +++ 184 ++ 185 +++ 186 +++ 187 +++ 188 + 189 + 190 ++ 191 + 192 ++ 193 + 194 + 195 ++ 196 ++ 197 +++ 198 +++ 199 +++ 200 + 201 + 202 +++ 203 ++ 204 +++ 205 +++ 206 +++ 207 ++ 208 + 209 + 210 + 211 +++ 212 +++ 213 +++ 214 ++ 215 +++ 216 ++ 217 + 218 + 219 ++ 220 + 221 ++ 222 ++ 223 ++ 224 ++ 225 +++ 226 +++ 227 +++ 228 +++ 229 +++ 230 +++ 231 +++ 232 +++ 233 +++ 234 + 235 ++ 236 ++ 237 +++ 238 +++ 239 + 240 ++ 241 +++ 242 + 243 + 244 ++ 245 ++ 246 +++ 247 +++ 248 +++ 249 +++ 250 +++ 251 + 252 + 253 +++ 254 +++ 255 ++ 256 ++ 257 ++ 258 +++ 259 ++ 260 +++ 261 +++ 262 +++ 263 ++ 264 +++ 265 ++ 266 +++ 267 +++ 268 ++ 269 ++ 270 ++ 271 ++ 272 +++ 273 +++ 274 +++ 275 +++ 276 +++ 277 +++ 278 +++ 279 + 280 ++ 281 + 282 ++ 283 ++ 284 ++ 285 +++ 286 ++ 287 +++ 288 +++ 289 +++ 290 ++ 291 + 292 ++ 293 +++ 294 +++ 295 +++ 296 +++ 297 ++ 298 ++ 299 +++ 300 ++ 301 +++ 302 ++ 303 ++ 304 + 305 ++ 306 +++ 307 ++ 308 ++ 309 ++ 310 +++ 311 + 312 +++ 313 +++ 314 +++ 315 +++ 316 + 317 +++ 318 +++ 319 +++ 320 +++ 321 +++ 322 ++ 323 ++ 324 +++ 325 +++ 326 +++ 327 +++ 328 +++ 329 +++ 330 + 331 ++ 332 ++ 333 +++ 334 +++ 335 +++ 336 +++ 337 +++ 338 +++ 339 ++ 340 ++ 341 +++ 342 ++ 343 ++ 344 +++ 345 ++ 346 +++ 347 + 348 +++ 349 + 350 ++ 351 ++ 352 ++ 353 ++ 354 ++ 355 + 356 ++ 357 ++ 358 ++ 359 ++ 360 +++ 361 +++ 362 +++ 363 +++ 364 +++ 365 +++ 366 +++ 367 +++ 368 ++ 369 ++ 370 +++ 371 +++ 372 +++ 373 +++ 374 +++ 375 +++ 376 +++ 377 ++ 378 +++ 379 +++ 380 ++ 381 +++ 382 +++ 383 +++ 384 +++ 385 ++ 386 ++ 387 ++ 388 +++ 389 ++ 390 +++ 391 +++ 392 +++ 393 +++ 394 +++ 395 ++ 396 +++ 397 ++ 398 +++ 399 +++ 400 ++ 401 +++ 402 +++ 403 +++ 404 +++ 405 +++ 406 +++ 407 +++ 408 ++ 409 ++ 410 ++ 411 ++ 412 ++ 413 +++ 414 + 415 + 416 + 417 + 418 ++ 419 + 420 ++ 421 ++ 422 ++ 423 ++ 424 + 425 + 426 +++ 427 ++ 428 ++ 429 +++ 430 +++ 431 ++ 432 +++ 433 ++ 434 +++ 435 + 436 + 437 ++ 438 ++ 439 +++ 440 +++ 441 +++ 442 ++ 443 ++ 444 +++ 445 +++ 446 +++ 447 +++ 448 +++ 449 + 450 + 451 + 452 + 453 + 454 +++ 455 + 456 + 457 + 458 +++ 459 +++ 460 + 461 +++ 462 + 463 + 464 + 465 + 466 + 467 +++ 468 + 469 +++ 470 +++ 471 +++ 472 ++ 473 ++ 474 + 475 + 476 ++ 477 +++ 478 ++ 479 + 480 + 481 + 482 +++ 483 +++ 484 +++ 485 +++ 486 + 487 + 488 + 489 + 490 + 491 ++ 492 ++ 493 +++ 494 ++ 495 ++ 496 +++ 497 + 498 +++ 499 +++ 500 +++ 501 +++ 502 +++ 503 +++ 504 + 505 +++ 506 +++ 507 +++ 508 +++ 509 +++ 510 +++ 511 + 512 ++ 513 ++ 514 ++ 515 ++ 516 + 517 +++ 518 ++ 519 ++ 520 ++ 521 +++ 522 +++ 523 ++ 524 ++ 525 +++ 526 +++ 527 +++ 528 ++ 529 +++ 530 +++ 531 +++ 532 +++ 533 + 534 ++ 535 + 536 +++ 537 + 538 ++ 539 ++ 540 + 541 +++ 542 +++ 543 +++ 544 +++ 545 ++ 546 ++ 547 ++ 548 + 549 ++ 550 +++ 551 ++ 552 + 553 + 554 + 555 + 556 ++ 557 ++ 558 ++ 559 ++ 560 ++ 561 ++ 562 +++ 563 + 564 ++ 565 + 566 ++ 567 ++ 568 + 569 + 570 ++ 571 + 572 ++ 573 ++ 574 ++ 575 +++ 576 + 577 ++ 578 ++ 579 ++ 580 ++ 581 + 582 + 583 + 584 + 585 + 586 + 587 +++ 588 ++ 589 ++ 590 + 591 + 592 +++ 593 + 594 + 595 ++ 596 ++ 597 ++ 598 ++ 599 +++ 600 ++ 601 ++ 602 ++ 603 ++ 604 +++ 605 ++ 606 ++ 607 + 608 + 609 +++ 610 +++ 611 + 612 + 613 ++ 614 + 615 + 616 ++ 617 ++ 618 ++ 619 +++ 620 ++ 621 +++ 622 +++ 623 +++ 624 +++ 625 +++ 626 +++ 627 +++ 628 +++ 629 +++ 630 ++ 631 ++ 632 ++ 633 ++ 634 +++ 635 + 636 + 637 +++ 638 ++ 639 + 640 ++ 641 ++ 642 +++ 643 ++ 644 +++ 645 ++ 646 ++ 647 + 648 + 649 ++ 650 ++ 651 +++ 652 +++ 653 ++ 654 + 655 +++ 656 +++ 657 +++ 658 ++ 659 ++ 660 + 661 + 662 ++ 663 ++ 664 ++ 665 + 666 + 667 ++ 668 +++ 669 ++ 670 +++ 671 +++ 672 +++ 673 + 674 ++ 675 ++ 676 + 677 + 678 + 679 + 680 + 681 + 682 ++ 683 + 684 + 685 + 686 + 687 + 688 ++ 689 ++ 690 ++ 691 +++ 692 + 693 ++ 694 ++ 695 +++ 696 +++ 697 +++ 698 ++ 699 + 700 + 701 +++ 702 +++ 703 ++ 704 +++ 705 ++ 706 +++ 707 ++ 708 +++ 709 ++ 710 ++ 711 +++ 712 ++ 713 ++ 714 +++ 715 +++ 716 ++ 717 ++ 718 +++ 719 ++ 720 + 721 + 722 ++ 723 ++ 724 +++ 725 + 726 ++ 727 ++ 728 ++ 729 ++ 730 ++ 731 + 732 ++ 733 + 734 +++ 735 +++ 736 ++ 737 +++ 738 ++ 739 ++ 740 + 741 ++ 742 +++ 743 +++ 744 ++ 745 + 746 + 747 + 748 +++ 749 ++ 750 ++ 751 + 752 ++ 753 + 754 +++ 755 ++ 756 + 757 + 758 +++ 759 +++ 760 +++ 761 + 762 + 763 + 764 ++ 765 +++ 766 + 767 +++ 768 +++ 769 +++ 770 +++ 771 ++ 772 +++ 773 +++ 774 +++ 775 +++ 776 + 777 + 778 + 779 + 780 + 781 + 782 + 783 + 784 + 785 ++ 786 +++ 787 +++ 788 + 789 ++ 790 ++ 791 ++ 792 ++ 793 + 794 ++ 795 +++ 796 ++ 797 + 798 ++ 799 +++ 800 ++ 801 +++ 802 +++ 803 +++ 804 ++ 805 ++ 806 ++ 807 ++ 808 +++ 809 +++ 810 +++ 811 +++ 812 +++ 813 + 814 + 815 ++ 816 + 817 + 818 ++ 819 ++ 820 + 821 ++ 822 +++ 823 +++ 824 ++ 825 ++ 826 +++ 827 +++ 828 +++ 829 ++ 830 ++ 831 + 832 +++ 833 +++ 834 +++ 835 +++ 836 ++ 837 ++ 838 ++ 839 + 840 + 841 + 842 +++ 843 + 844 + 845 + 846 ++ 847 + 848 +++ 849 +++ 850 +++ 851 + 852 + 853 ++ 854 +++ 855 ++ 856 +++ 857 +++ 858 ++ 859 +++ 860 +++ 861 +++ 862 ++ 863 + 864 ++ 865 + 866 +++ 867 + 868 ++ 869 + 870 ++ 871 + 872 +++ 873 +++ 874 +++ 875 +++ 876 +++ 877 +++ 878 +++ 879 + 880 ++ 881 + 882 + 883 ++ 884 ++ 885 + 886 + 887 ++ 888 ++ 889 + 890 ++ 891 ++ 892 ++ 893 + 894 + 895 + 896 ++ 897 + 898 + 899 ++ 900 +++ 901 + 902 ++ 903 +++ 904 +++ 905 +++ 906 +++ 907 +++ 908 +++ 909 +++ 910 +++ 911 ++ 912 +++ 913 +++ 914 +++ 915 +++ 916 +++ 917 ++ 918 + 919 ++ 920 + 921 + 922 + 923 ++ 924 ++ 925 + 926 + 927 ++ 928 ++ 929 + 930 ++ 931 ++ 932 +++ 933 + 934 ++ 935 +++ 936 ++ 937 +++ 938 ++ 939 ++ 940 + 941 + 942 + 943 + 944 ++ 945 +++ 946 ++ 947 + 948 +++ 949 +++ 950 +++ 951 +++ 952 +++ 953 +++ 954 ++ 955 +++ 956 ++ 957 +++ 958 +++ 959 ++ 960 ++ 961 + 962 ++ 963 +++ 964 ++ 965 ++ 966 +++ 967 ++ 968 +++ 969 +++ 970 + 971 + 972 +++ 973 ++ 974 ++ 975 +++ 976 ++ 977 +++ 978 +++ 979 +++ 980 +++ 981 ++ 982 ++ 983 +++ 984 ++ 985 +++ 986 ++ 987 +++ 988 +++ 989 +++ 990 +++ 991 +++ 992 +++ 993 ++ 994 ++ 995 ++ 996 +++ 997 ++ 998 ++ 999 ++ 1000 +++ 1001 +++ 1002 + 1003 ++ 1004 ++ 1005 + 1006 ++ 1007 ++ 1008 ++ 1009 ++ 1010 +++ 1011 +++ 1012 +++ 1013 +++ 1014 +++ 1015 ++ 1016 ++ 1017 +++ 1018 +++ 1019 ++ 1020 ++ 1021 ++ 1022 + 1023 ++ 1024 ++ 1025 +++ 1026 +++ 1027 +++ 1028 +++ 1029 +++ 1030 +++ 1031 +++ 1032 +++ 1033 +++ 1034 ++ 1035 +++ 1036 + 1037 +++ 1038 ++ 1039 ++ 1040 ++ 1041 ++ 1042 +++ 1043 +++ 1044 +++ 1045 +++ 1046 +++ 1047 +++ 1048 +++ 1049 +++ 1050 ++ 1051 +++ 1052 ++ 1053 + 1054 +++ 1055 + 1056 ++ 1057 +++ 1058 +++ 1059 +++ 1060 +++ 1061 +++ 1062 +++ 1063 +++ 1064 ++ 1065 +++ 1066 +++ 1067 + 1068 ++ 1069 + 1070 + 1071 +++ 1072 +++ 1073 +++ 1074 +++ 1075 +++ 1076 +++ 1077 +++ 1078 +++ 1079 +++ 1080 +++ 1081 ++ 1082 + 1083 ++ 1084 ++ 1085 ++ 1086 +++ 1087 +++ 1088 ++ 1089 ++ 1090 + 1091 ++ 1092 ++ 1093 + 1094 ++ 1095 + 1096 ++ 1097 +++ 1098 + 1099 + 1100 + 1101 ++ 1102 ++ 1103 ++ 1104 + 1105 ++ 1106 +++ 1107 +++ 1108 ++ 1109 ++ 1110 +++ 1111 ++ 1112 + 1113 + 1114 + 1115 + 1116 + 1117 ++ 1118 + 1119 ++ 1120 +++ 1121 + 1122 + 1123 + 1124 + 1125 + 1126 + 1127 + 1128 + 1129 +++ 1130 +++ 1131 +++ 1132 ++ 1133 + 1134 + 1135 +++ 1136 + 1137 +++ 1138 ++ 1139 ++ 1140 ++ 1141 ++ 1142 ++ 1143 +++ 1144 +++ 1145 +++ 1146 ++ 1147 +++ 1148 +++ 1149 +++ 1150 +++ 1151 +++ 1152 +++ 1153 +++ 1154 +++ 1155 +++ 1156 +++ 1157 ++ 1158 + 1159 ++ 1160 + 1161 ++ 1162 ++ 1163 ++ 1164 ++ 1165 + 1166 + 1167 +++ 1168 ++ 1169 + 1170 + 1171 ++ 1172 ++ 1173 +++ 1174 ++ 1175 + 1176 ++ 1177 + 1178 + 1179 + 1180 + 1181 + 1182 + 1183 + 1184 +++ 1185 +++ 1186 +++ 1187 +++ 1188 ++ 1189 ++ 1190 ++ 1191 ++ 1192 + 1193 ++ 1194 + 1195 +++ 1196 ++ 1197 ++ 1198 ++ 1199 +++ 1200 ++ 1201 ++ 1202 +++ 1203 +++ 1204 ++ 1205 +++ 1206 +++ 1207 +++ 1208 +++ 1209 ++ 1210 +++ 1211 +++ 1212 +++ 1213 ++ 1214 +++ 1215 +++ 1216 ++ 1217 +++ 1218 +++ 1219 +++ 1220 + 1221 ++ 1222 ++ 1223 + 1224 ++ 1225 ++ 1226 ++ 1227 ++ 1228 ++ 1229 ++ 1230 + 1231 ++ 1232 + 1233 +++ 1234 +++ 1235 ++ 1236 ++ 1237 +++ 1238 + 1239 +++ 1240 +++ 1241 +++ 1242 ++ 1243 +++ 1244 +++ 1245 ++ 1246 ++ 1247 ++ 1248 ++ 1249 +++ 1250 ++ 1251 ++ 1252 ++ 1253 ++ 1254 ++ 1255 +++ 1256 ++ 1257 ++ 1258 +++ 1259 +++ 1260 ++ 1261 + 1262 + 1263 + 1264 ++ 1265 ++ 1266 ++ 1267 + 1268 ++ 1269 + 1270 ++ 1271 + 1272 ++ 1273 ++ 1274 ++ 1275 + 1276 + 1277 ++ 1278 ++ 1279 +++ 1280 +++ 1281 ++ 1282 ++ 1283 + 1284 ++ 1285 + 1286 + 1287 + 1288 + 1289 + 1290 ++ 1291 + 1292 ++ 1293 ++ 1294 + 1295 +++ 1296 +++ 1297 ++ 1298 ++ 1299 +++ 1300 +++ 1301 +++ 1302 +++ 1303 + 1304 +++ 1305 ++ 1306 +++ 1307 + 1308 ++ 1309 ++ 1310 ++ 1311 ++ 1312 +++ 1313 ++ 1314 ++ 1315 ++ 1316 +++ 1317 +++ 1318 ++ 1319 ++ 1320 ++ 1321 ++ 1322 +++ 1323 +++ 1324 +++ 1325 +++ 1326 ++ 1327 ++ 1328 ++ 1329 + 1330 +++ 1331 + 1332 + 1333 ++ 1334 +++ 1335 +++ 1336 ++ 1337 +++ 1338 +++ 1339 +++ 1340 +++ 1341 ++ 1342 ++ 1343 ++ 1344 + 1345 ++ 1346 +++ 1347 ++ 1348 +++ 1349 ++ 1350 +++ 1351 + 1352 ++ 1353 ++ 1354 +++ 1355 ++ 1356 ++ 1357 +++ 1358 ++ 1359 ++ 1360 +++ 1361 +++ 1362 ++ 1363 + 1364 + 1365 + 1366 +++ 1367 +++ 1368 +++ 1369 +++ 1370 ++ 1371 +++ 1372 + 1373 +++ 1374 ++ 1375 ++ 1376 ++ 1377 ++ 1378 ++ 1379 + 1380 +++ 1381 + 1382 ++ 1383 ++ 1384 ++ 1385 ++ 1386 ++ 1387 +++ 1388 ++ 1389 ++ 1390 ++ 1391 ++ 1392 + 1393 ++ 1394 ++ 1395 +++ 1396 ++ 1397 ++ 1398 +++ 1399 + 1400 ++ 1401 ++ 1402 ++ 1403 ++ 1404 +++ 1405 +
INDUSTRIAL APPLICABILITY
[0969] The compound of the present invention is used as a pharmaceutical product.