US2015183812A1PendingUtilityA1
Pyrimidine compound and medical use thereof
Est. expiryJun 11, 2024(expired)· nominal 20-yr term from priority
Inventors:Hisashi KawasakiHiroyuki AbeKazuhide HayakawaTetsuya IidaShinichi KikuchiTakayuki YamaguchiToyomichi NanayamaHironori KurachiMasahiro TamaruYoshikazu HoriMitsuru TakahashiTakayuki YoshidaToshiyuki Sakai
A61P 35/00C07D 239/545C07D 239/62C07D 471/16C07C 275/50C07C 2601/16A61K 31/519C07D 471/04C07D 239/553C07F 9/53C07D 487/04A61P 29/00C07C 275/30C07C 2101/16
64
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Claims
Abstract
The present invention relates to a pyrimidine compound or a pharmaceutically acceptable salt thereof represented by the following formula [I] wherein each symbol is as defined in the specification and a method of therapeutically or prophylactically treating an undesirable cell proliferation, comprising administering such a compound. The compound of the present invention has superior activity in suppressing undesirable cell proliferation, particularly, an antitumor activity, and is useful as an antitumor agent for the prophylaxis or treatment of cancer, rheumatism, and the like. In addition, the compound of the present invention can be a more effective antitumor agent when used in combination with other antitumor agents such as an alkylating agent or metabolism antagonist.
Claims
exact text as granted — not AI-modified1 - 24 . (canceled)
25 . A method of preparing a compound of formula [I-3-2]
wherein
R 1 , R 2 , and R 6 are the same or different and each is
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, or
wherein m is 0 or an integer of 1 to 4,
ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B,
R 3 is
a hydrogen atom,
a hydroxyl group,
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A,
a C 3-12 carbon ring group or
a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B;
wherein group A is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-4 alkyl group,
5) —OR A1 wherein R A1 is a hydrogen atom or a C 1-4 alkyl group,
6) —SR A2 wherein R A2 is a hydrogen atom or a C 1-4 alkyl group,
7) —NR A3 R A4 wherein R A3 and R A4 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
8) —COOR A5 wherein R A5 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR A6 COR A7 wherein R A6 is a hydrogen atom or a C 1-4 alkyl group, R A7 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
10) —NR A8 COOR A9 wherein R A8 and R A9 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
11) a C 3-12 carbon ring group and
12) a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
each of the C 1-4 alkyl groups of the above-mentioned 4), R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 and R A9 is optionally substituted by the same or different 1 to 3 substituents selected from the following group C, and
each of the C 3-12 carbon ring groups of the above-mentioned 11) and R A7 , and the heterocyclic groups of 12) and R A7 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
group B is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-8 alkyl group,
5) a C 2-4 alkenyl group,
6) a C 2-4 alkynyl group,
7) —OR B1 wherein R B1 is a hydrogen atom or a C 1-4 alkyl group,
8) —SR B2 wherein R B2 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR B3 R B4 wherein R B3 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group, and R B4 is a hydrogen atom or a C 1-4 alkyl group,
10) —NR B5 COR B6 wherein R B5 is a hydrogen atom or a C 1-4 alkyl group, and R B6 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
11) —NR B7 COOR B8 wherein R B7 and R B8 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
12) —NR B9 CONR B10 R B11 wherein R B9 , R B10 and R B11 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
13) —NR B12 CONR B13 OR B14 wherein R B12 , R B13 and R B14 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
14) —NR B15 SO 2 R B16 wherein R B15 is a hydrogen atom or a C 1-4 alkyl group, and R B16 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
15) —SO 2 —R B17 wherein R B17 is a C 1-4 alkyl group or a heterocyclic group,
16) —SO 2 NR B18 R B19 wherein R B18 and R B19 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
17) —P(═O)(R B20 )(R B21 ) wherein R B20 and R B21 are the same or different and each is a C 1-4 alkyl group,
18) —COOR B22 wherein R B22 is a hydrogen atom or a C 1-4 alkyl group,
19) —CONR B23 R B24 wherein R B23 and R B24 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
20) —NR B25 SO 2 NR B26 R B27 wherein R B25 , R B26 and R B27 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
21) —NR B28 SO 2 NR B29 CONR B30 R B31 wherein R B28 , R B29 , R B30 and R B31 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
22) a C 3-12 carbon ring group and
23) a heterocyclic group
wherein each of the “C 1-8 alkyl group” of the above-mentioned 4), and the C 1-4 alkyl groups for R B1 to R B31 is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
each of the C 2-4 alkenyl group of 5) and the C 2-4 alkynyl group of 6) is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and
each of the C 3-12 carbon ring group of the above-mentioned 22), R B3 , R B6 and R B16 , and the heterocyclic group of the above-mentioned 23), R B3 , R B6 , R B16 , R B17 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and
group C is a group consisting of
1) a halogen atom,
2) a cyano group,
3) a C 1-4 alkyl group,
4) —OR C1 wherein R C1 is a hydrogen atom or a C 1-4 alkyl group,
5) —NR C2 R C3 wherein R C2 and R C3 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
6) —COOR C4 wherein R C4 is a hydrogen atom or a C 1-4 alkyl group and
7) an oxo group,
wherein the method comprises
(a) reacting a compound of formula [45]
H 2 N—R 6 [45],
wherein R 6 is defined above,
with a compound of formula [1 ]
H 2 N—R 1 [1],
wherein R 1 is defined above,
to form a compound of formula [28]
wherein R 1 and R 6 are defined above;
(b) reacting a compound of formula [28] with a compound of formula [38]
wherein R C1 is a hydrogen atom or C 1-6 alkyl group,
to form a compound of formula [46]
wherein R 1 and R 6 are defined above;
(c) converting a compound of formula [46] to a compound of formula [47]
wherein R 1 and R 6 are defined above;
(d) converting a compound of formula [47] to a compound of formula [48]
wherein R 1 and R 6 are defined above;
(e) converting a compound of formula [48] to a compound of formula [49]
wherein R 1 and R 6 are defined above;
(f) reacting a compound of formula [49] with a compound of formula [33]
wherein
R 3 is defined above; and
R c3 and R c4 are the same or different and each is a hydrogen atom or C 1-6 alkyl, to form a compound of formula [50]
wherein R 1 , R 3 , and R 6 are defined above;
(g) converting a compound of formula [50] to a compound of formula [51];
wherein
R 1 , R 3 , and R 6 are defined above, and
R c5 is a leaving group;
(h) reacting a compound of formula [51] with a compound of formula [36]
H 2 N—R 2 [36],
wherein R 2 is defined above;
to form a compound of formula [52]
wherein R 1 , R 2 , R 3 , and R 6 are defined above;
and
(i) converting a compound of formula [52] to a compound of formula [I-3-2]
26 . A method of preparing a compound of formula [I-3-2]
wherein
R 1 , R 2 , and R 6 are the same or different and each is
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, or
wherein m is 0 or an integer of 1 to 4,
ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B,
R 3 is
a hydrogen atom,
a hydroxyl group,
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A,
a C 3-12 carbon ring group or
a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B;
wherein group A is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-4 alkyl group,
5) —OR A1 wherein R A1 is a hydrogen atom or a C 1-4 alkyl group,
6) —SR A2 wherein R A2 is a hydrogen atom or a C 1-4 alkyl group,
7) —NR A3 R A4 wherein R A3 and R A4 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
8) —COOR A5 wherein R A5 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR A6 COR A7 wherein R A6 is a hydrogen atom or a C 1-4 alkyl group, R A7 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
10) —NR A8 COOR A9 wherein R A8 and R A9 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
11) a C 3-12 carbon ring group and
12) a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
each of the C 1-4 alkyl groups of the above-mentioned 4), R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 and R A9 is optionally substituted by the same or different 1 to 3 substituents selected from the following group C, and
each of the C 3-12 carbon ring groups of the above-mentioned 11) and R A7 , and the heterocyclic groups of 12) and R A7 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
group B is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-8 alkyl group,
5) a C 2-4 alkenyl group,
6) a C 2-4 alkynyl group,
7) —OR B1 wherein R B1 is a hydrogen atom or a C 1-4 alkyl group,
8) —SR B2 wherein R B2 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR B3 R B4 wherein R B3 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group, and R B4 is a hydrogen atom or a C 1-4 alkyl group,
10) —NR B5 COR B6 wherein R B5 is a hydrogen atom or a C 1-4 alkyl group, and R B6 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
11) —NR B7 COOR B8 wherein R B7 and R B8 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
12) —NR B9 CONR B10 R B11 wherein R B9 , R B10 and R B11 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
13) —NR B12 CONR B13 OR B14 wherein R B12 , R B13 and R B14 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
14) —NR B15 SO 2 R B16 wherein R B15 is a hydrogen atom or a C 1-4 alkyl group, and R B16 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
15) —SO 2 —R B17 wherein R B17 is a C 1-4 alkyl group or a heterocyclic group,
16) —SO 2 NR B18 R B19 wherein R B18 and R B19 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
17) —P(═O)(R B20 )(R B21 ) wherein R B20 and R B21 are the same or different and each is a C 1-4 alkyl group,
18) —COOR B22 wherein R B22 is a hydrogen atom or a C 1-4 alkyl group,
19) —CONR B23 R B24 wherein R B23 and R B24 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
20) —NR B25 SO 2 NR B26 R B27 wherein R B25 , R B26 and R B27 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
21) —NR B28 SO 2 NR B29 CONR B30 R B31 wherein R B28 , R B29 , R B30 , and R B31 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
22) a C 3-12 carbon ring group and
23) a heterocyclic group
wherein each of the “C 1-8 alkyl group” of the above-mentioned 4), and the C 1-4 alkyl groups for R B1 to R B31 is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
each of the C 2-4 alkenyl group of 5) and the C 2-4 alkynyl group of 6) is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and
each of the C 3-12 carbon ring group of the above-mentioned 22), R B3 , R B6 and R B16 , and the heterocyclic group of the above-mentioned 23), R B3 , R B6 , R B16 , and R B17 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and
group C is a group consisting of
1) a halogen atom,
2) a cyano group,
3) a C 1-4 alkyl group,
4) —OR C1 wherein R C1 is a hydrogen atom or a C 1-4 alkyl group,
5) —NR C2 R C3 wherein R C2 and R C3 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
6) —COOR C4 wherein R C4 is a hydrogen atom or a C 1-4 alkyl group and
7) an oxo group,
wherein the method comprises
(a) converting a compound of formula [50]
wherein R 1 , R 3 , and R 6 are defined above;
to a compound of formula [51];
wherein R 1 , R 3 , and R 6 are defined above and R c5 is a leaving group;
(b) reacting a compound of formula [51] with a compound of formula [36]
H 2 N—R 2 [36],
wherein R 2 is defined above,
to form a compound of formula [52]
wherein R 1 , R 2 , R 3 , and R 6 are defined above;
and
(c) converting a compound of formula [52] to a compound of formula [I-3-2]
27 . A method of preparing a compound of formula [50]
wherein
R 1 and R 6 are the same or different and each is
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, or
wherein m is 0 or an integer of 1 to 4,
ring Cy is a C 3-12 carbon ring group or a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B,
R 3 is
a hydrogen atom,
a hydroxyl group,
a C 1-6 alkyl group,
a C 2-6 alkenyl group,
wherein the C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A,
a C 3-12 carbon ring group or
a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B;
wherein group A is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-4 alkyl group,
5) —OR A1 wherein R A1 is a hydrogen atom or a C 1-4 alkyl group,
6) —SR A2 wherein R A2 is a hydrogen atom or a C 1-4 alkyl group,
7) —NR A3 R A4 wherein R A3 and R A4 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
8) —COOR A5 wherein R A5 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR A6 COR A7 wherein R A6 is a hydrogen atom or a C 1-4 alkyl group, R A7 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
10) —NR A8 COOR A9 wherein R A8 and R A9 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
11) a C 3-12 carbon ring group and
12) a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
each of the C 1-4 alkyl groups of the above-mentioned 4), R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 and R A9 is optionally substituted by the same or different 1 to 3 substituents selected from the following group C, and
each of the C 3-12 carbon ring groups of the above-mentioned 11) and R A7 , and the heterocyclic groups of 12) and R A7 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
group B is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-8 alkyl group,
5) a C 2-4 alkenyl group,
6) a C 2-4 alkynyl group,
7) —OR B1 wherein R B1 is a hydrogen atom or a C 1-4 alkyl group,
8) —SR B2 wherein R B2 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR B3 R B4 wherein R B3 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group, and R B4 is a hydrogen atom or a C 1-4 alkyl group,
10) —NR B5 COR B6 wherein R B5 is a hydrogen atom or a C 1-4 alkyl group, and R B6 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
11) —NR B7 COOR B8 wherein R B7 and R B8 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
12) —NR B9 CONR B10 R B11 wherein R B9 , R B10 and R B11 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
13) —NR B12 CONR B13 OR B14 wherein R B12 , R B13 and R B14 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
14) —NR B15 SO 2 R B16 wherein R B15 is a hydrogen atom or a C 1-4 alkyl group, and R B16 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
15) —SO 2 —R B17 wherein R B17 is a C 1-4 alkyl group or a heterocyclic group,
16) —SO 2 NR B18 R B19 wherein R B18 and R B19 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
17) —P(═O)(R B20 )(R B21 ) wherein R B20 and R B21 are the same or different and each is a C 1-4 alkyl group,
18) —COOR B22 wherein R B22 is a hydrogen atom or a C 1-4 alkyl group,
19) —CONR B23 R B24 wherein R B23 and R B24 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
20) —NR B25 SO 2 NR B26 R B27 wherein R B25 , R B26 and R B27 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
21) —NR B28 SO 2 NR B29 CONR B30 R B31 wherein R B28 , R B29 , R B30 , and R B31 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
22) a C 3-12 carbon ring group and
23) a heterocyclic group
wherein each of the “C 1-8 alkyl group” of the above-mentioned 4), and the C 1-4 alkyl groups for R B1 to R B31 is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
each of the C 2-4 alkenyl group of 5) and the C 2-4 alkynyl group of 6) is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A,
the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and
each of the C 3-12 carbon ring group of the above-mentioned 22), R B3 , R B6 and R B16 , and the heterocyclic group of the above-mentioned 23), R B3 , R B6 , R B16 and R B17 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and
group C is a group consisting of
1) a halogen atom,
2) a cyano group,
3) a C 1-4 alkyl group,
4) —OR C1 wherein R C1 is a hydrogen atom or a C 1-4 alkyl group,
5) —NR C2 R C3 wherein R C2 and R C3 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
6) —COOR C4 wherein R C4 is a hydrogen atom or a C 1-4 alkyl group and
7) an oxo group,
wherein the method comprises
(a) reacting a compound of formula [45]
H 2 N—R 6 [45],
wherein R 6 is defined above,
with a compound of formula [1 ]
H 2 N—R 1 [1],
wherein R 1 is defined above,
to form a compound of formula [28]
wherein R 1 and R 6 are defined above;
(b) reacting a compound of formula [28] with a compound of formula [38]
wherein R c1 is a hydrogen atom or C 1-6 alkyl group,
to form a compound of formula [46]
wherein R 1 and R 6 are defined above;
(c) converting a compound of formula [46] to a compound of formula [47]
wherein R 1 and R 6 are defined above;
(d) converting a compound of formula [47] to a compound of formula [48]
wherein R 1 and R 6 are defined above;
(e) converting a compound of formula [48] to a compound of formula [49]
wherein R 1 and R 6 are defined above;
(f) reacting a compound of formula [49] with a compound of formula [33]
wherein
R 3 is defined above; and
R c3 and R c4 are the same or different and each is a hydrogen atom or C 1-6 alkyl, to form a compound of formula [50]
28 . A method of preparing a compound, salt, or solvate of the formula:
comprising
(a) reacting
with cyclopropylamine to form
(b) reacting the product of step (a) with
to form
(c) converting the product of step (b) to
(d) converting the product of step (c) to
(e) converting the product of step (d) to
(f) reacting the product of step (e) with
to form
(g) converting the product of step (f) to
(h) reacting the product of step (g) with
to form
(i) converting the product of step (h) to
and
(j) optionally converting the product of step (i) to a salt or solvate.
29 . A method of preparing a compound, salt, or solvate of the formula:
comprising
(a) converting
to
(b) reacting the product of step (a) with
to form
(c) converting the product of step (b) to
and
(d) optionally converting the product of step (c) to a salt or solvate.
30 . The method of claim 28 or 29 , further comprising converting
to a solvate.
31 . A method of preparing a compound of the formula:
comprising
(a) reacting
with cyclopropylamine to form
(b) reacting the product of step (a) with
to form
(c) converting the product of step (b) to
(d) converting the product of step (c) to
(e) converting the product of step (d) to
and
(f) reacting the product of step (e) with
to form
32 . A compound of the formula:
or a salt or solvate thereof.
33 . A compound of the formula:
or a salt or solvate thereof.
34 . A compound of the formula:
or a salt or solvate thereof.
35 . A compound of the formula:
or a salt or solvate thereof.
36 . A compound of the formula:
or a salt or solvate thereof.
37 . A compound of the formula:
or a salt or solvate thereof.
38 . A compound of the formula:
or a salt or solvate thereof.
39 . A compound of the formula:
or a salt or solvate thereof.
40 . A compound of the formula:
or a salt or solvate thereof.
41 . A compound the formula [50] or a salt or solvate thereof:
wherein
R 3 is a methyl group, and
R 1 and R 6 are the same or different and each is a C 3-12 carbon ring group or a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B,
wherein group B is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-8 alkyl group,
5) a C 2-4 alkenyl group,
6) a C 2-4 alkynyl group,
7) —OR B1 wherein R B1 is a hydrogen atom or a C 1-4 alkyl group,
8) —SR B2 wherein R B2 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR B3 R B4 wherein R B3 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group, and R B4 is a hydrogen atom or a C 1-4 alkyl group,
10) —NR B5 COR B6 wherein R B5 is a hydrogen atom or a C 1-4 alkyl group, and R B6 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
11) —NR B7 COOR B8 wherein R B7 and R B8 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
12) —NR B9 CONR B10 R B11 wherein R B9 , R B10 and R B11 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
13) —NR B12 CONR B13 OR B14 wherein R B12 , R B13 and R B14 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
14) —NR B15 SO 2 R B16 wherein R B15 is a hydrogen atom or a C 1-4 alkyl group, and R B16 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
15) —SO 2 —R B17 wherein R B17 is a C 1-4 alkyl group or a heterocyclic group,
16) —SO 2 NR B18 R B19 wherein R B18 and R B19 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
17) —P(═O)(R B20 )(R B21 ) wherein R B20 and R B21 are the same or different and each is a C 1-4 alkyl group,
18) —COOR B22 wherein R B22 is a hydrogen atom or a C 1-4 alkyl group,
19) —CONR B23 R B24 wherein R B23 and R B24 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
20) —NR B25 SO 2 NR B26 R B27 wherein R B25 , R B26 and R B27 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
21) —NR B28 SO 2 NR B29 CONR B30 R B31 wherein R B28 , R B29 , R B30 , and R B31 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
22) a C 3-12 carbon ring group and
23) a heterocyclic group
wherein each of the “C 1-8 alkyl group” of the above-mentioned 4), and the C 1-4 alkyl groups for R B1 to R B31 is optionally substituted by the same or different 1 to 3 substituents selected from the following group A,
each of the C 2-4 alkenyl group of 5) and the C 2-4 alkynyl group of 6) is optionally substituted by the same or different 1 to 3 substituents selected from the following group A,
the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and
each of the C 3-12 carbon ring group of the above-mentioned 22), R B3 , R B6 , and R B16 , and the heterocyclic group of the above-mentioned 23), R B3 , R B6 , R B16 , and R B17 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
group A is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-4 alkyl group,
5) —OR A1 wherein R A1 is a hydrogen atom or a C 1-4 alkyl group,
6) —SR A2 wherein R A2 is a hydrogen atom or a C 1-4 alkyl group,
7) —NR A3 R A4 wherein R A3 and R A4 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
8) —COOR A5 wherein R A5 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR A6 COR A7 wherein R A6 is a hydrogen atom or a C 1-4 alkyl group, R A7 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
10) —NR A8 COOR A9 wherein R A8 and R A9 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
11) a C 3-12 carbon ring group and
12) a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
each of the C 1-4 alkyl groups of the above-mentioned 4), R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 and R A9 is optionally substituted by the same or different 1 to 3 substituents selected from the following group C, and
each of the C 3-12 carbon ring groups of the above-mentioned 11) and R A7 , and the heterocyclic groups of 12) and R A7 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and
group C is a group consisting of
1) a halogen atom,
2) a cyano group,
3) a C 1-4 alkyl group,
4) —OR C1 wherein R C1 is a hydrogen atom or a C 1-4 alkyl group,
5) —NR C2 R C3 wherein R C2 and R C3 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
6) —COOR C4 wherein R C4 is a hydrogen atom or a C 1-4 alkyl group and
7) an oxo group.
42 . A compound of the formula [51] or a salt or solvate thereof:
wherein
R 3 is a methyl group,
R 1 and R 6 are the same or different and each is a C 3-12 carbon ring group or a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, the C 3-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B, and
R c5 is a leaving group;
wherein group B is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-8 alkyl group,
5) a C 2-4 alkenyl group,
6) a C 2-4 alkynyl group,
7) —OR B1 wherein R B1 is a hydrogen atom or a C 1-4 alkyl group,
8) —SR B2 wherein R B2 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR B3 R B4 wherein R B3 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group, and R B4 is a hydrogen atom or a C 1-4 alkyl group,
10) —NR B5 COR B6 wherein R B5 is a hydrogen atom or a C 1-4 alkyl group, and R B6 is a hydrogen atom, a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
11) —NR B7 COOR B8 wherein R B7 and R B8 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
12) —NR B9 CONR B10 R B11 wherein R B9 , R B10 and R B11 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
13) —NR B12 CONR B13 OR B14 wherein R B12 , R B13 and R B14 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
14) —NR B15 SO 2 R B16 wherein R B15 is a hydrogen atom or a C 1-4 alkyl group, and R B16 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
15) —SO 2 —R B17 wherein R B17 is a C 1-4 alkyl group or a heterocyclic group,
16) —SO 2 NR B18 R B19 wherein R B18 and R B19 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
17) —P(═O)(R B20 (R B21 ) wherein R B20 and R B21 are the same or different and each is a C 1-4 alkyl group,
18) —COOR B22 wherein R B22 is a hydrogen atom or a C 1-4 alkyl group,
19) —CONR B23 R B24 wherein R B23 and R B24 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
20) —NR B25 SO 2 NR B26 R B27 wherein R B25 , R B26 and R B27 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
21) —NR B28 SO 2 NR B29 CONR B30 R B31 wherein R B28 , R B29 , R B30 and R B31 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
22) a C 3-12 carbon ring group and
23) a heterocyclic group
wherein each of the “C 1-8 alkyl group” of the above-mentioned 4), and the C 1-4 alkyl groups for R B1 to R B31 is optionally substituted by the same or different 1 to 3 substituents selected from the following group A,
each of the C 2-4 alkenyl group of 5) and the C 2-4 alkynyl group of 6) is optionally substituted by the same or different 1 to 3 substituents selected from the following group A,
the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and
each of the C 3-12 carbon ring group of the above-mentioned 22), R B3 , R B6 and R B16 , and the heterocyclic group of the above-mentioned 23), R B3 , R B6 , R B16 , and R B17 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
group A is a group consisting of
1) a halogen atom,
2) a nitro group,
3) a cyano group,
4) a C 1-4 alkyl group,
5) —OR A1 wherein R A1 is a hydrogen atom or a C 1-4 alkyl group,
6) —SR A2 wherein R A2 is a hydrogen atom or a C 1-4 alkyl group,
7) —NR A3 R A4 wherein R A3 and R A4 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
8) —COOR A5 wherein R A5 is a hydrogen atom or a C 1-4 alkyl group,
9) —NR A6 COR A7 wherein R A6 is a hydrogen atom or a C 1-4 alkyl group, R A7 is a C 1-4 alkyl group, a C 3-12 carbon ring group or a heterocyclic group,
10) —NR A8 COOR A9 wherein R A8 and R A9 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
11) a C 3-12 carbon ring group and
12) a heterocyclic group,
wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
each of the C 1-4 alkyl groups of the above-mentioned 4), R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 , and R A9 is optionally substituted by the same or different 1 to 3 substituents selected from the following group C, and
each of the C 3-12 carbon ring groups of the above-mentioned 11) and R A7 , and the heterocyclic groups of 12) and R A7 is optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and
group C is a group consisting of
1) a halogen atom,
2) a cyano group,
3) a C 1-4 alkyl group,
4) —OR C1 wherein R C1 is a hydrogen atom or a C 1-4 alkyl group,
5) —NR C2 R C3 wherein R C2 and R C3 are the same or different and each is a hydrogen atom or a C 1-4 alkyl group,
6) —COOR C4 wherein R C4 is a hydrogen atom or a C 1-4 alkyl group and
7) an oxo group.
43 . The compound of claim 41 or 42 , wherein R 1 is a C 3-12 carbon ring group, wherein the C 3-12 carbon ring group is optionally substituted by 1 to 5 substituents selected from group B.
44 . The compound of claim 43 , wherein R 1 is cyclopropyl.
45 . The compound of claim 41 or 42 , wherein R 6 is a phenyl group that is optionally substituted by 1 to 5 substituents selected from group B.
46 . The compound of claim 45 , wherein R 6 is a phenyl group that is di-substituted at the 2,4-position.
47 . The compound of claim 42 , wherein R c5 is a leaving group selected from the group consisting of a halogen, p-toluenesulfonyloxy, methanesulfonyloxy, and trifluoromethanesulfonyloxy.
48 . A compound that is N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide or a pharmaceutically acceptable salt or solvate thereof.
49 . A compound that is N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide.Join the waitlist — get patent alerts
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