US2004049032A1PendingUtilityA1
Processes for preparing substituted pyrimidines
Priority: Jun 20, 2002Filed: Jun 18, 2003Published: Mar 11, 2004
Est. expiryJun 20, 2022(expired)· nominal 20-yr term from priority
A61P 35/00A61P 35/02A61P 37/06A61P 37/00A61P 7/00A61P 37/04A61P 5/00A61P 43/00A61P 9/00A61P 37/08A61P 3/00A61P 25/00A61P 25/28A61P 29/00A61P 25/18A61P 19/00A61P 11/06C07D 453/02A61P 13/08C07D 403/14A61P 19/08A61P 1/16C07D 401/14C07D 403/12C07D 239/34A61K 31/506
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Claims
Abstract
The present invention provides a facile process for the preparation of tri- and tetra-substituted pyrimidines. The process is useful for preparing inhibitors of protein kinases, especially Aurora kinase. These inhibitors are useful for treating or lessening the severity of Aurora-mediated diseases or conditions.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A method for preparing a compound of formula I:
wherein:
Q and T are each independently selected from oxygen, sulfur or N(R);
each R is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic group, wherein:
two R bound to the same nitrogen atom are optionally taken together with the nitrogen to form an optionally substituted 3-7 membered monocyclic or 8-10 membered bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms, in addition to the nitrogen bound thereto, independently selected from nitrogen, oxygen, or sulfur;
R x is U-R 5 ;
R 5 is selected from halogen, NO 2 , CN, R, or Ar;
each U is independently selected from a valence bond or a C 1-4 alkylidene chain, wherein:
up to two methylene units of U are optionally and independently replaced by —O—, —S—, —SO—, —SO 2 —, —N(R)SO 2 —, —SO 2 N(R)—, —N(R)—, —C(O)—, —CO 2 —, —N(R)C(O)—, —N(R)C(O)O—, —N(R)CON(R)—, —N(R)SO 2 N(R)—, —N(R)N(R)—, —C(O)N(R)—, —OC(O)N(R)—, —C(R)═NN(R)—, or —C(R)═N—O—;
each Ar is independently selected from an optionally substituted ring selected from a 3-7 membered monocyclic or an 8-10 membered bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R y is —N(R 1 ) 2 , —OR 1 , or —SR 1 ;
each R 1 is independently selected from R or a 3-8 membered monocyclic, an 8-10 membered bicyclic, or a 10-12 membered tricyclic saturated, partially unsaturated, or fully unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein:
each R 1 is optionally and independently substituted by up to four substituents independently selected from R 2 ;
each R 2 is independently selected from —R 3 , —OR 3 , —SR 3 , —CN, —NO 2 , oxo, halogen, —N(R 3 ) 2 , —C(O)R 3 , —OC(O)R 3 , —CO 2 R 3 , —SO 2 R 3 , —SO 2 N(R 3 ) 2 , —N(R 3 )SO 2 R 3 , —C(O)NR(R 3 ), —C(O)N(R 3 ) 2 , —OC(O)NR(R 3 ), —OC(O)N(R 3 ) 2 , —NR 3 C(O)R 3 , —NR 3 C(O)N(R 3 ) 2 , or —NR 3 CO 2 (R 3 );
each R 3 is independently selected from R or Ar;
R z1 is selected from a C 1-6 aliphatic group or a 3-8 membered monocyclic, an 8-10 membered bicyclic, or a 10-12 membered tricyclic saturated, partially unsaturated, or fully unsaturated ring having 0-4 heteroatoms independently selected from oxygen, nitrogen or sulfur, wherein:
R z1 is substituted with 0-4 independently selected R 2 groups;
R z2 is C 1-6 aliphatic group or a 3-8 membered monocyclic or an 8-10 membered bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein:
R z2 is substituted by 0-4 substituents independently selected from oxo or U-R 5 ;
said process comprising the step of combining a compound of formula II and a compound of formula R y —H in a suitable medium:
wherein:
said suitable medium comprises:
i) a suitable solvent; and
ii) optionally, a suitable base; and
L 3 is a suitable leaving group.
2 . The method according to claim 1 , wherein said compound of formula II is prepared by combining a compound of formula III with a compound of formula R z1 -Q-H in a suitable medium:
wherein:
said suitable medium comprises:
i) a suitable solvent; and
ii) optionally, a suitable base; and
L 2 is a suitable leaving group.
3 . The method according to claim 2 , wherein said compound of formula III is prepared by combining a compound of formula IV with a compound of formula R z2 -T-H in a suitable medium:
wherein:
said suitable medium comprises:
i) a suitable solvent; and
ii) optionally, a suitable base; and
L 1 is a suitable leaving group.
4 . The method according to claim 1 , wherein L 3 is selected from halogen, optionally substituted arylsulfonyl, or optionally substituted alkylsulphonyl.
5 . The method according to claim 4 , wherein L 3 is fluoro, chloro, bromo, iodo, paratoluenesulfonyl, methanesulfonyl, paranitrophenylsulfonyl, parabromophenylsulfonyl, or trifluoromethanesulfonate.
6 . The method according to claim 5 , wherein L 3 is chloro or iodo.
7 . The method according to claim 2 , wherein L 2 is halogen, optionally substituted arylsulfonyl, or optionally substituted alkylsulphonyl.
8 . The method according to claim 7 , wherein L 2 is fluoro, chloro, bromo, iodo, paratoluenesulfonate, methanesulfonate, paranitrophenylsulfonyl, parabromophenylsulfonyl, or trifluoromethanesulfonate.
9 . The method according to claim 8 , wherein L 2 is chloro or Iodo.
10 . The method according to claim 3 , wherein L 1 is halogen, optionally substituted arylsulfonyl, or optionally substituted alkylsulphonyl.
11 . The method according to claim 10 , wherein L 1 is optionally substituted alkylsulfonyl.
12 . The method according to claim 11 , wherein L 1 is methanesulfonyl.
13 . The method according to claim 1 , wherein Q is N(R).
14 . The method according to claim 1 , wherein T is oxygen or sulfur.
15 . The method according to claim 14 , wherein T is sulfur.
16 . The method according to claim 1 , wherein R y is —OR 1 or —N(R 1 ) 2 .
17 . The method according to claim 16 , wherein R y is —N(R 1 ) 2 , and wherein:
R 1 is selected from R or a 3-7 membered monocyclic or an 8-10 membered bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
each R 1 is R such that the two R on the same nitrogen atom are taken together to form an optionally substituted 4-7 membered saturated ring having up to two additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein:
each R 1 is optionally and independently substituted by up to four substituents selected from —R 3 , —OR 3 , —SR 3 , —CN, —NO 2 , oxo, halogen, —N(R 3 ) 2 , —C(O)R 3 , —OC(O)R 3 , —CO 2 R 3 , —SO 2 R 3 , —SO 2 N(R 3 ) 2 , —N(R 3 )SO 2 R 3 , —C(O)NR(R 3 ), —C(O)N(R 3 ) 2 , —OC(O)NR(R 3 ), —OC(O)N(R 3 ) 2 , —NR 3 C(O)R 3 , —NR 3 C(O)N(R 3 ) 2 , or —NR 3 CO 2 (R 3 ).
18 . The method according to claim 17 , wherein R y is N(R 1 ) 2 , wherein:
each R 1 is independently selected from R, wherein R is hydrogen or an optionally substituted C 1-4 aliphatic group.
19 . The method according to claim 17 , wherein R y is N(R 1 ) 2 wherein:
each R 1 is R such that the two R groups are taken together to form an optionally substituted 4-7 membered saturated ring having up to two additional heteroatoms independently selected from nitrogen, oxygen, or sulfur.
20 . The method according to claim 19 , wherein R y is selected from pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, diazepanyl, or tetrahydroisoquinolinyl, wherein each ring is optionally substituted with one or two groups independently selected from methyl, ethyl, methylsulfonyl, (CH 2 ) 2 SO 2 CH 3 , cyclopropyl, CH 2 cyclopropyl, (CH 2 ) 2 OH, CO 2 t-butyl, CH 2 phenyl, phenyl, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , (CH 2 ) 2 NH 2 , (CH 2 ) 2 morpholin-4-yl, (CH 2 ) 2 N(CH 3 ) 2 , isopropyl, propyl, t-butyl, (CH 2 ) 2 CN, or (CH 2 ) 2 C(O)morpholin-4-yl.
21 . The method according to claim 1 , wherein R z1 is a 3-7 membered monocyclic or an 8-10 membered bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-4 heteroatoms independently selected from oxygen, nitrogen or sulfur, wherein said ring is optionally and independently substituted by up to three substituents selected from —R 3 , —OR 3 , —SR 3 , —CN, —NO 2 , oxo, halogen, —N(R 3 ) 2 , —C(O)R 3 , —OC(O)R 3 , —CO 2 R 3 , —SO 2 R 3 , —SO 2 N(R 3 ) 2 , —N(R 3 )SO 2 R 3 , —C(O)NR(R 3 ), —C(O)N(R 3 ) 2 , —OC(O)NR(R 3 ), —OC(O)N(R 3 ) 2 , —NR 3 C(O)R 3 , —NR 3 C(O)N(R 3 ) 2 , or —NR 3 CO 2 R 3 .
22 . The method according to claim 21 , wherein R z1 is a 5-6 membered fully unsaturated ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally and independently substituted by up to three substituents selected from —R 3 , —OR 3 , —SR 3 , —CN, —NO 2 , oxo, halogen, —N(R 3 ) 2 , —C(O)R 3 , —OC(O)R 3 , —CO 2 R 3 , —SO 2 R 3 , —SO 2 N(R 3 ) 2 , —N(R 3 )SO 2 R 3 , —C(O)NR(R 3 ), —C(O)N(R 3 ) 2 , —OC(O)NR(R 3 ), —OC(O)N(R 3 ) 2 , —NR 3 C(O)R 3 , —NR 3 C(O)N(R 3 ) 2 , or —NR 3 CO 2 R 3 .
23 . The method according to claim 22 , wherein R z1 is an optionally substituted ring selected from pyrazole or any one of the following 5-6 membered rings:
24 . The method according to claim 23 , wherein R z1 is a pyrazole ring having up to two substituents independently selected from —N(R 3 ) 2 , —OR 3 , or a C 1 -C 4 aliphatic group.
25 . The method according to claim 24 , wherein R z1 is a pyrazole optionally substituted with one substituent selected from methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, or phenyl.
26 . The method according to claim 1 , wherein R z2 is an optionally substituted ring selected from a 5-6 membered monocyclic or an 8-10 membered bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein said ring is optionally substituted by up to three substituents independently selected from halogen, —CN, —NO 2 , —C(O)R 3 , —CO 2 R 3 , —C(O)NR(R 3 ), —NR 3 C(O)R 3 , —N(R 3 ) 2 , —N(R 3 )SO 2 R 3 , —NR 3 C(O)N(R 3 ) 2 , or —NR 3 CO 2 R 3 .
27 . The method according to claim 26 , wherein:
R z2 is selected from phenyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrazinyl, naphthyl, tetrahydronaphthyl, benzimidazolyl, benzthiazolyl, quinolinyl, quinazolinyl, benzodioxinyl, isobenzofuran, indanyl, indolyl, indolinyl, indazolyl, or isoquinolinyl, wherein:
R z2 is optionally substituted with up to three substituents independently selected from —Cl, —Br, —F, —CN, —CF 3 , —COOH, —CONHMe, —CONHEt, —NH 2 , —NHAc, —NHSO 2 Me, —NHSO 2 Et, —NHSO 2 (n-propyl), —NHSO 2 (isopropyl), —NHCOEt, —NHCOCH 2 NHCH 3 , —NHCOCH 2 N(CO 2 t-Bu)CH 3 , —NHCOCH 2 N(CH 3 ) 2 , —NHCOCH 2 CH 2 N(CH 3 ) 2 , —NHCOCH 2 CH 2 CH 2 N(CH 3 ) 2 , —NHCO(cyclopropyl), —NHCO(isopropyl), —NHCO(isobutyl), —NHCOCH 2 (morpholin-4-yl), —NHCOCH 2 CH 2 (morpholin-4-yl), —NHCOCH 2 CH 2 CH 2 (morpholin-4-yl), —NHCO 2 (t-butyl), —NH(cyclohexyl), —NHMe, —NMe 2 , —OH, —OMe, methyl, ethyl, cyclopropyl, isopropyl, or t-butyl.
28 . The method according to claim 27 , wherein R z2 has one substituent selected from —NR 3 C(O)R 3 , wherein:
each R 3 is independently selected from R or Ar, and wherein:
R is hydrogen or an optionally substituted C 1-4 aliphatic group.
29 . The method according to claim 1 wherein said suitable solvent is a protic solvent, a halogenated hydrocarbon, an ether, an aromatic hydrocarbon, a polar or a non-polar aprotic solvent, or any mixtures thereof.
30 . The method according to claim 29 , wherein said solvent is a C 1-5 straight or branched alkyl alcohol, ether, or a polar or non-polar aprotic solvent.
31 . The method according to claim 1 wherein said suitable base is selected from an organic amine, an alkaline earth metal carbonate, an alkaline earth metal hydride, or an alkaline earth metal hydroxide.
32 . The method according to claim 31 , wherein said suitable base is selected from a trialkyl amine, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide, or potassium hydroxide.
33 . The method according to claim 1 , wherein said method is used to prepare a compound selected from the following Table 1 and Table 2 compounds:
TABLE 1
No. V-
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
TABLE 2
I-1
I-2
I-3
I-4
I-5
I-6
I-7
I-8
I-9
I-10
I-11
I-12
I-13
I-14
I-15
I-16
I-17
I-18
I-19
I-20
I-21
I-22
I-23
I-24
I-25
I-26
I-27
I-28
I-29
I-30
I-31
I-32
I-33
I-34
I-35
I-36
I-37
I-38
I-39
I-40
I-41
I-42
I-43
I-44
I-45
I-46
I-47
I-48
I-49
I-50
I-51
I-52
I-53
I-54
I-55
I-56
I-57
I-58
I-59
I-60 and
I-61.
34 . A compound of formula V:
or a pharmaceutically acceptable derivative or salt thereof, wherein:
R 5 is selected from hydrogen or C 1-4 aliphatic;
R 6 is selected from C 1-3 aliphatic; and
R 7 is selected from Cab aliphatic.
35 . The compound according to claim 34 , wherein R 5 is selected from hydrogen, methyl, ethyl, t-butyl, or isopropyl.
36 . The compound according to claim 35 , wherein R 6 is selected from methyl, ethyl, or cyclopropyl.
37 . The compound according to claim 36 , wherein R 7 is selected from methyl, ethyl, t-butyl, or cyclopropyl.
38 . A compound selected from the following Table 1 compounds:
TABLE 1
No. V-
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
39 . A compound selected from the following Table 3 compounds:
TABLE 3
V-1 i
V-1 ii
V-1 iii
V-1 iv
V-1 v
V-1 vi
V-1 vii
V-1 viii
V-1 ix
V-1 x
V-1 xi
V-20 i
40 . A composition comprising a compound according to claim 34 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
41 . The composition according to claim 40 , additionally comprising an anti-proliferative agent or a chemotherapeutic agent.
42 . A method of inhibiting Aurora-1 in a biological sample, comprising contacting said sample with:
(a) a compound according to claim 34; or (b) a composition according to claim 40 .
43 . A method of inhibiting Aurora-2 in a biological sample, comprising contacting said sample with:
(a) a compound according to claim 34; or (b) a composition according to claim 40 .
44 . A method of inhibiting Aurora-3 in a biological sample, comprising contacting said sample with:
(a) a compound according to claim 34; or (b) a composition according to claim 40 .
45 . A method of inhibiting FLT-3 in a biological sample, comprising contacting said sample with:
(a) a compound according to claim 34; or (b) a composition according to claim 40 .
46 . A method of inhibiting Aurora-1 in a patient, comprising administering to said patient:
(a) a compound according to claim 34; or (b) a composition according to claim 40 .
47 . A method of inhibiting Aurora-2 in a patient, comprising administering to said patient:
(a) a compound according to claim 34; or (b) a composition according to claim 40 .
48 . A method of inhibiting Aurora-3 in a patient, comprising administering to said patient:
(a) a compound according to claim 34; or (b) a composition according to claim 40 .
49 . A method of inhibiting FLT-3 in a patient, comprising administering to said patient:
(a) a compound according to claim 34; or (b) a composition according to claim 40 .
50 . A method of inhibiting Aurora-1, Aurora-2, Aurora-3, and FLT-3 in a patient, comprising administering to said patient:
(a) a compound according to claim 34; or (b) a composition according to claim 40 .
51 . A method of treating cancer in a patient comprising the step of administering to said patient a composition according to claim 40 .
52 . The method according to claim 51 comprising the step of administering to said patient an additional chemotherapeutic or anti-proliferative agent.
53 . The method according to claim 51 , wherein said cancer is selected from melanoma, lymphoma, neuroblastoma, leukemia, or a cancer selected from colon, breast, lung, kidney, ovary, pancreatic, renal, CNS, cervical, prostate, or cancer of the gastric tract.
54 . The method according to claim 51 , wherein said cancer is selected from acute-myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), mastocytosis or gastrointestinal stromal tumor (GIST).
55 . A method of treating or lessening the severity of a cancer in a patient comprising the step of disrupting mitosis of the cancer cells by inhibiting Aurora protein kinase with a compound according to claim 34 .
56 . The method according to claim 55 , comprising the step of administering to said patient a composition according to claim 40.Join the waitlist — get patent alerts
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