Imidazopyridines as cyclin dependent kinase inhibitors

专利摘要:

公开号:AU2003295332A1
申请号:U2003295332
申请日:2003-09-17
公开日:2004-04-08
发明作者:Ronald J. Doll；Michael P. Dwyer；Viyyoor M. Girijavallabhan；Timothy J. Guzi；Kartik M. Keertikar；Kamil Paruch
申请人:Schering Corp；
IPC主号:A61P35-00

专利说明:
WO 2004/026867 PCT/US2003/029498 NOVEL IMIDAZOPYRIDINES AS CYCLIN DEPENDENT KINASE INHIBITORS Field of the Invention The present invention relates to imidazo[1,2-a]pyridine compounds useful as protein kinase inhibitors (such as for example, the inhibitors of the cyclin dependent kinases, mitogen-activated protein kinase (MAPK/ERK), glycogen 5 synthase kinase 3(GSK3beta) and the like), pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat diseases such as, for example, cancer, inflammation, arthritis, viral diseases, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, and fungal diseases. This application claims the benefit 10 of priority from U.S. provisional patent application Serial No. 60/412,063, filed September 19, 2002. Background of the Invention Protein kinase inhibitors include kinases such as, for example, the inhibitors 15 of the cyclin-dependent kinases (CDKs), mitogen activated protein kinase (MAPK/ERK), glycogen synthase kinase 3 (GSK3beta), and the like. The cyclin dependent kinases are serine/threonine protein kinases, which are the driving force behind the cell cycle and cell proliferation. Individual CDK's, such as, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8 and the like, perform distinct 20 roles in cell cycle progression and can be classified as either G1, S, or G2M phase enzymes. Uncontrolled proliferation is a hallmark of cancer cells, and misregulation of CDK function occurs with high frequency in many important solid tumors. CDK2 and CDK4 are of particular interest because their activities are frequently misregulated in a wide variety of human cancers. CDK2 activity is required for 25 progression through G1 to the S phase of the cell cycle, and CDK2 is one of the key components of the G1 checkpoint. Checkpoints serve to maintain the proper sequence of cell cycle events and allow the cell to respond to insults or to WO 2004/026867 PCT/US2003/029498 2 proliferative signals, while the loss of proper checkpoint control in cancer cells contributes to tumorgenesis. The CDK2 pathway influences tumorgenesis at the level of tumor suppressor function (e.g. p52, RB, and p27) and oncogene activation (cyclin E). Many reports have demonstrated that both the coactivator, 5 cyclin E, and the inhibitor, p27, of CDK2 are either over - or underexpressed, respectively, in breast, colon, nonsmall cell lung, gastric, prostate, bladder, non Hodgkin's lymphoma, ovarian, and other cancers. Their altered expression has been shown to correlate with increased CDK2 activity levels and poor overall survival. This observation makes CDK2 and its regulatory pathways compelling 10 targets for the development years, a number of adenosine 5'-triphosphate (ATP) competitive small organic molecules as well as peptides have been reported in the literature as CDK inhibitors for the potential treatment of cancers. U.S. 6,413,974, col. 1, line 23- col. 15, line 10 offers a good description of the various CDKs and their relationship to various types of cancer. 15 CDK inhibitors are known. For example, flavopiridol (Formula I) is a nonselective CDK inhibitor that is currently undergoing human clinical trials, A. M. Sanderowicz et a/, J. Clin. Oncol. (1998) 16, 2986-2999.
CH
3 He HO O 1 CI OH 0 Formula 1 20 Other known inhibitors of the CDKs include, for example, olomoucine (J. Vesely et a/, Eur. J. Biochem., (1994) 224, 771-786) and roscovitine (I. Meijer et a/, Eur. J. Biochem., (1997) 243, 527-536). U.S. 6,107,305 describes certain pyrazolo[3,4-b] pyridine compounds as CDK inhibitors. An illustrative compound from the '305 patent has the Formula ll: WO 2004/026867 PCT/US2003/029498 3 0 o N N N H Formula I K. S. Kim et al, J. Med. Chem. 45 (2002) 3905-3927 and WO 02110162 disclose certain aminothiazole compounds as CDK inhibitors. 5 Pyrazolopyrimidines are known. For Example, W092/18504, W002/50079, W095/35298, W002/40485, EP94304104.6, EP0628559 (equivalent to US Patents 5,602,136, 5,602,137 and 5,571,813), U.S. 6,383,790, Chem. Pharm. Bull., (1999) 47 928, J. Med. Chem., (1977) 20, 296, J. Med. Chem., (1976) 19 517 and Chem. Pharm. Bull., (1962) 10 620 disclose various pyrazolopyrimidines. 10 There is a need for new compounds, formulations, treatments and therapies to treat diseases and disorders associated with CDKs. It is, therefore, an object of this invention to provide compounds useful in the treatment or prevention or amelioration of such diseases and disorders. 15 Summary of the Invention In its many embodiments, the present invention provides a novel class of imidazo[1,2-a]pyridine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations 20 comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions. In one aspect, the present application discloses a compound, or pharmaceutically acceptable salts or solvates of said compound, said compound 25 having the general structure shown in Formula IlIl: WO 2004/026867 PCT/US2003/029498 4
R
2
R
4 N R 3 N R H'N R Formula Ill wherein: R is selected from the group consisting of alkyl, aryl, heteroaryl, heteroarylalkyl, 5 heterocyclyl, heterocyclylalkyl, arylalkyl, cycloalkyl, -NR 6
R
7 , -C(O)R 7 , -C(O)OR', -C(O)NR R and -S(0 2 )R , wherein each of said alkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected 10 from the group consisting of halogen, alkyl, cycloalkyl, CF 3 , CN, -OCF 3 , -OR 6 , -C(O)R , -NR 6 R , -C(O)OR, -C(O)NR 5 R , -SR , -S(0 2 )R , -S(0 2 )NR R 6 ,
-N(R
5 )S(0 2
)R
7 , -N(R 5 )C(O)R and -N(R 5
)C(O)NR
5
R
6 and NO 2 ;
R
2 is selected from the group consisting of H, R 9 , alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, 15 cycloalkyl, -CF 3 , -C(O)R 7 , alkyl substituted with 1-6 R 9 groups which groups can be the same or different with each R 9 being independently selected,
-(CH
2 )m-N N-R 8
%_(CH
2 )n< -R8 -aryl-N N--R 8 aryl -/ N-R8 _--j and , wherein each of said aryl, heteroaryl, arylalkyl and heterocyclyl can be unsubstituted or optionally independently 20 substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, cycloalkyl, CF 3 , CN, -OCF 3 , -OR , -C(O)R , -NR R , -C(O)OR ,
-C(O)NR
5
R
6 , -SR 6 , -S(O 2
)R
7 , -S(0 2
)NR
5
R
6 , -N(R 5 )S(0 2
)R
7 , -N(R 5
)C(O)R
7 and
-N(R
5
)C(O)NR
5
R
6 ; 25 R 3 is selected from the group consisting of H, halogen, -NR R , CF 3 , alkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkynyl, alkenyl, -(CHR ),-aryl, - (CHR )n-heteroaryl, -(CHR 5 )n-OR 6 , -S(0 2 )R3, -C(O)R, WO 2004/026867 PCT/US2003/029498 5 -S(0 2
)NR
5
R
6 , -C(O)OR 6 , -C(O)NR 5
R
6 , -CH(aryl) 2 , -(CH 2 )m-NR 6 ,
(CH
2 )m N-R 8 N 2 1-2 (R) N (R)N (R1 1-2 and -2
(R
8 )/ 5 wherein each of said aryl, alkyl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which moieties can be the same or different, each moiety being independently selected from the group 10 consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, -OCF 3 , -OR , -C(R 4 R ),OR,
-NR
5
R
6 , -C(R 4
R
5
),NR
5
R
6 , -C(0 2
)R
5 , -C(O)R 5 , -C(O)NR 5
R
6 , -SR 6 , -S(0 2
)R
6 , -S(0 2
)NR
5
R
6 , -N(R 5 )S(0 2
)R
7 , -N(R )C(O)R and -N(R 5
)C(O)NR
5
R
6 ;
R
4 is selected from the group consisting of H, halogen, CF 3 , alkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkynyl, 15 alkenyl, -(CHR 5 )n-aryl, - (CHR 5 )n-heteroaryl, -(CHR ),-OR , -S(0 2
)R
6 , -C(O)R, -S(0 2
)NR
5
R
6 , -C(O)OR , -C(O)NR 5
R
6 , cycloalkyl, -CH(aryl) 2 , -(CH 2 )m 1
-NR
8 ,
(CH
2 )m NR8 and , wherein each of said aryl, alkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or 20 different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, -OCF 3 , -OR 5 , -NR 5
R
6 , -C(0 2
)R
5 ,
-C(O)NR
5
R
6 , -SR 6 and -S(0 2
)R
6 ;
R
5 is H, alkyl or aryl; R6 is selected from the group consisting of H, alkyl, aryl, heteroaryl, 25 arylalkyl, cycloalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein WO 2004/026867 PCT/US2003/029498 6 each of said alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of 5 halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, -OR 5 , -NR 5
R'
0 ,
-N(R
5 )Boc, -C(R 4
R
5 )OR', - C(O)R 6 , -C(O)OR 5 , -C(O)NR 5
R
0 , -SO 3 H, -SR 0 ,
-S(O
2
)R
7 , -S(O 2
)NR
5
R
0 , -N(R 5 )S(0 2
)R
7 , -N(R 5
)C(O)R
7 and
-N(R
5
)C(O)NR
5
R
0 ;
R
10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, 10 cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, 15 cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, -OR 5 , -NR 4
R
5 , -N(R 5 )Boc,
-(CR
4
R
5 )nOR 5 , -C(O 2
)R
5 , -C(O)NR 4
R
5 , -C(O)R , -SO 3 H, -SR 5 , -S(O 2 )R, -S(0 2
)NR
4
R
5 , -N(R 5 )S(0 2
)R
7 , -N(R 5 )C(O)R' and -N(R 5
)C(O)NR
4
R
5 ; or optionally (i) R 5 and R 10 in the moiety -NR 5
R
0 , or (ii) R 5 and R 6 in the moiety -NR 5
R
6 , may be joined together to form a cycloalkyl or heterocyclyl 20 moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently 25 substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, -OR 5 , -NR 5
R
10 , -CH 2
OR
5 , -C(0 2
)R
5 , -C(O)NR 5
R'
0 ,
-C(O)R
5 , -SR 0 , -S(0 2
)R'
0 , -S(0 2
)NR
5 R 0 , -N(R 5 )S(0 2
)R
0 , -N(R 5
)C(O)R'
0 and
-N(R
5
)C(O)NR
5 R0; 30 R 8 is selected from the group consisting of R 6 , -C(O)NR 5
R
1 4,
-S(O
2
)NR
5 R 0 , -C(O)R 7 , -C(O)OR 6 and -S(0 2
)R
7 ;
R
9 is selected from the group consisting of halogen, CN, NR 5
R
1 0
,
WO 2004/026867 PCT/US2003/029498 7
-C(O)OR
6 , -C(O)NR 5
R'
0 , -OR 6 , -C(O)R, -SR 6 , -S(0 2
)R
7 , -S(0 2
)NRR
10 ,
-N(R
5 )S(0 2
)R
7 , -N(R 5
)C(O)R
7 and -N(R 5
)C(O)NR
5
R
0 ;
R
11 is H, alkyl or aryl; m is 0 to 4; and 5 n is 1-4. The compounds of Formula Ill can be useful as protein kinase inhibitors and can be useful in the treatment and prevention of proliferative diseases, for example, cancer, inflammation and arthritis. They may also be useful in the treatment of neurodegenerative diseases such Alzheimer's disease, cardiovascular 10 diseases, viral diseases and fungal diseases. Detailed Description In one embodiment, the present invention discloses imidazo[1,2-a]pyridine compounds which are represented by structural Formula Ill, or a pharmaceutically 15 acceptable salt or solvate thereof, wherein the various moieties are as described above. In another embodiment, R is selected from the group consisting of aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkyl, -S(0 2
)R
7 , and -C(O)R 7 , wherein each of said aryl, arylalkyl, heteroaryl, heteroarylalkyl and alkyl can be unsubstituted or 20 optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, CF 3 , CN, -OCF 3 , -NR R , -N(R 5 )C(O)R , and -OR. In another embodiment, R 2 is selected from the group consisting of halogen, alkyl, aryl, heteroaryl, alkenyl and -C(O)R, wherein each of said alkyl, 25 aryl and heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, CF 3 , CN,
-OCF
3 , and -OR 6 . In another embodiment, R 3 is selected from the group consisting of H, aryl, 30 heteroaryl, -(CHR 5 )n-aryl, -(CHR 5 )n-heteroaryl,
(CH
2 )m
-(CHR
5 )n-OR 6 , -C(O)R 6 , cycloalkyl, -NR 5
R
6 , -CH(aryl)2, WO 2004/026867 PCT/US2003/029498 8 H3C RS N N N H H N ~(R8)nl 1 1-2 or 1-2 nN 1_2 5 wherein each of said aryl, cycloalkyl and heteroaryl and the heterocyclyl structures shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CF 3 , 10 OCF 3 , alkyl, CN, aryl, -C(O)R 5 , -C(0 2
)R
5 , -S(0 2
)R
6 , -C(=NH)-NH 2 , -C(=CN)-NH 2 , hydroxyalkyl, alkoxycarbonyl, -SR , and OR 5 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a - OR 5 moiety. In another embodiment of a compound of Formula Ill, R 4 is selected from the group consisting of H, alkyl, aryl, heteroaryl, -(CHR 5 ) -aryl, - (CHR 5
),
15 heteroaryl, -(CHR 5
),-OR
6 , -C(O)R 6 , cycloalkyl, -CH(aryl) 2 and (C 2 wherein each of said aryl and heteroaryl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, CF 3 , CN, -C(0 2
)R
5 and -S(0 2
)R
6 . 20 In another embodiment, R 5 is H, aryl or lower alkyl. In another embodiment of a compound of Formula ll, R" is H or lower alkyl. In another embodiment, m is 0 to 2.
WO 2004/026867 PCT/US2003/029498 9 In another embodiment, n is 1 to 3. In an additional embodiment, R is selected from the group consisting of phenyl, benzyl, benzoyl, phenylsulfonyl, thienyl, thienylalkyl, thienylcarbonyl, thienylsulfonyl, furyl, furylalkyl, furylcarbonyl, furylsulfonyl, pyridyl, pyridylalkyl, 5 pyridylcarbonyl, pyridylsulfonyl, pyrrolyl, pyrrolylalkyl, pyrrolylcarbonyl, pyrrolylsulfonyl, oxazolyl, oxazolylalkyl, oxazolylcarbonyl, oxazolylsulfonyl, thiazolyl, thiazolylalkyl, thiazolylcarbonyl, thiazolylsulfonyl, pyrazinyl, pyrazinylalkyl, pyrazinylcarbonyl, pyrazinylsulfonyl, pyridazinyl, pyridazinylalkyl, pyridazinylcarbonyl, pyridazinylsulfonyl, pyrimidinyl, pyrimidinylalkyl, 10 pyrimidinylcarbonyl, pyrimidinylsulfonyl, -S(0 2
)CH
3 , and -C(O)CH 3 , as well as their applicable N-oxides, wherein each of said phenyl (including the phenyl of the benzyl), thienyl, furyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, pyrazinyl, pyridazinyl and pyrimidinyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being 15 independently selected from the group consisting of Cl, Br, I, lower alkyl, CF 3 , CN, -C(O)OR, -NR3R 7 , -N(R 5
)C(O)R
7 , -OCF 3 , and -OH. In an additional embodiment, R is unsubstituted phenyl, unsubstituted pyridyl, benzyl whose phenyl can be unsubstituted or optionally substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, CF 3 , 20 -NH 2 , and -N(H)C(O)CH 3 , benzoyl whose phenyl can be unsubstituted or optionally substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, CF 3 , -NH 2 , and -N(H)C(O)CH 3 , phenylsulfonyl whose phenyl can be unsubstituted or optionally substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, -NH 2 , -N(H)C(O)CH 3 and CF 3 , pyridylmethyl 25 whose pyridyl can be unsubstituted or optionally substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, CF 3 , -NH 2 , and
-N(H)C(O)CH
3 , pyridylcarbonyl whose pyridyl can be unsubstituted or optionally substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, CF 3 , -NH 2 , and -N(H)C(O)CH3 , pyridylsulfonyl whose pyridyl can be 30 unsubstituted or optionally substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, -NH 2 , -N(H)C(O)CH 3 and CF 3 , pyrimidylmethyl WO 2004/026867 PCT/US2003/029498 10 whose pyrimidylmethyl can be unsubstituted or optionally substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, -NH 2 ,
-N(H)C(O)CH
3 and CF 3 , pyrimidylcarbonyl whose pyrimidyl can be unsubstituted or optionally substituted with one or more moieties selected from the group consisting 5 of F, Cl, Br, CN, -NH 2 , -N(H)C(O)CH 3 and CF 3 , or pyrimidylsulfonyl whose pyrimidyl can be unsubstituted or optionally substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, -NH 2 , -N(H)C(O)CH 3 and CF 3 . In an additional embodiment, R 2 is H, F, Cl, Br, I, hydroxyalkyl, alkoxyalkyl, or lower alkyl. 10 In an additional embodiment, R 3 is H, alkyl, aryl, -NR 5 R , N 1-2 r N (R ),or wherein said alkyl and aryl and the heterocyclyl moieties shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties (in addition to any R 8 ) which can be the same or different, each 15 moiety being independently selected from the group consisting of F, Cl, Br, CF 3 , lower alkyl, hydroxyalkyl, alkoxy, -S(0 2
)R
6 , and CN. In an additional embodiment, R 4 is H, alkyl or aryl, wherein said alkyl or aryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently 20 selected from the group consisting of F, Cl, Br, CF 3 , lower alkyl, hydroxyalkyl, alkoxy, -S(0 2
)R
6 , and CN. In an additional embodiment, R 5 is H. In an additional embodiment, R" is H. In an additional embodiment, m is 0. 25 In an additional embodiment, n is 1 or 2. An inventive group of compounds is shown in Table 1.
WO 2004/026867 PCT/US2003/029498 Table 1 Br 1 Brc IB /N /N *N /N~ /N~ N N -~N N HN HN HN HN INN N B B Br ~ Br N ~ N -~N~ HN HN HN HN 0 ~ NN NHBoc Br N N C N N CI CHN H N N H N l N H N H NyN N N N,,_N NH 2 Br N BrB Br N /lN -CF/ N ~ NN N ciF N CF 3 HN HN HN '.N 5 F 3 Nz~ N WO 2004/026867 PCT/US2003/029498 12 Br Br Br Cl B N Cl B N CF 3 NN N HN HN HN NN B NC N CF3 HN /~NC N' ' r N N HN O HN 0 Br H Br B NN /"N 7 N" CF 3 N N: N HN HN HN K N Br Br Br H N N N / - ' N-''/ N ~ N , S OH N OH N 5 OH HN HN HN Br H Br Br N N N NN N N HN OH N HN HN HN OH I 1N~ 1~ WO 2004/026867 PCT/US2003/029498 13 OHH OH Br H Br H Br H N N/, / N N N,, N ~ N 0 N HN HN HN Br H N N N HN N As used above, and throughout this disclosure, the following terms, unless 5 otherwise indicated, shall be understood to have the following meanings: "Patient" includes both human and animals. "Mammal" means humans and other mammalian animals. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about I to about 20 carbon atoms in the chain. 10 Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about I to about 6 carbon atoms in the chain which may be straight or branched. 15 The term "substituted alkyl" means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl) 2 , carboxy and -C(0)0-alkyl. Non-limiting examples of suitable alkyl groups include 20 methyl, ethyl, n-propyl, isopropyl and t-butyl. "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have WO 2004/026867 PCT/US2003/029498 14 about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may 5 be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term "substituted alkynyl" means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl. 10 "Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non limiting examples of suitable aryl groups include phenyl and naphthyl. 15 "Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally 20 substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of 25 suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-alpyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, 30 benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated WO 2004/026867 PCT/US2003/029498 15 heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. "Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non 5 limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl. "Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non limiting example of a suitable alkylaryl group is tolyl. The bond to the parent 10 moiety is through the aryl. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system 15 substituents" which may be the same or different, and are as defined above. Non limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like, as well as partially saturated species such as, for example, indanyl, 20 tetrahydronaphthyl and the like. "Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine. "Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on 25 the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, 30 aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarysulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -C(=N-CN)
NH
2 , -C(=NH)-NH 2 , -C(=NH)-NH(alkyl), Y 1
Y
2 N-, YIY 2 N-alkyl-, Y 1
Y
2
NC(O)-,
WO 2004/026867 PCT/US2003/029498 16
Y
1
Y
2
NSO
2 - and -SO 2
NY
1
Y
2 , wherein Y 1 and Y 2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon 5 atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH 3
)
2 - and the like which form moieties such as, for example: 0( 0 and "Heterocycly" means a non-aromatic saturated monocyclic or multicyclic 10 ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix 15 aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more "ring 20 system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, 25 tetrahydrothiophenyl, lactam, lactone, and the like. It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, 0 or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring: WO 2004/026867 PCT/US2003/029498 17 4 3l N H there is no -OH attached directly to carbons marked 2 and 5. It should also be noted that tautomeric forms such as, for example, the moieties: 5 H and N OH are considered equivalent in certain embodiments of this invention. "Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting 10 examples of suitable alkynylalkyl groups include propargylmethyl. "Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups. include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl. 15 "Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. "Acyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is 20 through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl. "Aroyl" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- naphthoyl. 25 "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, WO 2004/026867 PCT/US2003/029498 18 ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen. "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and 5 naphthoxy. The bond to the parent moiety is through the ether oxygen. "Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen. 10 "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur. "Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio 15 and naphthylthio. The bond to the parent moiety is through the sulfur. "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur. "Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of 20 suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl. "Aryloxycarbony" means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl. 25 "Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl. "Alkylsulfonyl" means an alkyl-S(0 2 )- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the 30 sulfonyl. "Arylsulfonyl" means an aryl-S(02)- group. The bond to the parent moiety is through the sulfonyl.
WO 2004/026867 PCT/US2003/029498 19 The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of 5 substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The term "optionally substituted" means optional substitution with the 10 specified groups, radicals or moieties. The term "isolated" or "in isolated form" for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. The term "purified" or "in purified form" for a compound refers to the physical state of said compound after being obtained 15 from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan. It should also be noted that any heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the hydrogen 20 atom(s) to satisfy the valences. When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by 25 reference to standard textbooks such as, for example, T. W. Greene et at, Protective Groups in organic Synthesis (1991), Wiley, New York. When any variable (e.g., aryl, heterocycle, R 2 , etc.) occurs more than one time in any constituent or in Formula III, its definition on each occurrence is independent of its definition at every other occurrence. 30 As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any WO 2004/026867 PCT/US2003/029498 20 product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug", as employed herein, denotes a 5 compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of Formula Il or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug 10 Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain 15 instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H 2 0. 20 "Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the CDK(s) and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect. The compounds of Formula IlIl can form salts which are also within the 25 scope of this invention. Reference to a compound of Formula Il herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula Ill contains both a basic moiety, 30 such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable WO 2004/026867 PCT/US2003/029498 21 (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formula Ill may be formed, for example, by reacting a compound of Formula IlIl respectively with an amount of acid or base, such as an equivalent amount, in a medium such as one in which 5 the salt precipitates or in an aqueous medium followed by lyophilization. Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, 10 phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by S. Berge et al, Journal of Pharmaceutical Sciences 15 (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto. 20 Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be 25 quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. 30 All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are WO 2004/026867 PCT/US2003/029498 22 considered equivalent to the free forms of the corresponding compounds for purposes of the invention. Compounds of Formula Ill, and salts, solvates and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such 5 tautomeric forms are contemplated herein as part of the present invention. All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs), such as those which may exist due to asymmetric carbons on various 10 substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other 15 isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the /UPAC 1974 Recommendations. The use of the terms "salt", "solvate" "prodrug" and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, 20 positional isomers, racemates or prodrugs of the inventive compounds. The compounds according to the invention have pharmacological properties; in particular, the compounds of Formula Ill can be inhibitors of protein kinases such as, for example, the inhibitors of the cyclin-dependent kinases, mitogen-activated protein kinase (MAPK/ERK), glycogen synthase kinase 25 3(GSK3beta) and the like. The cyclin dependent kinases (CDKs) include, for example, CDC2 (CDKI), CDK2, CDK4, CDK5, CDK6, CDK7 and CDK8. The novel compounds of Formula Ill are expected to be useful in the therapy of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurological/neurodegenerative disorders, arthritis, inflammation, 30 anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease. Many of these diseases and disorders are listed in U.S. 6,413,974 cited earlier, the disclosure of which is incorporated herein.
WO 2004/026867 PCT/US2003/029498 23 More specifically, the compounds of Formula IlIl can be useful in the treatment of a variety of cancers, including (but not limited to) the following: carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall bladder, ovary, pancreas, 5 stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T- cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma; 10 hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including 15 astrocytoma, neuroblastoma, glioma and schwannomas; and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma. Due to the key role of CDKs in the regulation of cellular proliferation in 20 general, inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, 25 hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections. Compounds of Formula Ill may also be useful in the treatment of Alzheimer's disease, as suggested by the recent finding that CDK5 is involved in the phosphorylation of tau protein (J. Biochem, (1995) 117, 741-749). 30 Compounds of Formula IlIl may induce or inhibit apoptosis. The apoptotic response is aberrant in a variety of human diseases. Compounds of Formula IlIl, as modulators of apoptosis, will be useful in the treatment of cancer (including but WO 2004/026867 PCT/US2003/029498 24 not limited to those types mentioned hereinabove), viral infections (including but not limited to herpevirus, poxvirus, Epstein- Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, 5 autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), 10 myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis) 15 aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain. Compounds of Formula 111, as inhibitors of the CDKs, can modulate the level of cellular RNA and DNA synthesis. These agents would therefore be useful in the treatment of viral infections (including but not limited to HIV, human 20 papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus). Compounds of Formula Ill may also be useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the 25 progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse. Compounds of Formula IlIl may also be useful in inhibiting tumor angiogenesis and metastasis. Compounds of Formula Ill may also act as inhibitors of other protein 30 kinases, e.g., protein kinase C, her2, raf 1, MEKI, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, P13 kinase, weel kinase, Src, AbI and thus be effective in the treatment of diseases associated with other protein kinases.
WO 2004/026867 PCT/US2003/029498 25 Another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition associated with the CDKs by administering a therapeutically effective amount of at least one compound of Formula 1ll, or a pharmaceutically acceptable salt or solvate of said compound to the mammal. 5 A preferred dosage is about 0.001 to 500 mg/kg of body weight/day of the compound of Formula Ill. An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of Formula II1, or a pharmaceutically acceptable salt or solvate of said compound. The compounds of this invention may also be useful in combination 10 (administered together or sequentially) with one or more of anti-cancer treatments such as radiation therapy, and/or one or more anti-cancer agents selected from the group consisting of cytostatic agents, cytotoxic agents (such as for example, but not limited to, DNA interactive agents (such as cisplatin or doxorubicin)); taxanes (e.g. taxotere, taxol); topoisomerase 11 inhibitors (such as etoposide); 15 topoisomerase I inhibitors (such as irinotecan (or CPT-1 1), camptostar, or topotecan); tubulin interacting agents (such as paclitaxel, docetaxel or the epothilones); hormonal agents (such as tamoxifen); thymidilate synthase inhibitors (such as 5-fluorouracil); anti-metabolites (such as methoxtrexate); alkylating agents (such as temozolomide (TEMODARTM from Schering-Plough Corporation, 20 Kenilworth, New Jersey), cyclophosphamide); Farnesyl protein transferase inhibitors (such as, SARASAR
T
m(4-[2-[4-[(1 R)-3,10-dibromo-8-chloro-6,1 1 dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-I I -yl-]-1 -piperidinyl]-2-oxoehtyl]-1 piperidinecarboxamide, or SCH 66336 from Schering-Plough Corporation, Kenilworth, New Jersey), tipifarnib (Zarnestra* or R1 15777 from Janssen 25 Pharmaceuticals), L778,123 (a farnesyl protein transferase inhibitor from Merck & Company, Whitehouse Station, New Jersey), BMS 214662 (a farnesyl protein transferase inhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, New Jersey); signal transduction inhibitors (such as, Iressa (from Astra Zeneca Pharmaceuticals, England), Tarceva (EGFR kinase inhibitors), antibodies to 30 EGFR (e.g., C225), GLEEVECTM (C-abl kinase inhibitor from Novartis Pharmaceuticals, East Hanover, New Jersey); interferons such as, for example, intron (from Schering-Plough Corporation), Peg-Intron (from Schering-Plough WO 2004/026867 PCT/US2003/029498 26 Corporation); hormonal therapy combinations; aromatase combinations; ara-C, adriamycin, cytoxan, and gemcitabine. Other anti-cancer (also known as anti-neoplastic) agents include but are not limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, 5 Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, oxaliplatin (ELOXATINTM from Sanofi-Synthelabo Pharmaeuticals, France), Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, 10 Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, 15 Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, or Hexamethylmelamine. 20 If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range. For example, the CDC2 inhibitor olomucine has been found to act synergistically with known cytotoxic agents in inducing apoptosis (J. Cell Sci., (1995) 108, 2897. 25 Compounds of Formula Il may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of Formula II1 may be administered either prior to or after administration of the known anticancer or cytotoxic agent. For example, the cytotoxic activity of the cyclin 30 dependent kinase inhibitor flavopiridol is affected by the sequence of administration with anticancer agents. Cancer Research, (1997) 57, 3375. Such WO 2004/026867 PCT/US2003/029498 27 techniques are within the skills of persons skilled in the art as well as attending physicians. Accordingly, in an aspect, this invention includes combinations comprising an amount of at least one compound of Formula Ill, or a pharmaceutically 5 acceptable salt or solvate thereof, and an amount of one or more anti-cancer treatments and anti-cancer agents listed above wherein the amounts of the compounds/ treatments result in desired therapeutic effect. The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. The exemplified 10 pharmacological assays which are described later have been carried out with the compounds according to the invention and their salts. This invention is also directed to pharmaceutical compositions which comprise at least one compound of Formula Ill, or a pharmaceutically acceptable salt or solvate of said compound and at least one pharmaceutically acceptable 15 carrier. For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised 20 of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. 25 Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, 30 suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
WO 2004/026867 PCT/US2003/029498 28 Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations that are intended to be converted, 5 shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or 10 reservoir type as are conventional in the art for this purpose. The compounds of this invention may also be delivered subcutaneously. Preferably the compound is administered orally. Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing 15 appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about I mg to about 100 mg, preferably from about I mg to about 50 mg, more preferably from about I mg to about 25 mg, according to the 20 particular application. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and 25 administered in portions during the day as required. The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being 30 treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
WO 2004/026867 PCT/US2003/029498 29 Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of Formula l1l, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier, vehicle or diluent. 5 Yet another aspect of this invention is a kit comprising an amount of at least one compound of Formula Ill, or a pharmaceutically acceptable salt or solvate of said compound and an amount of at least one anticancer therapy and/or anti-cancer agent listed above, wherein the amounts of the two or more ingredients result in desired therapeutic effect. 10 The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art. Where NMR data are presented, 1H spectra were obtained on either a 15 Varian VXR-200 (200 MHz, 1H), Varian Gemini-300 (300 MHz) or XL-400 (400 MHz) and are reported as ppm down field from Me4Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenthetically. Where LC/MS data are presented, analyses was performed using an Applied Biosystems API-I 00 mass spectrometer and Shimadzu SCL-10A LC column: Altech platinum 20 C18, 3 micron, 33mm x 7mm ID; gradient flow: 0 min - 10% CH 3 CN, 5 min - 95%
CH
3 CN, 7 min - 95% CH 3 CN, 7.5 min - 10% CH 3 CN, 9 min - stop. The retention time and observed parent ion are given. The following solvents and reagents may be referred to by their abbreviations in parenthesis: 25 Thin layer chromatography: TLC dichloromethane: CH 2
C
2 ethyl acetate: AcOEt or EtOAc methanol: MeOH trifluoroacetate: TFA 30 triethylamine: Et 3 N or TEA butoxycarbonyl: n-Boc or Boc nuclear magnetic resonance spectroscopy: NMR WO 2004/026867 PCT/US2003/029498 30 liquid chromatography mass spectrometry: LCMS high resolution mass spectrometry: HRMS milliliters: mL millimoles: mmol 5 microliters: pl grams: g milligrams: mg room temperature or rt (ambient): about 25*C. 10 EXAMPLES Scheme 1 0 R 'r 1 R 2 R R R 2 R R S Br R 1 N R RCHO, ZnCl 2
R
1 /N R 4
H
2 N R5 N R 5 NaCNBH 3 N * R
NH
2 NH 2 HNR B A C For the preparation of compounds (R 2 = H; R 4 = halo, alkyl, trifluoromethyl, 15 etc.) the known diaminopyridines (J. Med. Chem. 1997, 40, 3679) of Type A are treated under cycloaddition conditions to afford the parent imidazo[1,2-a]pyridine skeletons B. Reductive amination with aldehydes yields compounds of Type C.
WO 2004/026867 PCT/US2003/029498 31 Scheme 2 R2 R3
R
2
R
3 1) AcCI, pyr. R R B(OH) 2
R
4 2) NXS (X=Br or CI), GH 3 CN
R
1 N R4 Pd(O)
R
1 N R 3) HCI, EtOH N R5 N R
NH
2 NH 2 B D
R
2 =H
R
3 X R R4 RCHO, ZnC 2 R / N R'
NR
1 /N /___ N R NaCNBH 3 N R E NH 2 HN R F 5 For more highly elaborated derivatives (R 2 = Br, Cl; R 4 = aryl or heteroaryl), the parent compound of Type B is treated under Suzuki coupling conditions to afford compounds of Type D. N-Acetylation followed by regioselective halogenation affords compounds of Type E. The intermediate is elaborated via reductive amination to afford compounds of Type F as described previously in 10 Scheme 1. Scheme 3 R2 R k4 1) RB(OH) 2 , Cu(OAc) 2 R 4 R Et 3 N R 1 R N R 5 2)KOH,MeOH N R5 NHAc HN'R G H N-acylated derivatives of Type G are treated under arylation conditions followed by cleavage of the acetate under basic conditions to afford final products 15 oftype H. Scheme 4 WO 2004/026867 PCT/US2003/029498 32
R
2
R
3
R
2
R
3
R
1 N R Acylation or / N R QCOorSO 2 R N4 R Sulfonylation N R
NH
2 HN,'QR C I Treatment of aniline core structures of Type C under standard acylation or sulfonylation conditions affords the final products I. Scheme 5
R
2
R
3
R
2
R
3 SN R4 1) Boc 2 0, DMAP R/ N NRR7 N R 2) HNR 6
R
7 , Pd(O) N R NH2base NHBoc
R
2 =H; R 4 =Br 1) NBS, CH 3 CN X R 3 2) TFA, CH 2 C12 NR6R7 3) RCHO, ZnCl 2
R
1 / N then NaCNBH 3 N * R HN' R 5 K Nitrogen protection of aniline core I of Type I (R 2 = H, R 4 = Br) followed by palladium-mediated amination reaction affords the adduct J. In an analogous fashion to Scheme 2, bromination followed by deprotection and reductive amination affords the adducts of type K. 10 PREPARATIVE EXAMPLE 10 Br Br
H
2 NN NH 2
NH
2 To a soln of bromoacetaldehyde diethyl acetal (2.37 mL, 15.4 mmol) in dioxane/H20 (2:1/15 mL) at rt was added conc. HCI (0.3 mL) and the mixture was refluxed for 30 min- The mixture was cooled to rt whereupon NaHCO 3 (2.6 g, 30.8 15 mmol) was carefully added followed by dropwise addition of diamino derivative (1.5 g, 7.7 mmol) in dioxane/H 2 0 (2:1/15 mL). The resultant mixture was stirred at reflux for 14 h and was cooled to rt. The mixture was diluted with I M NaOH (30 WO 2004/026867 PCT/US2003/029498 33 mL) and was extracted with CH 2
CI
2 (3 x 35 mL). The organic layers were combined, washed with brine (1 x 20 mL), dried (Na 2
SO
4 ), filtered and concentrated under reduced pressure to afford 1.5 g (92%) of the desired compound [M + H = 214.0]. 5 PREPARATIVE EXAMPLES 11,12 Following the procedure set forth in Preparative Example 10 but by utilizing known diaminopyridines (J. Med. Chem. 1997, 40, 3679), the following imidazo[1,5-a]pyridine cores (Products) were prepared as indicated in Table 2. Table 2 Preparative 1.Yield(%) Pyridine Product Example 2. MH* N CI 1..~c73 11
H
2 N C , CN 168.0
NH
2 NH 2 1. 84 12 H2N N2. 148.0
NH
2
NH
2 10 EXAMPLE 20 Br N Br ____ ____ N -q HN
NH
2 N To a solution of aniline (0.10 g, 0.47 mmol) from Preparative Example 10 in MeOH (3 mL) at rt was added 4-pyridinecarboxyaldehyde (55 tL, 0.59 mmol) and 15 ZnC 2 (112 mg, 0.82 mmol). The resultant mixture was stirred for I h whereupon NaCNBH 3 (37 mg, 0.59 mmol) was added in one portion. The mixture was stirred at reflux for 14 h, cooled to rt, and concentrated under reduced pressure. The crude material was partitioned between CH 2
CI
2 (7 mL) and 2M NaOH (3 mL) and WO 2004/026867 PCT/US2003/029498 34 the layers were separated. The aqueous layer was extracted with CH 2
CI
2 (2 x 7 mL) and the organic layers were combined. The organic layer was dried (Na 2
SO
4 ), filtered and concentrated under reduced pressure. The crude material was purified by prep TLC (6 x 1000 ptM) using CH 2 Cl 2 /MeOH (20:1) as eluant to afford 52 mg 5 (37%) of a red-brown solid [M+H = 305.0]; mp 167-172 'C. EXAMPLES 21-26 Following the procedure set forth in Example 20 but using the prepared aniline derivatives (Preparative Examples 11 & 12) indicated in Table 3 and commercially available aldehydes, the substituted imidazo[1,2-a]pyridine adducts 10 were prepared (Products). Table 3 I.Yield (%) PrpEx. Ex. niline Aldehyde Product 2. MH* 3. mp (*C) N~ 1.73 SHN 2. 238.0 21 11 3.135-137 1.57 HN 2. 239.0 22 11 3.131-133 N
N
WO 2004/026867 PCT/US2003/029498 35 1.68 SHN 2. 239.0 23 11 3. 131-133 N N O H Cl 1.95 HN 2. 258.1 24 12 3. 119-122 cl O HN~ c 1.35 SHN 2. 259.0 25 12 3. 125-127 N N N c- 1.55 O H NH 2. 259.0 HN 26 12 3.127-130 N N PREPARATIVE EXAMPLE 20 Br
NH
2
NH
2 WO 2004/026867 PCT/US2003/029498 36 To a solution of bromo compound from Preparative Example 10 (1.0 g, 4.72 mmol) in DME/H 2 0 (4:1; 25 ml total) at rt was added PhB(OH) 2 (1.2 g, 9.4 mmol), K 3
PO
4 (3.0 g, 14.2 mmol), and Pd(PPh 3
)
4 (0.54 g, 0.47 mmol). The mixture was heated at reflux for 18 h and was cooled to rt. EtOAc (30 mL) and 5 water (10 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 30 mL) and the organic layers were combined. The organic layer was washed with brine (1 x 25 mL), dried (Na 2
SO
4 ), filtered, and concentrated under reduced pressure to afford a brown oil. The crude product was purified by prep TLC (10 x 1000 VM) using CH 2
CI
2 /MeOH (25:1) as eluant to 10 afford 0.9 g (91%) of a brown solid [M + H = 209.0]. PREPARATIVE EXAMPLES 21-25 Following the procedure set forth in Preparative Example 20 but by utilizing different boronic acid in the Suzuki coupling reaction with aniline from Preparative Example 10, the following aniline cores (Products) were prepared as indicated in 15 Table 4. Table 4 Preparative Boronic P 1.Yield (%) I Product Example Acid 2. MH* 1.78 21 CI N 2. 244.0 HO'B OH
NH
2 1.65 22
CF
3 /N 2.278.0 N ' CF 3 HOBOH
NH
2 CI IN Cl 1.87 23 N 2. 244.0 HO' B'OH
NH
2 WO 2004/026867 PCT/US2003/029498 37
CF
3 24 /N
CF
3 1.86 N 2. 278.0 HO' B,OH
NH
2 C I
(HO)
2 B S 1.15 25 /N N ~ 2. 250.0
NH
2 PREPARATIVE EXAMPLE 30 /N N
NH
2 NHAc To a solution of aniline from Preparative Example 20 (0.12 g, 0.59 mmol) in
CH
2
CI
2 (3 mL) at 00C was added pyridine (72 tL, 0.89 mmol) followed by 5 dropwise addition of AcCI (50 pL, 0.71 mmol). The resulting heterogeneous mixture was stirred for 2 h at 0"C and was concentrated under reduced pressure. The crude residue was suspended in CH 2 Cl 2 (10 mL) and sat. aq. NaHCO 3 (5 mL) and the layers were separated. The aqueous layer was extracted with CH 2
CI
2 (2 x 10 mL) and the organic layers were combined. The organic layer was washed 10 with brine (1 x 7 mL), dried (Na 2
SO
4 ), filtered and concentrated under reduced pressure. The crude product was purified by prep TLC (4 x 1000 pM) using
CH
2 Cl 2 /MeOH (25:1) as eluant to afford 0.12 g (78 % yield) of a yellowish solid [M+ H = 252.0]. PREPARATIVE EXAMPLES 31-36 15 Following the procedure set forth in Preparative Example 30 but by utilizing the following aniline cores described in Preparative Examples 10, 21-25, the acylated derivatives (Products) were prepared as indicated in Table 5.
WO 2004/026867 PCT/US2003/029498 38 Table 5 Preparative I1.Yield (%) Aniline Product I Example 2. MH* 1. 95 Prep. Ex. N 1 31 2. 286.0 21 N C1 NHAc 1.98 Prep. Ex. N 2. 320.1 32 22 N- CF 3 NHAc Prep. Ex. N C11.93 33 23 N' 2. 286.0 NHAc Prep. Ex. N CF 3 1.89 34 24 N' / 2. 320.1 NHAc C1 Prep. Ex. N 1.76 35 25 N - 2. 292.0 NHAc Br 1.89 36 Prep Ex. 10 2. 256.0 NHAc PREPARATIVE EXAMPLE 40 Br N XN N N : NHAc NHAc WO 2004/026867 PCT/US2003/029498 39 To a solution of acetate from Preparative Example 30 (0.12 g, 0.46 mmol) in
CH
3 CN (5 mL) at 0 'C was added NBS (73 mg, 0.41 mmol) in one portion to afford a heterogeneous mixture. The resulting solution was stirred for 1 h at 0 'C whereupon the reaction mixture was concentrated under reduced pressure. The 5 crude material was purified by prep TLC (6 x 1000 pM) using CH 2 Cl 2 /MeOH (20:1) as eluant to afford 0.14 g (89%) of a yellow solid [M + H = 330.1]. PREPARATIVE EXAMPLES 41-45 Following the procedure set forth in Preparative Example 40 but by utilizing the following aniline cores described in Preparative Examples 31-34, the 3-bromo 10 derivatives (Products) were prepared as indicated in Table 6. Table 6 Preparative 1.Yield (%) Acetate Product Example 2. MH* Br 1.79 41 2. 366.1 31 N' c NHAc Br 1.72 42 Prep. Ex. N 2. 400.1 32 N' CF3 NHAc Br Prep. Ex. / N cI 1.76 33 N-' 2. 366.1 NHAc Br Prep. Ex. / N -CF 3 1.89 44 34 N' / 2. 400.1 NHAc WO 2004/026867 PCT/US2003/029498 40 Br S CI Prep. Ex. N 1.98 35 N- 2. 370.6 NHAc PREPARATIVE EXAMPLE 50 Br Br N N NN NHAc
NH
2 To a solution of 3-bromo derivative from Preparative Example 40 (0.14 g, 5 0.41 mmol) in EtOH (3 mL) was added conc. HCI (0.2 mL) and the mixture was refluxed for 4 h. The mixture was cooled to rt and was concentrated under reduced pressure. The crude product was partitioned between CH 2
CI
2 (7 mL) and sat. aq. NaHCO 3 (3 mL) and the layers were separated. The aqueous layer was extracted with CH 2
CI
2 (2 x 7 mL) and the organic layers were combined. The 10 organic layer was dried (Na 2 SO4), filtered and concentrated under reduced pressure to afford 0.11 g (93 % yield) of an off-white solid [M + H = 288.0]. This material was carried on without further purification. PREPARATIVE EXAMPLES 51-54 Following the procedure set forth in Preparative Example 50 but by utilizing 15 the following 3-bromo acetylated aniline cores described in Preparative Examples 41-44, the aniline derivatives (Products) were prepared as indicated in Table 7. Table 7 Preparative 3-Bromo 1.Yield (%) ____ __ Product Example Derivative 2. M+H Br 1.88 51 Prep. Ex. N 2.322.1 41 N- C'
NH
2 WO 2004/026867 PCT/US2003/029498 41 Br Prep. Ex- N s 2.358.1 52 P E/ 42 N / CF 3
NH
2 Br Prep. Ex. / N -CI 1.99 53 43 N 2. 324.1
NH
2 Br Prep. Ex. -N CF 3 1.94 54 44 N' 2. 356.1
NH
2 EXAMPLE 100 Br Br N N N N' HN
NH
2 N To a solution of aniline (0.11 g, 0.36 mmol) from Preparative Example 50 in 5 MeOH (4 mL) at rt was added 4-pyridinecarboxyaldehyde (44 [L, 0.46 mmol) and ZnC 2 (87 mg, 0.64 mmol). The resultant mixture was stirred for 1 h whereupon NaCNBH 3 (29 mg, 0.46 mmol) was added in one portion. The mixture was stirred at reflux for 14 h, cooled to rt, and concentrated under reduced pressure. The crude material was partitioned between CH 2
CI
2 (7 mL) and 2M NaOH (3 mL) and 10 the layers were separated. The aqueous layer was extracted with CH 2
CI
2 (2 x 7 mL) and the organic layers were combined. The organic layer was dried (Na 2
SO
4 ), filtered and concentrated under reduced pressure. The crude material was purified by prep TLC (6 x 1000 pM) using CH 2 Cl 2 /MeOH (20:1) as eluant to afford 0.07 g (49%) of a brown solid [M+H = 379.1]; mp 167-172'C.
WO 2004/026867 PCT/US2003/029498 42 EXAMPLES 101 -118 Following the procedure set forth in Example 100 but using the prepared aniline derivatives (Preparative Example 50-54) indicated in Table 8 and commercially available aldehydes, the substituted imidazo[1,2-a]pyridine adducts 5 were prepared (Products). Table 8 Prep Ex. I.Yield Ex. Aniline Aldehyde Product 2. M+H 3. mp (*C) Br N 1.84 0 H N 2.379.1 101 50 HN 3. 190-192 .IN N Br N 1.85 o H N 2.380.1 102 50 HN 3.160-162 Br / N1.88 0 H N 2.386.1 103 50 HN 3. 186-189
-S
WO 2004/026867 PCT/US2003/029498 43 Br Br 1.89 N 2. 370.1 104 50 HN 3.179-181 0O 0 Br /N 1.53 O H N : 2.382.1 105 50 HN 3. 157-159 N yN N~ N Br H N 1.35 N 2. 495.1 106 50 N NHoHN 3.198-200 N N NHBoc B 0 N O H /N'~1.69 HN 2. 431.1 107 50 N 3.222-225 0 N
N
WO 2004/026867 PCT/US2003/029498 44 Br O H N CI1.47 108 51 HN 2. 415.1 3. 199-201 N 3.16-9 N N Br N o H N Ci 1.84 109 51 HN 2. 415.1 3. 196-199 >N Br NH2 N N N2.416.1 109 1 HN3. 206-208 N,.,N Br 0; H N~ C, 1.40 11l 51 NN.N H 2. 431.1 NYN 13.211-213
NH
2 NN
NH
2 WO 2004/026867 PCT/US2003/029498 45 Br N 1.90 o H N~ CF3 N 2. 421.1 11 5Ns HN 3.200-202 s Br N 1.695 o H N CF 3 113 52 HN 2. 449.1 3. 194-196 NN N N o H ~ -~CF 3 1.95 114 52 HN 2.447.0 3. 192-195 N~ Br N cl O H N ~-1.83 115 53 HN 2. 15.19 N'
N
WO 2004/026867 PCT/US2003/029498 46 Br N CI 1.42 O HN 1 5N 2. 413.0 116 53 HN 3.191-194 N Br N CF3
CF
3 1.44 o H N 117 54 HN 2. 449.1 NN N B N
CF
3 1.82 H N 2. 449.1 118' 54 HN 3. 188-190 N N CI Br S N 1.36 O H 2.421 119 55 HN 3.125-127
N
WO 2004/026867 PCT/US2003/029498 47 Cl Br s N 1.22 o HN 2.422 120 55 HN 8-121 N yN Br N O H N CI 1.83 HN 2.483 121 51 N 3.106-108
CF
3 N
CF
3 Br N o H N X CI HN 1.79 122 51 N N 2.492 N IN 3. 188-191 WO 2004/026867 PCT/US2003/029498 48 Br N o H N- / CI 1.98 123 51 HN 2.454 3. 197-200 Ci CI B / N O H N - CI N:( HN 1.22 124 51 N N IS 2. 561 So 2 3. 211-213 6 S02 PREPARATIVE EXAMPLE 60 CI Br N Br N N HN O HN 0 To a solution of acetate (100 mg, 0.39 mmol) from Preparative Example 36 5 in CH 3 CN (4 mL) at 0 *C was added NCS (47 mg, 0.35 mmol) in one portion. The mixture was warmed to rt and heated to reflux and stirred for 1 h. The mixture was cooled to rt and was concentrated under reduced pressure. The crude material was purified by prep TLC (6 x 1000 pM) using CH 2
CI
2 /MeOH (22:1) as eluent to afford 96 mg (86%) of a white solid [M+H = 290.0].
WO 2004/026867 PCT/US2003/029498 49 PREPARATIVE EXAMPLE 65 C1 C1 N Br N HN 0 HN 0 Following the procedure set forth in Preparative Example 20 but by utilizing the acetate derivative from Preparative Example 60, the final target was prepared 5 in 79% yield as and orange solid [M+H = 286.0]. PREPARATIVE EXAMPLE 70 C1 N C N N HN 0
NH
2 Following the procedure set forth in Preparative Example 50 but by utilizing the acetate derivative from Preparative Example 65, the final target was prepared 10 in 98% yield. [M+H = 244.0]. EXAMPLE 200 C1 C1 N N N N
NH
2 HN N Following the procedure set forth in Example 100 except using the prepared aniline from Preparative Example 70 with 4-pyridylcarboxaldehyde, the final 15 product indicated in Table 9 and commercially available aldehydes, the substituted imidazo[1,2-a]pyridine adduct was prepared as a light yellow solid in 35% yield. mp 202-205C; [M+H = 335.0].
WO 2004/026867 PCT/US2003/029498 50 PREPARATIVE EXAMPLE 80 Br B N N N N HN 0N To solution of acetate (30 mg, 0.09 mmol) from Preparative Example 40 in
CH
2
CI
2 (2 mL) at rt was added Cu(OAc) 2 (16 mg, 0.09 mmol), PhB(OH) 2 (22 mg, 5 0.18 mmol) and Et 3 N (25 pL, 0.18 mmol). The mixture was stirred for 24 h at rt and was concentrated under reduced pressure. The crude material was purified by prep TLC (4 x 1000 pM) using CH 2 Cl 2 /MeOH (25:1) as eluant to afford 15 mg (41%) of product [M+H = 408.1]. PREPARATIVE EXAMPLES 81-82 10 Following the procedure set forth in Preparative Example 80 but by utilizing the specified acetylated aniline cores described in Preparative Examples 43,44 the aniline derivatives (Products) were prepared as indicated in Table 10. Table 10 Preparative 1.Yield(%) Acetate Product Example 2. MH* Br N 'CI 1.21 Prep. Ex. 81 N ' 2. 442.1 43 N O Br /N -CF3 1. 32 Prep. Ex. 82 N 2. 474.1 44 N 0 WO 2004/026867 PCT/US2003/029498 51 EXAMPLE 200 Br Br N N N N N O NH To a solution of the acetate (15 mg, 0.037 mmol) in MeOH/H 2 0 (1:1; 2 mL total) at rt was added KOH (42 mg, 0.74 mmol) in one portion. The mixture was 5 stirred at reflux for 8 h, cooled to rt, and concentrated to dryness. The resultant residue was partitioned between H 2 0 (1 mL) and CH 2
CI
2 (3 mL) and the layers were separated. The aqueous layer was extracted with CH 2
CI
2 (2 x 3 mL) and the organic layers were combined. The organic layer was dried (Na 2
SO
4 ), filtered, and concentrated under reduced pressure. The crude material was purified by prep 10 TLC (4 x 1000 pM) using hexanes/EtOAc (5:1) as eluant to afford 9 mg (67%) of red-brown semisolid. [M+H = 366.1]. EXAMPLE 201 Following the procedure set forth in Example 200 but using the prepared acetate derivative (Preparative Example 50) indicated in Table 11 available, the N8 15 phenyl substituted imidazo[1,2-a]pyridine adducts were prepared (Products). Table 11 1.Yield (%) Ex. Product 2. MH* Aniline 3. mp ('C) Br 1.78 N CF3 N CF 3 2. 434.1 201 82 NH 3. 152-153 E L EXAMPLE 300 WO 2004/026867 PCT/US2003/029498 52 Br Br N N N N
NH
2 HN 0 Following the procedure set forth in Example 30 except using the prepared aniline from Preparative Example 50, the acylated derivative was prepared in 89% yield as a yellow solid, mp. 92-96OC; [M+H = 332.1]. 5 EXAMPLES 301-304 Following the procedure set forth in Example 300 but using various aniline cores as indicated in Table 12 reacting with designated acid chlorides, the N8 acylated substituted imidazo[1,2-a]pyridine adducts are prepared (Products). Table 12 Ex. Prep Ex. Acid Product Aniline Chloride Br B N0 CI / N CI N 301 N HN 0
NH
2 N (Prep Ex. 50) N Br Br 0 N 302 N HN 0
NH
2 N
N
WO 2004/026867 PCT/US2003/029498 53 Br B 0 Cl N 303 N C HN 0 N CN
NH
2 N B Br I0 CI /N'~ C N N BI NN C0 304 N- 7 C HN 0
NH
2 N N) EXAMPLE 400 Br B / N N N N
NH
2 HN, // The core aniline from Preparative Example 50 is reacted with 5 methanesulfonyl chloride in the presence of pyridine to afford the desired product. EXAMPLES 401-404 Following the procedure set forth in Example 400 but using various aniline cores as indicated in Table 13 reacting with designated acid chlorides, the N8 sulfonylated substituted imidazo[1,2-a]pyridine adducts are prepared (Products). 10 Table 13 Ex. Prep Ex. Sulfonyl Product Aniline Chloride WO 2004/026867 PCT/US2003/029498 54 Br Cl / N B O=S=O N 402 N HN 2 NH2 NHAc NHAc
NH
2 Br Br O-S=O N C 40 2 N N SO N Q~
NH
2 NHAc NHAc Br Br CNH2 NH o 403 -N HN N -~cj S02
NH
2 N so 2 N.
NH
2 NH2 N.~ WO 2004/026867 PCT/US2003/029498 55 STEP A: Treatment of aniline derivative from Preparative Example 10 under standard conditions (Boc 2 0, Et 3 N, DMAP) affords the corresponding carbamate derivative. 5 STEP B: Treatment of the derivative from Step A under standard amination conditions (Pd(OAc) 2 , BINAP, Cs 2
CO
3 ) and by employing cyclopentylamine affords the desired cyclopentyl amine derivative. PREPARATIVE EXAMPLES 91-100 10 Following the procedure set forth in Preparative Example 90 but by utilizing the carbamate described in Preparative Examples 90 Step A with various amines, the amino derivatives (Products) are prepared as indicated in Table 14. Table 14 Preparative Amine Product Example H 91
H
2 N N NHBoc N 92 HN OH N OH NHBoc N 93 HN N NH ~OH NHBoc H N 94
H
2 N NH OH NHBoc WO 2004/026867 PCT/US2003/029498 56 H 95 H2N N OH TOH NHBoc N N 96 HN OHNq OH OH NHBoc 97 HN N OH NHBoc OH HOH 98
H
2 N OH N NHBoc IOH "OH H 99
H
2 N ,, / N - N ,, 0 (+/-) NHBoc OH OH H 100 H 2 N,, N,, (+/-) NHBoc PREPARATIVE EXAMPLE 101 Br H H N / N NO STEP A /N --STEP B N ," NN NHBoc NH2 STEP A: 5 Treatment of Boc derivative from Preparative Example 90 according to the procedure set forth in Preparative Example 40 affords the 3-bromo adduct. STEP B: WO 2004/026867 PCT/US2003/029498 57 Treatment of the product from STEP A under acidic conditions (HCI) according to the procedure set forth in Preparative Example 50 affords the aniline derivative. PREPARATIVE EXAMPLES 102-111 5 Following the procedure set forth in Preparative Example 100 but by utilizing the carbamate derivatives described in Preparative Examples 91-95, the amino derivatives (Products) are prepared as indicated in Table 15. Table 15 Preparative Carbamate Product Example Br H 102 91 N N
NH
2 Br N NH2 103 92
NH
2 Br H 104 93 NH N: -OH
NH
2 Br H N N 105 94 BrN O N OH
NH
2 Br H N 106 95 N OH
NH
2 Br N 107 96 N Y N OH
NH
2 WO 2004/026867 PCT/US2003/029498 58 Br 108 97 N N
NH
2 OH Br H OH 109 98 N
NH
2 1OH Br H 110 99 N ' NH2 OH Br H 111 100 B N N
NH
2 EXAMPLE 500 Br H Br H N N N <
NH
2 HN N Treatment of aniline from Preparative Example 100 with 3-pyridine 5 carboxaldehyde according to the procedure outlined in Example 100 affords the title compound. EXAMPLES 501-510 Following the procedure set forth in Example 500 but by utilizing the aniline derivatives described in Preparative Examples 101-105, the final adducts 10 (Products) can be prepared as indicated in Table 16. Table 16 WO 2004/026867 PCT/US2003/029498 59 Aniline Example (Prep. Ex.) Product Br H N 501 102 HN N Br N OH 502 103 HN N N N O H 503 104 HN Br H N N OH 504 105 HN N Br H NN* N OH 505 106
HN
WO 2004/026867 PCT/US2003/029498 60 Br /NN N 506 107 HN OH Br N Br H H NN N ' 508 109 HN Br H 509 110 HN HN OH Br H N 510 111
".N
WO 2004/026867 PCT/US2003/029498 61 ASSAY: BACULOVIRUS CONSTRUCTIONS: Cyclin E was cloned into pVL1393 (Pharmingen, La Jolla, California) by PCR, with the addition of 5 histidine residues at the amino-terminal end to allow purification on nickel resin. The expressed 5 protein was approximately 45kDa. CDK2 was cloned into pVL1393 by PCR, with the addition of a haemaglutinin epitope tag at the carboxy-terminal end (YDVPDYAS). The expressed protein was approximately 34kDa in size. ENZYME PRODUCTION: Recombinant baculoviruses expressing cyclin E and CDK2 were co-infected into SF9 cells at an equal multiplicity of infection 10 (MOI=5), for 48 hrs. Cells were harvested by centrifugation at 1000 RPM for 10 minutes, then pellets lysed on ice for 30 minutes in five times the pellet volume of lysis buffer containing 50mM Tris pH 8.0, 150mM NaCI, 1% NP40, 1mM DTT and protease inhibitors (Roche Diagnostics GmbH, Mannheim, Germany). Lysates were spun down at 15000 RPM for 10 minutes and the supernatant 15 retained. 5ml of nickel beads (for one liter of SF9 cells) were washed three times in lysis buffer (Qiagen GmbH, Germany). Imidazole was added to the baculovirus supernatant to a final concentration of 20mM, then incubated with the nickel beads for 45 minutes at 40 C. Proteins were eluted with lysis buffer containing 250mM imidazole. Eluate was dialyzed overnight in 2 liters of kinase buffer 20 containing 50mM Tris pH 8.0, 1mM DTT, 10mM MgCI2, 1OuM sodium orthovanadate and 20% glycerol. Enzyme was stored in aliquots at -700C. IN VITRO KINASE ASSAY: Cyclin E/CDK2 kinase assays were performed in low protein binding 96-well plates (Corning Inc, Corning, New York). Enzyme was diluted to a final concentration of 50 pg/ml in kinase buffer 25 containing 50mM Tris pH 8.0, 10mM MgCl2,1mM DTT, and 0.1mM sodium orthovanadate. The substrate used in these reactions was a biotinylated peptide derived from Histone HI (from Amersham, UK). The substrate was thawed on ice and diluted to 2 pM in kinase buffer. Compounds were diluted in IO%DMSO to desirable concentrations. For each kinase reaction, 20 pl of the 50 tg/ml enzyme 30 solution (1 pg of enzyme) and 20 pl of the 2 pM substrate solution were mixed, then combined with 10 pI of diluted compound in each well for testing. The kinase WO 2004/026867 PCT/US2003/029498 62 reaction was started by addition of 50 d of 2 ptM ATP and 0.1 pCi of 33P-ATP (from Amersham, UK). The reaction was allowed to run for 1 hour at room temperature. The reaction was stopped by adding 200 1 A of stop buffer containing 0.1% Triton X-100, 1mM ATP, 5mM EDTA, and 5 mg/ml streptavidine coated 5 SPA beads (from Amersham, UK) for 15 minutes. The SPA beads were then captured onto a 96-well GF/B filter plate (Packard/Perkin Elmer Life Sciences) using a Filtermate universal harvester (Packard/Perkin Elmer Life Sciences.). Non-specific signals were eliminated by washing the beads twice with 2M NaCl then twice with 2 M NaCl with 1% phosphoric acid. The radioactive signal was 10 then measured using a TopCount 96 well liquid scintillation counter (from Packard/Perkin Elmer Life Sciences).
IC
5 o DETERMINATION: Dose-response curves were plotted from inhibition data generated, each in duplicate, from 8 point serial dilutions of inhibitory compounds. Concentration of compound was plotted against % kinase 15 activity, calculated by CPM of treated samples divided by CPM of untreated samples. To generate IC 50 values, the dose-response curves were then fitted to a standard sigmoidal curve and IC 50 values were derived by nonlinear regression analysis. The thus-obtained IC 50 values for some representative compounds of the invention are shown in Table 17. 20 WO 2004/026867 PCT/US2003/029498 63 Table 17 Examples CDK2 ICso (p.M) Br N HN 0.12 Br N N CI HN 0.036 N Br 0.076 N- Ci HN N N
NH
2 As demonstrated above by the assay values, the compounds of the present 5 invention exhibit excellent CDK inhibitory properties. While the present invention has been described with in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and 10 scope of the present invention.

权利要求:
Claims (31)
[1] 1. A compound represented by the structural formula: R 2 R 4 N R 3 N R/ H*- R" 5 Formula Il wherein: R is selected from the group consisting of alkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, arylalkyl, cycloalkyl, -NR 6 R 7 , -C(O)R 7 , -C(O)OR 6 , -C(O)NR 6 R 7 and -S(0 2 )R 7 , wherein each of said alkyl, aryl, heteroaryl, 10 heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyi and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, cycloalkyl, CF 3 , CN, -OCF 3 , -OR 6 , -C(O)R', -NR 6 R 7 , -C(O)OR 6 , -C(O)NR5R 6 , -SR 6 , -S(0 2 )R 7 , -S(0 2 )NR 5 R 6 , 15 -N(R 5 )S(0 2 )R 7 , -N(R 5 )C(O)R and -N(R 5 )C(O)NR 5 R 6 and NO 2 ; R 2 is selected from the group consisting of H, R, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, alkynyl, cycloalkyl, -CF 3 , -C(O)R 7 , alkyl substituted with 1-6 R 9 groups which groups can be the same or different with each R 9 being independently selected, ~~ V(CH2)mK 20 (CH2),,N /N--R8 N CH-R 8 20 ~-aryI-N N-Ra NaryI N-R8 - and , wherein each of said aryl, heteroaryl, arylalkyl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, 25 cycloalkyl, CF 3 , CN, -OCF 3 , -OR, -C(O)R, -NRR T , -C(O)OR, -C(O)NRR 6 , -SR 6 , -S(0 2 )R 7 , -S(O 2 )NRR, -N(R)S(0 2 )R 7 , -N(R 5 )C(O)R7 and -N(R 5 )C(O)NR 5 R 6 ; WO 2004/026867 PCT/US2003/029498 65 R 3 is selected from the group consisting of H, halogen, -NR 5 R 6 , CF 3 , alkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylakyl, alkynyl, alkenyl, -(CHR 5 ),-aryl, - (CHR 5 ) -heteroaryl, -(CHR 5 ),-OR 6 , -S(O 2 )R 6 , -C(O)R 6 , -S(0 2 )NR 5 R 6 , -C(O)OR 6 , -C(O)NR 5 R 6 , -CH(aryl) 2 , -(CH 2 )m-NR", 5 (CH 2 )m N--R 5 N 2-2 NrN (R 8 ) 2 (R 8 ) (R) N (R) ( Rn N 1 -2 a n d -2 (R 8 )n wherein each of said aryl, alkyl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl for R 3 and the heterocyclyl moieties whose 10 structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which moieties can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, -OCF 3 , -OR , -C(R 4 R )nOR, -NR 5 R 6 , -C(R 4 R 5 ),NR 5 R 6 , -C(0 2 )R 5 , -C(O)R 5 , -C(O)NR 5 R 6 , -SR 6 , -S(0 2 )R 6 , 15 .- S(0 2 )NR 5 R 6 , -N(R 5 )S(0 2 )R 7 , -N(R5)C(O)R and -N(R 5 )C(O)NR 5 R 6 ; R 4 is selected from the group consisting of H, halogen, CF 3 , alkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkynyl, alkenyl, -(CHR 5 ),-aryl, - (CHR 5 )n-heteroaryl, -(CHR )n-OR , -S(0 2 )R 6 , -C(O)R 6 , -S(0 2 )NR 5 R 6 , -C(O)OR 6 , -C(O)NR 5 R 6 , cycloalkyl, -CH(aryl) 2 , -(CH 2 )m-NRB, (CH2)m' N-R 20 and , wherein each of said aryl, alkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocycylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, -OCF 3 , -OR 5 , -NR R , -C(0 2 )R, 25 -C(O)NR 5 R", -SR 6 and -S(0 2 )R 6 ; WO 2004/026867 PCT/US2003/029498 66 R' is H, alkyl or aryl; R 6 is selected from the group consisting of H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl, heteroary(alkyl, heterocyclyl and heterocyclylalkyl, wherein each of said alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl, heteroarylalkyl, 5 heterocyclyl and heterocyclylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alky), ary), cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, -OR 5 , -NR 5 R 0 , -N(R 5 )Boc, -C(R 4 R 5 )OR 5 , - C(O)R, -C(O)OR 5 , -C(O)NR 5 R' 0 , -SO 3 H, -SR"), 10 -S(0 2 )R 7 , -S(O 2 )NR 5 R"', -N(R 5 )S(0 2 )R 7 , -N(R 5 )C(O)R 7 and -N(R 5 )C(O)NR 5 R'0; RG is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, 15 heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, -OR 5 , -NR 4 R 5 , -N(R 5 )Boc, -(CR 4 R 5 )nOR 5 , -C(0 2 )R 5 , -C(O)NR 4 R 5 , -C(O)R 5 , -SO 3 H, -SR, -S(0 2 )R, 20 -S(0 2 )NR 4 R 5 , -N(R 5 )S(0 2 )R, -N(R 5 )C(O)R 7 and -N(R 5 )C(O)NR 4 R 5 ; or optionally (i) R 5 and R1 0 in the moiety -NR 5 R 0 , or (ii) R 5 and R 6 in the moiety -NR 5 R , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups; 25 R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, 30 aryl, cycloalkyl, CF 3 , OCF 3 , CN, -OR 5 , -NR 5 R 0 , -CH 2 OR 5 , -C(0 2 )R 5 , -C(O)NR 5 R"', -C(O)R 5 , -SR", -S(0 2 )R' 0 , -S(0 2 )NRR 0 , -N(R 5 )S(0 2 )R 0 , -N(R 5 )C(O)R 0 and -N(R 5 )C(O)NRR 0 ; WO 2004/026867 PCT/US2003/029498 67 Ra is selected from the group consisting of R 6 , -C(O)NR 5 R 0 , -S(0 2 )NR 5 R D, -C(O)RJ, -C(O)OR 6 and -S(0 2 )R7; R 9 is selected from the group consisting of halogen, CN, NR 5 R 0 , -C(0)OR 6 , -C(O)NR 5 R", -OR 6 , -C(O)R, -SR 6 , -S(0 2 )R 7 , -S(0 2 )NR 5 R 0 , 5 -N(R 5 )S(O 2 )R 7 , -N(R 5 )C(O)R 7 and -N(R 5 )C(O)NR 5 R 1 ; R" is H, alkyl or aryl; m is 0 to 4; and n is 1-4.
[2] 2. The compound of claim 1, wherein R is selected from the group consisting 10 of aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkyl, -S(0 2 )R 7 , and -C(O)R 7 , wherein each of said aryl, arylalkyl, heteroaryl, heteroarylalkyl and alkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, CF 3 , CN, -OCF 3 , -NR 6 R 7 , 15 -N(R 5 )C(O)R 7 , and -OR 6 ; R 2 is selected from the group consisting of halogen, alkyl, aryl, heteroaryl, alkenyl and -C(O)R , wherein each of said alkyl, aryl and heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected 20 from the group consisting of halogen, alkyl, CF 3 , CN, -OCF 3 , and -OR; R 3 is selected from the group consisting of H, aryl, heteroaryl, -(CHR)n aryl, -(CHR 5 )n-heteroaryl, (CH2)m N-R 8 -(CHR 5 ),-OR 6 , -C(O)R 6 , cycloalkyl, -NR 5 R 6 , -CH(aryl) 2 , WO 2004/026867 PCT/US2003/029498 68 H 3 CI N NN N N H N Hj N 1-2 or 1-2 5 wherein each of said aryl, cycloalkyl and heteroaryl and the heterocyclyl structures shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CF 3 , OCF 3 , alkyl, CN, aryl, -C(O)R 5 , -C(0 2 )R, -S(0 2 )R, -C(=NH)-NH 2 , -C(=CN)-NH 2 , 10 hydroxyalkyl, alkoxycarbonyl, -SR, and OR, with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a - OR 5 moiety; R 4 is selected from the group consisting of H, alkyl, aryl, heteroaryl, (CHR 5 )n-aryl, - (CHR 5 )n-heteroaryl, -(CHR 5 )n-OR 6 , -C(O)R 6 , cycloalkyl, -CH(aryl) 2 (CH2)mgN I-RS and , wherein each of said aryl and heteroaryl can be 15 unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, CF 3 , CN, -C(0 2 )R 5 and -S(0 2 )R 6 ; R 5 is R 5 is H, aryl or lower alkyl; m is 0 to 2, and 20 n is 1 to 3.
[3] 3. The compound of claim 2, wherein R is selected from the group consisting of phenyl, benzyl, benzoyl, phenylsulfonyl, thienyl, thienylalkyl, thienylcarbonyl, thienylsulfonyl, furyl, furylalkyl, furylcarbonyl, furylsulfonyl, pyridyl, pyridylalkyl, WO 2004/026867 PCT/US2003/029498 69 pyridylcarbonyl, pyridylsulfonyl, pyrrolyl, pyrrolylalkyl, pyrrolylcarbonyl, pyrrolylsulfonyl, oxazolyl, oxazolylalkyl, oxazolylcarbonyl, oxazolylsulfonyl, thiazolyl, thiazolylalkyl, thiazolylcarbonyl, thiazolylsulfonyl, pyrazinyl, pyrazinylalkyl, pyrazinylcarbonyl, pyrazinylsulfonyl, pyridazinyl, pyridazinylalkyl, 5 pyridazinylcarbony, pyridazinylsulfonyl, pyrimidinyl, pyrimidinylalkyl, pyrimidinylcarbonyl, pyrimidinylsulfonyl, -S(0 2 )CH 3 , and -C(O)CH 3 , as well as their applicable N-oxides, wherein each of said phenyl (including the phenyl of the benzyl), thienyl, furyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, pyrazinyl, pyridazinyl and pyrimidinyl can be unsubstituted or optionally independently substituted with one or 10 more moieties which can be the same or different, each moiety being independently selected from the group consisting of CI, Br, I, lower alkyl, CF 3 , CN, -C(O)OR 6 , -NR 6 R 7 , -N(R 5 )C(O)R 7 , -OCF 3 , and -OH.
[4] 4. The compound of claim 2, wherein R is unsubstituted phenyl, unsubstituted pyridyl, benzyl whose phenyl can be unsubstituted or optionally 15 substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, CF 3 , -NH 2 , and -N(H)C(O)CH 3 , benzoyl whose phenyl can be unsubstituted or optionally substituted with one or more moieties selected from the group consisting of F, C, Br, CN, CF 3 , -NH 2 , and -N(H)C(O)CH 3 , phenylsulfonyl whose phenyl can 20 be unsubstituted or optionally substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, -NH 2 , -N(H)C(O)CH3 and CF 3 , pyridylmethyl whose pyridyl can be unsubstituted or optionally substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, CF 3 , -NH 2 , and -N(H)C(O)CH 3 , pyridylcarbonyl whose pyridyl can be unsubstituted or optionally 25 substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, CF 3 , -NH 2 , and -N(H)C(O)CH 3 , pyridylsulfonyl whose pyridyl can be unsubstituted or optionally substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, -NH 2 , -N(H)C(O)CH 3 and CF 3 , pyrimidylmethyl whose pyrimidylmethyl can be unsubstituted or optionally substituted with one or 30 more moieties selected from the group consisting of F, Cl, Br, CN, -NH 2 , -N(H)C(O)CH 3 and CF 3 , pyrimidylcarbonyl whose pyrimidyl can be unsubstituted or optionally substituted with one or more moieties selected from the group consisting WO 2004/026867 PCT/US2003/029498 70 of F, Cl, Br, CN, -NH 2 , -N(H)C(O)CH 3 and CF 3 , or pyrimidylsulfonyl whose pyrimidyl can be unsubstituted or optionally substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, -NH 2 , -N(H)C(O)CH 3 and CF 3 .
[5] 5. The compound of claim 2, wherein R is unsubstituted phenyl, unsubstituted 5 pyridyl or unsubstituted pyrimidinyl.
[6] 6. The compound of claim 2, wherein R is benzyl whose phenyl is unsubstituted or optionally substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, -NH 2 , -N(H)C(O)CH 3 and CF 3 .
[7] 7. The compound of claim 2, wherein R is pyridylmethyl whose pyridyl is 10 unsubstituted or optionally substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, -NH 2 , -N(H)C(O)CH 3 and CF 3 .
[8] 8. The compound of claim 7, wherein said pyridyl is 2-pyridyl, 3-pyridyl or 4 pyridyl.
[9] 9. The compound of claim 2, wherein R is phenyl, pyridyl or pyrimidinyl each of 15 which is substituted with one or more moieties which can be the same or different, each being independently selected from the group consisting of Cl, Br, -NH 2 , -N(H)C(O)CH 3 or -CF 3 .
[10] 10. The compound of claim 2, wherein R 2 is H, F, C, Br, I, hydroxyalkyl, alkoxyalkyl, or lower alkyl. 20
[11] 11. The compound of claim 10, wherein R 2 is Br, I, -CH 2 OH, -CH 2 0CH 3 , or methyl.
[12] 12. The compound of claim 2, wherein R 3 is H, alkyl, aryl, -NR 5 RG, N (1-2 (R')n or or1 wherein said alkyl and aryl and the heterocyclyl moieties shown immediately above 25 for R 3 can be unsubstituted or optionally independently substituted with one or more moieties (in addition to any RB) which can be the same or different, each moiety being independently selected from the group consisting of F, Cl, Br, CF 3 , lower alkyl, hydroxyalkyl, alkoxy, -S(0 2 )R 6 , and CN. WO 2004/026867 PCT/US2003/029498 71
[13] 13. The compound of claim 2, wherein R 4 is H, alkyl or aryl, wherein said alkyl or aryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of F, Cl, Br, CF 3 , lower alkyl, 5 hydroxyalkyl, alkoxy, -S(0 2 )R 6 , and CN.
[14] 14. The compound of claim 2, wherein R 5 is H.
[15] 15. The compound of claim 2, wherein R" is H.
[16] 16. The compound of claim 2, wherein m is 0.
[17] 17. The compound of claim 2, wherein n is 1. 10
[18] 18. A compound of the formula: Br Br C Br IN N N N N / N' N N HN HN HN HN NN N Br B Br B N B N N N HN HN HN HN SO NN N NHBoc Br Br N Br Br N N N N N- C N N- Cl N- CI HN HN HN HN OO ON N, N N ~ .N N. N NH 2 WO 2004/026867 PCT/US2003/029498 72 Br N lB Br Br N CF Br / N H ~/N /N " N s F CF 3 NN Br Br Br NcI /N'~ ci /N CF 3 N N N -N HN HN HN N N ~ N Br NC B r B r N ~ N CF -~ HN 0 HN 0 N. N Br H Br IB rN ~ >//- aNNCF 3 N N - N - HN HNC, HN C Br Br Br H N N N N ~ OH N OH N OH HN HN HN 5 -N N NN WO 2004/026867 PCT/US2003/029498 73 Br H Br Br N N N N OHOH O HN HN HN OH N N N OH B H OH O rBr H Br H /N N /N N, /NN,, N N /" N HN HN HN Br H N HN or 5 or a pharmaceutically acceptable salt or solvate thereof.
[19] 19. A compound of the formula: WO 2004/026867 PCT/US2003/029498 74 Br Br Br B N Br HN HN HN N N N ,N & N N ,N NH 2 Br H Br Br Br H N_0N N N~N NN ~ 'O OH N TOH HN HN HN HN Br H Br Br N N N N- N OH N OH NOH HN HN HN OH N N , N OH OH rBr H Br H N r N N rN N pu a b N N,, N N 0 HN HN HN Br H N N 5 or 6 or a pharmaceutically acceptable salt or solvate thereof. WO 2004/026867 PCT/US2003/029498 75
[20] 20. A method of inhibiting one or more cyclin dependent kinases, comprising administering a therapeutically effective amount of at least one compound of claim 1 to a patient in need of such inhibition.
[21] 21. A method of treating one or more diseases associated with cyclin 5 dependent kinase, comprising administering a therapeutically effective amount of at least one compound of claim 1 to a patient in need of such treatment.
[22] 22. The method of claim 21, wherein said cyclin dependent kinase is CDK2.
[23] 23. The method of claim 21, wherein said cyclin dependent kinase is mitogen activated protein kinase (MAPK/ERK). 10
[24] 24. The method of claim 21, wherein said cyclin dependent kinase is glycogen synthase kinase 3 (GSK3beta).
[25] 25. The method of claim 21, wherein said disease is selected from the group consisting of: cancer of the bladder, breast, colon, kidney, liver, lung, small cell lung 15 cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B cell lymphoma, T- cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma; 20 acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma 25 pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
[26] 26. A method of treating one or more diseases associated with cyclin dependent kinase, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound of claim 1, or a 30 pharmaceutically acceptable salt or solvate thereof; and WO 2004/026867 PCT/US2003/029498 76 an amount of at least one second compound, said second compound being an anti-cancer agent; wherein the amounts of the first compound and said second compound result in a therapeutic effect. 5
[27] 27. The method of claim 26, further comprising radiation therapy.
[28] 28. The method of claim 26, wherein said anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, CPT-1 1, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, 5FU, temozolomide, 10 cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 15 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATINTM, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17U-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone 20 propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, 25 Mitoxantrone, Levamisole, Navelbene, CPT- 1, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, or Hexamethylmelamine.
[29] 29. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim I in combination with at least one pharmaceutically acceptable carrier.
[30] 30 30. The pharmaceutical composition of claim 29, additionally comprising one or more anti-cancer agents selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, CPT-i 1, irinotecan, camptostar, WO 2004/026867 PCT/US2003/029498 77 topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, 5FU, temozolomide, cyclophosphamide, SCH 66336, R1 15777, L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, 5 Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, 10 Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17a Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, 15 Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, CPT-1 1, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, or Hexamethylmelamine.
[31] 31. A compound of claim 1 in purified form. 20

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法律状态:
2007-05-17| FGA| Letters patent sealed or granted (standard patent)|

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2012-10-11| DA2| Applications for amendment section 104|Free format text: THE NATURE OF THE AMENDMENT IS: AMEND THE PATENTEE TO READ MERCK SHARP & DOHME CORP. . |

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2015-04-09| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|

优先权:

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申请号 | 申请日 | 专利标题

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US41206302P| true| 2002-09-19|2002-09-19||

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US60/412,063||2002-09-19||

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PCT/US2003/029498|WO2004026867A2|2002-09-19|2003-09-17|Imidazopyridines as cyclin dependent kinase inhibitors|

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