AU2013201242B2 - Bicyclic heteroaryl compounds - Google Patents
Bicyclic heteroaryl compounds Download PDFInfo
- Publication number
- AU2013201242B2 AU2013201242B2 AU2013201242A AU2013201242A AU2013201242B2 AU 2013201242 B2 AU2013201242 B2 AU 2013201242B2 AU 2013201242 A AU2013201242 A AU 2013201242A AU 2013201242 A AU2013201242 A AU 2013201242A AU 2013201242 B2 AU2013201242 B2 AU 2013201242B2
- Authority
- AU
- Australia
- Prior art keywords
- alkyl
- group
- heteroaryl
- ring
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 NR R Chemical group 0.000 claims description 206
- 125000000217 alkyl group Chemical group 0.000 claims description 125
- 125000001072 heteroaryl group Chemical group 0.000 claims description 116
- 125000003118 aryl group Chemical group 0.000 claims description 113
- 239000000203 mixture Substances 0.000 claims description 97
- 125000000623 heterocyclic group Chemical group 0.000 claims description 94
- 238000000034 method Methods 0.000 claims description 88
- 125000003342 alkenyl group Chemical group 0.000 claims description 84
- 125000000304 alkynyl group Chemical group 0.000 claims description 80
- 206010028980 Neoplasm Diseases 0.000 claims description 79
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 68
- 229920006395 saturated elastomer Polymers 0.000 claims description 52
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 48
- 125000003545 alkoxy group Chemical group 0.000 claims description 46
- 125000005843 halogen group Chemical group 0.000 claims description 45
- 201000011510 cancer Diseases 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 44
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 43
- 229910052736 halogen Inorganic materials 0.000 claims description 36
- 150000002367 halogens Chemical group 0.000 claims description 36
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 36
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 34
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 34
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 34
- 229910052757 nitrogen Inorganic materials 0.000 claims description 34
- 125000004423 acyloxy group Chemical group 0.000 claims description 33
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 33
- 125000005195 alkyl amino carbonyloxy group Chemical group 0.000 claims description 33
- 125000003282 alkyl amino group Chemical group 0.000 claims description 33
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 33
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- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
H \SXD\IntMwie\NRMibl DCC SXD %5..-4 VO/2013 This invention relates to compounds of the general formula (1) in which the variable groups are as defined herein, and to their preparation and use. (RL6 A__3
Description
H:\5XD\EnLerweenp,,tthDtCC\SX0\4967550-1.doc-4/O3/20I3 Bicyclic Heteroaryl Compounds This is a divisional of Australian patent application No. 2006331673, the entire contents of which are incorporated herein by reference. 5 Background of the Invention The protein kinases are a large family of proteins which play a central role in the regulation of a wide variety of cellular processes. A partial, non limiting, list of such kinases includes abl, Akt, bcr-abl, Blk, Brk, o-kit, c-met, c-src, CDK1, CDK2, CDK3, 10 CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Pak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, fit-1, Fps, Frk, Fyn, Hok, IGF-1R, INS-R, Jak, KDR, Lek, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK and Zap7O. Abnormal protein kinase activity has been related to several disorders, ranging from non-life threatening diseases such as psoriasis to extremely 15 serious diseases such as cancers. In view of the large number of protein kinases and associated diseases, there is an ever existing need for new inhibitors selective for various protein kinases which might be useful in the treatment of related diseases. 20 This invention concerns a new family of acetylenic heteroaryl compounds and their use in treating cancers, bone disorders, metabolic disorders, inflammatory disorders and other diseases. 25 Description of the Invention 1. General description of compounds of the Invention The compounds of this invention have a broad range of useful biological and pharmacological activities, permitting their use in pharmaceutical compositions and 30 methods for treating a variety of diseases, including e.g., metabolic disorders, bone diseases (e.g,, osteoporosis, Paget's Disease, etc.), inflammation (including rheumatoid arthritis, among other inflammatory disorders) and cancer (including solid tumors and leukemias, especially those mediated by one or more kinases such as Src or kdr, or by dysregulation of a kinase such as Abi and mutant variants thereof), including, among 35 others, advanced cases and cases which are resistant or refractory to one or more other treatments.
Included are compounds of Formula 1: H (Rb), (R")m A 5 Fonnula I or a tautomer or an Individual isomer or a mixture of Isomers thereof in which: Ring T Is a 5-membered heteroaryl ring containing 1 - 2 nitogens with the remaining ring atoms being carbon, substituted on at least two ring atoms (each of which may be C or N) 10 with R' groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they am attached, forming a saturated, partially saturated or unsaturated 5- or 6- membered ring (Ring E), Qontalning 0-3 heteroatoms selected from 0, N, and S and being optionally substituted with 1-4 R' groups; 15 Ring A represents a 5- or 5-membered aryl or hetercaryl ring and is optionally substituted with 1-4 Re groups; Ring B represents a 6- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1-5 Rbgoupsl 20 L is selected from NR 7 C(O), C(O)NR 1 , NR'C(O)O, NR'C(O)NR', and OC(O)NR; each occurrence of Re, Re and R! Is Independently selected from the group consisting of halo, -CN, -NO 1 , -R 4 , -OR 2 , -NR 2
R
3 , -- C(O)YRa, -OC(O)YR 2 , -NR 2 C(0)YR 2 . -SC(O)YR . 25 -NR 2
C(=S)YR
2 , -0C( 6)YR 2 , -C(-S)YR 2 , -YC(-NR )YR 2 -yP(.O)(yR 4 )(YR4). -SI(R 2
)
3 , -NR"SO2R 2 , -S(O)rR 2 , SOsNRR3 and -NR 2
SONR
2
R
3 , wherein each Y is Independently a bond, -0-, -8- or -NR3 R', at each occurrence, is independently selected fron the group consisting of halo, =0, 30 CN, -NO2, -R 4 , -OR 2 , -NRIR3, -C(O)YR 2
-OC(O)YR
2 , -NR 2
C(O)YR
2 . -SC(O)YR 2 ,
-NR
2
C(=S)YR
2 , -OC(=S)YR 2 . -C(=S)YR 2 . -YC(yNR 3 )YR -YP(.O)(YR 4
)(YR
4 ), -Sl(R 2 ), 2 H:\rbr\Intrwoven\NRPortbl\DCC\RBR\7353404_I.docx-12/01/2015
-NR
2 S0 2
R
2 , -S(O),R 2 , -SO 2
NR
2
R
3 and -NR 2
SO
2
NR
2
R
3 , wherein each Y is independently a bond, -0-, S- or -NR3-; R1, R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, 5 cycloalkynyl, aryl, heterocyclic and heteroaryl; alternatively, R 2 and R 3 , taken together with the atom to which they are attached, form a 5- or 6 membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatorns selected from N, 0 and S(O)r; 10 each occurrence of R 4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and 15 heteroaryl moieties in this Section 1 is optionally substituted; m is 0, 1, 2, 3 or 4; n is 2 or 3; p is 0, 1, 2, 3, 4 or 5; and, 20 r is 0, 1 or 2; or a pharmaceutically acceptable salt, solvate or hydrate thereof. The foregoing definitions are further elaborated upon and exemplified below and apply to all 25 subsequent occurrences except to the extent otherwise specified. In an embodiment of the invention there is provided a compound of formula: (Re)s N H N' (Rb)p (Ra~m- s 1' L(Rd)w 30 wherein: 3 H:\rbr\nterwoven\NRPortbl\DCC\RBR\7353404_I.docx-12/01/2015 Ring D is a 5- or 6-membered heterocyclyl or heteroaryl ring comprising carbon atoms and 1-3 heteroatoms independently selected from the group consisting of 0, N, and S(O)r; L' is NR 1 C(O) or C(O)NR 1 ; 5 L 2 is -(CH 2 )z-; each occurrence of Ra is independently selected from the group consisting of halo, alkyl, and cycloalkyl; 10 each occurrence of R is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rd is independently selected from the group consisting of halo, alkyl, cycloalkyl, and -NR R 3 ; 15 each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, NR R , alkoxy, amino, -NH-alkyl, -C(O)NH-alkyl, -NHC(O)-alkyl, -NHC(O)NH-alkyl, -NHC(NH)-alkyl, NHC(NH)NH 2 , -NH(CH 2 )x-heteroaryl, -NH(CH 2 )x-heterocyclyl, -NH(CH 2 )x-aryl, and -(CH 2 )xC(O)NH 2 , wherein x is 0, 1, 2 or 3; 20 each of R1, R2 and R3 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, 2 3 cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R and R , taken together with the nitrogen atom to which at least one of R 2 and R 3 is attached, form a 5- or 6- membered heterocyclyl or heteroaryl ring; 25 each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, 30 dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2 R 3 , =NNHC(O)R 2 , =NNHCO 2
R
2 , and =NNHSO 2
R
2 , and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, 35 alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0,1, 2, 3, or 4; 3a H:\rbr\Interwoven\NRPortbl\DCC\RBR\7353404_I.docx-12/01/2015 p is 0, 1, 2, 3, or 4; r is 0, 1 or 2; s is 0, 1, 2, or 3; w is 0, 1, 2, 3, 4, or 5; and 5 z is 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. In an embodiment of the invention there is provided a compound selected from Formula Ilc and Illc: 10 H /NN (RI) N NZ H N (R(Ra Formula Ilc H (Re)s~ -,N/ Rd (Rb)p N (Ra)m- N 0 15 Formula IlIc wherein: each occurrence of Ra is independently selected from the group consisting of halo, alkyl, and 20 cycloalkyl; each occurrence of R is independently selected from the group consisting of halo, alkyl, and cycloalkyl; 3b H:\rbr\nterwoven\NRPortbl\DCC\RBR\7353404_I.docx-12/01/2015 each occurrence of R' is independently selected from the group consisting of halo, alkyl, and cycloalkyl; 5 Rd is a C1-C6 alkyl group, unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR 2
R
3 , =NNHC(O)R 2 , =NNHCO 2
R
2 , and 10 =NNHSO 2 R2; each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, NR R , alkoxy, amino, -NH-alkyl, -C(O)NH-alkyl, -NHC(O)-alkyl, -NHC(O)NH-alkyl, -NHC(NH)-alkyl, NHC(NH)NH 2 , -NH(CH 2 )x-heteroaryl, -NH(CH 2 )x-heterocyclyl, -NH(CH 2 )x-aryl, and -(CH 2 )xC(O)NH 2 , 15 wherein x is 0, 1, 2 or 3; each of R2 and R3 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, 2 3 cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R and R , taken together with the nitrogen atom to which at least one of R 2 and R 3 is attached, form a 5- or 6 20 membered heterocyclyl or heteroaryl ring; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, 25 heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2 R 3 , =NNHC(O)R 2 , =NNHCO 2
R
2 , and =NNHSO 2
R
2 , and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups 30 selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; 35 m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; s is 0, 1, 2, or 3; and v is 0, 1,2, 3, 4, or 5; 3c H:\rbr\nterwoven\NRPortbl\DCC\RBR\7353404_I.docx-12/01/2015 or a pharmaceutically acceptable salt thereof. In an embodiment of the invention there is provided a method of treating cancer in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of 5 Formula I: (Rt H (Rb)p (Ra)m A Formula I 10 or a tautomer, or an individual stereoisomer or a mixture of stereoisomers thereof wherein: Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with Rt groups, at least two of which being located on 15 adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from the group consisting of 0, N, and S and being optionally substituted with 1-4 Re groups; Ring A is a 5- or 6-membered aryl or heteroaryl ring; 20 Ring B is a 5- or 6-membered aryl or heteroaryl ring; Ll is selected from NR 1 C(O), C(O)NR 1 , NR 1 C(O)O, NR 1 C(O)NR or OC(O)NR; 25 each occurrence of Ra, Rb and Rt is independently selected from the group consisting of halo, -CN, NO 2 , -R 4 , -OR 2 , -NR 2
R
3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2
C(O)YR
2 , -SC(O)YR 2 , -NR 2
C(=S)YR
2 , OC(=S)YR 2 , -C(=S)YR 2 , -YC(=NR 3
)YR
2 , -YP(=O)(YR 4
)(YR
4 ), -Si(R 2
)
3 , -NR 2
SO
2
R
2 , -S(O)rR 2 , SO 2
NR
2
R
3 and -NR 2
SO
2
NR
2
R
3 , wherein each Y is independently a bond, -0-, -S- or -NR 3 -; 30 Re, at each occurrence, is independently selected from the group consisting of halo, =0, -CN, -NO 2 , R 4 , -OR 2 , -NR 2
R
3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2
C(O)YR
2 , -SC(O)YR 2 , -NR 2
C(=S)YR
2 , -OC(=S)YR 2 , 3d H:\rbr\nterwoven\NRPortbl\DCC\RBR\7353404_I.docx-12/01/2015
C(=S)YR
2 , -YC(=NR 3
)YR
2 , -YP(=O)(YR 4
)(YR
4 ), -Si(R 2
)
3 , -NR 2 S0 2
R
2 , -S(O),R 2 , -SO 2
NR
2
R
3 and NR 2
SO
2
NR
2
R
3 , wherein each Y is independently a bond, -0-, -S- or -NR 3 -; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, 5 cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; alternatively, R 2 and R 3 , taken together with the atom to which they are attached, form a 5- or 6 membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from the group consisting of N, 0 and S(O)r; 10 each occurrence of R 4 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is 15 unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2 R 3 , =NNHC(O)R 2 , =NNHCO 2
R
2 , and =NNHSO 2
R
2 , and 20 each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, 25 hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0,1, 2, 3 or 4; n is 2 or 3; p is 0, 1, 2, 3, 4 or 5; and, 30 r is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; wherein the cancer is selected from primary cancer, metastatic cancer, solid tumor, lymphoma, 35 leukemia, and cancer resistant to other therapies. In an embodiment of the invention there is provided a use of a compound of Formula I: 3e H:\rbr\nterwoven\NRPortbl\DCC\RBR\7353404_I.docx-12/01/2015 (Rt) H H (Rb)p (Ra)m L B Formula I 5 or a tautomer, or an individual stereoisomer or a mixture of stereoisomers thereof wherein: Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with Rt groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, 10 partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from the group consisting of 0, N, and S and being optionally substituted with 1-4 Re groups; Ring A is a 5- or 6-membered aryl or heteroaryl ring; 15 Ring B is a 5- or 6-membered aryl or heteroaryl ring; L' is selected from NR 1 C(O), C(O)NR 1 , NR 1 C(O)O, NR 1 C(O)NR or OC(O)NR; each occurrence of Ra, Rb and Rt is independently selected from the group consisting of halo, -CN, 20 NO 2 , -R 4 , -OR 2 , -NR 2
R
3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2
C(O)YR
2 , -SC(O)YR 2 , -NR 2
C(=S)YR
2 , OC(=S)YR 2 , -C(=S)YR 2 , -YC(=NR 3
)YR
2 , -YP(=O)(YR 4
)(YR
4 ), -Si(R 2
)
3 , -NR 2
SO
2
R
2 , -S(O)rR 2 , SO 2
NR
2
R
3 and -NR 2
SO
2
NR
2
R
3 , wherein each Y is independently a bond, -0-, -S- or -NR 3 -; Re, at each occurrence, is independently selected from the group consisting of halo, =0, -CN, -NO 2 , 25 R 4 , -OR 2 , -NR 2
R
3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2
C(O)YR
2 , -SC(O)YR 2 , -NR 2
C(=S)YR
2 , -OC(=S)YR 2 , C(=S)YR 2 , -YC(=NR 3
)YR
2 , -YP(=O)(YR 4
)(YR
4 ), -Si(R 2
)
3 , -NR 2 S0 2
R
2 , -S(O)rR 2 , -SO 2
NR
2
R
3 and NR 2
SO
2
NR
2
R
3 , wherein each Y is independently a bond, -0-, -S- or -NR 3 -; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, 30 cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; 3f H:\rbr\nterwoven\NRPortbl\DCC\RBR\7353404_I.docx-12/01/2015 alternatively, R 2 and R 3 , taken together with the atom to which they are attached, form a 5- or 6 membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from the group consisting of N, 0 and S(O)r; 5 each occurrence of R 4 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, 10 alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2 R 3 , =NNHC(O)R 2 , =NNHCO 2
R
2 , and =NNHSO 2
R
2 , and 15 each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; 20 m is 0,1, 2, 3 or 4; n is 2 or 3; p is 0, 1, 2, 3, 4 or 5; and, r is 0, 1 or 2; 25 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a mammal in need thereof, wherein the cancer is selected from primary cancer, metastatic cancer, solid tumor, lymphoma, leukemia, and cancer resistant to other therapies. 30 In an embodiment of the invention there is provided a method of inhibiting a tyrosine kinase using a compound of Formula I: 3g H:\rbr\nterwoven\NRPortbl\DCC\RBR\7353404_I.docx-12/01/2015 (Rt) H H (Rb)p (Ra)m L B Formula I 5 or a tautomer, or an individual stereoisomer or a mixture of stereoisomers thereof wherein: Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with Rt groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, 10 partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from the group consisting of 0, N, and S and being optionally substituted with 1-4 Re groups; Ring A is a 5- or 6-membered aryl or heteroaryl ring; 15 Ring B is a 5- or 6-membered aryl or heteroaryl ring; L' is selected from NR 1 C(O), C(O)NR 1 , NR 1 C(O)O, NR 1 C(O)NR or OC(O)NR; each occurrence of Ra, Rb and Rt is independently selected from the group consisting of halo, -CN, 20 NO 2 , -R 4 , -OR 2 , -NR 2
R
3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2
C(O)YR
2 , -SC(O)YR 2 , -NR 2
C(=S)YR
2 , OC(=S)YR 2 , -C(=S)YR 2 , -YC(=NR 3
)YR
2 , -YP(=O)(YR 4
)(YR
4 ), -Si(R 2
)
3 , -NR 2
SO
2
R
2 , -S(O)rR 2 , SO 2
NR
2
R
3 and -NR 2
SO
2
NR
2
R
3 , wherein each Y is independently a bond, -0-, -S- or -NR 3 -; Re, at each occurrence, is independently selected from the group consisting of halo, =0, -CN, -NO 2 , 25 R 4 , -OR 2 , -NR 2
R
3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2
C(O)YR
2 , -SC(O)YR 2 , -NR 2
C(=S)YR
2 , -OC(=S)YR 2 , C(=S)YR 2 , -YC(=NR 3
)YR
2 , -YP(=O)(YR 4
)(YR
4 ), -Si(R 2
)
3 , -NR 2 S0 2
R
2 , -S(O)rR 2 , -SO 2
NR
2
R
3 and NR 2
SO
2
NR
2
R
3 , wherein each Y is independently a bond, -0-, -S- or -NR 3 -; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, 30 cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; 3h H:\rbr\nterwoven\NRPortbl\DCC\RBR\7353404_I.docx-12/01/2015 alternatively, R 2 and R 3 , taken together with the atom to which they are attached, form a 5- or 6 membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from the group consisting of N, 0 and S(O)r; 5 each occurrence of R 4 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, 10 alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2 R 3 , =NNHC(O)R 2 , =NNHCO 2
R
2 , and =NNHSO 2
R
2 , and 15 each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; 20 m is 0,1, 2, 3 or 4; n is 2 or 3; p is 0, 1, 2, 3, 4 or 5; and, r is 0, 1 or 2; 25 or a pharmaceutically acceptable salt thereof. In an embodiment of the invention there is provided a use of a compound of Formula I: (Rt H (Rb)p 30 (Ra)m A Formula I 3i H:\rbr\nterwoven\NRPortbl\DCC\RBR\7353404_I.docx-12/01/2015 or a tautomer, or an individual stereoisomer or a mixture of stereoisomers thereof wherein: Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being 5 carbon, substituted on at least two ring atoms with Rt groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from the group consisting of 0, N, and S and being optionally substituted with 1-4 Re groups; 10 Ring A is a 5- or 6-membered aryl or heteroaryl ring; Ring B is a 5- or 6-membered aryl or heteroaryl ring; L' is selected from NR 1 C(O), C(O)NR 1 , NR 1 C(O)O, NR 1 C(O)NR or OC(O)NR; 15 each occurrence of Ra, Rb and Rt is independently selected from the group consisting of halo, -CN, NO 2 , -R 4 , -OR 2 , -NR 2
R
3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2
C(O)YR
2 , -SC(O)YR 2 , -NR 2
C(=S)YR
2 , OC(=S)YR 2 , -C(=S)YR 2 , -YC(=NR 3
)YR
2 , -YP(=O)(YR 4
)(YR
4 ), -Si(R 2
)
3 , -NR 2
SO
2
R
2 , -S(O)rR 2 , SO 2
NR
2
R
3 and -NR 2
SO
2
NR
2
R
3 , wherein each Y is independently a bond, -0-, -S- or -NR 3 -; 20 Re, at each occurrence, is independently selected from the group consisting of halo, =0, -CN, -NO 2 , R 4 , -OR 2 , -NR 2
R
3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2
C(O)YR
2 , -SC(O)YR 2 , -NR 2
C(=S)YR
2 , -OC(=S)YR 2 , C(=S)YR 2 , -YC(=NR 3
)YR
2 , -YP(=O)(YR 4
)(YR
4 ), -Si(R 2
)
3 , -NR 2 S0 2
R
2 , -S(O)rR 2 , -SO 2
NR
2
R
3 and NR 2
SO
2
NR
2
R
3 , wherein each Y is independently a bond, -0-, -S- or -NR 3 -; 25 R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; alternatively, R 2 and R 3 , taken together with the atom to which they are attached, form a 5- or 6 30 membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from the group consisting of N, 0 and S(O)r; each occurrence of R 4 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; 35 each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, 3j H:Vbr\Intrwovn\NRPortbl\DCC\RBR\7353404 L.docx-12/01/2015 dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2 R 3 , =NNHC(O)R 2 , =NNHCO 2
R
2 , and =NNHSO 2
R
2 , and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups 5 selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; 10 m is 0,1, 2, 3 or 4; n is 2 or 3; p is 0, 1, 2, 3, 4 or 5; and, r is 0, 1 or 2; 15 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting a tyrosine kinase. In an embodiment of the invention there is provided a method for making 3-(Imidazo[1,2-b]pyridazin-3 ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1 -yl)methyl)-3-(trifluoromethyl)phenyl)benzamide having 20 the chemical formula: wherein the method comprises: reacting 3-ethynylimidazo[1,2-b]pyridazine with 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1 -yl)methyl) 25 3-(trifluoromethyl)phenyl)benzamide. In an embodiment of the invention there is provided a method for making 3-(Imidazo[1,2-b]pyridazin-3 ylethynyl)-4-methyl-N-(4-((4- methylpiperazin-1 -yl)methyl)-3-(trifluoromethyl)phenyl)benzamide having the chemical formula: 30 3k H:Vbr\Introvn\NRPortbl\DCC\RBR\7605999 _Ldocx-10/04/2015 wherein the method comprises: reacting 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzoic acid with 4-((4-methylpiperazin-1 5 yl)methyl)-3-(trifluoromethyl)aniline. In an embodiment, there is a compound of formula: N/ H (Re)S N H N ' (Rb) (Ra)m c L1 L (R)w 10 wherein: Ll is NR 1 C(O) or C(O)NR 1 ; L2 (Rd) 15 (Rb)P has one of the following structures: 31 H:Vbr\Introvn\NRPortbl\DCC\RBR\7605999 L.docx-10/04/2015 4ONN $~~ or K each occurrence of Ra is independently selected from the group consisting of halo, alkyl, and cycloalkyl; 5 each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, NR R , alkoxy, amino, -NH-alkyl, -C(O)NH-alkyl, -NHC(O)-alkyl, -NHC(O)NH-alkyl, -NHC(NH)-alkyl, NHC(NH)NH 2 , -NH(CH 2 )x-heteroaryl, -NH(CH 2 )x-heterocyclyl, -NH(CH 2 )x-aryl, and -(CH 2 )xC(O)NH 2 , wherein x is 0, 1, 2 or 3; 10 each of R1, R2 and R3 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, 2 3 cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R and R , taken together with the nitrogen atom to which at least one of R 2 and R 3 is attached, form a 5- or 6- membered heterocyclyl or heteroaryl ring; 15 each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, 20 dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2 R 3 , =NNHC(O)R 2 , =NNHCO 2
R
2 , and =NNHSO 2
R
2 , and 3m H:Vbr\Introvn\NRPortbl\DCC\RBR\7605999 L.docx-10/04/2015 each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, 5 hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0,1, 2, 3, or 4; and s is 0, 1, 2, or 3; 10 or a pharmaceutically acceptable salt thereof. In an embodiment, there is a compound of formula: 'o' " 'k 15 wherein has one of the following structures: 7 (R 20 each occurrence of Ra is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rb is independently selected from the group consisting of halo, alkyl, and 25 cycloalkyl; 3n H:\rbr\ntrovn\NRPortbl\DCC\RBR\7605999_I.docx- 10/04/2015 each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, NR R , alkoxy, amino, -NH-alkyl, -C(O)NH-alkyl, -NHC(O)-alkyl, -NHC(O)NH-alkyl, -NHC(NH) alkyl, -NHC(NH)NH 2 , -NH(CH 2 )x-heteroaryl, -NH(CH 2 )x-heterocyclyl, -NH(CH 2 )x-aryl, and (CH 2 )xC(O)NH 2 , 5 wherein x is 0, 1, 2 or 3; each of R1, R2 and R3 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, 2 3 cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R and R , taken together with the nitrogen atom to which at least one of R 2 and R 3 is attached, form a 5- or 6- membered 10 heterocyclyl or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, 15 heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2 R 3 , =NNHC(O)R 2 , =NNHCO 2
R
2 , and =NNHSO 2
R
2 , and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups 20 selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; 25 m is 0,1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and s is 0, 1, 2, or 3; 30 or a pharmaceutically acceptable salt thereof. 2. Featured Classes of Compounds and their Use, Generally 35 Compounds of this invention include those in which Ring T has the following structure: 3o H:Vbr\Introvn\NRPortbl\DCC\RBR\7605999_I.docx-10/04/2015 where Ring E is a 5- or 6-membered unsaturated ring (formed by two Rtgroups together with the Ring T atoms to which they are attached, as described above) and s is 0, 1, 2, 3 3 p or 4. These are illustrated by the compounds of formula I In which the fused Ring T ring system is one of the following (in which one of the optional Re substituents Is depicted): 5 Other classes of particular Interest are compounds of Formula I, as described In Part 1, in which Ring E Is a 6-nmembered ring, otherwise as described above, Illustrative examples of such compounds Include compounds of Formula I In which Ring T (with Its attached Ring E) Is a fused bicyclic heteroaryl of the following types: 0 R*) (R .. ) 10 For the previously described class and subclasses of compounds, as In all compounds of this Inventlon, Ring A and Ring B are as previously defined In Part 1, 15 illustrative examples of substituted Ring A groups are: P F Ring B represents a 5 or 6-membered aryl or heteroaryl ring as defined above in Part 1. Illustrative examples of substituted Ring B groups include: 20 4 IF CI N N VA cF Yy F A rCl F N tK{ 2rNO '0S4 14 4 Of special interest Is the clase of compound of Formuta I as described above In Part 1, In 5 which one of the R substituento Is a 5- or 6-membered ring (Ring C). which may be heleroaryl or heterocyclic, comprising carbon atoms and 1-3 heterootons independently selected from 0, N and S(O), and Ring C being optionally substituted on carbon or heteroatom(s) with I to 5 substituents R" 10 This class is represented by Formula 11: (R% T H || (R'). A In which the previously defined varlables, e.g., . m, p, A, B, T, R, Rt, R and R, are as defined above in part 1, and 5 R", at each occurrence, Is Independently selected from halo, =0, -CN, -NO 2 , -R 4 , -OR', -NR 2
R
3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2
C(O)YR
2 , -SX(R 2 )s, -SC(O)YR,
-NRC(=S)YR
2 , -OC(=S)YR, -C('S)YR 2 , -YC(=NRS)YR, -YP(=O)(R 4 )(YR4) 5 -NRaSO 2
R
2 . -S(O)rR 2 , -SONR 2 R* and -NR 2
SONR
2 R, wherein each Y Is Independently . bond, -0-, -S- or -NR 3 - and r, R 2 , R 3 and R 4 ; are as defined previously in Part i and. v is 0. 1, 2. 3, 4 or 6. t0 Illustrative examples of Ring C systems include but are not limited to the following types: N In which R" and v are as defined above. 15 Of special Interest Is the class of compounds of formula 1I in which Ring T has the following structure: (R). H In which the Indicated variables, e.g., R', and Ring E, are as defined previously. 20 Illustrative subsets of such compounds include those having the following structures: 6 T TR H HH as embodied by the following non-limiting illustrative examples: NNHCHF OF, C~a In which several illustraive --[Ring AHLHRIng BNRing C}- portons are depicted. Compounds of interest Include among others, compounds of Formula II In which Ring C Is an imiderole ring, optionally substituted with one or more R* groups. Of particular Interest are 10 compounds of this subclass In which Ring C bears a single lower alkyl (e.g., methyl) Rgroup. A further feature of the Invention relates to compounds of Formula I es described In Part 1, in which one R' substiluent Is -[L-[Ring D). This class Is represented by Formula III; is CR') T II (R b ) P (RO). L 7 ||| in which the previously defined variables, e.g., n, m, p, Ring T, Ring A, Ring B, L, R', R', R' and R', are defined above in part 1, and Lls selected from (CHa), O(CHzh), NR'(CHah, S(CHa), and (CHac)NR 3 C(O)(CH), and the linker moiety L 2 can be Included in either direction; Ring D represents a 5- or 6-membered heterocyclic or heteroaryl ring comprilaing carbon 10 atoms and 1-3 heteroatoms Independently selected from 0, N and SCO), and Ring 0 Is optionally substituted on carbon or heteroaton(s) with 1-5 Rd groups: Rd. at each occurrence. Is Independently selected from halo, =O, CN, -NOt, -R 4 , -OR2, ,NR 2
R
3 -S(R)3, -C(O)YR 2 , -OC(O)YR 2 , .NRZC(0)YR 2 , -SC(O)YR 2 , -NRtC(-S)YR 2 , -OC(=S)YR 2 , -C(=S)YR 2 , -YC(4NR)VYR 2 , -YP(=O)(YRh(YR4, 15 -NR 2 SO2R. -S(ONR 2 , -8ONR2R and -NR 2 SOaNR 2 R ,wherein each Y Is independently a bond, -0-, -S- or -NRa- and r, R 2 , R' and Rd are as previously defined in Part 1; w is 0. 1. 2. 3, 4 or 5; xis 0, 1, 2 or 3; and, 20 als 1, 2,3or4. Non-limiting, lllustrative examples of -[Ring BHL4Ring DJ moieties in compounds of Formula III include among others: a"e 'aCD tco 8 Of special Interest Is the class of compounds of formula liI In which Ring T has the following structure: 5 In which the previously defined valiables, e.g., R*, s, and Ring E, are as defined previously. Non-limiting examples of such compounds Include those having the following structures; (Re), E - T (e a H T H (R')m t~l. (R611 0 (R 6 10 as illustrated by the following examplea: NO TCC9 H ~ t T N\H (R9 tOO 0y 0F Compounds of interest include among others, Compounds of Fomuila III In which Ring D is a piperazine ring, substituted on nitrogen with Rd. Of particular current Interest, are compounds 5 of this subclass in which R Is a substituted or unsubstituted lower (I.e., I - 6 carbon) alkyl as illustrated by N-methylpIperozIne molemls In some of the foregoing exampis. Of apelal Interest ae compounds of formula 11 and formula IlII in which Ring T is an optionally substituted Imldazo[1,2-tIpyridino, imidazo[1,2-bjpyridazine, imidazo[1,2-a]pyazine, 10 pyrazoo[1,5-ajpyrImIdine, pymazolo[1,5-alpyrldine, pyrzolo[1 ,5-c]pyrimidine, and pyrazolo[1,"-]1,3,5]triazine, Also of interest are compounds of formula Il and formula Ill in which Rings A and B are aryl. 15 Another subclass of interest arm compounds of Formulas l1 and III, In which Ring T Is any 6/5 fused heteroaryl ring system, optionally substituted with up to three R" groups. Of particular interest are compounds In which s Is 0, Also of interest are those in which a is 1 - 3 and at least one R' Is halo, lower alkyl, alkoxy, amino, -NH-alkyl, -C(O)N H.alkyl, -NHC(O)-olky, NHC(O)NH-alkyW, -NHQ(NH)-alkyl -NHC(NH)NHz, -NH(Cflg),heteroaryl, -NH(Cllz) 20 heterocycle. -NH(CI-) aryl or -(CH,)AC(O)NH2, in which x is 0, 1, 2 or 3 and "alky" includes straight (le., unbranched and acyclic), branched and cyclic alkyl groups and in which aryl, heteroaryi, heterocyclyl rings are optionally substituted. Illustrative, non limiting, examples of 1he foregoing Include compounds of formulas 11 and IlIl in which Ring T Is one of the following: NH
NJ
3
N,
2 25 10 Illustrative, non limiting examples of this subelses include compounds of formulas lIla, Ilb , Il, lis, Illb and Ili1: 5(R " )m ( R O ~ S~ Formulja Ils FormulisIlb N N ). NJ N( 10 Formuia I Formula Il N (Rg Formula IIb Formula Ili 15 In which the previously defined variables, e.g.. R", Rb, R*, Rd. R", ml and p, are as previously defined. e.g. in part 1, and a is an Integer from 0 to 4. One subset of interest includes compounds ofFormulas la, ilb and Ileln whlchsl s C; m, p 20 and v are 1; and, Ras is.a Rb Is CPa and R' I methl AnotherIncludescompounds ofFormulas ila, Illb, licin whichsisO; mand pFare 1;and, R is CH , Rb Is Cad and R is CHs orICHmHtOH, 1 1 Compounds of this invention of pardicularInterest Include thosewith one or more of the following characteristics: + a molecularwelght of less than 1000, preferably less than 750 and more preferably less than 500 mass units (not including the weightof any solvating or co-crystallzng species, of S any counter-lon In the case of a salt); or e Inhibitory activity against a wild type or mutant (especially a clinically relevant mutant) kinase, especially a Sre family kinase such as Sro, Yes, Lyn or Lek; a VEGF-R such as VEGF-RI (Flt-1), VEGF-R2 (kdr), or VEGF-R3; a PDGF-R; an Abi kinase or another kinase of Interestwith an IC50 value of I IM or less (as determined using any scientifically acceptable 10 kinase Inhibition assay), preferably with an IC50 of 500 nM or better, and optimally with an 1C50 value of250 nM or better; or * inhibitory activity against a given kinase with an 1050 value at least 100-fold lower than their IC50 values for other kinases of Interest; or * inhibitory activity against both Sm and kdr with a 1 pM or better 1050 value against each; or I 5 - a cytotoxic or growth Inhibitory effect on cancer cell lines maintained in vitro, or in anmal studies using a scientifically acceptable cancer cell xenograft model, (especially preferred are compounds of the invention which inhibit proliferation of cultured K562 ceill with a potency at least as great as Gleevec, preferably with a potency at least twice that of Glevoe, and more preferably with a potency at least 10 times that of Gleevec as determined by comparative 20 studies.). Also provided is a composition comprising at least one compound of the invention or a salt, hydrate or other solvate thereof, and at least one pharmaceutically acceptable exciplent or additive. Such composelions can be administered to a subject in need thereof 25 to inhibit the growth, development and/or metastasis of cancers, including solid tumors (e.g., breast, colon, pancreatl, CNS and head and neck cancers, among others) and various forms of leukemia, including leukemia and other cancers which are resistant to other treatment including those which are resistant to treatment with Gleevec or another kinae Inhibitor, and generally for the treatment and prophylaxis of diseases or 30 undesirable conditions mediated by one or more kineses which are Inhibited by a compound of this invention. The cancer treatment method of this Invention involves administering (a a monotherapy or in combination with one or more other anli-cancer agents, one or more agents for ameliorating 35 side effects, radiation, etc) a therapeutically effective amount of a compound of the Invention to a human or animal in need of it in order to Inhibit, slow or reverse the growth, development or spread of cancer, including solid tumors or other forms of cancer such as leukemias. In the recipient. Such administration constitutes a method for the treatment or prophylaxis of diseases mediated by one or more kinaes inhibited by one of the disolosed compounds or a 12 pharmaceutically acceptable derivative thereof. "Administratlon" of a compound of this invention encompasses the delivery to a recipient of a compound of the sort described herein, or a prodrug or other pharmaeuucally acceptable derivative thereof, using any suitable formulation or route of ad ministration, as discussed herein. Typically the compound Is 5 administered one or more times per month, often one or more times per week, e.g. daily, every other day, 5 dayslweek, etc. Oral and intravenous administrations am of particular current interest The phrase, -pharmaceutically acceptable derivative", as used herein, denotes any 10 pharnaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, Is capable of providing (directly or Indirectly) a compound as otherwise described herein, or a metabolite or residue (MW '300) thereof. Pharmaceutcally acceptable derivatives thus include among other pro-drugs. A pro-drug is a derivative of a compound, usually with slgnhicantly reduced phamscologlical 15 activity, which contains an additional moiety which is suscepible to removal In vivo yielding the parent molecule as the pharmacologloally active species. An example of a pro-drug Is an ester which is cleaved in vivo to yield a compound of Interest. Pro-drugs of a variety of compound$, and materials and methods for derlvatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present Invention. 20 Particularly favored derivatives and prodrugs of a parent compound arm those derivatives and prodrugs that Increase the bloavallability of the compound when administered to a mammal (e.g., by permitting enhanced absorption Into the blood following oral administration) or which enhance delivery to a biological compartment of Interest (e.g., the brain or lymphatic system) 25 relative to the parent compound. Preferred prodrugs Include derivatives of a compound of this invention with enhanced aqueous solubility or active transport through the gut membrane, relative to the parent compound. One important aspect of this invention Is a method for treating cancer In a subject In need 30 thereof, which comprises administering to the subject a treatment effective amount of a composition containing a compound of this invention. Various cancers which may be thus treated are noted elsewhere herein and Include, among others, cancers which are or have become resistant to another anticancer agent such as Gleevec, Iressa, Throeva or one of the other agents noted herein. Treatment may be provided In combination with one or more other 35 cancer therapies, Include surgery, radiotherapy (e.g., gamma-radIation, neutron beam radloherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, etc.), endocrine therapy, biologic response modifiers (e.g.. Interferon$, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia, cryotherapy, agents to attenuate ary adverse effects (e.g., anflemetics), and other cancer 40 chemotherapeutic drugs. TIe other agent(s) may be administered using a formulation, route 13 of administration and dosing schedule the same or different from lht used with the compound of this invention. Such other drugs include but not limited to one or more of the following: an anti-cancer 5 alkylating or intercalating agent (e.g., mechloethamine, chlorambucil, Cyclophosphamlde, Melphalen, and Ifosfamide): antimetabolite (e.g., Methotrexate); purine antagonist or pyrimldlne antagonist (e.g., 6-Mercaptopurine, 5-Fluorourecil, Cytarblile, and Gemcitabine); spindle poason (e.g., Vinblastlne, VincrIstIne, Vinorelbine and Paclitaxel); podophyllotoxin (e.g., Etoposide, Irinotecan, Topotecan); antibiotic (e.g., Doxorubicin, Bleomycin and 10 Mitrnycin); nitrosourea (e.g., Carmustine, Lamustine); inorganic [on (e.g., Cisplatin, Carboplatin, Oxallplatin or oxlplatin); enzyme (e.g., Asparaginase); hormone (e.g., Tamoxifen, Leuprolide, Flutamide and Megestrol): mTOR iNbitor (e.g., Sirolimus (rapamycin), Temelrollmus (CC1779), Everollmus (RAD001), AP23573 or other compounds disclosed In US Patent No. 7,091,213); proteasome inhibitor (such as Velcade, another proteasome Inhibitor IS (see e.g., WO 021096933) or another NF-kB inhibitor, including, e.g., an IkK Inhibitor); other kinase inhibitors (e.g., an inhibitor of Src, BRC/Ab., kdr, tIt3, aurora-2, glycogen synthese kinase 3 CGSK-3"), EGF-R kinase (e.g., Ires, Tarcevo, etc.), VEGF-R kinase, PDGF-R kinese, etc); an antibody, soluble receptor or other receptor antagonist against a receptor or hormone Implicated in a cancer (Including receptors such as EGFR, ErbB2, VEGFR, PDGFR, 20 and IGF-R; and agents such as Hercoptn, Avastin, Erbitux, etc.): etc. For a more comprehensive discussion of updated cancertherSpies se. http://ww.not.nihgov/, a list of the FDA approved oncology drugs at hitp;//www.fda.gov/<der/ancer/druglistframe.htm, and The Merck Manual, Seventeenth Ed. 1999, the entire contents of which are hereby Incorporated by reference. Examples of other therapeutic agents are noted elsewhere herein 25 and Include among others, Zyloprlm, olemtuzmab, altretamine, amifostine, nastrotole, antibodies against prostate-specific membrane antigen (such as MLN-591. MLN59IRL and MLN2704), arsenic trioxide, bexarotene, bleomycin, busulfan, capecltabine, GlIadel Wafer, celecoxb, chlorambucil, cisplatin-opinephrine gel, cladribine, cytarabine liposomal, daunotubloin liposomet, dounorubidn, daunomycn, dexrazoxane, docetaxel, doxorublcin. 30 Elliott's B Solution, epirubicin, estramusine, etoposide phosphate, etoposide. exemeslane, fludarabine, 5-FU, fulvestrant, gemciltabine, gemtuzumab-ozogamiclin, goserelin acetate, hydroxyurea, idarubicin, Idarubloin, Idomydn, ifosfamide, Imatinib mesylate, Irinotecan (or other topolsomerase Inhibitor, Including antibodles such as MLN576 (XR11576)), letrozole, leucovorin, leucovorin levamisole.ilposomal daunorubiin, melphalon, L-PAM, mena, 35 methotrexate, methoxsalen, mitomycin C, mitoxantrone, MLN518 or MLNGD (or other inhibitors of the fit-3 receptor tyrosine kinase, PDFG-R or c-kit), itoxantrone, paciltexel, Pegademase, pentostatin, porfimer sodurn, Rituximab (RITUXAN@), talc, tamoxfen, temozolamide, teniposide, VM-28, topotecan; toremliene, 204 (or other antibody which Interferes with HER2-mediated signaling), tretinon, ATRA, valrubicin, vinorelbine, or 40 parnidronate, zoledronate or another blsphosphonate, 14 This invention further cqrmprises the preparation of a compound of any of Formulas 1, 11, 111, Ila, llb. Itc, II.e Ila, 1le or of any other of the compounds of this invention. 5 The Invention also comprises the use of a compound of the invention, or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment either acutely or chronically of cancer (Including leukemlas and solid tumors, primary or metastatic, Including cancers such as noted elsewhere heroin and Including cancers which are resistant or refractory to one or more other therapies). The compounds of this Invention are useful in 10 the manufacture of an anfi-cancer medicamernt. The compounds of the present invention are also useful in the manufacture of a medicament to attenuate or prevent disorders through inhibition of one or more kinases ouch as Sro, kdr, abl, eo. Other disorders which may be treated with a compound of this invention Include metabolic 15 disorders, Inflammatory disorders and osteoporosis and other bone disorders. In such cases the compound of this Invention may be used as a monotherapy or may be administered in conjunction with administration of another drug for the disorder, e.g., a bisphosphonate in the case of osteoporosis or other bone-related Illnesses. 20 This Invention further encompasses a composition comprising a compound of the invention. including a compound of any of the described classes or subclasses, Including those of any of the formulas noted above, among others, preferably in a thempeuically-effeOtive amount, In association with a least one ph armacutically acceptable carier, adjuvant or diluent. 25 Compounds of this Invention are also useful as standards and reagents for charaoteriing various kinases, especially but not limited to kdr and Sm family kinases, as well as for studying the role of such kinases in biological and pathological phenomena; for studying Intracellular signal transduction pathways mediated by such kinases, for the comparative evaluation of new kinase inhibitors; and for studying various cancers in cell lines and animal 30 models. 3. Definitions In reading this document, the following inrnation and definitions apply unless otherwise 35 Indicated. In addition, unless otherwise Indicated, all occurrences of a functional group are Independently chosen, as te reader Is in some cases reminded by the use of a slash mark or prime to IndIcate simply that the two occurrences may be the same or different (eg., R, R', R". or Y, . Y'etc.). 15 The term "AlkyP Is intended to include linear (i.e., unbranched or acycic), branched, cyclic, or polycycio non aromatic hydrocarbon groups, which are optionally substituted with one or more functional groups. Unless otherwise specified, "alkyl" groups contain one to eight, and preferably one to six carbon atoms. 014 alkyl, is intended to Include C1, C2, C, C 4 , 0, and 5 Cs alkyl groups. Lower alkyl refers to alkyl groups containing I to 6 carbon atoms. Examples of Alkyl Include, but are not limited to, methyl, ethyl, n-pippyl, Isopropyl, cyclopropyl, butyl, Isobutyl, sec-butyl, tert-butyl, cyolobutyl, pentyl, Isopentyl ter-peltyl, cyclopentyl, hexyl, isobexyl, cyclohexyl, etc. Alkyl may be substituted or unsubstituted. illustratve subsituted alkyl groups Include, but are not limited to, fluoromethyl, ditluoromelbyl, trlfluoromethyl, 2 10 fluorethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, substituted benzyl, phenethyl, substituted phonethyl, etc. Th e term "Alkoxy" represent a subset of alkyl In which an alkyl group as defined above with the Indicated number of carbons attached through an oxygen bridge. For example, "alkoxy" 15 refers to groups -0-alkyl, wherein the alkyl group contains I to 8 carbons atoms of a near, branched, cyclic configuration. Examples of "alkoxy" include, but we not limited to, methoxy, ethoxy, n-propoxy, .- propoxy, t-butoxy, n-butcxy, s-pentoxy and the Ilke. "Hloalkyl" is Intended to include both branch hed and linear chain saturatod hydrocarbon 20 having one or more carbon substituted with a Halogen. Examples of haloalkyl, include, but are not limited to, trifluoromethyl, trichloromethyt pentafluroethyl and the like. The term "alkenyl' Is intended to include hydrocarbon chains of linear, branched, or Cycic configuration having one or more unsaturated Carbon-carbon bonds Ihat may occur In any 25 stable point along the chain or cycle. Unless otherwise specified, "alkenyr refers to groups usually having two to eight, often two to six carbon atoms. For example, "alkenyl" may refer to prop--2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-any, hex-2-enyl, hex-5-enyl, 2,3 dimethylbut-2-onyl, and the like. Furthermore, alkenyl groups may be substituted or unsubstituted. 30 The term "alkynyP ls intended to Include hydrocarbon chains of either linear or branched configuration, having one or more carborecarbon triple bond that may occur in any stable point along The chain. Unless otherwise specified, "alkynyP groups refer refers to groups having two to eight, preferably two to six carbons. Examples of'alkynyr Include, but are not 35 limited to prop-2-ynyl, tbut-2-ynyl, but-3-ynyl, pent-2-yny, 3-mehyipent-4-ynyl, hex-2-ynyl, hex-5-ynyl, etc. Furthermom, alkynyl groups may be substituted or unsubstltuted. Cycloalkyl is a subset of alkyi and includes any stable cyclic or polycyclic hydrocarbon groups of from 3 to 13 carbon atoms, any of which is saturated. Examples of such cyctoalkyl Include, 40 but are not limited to cyclopropyl, norbornyl, 12.2.2]biyclooctanO. [4.4.0]bicyclodecme, and 16 the like, which, as in the case of other alkyl moieties, may optionally be substituted, The tarm "cycloalky" may be used Interchangeably with the term "carbocycle" Cycloalkenyl is a subset of alkenyl and Includes any stable cyclic or polycyclic hydrocarbon 5 groups of from 3 to 13 carbon atoms, preferably from 5 to 8 carbon atoms, which contains one or more unsaturated carbon-carbon double bonds that may occur in any point along the cycle. Examples of such cycloalkenyl Include, but are not limited to oyclopentenyl. cyclohexenyl and the like. 10 Cycloalkynyl is a subset of alkynyl and includes any stable cyclic or polycyclio hydrocarbon groups of from 5 to 13 carbon atoms, whlh contains one ar more unsaturated carbon-carbon triple bonds that may occur in any point along the cycle. As in the case of other alkenyl and alkynyl moletles, cycloalkenyl and cyoloalkynyl may optionally be substituted. 15 "Heteracycle", "heteracyclyl", or "hteroylio" as used herein refers to non-aromatio ring systems having five to fourteen ring atoms, preferably five to ten. In which one or more ring carbons, preferably one to four, are cach replaced by a heteroatdm such as N, 0, or S. Non lmitling examples of heterocyclic rings Include 3-1H-benzimidazol-2-one, (1-substtuted)-2 oxo-benzimidazol-3-yi, 2-tetrshydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothlophenyl, 3 20 tetrehydrothlophenyl, 2-morphollnyl, 3-morpholinyl, 4.morpholnyl. 2-thimorpholinyl, 3 thiomorpholinyl, 4-thlomorphollnyl, 1-pyrrolidlny, 2-pyrroildiyi, 3-pyrrolldinyl, 1-plperaznyl, 2 piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidiny, 4-piperidinyl, 4-thiazolldInyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl, benzopyrroldinyl, benzopipeldinyl, benzoxclanyl, benzothiolanyl, and benzothiany. Also Included within the scope of the term 25 'heterocycyl" or "heteracyclio. as it is used herein. is a group in which a non-aromalic heterootom-oontaning ring is fused to one or more aromatio or non-aromatic rings, such as In an IndolInyl, chromanyl, phenaniridinyi, or tetrahydroquinllny, where the radical or point of attachment is on the non-aromallc heterostom-containing ring. The term "heterocycle", "hoterocyclyl". or "hoterocyollo" whether saturated or partally unsaturated, also refes to rings 30 that are optionally substituted, The term "aryl" used alone or as part of a larger moiety as In "aralkyl", "aralkoxy", or "aryloy alkyr', refers to aromatic ring groups having six to fourteen ring atoms, such as phenyl. 1 naphthyl, 2-naphthyl, 1-enthracyl and 2-anthracyl. An "aryP' 1ng may contain one or more 35 substituents. The term "aryr may be used Interchangeably with the term "iryl ring'. "Ary also Includes fused polycyclic aromatic ring systems in which an aromatic ring is fused to one or more rings. Non-limiting examples of useful aryl ring groups Include phenyl. hydroxyphenyl. halophenyl; alkoxyphenyl, dlalkoxyphenyl, trialkoxyphenyl, alkylenedioxyphenyl, naphthyl, phenanthryl, anthryl, phenanthro and the Ike, as well as 1-nophthyl, 2-naphthyl, 1-anthracyl 40 and 2-anthracyl. Also Included within the scope of the term "aryl, as it is used herein, is a 17 group in which an aromatic ring Is fused to one or more non-aromatic ings, such as In a Indenyl, phenenthrildinyl, or tefrohydronaphthyl, where the radical or point of attachment Is on the aromatic ring. 5 The term "heteroaryl as used herein refers to stable heterocycilo, and polyheterocylle aromatic moieties having 5 - 14 rIng atoms. Heteroaryl groups may be substituted or unsubstltuted and may comprise one or more rings. Examples of typical heteroaryl rings include 5-membered monocyclic ring groups such as thienyl, pyrotyl, ImIdazolyl, pyrazoyl, furyl, isothlazolyl, furezanyl, lsoxazolyl, thiazolyl and the Ike; 8-membered monocyclic groups 10 such as pyridyl, pyrazinyl, pyrimidinyl, pyridainyl, trIazinyl and the like; and polycyclic heterocyclic ring groups such as benzoibtienyl, naphtho[2,3-b]thienyI, thanthrenyl, isoberzofuranyl, chromenyl, xanthenyl, phenoxathlenyl, Indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, Isoquinolyl, quinolyl, phthalazInyl. nsphthyrldinyl, qulnoxallnyl, quinazolinyl, benzothlazole, benzlmidazole, tetrahydroquinoline cinnolinyl, pteridinyl, carbazolyl, beta 15 carbolnyl, phenonhlirdinyl, acridinyl, perimidInyl, phenanthrolinyl, phenazinyl, isothiazolyl. phenolhiazinyl, phenoxazinyl, and the like (see e.g. Katrilzky, Handbook of Heterocyclic Chamisiry). Further specific examples of heteroaryl rings Include 2furonyl, 3-furanyl, N imidazolyl, 2-imidazolyi, 4-imidawlyl, 5-imidazolyl. 3-Isoxazolyl, 4-Isoxazolyl, 5-isoxazolyl. 2 oxadiazolyl, 5-oxodlazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrolyl, 20 2-pyridyl. 3-pyridyl, 4-pyridyl. 2-pyrimidyl. 4-pyrmidyl, 5-pyrlmidyl, 3-pyridotinyl, 2-thiazolyl, 4 thlazolyl, 5-thIazolyl, 5-totrazolyl, 2-triazolyl, 5-triazolyl. 2-thienyt, 3-thienyl, carbazolyl, benzlmidazolyl, benrothienyl, benzofuranyl, Indolyl, quirlinyl, benzotriazoyl, benzothiazolyl, benzooxazolyl, benzimidaezoyl, isoqulnolinyl, indolyl, isoindolyl, soridinyl, or benzolsoxazoly. Heteroaryl groups further include a group in which a heteroaromatlo ring is fused to one or 25 more aromatic or nonaromatic rings where the radical or point of attachment Is on the heteroaromatIo ring. Examples include tetrahydrocjulnolnhe, tetahydrosoquinlne, and pyridoI3,4-dipyrimidinyl, imidao[1,2-elpyrimidyl,Imidazo[1,2]pyrzinyl, imidazo[1,2 alpyiridinyl, imidazo[1.2-cpyrimidyl, pyrazolo[1,5-a[1,3,5]trizinyI, pyrazolo[1 ,5-ojpyrimidyl imidazo[1,2-blpyridazinyl, Imldaco[1,5-apyrimldyl, pyrazoIo[1,5-b]j,2,4]triazine, quinoly, 30 isoquinoyl. quinoxalyl, ImIdazolrlazinyi, pyrrolo[2,3-dpyrimildyl, triazolopyrmidyl, pyridopyrazinyl. The term "hateroaryl" also refers to rings that are optionally substituted, The term "heteroaryl' may be used Interchangeably with the term 'hoteroaryl ring" or the term "heteroeromailo". An aryl group (including the aryl portion of an aralkyl, aralkoxy, or aryloxyalkyl molety and 35 the like) or heteroaryl 9 roup (including the heteroaryl portion of a heteroaralkyl or heteroarylaikoxy molety and the like) may contain one or more subeiltuents. Examples of suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group include halogen (F, Cl, Br or 1), -CN, -R, -OR, -S(O)rR', (wherein r is an integer of 0. 1 or 2), -SO 2 NRR, -NR 2 R3, -(CO)YR. -O(CO)YR 2 , -NR 2
(CO)YR
2 . -S(CO)YRe, 18
-NR
2
C(=S)YR
2 , -OC(=S)YR', -C(=S)YR 2 wherein each occurrence of Y is independently -0-,-S-, -NR 3 ~, or a chemical bond; -(CO)YR2 thus encompasses -C(aO)R 2 ,
-C(=O)OR
2 and,-C(=O)NRR. Additional substituents Include -YC(=NR 3
)YR
2 , -COCOR, -COMCOR 2 (whore M Is a 1- 8 carbon alkyl group), -YP(=O)(YR4)(YR 4 ) 5 (including among others -P(O)(R 4 )), -SI(R), -N02, -NR 2 80 2
R
2 and
-NRSO
2
NR
2 R. To illustrate further, substituents In which Y Is -NR 8 thus Include among others, -NRC(O)R -NRC(=O)NRR, -NR'C(=0)OR and -NRC(=NH)NR 2 Rs. R and R 3 substituents at each occurrence are independently selected from hydrogen, alkyl, alkenyl, alKynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, 10 heterceryl, heterocyclyl, and R 2 and R3 (and R 4 ) snbotituents may themselves be substituted or unsubstltuted. Examples of substituents allowed on R 2 , R 3 and R4 Include, among others amino, alkylamlino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl. alkynyl, aryl, heteroaryl, carbocycle, heterocycle, alkylaminocarbonryl, dialkylaminoar-bonyl, alkylamInocarbonyloxy, dlalkylaminocarbonyloxy, nitro, cyano, 15 carboxy, alkoxycar-bonyl, alkylcarbonyl, hydroxy, alkoxy, holoalkoxy groups. Additional Illusirative examples include protected OH (such as acyloxy), phenyl, substituted phenyl, 0-phenyl, -O-(substituted) phenyl, -benzyl, substituted benzyl, -O-phenelhyl (Le., -OCI-2CH 2
C
6 1 5 ), -O.-(substituted)phenethyl. Non-limiting ItluStrations Of a substituted
R
2 , R 3 or R 4 moiety include haloolkyl and trihaloelkyl, alkoxyalkyl, halqphenyl, 20 -M-heteroaryl,-M-heterocycle,-M-aryl,-M-OR 2 , -M-SR 2
,-M-NR
2
R
3
,-M-OC(O)NR"R
3
-M-C(-NR)NR
2
R
3 . -M-C(NRs)OR 3 , -M-P(O)R 2
R
3 , Sli(R) -M-NR 2
C(O)R
3 , -M-NR2C(O)CR , -M-C(O)R -M-C(=S)R 2 , -M-C(=S)NR 2
R
3 , -M-C(O)NR 2
R
3 ,
-MC(O)NR
2
-M-NR
2 R3, -M-NR 2
C(NR
3
)NR
2
RM-NR
2
C(S)NR
2
R
3 -M-S(O)R3,
-MC(O)R
3 , -M-OC(O)Ra, -MC(O)SR 2 , -M-S(O)NR 2 R3, -C(O)-M-C(O)R 2 , -MC0 2
R
2 , 25 -MC(=O)NR 2
R
3 . -M-C(=NH)NR 2
R
3 and -M-OC(=NHNR 2 R (wherein M Isa 1-6 carbon alkyl group). Some more specific examples Include but are not limited to chloromethyl, trichloromethyl, trifluoromethyl, methoxyethyl, alkoxyphenyl, halophenyl, -CH2a-aryl, -CH-heterccyole, 30 -CH 2
C(C)NIH
2 , -C(O)CH 2 N(CH3)2, -CHzCH2OH, -CH20C(O)NH2. -CH 2 CH2NH 2 , -CH2CH2CH2NEt 2 , -CH20CH3, -C(O)NH2 -CH-12CH 2 -heterocycle, .0QS)CH3, -C(=8)NH 2 ,
-C(=NH)NH
2 , -C(=NH)OEt, -C(O)NH-cydopropyi, C(O)NHCH2CH2-heterocycle,
-C(O)NHCH
2 CH2OCH, -C(O)CH 2 CH2NHCHt, -CH 2 CHzF, -C(O)CHz-hsterocycle, -CH2C(O)NHCH 3 , -CH2CH2P(O)(CHo), S)(CKs) 3 and the Ike, 35 An aliphatic, Le., alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl or ron-aromatic heterocyclic, group may thus also contain one or e substituente. Examples of suitable substituents on such groups include, but are not 19 limited to those listed above for the carbon atoms of an aryl or hetermaryl group and In addition include the following substituents for a saturated carbon atom: =0, =S, =NH,
=NNR
2 Re, =NNHC(O)R 2
,NNHCO
2 R, or -NNHSO 2 R, wherein R' at each occurrence is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cydoakynyl, styl, 5 heteroaryl, heterocyclyl, Illustrative examples of substItuents on an aliphatic, heteroaliphatlc or heteroqyIoc group include amino, alkylamino, dialkylamino, amlnocarbonyl, halogen, alkyl, alkylaminocar bonyl, dialkylanlhocarbonyl, alkylaminocarbonyloxy, dialkylaninocarbonyloxy, alkoxy, 10 nitro, -CN, carboxy, alkoxycarbonyl, alkylcarbonyl, -OH, haloalkoxy or haloalkyl groups. Illustrative substituents on a nitrogen, e.g., In an ary), heteroaryl or non-aromatic heterocyclic ring, include R 4
-NR
2
R
3 , -C(=O)R 2 . -C(=)OR 2 , -C(=0)SR 2 , -C(=O)NR2Ra, -C(=NR)N 2 RR, -C(mNR 2 )OR' -O(=NR)R, -COCOR2,-COMCOR 2 , -CN -SO 2
R
3 . S(O)R, 15 -P(=O)(YR)(YR 2
),NR
2 3O 2
R
3 and -NR'60 2
NR
2 Ra, wherein each occurrence of R 2 ond R' Is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, hetercary, heterocyclyl. This invention encompasses only those combinations of substituents and variables that result 20 In a stable or chemically feasible compound. A stable compound or chemically feasible compound is one that has stability sufficient to permit its preparation and detection. Preferred compounds of this Invention are sufficiently stable that they are not substantially altered when kept at a temperature of 40* C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week. 25 Certain compounds of this invention may exist in tautomeric forms, and this invention Includes all such tautomeric forms of those compounds unless otherwise specified, Unless otherwise stated, structures depicted herein are also meant to Include all stereochem 30 Ical forms of the structure; i.e. the R and s configurations for each asymmetric center. Thus, single stereochemoial Isomers as well as enntiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Thus, this Invention encompasses each diasterlomer or enantiomer substantially free of other isomers (>90%, and preferably >95%, free from other stereolsomers on a molar basis) as well as a mixture of such Isomers. 35 Particular optical Isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g. by formation of diastereolomeric salts, by treatment with an optically active acid or base, Examples of appropriate acids are tartaric, dlacetyltartarlo, dibenzoytarleric, ditoluoyltartaric, and comphorsufonic acid and then separaton of the 40 mIxture of diastereolsomers by crystallization followed by liberation of the optically active 20 bases from these calts. A different process for separation of optical Isomers Involves the use of a ohiral chromatography column opimally chosen to maximize the separation of the enantiomers, Still another method Involves synthesis of covalent diastereolsomerlo molecules by reacting compounds of the invention with an optically pure acid In an activated form or an 5 optically pure Isocyanate The synthesized diastereolsomers can be separated by conventional means such at chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerlcally pure compound. Optioally active compounds of the Invention can be obtained by using active starting 10 materials. These Isomers may be In the form of a free acid, a free base, an ester or a sak. The compounds ofthis Invention can exist In radlolabelled form, i.e., said compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number: ordinarily found In nature. Radioisotopes of hydrogen, carbon, 15 phosphorous, fluorine and chlorine Include 3H, 14 C, 32 p, 35S, 43F and 3601, respectively. Compounds of this invention which contain those redlolsotopes and/or other radioisotopes of other atoms are within the scope of this Invention. Tritlated, Le., 3H, and carbon-14, .e., 14C, radioisotopes are particularly preferred for their ease of preparation and detectability. 20 Radiolabelled compounds of this invention can generally be prepared by methods well known to those skilled In the art. Conveniently, such radiolabelled compounds can be prepared by carrying out the procedures disclosed herein except substituing a readily available redlolabelled reagent for a non-adiolabelled reagent. 25 4. Synthetic Overview The practitioner has a well-established literature of heterocyclic and other relevant chemical transformations. recovery and purification technologies to draw upon, In combination with the information contained In the examples which follow, for guidance on synthetic strategies, protecting groups, and other materials and methods useful for the 30 synthesis, recovery and characterization of the compounds of this invention, including compounds containing the various choices for the Rt, Ra ,Rb, R, R', R and Rings T. A, B. C and D. The following references, and the references cited therein, may be of particular interest: WO 01127109, WO 02/086478, WO 02/30428, WO 02/080911, WO 02/080914, WO 2004/033453, WO 2004/035578, WO 2004/23972,WO 2005/105796, US 35 2003/0119842, US 2004/0023972, US 2004/0122044, US 200410142961, US 2005/0239822, US 6420305 and US 6703404 are referring to the preparation of Imidazoli,2-alpyridines; WO 05/030218, WO 03/022150 are referring to Imidazo[1,2 olpyrlmidines; WO 05/047290, WO 03/089434, US 6589952 are referring to imidazopyrazines, WO 04/011466and US 5146850 are referring to the preparation of 21 Imidaz[1,2-bipyridazInes; and WO O5/070431, WO 96/35690, WO 04/089471 are referring to pyrazolo[1,5-alpyrnidines. Various synthetic approaches may be used to produce the compounds described herein, 5 Including those approaches depicted schematically below. The practitioner will appreciate that protecting groups may be used in these approaches. "Protecting groups", are moieties that are used to temporarily block chernical reactllon at a potentially reactive site (e.g., an amine, hydroxy, thil, eldehyde, etc.) so that a reaction can be carried out selectively at another site in a multifunctional compound. In preferred embodments, a 10 protectlng group rests seloctively In good yield to give a protected substrate that is suitable for the planned reactions; the protecting group should be selectively removable In good yIeld by readily available. preferably nontoxlc reagents that do not unduly attack the other functional groups present; the protecting group preferably forms an readily separable derivative (more preferably without the generation 61 new stereogenic centers); 15 and the protecting group preferably has a minimum of additional functionality to avoid the complication of further sites of reaction, A wide variety of protecting groups and strategies, reagents and conditions for deploying and removing them are known in the art. See, e.g., "Protective Groups In Organic SynthesIs" Third Ed. Greene, T.W. and WUits, P.G., Edo., John Wiley & Sons, New York: 1999. For additional background Information 20 on protecting group methodologies (materials, methods and strategies for protection and deprotection) and other synthetic chemistry transformations useful In producing the compounds described herein, see in R. Larock, Comprehensive organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protectlye Groups In Organic Synthesis, 3rd. Ed., John Wiley and Sons (1990); L Fleser and M. Fieser, Fesr and 25 Flesers Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ad., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995). The entire contents of these references re hereby incorporated by reference. Also, one may chose reagents enriched for a desired Isotope, e.g, deuterium in place of 30 hydrogen, to create compounds of thIs invention containing such Isotope(s). Compounds containing deuterium In place of hydrogen in one or more locations, or containing various Isotopes of C, N, P and 0, are encompassed by this invention and may be used, for instance, for studying metabolism and/or tissue distribution of the compounds or to alter the rate or path of metabolism or other aspects of biological functioning. 35 The compounds of the thIs invention can be synthesized using the methods desa-ibed below, together with synthetic methods known in the art of synthetic organic chenilstry, or by a variation thereon as appreciated by those skilled In the art. Preferred methods 22 include, but are not limited to those described below, The reactions are preformed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being elected, It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent the 5 transformations proposed. This will sometimes required some judgment to modify the order of the synthetic steps or to select one particular process scheme over anotherin order to obtain a desired compound of the invention. A compound of the present invention could be prepared as outlined in Scheme I to 10 Scheme XIX and via standard methods known to those skilled in the ar. A palladium catalyzed Sonogashire coupling reaction Is used to link the 'top' Ring T to the -bottom' [Ring AHL'HRing B] moiety as illustrated In Scheme I and II. In Scheme I the Sonogashira coupling reaction Is performed with an acetylenic 'to Ring T and a' 15 [Ring AHL'H-Rlng B] moiety which has been activated by the presence of a reactive group. W, which is an 1, a Br or another reactive group permitting the desired coupling reaction. The variables in the W-[Ring AHL'H-.IRing 0 are as defined previously, Rings A and B being substituted with permtted R" and Rt groups, respectively. Pd(Pfha T CM,. DMF, DEA, a 20 mf Scheme I: Sonogashira Coupling Reaction An alternative coupling reaction Is described in Scheme 11, in which Ring T Is "actlva0ed" by the presence of a reacive group W (such as I or Br) and Is coupled to the 'bottom' 25 acetylenic jRingA}-L-fRingBJ under similar Palladium catalyzed couplIng conditions. (A(R' Pd(P1 clA o, \\ DIA (RW (Ri)m Scheme II: Alternative Sonogashlra Coupling Reaction 23 The Sonogashira coupling conditions described In Scheme I and |1 are applicable to all bicyclic hetermaryl Ring Ts and useful to synthesize all compounds of this Invention. Severl Illustrative overall synthetic approaches to the preparation of the acelylenle Ring 5 T moieties, based on known transformations, are Illustrated below In Schemes IlII to Vill: Ha r C CH Pd (P Ph CWl, DiA, DMF H Ms Scheme III: Preparation of 3-EthynyilmIdazo[1,2-]pyamzIne 10 NN .PAPox Scheme IV: Preparation of C-8 Substituted 3-Ethynylmidawo[1.2-~pyrazIne" 15 rPdCh(Pfh,>), or Pd(PP TBAP, Br Cui, CHCN, SPC Twater, f X H orN TMs TMs Scheme V: Preparation of 3-EthynyiImIdazo[1,2-a]pyridIne or 3-Ethynylimidflo[-,2-b]pyridazine 20 24 H3 ". ACN.DIPA .B NCut, Refux. 2.A' T CP 2.,Br21 Br -1M$ dbt DMB TBAIF,THF H P- LLC vN Ms I-r MS Scheme VI; Preparation of C-S Amino Substituted 3-EthynylImidazo[1,2.aepyrIdInes Cul,CH,CN,W80C rchmo2.AH/ae Scheme Vil: Prparatlon of C-8 substituted 3..Ethynylmdazo1,2-alpyridines 10 Or Br R RX/WPA W02004026867 NHR NHR H.Pd(ph) HR N NBS A. IPA C.l, Rc~ha j CH 3 CN , r R=a2; yrl, acyl 2.BAF.THP Scheme Vill: PrpamtIon ofC-6 and C-8 Substituted 3-Ethynylimidazo [1,2-4 pyrldines. 25 For the coupling step, see Malleron, J-L., Flaud, J-C., Legros, J-Y. Handbook of Palladium Catalyzed Organic Reactions. San Diego: academic Press, 1997. As one of ordinary skill in the art would recognize, these methods for the preparation of 5 various substituted acelylenic Ring T group, are widely applicable to various other fused bicyclic ring systems not shown. Schemes IX to XIII below depict the synthesis of compounds of the fornula W-[Ring A) [L'-[Ring BI which am useful as intermediates In the coupling reaction described in 10 Schemes l and II. It should be apparent that intermediates of the formula; ()>L() are of particular interest as their coupling reaction with the 'top heteroaryl rings produces 15 compounds of the present Invention. The variable groups A, Li and B are as previously defined and are optionally substituted as described herein, and W is I or an alternative reactive group permitting the desired coupling reaction. Illustrative such intermediates include among others those of those following structures; 20 R& Rb NPR R N R~-yR R N' RbR NN wherein the previously defined variables, e.g., R0, R Re and Rd' are as previously 25 defined. For instance, Ra in Some embodiments is chosen from F or alkyl, e.g., Me, 26 among others, and Rb In some embodiments Is chosen from Cf, F. Me, t-butyl, -CF 3 or OCF 3 among others. Those and other compounds of the formula W.[Rlng AHL'-4RIng B] with the various permitted substituents are useful for preparing the corresponding compounds of the Invention as are defined In the various formulas, classes and 5 subclasses disclosed herein. Some Illustrative synthetic routes for the preparation of reagents and representative intermediates ar presented below: 10 Scheme IX describes an Illustrative synthesis of W-[Ring AHL 1 HRIng B] in which Rings A and B am phenyl and L 1 is NHC(O). H R H EVCIJHBT Scheme IX I5 Scheme X depicts the synthesis of a variant of the foregoing In which Ring B is a 2-pyridine and LI Is C(O)NH (i.e., in the other orientation). R. aNF DCM I + Scheme X 20 Schemes XI and XiI, below, Illustrate the synthesis of W-IRing AHL 1 HRng 8] In which Rings A and B are phenyl and Ring C is a heteroaryl ring. These intermediates are useful for making compounds of formula i. 25 More specifically, Scheme Xi describes the preparation of Intermedlates in which Ring C is an Imidazole ring, 27 H,. Rh DMSO O-hdrcxyquinoltlo H4.n Rb r CuXC0 3 .120 4 C + R 0 n. 1 2 Ht Scheme XI 5 Scheme Xil describes the preparation of Intermediates in which Ring 0 Is a pyrrole or an oxazvle ring,
K
2 b H tyyn .a a ta + ty& yq bl Val
-
Y A"- pat Co) Scheme XII 10 Scheme XIII illustrates the synthesis of W-IRing A-L n]Ring B] In which Rings A and B are phenyl and an R" substituent Is -L 2 -[Ring D]. These Intermediates are useful r making compounds offormula III in which Ring D Is a 5 or 6-membered heterocycle, containing one or two heteroatoms. NImmDK NN 2 151 ONDCN bflOz som byd.nte HN HcM INr Hw2 ttt Scheme XIll 28 In this scheme, non limiting examples of substituents R' on Ring B are halo, e.g., Ci; lower alkyl groups, e.g., isopropyl; and substituted lower alkyl groups, e.g. -CF 3 ; and non limiting examples of Ring D are NN-dimethylpyrrolidine, N-(2-hydroxyethyI)piperazine, and N-methylpiperazine. 5 Intermediates W-IRing AHL'I-[Ring BI, such as hose presented in thevarious synthetic schemes above, can be reacted with an acetylenic Ring T using the Sonogashira coupling conditions described In the general Scheme I. 10 An example is depicted below In Scheme XIV, in which Ring T moiety can be further derivatized after the So nogashira coupling step, to gene rate various Interesting substituted analogs of this Invention. AlternatIvely, the W-[Ring AH[L 1 JHRing B] can be reacted under Sonogashira Qonditlons with trimethyillylacetylene, prior to the coupling with an lodo- or a bromo- activated Ring T as otherwise described in the general SchemliI. 20 An example Is depioted in Scheme XV: S -5 SchemeXV 25 In other embodiments, the stops can be carried out in a different order For example, the Sonogoshira Oupling reaction can be used to Ring T to Ring A prior to linking that portion to Ring B andlor [Ring B[L h[Ri a/[ning j an or ing 0] as shown in Scheme XVL. 30 29 l7(~e T H LCulDEA~n T H + V t ]5 ~ ta ~ ~ i(I )m ( R % Scheme XVI in a non-limiting example in which Ring A and Ring B are phenyl and L'Is.CONH, 5 Scheme XVII describes Sonogashira Coupling of an acelylenic Ring T with 3-lodo-4 methylbenzoic acid (a Ring A moiety) to generate a fRIng T}-[RIng A] Intermediate which then undergoes an amide coupling with an optionally substituted Ring B moiety: (R T H 01 OuI.DWEAAemlL~tsd 10 Scheme XVII This approach Is Illustrated In Scheme XVIII which depicts the coupling of an acetylonic Ring T (i.e., 3. ethynylimidazo[1,2-b]pyridazine) with a substItuted WA-Ring A] (I.e., 3-lodo 4-methylbenzoic acid), followed by an arnide coupling of the resultant [Ring T]-Ring A] 15 GOGH Intermediate with a H 2 N-.[Rlng B}-L2-[Ring C] moiety (i.e., 4-((4-methylpiperazin 1-yl)methyl)-3-(trifluoromethylaniline). 30 - I Nd(Pm' NV., NMC4 Cul,DIEA,L CulD]EA.rt Z. TBAFOr KCO N Oxalyr Chiodide Scheme XVIII Alternatively, as another illustration of the practilloner's range of assembly options, the 3. 5 lodo-4-methylbenzolc sold Ring A intermediate can be reacted In a Sonogashirs reaction with trinethylsilylacetylene, which after silyl deprotection, can a second Sonogashira coupling reaction with an activated Ring T as Illustrated In Scheme XIX. (R(R II T H W Pd(Ph0,) CulDIEArt Pd(Pha} 0 CuI,DIEA,rt Z TSA!PrKCO, Scheme XIX 10 With synthetic approaches such as the foregoing, combined with the examples which follow, additional Information provided herein and conventional methods and materials, the practitioner can pmpare the full range of compounds disclosed herein. 15 5. Uses, Formulations, Administration Pharmaceutical Uses; indications This invention provides compounds having biological properties which make them of Interest for treating or amorliorating diseases in which kinases may be Involved, 20 symptoms ofsuch diseasO, or the effect of other physiological events mediated by kinases. For instance, a number of compounds of this Invention have been shown to inhibit tyrosine kinese activity of Sre and abi, among other tyrosine kinases which are believed to mediate the growth, development andlor metastasis of cancer. A number of 31 compounds of the Invention have also been found to possess potent in vitro activity against cancer cell lines, Including among others K-562 leukemia cells. Observed potencies have been as much as 10-fold more powerful than Ooevoc in conventional antlprollferation assays with K562 cells, 5 Such compounds are thus of interest for the treatment of cancers, Including both primary and metastatic cancers, including sold tumors as well as lymphomas and leukemias (including CML, AML and ALL), and including cancers which are resistant to other therapies, including other theraples Involving the administration of kinase inhibitors such 10 as Gleevec, Tarceva or Iressa. Such cancers include, among others, cancers of the breast, cervix, colon and rectum, lung, ovaries, pancreas, prostate, head and neck, gostroinlestinal stroma, as well as diseases such as melanoma, multiple myeloma, non-Hodgkir's lymphoma, melanoma, 15 gastric cancers and leukemia (e.g., myelold, lymphocytlo, myelocytic and lymphoblastic leukenlas) Including cases which are resistant to one or more other therapies, Including among others, Gleevec, Tarceva or fressa. Resistance to various anticancer agents can arise from one or more mutations in a 20 mediator or effector of the cancer (e.g., mutation In a kinase such as Src or Abt) which correlate with alteration In the protein's drug binding properties, phosphate binding properties, protein binding properties, autoregulatlon or other characteristics. For example, In the case of BCR-Abl, the kinase associated with chronic myeloid leukemia, resistance to Gleovec has been mapped to a varIety of BCR/Abl mutatIons which are 25 linked to a variety of functional consequences, Including arnong others, steric hindrance of drug occupancy at the kinse's active site, alteration In deformability of the phosphate bindng P loop, effects on the conformation of the activation loop surrounding the active site, and others. See ag. Shah at al, 2002, Canoer Cell 2, 117 - 125 and Azam et al, 2003, Cell 112, 831 -643 and references cited therein for representative examples of 30 such mutations in Bor/Abi which correlate with drug resistance. See also the following references for additional background information on BCR/AbI, its mechanisdo role in CML and drug-resistance-conferring mechanisms and mutations: Kurzrock et al., Philadelphia chromosome-potlive leukemlas: from basic mechanisms to molecular therapeutics, Ann Intern Med. 2003 May 20;138(10):819-3D; O'Dwyer et al., Demonstration of Philadelphia 35 chromosome negative abnormal clones in patients with chronic myelogenous leukemia during major cytogenetic responses induced by imatinib mesylate. LeukemIa. 2003 Mar; 17(3):481-7; Hochhaus et at, Molecular and chromosomal mechanIsms of resistance to imalinib (ST1571) therapy, Leukemia, 2002 Nov16(11):2190-6; O'Dwyer at al, The 32 Impact of clonal evolution on response to Imatinlb mesylate (STI571) In accelerated phase CML. Blood. 2002 Sep 1:100(5):1628-33; Braziet et a. Hematopathologic and cytogenetio findings In Imatinib mesylate-treated chronic nyelogenous leukemia patients: 14 months experience. Blood. 2002 Jul 15;100(2):435-41; Corbin et al., Analysis of the 5 Structural basis of specificity of Inhibition of the Abi kinase by ST1571. J Blol Chem. 2002 Aug 30;277(35):322149; Wertheim at al.,BCR-ABL-induced adhesion defects are tyrosine kinase4ndependent. Blood. 2002 Jun 1;99(11):4122-30; Kantarilan at a.,Hearntologio and cytogenetic responses to imetinib mesylate in chronic myelogenous leukemia, N EnIl J Med. 2002 Feb 28;346(9):645-52. Erratum In: N Engl J Med 2002 Jun 10 13;346(24):1923; Kochhaus et a., Roots of clinical resistance to STI-571 cancer therapy. Science. 2001 Sep 21:293(5538):2163; Druker et al., Activity of a specific inhibitor of the BCR-ABL tyrosine kinase In the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Mod. 2001 Apr 5;344(14):103842. Erratum In: N Engl J Med 2001 Jul 19;345(3):232; Mauro at al., 15 ChronIc myelogenous leukemia. Curr Opin Oncot, 2001 Jan;13(1):3-7, Review: Kollbabe at al., CRKL binding to BCR-ABL and BCR-ABL transformation. Leuk Lymphoma. 1999 Mar;33(1-2):119-2; Bhat at al., interactions of p62(dok) with p210(bor-abi) and Bor-Abl. associated proleins. J Bid Chem. 1998 Nov 27;273(48):32360-8; Senechal et a., Structural requirements for function of the Crkl adapter protein In fibroblasts and 20 hematopoletic cells. Mol Cell Bl. 1998 Sep;18(9): 50 82-90; Kolibaba et a., Protein tyroslne kinases and cancer. Blochim Blophys Acts. 1997 Dec 9;1333(3):F2174B. Review; Heaney et al.. Direct binding of CRKL to BCR-ABL is not required for BCR-ABL transformation. Blood. 1997 Jan 1;89(1);297-306; Hallek et al., interaction of the receptor tyrosine kinaso p14bo-kit with the p2lObcr/abl kInase In myelold cells. Br J Haematol. 25 1996 Jul;94(1):5-16; Ode at at, The SH2 domain of ABL is not required for Factor Independent growth induced by BCR-ABL In a murine myelold cell line. Leukemia. 1995 Feb;9(2):295-301; Carlesso at al., Use of a temperature-sensltive mutant to define the biological effects of the p210BCR-ABL tyroslne kinase on proliferation of a factor dependent murine myelold cell line. Onoogene. 1994 Jan; 9(1):149-56. 30 Again, we contemplate thatcompounds of this Invention, both as monotheraples and In combination therapies, will be useful against leukemlas and other cancers, including those which are resistant In whole or part to olher anticancer agents, specifically including Gleevec and other kinase Inhibitors, and specifically including leukemias involving one or 35 more mutations in BCR/Abl, within or outside the kinese domain, Including but not limited to those noted in any of the foregoing publications. See in particular Azan at a. and references cited therein for examples of such mutations in BCR/AbI, Including, among others, mutations In the drug binding cleft, the phosphate binding P loop, the activation 33 loop, the conserved VAVK of the kinase beta-3 sheet, the catalytic alpha-I helix of the small N lobe, the long alpha.3 helix within the large C lobe, and the region within the C lobe downstream of the activation loop. 5 Pharmeceuthcal Methods The method of the Invention comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the invention, A "therapeutically effective amount' is that amount effective for detectable killing or 10 inhibition of the growth or spread of cancer cells; the size or number of tumors; or other measure of the level, stage, progression or severity of the cancer. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, ihe severity of the disease, the particular anticancer agent, Its mode of administration, combination treatment with other therapies, and the like. 15 The compound, or a comporitlon containing the compound. may be adinistered using any amount and any route of administration effective for killing or inhibiting the growth of tumors or other forms of cancer. The anticancer compounds of the invention are preferably formulated in dosage unit form for 20 ease of administration and uniformly of dosage. The expression "dosage unit fornf as used herein refers to a physically discrete unit of anticancer agent appropriate for the patient to be treated. As Is normally the case, the total daly usage of the compounds and compositions of the present Invention will be decided by the attending physician using routine reliance upon sound medical judgment The specific therapeutloally effective dose level for any particular 25 patient or organism will depend upon a variety of factors Including the disorder being treated; lhe severity of the disorder; the potency of the specific compound employed the specific composition employed; the age, body weight, general health, sex and diet of the patient; the route and schedule of administration; the rate of metabollam and/or excretion of the compound; the duration of the treatment; drugs used In combination or colncident with 30 administration of the compound of this Invention; and like factors well known in the medical arts. Furthermore, after formulation with an appropriate pharmaceutically acceptable carrier in a desired dosage, the compositions of this invention can be administered to humans and other 35 animals orally, rectally, parenterally, Intracdsternay, Intrevaginalty, intraperitoneally, topically (as by transdermal patch, powders, ointments, or drops), subfingually, buclly, as an oral or nasal spray, or the like. 34 The effective systemic dose of the compound will typically be In the range of 0.01 to 600 mg of compound per kg of patient body weight, preferably 0.1 to 126 mg/kg, and In some cases I to 25 mgkg, administered In single or multiple doses. Generally, the compound may be administered to patients In need of such treatment in a daily dose range of about 50 to about S 2000 mg per patient Administration may be once or multiple times daily, weekly (or at some other multiple-day Interval) or on an Intermittent schedule. For example, the compound may be adminietered one or more times per day on a weekly basis (e.g. every Monday) Indefinitely or for a period of weeks, e.g. 4 - 10 weeks. Alternatively, it may be administered daily for a period of days (eg. 2 - 10 days) followed by a period of days (e.g. 1 - 3o days) without 10 administration of the compound, with that cycle repeated Indefinitely or for a given number of repitfions, e.g. 4 -10 cycles. As an example, a compound of the invention may be administered daily for 5 days, then discontinued for 9 days, then administered daly for another 5 day period, then discontinued for 9 day, and so on, repeating the cycle Indefinitely, or for a total of 4 - 10 times. 15 The amount of compound which will be effective in the treatment or prevention of a particular disorder or condition wil depend in part on welt known factors affecting drug dosage. In addition, In vitro or In vive assays may optionally be employed to help IdentIfy optimal dosage ranges. A rough guide to effective doses may be extrapolated from dose-response curves 20 derived from in vitro or animal model test systems. The precise dosage level should be determined by the attending physician or other health care provider and will depend upon well known factors, including route of administration, and the age, body weight, sex and general health of the individual; the nature, severity and clinical stage of the disease; the use (or not) of concomitant therapies; and the nature and extent of genetlo engineering of cella in the patient. 25 When administered for the treatment or inhibition of a particular disease slate or disorder, the effective dosage of the compound of this invention may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the IndMdiual being 30 treated. in many cases, satisfactory results may be obtained when the compound Is administered In a daily dosage of from about 0,01 mg/kg-500 mgAkg, preferably between 0.1 and 125 mglkg, and more preferably between 1 and 25 mg/kg. The projected daily dosage are expected to very with route of administrator. Thus. parenteral dosing will often be at levels of roughly 10% to 20% of oral dosing levels, 35 When the compound of this invention is used as part of a combination regimen, dosages of each of the components of the combination are administered during a desired treatment period. The components' of the combination may administered at the same time; either as a 35 unitary dosage form containing both components, or as separate dosage units; the components of the combination can also be administered at different times during a treatment period, or one may be administered as a pretreatment for the other. 5 RegardJing the Compounds Compounds of present invention can exist In free form for treatment, or where . appropriate, as a pharmaceutically acceptable at or other derivative. As used herein, the tern "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and 10 lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/rlsk ratio, Pharmaceutcally acceptable salts of mines, carboxylio acids, phosphonates and other types of compounds, are well known in the art. For example, S. M. Berge, et at. decrbe pharmaceutically acceptable salts in detall in J. Pharmaceutiosl Sciences, 66:1-19 (1977). incorporated herein by reference. 15 The salts can be prepared in situ during the Isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid of a compound of the Invention with a suitable base or acid, respectively. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amnio group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric mcid, sulfuric acid and 20 perchloric acid or with organic acids such as acetic acid, oxalic acid, malelo acid, tartarlc acid, citric acid, succinic add or malonic acid or by using other methods used In the at such as ion exchange. Other pharmaceutically acceptable salted include adipate, adginate, sscorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonale, citrate, cyclopentaneproplonate, digluconate, 25 dodocylsulfate, ethenesulfonate, formate, tumor.ate, glucoheptonate, glycerophosphate, gluconate, hernisuflate, heptancatu, hexanoate, hydrolodide, 2-hydroxy-othanesulfonate, lactoblonate, lactate, laureate, leuryl sulfate, malate. maleate, malonate, methane aulfonate, 2-naphihalenesuifonate, nicolinate, nitrate, dlate, oxlate. palmitate, pamoate, pectinate, persulate, 3-phonylpropionate, phosphate, picrate, pivalate, propionate, 30 stearate, succinate, sulfate, tartrate, thicoyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts Include sodium, lithium, potassium, calcium, magnesium. and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine catons formed using counterlons such as hallde, hydroxide, carboxylate, 35 sulfate. phosphate, nitrate, loweralkyl sulfonete and aryl sulfonate. Additionly, as used heroin, the term "pharmaceutically acceptable ester refers preferably to esers which hydrolyze In vivo and include those that break down readily in 36 the human body to leave the parent compound or a salt thereof. suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxyjic acids, particularly alkanolo, aikenoic, cycloalkanoic and alkanedlolo acids, in which each alkyl or alkenyl molety advantageously has not more than 6 carbon atoms. Examples of 5 particular esters include formates, acetates, proplonates. butyrates, atrylates and ethylouccinatee. Obviously, esters een be formed with a hydroxyl or carboxylic acid group ofthe compound of the Invention. Furthermore, the term pharmaceuticallyy acceptable prodrug" as used h erein refers to 10 those prodrugs of the compounds of the present Invention which are, within the scope of sound medical judgment, suitable for use In contact with the tissues of humans and lower animals with undue toxioity, Irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their Intended use, as well as the zwltterionic frms, where possible, of the compounds of the Invention. The term "prodrug" 15 refers to compounds that are transformed in viva to yield the parent compound of the above formula, for example by hydrolysis In blood. See, eg., T. Hlguchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and Edward B. Roche, ed., Bloreversible Cardners in Drug Design, American Pharmaceutical Assocn. and Pergamon Press, 1987, both of which are incorporated herein by reference. 20 Compositions Composillons are provided which comprise any one of the compounds described herein (or a prodrug, pharmaceutloally acceptable salt or other pharmaceutically acceptable derivative thereof), and one or more pharmaceutically acceptable carriers or exciplents. 25 These compositions optionally further comprise one Or more additional therapeutic agents. Alternatively, a compound of this Invention may be administered to a patient In need thereof in combination with the administration of one or more other therapeutic regimens (e.g. Gleevec or other kinase Inhlbitors. interferon, bone marrow transplant, farnesyl transferase inhibitors, bisphosphonates, thalldonide, cancer vaccines, hormonal 30 therapy. antibodiesradlation, eto). For example, additional therapeutic agents for conjoint administration af inclusion in a pharmaceutical composition with a compound of this invention may be another one or more anticancer agents. As described herein, the compositions of the present invention comprise a compound of 35 the invention together with a pharmaceutically acceptable carrier, w hich, as used herein, includes any and all solvents, diluents, or other vehicle, dispersion or suspension aids. surface active agents, Isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. 37 Remington's Pharmaceutical Sciences, Fifteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1975) discloses various carriers used In formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium Is incompatible with the compounds of the Invention, such as 5 by producing any undesirable biological effect or otherwise Interacting In a deleterious manner with any other components) of the pharmaceutical composition, its use is contemplated to be within the scope of this Inventlon. Some examples of materials which can serve as pharmaceutloally acceptable carriers Include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; 10 cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc: exciplenis such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower'oll; sesame oil; olive oil; corn oil and soybean oil; glycols; sudi a propylene glycol; esters such as ethyl aleate and ethyl iaurate agar; buffering agents such as magnesium 15 hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; Isotonic saline; Ringers solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, eating agents, sweetening, flavoring and perfuming agents. preservatives and antloxidants can also be present in the composition. 20 Formulations This invention also encompasses a class of compositions comprising the active compounds of this Invention In association with one or more pharmaceutlcally-soceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as carrierr' 25 materials) and, if desired. other active Ingredients. The activecompounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical compositlcn adapted to such a route, and In a dose effective for the treatment intended, The compounds and compositions of the present Invention may, for example, be administered orally. mucosally. typically, rectally, pulmonarly such as by 30 inhalation spray, or parentally Including Intravascularly. Intravenously, intraperitoneally, subcutaneously, intramuscularly, intrastemally and infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. 35 The pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals. 38 For oral administration, the pharmaceutical composition may be In the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the farm of a dosage unit contalhing a particular amount of the active Ingredient. 5 Examples of such dosage units ae tablets or capsules. For example, these may contain an amount of active Ingredient from about I to 2000 mg, preferably from about I to 500 mg, more commonly from about 5 to 200 mg. A suitable daily dose for a human or other mammal may vary depending on the condition of the patient and other factors, but, once 10 again, can be determined using routine methods. The amount of compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this Invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the 15 type of disease, the severity of the disease, the route and frequency of adminisntaflon, and the particular compound employed. Thus, the dosage regimen may vary widely, but an be determined routinely using standard methods. A typical daily dose Is in the range of 0.01 to 500 mg of compound per kg body weight, preferably between 0.1 and 125 mgkg body weight and in sorne cases between 1 and 25 mglkg body weight. As 20 mentioned previously, the daily dose can be given in one administration or may be divided between 2. 3, 4 or more administrations. For therapeutic purposes, the active compounds of tis invention are ordinarily combined with one or more adjuvants, excipients or carriers appropriate to the indicated route of 25 administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder. cellulose esters of alkanoic acids, cellulose alkyl enters, talc. stearic acid, magnesium stearao, magnesium oxide, sodlurn and calcium salts of phosphoric and sulfuric alks, gelatin, acacla gum, sodium alginate, polyvlnylpyrrotidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. 30 Such capsules or tablets may contain a controlled-release formulation as may be provided In a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of skin conditions, It may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day. Formulations suitable for topical administration Include liquid or sem-liquid preparations 35 suitable for penetration through the sin (e.g., liniments, ilons, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose. A suitable topical dose of active ingredient of a compound of the invention is 0.1 mg to 150 mg administered one to four, preferably one or two times daily. For topical administration, the 39 active ingredient may comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w/w, but preferably not more than 5% w/w, and more preferably from 0.1% to 1% of the formulation. 5 When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-misclble ointment base. Alternatively, the active ingredients may be formulated in a cream with an on-i-water cream base. If desired, the aqueous phase of the cream base may Include, for example at Least 30% wA of a polyhydric alcohol such as propylene glycl, butane-1,3-dlol, mannitol, sorbilol, glycerol, polyethylene glycol and 10 mbdures thereof. The topical formulation may desirably Include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. 15 The compounds of this Invention can also be administered by a transdermal device. Preferably transdermal ad ministration will be accomplished using a patch either of the reservoir and porous membrane type or of a sold matrix variety. in either case, the active agent I delivered - continuously from the reservoir or microcepsules th rough a membrane Into the active agent permeable adhesive, which Is in contact with the skin or 20 mucosa of the recipient If the active agent Is absorbed through the skin, a controlled and predetermined flow of the active agent is admInistered to the recipIent. In the case of microcapsules, the encapsulating agent may also function as the membrane. The oIly phase of the emulsions of this invention may be constituted from known Ingredients In a known manner. 25 Whle the phase may comprise merely an emulsifier, It may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a Ilpophillo emulsifier which acts as a stabIlizer, It is also preferred to include both an oil and a fat. Together, the emullfier(s) with or without 30 stabilizer(s) make-up the socalled emulsifying wax, and the wax together with the oIl and fat make up the so-called emulsifying ointment base which forms the oily dispered phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present InventIon include Twoeen 60, Span 80, cotostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or 35 with a was, or other materials wail known In the art The choice of suitable oils or fats for the formulation In based on achieving the desired cosmetic properties, since the solubilty of the active compound in most oils likely to be 40 used in pharmaceutical emulsion formulations Is very low. Thus, the cream should preferably be a non-greasy, non-slalning and washable productwith suitable consistency to avoid leakage from tubes or other containers, Straight or branched chain, mono- or dibaslc alkyl enters such as dl-Isoadipate, Isocatyl stearate, propylene glycol diester of 5 coconut fatty acids, Isopropyl myristote, decyl oleate, sopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain easters may be used, These may be used alone or in combinaion depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or 10 other mineral oils can be used. Formulations suitable for topical administration to the eye also Include eye drops wherein the active Ingredients are dissolved or suspended In suitable carrier, especally an aqueous solvent for the active ingredients. 15 The active Ingredients are preferably present in such formulations in a concentration of 0.8 to 20%, advantageously 0.5 to 10% and partIcularly about 1.5% wh. Formulations for parenteral administration may be In the form of aqueous or non-aqueous isotonic sterle Injection solutions or suspensions. These solutions and suspensions may 20 be prepared from sterile powders or granules using one or more of the careers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved In water, polyethylene glycol, propylene glycol, ethanol, com oil, cottonseed oil, peanut off, sesame oli, benzyl alcohol, sodium chloride, tragacanth gum, andlor various buflers. 25 Other aduvants and modes of adminletration are well and widely known in the pharmaceutical arl. The active Ingredient may also be administered by Injection as a composition with suitable canters Including saline, dextrose, or water, or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e. propylene glycol) or micellor solubtilzation (i.e. Tween 80). 30 The sterile Injeotable preparation may also be a sterile injectable solution or suspension In a non-toxic parenterally acceptable diluent or solvent, for example as a solution In 1,3 butanedll. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and Isctonic sodium chloride solution. In addition, sterile, fixed 35 oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acIds such as olelo acid find use In the preparation of injectables. 41 For pulmonary adminIstralon, the pharmaceutical composition may be administered in the form of an aerosol or with an inhaler Including dry powder aerosol. Suppositories for rectal administration of the drug can be prepared by mixing the drug 5 with a suitable nonfrritating exoipient such as cocoa butter and polyethylene glycols that aee solid at ordinary temperatures but liquid at the rectal temperature and will therefore mall In the rectum and release the drug. The pharmaceutical compositions may be subjected to conventional pharmaceutical 10 operations such as sterillzation and/or may contain conventional adjuvants, such as preservalves, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, Sweetening, flavorIng, and perfuming agents. Pharmaceulcal compositions of this invention comprise a compound of the form ulas 15 described herein or a pharmaceutically acceptable salt thereof an additional agent selected from a kinaso inhibitory agent (small moteule, polypeptde, antibody, etc.), an Immunosuppressant, an anticancer agent, an ant-viral agent, antilnflammalory agent, antifungal agent antibiotIc, or an anti-vascular hyperproliferatlon compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle. 20 Alternate compositions of this Invenuon comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutcally acceptable carrier, adjuvant or vehicle. Such compositions may optionally comprise one or mole additional therapeutic agents, Including, for example, kinase inhibitory agents (small 25 molecule, polypeptide, antibody, etc.), Immunosuppressants, ant-cancer agents, anti-viral agents, anllinflarmatory agents, antifungal agents, antibiotics, or antI-vascular hyperprollferation compounds. The term "pharmaceutically acceptable carder or adjuvant' refers to a carrier or adjuvant 30 that may be administered to a patient together with a compound of this invention, and which does not destroy the pharmacological activity thereof and Is nontodc when administered in doses sufficlent to deliver a therapeutic amount of the compound. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be usod in the pharmaceutical com positions of this invention Include, but are not limited to. Ion 35 exchangers, alumina, aluminum Stearate, lecithin, selfemulsifying drug delivery systems (SEDDS) such as d-otocopherol polyethyleneglycol 1 000 succlnate, surfactants used In pharmaceutical dosage torms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances Such as 42 phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, Baits or electrolytes, such as protarnine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium triallicate, polyvinyl pyrroldone, cellulose-based 5 substances, polyethylene glycol, sodium carboxymethycellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrina such as u-, P-, and y-cyclodexbrin, or chemically modified dedvalives such as hydroxyakylcyclodextrin., including 2and 3-hydroxypropyl-cyclodextrIns, or other solubilized derivativos may also be advantageously used to enhance delivery of 10 compounds of the formulae described herein. The pharmaceutical compollons may be orally administered in any orally acceptable dosage form Including. but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which 15 aem commonly used include lactose and com stench. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents Include lactose and dried corn stamh. When aqueous suspensions andfor emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase Is combined with emulsifying endfor suspending agents. 20 If desired, certain sweetening. flavoring andfor coloring agents may be added. The pharmaceutical compositions may comprise formulations utilizing ilposome or microencapsulation techniques, various examples of which are known In the rt, 25 The pharmaceutical compositions may be administered by naal aerosol r Inhoalton. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bloavaltablNty. fluorocarbons, ando other sokbliing or dispersing agents, examples of which are also 30 wellknownIn heart Combinations While the compounds of the Invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more olher 35 compounds ofthe Invention or with one or more other agents, When administered as a combinallon, the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition. 43 The phrase "combination therapy", In referring to the use of a compound of this Invention together with another pharmaceutical agent, means the coadministration of each agent In a substantially simultaneous manner as well as the administration of each agent In a sequential manner, in either case, in a regimen that will provide beneficial effects of the 5 drug combination. Coadministration Includes inter alsa the simultaneous delivery, e.g., In a single tablet, capsule, injection or other dosage fam having a flxed ratio of these active agents, as well as the simultaneous delivery In multiple, separate dosage frms for each agent respectively. 10 Thus, the administration of compounds of the present invention may be In conjunction with additional therapies known to those skilled in the art In the prevention or treatment of cancer, such as radiation therapy or cytostalic agents, cytotoxIc agents. other enti-canoer agents and other drugs to amerilorate symptoms of the cancer or side effects of any of the drugs . I5 If formulated as a fixed dose, such combination products employ the compounds of this Inventionwithin the accepted dosage ranges. Compounds of this Invention may also be administered sequentially with other anticancer or cyto4oxic agents when a combination formulation Is inappropriate. The Invention Is not limited In the sequence of administration; 20 compounds of this invention may be administered prior to, simulateously with, or after administration of the other anticancer or cytotoxic agent. Currently, standard treatment of primary tumors consists of surgical excision, when appropriate, followed by either radiation or chemotherapy, and typically administered 25 Intravenously (1V. The typical chemnotherapy regime consists of either DNA alkylating agents, DNA Intercalating agents, CDK inhibitors, or microtubule poisons. The chemotherapy doses used are just below the maximal tolerated dose and therefore dose limiting toxicitles typically Include, nausea, vomiting, diarrhea, hair loss, neutropenia and the like. 30 There are large numbers of antineoplastic agents available in commercial use, in clinical evaluaton and In pre-clinical development, which would be selected for treatment of cancer by combination drug chemotherapy. And there are several major categories of such antineoplastic agents, namely, aniblotic-type agents, aikylating agents, 35 antimetabollte agents, hormonal agents, immunological agents, Interferon-type agents and a category of miscellaneous agents. 44 A first family of antineoplastic agents which may be used In combination with compounds of the present invention includes antimetabolite-type/thymidilate synthase Inhibitor antineoplastlo agents. Suitable anlimetabollte antineoplastlic agents may be selected fRom but not limited to the group consisting of -PU-fibrinogen, acanthifolic acid, 5 aminothiodlazole, brequinar sodium, carnofur, ClbaGeigy CGP-30894, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lily DATHF, Merrel Dow DDFC, dezaguantne, dideoxycytlidine, dideoxyguanosine, dido=, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-01 5, fazarabine, floxuridine, fludarabine phosphate, filuorouracil, N-(21-furanidyl) fluorouracil, Dalichl Seiyaku FO-152, Isopropyl 10 pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobeansprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NC NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, pirItrexlm, plicamycin, Asahi Chemical PL-AC, Takeda TAC788, hloguanine, tiazofurin, Erbamont TIF, trimeirexate, tyrosine kinase inhibitors, Talho UFT and uricytin. 15 A second family of antineoplastic agents which may be used in combination with compounds of the present Invention consists of alkylatlng-type antineoplastic agents. Suitable alkylating-type antineoplastio agents may be selected from but not limited to the group consisting of Shionogi 264-S, aldo-phosphamide analogues, altrelamine, 20 anaxlrone, Boahringer Mannhelm BBR-2207, bestrabucl, budotliane, Wakunags CA-102, carbopatin, carmustine, Chiroin-139, Chinoin-163, chlorambucli, cisplatin, cyclophosphamide, Amerloan Cyanamid CL-286558, SanoiR CY-233, cyplatote, Degussa D 384, Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum cytostalc, Erba distamycin derivatives, Chugal DWA-2114R, ITI E09, elmustine Erbamont FCE-24517, 25 estranustine phosphate sodilum, fotemuotine, Unimed G M, Chinoin GYKi-17230, hepsulfam, ifosfamide, Iproplatin, lomustine, mefosfamlde, mitolactolf Nippon Kayaku NK 121, NCI NSC-264395, NCI NSC-342215, oxatiplatin, Upjohn PCNU, prednimustne, Proter PTIT-119, ranimusflne, semusine, SmithKlIln SK&F-101772, Yakult Honsha SN 22, spiromus-tine, Tanabe Selyaku TA-077, teuromustine, temozolomide, temxurone, 30 tetraplatin and rimetamol. A third family of anineoplastic agents which may be used in combination with compounds of the present invention consists of antibloo-type antineoplastic agents. Suitable antiblotlc-type anineoplastic agents may be selected from but not limited to the group 35 consisting ofTalho4181-A, aclarubicin, actinomycin D, sctlinoplanone. Erbamont ADR 456, aeroplysinin derivative, AlInomoto AN 1I, Ajinomoto ANS, NIppon Soda anisomycins, anthracycline, osino-mydn-A, bilucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY 28067, Bristol-Myers BNY-25551, Bristol-Myers BNY-266051BristolMyers BNY-27557, 45 Bristol-Myers BMY-28438, bleomyoln sulfate, bryosttin-1, Talho C-1027, calichemnyoin, ohromoxmyon, dactinomycin, dauiorublain, Kyowa Hakko DC-102, Kyowa Hakko DC, 79, Kyowa Hakko DC-88A, Kyowa Hakko, DOC8-Al, Kyowa Hakko DC92-6, ditrisarubicin B, Shionogi DOB-41, doxorublotn. doxorubloin-fibrinogen, elsmlioln-A. epirubleIn, 5 erbatatin, esorublin, esperamicln-AI, esperamicin-Alb, Erbamont FCE21 954, Fujisawa FK-973, fostriecin, Fullsowa FR-900482, glidobacfn, gregatin-A, grincamycin, herbimycin, Idarublcin. Illudins, kazusamycin, kesarirhodins, Kyowa Hakko KM-5639, Kin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko Kr-5594, Kyowo Hakko KT-6149. American Cyanamid LL~D49194, Meiji Selk ME 2303, menogarfl, nitomycin, 10 miltoantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313. Nippon Kayaku NKT-01, SRI Intomational NSO-357704, oxalysine, oxaunonyoln, peplomycin, pliatin, pirarubioIn, porothromycin, pyrindanycin A, Tobishi RA-, rapamycin, rhizoxin, rodorubicin. . sibenomiln, siwenmyoln, Sumitomo SM5B87, Snow Brand SN-708, Snow Brand SN-07, oorangicin-A, sparsomyoln. SS Pharmaceutical SS-21020, 8 Pharmacautloal SS-7313B, 15 SS Phamnaceutica 68-98168, stoffimycin B, Tatho 4181-2, talisomyoln, Takeda TAN 868A, terpentecin, thrazine, trlcrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3406, Yoshitomi Y-25024 and zorubloin. A fourth family of antfneoplastic agents which may be used in combination with 20 compounds of the present invention consists of a miscellaneous family of antineoplesuc agents, including tubulin Interaoting agents, topoisomerase It Inhibitors, topoisomrasee I Inhibitors and hormonal agents, selected from but not limited to the group consisting of (xcarotene, (X-dlluoromethyl-arginine, acitretin, Blotec AD-5, Kyorin AHC-52, alsronine, amonaide, amphothinile, amsorne, Anglostat, ankinorycin, anti-neoplaston Al 0, 25 antineoplaston A2, antineoplaston A3, antlneoplaston AS. antineoplaston AS2-1F Henkel APD, aphidicolln glycinale, asparaglnase, AvorMl, baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-2301 5, blsantrene, BristoMyers BNY-40481, Vestar boron-10, bromofosfamide, Wellcome BW-502, Wellcome BW-773, caracemide, oarmethlzole hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Cheres CHX-2053, 30 Chomex CHX-i00, Warner-Lambert CI-921, WamerLambert 01-937, Warner-Lambert Cl 941, Warner-Lambert C1958, clanfenur, clavirldenone, ION compound 1259, ION compound 4711, Contracan, Yakult Honsha CPT-I,1 crianatol, curaderm, cytochalsin B, cyterabine, cytocytin. Merz D-609, DABIS mateote, dacarbazine, datelliptinium, didemnin B, dlhaenatoporphyrIn other, dihydrolnperone. dinaline, distamycin, Toyo Pharmar DM 35 341, Toyo Pharmar DM-75, Dallchi Seiyaku DN-993, docetoxel elliprabin, elliptinium acetate, Tsumura EPMTC, the epothllones, ergotamine, toposide, eretinate, fenretinide. Fujisawa FR-57704t gallium nitrate, genkwadaphnin, Chugal GLA-43, Glaxo GR-63178. grifolon NMF5N, hexadecylphosphooholine, Green Cross HO-221, homoharringtonine, 46 hydroxyurea, BTG ICRF-187, Ilmofosine, isoglutamine, Isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, Anerloan Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU 1121 Lilly LY-186641, NCI (US) MAP, maryoin, Marrs1 Dow MDL-27048, Medco MEDR-340, merborone, merocyanine 5 derivatives, methylanillnoacrldine, Molecular Genetics MGI136, minactivin, mitonafide, miloquidone mopidamnol, motetnldA Zenyaku Kogyo MST-16, N(retlnoyl)omino acids, Nisshin Flour Milling N-021, N-acylated-dehydrolanines, nafazatrom, Taisho NCU-190, nocodazole derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC 604782, NCI NSC-98580, ocrotlde, Ono ONO-1 12, oquizanocine, Akzo Org-101 72, 10 paclitaxel, pancratistatln, pazelliptine, Warnerambert PD-I 11707, Warner-Lambert PD 116934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhoematoporphyrn, polyprelo acid, Efamal porphyrin, probimane, procarbezIno, proglumide, Invitron protease nexin I, Tobishl RA-700, razoxane, Sapporo Brewerles RBS, resrriofn-P, retellptine, retinoic acid, Rhcne-Poulenc RP-49532, Rhone IS Poulenc RP-56976, SmItIKline SK&F-104864, Sumitomo SM-108, Kurarsy SMANCS, SePharm SP10094, spetl, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldlone, Suntory SUN 0237, Suntory SUN 2071, superoxide dlsmutase, Toyama T-506, Toyama T-680, taxol, Tein TEI-0303, teniposide, thallblastile, Eastman Kodak TJB-29, tocotrienol, lopotecan, Toposin, Tobin 20 TT82. Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB 006, vinblastine sulfate, vincristine, vindesIne, vinestranide, vinorelbine, vintriptol, vinzolidine, withanoldes and Yamaroucil YM Alternatively, the present compounds may also be used in co-theraples with other anti-neoplastic agents, such as acemannan, actarubicin, oldesleukin, alemiuzumab, illtretinoin, altretamine, amifostine, aminolevullnic 25 acid, amrubicin, amsecrine, anagrelde, snastrozoe, ANCER, ancestim. ARGLABIN. asenlo trioxide, 8AM 002 (Novelos), bexarotene, bicalutamido, broxuridine, capecitabine, calmoleukin, cetrorelix, cladribine, clotrimaZol. cytarabine ofosiate, DA 3030 (DongA), dscilIumab, denileukin diftitox, desiorelln, dexrazoxane, dilazop, docetaxel. docosnol, doxercalciferol, doxituridine, doxorubicin, bromocriptine, carmustine, cytarebine, 30 fluorouracil, HIT diclofenac, Interferon slit, daunorubicin, doxorubioin. tretinoin, edelfosine. edrecolomab effornithine, emitefur. epirubln, epooin bela, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formeslane. folemustne, gallium nitrate, gemoltablne, gemtuzumab rogamicin, glmeracilloterocilitegafur combination, glycopine, goserelin, heptaplatin, 35 human chodonlo gonadotropin, human fetal alpha fotoprobin, ibandronlO acid, Idrubicin, (Imiquinod, Interferon alfa, interferon alfa, natural, interferon alfa-2, inierferon alfa-2a, Interferon alfa-2b, Interferon alfa-NI, Interferon elfa-n3, interferon alfaconi, Interferon alpha, natural, Interferon bete, interferon beta-la, Interferon beta-Ib, Interferon gamma, 47 natural Interferon gamma-la, interferon gamma-lb, interledin- beta, lobenguane, irinotecan, Irsogladine, Ianreotide, LC 9018 (Yakult), leflunormido, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorolin, levamisole + fluorouraollt tiarozole; ohaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metocopromide, 5 milepristone, mlltefoasine, mirimostim, mismatched double stranded RNA, miloguazone, mitolactol, mitoxantrone, moigramostlm, nafarelin, neloxone + pentazodne, nartograstim, nedaplatin, nllutamide, noscepine, novel erythropoieel. stimulating protein, NBC 631570 octreoilde, oprelvekin, osaerone, oxalplatin, paditaxel, pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan polysuilate sodium, pentostatin, picibanil, pirarubicin, 10 rabbit anlthymocyte polyclonal antibody, polyethylene glycol Interferon alfa-2a, porfimer sodium, raloxifene, raftitrexed, rasburicase, rhenium Re 18 etidronate, Ril reunamide, rituximab, romurtide. samarium (153 Sm) teddronam, sargramostlm, szofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfln, temozolomide, teniposide, tetrachlorodeoaoxide, thalidomide, thymairasin, 15 thyrotropin alfa, topoleoan, toremifene, tosltumomab-lodine 131, trastuzumab, treasuilfn, tretinoin, Irilostane, trimetrexate. triptorelin, tumor necrosis factor? alpha, natural, ubenimex, bladder cancer vaccine, Maruyama. vaccine, melanoma lysate vaccine, valrubicin, verteporfln, vinorelbine, VIRULIZIN, zinostatin stimalamer, orzoledronlu acid; abarelix; AE 941 (Aeterma), ambamustine, antisense ollgonucleotide, bel-2 (Genta), APC 20 8015 (Dendreon), cetuximoab, decitabine, dexarninoglutethimide, dlazquone, EL 532 (Elan), EM 800 (Endorecherche), enfluracil, etanidazole, anrelfnidel flgreetim SD01 (Amgen). fulvestrant, galocitabine, gastrin 17 Immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony stimulating factor, histamine dlhydrochloride, ibritumomob tiuxetan, liomastat, IM 862 (Cytran), Interleukin lproxifene, LDI 200 25 (Milkhaus), Ieridlatim, lintuzumab, CA 125 MAD (Blomira), cancer MAD (Japan Pharmaceutica Development). HER-2 and Fc MAb (Mdaemx), Idiotypic IOSAD7 MAb (CRC Technology), Idlotyplc CEA MAb (Trilex), LYM Iodine 131 MAb (Techniclone), polymorphic epithelial mucin-yttrlum 90 MAb (Antisoma), marimostat, menogarli, mitumomeb, motexafin, gadolinium, MX 5 (Galdemna), nelarabine, nolatrexed, P 30 30 protein, pegvisomant, pemetrexed, porfiromycIn, prinomastat, RL 0903 (Shire), rubftecan, satraplatin, sodium phenylacetate, sparfoslc sold, SRL 172 (SR Pharma), SU 5418 (SUGEN)y SU 6668 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoletin, tin ethyl etiopurpurin, tlrapazamine, cancer vaccine (Biomira). melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma 35 onoolysote vaccine (NOw York Medical College), viral melanoma celt lysales vaccine (Royal Newcastle Hospital), or valspodar. 48 Treatant Kfs In other embodiments, the present Invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention. In general, the pharmaceutIcal pack or kit comprises one or more containers filled with one or more 5 of the Ingredients of the pharmaceutical compositions of the invention. Such kits are especially suited for the delivery of solid oral forms such as tables or capsules. Such a kit preferably includes a number of unit doeages, and may also include a card having the dosages oriented In the order of their Intended use. If desred, a memory aid can be provided, for example, in the form of numbers, letters, or other markings or with a calendar 10 insert designating the days In the Imatment schedule in which the dosages can be administered. Optionally associated with such contalner(s) can be a notice In the form prescribed by a governmental agency regulating the manufacture, use or Sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration, 15 The following representative examples contain Important additional information, exemplification and guidance which can be adapted to the practIce of this invention in its various embodiments and the equivalents thereof. These examples are intended to help Illustrate the invention, aid are not intended to, nor should they be construed to, limit its 20 scope. Indeed, various modifications of the Invention, and many further embodiments thereof, In addition to those shown and descrbed herein, will become apparent to those skilled in the art upon review of this document, Including the examples which follow and the references to the scientific and patent literature cited herein. The contents of those cited references are Incorporated herein by reference to hep Illustrate the state of the art 25 In addition, for purposes of this Invention, the chemical elements are identified in accordance with the Periodic Table of the Elements. CAS version, Handbook of Chemistry and Phyaics, 75 th Ed., Inside cover. Additonally, general principles of organic chemlisky. as well as specific functional maletes and reactMity, are described in "Organic Chemistry', Thomas Sorrell, University Solence Books, Sausallto: 1999, and 'Organic 30 Chemistry", Morrison & Boyd (3d Ed), the entire contents of both of which are Incorporated herein by reference. 49 Examples Some of the compounds desribed in the following examples have been converted Into an HCI small. The general procedure for generating HCI sat Is described below: 5 To the final product was added just enough MeOH saturated with HCI (g) to dissolve, cooled to 0 C for 0.5-1 h, filtered, washed solid with loe cold MeH then Et 2 0, and the resulting solid dried In a vacuum desiccator to provide in most cases the tris HCI salt. EXAMPLE I 10 N-(3-('lH-imidarol-1-yl)-S-(trifluoromethyl)phonyl)-3-(midazo[1,2-a]py razin-3-yiethynyl) 4-methylbenzamido N CrC NN 105 Imidazo[1,2-aJpyr=ain.: A solution of aminopyrazine (1 g. 10.5 mmol) and chloroacetaldehyde (60% wt in HO; 1.98 9, 12.6 mm ol) in 1.6 mL of EtH was heated at 90'C in a sealed tube for 5 h. Upon codling to ambient temperature, the reaction mixture was concentrated and diluted with dchloromethane (DOCM). The organic layer washed with 20 saturated aqueous NaHC03then dried over MgSO 4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 10% MeOH/DCM) to provide 0.8 g of product. 34(TdrmelhylsilylethynyI)1mIdazo12-aJpyrazIne: A mixture of 3 25 bromoimidazo[1,2-sapyradne (0.15 g, 0.7B mmol; prepared according to J. Bradaoc, et at. J. Org. Chem. (1977), 42, 4197 - 4201), 0.09 9 (0.91 mmol) of ethynyltrimethylsllane 0.044 g (0.036 mmol) of Pd(PPhO) 4 , 0.014 g (0.078 mmol) of Cul, and 0.26 mL (1.52 mmol) of dilsopropylethylamine in 3.8 mL of DMF was heated at 0C overnight under an atmosphere of N 2 . Upon cooling to ambient temperature, the reaction mixture was concentrated and the 30 crude product was purified by sillca gel flash chromatography (eluted with 60% EtoAc/hexares) to provide 0.15 9 of product; 216 mA (M+H). 3-Ethynyimidaofl,2-alpyrarIne: To a solution of 3-((TrimethylsilyI)ethynyolmidezo [1,2-a]pyrazine (0.16 g, 0.7 mmOl) In 3.5 mL of THF was added 1.05 mL (1.05 mmol) of 35 tetiabutyiammonium luoide (l.OM in THF) at amblent temperature. The solution was stirred 50 for 15 min, concentrated, and the crude product purified by silica gel flash chromatography (eluted with 50% EtoAcihexanes) to provide 0.076 g of product. 3-(IH-fmidazoI1-Y4(trlfluoromethyaniline: A mixture of 3-Amlno-5 5 bromobenzotrifluorlde (4.0 9, 0.0167 mol), 8-hydroxy quinollne (0.362 g, 0.0025 mol), Cu (0.476 9, 0.025 mol), Imidazolo (1.30 g, 0.0199 mol), and potassium carbonate (2.52 g, 0.0183 mol) In 17 mL of DMSO (degassed with argon for -10 min) was heated at 120'C under an atmosphere of argon for 16 h; the HPLO Indicated no starting material. A 14% aqueous solution of ammonium hydroxide was added to the cooled mixture and this was 10 stirred for I h at ambient temperature. Water (50 ml) and EtOAc (200 ml.) were added and the aqueous layer was extracted with EtOAc (3x3OmL), The combined organic layers were dried over Na 2
SO
4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with EtOActhexanes) to provide 2.51 g of product. I5 N-&(1N-ImidazoI-yi)-5(trfluoomethy)pheny)-4-lodo4.mothylbenzamide: To 3-lodom4-ethylbenzolo acid (3.07 9, 0.0117 mcl) was added thionyl chloride (10 mL) and refluxed for 2 h. The excess thionyl chloride was carefully removed and the resulting acid chloride was dried in vacuo for 2 h. The residue was then dissolved in DOM (anhydrous, 25 ml) and cooled on Ice. To the cooled solution was added 3-(1H -imidazcl-1-yl)-5 20 (trifluoromethyl)aniline 6 (3.46 g. 0.I052mol) in DOM followed by the dropwise addition of dilsopropylethylamine (8.2 mIL, 0.047 mol). This was stirred at ambient temperature for 21 h. The white solid that separated was filtered and washed with water and dried to provide 4.65 g of product. Additional productoould be obtained from the filtrate following concentration and purification by silica gel flash chromatography In EtOAclhexenes. 25 N-(3-(1H-rmdRMzob1--ylituoromethylphenyl)3(Imidazo[1,2-alpyrazin3yfsthyny&-4-methylbenzamlde: A mixture of 3-EthynylImidao[1,2-a]pyrazinO (0.075 9, 0.52 mmol), 0.245 g (0.52 mmol) of N-(3-(IH-imdazol--y)-6-(trliuoromethyl)phenyl)-3-odo4 methylbenzamilde, 0.030 g (0.026 mmol) of Pd(PPhs), 0.007 g (0.039 mmol) of Cul, and 0.14 30 ml (0.78 mmol) of dlisopropylethylamine in 3.0 mL of DMF was atirred at ambient temperature overnight under an atmosphere of Ne. The reaction mixture was concentrated and the crude product was purifed by silica gel flash ch romatography (eluted with 10% EtOAc/hexanes, then 100% EtOAc, then 10% MeOH/EtOAc) to provide 0.090 g of product as a solid: 487 m/z (M+H). 35 51 Alternative Synthesis of N-(3-(1H-imidaol-1-yl)-5-(trifluoromethyl)phenyl)-3 (Imidazo[1,2-ajpyrazin-3-ylethynyl)-4-methylbenxamide: 3(fImethyIlsyl)ethyny)midazof1,2-aepyrnino can be prepared as described 5 previously. In one variation, the reaction can also be carried out in THF Instead of DMF. The crude product can also be purified by silica gel pad chromatography (eluted with ethyl acetatelhexane) and a brief treatment with activated charcoal (Daroo) can be carried out to help further reduce contamination with the homo coupling product 10 3-Ethynylfmidzcn1,2-alpyrazne: To a solution of 3-((trimethylsilyl)ethynyl) imidazo[1,2-a]pyrazne (1.39 mol) In lox volume of Ethyl acetate and 1.5x volume of Methanol is added two and a half equivalents of potassium carbonate at ambient temperature and the solution stirred for I hour. Potassium carbonate is filtered off and the organic stream .is washed with water and with saturated sodium chloride solution (two or more times). 15 Aqueous phases can be combined and re-extracted with ethyl acetate. Organic streams can then be combined and concentrated under vacuum to about 0.5L. Solids can be allowed to precipitate out upon concentration, Slurry is cooled, e.g. to about -5'C, stored overnight, filtered, and washed with about 0.3L of cold ethyl acetate. The solids can then be dried under vacuum. 20 3-lImidezo{t2-alpyrazI-3-yethynyl)4-merIylbenzoic acid can be prepared In a manner similar to that described above for the Sonogashira reaction. 3-Ethynylimidozo[1,2 alpyrazine and 3-lodo-4-methylbenzoic acid are used as coupling partners. Alternatively, the solvent (DMF) can be replaced by ethyl acetate and the base (Hunig base) can be replaced by trlethylarmine. The product can be Isolated by filtration of the crude reaction mixture. The 25 filter cake Is washed sequentially with a solvent such as ethyl acetate and then water, then dried in a vacuum oven. Further purification can be achieved by slurrying the solids In water adjusted to pH 3 with the addition of concentrated HCI. After fitration and water wash, the product can be dried In a vacuum oven. 30 N(3-(1H-imidazol-1-y)-5-(bMuoromethypheny-3-(Imidazo[1,2-apyradfn-3 ylethyny)-4-msthylbenzamider 3-(imidazo[1,2-]pyrazln-3.ylethynyl)-4-methylbenzoic aod (18 mmol) is dissolved in methylene chloride (100 mL). To tis solution is added 3 equivalents of 4-methylmorpholine (NMM) followed by 1.05 equivalents of oxal chloride. After stirring at ambient temperature for 30 minutes, 0.8 equivalents of 3-(1H-imidazol--yl)-5 35 (trfluoromethy)anillne (prepared as above) Is added along with 5 mole% of DMAP. After Initially stirring at ambient temperature, the mixture is brought to reflux and suirred overnight. After 16 h an additional 0.2 equivalents of the aniline Is added, bringing the total charge to 1 equivalent. The mixture can then be stirred for an additional 2 h, quenched with water, and the layers separated. The aqueous layer can be extracted with methylene chloride (2 X 50 40 ml.) and the combined extracts can be washed with water- The combined methylene chloride 52 layers can then be evaporated and the residue diesolved In 100 mL of ethyl acetate (20 mL). After standing for I h, the product Is allowed to crystallize. The mixture [a cooled, a-g. to o cC, filtered, and the solid product Is washed with cold ethyl acetate. 5 N-(3-(1H-ImIdaol-1-y)-5-(trIfluoromethypphenyl)-3-(Imidazol,2-apyrazlns yfethynyQ4.methylbenzamIde mono hydrochloride salt N-(3-(i H-imldzol-i-yl)-5-(trifluoromethyl)phenyl)-(imidazol,2..apyrazIn-3 ylelhynyl)-4-methylbenzamide (0.94mmol) can be suspended in MeCN (10ml) and heated with stirring to a temperature of 45 to 55'C (hot plate temperature). Hydrochloric acid (1,1eq 10 IM solution In Et0H) Is added to obtain dissolution, Within a few minutes, a precipitate Is allowed to form. The suspension can be cooled to ambient temperature and then filtered and washed with MeCN (1 x 1.6ml liquors + I x 1.mI fresh). The sold can be dried at 50"C under vacuum to constant weig ht. 15 EXAMPtE2 3-(Imidazo[1,2.a]pyrazn-3-yiethynyl)4-methyl-N-(4-((4-mthylpiperaZin-1-yl)methyl)-3 (trifluoromethyI)phenyl)benzamide CF, o N 20 The title compound was synthesIzed from 3-ethynyllmidkzo1.2-a]pyrazine and 3-Ivdo-4 methy-N-(4-((4-mothylpiperzin--yl)methyl)-3(trifuormethylpheny)benzamide in a manner similar to that described for E'xample 1. The product was obtaIned as a sold: 533 no (M+H). 25 1-(Bmmomethyl)4-nre2-&rfluoromet hyl)benzen:A suspension of2-methyl-5 nitrobenzotrifluoride (3.90 9, 19 mmol), N-bromosuccinimlde (NBS, 3.56 g. 20 mmol), 2,2' azobls(2-methyproponItrie) (AIUN, 94 mg. 0.6 mmol) In CCl (40 mL) was refluxed under N 2 for 10 h. HPLC Indicated ca. 60% conversIon. More NS (10 mmol) and AIBN (0.6 mmol) was added, and the mixture was refluxed for another 14 h. HPLC Indicated ca. 80% conversion. 30 The reaction mixture was cooled down, and the solid was filtered offend washed with EtOAc. The combined Illtrete was washed with 8q. NaHCO 3 , dried over NaoSO 4 , filtered, concentrated on rotovap and further dred under vacuum. IH NMR shows the ratio of desired product to ureacted 2-methyl-5-nitrobenzorfluoride is 75:25. This material was not purified but used directly in the next step. 53 1-Methy4-(4-nitro-2(trifuoromothyl)benzy))pIperazne: To a solution of rude 1 (bromothyl)+nitro-2-(ifluoromethyl)benzene (13.33 mmol, 76% pure) in DCM (10 ml) was added Et3N (.4 mL, 10 mmol) and 1-mthylpporazine (1,1 mL, 10 mmol). Afetr stirring 5 for 3 h at it, aq. NaHCOa was added, and the mixture was extroted with DCM. The combined organic layer was dried over NeaSO 4 , filtered, concentrated, and the resulting residue was purified by silica gel chromatography (ekited with 10% MeOH/DCM) to provide 2.21 9 of product as a pale yellow oil. 10 4-((4-Methylpiperazin1-yOmethyQ.3(trifluoromethy)anniIne: A suspension of 1 methyl-444-nitro-2-(trifluorometlyQbenzyl)piperazne (1.23 U, 4 mmol) and sodium hydrosulfite (7.0 g, 85% pure from Aldrich, 40 mmol) In acetone and water (1:1, 20 m L) was refluxed for 3 h. Upon cooling, the volatile components (mainly acetone) were removed on rotavap, and the resulting mixture was subjected to filtration. The solid was thoroughly 15 washed with EtOAc. The combined filtrate was extracted with rtBuOH (4x), and the combined organic layer was washed with saturated aq. NaHCOO, dried (Na 2 8O4), filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 5% MeOIl4DCM, MeOH was pre-saturated with ammonia gas) to provide 0.71 g or product as a pale yellow solid. 20 3-Iodo-4-mothyl--(4-((4-methypipoeflnl-y)mothyl)-3-(trfIuoromothyl)phnyl) Bentamidk: 3-lodo-4-methylbenzoyl chloride (0.48 9, 1.7 mmo), prepared from the reaction of 3-lodo-4-methylbenzoio acid and SOClz (as previously described), was added to a solution of 4-((4-methylpIperazin-1-ylmethyl-3-(trfiuommethyl)aniline (047 g, 1.7 mmol), N,N 25 dlisopropylethylamine (0.26 g, 2.0 mmol), and a catalytic amount of DMAP In THF (10 mL). After stirring at rt for 2 h. the reaction was quenched with water. EtOAc was added and the layers separated. The combined organic layers were concentrated to dryness and purified by allica gel chromatography (dluted with 5% MoOFlDCM, MeOH was pre-saturated with ammonle gas), to provide 0.51 g of product as on off-white solid. 30 Alternative synthesis of 3-(lnIdazo[1,2-apyrazin-3-ylethynyt).4-methyl-N-(4-(4 methylpIperazIn-1-yl)methyl3-(trifluoromethyl)phenyI)benzamide; 3-(lmidazo[1,2 alpyrazin-3-yethynyl)-4-methyl-N-(4-((4-methylpiperzin-1-yI)methyl3-(trfluoromethy0 phenyl)benzamide and Its mono hydrochloride salt can be prepared in an alternative 35 synthesis similar to that described In Example 1 from 3-(imidazol12-lprazin-3-yethynyl)-4 methylbenzoic acid and 4-(4-mefthlpiperazIn-1 -yl)methyl)-3-(trifluommethyl)aniline (as prepared above). 40 54 EXAMPLE 5 N.-(3-(2.(dimethylamino)methyl)-iH-imldazol-1.yl)-5(triluoromethylpheny).3 (im idazo[1,2-4pyrazin-3.ylthynyl)4methylbenzamide The title compound was synthesized from 3-ethynylimldazo[1,2-allpyrazine and N-(3-(2 10 ((dimethylamino)methy9-1 H-imidazol-1-yl)-5-(trlfluoromethyl)phenyl)--iodo methyibenzamide in a manner similar to that described for Example 1. The productwas obtaIned as a solid: 544 m/ (M+H). 1-r1H-imidaz.I-2-y)-N,N-dimothymethanamine: Toe two-necked round-bottomed 15 flask equipped with a reflux condenser and a pressure-equalizing addition funnel, was added 2-imidazolecarboxaldehyde (6 9. 62.5 mmol) in MeOH (60 mL). To this suspension (amblent temperature) was added a solution of dlmethylamine (40% aqueous, 60 ml) at a fast dropping rate (20 min). After the addlion was complete, solid sodium borohydride (7 g, 180.8 mmot,) was CAUTIOUSLY added portionwise over 45 min. Foaming occurred after each 20 portion, and the Internal temperature was allowed to maintain -50 'C without external cooling. The reaction mixture was then heated lo 65 "C for 3 h and allowed to cool to ambient temperature for overnight The reaction contents were concentrated In vacuo and the resultant residue was taken up In EtoAc (2 x30 mL) washed with brine and with CHCl 3 (4 xl100 ML), The EtOAc extract was discarded. The CHCla extract was dried over (NaSO4), 25 filtered, and concentrated in vacuo to give 3.7 g of the desired product as a waxy solid. 3-2g(Dimethylamino)methyQ-1lImtdaoI-1-yO-4r-sdfluoromethy)anline: 3 Amino-5-bromobenzorifluodde (6 9, 25 mmol) and 1-(1H-lmidarol-2-yl).N,N. dimethylmetharemine (3.7 g, 29.6 mmol) were dissolved in anhydrous DMSO (25 ml). To 30 this was added Cui (0.95 g, 7.5 mmol), 8-.ydroxy quinoline (0.72 g, 7.5 mmol) and KzC0 3 (6.9 g, 50 mmol). The mixture was stirred vigorously and degassed with N for 15 minutes. The ask was then equipped with a condenser and heated at 120*C for 18 h. The resultant heterogeneous mixture was cooled to ri, poured into 14% aq. NH 4 0H (100 mL) and extracted with EtOAc (3x3O0ml). The combined extracts were dried over NaSO 4 and concentrated in
SS
vacuo. The residue was chromatograhed over sillas gel eluting with MeOH/DCM (5:95) to famish 3.5 g of the desired product as a tan colored material: 285 mt (M+H). N.(34(2-((dfmethylamino)methyQ-1H-ImIdazof-1..yi-(trflommethy)pheny0+ 5 lodo-4-methylbenzanmke: 3-bodo-4-methylbenzoyl chloride (2.2 g, 7.88 mmol), dissolved In anhydrous THF (13 ml.), was added dropwiae to a solution of 3-(2-((dlmethylamino)methyl) IH-Imidazol-1-y)-5-(tdl1uoremethyl)anillne (1.5 g, 5.5 mmol), DIPEA (2.1mL, 11.8 mmd) In TIF ( 30 ml.) at - 5 "C. The resultant solution was stirred at ambient temperature overnight The solvent was removed In vacuo and the crude residue was redissolved In CH2Ci, and 10 washed with 1N NaOH. The organic layerwas then washed wiih water, and brine then dried over NaSO 4 before being concentrated In vacuo. The brown colored residue was then triturated in a mixture of hexanesDOM to precipitate 1.4 9 of the desired product as an off white powder: 529 mk (M+H). 15 Alternative Synthesis of N-(3-(2-((dimethylamlno)mothyl)-1 H-imidozol-I1-y)-5 (trifluoromethySphenyl)-3-(Imidtol,2-a]pyrai-3-yiethynyl)-4-methylbenZamide: N-(3 (2-((dimethylamino)methy)-1 H-Imidszol-1-yl-5-(trifluoromethyl)pheny-3-{+midazo[1,2 alpyrazin3-ylethynyD+-methylbenzamide and its mono hydrochloride salt can be prepared in an alternative synthesis similar to that described In Example I from 3-(Imidazo[l,2-apyrazin 20 3-ylethynyl)-4-methylbenzolc acid and 3-(2-((Dimethylamino)methyl)-1 H-imidazol-1-y0-5-. (trfluoromethyl)onhline (as prepared above). EXAMPLE4 25 3-(Imidazo[1,2-apyridin-3-yiethynyl)4methyl-N-3-(4-methyl-1H-ImidaWl.1-y).- (trifluoromethyl)phonyl)bentamide crr 3-Ethynylim(daz{1.2-alpyrldine: To 3-bromoImidazo[1,2-a]pyridIne {5 g. 0.0254 30 modl in acetouirile (50 mL) In a sealed tube was added bIstriphenyiphosphine) palladlum(l) dichloride( 0.4459, 0.634 mmol), CUI (0.17 g, 0.89 mmOI), dicyclohexylmine (5.6 ml. 0.028 mol and ethynyllidmethylsilane (7.2 mL, 0.051 mol). The solution was purged with argon for 15 minutes, sealed and heated at 80 0 C for 3h. At this point the HPLC did not show any starting bromide. The solvents were concentrated and to the residue was added water and 56 dlohloromethane (25 mL each). The organic layer was separated and the aqueous layer was repeatedly extracted with dichloromethane (3 X 20 mL). The combined extracts were dried (Na 2
SO
4 ), and concentrated ( Rf, 0.47 in II hexanes/ethyl acetate). The resulting residue was dissolved in THF (100 nL) and treated with tetrabutyl ammonium tuoride monohydrate 5 (8.3 g, 0.032 mot) in water (5 mL) and the mixture was sirred at rt for 2h. The solvents were concentrated and the reoudng residue was partitioned between water (25mL) and dichloromethane (150mL). The aquesous layer was extracted with dichloromethane (2 X SOmL). The combined extracts were dried (NasSO 4 ), and concentrated. The resulting residue was purified by comblilash on silica gel using hexanes/ethyl acetate. The desired 10 product was eluted with 50/60 hexane/ethyl acetate and salted as an off-whlte solid: MS (M + H) 200. 3-(4-MothyMH-imIdazoM-yI-5-(trifluoromethylban line: A suspenion of 3 bromo-5-(rtlluoromethyl)anillne (4.8 g, 20 mmol), 4-methyllmidazole (1.97 g, 24 mmol), 15 potassium carbonae (3.04 9,22 mmol), Cu (0.57 g, 3 mmol), and 8-hydroxyquinollne (0.44 g, 3 mmol,) In dry DMSO (20 mL) in a pressure tube was dassed by bubbling Nz into the suspension for 10 minutes while stirring. The tube was sealed tighfiy. The mixture was heated at 120 *C (oil both temperature) for 15 h. The mibdure was cooled down to 45- 50 'C and 14% aq, NH 4 0H (20 mL) was added. The mixturewas maintained at this temperature for 1 h, After 20 cooling to rt, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the combined organic layers were passed through a short silica gel column to remove most of green/blue Cu salts. The filtrate was ddqd over sodium sulfate and concentrated on a rotavap. The crude product was reorystallized from EIOAclhexanes, giving pure pale yellow needles. The mother liquor was concentrated and the residue was purified 25 on silica gel column (5% methanol/methylene chloride), yielding a second crop as pale yellow needles. 3-lodo-4-methfyl-(3-(4-methyl--Imldazo1-y-5-(trffluoromethyl)phenyl) BenzamIde: 3-odo-4-methylbenzoic acid (2.62 g, 10 mmol) was refluxed in 30012 (10 mL) 30 for I h. The volatile components were removed on a rotavap and the residue was dissolved in benzene (10 mL), concentrated to dryness on a rotavap and further dried under vacuum. The resulting acyl chloride was added to a solution 3-(4-methy1H-lmidazol1-yl)-5 (tdlluoromethyl)benzenamine (2.46 g, 10.2 mmol), N,N-dilsopropylethylamlne (1.56 g,12 mmol), and a catalytic amount of DMAP in THF (20 MIL), After stirring at rt for 2 h, the reaction 35 was quenched with water. EtOAC was added and the layers separated. The combined organic layers were concentrated to dryness and used without purification In next slap. 3-(Idazo(1,2-a pyrdn3-ylethynyQ.4-mehyl-N(3-(4-methyM-ImIdao-y 5-(rifluoromethyl)phobonxamld: Toa solution of 3-lodo4-methy-N-(3-(4.-methy-1I-H 40 imidazol-1-yl)-5-(trlfluoromethyl)phenyl)benzamide (0.11 g, 0.22 mmal.) in DMF (1 mL) In a 57 sealed tube was added Pd[(PPh 4 ] (0.013g, 0.OlImmol), Cul (3 mg, 0.016 mmol), diethyllsopropylamine (0.057 mL, 0.33 mmol.), followed by 3-ethynylimidazo[1,2-aIpyrIdino (0,040 g, 0.28 mrnol). the mixture was purged with argon for 15 minutes, sealed and stirred at rt for 28 Th. The solvent was concentrated and the residue was taken up In methylene 5 chloride (50 mL). The organic layer was washed with water, dried (NsaBO 4 ) and evaporated to leave a brown residue which was purified by combiflash (hexaneethyl ioetate/methano) lo yield the desired material MS (M + H)* 500. Alternative Synthesi, of 3-(lmidazo[,2.-4pyridln-3-ylethynyl)-4-methyl.N-(3-(4. TO mthyl--l.Imidazol-l)-(trifluoromethyl)phenyl)benzamide: 3-(Imldazo[1,2-a]pyridIn-3 ylelhynyl)-4-methyl-N-(3-(4.methyl-IH-Imidazol1-yl)-$(trfluoromethyl)phonyl)benzamid and Its mono hydrochloride salt can be prepared In an alternative synthesis similar to that described In Example I from 3-(imIdazo[1,2-apyridin-3-ylethynyl)4-methylbenzolc acid and 3-(4-Methyl-1H-lmIdazol-1-yl)-5-(iriftuoromothyl)aniline (as prepared above). The 3 15 (imldozo[1,2-alpyridin3-yTethynyl).4-methylbenzoic acid is prepared In a manner similar to that described In Example I using 3-EthynyInIdzo[1,2-alpyridine and 3-odc-4 methytbenzoic acid as Sonogashira coupling partners. ExAMPLE 6: 20 N-(3-(1H-imidazol4-y.Q-(trifluoromethy~pheny l)-3-(Imidao[1,2-apyrldln-3-ylethynyl) 4-methylbenzamide 25 The tiled compound was made as for example 1 using N43-(1H-Irndazo-1-yi)-+ (trifluoromethyl)phenyi-3-iodc4-methylbenzamide and 3-othynylmidozo(1,2-aJpyridine: MS (M + H)* 486. The titled compound can also be prepared according to the alternative synthesis described in example I from 3-(imldazo[1,2-apyridin-3-ylethynyt)-4-methybenzol 30 acid and 3-(1H-imidazol1-y)-5(trifluoroethyl)anline (as prepared In Example 1). The 3 (imideso[1,2-alpyridin-3-ylethyny)-4-methylbenzolc acid 14 prepared in a manner similar to that described in Example 1 using 3-Ethynylimidazo[1,2-ajpyridine and 3-lodo-4 methylbenzolo acid as Sonogashira coupling partners. 58 EKAMI'L 6: 3-(lmldazot ,2-.Jpyrldl n-3-yIothyrnyQ-4-rnothyl-N-(4-(trifluoromethyl)pyridin-2 yltbenzomlde Cor The titled compound was made as (at example, 1 using 3-Ido-4-hthyl-N-(4 (trifluormethyl)pyrldln-2-yl)benzmlds and 3-ethynyllmldezo(1,2-ejpyrldine IMS (M + ) 10 421.39, EXAMt9 7: N-(5-tofl-butyIlooxazoI-3y)-3-(Imidldnz(2-a]pyrldln-3-yhothynyl).4-mothylbenzanIde 15 The titled compound was made as for example I using N-([5-tert-butyllsoxazol-3-yO-3 lodo-4-methylbenzmlide and 3-ehynyhmldazo1 .2-sipyrdine: IMS (M + I)* 399. 20 EXAWLE 8± 3-fImIdazo1l,2-apyrIdIn-3-yIethyny)-4-mthy-.{4-((4-mothylppoain--ylmothyl)-3 (trIfluorom~ty)phonyl)benzomldO 25 59 3-Ethynylimidazo[1,2-aepyridne (37 mg, 0.26 mmol), 3-odo-4-methyl-N-(4-((4 methylpiperazIn-yl)methyl)-3-(trfluoromethyl)phenyl)benzamide (103,4 mg, 0,2 mmol), (prepared as In Example 2), Pd((PPha) 4 ] (1. mg, SmOl%), and Cu (2.9 mg, 7.5mmol%) was 5 placed In a vial with rubber septum. The mixture underwent 3 cycles of vacuum / filling with
N
2 , and DMF (1,5 ml) and N, N-dllsopropylethylamine (53 mL, 0.3 mmol) was added. The mixture was stirred at rt for 16 h, and the reaction was quenched with H20. EtDAc and more water were added for extraction. The combined organic layer was dred (Na 2 S04), filtered, concentrated, and the resulting residue was purified by silica get chromatography fluentt 5% 10 MeOH in mOthylene chloride, MeOH was pre-saturated with ammonia gs), giving the titled compound as an off-white solid (53%, 66 mg): MS (M . H)* 532. Alternative Synthesis of 341midazo[1,24pyridin-3ylethynyl)4methyl-N-(4-({4 methylpiperazin-1.yl)methyl)-3-(trifluoromethyl)phenyl)bonamido: 3-(Imidazo[12 alpyridin-3-ylefhynyi)-4methyl-N-4-((4-methylpiperazin-1-yl)methyl)-3.(trifluoroethyl) 15 phenylibenzanIde and Its mono hydrochloride salt can be prepared In an alternative synthesis similar to that described in Example I from 3-(Imlldazoll,2-apyddin-3ylethynyl)-4 methylbenzoic acid and 4-((4-methylpiperazin-i-yl)methyl)-3-(trfluoromethyl)anlilne (as prepared In example 2). The 3-(imidazo[1,2ajpyrldin-3-ylethynyl)-4-methylbenZOlo acid Is prepared In a manner similar to that described In Example 1 using 3-Ethynyllmidazo(1,2 20 alpyridine and 3-lodo-4-methylbenzoic acid as Sonogashira coupling partners. EXAMPLE 9: N-(3-(2-((dlmethylamino)methyl)-1 H-imIdazol.1yl)-5-(trifluoromethyl)phonyl)-3 25 (Imidazo[1,2.a]pyrldIn-3-ylethynyl)-4mthylbenzamide Cr 30 To 3-ethynyllmIdazoll,2-ajpyridine (0.032 g, 0.22 mmol) In anhydrous DMF (1.26 mL) was added N-(3-(2-((dimethylumino)methyl)-1 H-imidazol1-yI)-5-(riInuoromethyopheny)-3 iodo4-methylbenzamide (prepared as in Example 3), Pd( PPh) 4 (0.013 g, 0.011 mmol), Gu (0.0032 mg, 0.0165 mmol) and DIPEA (0.064 mL, 0.44 mmol). The solution was degassed 60 with argon for 15 minutes then stirred overnight at rt. The solvent was removed and the resultant residue was chromatographed over silica gel eluting Initally with EtoAO and then with methanol/methylene chloride (5:95) to furnish the desired product: (0.07 g, 59%) MS (M + H)* 542. 5 Alternative Synthesis of N3(2-((dimethylamino)methyl)-IH-imldaoliyl)4. (tdfluoromethyl)phonyl)+(Imidazo1,2-apyridin3-ylethynyl)4-.methylbeamide: N-(3 (2.((dlmethylamino)methyl)-1HImldazoolyl)5-(tldluoromethyOphenyQ.-(imidazo[1,2 alpyridin-3-ylethynyl-4-methylbenzamlde and Its mono hydrochloride salt can be prepared in 10 an alternative synithesis similar to that described In Example 1 from 3-(Imidazo[1,2-apyrIdin 3-ylethynyl)4-methylbenzoc acid and 3-(2-((Dimethyiamino)methy-1H-imidazol1yl-5 (trluoromethyl)aniline (as prepared in Example 3). The 3-.(ImIdazo1,2-apyldln-3-ylethynyl) 4-methybenzolc acid Is prepared In a manner similar to that described In Example 1 using 3 Ethynylimidazoll,2-elpyridine and 3-iodo-4-methylbenzoIo acid as Sonogashira coupling 15 partners. EYAWLE 10: 3-((8-Acetamidolmidezo[1,2-O3pyridin-3-yl)ethynyl)-4-methyl-N-(4 20 (trifluoromethyl)pyridin-2-yl)benzamide N.(3-Ethynylnmidazofl,2.alpyldin-B-y)acetamide: N-(3-EthynylImldazo[i,2 25 aepyridin-.ylacetamide was synthesized as for example 1A from N-(3-bromoImidazo[1,2 a]pyrldin-81-yfacetamide (E. Smakula Hand and William W. Paudier, J. Org. Chem., 1978, 43, 2900-2906). The titled compound was isolated as an off-white solid, R1, 0.6 . (hexanelethylacetate 50150): MS (M + H)* 200. 30 3.((8-AcetemidolmIdzof1,2-alpyddIn-3-yIethynyl.4-methyN-(4 (frifluoromethylpyrdin-2-yl)benzamide: The titled compound was made as for example I using 3-Iodo-4-methyl-N-(4-(trifuoromethyipyridln-2-yobenzamide and N-(3 ethynylimidazo[1 2-alpyridin-8yI)acetamide: MS (M + H) * 478.4. 35 61 EXAMPLE11: N-(3-1 H-Imtdazol--yl)-5-(trIfluoromethyl)p henyl)3-((8-aetamidolmldaZo[1,2-alpyridin. 3-yl)ethynyl)-4-methyIbenzamide 5 The tled compound was made as for example 10 using N-(3-(1H-imidazol.-yl)-5. (trifiuoromethyl)phenyl)-3-lodo-4.methylbenzam!de and N(3-ethynylimidazo[l.2-alpyridin-8 10 yI)acetamide: MS (M + H) 543. ExAMPLE 12: 4-Methyi-3-((8-(4-(methylsulfonylphenylamino)midazo[1,2-apyrkiln-3-yl)ethynyl)-N-(4 15 (trifluoromethyl)pyrdin-2-yl)bonzamide 0 8.(BeMyloxy)3-bromofmidazol,2-alpytidne: To a solution of 2-amino-3 20 benzyloxypyrldine (25.0 g, 124.9 mmol) and chloroacetaldohyde (50% wt in H2O; 16,7 mL. 131.2 mmol) in 250 mL of EtOH was heated at reflux in a sealed tube for 19 h. Upon cooling to anbient temperature, the reaction mixture was concentrated and the resulting brown oil added 125 mL IN NaOH then extracted with dichloromethane (DOM). The combined organic layers were washed with HO, dried over NaSO4 and concentrated. Upon concentrating the 25 solution, a tan solid formed which was filtered and dried to provide 25.8 g of crude product. To a solution of crude 8-(benzyloxy)imidazo[l,2-apyridine (8.73 g, 31.9 mMCI) in 100 mL of EtOH was added, dropwlse, 4.8 mL (46.7 mmol) of a solutlon of 1:1 BrdH 2 0 at ambient 62 temperature under an atmosphere of N2. The resulting dark orange suspension was stirred at arnbent temperature for 30 min, added (0 mL IN NaOH,.and the reaction mixture extracted with DCM. The combined organic layers were dried over Na260 4 and concentrated, The crude product was purified by silica gel Rash chromatography elutedd with 30% 5 EtOAcihexanes) to provide 7,04 g of product. 8.(Benzylxy).3-((trlmefhylsnyIJerhynj4)lmidato(1,2-aJpyrIdine: A mixture of 8 (benzyioxy)3brcmoimidazo(l-ojpyridine (10.0 9, 33.0 mmol), 9.39 mL (66.0 mmol) of ethynyltrimethylsilane, 0.5809 (0.825 mml) of Pd(PPha)aClt, 0.230g (1,19 rnol) of Cul, and 10 5.09 ML (36.3 mmol) of dilsopropylamine In 100 mL of acetonitrile was heated at reflux for 3 h under an atmosphere of Na. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gol flash chromatography elatedd with 20-50% EtOAcihexanes) to provide 6.74 g of product: 321 man (M+K). 15 34(Trimethylsilyl)ethynyl)Imda*ofl,2-fpyrdin--yf trilfurmethanesuffonaet.: To a cooled (0*C) solution of 8-(benzyloxy)-3-((trimethylsilyl)ethynyl)midazo[1,2-ajpyridine (3.44 g, 10.7 mmol) In 400 mL of DCM, under an atmosphere of N2, was added via cannulation 100 mL (100 mmol) of boron trichlorlde (1.M solution in hexanes). The reaction solution was stirred at O'C/ N, for 30 min, to which was added (OC) 200 mL H20 followed by 20 extractIon with DCM. The combined organic layers were washed with brine, dried over Na 1
SO
4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 30% EtOAc/hexanes then 10% MeOHiDCM) to provide 2.32 g of deprotected product: 231 na (M+H). To a cooled (-75'C) solution of 8-(hydroxy).3-((trimthylsilyI)ethynyDimidaxo[1,2 25 a]pyridine (2.32 g, 10.1 mmol) and 1.63 mL (20.1 mmo) of pyrldine In 50 mL of DCM, under an atmosphere of Nt, was added 2.03 mL (12.1 mmol) of trifluoromethanesulfonic anhydride via syringe. Upon removing the coolihg bath, the reaction solution was stirred at ambient temperature (N2) for 2 h. The reaction mixture was poured Into a stirring solution of 100 ML I.ON HCI, the layers separated, aid the organic layer washed successively with iON HCI, 30 H2O, saturated aqueous NaHCO, and brine. The organic layer was dried over Na2SO 4 and concentrated. The crude product was iftered through a small plug of silica gel (eluted with 30% EOAcohexanes), concentrated, and further dried In vacuo to provide 3.3 g of product: 363 min (M-H). 35 N-(4-(Mthylsuffony~phenyQ44(ftrmetMylslyothyny)fMidaZO(1,2-pydiny-8 amine: A mixture of 3-((trimethysilyl)ethynyl)imldoto[1.2-apyidlr-yI trifluoromethanesulfonate (0.329 g, 0.91 mmol), OASS (1.09 mmof) of 4 (methylsulfonyt)enflne. 0.083 g (u.u1 mmdo) of Pd 2 (dba)z, 0.087 g (0.181 mmol) of 2 dicyclohexylphoaphino-2',4'6'-risopropylblphny, and 0.385 g (1.81 mnnol) of potassium 40 phosphate In 8 mL of DME was heated at 80'C in a sealed tube ovemight under an 63 atmosphere of N 2 . Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silie gel flash chromatography (triethylamine-treated silica gel; eluted with 0-80% EtOAchexanes) to provide 0.058 g of product: 384 mk (M+H). 5 3-Etkynyl-N-(4-(mothylsulfonyl)phenyil)mdazo(1,2-aJpyridin-8-amIne: To a solution of N-(4-(methytsulfonyI)phenyl)-3.((tImethylsilyl)ethynyl)imidazo(12-apyrdin amine (0.058 g, 0.15 mmol) In 1.5 MIL of THIF was added 0.23 mL (0.23 mmol) of tetrabutylammonlkn fluoride (1.OM in THF) at ambient temperature. The solution was stirred 10 for 15 min, concentrated, and the crude product purified by lliea gel fash chromatography (triethylamine-treated silica gel; sluted with 100% DCM then 5Vo MeOHIDCM) to provide a quantitative yield (0.047 g) of product 312 mAZ (M+H). 4-Methyl-3-((8-(4-f(mthylsulionylphonylamino)Imidazo[1,2-4Jpyridin-3 15 ylethynyl)-N-(4-trInuoromethyl)pyrldin-2-yl)bonzamfdo: A mixture of 3-ethynyl-N-(4 (methylsulfonyl) phenyl)imidzo[1,2-aopyridin-8-amlne 6 (0.048 9, 0.154 mmol), 0,069 g (0.170 mmol) of 3. lodo-4-methyl-N-(4-(trliuoromethyopyridin-2-yl)benzamde, 0.009 g (0.008 mmol) of Pd(PPhs)4, 0.002 g (0.012 mmol) of Cul, and 0.04 mL (0.23 mmol) of dliopropylethylamlne In 20 0.8 mL of DIMF was stirred at ambient temperature overnight under an atmosphere of N2. The reacUon mixture was concentrated and the crude product was purified by silica gel gash chromatography (trlelhylamine-treated silica gel; eluted with 10% EtOAc/hexenes to 100% EtOAc) to provide 0.047 g of product as a solid: 590 m& (M-H). 25 EXAMPLE13: 4-methyl-3-((-(4-ulfamoylphenylamino)imldazo[1,2-IpyrIdin-3-yl)ethyny)-N-(4 (trifluoromothy0pyridin-2-yl)benzamide 30 soNH Hi, 64 The title compound was synthesized from 3-ethynyl-N-(4 sulfamoyhenyl)imidazo[1,2.aspyridn-8-amine and 3-lodo4-methyl-N-(4 (trliluoromethyl)pyrldin-2-yl)benzamide In a manner similar to that described for Example 12. The product was obtained as a solid: 591 m/ (M+H). 5 EXAMPLE 14: (R).N-(4-((-(Dimethylamino)pyrrolIldin-1.yl)methyQ-3-(trilluoromethyl)phenyl)-3 (Imidzo,24]bpyridailn-3-ylethyny-4methylbenzamide 10 OF, -N 3-({TImethylsflylI)thynyl)hmdazof1,2-bpyridazine: A mixture of 3 15 bromoimidazo[,2-blpyridazIne (3.78g, 0.186 mol; prepared according to Stanovnk, B. eta. Synthesis (1981), 12,987-989). othyrnyltrimethyisliane (21.89 g, 0.223 mol), Pd(PPh) 4 (10.73 g, 9.29 mmol), Cul (5.30 g, 0.028 moli, and dilsopropylethylamine (32.4 mL, 0.279 mol) in 150 mL of DMF was stirred at ambient temperature, under an atmosphere of Na, for I h. The reaction mixture was. concentrated and the crude product was purified by silica gel flash 20 chromatography (eluled with 0-5% MsOH/DCM) to provide 28.46 g of product. 3-EthynylImiddzo[1,2-hbpyrldazine: To a solution of 3-((trimethylsilyl)ethynyl) imidazo[1,2-bpiyridazine (28.46g, 0.132 mol) In 200 mL of THIF was added 145 miL (0.145 mol) of tetrabutylammonium fluoride (l.M InTHF) at ambient temperature. The solution was 25 stirred for 15 min, concentrated, and the crude product purified by sllica gel flash chromatography (Oluted wlth 0-5% MOIDCM) to provide 17.84 9 of product. 1-(Buomomethyl)-4.nro.2-(trifhoromehyl)benzene: A suspension of 2-methyl-5 nitrobenzotrfliuoride (3.90 g. Ie mmol), N-bromosuocinImide (NBS, 3.56 g, 20 mmol), and 30 2,2'ezobIs(2-methyproponItrle) (AIBN, 0.094 g, 0.6 mmol) In 40 mL of CC)4 was heated at reflux under N 2 for 16 h. HPLC indicated ca. 50% conversion. Additional NBS (10 mmol) and AIBN (0.6 mmol) were added and the mixture wes heated at reflux for another 14 h. HPLC Indicated ca, 80% conversion. The reaction mixture was cooled to ambient temperature, end 65 the solid was filtered and washed with EtOAo. The combined filtrate was washed with eq. NaHCO 3 , dried over NaS0 4 , filtered, concentrated on rotcap, and further dried under vacuum, 'H NMR Indicated the ratio of desired product to unreacled 2-methyl-..5 nitrobenzotrifiuorlde to be 75:25. This material was used directly in the next step. 5 (R)-N,N-DimthyI-1-(4-nitro-2-(trifuonmthytbenzyQpyroidin3amine: To a solution of crude 1-(bromomethyl.4-nitro-2-(trfltuoromethyl)benzene (17.5 mnmol, 75% pure) In 40 mL of DOM was added EtIN (2.69 mL, 19.3 mmal) and (R)-(+).3 (dimethylamino)pyrrolline (2.0 g, 17.5 mmol). Alter stirring overnight at ambient temperature 10 under an atmosphere of N, the reaction solution was concentrated, added aq. NaHCOs (100 mL), and the resulting mixture extracted with DCM (4 x 50 mL). The combined organic layer was dried over Na2SO, filtered, concentrated, end the resuming residue was purified by silica gel chromatography (eluted with 0-10% MeOHIDCM) to provide 3.35 g of product as a yellow oil. 15 (R)+(4-Amino.2-(MIuoromethybenzy)-N,N-dImethylpyrrolidIn4emIne: To a solution of (R)-N,N.dlmethyli-(4-nitro-2.(trifluoromethyl)benzyl)pyrrolldin-3-amine (1.20 g, 3.79 mmol) in 20 mL of wet EtOH was added 0.26 g of PdIC (10% Pd on C) and the mixture shaken In a Parr apparatus (pressure reaction vessel purged thoroughly with H2 and prbssure 20 regulated at 45 psI throughout) for 2-3 h. The reaction mixture was filtered through a small pad of cellte, washed with EtOAc, and the combined organis ooncentrated to provide a quantitative yield of a light yellow ol. This material was used directly In the next step. (R)-N-(4-(($(DImefhylamtno)pyIldn1yOmOthyQ. (t1uoromethyl)phnyl-3 25 lado-4-methylbenzamldo: To a cooled (0 *C) solution of (R)-1-(4-amrlno2 (tifluoromethyl)benzyl)-N,N-dimethylpyrrolldin-3-mlne (3.79 mmol) In 14 mL DCM, under an atmosphere of N, was added 3-lodo-4-methylbenzoyl chloride (1.17 g, 4.17 mmol; CAS# 52107-98-9, prepared from the reaction of 3Iodo-4-methylbenzdo said and SOCb) followed by dropwise addition of N,N-dilsopropylethylamine (2,64 mL, 15.2 immol), After stirring to 30 ambient temperature over 1.5 h, the reaction mitture was concentrated and the crude product was purified by silca gel chromatography (lud with 0-6% MeOHiDCM; MeDH was pre saturated with ammonia gas), to provide 0,71 g of product as a thick yellow oil. (R)-N-(4-((3-(dimothylamIno)pyrrofidin-yOmethyb-3.(trfluoromehyopheny.
35 (imidazo(1,2-bJpyridain.yIethynyO4-methylbenzamide: A mixture of 3 ethynylimidazo[1,2-bpyridzlne (0.051 g, 0.34 mmol), 0.150 g (0.28 mmol) of (R)-N-(4-((3 (dimethylamino)pyrrolldin-1-yi)methyl)-3-(trifiuoromethyl)phonyl)-3-lodo-4-methylbenzamide 0.016 g (0.014 mmal) of Pd(PP),. 0.004 9 (0.021 mmol) of Cul, and 0.09 mL (0.51 mmol) of N,N-diisopropylethylamine In 3.5 mL of DMF was stirred at ambient temperature, under an 40 atmosphere of N, for 3 days (reaction pushed to completion with additional equivalents of 66 reagents and heating to 80 *C). The reaction mixture was concentrated and the ends product was purified Dy silica gel chromatography (ejuted wIth 0-10% MeOHIDGM; MeOH was pre-saturated with ammonia gas) to provide 0.020 g of product as a solid: 847 m/Z (M+H). 5 Alternative Synthesis of (R)-N-(4-((3-(Dimethylamino)pyrrolidinA-yI)methyl)-3 (trifluoromehyl)phnyl)-3.(Imideo1,2-blpyridain-3-yletinyl)-4methylbenzamide: (R)-N-(4-((3-(DImethylamino)pyrrolldIn-1-ymethyl)-3-(tr1iuoromethyl)phenyi)-3-(imidazo[1,2 blpyrldszIn-3-ytethyny0-4-methyibenzaide and Its mono hydrochloride Baltcan be prepared 10 in an alternative synthesis similar to that described in Example I from 3-(imidazo[i,2 bjpyridazin-3-yettyny)-4-methylbenzoi acid and (R)-I-(4-Amlno-2-(triluorometIybenzyl) N,N-dmethyfpyrroiIdin-3-amIne (as prepared above). The 3-(imIdazo[1,2-b]pyrIdazIn-3 ylethynyl)-4-methylbenzclc acid is prepared In a manner similar to that described In Example I using 3-Ethynylimldozo(1,2-b]pyridazine and 3-iodo-4-methylbenzoio acid as Sonogashire 15 coupling partners. EXAMPLE 15 20 N-(3-(Imidaro[1,2.bpyridazin-3-yIethynyl)-4-methylphnyl)4((4-rmthylpiperazin+ yI)methyl)-3-(trifiuoromethyi)benxsmlde 25 The title compound was synthesized from 3-ethynylimidazoj1.2-bipyddazine and N (3-lodo-4-methylpheny)-4-((4-methyliperazin-1-yl)methyl)-3-(tdfluoromethyl)benzamlde In a manner Similar to that described for Example 14. The product Was obtained as a solid: 533 m/& (M+H). 30 N.(3-ldo-4-methylpheny)4((4-mthylpiporatin--yl)methyl)-3 (frfluoromethylbenzamide: To a flak containing 1.0 g (2.67 mmol) of 4-(4-methyl-1 piperezinyl)methyl]-3-(trifluoromethyl)-beozoIc acid (CAS# 859027-02-4; prepared according to Aski, T. oe at Bioony. Med. Chem. Left. (2006), 16, 1421-1425), 0.52 g (2-67 mmol) of 3 lodo-4-methyianiilne, 0.77 g (4.0 mmol) of N-(3-dimethylaminopropyl)-NthylOarbodlimide 67 hydrochloride (EDAC), and 0.43 g (3.2 mmo!) of N-hydroxybenzorlazole monohydrate (HOBt ' H2O) was added 5 mL of DaM and 6 mL of trIethylamine. The solution was stirred at ambient temperature under an atmosphere of N 2 for 3 days, concentrited, and the crude product purified by silica gel chromatography eludedd with 100% EtOAc then 10% 5 MeOHIEtOAG), to provide 0.69 9 of product as a white sold. 3-hknidazo[1,2-blpyridszIn-3-ylethynyl)-4-metyl-N(4-((4-methylpiprazin1Iyl)methyl) 10 3-(trlfluoromethyl)phenyl)benzamide The ltle compound was synthesized In a manner similar to that described for 15 Example 14, from 3-ethynylimldazotl.2-bipyridazine and 3-Iodo-4-mothyl-N-(4.((4 methylpiperazIn-1.yl)methyl)-3-(trilluoromethyl)phenyl)benzamlde (Prepared as described In Example 2) . The product was obtained as a solid: 533 mk (M+H). Alternative Synthesis of 3-(Imidazot1,2-b]pyridazin-3-ylethynyl)4-methyl-N.(4 20 ((4methylplperazin-yl)methyl)3trifluoromethyl)phnyl)benamide: 3-0indero[1,2-b]pyrldazine3ylethynyl)-4-methyl.N-(4-((4-mehylpIperaIn-1-ypmthyl)-3 (trfiuoromethyl)phenyl)benzamIde and Its Mono hydrochloride salt can be prepared In an alternative synthesis simIlar to that described In Example I from 3-(Imidoto[1,2-blpyddazln ylethynyl)-4-methylbenzoic acid and 4-((4-methylpperzin-1.yl)methyl)-3-(trifluoromthyl) 25 aniline (as prepared In example 2). The 3-(Imldazo[1,2-blpyridazin-3-ylethynyl)-4 methylbanzoico aid is prepared in a manner similar to that described In Example 1 using 3 EIhynylimIdazo[I,2-bjpyridezine and 3-lodo-4-methylbenzolo acid as Sonogashira coupling partners. 30 IrOWLS 17: N-(3-Chloro-4.(4-methylpiperain-1yl)methyl)phonyl)-(3imidazo[1,2-b]pyridain.3 S yIethynyl)4.,,ethylbeizamilde The title compound was synthesized according to Example 14, from 3 10 othynylimidazoll,2-bjpyridazine and N-(3-chloro-4-((4-methylpiperazin-yl)methyl)phenyl)-3. iodo-4-methylbenzamide. The product was obtained as a solid: 499 M* (M+H). 1-(romomthy)-2-chloro-4nltro-bonseno: A suspension of 2-chloro-4 nirotoluene (10.0 g, 58.3 mmol), N-bromosuccnilmide (NBS, 10.9 g, 61.2 mmol), and 2,2' 15 azobis(2-methylpropionitrle) (AIBN, 0.29 g, 1.75 mml) in 120 ML of CCle was heated at reflux under an abnosphere of Na for 12 h. The reaction mixture was cooled to ambient temperature, and-the solid was filtered and washed with EtOAc. The combined filtrate was washed with aq. NaHCO 3 , dried over Na*SO 4 , filtered, concentrated on rotovap, and further dried under vacuum. 'H NMR indicated the ratio of desired product to unreacted 2-chiloro-4 20 nitrotoluene to be 50:50. This material was used directly In the next step. 142.Chloro4nitrobenzyl)4methylpiperozine: To a solution of crude 1 (bromomethyl).2-chlorc-4-nito-benzene (29.1 mmol; 50% pure) In 30 mL of DCM was added Et 3 N (4.2 ML, 30 mmol) and 1-methylplperazlne (3.4 mL, 30 mmol). After string for 3 h at 25 ambient tenerature, aq NaHCOa was added and the mixture was extracted with DOM. The combined organic layer was dried over Na 2 80 4 , filtered, concentrated, and the resulting residue was purified by silica gel chromatography elutedd with 5% MeOH/DCM) to provide 6.80 g of product as a dark yellow oil. 30 3-ChIoros((4-metfhyipperozin-1.yl)methyaniline: To a solution of 1-(2-chloro-4 nitrobenzyl)-4-methylpiperazine (0.96 9, 3.6 mmol) In MeOHAater (4:1, 60 mL) was added 1.80 9 (33.7 mmol) of NH.CI and 1.47 9 (26.3 mmol) of Fe dust and the mixture heated at reflux under an atmosphere of Na for 2 h (HPLC Indicated no progress). To this was added 4 mL of glacial acetic acid and the mixture heated at reflux for an additional 2 h. The reaction 69 mixture was cooled to ambient temperature, filtered, and the 1iltrate concentrated. The residue was partitioned between EtOAc and saturated ar. NaHCO, the separated aqueous layer was extracted with EtOAc, and the combined organics washed with brine and dried over Na 2 3 4 , Upon concentration, the crude product was purified by silica gel chromatography 5 (eluted with 5-7% MeOHIDCM; silica gel deactivated with 1% triethylamine/DCM) to provide 0.53 g of product. Alternative Synthesis of N-[3-Chloro-4-((4-methylpiperazin4-yl)methyl)phenyi) 3-(Imidno[1,2-bpyrIdazin-3-yilthynyl)4-mthylbenzamide: N-(3-Chloro-4-((4.methy 10 piperazin1-yl)methyl)phenyl)-3(imidazoll,2-blpyridarin-3-yIethynyl)4-methylbenzamlde and Its mono hydrochloride salt can be prepared in an alternative synthesis similar to that described In Example I fion 3-(imidazoll,2-bipyridazin-3-ylethynyl)4-nethylbenzdc acid and 3-Chloro-4-((4-methylplperazin.eyl)methyl)nlline (as prepared above). The 3 (Imidazo[1,2-b]pyridazln-3-ylethynyl).4-methylbonzoic acid Is prepared In a manner similar to IS that described In Example I using 3-Ethynylimidazo[1.2-b)pyrldozlne and 3-iodo-4 methylbenzoic acid as Sonogashira coupling partners. EXAMPLE It8: 20 N.(3-Cyclopropy4-((4-methylpiperzineyl)mothyphonyl3-(mIdao1,2-bpyridazin 3-ylethynyI)4.methyIbenzamlde The title compound was synthesized from 3-ethynylimidazo[1,2-bpyridazine and N 25 (3-oyclopropyl-4-((4-methylpiperazin-1.yl)methyl)phenyl)--iodo-4-methylbenzOmide In a manner similar to that described for Example 14 (nitro reduction performed in a manner similar to that described for Example 17; 0.26M in MeOH/10%AQcOH). The product was obtained as a solid; 505 Mnf (M+H). 30 1-(2-Cyclopropyt-4-nitrobenzy.4-methylpiperaztne: A mixture of 1-(2-bromo-4 nitrobenzyl)4-methylpiperazine (094 g, 3,0 mmOl), 0.77 g (9.0 mmol) of cyclopropylboronic acid, 0.067 g (0.30 mmol) of Pd(OAC), 2.87 g (13.5 mmol) of KaPO4, and 0,168 9 (0.60 mml) of trlcylohexylphosphlne In 18 ml. of toluenewvater (5:1) was heated at renfux under an atmosphere of Ng for 19 h. The reaction mixture was concentrated and the crude product 70 was purified by silica gel chromatography (eluted with 5% MeOH/DCM; MeOH was pre saturated with ammonia gas) 1o provide 0.80 g of product EXAMPW.119; 5 3-(ImIdazo[1,2-bjpyridazIn-3.ylethynyl)-N-(4((4-methylpiperIn-1-yl)methyl)3 (trifluoromethiyl)phanylI)beizamide The title compound was synthesized from 3-ethynylImidazot1,2-bpyridazine and 3 10 lido-N-(4-4(4-mothylpiperazIn-1-yl)methyl)-3-(trIfluoromethyIpheny)benzemide In a manner similar to that described for Example 14. The product was obtained as a solid: 519 m/ (M+H), The titled compound can also be prepared according to the altemative synthesis described in example I from 3-(imidezo[1,2-b]pyridazin-3-ylethynyl)-4methylbenzol acid and 4-((4 15 methylpiperazin-I-y)methyl)-3-(trifluormethyl)aniline (as prepared in example 2). The 3 (Imidazo[1,2-b]pyridazin-3-yIethynyl)-methylbenzolo acid Is prepared In a manner similar to that described In Example 1 using 3-EthynylImidazoll,2-blpyrldazine and 3-lodo-4 methylbenzoic acid as Sonogashir coupling partners. 20 EAMPLE 20 N.(4.((4-(2-Hydroxyelhyt)piperazin-1-yl)methyl)-3-(trifluoromethyl)pheny)-3-(midazo[1,2 blpyridazin-3-ytehynyt)-4methylbenzamlde 25 The title compound was synthesized from 3-ethynylimIdazo[1,2-b]pyrldazine 0nd N (4-((4-(2-hydroxyethyl)plperazin-1-y)methyl)-3-(trfluoromethyl)phenyl)-3Iodo-4 mothylbenzamide in a manner similar to that described for Example 14. The product was obtained as a sold: 563 mz (M+H). 71 EXAMPLE 21: 3-(lmiduzo[1,2-bpyrdazIn-3-Y thyny)--methyl-N-(4-(piperazin-1-ylmothyl). (trifluoromethyl)phenyl)benamide 5 e -F. The title compound was synthesized from 3-ethynylimldezo[1,2-bpyridazine and tert butyl 4-(4--3-Iodo-4-methylbenzIdob2-(trlguoromethyl)benzyl)plperazine-1-rboxylate In a manner similar to that described for Example 14. Following deprotectlcn using saturated 10 MaOHiHCI (g), the product was obtained as a tris HCI salt: 519 mk (M+H). EXAMPLE 22: BIO10101 Evaluation of COMtpound. 15 Compounds of this Invention are evaluated In a variety of assays to determine their biological activities. For example, the compounds of the Invention con be tested for their ability to inhibit various protein kinases of interest. Some of the compounds tested displayed potent nanomolar activity against the following kinases: Abl, AbI T3151, Src and FGFR. Furthermore, several of these compounds were screened for antlproliferative actvIly In BaF3 20 cells Irensfooted with either wIld4ype Bor-AbI or the Bor-Abi T31 51 mutant and demonstrated activity In the range of 1-100 nM. The compounds con also be evaluated for their cytotoxic or growth Inhibitory effects on tumor cells of interest, e.g,, as described In more detal below and as shown above for some representative compounds. See e.g., WO 03/000188, pages 115 - 136, the full 25 contents of which are incorporated herein by reference. Some representative compounds are depicted below. 72 Cel e5 Compound ofe Ijnenon pr componsoarhenvenuon p nmff -1000 < 1000 < 1000 <1000 < 1000 <1000 1000 <1000 <1000 <1000 73 S1000 <1000 S1000 <1000 S1000 <1000 ~~ 00 1000 H3 000 1000 74 -1000 100 1000 <1000 <1000 <1000 <1000 <1000 0 1000 <1000 75 1000 1000D 110 1000 <1000 Ilk 0 1000 - 1000 W -,100 1000 1000 <1000 76 < <1000 < 1000 1000 <1000 <1000 '1000 77 1000 1000 1000 1000 41000 1000 < 1000 <1000 <1000 1000 78 1000 1000 1000 -1000 0' <1000 1000 <1000 IO 01000 1000 79 1000 <1000 1000 <1000 <1000 <1000 1000 1000 1000 81000 - 0so <1000 <1000 1 0 0 0 1 0 0 0 1000 1000 <1000 <1000 81 1000 <1000 1000 <1000 0 0 0 <1000 The compounds listed in the table below also showed Inhibitojy astivity against various protein kinase of interest. 82
C)
N a U I, / 0 C A 83 N - CF3 | 0 84 Kinrase Inhibition More specifically, the compounds described herein are screened for kinase inhibition activity as folows. Kinases suitable for use in the following protocol include, but re not limited to: Abi, Lck, Lyn, arc, Fyn, Syk, Zap-70, Ik, Tee, Bik, EGFR, ErbB2, Kdr, Fitl, FIt-3, 5 TeK c-Met InsR, and AKT. Kineses are expressed as either khase domains or full length constructs fused to glutathlone 8-transferase (GST) or polyHistidine tagged fusion proteins in either E. col or Baculovirus-High Five expression systems. They are purilled to near homogeneity by affinity chromatography as previously described (Lehr et al, 1996; Gish at al., 1995). In some 10 instances, kinases are co-expressed or mixed with purified or partially purified regulatory polypeptldes prior to measurement of activity, Kinase actIvity and inhibition can be measured by established protocols (see e.g., Braunwalder et a., 1996). In such cases, the transfer of 3 3 P04 from ATP to the synthetic substrates poly(Glu, Tyr) 4!1 or poly(Arg, ser) 3:1 attached to the bioactive surface of 1 5 mlcrotiter plates Is taken as a measure of enzyme activity. After an Incubation period, the amount of phosphate transferred Is measured by first washing the plate with 0.6% phosphoric acid, adding liquid schitlilant, and then counting in a liquid Scintiliation detector. The I050 is determined by the concentration of compound that causes a 50% reduction In the amount of 3 3 P incorporated onto the substrate bound to the plate. 20 In one method, the activated Idnose Is incubated with a biotinylated substrate peptide (containing tyr) with or without the presence of a compound of the invention. After the kinase-assay Incubation period, excess kinase Inhibitor is added to kill the kInese reaction along.with Europium -labeled anli-phospholyrosine antibody (Eu-Ab) and Allophycocyanin Streptavidin (SA-APC). The blotinylated substrate peptide (with or without phosphorylated 25 Tyrosine) in solution binds to the SA-APC via Blofin-Avidin binding. The Eu-Ab binds only to substrate with phosphorylated tryrosine. When the solution Is excited at e15nm, there is an energy transfer from the Europium to the APC when they are in close proximity (i.e. attached to the same molecule of biotinylated and phosphorylated substrate peptide). The APO then fluoresces at a wavelength of 685nm. Excitation and emission take place In a Walioo Victo V 30 plate reader where the plate is read fluorometrically and absorbances at 615 and 665nm are recorded. These data are then processed by an Excel plate processorwhich calculates IC50s of test compounds by converting the fluorescence into amounts of phosphorylated substrate made and determining the concentration of test compound that would be required to inhibit the development of phosphorylated substrate by 50% (IC50). 35 Other methods relying upon the transfer of phosphate to peptide Or polypeptide substrate containing tyrosine, shrine, threonine or histidine, alone, in combination with each other, or in combination with other amino acids, in solution or immobilized (i.e., solid phase) are also useful. For example, transfer of phosphate to a pepUde or polypeptide can also be detected 40 using scintillation proximity, Fluorescence Polarization or homogeneous time-resolved 85 fluorescence. Alternatively, kinase activity can be measured using antibody-based methods in which an antibody or polypeptido I used as a reagent to detect phospholylated target polypeptide. For additional background information on such assay methodologies, see e.g., 5 Braunwalder at al., 1996, Anal. Blochem. 234(1):23; Cleaveland et al., 1990, Anal Biochem, 190(2):249 Gish et at. (1995). Protein Eng, 8(6):609 Kolb et al (1998). Drug DIscov. TOda V. 3:333 Lehr et al (1990). Gene 169(2):27527 - 87 Seethala et al. (1998). Anal Biochem. 255(2):257 Wu et at, (2000) 1050 values In the low nanomlar range have been observed for Compounds of this 10 Invention against verous kineses, including Src, Abi and kdr. Cell-based assays Certain compounds of this invention have also been demonstrated cytotoxic or growth Inhibitory effects on tumor and other cancer coll lines and thus may be useful in the 1 5 treatment of cancer and other coll proliferative diseases. Compounds are assayed for anti tumor actiity using In vivo and in vitro assays which are well known to those skilled In the art. Generally, Initial screens of compounds to Identlfy candidate ant-cancer drugs are performed in cellular assays. Compounds identified as having anti-proliferative activity In such cell based assays can then be subsequently assayed in whole organisms for anti-tumor activity 20 and toxicity. Generally speaking, cell-based screens can be performed more rapidly and cost-effectively relative to assays that use whole organisms. For purposes of this invention, the terms "anti-tumor' and "antI-cancer" activity are used Interchangeably. Celi-based methods for measuring antiproliferatve activity are well known arid can be used for comparative characterization of compounds of this invention. In general, cell 25 proliferation and coll viability assays are designed to provide a detectable signal when cells are metaboilcally active. Compounds may be tested for antiproliferative activilty by measuring any observed decrease in metabolic activity of the colls after exposure of the cells to compound. Commonly used methods include, for example, measurement of membrane integrity (as a measure of cell vlability)(e.g. using byipan blue exclusion) or measurement of 30 DNA synthesis (e.g. by measuring incorporation of BrdU or SH-thymidine). Some methods for assaying coll proliferation use a reagent that Is converted into a detectable compound during cell proliferation. Particuiarty preferred compounds are tetrarolium salts and include without limitation MTT (3-(4, 5-dimethylthiazol-2-y)-2, 5 diphonyltetrazolum bromide; Sigma-Aldrich. St. Louis, MO), MTS (3-(4,5-dimethylthIazoe-2 35 yl)-5-(3-carboxymethoxypheny)- 2-(4-sulfophonyl)-2H-totrazollum), XTT (2,3-bIs(2-Methoxy 4-nitro-5-sulfophenyl).2H-tetrazolium-5-carboxannlide), INT, NBT. and MTV (Bombs at al. Blochimr Blophys Acta 1451t1):73-1i, 1999). Preferred assays utilizing tetraroliun salts d elect cell proliferation by detecting the prod uct of the enzymalc conversion of the tetrazollim salts into blue formazan derivatives, which are readily deected by spectroscopo 40 methods (Mosman. J. Immunol. Methods. 85:65-63, 1983). 86 Generally, preferred methods for assaying cell proliferation Involve incubating cells in a desired growth medium with and without the compounds to be tested. Growth conditions for various prokeryotic and eularyotic cells are well-known to those of ordinary skill In the art (Ausubel et al. Current Protocols In Molecular Biology. Wiley and Sons. 1999; Bonifacino et 5 at. Current Protocols in Cell Biology. Wiley and Sons. 1999 both Incorporated herein by reference). To detect cell proliferation, the tetrazollum salts are added to the Incubated cultured cells to allow enzymatIc conversion to the detectable product by active cells. Cells are processed, and the optical density of the cells Is determined to measure the amount of formazan derivatives. Furthermore, commercially available kIts, Including reagents and 10 protocols, ate avalalbe for examples, from Promega Corporation (Madison, W1), Sigma Aldrich (St. Louis, MO), and Trevigen (Galthersburg, MD). More specifically, the Cell proliferation assay we currently perform is using CellTiter 90 AQueous One Solution Coll Proliferation assay kit (Promaga, Cat#G3581). This assay Is a colorimetric method for determining the number of alive calls in proliferation or cytotoxicity 15 assays. The assay utilizing terazollum salts detect cell proliferation by detecting the product of the enzymollo conversion of the tetrazollum salts Into blue formazan d erivadves which can be measured by the absorbance at 490 nm In a plate reader, Walled Victor"V (PerkinElmer). An example of cell-based assay Is shown as below. The cei lines used In the assay are Ba/F3, a murine pro-B cell line, which have been stably transfected with full-length wid 20 type Scr-Abl or Bcr-Abi with various kinase domain point mutations (including T3511, Y253F, E255K, H396P, M351T etc) constructs. Parental BaF3 cell line Is used as control. These cell lines were obtained from Brian J. Druker (Howard Hughes Medical instltute, Oregon Health and Science University, Portland, Oregon, USA). BaJF3 cell expressing Ber-Abi or Bor-Abi mutants were maintained in PRMI 1640 growth medium with 200 IM L-gultamine, 10% FCS, 25 penicillin (200U/ml), and steptomycn (200 ugwml). Parental Ba/F3 cells were culture in the same medium supplemented with 10 nVmi IL-3. Parental Ba/F3 cells (supplemented with 1.-3) or BaF3 cells expressing WT or mutant Bor-AbI are plated In duplicate at 1x0 celswmeil in 90-well plates with the compounds In different concentrations in the media. The compounds are first desolved and diluted In 30 DM80 by preparation of 4-fold dilution; next equal volumes of compounds with DMSO are transferred to medium and then transferred to call plates. The final compound concentrations start from 10 pM to 6 nM. DMSO at same percentage is used as control. After compound was incubated with cells for 3 days, the numbers of active cells are measured using CellTiter gS AQueous One Solution Cell Proliferation assay kit following the kit Instruction. Basically, the 35 tetrszolium salts are added to the incubated cultured cells to yellow enzymatic conversion to the detectable product by active clls. Cells are processed, and the Opical density of the cells Is determined to measure the amount of formuzan derivatives. Mean +1- SD are generated from duplicated wells and reported as the percentage absorbance of controL I60s are calculated In best-fit curves using Micorsoft Excel-fit software. 40 87 . In addition, a wide variety of cell types may be used to screen compounds for antiprollferatlve activity, Including the following cell lines, among others: COLO 206 (colon cancer), DLD-1 (colon cancer), HCT-15 (colon cancer), HT29 (colon cancer), HEP G2 (Hepatoma), K.562 (Leukemia). A549 (Lung), NCI-H249 (Lung), MCF7 (Mammary), MDA 5 MB-231 (Mammary), SAOS-2 (Osteosarcom), OVCAR-3 (Ovarian), PANC-1 (Pancreas), DU-145 (Prostate), PC-3 (Prostate), ACHN (Renal), CAKi-1 (Renal), MG-63 (Sarcoma). While the cell line Is preferably mammallan, lower order eukaryotic cells such us yeast may also be used to screen compounds. Preferred rmammellan cell lines are derived from humans, rats, mice, rabbits, monkeys, hamsters, and guinea pigs since cell line, from 10 these organisms are well-studied and characterized. However, others may be ued as well, Suitable mammalian 01llIInes ae often derived from tumors. For example, the following tumor cell-types may be sources of calls for dulturing cells: melanoma, myelold leukemia, carcinomas of the lung, breast, ovaries, colon, kidney, prostate, pancreas and testes), cardlomyocytes, endothelial cells, epithellol cels, lymphocytes (T-cll and B cell), 15 mast cas, eosinophis, vascular Intimal cells, hopatocytos, leitocytes IncludIng mononuclear leukocytes, stem cells such as haemopoetic, neural, skin, lung, kidney, liver and myocyte stem cells (for use in screening for differentiation and de-differentiator factors), osteoclasts, chondrocytes and other connective tissue cells, keratinocytes, melanocytes, lver cels, kidney cells, and adipocytes. Non-limiting examples of mammalian coils lines that have been widely 20 used by researchers Include HeL, NIH/3T3, HT1050, CHO, GO8-i, 293T, WI-38 and CV1 /EBNA-1. Other cellular assays may be used which rely upon a reporter gone to detect metabolcally active cells. Non-limiting examples of reporter gene expression systems Include green fluorescent protein (GFP), and luciferase. As an example of the use of GrP to screen 25 for potential antitumor drugs, Sandman et al. (Chem BIOL 6:541-81; Incorporated herein by reference) used HeLa cells contaIning an Inducible varfant of GFP to detect compounds that Inhibited expression of the GFP, and thus Inhibited cell proliferation. Compounds Identified by such cellular assays as having anti-cell prolferation activity are then tested for anti-tumor activity in whole organisms. Preferably, the organisms are 30 mammalian. Well-chaacterized mammalians systems for studying cancer Include rodents such as rats and mice. Typically, a tumor of interest is transplanted into a mouse having a reduced ablity to mount an Immune response to the tumor to reduce the Ikelihood of rejection. Such mice Include for example, nude mice (athymic) and SCID (severe combined Immunodeficiency) mice. Other trangenic mice such as oncogene containing mice may be 35 used In the present assays (see for example USP 4,736,860 and USP 5175,353). Fore review and discussion on the use of rodent models for antitumor drug testing see Kerbel (CancerMetastasis Rev, 17:301-304. 199-99). In general, the tumors of interest are Implanted In a test organism preferably subcutaneously. The organism containing the tumor is treated with doses of candidate anti 40 tumor compounds. The size of the tumor is periodically measured to determine the effects of 88 the test compound on the tumor. Some tumor types are Implanted at sites other than suboutaneous sites (e.g. Intrapritoneal sites) and survival Is measured as the endpolnt. Parameters to be assayed with routine screening Include different tumor models, various tumor and drug routes, and dose amounts and schedule. For a review of the use of mice in 5 detecting antitumor compounds see Corbett et at (Invest New Drugs. 16:207-218. 1997; Incorporated herein by reference). 10 EXAMPLE 23z Pharmaceutical onmpositilons Representative pharmaceutical dosage forms of tihe compounds of this invention (the active 15 Ingredient being referred to as "Compound), are provided for therapeutic or prophylactic use In humans: (a) Tablet I mg/tablet 20 Com pound ........................................................ 100 Lactose Ph.Eur .......................... 182.75 Croscarmellose sodium .,................. 12.0 Maize starch paste (5% wlv paste).................. 2,26 Magnesium stearate ..................................... 3.0 25 (b) Tablet 11 mg/tablet Compound ...... - - ......................... ,.........50 Lactose Ph.Eur ..................... 223.75 30 Croscarmellose sodium................6.0 M aize starch ..................................................... 16.0 Polyvinylipyffolidone (5% w/v paste) ............... 2.25 Magnesium stearate .......................... :.................. 3.0 35 (c) Tablet III mg/tablet Compound..........................1.0 Lactose PhEur .,,...................... 93,25 Croscarmellose sodium .......................... 4.0 40 Malze starch paste (5% w/v paste).............. 0.75 Magnesium stearate ................................ 1.0 - 76 89 (d) Capsule m icapsule Com pound ......................................... ...... 10 Lactose Ph.Eur ..... ,..................................... 488.5 5 Magnesium .................................................... 1.b (e) Injection I (50 mg/ml) 10 Compound ......... .................. 5.0% wN 1M Sodium hydroxide solution ......................... 15.0% vNv 0. IM Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 .......... ,....................... 4.5% wtv Water for Injection to 100% is (1) Injection 11 (10 mgiml) Compound............. ..... ....... ,.............1.0% WNi 20 Sodium phosphate BP ..................................... 3.6% w/v Q. i M Sodium hydroxide solution .. ,................ 15.0% vv Water for injection to 100% 25 (g) Injection III (' mg/mI, buffered to pH6) Compound .,...................... ............................. 0. 1 % wN Sodium phosphate BP ...................................... 2.26% wv Citric acid ...................................................... 0.38% vN 30 Polyethylaleglyol400 ................. 3.5% w/v Water for Injectlon to 100% (h) Aerosol I mg/ml 35 Compound ...... , .................................... 10.0 Sorbitantrloleate ......................................... 13,5 Trichloroiluoromethane .................... 910,0 Dichblorodifluoromethano ................... ,.......... 490.0 40 90 (1) Aerosol I mg/ml Compound ................... ................... ..... 0.2 Sorbitan trioleate o........................................ 0.27 5 Tichlorofuoromethane ................... ..... 70.0 Dichlorodifluoromethane ................. ........... 280.0 Dichlorotetrafuomethane ....................... 1094.0 10 () Aerosol Ill mg/mi Compound ................................... ........... 2.5 Sorbitan trioleote .......................... 3,38 Trichlorofluoromethane ............... ~......... 67.5 15 Dlcltorodifluoromethane .................... 1086.0 Dlchlorotetreluoroethane............. 191.6 (k) Aerosol IV mg/ml 20 Com pound .................................................... 2.5 Soya lecithin.........................2,7 Trichlorofluoromethne........................ 67.5 Dichlorodfluoromethane ....................... 1086.0 Dichlorototraguoroethane........................191.6 25 (1) Ointment ml Compound .,.......................................... 40 mg Ethanol ........-- ................ .... .. 300 p1 W ater ............... -. ....................... ... 300 p1 30 1-Dodecylaracycloheptsn one -.......... 50 pl Propylene glyco ............. --................ l.... , to 1 ml Note: These formulations may be prepared using conventional procedures well known in the phormacetloal art. The tablets (a)-(o) may be enteric coated by conventional means, if 35 desired to provide a coating of cellulose acetate phthalate, for example. The aerosol formulations (h)-(k) my be used In conjunction with standard, metered dose aerosol dispensers, and the suspending agents sorbitan trioleate and soya lecithin may be replaced by an alternative suspending agent such as sorbltin monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol olet or olele acid. 40 91 -91A Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise', and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of Integers or steps but not the exclusion of any other integer or step or group of integers or steps, 5 The reference in this specification to any prior publication (or Information derived from It), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or Information derived from It) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
Claims (45)
1. A compound of formula: (R e) s-: H N / H (Rb)p 5 (aL1'0 L2 1 (Rd), wherein: Ll is NR 1 C(O) or C(O)NR 1 ; 10 L2 (Rd)w 0D (Rb)/ ( p has one of the following structures: 1j K'N or 92 H:\rbr\ntrovn\NRPortbl\DCC\RBR\7605999_I.docx- 10/04/2015 each occurrence of Ra is independently selected from the group consisting of halo, alkyl, and cycloalkyl; 5 each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, NR R , alkoxy, amino, -NH-alkyl, -C(O)NH-alkyl, -NHC(O)-alkyl, -NHC(O)NH-alkyl, -NHC(NH)-alkyl, NHC(NH)NH 2 , -NH(CH 2 )x-heteroaryl, -NH(CH 2 )x-heterocyclyl, -NH(CH 2 )x-aryl, and -(CH 2 )xC(O)NH 2 , wherein x is 0, 1, 2 or 3; 10 each of R1, R2 and R3 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, 2 3 cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R and R , taken together with the nitrogen atom to which at least one of R 2 and R 3 is attached, form a 5- or 6- membered heterocyclyl or heteroaryl ring; 15 each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, 20 acyloxy, haloalkoxy, =0, =S, =NH, =NNR2 R 3 , =NNHC(O)R 2 , =NNHCO 2 R 2 , and =NNHSO 2 R 2 , and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, 25 alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0,1, 2, 3, or 4; and s is 0, 1, 2, or 3; 30 or a pharmaceutically acceptable salt thereof.
2. A compound of formula: 93 H:Vbr\Introvn\NRPortbl\DCC\RBR\7605999_I.docx-10/04/2015 NL N N wherein has one of the following structures: 5 each occurrence of R a is independently selected from the group consisting of halo, alkyl, and cycloalkyl; 10 each occurrence of R b is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of R' is independently selected from the group consisting of halo, alkyl, cycloalkyl, 15 NR 2R 3, alkoxy, amino, -NH-alkyl, -C(O)NH-alkyl, -NHC(O)-alkyl, -NHC(O)NH-alkyl, -NHC(NH) alkyl, -NHC(NH)NH2, -NH(CH2)x-heteroaryl, -NH(CH2)x-heterocyclyl, -NH(CH2)x-aryl, and (CH2)xC(O)NH2, wherein x is 0, 1, 2 or 3; 20 each of R1, R 2 and R 3 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, 2 3 cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R and R , taken together with the nitrogen atom to which at least one of R 2 and R 3 is attached, form a 5- or 6- membered heterocyclyl or heteroaryl; 25 each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, 94 H:\rbr\Interwoven\NRPortbl\DCC\RBR\7605999_I.docx- 10/04/2015 alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2 R 3 , =NNHC(O)R 2 , =NNHCO 2 R 2 , and =NNHSO 2 R 2 , and 5 each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, 10 hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0,1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and 15 s is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof. 20
3. The compound of claim 1, in which Ring D is piperazinyl; Rd is C1-C6 alkyl; and w is 1.
4. A compound selected from Formula Ic and Illc: H (R*)R N H N (Ra)m (R\p 25 Formula IIc 95 H:\rbr\ntrovn\NRPortbl\DCC\RBR\7605999_I.docx- 10/04/2015 N H (Re) , ZN ,N Rd (Rb)p N (Ra)m NNH 0 Formula Ilc wherein: 5 each occurrence of Ra is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of R is independently selected from the group consisting of halo, alkyl, and 10 cycloalkyl; each occurrence of R' is independently selected from the group consisting of halo, alkyl, and cycloalkyl; 15 Rd is a C1-C6 alkyl group, unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR 2 R 3 , =NNHC(O)R 2 , =NNHCO 2 R 2 , and 20 =NNHSO 2 R2; each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, NR R , alkoxy, amino, -NH-alkyl, -C(O)NH-alkyl, -NHC(O)-alkyl, -NHC(O)NH-alkyl, -NHC(NH)-alkyl, NHC(NH)NH 2 , -NH(CH 2 )x-heteroaryl, -NH(CH 2 )x-heterocyclyl, -NH(CH 2 )x-aryl, and -(CH 2 )xC(O)NH 2 , 25 wherein x is 0, 1, 2 or 3; each of R2 and R3 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, 2 3 cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R and R , taken together with the nitrogen atom to which at least one of R 2 and R 3 is attached, form a 5- or 6 30 membered heterocyclyl or heteroaryl ring; 96 H:\rbr\ntrovn\NRPortbl\DCC\RBR\7605999_I.docx- 10/04/2015 each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, 5 dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2 R 3 , =NNHC(O)R 2 , =NNHCO 2 R 2 , and =NNHSO 2 R 2 , and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, 10 alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0, 1, 2, 3, or 4; 15 pis o,1,2,3,or4; s is 0, 1, 2, or 3; and v is 0, 1,2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof. 20
5. The compound of claim 4, wherein s is 0.
6. The compound of claim 4, wherein s is 1, 2, or 3 and at least one Re is halo, C1-C6 alkyl, amino, -NH-alkyl, -C(O)NH-alkyl, -NHC(O)-alkyl, -NHC(O)NH-alkyl, -NHC(NH)-alkyl, -NHC(NH)NH 2 , 25 NH(CH 2 )x-heteroaryl, -NH(CH 2 )x-heterocyclyl, -NH(CH 2 )x-aryl or -(CH 2 )xC(O)NH 2 , in which x is 0, 1, 2 or 3.
7. A composition comprising a mono-hydrochloride salt of (R)-N-(4-((3-(Dimethylamino)pyrrolidin 1 -yl)methyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1 ,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide, and 30 a pharmaceutically acceptable carrier.
8. A composition comprising a mono-hydrochloride salt of 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl) 4-methyl-N-(4-((4-methylpiperazin-1 -yl)methyl)-3-(trifluoromethyl)phenyl)benzamide, and a pharmaceutically acceptable carrier. 35
9. A composition comprising a mono-hydrochloride salt of N-(3-Chloro-4-((4-methylpiperazin-1 yl)methyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide, and a pharmaceutically acceptable carrier. 97 H:\rbr\ntrovn\NRPortbl\DCC\RBR\7605999_I.docx- 10/04/2015
10. A composition comprising the compound, N-(3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4 methylphenyl)-4-((4-methylpiperazin-1 -yl)methyl)-3-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 5
11. A composition comprising the compound, N-(3-Cyclopropyl-4-((4-methylpiperazin-1 yl)methyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. A composition comprising the compound, N-(4-((4-(2-Hydroxyethyl)piperazin-1 -yl)methyl)-3 10 (trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. A method of treating cancer in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of Formula I: 15 (Rt) H H (Rb)p (Ra)m A B Formula 1 20 or a tautomer, or an individual stereoisomer or a mixture of stereoisomers thereof wherein: Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with Rt groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, 25 partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from the group consisting of 0, N, and S and being optionally substituted with 1-4 Re groups; Ring A is a 5- or 6-membered aryl or heteroaryl ring; 30 Ring B is a 5- or 6-membered aryl or heteroaryl ring; L' is selected from NR 1 C(O), C(O)NR 1 , NR 1 C(O)O, NR 1 C(O)NR or OC(O)NR; 98 H:\rbr\ntrovn\NRPortbl\DCC\RBR\7605999_I.docx- 10/04/2015 each occurrence of Ra, Rb and Rt is independently selected from the group consisting of halo, -CN, NO 2 , -R 4 , -OR 2 , -NR 2 R 3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2 C(O)YR 2 , -SC(O)YR 2 , -NR 2 C(=S)YR 2 , OC(=S)YR 2 , -C(=S)YR 2 , -YC(=NR 3 )YR 2 , -YP(=O)(YR 4 )(YR 4 ), -Si(R 2 ) , -NR 2 SO 2 R 2 , -S(O)rR 2 , 5 SO 2 NR 2 R 3 and -NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, -0-, -S- or -NR 3 -; Re, at each occurrence, is independently selected from the group consisting of halo, =0, -CN, -NO 2 , R 4 , -OR 2 , -NR 2 R 3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2 C(O)YR 2 , -SC(O)YR 2 , -NR 2 C(=S)YR 2 , -OC(=S)YR 2 , C(=S)YR 2 , -YC(=NR 3 )YR 2 , -YP(=O)(YR 4 )(YR 4 ), -Si(R 2 ) 3 , -NR 2 S0 2 R 2 , -S(O)rR 2 , -SO 2 NR 2 R 3 and 10 NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, -0-, -S- or -NR 3 -; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; 15 alternatively, R 2 and R 3 , taken together with the atom to which they are attached, form a 5- or 6 membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from the group consisting of N, 0 and S(O)r; each occurrence of R 4 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, 20 cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, 25 heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2 R 3 , =NNHC(O)R 2 , =NNHCO 2 R 2 , and =NNHSO 2 R 2 , and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups 30 selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; 35 m is 0,1, 2, 3 or 4; n is 2 or 3; p is 0, 1, 2, 3, 4 or 5; and, r is 0, 1 or 2; 99 H:\rbr\ntrovn\NRPortbl\DCC\RBR\7605999_I.docx- 10/04/2015 or a pharmaceutically acceptable salt thereof; wherein the cancer is selected from primary cancer, metastatic cancer, solid tumor, lymphoma, leukemia, and cancer resistant to other therapies. 5
14. The use of a compound of Formula I: (Rt H (Rb)p (Ra)m A 10 Formula I or a tautomer, or an individual stereoisomer or a mixture of stereoisomers thereof wherein: Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being 15 carbon, substituted on at least two ring atoms with Rt groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from the group consisting of 0, N, and S and being optionally substituted with 1-4 Re groups; 20 Ring A is a 5- or 6-membered aryl or heteroaryl ring; Ring B is a 5- or 6-membered aryl or heteroaryl ring; L' is selected from NR 1 C(O), C(O)NR 1 , NR 1 C(O)O, NR 1 C(O)NR or OC(O)NR; 25 each occurrence of Ra, Rb and Rt is independently selected from the group consisting of halo, -CN, NO 2 , -R 4 , -OR 2 , -NR 2 R 3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2 C(O)YR 2 , -SC(O)YR 2 , -NR 2 C(=S)YR 2 , OC(=S)YR 2 , -C(=S)YR 2 , -YC(=NR 3 )YR 2 , -YP(=O)(YR 4 )(YR 4 ), -Si(R 2 ) 3 , -NR 2 SO 2 R 2 , -S(O)rR 2 , SO 2 NR 2 R 3 and -NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, -0-, -S- or -NR 3 -; 30 Re, at each occurrence, is independently selected from the group consisting of halo, =0, -CN, -NO 2 , R 4 , -OR 2 , -NR 2 R 3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2 C(O)YR 2 , -SC(O)YR 2 , -NR 2 C(=S)YR 2 , -OC(=S)YR 2 , 100 H:\rbr\ntrovn\NRPortbl\DCC\RBR\7605999_I.docx- 10/04/2015 C(=S)YR 2 , -YC(=NR 3 )YR 2 , -YP(=O)(YR 4 )(YR 4 ), -Si(R 2 ) 3 , -NR 2 S0 2 R 2 , -S(O),R 2 , -SO 2 NR 2 R 3 and NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, -0-, -S- or -NR 3 -; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, 5 cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; alternatively, R 2 and R 3 , taken together with the atom to which they are attached, form a 5- or 6 membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from the group consisting of N, 0 and S(O)r; 10 each occurrence of R 4 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is 15 unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2 R 3 , =NNHC(O)R 2 , =NNHCO 2 R 2 , and =NNHSO 2 R 2 , and 20 each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, 25 hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0,1, 2, 3 or 4; n is 2 or 3; p is 0, 1, 2, 3, 4 or 5; and, 30 r is 0, 1 or 2; or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a mammal in need thereof, wherein the cancer is selected from primary cancer, metastatic cancer, solid tumor, lymphoma, leukemia, and cancer resistant to other therapies. 35
15. The method of claim 13 or the use of claim 14, wherein the cancer is leukemia.
16. The method or use of claim 15, wherein the leukemia is selected from the group consisting of myeloid, lymphocyctic, myelocyctic and lymphoblastic leukemia. 101 H:\rbr\ntrovn\NRPortbl\DCC\RBR\7605999_I.docx- 10/04/2015
17. The method or use of claim 16, wherein the leukemia is chronic myeloid leukemia (CML).
18. The method or use of claim 16, wherein the leukemia is acute lymphoblastic leukemia (ALL). 5
19. The method of claim 13 or the use of claim 14, wherein the cancer is selected from the group consisting of cancers of the breast, cervix, colon, rectum, lung, ovaries, pancreas, prostate, head and neck, gastrointestinal stroma, melanoma, multiple myeloma, non-Hodgkin's lymphoma and gastric cancers. 10
20. A method of inhibiting a tyrosine kinase using a compound of Formula I: (Rt H (Rb)p (Ra)m A 15 Formula I or a tautomer, or an individual stereoisomer or a mixture of stereoisomers thereof wherein: Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being 20 carbon, substituted on at least two ring atoms with Rt groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from the group consisting of 0, N, and S and being optionally substituted with 1-4 Re groups; 25 Ring A is a 5- or 6-membered aryl or heteroaryl ring; Ring B is a 5- or 6-membered aryl or heteroaryl ring; Ll is selected from NR 1 C(O), C(O)NR 1 , NR 1 C(O)O, NR 1 C(O)NR or OC(O)NR 1 ; 30 each occurrence of Ra, Rb and Rt is independently selected from the group consisting of halo, -CN, NO 2 , -R 4 , -OR 2 , -NR 2 R 3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2 C(O)YR 2 , -SC(O)YR 2 , -NR 2 C(=S)YR 2 , 102 H:\rbr\ntrovn\NRPortbl\DCC\RBR\7605999_I.docx- 10/04/2015 OC(=S)YR 2 , -C(=S)YR 2 , -YC(=NR 3 )YR 2 , -YP(=O)(YR 4 )(YR 4 ), -Si(R 2 ) 3 , -NR 2 SO 2 R 2 , -S(O),R 2 , SO 2 NR 2 R 3 and -NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, -0-, -S- or -NR 3 -; Re, at each occurrence, is independently selected from the group consisting of halo, =0, -CN, -NO 2 , 5 R4, -OR 2 , -NR 2 R 3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2 C(O)YR 2 , -SC(O)YR 2 , -NR 2 C(=S)YR 2 , -OC(=S)YR 2 , C(=S)YR 2 , -YC(=NR 3 )YR 2 , -YP(=O)(YR 4 )(YR 4 ), -Si(R 2 ) 3 , -NR 2 S0 2 R 2 , -S(O)rR 2 , -SO 2 NR 2 R 3 and NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, -0-, -S- or -NR 3 -; R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, 10 cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; alternatively, R 2 and R 3 , taken together with the atom to which they are attached, form a 5- or 6 membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from the group consisting of N, 0 and S(O)r; 15 each occurrence of R 4 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is 20 unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2 R 3 , =NNHC(O)R 2 , =NNHCO 2 R 2 , and =NNHSO 2 R 2 , and 25 each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, 30 hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0,1, 2, 3 or 4; n is 2 or 3; p is 0, 1, 2, 3, 4 or 5; and, 35 r is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.
21. The use of a compound of Formula I: 103 H:\rbr\ntrovn\NRPortbl\DCC\RBR\7605999_I.docx- 10/04/2015 (R t ) H (Rb)p (Ra)m a Formula I 5 or a tautomer, or an individual stereoisomer or a mixture of stereoisomers thereof wherein: Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with Rt groups, at least two of which being located on 10 adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6- membered ring (Ring E), containing 0-3 heteroatoms selected from the group consisting of 0, N, and S and being optionally substituted with 1-4 Re groups; Ring A is a 5- or 6-membered aryl or heteroaryl ring; 15 Ring B is a 5- or 6-membered aryl or heteroaryl ring; L' is selected from NR 1 C(O), C(O)NR 1 , NR 1 C(O)O, NR 1 C(O)NR or OC(O)NR; 20 each occurrence of Ra, Rb and Rt is independently selected from the group consisting of halo, -CN, NO 2 , -R 4 , -OR 2 , -NR 2 R 3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2 C(O)YR 2 , -SC(O)YR 2 , -NR 2 C(=S)YR 2 , OC(=S)YR 2 , -C(=S)YR 2 , -YC(=NR 3 )YR 2 , -YP(=O)(YR 4 )(YR 4 ), -Si(R 2 ) 3 , -NR 2 SO 2 R 2 , -S(O)rR 2 , SO 2 NR 2 R 3 and -NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, -0-, -S- or -NR 3 -; 25 Re, at each occurrence, is independently selected from the group consisting of halo, =0, -CN, -NO 2 , R 4 , -OR 2 , -NR 2 R 3 , -C(O)YR 2 , -OC(O)YR 2 , -NR 2 C(O)YR 2 , -SC(O)YR 2 , -NR 2 C(=S)YR 2 , -OC(=S)YR 2 , C(=S)YR 2 , -YC(=NR 3 )YR 2 , -YP(=O)(YR 4 )(YR 4 ), -Si(R 2 ) 3 , -NR 2 S0 2 R 2 , -S(O)rR 2 , -SO 2 NR 2 R 3 and NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, -0-, -S- or -NR 3 -; 30 R1, R2 and R3 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; 104 H:\rbr\ntrovn\NRPortbl\DCC\RBR\7605999_I.docx- 10/04/2015 alternatively, R 2 and R 3 , taken together with the atom to which they are attached, form a 5- or 6 membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from the group consisting of N, 0 and S(O)r; 5 each occurrence of R 4 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl and heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, 10 alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2 R 3 , =NNHC(O)R 2 , =NNHCO 2 R 2 , and =NNHSO 2 R 2 , and 15 each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more groups selected from the group consisting of amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; 20 m is 0,1, 2, 3 or 4; n is 2 or 3; p is 0, 1, 2, 3, 4 or 5; and, r is 0, 1 or 2; 25 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting a tyrosine kinase.
22. The method of claim 20 or the use of claim 21, wherein the tyrosine kinase is Src or Abl. 30
23. The method or use of claim 22, wherein the tyrosine kinase is BCR/Abl or a mutant variant thereof.
24. The method or use of claim 23, wherein the mutant variant of BCR/Abl has a T3151 mutation. 35
25. A method for making 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4 methylpiperazin-1 -yl)methyl)-3-(trifluoromethyl)phenyl)benzamide having the chemical formula: 105 H:Vbr\Introvn\NRPortbl\DCC\RBR\7605999 _Ldocx-10/04/2015 wherein the method comprises: reacting 3-ethynylimidazo[1,2-b]pyridazine with 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1 -yl)methyl) 5 3-(trifluoromethyl)phenyl)benzamide.
26. The method according to claim 25, wherein the 3-ethynylimidazo[1,2-b]pyridazine is formed by the method comprising reacting 3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine in the presence of tetrabutyl ammonium fluoride. 10
27. The method according to claim 26, wherein the 3-((trimethylsilyl)ethynyl)imidazo[1,2-b] pyridazine is formed by the method comprising reacting 3-bromoimidazo[1,2-b]pyridazine in the presence of ethynyltrimethylsilane. 15
28. The method according to claim 27, wherein the 3-bromoimidazo[1,2-b]pyridazine is reacted with ethynyltrimethylsilane in the presence of Pd(PPh 3 )4.
29. The method according to claim 25, wherein the 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1 yl)methyl)-3-(trifluoromethyl)phenyl)benzamide is formed by the method comprising reacting 4-((4 20 methylpiperazin-1 -yl)methyl)-3-(trifluoromethyl)aniline with 3-iodo-4-methylbenzoyl chloride.
30. The method according to claim 29, wherein the 4-((4-methylpiperazin-1-yl)methyl)-3 (trifluoromethyl)aniline is reacted with the 3-iodo-4-methylbenzoyl chloride in the presence of N,N diisopropylethylamine and DMAP. 25
31. The method according to claim 30, wherein the 3-iodo-4-methylbenzoyl chloride is formed by the method comprising reacting 3-iodo-4-methylbenzoic acid with SOCl 2 .
32. The method according to claim 29, wherein the 4-((4-methylpiperazin-1-yl)methyl)-3 30 (trifluoromethyl)aniline is formed by the method comprising reacting 1-methyl-4-(4-nitro-2 (trifluoromethyl)benzyl)piperazine with sodium hydrosulfite. 106 H:Vbr\Interwoven\NRPortbl\DCC\RBR\7605999 L.docx-10/04/2015
33. The method according to claim 32, wherein the 1-methyl-4-(4-nitro-2-(trifluoromethyl) benzyl)piperazine is formed by the method comprising reacting 1-(bromomethyl)-4-nitro-2 (trifluoromethyl)benzene with 1 -methylpiperazine. 5
34. The method according to claim 33, wherein the 1-(bromomethyl)-4-nitro-2 (trifluoromethyl)benzene is formed by the method comprising reacting 2-methyl-5-nitrobenzotrifluoride in the presence of NBS and AIBN. 10
35. The compound, 3-ethynylimidazo[1,2-b]pyridazine.
36. The compound, 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1 -yl)methyl)-3 (trifluoromethyl)phenyl)benzamide. 15
37. A method for making 3-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4 methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide having the chemical formula: NN wherein the method comprises: 20 reacting 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzoic acid with 4-((4-methylpiperazin-1 yl)methyl)-3-(trifluoromethyl)aniline.
38. The method according to claim 37, wherein the 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4 25 methylbenzoic acid is formed by the method comprising reacting 3-ethynylimidazo[1,2-b]pyridazine with 3-iodo-4-methylbenzoic acid.
39. The method according to claim 38 wherein the 3-ethynylimidazo[1,2-b]pyridazine is formed by the method comprising reacting 3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine with 30 tetrabutylammonium fluoride. 107 H:\rbr\Intrwovn\NRPortbl\DCC\RBR\7605999_I.docx- 10/04/2015
40. The method according to claim 39, wherein the 3-((trimethylsilyl)ethynyl)imidazo[1,2 b]pyridazine is formed by the method comprising reacting 3-bromoimidazo[1,2-b]pyridazine in the presence of ethynyltrimethylsilane. 5
41. The method according to claim 40 wherein the 3-bromoimidazo[1,2-b]pyridazine is reacted with ethynyltrimethylsilane in the presence of Pd(PPh 3 )4.
42. The method according to claim 37, wherein the 4-((4-methylpiperazin-1-yl)methyl)-3 10 (trifluoromethyl)aniline is formed by the method comprising reacting 1-methyl-4-(4-nitro-2 (trifluoromethyl)benzyl)piperazine with sodium hydrosulfite.
43. The method according to claim 42, wherein the 1-methyl-4-(4-nitro-2 (trifluoromethyl)benzyl)piperazine is formed by the method comprising reacting 1 -(bromomethyl)-4 15 nitro-2-(trifluoromethyl)benzene with 1 -methylpiperazine.
44. The method according to claim 43, wherein the 1-(bromomethyl)-4-nitro-2 (trifluoromethyl)benzene is formed by the method comprising reacting 2-methyl-5-nitrobenzotrifluoride in the presence of NBS and AIBN. 20
45. A compound according to any one of claims 1-6, 35 or 36, a composition according to any one of claims 7 to 12, a method according to any one of claims 13, 15-20, 22-24 or 25-34, or a use according to any one of claims 14-19, 21-24 or 37-44, as hereinbefore described with reference to the examples. 25 108
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