AU2015210454B2 - Bicyclic heteroaryl compounds - Google Patents

Abstract

H:Vbr\Inte ovn\NRPortb\DCC\RBR\8I 83208_l.docx-6/08/2015 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. (Rt) T I I (Rb)p (Ra)m A B (5)

Description

H:\cbr\Jjitaw«v<r.vS'Ri»(.»ll:.J\DCC\RBR'j8J8'i2()8J..di3cx^6/08/20].5 2015210454 07 Aug 2015

Bicyclic Heteroaryl Compounds

This application is a divisional application of Australian Application No. 2013201242 the specification of which as originally filed is incorporated herein in its entirety 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-abi, Blk, Brk, c-kit, c-met, c-src, CDK1, CDK2, CDK3, 10 CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Pak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK and Zap70. 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 methods for treating a 30 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 Abl and mutant variants thereof), including, among others, advanced cases and cases which 35 are resistant or refractory to one or more other treatments. -1 - H:\sxdtfnterwoven\NRPortbl\DCC\SXD\l 1159717_l.docx.-20/09/2016 2015210454 20 Sep 2016

In accordance with one embodiment of the present invention, there is provided a compound of formula:

wherein 10 15 20 25

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 Ο, N, and S(0)r; L1 is C(0)NR1; L2 is -(CH2)z-; 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 cycloalkyl; each occurrence of Rd is independently selected from the group consisting of halo, alkyl, cycloalkyl, and -NR2R3; each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, -NR2R3, alkoxy, amino, -NH-alkyl, -C(0)NH-aikyl, -NHC(0)-aikyl, -NHC(0)NH-alkyl, -NHC(NH)-alkyl, -NHC(NH)NH2, -NH(CH2)x-heteroaryl, -NH(CH2)X-heterocyclyl, -NH(CH2)x-aryl, and -(CH2)xC(0)NH2, 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, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R2and R3, - 1A- H:\sxd\Interwoven\NRPortbl\DCC\SXD\l 1159717_1 .docx-20/09/2016 2015210454 20 Sep 2016 taken together with the nitrogen atom to which at least one of R2 and R3 is attached, form a 5-or 6- membered heterocyclyl or heteroaryl; each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl 5 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, haloalkoxy, =0, =S, =NH, =NNR2R3, =NNHC(0)R2, 10 =NNHC02R2, and =NNHS02R2, 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, 15 dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0,1,2, 3, or 4; 20 p is 0, 1,2, 3, or 4; s is 0, 1,2, or 3; 25 w is 0, 1,2, 3, 4, or 5; and z is 1,2, 3, or 4; or a pharmaceutically acceptable salt thereof. 30

In accordance with another embodiment of the present invention, there is provided a compound of formula: - IB - H:\sxd\Interwoven\NRPortbl\DCC\SXD\l 115 9717_1 .docx-20/09/2016

(RC)v 2015210454 20 Sep 2016 5 wherein

Ring C is a 5- or 6-membered heterocyclic or heteroaryl ring, comprising carbon atoms and 1-3 heteroatoms independently selected from Ο, N, and S(O); 10 L1 is C(0)NR1; each occurrence of Ra is independently selected from the group consisting of halo, alkyl, and cycloalkyl; 15 each occurrence of Rb is independently selected from the group consisting of halo, alkyl, and cycloalkyl; each occurrence of Rc is independently selected from the group consisting of halo, -CN, alkyl, cycloalkyl, and -NR2R3; 20 each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, -NR2R3, alkoxy, amino, -NH-alkyl, -C(0)NH-alkyl, -NHC(0)-alkyl, -NHC(0)NH-alkyl, -NHC(NH)-alkyl, -NHC(NH)NH2, -NH(CH2)x-heteroaryl, -NH(CH2)X-heterocyclyl, -NH(CH2)x-aryl, and -(CH2)xC(0)NH2, 25 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, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R2and R3, taken together with the nitrogen atom to which at least one of R2 and R3 is attached, form a 5-30 or 6- membered heterocyclyl or heteroaryl; - 1C- H:\sxd\Interwoven\NRPortbl\DCC\SXD\l 1159717_1 .docx-20/09/2016 2015210454 20 Sep 2016 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, 5 alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2R3, =NNHC(0)R2, =NNHC02R2, and =NNHS02R2, and each of the aryl and heteroaryl moieties is unsubstituted or substituted with one or more 10 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; 15 m is 0,1,2, 3, or 4; p is 0, 1,2, 3, or 4; 20 s is 0, 1,2, or 3; and v is 0, 1,2, 3, or 5; or a pharmaceutically acceptable salt thereof. 25 - ID- 2015210454 07 Aug 2015 included are compounds of Formula !:

Ή

(Rb)p s

Formula 1 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 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms (each of which may be C or N) 10 with R1 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 Ο, N, and S and being optionally substituted with 1-4 R® groups; 15 Ring A represents a 5- or 6-membered aryi or heteroaryl ring and Is optionally substituted with 1-4 Ra groups;

Ring B represents a 5- or 6-membered aryi or heteroaryl ring and is optionally substituted with 1-5 Rb goups; 20 L1 is selected from NR1C(0), C(0)NR1, NK1C(Q)Q, NR1C(0)NR\ and 0C(0)NR1; each occurrence of R®, Rb and R* is independently selected from the group consisting of halo, -CM, -NOj, -R4, -OR2, -NRZR3, -C(0)VR2, -OC(0)VR2, -NR2C(0)YR2, -SC(G)YR2, 25 -NR2C(«S)YR2 -OC(»S)YR2 -C(=>S)YR2, -YC(*NR3)YR2, -YP(«0)(YR4)(YR4), -Si(R2}3, ~NR2SOzR2, -SjOJrR2, -SOzNR2Rs and -NR2S02NR2R3, wherein each Y is independently a bond,-0-,-S-or-NR3-; R8, at each occurrence, is independently selected from the group consisting of haio, =0, -30 CN, -NOj. -R4, -OR2, -NR*R3, -C(0)YR2, -OC{0)YR2, -NR2C(0)YR2, -SC(0)YR2, -NR2C(=S)YR2, -OC(=S)YR2, -C(=S)YR2,-YC(=NR3)YR2, -YP(=0)(YR4)(YR4), -SI(R2)3, 2 2015210454 07 Aug 2015 (R%- -NR2SOsRz, -S{0),R2, -SOzNR2Ri and -NR2S02NRZR3, wherein each Y is independently a bond, Ό-, -S- or -NR3-; R1, R2 and R5 are independently selected from H, alky!, alkenyl, alkynyl, cycloalkyl, S cycloalkeny!, cycloalkynyl, aryl, heterocyclic and heteroaryl; alternatively, R2 and R3, taken together with the atom to which they are attached, form a 5- or 8- membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from Μ, O and S(0)r; ?0 each occurrence of R4 is independently selected from alkyl, alkenyl, alkynyl, cyctoalkyl, cycioaikenyt, cycloalkynyl, aryl, heterocyclic and heieroaryt; each of the alkyl, alkenyl, alkynyl, cycloaikyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic 15 and heieroary! moieties in this Section 1 is optionally substituted; m is 0,1, 2, 3 0r4; 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 2 5 all subsequent occurrences except to She extent otherwise specified. 2. Featured Classes of Compounds and their Use, Generally 30 Compounds of this invention include those in which Ring T has the following structure: r\

A T V., where Ring E Is a 5- or 6-membered unsaiurated ring (formed by two Rf- groups together with the Ring T atoms to which they are attached, as described above) and s is 0, 1,2,3 3 15 2015210454 07 Aug 2015 or 4, These are illustrated by the «impounds of formula I in which the fused Ring T ring system is one of the following (In which one of the optional R8 substituents is depicted): ( \VN^/ Re

N »N,

f V

Rrf) \ Λ"

5 Other classes of particular interest are compounds of Formula I, as described in Part 1, in which Ring E is a 6-membered ring, otherwise as described above, illustrative examples of such compounds include compounds of Formula l in which Ring T (with Sts attached Ring E) is a fused bicycilc heteroary! of the foliowing types:

For the previously described class and subclasses· of compounds, as in all compounds of this invention, Ring A and Ring B are as previously defined In Part 1. illustrative examples of substituted Ring A groups are:

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 2015210454 07 Aug 2015

Of special interest is the class of compounds of Formula i as described above in Part 1, in 5 which one of the R* substituents is a 5- or 6-membered ring {Ring C), which may be heteroaryl or heterocyclic, comprising carbon atoms and 1-3 heteroatoms independently selected from Ο, N and S{0)ri and Ring C being optionally substituted on carbon or heteroatom'(s) with 1 to 5 substituents R15, 10 This class is represented by Formula II: '

in which the previously defined variables, e.g., n, m, p, A, 8, T, L*, R1, R!, R8and Rb, are as defined above in part 1, and 5 2015210454 07 Aug 2015 R®, at each occurrence, is independently selected from halo, =0, -CN, -NO*, -R4, -OR2, -NR2R3, -C(05YR2, -0C(O>YR2, -NR2C(0)YR2, -Si{R2}3, -SG(0)YR2, -NR2C(-S)YR2, -OC{”S)YR2, -G(«S)YR2, -YC(sNR3)YR2, ~YP(eO)(YR4)(YR4), s. -NR2S02R2, -S(0)rR2, -SOaNR2Ra and -NR2S02NR2R3, wherein each Y is independently a bond, -0-, -S-or -NR3- and r, R^, r3 and R4·;areas detined previously in Part 1; and, vis 0,1,2, 3, 4 or 5. i 0 illustrative examples of Ring C systems include but are not limited to the following types:

In which Rc and v are as defined above. 15

Of special interest Is the class of compounds of formula SI in which Ring T has the following structure:

in which the-lndicated variables, e.g., R8, s and Ring E, are as defined previously, 20

Illustrative subsets of such compounds include those having the following structures: 6 2015210454 07 Aug 2015

5 !n which several illustrative -[Ring A]-[L1HR'n9 BHRfng CJ- portions are depicted,

Compounds of interest include among others, compounds of Formula II in which Ring C is an imidazole 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) R® group, A further feature of the invention relates to compounds of Formula I as described in Part 1, in which one Rb substituent is —{Lz]~[Ring D], This class Is represented by Formula ill·. . 15

7 2015210454 07 Aug 2015 5 10 15 20

In which the previously defined variables, e.g,, n, m, P, ^in'3 Ring A, Ring B, l„1, R1, r', Ra and Rs, are defined above in part 1, and Lz is selected from (CHj)Z) 0(CH2)x, NR3(CH2)«, S(CHa)s. and {CHs}2NR3C(0)(CHs),., and the linker moiety L* can be included in either direction; Ring D represents a 5- or 6-membered heterocyciic or beteroaryl ring comprising carbon atoms and 1-3 heteroatoms independently selected from Ο, N end S(G)r, and Ring D is optionally substituted on carbon or heteroatom(s) with 1-5 Re groups; R5*, at each occurrence, is Independently selected from haio, =0, -CM, -NOE. -R4, -OR2, -NR2R3, -SI(R2)3, -C{G)YR2, -0C(0)YR2, -NR2C(0)YR2s -SC(0)YR2, -NR2C(=S)YR2, -OC{=S)YR2, -C(=S)YR2 -YC(*NR3)YR2, -YP{*0){YR4)(YR4), -NR2S02R2, -S(0)rR2, -S02NR2R3 and -NR2SOaNR2R3, wherein each Y is independently a bond, -0-, -S- or -NR3- and r, R2, R3 arid R4 are as previously defined in Part 1; w is 0,1,2, 3, 4 or 5; x Is 0,1. 2 or 3; and, z Is 1, 2, 3 or 4. Non-limiting, illustrative examples of -[Ring 8j-[L2HRing D) moieties in compounds of Formula ill include among others:

8 2015210454 07 Aug 2015

Of special interest is the cisss of compounds of formula III in which Ring T has the following structure;

s in which the previously defined variables, e.g., R®, s, and Ring E, are as defined previous!'/.

Non-limiting examples of such compounds include those having the following structures;

10 as illustrated by the following examples: 15

2015210454 07 Aug 2015

Compounds of interest include among others, compounds of Formula IN 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 Rd is a substituted or unsubstituted lower (Le., 1 - 6 carbon) alkyl as illustrated by N-methylplperazine moieties In some of the foregoing examples.

Of special interest are compounds of formula il and formula Hi in which Ring T is an optionally substituted Imidazotl ,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazofi,2-a]pyrazine, 10 pyrazoio[1,5-eJpyrlmidinB, pyrazolo[1,5-e]pyrld!ne, pyrazob[1,5-c]pyrimidlne, and pyrazoio[1,5"a][1,3,5]lrlazine,

Aiso of interest are compounds of formula !! and formula III in which Rings A and B are aryi. 1 5 Another subclass of interest are compounds of Formulas IS and Hi, in which Ring T is any 6/5 fused heteroaryi ring system, optionally substituted with up to three R8 groups. Of particular Interest are compounds in which s is 0. Also of Interest are those in which s is 1 — 3 and at least one R8 is halo, lower alkyl, alkoxy, amino, -NH-alkyl, -C(0)NH-alkyl, -NHC(0)-alkyl,-NHC(0)NH-alkyl, -NHC(NH)-alkyl, -NHC(MH)NHZ, -NH(CHz)x-heteroaryi, -NH(CHa),<· 20 heterocycle, -NH(CM2)x-aryl or -(0Η2)κ0(Ο)ΝΗ2, in which x is 0,1,2 or 3 and “alkyl" includes straight (i.e,, unbranched and acyclic), branched and cyclic alkyl groups and in which aryl, heteroaryl, heterocyciyi rings are optionally substituted. Illustrative, non limiting, examples of the foregoing include compounds of formulas II and III in which Ring T Is one of the following:

25 10 2015210454 07 Aug 2015 illustrative, non limiting examples of this subclass include compounds of formulas ila, lib, iic, ills, iilb and i!ic;

15 ' in which the previously defined variables, e.g„ R8, Rb, R5, Rd, R®, m and p, are as previously defined, e.g., in part 1, and a is an integer from 0 ίο 4,

One subset of interest includes compounds of Formulas ila, lib and iic in which s Is 0; m, p 20 and v are 1; and, R3 is CH3, Rb Is CF3 and R° is methyl

Another includes compounds of Formulas ilia, lilb, life in which s is 0; m and p are 1; and, Re is CHS. Rb is CF3 and Rd is CHS or CHzCHzOH. 11 2015210454 07 Aug 2015

Compounds of this invention of particular Interest include those with one or more of the following characteristics; • a molecular weight o? less than 1000, preferably less than 750 and more preferably less than 600 mass units (not including the weight of any solvating or co-crystaiiizing species, of 5 any counter-ion In the case of a salt); or . · ‘ Inhibitory activity against a wild type or mutant (especially a clinically relevant mutant)

Kinase, especiaiiy a Src family kinase such as Src, Yes, Lyn or Lck; a VEGF-R such as VEGF-R1 (Fit-1), VEGF-R2 (kdr), or VEGF-R3; a PDGF-R; an Abl kinase or another kinase of interest with an IC50 vaiue of 1 pM or less (as determined using any scientifically acceptable 10 Kinase inhibition assay), preferably with an iC50 of 500 nM or better, and optimafiy with an 1C5G vaiue of 250 nM or better; or • inhibitory activity against a given kinase with an iGSO value at least 100-fold lower than their IC5Q values for other kinases of interest; or « inhibitory activity against both Srp and kdr with a 1 μΜ or better SG50 value against each; or 15 «a cytotoxic or growth inhibitory effect on cancer ceil lines maintained in vitro, or In animal studies using a scientifically acceptable cancer cell xenograft model, (especially preferred are compounds of the invention which inhibit proliferation of cultured K562 cells with a potency at least as great as Gleevec, preferably with a potency at least twice that of Gleevec, 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 excipient or additive. Such compositions 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, coion, pancreatic, CNS and head and neck cancers, among others) and various forms of leukemia, including leukemias and other cancers which are resistant to other treatment, including those which are resistant to treatment with Gleevec or another kinase inhibitor, and generally for the treatment and prophylaxis of diseases or 3 0 undesirable conditions mediated by one or more kinases which are inhibitsd by a compound of this invention.

The cancer treatment method of this invention involves administering (as a monotherapy or in combination with one or more other anti-cancer agents, one or more agents for ameliorating 3 5 side effects, radiation, etc) a therapeutically effective amount of a cornpound of the invention to a human or animai 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 kinases inhibited by one of the disclosed compounds or a 12 2015210454 07 Aug 2015 pharmaceutically acceptable derivative thereof. “Administration" 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 pharmaceutically acceptable derivative thereof, using any suitable formulation or route of administration, 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 days/week, etc. Oral and intravenous administrations are of particular current interest.

The phrase, "pharmaceutically acceptable derivative", as used herein, denotes any 10 pharmaceutically 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. Pharmaceutically acceptable derivatives thus include among others pro-drugs. A pro-drug is a derivative of a compound, usually with significantly reduced pharmacological 1 5 activity, which contains an additional moiety which is susceptible to removal in vivo yielding the parent molecule as the pharmacologically 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 compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention. 20

Pariiculariy favored derivatives and prodruga of a parent compound are those derivatives and prodrugs that Increase the bloavailabllity 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, Tarceva 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 radiotherapy, electron beam radiotherapy, proton therapy, brachyiherapy, and systemic radioactive isotopes, etc.), endocrine therapy, biologic response modifiers {e.g., interferons, interleukins, and tumor necrosis factor (TMF) to name a few), hyperthermia, cryotherapy, agents to attenuate any adverse effects {e.g., antiemetics), and other cancer 40 chemotherapeutic drugs. The other agent{s) may be administered using a formulation, route 13 2015210454 07 Aug 2015 of administration and dosing schedule the same or different from that 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., mechiorethamine, chlorambucil, Cyclophosphamide, Melphatan, and Ifosfamide); antimetaboifte (e.g., Methotrexate); purine antagonist or pyrimidine antagonist (e.g., β-Mercaptopurine, 5-Fluorouracil, Cytarablie, and Gemcltabina); spindle poison (e.g., Vinbiastine, Vincristine, Vinorelblne and Paciiiaxei),· podophyliotoxin (e.g., Etoposide, Irinotecan, Topotecan); antibiotic (e.g., Doxorubicin, Bleomycin and 10 Mitomycin); nitrosourea {e.g., Carmustine, Lomustine); inorganic ion (e.g., Cispiatin,

Carboplatin, Oxaliplatin or oxiplatin); enzyme (e.g., Asparaginase); hormone (e.g,. Tamoxifen, Leuproiide, Flutamide and Megestroi); mTOR inhibitor (e.g., Siroiimus (rapamycin), Temsirolimus (CCi779), Everoilmus (RAD001), AP23573 or other compounds disclosed in US Patent No. 7,091,213); proteasome inhibitor (such as Veicade, another proteasome inhibitor t S (see e.g., WO 02/096933) or another NF-kB inhibitor, including, e.g,, an fkK inhibitor): other kinase inhibitors (e.g., an inhibitor of Src, BRC/Abi, kdr, fits, aurora-2, glycogen synthase kinase 3 ("GSK-3”), EGF-R kinase (e.g., iressa, Tarceva, etc.), VEGF-R kinase, PDGF-R kinase, etc); an antibody, soiubie receptor or other receptor antagonist against a receptor or hormone implicated in a cancer (including receptors such as EGFR, Erb82, VEGFR, PDGFR, 20 and IGF-R; and agents such as Herceptin, Avastin, Erbitux, etc.); etc. Fora more comprehensive discussion of updated cancer therapies see, http 7/www. ncl.nih.gov/, a list of the FDA approved oncology drugs at http://Www.fda.9ov/cder/cancer/druglistframe.him, 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, alemtuzmab, altretamine, amifostine, nastrozole, antibodies against prostate-specific membrane antigen (such as MLN-591, MLN591RL and MLN2704), arsenic trioxide, bexarotene, bleomycin, busulfan, capecltablne, Gliadel Wafer, celecoxib, chlorambucil, cispiatin-epinepbrine gel, cladribime, cytarabine liposomal, daunorubicin liposomal, daunorubicin, daunomycin, dexrazoxane, docetaxel, doxorubicin, 30 Elliott's B Solution, epirubicin, estramusdne, etoposide phosphate, etoposide, exemesiane, fiudarablne, 5-FU, fuivesirant, gemcitabine, gemtuzumab-ozogamicin, gosereiin acetate, hydroxyurea, idarubioin, idaruhicin, Idamydn, ifosfamide, imatlnib mesylate, irinotecan (or other topoisomerase inhibitor, including antibodies such as MLN576 (XR11576)), ietrozoie, leucovorin, teucovorin levamlsole,liposomal daunorubicin, meiphalan, L-PAM, mesna, 35 methotrexate, methoxsaien, mitomycin C, mitoxantrone, MLN518 or MLN608 for other inhibitors of the fit-3 receptor tyrosine kinase, PDFG-R or c-kit), itoxantrone, paclltaxel, Pegademase, pentostatin, porflmer sodium, Rltuxlmab (RITUXAN®), talc, tamoxifen, temozolamide, teniposide, VM-26 , topotecan,' toremlfene, 2C4 (or other antibody which interferes with HER2-mediated signaiing), tretinoin, ATRA, vairubidn, vinorebine, or 40 pamidronate, zoledronate or another bisphosphonate, 14 2015210454 07 Aug 2015

This invention further comprises the preparation of a compound of any of Formulas I, II, {if, iia, ilb, iEc, ilia, l!!b, ilic or of any other of the compounds of this invention. S 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 leukemias and solid tumors, primary or metastatic, Including cancers such as noted elsewhere herein 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 anti-cancer medicament, Th© compounds of the present invention are also useful in the manufacture of a medicament to attenuate or prevent disorders through inhibition of on© or more kinases such as Src, kdr, abl, etc.

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 therapeufically-effective amount, In association with a least one pharmaceutically acceptable carrier, adjuvant or diluent. 2 S Compounds of this invention are also useful as standards and reagents for characterizing various kinases, especially but not limited to kdr and Src 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 ceil Sines and animal 30 models. 3, Definitions

In reading this document, the following information and definitions apply unless otherwise 3 5 indicated. In addition, unless otherwise indicated, all occurrences of a functional group are independently chosen, as the 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 (e,g„ R, R', R", orY, r.r’etc.). 15 2015210454 07 Aug 2015

The term "Alkyl" Is intended to include linear (i,e., unbranched or acyclic), branched, cyclic, or polycyclic non aromatic hydrocarbon groups, which are optionally substituted with one or more functional groups. Unless otherwise specified, “alky!" groups contain one to eight, and preferably one to six carbon atoms, alkyi, Is Intended to indude C*, C2, C&amp; C*, Cg, and 5 Cb alkyl groups. Lower alky! refers' to alky! groups containing 1 to 8 carbon atoms. Examples of Alkyl Include, but are not limited to, methyl, ethyl, n-prppyi, isopropyl, cyciopropyi, butyl, Isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl. Isopentyl tert-pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl, etc. Alkyl may be substituted or unsubstituted. Illustrative substituted alkyi groups include, but are not limited to, fluoromethyl, dlfluoromethyl, trlfluoromethyl, 2-10 fluoroethyl, 3-fiuoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, substituted benzyl, phenethyl, substituted phenethyl, efc.

The term “Alkoxv" represent a subset of alkyi 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 -O-aikyl, wherein the alkyl group contains 1 to 8 carbons atoms of a linear, branched, cyclic configuration, Examples of "alkoxy" include, but are not limited to, meihoxy, ethoxy, π-propoxy, i-propoxy, t-butoxy, n-butoxy, s-pentoxy and the like, ‘ Haloalkyl" Is intended to Include both branched and linear chain saturated hydrocarbon 20 having one or more carbon substituted with a Halogen. Examples of haloalkyl, include, but are not limited to, trifluoromethyi, irichloromethyi, pentafiuoroethy! and the like.

The term "alkenyl" is intended to indude hydrocarbon chains of linear, branched, or cyclic configuration having one or more unsaturated Carbon-carbon bonds that may occur in any 25 stable point along the chain or cycle. Unless otherwise specified, “aikenyf 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-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, and the like, Furthermore, alkenyl groups may be substituted or unsubstituted. 30

The term "aikynyr Is intended to Include hydrocarbon chains of either linear or branched configuration, having one or more carbon-carbon triple bond that may occur in any stable point along the chain. Unless otherwise specified, “alkynyl” groups refer refers to groups having two to eight, preferably two to six carbons. Examples of "alkynyl" include, but are not 35 limited to prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyi, etc. Furthermore, alkynyl groups may be substituted or unsubstituted.

Cycioalkyl is a subset of alkyl and Includes any stable cyclic or polycyclic hydrocarbon groups of from 3 to 13 carbon atoms, any of which is saturated. Examples of such cycioalkyl include, 40 but are not limited to cyciopropyi, norbornyi, [2.2.2)b!eyciooctane, i4.4.03bicyclodecane1 and 16 2015210454 07 Aug 2015 the like, which, as in the case of other alky! moieties, may optionally be substituted. The term "cycloaikyl" may be used interchangeably with the term “carbocycie”.

Cycloalkenyl is a subset of aikeny! 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 cycloaikenyl include, but are not limited to cvclopentenyl, cyclohexeny! and the like. 10 Cycloalkynyl Is a subset of alkynyl and includes any stable cyclic or polycyclic hydrocarbon groups of from 5 to 13 carbon atoms, which contains one or more unsaturated carbon-carbon triple bonds that may occur in any point along the cycle. As in the case of other alkenyl and alkynyl moieties, cycloaikenyl and cycloalkynyl may optionally be substituted. 15 "Heterocycle", "heterocyclyl", or "heterocyclic" as used herein refers to non-aromatic ring systems having five to fourteen ring atoms, preferably five to ten, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S. Non-limiting examples of heterocyclic rings include 3-1 H-benzimidazol-2-one. (1-substituted)-2-oxo-benzimldazol-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tefrahydroihiophenyl, 3-20 tetrahydrothlophenyl, 2-morphollnyl, 3-morphotinyl, 4-morpholinyl, 2*lhiomorphoiinyi, 3- thiomorphollnyl, 4-thiomorphoHny!, 1-pyrroiitiinyl, 2-pyrroildinyl, 3-pyrrolldlnyl. 1-piperazinyl, 2-pjperazlnyl, 1-plperidlnyl, 2-piperidinyl, 3-plperidinyi, 4-plperidlnyt, 4-thlazolidinyl, dlazolonyl, N-substituted diazoionyl, 1-phthalimidinyl, benzoxanyi, benzopyrrolidinyl, benzoplperidinyi, benzoxoianyl, benzofhiolanyi, and benzothianyl. Also included within the scope of the term 25 "heterocyciyl" or "heterocyclic", as It is used herein, is a group in which a non-aromaiio heteroatom-containing ring is fused to one or more aromatic or non-aromatic rings, such as in an Indolinyl, chromanyl, phenanthrldinyi, or tetrahydroquinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-coretaining ring. The term "heterocycle", "heterocyclyl", or "heterocyclic" whether saturated or partially unsaturated, also refers to rings 30 that are optionally substituted.

The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxy-alkyl", refers to aromatic ring groups having six to fourteen ring atoms, such as phenyl, 1-rtaphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. An "aryl" ring may contain one or more 35 substituents. The term "aryl" may be used Interchangeably with the term "aryl ring", "Aryl” 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 inciude phenyl, hydroxypbenyi, haiophenyi; alkoxyphenyi, dialkoxyphenyl, trlalkoxyphenyi, alkyienedioxyphenyl, naphthyl, phenanthryl, anihryl, phenanthro and the like, as well as 1-naphthyl, 2-naphthyl, 1-anthracy! 40 arsd 2-anthracyl. Also Included within the scope of the term "aryl", as it is used herein, is a i 7 2015210454 07 Aug 2015 group in which an aromatic ring is fused to one or mors non-aromatlc rings, such as in a Sndanyl, phenanthrkiiny!, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring, 5 The term “heteroaryi" as used herein refers to stable heterocyclic, and poiyheterocyciie aromatic moieties having 5-14 ring atoms. Heteroaryl groups may be substituted or unsubstituted and may comprise one or more rings, Examples of typical heteroaryi rings include 5-membered monocyclic ring groups such as thienyi, pyrroiyi, imidazolyi, pyrazolyl, furyi, Isothiazoiyl, furazanyl, Isoxazoiyl, thlazoiyi and the like; 6-merrsbered monocyclic groups 10 such as pyrldyl, pyrazlnyi, pyrlmidinyi, py'ridazlnyl, trlazinyl and the like; and polycyclic heterocyclic ring groups such as b8nzo[b)thlenyi, naphtho[2,3-b]thienyi, thianthrenyl, , isobenzofuranyi, chromenyl, xanthenyl, phenoxathienyl, Inelolizinyl, isoindoiyl, Indoiyt, indazolyi, purinyi, isoquinolyl, qulnclyl, phthalazlnyl, naphthyridinyi. qulnoxalinyl, quinazolinyi, benzoihiazoie, benzimidazole, tetrahydroqulnolin© cinnolinyl, pteridinyl, carbazolyl, beta-15 carboiinyi, phenanthridinyi, acridinyl, perimldinyi, phenanthrolinyi, phenazlnyl, Isothiazoiyl, phenothiazinyl, phenoxazinyl, and the like (see e.g. Katrftzky, Handbook of Heterocyclic Chemistry), Further specific examples of heteroaryl rings Include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imldazoiyi, 4-imidezolyl, 5-imldazoiyt, 3-lsoxazolyl, 4-teoxazoiyl, 5-lsoxazdyl, 2-oxadiazoiyl, 5-oxadiazoiyi, 2-oxazoSyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrroiyl, 8-pyrroiyl, 20 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrlmldyl, 4-pyrimldyl, 5-pyrimidyi, 3-pyridaziny!, 2-thiazo!yi, 4-thiazoiyi, δ-thiazolyi, 5-tetrazoiyl, 2-triazolyi, 5-triazoiyi, 2-thienyl, 3-thienyi, caibazolyi, benzimldazoiyl, benzothlenyl, benzofuranyl, indolyi, quinolinyi, benzotriazolyl, benzothiazoiyl, benzooxazolyi, benzimldazoiyl, isoqulnolinyi, indoiyi, isoindoiyi. acridinyl, or benzoteoxazolyl. Heteroaryl groups further include a group in which a heteroaromatic ring is fused to one or 25 more aromatic or nonaromatic rings where the radical or point of attachment is ors the heteroaromatic ring, Examples include tetrahydroquinoline, tetrahydroisoquinoline, and pyrido[3,4-dlpyrimidinyi, imldazot1l2-ajpyrimidyll,imidazo[1,2-a]pyrazinyl, imidazo[1,2-ajpyirldinyl, irnidazo[1,2-c]pyrimidyl, pyrazolo[1,5-a][1,3,5]triazinyl, pyrazolo[1,5-c]pyrimidyi, imidazo[1,2"b3pyridazlnyl, imldazo[1,5-aJpyrimidyi, pyrazoio[1,5-b]t1,2,4]trlazine, quinoiyi, 30 isoquinolyl, quinoxalyi, imidazotriazinyl, pyrroio[2,3-d]pyrlmidyl, triazpiopyrimidyl, pyridopyrazinyl. The term "heteroaryi" also refers to rings that are optionally substituted. Th© term "heteroaryi" may be used interchangeably with the term "heteroaryi ring" or the term "heteroaromatic".

An aryi group (Including She aryl portion of an araikyi, aralkoxy, or aryloxyalkyl moiety and 35 the like) or heteroaryi group (including the heteroaryi portion of a heteroaralkyi or heteroarylaikoxy moiety and the like) may contain one or more substituents. Examples of suitable substituents on the unsaturated carbon atom of an aryl or heteroaryi group include halogen (F, Cl, Br or I), -ON, -R*. -OR2, -S(0)rR2, (wherein r is an integer of 0,1 or 2), -S02NR2R3, ~NR2R3, -(CO)YR2, ~0{CO)YRa, -NR2(CO)YR2, -S(CO)YR2, 18 2015210454 07 Aug 2015 ~NRZC(«S)YR2, -00(=3)YR2, -C(=S)YR2, wherein each occurrence of Y is independently -0-, -S-, -NR3-, or a chemical bond; ~(CG)YR2 thus encompasses ~C(=0)Rz, ~C{=0)GR2 and-C(=0)NRzR3, Additional substituents include -YC(=NR3)Y‘R2, -COC0R2, -COMCOR2 (where M is a 1- 6 carbon alkyl group), ~YP(=Q)(YR4}(YR4} S (Including among others -P(=G){R4}2), -Si(R2)3, -NQg, -NR2S02R2 and —NR2SC>2NR2R3. To Illustrate further, substituents in which Y is -NR3 thus include among others, -NR3C(0)R2, -NR3C(=0)NR2R3, -NR3C(=0)OR2 and —NR3C(*NH)NR2R3. R2 and R3 substituents at each occurrence are independently selected from hydrogen, aikyl, alkenyl, alkynyl, cycloalkyl, cvcioalkenyl, cycloalkynyl, aryl, 10 heteroaryl, heierocyclyl, and R2 and R3 (and R4i substituents may themselves be substituted or unsubstKuted. Examples of substituents allowed on R2, R3 a nd R4 include, among others amino, aikylamino, dialkyiamino, amlnocarbonyl, halogen, alkyl, alkenyl, alkynyi, aryl, heteroaryl, oarbocycie, heterocycle, aikyiaminocarbonyi, dialkylaminocar-bonyl, alkyiaminccarbonyloxy, diaikyiamlnocarbonyioxy, niiro, cyano, 15 carboxy, alkoxycar-bonyl, aikyicarbonyl, hydroxy, alkoxy, haloalkoxy groups. Additional illustrative examples include protected OH (such as acyloxy), phenyl, substituted phenyl, -O-phenyl, -©-(substituted) phenyl, -benzyl, substituted benzyl, -O-phenethyi (1.8., -OCH2CH2CgHg), -0-(substituted)pherrethyl. Non-limiting Illustrations of a substituted R2, R3 or R4 moiety Include haioaikyl and trlhaloalkyl, alkoxyalkyl, halophenyl, 20 -M-heteroaryl, -M-hete recycle, -M-aryl, -M-OR2, -M-SR2 , -M-NRZR3, -M-0C(0)NR2R3, ~M-C(=NR£)NR2R3, -M'C(=NR2)OR3, -M-P(0)R2R3, SI(R2)9i -M-NR2C(0)R3, ' -fVl-NR2C(0)0R*, -M-C(0)R2, -M-C(=S)R2, -M-C(=S)NR2R3, -M-C(0)NRzR3, -M-C(0)NR2-M-NR2R3, -M-NR2C(NR3)NR2R3 -M-NR2C(S)NR2R3. -M-S(0)zR3, -M.-C(0)R3, -M-0C(0)R3, -MC(0)SR2, -M-S(0)jNR2R3, -C(O}-M-C(0)RZ -MC02R2, 2 5 -MC(=0)NR2R3, -M-C(*NH)NRsR3 and -M-0C(=NH)NR2R3 (wherein M is a 1-6 carbon alkyl group).

Some more specific examples include but are not limited to chioromethyl, frichloromethyi, trlfluoromethyl, methoxyethyl, alkoxyphenyl, halophenyl, -CHs-aryi, -CH?-heterocycle, 30 -CH2C(0)NH2, -C(0)CH2N(CH3)2, -CH2CH20H, -CH2OC(0)NH2, *CH2CH2NH2i -CHgCHsCHgNEtK, -CH2OCH3, -C(0)NH2, -CHaCHji-hetarocycie, -C(=S)CH3, -C(=S)NH2, -C(=NH)NH2, -C(=NH)OEt, -C(0)NH-cyclopropyl, C(0)NHCH2CH2-heterocycie, -C(0)NHCH2CH2OCH3, -C(0}CH2CH2NHCH3, -CH2CH2F, -C(0)CH2-heterocycle, -CH?.C(0)NHCH3, -CH2CH2P(0)(CH3)2, Si(CH3)3 and the like. 35

An aliphatic, i.e., alkyl, alkenyl, aikynyl, alkoxy, haloelkyi, cycloalkyl, cycioalkenyl, cycloalkynyl or non-aromatic heterocyclic, group may thus also contain one or more substituents. Examples of suitable substituents on such groups include, but are not 19 2015210454 07 Aug 2015 limited to those listed above for the carbon atoms of an ary! or heteroaryl group and In addition include the following substituents for a saturated carbon atom; =Q, "S, =NH, =MNRZR3, =NNHC(0)R2, =NNHC02R2, or=NNHS02R2, wherein R2 at each occurrence is independently H, alkyl, alkenyl, alkynyl, cycba'kyi, cycloalkenyl, cycloalkynyl, aryl, S heteroaryi, heterooyclyl. - illustrative examples of substituents on an aliphatic, heteroaiipbatic or heterocyclic group ' include amino, alkyiamlno, dialkylamlno, aminocarbonyl, halogen, alkyl, alkylaminocar-bonyl, dialkyiamlnocarbonyi, aikylaminocarbonyloxy, dialkylamlnocarbonyloxy, alkoxy, 10 nitre, -CM, carboxy, alkoxycerbonyl, alkyicarbonyl, -OH, haloalkoxy or haloalkyl groups. illustrative substituents on a nitrogen, e.g., Sn an aryl, heteroaryl or non-aromatic heterocyclic ring, include R4, ~NRJR3, -C(*0)R2, ~C(=0)0R2, -0(=O)SR2, -C{-0)NR2R3, -C(=NR2)NR2R3, -C(=NR2)OR2, ~C(=NR2)R3, -COCOR2, -COMCOR2, -CN, -S02Rs, S(0)R3, 15 -P(=0)(YR2)(YR2), -NR*S02.R3 and -NR2S02NR2R3, wherein each occurrence of R2and R3 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyi, cycloatkenyl, cycloalkynyl, aryl, heteroary, hetereoyclyi.

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 toe absence of moisture or other chemically reactive conditions, for at least a week. 25 '

Certain compounds of this invention msy 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 a!! stereochem-30 ical forms of the structure; i.e,, the R and S configurations for each asymmetric center, Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Thus, this invention encompasses each diasteriomer or enantiomer substantially free of other isomers {>90%, and preferably >95%, free from other stereoisomers 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 dlastereolsomeric salts, by treatment with an optically active add or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyhartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the 40 mixture of dlastereoisomers by crystallization followed by liberation of the optically active 20 2015210454 07 Aug 2015 bases from these salts. A different process for separation of optica! isomers Involves the use of a chiral chromatography column optimally chosen to maximise the separation of the enantiomers. Still another method Involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the Invention with an optically pure acid In an activated form or an S optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerlcally pure compound.

Optically 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 salt.

The compounds of this invention can exist in radiolabelied 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, ^C, 32pt 35§, 43p ancj 36ci, respectively. Compounds of this Invention which contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Treated, i.e., 3H, and carbon-14, i. e., 14C, radioisotopes are particularly preferred for their ease of preparation and detectability. 20 Radiolabelied compounds of this invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabelied compounds can bs prepared by carrying out the procedures disclosed herein except substituting a readily available radiolabelied reagent for a ηση-radiolabeiied reagent. 25 4. Synthetic Overview

The practitioner has a weii-estabiished literature of heterocyclic and other relevant chemical transformations, recovery and purification technologies io 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 R{, Ra ,Rb, Rs, Rd, R' and Rings T, A,

B, C and D. The following references, and the references cited therein, may be of particular interest: WO 01/27109, WO 02/066478, WO 02/30428, WO 02/080911, WO 02/080914, WO 2004/033453, WO 2004/035578, WO 2004/23972.WO 20.05/105798, US 35 2003/0119842, US 2004/0023972, US 2004/0122044, US 2004/0142961, US 2005/0239822, US 6420365 and US 6703404 are referring to the preparation of imidazo[1,2-a]pyridines; WO 05/030218, WO 03/022850 are referring to im!dazo[1,2-ajpyrlmidlnes; WO 05/047290, WO 03/089434, US 6589952 are referring to imidazopyrazlnes, WO 04/011468and US 5145850 are referring to the preparation of 21 2015210454 07 Aug 2015 imsd3Zoi1,2-b]pyridazines; and WO 05/070431, WO 96/35690, WO 04/089471 are referring to pyrazolo[1,5-a]pyrimidines.

Various synthetic approaches may be used to produce the compounds described herein, 5 including those approaches depicted schematicatiy below. The practitioner will appreciate that protecting groups may be used in these approaches, "Protecting groups", are moieties that are used to temporarily biocfc chemicai reaction at a potentially reactive site (e.g., an amine, hydroxy, thiol, aldehyde, etc.) so that a reaction can be carried out selectively at another site in a multifunctional compound. In preferred embodiments, a 10 protecting group reacts selectively 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 nontoxio reagents that do not unduly attack the other functional groups present; the protecting group preferably forms an readiiy separable derivative (more preferably without the generation o.f new stereogenie 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 Wuts, P.G., Eds., John Wiley &amp; 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 useftii in producing the compounds described herein, see in R. Larock, Comprehensive organic Transformations, VCH Pubiishers (1989); T.W. Greene and P.G.Wi. Wuts, Protective Groups In Organic Synthesis, 3rd, Ed., John Wiley and Sons (1999); L, Fieser and !VS, Fieser, Fieser and 25 Fieser's Reagents for Organic Synthesis, John Wiiey and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995). The entire contents of these references are hereby Incorporated by reference.

Also, one may chose reagents enriched for a desired isotope, e.g, deuterium in piaee 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 O, 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 bioiogicai functioning. 35

The compounds of the this invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by a variation thereon as appreciated by those skilled in the art. Preferred methods 22 2015210454 07 Aug 2015

Scheme I: Sonogashira Coupling Reaction if*'}.

Scheme li: Alternative Sonogashira Coupling Reaction 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 effected. 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 anotherln 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 art. A palladium catalyzed Sonogashira coupling reaction is used to ilnk the ‘top’ Ring T to the 'bottom' [Ring AJ-fl-1HRin9 B] moiety as illustrated in Scheme i and II. in Scheme i the Sonogashira coupling reaction Is performed with an acetylenic ‘top· Ring T and a' 1 5 [Ring AS-U-ViRing B] moiety which has been activated by the presence of a reactive group, W, which is an I, a Br or another reactive group permitting the desired coupling reaction. The variables in the W-[Ring AHL1]-[Rlng B] are as defined previously, Rings A and B being substituted with permitted R8 and Rb groups, respectively. 20

An alternative coupling reaction is described in Scheme ii, in which Ring T is "activated" by the presence of a reactive group W (such as ! or Br) and is coupled to the 'bottom’ 25 acetylenic [RingA)~L1—[RingBJ under similar Palladium catalyzed coupling conditions. 23 2015210454 07 Aug 2015

The Sonogashira coupling conditions described in Scheme! and li are applicable to ail bicyciic heteroaryi Ring Ts and useful to synthesize ai! compounds of this invention.

Several illustrative overall synthetic approaches to the preparation of the acetylenic Ring 5 T moieties, based on known transformations, are illustrated below in Schemes it! to Vlli:

Scheme tit: Preparation of 3-Ethynylimldazo[1,2-aJpyrazine 10 15

Reflux

XCH orN

Reflux jo, K*CH Refill x

Preparation of C-8 Substituted 3-Ethynylimidazo[1,2-a3pyrazines

PdCi^PPh^, or Pd(PPh3)4 Cut, CH5CN, 80°C sas~“TMS

THF/watw, rt TBAF,

I

Scheme V: Preparation of 3-Ethynylimidazo[1,2-a]pyrldlne or 3-EthynyllmldazoI1,2-b]pyrldazine 20 24

Br R: alkyl, aiyl, acyl carbamyl eic„ !. Pd(PPJi3)4 ACM, DiPA Cul, Reflux

2, TBAF, THF 2015210454 07 Aug 2015

Scheme Vi; Preparation of C-8 Amino Substituted 3-Ethynyllmldazoi1,2-a]pyridines 5

NH

f , / Bi-

l- PdClj(PP1ij)j( R Cut. CH3CN, 80°C msss—T.MS

Scheme Vfl: Preparation : 2, TBAF, THF/water it ! C-8 substituted 3-Ethynylimidazo[1,2-a]pyrldines

Br NH?

WO20Q4026867 BOCjO DMAP Bi

NHBOC

NHj 1. Coupling 2. TFA

KX/base

NHR λΑ i

Scheme Viii; Preparation of C-8 and C-8 Substituted 3-Ethynyiiroidazo [1,2·a} pyrldines. 25 2015210454 07 Aug 2015

W

For the coupling step, see Malleron, J-L., Fiaud, J-G., Legros, J-Y. Handbook of Palladium Catalyzed Organic Reactions. San Diego: academic Press, 1987.

As one of ordinary skill in the art would recognize, these methods for the preparation of 5 various substituted acetylenic Ring T groups, are widely applicable to various other fused bicyclic ring systems not shown.

Schemes IX to XII! below depict the synthesis of compounds of the formula W-[Ring A]-[L1HRing B) which are useful as Intermediates in the coupling reaction described in 10 Schemes I and II. it should be apparent that intermediates of the formula: are of particular interest as their coupling reaction with the ‘top’ heteroaryl rings produces 15 compounds of the present invention. The variable groups A, lJ and B are as previously defined and are optionally substituted as described herein, and W is ! or an alternative reactive group permitting the desired coupiing reaction.

Illustrative such Intermediates include among others those of those following structures: 20

wherein the previously defined variables, ©,g., R®, Rb, Rc and Rd, are as previously 25 defined. For instance, Ra in some embodiments is chosen from F or aikyi, e.g., Me, 26 2015210454 07 Aug 2015 ΙΟ among others, and Rb in some embodiments Is chosen from Cl, F, Me, t-butyl, -CF3 or-OCF3 among others, Those and other compounds of the formula W-[Ring AHt-1HRIng B] with the various permitted substituents are useful for preparing the corresponding compounds of the invention as are defined In the various formulae, classes and subclasses disclosed herein.

Some Illustrative synthetic routes for the preparation of reagents and representative Intermediates are presented beiovv:

Scheme IX describes an illustrative synthesis ofW-[Ring AHL1HRIrrg BJ in which Rings A and 8 are phenyl and L1 is MHC(O).

20

Scheme X depicts the synthesis of a variant of the foregoing in which Ring B is a 2-pyridlne and L1 is C{0)NH tie,, in the other orientation).

Schemes Xi and XII, below, illustrate the synthesis, of W-[Ring AH^HRing B] in which Rings A and B are phenyi and Ring C is a heteroaryi ring. These Intermediates are useful for making compounds of formula it.

More specifically, Scheme XI describes the preparation of Intermediates in which Ring C is an imidazois ring. 27 5 2015210454 07 Aug 2015

Scheme XI 10

Scheme XSi describes the preparation of intermediates in which Ring c is a pyrrole or an oxazote ring,

Scheme Xill illustrates the synthesis of W~[Rfng AHL HRing 8] in which Rings A and B are - , , . z4Ring Dj. These intermediates are useful for making

phenyi and an R" substituent is -L compounds of formula Hi in which Ring D is a 5 or β-membered heterocycls, containing one or two heteroatoms.

IS

Scheme Kill 28 2015210454 07 Aug 2015 in Shis scheme, non limiting examples of substituents Rb on Ring B are halo, e.g., Cl; lower alkyl groups, e.g,, Isopropyl; and substituted lower alkyl groups, e.g. -CFg; and non limiting examples of Ring D are Ν,Ν-dimethyipyrrolldlne, N-(2-hydroxyethyi)plperazine, and N-metbylpiperazine. intermediates W-[Rlng AHU1HRin9 Bl· such as those presented in the various synthetic schemes above, can be reacted with an acetylenic Ring T using the Sonogashira coupling conditions described In the genera! Scheme I. 10 An example Is depleted below In Scheme XIV, in which Ring T moiety can be further derivatlzed after the Sonogashira coupling step, to generate various interesting substituted analogs of this invention. 1 5

Alternatively, the W-[Ring A]-[L1HRitig B] can be reacted under Sonogashira conditions with trimethylsilylacetyiene, prior to the coupling with ari iodo- or a bromo- activated Ring T as otherwise described in the general Scheme II, 20

An example is depicted in

Scheme XV:

Scheme XV 25

In other embodiments, the steps can be carried out in a different order. For example, the Sonogashira Coupling reaction can be used to Ring T to Ring A prior to linking that portion to Ring B and/or [Ring BH^HRIhfl D; and/or [Ring Bj-[Ring C] as shown in Scheme XVI. 30 29 2015210454 07 Aug 2015

Scheme XVI in a non-limiting example In which Ring A and Ring B are phenyl and L1 IsCONH, 5 Scheme XVII describes Sonogashira Coupling of an acetylenic Ring T with 3-iodo-4-methylbenzoic acid {a Ring A moiety) to generate a [Ring T}-[Rlng A] Intermediate which then undergoes an amide coupling with an optionally substituted Ring B moiety:

Ί 0 Scheme XVII

This approach is illustrated in Scheme XVlil which depicts the coupling of an acetylenic Ring T{i.e., 3- ethynyiimidazofl.Z-bJpyridszine) with a substituted W-[Ring A] (i.e., 3-iodo- 4-methyiberizoic acid), followed by ars amide coupling of the resultant [Ring T]~[Rlng AJ-15 COOH intermediate with a HgN-png B}-L2-[Ring Cj moiety (i.e,, 4-<(4-methyipiperazin- 1-yS)methyS)-3-{trifluoromeihylani!ine): 30

Scheme XVIII 2015210454 07 Aug 2015 5

Alternatively, as another Illustration of the practitioner’s range of assembly options, ihs .3-lodo-4-methylbenzolc acid Ring A intermediate can be reacted in a.Sonogashira reaction with irimethylsilyiacetyiene, which after sllyl deprotection, can a second Sonogashlra coupling reaction with an activated Ring T as illustrated in Scheme XIX.

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 prepare the full range of compounds disclosed herein. 15 8, Uses, Formulations, Administration

Pharmaceutical Uses; indications

This invention provides compounds having biological properties which make them of interest for treating or amerlioratlng diseases in which kinases may be Involved, 20 symptoms of such disease, 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 kinase activity of Src and abl, among other tyrosine kinases which are , believed to mediate tbs growth, development and/or metastasis of cancer. A number of 31 2015210454 07 Aug 2015 compounds of the Invention have also been found to possess potent in vitro activity against cancer cell lines, including among others K-S62 leukemia cells. Observed potencies have been as much as 10-fold more powerful than Gleevec in conventional antiproiiferation assays with K582 cells, 5

Such compounds are thus of Interest for the treatment of cancers, including both primary and metastatic cancers, including solid tumors as well as lymphomas and leukemias (including CIVIL, AML and ALL), and Including cancers which are resistant to other therapies, including other therapies involving the administration of kinase inhibitors such 10 'as Gleevec, Taroevaor iressa.

Such cancers include, among others, cancers of the breast, cervix, colon and rectum, lung, ovaries, pancreas, prostate, head and neck, gastrointestinal stroma, as well as diseases such as melanoma, multiple myeloma, non-Hodgkin’s lymphoma, melanoma, 15 gastric cancers and leukemias (e.g„ myeloid, lymphocytic, myelocytic and lymphoblastic leukemias) including cases which are resistant to one or more other therapies, including among others, Gleevec, Taroeva or Iressa.

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 Abl) which correlate with alteration in the protein’s drug binding properties, phosphate binding properties, protein binding properties, autoreguiation or other characteristics. For example, in the case of BCR-Abl, the kinase associated with chronic myeloid leukemia, resistance to Gleevec has been mapped to a variety of BCR/Abi mutations which are 25 linked to a variety of functional consequences, including among others, steric hindrance of drug occupancy at the kinase’s active site, alteration in defonnabiiity of the phosphate binding P loop, effects on the conformation of the activation loop surrounding the active site, and others. See e.g. Shah et al, 2002, Cancer Cell 2,117-125 and Azam et af, 20Q3, Cell 112, 831 - 843 and references cited therein for representative examples of 30 such mutations in Bcr/Abl which correlate with drug resistance. See also the following references for additional background information on BCR/Abi, its mechanistic role in CML and drug-resistance-conferring mechanisms and mutations: Kurzrock et al., Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics, Ann Intern Med. 2003 May 20;138(10):819-30; O’Dwyer et al„ Demonstration of Philadelphia 3 5 chromosome negative abnormai clones in patients with chronic myelogenous leukemia during major cytogenetic responses Induced by imatlnib mesylate. Leukemia. 2003 Mar; 17(3):481-7; Hochhaus et a!., Molecular and chromosomal mechanisms of resistance to imatlnib (STI571) therapy, Leukemia. 2002 Nov;16(11):2190-6,- O'Dwyer et al„ The 32 2015210454 07 Aug 2015 impact of clonal evolution on response to imatinib mesylate (STi571) in accelerated phase CML. Blood, 2002 Sep 1;100(6):1628~33; Braziel et ai., Hematopathologlo-and cytogenetic findings In imatinib mesylate-treated chronic myelogenous leukemia patients: 14 months' experience. Blood. 2002 Jut 15;100(2):435-41; Corbin et ai., Analysis of the 5 structural basis of specificity of inhibition of the Abl kinase by STI671. J Biol Chem. 2002 Aug 30;277(36):322l4-9; Wertheim et al„BCR-ABL-induced adhesion defects are tyrosine kinase-independent. Blood, 2002 Jun 1;99(11):4122-30: Kantarjian et a|..Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia, N Eng! J Med. 2002 Feb 28;346(9}:645-52, Erratum In: N Engl J Med 2002 Jun 10 13;340(24):1923; Hochhaus et a!,, Roots of clinical resistance to STI-571 cancer therapy.

Science. 2001 Sep 21;293(5538):2163; Druker et ai., 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 Med, 2001 Apr 5:344(14):1038-42. Erratum in: N 'Eng! J Med 2001 Jui 19;345(3);232; Macro et ai., 1 5 Chronic myelogenous leukemia. CurrOpin Oncol. 2001 Jan;13(1):3-7, Review; Kolibaba et ai,, CRKL binding to BCR-ABL and BCR-ABL transformation. Leuk Lymphoma, 1999 ' Mar;33( 1-2):119-26; Bhat ei ai., Interactions of p62(dok) with p210(bcr-abl) and Bcr-Abl-assoclated proteins, J Biol Chem. 1998 Nov 27;273(48):32360-8; Senechal etaf., Structural requirements for function of the Crki adapter protein In fibroblasts and 20 hematopoietic cells. Mo! Ceil Bio!. 1998 Sep;18(9):5082-90: Kolibaba et a!., Protein tyrosine kinases and cancer. Biochim Bicphys Acta. 1997 Dec 9;1333(3):F217-48. Review; Heaney et at., Direct binding of CRKL to BCR-ABL is no! required for BCR-ABL transformation. Blood, 1997 Jan 1;89(1).-297-306: Halfek et ai., Interaction of the receptor tyrosine kinase pl48c-kit with the p210bor/abl kinase in myeloid celts. Br J Haematol. 25 1996 Jui;94(1):5-18: Odaei a!., The SH2 domain of ABL is not required for factor- independent growth induced by BCR-ABL in a murine myeloid cell line. Leukemia, 1995 Feb;9(2):285-301; Carlesso et ai,, Use of a temperature-sensitive mutant to define the biological effects of the p210BCR-ABL tyrosine kinase on proiiferation of a factor-dependent murine myeloid ceil Sine. Oncogene, 1994 Jan; 9(1):149-66. 30

Again, we contemplate that compounds of this invention, both as monotherapies and in combination therapies, wilt be useful against leukemias and other cancers, including those which are resistant in whole or part to other anticancer agents, specificaiiy including Gleevec and other kinase inhibitors, and specificaiiy including leukemias involving one or 3 5 more mutations in BCR/Abi, within or outside the kinase domain, including but not limited to those noted in any of the foregoing publications. See in particular Azam et ai. and references cited therein tor examples of such mutations In BCR/Abi, including, among others, mutations in the drug binding cleft, the phosphate binding P loop, the activation 33 2015210454 07 Aug 2015 loop, the conserved VAVK of the Kinase beta-3 sheet, the catalytic alpha-1 helix of the small M lobe, the tong alpha-3 helix within the large C lobe, and the region within the C lobe downstream of the activation loop. 5 Pharmaceutical 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, the 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 composition containing the compound, may be administered 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 uniformity of dosage. The expression "dosage unit term" 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 daily 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 therapeutically effective dose level for any particular 2 5 patient or organism wiil depend upon a variety of factors including the disorder being treated; the 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 metabolism and/or excretion of the compound; die duration of the treatment; drugs used in combination or coincident 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, rectaliy, parenterally, Intracisternaliy, intravaglnaily, intraperitoneally, topically . (as by iransdermal patch, powders, ointments, or drops), sublingually, bucaily, as an oral or nasal spray, or the like. 34 2015210454 07 Aug 2015

The effective systemic dose of the compound will typically be In the range of 0.01 to 500 mg of compound per kg of patient body weight, preferably 0.1 to 125 mg/kg, and in some cases 1 to 25 mg/kg, 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 5 2000 mg per patient. Administration may be once or muitipie limes daily, weekly (or at some other multiple-day interval) or on an intermittent schedule. For example, the compound may be administered 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 (e.g, 2-10 days) followed by a period of days (e.g. 1-30 days) without 10 administration of ihe compound, with that cycle repeated indefinitely or for a given number of repitiiions, 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 daily for another 5 day period, then discontinued for 9 days, 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 will depend in part on well known factors affecting drug dosage. In addition, in vitro or in vivo 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 mode! 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 genetic engineering of ceils in the patient. 25

When administered for the treatment or inhibition of a particular disease state 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 physioai factors related to the individual 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-5QG mg/kg, preferably between 0.1 and 125 mg/kg, and more preferably between 1 and 25 mg/kg. The projected daily dosages are expected to vary with route of administration. 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 2015210454 07 Aug 2015 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. S Regarding the Compounds

Compounds of present invention can exist in free form for treatment, or where .appropriate, as a pharmaoeuticaiiy acceptable sait or other derivative. As used herein, the term "pharmaceutically acceptable sait" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and TO lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/rtsK ratio. Pharmaoeuticaiiy acceptable salts of amines, carboxylic adds, phosphonates and other types of compounds, are well known in the art. For example, 8. M. Berge, et eh describe pharmaoeuticaiiy acceptable salts in detail in J. Pharmaceutical Sciences, 68:1-19 (1977), incorporated herein by reference. 1 5 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, nontoxlc acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and 20 perchloric acid or with organic acids such as acetic acid, oxalic acid, maielc acid, tartaric acid, citric acid, succinic acid or maionic acid or by using other methods used in the art such as Son exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzanesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, 25 dodecylsuifate, ethanesulfonate, formate, fumarate, glucoheptorsate, glycerophosphate, gluconate, hemisulfete, hepfanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, iaurate, iauryl sulfate, malate, maleate, malonete, methane-sulfonate, 2-naphthalenesulfonate, nlcotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenvlpropionate, phosphate, plcrate, pivalate, propionate, 30 stearate, succinate, sulfate, tartrate, thiocyanate, 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 cations formed using counterions such as halide, hydroxide, carboxylate, 3 5 sulfate, phosphate, nitrate, loworaikyl sulfonate and aryl sulfonate.

Additionally, as used herein, the term "pharmaoeuticaiiy acceptable ester" refers . preferably to esters which hydrolyze in vivo and include those that break down readily in 36 2015210454 07 Aug 2015 the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenolc, oycloalkanoic and alkanedlolc acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of S particular esters Include formates, acetates, propionates, butyrates, acrylates and ethylsucclnates. Obviously, esters can be formed with a hydroxyl or carboxylic acid group of the compound of the invention.

Furthermore, the term "pharmaceutically acceptable prodrugs" as used herein 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 undug toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their Intended use, as well as the zwitterionlc forms, where possible, of the compounds of the invention. The term "prodrug" 1 S refers to compounds that are transformed In vivo to yield the parent compound of the above formula, for example by hydrolysis In blood. See, e.g„ T. HSguchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and Edward B, Roche, ed., Bioreversibte Carriers in Drug Design, American Pharmaceutical Assocn, and Pergamon Press, 1987, both of which are incorporated herein by reference. 20 .

Compositions

Compositions are provided which comprise any one of the compounds described herein (or a prodrug, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative thereof), and one or more pharmaceutically acceptable carriers or excipients, 2 5 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 inhibitors, Interferon, bone marrow transplant, farnesy! transferase inhibitors, blsphosphonates, thalidomide, cancer vaccines, hormonal 30 therapy, antibodies,‘radiation, etc). For example, additional therapeutic agents for conjoint administration or inciuslon 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 3 5 the invention together with a pharmaceutically acceptable carrier, which, as used herein,

Includes any and aii 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 2015210454 07 Aug 2015

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 biologies! effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some exam pies of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as iactose, glucose and sucrose; starches such as corn starch and potato starch; 10 cellulose and its derivatives such as sodium carboxymethyi ceiiuiose, etbyi cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; oiive oil; com oii and soybean oil; giycois; such a propylene glycol; esters such as ethyl oieate and ethyl laurate; agar; buffering agents such as magnesium 15 hydroxide and aluminum hydroxide; aiginic acid; pyrogen-free water; isotonic saline;

Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium iauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants 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 pharmaceutically-acceptable carriers and/or diluents and/or adjuvants {collectively referred to herein as "carrier" 25 materials) and, if desired, other active ingredients. The active compounds of the present . invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition 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, mucosaliy, topically, rectaliy, pulmonariiy such as by 30 Inhalation spray, or parentally including intravasculariy, intravenously, intraperitoneally, subcutaneously, Intramuscularly, irrtrasternally and infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. 3 5 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 2015210454 07 Aug 2015

For ora! administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutics! composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.

S

Examples of such dosage units are 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 mammai 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 o? disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. A typical daiiy dose is in the range of 0.01 to 500 mg of compound per kg body weight, preferably between 0.1 and 125 mg/kg body weight and in some cases between 1 aid 25 mg/kg 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 this invention are orolnarliy 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 aikyi esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, geiatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl aicohol, and then tabieted or encapsulated for convenient administration. 30 Such capsules or tablets may contain a controlied-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 semi-liquid preparations 3 5 suitable for penetration through the skin (e.g., iiniments, lotions, 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 daiiy. For topical administration, the 39 2015210454 07 Aug 2015 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-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with art oll-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at Least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and 10 mixtures 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. 1 5 The compounds of this invention can aiso be administered by a transdermai device. Preferably transdermai administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety, in either case, the active agent is delivered - continuously from the reservoir or microcapsuies through 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 microcapsuies, the encapsulating agent may aiso function as the membrane.

The oily phase of the emulsions of this invention may be constituted from known ingredients In a known manner. 25

While 11¾ phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or sn oil or with both s fat and an oil. Preferably, a hydrophilic emulsifier is Included together with a lipophilic emulsifier which acts as a stabilizer. It is aiso preferred to include both an oil and a fat. Together, the emulsifier(s) with or without 30 stabilizers) make-up the socalied emulsifying wax, aid the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 60, cetostearyl alcohoi, myristyl alcohoi, glyceryl monostearate, sodium tauryl sulfate, glyceryl distearate alone or 3 5 with a wax, or other materials well known In the art.

The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be 40 2015210454 07 Aug 2015 used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers, Straight or branched chain, mono- or dibasic alkyi esters such as di-isoadipate, isocetyl stearate, propylene gjycoi diester of S coconut fatty acids, isopropyl myrlstate, decyl oieate, isopropyl palmitate, butyl stearate, 2-ethylhexy! palmitate ora blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required.

Alternatively, high malting 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 aye drops wherein the active ingredients are dissolved or suspended In suitable carrier, especiaify an aqueous solvent for the active ingredients, 15

The active ingredients are preferably present in such formulations in a concentration of 0,6 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w.

Formulations for parenteral administration may be In the form of aqueous or non-aqueous isotonic sterile Injection solutions or suspensions. These solutions and suspensions may 20 be prepared from sterile powders or granules using one or more of the carriers 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, ethsnoi, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers. 2 5 Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient may aiso be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (i,e. Captisoi), cosolvent solubilization (i,e. propylene glycoi) or miceilar solubilization (i.e. Tween 80}. 30

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenteraliy acceptable diluent or solvent, for example as a solution in 1,3-butanedloi. Among the acceptable vehicles and solvents that may be employed are water. Ringer's solution, and isotonic sodium chloride solution. In addition, steriie. fixed 3 5 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 oleic acid find use in the preparation of injectables. 41 2015210454 07 Aug 2015

For pulmonary administration, the pharmaceutics! composition may be administered in the form of an aerosol or with an inhaler including dry powder aerosol.

Suppositories For reels! administration of the drug can be prepared by mixing the drug S with a suitable nonirritating excipient such as cocoa butter and polyethylene giyools that are solid at ordinary temperatures but liquid a! the rectal temperature and will therefore rneit in the rectum and release the drug.

The pharmaceutical compositions may be subjected to conventional pharmaceutics! 10 operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, 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.

Pharmaceutical compositions of this invention comprise a compound of the formulas 15 described herein or a pharmaceutically acceptable salt thereof; an additional agent selected from a kinase inhibitory agent (small molecule, polypeptide, antibody, etc.), an immunosuppressant, an anticancer agent, an anti-viral agent, antiinflammatory agent, antifungal agent, antibiotic, or an anti-vascular hyperproliferation compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle. 20

Alternate compositions of this Invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle. Such compositions may optionally comprise one or more additional therapeutic agents, including, for example, kinase inhibitory agents (smaii 25 molecule, poiy peptide, antibody, etc ), immunosuppressants, anil-cancer agents, anti-viral agents, antiinflammatory agents, antifungal agents, antibiotics, or anti-vascular hyperproiiferation compounds.

The term ’’pharmaceutically acceptable carrier 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 nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion 35 exchangers, alumina, aluminum stearate, lecithin, seifemuislfying drug delivery systems (SEDDS) such as d-atocophero! poiyethylenegiycoi 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as 42 2015210454 07 Aug 2015 phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc saits, colloidal silica, magnesium trlsiiicate, polyvinyl pyrroiidone, ceilulose»based 5 substances, polyethylene glycol, sodium carboxymethylceliulose, poly acrylates, waxes, polyethyiene-polyoxypropylene-blcck polymers, polyethylene glycoi and -wool fat. Cyctodextrins such as u>, P«, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkyicyclodextrins, including 2and 3-hydroxypropyl-cyciodextrifis, or other soiubilized derivatives may also be advantageously used to enhance delivery of 10 compounds of the formulae described herein.

The pharmaceutical compositions may be oraiiy 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 era! use, carriers which 1 S are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents Include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active Ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. 20

If desired, certain sweetening, flavoring and/or coloring agents may be added.

The pharmaceutical compositions may comprise formulations utilizing ilposome or microencapsuiaiion techniques, various examples of which are known in the art 25 The pharmaceutical compositions may be administered by nasal aerosol or inhalation. 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 bioavallability, fluorocarbons, and/or other solubilizing or dispersing agents, examples of which are also 30 well known in the art.

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 other 3 5 compounds of the invention or with one or more other agents. When administered as a combination, 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 2015210454 07 Aug 2015

The phrase “combination therapy", in referring to the use of a compound of this invention together with another pharmaceutics! agent, means the coadministration of each agent in a substantially simultaneous manner as well as the administration of each agent fn a sequential manner. In either case, in a regimen that wli! provide beneficial effects of the 5 drug combination. Coadministration includes inter alia the simultaneous delivery, e.g., in a single tablet, capsule, Injection or other dosage form having a fixed ratio of these active agents, as well as the simultaneous delivery in.muitiple, separate dosage forms 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 cytostatic agents, cytotoxic agents, other anti-cancer agents and other drugs to ameliorate symptoms of the cancer or side effects of any of the drugs . 15 if formulated as a fixed dose, such combination products employ the compounds of this invention within the accepted dosage ranges. Compounds of this invention may also be administered sequentially with other anticancer or cytotoxic 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 2 5 intravenously <IV). The typical chemotherapy regime consists of either DNA alkylating agents, DNA intercalating agents, CDK inhibitors, or microtubule poisons, The chemotherapy doses used are just bsicw the maximal tolerated dose and therefore dose limiting toxioitles typically include, nausea, vomiting, diarrhea, hair ioss, neutropenia and the like. 30

There are large numbers of antineopiastic agents available in commercial use, in clinical evaluation and in pre-ciinica! development, which wouid be selected for treatment of cancer by combination drug chemotherapy. And there are several major categories of such antineopiastic agents, namely, antibiotic-type agents, alkylating agents, 3 5 antimetsboiite agents, hormonal agents, Immunological agents, interferon-type agents and a category of miscellaneous agents. 44 2015210454 07 Aug 2015 A first family of antlneoplastic agents which may be used in combination with compounds of the present invention includes antimetabciiie-type/thymidiiate synthase inhibitor antineopiastlc agents. Suitable antimetaboiite antineopiasiic agents may be selected from but not limited to the group consisting of 5-FU-fibrinogen, acanthifolic acid, 5 amincthiadiazoie, brequinar sodium, carmofur, CibaGeigy CGP-30694, cyclopenty! cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrei Dow DDFC, dezaguanine, dideoxycytWine, dkteoxyguanoslne, didox, Yoshitomi DMDC, doxifluridirte, Wellcome EHNA, Merck &amp; Co. EX-015, fazarabine, floxuridtne, fludarabine phosphate, 5fiuorourad!, N-(21-furanldy!) fluorouradl, Daiichi Seiyaku FO-152, isopropyl ; 0 pyrroiizine, Lilly LY-188011, Lilly LY-264818, methobenzaprtm, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127718, NCI NSC-264880, NCI NSC-39661, NCi NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asa hi Chemical PL-AC, Takeda TAC788, thioguanine, tiazofurin, Erbamont TIF, trimetrexafe, tyrosine kinase inhibitors, Taiho UFT and uricytin. 15 A second family of antineoplastic agents which may be used in combination with compounds of the present invention consists of alkyiating-type antineoplastic agents. Suitable alkylating-type antineoplastic agents may be selected from but not limited to the group consisting of Shionogi 254-S, aldo-phosphamlde analogues, aitrefamine, 20 anaxirone, Boehrlnger Mannheim BBR-2207, bestrabucii, budofitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Cbinoin-153, chiorambucll, cisptatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D 384, Sumlmofo DACHP{Myr)2, diphenylsplromustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R, ITI EQ9. eimustlne, Erbamont FCE-24517, 25 estramusline phosphate sodium, fotemustine, Unimed G Wl, Chinoin GYKI-17230, hepsulfam, ifosfamide, ipropiatin, lomustine, mafosfamide, mitoiactoif Nippon Kayaku NK-121, NCi NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, serrsustine, SmithKIine SK&amp;F-101772, Yakult Honsha SN-22. spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxlrone, 30 tefraplatin and trimetamol. A third family of antineopisstio agents which may be used in combination with compounds of the present invention consists of antibiotic-type antineoplastic agents. Suitable antibiotic-type antineoplastic agents may be selected from but not limited to the group 33 consisting of Taiho 4181-A, aeiarubicln, actinomycin D, actinopianone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN li, Ajinomoto AN3. Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisuoaberin, Bristol-Myers BL-6659, Bristol-Myers BMY-25067, Bristol-Myers BNY-25551, Bristol-Myers BNY-26605 IBrlstolMyers BNY-27557, 45 2015210454 07 Aug

ο <N

Bristol-Myers BMY-28438, bleomycin suifate, bryostatin-1, Taibo C-1027, caticbemycin, chromoximycin, dactinonnydn, deunorubicin, Kyowa HakKo DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko, DC89-AI, Kyowa Hakko DC92-B, ditrlsarubicin B, Sbionogi DOB-41, doxorubicin, 'doxorubicin-fibrinogen, elaamicin-A, epirubicln, 5 erbstatin, esorublcin, esperamlcin-Ai, esperamicin-Alb, Erbamont FCE21954, Fujisawa FK-973, fostrlecin, Fujisawa FR-900482, giidobaciin, gregstln-A, grlncamycirt, herblmycin, idarubicln, illudins, kazusamycin, kesarlrhodins, Kyowa Hakko ΚΜ-563Θ, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594. Kyowa Hakko KT-614S, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogarii, mitomycin, 10 mitoxantrone, Smith Kline M-TAG, ndoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRi International NSC-367704, oxalyeine, oxaunontydn, pepiomycin, piiatin, pirarubipin, porothramydn, pyrindanycin A, Tobishi RA-I, rapamydn, rhizoxin, rodorubicin, . sibanomioin, siwenmycin, Sumitomo SM5887, Snow Brand SN-70S, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceuticai SS-7313B, Ϊ S SS Pharmaceuticai SS-9S16B, eteffimycin S, Taiho 4181-2, ialisomydn, Takeda TAN-888A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubidn. A fourth family of antineopiastic agents which may be used in combination with 20 compounds of the present invention consists of a miscellaneous family of antineopiastic agents, including tubulin interacting agents, topoisomsrase II inhibitors, iopoisomerase I inhibitors and hormonal agents, selected from but not limited to the group consisting of (xoarotene, (X-difluoromethyl-arginine, adtretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonaflde, amphethirsiie, amsacrins, Anglostat, anklnomycin, antl-neoplaston A10, 25 antineoplaston A2, antineoplaston A3, antineoplaston A5. antineoplaston AS2-1F Henkel APD, aphldicolin glycinate, asparaginase, Avsroi, baccharin, batracyiin, benfiuron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, BristoMyars BNY-49481, Vestar boron-10, bromofosfamlde, Wellcome BW-502, Wellcome BW-773, carasamide, carmethizole hydrochloride, Ajinomoto CDAF, chtorsulfaquinoxalone, Cherries CHX-2053, 30 Chemex CHX-100, Warner-Lambert C1-921, WarnerLambert CI-937, Warner-Lambert Ci-941, Warner-Lambert CI958, clanfenur, clavirldenons, ION compound 12S9, !GN compound.4711, Contracan, Yakult Honsha CPT-11, crisnatol, ouraderm, cytochalasin B. cytarablne, cytocytin, Merz D-809, DABIS maleate, dacarbazine, dateliiptinium, dldemnln-B. dihaematoporphyrin ether, dihydroienperone, dlnaline, dlstamycin, Toyo Pharmar DM-35 341, Toyo Pharmar DM-75, Daiichl Seiyaku DN-9693, docetaxel ©lliprabln, ©iilptfnium acetate, Tsumura EPMTC, the epothilones, ergotamine, etoposlde, etretinate, fenretlnid®, Fujisawa FR-57704E gallium nitrate, genkwadaphnin, Chugal GLA-43, Glaxo GR-63178, grifolan NMF5N, hexadecylphosphochollne, Green Cross HO-221, homoharringtonine, 46 2015210454 07 Aug 2015 hydroxyurea, BTG ICRF-187, ilmofosine, iseglutamine, isotretinoin, Oisuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamlne, Lundbeck LU 1121 Lilly LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-2704B, Medco MEDR-340, merbarone, merocyanine 5 derivatives, mathyianlllnoacrldine, Molecular Genetics MGI136, minactivin, mltonafide, mltoquldone mopidamol, motre tinlde, Zenyaku Kogyo SVSST-16, N-(retinoy!)amino acids, Nisshin Flour Milling N-021, N-acylated-dehydroaisnines, nafazatrom, TaSsho NCU-190, nocodazoie derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCi NSC-95580, ocreotlde, Ono ONQ-112, oquizanocine, Akzo Org-10172, 10 paciitaxel, pancratisiatin, pazelllptlne, Wamert.amfcert PD-111707, Warner-Lambert PD-116934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, iCRT peptide D, plroxantrone, polyhaematoporphyrin, polypreis acid, Efarnoi porphyrin, probimsne, procarbazine, proglumide, Irsvitron protease nexin i, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrjstin-P, retelliptlne, retinoic acid, Rhone-Poulenc RP-49532, Rhone-1 5 Poulenc RP-56976, SmiihKiine SK&amp;F-104864, Sumitomo SM-108, Kuraray SMANCS,

SeaPharm SP10094, spatoi, spirocyciopropane derivatives, splrogermanium, Unimed. SS Pharmaceutical SS-554, strypoldinons, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dlsmutase, ToyamaT-503, Toyama T-680, taxol, Teijin TEi-0303, teniposide, thaliblastlne, Eastman Kodak TJB-29, tocotrlenoi, topoteoan, Topostin, Teijin 20 TT82, Kyowa Hakko UCN-G1, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB- 006, vinblastine sulfate, vincristine, vlndesine, vinestramide, vlnoreibine, vintriptoi, vlnzolldine, withanolldes and Yamanouchi YM Alternatively, the present compounds may also be used in co-therapies with other anti-neoplastlc agents, such as acemannan, aclarublcin, aldesleukin, alemtuzumab, alitretinoin, aiiretamine, amifostine, aminolevulinic 25 acid, amruhicin, amsacrine, anagrelide, anastrozole, ANGER, ancestim, ARGLABiN, arsenic trioxide, BAM 002 (Noveios), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladrlbine, clotrimazola, cytarabine ocfosfate, DA 3030 (Dong-A), daclzumab, denileukin dlftitox, desiorelin, dexrazoxana, dllazep, docetaxel, docosanoi, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, 30 fluorouracil, HIT diclofenac, interferon alfa, daunorubicln, doxorubicin, tretinoin, edelfosine, edrecoiomab eflornithine, emltefur, epirubicin, epoetin beta, etoposide phosphate, exemastane, exisulind, fadrozoie, filgrastim, finasteride, ftudarabine phosphate, formestan®, fotemustlne, gallium nitrate, gemcitabine, gemtuzumab zogamioin, glmeraoil/oteracii/tegafur combination, glycopine, goserelin, heptaplatin, 35 human chorionic gonadotropin, human fetal alpha fetoprotein, ibandronic acid, idarublcin, (Imiquimod, interferon alfa, interferon alfa, natural, interferon alfe-2, interferon aifa-2a, interferon aifa-2b, interferon aifa-NI, interferon alfa-n3, interferon alfaconl, interferon alpha, natural, Interferon beta, interferon beta-ia, interferon beta-ib, interferon gamma, 47 2015210454 07 Aug 2015 natural interferon gamma-la, interferon gamma-lb, interieukin-l beta, iobenguane, irinotecan, irsogladine, ianreotfde, LC 9018 (Yakult), ieflunomide, lenograstim, lentinan sulfate, tetrozote, leukocyte alpha interferon, fsuproreiin, levamlsole + fiuorouracil, iiarozoie' lobapiatin, ionidamine, lovastatln, masoprocol, melarsoproi, metoclopramlde, 5 mifepristone, miltefosine, mirimostlm, mismatched double stranded RNA, mitoguazone, mltelactol, mitoxantrone, molgramostlm, nafarelin, naloxone + pentazocine, nartograstim, nedaplafin, niiutamide, noscapine, novel erythropoiesls stimulating protein, NSC 631570 octreotide, opreivekin, osaterone, oxalipiatirs, paciitaxel, pamidronic acid, pegaspargase, peginterfaron a!fa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarublcln, f 0 rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon a!fa-2a, porfimer sodium, raloxifene, raititrexed, rasburksase, rhenium Re 186 etidronate, Hi) refinamide, rifuximab, romurtide, samarium (153 Sm) iexidronam, sargramostim, sizoflran, sobuzoxane, sonermin, strontium-88 chloride, suramin, tasonermin, tazarolene, tegafur, temoporfln, temozoiomide, teniposide, tetrachiorodecaoxide, thalidomide, ibymaiiasln, 15 thyrotropin aifa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfen, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimex, bladder cancer vaccine, Maruyama, vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, VIRUUZIN, zlnostatin stimalamer, or zoiedronic acid; abareiix; AE 941 (Aetema), ambamustine, antisense oligonucleotide, bcl-2 (Genta), ARC 20 8015 (Dendreon), cetuximab, deoltabine, dexamlnogiutethimide, diaziquone, EL 532 (Elan), EM 600 (Endoreeherche). eniluracii, etanidazole, fenretinldei filgrastim SD01 (Amgen), fuivestrant, gaiocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vica!), granulocyte macrophage colony stimulating factor, histamine dihydrochioride, ibritumomab tiuxetan, llomastat, IM 862 (Cytran), interleukin iproxifene, LDI200 25 (Milkhaus), ierldistim, ilntuzumab, CA 125 MAb (Biomira), cancer MAb (Japan

Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAb (Triiex), LYM iodine 131 MAb (Techniclane), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogarti, mitumomab, motexafin, gadolinium, MX 6 (Gaiderma), nelarabine, nolatrexed, P 3Q 30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satrapiaiin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN)y SU 6668 (SUGEN), TA 077 (Tanabe), teirathiomolybdate, thalibiastine, thrombopoietln, tin ethyl etiopurpurln, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering institute), melanoma 3 5 oncolysate vaccine (New York Medical College), viral melanoma cell lysates vaccine (Royal Newcastle Hospital), or vatspodar. 48 2015210454 07 Aug 2015

Treatment Kits

In other embodiments, the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention, fn 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 She invention. Such kits are especlaiiy suited for the delivery of solid oral forms such as tablets or capsules. Such a kit preferably includes a number of unit dosages, and may also include a card having the dosages oriented in the order of their Intended use. If desired, a memory aid can be provided, for example in the form of numbers, tetters, or other markings or with a calendar 10 insert, designating the days in the treatment schedule In which the dosages can be administered. Optionally associated with such container^) can be a notice in the form prescribed by a governments! 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, and 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 described 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 help 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 Physios, 75 Ed., inside cover. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in "Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1899, and “Organic 30 Chemistry", Morrison &amp; Boyd (3d Ed), the entire contents of both of which are Incorporated herein by reference. 49 2015210454 07 Aug 2015

Examples

Some of the compounds described in the following examples have been converted Into an HCI salt. The general procedure for generating HG! salts Is described below: 5 To the tire! product was added Just enough MeOH saturated with HOI (g) to dissolve, cooled to 0 °C for 0.5-1 h, filtered, washed solid with Ice cold MeOH then Et20, and the resulting solid dried In a vacuum desiccator to provide in most cases the iris HC! salt.

Example 1 I0 N-{3~(lH-imidazol--1~yl)'6-(tril1uoromethyl}phenyl)-3~(imidazo{1,2-a]pyrazin-3-yiethynyl)- 4-methylbenzamide

20 lmldago[1,2-a]pyrazine: A solution of aminopyrazlne (1 g, 10,5 mmol) and chloroacetaldehyde {50% wt in HjG; 1.98 g, 12.6 mmol) In 1,6 ml of EtOH was heated at 9Q°C in a sealed tube for 5 h. Upon cooling to ambient temperature, the reaction mixture was concentrated and diluted with dichloromethane (DOM). The organic layer washed with saturated aqueous NaHCQ3ihen dried over MgSO* and concentrated. The crude product was purified by silica gel fiash chromatography (eluted with 10% MeOH/DCM) to provide 0.8 g of product. 3-{(Tiim&amp;ihylsiiyi)eihyny!)lmidazo[1,2~8]pyrazine: A mixture of 3-25 bromoimidazo[1,2-a]pyrazine (0.15 g, 0.78 mmol; prepared according to J, Bradac. et al. J. Org. Ch&amp;m. (1977), 42, 4197 - 4201), 0.09 g (0.91 mmol) of ethynyltrimethytsitane, 0.044 g (0,036 mmol) of Pd(PPh®)4, 0.014 g (0.078 mmol) of Cul, and 0.28 ml (1,52 mmoi) of diisopropyletbylamine in 3.8 ml of DMF was heated at 50°C overnight under an atmosphere of Nz. Upon cooling to ambient temperature, the reaction mixture was concentrated and the 30 crude product was purified by silica gel fiash chromatography (eluted with 50% EtOAc/hexanes) to provide 0,15 g of product: 216 m/z (M+H). 3~Ethynyllmidazo[1,2-aJpyrez!n®: To a solution of 3-{(Trimethyisiiyl)ethyny!)imldazo [1,2-aJpyrazine (0.15 g, 0.7 mmol) in 3.5 ml of THE was added 1.05 ml (1.05 mmoi) of 35 tetrabutylammonlum fluoride (1 .OWi In THF) at ambient temperature. The solution was stirred

SO 2015210454 07 Aug 2015 for 15 min, concentrated, and the crude product purified by silica gel flash chromatography (eluted with 50% EtOAc/hexanes) to provide 0.078 g of product, A mixture of 3-Amino-5- 5 bromobenzotrifluoride (4,0 g, 0.0187 mol), 8-hydroxy quinoline (0.362 g, 0.0025 mol), Cui (0.476 g, 0,025 mol), imidazole (1,36 g, 0,0109 mol), and potassium carbonate (2,52 g, 0.0183 mol) in 17 ml of DMSO (degassed with argon for -10 min) was heaters at 120°C under an atmosphere of argon for 15 h; the HPLC indicated no starting material. A 14% aqueous solution of ammonium hydroxide was added to the cooied mixture and this was 10 stirred for 1 h at ambient temperature. Water (50 mL) and EtOAc (200 ml) were added and the aqueous layer was extracted with EtOAc (3x30mL). The combined organic layers were dried over Ma2S04 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with EtOAc/hexanes) to provide 2.51 g of product, 15 N-(3-(1H-lmidazoi-1~y!)-3-(trifluomm&amp;thyi)phoniyl)-3-iodo-4-ir}ethyiben2amiiiB; To 3-lodo-4-methylbenzolc acid (3.07 g, 0,0117 mol) was added thienyl chloride (10 mL) and refluxed for 2 h, The excess tbiony! chloride was carefully removed and the resulting acid chloride was dried in vacuo for 2 h. The residue was then dissolved in DCM (anhydrous. 25 mL) and cooied on ice. To the cooled solution was added 3-(1H-imldazol-1-yi}-5-20 (trifluoromethyl)aniline 5 (3.46 g, 0.0152moi) in DCM followed by the dropwise addition of diisopropylethylamine (8.2 mL, 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 lo provide 4.65 g of product. Additional product could be obiained from the filtrate following concentration and purification by silica gei flash chromatography in EtOAc/hexanes. 25 Ν-{3-{1Η·ίίηίΦ>ΖΌΜ-ν()-Β·{ΜίΗ>Όζοπκ^ν^βην()~3-((η}Ι(ίβζφ,Ζ-9]ρνζ8ζΙη-3- yiethynyl)~4-methy!b®nz&amp;mide: A mixture of 3-Ethynylimldazo[1,2-a]pyfazine (0.075 g, 0.52 mmol), 0.245 g (0.52 mmol) of N-(3-(1 H-lmidazoi-1-yl)-5-(!rif!uoromethyi)phenyi)-3-iodo-4-methylbenzamide, 0.030 g (0.026 mmol) of Pd(PPh3)«, 0.007 g (0.039 mmol) of Cui. and 0.14 30 mL (0.78 mmol) of diisopropyielhyfamine in 3.0 mL of DMF was stirred at ambient temperature overnight under an atmosphere of Nj- The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (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 2015210454 07 Aug 2015

Alternative Synthesis of N-(3-<1 H-imidazoM ~yl)-5-(trifluoromethyl)ph©rtyl)-3-(imidazo[1,2-a]pyraztn-3-ylethynyl)-4-methylbenzann»de; 3*{(T<imethylsi!yl)ethynyl)im!dazo[1,2~a}pyrazine 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 acetate/hexane) and a brief treatment with activated charcoal (Darco) can be carried out to help further reduce contamination with the homo coupling product. 10 3-ethyny!imldazo[ 1,2*a]pymzlno: To a solution of 3-<(triinethytsfly!)ethynyi) im!dazo[1,2-a]pyrazine (1.39 mol) in 10x 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 1 hour. Potassium carbonate is filtered off and the organic stream • Is washed with wafer and with saturated sodium chloride solution (two or more times). 15 Aqueous phases can be combined and re-extracted with ethyi acetate. Organic streams can then be combined and concentrated under vacuum to about 0.51. Solids can be allowed to precipitate out upon concentration. Slurry is cooled, ag. to about -5°C, stored overnight, filtered, and washed with about Q.3L of cold ethyl acetate. The solids can then be dried under vacuum. 20 3~{lmld8%a[1,2-@]pyr8Z!n“3-ylethyny!}-4-m@lhyShenzofo acid can be prepared in a manner similar to that described above for the Sonogashira reaction, 3-Ethynylimldazo[1,2-ajpyrazine and 3-iodo-4-methylbenzolc acid are used as coupling partners. Alternatively, the solvent (DMF) can be replaced by ethyi acetate and the base (Hunig bass) can be replaced by-triethylamlne. 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 filtration and water wash, the product can be dried in a vacuum oven. 30 N-{3^1H-intidazoh1’yl}~5-(trifhioromethyl)ph9nyl)~3~(imidazo[1,2-aJpyrazin-3- ytethynyl)~4-methylbsnmmidQ: 3-(imidazo[1,2-aJpyrazin-3-ylethynyi)-4"methyjbenzoic acid (18 mmol) is dissolved In methylene chloride (100 mL), To this solution is added 3 equivalents of 4-methylmorphoiine (NMM) followed by 1,05 equivalent of oxaiy! chloride. After stirring at ambient temperature for 30 minutes, 0.8 equivalents of 3-(1 H-imldazoM-yl)-5- 35 (trifluoromethyl)anHine (prepared as above) is added along with 5 moie% of DMAP. After initially stirring at ambient temperature, the mixture is brought to reflux and stirred overnight. After 18 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 2015210454 07 Aug 2015 20 layers can then be evaporated and the residue dissolved in 100 mL of ethyl acetate (20 mL). After standing for 1 h, the product is allowed to crystallize. The mixture is cooled, e.g. to 0 °C, filtered, and the solid product is washed with cold ethyl acetate. 5 N-(3~(1H"lmidazaM~yi)S-(trfflUQromethyl)phenyi)-3-(imlsiaza[1,2~a]pyrazw-3'’ ylethynyl}-4-methylbenzan^de mono hydrochloride salt: N-{3-{-iH-lmldazol-1-yl)-5-(irlfluoiOmethyi)ph8ny!)-3-(lmldazo[1,2-a)pyrazin-3-ylethynyl)-4-methylbenzamlde (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 1M solution in EtOH) 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 1.5ml liquors + 1 x 1.5ml fresh). The solid can be dried at 50’C under vacuum to constant weight. 15 example 2 3-(Imidazo[1,2-8]pyrazin-3-ylethynyl}-4-methyl-N-(4-((4-niethylplperaztn-1-yl)methy 1)-3-(trifluoromethyl}phenyl)benzainicie

The title compound was synthesised from 3~ethy.nyllmldazo[1,2-a]pyrazine and 3-iodo-4-methyl-/V-(4-((4-methylpiperazin-1-yl)methyl)-3-(trlfluoromethyl)phenyl)benzamide in a manner similar to that described for Example 1. The product was obtained as a solid: 533 m/z (M+H). 25 1~(BrQmomethyl)’4-nltro-2-(trlfluoromethyl)benzane: A suspension of 2-methyl-5« nitrobenzotrlfluorlde (3.90 g, 19 mmol), W-bromosuccinimlde (NBS, 3.58 g, 20 mmol). 2,2-azobi8(2-methylproplonltrile) (AI8N, 94 mg, 0.6 mmol) In CCU {40 mL) was refluxed under Nj for 1Θ h. HPLC Indicated ca. 50% conversion. More NBS (10 mmol) and AIBN (0,8 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 off and washed with EtOAc. The combined filtrate was washed with aq, MaHCCb, dried over NaxSO<, filtered, concentrated on rotovap and further dried under vacuum. 1Η N MR shews the ratio of desired product to unreacted 2-methyl-5-niirobenzoiriiluoride is 75:25. This material was not purified but used directly in the next step. S3 2015210454 07 Aug 2015 1·Ν!βΏιγ}·4-(4-ηΗΓο*2·(1ίΗΙϋθΓοίη9ϋιγΙ}&amp;βηζγΙ)ρ}ρβη>ζΙηΒ: To a solution of crude 1-{bromomethyi}-4-nitro-2-(trifluoromethyi)benzene {13,33 mmol, 75% pure) in DCM (10 mL) was added Et3N (1.4 mL, 10 mmol) and 1-methyipiperazine (1.1 mL, 10 mmol). Afetr stirring 5 for 3 h at rt, aq. NaHC03 was added, ana the mixture was extracted with DCM. The combined organic layer was dried over Na2S04, filtered, concentrated, and the resulting residue was purified by silica gei chromatography (eluted with 10% MeOH/DCM) to provide 2.21 g of product as a paie yelbw oii. 10 4-((4-Methylp(perazin-1-yl)methyl)-3-(trlf}uoromethyl)an!llne: A suspension of 1 - methyi-4-(4-nitro-2"(trifluoromethyl)benzyi)piperazine (1.23 g, 4 mmol) and sodium hydrosulfite (7,0 g, 85% pure from Aldrich, 40 mmol) in acetone and water (1:1,20 mL) 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 n-BuOH (4x), and the combined organic layer was washed with saturated aq. NaHCOs, dried, (NajSO^, filtered, concentrated, and the resuiting residue was purified by silica gel chromatography (eluted with 5% MeOH/DCM, MeOH was pre-saturated with ammonia gas) to provide 0.71 g of product as a pale yeliow solid, 20 3-/odo-4-mefhy/~W-f4-ff4-/i»e0i|//p/peraz/n-f-yl)mef/jy/)-3'('ffWuoromef/?yiipfteny/) ®ensam/«fe.· 3-lodo-4-methylbenzoyl chloride (0.48 g, 1,7 mmol), prepared from the reaction of 3-iodo-4-methylbenzoic acid and SOCI2 (as previously described), was added to a solution of 4-((4-methylpiperazIn-1-yl)methyl)-3-(trifluoromethy!)aniline (0,47 g, 1.7 mmol), N,N~ 25 diisopropylethylamine (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 silica ge! chromatography (eluted with 5% MeOH/DCM, MeOH was pre-saturated with ammonia gas), to provide 0,51 g of product as an off-white solid, 30

Alternative synthesis of 3-(imidazo[1,2-a]pyrazin-3-ylethynyi)-4-rnethyl-N-{4-({4-methyiplperazin-1-yl)methyl)-3-(trlfluoromethyl)phenyl)benzamide: 3-{imidazo[1,2-a]pyrazin-3-ylethynyi)“4-methy1-N-(4-((4-methyipiperazin-1-y!)methyi)-3-(irif!uoromethyi) phenyi)benzamide and its mono hydrochloride salt can be prepared in an alternative 35 synthesis similar to that described in Example 1 from 3'(imidazo[1,2-a]pyrazin-3-y!ethynyl)-4-roethyibenzoic acid and 4-((4-methySpiper3z!n-1-yi)methyi)~3-(frjflu0romethyi)aniiine (as prepared above). 54 2015210454 07 Aug 2015

Examples 5 N-(3-(2-<(dimetby!amino)methyl)-1M-imldazol-1-yl)-5-<triftuGroinethyl)pheny 1)-3-(imidazo[1,2>a]pyrazln»3-ylethynyf)-4-methy!benzamide

The title compound was synthesized from 3-e!hyny!imidazo[1,2-aJpyrazine and N-(3-(2-10 ((dlmethyiamino)methyl)-1 H-imidazol-1-yi}~5-(trifluoromethyl)phenyl)-3-iodo-4- methylbenzamide in a manner similar to that described for Example 1, The product was obtained as a solid: 544 m/z (SVH-H). 1‘{1H~imidazol‘2-y!)-N,N-dimethylmeiihimarnirie: To a two-necked round-bottomed 15 flask equipped with a reflux condenser end a pressure-equalizing addition funnel, was added 2-imidazQlecarboxaldehyde (6 g, 82.5 mmol) in MeOH (80 ml). To this suspension-(ambient temperature) was added a solution of dimethylamfne (40% aqueous, 60 ml) at a fast dropping rate (20 min). After the addition was complete, solid sodium borohydride (7 g, 188,8 mmol,) 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 to 65 SC for 3 h and allowed to coo! to ambient temperature for overnight. The reaction contents were concentrated in vacuo and the resultant residue was taken up In EtOAc (2 χ30 ml) washed with brine and with CHCI3 (4 *100 ml). The EtOAc extract was discarded. The CHCi3 extract was dried over (NaS04), 25 filtered, and concentrated In vacuo to give 3.7 g of the desired product as a waxy solid. $~(2-({D)methySsmin®}metfayi}~1H-lmici8zot-1~yl)S-{triftuQronr,®thyl)an!ttne: 3-Amino-5-bromobenzotrifluoride (8 g, 25 mmol) and 1-(1 H~imidazo!-2-yl)-N,N-dimethylmethanamine (3.7 g, 29,8 mmol) were dissolved in anhydrous DMSO (25 ml). To 30 this was added Cul (0.95 g, 7.5 mmol), 8-hydroxy quinoline (0,72 g, 7,5 mmol) and K2C03 (8.9 g, 50 mmol). The mixture was stirred vigorously and degassed with Ng for 15 minutes. The flask was then equipped with a condenser and heated at 120°C for 18 h. The resultant heterogeneous mixture was cooled to rt, poured into 14% aq, NH4OH (100 mL) and extracted with EtOAc (3x3£X)mi), The combined extracts were dried over NaSQ4 and concentrated in 55 2015210454 07 Aug 2015 vacuo. The residue was cbromatograhed oyer silica gei eluting with MeOH/DCM {5:95) to furnish 3.5 g of the desired product as a tan colored material: 286 m/z (M+H). N-(3-(2*((dim@tfty!ainism}misthyi)-lH-imldazoM“yi)"5~{Mfluoivni@tfoy!)ph@nyl)"3·· 5 iodo-4-methylbenzamido:3-lodo-4-methylbenzoyl chloride (2.2 g, 7.8B mmol), dissolved in anhydrous THF (13 mL), was added dropwise to a solution of 3-(2-((dimethyiamino)methyl)-1H-imid3zoi-1-yi)-5-(trifluoromethyl)aniline (1.5 g, 5,5 mmol), DiPEA (2.1ml, 11,8 mmol) in THF (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 fn CHjCfe and 10 washed with 1/V NaOH. The organic iayer was then washed with water, end brine then dried over NsS04 before being concentrated in vacuo. Tire brown colored residue was then triturated tn a mixture of hexanes/DCM to precipitate 1.4 g of the desired product as an off-white powder: 529 m/z (M+H). 1 5 Alternative Synthesis of N-(3-{2>((dimethylarnino)methyl)<-1H-lmidazoM»yl)«5» (triflucromethyI)phenyI)-3-(imidazQ[1,2--a]pyrazin-3-yI&amp;thyrsyS)-4"meibyibsri2amide: N-(3-(2-((dlmethylamino)methyl)-1H-imidazol-1-yi)-5-(trifluoromethyl)phenyl)-3-(imidazo(1l2-8jpyrazln-3-ylethynyl)-4-methylbenzamlde and sis mono hydrochloride salt can be prepared in an alternative synthesis similar to that described in Example 1 from 3-(imidazo[1,2-a]pyrazln-20 3-yiethynyi)-4-methyibenzolc acid and 3-(2-((Dimethylamino)methy!)-1H-imidazo!-1-yl)-5-(trifluoromethyl)aniline (as prepared above).

Example 4 2 5 3-{lmldazo[1,2-a]py ridjrv3-ytethynyl)-4«rnethyl-A#-(3-(4-methyl-1 H-imidazol-1 »yl}-5- {trifkioromethyt)phenyl)berttamide

3*Ethynylimidazo[1a2~a]pyrldine: To 3-bromoimidazo[1,2-a]pyrtdine (5 g, 0.0254 30 mol) in acetonitrile (50 ml) in a sealed tube was added bis(triphenylphosphine) pailadium(ll) dichiorldef 0.445g, 0.634 mmol), Cu! ¢0,17 g, 0.88 mmol), dicyciohexyiamlne (5.6 ml. 0.028 mol) and ethynyitrimethySsilane (7.2 ml, 0.051 mol). The solution was purged with argon for 15 minutes, sealed and heated at 80 °C for 3h, At this point the HFLC did not show any starting bromide. The solvents were concentrated and to the residue was added water and 56 2015210454 07 Aug 2015 . dichioromethane {26 mL each). The organic iayer was separated and the aqueous layer was repeatedly extracted with dichioromethane (3 X 20 mL), The combined extracts were dried (NaaSO^), and concentrated { Rf, 0,47 in 1/1 hexanes/ethy! acetate), The resulting residue was dissolved in THF (100 mL) and treated with tetrabutyi ammonium fluoride monohydrate 5 (8.3 g, 0.032 moi) in water (5 mL) and the mixture was stirred at rt for 2h. The solvents were concentrated and the resuting residue was partitioned between water (25m L) and dichioromethane (150mL). The aquesous iayer was extracted with dichioromethane (2 X 30mL). The combined extracts were dried (N%S04), and concentrated, The resulting' residue was purified by comblflash on silica gei using hexanes/ethy! acetate. The desired 10 product was eluted with 50/50 hexane/ethyi acetate and isolted as an off-white solid: MS (M + H)+ 200. S'ft-MsthyMH-imidazoM-ylf-S^trifluoromsiby^aniUns: A suspension of 3-bromo-5-(trif!uoromethy»afsi!ine (4.8 g, 20 mmol), 4-meihylim!dazole (1,97 g, 24 mmoi), 15 potassium carbonate (3.04 g, 22 mmol), Cu! (0.57 g, 3 mmol), and 8-hydroxyquinoline (0.44 g, 3 mmoi,) in dry DMSO (20 mL) in a pressure tube was degassed by bubbling Nz Into the suspension for 10 minutes whiie stirring. The tube was sealed tightly. The mixture was heated at 120 °C (oil bath temperature) for 15 h. The mixture was cooled down to 45- 50 ®C and 14% aq. NH4OH (20 mL) was added. The mixture was 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/biue Cu salts. The filtrate was dried over sodium suifate and concentrated on a rotavap. The crude product was recrystaliteed from EiQAc/hexanes,‘giving pure pale yellow needles. The mother liquor was concentrated and the residue was purified 25 on silica gel column (5% methanol/methyiene chloride), yielding a second crop as pale yellow needles. 3-l0do^4^mathyl·N‘{3·(4πι@thyl·1H'imidazoM’yi)·^5·(trϊfiuorαn}βthy!}ph¢ny!} . B&amp;nzamids: 3-!odo-4~methy!benzoic acid (2.62 g, 10 mmoi) was refiuxed In SOGfj (10 ml) 30 for 1 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-methyl*1W-lmidazol-1-yl}-5-(trifluoromethyl)benze.namlne (2.46 g, 10.2 mmol), N.N-diisopropylethyiamine (1.56 g, 12 mmol), and a catalytic amount of OMAR in THF (20 ml). 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 naxi step. 3·(ίηι!(ίιιζο[1,2·9]ρ}η’Ιζαη-3~γΙθϋιγηγΙ)-4Ηη&amp;Μ&amp;-Ν'(3-(4~ηΐθΜ)ΐ1-1Η*ίηίΜ8Ζοί·1·γΙ)- S-(trif!uoromsthyl)ph(myl}bmzamlde: To a solution of 3-iodo-4-methyl-A/-(3-(4-methy!-1 H-40 lmldazol-1-yl)-5-(trlfluoromethyl)phenyl)benzamide (0.11 g, 0.22 mmol.) In DMF (1 mL) in' a 57 2015210454 07 Aug 2015 s 10 15 20 seated tube was added Pd^PPhaM {0.0l3g, 0,011 mmol), Cu| (3 mg, 0.016 mmol), dietbyiisopropyiamine (0.057 ml, Q.33 mmol,), followed by 3-ethynylimidazojl,2-aJpyridine (0.040 g, 0.28 mmol,), the mixture was purged with argon for 15 minutes, sealed and stirred at rt for 28 h. The solvent was concentrated and the residue was taken up in methylene Chloride (50 ml). The organic layer was washed with water, dried (Na2S04) and evaporated to leave a brown residue which was purified by combifiash (hexane/ethyi acetate/methanoi) to yield the desired material; MS (M + M)+ 500. Alternative Synthesis of 3'(imidazo|1,2-a]pyridin'3-yiethyny!)*4-methyi'W-(3“(4-nf!ethyi-1H»imidazol"1-yl)'5«(trifiuoromethyS)phenyi)benzamide: 3-(lmidazo[1,2-8]pyrldin-3-y!ethynyt)-4-methyl-;V-{3“{4-methy!-1H-lmidazoS-1-y!)-5«{irii!uoromethyi)pnenyi)benzamide and its mono hydrochloride salt can be prepared in an alternative synthesis similar to that described in Example 1 from 3-(lmidazo(1,2-a3pyrldin-3*ylethynyi)-4-methylb^Tzoic acid and 3- (4-Methyl-1H-lmklazoH>yl)*5-(trifHjoromethyi)aniline (as prepared above). The 3-(lmldazoE1,2-a]pyridin-3-ytethynyl)-4-methyibenzoic acid is prepared in a manner similar to that described in Example 1 using 3-Ethynylimldazoil,2-alpyridine and 3-iodo-4-methyibenzoic acid as Sonogashira coupling partners. Example 5: N-(3-(1H-imidazoS-1-yi)-6-(trmuoror8iethyl)phenyl)-3-(imida2o[1,2-a3pyriciln-3-ytethynyi)» 4- methylbenzamide

25 30

The fitted compound was made as for example 1 using /V-(3-(1H-lmldazol-1-yl)-5-(trif!uorom8thyi)phenyi)-3-!odo-4-methylberizamlde and 3-ethynylimidazo[1,2-alpyridine: MS (M + H)+ 486. The tilled compound ram also be prepared according to the alternative synthesis described in example 1 from 3-(imidazo{1,2-a)pyridin-3-yiethynyi)-4--m8thylbenzoic acid and 3-(1H-imidazoM-y!)*5-(trifluoromethyi)ani!ine (as prepared in Example 1). The 3-(imidazo[1,2-a]pyr!din-3-y!ethynyl)-4-meihy!benzoic acid is prepared in a manner similar to that described in Example 1 using 3-Ethynyfim!dazo[1,2-aJ>yritflne and 3-iodo-4-methylbenzoic acid as Sonogashira coupling partners. 58 ΪΌ ?VJ m ο M«l U1 m

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O 2015210454 07 Aug 2015

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apjtM82U©qjiq^sm-Hl^u^m®S^“€"uiPM^rfie'2‘ U°zeP!lu!)"€"ll^"S*Je,ze>i;o®H^n{l‘WSH-S}-M

The titled compound was made as for example 1 using 3-iodo-4-methyl-/V-(4-(tfifluoromethyl)pyrIdin-2-yl)benzamide and 3-ethynyllir»ldazo[1,2-e]pyridine; MS {M + H) 42,1.39. 2015210454 07 Aug 2015 3-Ethynyiim!dazol1,2-s]pyrldine (37 mg, 0.26 mmol), 3-iodo-4-meiMyl-W-(4-({4-methylpiperazin-1-yl)methyl)-3-(trlfluoromethyi)phenyl)benzamide (103.4 mg, 0.2 mmol), (prepared as in Example 2). Pd^PPh^} {11.6 mg, 5mo!%), and Cul (2.9 mg, 7.5mmol%) was 5 placed In a vial with rubber septum. The mixture underwent 3 cycles of vacuum / filling with Ns, and DMF (1,5 ml) and N, A/-diisopropylethy famine (53 ml, 0.3 mmol) was added. The mixture was stirred at rt for 18 h, and the reaction was quenched with H20, EtOAc and more water were added for extraction. The combined organic layer was dried (Na2SC>4). filtered, concentrated, and the resuiting residue was purified by silica gel chromatography {eluent; 5% 10 MeOH in methylene chloride, MeOH was pre-saturated with ammonia gas), giving the titled compound as an off-white solid (53%, 66 mg): MS (M + H}* 632.

Alternative Synthesis of 3-(lmidazo|1 ,2-eJpyridin-3-ylethynyl)-4-methyl-N-(4-«4-methyipip&amp;razin-1-yt)methyi)-3-(trifluoromstbyl)phonyl}benz3iTiide: 3r(!midazol1,2- a]pyricin-3-y!ethynyi)-4“methyi-W-(4-((4-methylpipera2;in“1"yl)methyl)-3-{trifiuoromett5yS) i 5 phenyl)benzamide and its mono hydrochlofide salt can be prepared in an alternative synthesis similar to Shat described in Example 1 from 3-(imidazo[1,2-8)pyridin-3-ylethynyl)-4-methylbenzolc acid and 4-((4-meihy!piperazin-1-yi)meihyl}-3-(tfifluoromethyl}anillne (as prepared in example 2). The 3-{lmidazo[1,2-a]pyrldln-3-ylethynyl)'4-meihylbanzofc acid is prepared in a manner similar to that described in Example 1 using 3-Ethynylimidazo[1,2-20 ajpyrldine and 3-iodo-4-methyibenzoic acid as Sonogashira coupling partners.

Example 9: W-(3-(2-((dlmethylamino)methyf)-1 H»imidazo!«1-yl)-5>(ir)fluoromethyi)phenyt)-3-25 (lmidazo[1,2-a]pyridin-3-ylethyr»yl>-4-methylbenzamlde

30

To 3-ethynylimidazo[1,2-a]pyrldlne (0.032 g, 0,22 mmol) In anhydrous DMF (1.26 ml) was added W-(3-(2-((d!methylamlno)methyl)-1 W-lmldazol-1*yl)-5-{trlfiuoromathyl)phenyl)-3-iodo-4-methy!benzamide (prepared as in Example 3), Pd( PPha)< {0.013 g, 0.011 mmoi), Cui (0.0032 mg, 0.0165 mmoi) and DIPEA (0.064 mL, 0.44 mmoi). The solution was degassed 60 2015210454 07 Aug 2015 with argon for 15 minutes then stirred overnight at rt, The solvent was removed and the resultant residue was chromatographed over silica gel eluting initially with EiOAc 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 W-(3-(2-((iiimethylammo)methy1)-1H-imIda2oi-1-yi)-5-(trifiuorom©thyl)phenyI)«3>(Iinnidazo|1»2"a]pyridir!-3"y!ethynytH’»iriethyIben?:arfilde: W-{3-(2-((dlmethylamino)methyl)-1H-irtildazoi-1-yl)-5”(trifluoromethyl)phenyl)-3-(imldazo[1,2-a)pyrldin-3-ylethynyl)-4-methyltaenzamide and sis mono hydrochloride salt can be prepared in 10 an alternative synthesis similar to Shat described in Example 1 from 3-(tmidazo[1,2-a]pyridln- 3- y!sthynyl)-4-methylbenzolc add and 3-(2-({Dimethylamlno)mathyl)-1H-imldazol-1-yl)-5-(trifluoromethyl)aniline (as prepared in Example 3). The 3-(imldazo[1|2-a]pyrMln-3-ylethynyl)- 4- methylbsnzolo acid is.prepared In a manner similar to that described in Example 1 using 3-Ethynylimldazo[1,2-a]pyrldine and 3-lodo-4-methyil?er>zotc acid as Sonogashira coupling 15 partners. EXAMPLE 10: a'tiB-Acstamidoimidazofl.Z-alpyridin-S-ySIsthynyli-^RiethyiA?·^-20 (trifi«oromethyt)pyrtdin-2-yl)benzamid8

N-(3~Eihyny!lmidazo[1,2~aJpyrldin-8-yl)acetamlde: N-(Z~Ei\yrty\\mdazol'\,Z‘ 25 a3pyridln-8-yl)acetamide was synthesized as for example 1A from /V-(3-bromoimidazo[1,2- a]pyridin-B-yl)acetamlde (E. Smakula Hand and William VV, Paudler, J. Org. Chem., 1978, 43, 2900-2905). The titled compound was Isolated as an off-white solid, Rf, 0,6 (hexane/ethyiacetate 50/50): MS (M + H)+ 200, 3 0 3-({8-Acetamido!midaza[ 1,2-aJpyridln~3-yi)ethynyl)~4-methyl-N~(4~ (trifluoromethyl)pyrldln-2-yl)b0nzamtde: The titled compound was made as for example 1 using 3-iodo-4-methyi-Ai-{4-<trifiuoromethyi)pyridin-2-yl)benzarinlcie and N-{ 3-ethynyHmid8zo[1,2-a]pyridin-8-yi)acetemida: MS{M + H)* 478.4. 61 2015210454 07 Aug 2015

Example 11: W-(3-(1H>ImIdaEoI"1-yi}"5-itriSlMoro««ethy8)phBn5fi)-3-((8»aceiam5iiciimlda2oi1,2-a3pyridirs- 3-y!)ethynyi)>4»methyIben£atnide 5

' The titled compound was made as for example 10 using W-(3-( 1 H-!midazei-1-yi)-5- (tfifluoromethyl)phenyl)-3-iodo-4-methyibenzamide and /V-(3-ethy nylimidazojl ,2-a]pyrldin-8-10 yl)acetamide: MS (M + H) 543,

Example 12; 44Viethyl-3-{(8-(4-(methy!su!fonyi)ph0ny!amlno]iimida2:Q[1,2»a3pynitin«3-yl)eihynyS)"Af-(4* 15 (tr5fiuorcmethyl)pyrldln-2»yl)benMmide

8"(Benzyloxy}-3-ht&amp;moimidazoi1,2~s]pyndine: To a solution of 2-amino-3-20 benzyloxypyridine (25.0 g, 124.9 mmol) and chloroaoetaldehyde (50% wt in HaO; 16.7 ml, 131.2 mmol) in 250 mL of EtOH was healed at reflux in a sealed lube for 19 h. Upon cooling to ambient temperature, the reaction mixture was concentrated and the resulting brown oil added 125 mL IN NaOH then extracted with dichloromethane (DCM). The combined organic layers were washed with H20, dried over NajSOi 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-(benzyioxy)'mictezo[1 (2-a)pyridine (8.73 g, 38.9 mmol) in 100 mL of EiOH was added, dropwlse, 4.8 mL (48.7 mmol) of a solution of 1:1 Br2/H20 at ambient 62 2015210454 07 Aug 2015 temperature under an atmosphere of N2. The resuiting dark orange suspension was stirred at ambient temperature for 30 min, added 60 ml 1N NaOH,.and the reaction mixture extracted with DCM. The combined organic iayers were dried over N32SG4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 30% 5 EtOAc/hexanes) to provide 7.04 g of product. 6-(Benzytoxy}-3-((trimethylslly!)ethynyi)iinldazo[1,2~a]pyrlcline: A mixture of 6-{benzy!oxy)-3-bronrQimidazo[1,2-aipyridine (10,0 g, 33,0 mmol), 9.39 ml (66.0 mmoi) of ethynyltrimethyteilane, 0,580 g (0.825 mmol) of Pd(PPh3)2C!2, 0,230 g (1.19 mmol) of Cui, and 10 5.09 ml (36.3 mmol) of dilsopropyiamine In 100 mL of acetonitrile was heated at reflux for 3 h under an atmosphere of Ns. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica ge! flash chromatography (eluted with 20-50% EtOAc/hexanes) to provide 6.74 g of product: 321 mfz (M+H). 15 3~({Trimeihyfsllyi)ethynyl)tmidazo[1,2-a]pyrtdtn~8~yi trlfluoromBthanesulfomte:

To a cooied (0°G) solution of 8-(benzy|oxy)-3-((trimethylsllyl)ethyn^)imidazo[1,2-a]pyrldlne (3.44 g, 10.7 mmol) in 400 ml of DCM, under an atmosphere of N2, was added via cannulation 100 mL (100 rrsmoi) of boron trichloride (1.0M solution in hexanes). The reaction solution was stirred at 0'C/ Na for 30 min, to which was added (0°C) 200 mL HzO followed by 20 extraction with DCM. The combined organic iayers were washed with brine, dried over Ma2S04 and concentrated. The crude product was purified by silica gel Hash chromatography (eluted with 30% EtOAc/hexanes then 10% MeOH/DCM) to provide 2.32 g of deprotected product: 231 mfz (M+H).

To a cooled (-78*C) solution of 8-{hydroxy)~3-{(trlmethy!silyl)ethynyl)imidazo[1,2-25 ajpyridine (2,32 g, 10.1 mmol) and 1.63 mL (20.1 mmol) of pyridine in 50 mL of DCM, under an atmosphere of N2i was added 2.03 mL (12.1 mmoi) of triiluoromethanesuifonic anhydride via syringe. Upon removing the cooling 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 1.0N HCi, the iayers separated, and the organic layer washed successively with ION HCI, 30 HaO, saturated aqueous NaHCOs, and brine. The organic iayer was dried over Na2SOi and concentrated. The crude product was filtered through a small plug of silica gel (eluted with 30% EtOAc/hexanes), concentrated, and further dried in vacuo to provide 3,63 g of product: 363 mfz (M+H), 3 5 N-(4-(Methylsulfonyi)phenyl)-3-((trtmethylsl)yi)ethyny0imiciazo[1,2-aJpyridin-$· amino: A mixture of 3~((trlmethylsifyi)ethynyi)imidazoi1,2-a3pyridin-8-y! trifiuoromethanesulfonate (0.32Θ g, 0.91 mmol), 0.186 (1,09 mmoi) of 4- (methyteuifonytianiline, 0.083 g (0,091 mmol) of Pd2(dba)2, 0.087 g (0.181 mmol) of 2-dicyc!ohexylphasphin0-2',4’,6'-triisopropyibiphenyi, and 0.385 g <1.81 mmo!) of potassium 40 phosphate in 8 mL of DME was heated at 80°C In a sealed tube overnight under an 63 2015210454 07 Aug 2015 atmosphere of N2, Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gei flash chromatography (trfathylamlne-treated silica gei; eiuted with 0-80% EtGAc/hexanes) to provide 0,058 g of product; 384 m/z (M+H). 5 3^Ethynyl·N~(4-(m6thylsulfonyi)phenyl)lmld8Z(tf1,2‘a]pyrldln-8'8mlne: To a solution of /V-{4-{methyisuifcnyi5phenyl)-3-((trimethylsi!yi)ethynyi)fenida2of1,2-a3pyridin-8-amlne (0,058 g, 0,15 mmol) In 1,5 mL of THF was added 0,23 mL (0.23 mmol) of tetrabutyiammonlum fluoride (1.0M in THF) at ambient temperature. The solution was stirred 10 for 15 min, concentrated, and the crude product purified by silica gel flash chromatography (triethyiamine-treated silica gel; eluted with 100% DCM then S% MeOH/DCM) to provide a quantitative yield (0.047 g) of product; 312 m/z (M+H). 4-MeOiyl-3-((8‘(4-(mthylsulfonyljphenylamino)imMaz<^1,2"aJpyrl(iln’3~ 15 yl)ethynyl)-N-(4-(trifluoromethy0pyri(fln*2-yl)benzamMe: A mixture of 3-ethynyl-N-(4-(methylsulfonyi) phenyl)imldazo[1,2>a]pyridin*8-amine 8 (0.048 g, 0.154 mmol), 0,069 g (0,170 mmoi) of 3-lodo-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide, 0,009 g (0,008 mmol) of Pd(PPh3)4, 0.002 g (0.012 mmol) of Cul, and 0.04 ml (0.23 mmoi) of diisopropytethyiamine in 20 0.8 mL of DMF was stirred at ambient temperature overnight under an atmosphere of N2.

The reactioR mixture was concentrated and the crude product was purified by silica gei flash chromatography {triethyiamine-treated silica gel; eiuted with 10% EtOAc/hexanes to 100% EtOAc) to provide 0,047 g of product as a soiid: 590 m/z (M+H). 25

Example 13: . 4"methyl-3-((8-(4-sulfamoyiphenyiamino)imldazot1,2-a3pyrld!n'-3"yi)ethynyi)-W-(4- (trifluoromethy1)pyridin-2-yl)benzamfde

64 2015210454 07 Aug 2015

The title compound was synthesized from 3-ethyny!-A?-(4-sulfamoylpbenyi)imidazo[1,2-a]pyridin-8-amme and 3-iodo-4-methyi~N-(4- (Wfluoromethyl)pyridin-2"yl)ben2amide in a manner similar to that described for Example 12, The product was obtained as a solid: 591 m/z (M+H).

Example 14: (R)-N-{4-((3-{Dimethylamlno}pyrrolicHn-1-yl)methyl)~3-(trlf!uoromothy!)pheny!)-3-(imidazo[1,2-b] pyridazin-3-yietbynyl)-4-methyll>enzamide

3-((TrlmGthy1s(lyl}ethynyf)invd8zo{1t2-b}pyrMazine: A mixture of 3- 1 5 bromoimidazo[1,2-b3pyrldazine (36.78 g, 0.186 mol; prepared according to Stanovnik, B. et a/. Synthesis (1981), 12, 987-989), ethynyltrimethyisiane (2.1.89 g, 0,223 mol). Pd(PPh3}4 (10.73 g, 9,29 mmol), Cul {5.30 g, 0.028 mol), and diiscpropytethyiamine (32.4 ml, 0.279 mol) in 150 mL of DMF was stirred at ambient temperature, under an atmosphere of N2, for 1 h. The reaction mixture was concentrated and the crude product was purified by silica gel flash 20 chromatography (eluted with 0-5% MeQH/DCM) to provide 28.46 g o? product. 3-Ethynylimidozo[ 1,2~bjpyridazlne: To a solution of 3-{(trim©thytsilyl)ethyhyl) imidazo[1,2-b]pyridazine (28.46 g, 0.132 mol) in 200 mL of THF was added 145 ml (0.145 mol) of teirabutyiammoniurn fluoride (1,0M in THF) at ambient temperature. The solution was 25 stirred for 15 min, concentrated, arid the crude product purified by silica gel flash chromatography (eluted with 0-5% ΜθΟΗ/DCM) to provide 17,84 g of product 1«(Broir:omethyi}-4"nitro-2-(tri?<uorQ{nethy!}benzQn&amp;: A suspension of 2-maihyi-5-nitrobenzotrifluoride (3.90 g, 19 mmol), W-bromosuccInimide (MBS, 3.56 g, 20 mmol), and 30 2,2’-azobis(2-methylproplon!trlle) (AIBN, 0.094 g, 0,6 mmol) In 40 mL of CCU was heated at reflux under M2 for 16 h. HPLC indicated ca. 50% conversion. Additional NBS (10 mmol) and AIBN (0,6 mmol) were added and the mixture was heated at reflux for another 14 h. HPLC Indicated ca. 80% conversion. The reaction mixture was cooled to ambient temperature, and 65 2015210454 07 Aug 2015 the solid was filtered and washed with EtOAc. The combined filtrate was washed with aq, NaHCOj, dried over N82SO4, filtered, concentrated on rotovap, and further dried under vacuum, 1H NMR indicated the ratio of desired product to unreacted 2-methy!-5~ nitrobenzotrlfluorld8 to be 75:25, This materia! was used directly in the next step, 5 (R}-N,H-OimQtbyi~1’(4-nitrQ~2'(tr'<flUf)rQm<sthyl)bmzyl}p¥rFolMn»3-afntiw: To a solution of crude 1~{bromomethyiH-nitr©-2-(trif!uoromethy!)benzene <17.5 mmoi, 75% pure) in 40 mL of OCM was added EfeN (2,68 ml, 18.3 mmol) and {R)-(+)-3-(dimethyiamino)pyrrolidine {2.0 g, 17.5 mmoi). Alter stirring overnight at ambient temperature ] 0 under an atmosphere of M2, the reaction solution was concentrated, added aq. NaHCOi, (100 mL), and the resuiting mixture extracted with DCM (4 x 50 mL). The combined organic layer was dried over Na^SO^, filtered, concentrated, and the resulting, residue was purified by silica gel chromatography {eluted with 0-10% MeOH/DCM) to provide 3,35 g of product as a yellow oil. 15 {R)-1-(4-Amino-2-{ti1fluorani9thyl)bmzyl)’N,N-dim0thylpyrroiidfn~9'0min&amp;: To a solution of (R)-N,N-diniethyi-1-(4-nitro-2-(trifiuorc»nethy0benzyi)pyrro!idin-3-amine {1.20 g, 3.79 mmoi) in 20 mL of wet ESOH was added 0.26 g of Pd/G {10% Pd on C) and the mixture shaken in a Parr apparatus {pressure reaction vessel purged thoroughly with H2 and pressure 20 regulated at 45 psi throughout) for 2-3 h. The reaction mixture was filtered through a small pad of celite, washed with EtOAc, and the combined organics concentrated to provide a quantitative yield of a Sight yellow oil. This material was used directly in the next step. (R)-N~{4~{{3-{Difnathylafr,ino)pyrrolldln-i-yi}methy!}-3'{trifltiOirom0thyl)phenyl)-3~ 25 lQdQ’4~m0tbylb@nzamid®: To a cooled (0 °C) solution of <R)-1-(4-amino-2- {trif)uoromethyl)benzy!)-N,N-dimethylpyrroi!ciin-3-amine (3,79 mmoi) In 14 ml DGM, under an atmosphere of N2, was added 3-lodo-4-methylbenzoyl chloride (1.17 g, 4.17 mmoi; GAS# 52107-98-9, prepared from the reaction of 3-lodo-4-methylbenzoic add and SOC'b) followed by dropwise addition of /V,W-dllsopropylethylamine {2.64 mL, 15.2 mmol), After stirring to 30 ambient temperature over 1,5 h, the reaction mixture was concentrated and the crude product was purified by silica gel chromatography (eluted with 0-8% MeOH/DCM; MeOH was pre-saturated with ammonia gas), to provide 0.71 g of product as a thick yellow oil. (R)-N-(4-((3-(d!methyiamlno)pyirolMn-1-y!)methyi)-3-(trlfluoromethyl)phenyl)-3- 35 (imidazc[1,2~b]pyridaz!n~3~yi&amp;ihyny!)-4-m@thylbe!nzamide: A mixture of 3- ethynylimidazo[1,2-b]pyridazine (0.051 g, 0.34 mmoi), 0.150 g (0,28 mmoi) of (R)-N-<4-((3· (dlmethylamino)pyrrolldln-1-yi)methyl)-3-(trifluorom0thyl)phenyl).3-iodo-4-methylbenzamlde, 0.016 g {0,014 mmol) of Fd(PPhsk 0-004 g (0,021 mmol) of Cui, and 0.09 mL (0.51 mmol) of Af,A/-diisopropyiethyiamlne in 3.5 mL of DMF was stirred at ambient temperature, under an 40 atmosphere of Mj, for 3 days (reaction pushed to completion with additional equivalents of 66 2015210454 07 Aug 2015 reagents and healing to 80 'C). The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (eluted with 0-10% MeOH/DCM; MeOH was pre-saturated with ammonia gas) to provide 0.020 g of product as a solid: 547 m/z (M+H). 5

Alternative Synthesis of (R)-N-(4-((3-{Disnethyiamino)pyrroUdiri-1-yi)methyi)-3-(trifiuoromethyl)pheny!)-3'(imidazo[1,2-b)pyrldazin-3-ylethynyl)-4-mothySbenzamide: (R)-N-(4-{(3-(Dimethytamino)pyrroiidin-1-yl)methyl)-3-{triflucMromethyl)phenyi)-3-(imidazol1l2-bjpyridazin-3-yiethynyi)-4-methylbenzamide and its mono hydrochloride salt can be prepared 10 in an alternative synthesis similar to that described in Example 1 from 3-(imidazo[1,2-bJpyridazim3-ytethynyl)-4-methy!benza!c acid and (R)-1-(4-Amlno-2"(trifluoromethyl)benz:yl)-N,N-dlniethyipyrroiidin-3-amine (as prepared above). The 3-(imldazo[1,2-b]pyridazin-3-y!ethynyl)-4-methylbenzolo acid is prepared in a manner similar to that described in Example 1 using 3-Etbyny!im!dazot1,2~bjpyridazine and 3-lodo-4-methylbenzoic acid as Sonogashira t 5 coupling partners. EXAMPLS 15 20 N-(3-(!mldazo[1,2-b]pyi1<Jazin-3-ylethynyi)-4-inethyiphenylHM{4-methylplperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

25

The title compound was synthesized from 3-eShyny!imldazo[1,2"b]pyrldazine and N-(3-iodo-4-methylphenyl)-4-((4-methylpiperazin-1-y!)methyl)r3-(trifluoromethyl}benzamide in a manner similar to that described for Example 14. The product was obtained as a solid: 533 m/z (M+H). 30 N~(3-fQ(iO'4~m&amp;thySphenyl)'4~({4‘rn&amp;thylpip®tez!n’1-yi)in@thyl)~3- (trifluoromothyljbemamldc: To a flash containing 1.0 g (2.87 mmol) of 4-[(4-methyl-i-piperezinyl)methyl]-3-(trifluoromeihyi)-benzolc acid (CAS# 859027-02-4: prepared according to Asaki, T. ef aL Bloorg. Med. Chem. Lett. (2008), 16, 1421-1425), 0.82 g (2.87 mmol) of 3-iodo-4-methylanlline, 0.77 g (4.0 mmol) of N-(3-dimethy!amlnopropyl)-N'-ethylc0rbodlimida 67 15 20 25 2015210454 07 Aug 2015 5 ΙΟ hydrochloride (EDAC), and 0,43 g (3.2 mmci) of N-hydroxybenzotrlazole monohydrate (HOBt ' HjO) was added 5 mL of DCM and 5 ml of trleShylamlne, The solution was stirred at ambient temperature under en atmosphere of N2 for 3 days, concentrated, and the crude product purified by silica gel chromatography (eluted with 100% EtOAc then 10% MeOH/EtOAo), to provide 0 69 g of product as a white solid. Example 16; 3-<lmidaz0{1t2-bJpyrSclazin*3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-y!}meiby!)- 3-(trlftuoromethyl}phenyi)benzamide

30

The title compound was synthesized in a manner similar to that described for Example 14, from 3-ethynySimidazo[1,2-b3pyridazine and 3-iQdo-4-methy!-W-{4-((4-meihy!piperazln»1-yi3meihy!)"3-(triiiuorometby!)phenyi}benzarnide (Prepared as described in Example 2). The product was obtained as a soiid; S33 m/z (M+H).

Alternative Synthesis of 3-(imidazo[1,2«b3pyridazin"3-ylethynyt)«4-methyt-N'(4. ((4-methyIplpera2in-1-yi)mothyl3'3-(trifluoromethyl)pheirtyl)benzamido: 3-(lmidazo[1,2-b3pyridazin-3-y!ethynyi)-4-methyl-N-(4-((4-methyipiperazin-1-y|}rrieihy!)-3-(trifluoromethyI)phenyi)benzamide and its mono hydrochloride salt can be prepared in an alternative synthesis similar to that described in Example 1 from 3-(imidazo(1,2-b]pyridazin~3-yiethynyl)-4-methy!benzolc acid and 4~{{4-methylpipera2ln-1-yl5methy1)“3"(trifluoromethyl) aniline (as prepared In example 2), The 3-(imldazo[1,2-bJpyridazin-3-ytethynyi)-4-methylbenzoto acid is prepared in a manner similar to that described in Example 1 using 3-Ethyny!imidazo[1,2-b]pyrldazine and 3-iodo-4-methylbenzoic acid as Sonogashira coupling partners. 68 2015210454 07 Aug 2015

Example 17: N-(3>Chloro-4>((4'methylpipera2in>1>yl)methyl)phonyl)>3>(iniidazo[1,2-b]pyrldazin-3· 5 yfethynylM-methylbenzamlde

The title compound was synthesized according to Example 14, from 3-10 ethynylimldazoli,2-b]pyrldazine and N-(3-ohioro-4-{{4-m8thyipiperazin-1-yl)methyl>ph8nyl)-3-iodo-4-methylbenzamide. The product was obtained as a solid: 499 m/z (M+H). i~iBromomethyi)-2~ohloro~4-nftro-t)enzsne; A suspension of 2-ehioro*4-nitrotoluene (10,0 g, 58.3 mmol}, /V-bromosuodnimide (NBS, 10.9 g, 61.2 mmol), and 2,2’-] 5 azobis(2-methylpropSonitrile) (AiBN. 0.29 g, 1.75 mmol) in 120 ml of CCU was heated at reflux under an atmosphere of N* 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. NaHCOs, dried over NaaSO*, filtered, concentrated on rotovap, and further dried under vacuum. 1H NMR indicated the ratio of desired product to unreacted 2-chloro-4-20 nitrotoiuene to be 50:50. This materia! was used directly in the next step. 1-(2-Chloro-4-nStrobenzyi)~4~fiKthyfplpemzfne: To a solution of crude 1-(bromomethy!)-2-ch!oro-4-nitro-benzene (29.1 mmcH; 50% pure) in 30 mL of DCM was added EtjN (4.2 ml, 30 mmol) and 1-methyipiperazlne (3.4 mL, 30 mmol). Alter stirring for 3 h at 25 ambient temperature, aq. NaHCG3 was added and the mixture was extracted with DCM. The combined organic layer was dried over NaaSO^, fiitered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 5% MeOH/DCM) to provide 6.80 g of product as a dark yeliow oil. 30 3-Chforo~4-((4~methyipfp»r8zln-1-yl)m0thyl}anlflne: To a solution of 1-(2-chloro-4- nitrobenzy1)-4-methyipiperazine (0.96 g, 3.6 mmol) in MeOH/water (4:1, 50 mL) was added 1.80 g (33.7 mmol) of NH4CI and 1.47 g (26.3 mrnof) of Fe dust and the mixture heated at reflux under an atmosphere of Nz for 2 h (HPIC indicated no progress). To this was added 4 ml. of giacial acetic acid and the mixture heated at reflux for an additional 2 h. The reaction 69 2015210454 07 Aug 2015 5 10 1 5 20 mixture was cooied to ambient temperature, filtered, and the filtrate concentrated. The residue was partitioned between EtOAc and saturated aq. NaHCOj, the separated aqueous layer was extracted with EtOAc, and the combined organics washed with brine and dried over N02SO4. Upon concentration, the crude product was purified by silica gel chromatography (eluted with 5-7% MeOH/DCM; silica gel deactivated with 1% tr!eihylamine/DCM) to provide 0,53 g of product. Alternative Synthesis e? M>(3'ChlorO"4"((4-tn©thylpIperazin-1-y8)snethyi)phersyl)-3“(im!dszoi[1,2-b]pyridazii5-3-ylethy nyl}-4-methylban2amids: N>(3»Chioro-4-((4-methyl plperazin~1-yl)meihyi}phenyl)-3-(imidazo[1,2-b]pyridazln-3~ylethynyl)-4-methylbenzamlde and its mono hydrochloride salt can be prepared in an alternative synthesis similar to that described in Example 1 from 3-(lmldazo[1,2-blpyrldazin-3-ylethynyl)-4-methyibenzoic acid and 3-Chloro-4-((4-methylpipera*ln-1-y!)methyl)anillne (as prepared above). The 3-(lmIdazo[1,2-b]pyridazin-3-yiethynyl)-4-methylbenzoio acid is prepared In a manner similar to that described in Example 1 using 3-Ethynyiimidszo(1,2-bJpyridazine and 3-iodo-4-methylbenzoic acid as Sonogashlra coupling partners. Example 18: N-(3-Cyciopropyl-4-((4-methytpiJerazln*1-yl}methyl)phenyl)-3-(imidazo[1,2-b3pyridazin. 3-y lethy ny I )-4-methy Ibenzamfde

25 30

The title compound was synthesized from 3-ethynyiimidazop ,2-bJpyrldazine and N-(3-cyclopropyl-4-((4-m®thylpiperazln-1-yl)methyl)phenyi)-3-iodo-4-methylbenzamlde In a manner similar to that described for Example 14 (nitro reduction performed in a manner similar to that described for Example 17; 0.25M in MeOH/10%AsOH). The product was obtained as a solid: 505 mfz (M+H). 1*(2-GyclaprQpyl-4-t>ii<rQhenzyi)‘4'm@mylpiperazjn@: A mixture of 1-(2-bromo-4-nitrobenzyl)-4-methy!piperazine (0,94 g, 3.G mmol), 0.77 g (9,0 mmol) of cyciopropylboronlc acid, 0,067 g (0.30 mmo!) of Pd(OAc)4l 2.87 g (13.5 mmoi) of KsPO*. and 0.168 g (0.60 mmol) of tricyoiohexylphosphine In 18 mL of ioiuene/waier (5:1) was heated at reflux under an atmosphere of Nz for 19 h. The reaction mixture was concentrated and the crude product 70 2015210454 07 Aug 2015 5 10 15 was purified by silica gel chromatography (eluted with 5% MeOH/DCM; MeGH was presaturated with ammonia gas) to provide 0.80 g of product.

Example 19; 3-(lmldazo[1,2-b3pyridaz1n-3-yiethynyl)-N-(4-((4-m0thyipiperazin»1-yl)methy 1)-3-(trifluoroinethyl)phanyl)benzarfilcle

The title compound was synthesized from 3-ethynylimidazo{1,2-b]pyridazine and 3-iodo-N-(4-((4-rriethylpiperazin-1-yl)methyl)-3-(trlf!uoromethyl)phenyi)benzamide in a manner similar to that described for Example 14. The product was obtained as a solid: 619 m/z (M+H). The titled compound can aiso be prepared according to the alternative synthesis described in example 1 from 3-(imidazo[1,2-b]pyfidazi!v3-yl©thynyl}-4-methySbenzoic acid and 4-((4-methylpfperazin-1-yl)methyl)-3-(trif!uoromethyl)aniline (as prepared In example 2), The 3-(lmldazo[1,2-b]pyrldazln-3-ylethynyl)-4-nfiethyiberizolc acid is prepared in a manner similar to that described in Example 1 using 3-Ethynyllmldazo[1,2-bjpyridazlne and 3-todo-4-melhylbenzolc acid as Sonogashira coupiing partners. 20 Example 20: N-(4-((4-(2-Hydroxyethyl)piperazir»-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(lmld3zo[l,2· b]pyrldazin-3-yiethynyl)-4rmethylbenzamlde

25 The title compound was synthesized from 3-ethynyllmidazo[1,2-b]pyridazlne and N- (4-((4-(2-hydroxyethyl)plperazln-1-yl)methyl)-3-(trlfluoromethyl)phenyl)-3-iodo-4- methylbenzamide in a manner similar to that described for Example 14, The product was obtained as a solid: 563 m/z (Wl+H). 71 2015210454 07 Aug 2015 EXAMPLE 21: 3-{tmldaz©[1,2-foJpyridszi«-3-y let hyRyl)-4-methyi-N-<4-fpip©razm.1.yimethy 1)-3-(trifluoromethyl}phenyl)berezamide

The title compound was synthesized from 3-ethynyiimidazoI1,2-b]pyridazine and tert-buty! 4-(4-(3-iodo-4-methyibenzamldo)-2-(trifiuorom®thyi)beRzy!}p!perazine-1"Carboxylate in a manner similar to that described for Example 14. Following deprotection using saturated 10 MeOH/HC! (g), the product was obtained as a tris HC! sait: 519 m/z (M+H).

Example 22: Siological Evaluation of Compounds 1 5 Compounds of this Invention are evaluated in a variety of assays to determine their biological activities. For example, the compounds of the invention can be tested for their ability to inhibit various protein kinases of interest. Some of the compounds tested displayed potent nanomoiar activity against the following kinases: Abi, Abi T315I, Src and FGFR. Furthermore, several of these compounds were screened for antiproliferative activity in BaF3 20 cells transfected with either wild-type Bcr-Abi or the Bcr-Abi T3151 mutant and demonstrated activity in the range of 1-100 nM,

The compounds can also be evaluated for their cytotoxic or growth inhibitory effects on tumor ceils of interest, e.g,, as described in more detali below and as shown above for some representative compounds. See e,g,, WO 03/000188, pages 115 - 136, the foil 25 contents of which are incorporated herein by reference.

Some representative compounds are depicted below. 72 2015210454 07 Aug 2015

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The compounds listed in the table below also showed inhibitory activity against various protein kinase of interest,

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Kinase inhibition

More specifically, the compounds described herein are screened for kinase inhibition activity as follows. Kinases suitable for use in the following protocol Include, but are not limited to: Abl, Lek, Lyn, Src, Fyn, Syk, Zap-70, iik, Tec, BtK, EGFR, ErbB2, Kdr, Fit1, Flt-3, 5 Tek, c-Met, InsR, and AKT.

Kinases are expressed as.either kinase domains or full length constructs fused to glutathione S-transferase (GST) or polyHistldine tagged fusion proteins in either E, coli or Baculovirus-HIgh Five expression systems. They are purified to near homogeneity by affinity chromatography as previously described (Lehret al,, 1896; Gish et ai,, 1995). in some 10 instances, kinases are co-expressed or mixed with purified or partially purified regulatory polypeptides prior to measurement of activity.

Kinase activity and inhibition can be measured by established protocols (see e.g., Braunwalder et ah, 1998). In such cases, the transfer of 33P04 from ATP to the synthetic substrates po!y(G!u, Tyr) 4:1 or poly(Arg, Ser) 3:1 attached to the bioactive surface of 1 5 microtiter 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 0.5% phosphoric sicid, adding liquid scInlSISant, and then counting in a liquid scintillation detector. The iC50 is determined by the concentration of compound that causes a 50% reduction in the amount of 33P incorporated onto the substrate bound to the plate. 20 ' in one method, the activated kinase 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 kinase reaction along with Europium -labeled anti-phosphotyrosine antibody (Eu-Ab) and Allophycocyanin-Streptavidin (SA-APC). The biotinylated substrate peptide (with or without phosphoryiated 25 Tyrosine) in solution binds to the SA-AFC via Biotin-Avidin binding. The Eu-Ab binds only to substrate with phosphoryiated tryrosine. When the solution is excited at 615nm, 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 phosphoryiated substrate peptide). The APC then fluoresces ai a wavelength of 665nm. Excitation and emission take place in a Wallac Victor2 V 30 plate reader where the plate is read fluorometricaliy and absorbances at 815 and 665nm are recorded. These data are then processed by an Excel plate processor which calculates IC50s of test compounds by converting the fluorescence into amounts of phosphoryiated substrate made and determining the concentration of test compound that would be required to inhibit the development of phosphoryiated substrate by 50% (IC50). 3 5 Other methods relying upon the transfer of phosphate to peptide or polypeptide substrate containing tyrosine, serine, threonine or histidine, alone, In combination with each other, or in combination with other amino acids, In solution or immobilized (Le., solid phase) are aiso useful.

For example, transfer of phosphate to a peptide or polypeptide can also be detected 40 using scintillation proximity, Fluorescence Polarization or homogeneous time-resolved 85 2015210454 07 Aug 2015 fluorescence, Alternatively, kinase activity can be measured using antibody-based methods In which an antibody or polypeptide is used as a reagent to detect phosphor/laied target polypeptide,

For additional background information on such assay methodologies, see e,.g., 5 Braunwaider ei al„ 1996, Anal, Biochem, 234(1):23: Cleaveland et ei,t 1990, Ana! Biochem. 190(2):249 Gish et al. (1995). Protein Eng, 8(6):609 Kolb et al. (1998). Drug Discov, Toda V. 3:333 Lehr et al. (1996), Gene 169(2):27527 - 87 Seethata et al. (1998). Anal Biochem. 255(2):257 Wu et al. (2000). IC50 values in the low nanomolar range have been observed for compounds of this 10 invention against various kinases, 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 cel! lines and thus may be useful in the 1 5 treatment of cancer and other cell proliferative diseases. Compounds are assayed for anti tumor activity using in yivo and in vitro assays which are well known to those skiiied in the art. Generally, Initial screens of compounds to identify candidate anti-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.

Cell-based methods for measuring antiproliferative activity are well known and can be used for comparative characterisation of compounds of this invention. In general, cell 2 5 proliferation and cell viability assays are designed to provide a detectable signal when cells are metabolically active. Compounds may be tested for antiproliferative activity by measuring any observed decrease in metabolic activity oj the cells after exposure of the cells to compound. Commonly used methods include, for example, measurement of membrane integrity (as a measure of cel! viabiiiiy}(e.g, using trypan blue exclusion) or measurement of 30 DMA synthesis (e.g, by measuring incorporation of BrdU or 3H-ihymidine).

Some methods for assaying ceil proliferation use a reagent that is converted into a detectable compound during cel! proliferation. Particularly preferred compounds are tetrazolium sails and include without limitation iV1TT (3-(4, 5-dimelhylthiazof-2-yi)-2,5-dlphenyltetrazollum bromide; Sigma-Aldrich, St. Louis, MO), MTS (3-(4,5-dimeihyithiazol-2-35 yl)-5-(3-carboxymethoxypheriyl)- 2-(4-suifophenyl)-2H-tetrazolium), XTT (2,3-bls(2-Methoxy-4'nitro-5-sulfbphenyl)-2H-tetrazolium-5.'carboxanlllde), lNT, NBT, and NTV(Bernas eta!. Biochim Biophys Acta 1451(1):73-81, 1999). Preferred assays utilising tetrazolium salts detect cei! proliferation by detecting the product of the enzymatic conversion of the tetrazolium salts Into blue Formazan derivatives, which are readily detected by spectroscopic 40 methods (Liesman. J. immunoi. Methods. 66:55-63,1983). 86 2015210454 07 Aug 2015

Generally, preferred methods for assaying cel! proliferation involve incubating cells in ' a desired growth medium with and without the compounds to be tested, Growth conditions for various prokaryotic and eukaryotic ceils are well-known to those of ordinary skii! in the art (Ausube! et ai. Current Protocols in Molecular Biology, Wiley and Sons. 1999; Bonifacino et S ai. Current Protocols in Ceil Biology, Wiley and Sons. 1999 both incorporated herein by reference). To detect cel! proliferation, the tetrazolium salts are added to the incubated cultured celis to allow enzymatic conversion to the detectable product by active cells. Cells are processed, and the optica! density of the ceils Is determined to measure the amount of formazan derivatives. Furthermore, commercially available kits, including reagents and 10 protocols, ate avsilabe for examples, from Promega Corporation (Madison, Wl), Sigma-Aldrlch (St, Louis, MO), and Trevigen (Gaithersburg, MD),

More specifically, the cell proliferation assay we currently perform is using CeSiTiter 96 AGueous One Solution Cell proliferation assay kit (Promaga, Cat#G3S81), This assay is a colorimetric method for determining the number of alive ceils in proliferation or cytotoxicity 15 assays, The assay utilizing terazoiium sails detect cel! proliferation by detecting the product of the enzymatic conversion of the tetrazolium salts into blue formazan derivatives, which can be measured by the absorbance at 490 nm in a plate reader, Waiiac Victor2'/ (PsrkinElmer).

An example of ceil-based assay is shown as below. The cell lines used in the assay-are Bs/F3, a murine pro-B cel! line, which have been stably transfected with full-length wild-20 type Bcr-Abl or 8cr»Abl with various kinase domain point mutations (including T351I, Y2.53F, E255K, H396P, M351T etc) constructs. Parental BafF3 cell tine is used as control. These cell lines were obtained from Brian J. Darker (Howard Hughes Medical Institute, Oregon Health and Science University, Portland, Oregon, USA). Ba/F3 cell expressing Bcr-Abl or Bcr-Abl mutants were maintained in PRMI 1640 growth medium with 200 μΜ L-gultamlne, 10% FCS, 25 penicillin (200U/ml), and streptomycin (200 pg/ml). Parental Ba/F3 cells were culture in the same medium supplemented with 10 ng/ml IL-3,

Parental Ba/F3 cells (supplemented with IL-3) or Ba/F3 ceils expressing WT or mutant Bcr-Abl are plated In duplicate at 1x104celis/wel! in 96-well plates with the compounds in different concentrations In the media. The compounds are first dissolved and diluted in 30 DMSG by preparation of 4-fold dilution; next equal volumes of compounds with DMSO are transferred to medium and then transferred to cel! plates. The final compound concentrations start from 10 μΜ to 6 nM. DMSO at same percentage is used as coniroi. After compound was incubated with ceils for 3 days, the numbers of active cells are measured using CeliTiter 96 AGueous One Solution Cell Proliferation assay kit following the kit instruction. Basically, the 35 tetrazolium salts are added to the incubated cultured celis to allow enzymatic conversion to the detectable product by active celts. Cells are processed, and the optical density of ihs cells Is determined to measure the amount of formazan derivatives, Mean +/- SD are generated from duplicated wells and reported as the percentage absorbance of control, ICSOs are calculated In best-fit curves using Mlcorsoft Excel-fit software, 40 ' 87 2015210454 07 Aug 2015 in addition, a wide variety of cell types may be used to screen compounds for antiproliferative activity, including the following cei! lines, among others: COLO 206 (colon cancer), DLD-1 (colon cancer), HCT~16 (colon cancer), HT29 (colon cancer), HEP G2 (Hepatoma), K-562 (Leukemia), A549 (Lung), NCI-H249 (Lung), MGF7 (Mammary), MDA-5 MB-231 (Mammary), SAOS-2 (Osteosarcoma), OVCAR-3 (Ovarian), PANG-1 (Pancreas), DU-145 (Prostate), PC-3 (Prostate), ACHN (Renal), CAKI-1 (Renal), MG-63 (Sarcoma).

While the cell line is preferably mammalian, tower order eukaryotic ceils suets as yeast may also be used to screen compounds. Preferred mammalian cel! lines are derived from humans, rats, mice, rabbits, monkeys, hamsters, and guinea pigs since ceiis tines from 1 0 these organisms are well-studied and characterized^ However, others may be used as well. Suitable mammalian cell tines are often derived from tumors. For example, the following tumor cell-types may be sources of ceils for culturing cells: melanoma, myeloid leukemia, carcinomas of the lung, breast, ovaries, colon, kidney, prostate, pancreas and testes), cardiomyocytes, endothelial cells, epithelial ceils, lymphocytes (T-ce!i and B cell), 1 5 mast cells, eosinophils, vascular intimal cells, hepatocytes, leukocytes including mononuclear leukocytes, stem cells such as haemo poetic, neural, skin, lung, kidney, liver and myocyte stem cells (for use in screening for differentiation and de-differentiation factors), osteoclasts, chondrocytes and other connective tissue ceiis, keratinocytes, melanocytes, liver ceils, kidney cells, and adipocytes. Non-timiting examples of mammalian cells iinss that have been widely 20 used by researchers Include HeLa, NIH/3T3, HT1080, CHO, COS-1, 293T, WI-3B and CV1/EBNA-1.

Other cellular assays may be used which rely upon a reporter gene to detect metabolically active ceiis. Non-limiting examples of reporter gene expression systems include green fluorescent protein (GFP), and iuciferase. As an example of the use of GFP to screen 25 for potential antitumor drugs, Sandman et a!, (Chem Biol. 6:541-51; incorporated herein by reference) used HeLa cells containing an inducible variant of GFP to detect compounds that inhibited expression of the GFP, and thus inhibited ceil proliferation.

Compounds Identified by such cellular assays as having anti-cell proliferation activity are then tested for anti-tumor activity in whole organisms. Preferably, the organisms are 30 mammalian. Well-characterized mammalians systems for studying cancer Include rodents such as rats and mice. Typically, s tumor of interest is transplanted into a mouse having a reduced ability to mount an immune response to the tumor to reduce the likelihood of rejection. Such mice include for example, nude mice (afhymic) and SGiD (severe combined immunodeficiency) mice. Other transgenic mice such as oncogene containing mice may be 35 used in the present assays (see for example USP 4,736,866 and USP 6,175,383). For a review and discussion on the use of rodent models for antitumor drug testing see Kerbel (Cancer Metastasis Rev. 17:301-304, 1998-89).

In genera!, 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 2015210454 07 Aug 2015 the test compound on the tumor, Some tumor types are implanted at sites other than subcutaneous sites (e.g. Iniraperitoneai sites) and survival is measured as the endpoint. Parameters to be essayed with routine screening include different tumor models, various tumor and drug routes, and dose amounts and scbeduie. Fora review of the use of mice in 5 detecting antitumor compounds see Corbett et at. (Invest New Drugs, 15:207-218,1997; incorporated herein by reference).

Example 23: Pharmaceutical compositions

Representative pharmaceutical dosage forms of the compounds of this invention (the active 15 ingredient being referred to as "Compound"), are provided for therapeutic or prophylactic use in humans: (a) Tablets mg/tablet 20 Compound................... 100

Lactose Ph.Eur..................................................182.75

Cfoscarmellose sodium.....................................12.0

Maize starch paste (5% w/v paste)..................... 2.25

Magnesium stearate ........................................... 3.0 25 (b) Tablet I! mg/tablet

Compound .......................................................50

Lactose Ph.Eur............... 223.75 30 Croscarmellose sodium .....................................6.0

Maize starch....................... 15.0

PoiyvInylpyffoSidone (5% w/v paste) ................ 2.25

Magnesium stearate...........................'..................3.0 35 (c) Tablet III mg/tabiet

Compound............ 1.0

Lactose Ph.Eur............... 93.25

Croscarmeiose sodium........................... 4.0 40 Maize starch paste (5% w/v paste).............0.75

Magnesium stearate................ 1.0- 76 89 2015210454 07 Aug 2015 (d) Capsule mg/capsule

Compound ,,,..... Lactose Ph.Eur. 5 Magnesium ....... ,. 10 488.6 .....1.6 (e) injection i (50 mg/mi) ] 0 Compound..................,......................................5.0% w/v 1M Sodium hydroxide solution ..............15.0% v/v 0. IM Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 ,..,.................4.5% w/v Water for injection to 100% 15 (f) injection II (10 mg/mi) Compound..........................................................1.0% W/v 20 Sodium phosphate BP........................................3.6% w/v 0.1M Sodium hydroxide solution......................15.0% v/v Water for injection to 100% 25 (g) injection II! (1 mg/mi, buffered to pH6)

Compound..........................................................0. i % w/v

Sodium phosphate BP ........................................ 2.26% w/v

Citric acid ............................................................ 0,38% w/v 30 Polyethylene glycol 400 ...................................... 3,5% w/v

Water for Injection to 100% (h) Aerosol . t mg/mi 35

Compound .........................................10.0

Sorbitert trioleate.................>.......................... 13.5

Trichlorofiuoromethane.................................910.0

Dlchlorodlfluoromethane.............................. 490.0 40 90 2015210454 07 Aug 2015 (0 Aerosol II mg/ml

Compound................. 0,2

Sorbitan trioleate............................................0.27 5 T richlorofluoromethane.............. 70.0

Dichiorodifluoromethane.............................280.Q

Dlchlorotetrafiuoroethane...........,...,.......... 1094.0 10 05 Aerosol ill mg/m!

Compound .................. 2.5

Sorbitan trioleate.................. 3,38

Trichiorofluoromethane ..........................,,.67,5 15 Dichiorodifluoromeihane....................... 1086.0

Dlchlorotetrafiuoroethane..................... 191.6 (k) Aerosol IV mg/ml 20 ' Compound................................. 2.5 . Soya lecithin.............. 2.7

Trichlorofluoromethane............... 67.5

Dichiorodifluoromeihane ...............1086,0

Dlchlorotetrafiuoroethane...........................191.6 25 (l) Ointment ’ ml

Compound .................... 40 mg

Ethanol........................ 300 μ!

Water.................................................. 300 pi 30 1 -Dodecy lazacycloheptan one.....................50 pi

Propylene glycol.............................................to 1 ml

Note: These formulations may be prepared using conventional procedures well known in the pharmaceutical art. The tablets (a)-<c) may be enteric coated by conventional means, If 35 desired to provide a coating of cellulose acetate phthaiaie, for example. The aerosol formulations (h)-(k) may 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 sorbitan monooleate, sorbitan sesquicleate. potysorbate 80, polyglycerol oieate or oleic acid. 40 91 H:Vbr\Interwoven\NRPortbl\DCC\RBR\8183208_l .docx-7/08/2015 2015210454 07 Aug 2015

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) 5 or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

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 10 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. -91a-

Claims (32)

1. THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

   1. A compound of formula:

   wherein 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 Ο, N, and S(0)r; L1 is C(0)NR1; L2 is -(CH2)z-; 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 cycloalkyl; each occurrence of Rd is independently selected from the group consisting of halo, alkyl, cycloalkyl, and -NR2R3; each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, -NR2R3, alkoxy, amino, -NH-alkyl, -C(0)NH-alkyl, -NHC(0)-alkyl, -NHC(0)NH-alkyl, -NHC(NH)-alkyl, -NHC(NH)NH2, -NH(CH2)x-heteroaryl, -NH(CH2)X-heterocyclyl, -NH(CH2)x-aryl, and -(CH2)xC(0)NH2, 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, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R2and R3, taken together with the nitrogen atom to which at least one of R2 and R3 is attached, form a 5-or 6- membered 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, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2R3, =NNHC(0)R2, =NNHC02R2, and =NNHS02R2, 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, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; m is 0,1,2, 3, or 4; p is 0, 1,2, 3, or 4; s is 0, 1,2, or 3; w is 0, 1,2, 3, 4, or 5; and z is 1,2, 3, or 4; or a pharmaceutically acceptable salt thereof.
2. 2. The compound according to claim 1, wherein z is 1 and Ring D is a piperazine ring.
3. 3. The compound according to claims 1 or 2, wherein w is 1 and Rd is alkyl.
4. 4. The compound according to claim 3, wherein the alkyl is methyl.
5. 5. A compound of formula:

   wherein Ring C is a 5- or 6-membered heterocyclic or heteroaryl ring, comprising carbon atoms and 1-3 heteroatoms independently selected from Ο, N, and S(0); L1 is C(0)NR1; 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 cycloalkyl; each occurrence of Rc is independently selected from the group consisting of halo, -CN, alkyl, cycloalkyl, and -NR2R3; each occurrence of Re is independently selected from the group consisting of halo, alkyl, cycloalkyl, -NR2R3, alkoxy, amino, -NH-alkyl, -C(0)NH-alkyl, -NHC(0)-alkyl, -NHC(0)NH-alkyl, -NHC(NH)-alkyl, -NHC(NH)NH2, -NH(CH2)x-heteroaryl, -NH(CH2)X-heterocyclyl, -NH(CH2)x-aryl, and -(CH2)xC(0)NH2, 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, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, and heteroaryl, or R2and R3, taken together with the nitrogen atom to which at least one of R2 and R3 is attached, form a 5-or 6- membered 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, heterocyclyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, =0, =S, =NH, =NNR2R3, =NNHC(0)R2, =NNHC02R2, and =NNHS02R2, 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, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy; 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, or 5; or a pharmaceutically acceptable salt thereof.
6. 6. The compound according to claim 5, wherein Ring C is an imidazole ring.
7. 7. The compound according to claims 5 or 6, wherein Rc is alkyl and v is 1.
8. 8. The compound according to claim 7, wherein the alkyl is methyl.
9. 9. The compound according to any one of claims 1 -8, wherein Ra is alkyl and m is 1.
10. 10. The compound according to any one of claims 1 -9, wherein Rb is alkyl and p is 1.
11. 11. The compound according to any one of claims 1 -10, wherein s is 0.
12. 12. The compound according to any one of claims 1-11, wherein the pharmaceutically acceptable salt is hydrochloride salt.
13. 13. A composition comprising the compound according to any one of claims 1 -12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or vehicle.
14. 14. A composition according to claim 13, wherein said composition is a pharmaceutical composition for oral administration.
15. 15. The pharmaceutical composition of claim 14, wherein said composition is in the form of a tablet, capsule, suspension or liquid.
16. 16. The pharmaceutical composition of claim 15, wherein said composition is a tablet or capsule containing 5-200 mg of said compound.
17. 17. A method of treating cancer in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound according to any of claims 1-12, or a tautomer, or an individual stereoisomer or a mixture of stereoisomers thereof, wherein the cancer is selected from primary cancer, metastatic cancer, solid tumor, lymphoma, leukemia, and cancer resistant to other therapies.
18. 18. A use of a compound according to any of claims 1 -12, or a tautomer, or an individual stereoisomer or a mixture of stereoisomers 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.
19. 19. The method of claim 17 or the use of claim 18, wherein the cancer is leukemia.
20. 20. The method or use of claim of claim 19, wherein the leukemia is selected from the group consisting of myeloid, lymphocyctic, myelocyctic and lymphoblastic leukemia.
21. 21. The method or use of claim 20, wherein the leukemia is chronic myeloid leukemia (CML).
22. 22. The method or use of claim 20, wherein the leukemia is acute lymphoblastic leukemia (ALL).
23. 23. The method of claim 17, or the use of claim 18, 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.
24. 24. The method or use of any one of claims 17 to 23, wherein the compound according to any of claims 1 -12, or a tautomer, or an individual stereoisomer or a mixture of stereoisomers thereof is administered or used with another anti-cancer drug.
25. 25. The method or use of claim 24 wherein the other anti-cancer drug is selected from an anti-cancer alkylating or intercalating agent; antimetabolite; purine antagonist or pyrimidine antagonist; spindle poison; podophyllotoxin; antibiotic; nitrosourea; inorganic ion; enzyme; hormone; mTOR inhibitor; proteasome inhibitor; other kinase inhibitors; an antibody, soluble receptor and other receptor antagonist against a receptor or hormone implicated in cancer.
26. 26. The method or use of claim 24, wherein the other anti-cancer drug is selected from Zyloprim, alemtuzmab, altretamine, amifostine, nastrozole, antibodies against prostate-specific membrane antigen, arsenic trioxide, bexarotene, bleomycin, busulfan, capecitabine, Gliadel Wafer, celecoxib, chlorambucil, cisplatin-epinephrine gel, cladribine, cytarabine liposomal, daunorubicin liposomal, daunorubicin, daunomycin, dexrazoxane, docetaxel, doxorubicin, Elliott’s B Solution, epirubicin, estramustine, etoposide phosphate, etoposide, exemestane, fludarabine, 5-FU, fulvestrant, gemcitabine, gemtuzumab-ozogamicin, goserelin acetate, hydroxyurea, idarubicin, idarubicin, Idamycin, ifosfamide, imatinib mesylate, irinotecan (and other topoisomerase inhibitors including antibodies MLN576 (XR11576)), letrozole, leucovorin, leucovorin levamisole, liposomal daunorubicin, melphalan, L-PAM, mesna, methotrexate, methoxsalen, mitomycin C, mitoxantrone, MLN518 or MLN608 (and other inhibitors of the flt-3 receptor tyrosine kinase, PDFG-R or c-kit), itoxantrone, paclitaxel, Pegademase, pentostatin, porfimer sodium, Rituximab (RITUXAN®), talc, tamoxifen, temozolamide, teniposide, VM-26, topotecan, toremifene, 2C4 (and other antibodies which interfere with HER2-mediated signaling), tretinoin, ATRA, valrubicin, vinorelbine, pamidronate, zoledronate and other bisphosphonates.
27. 27. The method or use of any one of claim 17 to 26, provided in combination therapy with a cancer therapy selected from surgery, radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, endocrine therapy, biologic response modifiers, hyperthermia and cryotherapy.
28. 28. A method of inhibiting a tyrosine kinase using a compound according to any one of claims 1-12, or a tautomer or an individual stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.
29. 29. The use of a compound of any one of claims 12, or a tautomer or an individual stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting a tyrosine kinase.
30. 30. The method of claim 28 or the use of claim 29, wherein the tyrosine kinase is Src or Abl.
31. 31. The method or use of claim 30, wherein the tyrosine kinase is BCR/Abl or a mutant variant thereof.
32. 32. The method or use of claim 31, wherein the mutant variant of BCR/Abl has a T315I mutation.