US 20120065233Al (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0065233 A1 GREGOR (43) Pub. Date: Mar. 15, 2012

(54) INHIBITORS Publication Classi?cation (76) Inventor.. Vlad Edward GREGOR, Del Mar, ( 5 1) Int. Cl. CA (Us); Nelson Levy, legal A61K 31/4439 (2006.01) (21) App1.No.: representative,13/231,797 Lake Forest, IL (U S) Com 487/04Z0 (2006-01)

(22) F1 d s 13 2011 (52) US. Cl...... 514/338; 546/273.1; 435/184 1 e : ep. , Related US. Application Data (57) ABSTRACT (63) continuationdmpart of application NO 12/922 891 The present disclosure relates to the ?eld of tyrosine kinase ?led as a lication NO PCT/US2009/00'1 691 On’Mar’ inhibition, in particular anaplastic lymphoma kinase 18 2009131) ' ' (ALK) inhibition using novel small molecules. Provided are ’ ' compounds capable to modulate ALK activity, compositions (60) Provisional application No, 61 /038,032, ?led on Mar, that comprise the compounds, and methods of using the com 19, 2008, provisional application No. 61/382,485, pounds for the treatment or prevention of diseases or condi ?led on Sep. 13, 2010. tions that are characterized by ALK activity or expression.

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TYROSINE KINASE INHIBITORS quently occurring oncogenic ALK fusion in ALK-positive ALCL cases (“ALKomas”) is the NPM-ALK (~80% of ALK CROSS-REFERENCE TO RELATED positive ALCL cases), other ALK gene fusions have been APPLICATIONS consequently identi?ed in human hematological and solid cancers. These include TPM3-ALK (fusion of non-muscle [0001] This application is a Continuation-In-Part applica tion of Ser. No. 12/922,891, ?led Sep. 16, 2010 Which is a tropomyosin 3 With ALK), TPM4-ALK, ATIC-ALK, CLTC National Application from International Application No. ALK, RanBP2-ALK, TFGL/S-ALK, CARS-ALK, MSN PCT/US09/01691 ?led Mar. 18, 2009, Which claims priority ALK and others. from Us. Provisional Application Ser. No. 61/038,032, ?led [0005] All knoWn ALK fusion proteins (These include Mar. 19, 2008; and this Application claims priority from Us. ALK-positive ALCL, NPM-ALK, TPM3-ALK (fusion of Provisional Application Ser. No. 61/382,485, ?led Sep. 13, non-muscle tropomyosin 3 With ALK), TPM4-ALK, ATIC 2010; all of Which are hereby incorporated by reference in ALK, CLTC-ALK, RanBP2-ALK, TFGL/S-ALK, CARS their entirety. ALK, MSN-ALK and others) share the essential feature of having some type of the oligomeriZation domain in the FIELD OF THE INVENTION sequence of the ALK fusion partner Which mediates consti tuitive self-association of the ALK fusion that causes con [0002] The present disclosure relates to the ?eld of tyrosine stant, ligand-independent ALK kinase domain activation. kinase enzyme inhibition, in particular anaplastic lymphoma Similarly to NPM-ALK, the related ALK fusion proteins kinase (ALK) inhibition using novel small molecules. Pro have been shoWn to possess transforming and oncogenic vided are compounds capable to modulate ALK activity, potential, apparently mediated by their constitutive kinase compositions that comprise the compounds, and methods of activity. AlthoughALK-positive lymphomas have a relatively using the compounds for the treatment or prevention of dis benign prognosis, about 40% of patients do not respond or eases or conditions that are characterized by ALK activity or relapse after the standard therapy (CHOP). CHOP (cyclo expression. phosphamide, hydroxydoxorubicin, oncovin, prednisone) and CHOP-like multi-agent combination chemotherapy regi BACKGROUND OF THE INVENTION mens that are used for conventional treatment of non [0003] The anaplastic lymphoma kinase (ALK) is a recep Hodgkin lymphomas including ALCL are associated With tor tyrosine kinase that belongs to the super considerable acute and chronic toxicities, a problem speci? family and is normally expressed in neural tissues during cally bothersome in pediatric patients. Therefore, a highly embryogenesis (Morris et al., Oncogene, 1997, 14:2175 effective and targeted therapy Would be bene?cial and highly 2188; IWahara et al., Oncogene, 1997, 14:439-449). In par Warranted not only for relapsed patients but also as ?rst-line ticular, transcripts of ALK gene are highly expressed in spe therapy if Well tolerated and ef?cacious. ci?c regions of the central nervous system, including the [0006] In addition to ALKomas, several research groups diencephalon, midbrain, and the ventral half of the spinal have also described the presence of the NPM-ALK and the cord. In the peripheral nervous system, ALK expression has related fusion proteins like CLTC-ALK in a rare form of been detected in the trigeminal, sympathetic, and enteric gan B-cell non-Hodgkin lymphoma. Rearrangements of ALK glia. After birth, expression diminishes, but still persists in gene have been also identi?ed in the in?ammatory ?broblas certain areas such as the olfactory bulb and thalamus. Despite tic tumors (IMT). These rare spindle cell proliferations the apparent function of ALK in the development of the involve malignant myo?broblasts and in?ltrating non-malig nervous system, the physiologic role of ALK is still largely nant in?ammatory cells in a collagenous matrix and occur unclear. While the recent studies are proposing that pleiotro primarily in the soft tissue of children and young adults. phin (PTN) and midkine (MK) are cognate ligands for ALK [0007] More recently, a novel oncogenic ALK fusion, (Stoica et al., JBiol Chem, 2001, 276(20): 16772-16779; Sto EML4-ALK, comprising portions of the echinoderm micro ica et al., JBiol Chem, 2002, 277(16):14153-14158), exact tubule-associated protein-like 4 (EML4) gene and the ana mechanisms and biological consequences of ligand-depen plastic lymphoma kinase (ALK) gene, has been implicated in dent ALK activation are not fully understood at this time. a subset of non-small cell lung cancer (NSCLC) (Soda, [0004] ALK Was initially identi?ed because of its involve 2007). Mouse 3T3 ?broblast cells forced to express this ment in the human non-Hodgkin lymphoma subtype knoWn fusion tyrosine kinase generated transformed foci in culture as anaplastic large cell lymphoma (ALCL). Many cases of and subcutaneous tumors in nude mice. The EML4-ALK ALCL are associated With a reciprocal translocation, t(2;5) fusion transcript Was detected in 6.7% of the 75 NSCLC (p23;q35), Which juxtaposes the gene at 5q35 encoding patients examined; these individuals Were distinct from those nucleophosmin (NPM), a nucleolar-associated phosphopro harboring mutations in the epidermal tein, With the gene for a , the anaplas gene. Presence of the oncogenic TPM4-ALK fusion Was also tic lymphoma kinase (ALK), at 2p23. The resulting fusion detected by proteomics methods in esophageal cancer gene encodes a chimeric 80-kD protein in Which 40% of the samples from patients in Iran (JaZii, 2006) and China (Du, N-terminal portion of NPM is fused to the complete intracy 2007). These ?ndings strongly suggest that EML4-ALK and toplasmic portion of ALK containing the functional tyrosine TPM4-ALK fusions are promising candidates for a therapeu kinase domain (Morris et al., Science, 1994, 263:1281-1284). tic target in a siZable subset of NSCLC and possibly in some Constitutive activation of the NPM-ALK kinase domain esophageal carcinomas. stimulates anti-apoptotic and mitogenic signaling pathWays [0008] Certain additional facts concerning the possible rel such as PI3K-AKT, JAK-STAT, and PLCy, resulting in cel evance of deregulated full-length ALK signaling in some lular transformation (Bai, 1998; Slupianek, 2001; Zamo types of cancer and utility of the non-rearranged, full-length 2002). The transforming activity of NPM/ALK is dependent ALK as a therapeutic target are noteWor‘thy. The small on its kinase activity (Bischof 1997). While the most fre secreted groWth factors pleiotrophin (PTN) and midkine US 2012/0065233 A1 Mar. 15, 2012

(MK) have been shown to activate signaling of the normal, Well as other ALK-driven malignancies, using small mol full-length ALK receptor protein (Stoica et al., 2001, supra; ecule inhibitors is very likely to produce marked anti-tumor Stoica et al., 2002, supra). While the exact mechanism and responses. biological signi?cance of ALK stimulation by the different [0013] WO 2004/063151 reported a tyrosine kinase inhibi molecular forms of these ligands are not completely under tory activity of pyridones. Pyrroloquinixalinediones and their stood at this time (Lu, 2005; PereZ-Pinera, 2007), a functional derivatives Were shoWn to exhibit HIV integrase inhibitory connection betWeen PTN and/or midkine and ALK is Well activity (WO2004/096807). established. A large number of studies provide evidence that [0014] Only a feW inhibitors With activity against ALK PTN and MK contribute to tumor groWth, abnormal tumor have been reported. Sauville (Sauville et al, J. Clin. Oncol., associated and metastasis (Kadamatsu, 2004; 2001, 19, 2319-2333) disclosed a derivative of the natural Bemard-Pierrot 2002). For example, both PTN and ALK product staurosporine having an anti-tumor activity in a have been found to be overexpressed in human glioblastomas, patient With an ALK-positive anaplastic large cell lymphoma and doWnregulation of ALK expression by riboZymes Was that Was refractory to conventional chemo- and radio -therapy. shoWn to suppress human glioblastoma xenograft groWth in It is important to note that the compound’s ability to inhibit ALK Was not tested in this study, thus, it has not been formally mice and to prolong the survival of the tumor-bearing animals proven that it is an ALK inhibitor. Indeed, a recent report (Powers 2002; GrZhelinsky 2005). Expression or overexpres suggests that staurosporine possesses minimal ability to sion of the full-length ALK receptor in certain neuroblasto directly inhibit ALK (Gunby et al., Haematologica, 2005, 90, mas, diffuse large B-cell non-Hodgkin lymphomas, leiomyo 988-990). The naturally occurring, structurally related ben sarcomas, and malignant peripheral nerve sheath sarcomas Zoquinone analogues, geldanamycin and 17-allylamino-17 have been reported (Pullford et al., J Cell Physiol, 2004, demethoxygeldanamycin (Bonvini et al., Cancer Res. 2002, 199:330-358). Similarly, it has been reported that cell lines 62, 1559-1566) and herbimycinA (Turturro et al., Clin. Can established from common solid tumors of ectodermal origin, cer Res. 2002, 8, 240-245) have been reported to exert ALK such as melanoma and breast cancer, exhibit ALK receptor inhibition via heat shock protein pathWays, enhancing the mRNA expression (Pulford, 2004, supra). Additional analy proteasome-mediated degradation of the ALK protein. Most ses should elucidate the role of ALK signaling in the genesis recently, a series of pyraZolo[3,4-c]isoquinoline derivatives and progression of these various cancers over the next feW With ALK-inhibitory activity Was published in WO years. 2005009389. [0009] Studies in Which the mouse Alk gene Was knocked [0015] One of the challenges of developing an ATP-com out demonstrate that ALK-negative mice shoW no evident petitive small-moleculeALK inhibitor is to provide suf?cient gross anatomical, histological or functional abnormalities selectivity of the compound for ALK versus inhibition of and have a normal lifespan (Pulford, 2004, supra). Therefore, other structurally related protein kinases. Due to the existence the physiological functions of Alk, Which is normally of about 520 evolutionary related protein kinases in the human genome, this could be a demanding task. In particular, expressed primarily in neural tissues, appear to be largely inhibition of the insulin receptor kinase Which is closely redundant. These observations suggest that therapeutic structurally related to ALK is highly undesirable due to the approaches targeting the aberrant oncogenic functions of risk of blocking insulin action and the resultant hyperglyce ALK are not likely to be associated With limiting toxicities m1a. due to concomitant inhibition of normal ALK functions. [0016] Another highly related RTK is Insulin-Like GroWth [0010] Therefore, both the various cytoplasmic ALK fusion Factor Receptor I (IGFlR). In the recent years, IGFlR proteins and the full-length ALK in its transmembrane recep emerged as an attractive oncology target in a broad variety of tor form are valid molecular targets for anticancer drugs. malignancies (Riedman and Macaulay, 2006; Tao et al. 2007). Consequently, small-molecule inhibitors of ALK kinase are HoWever, suppression of IGFlR signaling may potentially likely to be a drug for suppressing of tumor groWth and have undesirable side-effects in a clinical context Where nor angiogenesis. mal cell/tissue proliferation and development are essential, [0011] Recently reported preclinical studies have provided such as treating pediatric patients (ALCL). Therefore, a suf compelling proof of principle for the e?icacy of the inhibition ?ciently high selectivity of ALK inhibition versus inhibition of NPM-ALK in ALK-positive ALCL, With marked anti of such related RTKs as Insulin Receptor and IGFlR is likely tumor activity observed experimentally. For instance, studies to be a desirable trait in a clinical ALK inhibitor. Conversely, performed by Novartis demonstrated regression of estab inhibition of a small subset of therapeutically relevant PTKs lished lymphoma tumors formed by subcutaneous injection (multitargeting), in addition to ALK, can improve the ef?cacy of the human NPM-ALK-positive ALCL cell line Karpas of an oncology drug, especially for solid tumors Which are 299 in mice When the animals Were treated With the small often heterogeneous and have complicated tumor biology. molecule ALK kinase inhibitor NVP-TAE684 (Galkin, [0017] Another group of tyrosine kinases evolutionary and 2007). structurally related to ALK is, Ret, Ros, Axl, and kinases that [0012] Other experimental approaches for the inhibition of are members of Trk family (Trk A, B and C). oncogenic ALK signaling have also indicated that the agents [0018] RET is a receptor tyrosine kinase that has a role in blocking this signaling are likely to possess very potent anti transducing groWth and differentiation signals in tissues cancer capabilities. Piva and colleagues recently shoWed that derived from the neural crest and is required for normal devel siRNA (small inhibitory ribonucleic acid)-mediated inhibi opment of the sympathetic, parasympathetic and enteric ner tion of NPM-ALK signaling markedly diminished the devel vous systems and the kidney. Gain of function mutations of opment of ALCL xenografts in mice (Piva, 2006). Collec Ret are associated With the development of several types of tively, these data indicate that the inhibition of the aberrant, human cancers, including medullar thyroid carcinoma and cancer-causing activity of ALK fusion proteins in ALCL, as multiple endocrine neoplasias type II and III (or MEN2A and US 2012/0065233 A1 Mar. 15, 2012

MEN2B). RET mutations have been also identi?ed in a small ranging from neuroblastomas to pancreatic ductal adenocar percentage of pheochromocytomas. Chromosomal rear cinomas, in Which it may alloW tumor expansion and contrib rangements involving the RET gene are one of the most ute to resistance to anti-tumor agents. TrkB acts as a potent common causes of a sporadic form of thyroid cancer called suppressor of anoikis (detachment-induced apoptosis), Which papillary thyroid carcinoma (also knoWn as RET/PTC). is associated With the acquisition of an aggressive tumori There is a compelling experimental evidence that thyroid cell genic and metastatic phenotype in vivo (Desmet, 2006; transformation to PTC is driven by hyperactivated Ret (San Douma, 2004). In summary, Trk family members have been toro, 2004]. Kinase inhibitors With activity against RET are implicated as oncogenes in a number of neoplasms including currently in preclinical or clinical development for these prostate, thyroid, pancreatic, colon, breast, ovarian cancers, types of cancers. melanomas and some leukemias. For prostate cancer and [0019] ROS or ROSl is a receptor tyrosine kinase that has thyroid carcinomas, TrkA is especially Well validated as a been found to be constitutively activated in a subset of glio drug target. blastomas as a result of genomic translocations (Charest, [0025] Strong and diverse experimental evidence suggests 2003; Charest, 2006) and may represent an emerging thera that nerve groWth factor (NGF), signaling through TrkA path peutic target in this highly malignant and deadly brain tumor. Way, is a mediator of some persistent pain states, including [0020] AXL is a unique tyrosine kinase receptor, impli neuropathic and in?ammatory pain (PeZet, 2006; Hefti, 2006; cated in the inhibition of apoptosis as Well as promoting Bennet, 2001). Function-neutralizing anti-NGF and anti neovasculariZation, and it is emerging as a viable therapeutic TrkA antibodies demonstrated therapeutic effect in models of target in a number of malignancies, both solid and hemato in?ammatory, neuropathic, skeletal and cancer pain (U golini, logic (Holland, 2005). In particular, it is a chronic myelog 2007; KoeWler, 2007; Sevcik, 2005). In such disease states as enous leukemia-associated oncogene (O’Bryan, 1991; Jan pro state cancer With metastatic bone pain and pancreatic can nsen, 1991) and is also associated With colon, prostate cancer cer With perineural invasion, cancer progression, pain and and melanoma (Van Ginkel, 2004; Sainaghi, 2005). Overex TrkA signaling has been shoWn to be all positively correlated pression of Axl in myeloid cells has been shoWn to be (Dang, 2006; Halvorson, 2005). Inhibition of the NGF/TrkA involved in Type II diabetes (Augustine, 1999). Modulation pathWay appears to be very Well validated for treatment of of Axl activity by small-molecule kinase inhibitors may have chronic pain of different natures: (i) in?ammatory pain; (ii) utility in therapy of the disease states mentioned above. neuropathic pain and (iii) cancer pain. [0021] TrkA is a receptor tyrosine kinase that belongs to a [0026] It is noteWorthy that in the skin, TrkA receptor medi subfamily of tyrosine kinases that also includes TrkB, and ates the ability of NGF to stimulate keratinocytes prolifera TrkC. TrkB and TrkC are structurally closely related to TrkA, tion and inhibit keratinocytes apoptosis. NGF is produced by but respond to different ligands in the neurotrophin (NT) keratinocytes to stimulate their cell proliferation With an auto family. Nerve groWth factor (NGF) signaling through TrkA crine loop and melanocyte proliferation With a paracrine has been Well characterized and is similar to signal transduc pathWay (Di Marco, 1993; Pincelli, 2000). NGF/TrkA sig tion mechanisms of other tyrosine kinase receptors. As out naling also modulates in?ammation (Frossard, 2004) and lined in more detail beloW, TrkA is a Well validated or a proliferation of terminal cutaneous nerves (Raychaudhury, potential drug target in a variety of malignancies as Well as in 2004), components of psoriasis and atopic dermatitis. Murine neuropathic pain and certain in?ammatory diseases. The models for psoriasis and atopic dermatitis have been estab roles of the tWo other members of the neurothropin receptor lished and K252a and AG879, both potent non-clinical TrkA TK family, TrkB and TrkC, in disease states has received less inhibitors, Were demonstrated to have therapeutic effect attention, hoWever the emerging evidence implicates both of [Raychaudhury, 2004; Takano, 2007] in the models. This data them in several types of neoplasias. indicates that TrkA is a potential drug target in skin disorders [0022] TrkA gene Was originally described as a chimeric characterized by keratinocytes hyperproliferation. oncogene in colon cancer (Martin-Zanca, 1986] and its acti [0027] Kelly cell lines are a human neuroblastoma cell line vating genomic translocations are common in papillary thy in Which a constitutively active mutant (F1174L) ALK pro roid carcinomas (BongarZone, 1989; Pierotti, 2006) and motes cell groWth. Various gain-of-function mutations occur occur in breast cancer as Well (BrZeZianska, 2007). Hyperac in approximately in 8% of primary neuroblastomas and are tivating deletion or fusion mutations of TrkA and TrkC Were believed to have a transforming in?uence. Neuroblastoma also identi?ed in some acute myeloid leukemias as Well as most often begins during early childhood, usually in children solid tumors (Reuther, 2000; Eguchi, 2005). younger than 5 years. Neuroblastoma often begins in the [0023] Overexpression of TrkA in malignant versus normal nerve tissue of the adrenal glands. By the time neuroblastoma tissues and association With poor prognosis Was shoWn in is diagnosed, the cancer has usually metastasiZed (spread), prostate, pancreatic cancers, melanomas, and mesotheliomas mo st often to the lymph nodes, bones, bone marroW, liver, and (Festuccia, 2007; MyknyocZki, 1999; Florenes, 2004; David skin. Neuroblastoma, accounts for approximately 15% of all son, 2004). TrkA is overexpressed in the majority of prostate deaths due to childhood cancer. High-risk neuroblastomas are carcinomas, and is further increased in androgen-indepen rapidly progressive; even With intensive myeloablative che dent tumors (Papatsoris, 2007). In prostatic carcinomas, an motherapy, relapse is common and almost uniformly fatal. autocrine loop involving NGF and TrkA is responsible for [0028] Thus, tyrosine kinases are noW Widely recogniZed as tumor progression (Dj akieW, 1993). An autocrine NGF/TrkA attractive proteins for molecularly targeted cancer therapy. loop and mitogenic role of NGF has been demonstrated in Blocking the ALK activity (e.g., inhibition of oncogenicALK breast cancer cells as Well (ChiarenZa, 2001 1; Dolle, 2003). It fusion proteins (NPM-ALK or others), gain-of-function ALK has also been shoWn that NGF signaling has angiogenesis mutations (F1174L or others), or aberrant overexpression of promoting effect (Cantarella, 2002). Wild-type or mutant ALK) represents a rational, targeted [0024] TrkB, sometimes in conjunction With its ligand approach to therapy of various diseases. As there are several BDNF, is often overexpressed in a variety of human cancers, tyrosine kinases that are evolutionary and structurally related US 2012/0065233 A1 Mar. 15, 2012

to ALK, such as Ret, Ros, Axl, and members of Trk family, Wherein R“ is optionally substituted aryl or heteroaryl; there is an opportunity to either identify a multitargeted R2 and R3 are each independently hydrogen, loWer alkyl, kinase inhibitor With a potential utility in other types of malig loWer alkoxy, halogen, cyano, loWer alkylamino or di-loWer nancies not targeted by selective ALK inhibition, or to ?ne alkylamino; and tune the inhibition selectivity towards a particular kinase of R5 is hydrogen, loWer alkyl, loWer alkoxy, halogen, cyano, interest by lead optimiZation. loWer alkylamino or di-loWer alkylamino. [0034] In one embodiment, the compounds of this inven SUMMARY OF THE INVENTION tion are inhibitors of ALK, ROS, and members of Trk family (Trk A, B and C). [0029] Provided herein are selective tyrosine kinase inhibi [0035] In one embodiment, this invention is directed to a tors, compositions that comprise the compounds, and meth pharmaceutical composition comprising the compound of ods of using the compounds for the treatment or prevention of this invention or its stereoisomer, tautomer, pharmaceutically diseases or conditions that are characteriZed by ALK activity acceptable salt, hydrate, or any combination thereof and one or expression in mammals. or more pharmaceutically acceptable diluents, excipients or [0030] Provided herein are selective inhibitors of tyrosine carriers. kinases evolutionary and structurally related to ALK, such as [0036] In one embodiment, this invention is directed to a Ros, and members of Trk family (Trk A, B and C) and are method of modulating a tyrosine kinase activity comprising useful for the treatment or prevention of diseases or condi the step of contacting the tyrosine kinase With an amount of a tions characterized by aberrant ALK, ROS, and Trk family of compound of this invention effective to modulate the tyrosine tyrosine kinase activity or expression in mammals. kinase activity. In another embodiment, the tyrosine kinase is [0031] The compounds provided herein are inhibitors of selected from the group consisting ofAlk, Axl, CSFR, DDR1, ALK, ROS, and Trk family of tyrosine kinases. DDR2, EphB4, EphA2, EGFR, Flt-1, Flt3, Flt4, FGFRl, [0032] In one embodiment, this invention is directed to FGFR2, FGFR3, FGFR4, HER2, HER3, HERO, IR, IGF1R, Compound (45) or its stereoisomer, tautomer, pharmaceuti IRR, Kit, KDR/Flk-l, Met, Mer, PDGFR.alpha, PDGFR. cally acceptable salt, hydrate, or any combination thereof beta, Ret, Ros, Ron, Tie1, Tie2, TrkA, TrkB and TrkC. represented by the following structure: [0037] In one embodiment, this invention is directed to a method of treating, suppressing, reducing the incidence, reducing the severity, inhibiting the progression a condition (Compound 45) or disorder related to tyrosine kinase activity comprising administering to a subject a compound of this invention. In O O another embodiment, the condition or disorder is selected HN N from the group consisting of ALK-positive anaplastic large / cell lymphoma, an in?ammatory myo?broblastic tumor, dif \ / N N\/\N/ fuse large B-cell non-Hodgkin lymphoma, non-small cell lung cancer, esophageal carcinoma, breast cancer, neuroblas NH H I toma and glioblastoma. [0038] In one embodiment, this invention is directed to a method of inhibiting a tyrosine kinase activity comprising contacting the tyrosine kinase With a compound of this inven tion. [0039] In one embodiment, this invention is directed to a method of treating, suppressing, reducing the incidence, reducing the severity, inhibiting the progression of neuroblas toma in a subject comprising administering to a subject a compound of this invention. [0033] In one embodiment, this invention is directed to a compound represented by the structure of formula (IX) or its BRIEF DESCRIPTION OF THE DRAWINGS stereoisomer, tautomer, pharmaceutically acceptable salt, hydrate, or any combination thereof: [0040] The subject matter regarded as the invention is par ticularly pointed out and distinctly claimed in the concluding portion of the speci?cation. The invention, hoWever, both as to organiZation and method of operation, together With objects, features, and advantages thereof, may best be under stood by reference to the folloWing detailed description When read With the accompanying draWings in Which: [0041] FIG. 1: depicts inhibition of ALK mediated KELLY cell line groWth With Compound 1 compared to Compound 3 1 . [0042] FIG. 2: depicts pharmacokinetics of Compound 1 compared With standard agent PF2341066 (see structure in Example 3, Table 4). FIG. 2A: Pharmacokinetics of racemic PF02341066 in rats (10 mg/kg IV. and PO.) FIG. 2B: Phar macokinetics of Compound 1 in rats (10 mg/kg IV. and PO.) [0043] FIG. 3: depicts pharmacokinetics of Compound 1 in guinea pigs, beagle dogs, and mice. US 2012/0065233 A1 Mar. 15, 2012

[0044] FIG. 4: Bioavailability of Compound 53 in compari [0055] The compounds provided herein can be used to treat son to P?zer’s compound PF2341066. FIG. 4A refers to bio and/ or prevent a mammal affected by tyrosine kinase related availability of Compound 53; FIG. 4B refers to PF2341066. disorder such as hyperproliferative skin disease selected [0045] FIG. 5: depicts Compound 45 activity in NB. Kelly from, but not limited to, psoriasis, acne vulgaris, acne rosa NB Cells (Full length ALK; Fl l74L Activating Point Muta cea, actinic keratosis, solar keratosis, BoWen’s disease, ich tion). Fl 174L is the most common NB mutation. Potency of thyosis, hyperkeratosis, disorders of keratinization such as Compound 45 is greater than PF2341066 (crizotinib). Dar'rier’s disease, palmoplanter keratoderma, pityriasis rubra [0046] FIG. 6: depicts EML4-ALK NSCLC Models. FIG. pilaris, epidermal naevoid syndrome, erythrokeratoderma 6A depicts Compound 45 results; FIG. 6B depicts variabilis, epidermolytic hyperkeratosis, non-bullous ichthy PF2341066 (crizotinib) results. osiform erythroderma, cutaneous lupus erythematosus and [0047] FIG. 7: depicts NPM-ALK ALCL Models. FIG. 7A lichen planus. depicts Compound 45 results; FIG. 7B depicts PF2341066 [0056] In one embodiment, this invention is directed to a (crizotinib) results. method of treating, suppressing, reducing the incidence, [0048] FIG. 8: depicts p-ALK in NPM-BaF3 Mutants. reducing the severity, inhibiting the progression of neuroblas [0049] FIG. 9: depicts HPLC of l -(2,3,5,6-Tetra?uorophe toma in a subject comprising administering to a subject a nyl)propan-2-amine-(Compound B) racemate using a chiral compound of this invention. column (FIG. 4A) and the purity of (2S)-l -(2,3,5,6-Tetra?uo [0057] In another aspect, provided are compounds of the rophenyl)propan-2-amine- Compound E (FIG. 4B); as formula (I) (see paragraph [0076]) that are ALK inhibitors, described in Example 1. selective especially With respect to IGFlR and/or IRK. [0058] In another aspect, provided are compounds of for DETAILED DESCRIPTION OF THE INVENTION mula I-XI that are ALK inhibitors, selective especially With respect to Kelly cell cytotoxicity. In another aspect, provided [0050] In one embodiment, this invention is directed to are compounds of formula I-XI that are ALK inhibitors, tyrosine kinase inhibitors, compositions that comprise the selective With respect to its ability to inhibit mutant ALK compounds, and methods of using the compounds of this activity and especially those mutant Which are present in invention for the treatment or prevention of diseases or con neuroblastomas. ditions that are characterized byALK activity or expression in [0059] In another embodiment, provided are pharmaceuti mammals. cal compositions comprising one or more compounds of for [0051] In one embodiment, this invention is directed to mula I-XI or a stereoisomer, tautomer, salt, hydrate or pro selective inhibitors of tyrosine kinases Which are evolution drug thereof useful for treatment of a disease or condition ary and structurally related to ALK, such as Ret, Ros, Axl characterized by Alk activity or expression. and members of Trk family (Trk A, B and C) and are useful for [0060] In yet another aspect, provided are pharmaceutical the treatment or prevention of diseases or conditions charac compositions comprising one or more compounds of formula terized by aberrant ALK, RET, ROS, Axl- and Trk family of I-XI or a stereoisomer, tautomer, salt, hydrate or prodrug tyrosine kinase activity or expression in mammals. thereof useful for treatment of a disease or condition charac [0052] The compounds provided herein can be used to treat terized by Alk, RET, ROS, AXL and TRK family tyrosine and/ or prevent a mammal affected by a neoplastic disease, in kinases activity or expression. particular ALK-positive anaplastic large cell lymphoma, [0061] A disease or condition characterized by ALK activ in?ammatory myo?broblastic tumors, diffuse large B-cell ity or expression includes but is not limited to ALK-positive non-Hodgkin lymphoma, non-small cell lung cancer, esoph anaplastic large cell lymphoma, an in?ammatory myo?bro ageal carcinoma, breast cancer, neuroblastoma and glioblas blastic tumor, diffuse large B-cell non-Hodgkin lymphoma, toma. non-small cell lung cancer, esophageal carcinoma, breast [0053] Certain compounds provided herein have therapeu cancer, neuroblastoma and glioblastoma. tic utility in treating various types of neoplasms and other [0062] A disease or condition characterized by ALK, RET, disease states, caused by the aberrant activity of Alk, RET, ROS, AXL and TRK family tyrosine kinases activity or ROS, AXL and TRK family tyrosine kinases. In particular, expression includes but is not limited to cancer, chronic pain provided compounds potently inhibit the catalytic activity of and certain hyperproliferative skin diseases. TrkA and/or other Trk family kinases and thereby provide [0063] In yet another aspect, provided are methods for neW treatment strategies for patients afflicted with cancer, treating a disease or disorder characterized by ALK activity or chronic pain and certain hyperproliferative skin diseases. expression comprising administration of one or more com [0054] The compounds provided herein can be used to treat pounds of this invention to a mammal. and/ or prevent a mammal affected by tyrosine kinase related [0064] In yet another aspect, provided are methods for disorder such as cancer selected from, but not limited to, treating a disease or disorder characterized by ALK, RET, astrocytoma, basal or squamous cell carcinoma, brain cancer, ROS, AXL and TRK family tyrosine kinases activity or gliobastoma, bladder cancer, breast cancer, colorectal cancer, expression comprising administration of one or more com chrondrosarcoma, cervical cancer, adrenal cancer, choriocar pounds of this invention to a mammal. cinoma, esophageal cancer, endometrial carcinoma, erythro [0065] In one embodiment, this invention is directed to leukemia, EWing’s sarcoma, gastrointestinal cancer, head and methods for modulating the activity of a tyrosine kinase. In neck cancer, hepatoma, glioma, hepatocellular carcinoma, one embodiment, the methods comprise the step of contacting leukemia, leiomyoma, melanoma, non-small cell lung can the tyrosine kinase With a compound provided herein. The cer, neural cancer, ovarian cancer, pancreatic cancer, prostate contacting can be in any environ knoWn to those of skill in the cancer, renal cell carcinoma, rhabdomyosarcoma, small cell art, for instance, in vitro, in vivo, ex vivo or otherWise. In lung cancer, thyoma, thyroid cancer, testicular cancer and certain embodiments, provided are methods of modulating osteosarcoma. the activity of a tyrosine kinase in a mammal in need thereof US 2012/0065233 A1 Mar. 15, 2012

comprising contacting the tyrosine kinase With a compound activity; or (4) decreased tyrosine kinase expression leading provided herein. Modulating can refer to the activation or to to unWanted reductions in cell proliferation, differentiation the inhibition of the tyrosine kinase. The tyrosine kinase can and/or groWth. be any tyrosine kinase knoWn to those of skill in the art. In [0076] The tyrosine kinase related disorder can be a cancer certain embodiments, the tyrosine kinase is a receptor selected from, but not limited to, astrocytoma, basal or squa tyrosine kinase or an intracellular tyrosine kinase. mous cell carcinoma, brain cancer, gliobastoma, bladder can [0066] In one embodiment, this invention provides cer, breast cancer, colorectal cancer, chrondrosarcoma, cer increasedpotency of Compound 1 in its ability to inhibitALK vical cancer, adrenal cancer, choriocarcinoma, esophageal promoted KELLY cell groWth as presented in Example 8 and cancer, endometrial carcinoma, erythroleukemia, EWing’s sarcoma, gastrointestinal cancer, head and neck cancer, FIG. 1. hepatoma, glioma, hepatocellular carcinoma, leukemia, lei [0067] In one embodiment, this invention provides omyoma, melanoma, non-small cell lung cancer, neural can increased potency of Compound 45 in its ability to inhibit cer, ovarian cancer, pancreatic cancer, prostate cancer, renal ALK promoted KELLY cell groWth as presented in Example cell carcinoma, rhabdomyosarcoma, small cell lung cancer, 11 and FIG. 5. In another embodiment, this invention pro thyoma, thyroid cancer, testicular cancer and osteosarcoma. vides increased potency of Compound 45 in its ability to [0077] The tyrosine kinase related disorder can be an inhibit EML4-ALK promoted cell groWth in PF2341066 IGFR-related disorder selected from diabetes, an autoim resistant cell lines (FIG. 6A, Example 11). mune disorder, AlZheimer’s and other cognitive disorders, a [0068] In one embodiment, this invention provides a com hyperproliferation disorder, aging, cancer, acromegaly, pound of this invention having the ability to inhibit ROSl Crohn’s disease, endometriosis, diabetic retinopathy, rest kinase. In another embodiment, this invention provides an enosis, ?brosis, psoriasis, osteoarthritis, rheumatoid arthritis, increasedpotency of Compound 1 in its ability to inhibitALK an in?ammatory disorder and angiogenesis. mediated ROSl kinase. ROSl is an oncogene that is overex [0078] In another embodiment, the tyrosine kinase related pressed in malignant brain tumors including gliomas. disorder is non-small cell lung cancer, non-Hodgkin’s lym [0069] In one embodiment, Compound I provides high phoma or neuroblastoma. In another embodiment, this inven tyrosine kinase inhibition activity against ALK, TRK (A/B/ tion provides methods of treating, suppressing, reducing the C) and R081 targets. incidence, reducing the severity, inhibiting the progression of [0070] In certain embodiments, the receptor tyrosine non-small cell lung cancer, nonHodgkin’s lymphoma or neu kinase is selected from the group consisting of EGFR, roblastoma in a subject comprising administering to a subject HBER2, HER3, HER4, IR, IGFlR, IRR, PDGFRot, PDG a compound of this invention. In another embodiment, this FRB, TrkA, TrkB, TrkC, HGFR, CSFIR, C-Kit, C-?ns, Flk4, invention provides methods of treating, suppressing, reduc KDR/Flk-l, Flt-l, FGFIR, FGF2R, FGF3R and FGF4R. ing the incidence, reducing the severity, inhibiting the pro gression of non-small cell lung cancer, nonHodgkin’s lym [0071] In certain embodiments, the intracellular tyrosine phoma or neuroblastoma in a subject comprising kinase is selected from the group consisting of Alk, Src, Frk, administering to a subject Compound 1 or its stereoisomer, Btk, Csk, Abl, ZAP70, Fes, Fps, Fak, Jakl, Jak2, Jak3, Jak4, tautomer, pharmaceutically acceptable salt, hydrate, or any Ack, Yes, Fyn, Lyn, , Blk, Hck, Fgr and Yrk. combination thereof. In another embodiment, this invention [0072] In speci?c embodiments, the intracellular tyrosine provides methods of treating, suppressing, reducing the inci kinase is Alk. dence, reducing the severity, inhibiting the progression of [0073] In another speci?c embodiment, the tyrosine non-small cell lung cancer, nonHodgkin’s lymphoma or neu kinases are those that are evolutionary and structurally related roblastoma in a subject comprising administering to a subject to ALK, such as Ret, Ros, Axl and members of Trk family Compound 45 or its stereoisomer, tautomer, pharmaceuti (Trk A, B and C). cally acceptable salt, hydrate, or any combination thereof. [0074] In another aspect, provided are methods for treating [0079] In one embodiment, this invention provides meth or preventing a tyrosine kinase related disorder in a subject in ods of treating, suppressing, reducing the incidence, reducing need thereof. In one embodiment, the methods comprise the severity, inhibiting the progression of cancer, or counter administering to the subject an amount of a disclosed com ing chemotherapy resistance, comprising administering to a pound of this invention effective to treat or prevent the disor subject a compound of this invention. In another embodi der. The compound can be in the form of a pharmaceutical ment, this invention provides methods of treating, suppress composition or a unit dose as described beloW. ing, reducing the incidence, reducing the severity, inhibiting [0075] A tyrosine kinase related disorder can be any disor the progression of cancer, or countering chemotherapy resis der knoWn to those of skill in the art to be related to tyrosine tance, comprising administering to a subject Compound 1 or kinase activity. Such disorders include those related to exces its stereoisomer, tautomer, pharmaceutically acceptable salt, sive tyrosine kinase activity, those related to reduced tyrosine hydrate, or any combination thereof. In another embodiment, kinase activity and to those that can be treated or prevented by this invention provides methods of treating, suppressing, modulation of tyrosine kinase activity. Excessive tyrosine reducing the incidence, reducing the severity, inhibiting the kinase activity can arise as the result of, for example: (1) progression of cancer, or countering chemotherapy resis tyrosine kinase expression in cells Which normally do not tance, comprising administering to a subject Compound 45 or express tyrosine kinases; (2) increased tyrosine kinase its stereoisomer, tautomer, pharmaceutically acceptable salt, expression leading to unWanted cell proliferation, differen hydrate, or any combination thereof. tiation and/or groWth; (3) activating alterations of a tyrosine [0080] In one embodiment, this invention provides a kinase such as translocation (e.g., NPM-ALK) and gain-of method of treating, suppressing, reducing the incidence, function mutations (e.g., Fl l74L ALK) Which lead to aber reducing the severity, inhibiting the progression of neuro rantly high and/or constitutive active receptor tyrosine kinase pathic pain comprising administering a compound of this US 2012/0065233 A1 Mar. 15, 2012

invention. In another embodiment, this invention provides a Wherein method of treating, suppressing, reducing the incidence, [0091] R“ is optionally substituted aryl or heteroaryl; reducing the severity, inhibiting the progression of neuro pathic pain comprising administering Compound 1 or its [0092] Rb is loWer alkyl, tri?uoromethyl, hydroxymethyl, stereoisomer, tautomer, pharmaceutically acceptable salt, methoxymethyl, aminomethyl, di-loWer alkylaminomethyl hydrate, or any combination thereof. In another embodiment, or heterocyclylaminomethyl; this invention provides a method of treating, suppressing, [0093] R” is selected from hydrogen, hydroxy, loWer reducing the incidence, reducing the severity, inhibiting the alkoxy, or loWer alkyl; progression of neuropathic pain comprising administering [0094] Rd is selected from hydrogen, or loWer alkyl; and Compound 45 or its stereoisomer, tautomer, pharmaceuti R5 is hydrogen, loWer alkyl, loWer alkoxy, halogen, cyano, cally acceptable salt, hydrate, or any combination thereof. loWer alkylamino or di-loWer alkylamino; [0081] Other disorders Which might be treated With com pounds provided herein include, Without limitation, immuno R1 is independently selected from hydrogen or optionally logical and cardiovascular disorders such as . substituted alkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, [0082] A disease or condition characterized by ALK activ heteroarylalkyl, heterocyclyloxyalkyl, heteroalkyl, heterocy ity or expression includes but is not limited to ALK-positive clylaminoalkyl, aminoalkyl, loWer alkylaminoalkyl, di anaplastic large cell lymphoma, an in?ammatory myo?bro (loWer alkyl)-aminoalkyl, aminocycloalkyl, alkylaminocy blastic tumor, diffuse large B-cell non-Hodgkin lymphoma, cloalkyl, di-(loWer alkyl)-aminocycloalkyl, di-(loWer alkyl) non-small cell lung cancer, esophageal carcinoma, breast aminocycloalkylalkyl, Wherein the substituents are selected cancer, neuroblastoma and glioblastoma. from hydrogen, loWer alkyl, hydroxy, loWer alkoxy, amino, [0083] In one embodiment, the methods, compositions and amidino, carboxamido, sulfonamido, cyano, primary, sec tyrosine kinase inhibitors make use of a compound of this ondary or tertiary amino, halo, aZido, loWer alkoxyalkyl, invention. cyanoalkyl, aZidoalkyl, haloalkyl, hydroxyalkyl, methane [0084] In one embodiment, this invention is directed to a sulfonylalkyl, primary, secondary or tertiary amino-alkyl, compound represented by the structure of formula (I) or its optionally substituted aryl, heteroaryl, heteroalkyl, heterocy stereoisomer, tautomer, pharmaceutically acceptable salt, clyl, cycloalkyl, alkenyl and alkynyl. hydrate or combination thereof: [0095] In another embodiment, R2 and R3 are hydrogen or methyl. (I) [0096] In another embodiment, W is 0 R2 0

HN N / N—R1 \ / T H H RfNH R5 R3 W [0097] In one embodiment, R“ is optionally substituted thienyl or phenyl Wherein the optional substituents are alkyl, Wherein: alkoxy or halo. [0085] R2 and R3 are each independently hydrogen, loWer [0098] In another embodiment, R“ is optionally substituted alkyl, loWer alkoxy, halogen, cyano, loWer alkylamino or thienyl or phenyl Wherein the optional substituents are di-loWer alkylamino; methyl, methoxy or ?uoro. [0086] W is O, S, or NR8, Wherein [0087] Re is hydrogen or loWer alkyl; [0099] In another embodiment, R“ is thiophene, phenyl, [0088] or W represents bonding of tWo atoms to a carbon methylthiophene, methylphenyl, ?uoromethylphenyl, ?uo atom, forming an optionally substituted methylene group: romethoxyphenyl, tri?uorophenyl or tetra?uorophenyl. [0100] In another embodiment, RC and Rd are hydrogen or hydroxy. [0101] In one embodiment, Rb is alkyl. [0102] In another embodiment, Rb is methyl. [0103] In another embodiment, Rl includes, but is not lim gmW Q»HH ghx,R/H ited to:

Wherein [0089] Rf is hydrogen, OH, alkoxy or loWer alkyl; [0090] R4 is

US 2012/0065233 A1 Mar. 15, 2012

F w a» K

‘KYLE W K w ‘WV W6