Patent Description:
The RTK family of receptors regulate cellular growth; they may also trigger neoplastic transformation when they are mutated, translocated, or otherwise expressed aberrantly (<NPL>); <NPL>);<NPL>)). Multiple mutations involving the ALK gene have been implicated in the pathogenesis of several cancers, including, for example, anaplastic large cell lymphoma (ALCL), rhabdomyosarcoma, inflammatory myofibroblastic pseudo tumor, neuro-blastoma and non-small cell lung cancer (NSCLC).

Deregulation of ALK was first identified in ALCL, a subtype of non-Hodgkin's lymphoma (<NPL>)). The deregulation of ALK was a result of a t(<NUM>;<NUM>)(p23;q35) chromosomal translocation. The altered form of the ALK gene encodes a fusion of nucleophosmin (NPM) to a truncated form of ALK - a chimeric receptor tyrosine kinase (RTK) that is de-regulated and constitutively activated leading to an "oncogene-addicted" state.

Aberrant ALK activity has also been identified in connection with non-small cell lung cancer (NSCLC) (<NPL>)). Here, a mutation in ALK, which arises from inv(<NUM>)(p21p23), leads to the fusion of the echinoderm microtubule-associated protein like-<NUM> (EMI,<NUM>) gene with the ALK gene. EMI,<NUM> is a member of the EMAP-like (EML) protein family and plays an important role in the correct formation of microtubules which is a critical step in the cell growth cycle (<NPL>)). The EMI,<NUM>-ALK gene expresses an EMI,<NUM>-ALK fusion protein that exhibits abnormal kinase activity and which has been shown to play a pivotal role in the malignant transformation of susceptible lung parenchyma (<NPL>)). Lung cancers with ALK rearrangements are highly sensitive to ALK tyrosine kinase inhibition, further underscoring the notion that such cancers are addicted to ALK kinase activity.

There are currently five FDA approved kinase inhibitors for the treatment of ALK-positive NSCLC: crizotinib, ceritinib (LDK378), alectinib, brigatinib, and lorlatinib. ALK-positive tumors are highly sensitive to ALK inhibition, indicating that these tumors addicted to ALK kinase activity. However despite initial dramatic responses of variable median duration, (<NUM> months for crizotinib; <NUM> months for alectinib), resistance to therapy typically develops (<NPL>); <NPL>); <NPL>); <NPL>); <NPL>)). Next-generation ALK inhibitors such as lorlatinib have been able to successfully target resistant tumors and have shown improvements in potency and overall response rates relative to approved inhibitors, resistance to these inhibitors still consistently arises in patients (<NPL>); <NPL>); <NPL>); <NPL>)). The FDA approved the use of lorlatinib for the treatment of lung cancer in November <NUM>.

Document <NPL>discloses the development of small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines.

<CIT> discloses compounds having degradation and inhibitory effect on ALK target proteins. The compounds are composed of four parts, the first part, ALK-TKI, being compounds with ALK tyrosine kinase inhibitory activity; the second part, LIN, being different kinds of linker (Linker); the third part, the ULM, being a small molecule ligand (ULM, ubiquitin ligase binding moiety) with ubiquitination of VHL, CRBN or other proteases; and the fourth part, the group A, being a carbonyl group or absent, which covalently bond ALK-TKI to LIN, wherein LIN and ULM are covalently bonded.

<CIT> discloses compounds designed and synthesized having a wide range of pharmacological activities such as the function of degrading specific proteins and/or inhibiting activity. They can be used in related tumor and cancer treatments.

Document <NPL> discloses the design, synthesis and biological evaluation of novel PROTACs (degraders) of ALK. Among them MS4077 (<NUM>) and MS4078 (<NUM>) potently decreased cellular levels of oncogenic active ALK fusion proteins in a concentration- and time-dependent manner in SU-DHL-<NUM> lymphoma and NCI-H2228 lung cancer cells. The ALK protein degradation induced by compounds <NUM> and <NUM> was cereblon and proteasome dependent. In addition, compounds <NUM> and <NUM> potently inhibited proliferation of SU-DHL-<NUM> cells.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated in order to facilitate the understanding of the present invention.

As used in the description and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions, reference to "an inhibitor" includes mixtures of two or more such inhibitors, and the like.

Unless stated otherwise, the term "about" means within <NUM>% (e.g., within <NUM>%, <NUM>% or <NUM>%) of the particular value modified by the term "about.

The transitional term "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. By contrast, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention.

With respect to compounds of the present invention, and to the extent the following terms are used herein to further describe them, the following definitions apply.

As used herein, the term "aliphatic" refers to a non-cyclic hydrocarbon group and includes branched and unbranched, alkyl, alkenyl, or alkynyl groups.

As used herein, the term "alkyl" refers to a saturated linear or branched-chain monovalent hydrocarbon radical. In one embodiment, the alkyl radical is a C<NUM>-C<NUM> group. In other embodiments, the alkyl radical is a C<NUM> -C<NUM>, C<NUM>-C<NUM>, C<NUM>-C<NUM>, C<NUM>-C<NUM>, C<NUM>-C<NUM>, C<NUM>-C<NUM>, C<NUM>-C<NUM>, C<NUM>-C<NUM> or C<NUM>-C<NUM> group (wherein C<NUM> alkyl refers to a bond). Examples of alkyl groups include methyl, ethyl, <NUM>-propyl, <NUM>-propyl, i-propyl, <NUM>-butyl, <NUM>-methyl-<NUM>-propyl, <NUM>-butyl, <NUM>-methyl-<NUM>-propyl, <NUM>-pentyl, n-pentyl, <NUM>-pentyl, <NUM>-pentyl, <NUM>-methyl-<NUM>-butyl, <NUM>-methyl-<NUM>-butyl, <NUM>-methyl-<NUM>-butyl, <NUM>-methyl-<NUM>-butyl, <NUM>-hexyl, <NUM>-hexyl, <NUM>-hexyl, <NUM>-methyl-<NUM>-pentyl, <NUM>-methyl-<NUM>-pentyl, <NUM>-methyl-<NUM>-pentyl, <NUM>-methyl-<NUM>-pentyl, <NUM>-methyl-<NUM>-pentyl, <NUM>,<NUM>-dimethyl-<NUM>-butyl, <NUM>,<NUM>-dimethyl-<NUM>-butyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl. In some embodiments, an alkyl group is a C<NUM>-C<NUM> alkyl group. In some embodiments, an alkyl group is a C<NUM>-C<NUM> alkyl group, or a methyl group.

As used herein, the term "alkylene" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to <NUM> carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain may be attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the alkylene group contains one to <NUM> carbon atoms (C<NUM>-C<NUM> alkylene). In other embodiments, an alkylene group contains one to <NUM> carbon atoms (C<NUM>-C<NUM> alkylene). In other embodiments, an alkylene group contains one to <NUM> carbon atoms (C<NUM>-C<NUM> alkylene). In other embodiments, an alkylene contains one to three carbon atoms (C<NUM>-C<NUM> alkylene). In other embodiments, an alkylene group contains one to two carbon atoms (C<NUM>-C<NUM> alkylene). In other embodiments, an alkylene group contains one carbon atom (C<NUM> alkylene).

As used herein, the term "alkenyl" refers to a linear or branched-chain monovalent hydrocarbon radical with at least one carbon-carbon double bond. An alkenyl includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In one example, the alkenyl radical is a C<NUM>-C<NUM> group. In other embodiments, the alkenyl radical is a C<NUM>-C<NUM>, C<NUM>-C<NUM>, C<NUM>-C<NUM>, C<NUM>-C<NUM> or C<NUM>-C<NUM> group. Examples include ethenyl or vinyl, prop-<NUM>-enyl, prop-<NUM>-enyl, <NUM>-methylprop-<NUM>-enyl, but-<NUM>-enyl, but-<NUM>-enyl, but-<NUM>-enyl, buta-<NUM>,<NUM>-dienyl, <NUM>-methylbuta-<NUM>,<NUM>-diene, hex-<NUM>-enyl, hex-<NUM>-enyl, hex-<NUM>-enyl, hex-<NUM>-enyl and hexa-<NUM>,<NUM>-dienyl.

As used herein, the term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical with at least one carbon-carbon triple bond. In one example, the alkynyl radical is a C<NUM>-C<NUM> group. In other examples, the alkynyl radical is C<NUM>-C<NUM>, C<NUM>-C<NUM>, C<NUM>-C<NUM>, C<NUM>-C<NUM> or C<NUM>-C<NUM>. Examples include ethynyl prop-<NUM>-ynyl, prop-<NUM>-ynyl, but-<NUM>-ynyl, but-<NUM>-ynyl and but-<NUM>-ynyl.

As used herein, the term "aldehyde" is represented by the formula-C(O)H. The terms "C(O)" and C=O are used interchangeably herein.

The terms "alkoxyl" or "alkoxy" as used herein refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl.

As used herein, the term "halogen" (or "halo" or "halide") refers to fluorine, chlorine, bromine, or iodine.

As used herein, the term "cyclic group" broadly refers to any group that used alone or as part of a larger moiety, contains a saturated, partially saturated or aromatic ring system e.g., carbocyclic (cycloalkyl, cycloalkenyl), heterocyclic (heterocycloalkyl, heterocycloalkenyl), aryl and heteroaryl groups. Cyclic groups may have one or more (e.g., fused) ring systems. Thus, for example, a cyclic group can contain one or more carbocyclic, heterocyclic, aryl or heteroaryl groups.

As used herein, the term "carbocyclic" (also "carbocyclyl") refers to a group that used alone or as part of a larger moiety, contains a saturated, partially unsaturated, or aromatic ring system having <NUM> to <NUM> carbon atoms, that is alone or part of a larger moiety (e.g., an alkcarbocyclic group). The term carbocyclyl includes mono-, bi-, tri-, fused, bridged, and spiro-ring systems, and combinations thereof. In one embodiment, carbocyclyl includes <NUM> to <NUM> carbon atoms (C<NUM>-C<NUM>). In one embodiment, carbocyclyl includes <NUM> to <NUM> carbon atoms (C<NUM>-C<NUM>). In another embodiment, carbocyclyl includes C<NUM>-C<NUM>, C<NUM>-C<NUM> or C<NUM>-C<NUM>. In another embodiment, carbocyclyl, as a monocycle, includes C<NUM>-C<NUM>, C<NUM>-C<NUM> or C<NUM>-C<NUM>. In some embodiments, carbocyclyl, as a bicycle, includes C<NUM>-C<NUM>. In another embodiment, carbocyclyl, as a spiro system, includes C<NUM>-C<NUM>. Representative examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, <NUM>-cyclopent-<NUM>-enyl, <NUM>-cyclopent-<NUM>-enyl, <NUM>-cyclopent-<NUM>-enyl, cyclohexyl, perdeuteriocyclohexyl, <NUM>-cyclohex-<NUM>-enyl, <NUM>-cyclohex-<NUM>-enyl, <NUM>-cyclohex-<NUM>-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicyclic carbocyclyls having <NUM> to <NUM> ring atoms include [<NUM>,<NUM>], [<NUM>,<NUM>], [<NUM>,<NUM>], [<NUM>,<NUM>], [<NUM>,<NUM>] or [<NUM>,<NUM>] ring systems, such as for example bicyclo[<NUM>. <NUM>]heptane, bicyclo[<NUM>. <NUM>]octane, naphthalene, and bicyclo[<NUM>. <NUM>]nonane. Representative examples of spiro carbocyclyls include spiro[<NUM>]pentane, spiro[<NUM>]hexane, spiro[<NUM>]heptane, spiro[<NUM>]octane and spiro[<NUM>]decane. The term carbocyclyl includes aryl ring systems as defined herein. The term carbocycyl also includes cycloalkyl rings (e.g., saturated or partially unsaturated mono-, bi-, or spiro-carbocycles). The term carbocyclic group also includes a carbocyclic ring fused to one or more (e.g., <NUM>, <NUM> or <NUM>) different cyclic groups (e.g., aryl or heterocyclic rings), where the radical or point of attachment is on the carbocyclic ring.

Thus, the term carbocyclic also embraces carbocyclylalkyl groups which as used herein refer to a group of the formula --Rc-carbocyclyl where Rc is an alkylene chain. The term carbocyclic also embraces carbocyclylalkoxy groups which as used herein refer to a group bonded through an oxygen atom of the formula --O--Rc-carbocyclyl where Rc is an alkylene chain.

As used herein, the term "aryl" used alone or as part of a larger moiety (e.g., "aralkyl", wherein the terminal carbon atom on the alkyl group is the point of attachment, e.g., a benzyl group), "aralkoxy" wherein the oxygen atom is the point of attachment, or "aroxyalkyl" wherein the point of attachment is on the aryl group) refers to a group that includes monocyclic, bicyclic or tricyclic, carbon ring system, that includes fused rings, wherein at least one ring in the system is aromatic. In some embodiments, the aralkoxy group is a benzoxy group. The term "aryl" may be used interchangeably with the term "aryl ring". In one embodiment, aryl includes groups having <NUM>-<NUM> carbon atoms. In another embodiment, aryl includes groups having <NUM>-<NUM> carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracyl, biphenyl, phenanthrenyl, naphthacenyl, <NUM>,<NUM>,<NUM>,<NUM>-tetrahydronaphthalenyl, <NUM>-indenyl, <NUM>,<NUM>-dihydro-<NUM>-indenyl, naphthyridinyl, and the like, which may be substituted or independently substituted by one or more substituents described herein. A particular aryl is phenyl. In some embodiments, an aryl group includes an aryl ring fused to one or more (e.g., <NUM>, <NUM> or <NUM>) different cyclic groups (e.g., carbocyclic rings or heterocyclic rings), where the radical or point of attachment is on the aryl ring.

Thus, the term aryl embraces aralkyl groups (e.g., benzyl) which as disclosed above refer to a group of the formula --Rc-aryl where Rc is an alkylene chain such as methylene or ethylene. In some embodiments, the aralkyl group is an optionally substituted benzyl group. The term aryl also embraces aralkoxy groups which as used herein refer to a group bonded through an oxygen atom of the formula --O-Rc--aryl where Rc is an alkylene chain such as methylene or ethylene.

As used herein, the term "heterocyclyl" refers to a "carbocyclyl" that used alone or as part of a larger moiety, contains a saturated, partially unsaturated or aromatic ring system, wherein one or more (e.g., <NUM>, <NUM>, <NUM>, or <NUM>) carbon atoms have been replaced with a heteroatom (e.g., O, N, N(O), S, S(O), or S(O)<NUM>). The term heterocyclyl includes mono-, bi-, tri-, fused, bridged, and spiro-ring systems, and combinations thereof. In some embodiments, a heterocyclyl refers to a <NUM> to <NUM> membered heterocyclyl ring system. In some embodiments, a heterocyclyl refers to a <NUM> to <NUM> membered heterocyclyl ring system. In some embodiments, a heterocyclyl refers to a saturated ring system, such as a <NUM> to <NUM> membered saturated heterocyclyl ring system. In some embodiments, a heterocyclyl refers to a heteroaryl ring system, such as a <NUM> to <NUM> membered heteroaryl ring system. The term heterocyclyl also includes C<NUM>-C<NUM> heterocycloalkyl, which is a saturated or partially unsaturated mono-, bi-, or spiro-ring system containing <NUM>-<NUM> carbons and one or more (<NUM>, <NUM>, <NUM> or <NUM>) heteroatoms.

The term heterocyclyl group means <NUM>-<NUM> ring atoms and includes monocycles, bicycles, tricycles and spiro ring systems, wherein the ring atoms are carbon, and one to <NUM> ring atoms is a heteroatom such as nitrogen, sulfur or oxygen. In some embodiments, heterocyclyl includes <NUM>- to <NUM>-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen. In some embodiments, heterocyclyl includes <NUM>- to <NUM>-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen. The term heterocyclyl includes <NUM>-membered monocycles. The term heterocyclyl also includes <NUM>-membered monocycles and <NUM>-<NUM> membered monocycles. The term heterocyclyl group also means that <NUM> to <NUM> double bonds are included. Heterocyclyl also includes <NUM>, <NUM>, <NUM> or <NUM> heteroatoms. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO<NUM>), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR<NUM>]+Cl-, [NR<NUM>]+OH-). Representative examples of heterocyclyls include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, <NUM>,<NUM>-dithietanyl, <NUM>,<NUM>-dithietanyl, pyrrolidinyl, dihydro-<NUM>-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, <NUM>,<NUM>-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, <NUM>,<NUM>-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, <NUM>,<NUM>-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, <NUM>,<NUM>,<NUM>,<NUM>-tetrahydro[<NUM>]indazolyl, tetrahydrobenzoimidazolyl, <NUM>,<NUM>,<NUM>,<NUM>-tetrahydrobenzo[d]imidazolyl, <NUM>,<NUM>-dihydroimidazol[<NUM>,<NUM>-d]pyrrolo[<NUM>,<NUM>-b]pyridinyl, thiazinyl, thiophenyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, <NUM>-pyrrolinyl, <NUM>-pyrrolinyl, <NUM>-pyrrolinyl, indolinyl, thiapyranyl, <NUM>-pyranyl, <NUM>-pyranyl, dioxanyl, <NUM>,<NUM>-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl, pyrimidin-<NUM>,<NUM>-dionyl, piperazinonyl, piperazindionyl, pyrazolidinylimidazolinyl, <NUM>-azabicyclo[<NUM>. <NUM>]hexanyl, <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]heptanyl, <NUM>-azabicyclo[<NUM>. <NUM>]heptanyl, <NUM>-azabicyclo[<NUM>. <NUM>]heptanyl, <NUM>-azabicyclo[<NUM>. <NUM>]heptanyl, azabicyclo[<NUM>. <NUM>]hexanyl, <NUM>-azabicyclo[<NUM>. <NUM>]octanyl, <NUM>-azabicyclo[<NUM>. <NUM>]octanyl, <NUM>-azabicyclo[<NUM>. <NUM>]octanyl, <NUM>-azabicyclo[<NUM>. <NUM>]octanyl, <NUM>-oxabicyclo[<NUM>. <NUM>]heptane, azaspiro[<NUM>]nonanyl, azaspiro[<NUM>]octanyl, azaspiro[<NUM>]decanyl, <NUM>-azaspiro[<NUM>]decan-<NUM>-only, azaspiro[<NUM>]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, <NUM>,<NUM>-dioxohexahydrothiopyranyl. Examples of <NUM>-membered heterocyclyls containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, including thiazol-<NUM>-yl and thiazol-<NUM>-yl N-oxide, thiadiazolyl, including <NUM>,<NUM>,<NUM>-thiadiazol-<NUM>-yl and <NUM>,<NUM>,<NUM>-thiadiazol-<NUM>-yl, oxazolyl, for example oxazol-<NUM>-yl, and oxadiazolyl, such as <NUM>,<NUM>,<NUM>-oxadiazol-<NUM>-yl, and <NUM>,<NUM>,<NUM>-oxadiazol-<NUM>-yl. Example <NUM>-membered ring heterocyclyls containing <NUM> to <NUM> nitrogen atoms include imidazolyl, such as imidazol-<NUM>-yl; triazolyl, such as <NUM>,<NUM>,<NUM>-triazol-<NUM>-yl; <NUM>,<NUM>,<NUM>-triazol-<NUM>-yl, <NUM>,<NUM>,<NUM>-triazol-<NUM>-yl, and tetrazolyl, such as <NUM>-tetrazol-<NUM>-yl. Representative examples of benzo-fused <NUM>-membered heterocyclyls are benzoxazol-<NUM>-yl, benzthiazol-<NUM>-yl and benzimidazol-<NUM>-yl. Example <NUM>-membered heterocyclyls contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-<NUM>-yl, pyrid-<NUM>-yl, and pyrid-<NUM>-yl; pyrimidyl, such as pyrimid-<NUM>-yl and pyrimid-<NUM>-yl; triazinyl, such as <NUM>,<NUM>,<NUM>-triazin-<NUM>-yl and <NUM>,<NUM>,<NUM>-triazin-<NUM>-yl; pyridazinyl, in particular pyridazin-<NUM>-yl, and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-<NUM>-yl, pyrimid-<NUM>-yl, pyridazinyl and the <NUM>,<NUM>,<NUM>-triazin-<NUM>-yl groups, are yet other examples of heterocyclyl groups. The term heterocyclic group also means to include a heterocyclic ring fused to one or more (e.g., <NUM>, <NUM> or <NUM>) different cyclic groups (e.g., carbocyclic rings or heterocyclic rings), where the radical or point of attachment is on the heterocyclic ring, and wherein the point of attachment is a heteroatom contained in the heterocyclic ring.

Thus, the term heterocyclic embraces N-heterocyclyl groups which as used herein refer to a heterocyclyl group containing at least one nitrogen and where the point of attachment of the heterocyclyl group to the rest of the molecule is through a nitrogen atom in the heterocyclyl group. Representative examples of N-heterocyclyl groups include <NUM>-morpholinyl, <NUM>-piperidinyl, <NUM>-piperazinyl, <NUM>-pyrrolidinyl, pyrazolidinyl, imidazolinyl and imidazolidinyl. The term heterocyclic also embraces C-heterocyclyl groups which as used herein refer to a heterocyclyl group containing at least one heteroatom and where the point of attachment of the heterocyclyl group to the rest of the molecule is through a carbon atom in the heterocyclyl group. Representative examples of C-heterocyclyl radicals include <NUM>-morpholinyl, <NUM>- or <NUM>- or <NUM>-piperidinyl, <NUM>-piperazinyl, and <NUM>- or <NUM>-pyrrolidinyl. The term heterocyclic also embraces heterocyclylalkyl groups which as disclosed above refer to a group of the formula --Rc-heterocyclyl where Rc is an alkylene chain. The term heterocyclic also embraces heterocyclylalkoxy groups which as used herein refer to a radical bonded through an oxygen atom of the formula --O--Rc-heterocyclyl where Rc is an alkylene chain.

As used herein, the term "heteroaryl" used alone or as part of a larger moiety (e.g., "heteroarylalkyl" (also "heteroaralkyl"), or "heteroarylalkoxy" (also "heteroaralkoxy"), refers to a monocyclic, bicyclic or tricyclic ring system having <NUM> to <NUM> ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom. The term heteroaryl means to includes <NUM>-<NUM> membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen that is independently optionally substituted. The term heteroaryl also means to include <NUM>-<NUM> membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen. Representative examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, imidazopyridyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[<NUM>,<NUM>-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indolyl, <NUM>,<NUM>-thiazol-<NUM>-yl, <NUM>,<NUM>,<NUM>-triazol-<NUM>-yl, <NUM>,<NUM>-oxazol-<NUM>-yl, <NUM>,<NUM>,<NUM>-oxadiazol-<NUM>-yl, <NUM>,<NUM>,<NUM>-oxadiazol-<NUM>-yl, <NUM>,<NUM>,<NUM>-thiadiazol-<NUM>-yl, <NUM>-tetrazol-<NUM>-yl, <NUM>,<NUM>,<NUM>-triazol-<NUM>-yl, and pyrid-<NUM>-yl N-oxide. The term "heteroaryl" also includes groups in which a heteroaryl is fused to one or more cyclic (e.g., carbocyclyl, or heterocyclyl) rings, where the radical or point of attachment is on the heteroaryl ring. Nonlimiting examples include indolyl, indolizinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, <NUM>-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[<NUM>,<NUM>-b]-<NUM>,<NUM>-oxazin-<NUM>(<NUM>)-one. A heteroaryl group may be mono-, bi- or tri-cyclic. The term heteroaryl group means to include a heteroaryl ring fused to one or more (e.g., <NUM>, <NUM> or <NUM>) different cyclic groups (e.g., carbocyclic rings or heterocyclic rings), where the radical or point of attachment is on the heteroaryl ring, and wherein the point of attachment is a heteroatom contained in the heterocyclic ring.

Thus, the term heteroaryl embraces N-heteroaryl groups which as used herein refer to a heteroaryl group as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl group to the rest of the molecule is through a nitrogen atom in the heteroaryl group. The term heteroaryl also embraces C-heteroaryl groups which as used herein refer to a heteroaryl group as defined above and where the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. The term heteroaryl also embraces heteroarylalkyl groups which as disclosed above refer to a group of the formula --Rc-heteroaryl, wherein Rc is an alkylene chain as defined above. The term heteroaryl also embraces heteroaralkoxy (or heteroarylalkoxy) groups which as used herein refer to a group bonded through an oxygen atom of the formula --O--Rc-heteroaryl, where Rc is an alkylene group as defined above.

Any of the groups described herein may be substituted or unsubstituted. As used herein, the term "substituted" broadly refers to all permissible substituents with the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e. a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. Representative substituents include halogens, hydroxyl groups, and any other organic groupings containing any number of carbon atoms, e.g., <NUM>-<NUM> carbon atoms, and which may include one or more (e.g., <NUM>, <NUM>, <NUM>, or <NUM>) heteroatoms such as oxygen, sulfur, and nitrogen grouped in a linear, branched, or cyclic structural format.

Representative examples of substituents may include alkyl, substituted alkyl (e.g., C1-C6, C1-<NUM>, C1-<NUM>, C1-<NUM>, C1-<NUM>, C1), alkoxy (e.g., C1-C6, C1-<NUM>, C1-<NUM>, C1-<NUM>, C1-<NUM>, C1), substituted alkoxy (e.g., C1-C6, C1-<NUM>, C1-<NUM>, C1-<NUM>, C1-<NUM>, C1), haloalkyl (e.g., CF<NUM>), alkenyl (e.g., C2-C6, C2-<NUM>, C2-<NUM>, C2-<NUM>, C2), substituted alkenyl (e.g., C2-C6, C2-<NUM>, C2-<NUM>, C2-<NUM>, C2), alkynyl (e.g., C2-C6, C2-<NUM>, C2-<NUM>, C2-<NUM>, C2), substituted alkynyl (e.g., C2-C6, C2-<NUM>, C2-<NUM>, C2-<NUM>, C2), cyclic (e.g., C3-C12, C5-C6), substituted cyclic (e.g., C3-C12, C5-C6), carbocyclic (e.g., C3-C12, C5-C6), substituted carbocyclic (e.g., C3-C12, C5-C6), heterocyclic (e.g., C3-C12, C5-C6), substituted heterocyclic (e.g., C3-C12, C5-C6), aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted benzyl or phenyl), heteroaryl (e.g., pyridyl or pyrimidyl), substituted heteroaryl (e.g., substituted pyridyl or pyrimidyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halo, hydroxyl, aryloxy (e.g., C6-C12, C6), substituted aryloxy (e.g., C6-C12, C6), alkylthio (e.g., C1-C6), substituted alkylthio (e.g., C1-C6), arylthio (e.g., C6-C12, C6), substituted arylthio (e.g., C6-C12, C6), cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, urea, substituted urea, carbamate, substituted carbamate, amino acid, and peptide groups.

The term "binding" as it relates to interaction between the targeting ligand and the targeted protein, refers to an inter-molecular interaction that is substantially specific in that binding of the targeting ligand with other proteinaceous entities present in the cell is functionally insignificant. The present bispecific compounds preferentially bind and recruit ALK for targeted degradation, including mutant forms thereof (e.g., EML4-ALK including the G1202R and L1196M mutants, and NPM-ALK) that manifest themselves in pathological states. The bispecific compounds may also bind and recruit one or more other kinases for degradation including, for example, c-ros oncogene <NUM> (ROS <NUM>), ret-proto oncogene (RET), insulin-like growth factor-<NUM> receptor (IGF-1R), hepatocyte growth factor receptor (HGFR or c-MET), FLT-<NUM>, and tropomyosin receptor kinase A (TrkA), TrkB and TrkC.

The term "binding" as it relates to interaction between the degron and the E3 ubiquitin ligase, typically refers to an inter-molecular interaction that may or may not exhibit an affinity level that equals or exceeds that affinity between the targeting ligand and the target protein, but nonetheless wherein the affinity is sufficient to achieve recruitment of the ligase to the targeted degradation and the selective degradation of the targeted protein.

The bispecific compounds of the present invention have a structure represented by formula I:
<CHM>.

In some embodiments, the ALK targeting ligand is an alectinib analog which has a structure represented by formula TL-1b:
<CHM>
wherein R<NUM> is H or Me.

Thus, in some embodiments, the bispecific compounds of the present invention may have a structure as represented by formula I-1b:
<CHM>
wherein R<NUM> is H or Me, or a pharmaceutically acceptable salt or stereoisomer thereof.

The linker ("L") provides a covalent attachment the targeting ligand and the degron. The structure of linker may not be critical, provided it does not substantially interfere with the activity of the targeting ligand or the degron. According to the invention, the linker is an alkylene chain or a bivalent alkylene chain, or polyethylene glycol chain either of which may be interrupted by, and/or terminate (at either or both termini) in at least one of -O-, -S-, -N(R')-, -C=C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-,-C(O)N(R')C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R')-,-C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)O-, -S(O)<NUM>-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)<NUM>-, -S(O)<NUM>O-, -N(R')S(O)<NUM>-, -S(O)<NUM>N(R')-, -N(R')S(O)-,-S(O)N(R')-, -N(R')S(O)<NUM>N(R')-, -N(R')S(O)N(R')-, C<NUM>-C<NUM> carbocyclene, <NUM>- to <NUM>-membered heterocyclene, <NUM>- to <NUM>-membered heteroarylene or any combination thereof, wherein R' is H or C<NUM>-C<NUM> alkyl, wherein the interrupting and the one or both terminating groups may be the same or different.

"Carbocyclene" refers to a bivalent carbocycle radical, which is optionally substituted.

"Heterocyclene" refers to a bivalent heterocyclyl radical which may be optionally substituted.

"Heteroarylene" refers to a bivalent heteroaryl radical which may be optionally substituted.

In some embodiments, the compound according to the inventionincludes a linker that is represented by any one of the following structures:
<CHM>
<CHM>
<CHM>.

In some embodiments, the compound according to the invention includes a linker that is represented by any one of the following structures:
<CHM>
<CHM>
<CHM>
<CHM>
wherein R is H or Me.

In certain embodiments, linkers L11-a to L11-g are particularly suitable for use with lorlatinib and TPX-<NUM> targeting ligands and analogs thereof.

In some embodiments, the bispecific compound of the present invention is represented by any one of the following structures:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

The Ubiquitin-Proteasome Pathway (UPP) is a critical cellular pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases include over <NUM> different proteins and are categorized into multiple classes defined by the structural element of their E3 functional activity.

According to the invention, the degron, which binds the E3 ubiquitin ligase which is cereblon (CRBN) is represented by any one of the following structures:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
and
<CHM>
wherein X is alkyl, halo, CN, CF<NUM>, OCHF<NUM> or OCF<NUM>.

In some embodiments, the compound of the present invention is represented by any one of the following structures:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
or a pharmaceutically acceptable salts and stereoisomers thereof.

Bispecific compounds of the present invention may be in the form of a free acid or free base, or a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable" in the context of a salt refers to a salt of the compound that does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the compound in salt form may be administered to a subject without causing undesirable biological effects (such as dizziness or gastric upset) or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The term "pharmaceutically acceptable salt" refers to a product obtained by reaction of the compound of the present invention with a suitable acid or a base. Examples of pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, <NUM>-methylbenzenesulfonate or p-toluenesulfonate salts and the like. Certain compounds of the invention can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin. Suitable base salts include aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc, salts.

Bispecific compounds of the present invention or a pharmaceutically acceptable salt thereof may have at least one chiral center and thus may be in the form of a stereoisomer, which as used herein, embraces all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers which include the (R-) or (S-) configurations of the compounds), mixtures of mirror image isomers (physical mixtures of the enantiomers, and racemates or racemic mixtures) of compounds, geometric (cis/trans or E/Z, R/S) isomers of compounds and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers). The chiral centers of the compounds may undergo epimerization in vivo; thus, for these compounds, administration of the compound in its (R-) form is considered equivalent to administration of the compound in its (S-) form. Accordingly, the compounds of the present invention may be made and used in the form of individual isomers and substantially free of other isomers, or in the form of a mixture of various isomers, e.g., racemic mixtures of stereoisomers.

In some embodiments, the bispecific compound according to the invention or a pharmaceutically acceptable salt or stereoisomer thereof is an isotopic derivative in that it has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. In one embodiment, the compound includes deuterium or multiple deuterium atoms. Substitution with heavier isotopes such as deuterium, i.e. <NUM>H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and thus may be advantageous in some circumstances.

In addition, bispecific compounds according to the invention and their pharmaceutically acceptable salts and stereoisomers embrace the use of N-oxides, crystalline forms (also known as polymorphs), active metabolites of the compounds having the same type of activity, tautomers, and unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, of the compounds. The solvated forms of the conjugates presented herein are also considered to be disclosed herein.

Another aspect of the present invention is directed to a pharmaceutical composition that includes a therapeutically effective amount of the bispecific compound according to the invention or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier," as known in the art, refers to a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present invention to mammals. Suitable carriers may include, for example, liquids (both aqueous and non-aqueous alike, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g., semi-solids), and gases, that function to carry or transport the compound from one organ, or portion of the body, to another organ, or portion of the body. A carrier is "acceptable" in the sense of being physiologically inert to and compatible with the other ingredients of the formulation and not injurious to the subject or patient. Depending on the type of formulation, the composition may include one or more pharmaceutically acceptable excipients.

Broadly, bispecific compounds according to the invention and their pharmaceutically acceptable salts and stereoisomers may be formulated into a given type of composition in accordance with conventional pharmaceutical practice such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping and compression processes (see, e.g., <NPL>and <NPL>). The type of formulation depends on the mode of administration which may include enteral (e.g., oral, buccal, sublingual and rectal), parenteral (e.g., subcutaneous (s. ), intravenous (i. ), intramuscular (i. ), and intrasternal injection, or infusion techniques, intra-ocular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, interdermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation, and inhalation) and topical (e.g., transdermal). In general, the most appropriate route of administration will depend upon a variety of factors including, for example, the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). For example, parenteral (e.g., intravenous) administration may also be advantageous in that the compound may be administered relatively quickly such as in the case of a single-dose treatment and/or an acute condition.

In some embodiments, the compounds according to the invention are formulated for oral or intravenous administration (e.g., systemic intravenous injection).

Accordingly, bispecific compounds of the present invention may be formulated into solid compositions (e.g., powders, tablets, dispersible granules, capsules, cachets, and suppositories), liquid compositions (e.g., solutions in which the compound is dissolved, suspensions in which solid particles of the compound are dispersed, emulsions, and solutions containing liposomes, micelles, or nanoparticles, syrups and elixirs); semi-solid compositions (e.g., gels, suspensions and creams); and gases (e.g., propellants for aerosol compositions). Compounds may also be formulated for rapid, intermediate or extended release.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the bispecific compound is mixed with a carrier such as sodium citrate or dicalcium phosphate and an additional carrier or excipient such as a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as crosslinked polymers (e.g., crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also include buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings. They may further contain an opacifying agent.

In some embodiments, bispecific compounds of the present invention may be formulated in a hard or soft gelatin capsule. Representative excipients that may be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, lactose anhydrous, microcrystalline cellulose and croscarmellose sodium. Gelatin shells may include gelatin, titanium dioxide, iron oxides and colorants.

Liquid dosage forms for oral administration include solutions, suspensions, emulsions, micro-emulsions, syrups and elixirs. In addition to the bispecific compound, the liquid dosage forms may contain an aqueous or non-aqueous carrier (depending upon the solubility of the compounds) commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, <NUM>,<NUM>-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Oral compositions may also include an excipients such as wetting agents, suspending agents, coloring, sweetening, flavoring, and perfuming agents.

Injectable preparations may include sterile aqueous solutions or oleaginous suspensions. They may be formulated according to standard techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in <NUM>,<NUM>-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. The effect of the compound may be prolonged by slowing its absorption, which may be accomplished by the use of a liquid suspension or crystalline or amorphous material with poor water solubility. Prolonged absorption of the compound from a parenterally administered formulation may also be accomplished by suspending the compound in an oily vehicle.

In certain embodiments, bispecific compounds according to the invention may be administered in a local rather than systemic manner, for example, via injection of the conjugate directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Injectable depot forms are made by forming microencapsule matrices of the compound in a biodegradable polymer, e.g., polylactide-polyglycolides, poly(orthoesters) and poly(anhydrides). The rate of release of the compound may be controlled by varying the ratio of compound to polymer and the nature of the particular polymer employed. Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ.

The bispecific compounds according to the invention may be formulated for buccal or sublingual administration, examples of which include tablets, lozenges and gels.

The bispecific compounds according to the invention may be formulated for administration by inhalation. Various forms suitable for administration by inhalation include aerosols, mists or powders. Pharmaceutical compositions may be delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In some embodiments, the dosage unit of a pressurized aerosol may be determined by providing a valve to deliver a metered amount. In some embodiments, capsules and cartridges including gelatin, for example, for use in an inhaler or insufflator, may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

Bispecific compounds according to the invention may be formulated for topical administration which as used herein, refers to administration intradermally by application of the formulation to the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions and sprays.

Representative examples of carriers useful in formulating compositions for topical application include solvents (e.g., alcohols, poly alcohols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g., hypotonic or buffered saline). Creams, for example, may be formulated using saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl, or oleyl alcohols. Creams may also contain a non-ionic surfactant such as polyoxy-<NUM>-stearate.

In some embodiments, the topical formulations may also include an excipient, an example of which is a penetration enhancing agent. These agents are capable of transporting a pharmacologically active compound through the stratum corneum and into the epidermis or dermis, preferably, with little or no systemic absorption. A wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for example, <NPL>), which surveys the use and testing of various skin penetration enhancers, and <NPL>). Representative examples of penetration enhancing agents include triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe-vera gel), ethyl alcohol, isopropyl alcohol, octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol <NUM>, propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate), and N-methylpyrrolidone.

Representative examples of yet other excipients that may be included in topical as well as in other types of formulations (to the extent they are compatible), include preservatives, antioxidants, moisturizers, emollients, buffering agents, solubilizing agents, skin protectants, and surfactants. Suitable preservatives include alcohols, quaternary amines, organic acids, parabens, and phenols. Suitable antioxidants include ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents like EDTA and citric acid. Suitable moisturizers include glycerine, sorbitol, polyethylene glycols, urea, and propylene glycol. Suitable buffering agents include citric, hydrochloric, and lactic acid buffers. Suitable solubilizing agents include quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates. Suitable skin protectants include vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

Transdermal formulations typically employ transdermal delivery devices and transdermal delivery patches wherein the compound is formulated in lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. Patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Transdermal delivery of the compounds may be accomplished by means of an iontophoretic patch. Transdermal patches may provide controlled delivery of the compounds wherein the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Absorption enhancers may be used to increase absorption, examples of which include absorbable pharmaceutically acceptable solvents that assist passage through the skin.

Ophthalmic formulations include eye drops.

Formulations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols, and retention enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. Compositions for rectal or vaginal administration may also be formulated as suppositories which can be prepared by mixing the compound with suitable non-irritating carriers and excipients such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycol, suppository waxes, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound.

As used herein, the term, "therapeutically effective amount" refers to an amount of a bispecific compound of formula I or a pharmaceutically acceptable salt or a stereoisomer thereof that is effective in producing the desired therapeutic response in a particular patient suffering from a disease or disorder mediated by aberrant ALK activity. The term "therapeutically effective amount" thus includes the amount of the bispecific compound or a pharmaceutically acceptable salt or a stereoisomer thereof, that when administered, induces a positive modification in the disease or disorder to be treated, or is sufficient to prevent development or progression of the disease or disorder, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject, or which simply kills or inhibits the growth of diseased (e.g., cancer) cells, or reduces the amounts of ALK in diseased cells.

The total daily dosage of the compounds and usage thereof may be decided in accordance with standard medical practice, e.g., by the attending physician using sound medical judgment. The specific therapeutically effective dose for any particular subject will depend upon a variety of factors including the disease or disorder being treated and the severity thereof (e.g., its present status); the activity of the bispecific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the bispecific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts (see, for example, <NPL>).

The bispecific compounds according to the invention and their pharmaceutically acceptable salts and stereoisomers may be effective over a wide dosage range. In some embodiments, the total daily dosage (e.g., for adult humans) may range from about <NUM> to about <NUM>, from <NUM> to about <NUM>, from <NUM> to about <NUM>, from about <NUM> to about <NUM>, from about <NUM> to about <NUM>, from <NUM> to about <NUM>-<NUM> per day, from about <NUM> to about <NUM> per day, from about <NUM> to about <NUM> per day, and in yet other embodiments from about <NUM> to about <NUM> per day. Individual dosages may be formulated to contain the desired dosage amount depending upon the number of times the compound is administered per day. By way of example, capsules may be formulated with from about <NUM> to about <NUM> of compound (e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>). In some embodiments, the compound may be administered at a dose in range from about <NUM> to about <NUM>/kg of body weight per day. In some embodiments, a dose of from <NUM> to <NUM>, e.g., from <NUM> to <NUM>/kg per day in one or more dosages per day may be effective. By way of example, a suitable dose for oral administration may be in the range of <NUM>-<NUM>/kg of body weight per day, and a suitable dose for intravenous administration may be in the range of <NUM>-<NUM>/kg of body weight per day.

In some embodiments, the bispecific compound is administered in a dose between <NUM> per day and <NUM> per day. In other embodiments the bispecific compound is administered in a dose between <NUM> per day and <NUM> per day, e.g., <NUM>-<NUM> per day.

In some aspects, the present invention is directed to the use of compounds or pharmaceutical compositions according to the invention for the treatment of a cancerous disease or disorder characterized or mediated by aberrant (e.g., elevated levels of ALK or otherwise functionally abnormal e.g., deregulated ALK activity relative to a non-pathological state. A "disease" is generally regarded as a state of health of a subject wherein the subject cannot maintain homeostasis, and wherein if the disease is not ameliorated then the subject's health continues to deteriorate. In contrast, a "disorder" in a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the subject's state of health.

The term "subject" (or "patient") as used herein includes all members of the animal kingdom prone to or suffering from the indicated disease or disorder. In some embodiments, the subject is a mammal, e.g., a human or a non-human mammal. The methods are also applicable to companion animals such as dogs and cats as well as livestock such as cows, horses, sheep, goats, pigs, and other domesticated and wild animals. A subject "in need of" the treatment may be suffering from or suspected of suffering from a specific disease or disorder may have been positively diagnosed or otherwise presents with a sufficient number of risk factors or a sufficient number or combination of signs or symptoms such that a medical professional could diagnose or suspect that the subject was suffering from the disease or disorder. Thus, subjects suffering from, and suspected of suffering from, a specific disease or disorder are not necessarily two distinct groups.

In some embodiments, the inventive compounds are for use in the treatment of cancer.

According to the invention, the compounds or pharmaceutical compositions are for use in methods directed to treating subjects having cancer. Broadly, the bispecific compounds of the present invention may be effective in the treatment of carcinomas (solid tumors including both primary and metastatic tumors), sarcomas, melanomas, and hematological cancers (cancers affecting blood including lymphocytes, bone marrow and/or lymph nodes) such as leukemia, lymphoma and multiple myeloma. Adult tumors/cancers and pediatric tumors/cancers are included. The cancers may be vascularized, or not yet substantially vascularized, or non-vascularized tumors.

Representative examples of cancers includes adrenocortical carcinoma, AIDS-related cancers (e.g., Kaposi's and AIDS-related lymphoma), appendix cancer, childhood cancers (e.g., childhood cerebellar astrocytoma, childhood cerebral astrocytoma), basal cell carcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, brain cancer (e.g., gliomas and glioblastomas such as brain stem glioma, gestational trophoblastic tumor glioma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodeimal tumors, visual pathway and hypothalamic glioma), breast cancer, bronchial adenomas/carcinoids, carcinoid tumor, nervous system cancer (e.g., central nervous system cancer, central nervous system lymphoma), cervical cancer, chronic myeloproliferative disorders, colorectal cancer (e.g., colon cancer, rectal cancer), polycythemia vera, lymphoid neoplasm, mycosis fungoids, Sezary Syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastrointestinal cancer (e.g., stomach cancer, small intestine cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST)), germ cell tumor, ovarian germ cell tumor, head and neck cancer, Hodgkin's lymphoma, leukemia, lymphoma, multiple myeloma, hepatocellular carcinoma, hypopharyngeal cancer, intraocular melanoma, ocular cancer, islet cell tumors (endocrine pancreas), renal cancer (e.g., Wilm's Tumor, clear cell renal cell carcinoma), liver cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), Waldenstrom's macroglobulinema, melanoma, intraocular (eye) melanoma, merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary, multiple endocrine neoplasia (MEN), myelodysplastic syndromes, essential thrombocythemia, myelodysplastic/myeloproliferative diseases, nasopharyngeal cancer, neuroblastoma, oral cancer (e.g., mouth cancer, lip cancer, oral cavity cancer, tongue cancer, oropharyngeal cancer, throat cancer, laryngeal cancer), ovarian cancer (e.g., ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor), pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, prostate cancer, retinoblastoma rhabdomyosarcoma, salivary gland cancer, uterine cancer (e.g., endometrial uterine cancer, uterine sarcoma, uterine corpus cancer), squamous cell carcinoma, testicular cancer, thymoma, thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter and other urinary organs, urethral cancer, gestational trophoblastic tumor, vaginal cancer and vulvar cancer.

Sarcomas that may be treatable with compounds of the present invention include both soft tissue and bone cancers alike, representative examples of which include osteosarcoma or osteogenic sarcoma (bone) (e.g., Ewing's sarcoma), chondrosarcoma (cartilage), leiomyosarcoma (smooth muscle), rhabdomyosarcoma (skeletal muscle), mesothelial sarcoma or mesothelioma (membranous lining of body cavities), fibrosarcoma (fibrous tissue), angiosarcoma or hemangioendothelioma (blood vessels), liposarcoma (adipose tissue), glioma or astrocytoma (neurogenic connective tissue found in the brain), myxosarcoma (primitive embryonic connective tissue) and mesenchymous or mixed mesodermal tumor (mixed connective tissue types).

In some embodiments, methods of the present invention entail treatment of subjects having cell proliferative diseases or disorders of the hematological system, liver (hepatocellular), brain, lung, colorectal (e.g., colon), pancreas, prostate, ovary, breast, skin (e.g., melanoma), and endometrium.

As used herein, "cell proliferative diseases or disorders of the hematologic system" include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid papulosis, polycythemia vera, chronic myelocytic leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia. Representative examples of hematologic cancers may thus include multiple myeloma, lymphoma (including T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and ALK+ anaplastic large cell lymphoma (e.g., B-cell non-Hodgkin's lymphoma selected from diffuse large B-cell lymphoma (e.g., germinal center B-cell-like diffuse large B-cell lymphoma or activated B-cell-like diffuse large B-cell lymphoma), Burkitt's lymphoma/leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, metastatic pancreatic adenocarcinoma, refractory B-cell non-Hodgkin's lymphoma, and relapsed B-cell non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin, e.g., small lymphocytic lymphoma, leukemia, including childhood leukemia, hairy-cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloid leukemia (e.g., acute monocytic leukemia), chronic lymphocytic leukemia, small lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell leukemia, myeloid neoplasms and mast cell neoplasms.

As used herein, "cell proliferative diseases or disorders of the liver (hepatocellular)" include all forms of cell proliferative disorders affecting the liver. Cell proliferative disorders of the liver may include liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma and hepatoblastoma), a precancer or precancerous condition of the liver, benign growths or lesions of the liver, and malignant growths or lesions of the liver, and metastatic lesions in tissue and organs in the body other than the liver. Cell proliferative disorders of the liver may include hyperplasia, metaplasia, and dysplasia of the liver.

As used herein, "cell proliferative diseases or disorders of the brain" include all forms of cell proliferative disorders affecting the brain. Cell proliferative disorders of the brain may include brain cancer (e.g., gliomas, glioblastomas, meningiomas, pituitary adenomas, vestibular schwannomas, and primitive neuroectodermal tumors (medulloblastomas)), a precancer or precancerous condition of the brain, benign growths or lesions of the brain, and malignant growths or lesions of the brain, and metastatic lesions in tissue and organs in the body other than the brain. Cell proliferative disorders of the brain may include hyperplasia, metaplasia, and dysplasia of the brain.

As used herein, "cell proliferative diseases or disorders of the lung" include all forms of cell proliferative disorders affecting lung cells. Cell proliferative disorders of the lung include lung cancer, precancer and precancerous conditions of the lung, benign growths or lesions of the lung, hyperplasia, metaplasia, and dysplasia of the lung, and metastatic lesions in the tissue and organs in the body other than the lung. Lung cancer includes all forms of cancer of the lung, e.g., malignant lung neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Lung cancer includes small cell lung cancer ("SLCL"), non-small cell lung cancer ("NSCLC"), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, squamous cell carcinoma, and mesothelioma. Lung cancer can include "scar carcinoma", bronchioveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer also includes lung neoplasms having histologic and ultrastructural heterogeneity (e.g., mixed cell types). In some embodiments, a compound of the present invention may be used to treat non-metastatic or metastatic lung cancer (e.g., NSCLC, ALK-positive NSCLC, NSCLC harboring ROS1 Rearrangement, Lung Adenocarcinoma, and Squamous Cell Lung Carcinoma).

As used herein, "cell proliferative diseases or disorders of the colon" include all forms of cell proliferative disorders affecting colon cells, including colon cancer, a precancer or precancerous conditions of the colon, adenomatous polyps of the colon and metachronous lesions of the colon. Colon cancer includes sporadic and hereditary colon cancer, malignant colon neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors, adenocarcinoma, squamous cell carcinoma, and squamous cell carcinoma. Colon cancer can be associated with a hereditary syndrome such as hereditary nonpolyposis colorectal cancer, familiar adenomatous polyposis, MYH associated polyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome and juvenile polyposis. Cell proliferative disorders of the colon may also be characterized by hyperplasia, metaplasia, or dysplasia of the colon.

As used herein, "cell proliferative diseases or disorders of the pancreas" include all forms of cell proliferative disorders affecting pancreatic cells. Cell proliferative disorders of the pancreas may include pancreatic cancer, a precancer or precancerous condition of the pancreas, hyperplasia of the pancreas, dysplasia of the pancreas, benign growths or lesions of the pancreas, and malignant growths or lesions of the pancreas, and metastatic lesions in tissue and organs in the body other than the pancreas. Pancreatic cancer includes all forms of cancer of the pancreas, including ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatoblastoma, papillary neoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma, and pancreatic neoplasms having histologic and ultrastructural heterogeneity (e.g., mixed cell types).

As used herein, "cell proliferative diseases or disorders of the prostate" include all forms of cell proliferative disorders affecting the prostate. Cell proliferative disorders of the prostate may include prostate cancer, a precancer or precancerous condition of the prostate, benign growths or lesions of the prostate, and malignant growths or lesions of the prostate, and metastatic lesions in tissue and organs in the body other than the prostate. Cell proliferative disorders of the prostate may include hyperplasia, metaplasia, and dysplasia of the prostate.

As used herein, "cell proliferative diseases or disorders of the ovary" include all forms of cell proliferative disorders affecting cells of the ovary. Cell proliferative disorders of the ovary may include a precancer or precancerous condition of the ovary, benign growths or lesions of the ovary, ovarian cancer, and metastatic lesions in tissue and organs in the body other than the ovary. Cell proliferative disorders of the ovary may include hyperplasia, metaplasia, and dysplasia of the ovary.

As used herein, "cell proliferative diseases or disorders of the breast" include all forms of cell proliferative disorders affecting breast cells. Cell proliferative disorders of the breast may include breast cancer, a precancer or precancerous condition of the breast, benign growths or lesions of the breast, and metastatic lesions in tissue and organs in the body other than the breast. Cell proliferative disorders of the breast may include hyperplasia, metaplasia, and dysplasia of the breast.

As used herein, "cell proliferative diseases or disorders of the skin" include all forms of cell proliferative disorders affecting skin cells. Cell proliferative disorders of the skin may include a precancer or precancerous condition of the skin, benign growths or lesions of the skin, melanoma, malignant melanoma or other malignant growths or lesions of the skin, and metastatic lesions in tissue and organs in the body other than the skin. Cell proliferative disorders of the skin may include hyperplasia, metaplasia, and dysplasia of the skin.

As used herein, "cell proliferative diseases or disorders of the endometrium" include all forms of cell proliferative disorders affecting cells of the endometrium. Cell proliferative disorders of the endometrium may include a precancer or precancerous condition of the endometrium, benign growths or lesions of the endometrium, endometrial cancer, and metastatic lesions in tissue and organs in the body other than the endometrium. Cell proliferative disorders of the endometrium may include hyperplasia, metaplasia, and dysplasia of the endometrium.

The bispecific compounds according to the invention may be administered to a patient, e.g., a cancer patient, as a monotherapy or by way of combination therapy. Therapy may be "front/first-line", i.e., as an initial treatment in patients who have undergone no prior anti-cancer treatment regimens, either alone or in combination with other treatments; or "second-line", as a treatment in patients who have undergone a prior anti-cancer treatment regimen, either alone or in combination with other treatments; or as "third-line", "fourth-line", etc. treatments, either alone or in combination with other treatments. Therapy may also be given to patients who have had previous treatments which have been partially successful but who became intolerant to the particular treatment. Therapy may also be given as an adjuvant treatment, i.e., to prevent reoccurrence of cancer in patients with no currently detectable disease or after surgical removal of a tumor. Thus, in some embodiments, the bifunctional compounds may be administered to a patient who has received another therapy, such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiation therapy, targeted therapy or any combination thereof.

The administration of compounds of the invention or pharmaceutical compositions thereof to the patient may be performed in a single dose or in multiple doses (e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or more doses). For example, the frequency of administration may range from once a day up to about once every eight weeks. In some embodiments, the frequency of administration ranges from about once a day for <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> weeks, and in other embodiments entails a <NUM>-day cycle which includes daily administration for <NUM> weeks (<NUM> days). In other embodiments, the bispecific compound may be dosed twice a day (BID) over the course of two and a half days (for a total of <NUM> doses) or once a day (QD) over the course of two days (for a total of <NUM> doses). In other embodiments, the bispecific compound may be dosed once a day (QD) over the course of five days.

These and other aspects of the present invention will be further appreciated upon consideration of the following Examples, which are intended to illustrate certain particular embodiments of the invention but are not intended to limit its scope, as defined by the claims.

Compounds SM-<NUM> and SM-<NUM> are commercially available.

<NUM>-ethyl-<NUM>,<NUM>-dimethyl-<NUM>-oxo-<NUM>-(<NUM>-(piperazin-<NUM>-yl)piperidin-<NUM>-yl)-<NUM>,<NUM>-dihydro-<NUM>-benzo[b]carbazole-<NUM>-carbonitrile was prepared according to the procedure described in<NPL>), followed by treatment with <NUM>% TFA in DCM (<NUM>) for <NUM> hour. The solvent was then removed under vacuum and the product was used without further purification. MS (ESI) m/z <NUM> (M+H)+.

To a stirred solution of <NUM>-ethyl-<NUM>,<NUM>-dimethyl-<NUM>-oxo-<NUM>-(<NUM>-(piperazin-<NUM>-yl)piperidin-<NUM>-yl)-<NUM>,<NUM>-dihydro-<NUM>-benzo[b]carbazole-<NUM>-carbonitrile (<NUM>, <NUM> mmol), <NUM>-((<NUM>-(<NUM>,<NUM>-dioxopiperidin-<NUM>-yl)-<NUM>,<NUM>-dioxoisoindolin-<NUM>-yl)amino)-<NUM>,<NUM>,<NUM>,<NUM>-tetraoxapentadecan-<NUM>-oic acid (<NUM>, <NUM> mmol), and HATU (<NUM>, <NUM> mmol) was added DIEA (<NUM>µL, <NUM> mmol). The mixture was stirred for <NUM> minutes and then purified by reverse phase HPLC using a gradient of <NUM>% to <NUM>% ACN in H<NUM>O to give the title compound as a yellow solid (<NUM>, <NUM>% yield). MS (ESI) m/z <NUM> (M+H)+.

Compound <NUM> was prepared in an analogous manner to compound <NUM> in example <NUM> with <NUM>-(<NUM>-(<NUM>-((<NUM>-(<NUM>,<NUM>-dioxopiperidin-<NUM>-yl)-<NUM>,<NUM>-dioxoisoindolin-<NUM>-yl)amino)ethoxy)ethoxy)propanoic acid. MS (ESI) m/z <NUM> (M+H)+.

Compound <NUM> was prepared in an analogous manner to compound <NUM> in example <NUM> with <NUM>-((<NUM>-(<NUM>,<NUM>-dioxopiperidin-<NUM>-yl)-<NUM>,<NUM>-dioxoisoindolin-<NUM>-yl)amino)nonanoic acid. MS (ESI) m/z <NUM> (M+H)+.

To a stirred solution of <NUM>-(<NUM>-(<NUM>-cyano-<NUM>-ethyl-<NUM>,<NUM>-dimethyl-<NUM>-oxo-<NUM>,<NUM>-dihydro-<NUM>-benzo[b]carbazol-<NUM>-yl)-<NUM>-pyrazol-<NUM>-yl)acetic acid (<NUM>) (<NUM>, <NUM> mmol), <NUM>-((<NUM>,<NUM>,<NUM>,<NUM>-tetraoxa-<NUM>-azahexadecan-<NUM>-yl)amino)-<NUM>-(<NUM>,<NUM>-dioxopiperidin-<NUM>-yl)isoindoline-<NUM>,<NUM>-dione (<NUM>) (<NUM>, <NUM> mmol) and HATU (<NUM>, <NUM> mmol) was added DIEA (<NUM>µL, <NUM> mmol). The mixture was stirred for <NUM> minutes and then purified by reverse phase HPLC using a gradient of <NUM>% to <NUM>% ACN in H<NUM>O to give the title compound as a yellow solid (<NUM>, <NUM>% yield). MS (ESI) m/z <NUM>. <NUM> (M+H)+.

Compound <NUM> was prepared in an analogous manner to compound <NUM> in example <NUM> with <NUM>-((<NUM>-(<NUM>-(<NUM>-aminoethoxy)ethoxy)ethyl)amino)-<NUM>-(<NUM>,<NUM>-dioxopiperidin-<NUM>-yl)isoindoline-<NUM>,<NUM>-dione. MS (ESI) m/z <NUM> (M+H)+.

Compound <NUM> was prepared in an analogous manner to compound <NUM> in example <NUM> with <NUM>-((<NUM>-amino-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-hexaoxaicosyl)amino)-<NUM>-(<NUM>,<NUM>-dioxopiperidin-<NUM>-yl)isoindoline-<NUM>,<NUM>-dione. MS (ESI) m/z <NUM> (M+H)+.

Compound <NUM> was prepared in an analogous manner to compound <NUM> in example <NUM> with <NUM>-((<NUM>-amino-<NUM>,<NUM>,<NUM>,<NUM>-tetraoxatetradecyl)amino)-<NUM>-(<NUM>,<NUM>-dioxopiperidin-<NUM>-yl) isoindoline-<NUM>,<NUM>-dione. MS (ESI) m/z <NUM> (M+H)+.

Compound <NUM> was prepared in an analogous manner to compound <NUM> in example <NUM> with <NUM>-((<NUM>, <NUM>,<NUM>-trioxa-<NUM>-azatridecan-<NUM>-yl)amino)-<NUM>-(<NUM>,<NUM>-dioxopiperidin-<NUM>-yl)isoindoline-<NUM>,<NUM>-dione. MS (ESI) m/z <NUM> (M+H)+.

Compound <NUM> was prepared according to the procedure described in <NPL>).

Compound <NUM> was prepared in an analogous manner to compound <NUM> in example <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br, <NUM>), <NUM> (s, <NUM>), <NUM> (br, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>). MS (ESI) m/z <NUM> (M+H)+.

SM-<NUM> was prepared according to <NPL>). To SM-<NUM> (<NUM>, <NUM> mmol) and glycine tert-butyl ester (<NUM>, <NUM> mmol) in anhydrous DMSO (<NUM>) was added N,N-diisopropylethylamine (DIEA) (<NUM>µL, <NUM> mmol). The reaction mixture was stirred under <NUM> for <NUM> day, then cooled down. The mixture was diluted with ethyl acetate (<NUM>), washed with water and brine, dried with Na2SO4, then filtered and concentrated, purified by column chromatography (dichloromethane/ethyl acetate = <NUM>:<NUM>) to give the title compound as a yellow oil (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>). MS (ESI) m/z <NUM> (M+H)+.

TFA (<NUM>) was added to a solution of tert-Butyl (<NUM>-(<NUM>,<NUM>-Dioxopiperidin-<NUM>-yl)-<NUM>,<NUM>-dioxoisoindolin-<NUM>-yl)glycinate (<NUM>, <NUM> mmol) in dichloromethane (<NUM>). The mixture was stirred at rt overnight, then was concentrated and dried under vacuum to give the title compound as a yellow solid, which was used in next step without purification. MS (ESI) m/z <NUM> (M-H)-.

SM-<NUM> was prepared according to <NPL>). TFA (<NUM>µL, <NUM> mmol) was added to a solution of SM-<NUM> (<NUM>, <NUM> mmol) and tert-butyl <NUM>-(<NUM>-amino-<NUM>-methoxyphenyl)piperazine-<NUM>-carboxylate (<NUM>, <NUM> mmol) in sec-butanol (<NUM>), and the mixture was stirred overnight at <NUM>. The mixture was then concentrated and purified by column chromatography (dichloromethane/methanol = <NUM>:<NUM>) to give the title compound as a white solid (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>). MS (ESI) m/z <NUM> (M+H)+.

TFA was added (<NUM>) to a solution of tert-Butyl <NUM>-(<NUM>-((<NUM>-Chloro-<NUM>-((<NUM>(isopropylsulfonyl)phenyl)-amino)pyrimidin-2yl)amino)-<NUM>-methoxyphenyl)piperazine-<NUM>-carboxylate (<NUM>, <NUM> mmol) in dichloromethane (<NUM>), and the mixture was stirred at rt for <NUM>, then was concentrated and dried under vacuum. To the obtained crude intermediate in acetonitrile (<NUM>) were added commercially available Int-<NUM> (<NUM>, <NUM> mmol) and potassium carbonate (<NUM>, <NUM> mmol). The resulting mixture was stirred under <NUM> overnight, then cooled to rt and diluted with <NUM> of dichloromethane. The precipitated was filtered, and the filtrate was concentrated and purified by column chromatography (dichloromethane/methanol = <NUM>:<NUM>) to give the title compound as a colorless oil (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>). MS (ESI) m/z <NUM> (M+H)+.

Under a nitrogen atmosphere, triphenylphosphine (<NUM>, <NUM> mmol) was added to a solution of N<NUM>-(<NUM>-(<NUM>-(<NUM>-(<NUM>-(<NUM>-Azidoethoxy)ethoxy)ethyl)piperazin-<NUM>-yl)-<NUM>-methoxyphenyl)-<NUM>-chloro-N<NUM>-(<NUM>-(isopropylsulfonyl)phenyl)-pyrimidine-<NUM>,<NUM>-diamine (<NUM>, <NUM> mmol) in tetrahydrofuran (<NUM>) and water (<NUM>). The reaction mixture was stirred overnight, then concentrated and dried under vacuum. To the obtained crude oil in anhydrous dichloromethane (<NUM>) were added (<NUM>-(<NUM>,<NUM>-Dioxopiperidin-<NUM>-yl)-<NUM>,<NUM>-dioxoisoindolin-<NUM>-yl)glycine (<NUM>, <NUM> mmol) and (<NUM>-[bis(dimethylamino)methylene]-<NUM>-<NUM>,<NUM>,<NUM>-triazolo[<NUM>,<NUM>-b]pyridinium <NUM>-oxide hexafluorophosphate) (HATU) and DIEA (<NUM>µL, <NUM> mmol). The reaction mixture was stirred for <NUM>, then concentrated and purified by column chromatography (dichloromethane/methanol = <NUM>:<NUM>) to give the title compound a yellow foam (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (br, <NUM>), <NUM> (s, <NUM>), <NUM> (br, <NUM>), <NUM> (H, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM>- <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>). MS (ESI) m/z <NUM> (M+H)+.

Compound <NUM> was prepared in an analogous manner to compound <NUM> in example <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>). MS (ESI) m/z <NUM> (M+H)+.

Compound <NUM> was prepared in an analogous manner to compound <NUM> in example <NUM>. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (br, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (m, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>). MS (ESI) m/z <NUM> (M+H)+.

To a solution of ethyl <NUM>-amino-<NUM>-pyrazole-<NUM>-carboxylate (<NUM>, <NUM> mmol) in DMF (<NUM>) was added ethyl (E)-<NUM>-ethoxyacrylate (<NUM>, <NUM> mmol) and the reaction mixture was stirred at <NUM> for <NUM>. The reaction mixture was diluted with water, adjusted pH to <NUM> with <NUM> N HCl aqueous. The mixture was filtrated and the residue was washed with water and ethyl acetate and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (<NUM>, <NUM> %), which used in next step without further purification. <NUM>H NMR (<NUM>, CDCl<NUM>): δ, <NUM> (t, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (brs, <NUM>). ESI-MS (EI+, m/z): <NUM>.

The mixture of ethyl <NUM>-oxo-<NUM>,<NUM>-dihydropyrazolo[<NUM>,<NUM>-a]pyrimidine-<NUM>-carboxylate (<NUM>, <NUM> mmol) in POCl<NUM> (<NUM>) was stirred at <NUM> for <NUM> hours. The mixture was cooled to room temperature (RT) and concentrated, and the residue was diluted in a mixture of saturated NaHCO<NUM> solution (<NUM>) and DCM (<NUM>). The mixture was extracted with DCM twice, the combined organic phases were washed with water and brine, dried with Na<NUM>SO<NUM> and concentrated to afford the title compound as a gray solid (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ, <NUM> (t, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>). ESI-MS (EI+, m/z): <NUM>. <CHM>
<CHM>
<CHM>
<CHM>.

To a solution of <NUM>-hydroxybenzaldehyde (<NUM>, <NUM> mmol) and (R)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) in DCM (<NUM>) was added Cs<NUM>CO<NUM> (<NUM>, <NUM> mmol). After being stirred at room temperature overnight, the mixture was quenched with water at <NUM> and extracted with ethyl acetate x <NUM>, the combined organic phases were dried with Na<NUM>SO<NUM> and concentrated. The residue was purified by column chromatography eluted with DCM/MeOH = <NUM>/<NUM> to afford the title compound as a white solid (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). ESI-MS (EI+, m/z): <NUM>.

To a solution of (R)-N-(<NUM>-Fluoro-<NUM>-hydroxybenzylidene)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) in THF (<NUM>) was added MeMgBr (<NUM> in <NUM>-methy-THF, <NUM>, <NUM> mmol) at -<NUM> under nitrogen. After stirring at room temperature overnight, the mixture was quenched with water at <NUM>, and the mixture was extracted with EtOAc x <NUM>. The combined organic phases was dried and concentrated, and the residue was purified by column chromatography eluted with Pet. ether/ ethyl acetate = <NUM>/<NUM> to afford the title compound as a light yellow solid (<NUM>, <NUM>%) and the S-enantiomer as a light yellow solid (<NUM>, <NUM>%). (R)-enantiomer: <NUM>H NMR (<NUM>, DMSO-d<NUM>): δ1. <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (quint, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>). ESI-MS (EI+, m/z): <NUM>. (S)-enantiomer: <NUM>H NMR (<NUM>, DMSO-d<NUM>): δ1. <NUM> (s, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (quint, J=<NUM>, <NUM>), <NUM> (dd, J=<NUM>, <NUM>, <NUM>), <NUM> (dt, J=<NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>).

To the solid of (R)-N-((R)-<NUM>-(<NUM>-Fluoro-<NUM>-hydroxyphenyl)ethyl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) was added HCl/Dioxane (<NUM> in dioxane, <NUM>). After stirring at room temperature for <NUM>, the reaction mixture was concentrated to give the title compound as the HCl salt as a while solid (<NUM>, <NUM>%), which was used directly in the next step without further purification. ESI-MS (EI+, m/z): <NUM>.

To a solution of (R)-<NUM>-(<NUM>-Aminoethyl)-<NUM>-fluorophenol hydrochloride (<NUM>, <NUM> mmol) and DIEA (<NUM>, <NUM> mmol) in n-BuOH (<NUM>) was added ethyl <NUM>-chloropyrazolo[<NUM>,<NUM>-a]pyrimidine-<NUM>-carboxylate (<NUM>, <NUM> mmol). After stirring at <NUM> overnight, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried with Na<NUM>SO<NUM> and concentrated, and the residue was purified by column chromatography eluted with DCM/MeOH = <NUM>/<NUM> to afford the title compound as a yellow solid (<NUM>, <NUM>%). <NUM>H NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (brs, <NUM>). ESI-MS (EI+, m/z): <NUM>.

A solution of ethyl (R)-<NUM>-((<NUM>-(<NUM>-fluoro-<NUM>-hydroxyphenyl)ethyl)amino)pyrazolo[<NUM>,<NUM>-a]pyrimidine-<NUM>-carboxylate (<NUM>, <NUM> mmol), tert-butyl (R)-(<NUM>-hydroxypropyl)carbamate (<NUM>, <NUM> mmol) and PPh<NUM> (<NUM>, <NUM> mmol) in THF (<NUM>) was stirred in ice bath (~<NUM>). After dropwise addition of DIAD (<NUM>, <NUM> mmol), the reaction mixture was stirred in an ice bath for <NUM> and the mixture was partitioned between ethyl acetate and water. The combined organic phases were washed with water and brine, dried over Na<NUM>SO<NUM> and concentrated. The crude product was purified by column chromatography eluted with hexanes/ethyl acetate = <NUM>/<NUM> to afford the title compound as a yellow solid (<NUM>, <NUM> %). ESI-MS (EI+, m/z): <NUM>.

To a mixture of ethyl <NUM>-(((R)-<NUM>-(<NUM>-(((R)-<NUM>-((tert-butoxycarbonyl)amino)propan-<NUM>-yl)oxy)-<NUM>-fluorophenyl)ethyl)amino)pyrazolo[<NUM>,<NUM>-a]pyrimidine-<NUM>-carboxylate (<NUM>, <NUM> mmol) in DCM (<NUM>) was added TFA (<NUM>) and the mixture was stirred at room temperature for <NUM>. The mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The combined organic phases were washed with water and brine, dried over Na<NUM>SO<NUM> and concentrated obtain the title compound as a yellow solid (<NUM>, <NUM> %), which was used without further purification. ESI-MS (EI+, m/z): <NUM>.

A solution of ethyl <NUM>-(((R)-<NUM>-(<NUM>-(((R)-<NUM>-aminopropan-<NUM>-yl)oxy)-<NUM>-fluorophenyl)ethyl)amino)pyrazolo[<NUM>,<NUM>-a]pyrimidine-<NUM>-carboxylate TFA salt (<NUM>, <NUM> mmol) and tert-butyl methyl(<NUM>-oxoethyl)carbamate (<NUM>, <NUM> mmol) in MeOH (<NUM>) was stirred at RT. After addition of NaBH<NUM>CN (<NUM>, <NUM> mmol), the reaction mixture was stirred in an ice bath for <NUM>. The mixture was partitioned between ethyl acetate and water and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over Na<NUM>SO<NUM> and concentrated. The crude product was purified by column chromatography eluted with DCM/MeOH = <NUM>/<NUM> to afford the title compound as a yellow solid (<NUM>, <NUM> %). ESI-MS (EI+, m/z): <NUM>.

A solution of NaOH aqueous (<NUM> N, <NUM>) was added to a mixture of ethyl <NUM>-(((R)-<NUM>-(<NUM>-(((R)-<NUM>-((<NUM>-((tert-butoxycarbonyl)(methyl)amino)ethyl)amino)propan-<NUM>-yl)oxy)-<NUM>-fluorophenyl)ethyl)amino)pyrazolo[<NUM>,<NUM>-a]pyrimidine-<NUM>-carboxylate (<NUM>, <NUM> mmol) in EtOH (<NUM>) and the resulting mixture was stirred at <NUM> for <NUM>. The mixture was concentrated and the residue was diluted with water (<NUM>). The mixture was adjusted pH to <NUM> and filtered, the solid was dried to afford the title compound as yellow solid (<NUM>, <NUM> %). ESI-MS (EI+, m/z): <NUM>.

The solution of <NUM>-(((R)-<NUM>-(<NUM>-(((R)-<NUM>-((<NUM>-((tert-butoxycarbonyl)(methyl)amino)ethyl)amino)propan-<NUM>-yl)oxy)-<NUM>-fluorophenyl)ethyl)amino)pyrazolo[<NUM>,<NUM>-a]pyrimidine-<NUM>-carboxylic acid (<NUM>, <NUM> mmol) and DIEA (<NUM>, <NUM> mmol) in DMF (<NUM>) and DCM (<NUM>) was stirred at RT. After addition of FDPP (<NUM>, <NUM> mmol), the reaction mixture was stirred at room temperature for <NUM>. The mixture was partitioned between ethyl acetate and water. The combined organic phases were washed with water and brine, dried over Na<NUM>SO<NUM> and concentrated. The crude product was purified by column chromatography eluted with PE/EA = <NUM>/<NUM> to afford the title compound as a white solid (<NUM>, <NUM> %). ESI-MS (EI+, m/z): <NUM>.

To a mixture of tert-Butyl (<NUM>-((<NUM><NUM>E,<NUM><NUM>E,<NUM>R,<NUM>S)-<NUM><NUM>-fluoro-<NUM>,<NUM>-dimethyl-<NUM>-oxo-<NUM>-oxa-<NUM>,<NUM>-diaza-<NUM>(<NUM>,<NUM>)-pyrazolo[<NUM>,<NUM>-a]pyrimidina-<NUM>(<NUM>,<NUM>)-benzenacyclononaphane-<NUM>-yl)ethyl)(methyl)carbamate (<NUM>, <NUM> mmol) in DCM (<NUM>) was treated with TFA (<NUM>) and the mixture was stirred at room temperature for <NUM>. The mixture was concentrated to give the title compound as a yellow solid (<NUM>, <NUM>%), which was used in the next step without further purification. ESI-MS (EI+, m/z): <NUM>.

A solution of ethyl (<NUM><NUM>E,<NUM><NUM>E,<NUM>R,<NUM>S)-<NUM><NUM>-fluoro-<NUM>,<NUM>-dimethyl-<NUM>-(<NUM>-(methylamino)ethyl)-<NUM>-oxa-<NUM>,<NUM>-diaza-<NUM>(<NUM>,<NUM>)-pyrazolo[<NUM>,<NUM>-a]pyrimidina-<NUM>(<NUM>,<NUM>)-benzenacyclononaphan-<NUM>-one (TFA salt) (<NUM>, <NUM> mmol) and <NUM>-((<NUM>-(<NUM>,<NUM>-dioxopiperidin-<NUM>-yl)-<NUM>,<NUM>-dioxoisoindolin-<NUM>-yl)amino)butanoic acid (<NUM>, <NUM> mmol) in DMF (<NUM>) was stirred at RT. After the addition of HATU (<NUM>, <NUM> mmol), the reaction mixture was stirred at room temperature for <NUM>. The mixture was partitioned between ethyl acetate and water. The combined organic phase was washed with water and brine, dried over Na<NUM>SO<NUM> and concentrated. The crude product was purified by prep-HPLC with ACN/water = <NUM>/<NUM> to afford the title compound as a yellow solid (<NUM>, <NUM> %). <NUM>H NMR (<NUM>, DMSO-d<NUM>): δ <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (s, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). ESI-MS (EI+, m/z): <NUM>.

CellTiter-Glo®: Cell viability was evaluated using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega™) following the manufacturer's standards. <NUM>-point dose titrations were tested in triplicate from <NUM> to <NUM> over <NUM> hours. Anti-proliferative best fit EC<NUM> values with <NUM>% CI are shown as calculated by Graphpad Prism™ <NUM> software.

As shown in <FIG>, compounds <NUM> and <NUM>, with PEG linkers, displayed anti-proliferative activity in H3122 cells that is comparable to compound <NUM>. Compound <NUM>, with a carbon linker, displayed <NUM>-fold lower activity than compound <NUM>. Additionally, compounds <NUM> and <NUM>, with PEG linkers, showed activity against EML4-ALK with secondary mutations L1196M, C1156Y, or G1202R that is comparable to the parental inhibitor alectinib.

Blotting: Cells were washed with PBS before being lysed with Cell Lysis Buffer (Cell Signaling Technology®) supplemented with protease and phosphatase inhibitor cocktails (Roche™) at <NUM> for <NUM> minutes. The cell lysate was vortexed every <NUM> minutes over a <NUM>-minute period before being centrifuged at <NUM>,<NUM> x g for <NUM> at <NUM>. Protein in cell lysate was quantified by BCA assay (Pierce™). Primary antibodies used in this study include ALK (Cell Signaling Technology®, D5F3), Aurora A (Cell Signaling Technology®, 1F8), FAK (PTK2) (Cell Signaling Technology®, #<NUM>), and GAPDH (Cell Signaling Technology®, 14C10). Blot quantification was performed using Image Studio™ <NUM> software, normalizing to loading control (GAPDH).

As shown in <FIG>, compounds <NUM> and <NUM>, with PEG linkers, displayed the ability to degrade ALK in a dose dependent manner in H3122 cells after <NUM>-hour treatments. Off target degradation of Aurora A was also seen. Notably, off target degradation of PTK2 was very low, unlike the previously reported compounds <NUM> and <NUM>. Compound <NUM>, with a carbon linker, induced only minimal ALK degradation; this complements the differences in anti-proliferative activity seen with compounds <NUM>-<NUM> in EML4-ALK expressing cell lines (<FIG>).

<FIG> shows a time course in H3122 cells with <NUM> doses of the compounds <NUM>-<NUM>, compound <NUM>, and alectinib. Compounds <NUM>-<NUM> were able to degrade ALK around <NUM> hours with maximum degradation seen around <NUM> hours. Compound <NUM> was also able to degrade ALK around <NUM> hours with maximum degradation seen around <NUM> hours. <FIG> confirms that compounds <NUM>-<NUM> lost the off target degradation activity against PTK2 that was seen with compound <NUM>, but maintained the off target degradation of Aurora A.

The experimental protocol was as in Example <NUM>.

<FIG> shows the anti-proliferative activity of compounds <NUM>-<NUM> in EMI,<NUM>-ALK expressing cell lines. Although some anti-proliferative effects were seen with these compounds, their activity was less than that of the previous ALK degrader compound <NUM> by an order of magnitude.

In <FIG> shows ALK and aurora A degradation in H3122 cells after <NUM> hour treatments with compounds <NUM>-<NUM>. Only the compound with the longest linker, compound <NUM>, demonstrated significant degradation of ALK. Compound <NUM> and <NUM> did not degrade ALK to a significant extent. This data complements the anti-proliferative activity seen in <FIG>, where compounds <NUM>-<NUM> showed low anti-proliferative effects compared to previous ALK degraders, with compound <NUM> showing slightly better activity than the other members of this group. Compounds <NUM>-<NUM> still induced off target degradation of aurora A.

Compound <NUM> has the same warhead as compounds <NUM>-<NUM> for engaging ALK and CRBN. However, compounds <NUM>-<NUM> have an N-H amide that could form an intramolecular hydrogen bond with the pyrazole, which could change the trajectory of the warhead. Compound <NUM> has an N-methyl amide, instead of the N-H amide, with the goal of improving on the activities of compound <NUM>-<NUM> by preventing the intramolecular hydrogen bond with the pyrazole. However, the anti-proliferative activity as seen in <FIG> showed that compound <NUM> has similar activity as compound <NUM> and has lower anti-proliferative activity than compound <NUM> and compound <NUM> in EMI,<NUM>-ALK expressing cells.

In <FIG> the degradation of ALK, aurora A, and PTK2 is shown after <NUM>- hour treatments with compound <NUM> in H3122 cells. Similar to compounds <NUM>-<NUM>, no ALK degradation was seen with this compound, but off target degradation of aurora A was still seen at higher doses. Some slight degradation of PTK2 was also seen a <NUM> of compound <NUM>.

Claim 1:
A compound of formula (I),
<CHM>
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein the ALK targeting ligand has a structure represented by formula (TL-1b)
<CHM>
wherein R<NUM> = H or Me;
wherein the linker is an alkylene chain or polyethylene glycol chain, either of which may be interrupted by, and/or terminate (at either or both termini) in at least one of - O-, -S-, -N(R')-, -C≡C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-, -C(O)N(R')C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)O-, -S(O)<NUM>-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)<NUM>-, -S(O)<NUM>O-, -N(R')S(O)<NUM>-, -S(O)<NUM>N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O)<NUM>N(R')-, -N(R')S(O)N(R')-, C<NUM>-C<NUM> carbocyclene, <NUM>- to <NUM>-membered heterocyclene, <NUM>- to <NUM>-membered heteroarylene or any combination thereof, wherein R' is H or C<NUM>-C<NUM> alkyl, wherein the interrupting and the one or both terminating groups may be the same or different; and
wherein the degron has a structure represented by any one of formulas D1a-q:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
and
<CHM>
wherein X is alkyl, halo, CN, CF<NUM>, OCHF<NUM> or OCF<NUM> or
the compound which is
<CHM>
or a pharmaceutically acceptable salt or stereoisomer thereof.