The present application provides compounds of Formula I and/or Formula Γ (Formula Ι/Γ)

Formula I Formula Γ or a salt thereof, wherein:

R ¹ and R ² are each independently selected from H, Ci_ ₆ alkyl optionally substituted with 1- 6 R ⁵ , Ci_ ₆ OR ⁴ optionally substituted with 1-6 R ⁵ , Ci_ ₆ (= O) Ci_ ₆ alkyl optionally substituted with 1-6 R ⁵ , Ci_ ₆ (= O) R ⁶ , or 4-15 membered heterocycloalkyl optionally substituted with 1-6 R ⁵ ; or R ^J and R ² are taken together to form a 5-15 membered heterocycloalkyl optionally substituted with 1-6 R ⁵ ;

Ring A is phenyl, a 6-7 membered cycloalkyl, or pyridinyl;

R ³ is Co-eOR ⁴ , S(0 ₂ )N(R ⁴ ) ₂ , S(0 ₂ )R ⁶ , C(=0)N(R ⁴ ) ₂ , NR ⁴ S(0 ₂ )R ⁴ , 5-15 membered heteroaryl optionally substituted with 1-6 R ⁵ , 4-15 membered heterocycloalkyl optionally substituted with 1 -6 R ⁵ , C ₀ _ ₆ OR ⁴ , halo, or P(=0)(R ⁴ ) ₂ ;

R ⁴ is H or Ci_ ₆ alkyl;

R ⁵ is Ci_ ₆ alkyl , C ₀ _ ₆ OR ⁴ , NR ⁴ R ⁴ , 5-15 membered heteroaryl, halo, or (=0); R ⁶ is 5-15 membered heteroaryl optionally substituted with 1-6 R ⁵ ; and "n" is an integer between 1-5; with the proviso that the compound is not

(2-[[5-chloro-2-[[(6S)-6-[4-(2-hydroxyethyl)piperazin-l-yl]- l-methoxy-6,7,8,9- tetrahydro-5H-benzo [7]annulen-2-yl] amino]pyrimidin-4-yl] amino] -N-methyl- benzamide).

Compounds of formula Ι/Γ have ALK and/or FAK inhibitory activity and may be used to treat disorders or conditions characterized by aberrant ALK and/or FAK activity in mammals, including humans.

The present application further provides pharmaceutical compositions comprising at least one compound of formula I/I' together with at least one pharmaceutically acceptable excipient.

BACKGROUND

Anaplastic Lymphoma Kinase (ALK) is a cell membrane-spanning receptor tyrosine kinase, which belongs to the insulin receptor subfamily. The most abundant expression of ALK occurs in the neonatal brain, suggesting a possible role for ALK in brain development (Duyster, J. et al, Oncogene, 2001, 20, 5623-5637).

ALK is also implicated in the progression of certain tumors. For example, approximately sixty percent of anaplastic large cell lymphomas (ALCL) are associated with a chromosome mutation that generates a fusion protein consisting of nucleophosmin (NPM) and the intracellular domain of ALK. (Armitage, J.O. et al., Cancer: Principle and Practice of Oncology, 6 ^th edition, 2001, 2256-2316; Kutok J.L. & Aster J.C., J. Clin. Oncol, 2002, 20, 3691-3702). This mutant protein, NPM- ALK, possesses a constitutively active tyrosine kinase domain that is responsible for its oncogenic property through activation of downstream effectors. (Falini, B. et al, Blood, 1999, 94, 3509-3515; Morris, S.W. et al, Brit. J. Haematol, 2001, 113, 275-295; Duyster et al; Kutok & Aster). In addition, the transforming EML4-ALK fusion gene has been identified in non-small-cell lung cancer (NSCLC) patients (Soda, M., et al, Nature, 2007, 448, 561 - 566) and represents another in a list of ALK fusion proteins that are promising targets for ALK inhibitor therapy. Experimental data have demonstrated that the aberrant expression of constitutively active ALK is directly implicated in the pathogenesis of ALCL and that inhibition of ALK can markedly impair the growth of ALK+ lymphoma cells (Kuefer, Mu et al. Blood, 1997, 90, 2901-2910; Bai, R.Y. et al, Mol. Cell Biol, 1998, 18, 6951-6961; Bai, R.Y. et al, Blood, 2000, 96, 4319-4327; Ergin, M. et al, Exp. Hematol., 2001, 29, 1082-1090; Slupianek, A. et al, Cancer Res., 2001, 61, 2194-2199; Turturro, F. et al, Clin. Cancer Res., 2002, 8, 240-245). The constitutively activated chimeric ALK has also been demonstrated in about 60% of inflammatory myofibroblastic tumors (IMTs), a slow- growing sarcoma that mainly affects children and young adults. (Lawrence, B. et al., Am. J. Pathol, 2000, 157, 377-384; Duyster et al). In addition, ALK and its putative ligand, pleiotrophin, are overexpressed in human glioblastomas (Stoica, G. et al, J. Biol. Chem., 2001, 276, 16772-16779). In mouse studies, depletion of ALK reduced glioblastoma tumor growth and prolonged animal survival (Powers, C. et al, J. Biol. Chem., 2002, 277, 14153-14158; Mentlein, R. et al, J. Neurochem., 2002, 83, 747-753). An ALK inhibitor would be expected to either permit durable cures when combined with current chemotherapy for ALCL, IMT, proliferative disorders, glioblastoma and possible other solid tumors, or, as a single therapeutic agent, could be used in a maintenance role to prevent cancer recurrence in those patients. Various ALK inhibitors have been reported, such as indazoloisoquino lines (WO 2005/009389), thiazole amides and oxazole amides (WO 2005/097765), pyrrolopyrimidines (WO 2005080393), and pyrimidinediamines (WO 2005/016894).

Focal adhesion kinase (FAK) is an evolutionarily conserved non-receptor tyrosine kinase localized at focal adhesions, sites of cellular contact with the ECM (extra-cellular matrix) that functions as a critical transducer of signaling from integrin receptors and multiple receptor tyrosine kinases, including EGF-R, HER2, IGF-R1, PDGF-R and VEGF-R2 and TIE-2 (Parsons, JT; Slack-Davis, J; Tilghman, R; Roberts, WG. Focal adhesion kinase: targeting adhesion signaling pathways for therapeutic intervention. Clin. Cancer Res., 2008, 14, 627-632; Kyu-Ho Han, E; McGonigal, T. Role of focal adhesion kinase in human cancer - a potential target for drug discovery. Anti-cancer Agents Med. Chem., 2007, 7, 681-684). The integrin-activated FAK forms a binary complex with Src which can phosphorylate other substrates and trigger multiple signaling pathways. Given the central role of FAK binding and phosphorylation in mediating signal transduction with multiple SH2- and SH3- domain effector proteins (Mitra, SK; Hanson, DA; Schlaeper, DD. Focal adhesion kinase: in command and control of cell motility. Nature Rev. Mol. Cell Biol, 2005, 6, 56-68), activated FAK plays a central role in mediating cell adhesion, migration, morphogenesis, proliferation and survival in normal and malignant cells (Mitra et al. 2005; McLean, GW; Carragher, NO; Avizzienyte, E; et al. The role of focal adhesion kinase in cancer - a new therapeutic opportunity. Nature Reviews Cancer, 2005, 5, 505-515; and Kyu-Ho Han and McGonigal, 2007). In tumors, FAK activation mediates anchorage-independent cell survival, one of the hallmarks of cancer cells. Moreover, FAK over expression and activation appear to be associated with an enhanced invasive and metastatic phenotype and tumor angiogenesis in these malignancies (Owens, LV; Xu, L; Craven, RJ; et al. Over expression of the focal adhesion kinase (pi 25 FAK) in invasive human tumors. Cancer Res., 1995, 55, 2752-2755; Tremblay, L; Hauck, W. Focal adhesion kinase (ppl25FAK) expression, activation and association with paxillin and p50CSK in human metastatic prostate carcinoma. Int. J. Cancer, 1996, 68, 164-171; Kornberg, IJ. Focal adhesion kinase in oral cancers. Head and Neck, 1998, 20: 634-639; Mc Clean et al 2005; Kyu-Ho Han and McGonigal, 2007) and correlated with poor prognosis and shorter metastasis-free survival.

Multiple proof-of-concept studies conducted in various solid tumors using siRNA (Haider, J; Kamat ,AA; Landen, CN; et al. Focal adhesion kinase targeting using in vivo short interfering RNA delivery in neutral liposomes for ovarian carcinoma therapy. Clin. Cancer Res., 2006, 12, 4916-4924), dominant-negative FAK, and small molecule FAK inhibitors (Haider, J; Lin, YG; Merritt, WM; et al. Therapeutic efficacy of a novel focal adhesion kinase inhibitor, TAE226 in ovarian carcinoma. Cancer Res., 2007, 67, 10976- 10983; Roberts, WG; Ung, E; Whalen, P; et al. Anti-tumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res., 2008, 68, 1935-1944; Bagi CM; Roberts GW; and Andersen CJ. Dual focal adhesion kinse/Pyk2 inhibitor has positive effects on bone tumors - implications for bone metastases. Cancer, 2008, 112, 2313-2321) have provided pre-clinical support for the therapeutic utility of FAK inhibition as an anti-tumor/anti-angiogenic strategy, particularly for androgen-independent prostate cancers, breast cancers, and FiNSCCs. In preclinical models of human breast cancer (MDA-MB-231) in nude rats, administration of a small molecule FAK inhibitor (PF- 562,271) inhibited primary tumor growth and intra-tibial tumor spread, and restored tumor-induced bone loss (Bagi et al, 2008). Roberts et al, (2008) showed that PF-562,271 inhibited bone metastases, prevented bone resorption, and increased osteogenesis in breast and androgen-independent prostate cancer patients with and without bone metastases, supporting an additional benefit of FAK inhibition in these specific malignancies.

In summary, there is clear genetic and biological evidence that links aberrant ALK activation and constitutive activation of FAK with the onset and progression of certain types of cancer in humans. Considerable evidence indicates that ALK- and FAK-positive tumor cells require these oncogenes to proliferate and survive, and in the case of FAK, to invade and metastasize to distant sites, while inhibition of both ALK and FAK signaling leads to tumor cell growth arrest or apoptosis, resulting in objective cytoreductive effects. Inhibition of FAK also results in attenuation of tumor motility, invasiveness, and metastatic spread, particularly in specific cancers characterized by bone metastatic dissemination and osteolytic disease. FAK activation protects tumor cells from chemotherapy-induced apoptosis, contributing to tumor resistance; modulation of FAK activity (by siRNA or pharmacologically) potentiates efficacy of chemotherapeutic agents in vivo (e.g., doxorubicin, docetaxel and gemcitabine), suggesting the utility for rational combination therapies in specific cancers. ALK and FAK are minimally expressed in most normal tissues in the healthy adult and are activated and/or dysregulated in specific cancers during oncogenesis and/or during early stages of malignant progression. Consequently, the on-target effects of treatment with a dual ALK and FAK inhibitor against normal cells should be minimal, creating a favorable therapeutic index.

WO 2008/051547 discloses fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors. The lead drug candidate disclosed in the '547 application is CEP-28122. This compound is a potent ALK inhibitor with oral efficacy against SUP-M2 and Karpas-299 ALK-dependent tumors in mouse xenograft models. CEP-28122 had progressed to IND-enabling studies until its development was terminated due to the unexpected occurrence of severe lung toxicity in CEP-28122-treated monkeys. The structure of CEP-28122 is shown below.

DETAILED DESCRIPTION

The following provides additional non-limiting details of the compounds described or disclosed herein, including compounds of the general Formula Ι/Γ, subgenuses and various species and/or embodiments of compounds of the general Formula Ι/Γ, intermediates, and other compounds of interest. The section titles used herein are for indexing and search purposes only and should not be construed as limiting in any way.

In one aspect, this application provides and describes compounds of the general Formula Ι/Γ

Formula I Formula Γ or a salt thereof, wherein:

R ¹ and R ² are each independently selected from H, Ci_ ₆ alkyl optionally substituted with 1- 6 R ⁵ , Ci_ ₆ OR ⁴ optionally substituted with 1-6 R ⁵ , Ci_ ₆ (= O) Ci_ ₆ alkyl optionally substituted with 1 -6 R ⁵ , Ci_ ₆ (= O) R ⁶ , or 4-15 membered heterocycloalkyl optionally substituted with 1-6 R ⁵ ; or R ¹ and R ² are taken together to form a 4-15 membered heterocycloalkyl optionally substituted with 1-6 R ⁵ ; Ring A is phenyl, a 6-7 membered cycloalkyl, or pyridinyl;

R ³ is Co- ₆ OR ⁴ , S(0 ₂ )N(R ⁴ ) ₂ , S(0 ₂ )R ⁶ , C(=0)N(R ⁴ ) ₂ , NR ⁴ S(0 ₂ )R ⁴ , 5-15 membered heteroaryl optionally substituted with 1-6 R ⁵ , 4-15 membered heterocycloalkyl optionally substituted with 1-6 R ⁵ , C ₀ _ ₆ OR ⁴ , halo, or P(=0)(R ⁴ ) ₂ ; R ⁴ is H or Ci_ ₆ alkyl;

R ⁵ is Ci_ ₆ alkyl , C ₀ _ ₆ OR ⁴ , NR ⁴ R ⁴ , 5-15 membered heteroaryl, halo, or (=0); R ⁶ is 5-15 membered heteroaryl optionally substituted with 1-6 R ⁵ ; and "n" is an integer between 1-5; with the proviso that the compound is not

(2-[[5-chloro-2-[[(6S)-6-[4-(2-hydroxyethyl)piperazin-l-y l]-l-methoxy-6,7,8,9- tetrahydro-5H-benzo [7]annulen-2-yl] amino]pyrimidin-4-yl] amino] -N-methyl- benzamide).

Definitions

The compounds and intermediates described herein may be named according to either the IUPAC (International Union for Pure and Applied Chemistry) or CAS (Chemical Abstracts Service) nomenclature systems. It should be understood that unless expressly stated to the contrary, "compounds of the general Formula I/I'" and "compounds of Formula I/I'" refer to and include any and all compounds described by and/or with reference to Formula I/I', inclusive, and all salts thereof.

The various carbon-containing moieties described herein may be described using a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e. "C _a -b". For example, C _a -balkyl indicates an alkyl moiety of the integer "a" to the integer "b" carbon atoms, inclusive. Certain moieties may also be described according to the minimum and maximum number of members with or without specific reference to a particular atom or overall structure. For example, the terms "a to b-membered" or "having between a to b members" refer to a moiety having the integer "a" to the integer "b" number of atoms, inclusive.

As used herein by themselves or in conjunction with another term or terms, "alkyl" and "Ci- ₆ alkyl" refer to straight or branched hydrocarbon groups containing the requisite number of carbon atoms as described above. As used herein, alkyl groups may be optionally substituted. Representative examples of alkyl groups include, but are not limited to, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, etc.

As used herein by itself or in conjunction with another term or terms, "aromatic" refers to monocyclic and polycyclic ring systems containing 4n+2 pi electrons, where n is an integer. As used herein, aromatic refers to and includes ring systems that contain only carbon atoms (i.e. "aryl") as well as ring systems that contain at least one heteroatom selected from N, O or S (i.e. "heteroaromatic" or "heteroaryl"). As used herein, an aromatic ring system may be optionally substituted.

As used herein by itself or in conjunction with another term or terms, "aryl" refers to monocyclic and polycyclic aromatic hydrocarbon ring systems containing the requisite number of carbon atoms as described above, which may be optionally substituted. Representative examples include phenyl and napthyl, either of which may be optionally substituted.

As used herein by itself or in conjunction with another term or terms, "cycloalkyl" refers to monocyclic and polycyclic hydrocarbon ring systems containing the requisite number of carbon atoms as described above, which may be optionally substituted. Cycloalkyl refers to and includes ring systems that are fully saturated or contain at least one double bond, as well as multi-ring systems with fully saturated and/or aromatic portions, such as, for example, 1 ,2,3,4-tetrahydro-naphthalenyl. It should be understood that these terms further refer to and include bridged and/or fused polycyclic structures such as, for example, tetrahydro-5H-benzocycloheptenyl, bicyclo[3.2.1]octanyl, bicyclo[5.2.0]nonanyl, bicyclo[2.2.1]heptenyl and the like, as well as spirocyclic ring systems such as, for example, spiro[3.4]octanyl, spiro[3.5]nonyl and the like. Other representative examples of cycloalkyl groups include, but are not limited to, e.g., cyclopropyl, methylcyclopropyl, cyclobutyl, cyclobutenyl, isopropylcyclobutyl, cyclopentyl, 1,3-dimethylcyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, 2,3-dihydro-lH-inden-2-yl, norbornyl, decahydronaphthalenyl, etc. As used herein by themselves or in conjunction with another term or terms, "halo" and "halogen" include fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo).

As used herein by itself or in conjunction with another term or terms, "heterocycloalkyl" refers to monocyclic and polycyclic ring systems containing the requisite number of carbon atoms as described above and at least one heteroatom selected from P, N, O, or S and may be optionally substituted. These terms further refer to and include ring systems that are fully saturated or contain at least one double bond, as well as ring systems with fully saturated, aromatic and/or non-aromatic portions, such as for example, 1,2,3,4- tetrahydroquinolinyl. It should be understood that polycyclic heterocycloalkyl groups further include fused, bridged and spirocyclic ring systems and ring systems in which the P, N or S is oxidized, such as for example, i.e., 1,1-dioxide-thiomorpholinyl (1,1- dioxidothiomorpholinyl), 1-oxo-piperidinyl or 4-oxo-azaphosphinanyl. Representative examples of heterocycloalkyl groups include, but are not limited to, e.g., oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, tetrahydrothiopyranyl, thiopyranyl, piperidinyl, 1 ,4-dioxanyl, 1,4-oxathianyl, morpholinyl, thiomorpholinyl, 1 ,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1 ,4-dioxepanyl, 1,4-oxathiepanyl, 1 ,4-oxaazepanyl, 1 ,4-dithiepanyl, 1,4-thieazepanyl, 1,4-azaphosphinanyl, 1,4- diazepanyl, 1 ,2-tetrahydrothiazin-2-yl, l,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, 1,2- tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-l-yl, tetrahydroazepinyl, chromanyl, chromenyl, isoxazolidinyl, l,3-oxazolidin-3-yl, isothiazolidinyl, l,3-thiazolidin-3-yl, 1 ,2-pyrazolidin-2- yl, 1,3-pyrazolidin-l-yl, 7-oxa-l-aza-spiro[4.4]nonanyl, 3-azabicyclo[3.1.0]hexanyl, indolinyl, octahydro-lH-indolyl, octahydro-2H-pyrido[l,2-a]pyrazinyl, 3- azabicyclo[4.1.0]heptanyl, 3,4-dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, 1,2,5,6- tetrahydropyridinyl, tetrahydro-lH-benzo[d]azepinyl, dihydro-lH-isoindolyl, etc.

As used herein by itself or in conjunction with another term or terms, "heteroaryl" refers to monocyclic and polycyclic aromatic ring systems containing the requisite number of carbon atoms, as described above, and at least one heteroatom selected from N, O, or S. As used herein, a heteroaromatic ring system refers to and includes polycyclic ring systems that contain aromatic portions, while other portions of the ring system may be fully saturated or non-aromatic. Heteroaromatic rings may be optionally substituted. Representative examples include, but are not limited to, e.g., pyrrolyl, furanyl, thiophenyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, tetrazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5- thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridinyl (pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[l]pyrindinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro- quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolinyl, quinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 2,3-dihydro-lH- isoindolyl, 1 ,3,4,5-tetrahydro-benzo[b]azepin-2-one, 1 ,3,4,5-Tetrahydro-benzo[d]azepin-2- one, 2,3,4,5-Tetrahydro-benzo[c]azepin-l-one, l,2,4,5-Tetrahydro-benzo[c]azepin-3-one, 2,3,4,5-Tetrahydro-lH-benzo[b]azepinyl, 2,3,4,5-Tetrahydro-lH-benzo[d]azepinyl, 2,3,4,5- Tetrahydro- lH-benzo[c]azepinyl, etc. As used herein by itself or in conjunction with another term or terms,

"pharmaceutically acceptable" indicates that the designated entity such as, for example, e.g. carrier, vehicle, diluent, excipient, or salt, is generally chemically and/or physically compatible with the other ingredients comprising a formulation and/or is generally physiologically compatible with the recipient thereof. As used herein by themselves or in conjunction with another term or terms,

"subject(s)" and "patient(s)", refer to mammals, including humans.

As used herein by itself or in conjunction with another term or terms, "substituted" indicates that a hydrogen atom on a molecule has been replaced with a different atom or group of atoms and the atom or group of atoms replacing the hydrogen atom may be referred to a "substituent." It should be understood that the terms "substituent", "substituents", "moiety", "moieties", "group", or "groups" refer to substituent(s) when used in conjunction with the phrase "...optionally substituted..." unless otherwise specified.

As used herein, "treating", "treated", and "treatment", whether used alone or in conjunction with another term or terms, include preventative (e.g., prophylactic), ameliorative, palliative, and curative uses and results, or any combination thereof. It should be understood that the terms "preventing" and "preventative" and "prophylactic" are not absolute but rather refer to uses and results where the administration of a compound or composition diminishes the likelihood or seriousness of a condition, symptom, or disease state, and/or delays the onset of a condition, symptom, or disease state for a period of time. In some embodiments, the terms "treating", "treated", and "treatment" refer to curative uses and results as well as uses and results that diminish or reduce the severity of a particular condition, symptom, disorder, or disease described herein.

As used herein, the terms "therapeutic" and "therapeutically effective amount", whether used alone or in conjunction with another term or terms, denote an amount of a compound, composition or medicament that (a) treats or prevents a particular disease, condition or disorder; (b) attenuates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder; (c) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein. It should be understood that the terms "therapeutic" and "therapeutically effective" encompass any one of the aforementioned effects (a)-(c), either alone or in combination with any of the others (a)-(c).

As used herein, a "therapeutically active agent", whether used alone or in conjunction with another term or terms, refers to any compound, i.e. a drug, that has been found to be useful in the treatment of a disease or disorder and is not described by Formula Ι/Γ. The compounds (including final products and intermediates) described herein may be isolated and used per se or may be isolated in the form of a salt. It should be understood that the terms "salt(s)" and "salt form(s)" used by themselves or in conjunction with another term or terms encompasses all inorganic and organic salts, including industrially acceptable salts, as defined herein, and pharmaceutically acceptable salts, as defined herein, unless otherwise specified. As used herein, industrially acceptable salts are salts that are generally suitable for manufacturing and/or processing (including purification) as well as for shipping and storage, but may not be salts that are typically administered for clinical or therapeutic use. Industrially acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more. Pharmaceutically acceptable salts, as used herein, are salts that are generally chemically and/or physically compatible with the other ingredients comprising a formulation, and/or are generally physiologically compatible with the recipient thereof. Pharmaceutically acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are typically administered or approved (by a regulatory authority such as FDA) for clinical or therapeutic use in humans. A practitioner of ordinary skill will readily appreciate that some salts are both industrially acceptable as well as pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of the application.

In general, salts of the present application can be prepared in situ during the isolation and/or purification of a compound (including intermediates), or by separately reacting the compound (or intermediate) with a suitable organic or inorganic acid or base (as appropriate) and isolating the salt thus formed. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised. In practice, the various salts may be precipitated (with or without the addition of one or more co-solvents and/or anti-solvents) and collected by filtration or the salts may be recovered by evaporation of solvent(s). Salts of the present application may also be formed via a "salt switch" or ion exchange/double displacement reaction, i.e. reaction in which one ion is replaced (wholly or in part) with another ion having the same charge. One skilled in the art will appreciate that the salts may be prepared and/or isolated using a single method or a combination of methods.

Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate and the like. Other examples of representative salts include alkali or alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine and the like.

Certain compounds of Formula I/I' may have one or more asymmetric centers and therefore can exist in a number of stereoisomeric configurations. Consequently, such compounds can be synthesized and/or isolated as mixtures of enantiomers and/or as individual (pure) enantiomers, as well as diastereomers and mixtures of different diastereomers. It should be understood that the present application includes all such enantiomers and diastereomers and mixtures thereof in all ratios. In practice, resolution and isolation of pure enantiomers can be achieved using methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, the specific stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation or inversion.

Compounds of Formula Ι/Γ that exist as diastereoisomers may be isolated by methods known to those skilled in the art, for example, by crystallization, gas-liquid or liquid chromatography. Alternatively, intermediates in the course of a synthesis that exist as racemic mixtures may be subjected to resolution by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation or inversion.

It should be understood that the terms "compounds of Formula I/I'", "compounds of the general Formula I and/or Formula Γ" or simply "compounds", whether used in isolation or in combination with another term or terms, encompass stereochemically undefined/unspecified compounds, individual stereoisomers, diastereomers, racemates, and all salts thereof, in substantially pure form and/or any mixtures of the foregoing in any ratio. This understanding extends to pharmaceutical compositions and methods of treatment that employ or comprise one or more compounds of the general Formula Ι/Γ, either by themselves or in combination with additional agents.

Compounds of the application may be administered as prodrugs. The term "prodrug" refers to a compound that is transformed in vivo to yield a compound of Formula I. The in vivo transformation may occur by various mechanisms, such as hydrolysis, in the blood or other biological fluids. A prodrug of a compound of Formula I may be formed in a conventional manner with one or more functional groups in the compound, such as an amino, hydroxyl or carboxyl group. For example, if a compound of Formula I contains a carboxylic acid functional group, a prodrug can comprise: (1) an ester formed by the replacement of a hydrogen of the acid group with a group such as (Ci-C ₆ )alkyl or (C ₆ -Cio) aryl; (2) an activated ester formed by the replacement of the hydrogen of the acid group with groups such as -(CR ₂ )COOR' , where CR ₂ is a spacer and R can be groups such as H or methyl and R' can be groups such as (Ci-C ₆ )alkyl or (C ₆ -Cio) aryl; and/or (3) a carbonate formed by the replacement of the hydrogen of the acid with groups such as CHROCOOR' where R can be groups such as H or methyl and R' can be groups such as (Ci-C ₆ )alkyl or (C ₆ - Cio)aryl. Similarly, if a compound of Formula I contains an alcohol functional group, a prodrug can be formed via the replacement of the hydrogen of the alcohol with groups such as (Ci-C ₆ )alkanoyloxymethyl or (Ci-Ce)alkanoyloxyaryl or by forming an ester via condensation with, for example, an amino acid. Where a compound of Formula I contains a primary or secondary amino group, a prodrug may comprise, for example, an amide formed by the replacement of one or both of the hydrogens of the amino group with (Ci- Cio)alkanoyl or (C ₆ -Cio)aroyl. Other prodrugs of amines are well known to those skilled in the art. Alternatively, certain compounds of Formula I may themselves act as prodrugs of other compounds of Formula I.

Discussions regarding prodrugs and their the use can be found in, for example, "Prodrugs as Novel Delivery Systems," T. Higuchi and W. Stella, Vol. 14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association). Further examples of replacement groups may be found in the aforementioned references.

Preparation and Examples In general, compounds of Formulas I and Γ may be prepared by the methods described in the General Synthesis, Schemes, and Experimental sections of the present application and/or by additional or alternative processes and procedures known in the chemical arts in combination with the knowledge of the skilled practitioner. It should be understood that the methods described herein are intended for illustrative purposes and are not to be construed as limiting the scope of the disclosure or claims. Alternative reagents, solvents, starting materials, intermediates, reaction conditions, synthetic routes and preparative methods can be used or adapted in practice by one of skill in the art. Such alternatives can be found in various texts such as, for example, "Encyclopedia of Reagents for Organic Synthesis" Leo A. Paquette , John Wiley & Son Ltd (1995) or "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" Richard C. Larock. Wiley- VCH and "Strategic Applications of Named Reactions in Organic Synthesis" Kurti and Czako, Elsevier, 2005 and references therein. In light of the scope of the present disclosure in combination with the knowledge of one of ordinary skill in the art such alternatives and modifications should be understood as being within the spirit and scope of the present application and the claims.

Unless otherwise indicated, all reagents and solvents were obtained from commercial sources and used as received. Starting materials were either of commercial origin or may be readily synthesized by standard methods well known to one skilled in the art of organic synthesis. 1H NMRs were obtained on a Bruker Avance at 400 MHz in the solvent indicated with tetramethylsilane as an internal standard. Analytical HPLC was run using a Zorbax RX-C8, 5 x 150 mm column eluting with a mixture of acetonitrile and water containing 0.1% trifluoroacetic acid with a gradient of 10-100%. LCMS results were obtained on either of two instruments: Waters Aquity Ultra Performance LC with a 2.1 mm x 50 mm Waters Aquity UPLC BEH CI 8 1.7 μιη column. The target column temperature was 45°C, with a run time of two (2) minutes, a flow rate of 0.600 mL/min, and a solvent mixture of 5% (0.1% formic acid/water): 95% (acetonitrile/0.1% formic acid) or a Micromass LC-ZQ 2000 quadrupole mass spectrometer. Automated column chromatography was performed on a CombiFlash Companion (ISCO, Inc.). Melting points were taken on a Mel-Temp apparatus and are uncorrected.

Unless otherwise indicated, the variables Ring A, R ¹ , R ² , and R ³ shown or referenced in the Schemes are defined as set forth above or as defined in the Claims.

General Synthesis

Compounds of Formulas I and Γ may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents, and materials employed are suitable for the transformations being effected. Also, in the description of the synthetic methods below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and workup procedures are standard for that reaction and should be readily recognized by one skilled in the art of organic synthesis. One of skill in the art will also readily recognize and appreciate that these reaction conditions can be modified or adapted as needed.

Formula I Formula Γ

The following Schemes (Scheme 1, Steps 1-7 and Scheme 2, Steps -7') are indicative of reaction sequences that may be utilized to synthesize compounds of Formula Ι/Γ. Both Scheme 1 and Scheme 2 rely on an alpha-tetralone starting material that is treated with a Wittig reagent (Steps 1 and ). The olefin is then treated with a thallium reagent to undergo a ring-expansion reaction to generate the 6/7-fused bicyclic ring system (Steps 2 and 2'). A nitration reaction installs the requisite nitrogen functionality (though this reaction is not stereospecific, separation is easily carried out on silica gel) to afford the nitro-derivatives (Steps 3 and 3'). The requisite amine may be introduced via reductive amination (Steps 4 and 4'). This amine can either be functionalized in the next reaction or at a later point in the reaction sequence. A variety of amines will undergo this transformation. An exemplary list of amines is provided below the reaction schemes. A person of ordinary skill will readily appreciate that amines of a wide structural variety may be used and are not limited to those listed herein. The reduction of the nitro group can be achieved via hydrogeno lysis (Steps 5 and 5') to give the desired amine. Steps 6 and 6' yield the desired coupling partner to the product of reactions 5 and 5', respectively. One of ordinary skill in the art will readily appreciate that the Ring A amine of Step 6 and 6' can be structurally diverse. An exemplary list of amines is provided below the schemes. A person of ordinary skill will readily appreciate that amines of a wide structural variety may be used and are not limited to those listed herein. The products of Steps 5,/5' and 6/6' can be coupled using acidic catalysis in an alcoholic solvent to give compounds of Formula Ι/Γ.

Scheme 1

NaBH(OAc

Exemplary amines of the formula R ^J R ² NH that can be used in Steps 4 and 4 'include, but are not limited to, the following:

Exemplary amines that can be used in Steps 6 and 6 'include, but are not limited to, the following:

The following compounds are non-limiting examples of compounds encompassed by Formula I and Formula Γ that were synthesized using reaction schemes and/or procedures similar to those described herein. Unless expressly indicated otherwise, compounds having a undefined stereocenter were prepared as mixtures of enantiomers or diastereomers.

dimethyl-benzenesulfonamide 2,4-diamine

OH ethanol

benzocyclohepten-6-yl}-amide

benzenesulfonamide

/° O^NH ₂ acid amide

"° o^m ₂ carboxylic acid amide (lS,2S,3R,4R)-3-(5-Chloro-2-{6-[4-((R)-

HO N-\ 2,3-dihydroxy-propyl)-piperazin-l-yl]-l- N methoxy-6,7,8,9-tetrahydro-5H-

612.23

benzocyclohepten-2-ylamino}-pyrimidin- 4-ylamino)-bicyclo[2.2.1]hept-5-ene-2- carboxylic acid amide

(R)-3-[4-(2-{5-Chloro-4-[2-(l,l-dioxo-

HO

llambda*6*-isothiazolidin-2-yl)- phenylamino]-pyrimidin-2-ylamino}-l-

672.17

methoxy-6,7,8,9-tetrahydro-5H-

O ^{H H} N P benzocyclohepten-6-yl)-piperazin-l-yl]-

Oo propane-l,2-diol

HO - ^ 2-[4-(2-{5-Chloro-4-[2-(l,l-dioxo- llambda*6*-isothiazolidin-2-yl)- phenylamino]-pyrimidin-2-ylamino}-l-

642

methoxy-6,7,8,9-tetrahydro-5H- benzocyclohepten-6-yl)-piperazin-l-yl]- ethanol

N-[2-(5-Chloro-2-{6-[4-(2-hydroxy-ethyl)- piperazin-l-yl]-l-methoxy-6,7,8,9-

616.18 tetrahydro-5H-benzocyclohepten-2- ylamino}-pyrimidin-4-ylamino)-phenyl]- methanesulfonamide

2-(4-{2-[5-Chloro-4-(2-pyrazol-l-yl- phenylamino)-pyrimidin-2-ylamino]-l-

589.1 methoxy-6,7,8,9-tetrahydro-5H- benzocyclohepten-6-yl}-piperazin-l-yl)- ethanol

HO^ -^ N-[2-(5-Chloro-2-{6-[4-(2-hydroxy-ethyl)- piperazin-l-yl]-l-methoxy-6,7,8,9-

644.1 tetrahydro-5H-benzocyclohepten-2- ylamino}-pyrimidin-4-ylamino)-phenyl]- r f¾ N-ethyl-methanesulfonamide 2-(5-Chloro-2-{6-[4-(2-hydroxy-ethyl)- piperazin-l-yl]-l-methoxy-6,7,8,9- tetrahydro-5H-benzocyclohepten-2- ylamino}-pyrimidin-4-ylamino)-3-fluoro- N-methyl-benzamide

2-(4-{2-[5-Chloro-4-(2-methoxy-4- morpholin-4-yl-phenylamino)-pyrimidin-

2-ylamino]-l-methoxy-6, 7,8,9- tetrahydro-5H-benzocyclohepten-6-yl}- piperazin-l-yl)-ethanol

2-(4-{2-[5-Chloro-4-(4-methoxy-2- pyrazol-l-yl-phenylamino)-pyrimidin-2- ylamino]-l-methoxy-6,7,8,9-tetrahydro- 5H-benzocyclohepten-6-yl}-piperazin-l- yl)-ethanol

2-[4-(2-{5-Chloro-4-[2-(l-methyl-lH- imidazol-2-yl)-phenylamino]-pyrimidin-

2-ylamino}-l-methoxy-6, 7,8,9- tetrahydro-5H-benzocyclohepten-6-yl)- piperazin-l-yl]-ethanol

2-(5-Chloro-2-{6-[4-(2-hydroxy-ethyl)- piperazin-l-yl]-l-methoxy-6,7,8,9- tetrahydro-5H-benzocyclohepten-2- ylamino}-pyrimidin-4-ylamino)-3,5- difluoro-N-methyl-benzamide

2-(5-Chloro-2-{(R)-6-[4-(2-hydroxy- ethyl)-piperazin-l-yl]-l-methoxy-6,7,8,9- tetrahydro-5H-benzocyclohepten-2- ylamino}-pyrimidin-4-ylamino)-3-fluoro- N-methyl-benzamide 2-(4-{(R)-2-[5-Chloro-4-(2-methoxy- phenylamino)-pyrimidin-2-ylamino]-l-

87 553.1 methoxy-6,7,8,9-tetrahydro-5H- benzocyclohepten-6-yl}-piperazin-l-yl)- ethanol

2-(5-Chloro-2-{(R)-6-[4-(2-hydroxy- ethyl)-piperazin-l-yl]-l-methoxy-6,7,8,9-

88 594.1 tetrahydro-5H-benzocyclohepten-2- ylamino}-pyrimidin-4-ylamino)-N-ethyl- benzamide

H N-^

2-(5-Chloro-2-{(R)-6-[4-(2-hydroxy- ethyl)-piperazin-l-yl]-l-methoxy-6,7,8,9-

89 608.1 tetrahydro-5H-benzocyclohepten-2- ylamino}-pyrimidin-4-ylamino)-N- isopropyl-benzamide

H

HO^ -^ 2-(4-{2-[5-Chloro-4-(2-methoxy-4- morpholin-4-yl-phenylamino)-pyrimidin-

90 638 2-ylamino]-l-methoxy-6, 7,8,9- tetrahydro-5H-benzocyclohepten-6-yl}- piperazin-l-yl)-ethanol

HO^N-X 2-(4-{2-[5-Chloro-4-(4-methoxy-2- pyrazol-l-yl-phenylamino)-pyrimidin-2-

91 619 ylamino]-l-methoxy-6,7,8,9-tetrahydro- 5H-benzocyclohepten-6-yl}-piperazin-l- yl)-ethanol

2-[4-(2-{5-Chloro-4-[2-(l-methyl-lH- imidazol-2-yl)-phenylamino]-pyrimidin-

92 619 2-ylamino}-l-methoxy-6, 7,8,9- tetrahydro-5H-benzocyclohepten-6-yl)-

\=/ piperazin-l-yl]-ethanol

Compounds of Formula Ι/Γ may be prepared according to the procedures described below using the appropriate reagents and starting materials.

Example 10 2- {5-Chloro-2-[ 1 -methoxy-6-(4-methyl-piperazin- 1 -yl)-6,7,8,9-tetrahydro-5H- benzocyclohepten-2-ylamino] -pyrimidin-4-ylamino } -N,N-dimethyl-benzenesulfonamide

Stepl : 5-Methoxy-l-methylene-l,2,3,4-tetrahydro-naphthalene: To a slurry of 5- Methoxy-3,4-dihydro-2H-naphthalen-l-one (25g, 0.14 mol) and

methyltriphenylphosphonium iodide (1.13 eq) in THF (250 mL) at RT was added potassium t-butoxide (1.6 eq) at such a rate as to maintain a temperature no higher than warm to the touch. The reaction was stirred for one hour and concentrated. The reaction was then azeotroped with three volumes of hexane to remove excess t-butanol. Fresh hexane was added the solution was let to stand overnight to effect trituration. The red- brown solid was removed by filtration and the filtrate was washed twice with water and was concentrated. Purification by chromatography on ISCO (330g, Si02 cartridge:

stepwise hexane and then DCM) affords the title compound as a pale yellow oil (24 g, 99%). 1H-NMR (400 MHz, CDC1 ₃ ) 7.29 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.49 (s, 1H), 4.98 (s, 1H), 3.85 (s, 3H), 2.77 (t, J = 6.4 Hz, 2H), 2.53- 2.50 (m, 2H), 1.93-1.87 (m, 2H).

Step 2: l-Methoxy-5,7,8,9-tetrahydro-benzocyclohepten-6-one: 5-Methoxy-l-methylene- 1,2,3,4-tetrahydro-naphthalene (23.8 g, 0.137 mol) in 150 mL MeOH added in one portion to freshly prepared solution of thallium(III)nitrate trihydrate (1.0 eq) in 300 mL MeOH. Stirred one minute and 400 mL chloroform added. The solution was filtered and the organics partitioned between dichloromethane and water. The organics were dried (MgS04) and concentrated. Purification by chromatography (ISCO, 330g silica cartridge; stepwise elution hexane (5 min) then 7 minute gradient to 100% dicloromethane (20 min) affords the title compound as the most polar of the products as a pale yellow oil (26g,

97%). 1H-NMR (400 MHz, CDC1 ₃ ) 7.16 (t, J = 7.9 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 7.5 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 2H), 3.05-3.01 (m, 2H), 2.55 (t, J = 7.0 Hz, 2H), 2.01-1.96 (m, 2H). LC/MS (ESI+) m/z = 191 (M+H)+ Step 3: l-Methoxy-2-nitro-5,7,8,9-tetrahydro-benzocyclohepten-6-one To potassium nitrate in acetonitrile (50 mL) and trifluoroacetic anhydride (100 mL) at 0°C was added dropwise l-methoxy-5,7,8,9-tetrahydro-benzocyclohepten-6-one (25 g, 0.131 mol) in 50 mL acetonitrile. The reaction was stirred for 2.5 hours while warming to RT. The reaction was concentrated without heat on a rotary evaporator. MeOHwas added and stirred briefly. Reconcentrated and worked-up by partitioning between dichloromethane and sat. sq.

sodium bicarbonate solution. The organic layer was separated and dried (Mg2S04), concentrated and purified by chromatography ISCO (330g silica cartridge: gradient elution - 10 to 50% EA:HEX over 60 minutes) affording two isomers. The title compound was the later eluting (10.7 grams, 34.6% yield). 1H-NMR (400 MHz, CDC1 ₃ ) 7.70 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 3.92 (s, 3H), 3.80 (s, 2H), 3.13-3.09 (m, 2H), 2.60 (t, J = 7.0 Hz, 2H), 2.10-2.03 (m, 2H). Step 4: l-(l-Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten- 6-yl)-4-methyl- piperazine: l-Methoxy-2-nitro-5,7,8,9-tetrahydro-benzocyclohepten-6-one (0.475 g, 0.00202 mol) in methylene chloride was treated with 1-Methylpiperazine (1.12 mL, 0.0101 mol) followed by Acetic acid (1.15 mL, 0.0202 mol) The mixture was stirred @ 50°C for 2 hrs, cooled to 0°C. Sodium triacetoxyborohydride (2.14 g, 0.0101 mol) was added, then the reaction was warmed to RT. After 1 h, HPLC and LC/MS noted conversion to product (ca. 10%) continued stirring overnight . After Stirring for 12h total, HPLC Indicated complete conversion to desired product. Poured into Sodium

bicarbonate/ice mixture and made basic to pH 10 with dilute sodium hydroxide, extracted 2X methylene chloride, dried MgS04, filtered and concentrated. Partitioned between ether and water, washed brince, Dried MgS04, filtered and concentrated isolated 0.408 g (63%> yield)Taking on without further purification. 1H-NMR (400 MHz, CDC1 ₃ ) 7.60 (d, J = 8.1 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 3.86 (s, 3H), 3.34-3.28 (m, 1H), 3.01-2.90 (m, 2H), 2.76-2.70 (m, 2H), 2.63-2.58 (m, 2H), 2.52-2.40 (m, 5H), 2.32 (s, 3H), 2.15-2.11 (m, 2H), 1.91-1.81 (m, 1H), 1.41-1.27 (m, 2H).

Step 5 : 1 -Methoxy-6-(4-methyl-piperazin- 1 -yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten- 2-ylamine: l-(l-Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten- 6-yl)-4- methyl-piperazine (0.408 g, 1.28 mmol) combined with Ethanol (10 mL, 200 mmol), Hydrazine hydrate (205 uL, 4.22 mmol), 10% Pd/C, 50% wet (5:45:50, Palladium: carbon black:Water, 0.272 g, 0.128 mmol), heat to 90°C, for 1.5h, cooled to rt and stirred overnight. HPLC indicated complete consumption of starting materuak. Cooled to rt, filtered and concentrated from toluene to obtain the title compound (370 mg, quantitative yield) 1H-NMR (400 MHz, CDC1 ₃ ) 6.76 (d, J = 7.9 Hz, 1H), 6.53 (d, J = 7.9 Hz, 1H),

3.70 (s, 3H), 3.25-3.20 (m, 1H), 2.85-2.33 (complex series of m, 11H), 2.32 (s, 3H), 2.12- 2.08 (m, 2H), 1.89-1.78 (m, 3H), 1.39-1.28 (m, 1H).

Step 6: 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesul fonamide: 2- Amino-N,N-dimethyl-benzenesulfonamide (10.00 g, 49.94 mmol) in N,N-

Dimethylformamide (200 mL, 2000 mmol) was treated with Sodium Hydride 60 %

Dispersion in Mineral Oil(6:4, Sodium hydride: Mineral Oil, 3.99 g, 99.9 mmol) at at 0 °C, then 2,4,5-Trichloro-pyrimidine (8.587 mL, 74.90 mmol) was added and the reaction was stirred for 5 minutes at 0 °C, then for 3 hours at room temperature. The reaction was quenched with aq. saturated ammonium chloride, then water. The precipitate was collected by filtration and recrystallized from methanol to give title compound 9.3 grams (52% yield). LC/MS found (M+H)+ = 346.93.

Step 7: 2-{5-Chloro-2-[l-methoxy-6-(4-methyl-piperazin-l-yl)-6,7,8,9 -tetrahydro-5H- benzocyclohepten-2-ylamino] -pyrimidin-4-ylamino } -Ν,Ν-dimethyl-benzenesulfonamide : Combined [A] 1 -Methoxy-6-(4-methyl-piperazin- 1 -yl)-6,7,8,9-tetrahydro-5H- benzocyclohepten-2-ylamine (83.4 mg, 0.288 mmol) and 2-(2,5-Dichloro-pyrimidin-4- ylamino)-N,N-dimethyl-benzenesulfonamide (100 mg, 0.3 mmol) with 4 M ofHydrogen Chloride in 1,4-Dioxane(0.40 mL, 0.0016 mol) in 2-Butanol (3.0 mL, 0.033 mol) and heated @120C for six hrs. Concentrated. Worked up by partitioning between

dichloromethane and sat bicarbonate solution. The organics were combined, dried, filtered and concentrated and purified om ISCO Column (12g reverse phase cartridge: gradient elution - 5 to 40%MeCN: water) to afford a pale yellow foam (55 mg, 32% yield). LC/MS found M+H+ = 600.27 1H-NMR (400 MHz, CDC1 ₃ ) 9.61 (s, 1H), 8.57 (d, J = 9.1 Hz, 1H), 8.1 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.3-7.26 (m, 1H), 6.88 (d, J = 9.1 Hz, 1H), 3.74 (s, 3H), 3.29-3.22 (m, 1H), 2.89-2.39 (complex series ofm, 18H), 2.33 (s, 3H), 2.16-2.11 (m, 2H), 1.85-1.76 (m, 1H), 1.42-1.28 (m, 2H). Methods of Treatment

This application further provides a method of treating an ALK- or FAK-mediated disorder or condition in a subject comprising: administering to the subject in recognized need thereof a compound of formula Ι/Γ or a pharmaceutically acceptable salt thereof. In another aspect, the present invention provides a compound of formula Ι/Γ or a pharmaceutically acceptable salt thereof for use in treating an ALK- or FAK-mediated disorder or condition in a subject in recognized need thereof. Preferably the compound of formula Ι/Γ or a pharmaceutically acceptable salt thereof is administered to the subject as a composition comprising a pharmaceutically acceptable excipient. Preferably, the compound of formula Ι/Γ or a pharmaceutically acceptable salt thereof is administered to the subject in a therapeutically effective amount.

In one embodiment, the ALK- or FAK-mediated condition or disorder is cancer. In another embodiment, the ALK- or FAK-mediated condition or disorder is selected from anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), neuroblastoma, glioblastoma, prostate cancer, squamous cell carcinoma (SCC), and breast cancer. In certain embodiments, the ALK- or FAK-mediated condition or disorder is selected from ALK-positive ALCL, EML4-ALK-positive NSCLC, neuroblastoma, glioblastoma, androgen-independent prostate cancers, breast cancers, and head and neck squamous cell carcinomas (FINSCCs). In certain embodiments, the ALK- or FAK- mediated condition or disorder is selected from ALK-positive ALCL, EML4-ALK- positive NSCLC, neuroblastoma, androgen-independent prostate cancers, breast cancers, and FINSCCs. In certain embodiments, the ALK- or FAK-mediated condition or disorder is selected from ALK-positive ALCL, EML4-ALK-positive NSCLC, neuroblastoma, and glioblastoma. In certain embodiments, the ALK- or FAK-mediated condition or disorder is selected from ALK-positive ALCL, EML4-ALK-positive NSCLC, and neuroblastoma. In certain embodiments, the ALK- or FAK-mediated condition or disorder is selected from ALK-positive ALCL and EML4-ALK-positive NSCLC. In certain embodiments, the ALK- or FAK-mediated condition or disorder is selected from androgen-independent prostate cancers, breast cancers, and HNSCCs. In certain embodiments, the ALK- or

FAK-mediated condition or disorder is an ALK-mediated condition or disorder. In certain embodiments, the ALK- or FAK-mediated condition or disorder is a FAK-mediated condition or disorder. In certain embodiments, the ALK- or FAK-mediated condition or disorder is a myofibroblastic tumor. In certain embodiments, the ALK- or FAK-mediated condition or disorder is a myo fibroblastic tumor with TPM3-ALK or TPM4-ALK oncogenes. In certain embodiments, the ALK- or FAK-mediated condition or disorder is a myofibroblastic tumor with TPM3-ALK oncogenes. In certain embodiments, the ALK- or FAK-mediated condition or disorder is a myofibroblastic tumor with TPM4-ALK oncogenes.

The ALK- or FAK- mediated disorder can be treated prophylactically, acutely, or chronically using compounds of the present invention, depending on the nature of the disorder or condition. Preferably, the subject in each of these methods is human.

In therapeutic applications, the compounds of the present invention can be prepared and administered in a wide variety of dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. In certain embodiments, the compounds of the present invention are administered intravenously or subcutaneously. Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. In another embodiment, the compounds of the present invention are delivered orally. The compounds can also be delivered rectally, bucally or by insufflation.

Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. A typical dose is about 1 mg to about 1,000 mg per day, such as about 5 mg to about 500 mg per day. In certain embodiments, the dose is about 10 mg to about 300 mg per day, such as about 25 mg to about 250 mg per day.

Assays and Model Systems and Methods

The compounds described herein were tested for their ability to inhibit the activity of a number of different kinases as described below. In general, the compounds of Formula Ι/Γ were found to effectively inhibit the activity of at least one or more of the kinases tested. In vitro assays:

FAK enzyme assay

The ability of compounds to inhibit the kinase activity of baculovirus-expressed human FAK was measured using a 96-well plate time-resolved fluorescence (TRF) assay system. Recombinant human full-length GST-tagged FAK (activated in vitro by His-tagged src) was obtained from Invitrogen (Cat# PV3832). For the FAK kinase assay, the reaction mixture (total volume = 100 μΙ,ΛνβΙΙ) contained 20 mM HEPES (pH 7.2), 10 μΜ ATP, 5 mM MgCl ₂ , 0.5 mM DTT, 0.1% BSA, and test compound (diluted in DMSO; 2.5% DMSO final in assay). Enzyme (10 ng/mL FAK) was added and the reaction was allowed to proceed at room temperature for 30 min. Detection of the phosphorylated product was performed by adding 100 μΙ,ΛνβΙΙ of Eu-Nl labeled PY100 antibody diluted 1 :75000 in 0.25% BSA in TBS-T (PerkinElmer #AD0041). Samples were incubated at room temperature for 1 h, followed by addition of 100 enhancement solution (PerkinElmer #1244-105). Plates were agitated for 10 min and fluorescence of the resulting solution measured using the PerkinElmer En Vision ^® 2102 or 2104 multi-label plate reader. Inhibition data were analyzed using ActivityBase and IC ₅₀ curves generated using XLFit.

ALK Kinase Assay

Example compounds were tested for their ability to inhibit the kinase activity of baculovirus-expressed ALK using a modification of the ELISA protocol reported for trkA in Angeles, T. S. et al, Anal. Biochem. 1996, 236, 49-55, which is incorporated herein by reference in its entirety. Phosphorylation of the substrate, phospholipase C-gamma (PLC- γ) generated as a fusion protein with glutathione S-transferase (GST) as reported in Rotin, D. et al, EMBO J. 1992, 11, 559-567, which is incorporated herein by reference in its entirety, was detected with a europium-labeled anti-phosphotyrosine antibody and measured by time-resolved fluorescence (TRF). Briefly, each 96-well plate was coated with 100 μίΛνεΙΙ of 10 μg/mL substrate (phospholipase C-γ) in Tris-buffered saline (TBS). The assay mixture (total volume = 100 μίΛνεΙΙ) consisting of 20 mM HEPES (pH 7.2), 1 μΜ ATP (K _m level), 5 mM MnCl ₂ , 0.1% BSA, 2.5% DMSO, and various concentrations of test compound was then added to the assay plate. The reaction was initiated by adding enzyme (30 ng/ml ALK) and was allowed to proceed at 37°C for 15 minutes. Detection of the phosphorylated product was performed by adding 100 μΐ/well of Eu-Nl labeled PT66 antibody (Perkin Elmer # AD0041). Incubation at 37°C then proceeded for one (1) hour, followed by addition of 100 μΐ, enhancement solution (Wallac #1244-105). The plate was gently agitated and after thirty minutes, the fluorescence of the resulting solution was measured using the En Vision 2100 (or 2102) multilabel plate reader (Perkin Elmer).

Data analysis was performed using ActivityBase (IDBS, Guilford, UK). IC ₅₀ values were calculated by plotting percent inhibition versus logio of the concentration of compound and fitting to the nonlinear regression sigmoidal dose-response (variable slope) equation in XLFit (IDBS, Guilford, UK)

The compounds described herein were tested according to procedures described above. The results of these tests are set forth below:

ALK ALK ALK

Example Potency Example Potency Example Potency

1 ++++ 45 ++++ 89 ++++

2 ++++ 46 ++++ 90 ++++

3 ++++ 47 ++++ 91 ++++

4 ++++ 48 ++++ 92 ++++

5 ++++ 49 ++++ 93 ++++

6 ++++ 50 ++++ 94 +

7 + 51 ++++ 95 ++++

8 ++++ 52 ++++ 96 ++++

9 ++++ 53 ++++ 97 ++++

10 ++++ 54 ++++ 98 ++++

11 ++++ 55 ++++ 99 ++++

12 ++++ 56 ++++ 100 ++++

13 ++++ 57 ++++ 101 ++++

14 ++++ 58 ++++ 102 ++++

15 ++++ 59 ++++ 103 ++++

16 ++++ 60 ++++

17 ++++ 61 ++++ ++++ < lOO nM

18 +++ 62 ++++ +++ < 1,000 nM

19 ++++ 63 ++++ ++ < 10,000 nM

20 ++++ 64 ++++ 5 + > 10,000 nM

21 ++++ 65 ++++

22 ++++ 66 ++++

23 ++++ 67 ++++

24 ++++ 68 ++++

25 ++++ 69 ++++

26 ++++ 70 ++++

27 ++++ 71 ++++

28 ++++ 72 ++++

29 ++++ 73 ++++

30 ++++ 74 ++++

31 ++++ 75 ++++

32 ++++ 76 ++++

33 ++++ 77 ++++

34 ++++ 78 ++++

35 ++++ 79 ++++

36 ++++ 80 ++++

37 ++++ 81 ++++

38 +++ 82 ++++

39 +++ 83 ++++

40 +++ 84 ++++

41 ++++ 85 +++

42 ++++ 86 ++++

43 ++++ 87 ++++

44 ++++ 88 ++++