Macrocycles for use in the treatment of disease - Patents.com

Abstract

The present invention relates to certain chiral diaryl macrocyclic derivatives, pharmaceutical compositions containing same, and methods of their use in the treatment of cancer.

Description

[Technical field]

[0001] Technical Field The present invention relates to certain diaryl macrocyclic derivatives, pharmaceutical compositions containing same and methods of use thereof in the treatment of cancer. [Background technology]

[0002] background Protein kinases are key regulators of cell growth, proliferation and survival. Genetic and epigenetic modifications accumulate in cancer cells, leading to the aberrant activation of signaling pathways that drive the malignant process. Manning, G. et al., Science 2002, 298, 1912-1934. Pharmacological inhibition of these signaling pathways represents a promising intervention opportunity for targeted cancer therapy. Sawyers, C., Nature 2004, 432, 294-297.

[0003] Anaplastic lymphoma kinase (ALK) is classified, along with leukocyte tyrosine kinase (LTK), within the insulin receptor (IR) superfamily of receptor tyrosine kinases. ALK is expressed primarily in the central and peripheral nervous system, suggesting a possible role in normal development and function of the nervous system. Pulford, K. et al., Cell Mol. Life Sci. 2004, 61, 2939. ALK was originally discovered as a fusion protein, NPM (nucleophosmin)-ALK, encoded by a fusion gene resulting from the t(2;5)(p23;q35) chromosomal translocation in anaplastic large cell lymphoma (ALCL) cell lines. Morris, SW et al., Science 1994, 263, 1281. More than 20 distinct ALK translocation partners have been found in many cancers, including ALCL (60-90% incidence), inflammatory myofibroblastic tumors (IMT, 50-60%), non-small cell lung cancer (NSCLC, 3-7%), colorectal cancer (CRC, 0-2.4%), breast cancer (0-2.4%) and others. Grande, E. et al., Mol. Cancer Ther. 2011, 10, 569-579. ALK-fusion proteins are located in the cytoplasm, and fusion partners with ALK play a role in dimerization or oligomerization of the fusion protein via coil-coil interactions that result in constitutive activation of ALK kinase function. Bischof, D. et al., Mol. Cell Biol., 1997, 17, 2312-2325. EML4-ALK, which comprises the echinoderm microtubule-associated protein-like 4 (EML4) gene and part of the ALK gene, was first discovered in NSCLC and was found to be highly oncogenic and cause lung adenocarcinoma in transgenic mice. Soda, M. et al., Nature 2007, 448, 561-566. Oncogenic point mutations in ALK occur in both familial and sporadic cases of neuroblastoma. Mosse, YP et al., Nature 2008, 455, 930-935. ALK is an attractive molecular target for cancer therapeutic intervention due to its important role in hematopoietic, solid and mesenchymal tumors. Grande, supra.

[0004] Since the initial discovery of the NPM (nucleophosmin)-ALK fusion gene in an anaplastic large cell lymphoma cell line in 1994 (Morris SW, et al Science. 1994; 263(5151):1281-4), ALK alterations have been found in a wide range of cancer types, including anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, diffuse large B-cell lymphoma, NSCLC, renal medullary carcinoma, renal cell carcinoma, breast cancer, colon cancer, serous ovarian cancer and esophageal squamous cell carcinoma (Hallberg B, et al Nat Rev Cancer. 2013;13(10):685-700). The clinical benefit of targeting oncogenic ALK fusions over chemotherapy in patients with ALK+ NSCLC has led to the full routine approval of crizotinib (Malik SM, et al Clin Cancer Res. 2014;20(8):2029-34.). However, resistance to crizotinib treatment developed within a mean of 7.3-10.9 months. Resistance mechanisms include ALK gene amplification, acquired mutations in the kinase domain, bypass signaling, EMT, and CNS metastasis (Katayama R, et al Clin Cancer Res. 2015;21(10):2227-35). The more potent second-generation ALK inhibitors ceritinib, alectinib, and brigatinib are initially effective in overcoming crizotinib resistance, but patients ultimately relapse with these inhibitors as well. Analysis of post-progression biopsy specimens indicates that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations, with ALK G1202R being a common resistance mutation for first- and second-generation ALK inhibitors (Gainor JF, et al Cancer Discov. 2016 Oct;6(10):1118-1133). Solvent-front mutations, including ALK G1202R, G1202del, D1203N, S1206Y / C, and E1210K, increased significantly after treatment with second-generation ALK inhibitors, with brigatinib in particular leading to up to 71% of biopsied resistant patients with solvent-front mutations (Gainor JF, et al Cancer Discov. 2016 Oct;6(10):1118-1133).

[0005] The current treatment paradigm for patients with ALK+ cancer is to treat with sequential ALK-targeted therapy. The third-generation ALK inhibitor lorlatinib has shown clinical activity in patients who have previously failed ALK inhibitors and has been approved for patients with ALK-positive metastatic NSCLC after crizotinib and at least one other ALK inhibitor treatment (Shaw A, et al J. Clin Oncol 2019, 37:1370-1379). However, composite mutations have emerged as a new challenge after more than one ALK TKI treatment. Seven out of 20 samples (35%) have composite ALK mutations after lorlatinib treatment, and for example, lorlatinib is no longer active against the composite gatekeeper and solvent front mutation ALK L1196M / G1202R (Yoda S., et al Cancer Discovery 2018, 8(6):714-729).

[0006] Endochondral ossification is a process that results in both replacement of the embryonic cartilaginous skeleton during organogenesis and growth of long bones until adult height is achieved. Fibroblast growth factor (FGF) / FGF receptor (FGFR) signaling has a crucial role in the development and maintenance of the growth plate during the endochondral ossification process (Xie Y 2014). Missense mutations in FGFs and FGFRs can cause multiple genetic skeletal disorders with impaired endochondral ossification. Activating mutations in FGFR3 cause achondroplasia, the most common form of dwarfism in live births (Samsa WE 2017). Growth plates in humans with FGFR3 mutations have disrupted chondrocyte columns and reduced numbers of hypertrophic chondrocytes. FGFR1 and FGFR2 have many essential and largely redundant roles during development, including growth plate formation. FGFR2-deficient embryos fail to form limb buds (Ornitz DM 2015). Moreover, overexpression of FGFR1 in chondrocytes leads to joint adhesions. Deletion of both FGFR1 and FGFR2 in mice was associated with a decreased number of proliferating chondrocytes and caused a decrease in the length of the growth plate (Karuppaiah K 2016). Therefore, selectivity over FGFRs is an important parameter for a good safety profile, especially for the pediatric population. Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, there is an emerging need to develop next-generation ALK inhibitors that exhibit potent activity against a broad range of resistance mutations, particularly solvent front mutations such as ALK G1202R and combined mutations such as ALK L1196M / G1202R. Furthermore, there is a need for such ALK inhibitors to exhibit selectivity over FGFR. Certain chiral diaryl macrocycles have been found in the present invention to have this advantageous activity profile. [Means for solving the problem]

[0008] overview In one embodiment, the present invention provides a compound of formula [ka]

[0009] [During the ceremony,

[0010] Each R 1 and R 2 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, monocyclic or bicyclic heteroaryl, -OR a , -OC(O)R a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)NR a R b , -OS(O)NRa R b , -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O)2R a R b , -P(O)NR a R b , -P(O)NR a R b , -P(O)OR a , -P(O)2OR a , -CN or -NO2; or R 1 and R 2 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and monocyclic or bicyclic heteroaryl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f, -OC(=N)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)NR e R f , -P(O)OR e , -P(O)2OR e , substituted with -CN or -NO2;

[0011] Each R 3 and R 3’are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, monocyclic or bicyclic heteroaryl, -OR a , -OC(O)R a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O)2R a R b , -P(O)NR a R b , -P(O)NRa R b , -P(O)OR a , -P(O)2OR a , -CN or -NO2, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl, monocyclic or bicyclic heteroaryl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OC(=N)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PRe R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)NR e R f , -P(O)OR e , -P(O)2OR e , -CN or -NO2; or R 3 and R 3’ together with the carbon atom to which they are attached form a C3-C6 cycloalkyl; wherein each hydrogen atom in the C3-C6 cycloalkyl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OC(=N)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NRe S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)NR e R f , -P(O)OR e , -P(O)2OR e , -CN or -NO2; or both R 3’ are combined to form the divalent group -(CR 1 R 2 ) m - Formation;

[0012] Each R 4 and R 5 are independently hydrogen, deuterium, halogen, -OR c , -OC(O)R c , -OC(O)NR c R d , -OC(=N)NR c R d , -OS(O)R c , -OS(O)2R c , -OS(O)NR c R d , -OS(O)2NR c R d , -SR c , -S(O)R c , -S(O)2R c , -S(O)NR c R d , -S(O)NR c R d , -NR c R d , -NR c C(O)R d , -NR c C(O)OR d , -NR cC(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d , -NR c S(O)NR c R d , -NR c S(O)2NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(=N)NR c R d , -PR c R d , -P(O)R c R d , -P(O)2R c R d , -P(O)NR c R d , -P(O)NR c R d , -P(O)OR c , -P(O)2OR c , -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl or monocyclic or bicyclic heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl, monocyclic or bicyclic heteroaryl, C5-C8 cycloalkyl or 5-8 membered heterocycloalkyl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OC(=N)NR e R f , -OS(O)Re , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)NR e R f , -P(O)OR e , -P(O)2OR e , substituted with -CN or -NO2;

[0013] R 6 is H, deuterium, or C1-C6 alkyl, where each hydrogen atom in the C1-C6 alkyl is independently optionally selected from deuterium, halogen, -OR e, -SR e or -NR e R f is replaced by;

[0014] Each R 7 are independently hydrogen or deuterium;

[0015] Each R 8 and R 9 are independently H, deuterium, halogen, -CN, -OR e , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl or monocyclic or bicyclic heteroaryl or R 8 and R 9 together with the carbon to which they are attached form a C3-C6 cycloalkyl or 4- to 6-membered heterocycloalkyl, or R 8 and R 9 together with the carbons to which they are attached form an exocyclic ethylene group, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom of an aryl, an exocyclic ethylene group or a monocyclic or bicyclic heteroaryl is optionally halogen, -N, -CN, -OR e , -OC(O)R e , -OC(O)NR e R f , -OC(=N)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f, -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)NR e R f , -P(O)OR e OR -P(O)2OR e is replaced by;

[0016] Each R a , R b , R c , R d , R e and R f are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 selected from the group consisting of aryl and 5-7 membered heteroaryl;

[0017] m is 1 or 2; and

[0018] n is 0, 1, 2 or 3.

[0019] or a pharma- ceutically acceptable salt thereof.

[0020] In another aspect, the present invention provides a compound of formula [ka]

[0021] [During the ceremony,

[0022] Each R 1 and R 2 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, monocyclic or bicyclic heteroaryl, -OR a , -OC(O)R a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a Rb , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O)2R a R b , -P(O)NR a R b , -P(O)NR a R b , -P(O)OR a , -P(O)2OR a , -CN or -NO2; or R 1 and R 2 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and monocyclic or bicyclic heteroaryl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OC(=N)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR eC(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)NR e R f , -P(O)OR e , -P(O)2OR e , substituted with -CN or -NO2;

[0023] Each R 3 and R 3’ are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, monocyclic or bicyclic heteroaryl, -OR a , -OC(O)R a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b, -S(O)NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O)2R a R b , -P(O)NR a R b , -P(O)NR a R b , -P(O)OR a , -P(O)2OR a , -CN or -NO2, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl, monocyclic or bicyclic heteroaryl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OC(=N)NR e R f, -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)NR e R f , -P(O)OR e , -P(O)2OR e , -CN or -NO2; or R 3 and R 3’together with the carbon atom to which they are attached form a C3-C6 cycloalkyl; wherein each hydrogen atom in the C3-C6 cycloalkyl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OC(=N)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f, -P(O)NR e R f , -P(O)OR e , -P(O)2OR e , substituted with -CN or -NO2;

[0024] Each R 4 and R 5 are independently hydrogen, deuterium, halogen, -OR c , -OC(O)R c , -OC(O)NR c R d , -OC(=N)NR c R d , -OS(O)R c , -OS(O)2R c , -OS(O)NR c R d , -OS(O)2NR c R d , -SR c , -S(O)R c , -S(O)2R c , -S(O)NR c R d , -S(O)NR c R d , -NR c R d , -NR c C(O)R d , -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d , -NR c S(O)NR c R d , -NR c S(O)2NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c R d, -C(=N)NR c R d , -PR c R d , -P(O)R c R d , -P(O)2R c R d , -P(O)NR c R d , -P(O)NR c R d , -P(O)OR c , -P(O)2OR c , -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl or monocyclic or bicyclic heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl, monocyclic or bicyclic heteroaryl, C5-C8 cycloalkyl or 5-8 membered heterocycloalkyl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OC(=N)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f, -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)NR e R f , -P(O)OR e , -P(O)2OR e , substituted with -CN or -NO2;

[0025] R 6 is H, deuterium, or C1-C6 alkyl, where each hydrogen atom in the C1-C6 alkyl is independently optionally selected from deuterium, halogen, -OR e , -SR e or -NR e R f is replaced by;

[0026] Each R 7 are independently hydrogen or deuterium;

[0027] Each R a , R b , R c , R d , R e and R f are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 selected from the group consisting of aryl and 5- to 7-membered heteroaryl; and

[0028] n is 0, 1, 2 or 3.

[0029] or a pharma- ceutically acceptable salt thereof.

[0030] In certain embodiments of the compound of Formula I or a pharma- ceutically acceptable salt thereof:

[0031] Each R 1 and R 2 is independently H or C1-C6 alkyl;

[0032] Each R 3 and R 3’ are independently H or C1-C6 alkyl; or R 3 and R 3’ together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl;

[0033] Each R 4 and R 5 are independently hydrogen or halogen;

[0034] R 6 is H or C1-C6 alkyl;

[0035] Each R 7 is hydrogen; and

[0036] n is 0 or 1.

[0037] In certain embodiments of the compound of Formula I or a pharma- ceutically acceptable salt thereof:

[0038] Each R 1 and R 2 are independently H or C1-C3 alkyl;

[0039] Each R 3 and R 3’are independently H or C1-C3 alkyl; or R 3 and R 3’ together with the carbon atoms to which they are attached form a C3-C4 cycloalkyl;

[0040] Each R 4 and R 5 are independently hydrogen or halogen;

[0041] R 6 is H;

[0042] Each R 7 is hydrogen; and

[0043] n is 0 or 1.

[0044] In certain embodiments of the compound of Formula I or a pharma- ceutically acceptable salt thereof:

[0045] Each R 1 and R 2 are independently hydrogen or methyl;

[0046] Each R 3 and R 3’ are independently hydrogen or methyl; or R 3 and R 3’ together with the carbon atom to which they are attached form a cyclopropyl;

[0047] Each R 4 and R 5 are independently hydrogen or fluorine;

[0048] R 6 is hydrogen;

[0049] Each R 7 is hydrogen; and

[0050] n is 0 or 1.

[0051] In certain embodiments, the compound of Formula I, or a pharma- ceutically acceptable salt thereof, has the structure of Formula II, IIa, III, or IIIa.

[0052] In another aspect, the present invention provides a compound represented by formula II [ka]

[0053] or a pharma- ceutically acceptable salt thereof.

[0054] In another aspect, the present invention relates to a compound of formula IIa [ka]

[0055] or a pharma- ceutically acceptable salt thereof.

[0056] In another aspect, the present invention relates to a compound of formula III [ka]

[0057] or a pharma- ceutically acceptable salt thereof.

[0058] In another aspect, the present invention relates to a compound of formula IIIa [ka]

[0059] or a pharma- ceutically acceptable salt thereof.

[0060] In another embodiment, the invention provides a pharmaceutical composition comprising a compound according to any of the described embodiments, or a pharma- ceutically acceptable salt thereof, and optionally at least one diluent, carrier, or excipient.

[0061] In another embodiment, the present invention provides a method of treating cancer comprising administering to a subject in need of such treatment an effective amount of at least one compound of any of the described embodiments, or a pharma- ceutically acceptable salt thereof.

[0062] In other embodiments, the invention provides the use of a compound of any of the described embodiments, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[0063] In other embodiments, the invention provides the use of a compound of any of the described embodiments, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer.

[0064] In another embodiment, the invention provides a compound of the disclosed embodiments, or a pharma- ceutically acceptable salt thereof, for use in treating cancer in a subject.

[0065] In another embodiment, the present invention provides a method for inhibiting ALK receptor tyrosine kinase, comprising contacting a cell containing one or more such kinases with an effective amount of at least one compound of any of the described embodiments or a pharma- ceutically acceptable salt thereof and / or at least one pharmaceutical composition of the present invention, wherein the contacting is in vitro, ex vivo or in vivo.

[0066] Further embodiments, features and advantages of the present invention will become apparent through the following detailed description and practice of the invention. The compounds of the present invention may be described as embodiments in any of the following numbered paragraphs. It is understood that any of the embodiments described herein may be used in combination with any other embodiment described herein, unless the embodiments are mutually inconsistent.

[0067] 1. Formula I [ka]

[0068] [During the ceremony,

[0069] Each R 1 and R 2 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, monocyclic or bicyclic heteroaryl, -OR a , -OC(O)R a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O)2R a Rb , -P(O)NR a R b , -P(O)NR a R b , -P(O)OR a , -P(O)2OR a , -CN or -NO2; or R 1 and R 2 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and monocyclic or bicyclic heteroaryl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OC(=N)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NRe S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)NR e R f , -P(O)OR e , -P(O)2OR e , substituted with -CN or -NO2;

[0070] Each R 3 and R 3’ are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, monocyclic or bicyclic heteroaryl, -OR a , -OC(O)R a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR aC(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O)2R a R b , -P(O)NR a R b , -P(O)NR a R b , -P(O)OR a , -P(O)2OR a , -CN or -NO2, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl, monocyclic or bicyclic heteroaryl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OC(=N)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR eR f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)NR e R f , -P(O)OR e , -P(O)2OR e , -CN or -NO2; or R 3 and R 3’ together with the carbon atom to which they are attached form a C3-C6 cycloalkyl; wherein each hydrogen atom in the C3-C6 cycloalkyl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OC(=N)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e Rf , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)NR e R f , -P(O)OR e , -P(O)2OR e , substituted with -CN or -NO2;

[0071] Each R 4 and R 5 are independently hydrogen, deuterium, halogen, -OR c , -OC(O)R c , -OC(O)NR c R d , -OC(=N)NR c R d , -OS(O)R c、-OS(O)2R c 、-OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、-S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、-S(O)2NR c R d 、-NR c R d 、-NR c C(O)R d 、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=N)NR c R d 、-NR c S(O)R d 、-NR c S(O)2R d 、-NR c S(O)NR c R d 、-NR c S(O)2NR c R d 、-C(O)R c 、-C(O)OR c 、-C(O)NR c R d 、-C(=N)NR c R d , -PR c R d 、-P(O)R c R d 、-P(O)2R c R d 、-P(O)NR c R d 、-P(O)2NR c R d 、-P(O)OR c 、-P(O)2OR c , -CN, -NO2, C1-C6 アルキル, C2-C6 アルケニル, C2-C6アルキニル, C3-C6 シクロアルキル, 3~7 member ヘテロシクロアルキル, C6-C10 aryl or monocyclic or bicyclic heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 Each hydrogen atom in an aryl, monocyclic or bicyclic heteroaryl, C5-C8 cycloalkyl or 5-8 membered heterocycloalkyl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OC(=N)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e Rf , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)NR e R f , -P(O)OR e , -P(O)2OR e , substituted with -CN or -NO2;

[0072] R 6 is H, deuterium, or C1-C6 alkyl, where each hydrogen atom in the C1-C6 alkyl is independently optionally selected from deuterium, halogen, -OR e , -SR e or -NR e R f is replaced by;

[0073] Each R 7 are independently hydrogen or deuterium;

[0074] Each R a , R b , R c , R d , R e and R f are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 selected from the group consisting of aryl and 5- to 7-membered heteroaryl; and

[0075] n is 0, 1, 2 or 3.

[0076] or a pharma- ceutically acceptable salt thereof.

[0077] 2. The compound of item 1 or a pharma- ceutically acceptable salt thereof, wherein n is 0 or 1.

[0078] 3. The compound according to item 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein n is 0.

[0079] 4. The compound according to item 1 or 2, wherein n is 1, or a pharma- ceutically acceptable salt thereof.

[0080] 5. Formula II [ka]

[0081] 4. The compound according to any one of items 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein:

[0082] 6. Formula IIa [ka]

[0083] Item 6. The compound of any one of items 1 to 3 or 5, or a pharma- ceutically acceptable salt thereof, having the formula:

[0084] 7. Formula III [ka]

[0085] 5. The compound of any one of items 1, 2, or 4, or a pharma- ceutically acceptable salt thereof, having the formula:

[0086] 8. Formula IIIa [ka]

[0087] 8. The compound of any one of items 1, 2, 4, or 7, or a pharma- ceutically acceptable salt thereof, wherein:

[0088] 9. Each R 1 and R 2 when present, is independently H, deuterium, C1-C6 alkyl or R 1 and R 2taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl, or a pharma- ceutically acceptable salt thereof.

[0089] 10. Each R 3 and R 3’ are independently H, deuterium, C1-C6 alkyl or R 3 and R 3’ taken together with the carbon atom to which they are attached form a C3-C6 cycloalkyl, or a pharma- ceutically acceptable salt thereof.

[0090] 11. Each R 3’ 5. The compound of any of the preceding claims, or a pharma- ceutically acceptable salt thereof, wherein is H or deuterium.

[0091] 12. Each R 4 5. The compound of any of the preceding claims, or a pharma- ceutically acceptable salt thereof, wherein is H or deuterium.

[0092] 13. R 5 4. The compound of any of the preceding clauses, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

[0093] 14. R 6 A compound according to any of the preceding clauses, wherein is H, or a pharma- ceutically acceptable salt thereof.

[0094] 15. Each R 7 A compound according to any of the preceding clauses, wherein is H, or a pharma- ceutically acceptable salt thereof.

[0095] 16. [ka]

[0096] The compound of item 1, selected from the group consisting of:

[0097] 17. A pharmaceutical composition comprising a compound according to any of the preceding clauses or a pharma- ceutically acceptable salt thereof and optionally at least one diluent, carrier or excipient.

[0098] 18. A method for treating cancer, pain, a neurological disease, an autoimmune disease or inflammation, comprising administering to a subject in need of such treatment an effective amount of at least one compound according to any one of items 1 to 16 or a pharma- ceutically acceptable salt thereof.

[0099] 19. The method according to item 18, wherein the disease is cancer.

[0100] 20. The method of paragraph 18 or 19, wherein the subject is a human.

[0101] 21. The method of any of items 18 to 20, wherein the disease is cancer mediated by ALK.

[0102] 22. The method according to any one of items 18 to 21, wherein the disease is cancer mediated by genetically altered ALK.

[0103] 23. The method of any of items 18 to 22, wherein the disease is cancer mediated by a fusion protein comprising a fragment of a protein encoded by the ALK gene and a fragment of a protein encoded by a gene selected from the group consisting of NPM, EML4, TPR, TFG, ATIC, CLTC1, TPM4, MSN ALO17 and MYH9.

[0104] 24. The method of paragraph 23, wherein the fusion protein comprises a fragment of a protein encoded by the ALK gene and a fragment of a protein encoded by the EML4 gene.

[0105] 25. The method of paragraph 23, wherein the genetically modified ALK is an EML4-ALK fusion protein.

[0106] 26. The method of paragraph 25, wherein the EML4-ALK fusion protein is a wild-type protein.

[0107] 27. The method of paragraph 25, wherein the EML4-ALK fusion protein contains at least one resistance mutation.

[0108] 28. The method of paragraph 25, wherein the EML4-ALK fusion protein comprises at least one mutation selected from the group consisting of L1196M, G1202R, C1156Y, D1203N, G1202 deletion, E1210K, S1206C, F1174C, F1174L, F1174S, F1174V, F1245C, G1269A, G1269S, I1171N, L1152P, L1152R, L1198F, R1275Q, S1206R, T1151-L1152insT, T1151M, V1180L, and combinations thereof.

[0109] 29. The method of paragraph 25, wherein the EML4-ALK fusion protein comprises a combination of mutations selected from the group consisting of E1210K / D1203N, E1210K / S1206C, L1198F / C1156Y, L1198F / G1202R, L1198F / L1196M, L1196M / G1202R, L1198F / C1156Y, G1202R / G1269A and G1202R / G1269A / L1204V.

[0110] 30. Diseases include ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER + 30. The method according to any one of items 18 to 29, wherein the cancer is selected from the group consisting of breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, papillary thyroid carcinoma, Spitz tumor, sarcoma, astrocytoma, brain low-grade glioma, breast secretory carcinoma, breast analogue carcinoma, acute myeloid leukemia, congenital mesodermal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, cutaneous melanoma, squamous cell carcinoma of the head and neck, childhood glioma CML, prostate cancer, squamous cell carcinoma of the lung, ovarian serous cystadenocarcinoma, castration-resistant prostate cancer, Hodgkin's lymphoma, and serous and clear cell endometrial carcinoma.

[0111] 31. Use of a compound according to any one of items 1 to 16 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating cancer.

[0112] 32. Use of the compound according to any one of items 1 to 16 or a pharma- ceutically acceptable salt thereof for the treatment of cancer.

[0113] 33. The use of paragraph 31 or 32, wherein the disease is a cancer mediated by ALK.

[0114] 34. The use of any of items 31 to 33, wherein the disease is cancer mediated by genetically altered ALK.

[0115] 35. The use of any of paragraphs 31 to 35, wherein the disease is a cancer mediated by a fusion protein comprising a fragment of a protein encoded by the ALK gene and a fragment of a protein encoded by a gene selected from the group consisting of NPM, EML4, TPR, TFG, ATIC, CLTC1, TPM4, MSN ALO17 and MYH9.

[0116] 36. The use of paragraph 35, wherein the fusion protein comprises a fragment of a protein encoded by the ALK gene and a fragment of a protein encoded by the EML4 gene.

[0117] 37. The use of paragraph 35, wherein the genetically modified ALK is an EML4-ALK fusion protein.

[0118] 38. The use of paragraph 37, wherein the EML4-ALK fusion protein is a wild-type protein.

[0119] 39. The use of paragraph 37, wherein the EML4-ALK fusion protein comprises at least one resistance mutation.

[0120] 40. The use of paragraph 37, wherein the EML4-ALK fusion protein comprises at least one mutation selected from the group consisting of L1196M, G1202R, C1156Y, D1203N, G1202 deletion, E1210K, S1206C, F1174C, F1174L, F1174S, F1174V, F1245C, G1269A, G1269S, I1171N, L1152P, L1152R, L1198F, R1275Q, S1206R, T1151-L1152insT, T1151M, V1180L, and combinations thereof.

[0121] 41. The use of paragraph 37, wherein the EML4-ALK fusion protein comprises a combination of mutations selected from the group consisting of E1210K / D1203N, E1210K / S1206C, L1198F / C1156Y, L1198F / G1202R, L1198F / L1196M, L1196M / G1202R, L1198F / C1156Y, G1202R / G1269A and G1202R / G1269A / L1204V.

[0122] 42. Cancer is ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER + 42. The use of any of items 31 to 41, wherein the cancer is selected from the group consisting of breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, papillary thyroid carcinoma, Spitz tumor, sarcoma, astrocytoma, brain low-grade glioma, breast secretory carcinoma, breast analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, cutaneous melanoma, squamous cell carcinoma of the head and neck, childhood glioma CML, prostate cancer, squamous cell carcinoma of the lung, ovarian serous cystadenocarcinoma, castration-resistant prostate cancer, Hodgkin's lymphoma, and serous and clear cell endometrial carcinoma.

[0123] 43. A method for inhibiting ALK receptor tyrosine kinase, comprising contacting a cell containing one or more such kinases with an effective amount of any one of the compounds of paragraphs 1 to 16 or a pharma- ceutically acceptable salt thereof and / or at least one pharmaceutical composition containing any one of the compounds of paragraphs 1 to 16, wherein the contacting is in vitro, ex vivo or in vivo.

[0124] 44. A compound of any of paragraphs 1 to 16 for use in treating cancer in a subject.

[0125] 45. The compound of paragraph 44, wherein the disease is cancer mediated by ALK.

[0126] 46. ​​The compound of paragraph 44 or 45, wherein the disease is cancer mediated by genetically altered ALK.

[0127] 47. The compound according to any of items 44 to 46, wherein the disease is cancer mediated by a fusion protein comprising a fragment of a protein encoded by the ALK gene and a fragment of a protein encoded by a gene selected from the group consisting of NPM, EML4, TPR, TFG, ATIC, CLTC1, TPM4, MSN ALO17 and MYH9.

[0128] 48. The compound of paragraph 47, wherein the fusion protein comprises a fragment of a protein encoded by the ALK gene and a fragment of a protein encoded by the EML4 gene.

[0129] 49. The compound according to item 47, wherein the genetically modified ALK is an EML4-ALK fusion protein.

[0130] 50. The compound of paragraph 49, wherein the EML4-ALK fusion protein is a wild-type protein.

[0131] 51. The compound of paragraph 49, wherein the EML4-ALK fusion protein comprises at least one resistance mutation.

[0132] 52. The compound of paragraph 49, wherein the EML4-ALK fusion protein comprises at least one mutation selected from the group consisting of L1196M, G1202R, C1156Y, D1203N, G1202 deletion, E1210K, S1206C, F1174C, F1174L, F1174S, F1174V, F1245C, G1269A, G1269S, I1171N, L1152P, L1152R, L1198F, R1275Q, S1206R, T1151-L1152insT, T1151M, V1180L and combinations thereof.

[0133] 53. The compound of clause 49, wherein the EML4-ALK fusion protein comprises a combination of mutations selected from the group consisting of E1210K / D1203N, E1210K / S1206C, L1198F / C1156Y, L1198F / G1202R, L1198F / L1196M, L1196M / G1202R, L1198F / C1156Y, G1202R / G1269A and G1202R / G1269A / L1204V.

[0134] 54. Cancer is ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER + 54. The compound according to any one of items 44 to 53, which is selected from the group consisting of breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, papillary thyroid carcinoma, Spitz tumor, sarcoma, astrocytoma, brain low-grade glioma, breast secretory carcinoma, breast analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, cutaneous melanoma, squamous cell carcinoma of the head and neck, childhood glioma CML, prostate cancer, squamous cell carcinoma of the lung, ovarian serous cystadenocarcinoma, castration-resistant prostate cancer, Hodgkin's lymphoma, and serous and clear cell endometrial carcinoma. [Brief description of the drawings]

[0135] [Figure 1A]Tumor volumes of xenograft tumor models in mice bearing Ba / F3 cell-derived xenograft tumors harboring EML4-ALK fusion with G1202R mutation.(●) Vehicle;(■) Compound 1 (2 mg / kg BID);(▲) Compound 1 (5 mg / kg BID);(▼) Compound 1 (10 mg / kg BID);(○) Compound 2 (3 mg / kg BID);(△) Compound 2 (10 mg / kg BID);(◆) Lorlatinib (5 mg / kg).

[0136] [Figure 1B] Body weights of mice bearing Ba / F3 cell-derived xenograft tumors carrying the EML4-ALK fusion with the G1202R mutation are shown. (●) vehicle; (■) compound 1 (2 mg / kg BID); (▲) compound 1 (5 mg / kg BID); (▼) compound 1 (10 mg / kg BID); (○) compound 2 (3 mg / kg BID); (△) compound 2 (10 mg / kg BID); (◆) lorlatinib (5 mg / kg).

[0137] [Figure 2A] Tumor volumes of xenograft tumor models in mice bearing Ba / F3 cell-derived xenograft tumors harboring EML4-ALK fusions with L1198F / G1202R mutations: (●) vehicle; (■) compound 1 (2 mg / kg BID); (▲) compound 1 (5 mg / kg BID); (▼) compound 1 (10 mg / kg BID); (◆) lorlatinib (5 mg / kg).

[0138] [Figure 2B] Body weights of mice bearing Ba / F3 cell-derived xenograft tumors harboring the EML4-ALK fusion with the L1198F / G1202R mutation are shown. (●) vehicle; (■) compound 1 (2 mg / kg BID); (▲) compound 1 (5 mg / kg BID); (▼) compound 1 (10 mg / kg BID); (◆) lorlatinib (5 mg / kg).

[0139] [Figure 3A]Tumor volumes of xenograft tumor models in mice bearing Ba / F3 cell-derived xenograft tumors harboring EML4-ALK fusions with L1196M / G1202R mutations.(●) Vehicle;(○) Compound 1 (0.6 mg / kg BID);(■) Compound 1 (2 mg / kg BID);(▲) Compound 1 (5 mg / kg BID);(▼) Compound 1 (10 mg / kg BID);(◆) Lorlatinib (5 mg / kg).

[0140] [Figure 3B] Body weight in mice bearing Ba / F3 cell-derived xenograft tumors harboring the EML4-ALK fusion with the L1196M / G1202R mutation: (●) vehicle; (○) compound 1 (0.6 mg / kg BID); (■) compound 1 (2 mg / kg BID); (▲) compound 1 (5 mg / kg BID); (▼) compound 1 (10 mg / kg BID); (◆) lorlatinib (5 mg / kg).

[0141] [Figure 4] Figure 1 shows inhibition of phosphorylation of ALK fusion at Y1282 / 1283 and Y1604 and reduction of ALK fusion expression levels in mice treated with 10 mg / kg BID of Compound 1. As a control, actin expression levels were not affected by Compound 1 treatment.

[0142] [Diagram 5] Figure 1 shows inhibition of phosphorylation of ALK fusion as a function of compound free plasma concentration 2 or 12 hours after administration of 0.6 mg / kg, 2 mg / kg or 5 mg / kg of Compound 1 in mice bearing Ba / F3 cell-derived xenograft tumors harboring the EML4-ALK fusion with the L1196M / G1202R mutation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0143] Detailed Description Before the present invention is further described, it is to be understood that the invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0144] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications, and other publications mentioned herein are incorporated herein by reference in their entirety. When a definition set forth in this section contradicts or otherwise conflicts with a definition set forth in a patent, application, or other publication incorporated herein by reference, the definition set forth in this section shall take precedence over the definition incorporated herein by reference.

[0145] As used herein and in the appended claims, the singular terms "a," "an," and "the" include plural referents unless the context clearly dictates not. Moreover, it should be noted that a patent or other description may be drafted to exclude any optional element. That is, this description is intended to serve as a basis for preference over the use of exclusive language such as "solely," "only," and the like or "negative" limitations in connection with reciting claim elements.

[0146] As used herein, the terms "comprise", "include", and "contain" are used in their open, non-limiting sense.

[0147] For the sake of brevity, some of the quantitative expressions described herein are not modified with the term "about". Regardless of whether the term "about" is explicitly used, it is understood that all amounts described herein refer to the exact indicated value and also refer to the approximation of such indicated value that is reasonably estimated based on ordinary skill in the art, including the equivalent and approximation of such indicated value by experimental and / or measurement conditions. When a yield is given as a percentage, such a yield refers to the mass of a substance, and for which the yield is given with respect to the maximum amount that can be obtained with the same substance under specific stoichiometric conditions. Concentrations given as percentages refer to mass ratios, unless otherwise indicated.

[0148] Except where otherwise indicated, the methods and techniques of the present embodiments are generally carried out according to conventional methods well known in the art and as described in the various general and more specific references cited and described throughout this specification. See, for example, Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.

[0149] Chemical names of compounds described herein were generally derived using the commercially available ACD / Name 2014 (ACD / Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).

[0150] It is also understood that certain features of the invention that are described in separate embodiments for clarity may be provided in combination in one embodiment. Conversely, it is also understood that for brevity, various features of the invention described in one embodiment may be provided separately or in any suitable subcombination. All combinations of the embodiments with respect to the chemical groups represented by the variables are specifically embraced by the present disclosure and disclosed herein as if each and every such combination were individually and explicitly disclosed, so long as such combinations include compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). Furthermore, all subcombinations of the chemical groups listed in the embodiments describing the variables are also specifically embraced by the present disclosure and disclosed herein as if each and every such subcombination were individually and explicitly disclosed.

[0151] definition The term "alkyl" as used herein refers to a chain of carbon atoms, optionally branched, containing 1 to 20 carbon atoms. In some embodiments, alkyl is preferably C1-C 12 , C1-C 10It is further understood that alkyl groups may be of limited length, including C1-C8, C1-C7, C1-C6, and C1-C4. By way of illustration, such particularly limited length alkyl groups, including C1-C8, C1-C7, C1-C6, and C1-C4, may also be referred to as "lower alkyls." Illustrative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl, and the like. Alkyl may be substituted or unsubstituted. Exemplary substituents include cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, oxo, (=O), thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, and amino, or as described in the various embodiments provided herein. It is understood that "alkyl" can be combined with other groups, such as those described above, to form functionalized alkyls. By way of example, the combination of an "alkyl" group and a "carboxy" group described herein can be referred to as a "carboxyalkyl" group. Other non-limiting examples include hydroxyalkyl, aminoalkyl, and the like.

[0152] The term "alkenyl" as used herein includes a chain of carbon atoms, which is optionally branched, containing 2 to 20 carbon atoms and also containing at least one carbon-carbon double bond (i.e., C=C). In certain embodiments, alkenyl is preferably C2-C 12It is understood that alkenyl groups may be limited in length, including C2-C9, C2-C8, C2-C7, C2-C6, and C2-C4. By way of illustration, such particularly limited length alkenyl groups, including C2-C8, C2-C7, C2-C6, and C2-C4, may be referred to as lower alkenyl. Alkenyl may be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.

[0153] The term "alkynyl" as used herein includes a chain of carbon atoms, which is optionally branched, containing 2 to 20 carbon atoms and also containing at least one carbon-carbon triple bond (i.e., C≡C). In certain embodiments, alkynyl is preferably C2-C 12 It is understood that alkynyl groups may be of limited length, including C2-C9, C2-C8, C2-C7, C2-C6, and C2-C4. By way of illustration, such particularly limited length alkynyl groups, including C2-C8, C2-C7, C2-C6, and C2-C4, may be referred to as lower alkynyl. Alkynyl may be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.

[0154] The term "aryl" as used herein refers to an all-carbon monocyclic or fused polycyclic group of 6 to 12 carbon atoms having a completely conjugated pi-electron system. In certain embodiments, aryl is preferably a C6-C 10 It is understood that aryl and the like may be limited in size. Illustrative aryl groups include, but are not limited to, phenyl, naphthylenyl, and anthracenyl. Aryl groups may be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein.

[0155] The term "cycloalkyl" as used herein refers to 3-15 membered all-carbon monocyclic rings, including carbocyclic rings fused to other groups, such as heterocycles, such as 5- or 6-membered cycloalkyls fused to 5- to 7-membered heterocyclic rings, all carbon 5-membered / 6-membered or 6-membered / 6-membered fused bicyclic or polycyclic fused rings ("fused" ring systems means that each ring of the system shares an adjacent pair of carbon atoms with another ring in the system) where one or more of the groups or rings may contain one or more double bonds, but where the cycloalkyl does not contain a completely conjugated pi-electron system. In certain embodiments, cycloalkyl is preferably a C3-C6 13 It is understood that cycloalkyl can be of limited size, such as C3-C9, C3-C6, and C4-C6. Cycloalkyl can be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, norbornyl, norbornenyl, 9H-fluoren-9-yl, and the like. Illustrative examples of cycloalkyl groups shown in the figures, in the form of appropriately attached moieties, include the following: [ka]

[0156] The term "heterocycloalkyl" as used herein refers to a monocyclic or fused ring group having a ring of 3 to 12 ring atoms in which at least one ring atom is a heteroatom such as nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon atoms. Heterocycloalkyls can optionally contain 1, 2, 3, or 4 heteroatoms. Heterocycloalkyl groups can be fused to other groups, such as other heterocycloalkyl or heteroaryl groups. Heterocycloalkyls can have one or more double bonds, including a double bond to nitrogen (e.g., C=N or N=N), but do not contain a fully conjugated pi-electron system. It is understood that in certain embodiments, heterocycloalkyls can be advantageously limited in size, such as 3- to 7-membered heterocycloalkyls, 5- to 7-membered heterocycloalkyls, 3-, 4-, 5-, or 6-membered heterocycloalkyls, etc. Heterocycloalkyls can be unsubstituted or substituted as described for alkyls or as described in the various embodiments provided herein. Illustrative heterocycloalkyl groups include, but are not limited to, oxiranyl, thianaryl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, oxepanyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, etc. Illustrative examples of heterocycloalkyl groups shown in the figures, in the form of appropriately attached moieties, include the following: [ka]

[0157] The term "heteroaryl" as used herein refers to a monocyclic or fused ring group containing 1, 2, 3 or 4 ring heteroatoms selected from nitrogen, oxygen and sulfur, with 5-12 ring atoms, the remaining ring atoms being carbon atoms, and having a fully conjugated pi-electron system. It is understood that in certain embodiments, the heteroaryl may be advantageously limited in size, such as a 3- to 7-membered heteroaryl, a 5- to 7-membered heteroaryl, etc. The heteroaryl may be unsubstituted or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl, pyrazinyl, tetrazinyl, quinazolinyl, quinoxalinyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl, and carbazolyl, etc. Illustrative examples of heteroaryl groups shown in the figures, in the form of appropriately attached moieties, include the following: [ka]

[0158] As used herein, "hydroxy" or "hydroxyl" refers to an --OH group.

[0159] As used herein, "alkoxy" refers to an -O-(alkyl) or -O-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0160] As used herein, "aryloxy" refers to an -O-aryl or -O-heteroaryl group. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like.

[0161] As used herein, "mercapto" refers to the group --SH.

[0162] As used herein, "alkylthio" refers to an -S-(alkyl) or -S-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.

[0163] As used herein, "arylthio" refers to the group -S-aryl or -S-heteroaryl. Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like.

[0164] As used herein, "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0165] As used herein, "cyano" refers to the group --CN.

[0166] The term "oxo" refers to the carbonyl oxygen. For example, cyclopentyl substituted with oxo is cyclopentanone.

[0167] As used herein, "bond" refers to a covalent bond.

[0168] The term "substituted" means that the specified group or moiety has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. When the term "substituted" is used to describe a structural system, substitution can occur at any valence-allowed position in the system. In some embodiments, "substituted" means that the specified group or moiety has one, two, or three substituents. In other embodiments, "substituted" means that the specified group or moiety has one or two substituents. In yet other embodiments, "substituted" means that the specified group or moiety has one substituent.

[0169] As used herein, "optionally" or "optionally" means that the event or circumstance described thereafter may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 "Each hydrogen atom in an aryl or monocyclic or bicyclic heteroaryl is independently optionally substituted with C1-C6 alkyl" means that alkyl is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 In either the aryl or monocyclic or bicyclic heteroaryl, the following may be present by replacing a hydrogen atom of each alkyl group, but may not be present. This description includes C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 In the case where the aryl or monocyclic or bicyclic heteroaryl is substituted with an alkyl group, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Includes situations where the aryl or monocyclic or bicyclic heteroaryl is not substituted with an alkyl group.

[0170] As used herein, "independently" means that the event or situation described thereafter holds its own relationship to other similar events or situations. For example, in a situation where several equivalent hydrogen groups are optionally replaced with other groups described in the situation, the use of "independently and optionally" means that each of the hydrogen atoms of the group may be replaced with other groups, and the groups replacing each of the hydrogen atoms may be the same or different. Or, for example, when there are multiple groups, all of which can be selected from a set of possible ones, the use of "independently" means that each of these groups can be selected from a set of possible ones separately from any other group, and the groups selected in the situation may be the same or different.

[0171] As used herein, the term "together with the carbon atom to which they are attached" refers to two substituents (e.g., R 1 and R 2 ) form a group as defined in the claims, such as C3-C6 cycloalkyl. In particular, the terms "together with the carbon atom to which they are attached" means, for example, R 1 and R 2 and if the carbon atoms to which they are attached form a C3-C6 cycloalkyl, then the rings formed are meant to be attached to the same carbon atom. For example, the term "R 1 and R 2 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl" includes the following compounds: [ka]

[0172] wherein said spirocyclic ring is optionally substituted as defined in certain embodiments.

[0173] The term "pharmaceutically acceptable salts" as used herein refers to salts whose counterions can be used in medicines. See generally SM Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of a subject without undue toxicity, irritation, or allergic response. The compounds described herein may contain sufficiently acidic groups, sufficiently basic groups, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. Such salts include:

[0174] (1) Acid addition salts obtainable by reaction of the free base parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid, or malonic acid; or

[0175] (2) Salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when coordinated with an organic base, such as ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine, etc. Includes.

[0176] Pharmaceutically acceptable salts are well known to those of skill in the art, and any such pharma- ceutically acceptable salt may be contemplated in connection with the embodiments described herein. Examples of pharma- ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen-phosphate, dihydrogen-phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioxide, hex ... ,6-diacidote, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate and mandelate. A list of other suitable pharma- ceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0177] For compounds of Formulae I-IIIA that contain a basic nitrogen, pharma- ceutically acceptable salts can be prepared by any suitable method available in the art, for example, by the addition of the free base to an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, or to an acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidyl acid, e.g., glucuronic acid or galacturonic acid. , alpha-hydroxy acids, such as mandelic acid, citric acid or tartaric acid, amino acids, such as aspartic acid or glutamic acid, aromatic acids, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid, sulfonic acids, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid, or any compatible mixture of the acids mentioned herein as examples, and any other acids and mixtures thereof which, in view of the ordinary skill in the art, are considered equivalent or acceptable substitutes.

[0178] The present invention also relates to pharma- ceutically acceptable prodrugs of the compounds of formula I-IIIA and methods of treatment using such pharma- ceutically acceptable prodrugs. The term "prodrug" refers to a precursor of a specified compound that, after administration to a subject, yields the compound through a chemical or physiological process, such as solvolysis or enzymatic cleavage in vivo or under physiological conditions (e.g., the prodrug exposed to physiological pH is converted to a compound of formula I-IIIA). A "pharma- ceutically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerable and otherwise biologically suitable for administration to a subject. Illustrative methods for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

[0179] The present invention also relates to pharma- ceutically active metabolites of the compounds of formula I-IIIA and the use of such metabolites in the methods of the present invention. "Pharmaceutically active metabolites" refer to the pharmacologically active products of metabolism in the body of the compounds of formula I-IIIA or salts thereof. Prodrugs and active metabolites of a compound can be determined using routine techniques known or available in the art. For example, Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; see Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

[0180] Any formula depicted herein represents a compound of that structural formula as well as certain variations or forms. For example, any formula depicted herein is intended to include a racemate or one or more enantiomers, diastereomers, or geometric isomers, or mixtures thereof. Additionally, any formula depicted herein is also intended to refer to a hydrate, solvate, or polymorph of such a compound, or mixtures thereof. For example, the symbol [ka] Compounds described by a structural formula containing the symbol [ka] includes both stereoisomers for the carbon atom to which the bond is attached, especially the bond [ka] Both [ka] For example, in certain exemplary embodiments, certain compounds provided herein have the formula [ka]

[0181] This formula is representative of compounds having both stereochemical configurations at the relevant carbon atoms, particularly in this example [ka]

[0182] and each R 3 and R 3’ It is understood that by the definition other stereochemical combinations are included.

[0183] Any formula given herein is also intended to represent unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have structures represented by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of the invention include, respectively: 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 36 Cl and 125 I and other isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine. Such isotopically labeled compounds are useful in metabolic studies, preferably 14 C), reaction kinetic studies (e.g. 2 H or3 3H), detection or imaging techniques including drug or substrate tissue distribution assays [e.g., positron emission tomography (PET) or single photon emission computed tomography (SPECT)], or radioactive treatment of a subject. 2 Substitution with heavy isotopes such as H) may provide certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, due to greater metabolic stability. Isotopically labeled compounds of the invention and prodrugs thereof can generally be prepared by substituting readily available reagents for non-isotopically labeled reagents and following the methods disclosed in the schemes or in the examples and preparations below.

[0184] As used herein, "ALK" refers to anaplastic lymphoma kinase, which, together with leukocyte tyrosine kinase (LTK), belongs to the insulin receptor (IR) superfamily of receptor tyrosine kinases. It is recognized that ALK refers to the ALK gene, the corresponding mRNA transcribed from the ALK gene, the protein product of translation of the corresponding mRNA, and each of the above involving rearrangements or fusions of portions of ALK with other genes or gene products, including, but not limited to, NPM, EML4, TPR, TFG, ATIC, CLTC1, TPM4, MSN, ALO17, MYH9, etc. It is further recognized that "ALK" refers to mutations in the ALK gene oral K protein, which may result in acquired resistance mechanisms to treatment with ALK inhibitors, as described above. It is recognized that ALK mutations are not necessarily dependent on the nature of the rearrangement or fusion partner, e.g., EML4, NPM, etc., and that the mutations may be, for example, missense mutations, insertions, or deletions occurring in the ALK portion of the ALK rearrangement or fusion protein. Examples of mutation sites include, but are not limited to, L1196, L1198, G1202, D1203, S1206, T1151, L1152, E1210, F1174, C1156, I1171, V1180, F1245, G1269, R1275, and the like, and combinations thereof. Examples of ALK mutations include, but are not limited to, L1196M, G1202R, C1156Y, D1203N, G1202 deletion, E1210K, S1206C, F1174C, F1174L, F1174S, F1174V, F1245C, G1269A, G1269S, I1171N, L1152P, L1152R, L1198F, R1275Q, S1206R, T1151-L1152insT, T1151M, V1180L, and the like, and combinations thereof. Examples of multiple ALK mutations include, but are not limited to, E1210K / D1203N, E1210K / S1206C, L1198F / C1156Y, L1198F / G1202R, L1198F / L1196M, L1196M / G1202R, L1198F / C1156Y, G1202R / G1269A, G1202R / G1269A / L1204V, and the like.

[0185] As used herein, the term "cancer" includes ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER cancer, and ALCL. + These include, but are not limited to, breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian carcinoma, gastric adenocarcinoma, colorectal carcinoma, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, papillary thyroid carcinoma, Spitz tumor, sarcoma, astrocytoma, brain low-grade glioma, breast secretory carcinoma, breast analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, cutaneous melanoma, squamous cell carcinoma of the head and neck, childhood glioma CML, prostate cancer, squamous cell carcinoma of the lung, ovarian serous cystadenocarcinoma, castration-resistant prostate cancer, Hodgkin's lymphoma, and serous and clear cell endometrial carcinoma.

[0186] Representative Embodiments In certain embodiments, each R 1 and R 2 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, monocyclic or bicyclic heteroaryl, -OR a , -OC(O)R a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)ORb , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O)2R a R b , -P(O)NR a R b , -P(O)NR a R b , -P(O)OR a , -P(O)2OR a , -CN or -NO2, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and monocyclic or bicyclic heteroaryl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OC(=N)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e Rf , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)NR e R f , -P(O)OR e , -P(O)2OR e , -CN or -NO2. 1 and R 2 together with the carbon atom to which they are attached form a C-C cycloalkyl. In some embodiments, each R 1 and R 2 when present, are independently H, deuterium, or C1-C6 alkyl.

[0187] In certain embodiments, each R 3 and R 3’are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Aryl, monocyclic or bicyclic heteroaryl, -OR a , -OC(O)R a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O)2R a , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)NR a R b , -OS(O)NR a R b , -OS(O)2NR a R b , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR a R b , -NR a S(O)R b , -NR a S(O)2R b , -NR a S(O)NR a R b , -NR a S(O)2NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -PR a R b , -P(O)R a R b , -P(O)2R a R b , -P(O)NR a R b , -P(O)NRa R b , -P(O)OR a , -P(O)2OR a , -CN or -NO2, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl, monocyclic or bicyclic heteroaryl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OC(=N)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PRe R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)NR e R f , -P(O)OR e , -P(O)2OR e , -CN or -NO2. 3 and R 3’ together with the carbon atom to which they are attached form a C3-C6 cycloalkyl, where each hydrogen atom in the C3-C6 cycloalkyl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OC(=N)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e Rf , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)NR e R f , -P(O)OR e , -P(O)2OR e , -CN, or -NO2. 3 and R 3’ are independently H, deuterium, or C1-C6 alkyl. In some embodiments, R 3 and R 3’ together with the carbon atom to which they are attached form a C-C cycloalkyl. In some embodiments, each R 3’ are H or deuterium. In some embodiments, both R 3’ are combined to form the divalent group -(CR 1 R 2 ) m -, where m is 1 or 2.

[0188] In certain embodiments, each R 4 and R 5 are independently hydrogen, deuterium, halogen, -OR c , -OC(O)R c , -OC(O)NR c R d , -OC(=N)NR c R d , -OS(O)R c , -OS(O)2R c , -OS(O)NR c R d , -OS(O)2NR c R d , -SR c, -S(O)R c , -S(O)2R c , -S(O)NR c R d , -S(O)NR c R d , -NR c R d , -NR c C(O)R d , -NR c C(O)OR d , -NR c C(O)NR c R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O)2R d , -NR c S(O)NR c R d , -NR c S(O)2NR c R d , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(=N)NR c R d , -PR c R d , -P(O)R c R d , -P(O)2R c R d , -P(O)NR c R d , -P(O)NR c R d , -P(O)OR c , -P(O)2OR c , -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C 10 aryl or monocyclic or bicyclic heteroaryl, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-7 membered heterocycloalkyl, C6-C10 Each hydrogen atom in an aryl, monocyclic or bicyclic heteroaryl, C5-C8 cycloalkyl or 5-8 membered heterocycloalkyl is independently optionally selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OC(=N)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f, -P(O)NR e R f , -P(O)OR e , -P(O)2OR e , -CN, or -NO2. 4 is H or deuterium is In one embodiment, R 5 is fluoro.

[0189] In one embodiment, R 6 is H, deuterium, or C1-C6 alkyl, where each hydrogen atom in the C1-C6 alkyl is independently optionally selected from deuterium, halogen, -OR e , -SR e or -NR e R f In one embodiment, R 6 is H.

[0190] In certain embodiments, each R 7 are independently hydrogen or deuterium is In one embodiment, R 7 is H.

[0191] In certain embodiments, each R a , R b , R c , R d , R e and R f are independently H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C 10 It is selected from the group consisting of aryl and 5- to 7-membered heteroaryl.

[0192] In some embodiments, n is 0, 1, 2 or 3. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0193] The following represent illustrative embodiments of compounds of Formulas I-IIIA. [Table 1] [Table 2] [Table 3]

[0194] Those of skill in the art will recognize that the species listed or described herein are not exhaustive and that additional species may be selected that fall within the scope of these defined terms.

[0195] Pharmaceutical Compositions For treatment purposes, pharmaceutical compositions containing the compounds described herein may further contain one or more pharma- ceutically acceptable additives. Pharmaceutically acceptable additives are substances that are non-toxic and otherwise biologically suitable for administration to subjects. Such additives facilitate the administration of the compounds described herein and are compatible with the active ingredient. Examples of pharma-ceutically acceptable additives include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, colorants, bulking agents, emulsifiers or taste modifiers. In a preferred embodiment, the pharmaceutical compositions of the present invention are sterile compositions. Pharmaceutical compositions can be prepared using mixing techniques that are known or available to those skilled in the art.

[0196] Sterile compositions are also contemplated by the present invention, including compositions that comply with regulations of national or local authorities having jurisdiction over such compositions.

[0197] The pharmaceutical compositions and compounds described herein can be formulated in a variety of dosage forms by conventional methods known in the art. They may be formulated as solutions, emulsions, suspensions or dispersions in suitable pharmaceutical solvents or carriers, or with solid carriers as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution or capsules. The pharmaceutical compositions of the present invention may be administered by a suitable delivery route, such as oral, parenteral, rectal, nasal, topical or ocular routes, or by inhalation. Preferably, the compositions may be formulated for intravenous or oral administration.

[0198] For oral administration, the compounds of the present invention may be provided in solid form, such as tablets or capsules, or as a solution, emulsion, or suspension. To prepare oral compositions, the compounds of the present invention may be formulated to provide a dosage of, for example, about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 to 250 mg per day, or about 250 mg to 1 g per day. Oral tablets may contain the active ingredient mixed with compatible pharma- ceutically acceptable excipients, such as diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, coloring agents, and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Examples of liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are examples of disintegrants. Binders may include starch and gelatin. Lubricants, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0199] Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, active ingredient can be mixed with solid, semi-solid or liquid diluents.Soft gelatin capsules can be prepared by mixing active ingredient with water, oil, such as peanut oil or olive oil, liquid paraffin, short chain fatty acid mono- and diglyceride mixture, polyethylene glycol 400 or propylene glycol.

[0200] Orally administered liquids may be in the form of suspensions, solutions, emulsions or syrups, or may be provided as lyophilized or dry products for reconstitution with water or other suitable medium before use.Such liquid compositions may optionally contain pharma- ceutically acceptable additives, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous media, such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water; preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents, such as lecithin; and, optionally, flavorings or colorings.

[0201] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal or subcutaneous routes, the agents of the invention may be provided in a sterile aqueous solution or suspension buffered to an appropriate pH and isotonicity or in a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be provided in unit dose forms, such as ampoules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose can be withdrawn, or in solid forms or pre-concentrates that can be used to prepare injectable formulations. Illustrative infusion doses range from about 1 to 1000 μg / kg / min of drug mixed with a pharmaceutical carrier over a period ranging from a few minutes to a few days.

[0202] For nasal, inhaled or oral administration, the pharmaceutical compositions of the present invention may be administered using, for example, an aerosol formulation which also contains a suitable carrier. The compositions of the present invention may be formulated for rectal administration as suppositories.

[0203] For topical application, the compound of the present invention is preferably formulated as a cream or ointment or similar vehicle suitable for topical administration.For topical administration, the compound of the present invention can be mixed with a pharmaceutical carrier at a drug concentration of about 0.1% to about 10% to the vehicle.Another method of administering the drug of the present invention can utilize a patch formulation for transdermal delivery.

[0204] As used herein, the term "treat" or "treatment" includes both "prophylactic" and "curative" treatment. "Prophylactic" treatment is meant to indicate the delay of progression of a disease, disease symptom, or medical condition, the suppression of symptoms that may appear, or the reduction of the risk of progression or recurrence of a disease or condition. "Curative" treatment includes the reduction of the severity or suppression of the worsening of an existing disease, symptom, or condition. Thus, treatment includes the reduction or prevention of existing disease symptoms, the prevention of further symptoms from occurring, the reduction or prevention of the underlying systemic cause of the symptoms, the prevention of a disorder or disease, for example, the arrest of the progression of a disorder or disease, the alleviation of a disorder or disease, the induction of regression of a disorder or disease, the alleviation of the condition that causes the disease or disorder, or the arrest of the symptoms of a disease or disorder.

[0205] The term "subject" refers to a mammalian patient, such as a human, who needs such treatment, or in the case of veterinary applications, it may be a laboratory animal, agricultural or domestic animal. In some embodiments, the subject may be a human. In some embodiments, the subject may be a domestic animal for veterinary use, such as a dog or cat. In some embodiments, the subject may be an agricultural animal, such as a cow, a pig, a horse, etc. In some embodiments, the subject may be a laboratory animal, such as a rodent (e.g., a mouse, a rat, etc.), a primate (e.g., a rhesus monkey, etc.), a dog, etc.

[0206] Examples of diseases include cancer, pain, neurological diseases, autoimmune diseases and inflammation. Cancer includes, for example, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophageal cancer, glioblastoma, head and neck cancer, inflammatory myofibroblastic tumor and anaplastic large cell lymphoma. Pain includes pain from any source or etiology, including, for example, cancer pain, chemotherapy treatment pain, neuralgia, injury pain or other sources. Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren's syndrome, type I diabetes and lupus. Examples of neurological diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. Examples of inflammatory diseases include atherosclerosis, allergy and inflammation due to infection or injury.

[0207] In some embodiments, the compounds and pharmaceutical compositions of the present invention specifically target tyrosine receptor kinases, particularly ALK, more particularly ALK with one or more mutations as described herein.Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, delay or inhibit ALK activity.In a preferred embodiment, the target of the treatment method is cancer.In another embodiment, the method is the treatment method for lung cancer, particularly non-small cell lung cancer.

[0208] In the inhibitory methods of the present invention, "effective amount" refers to an amount sufficient to inhibit the target protein. Such target modulation measurements can be performed by routine analytical methods, such as those described below. Such modulation is useful in a variety of contexts, including in vitro assays. In such methods, the cells are preferably cancer cells with signaling abnormalities due to upregulation of ALK, particularly ALK with one or more mutations, particularly as described herein.

[0209] In certain embodiments, the uses and methods described herein for any compound of Formulae I-IIIa may be for the treatment of cancers mediated by ALK or by rearrangements or fusions of ALK with other genes or gene products, including, but not limited to, NPM, EML4, TPR, TFG, ATIC, CLTC1, TPM4, MSN, ALO17, MYH9, etc. In certain embodiments, the uses and methods described herein for any compound of Formulae I-IIIa may be for the treatment of cancers mediated by rearrangements or fusions of ALK or ALK with other genes or gene products, including but not limited to NPM, EML4, TPR, TFG, ATIC, CLTC1, TPM4, MSN, ALO17, MYH9, etc., and having at least one mutation, such as a missense mutation, insertion or deletion, occurring in the ALK portion of the ALK rearrangement or fusion protein, where the mutation sites include, but are not limited to, L1196, L1198, G1202, D1203, S1206, T1151, L1152, E1210, F1174, C1156, I1171, V1180, F1245, G1269, R1275, etc., and combinations thereof.

[0210] In certain embodiments, the uses and methods described herein for any of the compounds of Formulae I-IIIa are directed to a cancer that has at least one mutation, such as a missense mutation, insertion or deletion, that is mediated by ALK or a rearrangement or fusion of ALK with another gene or gene product, including, but not limited to, NPM, EML4, TPR, TFG, ATIC, CLTC1, TPM4, MSN, ALO17, MYH9, etc., that occurs in the ALK portion of the ALK rearrangement or fusion protein. It may be for the treatment of cancer, wherein the ALK mutation is L1196M, G1202R, C1156Y, D1203N, G1202 deletion, E1210K, S1206C, F1174C, F1174L, F1174S, F1174V, F1245C, G1269A, G1269S, I1171N, L1152P, L1152R, L1198F, R1275Q, S1206R, T1151-L1152insT, T1151M, V1180L, etc. and combinations thereof. In certain embodiments, the uses and methods described herein for any compound of Formulae I-IIIa include those that involve missense mutations, insertions, or mutations mediated by ALK or rearrangements or fusions of ALK with other genes or gene products, including, but not limited to, NPM, EML4, TPR, TFG, ATIC, CLTC1, TPM4, MSN, ALO17, MYH9, and the like, that occur in the ALK portion of the ALK rearrangement or fusion protein. or deletion, wherein the mutations are multiple ALK mutations selected from E1210K / D1203N, E1210K / S1206C, L1198F / C1156Y, L1198F / G1202R, L1198F / L1196M, L1196M / G1202R, L1198F / C1156Y, G1202R / G1269A and G1202R / G1269A / L1204V.

[0211] In the treatment methods of the present invention, an "effective amount" means an amount or dosage sufficient to generally provide the desired therapeutic benefit to a subject in need of such treatment. An effective amount or dosage of a compound of the present invention can be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, such as the method or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the infection, the subject's health, condition, and weight, and the judgment of the treating physician. Exemplary dosages range from about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 to 250 mg per day, or about 250 mg to 1 g per day. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).

[0212] Once the subject's disease begins to improve, the dosage can be adjusted to preventive or maintenance treatment.For example, the dosage or frequency of administration or both can be reduced as a function of symptoms to a level at which desired therapeutic or preventive effects are maintained.Of course, once symptoms are alleviated to an appropriate level, treatment can be discontinued.However, the subject may require intermittent treatment on a long-term basis based on the recurrence of any symptoms.The subject may also require chronic treatment on a long-term treatment basis.

[0213] Drug Combinations The compounds of the present invention described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of diseases and disorders described herein. Additionally, the additional active ingredients include other treatments or drugs that reduce the adverse effects of the intended disease target treatment. Such combinations may help to increase efficacy, reduce other disease symptoms, reduce one or more side effects, or reduce the required dose of the compounds of the present invention. The additional active ingredients may be administered in a pharmaceutical composition separate from the compounds of the present invention or may be included in a single pharmaceutical composition with the compounds of the present invention. The additional active ingredients may be administered simultaneously, before, or after the administration of the compounds of the present invention.

[0214] The additional active ingredient contained in the combination drug is known or discovered to be effective in treating the diseases and disorders described herein, including those that are active against other targets associated with the disease.For example, the compositions and formulations and treatment methods of the present invention may further comprise other drugs or medicines, such as other active agents useful for treating or alleviating the target disease or related symptoms or conditions.For cancer indications, such additional agents include, but are not limited to, kinase inhibitors, such as EGFR inhibitors (e.g., erlotinib, gefitinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), ALK inhibitors (e.g., crizotinib), standard chemotherapeutic agents, such as alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormonal therapy, or corticosteroids.For pain indications, suitable combination agents include anti-inflammatory agents, such as NSAIDs. The pharmaceutical compositions of the present invention may further comprise one or more of such active agents, and the methods of treatment may further comprise administration of an effective amount of one or more of such active agents.

[0215] chemical synthesis Chemicals useful in the methods of the invention will now be described with reference to the following illustrative synthetic schemes for general preparation followed by specific examples. Those skilled in the art will recognize that to obtain the various compounds herein, starting materials may be appropriately selected such that the ultimately desired substituents are carried through the performance of the reaction schemes, with or without appropriate protection to obtain the desired products. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituents, suitable groups that may be carried through the reaction schemes, substituting the desired substituents, if appropriate. Furthermore, those skilled in the art will recognize that the conversions shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups.

[0216] Abbreviation The embodiments described herein use materials that are known to those of skill in the art, including, but not limited to, those described using the following abbreviations: [Table 4] EXAMPLES

[0217] Comparative Example Comparative Examples 1 and 2 were prepared as described in International PCT Publication WO2019126122, which corresponds to International PCT Application PCT / US2018 / 066159, filed December 18, 2018. [Table 5]

[0218] Example 1: General Method A Preparation of tert-butyl {1-[2-(chloromethyl)-4-fluorophenoxy]-2-methylpropan-2-yl}carbamate (A-1) [ka]

[0219] Step 1: To a solution of A-1-1 (259 mg, 1.52 mmol) in anhydrous DMF (7.35 mL) was added NaH (60% in mineral oil, 91.3 mg, 2.28 mmol) under argon at 0°C. The reaction was stirred and warmed for 1 h. The reaction was cooled to 0°C and A-1-2 was added. The reaction was stirred and the temperature was raised to 50°C and stirred for 18 h. The reaction was quenched with saturated NH4CL (aqueous 5 mL) at 0°C and stirred vigorously. Water (25 mL) was added and extracted with DCM (3 x 25 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Flash column chromatography (12 g silica, ISCO, 0-50% EA in hexanes) afforded A-1-3 (267 mg, 51% yield).

[0220] Step 2: To a solution of A-1-3 (267 mg, 0.782 mmol) in anhydrous THF (3.9 mL) was added LiBH4 (34 mg, 1.56 mmol) at 0 °C. The reaction was stirred for 18 h, allowing the temperature to rise to ambient. It was quenched with water (5 mL) and 2 M NaOH (1 mL), then extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Flash column chromatography (12 g silica, ISCO, using ELSD detection with 0-50% EA in hexanes) afforded A-1-4 (29.3 mg, 12% yield).

[0221] Step 3: To a solution of A-1-4 (29.3 mg, 93.5 μmol) in DCM (1 mL) was added Hunig's base (36.2 mg, 280.5 μmol, 48.8 μL). The reaction was cooled to 0 °C and mesyl chloride (13.9 mg, 121.5 μmol, 9.4 μL) was added. The reaction was stirred with the temperature increasing from 0 to 22 °C over 18 h. The reaction was quenched with 2 M HCL (aq) (1 mL) at 0 °C. Diluted with water and DCM (5 mL each), the layers were separated and the aqueous layer was extracted with DCM (2 x 5 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Flash column chromatography (12 g silica, ISCO, 0-50% EA in Hex) afforded A-1 (25.2 mg, 75.9 μmol, 81% yield).

[0222] Example 2: General Method B Preparation of tert-butyl [(1-{[2-(chloromethyl)-4-fluorophenoxy]methyl}cyclopropyl)methyl]carbamate (A-2) [ka]

[0223] Step 1: To a solution of A-1-1 (100 mg, 587.7 μmol), A-2-1 (118.2 mg, 587.7 μmol) and PPh3 (231.2 mg, 881.6 μmol) in anhydrous DCM (403.14 μL) was added DIAD (190.2 mg, 940.4 μmol, 184.6 μL) with stirring at 0 °C. The mixture was stirred for 18 h and warmed to RT. Flash column chromatography (ISCO, 12 g silica, 0-50% ethyl acetate in hexanes) afforded A-2-2 (163.1 mg, 433.3 μmol, 73.7% yield).

[0224] Step 2: Compound A-2 was prepared according to general method A starting from B-1-2 in step 2.

[0225] Compound A-3 was prepared according to general procedure B

[0226] Compounds A-5, A-6, A-7 and A-8 were prepared according to general procedure B.

[0227] Example 3: General Method C Preparation of tert-butyl (1-((2-(chloromethyl)-4-fluorophenoxy)methyl)cyclopropyl)carbamate (A-4) [ka]

[0228] Compound A-4 was prepared according to general procedure C

[0229] Step 1. To a solution of A-4-1 (500 mg, 2.67 mmol) in DCM (12.25 mL) was added triethylamine (811 mg, 8.0 mmol, 1.12 mL). The mixture was cooled to 0 °C and p-toluenesulfonyl chloride (TosCl, 611 mg, 3.2 mmol) and DMAP (6.5 mg, 53 μmol) were added. The reaction was warmed to 22 °C and stirred for 18 h. Water (15 mL) and DCM (10 mL) were added and the organic layer was separated. The aqueous layer was extracted with DCM (2 × 10 mL), dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography (ISCO system, 24 g silica, 0-30% ethyl acetate in hexanes) afforded A-4-2 (608 mg, 1.78 mmol, 67%).

[0230] Step 2. To a solution of A-1-1 (100 mg, 588 μmol) in DMF (3.00 L) was added cesium carbonate (479 mg, 1.5 mmol) and A-4-2 (200 mg, 588 mol). The mixture was stirred at 70 °C for 17 h. The reaction mixture was cooled, diluted with DCM (5 mL), filtered through a syringe filter, and concentrated under reduced pressure. Flash column chromatography (12 g silica, ISCO, 0-80% ethyl acetate in hexane) afforded A-4-3 (47 mg, 138 μmol, 23% yield).

[0231] Step 3. To a solution of A-4-3 (47 mg, 138 μmol) in anhydrous THF (3.9 mL) was added LiBH4 (9 mg, 415 μmol) at 0 °C. The reaction was warmed to 22 °C and stirred for 21 h. The reaction was cooled to 0 °C, quenched with 2M NaOH (3 mL) and water (3 mL), then extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash column chromatography (12 g silica, ISCO, 0-12.5% ​​methanol in dichloromethane) afforded A-4-4 (37.1 mg, 119 μmol, 86% yield).

[0232] Step 4. To a solution of A-4-4 (37.1 mg, 120 μmol) in DCM (1 mL) was added mesyl chloride (20.5 mg, 179 μmol, 14 μL). The reaction was cooled to 0° C. and Hunig's base (46 mg, 357 μmol, 62 μL) was added. The reaction was slowly warmed to 22° C. and stirred for 71 h. The reaction was cooled to -20° C. and quenched with 2M HCL (aq) (2 mL). Diluted with water and DCM (2 mL each), the layers were separated and the aqueous layer was extracted with DCM (2×5 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Flash column chromatography (12 g silica, ISCO, 0-40% ethyl acetate in hexanes) afforded A-4 (25.2 mg, 75.9 μmol, 75% yield). [Table 6]

[0233] Example 4: General Method D Preparation of Ethyl 5-chloro-6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylate (B) [ka]

[0234] Step 1. To a solution of B-1 (150 g, 1.44 mol, 143 mL, 1.00 equiv.) and B-1A (104 g, 1.73 mol, 105 mL, 1.20 equiv.) in tetrahydrofuran (3.00 L) was slowly added sodium hydride (80.7 g, 2.02 mol, 60.0% purity, 1.40 equiv.) at 0° C. over 30 min under nitrogen while maintaining the temperature below 0° C. The reaction mixture was stirred at 0° C. for 12 h. Formation of a white solid was observed, methyl tert-butyl ether (2.00 L) was added, filtered, and the filter cake was dried under reduced pressure to give crude B-2 (283 g, crude) as a light yellow solid.

[0235] Step 2. To a solution of B-2A (165 g, 1.06 mol, 1.00 equiv) in DMF (3.00 L) was added cesium carbonate (624 g, 1.91 mol, 1.80 equiv) and B-2 (279 g, 1.91 mol, 1.80 equiv). The mixture was stirred at 110° C. for 12 h. The reaction mixture was diluted with water (3.00 L) and hydrochloric acid (5.00 M, 1.80 L) was added slowly to the mixture at 20° C., and the resulting precipitated solid was filtered and washed with methyl alcohol (300 mL). The filter cake was concentrated under reduced pressure to give crude B-3 (162 g, 609 mmol, 57.4% yield, 89.3% purity) as a yellow solid.

[0236] Step 3. B-3 (100 g, 375 mmol, 1.00 equiv) was added to phosphorus oxychloride (300 mL). The mixture was stirred at 110° C. for 12 h. The reaction mixture was concentrated under reduced pressure until the solvent was removed and the product precipitated. The residue was diluted with ice water (1.00 L), filtered, and the solvent was removed. The filter cake was then dissolved in dichloromethane (2.00 L) and water (2.00 L) was added. The organic phase was separated, washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give B-4 (64.0 g, 213 mmol, 56.7% yield, 85.0% purity) as a grey solid.

[0237] Step 4. Aluminum trichloride (752 g, 5.64 mol, 308 mL, 5.00 equiv) was added in one portion to anhydrous dichloroethane (4.90 L), the mixture was stirred at 20° C. for 10 min under nitrogen, then B-4 (324 g, 1.13 mol, 1.00 equiv) was added in 5 equal portions to the mixture. The mixture was stirred at 20° C. for 24 h. The reaction mixture was quenched by addition of hydrochloric acid (5.00 M, 2.00 L) at 0° C., diluted with water (1.00 L), and then extracted with ethyl acetate (3.00 L×3). The combined organic layers were washed with water (2.00 L) and brine (1.00 L×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product B (280 g, 920 mmol, 81.6% yield, 79.4% purity) as a grey solid.

[0238] Example 5: General Method E Preparation of compound ethyl (3S)-3-(difluoromethyl)-3,4-dihydro-2H-pyrazolo[1,2]pyrimido[2,4-d][1,4]oxazine-6-carboxylate (C) [ka]

[0239] Step 1: To a solution of C-1 (5.00 g, 22.1 mmol, 1.00 equiv) in DCM (120 mL) was added pyridine (2.80 g, 35.4 mmol, 2.85 mL, 1.60 equiv) and trifluoroacetic anhydride (7.48 g, 26.5 mmol, 4.37 mL, 1.20 equiv) at -20 °C. The mixture was stirred at -20 °C to 0 °C for 5 h. The reaction mixture was concentrated under reduced pressure at 30 °C to remove the solvent. The residue was diluted with water (50.0 mL) and extracted with petroleum ether / ethyl acetate = 10:1 (50.0 mL x 3). The combined organic layer was washed with brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 50 / 1) to give C-2 (6.70 g, 16.8 mmol, 76.2% yield, 90.0% purity) as a light yellow oil.

[0240] Step 2. To a solution of C-2 (0.50 g, 1.40 mmol, 1.00 equiv) in dioxane (5.00 mL), (4-methoxyphenyl)methanamine (229 mg, 1.67 mmol, 216 μL, 1.20 equiv) and triethylamine (169 mg, 1.67 mmol, 233 μL, 1.20 equiv) were added. The mixture was stirred at 90 °C for 12 h. The reaction mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (20.0 mL × 2). The combined organic layers were washed with brine (15.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give C-3 (0.35 g, 1.01 mmol, 72.3% yield, 99.5% purity) as a light yellow oil.

[0241] Step 3. To a solution of C-3 (3.35 g, 9.70 mmol, 1.00 equiv) in tetrahydrofuran (34.0 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.00 M, 9.70 mL, 1.00 equiv). The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with water (80.0 mL) at 20 °C and extracted with ethyl acetate (50.0 mL × 2). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to give C-4 (2.10 g, 8.99 mmol, 92.7% yield, 99.0% purity) as a light yellow oil.

[0242] Step 4. To a solution of C-4 (2.60 g, 11.2 mmol, 1.00 equiv.) in dimethyl sulfoxide (50.0 mL), potassium fluoride (1.63 g, 28.1 mmol, 658 μL, 2.50 equiv.) and B (2.74 g, 11.2 mmol, 1.00 equiv.) were added. The mixture was stirred at 120 °C for 3 h. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic layers were washed with brine (50.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give compound C-5 (1.00 g, 1.83 mmol, 16.3% yield, 80.3% purity) as a yellow oil.

[0243] Step 5. To a solution of C-5 (1.00 g, 2.28 mmol, 1.00 equiv) in dimethyl sulfoxide (70.0 mL) was added cesium carbonate (2.97 g, 9.12 mmol, 4.00 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (50.0 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give C-6 (0.75 g, 1.43 mmol, 62.9% yield, 80.0% purity) as a yellow solid.

[0244] Step 6. C-6 (0.51 g, 1.22 mmol, 1.00 equiv) was added to trifluoroacetic acid (10.0 mL). The mixture was stirred at 70 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give C (0.27 g, 862 μmol, 70.8% yield, 96.0% purity) as a grey solid.

[0245] Example 6: General Method F Preparation of (4S)-4-(difluoromethyl)-8-fluoro-13,13-dimethyl-3,4,13,14-tetrahydro-6H-18,1-(metheno)[1,4]oxazino[3,4-i]pyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-15(12H)-one (1) [ka]

[0246] Step 1: A-1 (R = Cl, 25.2 mg, 75.95 μmol) was dissolved in DMF (0.5 mL) at room temperature. Cs2CO3 (65.55 mg, 201.18 μmol) was added followed by C (20 mg, 67.06 μmol). The mixture was stirred at 22 °C for 18 h. The reaction was diluted with DCM (5 mL) and cooled. The solution was filtered and the filtrate was concentrated under reduced pressure. Flash column chromatography (ISCO, 12 g, 20-80% ethyl acetate in hexanes) afforded 1-1 (23.4 mg, 39.42 μmol, 59% yield).

[0247] Step 2: 1. To a solution of 1-1 (23.4 mg, 39.42 μmol) in THF (1 mL), 2 mL of ethanol (2 mL) and methanol (1 mL) was added aqueous LiOH (2M, 2 mL) at ambient temperature. The mixture was stirred at 22° C. for 36 h. It was cooled to −20° C. and then quenched with aqueous HCl solution (2.0 M, 2.1 mL) to acidic pH. The mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine and then dried over Na2SO4. The salts were filtered and the filtrate was concentrated under reduced pressure and dried under high vacuum. The crude was used directly without further purification and assumed quantitative yield. 2. The crude was dissolved in anhydrous DCM (2 mL) and HCl / 4M dioxane (4M, 2 mL) was added. The mixture was stirred for 45 min at 22° C. and then concentrated to dryness under reduced pressure followed by high vacuum. The resulting crude was used directly without further purification and assumed quantitative yield. 3. Anhydrous DCM (1.90 mL) was added in one portion, followed by Hunig's base (50.93 mg, 394.05 μmol, 68.64 μL) and FDPP (22.71 mg, 59.11 μmol). The reaction mixture was stirred for 18 h and then quenched with 2M Na2CO3 solution (5 mL). The mixture was stirred for 5 min and then extracted with DCM (3×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (ISCO system, 12 g silica, 0–10% methanol in dichloromethane) afforded compound 1 (10.8 mg, 24.14 μmol, 61.26% yield, 3 steps).

[0248] Compounds 2-8 were prepared according to general method F using starting materials A-2-A-8 and compound B, respectively. [Table 7] [Table 8]

[0249] Example 7: Biological Assays In vitro assays material and method Biochemical Kinase Assay Methods Biochemical kinase assays were performed at Reaction Biology Corporation (Malvern, PA) according to the method described in reference (Anastassiadis T, et al Nat Biotechnol. 2011, 29, 1039). Specific kinase / substrate pairs and required cofactors were prepared in reaction buffer (20 mM Hepes pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO). Compounds were added to the reaction and after approximately 20 minutes, ATP (Sigma, St. Louis MO) and 33 A mixture of P ATP (Perkin Elmer, Waltham MA) was added to a final concentration of 10 μM. Reactions were allowed to proceed for 120 min at room temperature, followed by spotting of reactions onto P81 ion exchange filters (Whatman Inc., Piscataway, NJ). Unbound phosphate was removed by extensively washing the filters with 0.75% phosphoric acid. After subtracting background from control reactions containing inactive enzyme, kinase activity data were expressed as percent remaining kinase activity in the test samples compared to vehicle (dimethylsulfoxide) reactions. IC 50 Values ​​and curve fits were obtained using Prism (GraphPad Software).

[0250] Cell lines and cell culture: The colorectal cell line KM 12 (carrying an endogenous TPM3-TRK fusion gene) was obtained from NCI. The acute myeloid cell line KG-1 (carrying an endogenous OP2-FGFR1 fusion gene) was obtained from ATCC.

[0251] Cloning and stable Ba / F3 cell line generation EML4-ALK gene (variant 1) wild type, G1202R, G1202R / L1196M, G1202R / L1198F, G1202R / C1156Y and L1196M / L1198F were synthesized by GenScript and cloned into pCDH-CMV-MCS-EF1-Puro plasmid (System Biosciences, Inc). Ba / F3 EML4-ALK wild-type, G1202R, G1202R / L1196M, G1202R / L1198F, G1202R / C1156Y, L1196M / L1198F, L1198F / C1156Y, G1202R / G1269A and G1202R / G1269A / L1204V were cultured in 100% PBS-Cells. The cells were generated by transduction with lentiviruses containing L1198F / C1156Y, G1202R / G1269A or G1202R / G1269A / L1204V. Stable cell lines were selected by puromycin treatment followed by IL-3 withdrawal. Briefly, 5×10 6 Ba / F3 cells were transduced with lentiviral supernatant in the presence of 8 μg / mL protamine sulfate. Transduced cells were then selected with 1 μg / mL puromycin in the presence of IL3-containing medium RPMI1640 + 10% FBS. After 10-12 days of selection, surviving cells were further selected for IL3-independent growth.

[0252] Cell proliferation assay: 2000 cells / well were seeded in 384-well white plates for 24 h and then treated with compounds for 72 h (37° C., 5% CO2). Cell proliferation was measured using the CellTiter-Glo luciferase-based ATP detection assay (Promega) according to the manufacturer's protocol. IC 50 Determinations were performed using GraphPad Prism software (GraphPad, Inc., San Diego, Calif.).

[0253] Immunoblotting of cellular kinase phosphorylation assays Half of 1000 cells (Ba / F3 EML4-ALK WT or G1202R) / well were seeded in 24-well plates for 24 hours and then treated with compounds for 4 hours. After treatment, cells were collected and lysed in RIPA buffer (50 mM Tris, pH 7.4, 150 mM NaCl, 1% NP-40, 0.5% deoxycholate, 0.1% SDS) supplemented with 10 mM EDTA, 1x Halt protease and phosphatase inhibitors (Thermo Scientific). Protein lysates (approximately 20 μg) were dispersed in 4–12% Bolt Bis-Tris precast gels with MES running buffer (Life Technologies), transferred to nitrocellulose membranes using the Trans-Blot Turbo Transfer System (Bio-Rad) and probed with antibodies targeting phosphorylated ALK (Y1282 / 1283) (Cell Signaling Technology), ALK (Y1604), total ALK (Cell Signaling Technology), and actin (Cell Signaling Technology). Antibodies were typically incubated overnight at 4°C with gentle shaking, followed by washing and incubation with the appropriate HRP-conjugated secondary antibody. Membranes were incubated with chemiluminescent substrate for 5 min at room temperature (SuperSignal West Femto, Thermo Scientific). Chemiluminescent images were acquired with a C-DiGit Imaging System (LI-COR Biosciences). Relative density of chemiluminescent bands was quantified with LICOR's Image Studio Digits.

[0254] Solubility Test An aliquot of 1.035 mL phosphate buffer (PB) (pH 7.4) was added to a 1.5 mL tube containing 2.07 mg of test compound (2 mg mL -1The mixture was sonicated for 10 min and rotated in a rotor for >8 h at room temperature. After rotation, the tube was sonicated for 10 min and centrifuged at 13000 rpm for 15 min. 0.3 mL of the supernatant was transferred to a 0.6 mL tube and discarded for rinsing after spinning for 5 min, then approximately 0.6 mL of the remaining supernatant was transferred to the rinsed tube and centrifuged again at 13000 rpm for 15 min. All post-centrifugation supernatants were appropriately diluted and transferred for LC-MS / MS analysis and standard curves were run at 7 concentration levels (2, 4, 10, 20, 40, 100 and 200 μg mL -1 ) and used to quantify analytes in PB.

[0255] Liver microsome stability test 1. Preparation of storage and working solutions

[0256] Test compound stock solutions were prepared by measuring 1.07 mg and dissolving in 0.261 mL DMSO to achieve a 10 mM concentration. Test compound working solutions were prepared by diluting the stock solutions with DMSO to a concentration of 300 μM.

[0257] 2. Incubation

[0258] The assay was carried out in a 96-well microtiter plate. In each well, the reaction mixture (25 μL) contained test compound at a final concentration of 1 μM, 0.5 mg / mL liver microsomal protein, and 1 mM NADPH in 100 mM potassium phosphate, pH 7.4, buffered with 3.3 mM MgCl2. The mixtures were incubated in duplicate at 37° C. for 0, 15, 30, or 60 min, and 150 μL of stop solution (acetonitrile and 0.1% formic acid) and an internal standard (bucetin for positive ESI mode) were added to each reaction well to stop the reaction. The plate was then sealed and centrifuged at 4000 rpm for 15 min at 4° C. The resulting supernatant was transferred to a fresh plate for LC-MS / MS analysis of the test compounds. Verapamil was used as a positive control to validate the assay system.

[0259] 3. LC-MS / MS analysis

[0260] All samples were analyzed by LC-MS / MS using an AB Sciex API 4000 instrument connected to a Shimadzu LC-20AD LC pump system. Analytical samples were separated using a Waters Atlantis T3 dC18 reversed-phase HPLC column (20 mm x 2.1 mm) at a flow rate of 0.5 mL / min. The mobile phase consisted of 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B).

[0261] 4. Calculation

[0262] The extent of metabolism was calculated based on the disappearance of the test compound relative to the initial concentration. The initial clearance rate of the test compound was calculated using a linear regression plot of semi-log % compound remaining versus time. The elimination rate constant (equal to the negative slope) of the linear regression plot was then used to calculate the t 1 / 2 and intrinsic clearance (CL int ) was calculated as follows: k=-slope t 1 / 2 =0.693 / k CL int =k / C タンパク質

[0263] Here, C タンパク質 (mg / mL) is the microsomal protein concentration of the incubation system. This method of intrinsic clearance determination leads to the assumption that the test compound concentration is much lower than the Michaelis-Menten constant of the compound for its metabolic enzyme.

[0264] In vivo testing Subcutaneous xenograft model in immunodeficient mice Female SCID / Beige mice (5-8 weeks old) were obtained from Charles River Laboratory and housed in Innovive IVC disposable cages in HEPA filtered ventilated racks with rodent chow and water ad libitum. Approximately 5 million cells in 100 μL serum-free supplemented with 50% Matrigel (Corning, Inc) were implanted subcutaneously in the right flank region of the mice. Tumor size and body weight were measured on the indicated days. Tumor size was measured with electronic calipers and tumor volume was calculated as length*width. 2 * Calculated as a product of 0.5. Mice were cultured at 100-200 mm 3 When tumor size reached 100 mg / kg, subjects were randomized into treatment groups according to tumor size. Compound 1 or 2 was administered orally at the scheduled schedule and dose. Vehicle was used as a negative control. Lorlatinib was used as a reference for efficacy evaluation. Tumor growth inhibition (TGI) was calculated as follows: TV t If >TV0, TGI = 100% × (1-(TVt-TV0) / (CV t -CV0));TV t <TV0であるならば、TGI=100%×(2-TV t / TV0); where TV0 is the mean tumor volume of the treatment group at the start of treatment, and TV t is the mean tumor volume of the treatment group at the end of treatment, CV0 is the mean tumor volume of the vehicle control group at the start of treatment, and CV t was the mean tumor volume of the vehicle control group at the end of treatment. A TGI greater than 100% indicates tumor regression. Statistical analysis was performed using GraphPad Prism 8.4.0, and p<0.05 was considered statistically significant.

[0265] Tumor processing and immunoblotting for in vivo pharmacodynamic studies Humanely graft tumor-bearing mice slaughterAfter centrifugation, tumors were excised, flash frozen in liquid nitrogen, and stored at -80°C. Frozen tumor samples were treated with 1× cell lysis buffer (Cell Signaling Technologies) at 4°C to extract proteins. SDS-loaded samples were prepared by adding 4× LDS sample buffer and 10× reducing agent (Life Technologies, Inc) to the protein lysates. Tumor SDS protein samples were subjected to SDS-PAGE and immunoblotted with rabbit anti-phosphorylated ALK Y1282 / 1283, rabbit anti-phosphorylated ALK Y1604, rabbit anti-ALK, and mouse anti-actin antibodies (Cell Signaling Technologies). Signals from immunoblots were detected with a C-DiGit Blot Scanner from LI-COR, and signal intensity was quantified using Image Studio Digit software (LI-COR).

[0266] Pharmacokinetic study in mice Preparation of test article medium solution

[0267] To prepare 1 L of vehicle solution (0.5% CMC and 1.0% Tween 80), 10 g of Tween 80 was mixed with 985 mL of water in a 1 L bottle. The mixture was stirred until the Tween 80 was completely dissolved. With continued stirring, 5 g of CMC was dispersed very slowly into the solution. Stirring was continued until all the CMC was dissolved, which should take several hours. The resulting vehicle solution was stored at 4°C.

[0268] PK Blood Sample Processing and Bioanalytical Methods

[0269] Compounds were suspended in vehicle solution and mice were orally administered a single dose of compound at the selected dose level. Blood samples were collected into K2-EDTA-containing tubes according to a defined timetable, followed by gentle mixing to ensure dispersion of the anticoagulant. Blood samples were collected and mixed immediately before being placed on ice. Samples were then centrifuged at 5,000 RPM for 10 minutes at 4°C. Plasma was collected into pre-labeled tubes and stored at -80°C until analysis by LC-MS / MS.

[0270] In vitro results Enzyme kinase activity for ALK and mutant ALK The compounds were tested against ALK and mutant ALK in an enzyme kinase catalytic activity assay at Reaction Biology Corporation. The results are shown in Table 1. Compound 1 ("Cpd 1") and Compound 2 ("Cpd 2") each exhibited potent kinase inhibitory activity and IC2 inhibitory activity against ALK and mutant ALK. 50 Shown as <10 nM. [Table 9]

[0271] Anti-cell proliferation activity The compounds were tested in cell proliferation assays in Ba / F3 cells engineered with EML4-ALK and EML4-ALK G1202R, and also in KM12 cells carrying the TPM3-TRKA fusion and KG-1 cells carrying the OP2-FGFR1 fusion. The results are summarized in Table 2. [Table 10]

[0272] Comparative Examples 1 and 2 were also evaluated for anti-cell proliferation activity, and the results are summarized in Table 2-A. [Table 11] [Table 12]

[0273] Anti-cell proliferation of Ba / F3 cells engineered with mutant ALK The compounds were tested in cell proliferation assays in EML4-ALK wild-type (WT) and mutant ALK engineered Ba / F3 cells, and the results are summarized in Tables 3 and 3-A. [Table 13]

[0274] A side-by-side comparison of compound 1 with known kinase inhibitors in EML4-ALK wild-type (WT) and mutant ALK engineered Ba / F3 cells is shown in Table 3-A. [Table 14]

[0275] solubility The solubility was tested at pH 7.4 and the results are summarized in Table 4. [Table 15]

[0276] Liver Microsome Stability Liver microsomal stability was tested and the results are summarized in Table 5. [Table 16]

[0277] In vivo results Mouse PK Mouse PK was determined and the results are summarized in Table 6. [Table 17]

[0278] Effect of compounds 1 and 2 on Ba / F3 cell-derived xenograft tumors harboring the EML4-ALK G1202R fusion SCID / Beige mice bearing Ba / F3 cell-derived tumors with EML4-ALK G1202R fusion were randomized into 7 groups of 8 mice / group 8 days after inoculation and treated with vehicle BID, 2 mg / kg Compound 1 BID, 5 mg / kg Compound 1 BID, 10 mg / kg Compound 1 BID, 3 mg / kg Compound 2 BID, 10 mg / kg Compound 2 BID and 5 mg / kg lorlatinib BID, respectively. Tumor volume versus time data are shown in Figure 1A as mean ± sem. After 7 days of treatment, Compound 1 treatment inhibited tumor growth or caused tumor regression with TGI of 64%, 120% and 200% at doses of 2 mg / kg, 5 mg / kg and 10 mg / kg BID, respectively; in comparison, lorlatinib inhibited tumor growth with TGI of 154% at 5 mg / kg BID. Statistical evaluation of the effect of Compound 1 on tumor volume included vehicle-treated, 2 mg / kg, 5 mg / kg, 10 mg / kg BID Compound 1-treated, and lorlatinib-treated groups using a mixed effects model followed by post-hoc Tukey multiple comparison test. The efficacy of Compound 1 against this model with EML4-ALK G1202R fusion began to be detectable by day 10, with tumor volumes in groups treated with Compound 1 at all three dose levels being significantly smaller than the vehicle-treated group until the last day of treatment (day 15, p=0.0007 for Compound 1 at 2 mg / kg vs. vehicle and p<0.0001 for Compound 1 at 5 mg / kg or 10 mg / kg vs. vehicle). In this model harboring the EML4-ALK G1202R fusion, treatment with 10 mg / kg Compound 1 BID was more effective than treatment with 5 mg / kg lorlatinib, as demonstrated by significantly smaller tumor volumes in the 10 mg / kg Compound BID treated group than in the lorlatinib treated group on days 13, 14, and 15 post-inoculation (p<0.0001 on days 13 and 14, p=0.0003 on day 15).

[0279] Body weight versus time data are shown in Figure 1B as mean ± sem. After 7 days of treatment, there was no weight loss in the groups treated with 2 mg / kg, 5 mg / kg, 10 mg / kg compound 1 BID. Statistical evaluation of the effect of compound 1 on body weight included vehicle-treated, 2 mg / kg, 5 mg / kg, 10 mg / kg compound 1 BID-treated, and lorlatinib-treated groups using a mixed effects model followed by post-hoc Tukey multiple comparison test. Body weight of the 2 mg / kg compound 1 BID-treated group was significantly higher than that of the vehicle-treated group on days 13, 14, and 15 after inoculation (day 13 p = 0.0012, day 14 p = 0.0001, day 15 p < 0.0001). Body weights of the 5 mg / kg Compound 1 BID treated group were significantly higher than the vehicle treated group on days 13, 14, and 15 after inoculation (day 13 p=0.0392, day 14 p=0.0126, day 15 p=0.0048). Body weights of the 10 mg / kg Compound BID treated group were significantly higher than the vehicle treated group on days 13 and 14 after inoculation (day 13 p=0.0495, day 14 p=0.0250).

[0280] After 7 days of treatment, Compound 2 treatment inhibited tumor growth with 51% and 77% TGI at doses of 3 mg / kg and 10 mg / kg BID, respectively; whereas lorlatinib inhibited tumor growth with 154% TGI at 5 mg / kg BID. Statistical evaluation of the effect of Compound 2 on tumor volume included vehicle-treated groups, Compound 2-treated groups at 3 mg / kg and 10 mg / kg BID, and lorlatinib-treated groups using a mixed effects model followed by post-hoc Tukey multiple comparison test. The effect of Compound 2 on tumor growth inhibition began to be detectable by day 13 at the 3 mg / kg dose level (p=0.0019 vs. vehicle) and day 10 at the 10 mg / kg dose level (p=0.0396 vs. vehicle). On day 15, the final day of treatment, tumor volumes in the compound 2-treated group were significantly smaller than those in the vehicle-treated group (p=0.0272 for compound 2 3 mg / kg vs. vehicle; p=0.0052 for compound 2 10 mg / kg vs. vehicle).

[0281] After 7 days of treatment, there was no weight loss in the groups treated with Compound 2 at 3 mg / kg and 10 mg / kg BID. Statistical evaluation of the effect of Compound 2 on body weight included the vehicle-treated group, the Compound 2-treated group at 3 mg / kg and 10 mg / kg BID, and the lorlatinib-treated group using a mixed-effects model followed by post-hoc Tukey multiple comparison test. The body weight of the 3 mg / kg Compound 2 BID-treated group was significantly higher than the vehicle-treated group on days 13, 14, and 15 after inoculation (day 13 p=0.0282, day 14 p=0.0229, day 15 p=0.0043). The body weight of the 10 mg / kg Compound 2 BID-treated group was significantly higher than the vehicle-treated group on days 13, 14, and 15 after inoculation (day 13 p=0.0017, day 14 p=0.0009; day 15 p=0.0003).

[0282] Effect of Compound 1 on Ba / F3 cell-derived xenograft tumors harboring the EML4-ALKL1198F / G1202R fusion SCID / Beige mice bearing Ba / F3 cell-derived tumors with EML4-ALKL1198F / G1202R fusion were randomized into 5 groups of 10 mice / group on day 7 post-inoculation and treated with vehicle BID, 2 mg / kg compound 1 BID, 5 mg / kg compound 1 BID, 10 mg / kg compound 1 BID and 5 mg / kg lorlatinib BID, respectively. Tumor volume versus time data are shown in Figure 2A as mean ± sem. After 7 days of treatment, compound 1 treatment resulted in complete tumor regression of 200% TGI at all three dose levels of 2 mg / kg, 5 mg / kg and 10 mg / kg BID. Tumors in all three groups treated with compound 1 showed complete regression at the end of the study on day 14 post-inoculation. The inhibitory activity of compound 1 in this model harboring the EML4-ALKL1198F / G1202R fusion was much better than that of lorlatinib, which showed a much lower inhibition of tumor growth with a TGI of 31% at 5 mg / kg BID after 7 days of treatment. Statistical evaluation of the effect of compound 1 on tumor volume was performed using a two-way repeated measures ANOVA followed by a post-hoc Tukey multiple comparison test. The tumor volumes of the treatment groups at all three dose levels of compound 1 were significantly smaller than the vehicle-treated group on days 10, 12, 13, and 14 after inoculation (p<0.0001 for compound 1 2 mg / kg, 5 mg / kg, or 10 mg / kg vs. vehicle on days 10, 12, 13, or 14). Furthermore, tumor volumes in compound 1 treatment groups at all three dose levels were significantly smaller than the lorlatinib treatment group on days 10, 12, 13, and 14 post-inoculation (p<0.0001 for compound 1 2 mg / kg, 5 mg / kg, or 10 mg / kg vs. lorlatinib on days 10, 12, 13, or 14).

[0283] Body weight versus time data are shown in Figure 2B as mean ± sem. After 7 days of treatment, there was no weight loss in the groups treated with 2 mg / kg, 5 mg / kg, or 10 mg / kg compound 1 BID. Statistical evaluation of the effect of compound 1 on body weight was performed using a two-way repeated measures ANOVA followed by post-hoc Tukey multiple comparison test. Body weight of the 2 mg / kg compound 1 BID treatment group was significantly higher than the vehicle treatment group on days 10, 12, 13, and 14 after inoculation (day 10 p = 0.0478, day 12 p = 0.0044, day 13 p = 0.0008, day 14 p = 0.0013). Body weights of the 5 mg / kg Compound 1 BID treated group were significantly higher than the vehicle treated group on days 12, 13, and 14 after inoculation (p=0.0308 on day 12, p=0.0056 on day 13, p=0.0050 on day 14). Body weights of the 10 mg / kg Compound BID treated group were significantly higher than the vehicle treated group on days 10, 12, and 13 after inoculation (p=0.0390 on day 10, p=0.0048 on day 12, p=0.0119 on day 13).

[0284] Effect of Compound 1 on Ba / F3 cell-derived xenograft tumors harboring the EML4-ALKL1196M / G1202R fusion SCID / Beige mice bearing Ba / F3 cell-derived tumors with EML4-ALKL1196M / G1202R fusion were randomized into 6 groups of 8 mice / group on day 7 post-inoculation and treated with vehicle BID, 0.6 mg / kg compound 1 BID, 2 mg / kg compound 1 BID, 5 mg / kg compound 1 BID, 10 mg / kg compound 1 BID and 5 mg / kg lorlatinib BID, respectively. Tumor volume versus time data are shown in Figure 3A as mean ± sem. After 7 days of treatment, compound 1 treatment resulted in TGI of 19%, 44%, 83% and 200% at dose levels of 0.6 mg / kg, 2 mg / kg, 5 mg / kg and 10 mg / kg BID, respectively; whereas lorlatinib inhibited tumor growth with a TGI of 18% at 5 mg / kg BID after 7 days of treatment. Statistical evaluation of the effect of Compound 1 on tumor volume was performed using a mixed effects model followed by post-hoc Tukey multiple comparison test. Tumor growth in the 0.6 mg / kg Compound 1 BID or 5 mg / kg lorlatinib BID treatment groups was not significantly different from the vehicle treatment group after 7 days of treatment (p>0.05 for vehicle vs. lorlatinib or Compound 1 0.6 mg / kg on day 14). Compound 1 at 2 mg / kg, 5 mg / kg and 10 mg / kg BID showed efficacy in this model harboring the EML4-ALKL1196M / G1202R fusion. After 7 days of treatment, the tumor volumes in the 2 mg / kg, 5 mg / kg, or 10 mg / kg BID treatment groups of Compound 1 were significantly smaller than those in the vehicle treatment group (day 14, p=0.0013 for Compound 1 2 mg / kg vs. vehicle, p=0.0001 for Compound 1 5 mg / kg vs. vehicle, p<0.0001 for Compound 1 10 mg / kg vs. vehicle). Furthermore, after 7 days of treatment, the tumor volumes in the 2 mg / kg, 5 mg / kg, or 10 mg / kg BID treatment groups of Compound 1 were significantly smaller than those in the lorlatinib treatment group (day 14, p=0.0070 for Compound 1 2 mg / kg vs. lorlatinib, p=0.0018 for Compound 1 5 mg / kg vs. lorlatinib, p<0.0001 for Compound 1 10 mg / kg vs. lorlatinib).

[0285] Body weight versus time data are shown in Figure 3B as mean ± sem. After 7 days of treatment, there was no weight loss in the groups treated with 2 mg / kg, 5 mg / kg, or 10 mg / kg compound 1 BID. Statistical evaluation of the effect of compound 1 on body weight was performed using a mixed-effects model followed by post-hoc Tukey multiple comparison test. Body weight of the 0.6 mg / kg compound 1 BID treatment group was significantly higher than the vehicle treatment group on days 12, 13, and 14 after inoculation (day 12 p = 0.0005, day 13 p = 0.0163, day 14 p = 0.0011). Body weight of the 2 mg / kg compound 1 BID treatment group was significantly higher than the vehicle treatment group on day 14 after inoculation (day 14 p = 0.0391). Body weights of the 5 mg / kg Compound 1 BID treated group were significantly higher than the vehicle treated group on days 10, 12, 13, and 14 post-inoculation (day 10 p=0.0413, day 12 p=0.0018, day 13 p<0.0001, day 14 p=0.0011). Body weights of the 10 mg / kg Compound BID treated group were not significantly different from the vehicle treated group (days 10, 12, 13, and 14, p>0.05).

[0286] Effect of Compound 1 on phosphorylation of ALK fusion protein in Ba / F3 cell-derived xenograft tumors harboring the EML4-ALKL1196M / G1202R fusion The pharmacodynamic effects of Compound 1 were evaluated in Ba / F3 cell-derived xenograft tumors harboring the EML4-ALKL1196M / G1202R fusion after a single oral dose of 10 mg / kg compound. Two hours after administration, tumor samples were obtained from vehicle- or Compound 1-treated mice, with 3 mice per treatment. Samples were processed and immunoblotted, and the results are shown in Figure 4. The phosphorylation levels of ALK fusion at Y1282 / 1283 and Y1604 were both decreased in samples from Compound 1-treated mice compared to vehicle-treated mice. The levels of ALK fusion expression were also decreased in samples from Compound 1-treated mice compared to vehicle-treated mice. As a control, the expression levels of actin were not affected by Compound 1 treatment.

[0287] Figure 5 shows in vivo ALK phosphorylation levels at 2 or 12 hours after administration of 0.6 mg / kg, 2 mg / kg, or 5 mg / kg Compound 1. At each dose, phosphorylation levels were significantly decreased compared to controls at 2 hours, but only the highest dose showed a decrease at 12 hours.

Claims

1. Formula II or III 【Chemistry 1】 [During the ceremony, Each R １ and R ２ are independently H or C １ -C ６ alkyl; or R １ and R ２ Together with the carbon atom to which they are attached, ３ -C ６ Forming a cycloalkyl; Each R ３ and R ３’ are independently H, deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ -C １０ Aryl, monocyclic or bicyclic heteroaryl, -OR ａ , -OC(O)R ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -OS(O)R ａ , -OS(O) ２ R ａ , -SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O)NR ａ R ｂ , -S(O) ２ N.R. ａ R ｂ , -OS(O)NR ａ R ｂ , -OS(O) ２ N.R. ａ R ｂ , -NR ａ R ｂ , -NR ａ C(O)R ｂ , -NR ａ C(O)OR ｂ , -NR ａ C(O)NR ａ R ｂ , -NR ａ S(O)R ｂ , -NR ａ S (O) ２ R ｂ , -NR ａ S(O)NR ａ R ｂ , -NR ａ S (O) ２ N.R. ａ R ｂ , -C(O)R ａ , -C(O)OR ａ , -C(O)NR ａ R ｂ , -PR ａ R ｂ , -P(O)R ａ R ｂ , -P(O) ２ R ａ R ｂ , -P(O)NR ａ R ｂ , -P(O) ２ N.R. ａ R ｂ , -P(O)OR ａ , -P(O) ２ OR ａ , -CN or -NO ２ or R ３ and R ３’ Together with the carbon atom to which they are attached, ３ -C ６ Forming a cycloalkyl; Each R ４ and R ５ are independently hydrogen, deuterium, halogen, -OR ｃ , -OC(O)R ｃ , -OC(O)NR ｃ R ｄ , -OC(=N)NR ｃ R ｄ , -OS(O)R ｃ , -OS(O) ２ R ｃ , -OS(O)NR ｃ R ｄ , -OS(O) ２ N.R. ｃ R ｄ , -SR ｃ , -S(O)R ｃ , -S(O) ２ R ｃ , -S(O)NR ｃ R ｄ , -S(O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｃ C(O)R ｄ , -NR ｃ C(O)OR ｄ , -NR ｃ C(O)NR ｃ R ｄ , -NR ｃ C(=N)NR ｃ R ｄ , -NR ｃ S(O)R ｄ , -NR ｃ S (O) ２ R ｄ , -NR ｃ S(O)NR ｃ R ｄ , -NR ｃ S (O) ２ N.R. ｃ R ｄ , -C(O)R ｃ , -C(O)OR ｃ , -C(O)NR ｃ R ｄ , -C(=N)NR ｃ R ｄ , -PR ｃ R ｄ , -P(O)R ｃ R ｄ , -P(O) ２ R ｃ R ｄ , -P(O)NR ｃ R ｄ , -P(O) ２ N.R. ｃ R ｄ , -P(O)OR ｃ , -P(O) ２ OR ｃ , -CN, -NO ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ -C １０ aryl or monocyclic or bicyclic heteroaryl; R ６ is H; Each R ７ is hydrogen; and Each R ａ , R ｂ , R ｃ and Rd are independently H, deuterium, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, 3- to 7-membered heterocycloalkyl, C ６ -C １０ aryl and 5- to 7-membered heteroaryl. or a pharma- ceutically acceptable salt thereof.

2. Formula II 【Chemistry 2】 2. The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt thereof.

3. Formula IIa 【Chemistry 3】 3. The compound of claim 1 or 2, having the formula: or a pharma- ceutically acceptable salt thereof.

4. Formula III 【Chemistry 4】 2. The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt thereof.

5. Formula IIIa 【Chemistry 5】 5. The compound of claim 1 or 4, having the formula: or a pharma- ceutically acceptable salt thereof.

6. Each R １ and R ２ is H or R １ and R ２ together with the carbon atom to which they are attached, ３ -C ６ 6. The compound of claim 1, which forms a cycloalkyl, or a pharma- ceutically acceptable salt thereof.

7. Each R ３ and R ３’ became independent and C １ -C ６ 7. The compound of claim 1, wherein R is an alkyl group, or a pharma- ceutically acceptable salt thereof.

8. Each R ３’ The compound of any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein

9. Each R ４ The compound of any one of claims 1 to 8, or a pharma- ceutically acceptable salt thereof, wherein

10. R ５ 10. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

11. 【Chemical 6】 2. The compound of claim 1 selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

12. Structure 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof.

13. structure 【Chemistry 8】 13. The compound of claim 12 having the formula:

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt thereof and optionally at least one diluent, carrier or excipient.

15. A drug for treating cancer in a subject in need of such treatment, comprising at least one compound of any one of claims 1 to 13, or a pharma- ceutically acceptable salt thereof.

16. The method of claim 15, wherein the subject is a human.

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