MACROCYCLES FOR USE IN TREATING DISEASE

CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional

Application Serial No. 62/863,492 filed on June 19, 2019, and U.S. Provisional Application Serial No. 62/943,003 filed on December 3, 2019 the entire disclosures of which are incorporated herein by reference.

TECHNICAL FIELD

[002] The present disclosure relates to certain chiral diaryl macrocyclic derivatives, pharmaceutical compositions containing them, and methods of using them to treat cancer, pain, neurological diseases, autoimmune diseases, and inflammation.

BACKGROUND

[003] Protein kinases are key regulators for cell growth, proliferation and survival. Genetic and epigenetic alterations accumulate in cancer cells leading to abnormal activation of signal transduction pathways which drive malignant processes. Manning, G. et al., Science 2002, 298, 1912-1934. Pharmacological inhibition of these signaling pathways presents promising intervention opportunities for targeted cancer therapies. Sawyers, C., Nature 2004, 432, 294- 297.

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

[005] The tropomyosin-related receptor tyrosine kinases (Trks) are the high-affinity receptor for neurotrophins (NTs), a nerve growth factor (NGF) family of proteins. Members of the Trk family are highly expressed in cells of neural origin. Activation of Trks (TrkA, TrkB, and TrkC) by their preferred neurotrophins (NGF to TrkA, brain-derived neurotrophic factor

[BDNF] and NT4/5 to TrkB, and NT3 to TrkC) mediates the survival and differentiation of neurons during development. The NT/Trk signaling pathway functions as an endogenous system that protects neurons after biochemical insults, transient ischemia, or physical injury. Thiele, C. J. et al., Clin. Cancer Res. 2009, 15, 5962-5967. However, Trk was originally cloned as an oncogene fused with the tropomyosin gene in the extracellular domain. The activating mutations caused by chromosomal rearrangements or mutations in NTRK1 (TrkA) have been identified in papillary and medullary thyroid carcinoma, and recently in non-small cell lung cancer. Pierotti, M. A. et al., Cancer Lett. 2006, 232, 90-98; Vaishnavi, A. et al., Nat. Med. 2013, 19, 1469-1472. Because Trks play important roles in pain sensation as well as tumor cell growth and survival signaling, inhibitors of Trk receptor kinases may provide benefits as treatments for pain and cancer.

[006] ROS1 kinase is a receptor tyrosine kinase with an unknown ligand. The normal functions of human ROS 1 kinase have not been fully understood. However, it has been reported that ROS 1 kinase undergoes genetic rearrangements to create constitutively active fusion proteins in a variety of human cancers including glioblastoma, non-small cell lung cancer (NSCLC), cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, and epithelioid hemangioendothelioma (Davies, K. D. et al., Clin Cancer Res 2013, 19 (15): 4040-4045). Targeting ROS1 fusion proteins with crizotinib has demonstrated promising clinical efficacy in NSCLC patients whose tumors are positive for ROS1 genetic abnormalities (Shaw, A. T. et al., N Engl J Med. 2014,

371(21): 1963-1971). Acquired resistant mutations have been observed in crizotinib treatment patients (Awad, M. M. et al., N Engl J Med. 2013, 368(25):2396-2401). It is urgent to develop the second generation of ROS 1 inhibitors for overcoming crizotinib ROS1 resistance.

[007] Endochondral ossification is a process that results in both the replacement of the embryonic cartilaginous skeleton during organogenesis and the growth of long bones until adult height is achieved. Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling plays a vital role in the development and maintenance of growth plates in endochondral ossification process (Xie Y 2014). Missense mutations in FGFs and FGFRs can cause multiple genetic skeletal diseases with disordered endochondral ossification. Activating mutations in FGFR3 cause achondroplasia, the most common form of dwarfism among live births (Samsa WE 2017). The growth plates of humans with FGFR3 mutations show disrupted chondrocyte columns and reduced numbers of hypertrophic chondrocytes. FGFR1 and FGFR2 play many essential and mostly redundant roles during development, including growth plate formation. FGFR2- deficient embryos fail to form limb buds (Omitz DM 2015). In addition, Overexpression of FGFR1 in chondrocytes causes joint fusion. Deletion of both FGFR1 and FGFR2 in mice caused a decreased length of the growth plate with a reduced number of proliferating chondrocytes (Karuppaiah K 2016). Therefore, the selectivity over FGFRs is an important parameter for better safety profile, especially for pediatric population.

[008] Crizotinib (PF-02341066) is a tyrosine kinase drug targeting MET/ALK/ROS1/RON with moderate activity against TRKs and AXL. Cui, J. J. et al., J. Med. Chem. 2011, 54, 6342- 6363. It was approved to treat certain patients with late-stage (locally advanced or metastatic) NSCLC that expresses the abnormal ALK fusion gene identified by a companion diagnostic test (Vysis ALK Break Apart FISH Probe Kit). Similar to imatinib and other kinase inhibitor drugs, resistance invariably develops after a certain time of treatment with crizotinib. The resistance mechanisms include ALK gene amplification, secondary ALK mutations, and aberrant activation of other kinases including KIT and EGFR. Katayama, R. et al., Sci. Transl. Med. 2012, 4, 120ral7. Based on the clinical success of second-generation ABL inhibitors for the treatment of imatinib resistance in CML patients, a second generation of ALK inhibitors is emerging. These drugs target the treatment of crizotinib-refractory or resistant NSCLC patient with more potent inhibition against both wild and mutant ALK proteins. Gridelli, C. et al., Cancer Treat Rev. 2014, 40, 300-306.

[009] There remains a need for small molecule inhibitors of these multiple protein or tyrosine kinase targets with desirable pharmaceutical properties. Certain chiral diaryl macrocyclic compounds have been found in the context of this disclosure to have this advantageous activity profile.

SUMMARY

[010] In one aspect, the disclosure relates to a compound of the formula I

[011] wherein

[012] each R ¹ and R ² is 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, mono- 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 NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^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 NR ^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 NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN, or -NO ₂ , wherein each hydrogen atom in 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 mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ 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) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ 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) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^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) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN, or -NO ₂ ;

[013] each R ³ is independently H, deuterium, or C ₁ -C ₆ alkyl, wherein each hydrogen atom in C ₁ -C ₆ alkyl is independently optionally substituted by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ 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) ₂ R ^e ,

-OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ 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) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^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) ₂ R ^e R ^f ,

-P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN, or -NO ₂ ;

[014] each R ⁴ and R ⁵ is 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 NR ^c R ^d , -SR ^C , -S(O)R ^c , -S(O) ₂ R ^c , -S(O)NR ^c R ^d , -S(O) ₂ 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) ₂ R ^d , -NR ^c S(O)NR ^c R ^d ,

-NR ^c S(O) ₂ NR ^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 NR ^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 mono- or bicyclic heteroaryl, wherein each hydrogen atom in 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, mono- or bicyclic heteroaryl, C ₅ -C ₈ cycloalkyl, or 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ 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) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ 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) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^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) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN, or -NO ₂ ;

[015] R ⁶ is H, deuterium, or C ₁ -C ₆ alkyl, wherein each hydrogen atom in C ₁ -C ₆ alkyl is independently optionally substituted by deuterium, halogen, -OR ^e , -SR ^e , or -NR ^e R ^f

[016] each R ⁷ is independently hydrogen or deuterium,

[017] each R ⁸ and R ⁹ is independently H, deuterium, halogen, -CN, -OR ^e , 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 mono- or bicyclic heteroaryl, or alternatively, R ⁸ and R ⁹ taken together with the carbon to which they are attached form a C ₃ -C ₆ cycloalkyl or a 4- to 6-membered heterocycloalkyl, or alternatively, R ⁸ and R ⁹ taken together with the carbon to which they are attached form an exocyclic ethylene group, wherein each hydrogen atom in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 4- to 6-membered heterocycloalkyl, 3- to 7-membered

heterocycloalkyl, C ₆ -C ₁₀ aryl, exocyclic ethylene group, or mono- or bicyclic heteroaryl is optionally substituted by a halogen, -N3, -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) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ 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) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^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) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , or -P(O) ₂ OR ^e ;

[018] each R ^a , R ^b , R ^c , R ^d , R ^e , and R ^f is independently selected from the group consisting of 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;

[019] m is 1 or 2; and

[020] n is i, 2, or 3; [021] or a pharmaceutically acceptable salt thereof.

[022] In another aspect, the disclosure relates to a compound of the formula II

[023] or a pharmaceutically acceptable salt thereof.

[024] In another aspect, the disclosure relates to a compound of the formula III

[025] or a pharmaceutically acceptable salt thereof.

[026] In another aspect, the disclosure relates to a compound of the formula IV

[027] or a pharmaceutically acceptable salt thereof.

[028] In another aspect, the disclosure relates to a compound of the formula V

[029] or a pharmaceutically acceptable salt thereof.

[030] In another aspect, the disclosure relates to a compound of the formula VI

[031] or a pharmaceutically acceptable salt thereof. [032] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of any one of the disclosed aspects, or a pharmaceutically acceptable salt thereof, and optionally at least one diluent, carrier or excipient.

[033] In another aspect, the disclosure 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 one of the disclosed aspects, or a pharmaceutically acceptable salt thereof.

[034] In another aspect, the disclosure provides a use of a compound of any one of the disclosed aspects, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of cancer.

[035] In another aspect, the disclosure provides a use of a compound of any one of the disclosed aspects, or a pharmaceutically acceptable salt thereof, for treating cancer.

[036] In another aspect, the disclosure provides a compound of the disclosed aspects, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a patient.

[037] In another aspect, the disclosure provides a method of inhibiting ALK receptor tyrosine kinase, comprising contacting a cell comprising one or more of such kinases with an effective amount of at least one compound of any one of the disclosed aspects, or a pharmaceutically acceptable salt thereof, and/or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.

[038] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure. The compounds of the present disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another.

[039] 1. A compound of the formula I

[040] wherein

[041] each R ¹ and R ² is 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, mono- 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 NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^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 NR ^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 NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN, or -NO ₂ , wherein each hydrogen atom in 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 mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ 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) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ 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) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^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) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN, or -NO ₂ ;

[042] each R ³ is independently H, deuterium, or C ₁ -C ₆ alkyl, wherein each hydrogen atom in C ₁ -C ₆ alkyl is independently optionally substituted by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ 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) ₂ R ^e ,

-OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ 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) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^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) ₂ R ^e R ^f ,

-P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN, or -NO ₂ ;

[043] each R ⁴ and R ⁵ is 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 NR ^c R ^d , -SR ^C , -S(O)R ^c , -S(O) ₂ R ^c , -S(O)NR ^c R ^d , -S(O) ₂ 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) ₂ R ^d , -NR ^c S(O)NR ^c R ^d ,

-NR ^c S(O) ₂ NR ^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 NR ^c R ^d , -P(O)OR ^c , -P(O) ₂ OR ^c , -CN, -NO ₂ , Ci-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 mono- or bicyclic heteroaryl, wherein each hydrogen atom in 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, mono- or bicyclic heteroaryl, C ₅ -C ₈ cycloalkyl, or 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ 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) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ 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) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^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) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN, or -NO ₂ ;

[044] R ⁶ is H, deuterium, or G-G alkyl, wherein each hydrogen atom in C ₁ -C ₆ alkyl is independently optionally substituted by deuterium, halogen, -OR ^e , -SR ^e , or -NR ^e R ^f each R ⁷ is independently hydrogen or deuterium,

[045] each R ⁸ and R ⁹ is independently H, deuterium, halogen, -CN, -OR ^e , C ₁ -C ₆ alkyl, C ₂ -G alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or mono- or bicyclic heteroaryl, or alternatively, R ⁸ and R ⁹ taken together with the carbon to which they are attached form a C ₃ -C ₆ cycloalkyl or a 4- to 6-membered heterocycloalkyl, or alternatively, R ⁸ and R ⁹ taken together with the carbon to which they are attached form an exocyclic ethylene group, wherein each hydrogen atom in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 4- to 6-membered heterocycloalkyl, 3- to 7-membered

heterocycloalkyl, C ₆ -C ₁₀ aryl, exocyclic ethylene group, or mono- or bicyclic heteroaryl is optionally substituted by a halogen, -N3, -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) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ 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) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^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) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , or -P(O) ₂ OR ^e ;

[046] each R ^a , R ^b , R ^c , R ^d , R ^e , and R ^f is independently selected from the group consisting of 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;

[047] m is 1 or 2; and

[048] n is i, 2, or 3;

[049] or a pharmaceutically acceptable salt thereof.

[050] 2. The compound of clause 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1.

[051] 3. The compound of clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

[052] 4. The compound of any one of the preceding clauses, having the formula II

[053] or a pharmaceutically acceptable salt thereof.

[054] 5. The compound of any one of the preceding clauses, having the formula III

[055] or a pharmaceutically acceptable salt thereof.

[056] 6. The compound of any one of the preceding clauses, having the formula IV

[057] or a pharmaceutically acceptable salt thereof. [058] 7. The compound of any one of clauses 1 to 3, having the formula V

[059] or a pharmaceutically acceptable salt thereof.

[060] 8. The compound of any one of clauses 1 to 3 or 7, having the formula VI

[061] or a pharmaceutically acceptable salt thereof.

[062] 9. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R ³ , when present, is H or C ₁ -C ₆ alkyl.

[063] 10. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R ⁴ is H or deuterium.

[064] 11. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R ¹ is H.

[065] 12. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R ² is H.

[066] 13. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R ⁷ is H. [067] 14. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is F.

[068] 15. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R ⁹ is independently H.

[069] 16. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R ⁸ is independently methyl or difluoromethyl.

[070] 17. The compound of clause 1, selected from the group consisting of

[071] or a pharmaceutically acceptable salt thereof.

[072] 18. A pharmaceutical composition comprising a compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, and optionally at least one diluent, carrier or excipient.

[073] 19. A method of treating cancer, pain, neurological diseases, autoimmune diseases, or inflammation comprising administering to a subject in need of such treatment an effective amount of at least one compound of any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof.

[074] 20. Use of a compound of any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of cancer.

[075] 21. Use of a compound of any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof, for treating cancer.

[076] 22. A method of inhibiting ALK receptor tyrosine kinase, comprising contacting a cell comprising one or more of such kinases with an effective amount of at least one compound of any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof, and/or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo. [077] 23. A compound of any one of clauses 1 to 17, for use in treating cancer in a patient.

DETAILED DESCRIPTION

[078] Before the present disclosure is further described, it is to be understood that this disclosure 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 disclosure will be limited only by the appended claims.

[079] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.

[080] As used herein and in the appended claims, the singular forms“a,”“an,” and“the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as“solely,”“only” and the like in connection with the recitation of claim elements, or use of a“negative” limitation.

[081] As used herein, the terms“including,”“containing,” and“comprising” are used in their open, non-limiting sense.

[082] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term“about.” It is understood that, whether the term“about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently. [083] Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., 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.

[084] Chemical nomenclature for compounds described herein has generally been derived using the commercially-available ACD/Name 2014 (ACD/Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).

[085] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein.

Definitions

[086] As used herein, the term“alkyl” includes a chain of carbon atoms, which is optionally branched and contains from 1 to 20 carbon atoms. It is to be further understood that in certain embodiments, alkyl may be advantageously of limited length, including C ₁ -C ₁₂ , C ₁ -C ₁₀ , C ₁ -C ₉ , C ₁ -C ₈ , C ₁ -C ₇ , C ₁ -C ₆ , and C ₁ -C ₄ , Illustratively, such particularly limited length alkyl groups, including C ₁ -C ₈ , C ₁ -C ₇ , C ₁ -C ₆ , and C ₁ -C ₄ , and the like may be referred to as“lower alkyl.” 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. Typical substituent groups 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 will be understood that“alkyl” may be combined with other groups, such as those provided above, to form a functionalized alkyl. By way of example, the combination of an“alkyl” group, as described herein, with a “carboxy” group may be referred to as a“carboxyalkyl” group. Other non-limiting examples include hydroxyalkyl, aminoalkyl, and the like.

[087] As used herein, the term“alkenyl” includes a chain of carbon atoms, which is optionally branched, and contains from 2 to 20 carbon atoms, and also includes at least one carbon-carbon double bond (i.e., C=C). It will be understood that in certain embodiments, alkenyl may be advantageously of limited length, including C ₂ -C ₁ 2, C ₂ -C ₉ , C- ₂ C ₈ , C-C _{2 7} , C ₂ -C ₆ , and - C ₂ - ₄ . Illustratively, such particularly limited length alkenyl groups, including C ₂ -C ₈ , C ₂ -C ₇ , C ₂ -C ₆ , and C ₂ -C ₄ 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.

[088] As used herein, the term“alkynyl” includes a chain of carbon atoms, which is optionally branched, and contains from 2 to 20 carbon atoms, and also includes at least one carbon-carbon triple bond (i.e., CºC). It will be understood that in certain embodiments, alkynyl may each be advantageously of limited length, including C ₂ -C ₁₂ , C ₂ -C ₉ , C ₂ -C ₈ , C ₂ -C ₇ , C ₂ -C ₆ , and C ₂ -C ₄ . Illustratively, such particularly limited length alkynyl groups, including C ₂ -C ₈ , C ₂ -C ₇ , C ₂ -C ₆ , and C ₂ -C ₄ 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.

[089] As used herein, the term“aryl” refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system.

It will be understood that in certain embodiments, aryl may be advantageously of limited size such as C ₆ -C ₁₀ aryl. Illustrative aryl groups include, but are not limited to, phenyl, naphthylenyl and anthracenyl. The aryl group may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.

[090] As used herein, the term“cycloalkyl” refers to a 3 to 15 member all-carbon monocyclic ring, including an all-carbon 5-member/6-member or 6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a“fused” ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group, or a carbocyclic ring that is fused to another group such as a heterocyclic, such as ring 5- or 6-membered cycloalkyl fused to a 5- to 7- membered heterocyclic ring, where one or more of the rings may contain one or more double bonds but the cycloalkyl does not contain a completely conjugated pi-electron system. It will be understood that in certain embodiments, cycloalkyl may be advantageously of limited size such as C ₃ -C ₁₃ , C ₃ -C ₉ , C ₃ -C ₆ and C ₄ -C ₆ . Cycloalkyl may 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 graphical representations include the following entities, in the form of properly bonded moieties:

[091] As used herein, the term“heterocycloalkyl” refers to a monocyclic or fused ring group having in the ring(s) from 3 to 12 ring atoms, in which at least one ring atom is a heteroatom, such as nitrogen, oxygen or sulfur, the remaining ring atoms being carbon atoms.

Heterocycloalkyl may optionally contain 1, 2, 3 or 4 heteroatoms. A heterocycloalkyl group may be fused to another group such as another heterocycloalkyl, or a heteroaryl group.

Heterocycloalkyl may also have one of more double bonds, including double bonds to nitrogen (e.g., C=N or N=N) but does not contain a completely conjugated pi-electron system. It will be understood that in certain embodiments, heterocycloalkyl may be advantageously of limited size such as 3- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, 3-, 4-, 5- or 6-membered heterocycloalkyl, and the like. Heterocycloalkyl may be unsubstituted, or substituted as described for alkyl 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, and the like. Illustrative examples of heterocycloalkyl groups shown in graphical representations include the following entities, in the form of properly bonded moieties:

[092] As used herein, the term“heteroaryl” refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon atoms, and also having a completely conjugated pi-electron system. It will be understood that in certain embodiments, heteroaryl may be advantageously of limited size such as 3- to 7-membered heteroaryl, 5- to 7-membered heteroaryl, and the like. 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 carbazoloyl, and the like. Illustrative examples of heteroaryl groups shown in graphical representations, include the following entities, in the form of properly bonded moieties:

[093] As used herein,“hydroxy” or“hydroxyl” refers to an -OH group.

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

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

[096] As used herein,“mercapto” refers to an -SH group.

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

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

[099] As used herein,“halo” or“halogen” refers to fluorine, chlorine, bromine or iodine.

[0100] As used herein,“cyano” refers to a -CN group.

[0101] The term“oxo” represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone.

[0102] As used herein,“bond” refers to a covalent bond.

[0103] The term“substituted” means that the specified group or moiety bears one or more substituents. The term“unsubstituted” means that the specified group bears no substituents. Where the term“substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In some embodiments,“substituted” means that the specified group or moiety bears one, two, or three substituents. In other embodiments,“substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments,“substituted” means the specified group or moiety bears one substituent.

[0104] As used herein,“optional” or“optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example,“wherein each hydrogen atom in 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 mono- or bicyclic heteroaryl is independently optionally substituted by C ₁ -C ₆ alkyl” means that an alkyl may be but need not be present on any of the 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 mono- or bicyclic heteroaryl by replacement of a hydrogen atom for each alkyl group, and the description includes situations where the 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 mono- or bicyclic heteroaryl is substituted with an alkyl group and situations where the 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 mono- or bicyclic heteroaryl is not substituted with the alkyl group.

[0105] As used herein,“independently” means that the subsequently described event or circumstance is to be read on its own relative to other similar events or circumstances. For example, in a circumstance where several equivalent hydrogen groups are optionally substituted by another group described in the circumstance, the use of“independently optionally” means that each instance of a hydrogen atom on the group may be substituted by another group, where the groups replacing each of the hydrogen atoms may be the same or different. Or for example, where multiple groups exist all of which can be selected from a set of possibilities, the use of “independently” means that each of the groups can be selected from the set of possibilities separate from any other group, and the groups selected in the circumstance may be the same or different.

[0106] As used herein, the phrase“taken together with the carbon to which they are attached” or“taken together with the carbon atom to which they are attached” means that two substituents (e.g., R ⁸ and R ⁹ ) attached to the same carbon atom form the groups that are defined by the claim, such as C ₃ -C ₆ cycloalkyl or a 4- to 6-membered heterocycloalkyl. In particular, the phrase“taken together with the carbon to which they are attached” means that when, for example, R ⁸ and R ⁹ , and the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl, then the formed ring will be attached at the same carbon atom. For example, the phrase“R ⁸ and R ⁹ taken together with the carbon to which they are attached form a C ₃ -C ₆ cycloalkyl” used in connection with the embodiments described herein includes the compounds represented as follows:

[0107] where the above spirocyclic rings can be optionally substituted as defined in the given embodiment.

[0108] As used herein, the term“pharmaceutically acceptable salt” refers to those salts which counter ions which may be used in pharmaceuticals. See, generally, S.M. 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 subjects without undue toxicity, irritation, or allergic response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, 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 a pharmaceutically acceptable salt.

Such salts include:

[0109] (1) acid addition salts, which can be obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid,

ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or

[0110] (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine, and the like.

[0111] Pharmaceutically acceptable salts are well known to those skilled in the art, and any such pharmaceutically acceptable salt may be contemplated in connection with the

embodiments described herein. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, g-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable

pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0112] For a compound of Formula I- VI that contains a basic nitrogen, a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic 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, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

[0113] The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula I- VI, and treatment methods employing such pharmaceutically acceptable prodrugs. The term“prodrug” means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula I- VI). A

“pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in“Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

[0114] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula I- VI, and uses of such metabolites in the methods of the disclosure. A

“pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula I- VI, or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., 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; 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).

[0115] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof. For example, it will be appreciated that compounds depicted by a structural formula containing the symbol include both stereoisomers for the carbon atom to which the symbol is attached, specifically both the bonds and are encompassed by the meaning of .

For example, in some exemplary embodiments, certain compounds provided herein can be described by the formula

[0116] which formula will be understood to encompass compounds having both stereochemical configurations at the relevant carbon atom, specifically in this example

[0117] and other stereochemical combinations.

[0118] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted 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 can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ 0, ¹⁷ 0, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, and ¹²⁵ I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with ¹⁴ C), reaction kinetic studies (with, for example ² H or ³ H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Further, substitution with heavier isotopes such as deuterium (i.e., ² H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0119] Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent -A-B-, where A ¹ B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.

Representative Embodiments

[0120] In some embodiments, compounds described herein comprise a moiety of the formula

[0121] wherein the substituents on the non-aromatic ring marked by a bond and ~ correspond to R ⁸ and/or R ⁹ as described herein.

[0122] In some embodiments, each R ¹ and R ² is 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, mono- 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 NR ^a R ^b , -OS(O)NR ^a R ^b , -OS(O) ₂ NR ^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 NR ^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 NR ^a R ^b , -P(O)OR ^a , -P(O) ₂ OR ^a , -CN, or -NO ₂ , wherein each hydrogen atom in 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 mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ 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) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ 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) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^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) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN, or -NO ₂ . In some embodiments, R ¹ is H. In some embodiments, R ² is H.

[0123] In some embodiments, each R ³ is independently H, deuterium, or C ₁ -C ₆ alkyl, wherein each hydrogen atom in C ₁ -C ₆ alkyl is independently optionally substituted by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ 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) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ 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) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^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) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN, or -NO ₂ . In some embodiments, each R ³ , when present, is H or C ₁ -C ₆ alkyl.

[0124] In some embodiments, each R ⁴ and R ⁵ is 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 NR ^c R ^d , -SR ^C , -S(O)R ^c , -S(O) ₂ R ^c , -S(O)NR ^c R ^d , -S(O) ₂ 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) ₂ R ^d ,

-NR ^c S(O)NR ^c R ^d , -NR ^c S(O) ₂ NR ^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 NR ^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 mono- or bicyclic heteroaryl, wherein each hydrogen atom in 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, mono- or bicyclic heteroaryl, C ₅ -C ₈ cycloalkyl, or 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ 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) ₂ R ^e , -OS(O)NR ^e R ^f ,

-OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ 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) ₂ R ^f , -NR ^e S(O)NR ^e R ^f ,

-NR ^e S(O) ₂ NR ^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) ₂ R ^e R ^f ,

-P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , -P(O) ₂ OR ^e , -CN, or -NO ₂ . In some embodiments, R ⁴ is H or deuterium. In some embodiments, R ⁵ is F. [0125] In some embodiments, R ⁶ is H, deuterium, or C ₁ -C ₆ alkyl, wherein each hydrogen atom in C ₁ -C ₆ alkyl is independently optionally substituted by deuterium, halogen, -OR ^e , -SR ^e , or -NR ^e R ^f . In some embodiments R ⁶ is H.

[0126] In some embodiments, each R ⁷ is independently hydrogen or deuterium. In some embodiments, R ⁷ is H.

[0127] In some embodiments, each R ⁸ and R ⁹ is independently H, deuterium, halogen, -CN, -OR ^e , 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 mono- or bicyclic heteroaryl, or alternatively, R ⁸ and R ⁹ taken together with the carbon to which they are attached form a C ₃ -C ₆ cycloalkyl or a 4- to 6- membered heterocycloalkyl, or alternatively, R ⁸ and R ⁹ taken together with the carbon to which they are attached form an exocyclic ethylene group, wherein each hydrogen atom in C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 4- to 6-membered heterocycloalkyl, 3- to 7-membered heterocycloalkyl, C ₆ -C ₁₀ aryl, exocyclic ethylene group, or mono- or bicyclic heteroaryl is optionally substituted by a halogen, -N ₃ , -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) ₂ R ^e , -OS(O)NR ^e R ^f , -OS(O) ₂ NR ^e R ^f , -SR ^e , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)NR ^e R ^f , -S(O) ₂ 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) ₂ R ^f , -NR ^e S(O)NR ^e R ^f , -NR ^e S(O) ₂ NR ^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) ₂ R ^e R ^f , -P(O)NR ^e R ^f , -P(O) ₂ NR ^e R ^f , -P(O)OR ^e , or -P(O) ₂ OR ^e . In some embodiments, each R ⁸ is independently methyl or difluoromethyl. In some embodiments, each R ⁹ is independently H.

[0128] In some embodiments, each R ^a , R ^b , R ^c , R ^d , R ^e , and R ^f is independently selected from the group consisting of 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.

[0129] In some embodiments, m is 1 or 2. In some embodiments, m is 1.

[0130] In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2.

[0131] The following represent illustrative embodiments of compounds of the Formula I- VI

exhaustive, and that additional species within the scope of these defined terms may also be selected.

[0133] These and other embodiments described herein can bemade and used according to the processes and methods described in International PCT Publication No. WO 2019126122, corresponding to International PCT Application No. PCT/US2018/066159, filed December 18, 2018, which is incorporated herein by reference. Pharmaceutical Compositions

[0134] For treatment purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients. A pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti- oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents. In preferred embodiments, pharmaceutical compositions according to the invention are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.

[0135] Sterile compositions are also contemplated by the invention, including compositions that are in accord with national and local regulations governing such compositions.

[0136] The pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. Pharmaceutical

compositions of the invention may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.

[0137] For oral administration, the compounds the invention may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds of the invention may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl -pyrrolidone (PVP), sodium starch glycolate,

microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, 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.

[0138] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0139] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain:

pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

[0140] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 mg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0141] For nasal, inhaled, or oral administration, the inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier. The inventive compositions may be formulated for rectal administration as a suppository.

[0142] For topical applications, the compounds of the present invention are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration· For topical administration, the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the invention may utilize a patch formulation to effect transdermal delivery. [0143] As used herein, the terms“treat” or“treatment” encompass both“preventative” and “curative” treatment.“Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.

[0144] The term“subject” refers to a mammalian patient in need of such treatment, such as a human.

[0145] Exemplary 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 esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma. Pain includes, for example, pain from any source or etiology, including cancer pain, pain from chemotherapeutic treatment, nerve pain, pain from injury, or other sources. Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren syndrome, Type I diabetes, and lupus. Exemplary neurological diseases include Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, and Huntington’s disease.

Exemplary inflammatory diseases include atherosclerosis, allergy, and inflammation from infection or injury.

[0146] In one aspect, the compounds and pharmaceutical compositions of the invention specifically target tyrosine receptor kinases, in particular ALK, ROS1, and TRK. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of one or more of these kinases. In preferred embodiments, methods of treatment target cancer. In other embodiments, methods are for treating lung cancer or non-small cell lung cancer.

[0147] In the inhibitory methods of the invention, an“effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a cancer cell with abnormal signaling due to upregulation of ALK, ROS1, and TRK. [0148] In treatment methods according to the invention, an“effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment. Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject's health status, condition, and weight, and the judgment of the treating physician. An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).

[0149] Once improvement of the patient's disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.

Drug Combinations

[0150] The inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. Further additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound. The additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present invention or may be included with a compound of the present invention in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present invention.

[0151] Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease. For example, compositions and formulations of the invention, as well as methods of treatment, can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions. For cancer indications, additional such 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 chemotherapy agents such as alkylating agents,

antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapies, or corticosteroids. For pain indications, suitable combination agents include anti-inflammatories such as NSAIDs. The pharmaceutical compositions of the invention may additionally comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents.

[0152] Chemical Synthesis

[0153] Exemplary chemical entities useful in methods of the description will now be described by reference to illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups.

[0154] Abbreviations The examples described herein use materials, including but not limited to, those described by the following abbreviations known to those skilled in the art:

General Method A

Preparation of ethyl 5-chloro-6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylate (A-1)

[0155] Step 1. To a solution of A-1-1 (150 g, 1.44 mol, 143 mL, 1.00 eq, methyl 2- methoxyacetate, available from e.g. Sigma- Aldrich.) and A-1-1A (104 g, 1.73 mol, 105 mL, 1.20 eq. , methyl formate, available from e.g. Sigma- Aldrich) in tetrahydrofuran (3.00 L) was added sodium hydride (80.7 g, 2.02 mol, 60.0% purity, 1.40 eq.) slowly at 0 °C over a period of 30 minutes under nitrogen. During which the temperature was maintained below 0 °C. The reaction mixture was stirred at 0 °C for 12 hours. The formation of white solids was observed, methyl tert-butyl ether (2.00 L) was added, filtered, and the filtered cake was dried under reduced pressure to give the crude A-1-2 (283 g, crude) as light-yellow solid.

[0156] Step 2. To a solution of A-1-2A (165 g, 1.06 mol, 1.00 eq., ethyl 3-amino-1H-pyrazole- 4-carboxylate, available from e.g. Sigma- Aldrich) in dimethyl formamide (3.00 L) was added cesium carbonate (624 g, 1.91 mol, 1.80 eq.) and A-1-2 (279 g, 1.91 mol, 1.80 eq.). The mixture was stirred at 110 °C for 12 hours. The reaction mixture was diluted with water (3.00 L), hydrochloric acid (5.00 M,1.80 L) was added to the mixture slowly at 20 °C, and the resulting precipitated solids was filtered and washed with methyl alcohol (300 mL). The filtered cake was concentrated under reduced pressure to give the crude A-1-3 (162 g, 609 mmol, 57.4% yield, 89.3% purity) as yellow solid.

[0157] Step 3. A-1-3 (100 g, 375 mmol, 1.00 eq.) was added into phosphorus oxychloride (300 mL). The mixture was stirred at 110 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove solvent and until product precipitated. The residue was diluted with ice water (1.00 L) and filtered to remove the solvent. Then the filter cake was dissolved in dichloromethane (2.00 L) and water (2.00L) 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 A-1-4 (64.0 g, 213 mmol, 56.7% yield, 85.0% purity) as gray solid.

[0158] Step 4. Aluminum trichloride (752 g, 5.64 mol, 308 mL, 5.00 eq.) was added in one portion to anhydrous dichloroethane (4.90 L) and the mixture was stirred under nitrogen at 20 °C for 10 minutes, then A-1-4 (324 g, 1.13 mol, 1.00 eq.) was added to the mixture in five equal portions. The mixture was stirred at 20 °C for 24 hours. 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 x 3). The combined organic layers were washed with water (2.00 L) and brine (1.00 L x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product A-1 (280 g, 920 mmol, 81.6% yield, 79.4% purity) as gray solid.

General Method B.

Preparation of ethyl 5-chloro-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate (A-2)

[0159] Step 1. To a solution of A-1-2A (2.50 g, 16.1 mmol, 1.00 eq., ethyl 3-amino-1H- pyrazole-4-carboxylate, available from e.g. Sigma- Aldrich) in methanol (20.0 mL) was added sodium methoxide (4.00 g, 74.0 mmol, 4.60 eq.) and dimethyl 2-fluoropropanedioate (3.75 g, 25.0 mmol, 1.55 eq., available from e.g. Sigma- Aldrich). The mixture was stirred at 80 °C for 5 hrs. The mixture was concentrated, and residue was dissolved in water (50 mL). The mixture was adjusted pH=3 with HC1 (2.00 M, 2.00 mL) and lyophilized to give crude A-2-2 (2.5 g,

10.4 mmol, 64.3% yield) as a white solid.

[0160] Step 2. A-2-2 (2.0 g, 8.29 mmol, 1 eq.) was combined with phosphorus oxychloride (64.9 g, 423 mmol, 39.3 mL, 51 eq.). The mixture was stirred at 100 °C for 12 hrs. The mixture was concentrated to give crude product. The residue was purified by Prep-TLC (SiO ₂ , petroleum ether: ethyl acetate = 2:1) to give A-2-3 (1.0 g, 3.60 mmol, 43.4% yield) as a white solid.

[0161] Step 3. To a solution of A-2-3 (865 mg, 3.11 mmol, 1.0 eq.) in ethanol (16.0 mL), THF (6.00 mL) and water (11.0 mL) was added zinc powder (1.02 g, 15.6 mmol, 5.0 eq.) and ammonium chloride (700 mg, 13.1 mmol, 4.21 eq.) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. The mixture was filtered, and the filtrate was diluted with water (50.0 mL). The mixture was extracted with ethyl acetate (30.0 mL × 3) and the organic layer was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by Prep-TLC (SiO ₂ , petroleum ether: ethyl acetate = 3:1) to give A-2 (465 mg, 1.91 mmol, 61.4% yield) as a white solid.

General Method C.

Preparation of ethyl (3R )-3-methyl-3,4-dihydro-2H -pyrazolo[1,2] pyrimido[2,4- d] [ 1 ,4]oxazine-6-carboxylate (B-1)

[0162] Step 1. To a solution of A-1 (290 g, 953 mmol, 1.00 eq.) in ethyl acetate (7.00 L) and dimethyl formamide (700 mL) was added potassium carbonate (527 g, 3.81 mol, 4.00 eq.) and B-1-1A (305 g, 1.29 mol, 1.35 eq. , tert-butyl (R)-5-methyl-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide, available from e.g. Advanced ChemBlocks Inc)). The mixture was stirred at 25 °C for 48 hrs. The reaction mixture was filtered through a celite pad, the filtrate was washed with citric acid solution (1.00 M, 4.00 L), then the layers were separated, and the water phase was extracted with ethyl acetate (2.00 L × 2). The combined organic layers were washed with water (6.00 L × 2) and brine (2.00 L), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give the crude B-1-2 (380 g, 953 mmol, 99.9% yield) as a brown liquid and was used directly.

[0163] Step 2. To a solution of B-1-2 (380 g, 953 mmol, 1.00 eq.) in ethyl acetate (3.00 L) was added hydrochloric acid/dioxane (4.00 M, 2.38 L, 10.0 eq.). The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to remove solvent. The filter cake was triturated with dichloromethane (1.00 L) at 25 °C for 1 hr, filtered and concentrated under reduced pressure to give the crude product. The concentrated filtrate was re-dissolved in water (200 mL) and adjusted pH to 9 with

triethylamine, ethyl acetate (1.00 L) was added to the mixture and the mixture was stirred for 1 hours at 25 °C, then the organic phase was separated, the water phase extracted with ethyl acetate (500 mL) and the combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude B- 1-3 (396 g, crude, hydrochloride) as a yellow solid.

[0164] Step 3. To a solution of B-1-3 (396 g, 1.02 mol, 1.00 eq.) in water (2.00 L) was added triethylamine (411 g, 4.06 mol, 566 mL, 4.00 eq.), then ethyl acetate (4.00 L) was added to the mixture and the mixture was stirred at 20 °C for 2 hrs. The reaction mixture was partitioned between ethyl acetate (4.00 L) and water (2.00 L). The organic phase was separated, the water phase was extracted with ethyl acetate (1.00 L x 2), the combined organic layers were washed with brine (2.00 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product B-1 (213 g, 685 mmol, 67.4% yield, 84.3% purity) as a yellow solid.

General Method D.

Preparation of Compound ethyl (3S)-3-(difluoromethyl)-3,4-dihydro-2H- pyrazolo[1,2]pyrimido[2,4-d][l,4]oxazine-6-carboxylate (B-2)

[0165] Step 1: To a solution of B-2-1 (5.00 g, 22.1 mmol, 1.00 eq., prepared by known methods, e.g. USPN9643980) in dichloromethane (120 mL) was added pyridine (2.80 g, 35.4 mmol, 2.85 mL, 1.60 eq.) and trifluoroacetic anhydride (7.48 g, 26.5 mmol, 4.37 mL, 1.20 eq.) at -20 °C. The mixture was stirred at -20°C - 0 °C for 5 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent at 30 °C. The residue was diluted with water (50.0 mL) and extracted with Petroleum ether/Ethyl acetate=10:1 (50.0 mL × 3). The combined organic layers were 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 (SiO ₂ , Petroleum ether/Ethyl acetate=l/0 to 50/1) to give B-2-2 (6.70 g, 16.8 mmol, 76.2% yield, 90.0% purity) as a light-yellow oil.

[0166] Step 2. To a solution of B-2-2 (0.50 g, 1.40 mmol, 1.00 eq.) in dioxane (5.00 mL) was added (4-methoxyphenyl)methanamine (229 mg, 1.67 mmol, 216 uL, 1.20 eq.) and triethylamine (169 mg, 1.67 mmol, 233 uL, 1.20 eq.). The mixture was stirred at 90 °C for 12 hrs. The reaction mixture was diluted with water (30.0 mL) and extracted with ethyl acetate (20.0 mL x 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 (SiO ₂ , Petroleum ether/Ethyl acetate=50/1 to 10/1) to give B-2-3 (0.35 g, 1.01 mmol, 72.3% yield, 99.5% purity) as a light-yellow oil.

[0167] Step 3. To a solution of B-2-3 (3.35 g, 9.70 mmol, 1.00 eq.) in tetrahydrofuran (34.0 mL) was added a solution of tetrabutyl ammonium fluoride in tetrahydrofuran (1.00 M, 9.70 mL, 1.00 eq.). The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was quenched by 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 (SiO ₂ , Petroleum ether/Ethyl acetate=30/1 to 10/1) to give B-2-4 (2.10 g, 8.99 mmol, 92.7% yield, 99.0% purity) as a light-yellow oil.

[0168] Step 4. To a solution of B-2-4 (2.60 g, 11.2 mmol, 1.00 eq.) in dimethyl sulfoxide (50.0 mL) was added potassium fluoride (1.63 g, 28.1 mmol, 658 uL, 2.50 eq.) and A-2 (2.74 g, 11.2 mmol, 1.00 eq.). The mixture was stirred at 120 °C for 3 hours. 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 (SiO ₂ , Petroleum ether/Ethyl acetate= 10/1 to 2/1) to give compound B-2-5 (1.00 g, 1.83 mmol, 16.3% yield, 80.3% purity) as a yellow oil.

[0169] Step 5. To a solution of B-2-5 (1.00 g, 2.28 mmol, 1.00 eq.) in dimethyl sulfoxide (70.0 mL) was added cesium carbonate (2.97 g, 9.12 mmol, 4.00 eq.). The mixture was stirred at 25 °C for 2 hours. 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 B-2-6 (0.75 g, 1.43 mmol, 62.9% yield, 80.0% purity) as a yellow solid.

[0170] Step 6. B-2-6 (0.51 g, 1.22 mmol, 1.00 eq.) was added into trifluoroacetic acid (10.0 mL). The mixture was stirred at 70 °C for 4 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 1/1) to give B-2 (0.27 g, 862 umol, 70.8 % yield, 96.0% purity) as a gray solid.

General Method E

Preparation of ethyl (3R )-4-[(5-fluoro-2-hydroxyphenyl)methyl]-3-methyl-3,4-dihydro- 2H -pyrazolo[1',5': 1,2]pyrimido[5,4-b ][1,4]oxazine-6-carboxylate (C-1)

[0171] Step 1: To C-1-1 (1 g, 7.14 mmol, 5-fluoro-2-hydroxybenzaldehyde, available from e.g. Sigma-Aldrich) in THF (29.63 mL) was added Hunig's base (3.69 g, 28.55 mmol, 4.97 mL). Cooled to -78 °C and MOM-CI (1.15 g, 14.27 mmol, and 1.08 mL) was added. Stirred as temperature increased from -78 °C to 22 °C over 60 hr. Diluted NaHCO ₃ (1:1 water: saturated NaHCO ₃ , 100 mL) was added followed by DCM (100 mL). The layers were partitioned, and the aqueous layer was extracted 2x with DCM (30 mL). Combined organic layers was washed with brine and dried over sodium sulfate. Flash column chromatography (ISCO, 24 g, 0-25%

EA in Hex) to afford C-1-2 (1.01 g, 5.48 mmol, 76.84% yield).

[0172] Step 2. C-1-2 (1.01 g, 5.48 mmol) was dissolved in methanol (18.28 mL) and the mixture cooled to 0 °C in an ice bath. NaBH4 (414.97 mg, 10.97 mmol) was added slowly and the mixture was stirred as temperature increased over 18 hrs. Reaction was quenched with water (5 mL) and stirred vigorously. Volume was decreased to 1/3 under reduced pressure and the remaining solution was partitioned between water and DCM (20 mL each). The aqueous layer was extracted twice more with DCM (5 mL × 2) and the combined organic layer was washed with brine and then dried over sodium sulfate. Flash column chromatography (ISCO, 24g silica, 0-60% EA in Hexanes) provided C-1-3 (845.1 mg, 4.54 mmol, 82.77% yield).

[0173] Step 3. To C-1-3 (845.1 mg, 4.54 mmol) in DCM (19.15 mL) was added Hunig's base (2.35 g, 18.16 mmol, 3.16 mL). Cooled to 0 °C and mesyl chloride (571.96 mg, 4.99 mmol, 386.46 uL) was added. Stirred as temperature increased to 0-22 °C over 18 hr. Quenched with 2M HCl(aq) (5 mL) at 0 °C. Diluted with water and DCM (20 mL each), layers partitioned, and the aqueous layer extracted with DCM (10 mL × 2). Combined organic layers was washed with brine and dried over sodium sulfate. Flash column chromatography (ISCO, 12 g silica, 0-50% EA in Hexanes) to afford C-1-4 as the chloride (834.3 mg, 4.08 mmol, 89.82% yield).

[0174] Step 4. To B-1 (300 mg, 1.14 mmol) in DMF (5.72 mL) was added CS2CO3 (1.12 g,

3.43 mmol) followed by C-1-4 (304.29 mg, 1.49 mmol). Stirred at 22 °C for 18 hr. Diluted with water (50 mL) and extracted with DCM (3 × 25 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Flash column chromatography (ISCO, 12g silica, 0-60% ethyl acetate in hexanes) provided C-1-5 with a small impurity (532 mg, assumed quantitative).

[0175] Step 5. To a solution of C-1-5 (492 mg, 1.14 mmol) in anhydrous DCM (5.72 mL) was added HC1/4 M DIOXANE (4 M, 5 mL). Stirred for 1.5 hr at 22 °C, then concentrated to dryness under reduced pressure. TEA (1 mL) was added and the crude was purified by flash column chromatography (ISCO, 12 g silica, 20-100% EA in Hexanes) to afford C-1 (353 mg, 913.62 mmol, 79.93% yield).

General Method F

Preparation of (6S,8S,16R)-12-Fluoro-6,16-dimethyl-5,6,7,8,16,17-hexahydro- 4H,14H-6,8- methano-1,19-(metheno)[l,4]oxazino[3,4-y]pyrazolo[4,3- g][1,5,9,11]benzoxatriazacyclotetradecin-4-one (1)

[0176] Step 1. Added Boc ₂ O (436.16 mg, 2.00 mmol) to 1-1 (250 mg, 1.82 mmol, (1r,3r)-3- amino-3-methylcyclobutan-1-ol, available from e.g. Advanced ChemBlocks Inc.) and NaHCO ₃ (2 M, 2.5 mL) in THF (6.36 mL) and stirred for 21 hr. The reaction was diluted with ethyl acetate and water (20 mL) and layers were partitioned. The aqueous layer was extracted with ethyl acetate (2 × 5 mL), the combined organic layer was dried with Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (ISCO with ELSD detection, silica 40 g, 20- 100% EA in Hexanes) to provide 1-2 (279.6 mg, 1.39 mmol, 76% yield).

[0177] Step 2. Added DMAP (303.50 ug, 2.48 umol) to 1-2 (100 mg, 496.86 mmol) and tosyl chloride (99.46 mg, 521.71 mmol) in DCM (2.31 mL) at 0 °C. Reaction was warmed to room temperature and stirred for 5 hr then quenched by addition to water (5 mL). The mixture was extracted with DCM (3 × 5 mL), dried with Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (ISCO, system, silica 24 g, 0-35% EA in Hexanes) to provide 1-3 (83.6 mg, 235 mmol, 47% yield).

[0178] Step 3. To a solution of NaH (6.14 mg, 255.71 umol, 10.23 uL, 60% in mineral oil), [washed and dried] in DMF (750 uL) at 0 °C was added C-1 (49.4 mg, 127.85 mmol) and the mixture was stirred for 15 min. To this solution was added 1-3 (79.53 mg, 223.75 mmol) and the mixture heated to 60 °C for 2 days then cooled and quenched by addition of

saturated NH ₄ CI solution (3 mL). The mixture was extracted with DCM (4 × 4 mL), dried with Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (ISCO, silica 12 g, 0- 50% EtOAc in Hexanes) to provide 1-4 (14.7 mg, 25.8 mmol, 20% yield).

[0179] Step 4. To a solution of 1-4 (14.7 mg, 25.81 mmol) in EtOH (3 mL) at ambient temperature was added aqueous LiOH (2 M, 1 mL). The mixture was heated at 80 °C for 2 hr, cooled to -20 °C then quenched with aqueous HC1 solution (2.0 M) to acidic. The mixture was extracted with DCM (3 × 5 mL), dried with Na ₂ SO ₄ , concentrated under reduced pressure, and dried under high vacuum to afford crude 1-5.

[0180] Step 5. 1-5 was dissolved in DCM (4 mL) followed by addition of HC1/4 M DIOXANE (4 M, 3 mL). The mixture was stirred at ambient temperature for 2 hr, concentrated under reduced pressure, and dried under high vacuum to afford crude 1-6.

[0181] Step 6. Crude 1-6 was dissolved in DCM (8 mL), DMF (2 mL) and DIPEA (111.30 mg, 861.19 umol, 150 pL) then FDPP (29.8 mg, 77 mmol) was added in one portion. Let stir for 4 hr then quenched reaction with 2 M Na ₂ CO ₃ solution (5 mL). Mixture was stirred for 5 min then extracted with DCM (3 × 10 mL). Combined extracts were dried with Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (ISCO, 12 g silica, 0-5% methanol in dichloromethane) provided 1 (7.85 mg, 18.5 mmol, 72% yield).

General Method G

Preparation of (6R,8,1S )-16-(Difluoromethyl)-12-fluoro-5,6,7,8,16,17-hexahydro-

4H ,14H -6,8-methano-1,19-(metheno)[l,4]oxazino[3,4-y]pyrazolo[4,3- g] [ 1 ,5,9, 11 ]benzoxatriazacyclotetradecin-4-one (2)

[0182] Step 1. To a solution of 2-1 (374.47 mg, 2 mmol, tert-butyl ((1R,3R)-3- hydroxycyclobutyl)carbamate, available from e.g. Hnamine Ltd.), 2-2 (408.33 mg, 2.40 mmol, methyl 5-fluoro-2-hydroxybenzoate, available from e.g. Sigma- Aldrich), and PPh ₃ (786.86 mg, 3.00 mmol) in anhydrous DCM (2.23 mL) at 0 °C was added DIAD (647.07 mg, 3.20 mmol, 628.22 mL) with stirring. Mixture was stirred for 3 hr as it warmed to ambient temperature. Purified by flash column chromatography (ISCO, 12 g silica, 0-60% ethyl acetate in hexanes) twice to afford 2-3 (602 mg, 1.77 mmol, 88.70% yield).

[0183] Step 2. 2-6 was obtained in a manner similar to that of steps 2 through 4 as detailed in Method E from 2-3.

[0184] Step 3. Compound 2 was prepared according to General Method F using 2-6 in step 4 in 48% yield.

General Method H

Preparation of (6S,9R , 17R)- 13-Fluoro- 17 -methyl-6,7,8,9, 17, 18-hexahydro- 15H -6,9- methano-1,20-(metheno)[1,4]oxazino[3,4-k]pyrazolo[4,3- L ][ 1 ,6, 10, 12]benzoxatriazacyclopentadecin-4(5H )-one (3)

[0185] Step 1. This step was performed in a manner similar to that of step 1 in General Method G from C-1 and 3-1A (tert-butyl ((1S,3S)-3-hydroxycyclopentyl)carbamate, available from e.g. Sigma- Aldrich) to provide 3-1 in 98% yield.

[0186] Step 2. This step was performed in a manner similar to that of step 4 in General Method F from 3-1 to give compound 3 in 23% yield. General Method H

Preparation of tert-butyl ((1s,3s)-3-(2-(chloro- or mesyl-methyl)-4-fluorophenoxy)-1- methylcyclobutyl)carbamate (6-6)

[0187] Step 1. Added Boc ₂ O (436.16 mg, 2.00 mmol) to 6-1 (250 mg, 1.82

mmol) and NaHCO ₃ (2 M, 2.5 mL) in THF (6.36 mL) and stirred for 21 hr. The reaction was diluted with ethyl acetate and water (20 mL) and layers were partitioned. The aqueous layer was extracted with ethyl acetate (2 x 5 mL), the combined organic layer was dried with Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (ISCO with ELSD detection, silica 40 g, 20-100% EA in Hexanes) to provide 6-2 (279.6 mg, 1.39 mmol, 76% yield).

[0188] Step 2. Added DMAP (303.50 ug, 2.48 umol) to 6-2 (100 mg, 496.86 mmol) and tosyl chloride (99.46 mg, 521.71 mmol) in DCM (2.31 mL) at 0 °C. Reaction was warmed to room temperature and stirred for 5 hours then quenched by addition to water (10 mL). The mixture was extracted with DCM (3 × 10 mL), dried with Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (ISCO, system, silica 24 g, 0-35% EA in Hexanes) to provide 6-3 (83.6 mg, 235 mmol, 47% yield).

[0189] Step 3: 2-2 (300 mg, 1.76 mmol) was dissolved in DMF (8.82 mL) at room temperature. K ₂ CO ₃ (731.08 mg, 5.29 mmol) was added followed by 6-3 (689.43 mg, 1.94 mmol). The mixture stirred at 70 °C for 16 hr. Reaction diluted with DCM (20mL) and cooled. The solution was filtered through a celite pad and the filtrate was concentrated under reduced pressure. Flash column chromatography (ISCO, 12g, ethyl acetate in hexanes) to afford 6-4 (71.4 mg, 189.70 umol, 11% yield).

[0190] Step 4: Compound 6-6 was prepared according to General Method E, step 3.

[0191] Compound 4 was prepared according to General Method F.

[0192] Compound 5 was synthesized according to General Method G. [0193] Compound 6 was synthesized according to General Method G, where 2-5 is replaced by 6-6 that was prepared according to General Method I.

[0194] Biologic assays

[0195] In-Vitro Assays

[0196] Materials and Methods

[0197] Cell lines and cell culture:

[0198] Colorectal cell line KM 12 (harboring endogenous TPM3-TRKA fusion gene) was obtained from NCI. Acute myelogenous cell line KG-1 (harboring endogenous OP2-FGFR1 fusion gene) was purchased from ATCC.

[0199] Cloning and Ba/F3 stable cell lines creation

[0200] The EML4-ALK gene (variant 1) wild type and G1202R were synthesized at GenScript and cloned into pCDH-CMV-MCS-EFl-Puro plasmid (System Biosciences, Inc). Ba/F3 EML4-ALK wild type and solvent front mutation G1202R were generated by transducing Ba/F3 cells with lenti virus containing EML4-ALK wide type or G1202R. Stable cell lines were selected by puromycin treatment, followed by IL-3 withdrawal. Briefly, 5X10 ⁶ Ba/F3 cells were transduced with lentivirus supernatant in the presence of 8mg/mL protamine sulfate. The transduced cells were subsequently selected with 1 mg/mL puromycin in the presence of IL3- containing medium RPMI1640, plus 10% FBS. After 10-12 days of selection, the surviving cells were further selected for IL3 independent growth.

[0201] Cell proliferation assays: [0202] Two thousand cells per well were seeded in 384 well white plate for 24 hrs, and then treated with compounds for 72 hours (37 °C, 5% CO ₂ ). Cell proliferation was measured using CellTiter-Glo luciferase-based ATP detection assay (Promega) following the manufactures 's protocol. IC ₅₀ determinations were performed using GraphPad Prism software (GraphPad, Inc., San Diego, CA).

[0203] Data and Results:

Anti-cell proliferation activity