BR112016016961B1 - COMPOUNDS, COMPOSITIONS AND RELATED USES - Google Patents

Abstract

COMPOSITIONS OF COMPOUNDS AND THEIR USES. The present disclosure relates to novel synthetic substituted heterocyclic compounds and pharmaceutical compositions containing them. The disclosure further relates to the use of these compounds in the treatment and/or prevention of certain types of cancers, pain, inflammation, restenosis, atherosclerosis, psoriasis, thrombosis, Alzheimer's disease, a disease, disorder, injury or malfunction related to demyelination.

Description

CROSS REFERENCE WITH RELATED ORDERS

[001] The present application claims the benefit of priority to U.S. Provisional Application No. 61/936,267, filed on February 5, 2014, the entire contents of which are incorporated herein by reference in their entirety for all purposes.

1. FIELD OF REVELATION

[002] The present disclosure relates to synthetic substituted heterocyclic compounds and pharmaceutical compositions containing them that are capable of inhibiting or antagonizing protein kinase activities. The disclosure further concerns the use of these compounds in the treatment and/or prevention of certain types of cancers, pruritus, atopic dermatitis, scabies, pityriasis, inflammation, restenosis, atherosclerosis, psoriasis, thrombosis, Alzheimer's disease, pain, a disease, disorder , injury or malfunction related to demyelination or the disease or disorder associated with abnormal protein kinase activities.

2. FUNDAMENTALS OF REVELATION

[003] Trk family proteins are receptor tyrosine kinases composed of three family members, TrkA, TrkB and TrkC. They bind with high affinity and mediate signal transduction induced by the neurotrophin family of ligands whose prototype members are nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3-5 (NT 3-5 ). Furthermore, a co-receptor devoid of enzymatic activity, p75, was identified, which binds to all low-affinity neurotrophins (NTs) and regulates neurotrophin signaling. A crucial role of Trks and their ligands during the development of the central and peripheral nervous system was established through gene disruption studies in mice. In particular, the TrkA-NGF interaction has been shown to be a condition for the survival of certain populations of peripheral neurons involved in mediating pain signaling. It has been shown that increased expression of TrkA is also correlated with an increased level of pain in the case of pancreatic cancer (Zhu, et al., Journal of Clinical Oncology, 17: 2419-2428 (1999)). Increased expression of NGF and TrkA has also been observed in chondrocytes of human osteoarthritis (Iannone et al., Rheumatology 41: 1413-1418 (2002)).

[004] TrkA (troponiosin receptor kinase A) is a cell surface receptor kinase that contains an extracellular, a transmembrane and a cytoplasmic kinase domain. Binding of a neurotrophin triggers receptor oligomerization, phosphorylation of tyrosine residues in the kinase domain, and activation of intercellular signaling pathways, including the Ras/MAPK cascade, PI3K/AKT, and IP3-dependent Ca2+ release. Tyrosine kinase activity is an absolute requirement for signal transduction through this class of receptor. NGF receptors have also been found in several cell types outside the nervous system. For example, TrkA has also been found in human monocytes, T and B lymphocytes, and mast cells.

[005] There are several examples of anti-TrkA antibodies or anti-NGF antibodies known in the art. For example, PCT Publications Nos. WO 2006/131952, WO 2005/061540 and EP 1181318 disclose the use of anti-TrkA antibodies as effective analgesics in in vivo animal models of inflammatory and neuropathic pain. PCT Applications Nos. WO 01/78698, WO 2004/058184 and WO 2005/019266 disclose the use of an NGF antagonist for prevention or treatment of pain. PCT Application WO 2004/096122 describes a method for treating or preventing pain with the co-administration of an anti-NGF antibody and an opioid analgesic. PCT Application WO 2006/137106 discloses a method for treating or preventing pain with the co-administration of an anti-TrkA antibody and an opioid analgesic. Furthermore, a profound or significantly attenuated reduction in bone pain caused by prostate cancer metastasis was obtained by using an anti-NGF antibody (Sevik, M.A., et al., Pain 115: 128-141 (2005)).

[006] Loss-of-function mutations in TrkA (NTRK1) lead to congenital insensitivity to pain with anhidrosis [Nat. Genet. 1996; 13: 485-8] and the anti-NGF antibody tanezumab demonstrated clinical efficacy in porosteoarthritis pain and diabetic neuropathic pain [N. Engl. J. Med. 2010; 363: 1521-31; Arthritis Rheum. 2013; 65: 1795-803]. Additionally, Trk inhibitors exhibit excellent efficacy in preclinical pain models [Mol. Pain 2010; 6: 87-100]. Array has recently demonstrated equivalent efficacy with TrkA-selective allosteric inhibitors in pain models, which have the potential to be safer than pan-Trk inhibitors, as discussed later [Array website, 2012. Available: http://www.arraybiopharrna.conm/_documents/Pubbcation/ PubAt tachment587.pdf [last accessed January 22, 2014].

[007] There is some evidence that inhibition of Trks may be beneficial in the treatment of Alzheimer's disease. NGF and TrkA levels are elevated in the airways of asthmatics (asthma) [J. Asthma 2013; 50: 712-17; Respirology (2009) 14, 60-68; and PLoS ONE 4 (7): e6444. doi:10.1371/journal.pone.0006444] and may contribute to inflammation, hyperresponsiveness and remodeling. NGF and TrkA have also been shown to exacerbate ovalbumin-induced airway inflammation in rodents [Exp. The R. Med. 2013; 6: 1251-8]. CT327 is a topical TrkA inhibitor that has been clinically evaluated by Creabilis for chronic pruritus in diseases such as atopic dermatitis, psoriasis, and itch [http://clinicaltrials.gov/show/NCT01808157]. Inhibition of TrkA may be useful in the treatment of Chagas disease. Trypanosoma cruzi, the agent of Chagas disease, uses Trk to invade multiple cell types in the human host [Infect. Immun. 2009; 77: 1368-75; Infect. Immun. 2011; 79: 4081-7].

[008] Selective inhibition of TrkA kinase activity may also be useful in the treatment of otological diseases [Laryngoscope, October 2011; 121 (10): 2,199 213], liver cirrhosis and hepatocellular carcinoma [World J. Gastroenterol. October 7, 2007; 13 (37): 4,986-4,995], inflammatory lung diseases [“Immunology and Microbiology” - “Inflammatory Diseases - A Modern Perspective”, book edited by Amit Nagal, ISBN 978-953307-444-3, Published: December 16, 2011, Chapter 5: “Expression and Role of the TrkA Receptor in Pulmonary Inflammatory Diseases”], fibrosis [J. Cell. Commun. Signal. March 2010; 4 (1): 15-23. Patent Application: PCT/GB2004/004795], pterygeus [Int. J. Exp. Path. (2009), 90, 615-620], lung diseases [Expert Rev. Respir. Med. June 2010; 4 (3): 395-411], pulmonary sarcoidosis [Dagnell et al. Respiratory Research 2010, 11: 156], bladder dysfunction [Neurourology and Urodynamics 30: 1227-1241 (2011); BJU International 111, 372-380; J. Urol. August 2013; 190 (2): 757-764; Neurourology and Urodynamics 33: 39-45 (2014)], lower urinary tract dysfunction [International Journal of Urology (2013) 20, 1320], Paget's disease [J. Cutan. Pathol. 2010: 37: 1,150 1,154], diabetic nephropathy [Diabetes, September 2012, Vol. 61 Issue 9, pages 2,280-2,288; Regulatory Peptides 135 (2006) 30-38], irritable bowel syndrome [Neurogastroenterol Motil. (2013) 25, e740-e754], radiation protection [Radiother. Oncol. June 2012; 103 (3): 380-387].

[009] Furthermore, pain, which can be caused by the disease itself or by treatments, is common in people with cancer, although not all people with cancer will experience pain. Approximately 30% to 50% of people with cancer experience pain during treatment, and 70% to 90% of people with advanced cancer experience pain [Lesage P. and Portenoy R.K. “Cancer Control”; Journal of the Moffitt Cancer Center 1999; 6 (2): 136-145]. Cancer pain is a complex, temporally changing symptom that is the end result of mixed mechanism pain. It involves inflammatory, neuropathic, ischemic and compression mechanisms in several locations [“Pathophysiology of Cancer Pain and Opioid Tolerance”. In: “The British Pain Society’s Cancer Pain Management”. “British Pain Society” website: www.britishpainsociety.org. Published in January 2010. Accessed on January 29, 2013]. It is a subjective, heterogeneous experience, which is modified by individual genetics, past history, mood, expectations and culture. Cancer pain syndromes are categorized as acute and chronic based on onset and duration. Acute pain syndromes have a sudden, well-defined onset, an identifiable cause (for example, surgery), are subject to sympathetic response (fight or fight response), and are expected to improve with treatment. Chronic pain, on the other hand, has a less distinct onset, has a prolonged and fluctuating evolution, and is largely driven by central sensitization and neuroplastic responses to acute injury [Fornasari D. “Pain Mechanisms in Patients with Chronic Pain”. Clinic. Drug Investig. 2012; 32 (suppl. 1): 45-52; Latremoliere A., Woolf C.J. “Central Sensitization: a Generator of Pain Hypersensitivity by Central Neural Plasticity.” J.Pain 2009; 10: 895-926]. It is often characterized by “pain attacks” referred to as penetrating pain [Portenoy R.K., Dhingra L.K. “Assessment of Cancer Pain”. In: Drews R.E., ed. UpToDate. Waltham, M.A.: Update; 2013].

[0010] The therapeutic implications of an effective Trk inhibitor may extend beyond pain therapy. A TrkA polymorphism has been identified as being associated with schizophrenia [J. Psychiatr. Res. October 2009; 43 (15): 1,195-9]. Subversion of this receptor and its signaling pathway in certain malignancies has also been documented. The potential usefulness of Trk inhibitors in oncology has been covered previously (for reviews, see, Expert Opin. Ther. Pat. 2014 Jul; 24(7): 731-44; Nat. Rev. Cancer, 2004: 4: 361-70; Clin. Cancer Res., 2009; 15: 5,962-7). TrkA and/or Trk(B/C) have been implicated in prostate cancer survival and metastasis [Expert Opin. Investigation. Drugs, 2007; 16: 303-9; Prostate, 2000: 45: 140-8], breast cancer [Cytokine Growth Factor Rev., 2012; 23; 357-65], hepatocellular carcinoma (liver cancer) and liver cirrhosis [World J. Gastroenterol. October 7, 2007; 13 (37): 4,986-95; Gastroenterology. June 2002; 122 (7): 1978-86; Biochem. Biophys. Res. Commun. March 4, 2011; 406 (1): 89-95; “Digestive Diseases and Sciences”, Vol. 55, No. 10, (October 2010), pages 2,744-55, ISSN 0163-2116], intrahepatic cholangiocarcinoma [World J. Gastroenterol. April 14, 2014; 20 (14): 4,076-4,084], liver fibrosis [Expert Rev. Mol. Med.; 11: e7. doi:10.1017/S1462399409000994], ovarian cancer [Gynecol. Oncol. January 2007; 104 (1): 168-75], pancreatic cancers [Clin. Cancer Res., 2005; 11: 440-9], oral cancer [Dermatol. Surg. 2004; 30: 1009-1016] and oral cancer pain [J. Dent. Res. 91 (5): 447-453, 2012], skin cancer [Am. J. Clin. Pathol. 2004; 122: 412-420], cervical cancer [African Journal of Biotechnology Vol. 10 (38), pages 7503-7509, 25 July 2011], bone cancer [J. Intern Vet. Med. 2008; 22: 1181-1188]. Other rare cancers, for example, congenital nephramomesoblastic, infantile fibrosarcoma [Am. J. Pathol., 1998; 153: 1451-8] and secretory carcinoma of the breast [Cancer Cell, 2002; 347-8] carry rearrangements of the Tel-TrkC gene. Somatic TrkA rearrangements have been detected in a small but consistent subset of papillary thyroid tumors [Cancer Lett. 2006; 232: 90-8; Mol. Cell. Endocrinol. 2010; 321: 44-9; Genomics. July 1, 1995; 28 (1): 15-24; Int. J. Cancer. March 15, 1999; 80 (6): 842-7].

[0011] An exciting new avenue in the field has recently opened with the discovery of oncogenic TrkA (NTRK1) rearrangements in a small subset of lung cancer patients [Nat. Med. 2013; 19: 1,469-72], and in colorectal cancer (TPM3-TrkA fusion comomutation) [Mol. Oncol. June 12, 2014. pages: S1574-7891 (14) 00125 2]. Tumor samples from 3 of a total of 91 lung cancer patients without previously identified genetic alterations demonstrated evidence of TrkA (NTRK1) gene fusions. These gene fusion mutations are intracellular oncogenic proteins, and constitutively activated the intracellular activity of TrkA kinase and transformed fibroblast cells. Fusions of TrkA (NTRK1), TrkB (NTRK2) or TrkC (NTRK3) have also been identified in glioblastoma, Spitz tumors, spitzoid melanomas, acute myelogenous leukemia and secretory breast cancer [Greco A., et al. Mol. Cell. Endocrinol. 2009; Alberti L., et al. J. Cell. Physiol. 2003; Martin-Zanca D. et al. Nature 1986; Wiesner T., et al. Nat. Commun. 2013; Vaishnavi A., et al., Nat. Med. 2013]. Identification of this gene rearrangement or fusion mutation may enable a patient stratification approach, similar to that used effectively by Pfizer, allowing for rapid registration and approval of crizotinib [Drugs 2013; 73: 2031-51].

[0012] In fact, a patient with TrkA-positive metastatic colorectal cancer was recently treated clinically with RXDX-101, a pan-Trk inhibitor, and obtained a partial response [Ignyta, Inc. News Release. May 31, 2014. Website: http://finance.yahoo.com/news/ignyta-announces-interim-data-rxdx-190000889.html]. Our own search of public human cancer genomic databases has found that many types of human cancers have TrkA fusions or fusion mutations, for example, breast cancer (e.g., CAL-51, CAMA-1, and 3 other human breast cancer cells from 5 patients), endometrial cancer (e.g., RK95-2 and 7 other human cancer cells from 8 patients), blood cancer (e.g., CML-T1 and 3 other cancer cells from 4 patients), liver cancer (SNU-878 and 2 other cells cancer cells from 3 patients), colorectal cancer (e.g., SNU-C4 and 10 other cancer cells from 11 patients), pancreatic cancer (e.g., panc 02.13 and panc 03.27 from 2 patients), and skin cancer (e.g., LOX IMVI and 4 other cancer cells from 5 patients), that a selective inhibitor for TrkA, such as those disclosed in the present disclosure or a compound of the present disclosure, can be used to precisely inactivate the intracellular activity of TrkA kinases and those constitutively activated intracellular oncogenic proteins, i.e., TrkA infusion mutations, and thus , as an effective human cancer treatment therapy for the types of human cancers listed above.

[0013] The tyrosine kinase activity of Trk is believed to promote the unregulated activation of the cell proliferation machinery. Inhibitors of TrkA, TrkB or TrkCkinases, individually or in combination, are believed to have utility against some of the most common cancers such as, for example, brain cancer, melanoma, multiple myeloma, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, breast cancer, head cancer , neck cancer, esophageal cancer, prostate cancer, colorectal cancer, lung cancer, kidney cancer, ovarian cancer, gynecological cancer, thyroid cancer, and certain types of hematologic malignancies. Lestaurtinib (CEP-701, Cephalon), an indolocarbazole inhibitor of multiple tyrosine kinases including Flt-3 and TrkA, and CEP-751, a pan-Trk inhibitor, have entered Phase II clinical trials for the treatment of acute myelogenous leukemia (AML). ), pancreatic cancer and multiple myeloma (MM) and/or prostate cancer.

[0014] It should be highlighted reports that aberrant expression of NGF and TrkA receptor kinase is implicated in the development and progression of human prostate carcinoma and pancreatic ductal adenocarcinoma and activation of Trks chromosomal rearrangements in acute myelogenous leukemia (AML), thyroid and breast cancers and Receptor point mutations predicted to be constitutively activating in colon tumors. In addition to these activation mechanisms, elevated Trk receptor and ligand have also been reported in several tumor types, including multiple myeloma, melanoma, neuroblastoma, ovarian and pancreatic carcinoma. Neurotrophins and their corresponding Trk receptor subtypes have been shown to exert diverse pleiotropic responses in malignant cells, including increased tumor invasiveness and chemotaxis, activation of apoptosis, stimulation of clonal growth, and altered cell morphology. These effects have been observed in prostate, breast, thyroid, colon carcinomas, malignant melanomas, lung carcinomas, glioblastomas, pancreatic carcinoids, and a wide variety of pediatric and neuroectoderm-derived tumors, including Wilm's tumor, neuroblastomas, and medulloblastomas. Neurotrophins and their receptor subtypes have been implicated in these cancers through autocrine or paracrine mechanisms involving carcinoma cells and surrounding parenchymal and stromal tissues. Overall, the soncogenic properties of Trk signaling in multiple tumor types make modulation of Trk receptor signaling a potentially attractive therapeutic intervention point in different malignancies.

[0015] In addition to antibodies, however, few TrkA inhibitors are known and very few (if any) show high selectivity for TrkA kinase (including TrkA inhibitors, CEP-751 and CEP-701 derived from staurosporine). It is rarely known in the art that a synthetic organic molecule or compound has been used as a direct inhibitor or antagonist of TrkA or NGF for the treatment or prevention of particular pain. This may be mainly due to the difficulty in identifying potent and particularly selective small organic anti-TrkA or anti-NGF compounds, through the crystal structure of NGF in complex with the TrkA receptor (Nature 401: 184-188 (1996) & 254: 411 (1991)).

[0016] The therapeutic implications of an effective Trk inhibitor may extend beyond pain therapy. Subversion of this receptor and its signaling pathway in certain malignancies has also been documented. The tyrosine kinase activity of Trk is believed to promote unregulated activation of the cell proliferation machinery. Inhibitors of TrkA, TrkB or TrkCkinases, individually or in combination, are believed to have utility against some of the most common cancers such as, for example, brain cancer, melanoma, multiple myeloma, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, breast cancer, head cancer , neck cancer, esophageal cancer, prostate cancer, colorectal cancer, lung cancer, kidney cancer, ovarian cancer, gynecological cancer, thyroid cancer, and certain types of hematologic malignancies. Lestaurtinib (CEP-701, Cephalon), an indolocarbazole inhibitor of multiple tyrosine kinases including Flt-3 and TrkA, and CEP-751, a pan-Trk inhibitor, have entered Phase II clinical trials for the treatment of acute myelogenous leukemia (AML). ), pancreatic cancer and multiple myeloma (MM) and/or prostate cancer.

[0017] Due to the therapeutic promise associated with TrkA inhibition, and the relative absence of potent and selective inhibitors, it is very necessary to discover potent and selective TrkA inhibitors for a particular isoform, especially small orally active synthetic molecules for possible treatment or prevention of diseases or disorders associated with TrkA activity. .

3. SUMMARY OF THE REVELATION

[0018] The objective of the present disclosure is the use of a small synthetic molecule, and its salts or solvate or prodrug, as a protein kinase inhibitor and/or antagonists, in particular as an inhibitor and/or antagonist of the NGF TrkA receptor for the preparation of a medicament for the treatment and/or or prevention of diseases associated, directly or indirectly, with TrkA inhibition, which include certain cancers (e.g., pancreatic cancer, gastric cancer, esophageal cancer, gastrointestinal cancer, colorectal cancer, lung cancer (small cell and non-small cell), liver cancer , hepatocellular carcinoma, intrahepatic cholangiocarcinoma, brain cancer or human neuroblastoma, glioblastoma and medulloblastoma, retinoblastoma, leukemia, lymphoma, melanoma, malignant mesothelioma, breast cancer, bladder cancer, ovarian cancer, prostate cancer or metastasis, thyroid cancer, carcinomas squamous cell tumors, Spitz tumors, spitzoid melanomas, acute myelogenous leukemia, endometrial cancer, skin cancer, oral cancer, bone cancer, melanoma), pruritus, atopic dermatitis, scabies, pityriasis, inflammatory bowel disease, inflammatory arthritis, asthma, airway diseases human, respiratory disease, fibrotic disease, renal fibrosis, liver fibrosis, liver cirrhosis, restenosis, atherosclerosis, psoriasis, thrombosis, Chagas disease, parasitic diseases, Alzheimer's disease, pain (that is, pain reduction for an individual who needs it, including acute pain, chronic pain, inflammatory pain, neuropathic pain, cancer pain and generalized pain disorder), inflammatory lung diseases, sarcoidosis and lung, bladder dysfunction or lower urinary tract dysfunction, Paget's disease, diabetic nephropathy, irritable bowel syndrome, radiation, schizophrenia, a disease, disorder, injury or malfunction related to demyelination or disease or disorder associated with abnormal protein kinase activities.

[0019] In one aspect, the present disclosure provides, among other things, small molecule compounds and their salts or solvate or prodrugs, such as an NGF TrkA receptor inhibitor and/or antagonist for the preparation of a medicament for the treatment and/or prevention of diseases associated, directly or indirectly, with modulation of TrkA protein kinase activity or expression or activity in certain populations of patients with the following types of cancer with TrkA-positive mutations, fusions or fusion mutations or genetically abnormal TrkA kinase activity, which can be diagnosed clinically by current or future diagnostic tools, e.g., pancreatic cancer, prostate cancer or metastasis, breast cancer , hepatocellular carcinoma, intrahepatic cholangiocarcinoma, liver cancer, ovarian cancer, thyroid cancer, lung cancer (small cell and non-small cell), colorectal cancer, glioblastoma, Spitz tumors, spitzoid melanomas, acute myelogenous leukemia, cancer endometrial, skin cancer, oral cancer, bone cancer, melanoma, gastric cancer, esophageal cancer, gastrointestinal cancer, brain cancer or human neuroblastoma, medulloblastoma, retinoblastoma, leukemia, lymphoma, malignant mesothelioma, bladder cancer, squamous cell carcinomas.

[0020] In one aspect, the present disclosure provides compounds having structural Formula (I): or a salt, solvate, ester or prodrug thereof; where: A1 and A2 are independently oxygen or sulfur; R1 represents NH2 or R7; R2 represents NR7or CR7R10; R3, R5, R6 and R9 are independently R7; or, alternatively, R6 and R9, taken together with the atom(s) to which they are attached, form a 3- to 6-membered optionally substituted heterocyclic group that contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; R4 representshalogen, CN, NO2, CF3, -(CHR)nCOOR11, - (CHR)nSO2R11, C1-4 haloalkyl, -OC1-4 haloalkyl, C2-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CHR) nC6-10 aryl, -(CHR)nC5-8 heterocycle, -(CHR)nC3-8 cycloalkyl, -O-C6-10 aryl, -O-C5-10 heterocycle, -(CHR)nC(O)CF3, - (CHR)nC(OH)(CF3)2,- (CH2)halogen, -OR10, -NR11R12, -NRaCOR11, -NRaCOOR11, - NRaSO2R11, -NRaCONR11R12, -COR11, tetrazole, -(CHR)ntetrazol, - S- C1-6 alkylor -CONR11R12, wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl and heterocycle is independently optionally substituted with 1 to 2 R8 groups; or, alternatively, R4 and R5, taken together with the atom(s) to which they are attached, form a 3- to 6-membered optionally substituted heterocyclic group that contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; R7 and R10 are selected independently from the group consisting of hydrogen, halogen, CN, NH2, NO2, C1-4 haloalkyl, -OC1-4 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CHR)nC6-10 aryl , -(CHR)nC5-8 heterocycle, - (CHR)nC3-8 cycloalkyl, -O-C6-10 aryl, -O-C5-10 heterocycle, - C(O)CF3, -(CH2)nhalogen, -( CHR)n-(O)nC(=O)R8, -(CHR)n- (S)nC(=O)R8, -ORa, -NR11R12, -NRaCOR11, -NRaCOORa, -NRaSO2R, - NRaCONR11R12, -CORa , -(CHR)nCOORa, -S-C1-6 alkyl and -CONR11R12, wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl and heterocyclo is independently optionally substituted with 1 to 2 R8 groups; R11 and R12 are selected independently from the group consisting of hydrogen, N(Ra)C(=O)R, halogen, CN, NH2, NHRa, NO2, C1-4 haloalkyl, -OC1-4 haloalkyl, C1-6 alkyl, C2-8 alkenyl, -S-C1-6 alkyl, -C(=O)-(O)n-Ra, - (CHR)n-(O)nC(=O)R8, -(CHR)n-(S)nC(= O)R8, -ORa, -(CHR)nC3-10 cycloalkyl, -(CHR)nC6-10 aryl, -(CHR)nC5-10 heteroaryl and - (CHR)nC5-10 heterocycle, wherein each of said alkyl , alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclois independently optionally substituted with 1 to 2 groups of R8, and wherein one or more carbon atoms of said alkyl may be replaced with one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; or, alternatively, R11 and R12, taken together with the atom(s) to which they are attached, form a 3- to 6-membered optionally substituted heterocyclic group that contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the optional substituent is R8; and each R independently represents hydrogen, halogen, CN, NO2, NH2 or C1-6 alkyl; each Ra independently represents hydrogen or C1-6 alkyl; each R8 independently represents C1-6 alkyl, halogen, CN, NO2, NH2, NHRa, SO2R11or NRaSO2R11; en represents an integer from 0 to 3; with the following conditions: when R2 is CH2, R4 is not H or CH3; when R2 is NCH2CH2OH, (a) R4 is not H or OCH3, or (b) R5 is not OCH3; and when R2 is N(CH3), R4 is not H, CH3, OCH3 or F.

[0021] In one embodiment of formula (I), R1 is selected from the group consisting of hydrogen, - (CH2) halogen, -CN, -CH3, NH2, NHRae -C1-3 alkyl.

[0022] In one embodiment of formula (I), R4 is selected from the group consisting of -C(O)OR11, -SO2NHC(=O)CH3, -C(CF3)(CF3)OH, -SO2NH2, -C (O)NR11R12, -CN, - CF3, -NO2, -C(O)CF3, -(CH2)halogen, are hydrogen.

[0023] In one embodiment of formula (I), R3, R5, R6 and R9 are hydrogen.

[0024] In a formula modality (I), R2 is selected from

[0025] In another aspect, the present disclosure provides compounds that have structural Formula (II): (CHR)nC(OH)(CF3)2, wherein each of said heterocycles is independently optionally substituted with 1 to 2 R8 groups; R11 is independently selected from the group consisting of hydrogen, C1-6 alkyl, NH2, NHRa, and NRaC(=O)R, wherein each said alkyl is independently optionally substituted with 1 to 2 groups of R8, and wherein a carbon atom of said alkyl may be replaced with a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; each R8 independently represents C1-6 alkyl, halogen, CN, NO2, NH2, NHRa, SO2R11or NRaSO2R11; each R independently represents hydrogen, halogen, CN, NO2, NH2 or C1-6 alkyl; each Ra independently represents hydrogen or C1-6 alkyl; en represents 0.

[0026] In a form of formula (II), X represents N.

[0027] In an embodiment of formula (II), R4 represents -COOR11, where R11 is hydrogen. In one embodiment of formula (II), R4 represents -COOR11, where R11 is C1-6 alkyl. In some embodiments of formula (II), R4 represents -COOR11, wherein R11 is C1-6 alkyl, wherein a carbon atom of said C1-6 alkyl is replaced with a nitrogen atom.

[0028] In one embodiment of formula (II), X represents N and R4 represents -COOR11, where R11 is hydrogen.

[0029] In another embodiment of formula (II), R4 represents -SO2R11, where R11 is NH2 or NRaC(=O)R. In some embodiments of formula (II), R4 represents -SO2R11, where R11 is NHC(=O)R and where R is C1-6 alkyl.

[0030] In an embodiment of formula (II), R4 represents C5 heterocycle, where the heterocycle is a tetrazole.

[0031] In another aspect, the present disclosure provides pharmaceutical compositions comprising one or more compounds as described above or a salt, solvate, ester, prodrug or physiologically functional derivative thereof; and a pharmaceutically acceptable carrier.

[0032] In yet another aspect, the present disclosure provides methods for selective inhibition or antagonism of NGF TrkA receptor for treatment and/or prevention of certain disease, disorder, symptom or condition, including cancer (e.g., pancreatic cancer, gastric cancer, esophageal cancer, gastrointestinal cancer, colorectal cancer , lung cancer, liver cancer, brain cancer or human neuroblastoma, glioblastoma and medulloblastoma, retinoblastoma, leukemia, lymphoma, melanoma, malignant mesothelioma, breast cancer, bladder cancer, ovarian cancer, prostate cancer, thyroid cancer, carcinomas squamous cell disease, pruritus, atopic dermatitis, scabies, pityriasis, inflammatory bowel disease, inflammatory arthritis, asthma, human airway diseases, restenosis, atherosclerosis, psoriasis, thrombosis, Chagas disease, parasitic diseases, Alzheimer's disease, pain, disease, disorder , injury or malfunction related to demyelination or disease or disorder associated with abnormal protein kinase activities, with a therapeutically effective amount of the compound as described above, or a salt, solvate, or physiologically functional derivative thereof.

[0033] In yet another aspect, the present disclosure provides methods for treating and/or preventing certain cancers (e.g., pancreatic cancer, gastric cancer, esophageal cancer, gastrointestinal cancer, colorectal cancer, lung cancer, liver cancer, brain cancer or neuroblastoma human, glioblastoma and medulloblastoma, retinoblastoma, leukemia, lymphoma, melanoma, malignant mesothelioma, breast cancer, bladder cancer, ovarian cancer, prostate cancer, thyroid cancer, squamous cell carcinomas, pruritus, atopic dermatitis, scabies, pityriasis, inflammatory disease intestinal, inflammatory arthritis, asthma, human airway diseases, restenosis, atherosclerosis, psoriasis, thrombosis, Chagas disease, parasitic diseases, Alzheimer's disease, pain, a disease, disorder, injury or malfunction related to demyelination or a disease or disorder associated with abnormal protein activity. kinases, with a combination of: (a) a therapeutically effective amount of the compound as described above, or a salt, solvate, or ester, prodrug or physiologically functional derivative thereof, and (b1) an opioid analgesic or at least one analgesic agent that acts by a mechanism other than a TrkA antagonist or (b2 ) an existing or approved anti-cancer agent or at least one existing or approved anti-cancer agent.

[0034] Additional modalities include a combination of any of the previously mentioned modalities and one or more pharmaceutically acceptable excipients. Other embodiments include a dosage form, for example, a solid or semi-solid dosage form, comprising any of the above-mentioned crystal forms, amorphous forms, or combinations. In still other embodiments, a dosage form comprising any of the foregoing crystal forms, amorphous forms, or combinations comprises one or more of a tablet, hard capsule, soft capsule, powder, suppository, and gel, or one or more of an injectable form, a transdermal patch, a sprayable form, and a depot. implantable.

[0035] Other modalities are a use of any of the previously mentioned modalities in producing a dosage form for inhibiting an NGF receptor, TrkA. Still other modalities are a use of any of the previously cited modalities in producing a dosage form for the treatment of a disorder, disease or condition selected from the group consisting of pain (i.e., reduction of pain for an individual in need thereof, including acute pain, chronic pain, inflammatory pain, neuropathic pain, cancer pain and generalized pain disorder), cancer (e.g., pancreatic cancer, prostate cancer or metastasis, breast cancer, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, liver cancer, ovarian cancer, thyroid cancer, lung cancer (small cell and non- small), colorectal cancer, glioblastoma, Spitz tumors, spitzoid melanomas, acute myelogenous leukemia, endometrial cancer, skin cancer, oral cancer, bone cancer, melanoma, gastric cancer, esophageal cancer, gastrointestinal cancer, brain cancer or human neuroblastoma , medulloblastoma, retinoblastoma, leukemia, lymphoma, malignant mesothelioma, bladder cancer, squamous cell carcinomas), atopic dermatitis, psoriasis, skin diseases, pruritus, liver fibrosis, liver cirrhosis, scabies, pityriasis, inflammatory bowel disease, inflammatory arthritis, asthma, diseases of human airways, Chagas disease, parasitic diseases, Alzheimer's disease, restenosis, atherosclerosis, thrombosis, liver cirrhosis, liver fibrosis, inflammatory pulmonary diseases, pulmonary sarcoidosis, bladder dysfunction or lower urinary tract dysfunction, Paget's disease, diabetic nephropathy, irritable bowel syndrome, radiation, schizophrenia, or a disease, disorder or injury in relation to demyelination or a disease or disorder associated with abnormal activities of TrkA protein kinases or fusions or mutations of the TrkA protein (NTRK1), with a therapeutically effective amount of the compound as described above, or a salt, solvate, or physiologically functional derivative thereof.

[0036] In another aspect, the disclosure provides pharmaceutical compositions comprising the compound described above, and a pharmaceutically acceptable carrier.

[0037] In another aspect, the disclosure provides a method of using a compound having structural Formula (I) and/or Formula (II) in medical treatment and prevention.

[0038] In another aspect, the disclosure provides a method of using a compound having structural Formula (I) and/or Formula (II) in medical treatment and prevention of pain (that is, reducing pain for an individual in need thereof, including acute pain, chronic pain, inflammatory pain, neuropathic pain, cancer pain, and generalized pain disorder), cancer (e.g., pancreatic cancer, prostate cancer or metastasis, breast cancer, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, liver cancer, ovarian cancer, thyroid cancer , lung cancer (small cell and non-small cell), colorectal cancer, glioblastoma, Spitz tumors, spitzoid melanomas, acute myelogenous leukemia, endometrial cancer, skin cancer, oral cancer, bone cancer, melanoma, gastric cancer, cancer esophageal cancer, gastrointestinal cancer, brain cancer or human neuroblastoma, medulloblastoma, retinoblastoma, leukemia, lymphoma, malignant mesothelioma, bladder cancer, squamous cell carcinomas), atopic dermatitis, psoriasis, skin diseases, pruritus, liver fibrosis, liver cirrhosis, scabies, pityriasis, inflammatory bowel disease, inflammatory arthritis, asthma, human airway diseases, Chagas disease, parasitic diseases, Alzheimer's disease, restenosis, atherosclerosis, thrombosis, liver cirrhosis, liver fibrosis, inflammatory pulmonary diseases, pulmonary sarcoidosis, bladder dysfunction or lower urinary tract dysfunction, Paget's disease, diabetic nephropathy, irritable bowel syndrome, radiation, schizophrenia, or a disease, disorder or injury in relation to demyelination or a disease or disorder associated with abnormal activities of TrkA protein kinases or TrkA (NTRK1) protein fusions or mutations, with a combination of: (a ) a therapeutically effective amount of the compound as described above, or a salt, solvate, or ester, prodrug or physiologically functional derivative thereof, and (b1) an opioid analgesic or at least one analgesic agent that acts by a mechanism other than a Trk antagonist or, (b2) an existing or approved anticancer or chemotherapeutic agent or at least one anticancer agent existing or approved.

[0039] In another aspect, the disclosure provides a method for preparing a compound having the structural Formula (I) and/or Formula (II) described above.

[0040] In another aspect, the disclosure provides a method for treating a disease, disorder, symptom or condition associated with irregular TrkA activity, or fusion or mutation of the TrkA protein or NTRK1 gene in a patient suffering therefrom, which comprises administering to the patient a a pharmaceutical composition, comprising a therapeutically effective amount of a compound having structural Formula (I) and/or Formula (II), wherein the pharmaceutical composition is formulated in a unit dosage form selected from the group consisting of: a unit oral dosage form (including powder, tablets, pills, pellets, capsules, powders, lozenges, granules, solutions, suspensions, emulsion, syrups, elixirs, sustained-release formulations, aerosols, sprays and tablets), an inhalation unit dosage form (including spray, aerosol, inhaler, nebulizer, fumigation and vaporizer), a parenteral unit dosage form (including intradermal, intramuscular, intraosseous, intraperitoneal, intravenous, epidural, intracardiac, intraocular, intraarticular, subcutaneous, and intrathecal unit dosage forms), a topical unit dosage form (including cream, gel, liniment or balm, lotion or ointment, hot drops, eye drops, skin patch and vaginal rings), an intranasal unit dosage form, a suppository unit dosage form (including vaginal, douche, pessary and rectal), an epidural unit dosage form, a sublingual unit dosage form (including lozenge and troche) and an intracerebral unit dosage form.

[0041] In another aspect, the disclosure provides a method for treating a disease, disorder, symptom or condition associated with irregular TrkA activity, or fusion or mutation of the TrkA protein or NTRK1 gene in a patient suffering therefrom, which comprises administering to the patient a a pharmaceutical composition comprising a therapeutically effective amount of a compound having structural Formula (I) and/or Formula (II), wherein the pharmaceutical composition is formulated in a unit oral dosage form comprising about 0.02 mg of the compound per kg of body weight up to approximately 60 mg of the compound per kg of body weight.

[0042] In another aspect, the disclosure provides a method for treating a disease, disorder, symptom or condition associated with irregular TrkA activity, or fusion or mutation of the TrkA protein or NTRK1 gene in a patient suffering therefrom, which comprises administering to the patient a a pharmaceutical composition, comprising a therapeutically effective amount of a compound having structural Formula (I) and/or Formula (II), wherein the pharmaceutical composition is formulated in an intravenous unit dosage form comprising from about 0.002 mg of the compound per kg of body weight to about 60 mg of the compound per kg of body weight.

[0043] In another aspect, the disclosure provides a method for treating a disease, disorder, symptom or condition associated with irregular TrkA activity, or fusion or mutation of the TrkA protein or NTRK1 gene in a patient suffering therefrom, which comprises administering to the patient of a pharmaceutical composition, comprising a therapeutically effective amount of a compound having structural Formula (I) and/or Formula (II), wherein the pharmaceutical composition is formulated in an intranasal unit dosage form comprising from about 0.002 mg of the compound per kg of body weight to about 6 mg of the compound per kg of body weight.

[0044] In another aspect, the disclosure provides a method for treating a disease, disorder, symptom or condition associated with irregular TrkA activity, or fusion or mutation of the TrkA protein or NTRK1 gene in a patient suffering therefrom, which comprises administering to the patient a a pharmaceutical composition, comprising a therapeutically effective amount of a compound having structural Formula (I) and/or Formula (II), wherein the pharmaceutical composition is formulated in a suppository unit dosage form comprising from about 0.001 mg of the compound per kg of body weight to about 50 mg of the compound per kg of body weight and comprises active ingredient in the range of about 0.5% to about 10% by weight.

[0045] In another aspect, the disclosure provides a method for treating a disease, disorder, symptom or condition associated with irregular TrkA activity, or fusion or mutation of the TrkA protein or NTRK1 gene in a patient suffering therefrom, which comprises administering to the patient a a pharmaceutical composition, comprising a therapeutically effective amount of a compound having structural Formula (I) and/or Formula (II), wherein the pharmaceutical composition is formulated in a unit dosage form selected from the group consisting of: a parenteral unit dosage form (including intradermal injection unit dosage forms , intramuscular, intraosseous, intraperitoneal, intravenous, epidural, intracardiac, intraocular, intraarticular, subcutaneous, and intrathecal), a topical unit dosage form (including cream, gel, liniment or balm, lotion or ointment, hot drops, eye drops, skin patch, and vaginal rings), an intranasal unit dosage form, a suppository unit dosage form (including vaginal, douche, pessary and rectal), an epidural unit dosage form, a sublingual unit dosage form (including lozenge and troche) and an intracerebral unit dosage form, a an intradermal unit dosage form, an intramuscular unit dosage form, an intraperitoneal unit dosage form, a subcutaneous unit dosage form, an epidural unit dosage form, a sublingual unit dosage form and an intracerebral unit dosage form, wherein said unit dosage forms comprise about from 0.001 mg of the compound per kg of body weight to about 60 mg of the compound per kg of body weight.

5. DETAILED DESCRIPTION OF THE REVELATION

[0046] The present disclosure is related to new small synthetic molecules that act as inhibitors and/or antagonists of members of the protein kinases of the Trk family, particularly the NGF receptor, TrkA.

5.1 DEFINITIONS

[0047] Terms used in the claims and specification are defined as set forth below, unless otherwise specified.

[0048] The terms “a compound of the present disclosure”, “the compound of the present disclosure”, “compounds of the present disclosure” or “the present compounds” refer to one or more compounds encompassed by the structural formulas and/or any subgeneric formulas disclosed in this descriptive report and include any specific compounds within these generic formulas whose structure is disclosed in this descriptive report. Compounds of the disclosure may contain one or more chiral centroids and/or double bonds and, therefore, may exist as stereoisomers, for example, double bond isomers (i.e., geometric isomers), racemic mixtures, enantiomers or diastereomers. Consequently, the chemical structures disclosed here encompass all possible senantiomers and stereoisomers of the illustrated compounds, including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and senantiomeric and stereoisomeric mixtures. The compounds of the disclosure may also exist in various automeric forms. Consequently, the chemical structures disclosed here encompass all possible automeric forms of the illustrated compounds. Compounds also include isotopically labeled compounds in which one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that can be incorporated into compounds include, without limitation, 2H, 3H, 13C, 14C, 15N, 17O, 18O, etc. Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, salt, hydrated, solvated and N-oxide forms are within the scope of the present disclosure. Certain compounds of the present invention may exist in multiple crystalline forms or as an amorphous form. In general, all physical forms are equivalent for the uses contemplated by the present revelation and are intended to be within the scope of the present revelation.

[0049] The term "physiologically functional derivative(s)" used herein refers to any physiologically tolerated derivative of a compound of the present disclosure, e.g., an ester or prodrug, which, upon administration to a mammal, e.g. , a human being, is transformed directly or indirectly into a compound of formula (I) and/or formula (II), or an active metabolite thereof. Physiologically functional derivatives include prodrugs of the compounds of the present disclosure. Examples of prodrugs drug are described in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. These prodrugs can be metabolized in vivo to a compound of the disclosure. These prodrugs themselves can be active or not .

[0050] “Alkyl”, by itself or as part of another substituent, refers to a monovalent saturated or unsaturated, branched, straight-chain or cyclic hydrocarbon radical derived by the removal of a hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne. The term “alkyl” is specifically intended to include groups that have any degree or level of saturation, that is, groups that have exclusively carbon-carbon single bonds, groups that have one or more carbon-carbon double bonds, groups that have one or more carbon-carbon triple bonds, and groups that have mixtures of single bonds. , double and triple carbon-carbon. When a specific level of saturation is desired, the expressions “alkanyl”, “alkenyl” and “alkynyl” are used. In some embodiments, an alkyl group comprises from 1 to 20 carbon atoms (C1-C20 alkyl). In other embodiments, an alkyl group comprises from 1 to 10 carbon atoms (C1-C10 alkyl). In still other embodiments, an alkyl group comprises 1 to 6 carbon atoms (C1-C6 alkyl). Typical alkyl groups include, without limitation, methyl; ethyl, for example, ethanol, ethenyl, ethinyl; propis such as, for example, propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1- yl (allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-en-1-yl, prop-2-en-1-yl etc.; butyls, such as, for example, butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en- 1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta- 1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien- 1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl etc.; and the like.

[0051] ““Alkanyl”, by itself or as part of another substituent, refers to a branched, straight-chain or cyclic saturated alkyl radical derived by the removal of a hydrogen atom from a single carbon atom of an alkane relative. Typical alkanyl groups include, without limitation, methanyl; ethanol; propanols - such as, for example, propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl etc.; butanis such as, for example, butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan -1-il etc.; and the like.

[0052] “Alkenyl”, by itself or as part of another substituent, refers to a branched, straight-chain or cyclic unsaturated alkyl radical that has at least one double carbon-carbon bond derived by the removal of a hydrogen atom of a single carbon atom of a parent alkene. The group can be in the cis or trans conformation around the double bond (or double bonds). Typical alkenyl groups include, without limitation, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop -1-en-1-il; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en- 1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl etc.; and the like.

[0053] “Alkynyl”, by itself or as part of another substituent, refers to a branched, straight-chain or cyclic unsaturated alkyl radical that has at least one triple carbon-carbon bond derived by the removal of a hydrogen atom of a single carbon atom of a parent alkyne. Typical alkynyl groups include, without limitation, ethynyl; propinis such as prop-1-in-1-yl, prop-2-in-1-yl etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl etc.; and the like.

[0054] “Alkyldiyl”, by itself or as part of another substituent, refers to a saturated or unsaturated, branched, straight-chain or branched divalent hydrocarbon group, derived by removing one hydrogen atom from each of two atoms different carbon atoms from a parent alkane, alkene or alkyne, or by removing two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne. The two centers of the monovalent radical or each valence of the center of the divalent radical can form bonds with the same atom or with different atoms. Typical alkyldiyl groups include, without limitation, metandiyl; ethyl diyls such as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such as, for example, propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1, 2-diyl, prop-1-en-1,1-diyl, prop-1-en- 1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3- diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl, cycloprop-2-en-1,1-diyl, prop-1-en-1,3-diyl etc .; butyldiyls such as butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl, butan-2,2-diyl, 2-methyl- propan-1,1-diyl, 2-methyl-propan-1,2-diyl, cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl, but-1-en-1,1- diyl, but-1-en-1,2-diyl, but-1-en-1,3- diyl, but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl, 2-methanylidene-propan- 1,1-diyl, buta-1,3-dien- 1,1-diyl, buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl, buta-1,3-dien-1,4-diyl, cyclobut- 1-en-1,2-diyl, cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl, cyclobuta-1,3-dien-1,2-diyl, cyclobuta- 1,3-dien-1,3-diyl, but-1-in-1,3-diyl, but-1-in-1,4-diyl, buta-1,3-diin- 1,4-diyl etc .; and the like. When specific saturation levels are desired, the nomenclature alkenyldiyl, alkenyldiyl and/oralkynyldiyl is used. In some embodiments, the alkyldiyl group is (C1-C20) alkyldiyl, more preferably, (C1-C10) alkyldiyl, most preferably, (C1-C6) alkyldiyl.

[0055] "Alkylene", by itself or as part of another substituent, refers to a straight-chain alkyldiyl group that has two monovalent radical terminal centers derived by removing one hydrogen atom from each of the two carbon atoms terminals of the parent straight-chain alkane, alkene or alkyne. Typical alkylene groups include, without limitation, methane; ethylenes such as ethane, ethene, ethyne; propylenes such as propane, prop[1]ene, propa [ 1,2]diene, prop [1]yne, etc.; butylenes such as butane, but [1]ene, but [2]ene, buta [1,3]diene, but [1]yne, but [ 2]yne, but [1,3]diyne etc., and the like.When specific saturation levels are desired, alkane, alkene and/or alkyne nomenclature is used.

[0056] "Acyl", by itself or as part of another substituent, refers to a radical -C(O)R200, where R200 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl , substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkyl, as defined herein. Representative examples include, without limitation, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

[0057] “Amino”, by itself or as part of another substituent, refers to a -NRaRb radical, where Ra and Rb are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkyl, as defined herein, or, alternatively, Rae Rb, taken together with the atoms to which they are attached, form a cycloheteroalkyl ring. Representative examples include, without limitation, -NH2, -NHCH3, -N(CH3)2, -NH-phenyl, -NH-CH2-phenyl, pyrrolidine, and the like.

[0058] “Aryl”, by itself or as part of another substituent, refers to a monovalent aromatic hydrocarbon group derived by removing a hydrogen atom from a single carbon atom of a parent aromatic ring system, as defined herein . Typical aryl groups include, without limitation, groups derived from aceanthrylene, cenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene , octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyrantrene, rubicene, triphenylene, trinaphthalene, and the like. In some embodiments, an aryl group comprises 6 to 20 carbon atoms (C6-C20 aryl). In other embodiments, an aryl group comprises 6 to 15 carbon atoms (C6-C15 aryl). In still other embodiments, an aryl group comprises 6 to 10 carbon atoms (C6-C10 aryl).

[0059] “Arylalkyl”, by itself or as part of another substituent, refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal carbon atom or sp3, is replaced with an aryl group, as defined herein. Typical arylalkyl groups include, without limitation, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthylethan- 1-il, and the like. When specific alkyl moieties are desired, the nomenclature arylalkanyl, arylalkenyl and/or arylalkynyl is used. In some embodiments, an arylalkyl group is (C6-C30) arylalkyl, for example, the alkanyl, alkenyl, or alkynyl portion of the arylalkyl group is (C1-C10) alkyl and the aryl portion is (C6-C20) aryl. In other embodiments, an arylalkyl group is (C6-C20) arylalkyl, for example, the alkanyl, alkenyl or alkynyl portion of the arylalkyl group is (C1-C8) alkyl and the aryl portion is (C6-C12) aryl. In still other embodiments, an arylalkyl group is (C6-C15) arylalkyl, for example, the alkanyl, alkenyl or alkynyl portion of the arylalkyl group is (C1-C5) alkyl and the aryl portion is (C6-C10) aryl.

[0060] “Aryloxy”, by itself or as part of another substituent, refers to a radical of the formula -O-R201, where R201 is aryl, substituted aryl, arylalkyl or substituted arylalkyl.

[0061] “Aryloxycarbonyl”, by itself or as part of another substituent, refers to a radical of the formula - C(O)-O-R201, where R201 is aryl, substituted aryl, arylalkyl or substituted arylalkyl.

[0062] “Bioisosteric carboxy,” by itself or as part of another substituent, as used herein, refers to a portion that is expected, at physiological pH, to produce similar chemical or biological properties of a portion of carboxylic acid in the same position of the compound. In certain embodiments, the carboxylate bioisostere is a selected portion of the group consisting of -C(O)OR11, -SO2R11, -C5-8 heterocycle, and C(OH)(CF3)2; R11 is independently selected from the group consisting of hydrogen, C1-6 alkyl, NH2, NHRa, and NRaC(=O)R, wherein each said alkyl is independently optionally substituted, and wherein a carbon atom of said alkyl may be replaced with a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; each R independently represents hydrogen, halogen, CN, NO2, NH2 or C16alkyl; each Ra independently represents hydrogen or C1-6 alkyl.

[0063] "Cycloalkyl" or "carbocyclyl", by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical, as defined herein. When a specific saturation level is desired, the nomenclature “cycloalkanyl” or “cycloalkenyl” is used. Typical cycloalkyl groups include, without limitation, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. In some embodiments, a cycloalkyl group comprises 3 to 10 ring atoms (C3C10cycloalkyl). In other embodiments, a cycloalkyl group comprises 3 to 7 ring atoms (C3-C7 cycloalkyl).

[0064] "Cycloheteroalkyl" or "heterocyclyl", by itself or as part of another substituent, refers to a saturated or unsaturated alkylcyclic radical in which one or more carbon atoms (and, optionally, any associated hydrogen atoms) are independently replaced with the same heteroatom or with a different heteroatom. Typical heteroatoms to replace the carbon atom(s) include, without limitation, B, N, P, O, S, Si, etc. When a specific saturation level is desired, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl” is used. Typical cycloheteroalkyl groups include, without limitation, groups derived from epoxides, azirines, thirans, imidazolidine, morpholino, piperazine, piperidine, pyrazolidine, pyrrolidone, quinuclidine, borolane, dioxaborolane, and the like. In some embodiments, the cycloheteroalkyl group comprises 3 to 10 ring atoms (3-10 membered cycloheteroalkyl). In other embodiments, the cycloalkyl group comprises 5 to 7 ring atoms (5-7 membered cycloheteroalkyl).

[0065] "Halogen” or "halo” by itself or as part of another substituent, refers to any of the elements fluorine, chlorine, bromine, iodine and statin, which occupy group VIIA (17) of the periodic table.

[0066] A cycloheteroalkyl group can be replaced on a heteroatom, for example, a nitrogen atom, with a (C1-C6) alkyl group. As specific examples, N-methyl-imidazolidinyl, N-methyl-morpholinyl, N-methyl-piperazinyl, N-methyl-piperidinyl, N-methyl-pyrazolidinyl and N-methyl-pyrrolidinyl are included in the definition of “cycloheteroalkyl”. cycloheteroalkyl can be attached to the remainder of the molecule via a ring carbon atom or a ring heteroatom.

[0067] "Heteroalkyl, heteroalkanyl, heteroalkenyl, heteroalkanyl, heteroalkyldiyl and heteroalkylene", by themselves or as part of another substituent, refer to the alkyl, alkanyl, alkenyl, alkynyl, alkyldiyl and alkylene groups, respectively, in which one or more of the carbon atoms (and any hydrogen atoms associated) are each independently substituted with the same heteroatomic group or with different heteroatomic groups. Typical heteroatomic groups that may be included in these groups include, without limitation, -O-, -S-, -O-O-, -S-S-, -O-S-, -NR203R204 , =N-N=, -N=N-, -N=N-NR205R206, -PR207-, -P(O)2-, -POR208-, -O-P(O)2-, -SO-, -SO2-, -SnR209R210-, -BR211R212, BOR213OR214, and the like, wherein R203, R204, R205, R206, R207, R208, R209, R210, R211, R212, R213, and R214 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylal kyl, substituted arylalkyl , cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.

[0068] "Heteroaryl", by itself or as part of another substituent, refers to a monovalent heteroaromatic radical derived by the removal of a hydrogen atom from a single atom of a parent heteroaromatic ring system, as defined herein. Typical heteroaryl groups include, without limitation, groups derived from acridine, ß-carboline, chromane, chromene, cinoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, fluorpyridine, and the like. , the heteroaryl group comprises 5 to 20 ring atoms (5-20 membered heteroaryl).In other embodiments, the heteroaryl group comprises 5 to 10 ring atoms (5-10 membered heteroaryl). Exemplary heteroaryl groups include those derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole and pyrazine.

[0069] ““Heteroarylalkyl”, either by itself or as part of another substituent, refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal carbon atom or sp3, is substituted with a heteroaryl group. When specific alkyl moieties are desired, the nomenclature heteroarylalkanyl, heteroarylalkenyl and/or heteroarylalkynyl is used. In some embodiments, the heteroarylalkyl group is a 6-21 membered heteroarylalkyl, for example, the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is (C1-C6) alkyl and the heteroaryl moiety is a 5-15 membered heteroaryl. In other embodiments, the heteroarylalkyl is a 6-13 membered heteroarylalkyl, for example, the alkanyl, alkenyl or alkynyl moiety is (C1-C3) alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.

[0070] "Heteroaryloxy", by itself or as part of another substituent, refers to a radical of the formula -O- R201, where R201 is heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.

[0071] "Heteroaryloxycarbonyl", by itself or as part of another substituent, refers to a radical of the formula -C(O)-O-R201, where R201 is heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.

[0072] "Modulation” refers to adjustment, variation or change. As used herein, modulation of the calcium ion channel includes antagonism, agonism or partial antagonism. That is, the compounds of the present disclosure can act as antagonists, agonists or partial antagonists of calcium ion channel activity.

[0073] “Parent aromatic ring system” refers to a cyclic or polycyclic unsaturated ring system that has a conjugated p-electron system. Specifically included in the definition of “parent aromatic ring system” are fused ring systems in which a or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as fluorene, indane, indene, phenalene, etc. Typical parent aromatic ring systems include, but are not limited to, aceantrylene, cenaphthylene, acephenantrilene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene , octacene, octaphene, octacene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyrantrene, rubicene, triphenylene, trinaphthalene, and the like.

[0074] "Parent heteroaromatic ring system" refers to a parent aromatic ring system in which one or more carbon atoms (and optionally any associated hydrogen atoms) are each independently substituted with the same heteroatom or with a different heteroatom. Typical heteroatoms to replace carbon atoms include, without limitation, B, N, P, O, S, Si, etc. Specifically included in the definition of “parent heteroaromatic ring system” are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, for example, benzodioxane, benzofuran, chromane, chromene, indole, indoline, xanthene, etc. Typical parent heteroaromatic ring systems include, without limitation, arsindole, carbazole, ß-carboline, chromane, chromene, cinoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole , naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole , thiophene, triazole, xanthene, and the like.

[0075] "Patient" or "individual" includes, without limitation, animals such as, for example, mammals. Preferably, the patient is a human being.

[0076] "Prevention" refers to a reduction in the risk of acquiring a disease or disorder (that is, ensuring that at least one of the clinical symptoms of the disease does not develop in a patient who may have been exposed or be predisposed to the disease, but does not yet present or exhibit symptoms of the disease).

[0077] “Protecting group” refers to a grouping of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. Examples of protecting groups can be found in Green and cols., "Protective Groups in Organic Chemistry”, (Wiley, 2nd Edition, 1991) and Harrison et al., "Compendium of Synthetic Organic Methods”, Vols. 1-8 (John Wiley and Sons, 1971-1996). Groups Representative amino protection compounds include, without limitation, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES") ), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitroveratryloxycarbonyl ("NVOC") and the like. Representative hydroxy protecting groups include, without limitation, those in which the hydroxy group is acylated or alkylated such as, for example, benzyl and trityl ethers, in addition to alkyl ethers, tetrahydropyranyl ethers, trialkysylyl ethers and allyl ethers.

[0078] "Salt" refers to a salt of a compound, which possesses the desired pharmacological activity of the parent compound. These salts include: (1) acid addition salts, formed with inorganic acids such as, for example, hydrochloric acid, acid hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanopropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, acid malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, acid 2 - hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glycoheptonic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as, for example, ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like.

[0079] ““Solvate” means a compound formed by solvation (the combination of solvent molecules with solute molecules or ions, i.e., a compound of the present disclosure), or an aggregate consisting of a solute ion or molecule ( the compound of the present disclosure) with one or more solvent molecules.

[0080] "Pharmaceutically acceptable" means suitable for use in contact with the tissues of humans and animals, without unnecessary toxicity, irritation, allergic response, and the like, proportionate to a reasonable risk/benefit ratio, and effective for the intended use within the scope of a consistent medical evaluation.

[0081] "Prodrug or soft drug" refers to a precursor of a pharmaceutically active compound, wherein the precursor itself may or may not be pharmaceutically active, but, upon administration, will be converted, metabolically or in some other way, into the pharmaceutically active compound or drug of interest. For example, a prodrug or “soft” drug is an ester or ether form of a pharmaceutically active compound. Various prodrugs have been prepared and disclosed for various pharmaceutical substances. See, for example, Bundgaard, H. and Moss, J., J. Pharm. Sci. 78: 122-126 (1989). Thus, those skilled in the art know how to prepare these precursors, prodrugs or "soft" drugs with commonly used organic synthesis techniques.

[0082] "Substituted", when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are, each independently of the other, replaced with the same or different substituent(s). (s). Substituent groups useful for replacing saturated carbon atoms in the specified group or radical include, without limitation, -Ra, halogen, -O-, =O, -ORb, -SRb, -S-, =S, -NRcRc, =NRb, =N-ORb, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2Rb, -S(O)2NRb , -S(O)2O-, -S(O)2ORb, -OS(O)2Rb, -OS(O)2O-, -OS(O)2ORb, -P(O)(O-)2, - P(O)(ORb)(O), - P(O)(ORb)(ORb), -C(O)Rb, -C(S)Rb, -C(NRb)Rb, -C(O)O -, - C(O)ORb, -C(S)ORb, -C(O)NRcRc, -C(NRb)NRcRc, -OC(O)Rb, - OC(S)Rb, -OC(O)O -, -OC(O)ORb, -OC(S)ORb, -NRbC(O)Rb, - NRbC(S)Rb, -NRbC(O)O, -NRbC(O)ORb, -NRbC(S)ORb , -NRbC(O)NRcRc, -NRbC(NR)Rbe -NRbC(NRb)NRcRc, wherein Ra is selected from the group consisting of alkyl, substituted alkyl, arylalkyl, alkyldiyl, substituted alkyldiyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroalkyldiyl, substituted heteroalkyldiyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl; each R is independently hydrogen or Ra; and each Rc is independently Rbou, alternatively, the two Rcs are taken together with the nitrogen atom to which they are attached, to form a cycloheteroalkyl ring which may optionally include from 1 to 4 of the same heteroatoms or from different additional heteroatoms selected from the group consisting of O, N and S. As specific examples, - NRcRc is intended to include -NH2, -NH-alkyl, -N-pyrrolidinyl and N-morpholinyl.

[0083] Similarly, useful substituent groups for replacing unsaturated carbon atoms in the specified group or radical include, without limitation, -Ra, halo, -O, -ORb, -SRb, -S-, NRcRc, trihalomethyl, -CF3, -CN, -OCN, - SCN, -NO, -NO2, -N3, -S(O)2Rb, -S(O)2O-, -S(O)2ORb, -OS(O)2Rb, -OS(O)2O-, - OS(O)2ORb, -P(O)(O-)2, -P(O)(ORb)(O), - P(O)(ORb)(ORb), -C(O)Rb, -C (S)Rb, -C(NRb)Rb, -C(O)O-, - C(O)ORb, -C(S)ORb, -C(O)NRcRc, -C(NR)NRcRc, -OC (O)Rb, - OC(S)Rb, -OC(O)O-, -OC(O)ORb, -OC(S)ORb, -NRbC(O)Rb, - NRbC(S)Rb, -NRbC (O)O-, -NRbC(O)ORb, -NRbC(S)ORb, - NRbC(O)NRcRc, -NRbC(NRb)Rbe -NRbC(NRb)NRcRc, where Ra, Rbe and Rc are as previously defined.

[0084] Substituent groups useful for replacing nitrogen atoms in heteroalkyl and cycloheteroalkyl groups include, without limitation, -Ra, -O-, -ORb, -SRb, -S-, -NRcRc, trihalomethyl, -CF3, -CN, -NO, -NO2, - S(O)2Rb, -S(O)2O-, -S(O)2ORb, -OS(O)2Rb, -OS(O)2O-, - OS(O)2ORb, -P(O)(O-)2, -P(O)(ORb)(O), -P(O)(ORb)(ORb), - C(O)Rb, -C(S)Rb, - C(NRb)Rb, -C(O)ORb, -C(S)ORb, -C(O)NRcRc, - C(NRb)NRcRc, -OC(O)Rb, -OC(S)Rb, -OC (O)ORb, -OC(S)ORb, - NRbC(O)Rb, -NRb C(S)Rb, -NRbC(O)ORb, -NRbC(S)ORb, - NRbC(O)NRcRc, -NRbC (NRb)Rbe -NRbC(NRb)NRcRc, where Ra, Rbe Rc are as previously defined.

[0085] Substituent groups from the above lists useful for replacing other specified groups or atoms will be evident to those skilled in the technique. Substituents used to replace a specified group may still be substituted, typically with one or more of the same or different groups selected from the various groups specified above. The term “optionally substituted”, when used with a specific group, means that the specific group can be substituted or unsubstituted. For example, an optionally substituted alkyl represents a substituted alkyl or unsubstituted alkyl.

[0086] ““Treating”, ““treating” or “treatment” of any disease or disorder refers, in some embodiments, to the improvement or prevention of the disease or disorder (i.e., interruption, prevention, containment or reduction of development of the disease or at least one of its clinical symptoms). In other modalities, “that treats”, “to treat” or “treatment” refers to the improvement of at least one physical parameter, which may not be discernible by the patient. ” or “treatment” refers to the inhibition, or containment, or prevention of the progress of the disease or disorder, physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In still other modalities, “that treats,” “Treat” or “treatment” refers to delaying the onset of the disease or disorder.

[0087] "Therapeutically effective amount" means the amount of a compound that, when administered to a patient for treatment of a disease, is sufficient to effect that treatment for the disease. The "therapeutically effective amount" will vary, depending on the compound, of the disease and its severity, and the age, weight, etc., of the patient to be treated.

[0088] "Vehicle" refers to a diluent, adjuvant, excipient or carrier with which a compound is administered.

[0089] Reference will now be made in detail to the preferred embodiments of disclosure. Although the disclosure is described in conjunction with preferred embodiments, it will be understood that the disclosure is not limited to those preferred embodiments. Rather, it encompasses alternatives, modifications and equivalents that may be included within the spirit and scope of the disclosure, as defined by the appended claims.

[0090] The term “receptor” refers to a molecule or complex of molecules, typically (although not necessarily) a protein (or proteins), that is specifically bound by one or more particular ligands. The receptor is said to be a receptor for that ligand(s). The ligand-receptor connection, in many cases, induces one or more biological responses. A “modulator” of a polypeptide is an inhibitor or enhancer of an action or function of the polypeptide. Similarly, a “modulator” of a signaling pathway is an inhibitor or enhancer of at least one function mediated by the signaling pathway. Aspects of modulators are defined below with respect to polypeptides; however, those skilled in the technique readily observe that these definitions also apply to signaling pathways.

[0091] A “non-selective” modulator of a polypeptide is an agent that modulates other members of the same family of polypeptides at concentrations typically employed for modulation of the particular polypeptide.

[0092] A “selective” modulator of a polypeptide significantly modulates the particular polypeptide at a concentration in which other members of the same polypeptide family are not significantly modulated.

[0093] A modulator “acts directly on” a polypeptide when the modulator exerts its action by interacting directly with the polypeptide.

[0094] A modulator “acts indirectly on” a polypeptide when the modulator exerts its action by interacting with a molecule other than the polypeptide, which interaction results in modulation of an action or function of the polypeptide.

[0095] An “inhibitor” or “antagonist” of a polypeptide is an agent that reduces, by any mechanism, any action or function of the polypeptide, when compared to that observed in the absence (or presence of a smaller amount) of the agent. An inhibitor of a polypeptide may affect: (1) the expression, mRNA stability, protein trafficking, modification (e.g., phosphorylation) or degradation of a polypeptide, or (2) one or more of the normal actions or functions of the polypeptide. An inhibitor of a polypeptide may be non-selective or selective. Preferred inhibitors (antagonists) are generally small molecules that act directly on, and are selective for, the target polypeptide.

[0096] A “reversible” inhibitor is one whose effects can be reversed (that is, one that does not irreversibly inactivate the target polypeptide).

[0097] A “competitive” inhibitor of a polypeptide is one that competes for binding to the polypeptide with another component necessary for the function of the polypeptide. For example, the function of TrkA requires the binding of ATP and substrate. Consequently, a competitive inhibitor of TrkA can act, for example, by binding to ATP or substrate binding sites. This inhibition is generally reversible by increasing the concentration of ATP or substrate in the reaction mixture. An inhibitor of this type is said to inhibit TrkA competitively with respect to ATP or substrate, respectively.

[0098] A “non-competitive” inhibitor of a polypeptide generally binds to the polypeptide in a site different from the binding site of another component necessary for the function of the polypeptide. This inhibition cannot be reversed by increasing the concentration of component(s) necessary for the function of the polypeptide.

[0099] As used herein, a “losteric modulator” of a polypeptide, typically an enzyme or receptor, is a modulator that binds at a location other than the active site of the target polypeptide, altering the activity by inducing an allosteric change in the shape of the target polypeptide.

[00100] The terms “polypeptide” and “protein” are used interchangeably here to refer to a polymer of amino acids and, unless otherwise limited, include atypical amino acids that may function in a similar way to naturally occurring amino acids.

[00101] The term “specific binding” is defined here as the preferential binding of binding partners to each other (for example, two polypeptides, a polypeptide and a nucleic acid molecule, or two nucleic acid molecules) at specific sites. The term “specifically binds” indicates that the binding preference (e.g., affinity) for the target molecule/sequence is at least 2-fold, more preferably at least 5-fold, and most importantly at least 10- or 20-fold relative to a non-specific target molecule (e.g., a randomly generated without the specifically recognized site(s).

[00102] The phrases “an effective amount” and “an amount sufficient for” refer to amounts of a biologically active agent that produce a desired biological activity

[00103] The term “co-administer” or “co-administration”, when used in reference to the administration of Trk antagonists (i.e., TrkA) and other agents, indicates that the antagonist and the other agent(s) they are administered in a coordinated manner so that there is at least some chronological overlap in their physiological activity in the individual. Thus, a TrkA antagonist can be administered simultaneously and/or sequentially with another agent. In sequential administration, there may even be some substantial delay (e.g., minutes or even hours or days) before administration of the second agent, provided that the first administered agent is exerting some physiological effect on the organism when the second administered agent is administered or becomes active in the individual.

[00104] The term “pain reduction”, as used herein, refers to the decrease in the level of pain that an individual perceives in relation to the level of pain that the individual would perceive without the intervention. When the individual is a person, the level of pain that the person perceives can be assessed by asking the person to describe the pain or compare it to other painful experiences. Alternatively, pain levels can be determined by measuring the individual's physical responses to pain, for example, the release of stress-related factors or the activity of pain-transducing nerves in the peripheral nervous system or central nervous system (CNS). One can also determine pain levels by measuring the amount of a well-characterized analgesic required for a person to report that pain is not present or for an individual to stop exhibiting pain symptoms. A nador reduction can also be measured as an increase in the threshold at which an individual experiences a certain stimulus as painful. In certain modalities, a reduction in pain is achieved by decreasing “hyperalgesia,” the weighted sensitivity to a noxious stimulus, and this inhibition can occur without transmitting “nociception,” the individual's normal sensitivity to a “noxious” stimulus. The term “pain”, as used here, also refers, for example, to acute pain, chronic pain, inflammatory pain, neuropathic pain and generalized pain disorder.

[00105] As used with reference to pain reduction, “an individual in need thereof” refers to an animal or person, preferably a person, who is likely to experience pain in the near future. That animal or person may have a present condition that is currently causing pain and will likely continue to cause pain. Alternatively, the animal or person has been, is being or will be subjected to a procedure or event that normally has painful consequences. Chronic painful conditions, such as diabetic neuropathic hyperalgesia and collagen vascular diseases, are examples of the first type; Dental work, particularly that accompanied by inflammation or nerve injury, and exposure to toxins (including exposure to chemotherapy agents), are examples of the latter type.

[00106] “Inflammatory pain” refers to pain that arises from inflammation. Inflammatory pain often manifests as increased sensitivity to mechanical stimuli (hyperalgesia or mechanical sensitivity). For example, inflammatory pain is caused by a condition selected from the group consisting of: burn, sunburn, arthritis, osteoarthritis, colitis, carditis, dermatitis, myositis, neuritis, mucositis, urethritis, cystitis, gastritis, pneumonitis and collagen vascular disease.

[00107] “Neuropathic pain” refers to pain that arises from conditions or events that result in nerve injury. “Neuropathy” refers to a disease process that results in nerve damage. “Causalgia” represents a state of chronic pain following nerve injury. “Allodynia” refers to a condition in which a person presents in response to a normally non-painful stimulus, for example, a gentle touch. For example, neuropathic pain is caused by a condition selected from the group consisting of: causalgia, diabetes, peripheral diabetic neuropathy, collagen vascular disease, trigeminal neuralgia, spinal cord injury, brain stem injury, thalamic pain syndrome, complex regional pain syndrome type I/reflex sympathetic dystrophy , Fabry syndrome, small fiber neuropathy, cancer, cancer chemotherapy, chronic alcoholism, stroke, abscess, demyelinating disease, viral infection, antiviral therapy, AIDS and AIDS therapy. Neuropathic pain is caused by an agent selected from the group consisting of: trauma, surgery, amputation, toxin and chemotherapy.

[00108] As used herein, the term “generalized pain disorder” refers to a group of idiopathic pain syndromes (e.g., fibromyalgia, irritable bowel syndrome, and temporomandibular disorders) for which the pathogenic mechanism is currently unknown, characterized by diffuse or generalized pain, and for which a diagnosis of inflammation or neuropathy as the direct cause of pain is excluded.

[00109] An “analgesic agent” refers to a molecule or combination of molecules that causes a reduction in pain.

[00110] The difference between “acute” and “chronic” pain is timing: acute pain is felt soon (e.g., usually within about 48 hours, more typically within about 24 hours, and most typically within about 12 hours) after the occurrence of the event (for example, inflammation or nerve injury) that led to this pain. In contrast, there is a significant time lag between the perception of chronic pain and the occurrence of the event that led to that pain. This time interval is generally at least about 48 hours after that event, more typically at least about 96 hours after that event, and most typically at least about a week after that event.

[00111] The term “maladaptive substance use” refers to the use of any substance that results in adverse consequences for the user that override any benefits derived from the substance. Substances that are used in a maladaptive manner are generally consumed or administered (usually self-administered) to the body, by any route of administration, to produce an effect on the body that the user generally experiences as pleasant. The substance can be a single substance (cocaine, for example) or a type of substance (for example, food, in general). Adverse consequences may include, for example, adverse effects on health, on the ability to care for oneself, on the ability to form and maintain human relationships and/or on the ability to work. Adverse consequences are usually significant enough that the user wants to control, reduce, or stop the use of the substance or, alternatively, the user's family members and/or friends want the user to control, reduce, or stop the use of the substance. Maladaptive substance use may include uncontrolled craving for the substance; substance dependence, including psychological and/or physical dependence; and maladaptive substance use; in addition to any of the individual symptoms of dependence and/or substance abuse listed below.

[00112] The term “neurosteroid” refers to a class of steroids, whose natural forms are produced by cells of the central or peripheral nervous system, independently of the steroidogenic activity of the endocrine glands. Neurosteroids are derivatives of cholesterol, and examples of neurosteroids include 3a,5a-tetrahydroprogesterone, 3a,5ß-tetrahydroprogesterone and 3a,5a-tetrahydrodeoxycorticosterone. For example, ganaxalone and alfaxalone.

[00113] A “benzodiazepine” refers to an agent selected from the group consisting of: alprazolam, chlordiazepoxide, chlordiazepoxide hydrochloride, chlormezanone, clobazam, clonazepam, clorazepatodipotassium, diazepam, droperidol, estazolam, fentanyl citrate, flurazepam hydrochloride, halazepam, lorazepam , midazolam hydrochloride, oxazepam, prazepam, quazepam, temazepam and triazolam.

[00114] A "barbiturate" refers to an agent selected from the group consisting of: amobarbital, amobarbital sodium, aprobarbital, butabarbitalsodium, hexobarbital sodium, mephobarbital, metarbital, methohexithalsodium, pentobarbital, pentobarbital sodium, phenobarbital, phenobarbitalsodium, secobarbital, secobarbital sodium, such butal , thiamylalsodium and thiopentalsodium.

[00115] The term “composition”, as used herein, is intended to encompass a product that comprises specified ingredients in specified quantities, in addition to any product that results, directly or indirectly, from the combination of specified ingredients in specified quantities. This term in relation to pharmaceutical composition aims to encompass a product that comprises the active ingredient(s) and the inert ingredient(s) that constitute the carrier, in addition to any product that results, directly or indirectly, from the combination, complexation or aggregation of any two or more of the ingredients, or the dissociation of one or more of the ingredients, or other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition made by mixing a compound of the present disclosure and a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable” means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

[00116] The term “cancer” refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, for example, leukemia, lymphoma, blastoma, carcinoma and sarcoma. More particular examples of these cancers include chronic myeloid leukemia, acute lymphoblastic leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), squamous cell carcinoma, lung cancer (e.g., small cell lung cancer, and non-small cell lung cancer), glioma, gastrointestinal cancer , kidney cancer, ovarian cancer, liver cancer (e.g., hepatocellular carcinoma, fibrolamellar carcinoma, cholangiocarcinoma, angiosarcoma, hepatoblastoma, hemangioma, hepatic adenomas and focal nodular hyperplasia, and metastatic liver cancer), colorectal cancer, endometrial cancer, cancer renal, prostate cancer, thyroid cancer, neuroblastoma, pancreatic cancer (e.g., adenocarcinoma, islet cell carcinoma, pancreatic blastoma, isolated sarcomas and lymphomas, pseudopapillary neoplasms, ampullary cancer, exocrine tumors, neuroendocrine tumors, and endocrine tumors), glioblastoma multiforme, cancer cervical, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma and head and neck cancer, gastric cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, multiple myeloma, metastasis, acute myelogenous leukemia (AML) and Chronic lymphocytic leukemia (CML).

[00117] It should be understood that this disclosure is not limited to particular methods, reagents, compounds, compositions or biological systems, which may, of course, vary. It must also be understood that the terminology used here has the sole purpose of describing particular aspects, and is not intended to be limiting. As used in this specification and in the appended claims, the singular forms “a”, “an”, “the” and “a” include plural referents unless the content clearly defines otherwise. Thus, for example, reference to “a compound” includes a combination of two or more compounds or molecules, and the like.

5.2 COMPOUNDS

[00118] In one aspect, the present disclosure provides compounds having structural Formula (I), or a salt, solvate, ester or prodrug thereof; where: A1 and A2 are independently oxygen or sulfur; R1 represents NH2 or R7; R2 represents NR7 or CR7R10; R3, R5, R6 and R9 are independently R7; or, alternatively, R6 and R9, taken together with the atom(s) to which they are attached, form a 3- to 6-membered optionally substituted heterocyclic group that contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; R4representshalogen, CN, NO2, CF3, -(CHR)nCOOR11, - (CHR)nSO2R11, C1-4 haloalkyl, OC1-4 haloalkyl, C2-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CHR)nC6- 10 aryl, (CHR)nC5-8 heterocycle, (CHR)nC3-8 cycloalkyl, O-C6-10 aryl, O-C5-10 heterocycle, (CHR)nC(O)CF3, (CHR)nC(OH)( CF3)2, (CH2)halogen, OR10, NR11R12, NRaCOR11, NRaCOOR11, -NRaSO2R11, -NRaCONR11R12, -COR11, tetrazole, (CHR)ntetrazol, -S-C1-6 alkylated -CONR11R12, wherein each of said alkyl , alkenyl, alkynyl, aryl, cycloalkyl and heterocycle is independently optionally substituted with 1 to 2 R8 groups; or, alternatively, R4 and R5, taken together with the atom(s) to which they are attached, form an optionally substituted 3- to 6-membered heterocyclic group containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; R7 and R10 are independently selected from the group consisting of hydrogen, halogen, CN, NH2, NO2, C1-4 haloalkyl, -OC1-4 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CHR)nC6 -10 aryl, -(CHR)nC5-8 heterocycle, - (CHR)nC3-8 cycloalkyl, -O-C6-10 aryl, -O-C5-10 heterocycle, - C(O)CF3, -(CH2)nhalogen , -(CHR)n-(O)nC(=O)R8, -(CHR)n- (S)nC(=O)R8, -ORa, -NR11R12, -NRaCOR11, -NRaCOORa, -NRaSO2R, - NRaCONR11R12 , -CORa, -(CHR)nCOORa, -S-C1-6 alkyl and -CONR11R12, wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl and heterocycle is independently optionally substituted with 1 to 2 R8 groups; R11 and R12 are independently selected from the group consisting of hydrogen, NRaC(=O)R, halogen, CN, NH2, NHRa, NO2, C1-4 haloalkyl, -OC1-4 haloalkyl, C1-6 alkyl, C28 alkenyl, -S- C1-6 alkyl, -C(=O)-(O)n-Ra, -(CHR)n-(O)n- C(=O)R8, -(CHR)n-(S)nC(=O )R8, -ORa, -(CHR)nC3-10 cycloalkyl, -(CHR)nC6-10 aryl, -(CHR)nC5-10 heteroaryl and -(CHR)nC5-10 heterocycle, wherein each of said alkyl, alkenyl , cycloalkyl, aryl, heteroaryl and heterocycle is independently optionally substituted with 1 to 2 groups of R8, and wherein one or more carbon atoms of said alkyl may be replaced with one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; or, alternatively, R11 and R12, taken together with the atom(s) to which they are attached, form a 3- to 6-membered optionally substituted heterocyclic group that contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the optional substituent is R8; and each R independently represents hydrogen, halogen, CN, NO2, NH2 or C1-6 alkyl; each Ra independently represents hydrogen or C1-6 alkyl; each R8 independently represents C1-6 alkyl, halogen, CN, NO2, NH2, NHRa, SO2R11or NRaSO2R11; en represents an integer from 0 to 3, that is, 0, 1, 2, or 3; with the following conditions: when R2 is CH2, R4 is not H or CH3; when R2 is NCH2CH2OH, (a) R4 is not H or OCH3, or (b) R5 is not OCH3; and when R2 is N(CH3), R4 is not H, CH3, OCH3 or F.

[00119] In one embodiment of formula (I), R1 is selected from the group consisting of hydrogen, (CH2) halogen, -CN, -CH3, NH2

[00120] In an embodiment of formula (I), R4 is selected from the group consisting of -C(O)OR11, are hydrogen.

[00121] In one embodiment of formula (I), R3, R5, R6 and R9 are hydrogen.

[00122] In an embodiment of formula (I), R2 is selected from the group consisting of oxygen; R1 represents NH2; R2 represents NR7 or CHR7; R3, R5, R6and R9are hydrogen; R7 is C5-8 heterocycle or C3-8 cycloalkyl; and R4 is selected from the group consisting of - C(O)OR11, -SO2NHC(=O)CH3, -C(CF3)(CF3)OH, -SO2NH2, - C(O)NR11R12, -CN, -CF3, - NO2, -C(O)CF3, -(CH2)halogen,

[00123] In an embodiment of formula (I), A1 and A2 are oxygen; R1 represents NH2; R2 represents NR7 or CHR7; R3, R5, R6 and R9 are hydrogen; R7 is C5-8 heterocycloor C3-8cycloalkyl; and R4 is selected from the group consisting of - C(O)OR11, -SO2NHC(=O)CH3, -C(CF3)(CF3)OH, -SO2NH2, - C(O)NR11R12, -CN, -CF3, - NO2, -C(O)CF3, -(CH2)halogen,

[00124] In one embodiment of R2, this is selected from the group consisting of

[00125] In another aspect, the present disclosure provides compounds that have structural Formula (II): or a salt, solvate, ester or prodrug thereof; where: X represents N or CH; R4 represents carboxy bioisostere selected from -(CHR)nCOOR11, -(CHR)nSO2R11, -(CHR)nC5-8 heterocycle or (CHR)nC(OH)(CF3)2, wherein each of said heterocycles is independently optionally substituted with 1 to 2 groups of R8; R11 is independently selected from the group consisting of hydrogen, C1-6 alkyl, NH2, NHRa, and NRaC(=O)R, wherein each said alkyl is independently optionally substituted with 1 to 2 groups of R8, and wherein a carbon atom of said alkyl may be replaced with a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; each R8 independently represents C1-6 alkyl, halogen, CN, NO2, NH2, NHRa, SO2R11or NRaSO2R11; each R independently represents hydrogen, halogen, CN, NO2, NH2 or C1-6 alkyl; each Ra independently represents hydrogen or C1-6 alkyl; en represents 0.

[00126] In a form of formula (II), X represents N.

[00127] In an embodiment of formula (II), R4 represents COOR11, where R11 is hydrogen. In one embodiment of formula (II), R4 represents -COOR11, where R11 is C1-6 alkyl. In some embodiments of formula (II), R4 represents -COOR11, wherein R11 is C1-6 alkyl, wherein a carbon atom of said C1-6 alkyl is replaced with a nitrogen atom.

[00128] In an embodiment of formula (II), X represents N and R4 represents -COOR11, where R11 is hydrogen.

[00129] In another embodiment of formula (II), R4 represents -SO2R11, where R11 is NH2 or NRaC(=O)R. In some embodiments of formula (II), R4 represents -SO2R11, where R11 is NHC(=O)R and where R is C1-6 alkyl.

[00130] In an embodiment of formula (II), R4 represents C5 heterocycle, where the heterocycle is a tetrazole.

[00131] In certain specific embodiments, compounds of formula (I) and/or formula (II) are selected from the group consisting of: Table 1.

[00132] The Compounds listed in Table 1 can also be represented by their chemical names as follows: ID Name IUPAC 10 4-{ [4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1 -yl]amino}benzenesulfonamide; 12 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic acid; 14 N-[(4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl]acetamide; 16 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 18 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 20 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino} anthracene-9,10-dione; 22 methyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; 24 2-(dimethylamino)ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; 26 ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; 30 4-{[4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide; 32 4-{[4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic acid; 34 N-[(4-{[4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl ]acetamide; 36 1-amino-2-(1,4'-bipiperidin-1'-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 38 2-(dimethylamino)ethyl 4-{[4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate ; and 40 1-amino-2-(1,4'-bipiperidin-1'-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl )phenyl]amino}anthracene-9,10-dione.

[00133] In one embodiment of the present disclosure, the Compounds listed in Table 2 based on Formula (III) are excluded.

5.3 SYNTHESIS OF COMPOUNDS

[00134] Various methods for preparing the compounds of this disclosure will be illustrated in the following Schemes and Examples. The starting materials are made according to procedures known in the art or as illustrated herein. The following abbreviations are used here: Me: methyl; Et: ethyl; t-Bu: tert-butyl; Air: aryl; Ph: phenyl; Bn: benzyl; BuLi: butyl lithium; Piv: pivaloil; Ac: acetyl; THF: tetrahydrofuran; DMSO: dimethyl sulfoxide; EDC: N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide; Boc: tert-butyloxy carbonyl; Et3N: triethylamine; DCM: dichloromethane; DCE: dichloroethane; DME: dimethoxyethane; DBA: diethylamine; DAST: diethylaminosulfur trifluoride; EtMgBr: ethyl magnesium bromide; BSA: bovine serum albumin; TFA: trifluoroacetic acid; DMF: N,N-dimethylformamide; SOCl2: thionyl chloride; CDI: carbonyldiimidazole; rt: ambient temperature; HPLC: high performance liquid chromatography; TLC: thin layer chromatography. The compounds described herein can be prepared in a variety of ways known to those skilled in the art.

[00135] The procedures described here for the synthesis of compounds of the present disclosure may include one or more protection and deprotection steps (for example, the formation and removal of acetal groups). Furthermore, the synthetic procedures disclosed below may include various purifications, for example, column chromatography, flash chromatography, thin layer chromatography (TLC), recrystallization, distillation, high pressure liquid chromatography (HPLC), and the like. In addition, several methodologies known in chemical techniques for the identification and quantification of chemical reaction products, for example, proton and carbon-13 nuclear magnetic resonance (1H and 13C NMR), infrared and ultraviolet spectroscopy (IR and UV), X-ray crystallography, Elemental analysis (EA), HPLC and mass spectroscopy (MS) can also be used. Methods of protection and deprotection, purification and identification and quantification are well known in chemical techniques.

[00136] An example of a synthetic scheme for compounds in Formula (I) and/or Formula (II):

[00137] Preparation of Intermediate 2. 30.0 kg of 4-Amino-10-hydroxyanthracen-9(10H)-one (starting material 1) were suspended in MeOH (70 liters). To the suspension, 53.7 kg of bromine was added to the suspension at 60°C for about 1 hour. After addition of bromine, the reaction mixture was stirred at 50-60°C for about 18-24 hours. The reaction mixture was then cooled. The resulting suspension was filtered, washed with MTBE. The red solid was dried to give Intermediate 2 as a red solid (approximately 50.0 kg, 98% yield). HPLC analysis showed 96% purity. 1H-MRI (CDCl3, 300 Hz) δ 8.26 (m, 2H), 8.09 (s, 1H), 7.80 (m, 2H).

[00138] Intermediate Preparation 3a. 2.99 kg of NaNO2 was added to a cooled H2SO4 solution (27.8 liters) gently. The mixture was stirred at 35°C for 1 hour. Intermediate 2 (15.0 kg) was then added to the mixture and stirred at 50-55°C for 4 hours. After cooling to room temperature, the reaction mixture was poured onto crushed ice. The yellow solid was removed by precipitation. The solid was collected by filtration, washed with ice water, followed by a 1:1 ethanol/MTBE mixture to generate a wet solid, which was dried. 24.7 kg of wet crude product were obtained. The product was used for the next step without further purification.

[00139] Preparation of Intermediate 3. A 100 liter jacketed reactor was charged with the NaN3 solution (2.73 kg) in water. Intermediate 3a was added at room temperature, and the mixture was stirred at room temperature overnight. An aqueous NaOH solution (6N) was then slowly added to the mixture. Next, the solid was collected by filtration and washed with water. Filtrate cake was mixed with water, filtered and washed with water, and followed by acetone/water mixture (9:1), air dried to generate crude Intermediate 3 (23.2 kg of wet solid). HPLC analysis showed 95% purity. 1H-MRI (300 MHz, DMSO-d6) d 8.51 (s, 1H), 8.11-8.15 (m, 2H), 7.91-7.94 (m, 2H).

[00140] Preparation of Intermediate 4. 26.5 kg of crude Intermediate 3 were added to toluene at around 50-70°C. The mixture was then stirred at 50-70°C overnight. After the reaction temperature was cooled to room temperature, the solid product was collected. Filter cake was washed with MeOH. The solid obtained was resuspended in MeOH and stirred at room temperature for about 1-3 hours. After filtration, 13.3 kg of the wet product of Intermediate 4 was obtained as a yellow solid. HPLC analysis showed 98.7% purity. 1H-MRI (300 MHz, DMSO-d6): d 8.27 (m, 2H), 8.13 (m, 1H), 7.91 (m, 1H), 7.78 (m, 1H).

[00141] Preparation of Intermediate 5. Mixing 4-amino benzoic acid and lithium hydroxide in DMAc, and then adding 3,5-dibromo-6H-anthra [1,9-cd]isoxazol-6-one to the mixture at around 40 -60°C. Stir the reaction mixture for up to 24 hours. Addition of MTBE to the reaction mixture. Filtration of the solid and drying to obtain 4- ((3-bromo-6-oxo-6H-antra [1,9-cd]isoxazol-5-yl)amino)benzoic acid (Intermediate 5).

[00142] Preparation of Intermediate 6. Dissolving Intermediate 5 in DMSO, and then adding triethylamine and 1-cyclohexyl piperazine to the solution at a temperature of about 50-70°C. Addition of MTBE and MeOH solution. Isolation and washing of the wet cake with MTBE and MeOH, followed by filtration, provided Intermediate 6 as a solid.

[00143] Preparation of Compound 12. In a flask, Intermediate 6, Pd/C and hydrazine were mixed and heated for about 4 hours. The reaction mixture was cooled to room temperature and filtered, and then it was redissolved in TFA/DMAc and active carbon, and then filtered through celite. NaHCO3 was added to neutralize the mixture and the solid was collected by filtration. Compound 12 was purified and dried. It was about 99% (HPLC, area %) purity. Spectra of massaged [M+1] = 525.5. 1H-MRI (300 MHz, DMSO-d6), ppm (d): 12.36 (1H, s), 8.27 (2H, d), 7.95 (2H, d), 7.85 (2H, t), 7.42 (2H, d), 7.25 (1H, s), 2.96 (4H, m), 2.74 (4H, m), 2.27 (2H, m), 1, 57-1.80 (6H, m), 1.06-1.23 (5H, m).

5.3 BIOLOGICAL ACTIVITIES

[00144] Compound inhibition in a radiometric-based micelleam assay: In a final reaction volume of 25 µl, TrkA (h) (3 nM) is incubated with the kinase reaction buffer (20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij 35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO, 0.2 mg/ml substratePolyEY (4:1) and 2 nM MnCl2 and [33P-ATP] (specific activity approximately 500 cpm/pmol, concentration as required). The reaction is started by adding the MgATP mixture. After incubation for at least 40 minutes at room temperature, the reaction is stopped by adding 5 µl of a 3% phosphoric acid solution. 10 µl of the reaction is then added onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol before drying and scintillation counting. TrkA: Recombinant Human Cytoplasmic Domain (amino acids 441-796), with Histidine tag, expressed in insect cells. Activated in vitrothrough autophosphorylation. Mw = 42.8 kDa. Substrates for kinases: poly(EY) for TRKA; poly(EY) (4:1) with 2 mM MnCl2, average Mw = 16 kDa under standard conditions (unless otherwise specified): 30 nM TRKA, 0.2 mg/ml poly(EY) + 2 mM MnCl2 and 10 µM ([y-33P]) ATP. Using similar assay condition with other recombinant human cytoplasmic domain kinases, the activities of other kinases could also be measured.

[00145] The TrkA kinase antagonist activity of a compound that can be used in the present disclosure can be determined by these assays. In particular, the compounds of the previously mentioned examples of the present disclosure, including Table 1, had activity in antagonizing TrkA kinase activity in the aforementioned assays, generally with an IC50 of less than about 25 µM. Preferred compounds within the present disclosure had activity in antagonizing TrkA kinase activity in the aforementioned assays with an IC50 of less than about 2.5 µM. Additional preferred compounds within the present disclosure had activity in antagonizing TrkA kinase activity in the aforementioned assays with an IC50 of less than about 0.25 µM. Far more preferred compounds within the present disclosure had activity in antagonizing TrkA kinase activity in the aforementioned assays with an IC50 of less than about 0.1 µM. For example, Compound A of the present disclosure has an IC50 of 0.085 µM; Compound 12 of the present disclosure has about 99.6% inhibition of TrkA kinase at a concentration of 10 µM, or an IC50 of about 50 to 150 nM and has more than about 10 µM of the IC50 values of antagonism, e.g. the following structurally related protein kinases and over 400 other kinases, including TrkB, TrkC, ABL1, AKT1, ALK5/TGFB-R1, ARAF, AXL, BMX, BTK, CDK1/cyclin B, CDK2/cyclin A, CDK2/cyclin E, c-MET, c-Src, EPHA1, FES/FPS, FGFR1, FGR, FLT1, FLT3 (CD), FMS, FYN, IGF-1R, IR, ITK, JAK3, JNK3, LCK, LYN, MEK1, MEK2 , MLK1/MAP3K9, MUSK, P38a/MAPK14, P38b/MAPK11, PDGFRa, PDGFRb, PKA, PKC-alpha, PKC-beta I, PKC-beta II, PKC-delta, PKC-epsilon, PKC-eta, PKC-gamma , PKC-iota, PKC-mu/PKD1, PKC-theta, PKC-zeta, PKD2/PRKD2, PKG1a, PKG1b, RAF1, RET, TEC, TGFbR2, TIE2/TEK, VEGFR2/KDR, VEGFR3/FLT4 (duplicate, with a positive control compound of a pan-kinase inhibitor, staurosporine or K-252a). This result is indicative of the intrinsic activity of the compounds being used as isoform-selective antagonists of TrkA kinase activity.

[00146] Compound inhibition in a living whole cell-based functional assay: There are several methods to measure the activation of full-length TrkA stimulated by its natural ligand or NGF agonist in living cells. For example, the “PathHunter Profiling” services offered by DiscoverRx (Fremont, CA). The PathHunter technology is an adaptation of enzyme fragment complementation that provides a new generic cell-based functional assay format for detecting protein-protein interactions. In this cell-based assay approach, with a U2OS cell background, a small peptide epitope (PK) is expressed recombinantly at the intracellular C terminus of TrkA (full-length, human). This is co-expressed with a larger sequence, called enzyme acceptor (EA), which is attached to a cytoplasmic protein SHC1, which will interact with TrkA intracellularly. NGF-induced activation of the TrkA receptor causes homo- or heterodimerization of TrkA, resulting in cross-phosphorylation. The SHC1-EA fusion protein then binds to the forphorylated TrkA receptor, forcing complementation of the PK and EA fragment. This interaction generates an active beta-galactosidase enzyme, which is detected using a chemiluminescent substrate.

[00147] In these cell-based functional assays, for example, Compound 12 of the present disclosure inhibits NGF-stimulated TrkA activation at low nanomolar concentration (cellular IC50 is about 50-150 nM), while having virtually no effect on BDNF-stimulated TrkB activation, or NT3-stimulated TrkC activation (IC50 > 10 µMem both cases, in triplicate, with a positive control compound of pan-kinase inhibitor, staurosporine or K-252a, an internal agonist control and a negative control compound).

[00148] Mode of inhibition in relation to ATP. TrkA kinase assays were performed at room temperature. Four concentrations of compounds (0, 0.037, 0.11, and 0.33 µM) were added into the enzyme/substrate mixture using acoustic technology, and incubated for 40 min to ensure that all compounds were equilibrated and bound to the enzyme. Next, various concentrations of ATP (10, 100, 200, 350 and 500 µM of ATP with 0.2 mg/ml of poly(EY)) were added to start the reaction. Activity was monitored every 5–15 min for the time course. This kinetic analysis shows that Compound D, for example, inhibits TrkA non-competitively with respect to ATP: Lineweaver-Burk double reciprocal plots showing differences in Vmax, but not in km, for the 4 conditions.

[00149] Inhibition mode in relation to the substrate. Kinase assays were performed in a similar way to the ATP study. Various concentrations of compounds (0, 0.037, 0.11, and 0.33 µM) were added into an enzyme/substrate mixture using acoustic technology, and incubated for 40 min to ensure that all compounds were equilibrated and bound to the enzyme. Next, 10 µM of ATP and various concentrations of substrate (0.02, 0.05, 0.1, 0.2 and 0.5 mg/ml poly(EY)) were added to start the reaction. Activity was monitored every 5-15 min over time. This kinetic analysis shows that Compound D, for example, inhibits TrkA non-competitively with respect to the substrate: Lineweaver-Burk double reciprocal plots that show differences in Vmax, but not in km, for the 4 conditions.

[00150] Cell viability and proliferation assays. To assess the chemosensitivity of tumor cells, cell viability is measured by the CellTiter-Glo® Chemiluminescent Cellular Viability Assay (Promega; WI, USA) according to the manufacturer's instructions. Briefly, 5 x 103 to 7 x 105 cells/ml are cultured in sterile 96-well plates in the presence of increasing concentrations of the drugs (test article, 0 to 100 µM), in the ear in RPMI medium. The plates are then incubated for 24 to 96 h, and then 100 µl of CellTiter-Glo reagent is added to lyse the cells. After incubation for 10 min at room temperature, luminescence is recorded in a luminometer, with an integration time of 1 s per well. Luminescence signals for drug-treated cells are normalized by the luminescence signal obtained from vehicle-treated cells. As an alternative method to quantify cell viability, the trypane blue dye exclusion method was used. Vehicle- or drug-treated cells were tested by adding trypan blue solution (0.4% in phosphate-buffered saline [PBS]) to the culture medium. After 3 min, the number of dead cells that contained the dye is compared to the total number of cells to calculate cell viability. The GraphPad Prism 5 software is used to calculate the IC50 and tabulate the drug dose-effect curve. Multiplate reader: EnVision 2104 (PerkinElmer). % control variability = 100* [(X(drug treated) - L(basal level))/(H(vehicle control) - L(basal level))]. These assays show that, for example, Compound 12, has IC50 values of about 2 to 5 µM in human pancreatic cancer cells (from ATCC) of AsPC-1, MIA PaCa-2, BxPC-3, Capan-1 and Panc-1; about 5 µMem SK-HEP-1 and HepG2 human liver cancer cells; and about 7 µMem human stomach cancer cells from NCI-N87, after incubation for 24 hours. Taxol, erlotinib, sorafenib and gemcitabine are used as controls, and the compounds of the present disclosures are synergistic or additive with gemcitabine in pancreatic cancer cells or are synergistic or additive with sorafenib in liver cancer cells.

[00151] Pharmacokinetics and bioavailability after oral and intraperitoneal (i.p.) treatment - bioavailability in CD-1 mice. The pharmacokinetics and bioavailability after oral and i.p. in CD-1 mice (n = 4 per dose group) are determined. For example, for Compound 12, oral bioavailability in CD-1 mice is about 100% after 50 mg/kg oral dosing of the drug; i.p. bioavailability is about 100% after 50 mg/kg i.p. dosing. of the drug; the elimination half-life is about 1 h after intravenous dosing and about 3.5 h after i.p. dosing. and about 4.5 h after oral dosing, of Compound 12.

[00152] Chronic constriction injury (CCI) - Neuropathic pain model in rats. The CCI model is one of the most commonly used mononeuropathic pain models, first described in detail by Bennett and Xie (Bennett G.J., Xie YK. Pain. 1988; 33 (1): 87-107). It mimics important clinical symptoms of chronic pain, such as allodyniamechanics and hyperalgesiathermic pain. Chronic constriction injury to the sciatic nerve was produced by tying four loose ligatures around the left sciatic nerve according to the method of Bennett and Xie. This procedure resulted in tactile lodynia on the left hind paw. Calibrated von Frey filaments were used to determine the lowest mechanical (tactile) threshold necessary to trigger a sharp withdrawal reflex of the rat's hind paws. Mice were allowed to acclimatize in wire cages for 15-20 min before the von Frey test. Assessment of paw withdrawal thresholds (PWTs) using von Frey filaments was performed prior to CCI surgery (pre-surgery baseline on Day 0). Prior to drug dosing on Day 14, the pre-dose basal level was recorded for each dose. Rats were included in the study only if they did not exhibit motor dysfunction (e.g., paw dragging or dropping) and their PWT was below 4 g. Drug-naïve CCI rats (n = 4 - 6 per group) were used. The oral vehicle was 0.5% CMC-Na/0.1% Tween 80 in distilled water. The positive control gabapentin was dissolved in the vehicle and orally administered at 100 mg/kg (by forced oral fattening). The test compound was suspended in the vehicle and administered orally at 50 mg/kg and 100 mg/kg. Each CCI rat received a single oral dose of test compound, gabapentin, or vehicle control, 2 hours prior to PWT assessment. It was demonstrated in this model of neuropathic pain in rats that, for example, Compound 12, exhibited about 48% of the analgesic effect relative to 150 mg/kg oral dose, compared to the analgesic effect produced by morphine (HCl) at 3 mg/kg, s.c.

[00153] The results demonstrated that oral administration, for example, of Compound D of the present disclosure significantly reduced mechanical allodynamia in rats with CCI of the neuropathic pain model in a dose-dependent manner. Furthermore, at the same oral dose of 100 mg/kg, Compound D is about 98% more effective in suppressing allodynamia mechanics in neuropathic pain due to CCI, compared with gabapentin, the current gold standard medication for neuropathic pain, while even 50 mg/kg of oral Compound D are about 28% more effective than 100 mg/kg oral gabapentin. Of note, rats with CCI dosed with gabapentin demonstrated torpor or motor incoordination, which is consistent with a known side effect of gabapentin. However, no such effects or other abnormalities were observed in CCI rats dosed with Compound D.

[00154] Furthermore, there is no statistically significant difference in anti-allodynia effects, as measured on Day 14 and Day 20 for the same group of CCI rats treated with the same single oral dose of Compound D at 100 mg/kg, indicating that no there are issues of tolerance.

[00155] Spinal Nerve Ligation (SNL) - Model of mononeuropathic pain in rats. The surgical procedure will be performed according to the method first described by Kim and Chung (Kim S.H., Chung J.M. Pain. 1992; 50 (3): 355-63). This procedure will result in tactile malodynia on the left hind leg. Rats will be included in the study only if they do not exhibit motor dysfunction (e.g., paw dragging or dropping) and their PWT is below 4.0 g.

[00156] Anti-allodynia dose-response effects of test compound: on Day 14 after surgery, mice will be treated with test compound at one of four doses, vehicle, or positive control by forced oral fattening, and PWT is determined by calibrated von Frey filaments at time points of 0 (just before drug dosing, Pre-Dose Basal Level), 0.5, 1, 2, 4 and 6 hours.

[00157] Tolerance effects: Six days after the day 14 test, that is, on Day 20 after surgery, the same procedure on Day 14 will be repeated on Day 20 with the same group of rats with CCI treated with the same (effective) dose as in Day 14. The results of anti-allodynia effects of the test compound as tested on Day 14 and Day 20 will be compared to see if there is any tolerance effect of the test compound in animals.

[00158] The anti-allodynia effects of repeated administration of test compound: Administration of the test compound will begin on Day 7 after surgery, once a day for 7 days. PWT will be determined by calibrated von Frey filaments once a day, 2 hours after compound dosing. After dosing for 7 days, the measurement will be continued, on alternating days without compound dosing for another 7 days. PWT will be determined at the time points presented above.

[00159] Hyperalgesiathermic effects. Thermic hyperalgesia can be assessed in rats with SNL by plantar testing with a single dose of TEST COMPOUND at the time points presented above.

[00160] Streptozotocin-induced diabetic polyneuropathic pain model. Diabetic peripheral neuropathy is a long-term complication of diabetes mellitus. The rats will receive i.p. injections. of streptozotocin (STZ, 50 mg/kg dissolved in citrate buffer at pH 4.5 immediately before injection) to induce insulin-dependent diabetes mellitus and produce tactile allodynia. One week later, the blood glucose level will be measured, from samples taken from the tail vein, using standardized test strips and a colorimeter. Only animals with a blood glucose level > 350 mg/dl will be considered diabetic and will be included for testing. Typical features of neuropathic pain (tactile allodynia) will develop in the hindpaws starting around 2 to 3 weeks after STZ injection. After 4 weeks, a stable level of allodynia will normally be achieved. At this point, mice with PWT below 4.5 g will be included for compound testing. The allodynia state will remain intact until the 8th week after STZ injection. All animals will be observed daily and weighed regularly during the study period. This model of neuropathic pain mimics the symptoms of neuropathy in diabetic patients (Lynch J.J., 3°, et al. Eur. J. Pharmacol. 1999; 364 (2-3): 141-6; Calcutt N.A., J. Neurol. Sci .2004;220(1-2):137-9).

[00161] Anti-allodynia dose-response effects of test compound: On day 28 after STZ injection, rats will be treated with test compound at one of four doses or Controls (vehicle and positive) by forced oral fattening, and the PWT will be determined by calibrated von Frey filaments at time points of 0 (just before drug dosing, Pre-Dose Basal Level), 0.5, 1, 2, 4 and 6 hours.

[00162] Tolerance effects: Six days after the day 28 test, that is, on Day 34 after STZ injection, the same procedure on Day 28 will be repeated on Day 34 with the same group of rats treated with STZ with the same (effective) dose as on Day 28. The two results of anti-allodynia effects of the test compound, as measured on Day 28 and Day 34, will be compared to see if there is any tolerance effect of the test compound in animals.

[00163] Anti-allodynia effects of repeated administration of test compound: Administration (orally - p.o.) of the test compound will begin on Day 21 after STZ injection, once a day for 7 days. The PWT will be determined by calibrated von Frey filaments once a day, 1 hour after compound dosing. After dosing for 7 days, the measurement will be continued, on alternate days, without compound dosing for another 7 days. PWT is determined at the time points presented above. Assessment of hyperalgesiathermic by plantar testing can be performed on a single dose STZ model and the PWL will be determined at time points as presented above.

[00164] Carrageenan pain model. The carrageenan model is a rapid, reliable model used to evaluate the ability of analgesics to block inflammatory pain. The analgesic effects of test article combinations on pain generation were tested using the carrageenan-induced pain model in rats. Adult male Sprague-Dawley rats are administered the study drugs orally (vehicle, compounds of the present disclosure) once a day for 2 days (day -2 and day -1) and 30 minutes before carrageenan injection on Day 0 (time = 0). For the carrageenan injection, the animals are lightly anesthetized and 0.1 ml of 2% carrageenan is injected into the plantar surface of the right hind paw. The positive control indomethacin (30 mg/kg, p.o.) is administered orally immediately before carrageenan injection. Paw volumes (right and left) are measured using a plethysmometer prior to drug administration on Day -2 and serve as a baseline measurement. Foot volumes are measured again two hours post-carrageenan injection. The degree of mechanical allodynamia is measured by a blinded observer using Von Frey filaments applied to the plantar surface of the hind paws in an ascending numerical order. Each filament increases the force applied to the paw. The filaments are applied until the animal's paw is removed. This procedure is performed before drug administration (day -2), on Day -1 and on Day 0 at times = 0, 20, 40, 60, 80 and 120 minutes post-carrageenan. The force (expressed in grams) required to remove the paw after carrageenan injection is subtracted from the force required to remove the paw before carrageenan injection. Results are expressed as mean change from baseline across five time points post-carrageenan injection. It was demonstrated in this rat pain model that, for example, Compound 12, exhibited about 85% analgesic effect relative to 150 mg/kg oral dose, compared to the analgesic effect, about 100% produced by indomethacin (30 mg/kg, p.o.).

In vivo evaluation of the antitumor efficacy of a compound of Formula (I) and/or Formula (II) in the PANC-1 human pancreatic cancer mouse subcutaneous xenograft model.

[00165] Evaluation of the in vivo therapeutic efficacy of a Compound of Formula (I) and/or Formula (II) (test article) and its combination with gemcitabine in subcutaneous xenografts of human pancreatic cancer PANC-1 in female BALB/c nude mice (with body weight which ranged from 18-23 grams).

[00166] Animal shelter: The animals were kept in rooms with laminar flow at constant temperature and humidity with 4 or 3 animals in each cage. Temperature: 22 ± 3°C. Humidity: 50 ± 20%. Light cycle: 12 hours of light and 12 hours of dark. Cages: 300 mm x 180 mm x 150 mm polycarbonate cages lined with soft wood material were used. The bed was changed twice a week. Diet: The animals had free access to a certified commercial laboratory diet. Contaminant concentrations in the diet are routinely analyzed by manufacturers to ensure that contaminants are below the maximum allowable and therefore would not affect tumor growth.

[00167] Water: The animals had free access to sterile drinking water. Cage identification: The identification labels for each cage contained the following information: number of animals, sex, strain, data received, treatment, group number and data on the start of treatment. Briefly, the PANC-1 cell line was originally purchased from ATCC (CRL-1469) and the PANC-1 primary cell line was derived from PANC-1 subcutaneous xenograft tumors. Primary PANC-1 cells were maintained in vitro as a monolayer culture in DMEM medium supplemented with 10% heat-inactivated fetal bovine serum, 100 U/ml penicillin, and 100 µg/ml streptomycin and L-glutamine (2 mM) at 37°C in a 5% air atmosphere. of CO2. Cells growing in exponential phase were collected and counted for tumor inoculation.

[00168] Tumor cell inoculation and randomization: Each animal was inoculated subcutaneously on the right flank with PANC-1 primary tumor cells (5 x 106/animal) in 0.1 ml of PBS. Tumor development was allowed without interruption until the average tumor volume reached approximately 85 mm3. The animals were then randomized into 6 groups, with each group consisting of 8 animals. Test articles were administered to tumor-bearing animals according to predetermined regimens. All procedures related to the handling, care and treatment of animals in this study were carried out in accordance with guidelines approved by the “Institutional Animal Care and Use Committee” (IACUC) of the testing laboratory, following the guidelines of the “Association for Assessment and Accreditation of Laboratory Animal Care” (AAALAC). At the time of routine monitoring, animals were checked for any effects of tumor growth on normal behavior such as mobility, feed and water consumption (by observation only), body weight (BW) gain/loss (BW was measured twice a week), eyes/hair covering and any other abnormal effect. Death and observed clinical signs were recorded based on the numbers of animals within each subset.

[00169] Tumor measurement and endpoints: The main endpoint was to assess whether tumor growth could be inhibited. Tumor measurement was performed twice a week with a caliper and the tumor volume (mm3) was estimated by using the formula: TV = a x b2/2, where a and b are long and short diameters of a tumor, respectively. Tumor sizes were then used for T/C value and TGI (tumor growth inhibition), which are indicators of antitumor efficacy. The T/C value (in percentage) is an indication of antitumor effect. T and C are the average volumes of the treated and control groups, respectively, on a given day. The BW change, expressed as a %, is calculated using the following formula: BW change (%) = (BW_DayX/ BW_Day0) x 100, where BW_DiaX is the BW on a certain day, and BW_Dia0 was the BW on Day 0 (tumor inoculation).

[00170] Tumor sample collection: Two tumor samples from Groups 1, 2 and 3, respectively, six tumor samples from Group 4, five tumor samples from Groups 5 and 6, respectively, were flash frozen in liquid nitrogen and kept at -80° W. In total, 22 tumor samples were collected.

[00171] Statistical analyses: A one-way ANOVA was performed to compare tumor volumes between groups. All data were analyzed using SPSS 17.0 software; p < 0.05 was considered statistically significant. The in vivo antitumor efficacy of Compound 12, alone or in combination with gemcitabine, is listed in the following two tables.

[00172] The results indicated that Compound 12 was effective in reducing tumor growth, alone or in combination with the current standard medicine, gemcitabine, and the combination of Compound 12 and gemcitabine showed great synergistic effects, having greater tumor reduction than Compound 12 or gemcitabine alone. Average tumor volumes of different groups. Antitumor activity of Compound 12 and its combination with in the treatment of PANC-1 human pancreatic cancer subcutaneous xenograft model.

5.4 THERAPEUTIC USES

[00173] According to the present disclosure, a compound of the present disclosure, or a salt, solvate, ester, and/or the prodrug thereof, or a pharmaceutical composition containing the compound, or a salt, solvate, ester, and/or the The prodrug thereof is administered to a patient, preferably a human, who suffers from various disorders. These include cancers, anxiety, generalized pain disorder, acute pain, chronic pain, inflammatory pain, and neuropathic pain.

[00174] Although the disclosure has been described and illustrated with reference to certain preferred embodiments, those skilled in the art will note that various changes, modifications and substitutions can be made thereto without departing from the spirit and scope of the disclosure.

5.5 THERAPEUTIC/PROPHYLACTIC ADMINISTRATION

[00175] The present compounds, or salts, solvates, esters and/or prodrugs thereof, or pharmaceutical compositions that contain the present compounds, or salts, solvates, esters and/or prodrugs thereof, can be advantageously used in human medicine. As previously described in Section 6.4 above, the present compounds are useful for the treatment or prevention of various diseases.

[00176] When used to treat or prevent the diseases or disorders mentioned above, the present compounds can be administered or applied alone or in combination with other active agents (for example, other anti-pain agents).

[00177] The present disclosure provides methods of treatment and prophylaxis by administering to a patient in need of such treatment a therapeutically effective amount of one or more compounds of the present disclosure, or salts, solvates, esters and/or prodrugs thereof. The patient may be an animal, more preferably a mammal and, most preferably, a human being.

[00178] The present compounds, or salts, solvates, esters and/or prodrugs thereof, can be administered orally. The present compounds, or salts, solvates, esters and/or prodrugs thereof, can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (for example, oral mucosa, rectal and intestinal mucosa, etc.). Administration can be systemic or local. Various delivery systems are known (for example, encapsulation in liposomes, microparticles, microcapsules, capsules, etc.) that can be used to administer a compound and/or pharmaceutical composition thereof. Methods of administration include, without limitation, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topically administration, particularly to the ears, nose, eyes, or skin. The preferred mode of administration will be chosen at the discretion of the responsible professional and will depend, in part, on the location of the medical condition. In most cases, administration will result in the release of the present compounds, salts, solvates, esters and/or prodrugs thereof into a patient's bloodstream.

[00179] In specific embodiments, it may be desirable to administer one or more of the present compounds, or salts, solvates, esters and/or prodrugs thereof, locally to the area in need of treatment. This can be achieved, for example, and not limited to, by local infusion during surgery, topical application, for example, in conjunction with a dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous material, non-porous or gelatinous, including membranes, for example Silastic membranes or fibers. In some embodiments, administration can be achieved by direct injection into the site (or previous site) of cancer or arthritis.

[00180] In certain embodiments, it may be desirable to introduce one or more of the present compounds, or salts, solvates, esters and/or prodrugs thereof, into a patient's central nervous system by any suitable route, including intraventricular, intrathecal and epidural injection. Intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, for example, an Ommaya reservoir.

[00181] The present compounds, or salts, solvates, esters and/or prodrugs thereof, can also be administered directly to the lung by inhalation. For administration by inhalation, the present compounds, or salts, solvates, esters and/or prodrugs thereof, can be conveniently delivered to the lung by several different devices. For example, a metered dose inhaler (“MDI”), which uses canisters containing a low boiling point propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or any other suitable gas), can be used to deliver the disclosure compounds directly to the lung. .

[00182] Alternatively, a dry powder inhaler (“DPI”) device can be used to administer the present compounds, or salts, solvates, esters and/or prodrugs thereof, to the lung. DPI devices typically use a mechanism, such as a gas charge, to create a cloud of dry powder within a container, which can then be inhaled by the patient. DPI devices are also well known in the art. A popular variation is the multiple dose DPI (“MDDPI”) system, which allows for the delivery of more than one therapeutic dose. For example, gelatin capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mixture of a compound of the disclosure and a suitable powder base such as, for example, lactose or starch for such systems.

[00183] Another type of device that can be used to deliver the present compounds, or salts, solvates, esters and/or prodrugs thereof, to the lung is a liquid spray device provided, for example, by Aradigm Corporation, Hayward, CA. Liquid spray systems use nozzles with extremely small orifices to form aerosols of liquid pharmaceutical formulations that can be inhaled directly into the lung.

[00184] In some embodiments, a nebulizer is used to deliver the present compounds, salts, solvates, esters and/or prodrugs thereof, to the lung. Nebulizers create aerosols from liquid pharmaceutical formulations by using, for example, ultrasonic energy to form fine particles that can be easily inhaled (see, for example, Verschoylee cols., British J. Cancer, 1999, 80, Suppl. 2, 96). Nebulizers are available from several commercial sources such as Sheffield/Systemic Pulmonary Delivery Ltd. Aventis and Batelle Pulmonary Therapeutics.

[00185] In another modality, an aerosolelectrohydrodynamic device (“EHD”) is used to release the present compounds, salts, solvates, esters and/or prodrugs thereof, to the lung. EHD aerosol devices use electrical energy to form aerosols from liquid pharmaceutical solutions or suspensions (see, for example, Noakes et al., U.S. Patent No. 4,765,539). The electrochemical properties of the formulation can be important parameters to be optimized when delivering the present compounds, or salts, solvates, esters and/or prodrugs thereof, to the lung with an EHD aerosol device, and this optimization is routinely done by those qualified in the technique. EHD aerosol devices can more efficiently deliver drugs to the lung than existing pulmonary delivery technologies.

[00186] In other embodiments, the present compounds, or salts, solvates, esters and/or prodrugs thereof, can be released in a vesicle, in particular a liposome (see, Langer, 1990, Science, 249: 1,527-1,533 ; Treat et al., in “Liposomes in the Therapy of Infectious Disease and Cancer”, Lopez-Berestein and Fidler (eds.), Liss, New York, pages 353-365 (1989); see generally “Liposomes in the Therapy of Infectious Disease and Cancer”, Lopez-Berestein and Fidler (eds.), Liss, New York, pages 353-365 (1989)).

[00187] In other modalities, the present compounds, or salts, solvates, esters and/or prodrugs thereof, can be released through sustained release systems. In still other embodiments, the sustained release system is an oral sustained release system. In still other modalities, a pump may be used (see, Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14: 201; Saudeke cols., 1989, N. Engl. J. Med. 321: 574).

[00188] In still other embodiments, polymeric materials can be used in pharmaceutical compositions containing the present compounds, or salts, solvates, esters and/or prodrugs thereof (for exemplary polymeric materials, see “Medical Applications of Controlled Release”, Langer and Wise (eds.), CRC Pres. , Boca Raton, Florida (1974); “Controlled Drug Bioavailability”, “Drug Product Design and Performance”, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci Rev. Macromol Chem. 23: 61; see also Levy et al., 1985, Science 228: 190; During et al., 1989, Ann. Neurol. 25: 351; Howard et al., 1989, J. Neurosurg. 71 : 105). In still other embodiments, polymeric materials are used for the sustained release of oral pharmaceutical compositions. Exemplary polymers include, without limitation, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose (primarily, hydroxypropyl methylcellulose). Other cellulose ethers have been described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr., 1984, 5(3) 19). Factors affecting drug release are well known to those skilled in the art and have been described in the art (Bamba et al., Int. J. Pharm., 1979, 2, 307).

[00189] In other embodiments, enteric-coated preparations can be used for sustained-release oral administration. Coating materials include, without limitation, polymers with a pH-dependent solubility (i.e., pH-controlled release), polymers with a slow or pH-dependent swelling, dissolution, or erosion rate (i.e., time-controlled release), polymers that are degraded by enzymes (i.e., enzyme-controlled release). ) and polymers that form firm layers that are destroyed by an increase in pressure (i.e., pressure-controlled release).

[00190] In still other modalities, osmotic release systems are used for sustained release oral administration (Verma et al., Drug Dev. Ind. Pharm., 2000, 26: 695-708). In still other embodiments, OROSTM osmotic devices are used for sustained oral release devices (Theeuwese cols., U.S. Patent No. 3,845,770; Theeuwese cols., U.S. Patent No. 3,916,899).

[00191] In still other embodiments, a controlled release system can be placed in the vicinity of the target of the present compounds, salts, solvates, esters and/or prodrugs thereof, which thus require only a fraction of the systemic dose (see, for example, Goodson, in “ Medical Applications of Controlled Release”, supra, vol 2, pages 115-138 (1984)). Other controlled release systems discussed in Langer, 1990, Science 249: 1527-1533 can also be used.

5.6 PHARMACEUTICAL COMPOSITIONS OF THE REVELATION

[00192] In one aspect, the present disclosure provides pharmaceutical compositions comprising one or more compounds of the present disclosure, including the compound having structural formula (I) and/or formula (II) and any of its subgeneric groups and specific modalities described above in Section 5.2.

[00193] The present pharmaceutical compositions contain a therapeutically effective amount of one or more compounds of the present disclosure, or salts, solvates, esters and/or prodrugs thereof, preferably in purified form, together with a suitable amount of a pharmaceutically acceptable carrier, so as to provide a form for suitable administration to a patient. . When administered to a patient, the present pharmaceutically acceptable compounds and carriers are preferably sterile. Water is a preferred vehicle when a compound is administered intravenously. Saline solutions and aqueous solutions of dextrose and glycerol can also be used as liquid vehicles, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene, glycol , water, ethanol, and the like. The present pharmaceutical compositions, if desired, may also contain small amounts of wetting or emulsifying agents, or pH buffering agents. In addition, auxiliary agents, stabilizers, thickeners, lubricants and colorants may be used.

[00194] Pharmaceutical compositions can be manufactured through conventional mixing, dissolving, granulating, tablet production, grinding, emulsification, encapsulation, capture or freeze-drying processes. Pharmaceutical compositions can be formulated in a conventional manner by using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries, which facilitate the processing of the compounds of the disclosure into preparations that can be used pharmaceutically. The appropriate formulation depends on the chosen route of administration.

[00195] The present pharmaceutical compositions may take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other suitable for use. In some embodiments, the pharmaceutically acceptable carrier is a capsule (see, for example, Grosswald et al., U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical carriers have been described in the art (see “Remington: The Science and Practice of Pharmacy”, Philadelphia College of Pharmacy and Science, 20th Edition, 2000).

[00196] For topical administration, a compound can be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art.

[00197] Systemic formulations include those designed for administration by injection, for example, subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, in addition to those designed for transdermal, oral transmucosal or pulmonary administration. Systemic formulations can be made in combination with an additional active agent, such as another anticancer agent.

[00198] In some embodiments, the present compounds, or salts, solvates, esters and/or prodrugs thereof, are formulated according to routine procedures as a pharmaceutical composition adapted for intravenous administration to humans. Typically, compounds for intravenous administration are solutions in sterile aqueous isotonic buffer. For injection, the present compounds, or salts, solvates, esters and/or prodrugs thereof, can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as, for example, Hanks' solution, Ringer's solution or saline buffer. The solution may contain formulation containants such as, for example, suspending agents, stabilizers and/or dispersants. When necessary, pharmaceutical compositions may also include a solubilizing agent. Pharmaceutical compositions for intravenous administration may optionally include a local anesthetic, for example, lignocaine, to reduce pain at the injection site. Generally, the ingredients are supplied separately or mixed together in unit dosage form, for example, as a lyophilized powder or concentrated in water in a hermetically sealed container such as, for example, an ampoule or sachet that indicates the amount of active agent. When the present compounds, or salts, solvates, esters and/or prodrugs thereof, are administered by infusion, they may be dispensed, for example, with an infusion bottle containing water or sterile pharmaceutical grade saline. When the present compounds, or salts, solvates, esters and/or prodrugs thereof, are administered by injection, an ampoule of water for injection or sterile saline solution may be provided so that the ingredients may be mixed before administration.

[00199] For transmucosal administration, penetrating formulations appropriate to the barrier to be permeated are used. Such penetrants are generally known in the art.

[00200] Pharmaceutical compositions for oral release may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs, for example. Orally administered pharmaceutical compositions may contain one or more optional agents, for example, sweetening agents such as, for example, fructose, aspartame or sucrose; flavoring agents, for example, mint, mint or cherry oil, coloring agents and preservative agents, to provide a pharmaceutically palatable preparation. Furthermore, in tablet or pill form, the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active conductive compound are also suitable for orally administered compounds of the disclosure. In the latter platforms, the fluid from the environment surrounding the capsule is imbibed by the conductive compound, which swells to displace the agent or agent composition through an opening. These release platforms can provide a virtually zero-order release profile, unlike the peaked profiles of immediate release formulations. A time delay material, such as glycerol monostearate or glycerol stearate, can also be used. Oral compositions may include standard vehicles such as, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. These vehicles are preferably of pharmaceutical grade.

[00201] For oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, saline, alkylene glycols (e.g. propylene glycol), polyalkylene glycols (e.g. polyethylene glycol) oils, alcohols, slightly acidic buffers between pH 4 and pH 6 (e.g. , acetate, citrate, ascorbate between about 5.0 mM to about 50.0 mM) etc. Additionally, flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines, and the like, may be added.

[00202] For buccal administration, pharmaceutical compositions may take the form of tablets, lozenges, etc. formulated in a conventional way.

[00203] Liquid pharmacological formulations suitable for use with nebulizers and EHD liquid aerosol spray devices and devices will typically include a compound of the disclosure with a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier is a liquid, for example, alcohol, water, polyethylene glycol, or a perfluorocarbon. Optionally, other material may be added to alter the aerosol properties of the solution or suspension of compounds revealed here. Preferably, this material is liquid, such as, for example, an alcohol, glycol, polyglycol or a fatty acid. Other methods of formulating liquid pharmaceutical solutions or suspensions suitable for use in aerosol devices are known to those skilled in the art (see, for example, Biesalski, U.S. Patent No. 5,112,598; Biesalski, U.S. Patent No. 5,556,611).

[00204] The present compounds, or salts, solvates, esters and/or prodrugs thereof, can also be formulated in rectal or vaginal pharmaceutical compositions, for example, suppositories or retention enemas, which contain, for example, conventional bases of suppository such as cocoa butter or other glycerides.

[00205] In addition to the formulations previously described, the present compounds, or salts, solvates, esters and/or prodrugs thereof, can also be formulated as a depot preparation. These long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, the present compounds, or salts, solvates, esters and/or prodrugs thereof, can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as moderately soluble derivatives, for example, as a moderately soluble salt.

5.7 THERAPEUTIC DOSES

[00206] The present compounds, or a salt, prodrug or soft drug, salt of prodrug or soft drug, solvate or hydrate thereof, and a pharmaceutically acceptable carrier, will generally be used in an effective amount to obtain the desired purpose. For use to treat or prevent diseases or disorders characterized by downregulated poptosis, the compounds and/or pharmaceutical compositions thereof are administered or applied in a therapeutically effective amount.

[00207] The amount of the present compounds, or salts, solvates, esters and/or prodrugs thereof, which will be effective in treating a particular disorder or condition disclosed herein will depend on the nature of the disorder or condition, and can be determined by standard clinical methodologies in the art. Additionally, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The amount of these compounds, salts, solvates, esters and/or prodrugs thereof administered will obviously depend, among other factors, on the individual being treated, the individual's weight, the severity of the illness, the method of administration and the doctor's assessment. responsible for prescribing.

[00208] For example, the dosage can be released in a pharmaceutical composition by a single administration, by multiple applications or controlled release. In some embodiments, the present compounds, or salts, solvates, esters and/or prodrugs thereof, are released by sustained-release oral administration. The dosage may be repeated intermittently, may be provided alone or in combination with other drugs, and may continue for as long as necessary for effective treatment of the disease state or disorder.

[00209] Suitable dosage ranges for oral administration (the unit oral dosage form) to a patient in need depend on the potency of the present compounds, but are generally between about 0.001 mg and about 200 mg of a compound of the disclosure per kilogram of body weight; more preferably, between about 0.01 mg to about 50 mg of a compound of the disclosure per kilogram of body weight; even more preferably, between about 0.05 mg to about 20 mg of a compound of the disclosure per kilogram of body weight; and the patient is an animal; more preferably, a mammal; and, most importantly, a human. Dosage ranges can be readily determined by methods known to those skilled in the art.

[00210] Suitable dosage ranges for intravenous (i.v.) administration to a patient in need are about 0.001 mg to about 100 mg per kilogram of body weight; more preferably, between about 0.01 mg to about 20 mg of a compound of the disclosure per kilogram of body weight; and the patient is an animal; more preferably, a mammal; and, most importantly, a human. Suitable dosage ranges for intranasal administration to a patient in need are generally about 0.001 mg/kg of body weight to about 10 mg/kg of body weight; more preferably, between about 0.01 mg to about 1 mg of a compound of the disclosure per kilogram of body weight; and the patient is an animal; more preferably, a mammal; and, most importantly, a human. Suppositories generally contain about 0.01 milligram to about 50 milligrams of a compound of the disclosure per kilogram of body weight and comprise active ingredient in the range of about 0.5% to about 10% by weight. Recommended dosages for intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual or intracerebral administration to a patient in need are in the range of about 0.001 mg to about 200 mg per kilogram of body weight; and the patient is an animal; more preferably, a mammal; and, most importantly, a human. Effective doses can be extrapolated from dose-response curves derived from in vitro test systems or animal models. These animal models and systems are well known in the art.

[00211] The present compounds, or salts, solvates, esters, and/or prodrugs thereof, are preferably in vitro and in vivo, in terms of the desired therapeutic or prophylactic activity, before use in humans. For example, in vitro assays can be used to determine whether administration of a specific compound of the disclosure or a combination of compounds is preferred for induction of apoptosis or signal transduction in cells that overexpress bcl-2 proteins or protein kinases. The present compounds, or salts, solvates, esters and/or prodrugs thereof, can also be demonstrated to be effective and safe with the use of animal model systems.

[00212] Preferably, a therapeutically effective dose of the present compounds, or salts, solvates, esters and/or prodrugs thereof, will provide therapeutic benefit without causing substantial toxicity. The toxicity of the present compounds, or salts, solvates, esters and/or prodrugs thereof, can be determined using standardized pharmaceutical procedures, and can be easily verified by those skilled in the art. The dose ratio between the toxic and therapeutic effect is the therapeutic index. The present compounds, salts, solvates, esters and/or prodrugs thereof generally exhibit particularly high therapeutic indices in the treatment of disease and disorders associated with apoptosis. The dosage of the present compounds, salts, solvates, esters and/or prodrugs thereof will preferably be in a range of circulating concentrations that includes an effective dose with little or no toxicity.

5.8 COMBINED THERAPY

[00213] In certain embodiments of the present disclosure, the present compounds, or salts, solvates, esters and/or prodrugs thereof, can be used in combined therapy with at least one additional active or therapeutic agent. The present compounds, or salts, solvates, esters and/or prodrugs thereof, and the (at least one) additional active or therapeutic agent, may act additively or, more preferably, synergistically. In some embodiments, the present compounds, or salts, solvates, esters and/or prodrugs thereof, are administered concomitantly, sequentially or separately with the administration of another therapeutic agent. Exemplary active agents or chemotherapeutics include, without limitation, aceglatone, aclarrubicin, altretamine, aminoglutethimide; 5-aminoglevulinic acid, amsacrine, anastrozole, ancitabine hydrochloride, antibody 17-1a, antilymphocyte immunoglobulins, antineoplaston a10, asparaginase, pegaspargase, azacitidine, azathioprine, batimastat, benzoporphyrin derivative, bicalutamide, bisantrene hydrochloride, bleomycin sulfate, brequinarsodium, broxuridine , busulfan, campat-ih, characemide, carbetimer, carboplatin, carboquone, carmofur, carmustine, chlorambucil, chlorozotocin, chromomycin, cisplatin, cladribine, Corynebacterium parvum, cyclophosphamide, cyclosporine, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, diazoquone, dichlorodiethylsulfide, didemnin b., docetaxel, doxifluridine, doxorubicin hydrochloride, droloxifene, echinomycin, edatrexate, elliptinium, elmustine, enloplatin, enocitabine, epirubicin hydrochloride, estramustine sodium phosphate, etanidazole, ethoglucid, etoposide, fadrozole hydrochloride, fazarabin, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, flutamide, formestane, fotemustine, gallium nitrate, gemcitabine, gusperimus, homoharringtonine, hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofosine, improsulfan tosylate, inolimomab, interleukin-2; Irinotecan, JM-216, Letrozole, Lithium Gamolenato, Lobaplatin, Lomustine, Lonidamine, Maphosphamide, Meifalan, Minor, Mercaptopine, Methotrexate, Mibplatin, Miltefosine, Mitobronitol, Mitoguratic Diclorion LACTOL, Mitomycin, Mitotano, Hydrochloride Mitozanetron, myoribine, mopidamol, very much, Muromonab-CD3, mustina hydrochloride, mycophenolic acid, mycophenolate mofetil, nydatlatin, nilutamide, nimustine hydrochloride, oxaliplain, paclistaxel, pcnu, pensatin, peplomycin sulfate, pipobroma sulfate, pipobroma sulfate n, puprrubicin, pyritrexim isetionate, pyroxantrone hydrochloride, plicamycin, porfimer sodium, prednimustine, procarbazine hydrochloride, raltitrexed, ranimustine, razoxan, rogletimide, roquinimex, sebriplatin, semustine, sirolimus, sizofiran, sobuzoxan, sodium bromebrate, sparphosic acid, sparfosatosodium, streptozocin, sul ofenur, tacrolimus, tamoxifen, tegafur, teloxantrone hydrochloride, temozolomide, teniposide, testolactone, mesotetraphenylporphin-tetrasodium sulfonate, thioguanine, thioinosine, thiotepa, topotecan, toremifene, treosulfan, trimetrexate, trophosphamide, tumor necrosis factor, ubenimex, uramustine, vinblastine sulfate, sulfate vincristine act , vindesine sulfate, vinorelbine tartrate, vorozole, zinostatin, zolimomab aritox and zorubicin hydrochloride, and the like, individually or in any combination, a protein kinase A (PKA) inhibitor, an inhibitor of cAMP signaling, an inhibitor of a PKC (epsilon or alpha or beta) protein kinase, a Bcl-2 inhibitor (Bcl-2, or MCL-1 or Bcl-xL), a nonsteroidal anti-inflammatory drug, a prostaglandin synthesis inhibitor, a local anesthetic, an anticonvulsant, an antidepressant , an opioid receptor agonist and a neuroleptic, a benzodiazepine, a barbiturate, a neurosteroid and an inhalation anesthetic, an anesthetic and another analgesic.

[00214] The detailed description presented above was given to facilitate its understanding and unnecessary limitations should not be implied, as modifications will be obvious to those skilled in the technique. It is not an admission that any of the information provided here is established technique or relevant to the currently claimed disclosures, or that any specific or implicitly cited publication is established technique.

[00215] Modalities of disclosure are described here, including the best way known to the inventors for carrying out the disclosure. Variations of those preferred modalities may become apparent to those skilled in the technique upon reading the description presented above. Inventors expect those skilled in the art to employ these variations appropriately, and inventors desire disclosure to be practiced in a manner other than that specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject matter cited in the attached claims, as permitted by applicable laws. Furthermore, any combination of the elements described above in all possible variations thereof is encompassed by the disclosure unless otherwise indicated here or in some other way clearly contraindicated by the context.

INCORPORATION BY REFERENCE

[00216] All references, articles, publications, patents, patent publications and patent applications filed are incorporated by reference in their entirety for all purposes.

[00217] However, the mention of any reference, article, publication, patent, patent publication and patent application cited here is not, and should not be considered as, an acknowledgment or any form of suggestion that they constitute valid established technique or form part of common general knowledge in any country in the world.

Claims (18)

1. Compound characterized by having a structural formula or a salt thereof; where: A1 and A2 are independently oxygen or sulfur; R1 is selected from the group consisting of hydrogen, -(CH2)halogen, -CN, -CH3, NH2, NHRa, C1-6 alkyl, N(CHR)nC3-10cycloalkyl, wherein said cycloalkyl may be independently optionally substituted with 1 or 2 groups of C1-6 alkyl, halogen, CN, NO2, NH2, NHRa, SO2R11, and NRaSO2R11; R is selected from hydrogen, halogen, CN, NO2, NH2 or C1-6 alkyl; R2 is selected from the group consisting of: wherein each cycloalkyl or heterocycle of R2 recited can be independently optionally substituted with 1 or 2 C1-6 alkyl groups, halogen, CN, NO2, NH2, NHRa, SO2R11 and NRaSO2R11, R3, R5, R6 and R9 are independently R7; R4 is selected from the group consisting of halogen, CN, NO2, CF3, -(CHR)nCOOR11, -(CHR)nSO2R11, C1-4 haloalkyl, -OC1-4 haloalkyl, C2-6 alkyl, -(CHR)nC(O )CF3, - (CHR)nC(OH)(CF3)2, -(CH2)halogen, -OR10, -NR11R12, -NRaCOR11, -NRaCOOR11, -NRaSO2R11, -NRaCONR11R12, -COR11, tetrazole, - (CHR)ntetrazol , -S-C1-6 alkylated -CONR11R12, C(O)OR11, -SO2NHC(=O)CH3, -C(CF3)(CF3)OH, -SO2NH2, -C(O)CF3, R7 and R10 are independently selected from the group consisting of hydrogen, halogen, CN, NH2, NO2, C1-4 haloalkyl, -OC1-4 haloalkyl, C1-6 alkyl, -C(O)CF3, -(CH2)nhalogen, -ORa, and NRaRa ; R11 and R12 are selected independently from the group consisting of hydrogen, NRaC(=O)R, halogen, CN, NH2, NHRa, NO2, C1-4 haloalkyl, -OC1-4 haloalkyl, C1-6 alkyl, -S-C1-6 alkyl, - C(=O)-(O)n-Ra, and -ORa, wherein one or more carbon atoms of said alkyl may be replaced with one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; each Ra independently represents hydrogen or C1-6 alkyl; en represents an integer from 0 to 3. 2. Compound according to claim 1, characterized in that it is selected from the group consisting of 4-{ [4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9, 10-dihydroanthracen-1-yl]amino}benzenesulfonamide; 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic acid; N-[(4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl] acetamide; 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino} anthracene -9,10-dione; methyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino} benzoate; 2-(dimethylamino)ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino} benzoate; ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino} benzoate; 4-{[4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide; 4-{[4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic acid; N- [(4-{ [4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl] acetamide; 1-amino-2-(1,4'-bipiperidin-1'-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 2-(dimethylamino)ethyl 4-{[4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; 1-amino-2-(1,4'-bipiperidin-1'-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl ]amino}anthracene-9,10-dione, or a salt thereof. 3. Compound, according to claim 1, characterized by being: 4. Compound characterized by having a structural formula (II): or a salt thereof wherein: X represents N or CH; R4 is selected from the group consisting of -C(O)OR11, -C(CF3)(CF3)OH, -CF3, -(CHR)nCOOR11, -(CHR)nSO2R11, -(CHR)nC(OH)(CF3) two R11 is selected from the group consisting of hydrogen, NRaC(=O)R, halogen, CN, NH2, NHRa, NO2, C1-4 haloalkyl, -OC1-4 haloalkyl, -S-C1-6 alkyl, -C(=O)- (O)n-Ra, -ORa, or C1-6 alkyl, wherein one or more carbon atoms of said alkyl may be replaced with one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; R represents hydrogen, halogen, CN, NO2, NH2 or C1-6 alkyl; each Ra independently represents hydrogen or C1-6 alkyl; en represents 0. 5. Compound according to claim 4, characterized in that it is selected from the group consisting of: 4-{ [4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo- 9,10 -dihydroanthracen-1-yl]amino}benzenesulfonamide; 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic acid; N-[(4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl] acetamide; 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino} anthracene -9,10-dione; methyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; 2-(dimethylamino)ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; and ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; or a salt thereof. 6. Pharmaceutical composition characterized by comprising: a) a therapeutically effective amount of a compound, as defined in any one of claims 1 to 5, or a salt thereof; and b) a pharmaceutically acceptable vehicle or carrier. 7. Pharmaceutical composition according to claim 6, characterized by the fact that the compound is selected from the group consisting of: 4-{ [4-amino-3-(4-cyclohexylpiperazin-1-yl)-9, 10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide; 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic acid; N-[(4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl] acetamide; 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino} anthracene -9,10-dione; methyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; 2-(dimethylamino)ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; 4-{[4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide; 4-{[4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic acid; N- [(4-{ [4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl] acetamide; 1-amino-2-(1,4'-bipiperidin-1'-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 2-(dimethylamino)ethyl 4-{[4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; and 1-amino-2-(1,4'-bipiperidin-1'-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) phenyl]amino}anthracene-9,10-dione, or a salt thereof. 8. Pharmaceutical composition according to claim 6, characterized by the fact that the compound is: 9. Pharmaceutical composition according to claim 6, characterized by the fact that said pharmaceutical composition is formulated in a unit dosage form selected from the group consisting of: an oral unit dosage form, a unit dosage form of injection, a transdermal patch unit dosage form, or an implantation of a depot formulation unit dosage form. 10. Pharmaceutical composition according to claim 6, characterized by the fact that the compound is: ethyl 4-{ [4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10 -dihydroanthracen-1-yl]amino}benzoate; or a salt thereof. 11. Pharmaceutical composition according to claim 10, characterized by the fact that said pharmaceutical composition is formulated in a unit dosage form selected from the group consisting of: an oral unit dosage form, a unit dosage form of injection, a transdermal patch unit dosage form, or an implantation of a depot formulation unit dosage form. 12. Use of a compound as defined in any one of claims 1 to 5, characterized by the fact that it is for the manufacture of a medicine to treat acute pain, chronic pain, inflammatory pain, neuropathic pain, tonic pain, persistent pain, postoperative pain, pain osteoarthritis, diabetic neuropathic pain, chemical-induced pain, chemotherapy-induced pain, cancer pain, drug-induced pain, bone pain, pain associated with alcohol-induced hyperalgesia, a generalized pain disorder, and combinations thereof. 13. Use according to claim 12, characterized by the fact that the compound is selected from the group consisting of: 4-{ [4-amino-3-(4-cyclohexylpiperazin-1-yl)-9, 10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide; 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic acid; N-[(4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl] acetamide; 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino} anthracene -9,10-dione; methyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; 4-{[4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide; 4-{[4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic acid; N- [(4-{ [4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl] acetamide; 1-amino-2-(1,4'-bipiperidin-1'-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 2-(dimethylamino)ethyl 4-{[4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; and 1-amino-2-(1,4'-bipiperidin-1'-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) phenyl]amino}anthracene-9,10-dione, or a salt thereof. 14. Use according to claim 12, characterized by the fact that the compound is: 15. Use of a compound, as defined in any one of claims 1 to 5, characterized by the fact that it is for the manufacture of a medicine to treat pancreatic cancer, wherein the medicine comprises a combination of gemcitabine and a compound having the following structure: or a pharmaceutically acceptable salt thereof. 16. Use of a compound, as defined in any one of claims 1 to 5, characterized by the fact that it is for the manufacture of a medicine to treat pancreatic cancer, wherein the compound has a structural formula (I): independentlyoptionally substituted with 1 or 2 groups of C1-6 alkyl, halogen, CN, NO2, NH2, NHRa, SO2R11and NRaSO2R11; R is selected from hydrogen, halogen, CN, NO2, NH2 or C1-6 alkyl; R2 is selected from the group consisting of wherein each cycloalkyl or heterocycle of R2 recited can be independently optionally substituted with 1 or 2 C1-6 alkyl groups, halogen, CN, NO2, NH2, NHRa, SO2R11 and NRaSO2R11, R3, R5, R6 and R9 are independently R7; R4 is selected from the group consisting of: halogen, CN, NO2, CF3, -(CHR)nCOOR11, -(CHR)nSO2R11, C1-4 haloalkyl, -OC1-4 haloalkyl, C2-6 alkyl, -(CHR)nC (O)CF3, - (CHR)nC(OH)(CF3)2, -(CH2)halogen, -OR10, -NR11R12, -NRaCOR11, -NRaCOOR11, -NRaSO2R11, -NRaCONR11R12, -COR11, tetrazole, - (CHR )ntetrazol, -S-C1-6 alkylated -CONR11R12, -C(O)OR11, -SO2NHC(=O)CH3, -C(CF3)(CF3)OH, -SO2NH2, -C(O)CF3, R7 and R10 are independently selected from the group consisting of hydrogen, halogen, CN, NH2, NO2, C1-4 haloalkyl, -OC1-4 haloalkyl, C1-6 alkyl, -C(O)CF3, -(CH2)nhalogen, -ORa, and NRaRa ; R11 and R12 are selected independently from the group consisting of: hydrogen, NRaC(=O)R, halogen, CN, NH2, NHRa, NO2, C1-4 haloalkyl, -OC1-4 haloalkyl, C1-6 alkyl, -S-C1-6 alkyl , -C(=O)-(O)n-Ra, -ORa, wherein one or more carbon atoms of said alkyl may be replaced with one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; each Ra independently represents hydrogen or C1-6 alkyl; en represents an integer from 0 to 3. 17. Use according to claim 16, characterized in that the compound is selected from the group consisting of: 4-{ [4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10- dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide; 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic acid; N-[(4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl] acetamide; 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 1-amino-2-(4-cyclohexylpiperazin-1-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]amino} anthracene -9,10-dione; methyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; 2-(dimethylamino)ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; ethyl 4-{[4-amino-3-(4-cyclohexylpiperazin-1-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; 4-{[4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzenesulfonamide; 4-{[4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoic acid; N- [(4-{ [4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}phenyl)sulfonyl] acetamide; 1-amino-2-(1,4'-bipiperidin-1'-yl)-4-{[4-(2H-tetrazol-5-yl)phenyl]amino}anthracene-9,10-dione; 2-(dimethylamino)ethyl 4-{[4-amino-3-(1,4'-bipiperidin-1'-yl)-9,10-dioxo-9,10-dihydroanthracen-1-yl]amino}benzoate; and 1-amino-2-(1,4'-bipiperidin-1'-yl)-4-{[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) phenyl]amino}anthracene-9,10-dione, or a salt thereof. 18. Use according to claim 17, characterized by the fact that the compound is: or a salt thereof.