PHARMACEUTICALLY ACCEPTABLE COMPOUND OR SALT, PHARMACEUTICAL COMPOSITION AND USE OF THE SAME

专利摘要:
pharmaceutically acceptable compound or salt, pharmaceutical composition and use thereof. indazole compounds are described for the treatment of various diseases and pathologies. more particularly, the present invention relates to the use of an indazole compound or its analogs in the treatment of disorders characterized by activation of the wnt signaling pathway (e.g., cancer, abnormal cell proliferation, angiogenesis, alzheimer's disease and osteoarthritis) , the modulation of cellular events mediated by the wnt signaling pathway, as well as genetic diseases due to mutations in the components of wnt signaling. methods are also provided to treat wnt-related disease states.
公开号:BR112012002854B1
申请号:R112012002854-5
申请日:2010-08-09
公开日:2020-02-18
发明作者:John Hood；David Mark Wallace；Sunil Kumar KC
申请人:Samumed, Llc；
IPC主号:

专利说明:

Invention Patent Descriptive Report for PHARMACEUTICALLY ACCEPTABLE COMPOUND OR SALT, PHARMACEUTICAL COMPOSITION AND USE OF THE SAME.
RELATED REQUESTS
Cross Reference with Related Orders [001] This order claims the benefit of the U.S. Interim Order
No. 61 / 232,603, filed on August 10, 2009 and U.S. Provisional Application No. 61 / 305,459, filed on February 17, 2010, which are incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION
Field of the Invention [002] This invention relates to inhibitors of one or more proteins in the Wnt pathway, including inhibitors of one or more Wnt proteins and compositions comprising them. More particularly, it refers to the use of an indazole compound or salts or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (for example, cancer, abnormal cell proliferation, angiogenesis, Alzheimer's disease and osteoarthritis) , the modulation of cellular events mediated by signaling the Wnt pathway, as well as genetic diseases due to mutations in the components of Wnt signaling.
Description of the Related Technique [003] Formation pattern is the activity by which embryonic cells form ordered spatial arrangements of differentiated tissues. Speculation about the mechanisms underlying these modeling effects generally center on the secretion of a signaling molecule that triggers an appropriate response from the tissues to be modeled. More recently, a study that aimed at identifying such signaling molecules involves secreted proteins encoded by individual members of
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2/68 a small number of gene families.
[004] An idea that has existed for a long time in the biology of cancer is that cancer arises and develops due to the formation of cancerous stem cells, which may constitute only a minority of cells within the tumor, but are nevertheless critical to its spread. Stem cells are interesting as the cancer originating cell due to their pre-existing capacity for self-renewal and unlimited replication. In addition, stem cells are relatively long-lived compared to other cells within tissues, providing a greater opportunity to accumulate the multiple additional mutations that may be needed to increase the rate of cell proliferation and produce clinically significant cancers. Of recent particular interest in the origin of cancer is the observation that the Wnt signaling pathway, which has been implicated in stem cell self-renewal in normal tissues, after continuous activation has been associated with the onset and development of various types cancer. This pathway therefore provides a potential link between normal stem cell self-renewal and aberrantly regulated cancer stem cell proliferation.
[005] The Wnt growth factor family includes more than 10 genes identified in the mouse and at least 7 genes identified in humans. Members of the Wnt family of signaling molecules mediate several short- and long-term standardization processes during the development of vertebrates and invertebrates. The Wnt signaling pathway is known for its important role in inductive interactions that regulate growth and differentiation and also possibly plays important roles in homeostatic maintenance of post-embryonic tissue integrity. Wnt stabilizes cytoplasmic p-catenin, which stimulates the expression of genes including c-myc, c-jun, fra-1 and cyclin D1. Additionally, the deregulation of
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3/68 Wnt signaling can cause developmental defects and is implicated in the genesis of several human cancers. More recently, the Wnt pathway has been implicated in maintaining stem or progenitor cells in a growing list of adult tissues that now include the skin, blood, intestines, prostate, muscle and nervous system. [006] Pathological activation of the Wnt pathway is also considered to be the initial event that leads to colorectal cancer in more than 85% of all sporadic cases in the western world. Activation of the Wnt pathway has also been widely reported in hepatocellular carcinoma, breast cancer, ovarian cancer, pancreatic cancer, melanomas, mesotheliomas, lymphomas and leukemias. In addition to cancer, inhibitors of the Wnt pathway can be used for stem cell research or for the treatment of any diseases characterized by aberrant Wnt activation such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, psoriasis, as well as mycotic and viral infections. bone and cartilage diseases. As such, it is a therapeutic target that has great interest in the area.
[007] In addition to cancer, there are several cases of genetic diseases due to mutations in the components of Wnt signaling. Examples of some of the various diseases are Alzheimer's disease [Proc. Natl. Acad. Sci. US A (2007), 104 (22), 9434-9], osteoarthritis, intestinal polyposis [Science (1991), 253 (5020), 665-669], osteoporosis-pseudoglioma syndrome [N. Engl. J. Med. (2002), 346 (20), 1513-21], familial exudative vitreous-retinopathy [Hum. Mutat. (2005), 26 (2), 10412], retinal angiogenesis [Nat. Genet. (2002), 32 (2), 326-30], early coronary disease [Science (2007), 315 (5816), 1278-82], tetramelia syndrome [Am. J. Hum. Genet. (2004), 74 (3), 558-63], virilization and duct regression Mülleriano [Engl. J. Med. (2004), 351 (8), 792-8], SERKAL syndrome [Am. J. Hum. Genet. (2008), 82 (1), 39-47], type 2 diabetes mellitus [Am. J. Hum. Genet. (2004), 75 (5), 832-43; N. Engl. J.
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4/68
Med. (2006), 355 (3), 241-50], Fuhrmann's syndrome [Am. J. Hum. Genet. (2006), 79 (2), 402-8], Al-Awadi / RaasRothschild / Schinzel's focomelia syndrome [Am. J. Hum. Genet. (2006), 79 (2), 402-8], odonto-onico-dermal dysplasia [Am. J. Hum. Genet. (2007), 81 (4), 821-8], obesity [Diabetologia (2006), 49 (4), 678-84], ectrodactyly [Hum. Mol. Genet. (2008), 17 (17), 2644-53], caudal duplication syndrome [Am. J. Hum. Genet. (2006), 79 (1), 155-62], tooth agenesis [Am. J. Hum. Genet. (2004), 74 (5), 1043-50], Wilms tumor [Science (2007),
315 (5812), 642-5], skeletal dysplasia [Nat. Genet. (2009), 41 (1), 95100], focal dermal hypoplasia [Nat. Genet. (2007), 39 (7), 836-8], autosomal recessive anonychia [Nat. Genet. (2006), 38 (11), 1245-7], neural tube defects [N. Engl. J. Med. (2007), 356 (14), 1432-7], alpha-thalassemia syndrome (ATRX) syndrome [The Journal of Neuroscience (2008), 28 (47), 12570-12580], fragile X syndrome [PLoS Genetics (2010), 6 (4), e1000898], ICF syndrome, Angelman syndrome [Brain Research Bulletin (2002), 57 (1), 109-119], Prader-Willi syndrome [Journal of Neuroscience (2006 ), 26 (20), 5383-5392], Beckwith-Wiedemann syndrome [Pediatric and Developmental Pathology (2003), 6 (4), 299-306] and Rett syndrome.
SUMMARY OF THE INVENTION [008] The present invention makes available methods and reagents, involving contacting a cell with an agent, such as an aromatic compound, in an amount sufficient to antagonize Wnt activity, for example, to reverse or control a state of aberrant growth or correct a genetic disorder due to mutations in the components of Wnt signaling.
[009] Some modalities described here include inhibitors of
Wnt that contain an indazole core. Other embodiments described herein include pharmaceutical compositions and methods of treatment using these compounds.
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5/68 [0010] One embodiment described herein includes a compound that has the structure of formula I:
[0011] as well as prodrugs and pharmaceutically acceptable salts thereof.
[0012] In some modalities of formula (I):
[0013] R ¹ , R ² , R ⁴ , R ⁶ , R ⁷ 'R ⁸ and R ⁹ are independently selected from the group consisting of H, C1-9alkyl, halide, CF ₃ , - (C1-9 alkyl ) _n carbocyclylR ¹³ , - (C1-9 alkyl) nheterocyclylR ¹³ , - (C1-9 alkyl) narylR ¹³ , - (C1-9 alkyl) nheteroarylR ¹³ , - (C1-9 alkyl) nOR ¹⁰ , - (C1-9 alkyl) nSR ¹⁰ , - (C1-9 alkyl) nS (= O) R ¹¹ , - (C1-9 alkyl) nSO ₂ R ¹⁰ , - (C1-9 alkyl) nN (R ¹⁰ ) SO2R ¹⁰ , - (C1 -9 alkyl) nSO2N (R ¹⁰ ) 2, - (C1-9 alkyl) _n N (R ¹⁰ ) 2, (C1-9 alkyl) nN (R ¹⁰ ) C (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) _n C (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) C (= A) R ¹⁰ , -NO2, -CN, - (C1-9 alkyl) _n CO ₂ R ¹⁰ e - (C 1-9 alkyl) nC (= A) R ¹⁰ ;
[0014] R ³ is selected from the group consisting of -NRS (= O) R ¹⁴ , (Ci-galkyl) R ¹⁴ , -carbocyclylR ¹⁴ R ¹⁵ , -heterocyclyl R ¹⁴ R ¹⁵ , -arylR ¹⁴ R ¹⁵ and heteroarylR ¹⁴ R ¹⁵ ;
[0015] alternatively, one of each R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ , R ⁶ and R ⁷ , R ⁷ and R ⁸ or R ⁸ and R ⁹ are joined to form a ring that is selected from the group consisting of aryl, heteroaryl,
[0016] in which each connection represented by a dotted line
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6/68 and a solid represents a bond selected from the group consisting of a single bond and a double bond;
[0017] each R ¹⁰ is independently selected from the group consisting of H, -C1-9 alkyl, -CF3, - (C1-9 alkyl) ncarbocyclyl, - (C1-9 alkyl) nheterocyclyl, - (C1-9 alkyl) narila and - (C1-9 alkyl) nheteroaryl;
[0018] each R ¹¹ is independently selected from the group consisting of -C1-9 alkyl, -CF3, - (C1-9 alkyl) ncarbocyclyl, - (C1-9 alkyl) nheterocyclyl, - (C1-9 alkyl) narila e - (C1-9 alkyl) nheteroaryl;
[0019] each R ¹² is selected, independently, from the group consisting of -OR ¹⁰ and R ¹⁰ ;
[0020] each R ¹³ has 1 to 5 substituents, each selected from the group consisting of H, C1-9 alkyl, halide, -CF3, carbocyclylR ¹³ , heterocyclylR ¹³ , arylR ¹³ , heteroarylR ¹³ , - (C1-9 alkyl ) nOR ¹⁰ , - (C1-9 alkyl) nSR ¹⁰ , - (C1-9 alkyl) nS (= O) R ¹¹ , - (C1-9 alkyl) nSO2R ¹⁰ , - (C1-9 alkyl) nN (R ¹⁰ ) SO2R ¹⁰ , - (C1-9 alkyl) nSO2N (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) 2, (C1-9 alkyl) nN (R ¹⁰ ) C (= A) N ( R ¹⁰ ) 2, - (C1-9 alkyl) nC (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) C (= A) R ¹⁰ , -NO2, -CN, - (C1-9 alkyl) nCO2R ¹⁰ and - (C1-9 alkyl) nC (= A) R ¹⁰ ;
[0021] R ¹⁴ is selected from the group consisting of -NR ¹⁰ C (= A) R ¹⁰ ,
-NR ¹⁰ S (= O) R11, -NR ¹⁰ SO2R ¹⁰ , -NR ¹⁰ C (= O) N (R ¹⁶ ) 2, -NR ¹⁰ C (= S) N (R ¹⁰ ) 2, NR ¹⁰ C ( = NR ¹² ) N (R ¹⁰ ) 2, -N (R ¹⁶ ) 2, -C (= O) NR ¹⁰ R ¹⁷ , -C (= S) N (R ¹⁰ ) 2, C (= NR ¹² ) N (R ¹⁰ ) 2, -OC (= A) R ¹⁰ , -C (= A) R ¹⁰ , -NR ¹⁰ C (= A) OR ¹⁰ and OC (= A) NR ¹⁰ R ¹⁰ ;
[0022] R ¹⁵ has 1 to 4 substituents, each selected from the group consisting of H, C1-9 alkyl, halide, -CF3, carbocyclylR ¹³ , heterocyclylR ¹³ , arylR ¹³ , heteroarylR ¹³ , - (C1-9 alkyl) nOR ¹⁰ , - (C1-9 alkyl) nSR ¹⁰ , - (C1-9 alkyl) nS (= O) R ¹¹ , - (C1-9 alkyl) nSO2R ¹⁰ , - (C1-9 alkyl) nN (R ¹⁰ ) SO2R ¹⁰ , - (C1-9 alkyl) nSO2N (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) 2, (C1-9 alkyl) nN (R ¹⁰ ) C (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nC (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) C (= A) R ¹⁰ , -NO2, -CN, - (C1-9 alkyl) nCO2R ¹⁰ e - (C1-9
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7/68 alkyl) nC (= A) R ¹⁰ ;
[0023] R ¹⁶ is -C1-9 alkyl;
[0024] each R ¹⁷ is independently selected from the group consisting of -heterocyclyl R ¹³ , - (C1-9 alkyl) heterocyclyl R ¹³ and - (C1-9 alkyl) carbocyclyl R ¹³ ;
[0025] R ¹⁸ and R ¹⁹ are independently selected from the group consisting of H, C1-9 alkyl, halide, - (C1-9 alkyl) ncarbocyclylR ¹³ , - (C1-9 alkyl) nheterocyclylR ¹³ , - (C1 -9 alkyl) narilR ¹³ , - (C1-9 alkyl) nheteroarylR ¹³ , (C1-9 alkyl) nOR ¹⁰ , - (C1-9 alkyl) nSR ¹⁰ , - (C1-9 alkyl) nS (= O) R ¹¹ , - (C1-9 alkyl) nSO2R ¹⁰ , - (C1-9 alkyl) nN (R ¹⁰ ) SO2R ¹⁰ , - (C1-9 alkyl) nSO2N (R ¹⁰ ) 2, (C1-9 alkyl) nN (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) C (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nC (= A) N (R ¹⁰ ) 2, - (C1- 9 alkyl) nN (R ¹⁰ ) C (= A) R ¹⁰ , -NO2, -CN, - (C1-9 alkyl) nCO2R ¹⁰ and - (C1-9 alkyl) nC (= A) R ¹⁰ ;
[0026] alternatively, R ¹⁸ and R ¹⁹ are linked to form a ring selected from the group consisting of benzene and pyridine;
[0027] each A is selected, independently between O, S and
NR ¹² ;
[0028] Y ¹ , Y ² , Y ³ and Y ⁴ are selected, independently, from the group consisting of carbon and nitrogen, with the proviso that at least one of Y ¹ , Y ² , Y ³ and Y ⁴ is nitrogen ;
[0029] if Y ¹ is nitrogen, then R ⁶ is absent;
[0030] if Y ² is nitrogen, then R ⁷ is absent;
[0031] if Y ³ is nitrogen, then R ⁸ is absent;
[0032] if Y ⁴ is nitrogen, then R ⁹ is absent; and [0033] each n is 0 or 1.
[0034] In other modalities of formula (I):
[0035] R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are independently selected from the group consisting of H, C1-9 alkyl, halide, CF3, - (C1-9 alkyl) ncarbocyclylR ¹² , - (C1-9 alkyl) nheterocyclylR ¹² , - (C1-9 alkyl) narylR ¹² , - (C1-9 alkyl) nheteroarylR ¹² , - (C1-9 alkyl) nOR ⁹ , - (C1-9
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8/68 alkyl) _n SR ⁹ , - (C1-9 alkyl) nS (= O) R ¹⁰ , - (C1-9 alkyl) nSO ₂ R ⁹ , - (C1-9 alkyl) nN (R ⁹ ) S ( = O) R ¹⁰ , - (C1-9 alkyl) nN (R ⁹ ) SO2R ⁹ , - (C1-9 alkyl) nSO ₂ N (R ⁹ ) 2, - (C1-9 alkyl) nN (R ⁹ ) 2, - (Ci- ₉ alkyl) _n N (R ⁹ ) C (= A) N (R ⁹ ) 2, (C1-9 alkyl) nNR ⁹ C (= O) OR ⁹ , - (C1-9 alkyl) nC ( = A) N (R ⁹ ) 2, - (C1-9 alkyl) nN (R ⁹ ) C (= A) R ⁹ , - (C1-9 alkyl) nOC (= O) NR ⁹ R ⁹ , -NO2, -CN, - (C1-9 alkyl) nCO2R ⁹ and - (C1-9 alkyl) _n C (= A) R ⁹ ;
[0036] alternatively, one of each R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ , R ⁶ and R ⁷ , R ⁷ and R ⁸ or R ⁸ and R ⁹ are linked to form a selected ring the group consisting of aryl, heteroaryl, [0037] in which each bond represented by a dotted line and a solid represents a bond selected from the group consisting of a single bond and a double bond;
[0038] each R ¹⁰ is independently selected from the group consisting of H, -C1-9 alkyl, -CF ₃ , - (C1-9 alkyl) _n carbocyclyl, - (C1-9 alkyl) _n heterocyclyl, - ( C1-9alkyl) _n- aryl and - (C1--alkyl) n-heteroaryl;
[0039] each R ¹¹ is independently selected from the group consisting of -C1-9 alkyl, -CF ₃ , - (C1-9 alkyl) _n carbocyclyl, - (C1-9 alkyl) _n heterocyclyl, - (C1- 9alkyl) _n aryl and - (Ci-galkyl) n heteroaryl;
[0040] each R ¹² is selected, independently, from the group consisting of CN, -OR ¹⁰ and R ¹⁰ ;
[0041] R ¹³ has 1 to 5 substituents, each selected from the group consisting of H, C1-9 alkyl, halide, -CF ₃ , carbocyclylR ¹² , heterocyclylR ¹² , arylR ¹² , heteroarylR ¹² , - (Ci-galkyl) nOR ⁹ , - (C1-alkyl) nSR ⁹ , - (C1-9 alkyl) nS (= O) R ¹⁰ , - (C1-9 alkyl) nSO2R ⁹ , - (C1-9 alkyl) nN (R ⁹ ) SO2R ⁹ , (C1-9 alkyl) nSO ₂ N (R ⁹ ) 2, - (C1-9 alkyl) nN (R ⁹ ) 2, - (C1-9 alkyl) _n N (R ⁹ ) C (= A) N (R ⁹ ) 2, - (C1-9 alkyl) nC (= A) N (R ⁹ ) 2, - (C1-9 alkyl) _n NR ⁹ C (= O) OR ⁹ , - (C1-9 alkyl) nN (R ⁹ ) C (= A) R ⁹ , - (C1-9 alkyl) nOC (= O) N (R ⁹ ) 2, -NO2, -CN, - (C1-9 alkyl) _n CO ₂ R ⁹ and - (C1-9
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9/68 alkyl) nC (= A) R ⁹ ;
[0042] R ¹⁸ and R ¹⁹ are independently selected from the group consisting of H, C1-9 alkyl, halide, - (C1-9 alkyl) nCarbocyclylR ¹³ , - (C1-9 alkyl) nheterocyclylR ¹³ , - (C1 -9 alkyl) narilR ¹³ , - (C1-9 alkyl) nheteroarylR ¹³ , (C1-9 alkyl) nOR ¹⁰ , - (C1-9 alkyl) nSR ¹⁰ , - (C1-9 alkyl) nS (= O) R ¹¹ , - (C1-9 alkyl) nSO2R ¹⁰ , - (C1-9 alkyl) nN (R ¹⁰ ) SO2R ¹⁰ , - (C1-9 alkyl) nSO2N (R ¹⁰ ) 2, (C1-9 alkyl) nN (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) C (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nC (= A) N (R ¹⁰ ) 2, - (C1- 9 alkyl) nN (R ¹⁰ ) C (= A) R ¹⁰ , -NO2, -CN, - (C1-9 alkyl) nCO2R ¹⁰ and - (C1-9 alkyl) nC (= A) R ¹⁰ ;
[0043] alternatively, R ¹⁸ and R ¹⁹ are linked to form a ring selected from the group consisting of benzene and pyridine;
[0044] each A is selected, independently between O, S and
NR ¹² ;
[0045] X is carbon;
[0046] Y ¹ , Y ² , Y ³ and Y ⁴ are selected, independently, from the group consisting of carbon and nitrogen, with the proviso that at least one of Y ¹ , Y ² , Y ³ and Y ⁴ is nitrogen ;
[0047] if Y ¹ is nitrogen, then R ⁶ is absent;
[0048] if Y ² is nitrogen, then R ⁷ is absent;
[0049] if Y ³ is nitrogen, then R ⁸ is absent;
[0050] if Y ⁴ is nitrogen, then R ⁹ is absent; and [0051] each n is 0 or 1 or a pharmaceutically acceptable salt or prodrug thereof.
[0052] Some embodiments include stereoisomers and pharmaceutically acceptable salts of a compound of general formula (I).
[0053] Some embodiments include prodrugs of a compound of general formula (I).
[0054] Some embodiments of the present invention include pharmaceutical compositions that comprise a compound of general formula (I) and a pharmaceutically acceptable carrier.
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10/68 [0055] Other modalities described herein include methods of inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins, by administering to an individual affected by a disorder or disease, in which aberrant Wnt signaling is present. implicated, such as cancer and other diseases associated with abnormal angiogenesis, cell proliferation, cell cycle and mutations in the signaling components of Wnt, of a compound according to any of the formulas above. Consequently, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cell proliferation and to correct a genetic disorder due to mutations in the components of Wnt signaling. Non-limiting examples of diseases that can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, psoriasis, mycotic and viral infections, osteochondrodysplasia, Alzheimer's disease, osteoarthritis, intestinal polyposis, syndrome rosepseudoglioma osteoporosis, familial exudative vitreo-retinopathy, retinal angiogenesis, early coronary disease, tetramelia syndrome, Müllerian duct virilization and regression, SERKAL syndrome, type 2 diabetes mellitus, Fuhrmann syndrome, AlAwadi / Raas-Rothschild focomelia syndrome / Raas-Rothschild / Schinzel, odonto-onico-dermal dysplasia, obesity, ectrodactyly, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia syndrome (ATRX) , fragile X syndrome, ICF syndrome, Angelm syndrome an, Prader-Willi syndrome, BeckwithWiedemann syndrome and Rett syndrome.
[0056] Another embodiment described herein includes a pharmaceutical composition that has a compound according to any of the
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11/68 above formulas and a pharmaceutically acceptable carrier, diluent or excipient.
[0057] Some embodiments of the present invention include methods for preparing a compound of general formula (I).
[0058] It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
DETAILED DESCRIPTION OF THE INVENTION [0059] Compositions and methods for inhibiting one or more members of the Wnt pathway, including one or more proteins, could be extremely beneficial. Certain modalities provide such compositions and methods. [0060] Some modalities refer to a method of treating a disease such as cancers, diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, psoriasis, mycotic and viral infections, osteochondrodysplasia, Alzheimer's disease, osteoarthritis, intestinal polyposis, osteoporosis syndrome -pseudoglioma, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetramelia syndrome, virilization and Müllerian duct regression, SERKAL syndrome, type 2 diabetes, Fuhrmann syndrome, Al-Awadi focomelia syndrome / RaasRothschild / Schinzel, odonto-onico-dermal, obesity, ectrodactyly, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia syndrome (ATRX), fragile X syndrome , ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Bec syndrome kwithWiedemann and Rett syndrome.
[0061] In some embodiments, pharmaceutical compositions are provided that are effective for the treatment of a disease of
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12/68 an animal, for example a mammal, caused by pathological activation or mutations in the Wnt pathway. The composition includes a pharmaceutically acceptable carrier and an inhibitor of the Wnt pathway as described herein.
Definitions [0062] Unless otherwise defined, all technical and scientific terms used here have the same meaning as commonly understood by one versed in the technique to which this description belongs. All patents, orders, published orders and other publications are incorporated in their entirety. In the event that there are a plurality of definitions for an expression in that one, those in that section will prevail unless otherwise stated.
[0063] In this specification and in the claims, the following expressions have the meanings as defined. As used herein, alkyl means a branched or straight chain chemical group containing only carbon and hydrogen, such as methyl, isopropyl, isobutyl, sec-butyl and pentyl. Alkyl groups can be unsubstituted or substituted with one or more substituents, for example, halogen, alkoxy, acyloxy, amino, amide, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxyl, aryl, heteroaryl or other functionality that may be suitably blocked, if necessary for the purposes of the invention, with a protecting group. Alkyl groups can be saturated or unsaturated (for example, containing C = C- or -C ^ C- subunits) at one or more positions. Typically, alkyl groups will comprise 1 to 9 carbon atoms, preferably 1 to 6 and more preferably 1 to 4 carbon atoms.
[0064] As used here, carbocyclyl means a cyclic ring system containing only carbon atoms in the ring system framework, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
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13/68 cyclohexenyl. Carbocyclics can include multiple fused rings. Carbocyclics can have any degree of saturation as long as at least one ring of the ring system is not aromatic. Carbocyclyl groups can be unsubstituted or substituted with one or more substituents, for example, halogen, alkoxy, acyloxy, amino, amide, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxyl, aryl, heteroaryl or other functionality that may be suitably blocked, if necessary for the purposes of the invention, with a protecting group. Typically, carbocyclyl groups will comprise 3 to 10 carbon atoms, preferably 3 to 6.
[0065] As used here, lower alkyl means a subgroup of alkyl and is therefore a hydrocarbon substituent, which can be linear or branched. Preferred lower alkyls have 1 to about 4 carbons and can be branched or linear. Examples of lower alkyl include butyl, isopropyl, ethyl and methyl. Likewise, radicals using the lower terminology refer to radicals preferably having 1 to about 4 carbons in the alkyl portion of the radical.
[0066] As used herein, starch means an H-CON- or alkyl-CON-, carbocyclyl-CON-, aryl-CON-, heteroaryl-CON- or heterocyclyl-CON group, wherein the alkyl, aryl or heterocyclyl groups are as described herein.
[0067] As used here, aryl means an aromatic radical that has a single ring (eg, phenyl) or multiple condensed rings (eg, naphthyl or anthranyl) with only carbon atoms present in the ring framework. Aryl groups can be substituted or unsubstituted with one or more substituents, for example, amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto and other substituents. A preferred carbocyclic aryl is phenyl.
[0068] As used here, the expression heteroaryl means a
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14/68 aromatic radical that has one or more heteroatoms (for example, N, O or S) in the ring framework and can include a single ring (for example, pyridine) or multiple condensed rings (for example, quinoline). Heteroaryl groups can be unsubstituted or substituted by one or more substituents, for example, amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto and other substituents. Examples of heteroaryl include thienyl, pyridyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazinyl, thiazinyl, thiazinyl
[0069] In these definitions, it is clearly contemplated that the substitution on the aryl or heteroaryl rings is within the scope of certain modalities. Where the substitution occurs, the radical is called substituted aryl or substituted heteroaryl. Preferably, one to three and, more preferably, one or two substituents occur on the aryl ring. Although various substituents may be useful, preferred substituents include those commonly found in aryl compounds, such as alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo, haloalkyl, mercapto and the like.
[0070] As used here, amide includes both, RNR'CO- (in the case of R = alkyl, alkaminocarbonyl-) and RCONR'- (in the case of R = alkyl, alkyl carbonylamino).
[0071] As used here, the term ester includes both ROCO (in the case of R = alkyl, alkoxycarbonyl-) and RCOO- (in the case of R = alkyl, carbonyloxy-).
[0072] As used herein, acyl means an H-CO- or alkylCO-, carbocyclyl-CO-, aryl-CO-, heteroaryl-CO- or heterocyclyl-CO- group in which the alkyl, carbocyclyl, aryl or heterocyclyl group is as described here. Preferred acyls contain lower alkyl. Exemplary alkyl acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl,
Petition 870190062330, of 07/04/2019, p. 11/22
15/68 t-butylacetyl, butanoyl and palmitoyl.
[0073] As used here, halo or halide is a radical of chlorine, bromine, fluorine or iodine atom. Chlorine, bromine and fluorine are preferred halides. The expression halo also includes expressions sometimes referred to as a halogen or halide.
[0074] As used here, haloalkyl means a hydrocarbon substituent, which is linear or branched or cyclic alkyl, alkenyl or alkynyl substituted with chlorine, bromine fluorine or iodine atoms. The most preferred of these are fluoralkyls, in which one or more of the hydrogen atoms have been replaced by fluorine. Preferred haloalkyls are 1 to about 3 carbons in length, the most preferred haloalkyls are 1 to about 2 carbons and the most preferred is 1 carbon in length. The skilled technician will recognize that, as used here, haloalkylene means a di-radical variant of haloalkyl, such di-radicals can act as spacers between radicals, other atoms or between the parent ring and another functional group. [0075] As used here, heterocyclyl means a cyclic ring system that comprises at least one heteroatom in the framework of the ring system. Heterocyclyl can include multiple fused rings. Heterocyclyl can have any degree of saturation as long as at least one ring of the ring system is not aromatic. Heterocyclyl can be substituted or unsubstituted with one or more substituents, for example, halogen, alkoxy, acyloxy, amino, starch, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl and other substituents and are coupled to other groups through any available valence, preferably any available carbon or nitrogen. The most preferred heterocyclyls have 5 to 7 members. In 6-membered monocyclic heterocycles, heteroatoms are selected from one to three of O, N or S and when the heterocycle has 5 members, preferably it has one or two
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16/68 heteroatoms selected from O, N or S.
[0076] As used herein, substituted amino means an amino radical that is substituted by one or two alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl groups, where alkyl, aryl, heteroaryl or heterocyclyl are as defined above.
[0077] As used herein, substituted thiol means an RS group in which R is an alkyl, an aryl, heteroaryl or a heterocyclyl group, where the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are as defined above.
[0078] As used herein sulfonyl means an alkylSO2, arylSO2, heteroarylSO2, carbocyclyl SO2, or heterocyclyl-SO2 group in which the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl are as defined above.
[0079] As used herein, sulfamido means an alkyl-NS (O) 2N-, aryl-NS (O) 2N-, heteroaryl-NS (O) 2N-, carbocyclyl-NS (O) 2N or heterocyclyl-NS ( O) 2N- in which the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl groups are as defined herein.
[0080] As used herein, sulfonamido means an alkyl group S (O) 2N-, aryl-S (O) 2N-, heteroaryl-S (O) 2N-, carbocyclyl-S (O) 2N- or heterocyclyl-S ( O) 2N-, wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl groups are as described herein.
[0081] As used herein, ureido means an alkyl-NCON-, aryl-NCON-, heteroaryl-NCON-, carbocyclyl-NCON- or heterocyclyl-NCON group, where the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl groups are like described here.
[0082] As used here, when two groups are indicated to be linked or coupled to form a ring, it should be understood that a bond is formed between the two groups and may involve the replacement of a hydrogen atom in one or both groups with the connection, thus forming a ring of
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17/68 carbocyclyl, heterocyclyl, aryl or heteroaryl. The experienced technician will recognize that such rings can and are readily formed by routine chemical reactions and it is within the scope of the experienced technician to devise such rings and the methods for their formation. Rings having between 3 to 7 members are preferred, more preferably 5 or 6 members. As used herein, the term ring or rings, when formed by the combination of two radicals, refers to heterocyclic, carbocyclic, aryl or heteroaryl rings.
[0083] The skilled technician will recognize that some structures described here may be resonance forms or tautomers of compounds that can be correctly represented by other chemical structures until, kinetically, the verse recognizes that such structures are only a very small portion of a sample of such compounds. Such compounds are clearly contemplated within the scope of this invention, although such forms of resonance or tautomers are not represented here.
[0084] The compounds provided herein cover various stereochemical forms. The compounds also comprise diastereoisomers as well as optical isomers, for example, mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereoisomers, which arise as a result of structural asymmetry in certain compounds. The separation of individual isomers or selective synthesis of individual isomers is achieved by applying several methods that are well known to those skilled in the art. Unless otherwise indicated, when a described compound is named or illustrated by a structure without specifying stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.
[0085] The term administration or administering refers to a
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18/68 method of providing a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, bird, fish or amphibian, where the method is, for example, intra-respiratory, topical, oral, intravenous, intraversadoneal, intramuscular, buccal, rectal, sublingual. The preferred method of administration can vary depending on several factors, for example, the components of the pharmaceutical composition, the location of the disease, the disease involved and the severity of the disease.
[0086] A diagnosis as used here is a compound, method, system or device that helps in the identification and characterization of the state of health or disease. The diagnosis can be used in standardized tests as is known in the art.
[0087] The term mammal is used in its common biological sense. Therefore, it specifically includes humans, cattle, horses, dogs and cats, but it also includes several other species.
[0088] The term pharmaceutically acceptable carrier or pharmaceutically acceptable excipient includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and retarding agents and the like. The use of such means and agents for pharmaceutically active substances is well known in the art. Its use in therapeutic compositions is contemplated, except when, as far as possible, any conventional medium or agent is incompatible with the active ingredient. Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants such as are commonly used in the art can be included. These and other compounds are described in the literature, for example, in the Merck Index, Merck & Company, Rahway, NJ. Considerations regarding the inclusion of various components in pharmaceutical compositions are described, for example in Gilman et
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19/68 al. (Eds.) (2006); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 11th Ed., The McGraw-Hill Companies.
[0089] The term pharmaceutically acceptable salt refers to salts that retain the biological efficacy and properties of the compounds of the preferred embodiments and that are not biologically or otherwise undesirable. In several cases, compounds of the preferred embodiments are capable of forming acidic and / or basic salts by virtue of the presence of amino and / or carboxyl groups or groups similar to these. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, acid benzoic, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutically acceptable basic addition salts can be formed with inorganic bases and organic bases Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonia, calcium, magnesium, iron, zinc, copper, manganese , aluminum and the like; ammonia, potassium, sodium, calcium and magnesium salts are particularly preferred. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like, specifically such as isopropylamine, trimethylamine , diethylamine, triethylamine, tripropylamine and
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20/68 ethanolamine. Several of such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., Published September 11, 1987 (incorporated herein by reference). [0090] Solvate refers to the compound formed by the interaction of a solvent and an inhibitor of the Wnt pathway, a metabolite or a salt thereof. Suitable solvates are pharmaceutically acceptable solvates that include hydrates.
[0091] Individual as used here, means a human or a non-human mammal, for example, a dog, a cat, mouse, rat, a cow, a pig, a goat, a non-human primate or a bird, for example, a chicken, just like any other vertebrate or invertebrate.
[0092] A therapeutically effective amount or a pharmaceutically effective amount is typically that which is sufficient to achieve the desired effect and may vary according to the nature and severity of the disease condition and the potency of the compound. It will be considered that different concentrations may be used more for prophylaxis than for the treatment of active disease. This amount may later depend on the patient's height, weight, sex, age and medical history.
[0093] A therapeutic effect relieves, to some extent, one or more of the symptoms of the disease and includes curing the disease. Healing means that the symptoms of the active disease are eliminated. However, certain long-term or permanent effects of the disease may exist even after healing is achieved (such as extensive tissue damage).
[0094] Treating, treating or treating as used herein refers to administering a pharmaceutical composition for therapeutic purposes. The term therapeutic treatment refers to administering treatment to a patient who is already suffering from a disease thus causing a therapeutically beneficial effect, such as
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21/68 improve existing symptoms, prevent additional symptoms, improve or prevent the underlying metabolic causes of symptoms, postpone or prevent the further development of a disorder and / or reduce the severity of symptoms that will or are expected to develop.
Compounds [0095] The compounds and compositions described herein can be used as anti-proliferative agents, for example, anticancer and anti-angiogenesis agents and as inhibitors of the Wnt signaling pathway, for example, to treat diseases or disorders associated with road and aberrant Wnt signaling. In addition, the compounds can be used as inhibitors of one or more kinases, kinase receptors or kinase complexes (for example, VEGF, CHK-1, CLK, HIPK, Abl, JAK and / or CDK complexes). Such compounds and compositions are also useful for controlling cell proliferation, differentiation and / or apoptosis.
[0096] Some embodiments of the present invention include compounds, salts, pharmaceutically acceptable salts or prodrugs of those of formula (Ia):
[0097] In some modalities, R ¹ , R ² , R4, R ⁶ , R ^7, R ⁸ and R ⁹ are independently selected from the group consisting of H, C1-9 alkyl, halide, -CF3, - ( C1-9 alkyl) ncarbocyclylR ¹³ , - (C1-9 alkyl) nheterocyclylR ¹³ , - (C1-9 alkyl) narylR ¹³ , - (C1-9 alkyl) nheteroarylR ¹³ , (C1-9 alkyl) nOR ¹⁰ , - (C1 -9 alkyl) nSR ¹⁰ , - (C1-9 alkyl) nS (= O) R ¹¹ , - (C1-9
Petition 870190062330, of 07/04/2019, p. 11/29
22/68 alkyl) nSO ₂ R ¹⁰ , - (C1-9 alkyl) nN (R ¹⁰ ) SO2R ¹⁰ , - (C1-9 alkyl) nSO2N (R ¹⁰ ) 2, (C1-9 alkyl) _n N (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) C (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) _n C (= A) N (R ¹⁰ ) 2, - (C1 -9 alkyl) nN (R ¹⁰ ) C (= A) R ¹⁰ , -N02, -CN, - (C1-9 alkyl) _n CO ₂ R ¹⁰ and - (Ci- ₉ alkyl) nC (= A) R ¹⁰ .
[0098] In some embodiments, R ³ is selected from the group consisting of -NRS (= O) R ¹⁴ , - (Ci-galkyl) R ¹⁴ , -carbocyclylR ¹⁴ R ¹⁵ , heterocyclylR ¹⁴ R ¹⁵ , -arylR ¹⁴ R ¹⁵ and -heteroarylR ¹⁴ R ¹⁵ .
[0099] In some modalities, one of each R ¹ and R ² , R ² and R ³ , R ³ and R ⁴ , R ⁶ and R ⁷ , R ⁷ and R ⁸ or R ⁸ and R ⁹ are joined to form one ring that is selected from the group consisting of aryl, heteroaryl, [00100] where each bond represented by a dotted line and a solid represents a selected bond from the group consisting of a single bond and a double bond.
[00101] In some embodiments, each R ¹⁰ is independently selected from the group consisting of H, -C1-9alkyl, -CF ₃ , (C1-9 alkyl) _n carbocyclyl, - (C1-9 alkyl) _n heterocyclyl, - (C1-9 alkyl) _n aryl and (C 1-9 alkyl) _n heteroaryl.
[00102] In some embodiments, each R ¹¹ is independently selected from the group consisting of -C1-9alkyl, -CF ₃ , - (C1-9 alkyl) _n carbocyclyl, - (C1-9 alkyl) _n heterocyclyl, - (C1-9 alkyl) _n aryl and - (C 1-9 alkyl) _n heteroaryl.
[00103] In some modalities, each R ¹² is selected, independently, from the group consisting of -OR ¹⁰ and R ¹⁰ .
[00104] In some embodiments, each R ¹³ has 1 to 5 substituents, each selected from the group consisting of H, C1-9alkyl, halide, CF3, carbocyclylR ¹³ , heterocyclylR ¹³ , arylR ¹³ , heteroaryl R ¹³ , - (C1- 9 alkyl) nOR ¹⁰ , - (C1-9 alkyl) nSR ¹⁰ , - (C1-9 alkyl) nS (= O) R ¹¹ , - (C1-9 alkyl) nSO2R ¹⁰ , - (C1-9 alkyl) nN ( R ¹⁰ ) SO2R ¹⁰ , - (C1-9 alkyl) nSO2N (R ¹⁰ ) 2, Petition 870190062330, of 07/04/2019, p. 11/30
23/68 (C1-9 alkyl) nN (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) C (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nC (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) C (= A) R ¹⁰ , -NO2, -CN, - (C1-9 alkyl) nCO2R ¹⁰ e - (C1-9 alkyl) nC (= A) R ¹⁰ .
[00105] In some embodiments, R ¹⁴ is selected from the group consisting of -NR ¹⁰ C (= A) R ¹⁰ , -NR ¹⁰ S (= O) R ¹¹ , -NR ¹⁰ SO2R ¹⁰ , NR ¹⁰ C (= O ) N (R ¹⁶ ) 2, -NR ¹⁰ C (= S) N (R ¹⁰ ) 2, -NR ¹⁰ C (= NR ¹² ) N (R ¹⁰ ) 2, -N (R ¹⁶ ) 2, -C ( = O) NR ¹⁰ R ¹⁷ , -C (= S) N (R ¹⁰ ) 2, -C (= NR ¹² ) N (R ¹⁰ ) 2, -OC (= A) R ¹⁰ , C (= A) R ¹⁰ , -NR ¹⁰ C (= A) OR ¹⁰ and -OC (= A) NR ¹⁰ R ¹⁰ .
[00106] In some embodiments, R ¹⁵ has 1 to 4 substituents, each selected from the group consisting of H, C1-9 alkyl, halide, -CF3, carbocyclyl ¹³ , heterocyclyl ¹³ , aryl R ¹³ , heteroaryl ¹³ , - (C 1 -9 alkyl) nOR ¹⁰ , (C1-9 alkyl) nSR ¹⁰ , - (C1-9 alkyl) nS (= O) R ¹¹ , - (C1-9 alkyl) nSO2R ¹⁰ , - (C1-9 alkyl) nN ( R ¹⁰ ) SO2R ¹⁰ , - (C1-9 alkyl) nSO2N (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) 2, (C1-9 alkyl) nN (R ¹⁰ ) C (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nC (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) C (= A) R ¹⁰ , -NO2, - CN, - (C1-9 alkyl) nCO2R ¹⁰ and - (C1-9 alkyl) nC (= A) R ¹⁰ .
[00107] In some embodiments, R ¹⁶ is -C1-9 alkyl.
[00108] In some embodiments, each R ¹⁷ is independently selected from the group consisting of -heterocyclyl R ¹³ , - (C 1-9 alkyl) heterocyclyl ¹³ and - (C 1-9 alkyl) carbocyclyl ¹³ .
[00109] In some embodiments, R ¹⁸ and R ¹⁹ are independently selected from the group consisting of H, C1-9 alkyl, halide, (C1-9 alkyl) ncarbocyclylR ¹³ , - (C1-9 alkyl) nheterocyclylR ¹³ , - (C1-9 alkyl) narilR ¹³ , - (C1-9 alkyl) nheteroarylR ¹³ , - (C1-9 alkyl) nOR ¹⁰ , - (C1-9 alkyl) nSR ¹⁰ , - (C1-9 alkyl) nS (= O) R ¹¹ , - (C1-9 alkyl) nSO2R ¹⁰ , - (C1-9 alkyl) nN (R ¹⁰ ) SO2R ¹⁰ , - (C1-9 alkyl) nSO2N (R ¹⁰ ) 2, - (C1-9 alkyl ) nN (R ¹⁰ ) 2, (C1-9 alkyl) nN (R ¹⁰ ) C (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nC (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) C (= A) R ¹⁰ , -NO2, -CN, - (C1-9 alkyl) nCO2R ¹⁰ e - (C1-9 alkyl) nC (= A) R ¹⁰ .
[00110] In some modalities, R ¹⁸ and R ¹⁹ are linked to form
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24/68 a ring selected from the group consisting of benzene and pyridine. [00111] In some modalities, each A is selected, independently from O, S and NR ¹² .
[00112] In some modalities, Y ¹ , Y ² , Y3 and Y ⁴ are selected, independently, from the group consisting of carbon and nitrogen, with the proviso that at least one of Y ¹ , Y ² , Y3 and Y ⁴ be nitrogen. [00113] In some modalities, Y ¹ is nitrogen and R ⁶ is absent.
[00114] In some modalities, Y ² is nitrogen and R7 is absent.
[00115] In some modalities, Y ³ is nitrogen and R ⁸ is absent.
[00116] In some modalities, Y ⁴ is nitrogen and R9 is absent.
[00117] In some modalities, each n is 0 or 1.
[00118] Some embodiments of the present invention include compounds, salts, pharmaceutically acceptable salts or prodrugs
[00119] In some modalities, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R 7, R ⁸ and R ⁹ are selected, independently, from the group consisting of H, C 9 alkyl, halide, - CF3, - (C1-9 alkyl) ncarbocyclylR ¹³ , - (C1-9 alkyl) nheterocyclylR ¹³ , - (C1-9 alkyl) narylR ¹³ , - (C1-9 alkyl) nheteroarylR ¹³ , (C1-9 alkyl) nOR ¹⁰ , - (C1-9 alkyl) nSR ¹⁰ , - (C1-9 alkyl) nS (= O) R ¹¹ , - (C1-9 alkyl) nSO2R ¹⁰ , - (C1-9 alkyl) nN (R ¹⁰ ) SO2R ¹⁰ , - (C1-9 alkyl) nSO2N (R ¹⁰ ) 2, (C1-9 alkyl) nN (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) C (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nC (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) C (= A) R ¹⁰ , -NO2, -CN, - (C1 -9 alkyl) nCO2R ¹⁰ and - (C1-9 alkyl) nC (= A) R ¹⁰ .
[00120] In some modalities, each of R ¹ and R ² , R ² and R ³ , R ³
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25/68 and R ⁴ , R ⁶ and R ⁷ , R ⁷ and R ⁸ or R ⁸ and R ⁹ are joined to form a ring that is selected from the group consisting of aryl, heteroaryl,
[00121] in which each link represented by a dotted line and a solid link represents a link selected from the group consisting of a single link and a double link.
[00122] In some embodiments, each R ¹⁰ is independently selected from the group consisting of H, -C1-9alkyl, -CF ₃ , (C1-9 alkyl) ncarbocyclyl, - (C1-9 alkyl) _n heterocyclyl, - (C1-9 alkyl) _n aryl and (C 1-9 alkyl) _n heteroaryl.
[00123] In some embodiments, each R ¹¹ is independently selected from the group consisting of -C1-9alkyl, -CF ₃ , - (C1-9 alkyl) ncarbocyclyl, - (C1-9 alkyl) _n heterocyclyl, - ( C1-9 alkyl) _n- aryl and - (C1-9 alkyl) _n- heteroaryl.
[00124] In some modalities, each R ¹² is selected, independently, from the group consisting of -OR ¹⁰ and R ¹⁰ .
[00125] In some embodiments, each R ¹³ has 1 to 5 substituents, each selected from the group consisting of H, C1-9alkyl, halide, CF3, carbocyclyl ¹³ , heterocyclyl ¹³ , ariIR ¹³ , heteroariIR ¹³ , - (C1- 9 alkyl) nOR ¹⁰ , - (C1-9 alkyl) nSR ¹⁰ , - (C1-9 alkyl) nS (= O) R ¹¹ , - (C1-9 alkyl) nSO2R ¹⁰ , - (C1-9 alkyl) nN ( R ¹⁰ ) SO2R ¹⁰ , - (C1-9 alkyl) nSO2N (R ¹⁰ ) 2, (C1-9 alkyl) _n N (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) C (= A ) N (R ¹⁰ ) 2, - (C1-9 alkyl) nC (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) C (= A) R ¹⁰ , -NO2, -CN, - (C1-9 alkyl) _n CO ₂ R ¹⁰ and - (C- ₉ alkyl) _n C (= A) R ¹⁰ .
[00126] In some embodiments, R ¹⁸ and R ¹⁹ are independently selected from the group consisting of H, C1-9alkyl, halide, (C1-9 alkyl) nCarbocyclylR ¹³ , - (C1-9 alkyl) nheterocyclylR ¹³ , - (C1-9 alkyl) narilR ¹³ , - (C1-9 alkyl) nheteroarylR ¹³ , - (C1-9 alkyl) nOR ¹⁰ , - (C1-9 alkyl) nSR ¹⁰ , - (C1-9 alkyl) nS (= O ) R ¹¹ , - (C1-9 alkyl) nSO ₂ R ¹⁰ , - (C1-9
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26/68 alkyl) nN (R ¹⁰ ) SO2R ¹⁰ , - (C1-9 alkyl) nSO2N (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) 2, (C1-9 alkyl) nN (R ¹⁰ ) C (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nC (= A) N (R ¹⁰ ) 2, - (C1-9 alkyl) nN (R ¹⁰ ) C (= A) R ¹⁰ , -NO2, -CN, - (C1-9 alkyl) nCO2R ¹⁰ and - (C1-9 alkyl) nC (= A) R ¹⁰ .
[00127] In some embodiments, R ¹⁸ and R ¹⁹ are linked to form a ring selected from the group consisting of benzene and pyridine.
[00128] In some modalities, each A is selected, independently from O, S and NR ¹² .
[00129] In some modalities, Y ¹ , Y ² , Y3 and Y4 are selected, independently, from the group consisting of carbon and nitrogen with the proviso that at least one of Y ¹ , Y ² , Y3 and Y4 is nitrogen. [00130] In some modalities, Y ¹ is nitrogen and R ⁶ is absent.
[00131] In some modalities, Y ² is nitrogen and R ⁷ is absent.
[00132] In some modalities, Y ³ is nitrogen and R ⁸ is absent.
[00133] In some modalities, Y4 is nitrogen and R ⁹ is absent.
[00134] In some modalities, each n is 0 or 1.
[00135] Illustrative compounds of Formula (Ia) and (Ib) are shown in Table 1.
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27/68
3 / HçN^N H 8 ^ -NH / ^N NW~~~ NTHEO-'NH 4L NHL / ^NHN ^ /~ NyouNH 5£^N NHo ¹H ''ON ^ /~ NO-NH 6£ 5N X HH Ό 0H7 o _; THE ^ HH ^ N ^ y ^N yNH li O H
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28/68
8 > ^H Λ \ NH NH Yz ² 1 n; i r il Ά ^ν η TX H 9 HN..NH ^N Y ξ 1 N I A and ^NH τχ> H 10 > f 1 « ^{0 NH} A / './ H 11 Y fX ^ _N 1 N ^ Y » ^{0 NH} X / Λ p Λχ Η 12 οΑη ^Ν ^ Α J -; Η
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29/68
13 v Ck ^ ^{0 NH} Λ y ~ H 14 X \cr NH / ==== /H 15 1 k ^ N 1 X ) NH / ===== / 1 n; 1 r il V-nh T X> ⁿ H 16 9 k ^ N ll ^NH / ^ = Z ^ν λ i r il V-nh T x X ^ N H 17 N ^ ^{1 N} «1 r il V ^ nh TX> ⁿ H
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30/68
18 1 KYn> L 1 \nh / ==== ^Ã n; 1r il V ^ nhT XX / ^ NH 19 9 Xz ^ N / A \ i ^NH γ ^ γ L v A ⁿ Í i // r π V ⁿ h XXX // ^ N H 20 / ^N / / A \ NH / == / N Ί r il V-nh T Aa / ^ N H 21 / ^N / 9 Y ^ N / —- [nh // Z - 7 H 22 N ^Yii Y ^ nL X X «nh Z ==== ZH
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[00136] The starting materials used in the preparation of the compounds of the invention are known, made by known methods or are commercially available. It will be clear to one skilled in the art that the methods for preparing precursors and the functionality related to the compounds claimed herein are described generally in the literature. The experienced technician, given the literature and this description, is well equipped to prepare any of the compounds.
[00137] It is recognized that the person skilled in the organic chemistry technique can quickly perform the manipulations without further instructions, that is, it is within the scope and practice of the person skilled in the technique to perform these manipulations. These include the reduction of carbonyl compounds in their corresponding alcohols, oxidations, acylations, aromatic, electrophilic and nucleophilic substitutions, etherifications, esterification and saponification and the like. These manipulations are discussed in standard texts such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure
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6 ^th Ed., John Wiley & Sons (2007), Carey and Sundberg, Advanced Organic Chemistry 5 ^th Ed., Springer (2007), Comprehensive Organic Transformations: A Guide to Functional Group Transformations, 2 ^nd Ed., John Wiley & Sons (1999) (incorporated herein by reference in its entirety) and the like.
[00138] Those skilled in the art will readily appreciate that certain reactions are best performed when another functionality is masked or protected in the molecule, thus preventing any undesirable side reactions and / or increasing the reaction yield. Generally, the person skilled in the art uses protective groups to obtain such increased yields or to avoid unwanted reactions. These reactions are found in the literature and are also within the scope of those skilled in the art. Examples of several of these manipulations can be found, for example, in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007), incorporated here by reference in their entirety.
[00139] The following exemplary schemes are provided as a guide for the reader and represent preferred methods for making the compounds exemplified herein. These methods are not limiting and it will be clear that other routes can be employed to prepare these compounds. Such methods specifically include solid phase based chemicals, including combinatorial chemistry. The experienced technician is perfectly equipped to prepare these compounds by the methods provided in the literature and in that description. The numbering of the compounds used in the synthetic schemes illustrated below has meaning only for those specific schemes and should not be considered or confused with the same numbers in other sections of the application.
[00140] To further illustrate this invention, the examples to be
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33/68 following are included. Variations of these examples within the scope of the claims are within the scope of the person skilled in the art and are considered within the scope of the invention as described and claimed herein. The reader will recognize that the experienced technician, equipped with the present description and versed in the technique, is able to prepare and use the invention without exhaustive examples.
[00141] The trademarks used here are examples only and reflect illustrative materials used at the time of the invention. The experienced technician will recognize that batch variations, production processes and the like are expected. Therefore, the examples and trademarks used are not limiting and they are not intended to be limiting, but are merely an illustration of how the experienced technician can choose to carry out one or more of the modalities of the invention.
[00142] ¹ H nuclear magnetic resonance (NMR) spectra were measured in the solvents indicated on a Bruker NMR spectrometer (Avance TM DRX300, 300 MHz for 1H). Peak positions are expressed in parts per million (ppm) downfield of tetramethylsilane. Peak multiplicities are designated as follows: s, singlet; d, doublet; t, triplet; m, multiplet.
[00143] The following abbreviations have the meanings indicated: brine = saturated aqueous sodium chloride
CDCl3 = deuterated chloroform
DCM = dichloromethane
DHP = 3,4-dihydro-2H-pyran
DMF = dimethylformamide
DMSO-d6 = deuterated dimethyl sulfoxide
ESIMS = electrospray ionization mass spectrometry
EtOAC = ethyl acetate
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EtaSiH = triethylsilane
HCl = hydrochloric acid
HOAc = acetic acid
KOH = potassium hydroxide K3PO4 = potassium phosphate LAH = lithium aluminum hydride MeOH = methanol MgSO4 = magnesium sulfate Na2CO3 = sodium carbonate NaHCO3 = sodium bicarbonate NaHSO3 = sodium bisulfite NaOAc = sodium acetate NMR = magnetic resonance Pd / C = palladium on carbon PdCb (dppf) 2 = 1,1'-bis (diphenylphosphine) ferrocenopalladium (II) dichloride
Pd (PPh3) 2Cl2 = dichloro-bis (triphenylphosphine) palladium (II)
PPTS = pyridinium p-toluenesulfonate
RT = room temperature
TFA = trifluoroacetic acid
THF = tetrahydrofuran
TLC = thin layer chromatography [00144] The following example schemes are provided as a guide for the reader and collectively represent an example method for making the compounds provided here. In addition, other methods for preparing the compounds will become clear to the person of ordinary skill in the light of the following reaction schemes and examples. Unless otherwise stated, all variables are as defined above. General Procedures
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[00145] Compounds of Formula Ia of the present invention can be prepared as illustrated in Scheme 1.
[00146] Scheme 1 describes a method for the preparation of indazole (VII) derivatives by the initial reaction of 5-iodo-1- (tetrahydro-2Hpiran-2-yl) -1H-indazol-3-carbaldehyde (I) with bi s (pi naco lato) d ibero to form the borate (II) ester. Suzuki coupling with various bromides (III) provides indazole derivatives (IV). The aldehyde (IV) is reacted with several 1,2-diamines (V) to produce (VI). The final deprotection of pyrazole nitrogen provides the desired indazole derivatives (VII).
Illustrative Examples of Compounds [00147] The preparation of intermediate (I) is illustrated below in Scheme 2.
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Layout 2
I XI and conditions: a) NHOMe (Me) .HCl, [00148] Reagents carbonyldiimidazole, imidazole, DMF, 65 ^o C; B)
Bis (trifluoracetoxy) iodobenzene, I2, DCM r.t; c) DHP, PPTS, DCM, refluxed; d) LAH, THF, 0 ° C.
Step a [00149] 1H-indazole-3-carboxylic acid (VIII) (100 g, 617 mmol) in
DMF was treated with carbonyldiimidazole (110 g, 678 mmol) at r.t. until evolution of the gas ceased (ca. 15 minutes). The reaction was heated to
60-65 ° C for two hours and then allowed to cool to r.t. N, ODimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solid and the mixture was heated to 65 ° C for 3 hours. The reaction was concentrated to a paste and removed in DCM and washed, subsequently with water and 2N HCl. The product can be seen out of the solution. The solid was filtered and washed separately with EtOAc. The EtOAc and DCM layers were washed separately with sodium bicarbonate followed by brine, dried over MgSO4 and concentrated under reduced pressure. The resulting solids were combined, ground with a 1: 1 DCM-ether mixture, filtered and
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37/68 dry to produce N-methoxy-N-methyl-1H-indazol-3-carboxamide (IX) as a white solid (100 g, 487 mmol, 79% yield). 1H NMR (DMSO-d6) δ ppm 3.46 (s, 3H), 3.69-3.85 (m, 3H), 7.13-7.31 (m, 1H),
7.41 (t, J = 7.25 Hz, 1H), 7.56-7.65 (m, 1H), 7.93-8.08 (m, 1H); ESIMS found for C10H11N3O2 m / z 206 (M + H).
Step b [00150] A N-methoxy-N-methyl-1H-indazol-3-carboxamide (IX) (20 g,
97.4 mmol) in 1 L of DCM was added bis (trifluoracetoxy) iodobenzene (46 g, 107 mmol) followed by the addition in portions of iodine (14.84 g, 58.5 mmol) in rt. After 1 hour, 600 ml of saturated NaHSO3 was added and a solid started to precipitate which was filtered and washed with excess DCM. The filtrate was washed with brine, dried over MgSO4, concentrated and the remaining solid was triturated with a minimal amount of DCM. The combined solids were dried under vacuum over KOH to yield 5-iodo-Nmethoxy-N-methyl-1H-indazol-3-carboxamide (X) as a white solid (23.2 g, 70 mmol, 72% yield). ¹ H NMR (DMSO-d6) δ ppm 3.45 (s, 4H), 3.77 (s, 4H), 7.45-7.54 (m, 1H), 7.66 (dd, J = 8 , 81, 1.51 Hz, 1H), 8.40 (d, J = 1.01 Hz, 1H); ESIMS found for C10H10IN3O2 m / z 331 (M + H).
Step c [00151] A mixture of 5-iodo-N-methoxy-N-methyl-1H-indazol-3carboxamide (X) (16.5 g, 50 mmol), 3,4-dihydro-2H-pyran (10, 3 mL, 113 mmol) and PPTS (0.12 g, 0.6 mmol) in DCM was heated to reflux for 5 hours. The solution was poured into a saturated NaHCO3 solution, the layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with 5% aqueous citric acid and brine, dried over MgSO4, and concentrated. The crude product was purified on a silica gel column (100% EtOAc 3:97 MeOH: DCM) to provide 5-iodo-N-methoxy-N-methyl-1- (tetrahydro-2H
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38/68 pyran-2-yl) -1H-indazol-3-carboxamide (XI) as a viscous white oil (19.1 g, 46 mmol, 92% yield). 1H NMR (DMSO-d6) δ ppm 1,281.84 (m, 6H), 3.43 (s, 3H), 3.60-4.04 (s, 5H), 5.86-6.08 (m, 1H), 7.45-
7.87 (m, 2H), 8.39 (s, 1H); ESIMS found for C15H18IN3O3 m / z 416 (M + H).
Step d [00152] Lithium aluminum hydride (160 mg, 4.21 mmol) was added portionwise to a cooled (0 ° C) solution of 5-iodo-N-methoxy-N-methyl-
1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-carboxamide (XI) (, 46 g, 3.5 mmol) in THF. Stirring was continued at 0 ° C until the reaction was completed, approximately 30 min. The reaction was stopped by the slow addition of EtOAc at 0 ° C, and the whole mixture was poured into 0.4 N NaHSO4. The organic layer was washed with brine, dried over MgSO4, concentrated and purified on a column of silica gel ( 100% EtOAc 3:97 MeOH: DCM) to give 5-iodine-1- (tetrahydro-2H-pyran-2-yl) -1Hindazole-3-carbaldehyde (I) as a white solid (0.90 g, 3, 15 mmol, 72% yield). ¹ H NMR (DMSO-de) δ ppm 1.50-1.71 (m, 2H), 1.71-1.87 (m, 1H), 1.97-2.15 (m, 2H), 2 , 31-2.42 (m, 1H), 3.66-3.99 (m, 2H), 5.96-6.17 (m, 1H), 7.78 (d, J = 6 Hz, 1H ), 7.84 (d, J = 6 Hz, 1H), 8.50 (s, 1H), 10.13 (s, 1H); ESIMS found for C13H13IN2O2 m / z 357 (M + H).
[00153] The preparation of the intermediate (XV) is illustrated below in Scheme 3.
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Layout 3
xv [00154] Reagents and conditions: a) HOAc, NaOAc, Br2, 100 ^o C, 28 h,
b) 1,4-Dioxane, pyridyl-3-boronic acid, Na2CO3, H2O, Pd (PPha) 2Cb, reflux, 15 h, c) MeOH, Pd / C, H2, rt, 15 h.
Step a [00155] A mixture of 3-nitropyridin-4-amine (XII) (10 g, 71.94 mmol) and acetate (120 ml) was added to a sealed tube followed by the addition of NaOAc (29.50 g, 93.52mmol) and bromine drip addition (4.7ml, 359.7mmol) with stirring. The sealed tube was heated to 100 ^o C for 28 h until TLC showed the consumption of the starting material. The reaction mixture was concentrated to obtain a solid that was dissolved in water, basified with NaHCOa and extracted with ethyl acetate. The combined organic extracts were dried and concentrated to produce 3-bromo-5-nitropyridin-4-amine (XIII) as a yellow solid (12 g, 55 mmol, 77% yield). ¹ H NMR (DMSO-d6) δ ppm 9.19 (s, 1H), 8.58 (s, 1H); ESIMS found for CõH4BrNaO2 m / z 217, 219 (M +, M + 2).
Step b [00156] A solution of 3-bromo-5-nitropyridin-4-amine (XIII) (6 g, 26 mmol), pyridin-3-ylboronic acid (3.54 g, 29 mmol), Na2CO3 solution 1 N (78 ml) and 1,4-dioxane (150 ml) was degassed three times with
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40/68 argon. Pd (PPh ₃ ) ₂ Cl2 (927 mg, 5 mmol%) was added to the reaction and the solution was refluxed for 15 h until TLC showed that the reaction was complete. The reaction was passed through a pad of Celite and then concentrated under reduced pressure. The reaction mixture was concentrated and the residue was removed with ethyl acetate. The organic extract was washed with water, dried and concentrated in vacuo. The crude product was purified on a silica gel column (100% EtOAc ^ 2:98 MeOHOCM) to give 5-nitro-3,3'-bipyridin-4-amine (XIV) as a yellow solid (5 g, 23 , 1 mmol, 87% yield). ¹ H NMR (CDCh, 400 MHz,) δ ppm 9.31 (s, 1H), 8.80-8.79 (m, 1H), 8.70 (s, 1H), 8.23 (s, 1H ), 7.80-7.73 (m, 1H), 7.52-7.48 (m, 1H). ESIMS found for CioH ₈ N ₄ 02m / z 216.95 (M + H).
Step c [00157] To a solution of 5-nitro-3,3'-bipyridin-4-amine (XIV) (5 g, 23 mmol) in MeOH (20 mL) was added 10% Pd / C. The solution was purged with hydrogen and stirred at rt under hydrogen for 15 h. The suspension was filtered through Celite and concentrated in vacuo to yield 3,3'-bipyridine-4,5-diamine (XV) as an off-white solid (3.3 g, 17.7 mmol, 76% yield). ¹ H NMR (DMSO-d6,400 MHz,): δ 8.63-8.53 (m, 1H), 7.90-7.83 (m, 1H), 7.75 (s, 1H), 7 , 58 (s, 1H), 7,487.43 (m, 2H), 6.13 (bs, 2H), 5.31 (bs, 2H). ESIMS found C10H10N4 m / z 187.10 (M + H).
[00158] Preparation of the intermediate (XVII) is illustrated below in Scheme 4.
Layout 4
1. straight oxal oxide, DCM. DMF, r.t., 30 mill
r.t., 2h
Step 1 -2 [00159] To a solution of 5-bromonicotinic acid (XVI) (1.01 g, 5
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41/68 mmol) in dry DCM (10 mL) under nitrogen, oxalyl chloride (0.654 mL, 7.5 mmol) was added followed by dry DMF (0.1 mL). The solution was stirred at rt for 30 min. The solvent was evaporated in vacuo before adding dry pyridine (10 ml) followed by cyclopropylmethanamine (0.39 ml, 4.5 mmol). The solution was stirred at rt under nitrogen for 2 h. The solution was poured into ice water, basified with sat. NaHCO ₃ . aq. and extracted with DCM. The combined organic phases were dried over MgSO4, concentrated and dried in vacuo to provide 5-bromoN- (cyclopropylmethyl) nicotinamide (XVII) as an off-white solid (0.82 g, 3.2 mmol, 71% yield). ¹ H NMR (DMSO-d ₆ ) δ ppm 0.07-0.07 (m, 2H), 0.15-0.29 (m, 2H), 0.68-0.88 (m, 1H), 2.93 (t, J = 6.22 Hz, 2H), 8.20 (t, J = 1.88 Hz, 1H), 8.62 (d, J = 1.70 Hz, 2H), 8, 75 (s, 1H); ESIMS found CioHnBrN ₂ Om / z 254, 256 (M +, M + 2).
[00160] The preparation of the intermediate (XX) is illustrated below in
Layout 5.
Layout 5
Pyridine
0C-rt _f 15 h
Step 1 [00161] 3-amino-5-bromo pyridine (XVIII) (1 eq) was dissolved in DCM and cooled to 0 ° C before the addition of pyridine (2.2 eq) and isobutyryl chloride (XIX) (1 , 1 eq). The reaction mixture was stirred at rt for 15 h until TLC showed that the reaction was complete. The reaction mixture was diluted with DCM and washed with water. The organic extract was dried, concentrated and purified by column chromatography using silica gel (100-200 mesh) to provide N- (5-bromopyridin-3yl) isobutyramide (XX) as an almost white solid, (71% yield). Ή NMR (CDCI ₃ ) δ ppm 8.55-8.35 (m, 3H), 7.32 (s, 1H), 2.59-2.48 (m, 1H), 1.28-1.27 (d, 6H); ESIMS found CgHnBrN ₂ O m / z
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243.05 (M + H).
[00162] The following intermediates were prepared according to the procedure described in Scheme 5 above.
[00163]
O
H N
Br
XXI
N- (5-bromopyridin-3-yl) pivalamide (XXI):
Off-white solid, (67% yield), 1H NMR (CDCF, 400 MHz) δ ppm 8.48-
8.39 (m, 3H), 7.48 (bs, 1H), 1.32 (s, 9H); ESIMS found
CwHnBr ^ O m / z 256.80 (M + H).
H
XXII [00164] N- (5-bromopyridin-3-yl) -3-methylbutanamide (XXII): Off-white solid, (67% yield), 1H NMR (CDCF, 400 MHz) δ ppm
8.55-8.42 (m, 3H), 7.62 (s, 1H), 2.31-2.18 (m, 3H), 1.02-1.01 (d, J = 6Hz,
6H); ESIMS found CwHnBr ^ O m / z 258.80 (M + H).
H
N ^^ Br
Λ XXIII [00165] N- (5-bromopyridin-3-yl) -3,3-dimethylbutanamide (XXIII): light yellow solid (yield 64%), ^1H NMR (CDCls, 400 MHz) δ ppm 8.48 (s, 1H), 8.40 (s, 1H), 7.62 (s, 1H), 7.20 (bs, 1H), 2.26 (s, 3H), 1.10 (s , 9H); ESIMS found CnH1õBrN2O m / z 272.80 (M + H).
H
N./^.Br Ύ T ^Ο XXIV [00166] N- (5-bromopyridin-3-yl) butyramide (XXIV): Yellow solid, (86% yield), ¹ H NMR (CDCb, 400 MHz) δ ppm 8.48-8.39 (m, 3H), 7.38 (bs, 1H), 2.40-2.36 (t, J = 7.2 Hz, 2H), 1.81-1.72 (m, 2H), 1.03-0.98 (t, J = 7.2 Hz, 3H); ESIMS found CgHuBrNkO m / z242.90 (M + H).
H ⁰ XXV
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43/68 [00167] N- (5-bromopyridin-3-yl) pentanamide (XXV): Off-white solid, (75% yield), 1H NMR (CDCl ₃ , 400 MHz) δ ppm 8.47-
8.39 (m, 3H), 7.33 (bs, 1H), 2.41-2.38 (t, 2H, J = 7.6 Hz, 2H), 1.75-1.68 (m, 2H), 1.45-1.36 (m, 2H), 0.97-0.93 (t,, J = 7.2 Hz, 3H); ESIMS found CwH1 ₃ BrN ₂ O m / z 256.90 (M + H).
Br
XXVI [00168] N- (5-bromopyridin-3-yl) cyclopropanecarboxamide (XXVI):
Off-white solid, (83% yield), ¹ H NMR (CDCl3, 400 MHz) δ ppm 8.46-8.39 (m, 3H), 7.54 (bs, 1H), 1.56-1, 50 (m, 1H), 1.13-1.07 (m, 2H), 0.96-0.90 (m, 2H); ESIMS found C9H9BrN2O m / z 240.85 (M + H).
Br
XXVII [00169] N- (5-bromopyridin-3-yl) cyclobutanecarboxamide (XXVII):
Off-white solid, (54% yield), ¹ H NMR (CDCl ₃ , 400 MHz) δ ppm 8.97-8.39 (m, 3H), 7.21 (bs, 1H), 3.20-3 , 16 (m, 1H), 2.42-2.24 (m, 4H), 2.05-1.94 (m, 2H); ESIMS found CwHnBrN ₂ O m / z 256.90 (M + H).
Br
XXVIII [00170] N- (5-bromopyridin-3-yl) cyclohexanecarboxamide (XXVIII):
Light yellow solid, (89% yield), ¹ H NMR (CDCl3, 400 MHz) δ ppm 8.49-8.38 (m, 3H), 7.61 (bs, 1H), 2.30-2, 23 (dd, 1H, J = 3.2 Hz, J = 11.6 Hz, 1H), 1.96-1.49 (m, 4H), 1.34-1.19 (m, 3H); ESIMS found C1 ₂ H1 ₃ BrN ₂ O m / z 284.75 (M + H).
Br ^{ο N} '^ XXIX [00171] N- (5-bromopyridin-3-yl) benzamide (XXIX): Almost solid
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44/68 white, (85% yield), ¹ H NMR (CDCI3, 400 MHz) δ ppm 8.58-
8.57 (m, 2H), 8.44-4.43 (d, J = 1.6 Hz, 1H), 8.03 (bs, 1H), 7.88-7.86 (d, J = 7.2 Hz, 2H), 7.61-7.49 (m, 3H); ESIMS found C ^ HgBr ^ O m / z
278.75 (M + H).
H
Br
XXX [00172] N- (5-bromopyridin-3-iI) -2-phenylacetamide (XXX): Off-white solid, (59% yield), ¹ H NMR (CDCl3, 400 MHz) δ ppm 8,378.31 (m , 3H), 7.41-7.30 (m, 6H), 3.75 (s, 2H); ESIMS found
C13HnBrN ₂ O m / z 292.72 (M + H).
Example 1.
[00173] Preparation of compound (3) is illustrated below in
Scheme 6.
Layout 6
[00174] Reagents and conditions: a) KOAc, PdCI ₂ (dppf) ₂ , DMF, 80 ^o C,
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45/68 h; b) K2PO4, Pd (PPh3) 4, DMF, H2O, 90 ^o C, 3 h; c) DMF, sulfur, 140 ^o C, ON; d) Et3 SiH, DCM, TFA, rt, 2 h.
Step ab [00175] A solution of 5-iodo-1- (tetrahydro-2H-pyran-2-yl) -1Hindazol-3-carbaldehyde (I) (1.068 g, 3.0 mmol), bis (pinacolate) diboro ( 0.914 g, 3.6 mmol), KOAc (0.883 g, 9.0 mmol) and dry DMF (20 mL) was purged with nitrogen. PdCk (dppf) 2 was added to the reaction and purged again. The solution was heated to 80 ^o C for 2 h. Since TLC showed the disappearance of (I), the solution was cooled to rt. To this solution were added K3PO4 (0.955 g, 4.5 mmol), 5-bromo-N (cyclopropylmethyl) nicotinamide (XVII) (0.765 g, 3.0 mmol), Pd (PPh3) 4 (104 mg, 0.09 mmol) and water (2 mL). The solution was purged with nitrogen and heated to 90 ^o C for 3 h. The reaction was passed through a pad of Celite and then concentrated under reduced pressure. The residue was dissolved in DCM and washed with water and brine, dried over MgSO4 and then evaporated in vacuo. The crude product was purified on a silica gel column (100% EtOAc 2:98
MeOH: DCM) to give N- (cyclopropylmethyl) -5- (3-formyl-1- (tetrahydro-2Hpyran-2-yl) -1H-indazol-5-yl) nicotinamide (XXXI) as a yellow solid (1, 09 g, 2.7 mmol, 90% yield). ¹ H NMR (DMSO-d6) δ ppm 0,200.31 (m, 2H), 0.35-0.57 (m, 2H), 1.65 (m, 2H), 1.74-1.87 (m , 1H), 2.10 (d, J = 12.06 Hz, 2H), 2.35-2.44 (m, 1H), 3.10-3.27 (m, 3H), 3.78- 3.99 (m, 2H), 6.14 (d, J = 7.35 Hz, 1H), 7.90-8.14 (m, 2H), 8.50 (d, J = 12.5, 2H), 9.05 (dd, J = 14.60, 1.98 Hz, 2H), 10.25 (s, 1H); ESIMS found C23H24N4O3 m / z 405 (M + H).
Step c [00176] A solution of N- (cyclopropylmethyl) -5- (3-formyl-1- (tetrahydro2H-pyran-2-yl) -1H-indazol-5-yl) nicotinamide (XXXI) (0.404 g, 1 , 0 mmol), 3,3'-bipyridine-4,5-diamine (XV) (186 mg, 1.0 mmol) and sulfur (35 mg, 1.1 mmol) in dry DMF (10 mL) was heated to 140 ^o C for one night. THE
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The reaction was cooled and evaporated in vacuo. The residue was suspended in water, sonicated and filtered. The solid was washed with cold water and dried under vacuum. The crude product was dissolved in DCM and cooled to 4 ° C overnight to give N- (cyclopropylmethyl) -5- (3- (7- (pyridin-3-yl) -3Himidazo [4,5-c] pyridin- 2-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl) nicotinamide (XXXII) as a brown solid (130 mg, 0.23 mmol, 23% yield). 1H NMR (DMSO-d6) δ ppm 0.19-0.37 (m, 2H), 0.36-0.58 (m, 2H), 0.97-1.115 (m, 1H), 1.67 ( br, 2H), 2.14 (d, J = 9.98 Hz, 2H), 2.40-2.46 (m, 1H), 3.20-3.33 (m, 3H), 3.75 -4.14 (m, 2H), 6.13 (d, J = 8.29 Hz, 1H), 7.60 (dd, J = 7.82, 4.80 Hz, 1H), 7.92- 8.12 (m, 3H), 8.20 (d, J = 8.67 Hz, 1H), 8.55-8.67 (m, 2H), 8.94 (br s, 3H), 9, 06 (d, J = 1.88 Hz, 1H), 9.19 (d, J = 1.87 Hz, 1H); ESIMS found C33H30N8O2 m / z 571 (M + H).
Step d [00177] A solution of N- (cyclopropylmethyl) -5- (3- (7- (pyridin-3-yl) -3Himidazo [4,5-c] pyridin-2-yl) -1- (tetrahydro- 2H-pyran-2-yl) -1H-indazol-5-yl) nicotinamide (XXXII) (125 mg, 0.22 mmol) and Et3SiH (87 μ_, 0.55 mmol) in DCM (5 m_) was added slowly to TFA (2.5 m). The reaction was stirred at rt for 3 h. The reaction was evaporated in vacuo and the residue was treated with water, basified with aq. The solids were filtered, washed with cold water and dried. The crude product was heated in MeOH and filtered hot to remove impurities. The hot MeOH solution was allowed to cool slowly to rt to produce N (cyclopropylmethyl) -5- (3- (7- (pyridin-3-yl) -3H-imidazo [4,5-c] pyridin-2-yl ) -1Hindazol-5-yl) nicotinamide (3) as an off-white solid (48 mg, 0.10 mmol, 44% yield). ¹ H NMR (DMSO-de) δ ppm 0.28 (d, J = 4.28 Hz, 2H), 0.42-0.58 (m, 2H), 1.09 (br s, 1H), 3 , 25 (t, J = 6.06 Hz, 2H), 7.507.70 (m, 1H), 7.79-8.11 (m, 2H), 8.48-8.68 (m, 1H), 8.69-8.82 (m, 1H), 8.81-8.97 (m, 3H), 9.00-9.18 (m, 2H), 9.46 (br s, 1H); ESIMS found C28H22N8O m / z 487 (M + H).
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47/68 [00178] The following compounds were prepared according to the procedure described in Example 1 above.
HN, [00179] 5- (3- (3H-imidazo [4,5-c] pyridin-2-yl) -1H-indazol-5-yl) -N (piperidin-4-yl) nicotinamide 1 [00180] 1H NMR (DMSO-d6) δ ppm 1.55-1.75 (m, 2H), 1.90-2.05 (m,
2H), 2.78-2.90 (t, 2H), 3.15-3.25 (d, 2H), 3.95-4.12 (m, 1H), 7.65 (br s, 1H ), 7.87 (dd, 2H), 8.31 (d, 1H), 8.53 (s, 1H), 8.79 (s, 1H), 8.98 (s, 2H), 9.13 (s, 1H); ESIMS found for C24H22N8O m / z 439 (M + H).
[00181] 5- (3- (3H-imidazo [4,5-c] pyridin-2-yl) -1H-indazol-5-yl) -N (cyclohexyl methyl) nicotinamide 2 [00182] ¹ H NMR (DMSO -d6) δ ppm 0.98-1.15 (m, 2H), 1.2-1.39 (m,
3H), 1.64-1.89 (m, 6H), 3.21-3.35 (m, 2H), 7.73 (d, 1H), 7.82 (d, 1H),
7.88 (d, 1H), 8.34 (s, 1H), 8.62 (s, 1H), 8.86 (s, 1H), 8.96 (s, 1H), 8.99 (s , 1H), 9.12 (s, 1H); ESIMS found for C26H25N7O m / z 452 (M + H).
[00183] N- (5- (3- (7- (pyridin-3-yl) -3H-imidazo [4,5-c] pyridin-2-yl) -1H
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48/68 indazol-5-yl) pyridin-3-yl) propionamide 4 [00184] ¹ H NMR (DMSO-d6) δ ppm 1.15 (t, J = 7.16 Hz, 3H), 2.40 ( q,
2H), 7.60 (br s, 1H), 7.85 (br s, 3H), 8.39-8.54 (m, 1H), 8.66 (br s, 2H), 8.77 ( s, 1H), 8.82 (s, 1H), 8.97 (br s, 1H); ESIMS found for C26H20N8O m / z 461 (M + H).
N
H 11 [00185] N- (5- (3- (7- (pyridin-3-yl) -3H-imidazo [4,5-c] pyridin-2-yl) -1Hindazol-5-yl) pyridin-3 -il) isobutyramide 11 [00186] Dark brown solid (40% yield). ¹ H NMR (DMSO-d6, 400 MHz,) δ ppm 14.01 (br s, 1H), 13.79 (br s, 1H), 10.19 (s, 1H), 9.42 (s, 1H ), 8.87-8.47 (m, 8H), 7.83-7.78 (m, 2H), 7.57-7.54 (m, 1H), 2.69-2.62 (m , 2H), 1.14-1.13 (d, J = 6.8 Hz, 6H). ESIMS found for C27H22N8O m / z 475.10 (M + H).
h 12 [00187] N- (5- (3- (7- (pyridin-3-yl) -3H-imidazo [4,5-c] pyridin-2-yl) -1Hindazol-5-yl) pyridin-3 -il) cyclopropanecarboxamide 12 [00188] Dark brown solid (23% yield). ¹ H NMR (DMSO-d6, 400 MHz,) δ ppm 14.03 (s, 1H), 13.80 (s, 1H), 10.59 (s, 1H),
9.45 (s, 1H), 8.92-8.65 (m 7H), 8.47 (s, 1H), 7.83 (s, 2H), 7.57 (s, 1H), 1, 88-1.86 (m, 1H), 0.88-0.87 (m, 4H). ESIMS found for
C27H20N8O m / z 473.15 (M + H).
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[00189] 3-methyl-N- (5- (3- (7- (pyridin-3-yl) -3H-imidazo [4,5-c] pyridin-2-yl) 1H-indazol-5-yl) pyridin-3-yl) butanamide 15 [00190] Dark brown solid (14% yield). 1H NMR (DMSO-d6, 400 MHz,) δ ppm 14.03 (s, 1H), 13.78 (br s, 1H), 10.24 (s, 1H), 9.46 (s, 1H), 8.89-8.76 (m, 4H), 8.75-8.39 (m, 4H), 7.86-7.82 (m, 2H), 7.59-7.58 (m, 1H ), 2.30-2.28 (d, J = 6.8 Hz, 2H), 2.18-2.12 (m, 1H), 0.99-097 (d, J = 6.4 Hz, 6H). ESIMS found for C28H24N8O m / z
489.20 (M + H).
[00191] N- (5- (3- (7- (pyridin-3-yl) -3H-imidazo [4,5-c] pyridin-2-yl) -1Hindazol-5-yl) pyridin-3-yl ) benzamide 16 [00192] Dark brown solid (30% yield). ¹ H NMR (DMSO-d6, 400 MHz,) δ ppm 14.04 (s, 1H), 13.80 (s, 1H), 10.63 (s, 1H),
9.45 (s, 1H), 9.00-8.74 (m, 6H), 8.63 (s, 1H), 8.36 (s, 1H), 8.07-8.05 (m,
2H), 7.88-7.86 (m, 2H), 7.67-7.52 (m, 4H). ESIMS found for C30H20N8O m / z 509.05 (M + H).
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[00193] N- (5- (3- (7- (pyridin-3-yl) -3H-imidazo [4,5-c] pyridin-2-yl) -1H indazol-5-yl) pyridin-3- il) pivalamide 17 [00194] Dark brown solid (43% yield). 1H NMR (DMSO-d6, 400 MHz,) δ ppm 14.03 (s, 1H), 13.79 (br s, 1H), 9.57 (s, 1H), 9.46 (s, 1H), 8.92-8.81 (m, 4H), 8.75-8.49 (m, 4H), 7.84 (s, 2H),
7.59-7.56 (m, 1H), 1.29 (s, 9H). ESIMS found for C28H24N8O m / z 489.15 (M + H).
[00195] 3,3-dimethyl-N- (5- (3- (7- (pyridin-3-yl) -3H-imidazo [4,5-c] pyridin-
2-yl) -1H-indazol-5-yl) pyridin-3-yl) butanamide 18 [00196] Dark brown solid (32% yield). ¹ H NMR (DMSO-d6, 400 MHz,) δ ppm 14.03 (s, 1H), 13.77 (s, 1H), 10.18 (s, 1H),
9.46 (s, 1H), 8.89-8.75 (m, 4H), 8.65-8.40 (m, 2H), 7.86-7.79 (m, 2H),
7.59-7.56 (m, 2H), 2.29 (s, 2H), 1.06 (s, 9H). ESIMS found for C29H26N8O m / z 503.15 (M + H).
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N
Ο
Η 19 [00197] N- (5- (3- (7- (pyridin-3-yl) -3H-imidazo [4,5-c] pyridin-2-yl) -1Hindazol-5-yl) pyridin-3 -il) cyclohexanecarboxamide 19 [00198] Off-white solid (17% yield). 1H NMR (DMSOd ₆ , 400 MHz,) δ ppm 14.04 (s, 1H), 13.78 (s, 1H), 10.20 (s, 1H), 9.45 (s, 1H), 8, 89-8.51 (m, 7H), 7.83 (s, 2H), 7.59 (s, 2H), 1.90-1.66 (m, 5H), 1.47-1.22 ( m, 6H), ESIMS found for C30H26N8O m / z 515.15 (M + H).
h 20 [00199] N- (5- (3- (7- (pyridin-3-yl) -3H-imidazo [4,5-c] pyridin-2-yl) -1Hindazol-5-yl) pyridin-3 -il) butyramide 20 [00200] Dark brown solid (34% yield). ¹ H NMR (DMSO-d6, 400 MHz,) δ ppm 14.07 (s, 1H), 10.26 (s, 1H), 9.40 (s, 1H), 8.96 (s, 1H), 8.80-8.65 (m, 6H), 8.48 (s, 2H), 7.87-7.81 (m, 2H), 7.62-
7.59 (m, 1H), 2.41-2.38 (t, J = 7.2 Hz, 2H), 1.70-1.64 (m, 2H), 0.98-0.94 ( t, J = 7.2 Hz, 3H). ESIMS found for C27H22N8O m / z 475.10 (M + H).
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52/68 [00201]
N- (5- (3- (7- (pyridin-3-yl) -3H-imidazo [4,5-c] pyridin-2-yl) -1H indazol-5-yl) pyridin-3-yl) cyclobutanecarboxamide 21 [00202] Almost white solid (21% yield). 1H NMR (DMSOd ₆ , 400 MHz,) δ ppm 13.09 (s, 1H), 13.06 (s, 1H), 10.11 (s, 1H), 9.43 (bs,
1H), 8.92-8.78 (m 6H), 8.49 (s, 2H), 7.82 (s, 2H), 7.58-7.56 (m, 1H), 2,312.27 ( m, 4H), 2.19-2.17 (m, 2H), 2.02-1.95 (m, 1H). ESIMS found for C28H22N8O m / z 487.10 (M + H).
[00203] 2-phenyl-N- (5- (3- (7- (pyridin-3-yl) -3H-imidazo [4,5-c] pyridin-2-yl) 1H-indazol-5-yl) pyridin-3-yl) acetamide 22 [00204] Off-white solid (40% yield). ¹ H NMR (DMSOd6, 400 MHz,) δ ppm 13.99 (s, 1H), 13.00 (s, 1H), 10.58 (s, 1H), 9.41 (s,
1H), 8.90-8.49 (m, 8H), 7.85-7.83 (m, 2H), 7.52-7.27 (m, 6H), 3.76 (s,
2H). ESIMS found for C31H22N8O m / z 523.15 (M + H).
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53/68 [00205] N- (5- (3- (7- (pyridin-3-yl) -3H-imidazo [4,5-c] pyridin-2-yl) -1Hindazol-5-yl) pyridin- 3-yl) pentanamide 23 [00206] Dark brown solid (28% yield). 1H NMR (DMSO-d6, 400 MHz,) δ ppm 14.05 (s, 1H), 13.01 (s, 1H), 10.26 (s, 1H),
9.39 (s, 1H), 8.95-8.65 (m 7H), 8.47 (s, 1H), 7.86-7.80 (m, 2H), 7.61-
7.58 (m, 1H), 2.43-2.40 (t, J = 7.2 Hz, 2H), 1.65-1.59 (m, 2H), 1.40-1.34 ( m, 2H), 0.94-0.90 (t, J = 7.2 Hz, 3H). ESIMS found for C28H24N8O m / z 489.15 (M + H).
Pharmaceutical Administration and Compositions [00207] Some embodiments include pharmaceutical compositions that comprise: (a) a safe and therapeutically effective amount of indazole or its corresponding enantiomer, diastereoisomer or tautomer or pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier.
[00208] The administration of the compounds described herein or their pharmaceutically acceptable salts can be through any of the accepted modes of administration for agents having similar uses including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal , intraversadoneal, intramuscular, intrapulmonary, vaginal, rectal or intraocular. Oral and parenteral administrations are routine in the treatment of indications.
[00209] The compounds of the invention intended for pharmaceutical use can be administered as crystalline or amorphous products. Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as, for example, tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or the like. They can be obtained, for example, as films by methods such as precipitation, crystallization, lyophilization, spray drying or
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54/68 evaporation. Microwave or radio frequency drying can be used for this purpose. The compounds can also be administered in sustained or controlled release dosage forms, including deposit injections, osmotic pumps, pills, transdermal patches (including electron transport) and the like, for prolonged and / or regulated administration, pulsed in dosage forms unitary dose for the single administration of an accurate dose.
[00210] The compounds can be administered alone or more typically in combination with a pharmaceutically acceptable carrier, excipient or the like. The term excipient is used here to describe any ingredient other than the compound of the invention. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as polyethylene glycol 1000 da-tocopherol succinate, surfactants used in dosage forms pharmaceutical products such as Tweens or other polymeric release matrices, serum proteins, such as serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes , such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes , block copolymers of polyethylene-polyoxypropylene and fat of l . Cyclodextrins such as α, β and γ-cyclodextrin or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2 and 3-hydroxypropyl-b-cyclodextrins or other solubilized derivatives can also be advantageously used for
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55/68 to intensify the release of compounds of the formulas described here. Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance composed of a non-toxic vehicle can be prepared. The contemplated compositions can contain 0.001% to 100% of the active ingredient, in a 0.1 to 95% modality, in another 75% to 85% modality. Current methods of preparing such dosage forms are known or will become apparent to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 21st. Edition (Lippincott Williams & Wilkins, 2005).
[00211] In a preferred embodiment, the compositions will take the form of a unit dosage such as a pill or tablet and, therefore, the composition may contain, together with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives and the like. In another solid dosage form, a powder, marume, solution or suspension (for example, in propylene carbonate, vegetable oils or triglycerides) is encapsulated in a gelatin capsule. Unit dosage forms in which the two active ingredients are physically separated are also contemplated; for example, capsules with granules of each drug; two-layer tablets; gel capsules with two compartments, etc.
[00212] Pharmaceutically administrable liquid compositions can, for example, be prepared by dissolving, dispersing, etc. of an active compound as defined above and optional pharmaceutical adjuvants in a vehicle (for example, water, saline, aqueous dextrose, glycerol. glycols, ethanol and the like) to form a solution or suspension. If desired, the pharmaceutical composition can also
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56/68 contain small amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (eg sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate and the like). Injectables can be prepared in conventional forms, as liquid solutions or suspensions, as emulsions or in solid forms suitable for dissolution or suspension in liquid before injection. The percentage of active compound contained in such parenteral compositions is highly dependent on its specific nature, as well as on the activity of the compound and the needs of the individual. However, percentages of the active ingredient of 0.01% to 10% in solution are employable and may be higher if the composition is a solid, which will subsequently be diluted in the percentages above. In some embodiments, the composition will comprise 0.2 to 2% of the active agent in solution.
[00213] It is to be noted that the values of concentrations and dosages may also vary with the severity of the condition to be relieved. In addition, it should be understood that for any particular patient specific dosing regimens must be adjusted over time, according to the individual need and the professional judgment of the person who administers or supervises the administration of the compositions and that the concentration ranges here described are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
[00214] Solid compositions can be provided in several types of different dosage forms, depending on the physicochemical properties of the drug, the desired dissolution rate, cost considerations and other criteria. In one of the modalities, the solid composition is only one unit. This implies that a dose
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57/68 unit of the drug is comprised of a single solid form or article, physically shaped. In other words, the solid composition is coherent, which contrasts with the multiple dosage unit form, in which the units are not coherent.
[00215] Examples of isolated units that can be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, sheet-like units, wafers, lyophilized matrix units and the like. In a preferred embodiment, the solid composition is a highly porous lyophilized form. Such lyophilisates, sometimes called wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also allows for the rapid dissolution of the active compound.
[00216] On the other hand, for some applications, the solid composition can also be formed as a multiple dosage unit form as defined above. Examples of multiple units are powders, granules, microparticles, pellets, spheres, lyophilized powders and the like. In one embodiment, the solid composition is a lyophilized powder. Such a dispersed lyophilized system comprises a multiplicity of powder particles and, due to the lyophilization process used in the formation of the powder, each particle has an irregular, porous microstructure through which the powder is able to absorb water very quickly, resulting in dissolution fast.
[00217] Another type of micro-particulate system that is also capable of achieving rapid dissolution of the drug is that of powders, granules or pellets of water-soluble excipients that are coated with the drug, such that the drug is located on the outer surface of the individual particles. In this type of system, the water-soluble low molecular weight excipient is useful for preparing the cores of such coated particles, which can be subsequently coated
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58/68 with a coating composition comprising the drug and preferably one or more additional excipients, such as a binder, a pore former, a saccharide, a sugar alcohol, a film forming polymer, a styler or other excipients used in pharmaceutical coating compositions.
[00218] Kits are also provided. Typically, a kit includes one or more compounds or compositions described herein. In certain embodiments, a kit may include one or more delivery systems, for example, for the delivery or administration of a compound as provided above and guidelines for using the kit (for example, instructions for treating a patient). In another embodiment, the kit may include a compound or composition as described herein and a package insert that indicates that the contents are to be administered to a cancer patient. In another embodiment, the kit may include a compound or composition as described herein and a package insert indicating that the contents are to be administered to a patient with one or more hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma, ovarian cancer , diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, psoriasis, mycotic and viral infections, osteochondrodysplasia, Alzheimer's disease, osteoarthritis, intestinal polyposis, osteoporosis-pseudoglioma syndrome, vitreous-retinopathy exudative familial syndrome, angiogenesis retiniana , Müllerian duct virilization and regression, SERKAL syndrome, type 2 diabetes mellitus, Fuhrmann syndrome, Al-Awadi / Raas-Rothschild / Schinzel focomelia syndrome, odonto-onico-dermal dysplasia, obesity, ectrodactyly, caudal duplication syndrome, tooth agenesis, Wilms' tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal anonychia ica recessive, neural tube defects, alpha-thalassemia syndrome (ATRX), fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,
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59/68 Beckwith-Wiedemann syndrome and Rett syndrome.
[00219] The actual dose of the active compounds of the present invention depends on the specific compound and the condition to be treated; the selection of the appropriate dose is within the knowledge of the experienced technician. Treatment Methods [00220] The compounds and compositions provided herein can be used as inhibitors of one or more members of the Wnt pathway, including one or more Wnt proteins, and therefore can be used to treat a variety of disorders and diseases in which aberrant Wnt signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cell proliferation and cell cycle. Consequently, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cell proliferation and to correct a genetic disorder due to mutations in the components of Wnt signaling. Non-limiting examples of diseases that can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, psoriasis, mycotic and viral infections, osteochondrodysplasia, Alzheimer's disease, osteoarthritis, intestinal polyposis, syndrome osteoporosis-pseudoglioma, familial exudative vitreo-retinopathy, retinal angiogenesis, early coronary disease, tetramelia syndrome, Müllerian duct virilization and regression, SERKAL syndrome, type 2 diabetes mellitus, Fuhrmann syndrome, Al-Awadi focomelia syndrome / Raas -Rothschild / Schinzel, odonto-onico-dermal dysplasia, obesity, ectrodactyly, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia syndrome (ATRX), fragile X syndrome, ICF syndrome, Angel syndrome man, Prader-Willi syndrome,
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60/68 Beckwith-Wiedemann syndrome and Rett syndrome.
[00221] With respect to cancer, the Wnt pathway is known to be constitutively activated in a variety of cancers that include, for example, colon cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer, pancreatic cancer and leukemias, such as CML, CLL and T-ALL. Constitutive activation is due to constitutively active β-catenin, perhaps due to its stabilization by interacting factors or inhibition of the degradation pathway. Consequently, the compounds and compositions described herein can be used to treat those cancers in which the Wnt pathway is constitutively activated. In certain modalities, cancer is chosen from hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma and ovarian cancer.
[00222] Other cancers can also be treated with the compounds and compositions described here.
1) Breast Cancers, including, for example, breast cancer , ER ^+, ER breast cancer ^- HER2 breast cancer ^- breast cancer HER2 ^+, stromal tumors such as fibroadenoma, phyllodes tumor , and sarcomas , and epithelial tumors such as papillomas of the main duct; breast carcinomas including carcinoma in situ (non-invasive) which includes ductal carcinoma in situ (including Paget's disease) and lobular carcinoma in situ and invasive (infiltrating) carcinoma including, but not limited to invasive ductal carcinoma, invasive lobular carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular carcinoma and invasive papillary carcinoma; and mixed malignancies. Additional examples of breast cancers include luminal A, luminal B, basal A, basal B and triple negative breast cancer that is negative for the estrogen receptor (ER ^- ), negative for the progesterone receptor and negative for her2 (her2 ^- ). In some modalities, breast cancer may have a high risk Oncotype score.
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2) Cardiac cancers including, for example, sarcoma, for example, angiosarcoma, fibrosarcoma, rhabdomyosarcoma and liposarcoma; myxoma, rhabdomyoma; fibroma; lipoma and teratoma.
3) Lung cancers, including, for example, bronchogenic carcinoma, for example, squamous cell, small undifferentiated cell, large undifferentiated cell and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma.
4) Gastrointestinal cancer including, for example, cancers of the esophagus, for example, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma and lymphoma; stomach cancers, for example, carcinoma, lymphoma and leiomyosarcoma; pancreatic cancers, for example, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors and vipoma; cancers of the small intestine, for example, adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma and fibroma; cancers of the large intestine, for example, adenocarcinoma, tubular adenoma, villous adenoma, hamartoma and leiomyoma.
5) Cancers of the genitourinary tract including, for example, cancers of the kidney, for example, adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma and leukemia; bladder and urethra cancers, for example, squamous cell carcinoma, transitional cell carcinoma and sarcoma; testicular cancer, for example, seminoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroadenoma, adenomatoid tumors and lipoma.
6) Liver cancers, including, for example, hepatoma, for example, hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma.
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7) Bone cancers including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteocartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors.
8) Cancers of the nervous system including, for example, cancers of the skull, for example, osteoma, hemangioma, granuloma, xanthoma and deforming osteitis; cancers of the meninges, for example, meningioma, meningiosarcoma and gliomatosis; brain cancers, for example, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma and congenital tumors; and cancers of the spinal cord, for example, neurofibroma, meningioma, glioma and sarcoma.
9) Gynecological cancers including, for example, cancers of the uterus, for example, endometrial carcinoma; cervical cancers, for example, cervical carcinoma and pre-tumor cervical dysplasia; ovarian cancers, for example, ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granular teak cell tumors, Sertoli Leydig cell tumors, dysgerminoma and malignant teratoma; vulvar cancers, for example, squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma and melanoma; cancers of the vagina, for example, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma and embryonic rhabdomyosarcoma; and fallopian tube cancers, for example, carcinoma.
10) Hematological cancers including, for example, blood cancers, for example, acute myeloid leukemia, leukemia
Petition 870190062330, of 07/04/2019, p. 70/117
63/68 chronic myeloid, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma and myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma (malignant lymphoma) and Waldenstrom's macroglobulinemia.
11) Skin cancers and skin disorders including, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic soft nevi, lipoma, angioma, dermatofibroma, keloids and psoriasis.
12) Cancers of the adrenal gland including, for example, neuroblastoma.
[00223] Cancers can be solid tumors that may or may not be metastatic. Cancers can also occur, as in leukemia, as a diffuse tissue. Therefore, the term tumor cell, as provided herein, includes a cell affected by any of the disorders identified above.
[00224] A cancer treatment method using a compound or composition as described herein can be combined with existing cancer treatment methods, for example, by chemotherapy, irradiation or surgery (for example, oophorectomy). In some embodiments, a compound or composition can be administered before, during or after another anti-cancer agent or treatment.
[00225] The compounds and compositions described herein can be used as anti-angiogenesis agents and as agents to modulate and / or inhibit the activity of protein kinases thereby providing treatments for cancer and other diseases associated with protein kinase-mediated cell proliferation. For example, the compounds described herein can inhibit the activity of one or more kinases, such as CDKs, VEGF, CLK, HIPK, Ab1, JAK and CHK-1 or such cyclin complexes. Consequently, a method is provided here to treat cancer or prevent or reduce angiogenesis
Petition 870190062330, of 07/04/2019, p. 71/117
64/68 by inhibiting kinase, such as by inhibiting VEGF, CHK-1, CLK, HIPK, Ab1, JAK, CDK4 or cyclin complexes of the CDK4 / D and / or CDK2 type or cyclin complexes of the type of CDK2 / E.
[00226] Additionally and including the treatment of cancer, the compounds and compositions described herein can function as cell cycle control agents for treating proliferative disorders in a patient. Disorders associated with excessive proliferation include, for example, cancers, psoriasis, immune disorders that involve unwanted leukocyte proliferation and restenosis and other smooth muscle disorders. In addition, such compounds can be used to prevent postmitotic de-differentiation of tissues and / or cells.
[00227] Diseases or disorders associated with uncontrolled or abnormal cell proliferation include, but are not limited to, the following:
• a variety of cancers, including but not limited to carcinoma, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system and other tumors including melanoma, seminoma and Kaposi's sarcoma.
• A disease process that presents abnormal cell proliferation, for example, benign prostatic hyperplasia, polyposis familial adenomatosis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis that accompanies angioplasty or vascular surgery, scar formation hypertrophic, inflammatory bowel disease, transplant rejection, endotoxic shock and fungal infections.
• conditions associated with deficient apoptosis such as cancers (including but not limited to the types mentioned here above), viral infections (including, but not limited to herpesviruses,
Petition 870190062330, of 07/04/2019, p. 72/117
65/68 poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including, but not limited to systemic lupus erythematosus, rheumatoid arthritis, psoriasis, auto glomerulonephritis -immune, inflammatory bowel disease and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited to, Alzheimer's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, atrophy of the spinal muscles and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarction, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin or alcohol related liver diseases, hematological diseases (including, but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (i (including, but not limited to, osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease and cancer pain.
• genetic diseases due to mutations in the components of Wnt signaling, such as intestinal polyposis, osteoporosis-pseudoglioma syndrome, familial exudative vitreous-retinopathy, retinal angiogenesis, early coronary heart disease, tetramelia syndrome, virilization and Müllerian duct regression, SERKAL syndrome , type 2 diabetes mellitus, Fuhrmann syndrome, Al-Awadi / Raas-Rothschild / Schinzel focomelia syndrome, odontoonic-dermal dysplasia, obesity, ectrodactyly, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, hypoplasia focal dermal, autosomal recessive anonychia, neural tube defects, alpha-thalassemia syndrome (ATRX), fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann syndrome and Rett syndrome.
Petition 870190062330, of 07/04/2019, p. 73/117
[00228] The compounds and compositions may also be useful in inhibiting the development of invasive cancer, tumor angiogenesis and metastasis.
[00229] Furthermore, compounds and compositions, for example, as CDK inhibitors, can modulate the level of cellular RNA and DNA synthesis and are therefore expected to be useful in the treatment of viral infections such as HIV, human papilloma, herpes virus, Epstein-Barr virus, adenovirus, Sindbis virus, poxvirus and the like.
[00230] The compounds and compositions described herein can inhibit kinase activity, for example of CDK / cyclin complexes, such as those active in the G0 or G1 stages of the cell cycle, for example, CDK2, CDK4 and / or CDK6 complexes .
Assessment of Biological Activity [00231] The biological activity of the compounds described herein can be tested using any suitable assay known to those skilled in the art, for example, WO 2001/053268 or WO 2005/009997. For example, the activity of a compound can be tested using one or more of the test methods outlined below.
[00232] In one example, tumor cells can be screened for independent growth of Wnt. In such a method, the tumor cells of interest are contacted with a compound (i.e., inhibitor) of interest and the proliferation of the cells is monitored, for example, by the entry of tritiated thymidine. In some embodiments, the tumor cells can be isolated from a candidate patient who has been screened for the presence of a cancer that is associated with a mutation in the Wnt signaling pathway. Candidate cancers include, without limitation, those listed above.
[00233] In another example, one can use in vitro assays for the biological activity of Wnt, for example, stabilization of β-catenin and
Petition 870190062330, of 07/04/2019, p. 74/117
67/68 promoting the growth of stem cells. Assays for the biological activity of Wnt include the stabilization of β-catenin, which can be measured, for example, by the serial dilutions of a candidate composition for inhibitor. An exemplary assay of the biological activity of Wnt contacts a composition of Wnt in the presence of a candidate inhibitor with cells, for example, mouse L cells. The cells are cultured for a period of time sufficient to stabilize β catenin, usually at least about 1 hour and lysed. The cell lysate is resolved by SDS-PAGE, then transferred to nitrocellulose and probed with specific antibodies to β-catenin.
[00234] In an additional example, the activity of a candidate compound can be measured in a secondary axis bioassay in Xenopus (Leyns, L. et al., Cell (1997), 88 (6), 747-756).
Example 2.
[00235] Another screening test for Wnt activity is described below. Reporter cell lines can be generated by cells stably transduced from cancer cell lines (eg, colon cancer) with a lentiviral construct that includes a wnt responsive promoter that directs the expression of the firefly luciferase gene.
[00236] Lentiviral constructs can be made in which the SP5 promoter, a promoter that has eight TCF / LEF binding sites derived from the SP5 promoter, is linked upstream of the firefly luciferase gene. Lentiviral constructs can also include a hygromycin resistance gene as a selectable marker. The SP5 promoter construct can also be used to transduce SW480 cells, a colon cancer cell line that has a mutated APC gene that generates a truncated APC protein, which leads to unregulated accumulation of β-catenin. A control cell line can be generated using another lentiviral construct that contains the gene for
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68/68 luciferase under the control of the SV40 promoter that does not require β-catenin for activation.
[00237] Cultured SW480 cells that harbor a reporter construct can be distributed into approximately 10,000 cells per well in 384-well multi-well plates. Compounds from a small molecule compound library can then be added to the wells in semi-logarithmic dilutions using a maximum concentration of three micromolar. A series of wells for each cell type receives only buffer and solvent from the compound. Twenty-four hours after adding the compound, the luciferase reporter activity can be tested, for example, by diluting the luminescent reagent BrightGlo (Promega) and the Victor3 plate reader (Perkin Elmer). Readings can be normalized for DMSO only in treated cells and normalized activities can be used in the calculation of IC50s. Table 2 shows the activity of the selected indazole analogs.
Table 2.
Compound inhibition of Wnt, IC50 Compound inhibition of Wnt, IC50 1 > 10 μΜ 16 0.38-1.17 μM 2 > 10 μΜ 17 32- 50 nM 3 > 10 μΜ 18 21-39 nM 4 29-50 nM 19 86-206 nM 11 4 nM 20 63 nM 12 26-35 nM 21 29 nM 15 5.6 nM 23 34-64 nM
[00238] The term comprising as used here is synonymous with including, containing or characterized by and is inclusive or broad in scope and does not exclude additional or unmentioned elements or steps of the method.

权利要求:
Claims (12)
[1]
1. Compound or pharmaceutically acceptable salt thereof, characterized by the fact that it has the structure of formula Ia:

on what:
R ¹ , R2, R4, R7, R8 and R9 are selected, independently, from the group consisting of H and halide;
R3 is selected from the group consisting of -arylR ¹⁴ R ¹⁵ and heteroarylR ¹⁴ R ¹⁵ ;
R ⁶ is selected from the group consisting of H, - (C1-9 alkyl) narylR ¹³ , and - (C1-9 alkyl) nheteroarylR ¹³ ;
each R ¹⁰ is independently selected from the group consisting of H, -C1-9 alkyl, -CF3, - (C1-9 alkyl) ncarbocyclyl, - (C1-9 alkyl) nheterocyclyl, - (C1-9 alkyl) narila and - (C1-9 alkyl) nheteroaryl;
each R ¹² is selected, independently, from the group consisting of -OR ¹⁰ and R ¹⁰ ;
each R ¹³ has 1 to 5 substituents, each selected from the group consisting of H, C 1-9 alkyl and halide;
R ¹⁴ is selected from the group consisting of NR ¹⁰ C (= A) R ¹⁰ , -NR ¹⁰ SO2R ¹⁰ , -NR ¹⁰ C (= O) N (R ¹⁶ ) 2, NR ¹⁰ C (= NR ¹² ) N ( R ¹⁰ ) 2, -C (= O) NR ¹⁰ R ¹⁷ , -C (= NR ¹² ) N (R ¹⁰ ) 2, and NR ¹⁰ C (= A) OR ¹⁰ ;
R ¹⁵ has 1 to 4 substituents, each selected from the group consisting of H, C1-9 alkyl, halide, and -CF3;
Petition 870190110431, of 10/30/2019, p. 6/15
[2]
2/6
R ¹⁶ is -C1-9 alkyl;
each R ¹⁷ is independently selected from the group consisting of -heterocyclyl R ¹³ , - (C 1-9 alkyl) heterocyclyl R ¹³ and - (C 1-9 alkyl) carbocyclyl R ¹³ ;
each A is selected, independently between O and S;
Y ¹ , Y ² , and Y4 are carbon;
Y ³ is nitrogen and R8 is absent; and each n is 0 or 1;
each alkyl, as used here alone or as part of another group, refers to a branched or straight chain containing 1 to 3 or 1 to 9 carbon atoms, which can be unsubstituted or substituted with one or more substituents, selected from halide, alkoxy, amino, amide, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl and heteroaryl;
each aryl, as used here alone or as part of another group, refers to an aromatic radical that has a single ring or multiple 6 to 10 membered condensed rings, which can be substituted or unsubstituted with one or more selected amino substituents , cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halide and mercapto;
each heteroaryl, as used here alone or as part of another group, refers to a 5- to 10-membered aromatic radical, having one or more hetero atoms in the ring framework, selected from N, O, or S, and may include a ring single or multiple condensed rings, which can be unsubstituted or substituted by one or more substituents selected from mino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxyl, nitro, halide and mercapto;
each heterocyclyl, as used here alone or as part of another group, refers to a 5- to 7-membered cyclic ring system that comprises at least one heteroatom in the framework
Petition 870190110431, of 10/30/2019, p. 7/15
[3]
3/6 of the ring system selected from O, N, or S, and can have any degree of saturation as long as at least one ring of the ring system is not aromatic; and can be substituted or unsubstituted with one or more substituents selected from alkyl, halide, alkoxy, acyloxy, amino, starch, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, and heteroaryl;
each carbocyclyl, as used here alone or as part of another group, refers to a cyclic ring system containing 3 to 10 carbon atoms, which can be unsubstituted or substituted with one or more substituents selected from alkyl, halide, alkoxy, acyloxy, amino, starch, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, and heteroaryl; and each halo or halide, as used here alone or as part of another group, refers to chlorine, bromine, fluorine or iodine atoms.
2. Compound according to claim 1, characterized by the fact that R ¹ , R ² and R4 are H and R ³ is selected,
regardless of the group consisting of -arylR ¹⁴ R ¹⁵ and - heteroarylR ¹⁴ R ¹⁵ .3. Compound in wake up with Any of them of claims 1 or 2, featured fur fact that R ³is -
heteroarylR ¹⁴ R ¹⁵ .
[4]
A compound according to any one of claims 1 to 3, characterized in that the heteroaryl is a pyridine.
[5]
Compound according to any one of claims 1 to 4, characterized in that R ¹⁴ is NHC (= O) R ¹⁰ and R ¹⁰ is selected from the group consisting of -C1-9 alkyl, carbocyclyl, aryl and - (C 1-9 alkyl) aryl.
[6]
6. A compound according to any one of claims 1 to 4, characterized by the fact that ^R14 is C (= O) NHR ^17, R ¹⁷ is - (1-9C alkyl) carbociclilR ¹³ and R ¹³ is H.
Petition 870190110431, of 10/30/2019, p. 8/15
4/6
[7]
7. A compound according to any umadas claims 1 to 6, characterized by the fact that R ⁶ is selected from the group consisting of H, arylating ¹³ and R ¹³ is heteroaryl.
[8]
A compound according to any one of claims 1 to 6, characterized in that R ⁶ is phenylR ¹³ and R is halide.
[9]
9. Compound according to claim 1, characterized by the fact that it has a structure selected from the group consisting of:

Petition 870190110431, of 10/30/2019, p. 9/15
5/6

or a pharmaceutically acceptable salt thereof.
[10]
Pharmaceutical composition characterized by the fact that it comprises a compound as defined in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
[11]
11. Use of a compound as defined in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, characterized in that it is for the preparation of a medicament for the treatment of a disorder or disease, wherein the disorder or disease is selected from the group consisting of diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, psoriasis, viral or mycotic infection, a bone or cartilage disease, Alzheimer's disease, osteoarthritis and cancer.
[12]
12. Use according to claim 11, characterized by the fact that the disorder or disease is selected from the group consisting of intestinal polyposis, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-melia syndrome, virilization and Müllerian duct regression, SERKAL syndrome, type 2 diabetes mellitus, Fuhrmann syndrome,
Petition 870190110431, of 10/30/2019, p. 10/15
6/6 Al-Awadi / Raas-Rothschild / Schinzel focomelia, odontoonic-dermal dysplasia, obesity, ectrodactyly, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anomalies, defects of the autosomal recessive neural tube, alpha-thalassemia syndrome (ATRX), fragile X syndrome, ICF syndrome, Angelman syndrome, PraderWilli syndrome, Beckwith-Wiedemann syndrome and Rett syndrome.

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法律状态:
2016-09-13| B25A| Requested transfer of rights approved|Owner name: SAMUMED, LLC (US) |

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2016-10-04| B25G| Requested change of headquarter approved|Owner name: SAMUMED, LLC (US) Free format text: ALTERADA ENDERECO DO TITULAR CONFORME REQUERIDO NA PETICAO 020130062359 DE 16/07/2013. |

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2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-04-24| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-05-07| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2019-08-06| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|

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2019-12-17| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-02-18| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 09/08/2010, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US23260309P| true| 2009-08-10|2009-08-10|

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US61/232,603|2009-08-10|

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US30545910P| true| 2010-02-17|2010-02-17|

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US61/305,459|2010-02-17|

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PCT/US2010/044872|WO2011019651A1|2009-08-10|2010-08-09|Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof|

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