NZ622483B2 - Indazole-3-carboxamides and their use as wnt/b-catenin signaling pathway inhibitors - Google Patents

Indazole-3-carboxamides and their use as wnt/b-catenin signaling pathway inhibitors Download PDF

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NZ622483B2
NZ622483B2 NZ622483A NZ62248312A NZ622483B2 NZ 622483 B2 NZ622483 B2 NZ 622483B2 NZ 622483 A NZ622483 A NZ 622483A NZ 62248312 A NZ62248312 A NZ 62248312A NZ 622483 B2 NZ622483 B2 NZ 622483B2
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NZ622483A (en
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John Hood
Sunil Kumar Kc
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Priority claimed from PCT/US2012/055172 external-priority patent/WO2013040215A1/en
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Publication of NZ622483B2 publication Critical patent/NZ622483B2/en

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Abstract

Provided are indazole-3-carboxamide derivative compounds of the general formula (I), wherein the variables are as defined in the specification. Examples of the compounds include 5-(Pyridin-3-yl)-N-(pyridin-4-yl)-1H-indazole-3-carboxamide and N-(6-carbamoylpyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide. The compounds are Wnt/?-catenin signalling pathway inhibitors and may be useful in the treatment of various diseases associated with the aforementioned pathway including cancer. idin-3-yl)-1H-indazole-3-carboxamide. The compounds are Wnt/?-catenin signalling pathway inhibitors and may be useful in the treatment of various diseases associated with the aforementioned pathway including cancer.

Description

INDAZOLE—S-CARBOXAMIDES AND THEIR USE AS WNT/B-CATENIN SIGNALING PATHWAY INHIBITORS RELATED APPLICATIONS Cross—Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 61/534,601, filed September 14, 2011, and U.S. Provisional Application No. 61/624,646, filed April 16, 2012, which are incorporated herein by reference in their entirety.
BACKGROUND OF THE INVENTION Field of the Invention This invention relates to the field of therapeutic oncology. More particularly, it concerns the use of an indazole-3—carboxamide compound or salts or s thereof, in the treatment of cancer, particularly colon, ovarian, atic, breast, liver, te and hematologic s.
Description of the Related Art Pattern formation is the activity by which embryonic cells form ordered spatial arrangements of entiated tissues. Speculation on the mechanisms underlying these patterning s usually centers on the secretion of a signaling molecule that elicits an appropriate response from the tissues being patterned. More recent work aimed at the identification of such signaling molecules implicates secreted proteins encoded by individual members of a small number of gene families.
A anding idea in cancer biology is that cancers arise and grow due to the formation of cancer stem cells, which may constitute only a minority of the cells within a tumor but are nevertheless critical for its propagation. Stem cells are appealing as the cell of origin for cancer because of their pre—existing capacity for self— renewal and for unlimited" ation. In addition, stem cells are relatively long-lived in comparison to other cells within s, providing a greater opportunity to accumulate the multiple additional ons that may be required to increase the rate of cell eration and produce clinically significant cancers. Of particular recent interest in the origin of cancer is the observation that the Wnt signaling pathway, which has been ated in stem cell self-renewal in normal s, upon continuous activation has also been associated with the initiation and growth of many types of cancer. This pathway thus provides a potential link n the normal self—renewal of stem cells and the aberrantly regulated proliferation of cancer stem cells.
The Wnt growth factor family includes more than 10 genes fied in the mouse and at least 19 genes identified in the human. Members of the Wnt family of signaling molecules mediate many important short-and long-range patterning processes during invertebrate and vertebrate development. The Wnt signaling pathway is known for its important role in the ive interactions that regulate growth and differentiation, and plays important roles in the homeostatic maintenance of post—embryonic tissue integrity. Wnt stabilizes cytoplasmic B-catenin, which stimulates the sion of genes including c-myc, c jun, fra—l, and cyclin D1. In addition, misregulation of Wnt signaling can cause developmental'defects and is implicated in the genesis of several human s. More recently, the Wnt pathway has been implicated in the maintenance of stem or progenitor cells in a growing list of adult tissues that now includes skin, blood, gut, prostate, muscle and the nervous system.
Pathological activation of the Wnt pathway is also believed to be the initial event leading to colorectal cancer in over 85% of all sporadic cases in the Western world. Activation of the Wnt pathway has also been extensively reported for hepatocellular oma, breast cancer, ovarian cancer, pancreatic cancer, mas, mesotheliomas, lymphomas and leukemias. In addition to cancer, inhibitors of the Wnt pathway can be used for stem cell ch or for the treatment of any diseases characterized by aberrant Wnt activation such as diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma as well as mycotic and viral infections and bone and cartilage diseases. As such, it is a eutic target that is of great interest to the field.
In addition to cancer, there are many cases of genetic diseases due to mutations in Wnt signaling components. Examples of some of the many diseases are Alzheimer's disease [Proc Natl. Acad. Sci. U S A (2007), 104(22), 9434-9], osteoarthritis, polyposis coli ce (1991), 253(5020), 665—669], bone density and vascular defects in the eye porosis-pseudoglioma syndrome, OPPG) [N. Engl. J Med. (2002), 346(20), 1513-21], familial exudative vitreoretinopathy [Hum Mutat. (2005), 26(2), 104—12], retinal angiogenesis [Nat Genet. (2002), 32(2), 326-30], early coronary e [Science (2007), 315(5816), 1278-82], tetra-amelia syndrome [Am J.
Hum Genet. (2004), 74(3), 558-63], Mullerian-duct regression and virilization [Eng]. J Med. (2004), 351(8), 792—8], SERKAL syndrome [Am J. Hum Genet. (2008), 82(1), 39- 47], diabetes mellitus type 2 [Am J Hum Genet. , 75(5), 832-43; N. Engl. J. Med (2006), 355(3), 241-50], Fuhrmann syndrome [Am J Hum Genet. (2006), 79(2), 402-8], Al-Awadi/Raas—Rothschild/Schinzel phocomelia syndrome [Am J. Hum Genet. (2006), 79(2), 402-8], odonto-onycho—dermal dysplasia [Am J. Hum Genet. (2007), 81(4), 821— 8], obesity tologia (2006), 49(4), 678—84], hand/foot malformation [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 , 12), 642-5], skeletal dysplasia [Nat Genet. (2009), 41(1), 95—100], focal dermal hypoplasia [Nat Genet. (2007), 39(7), , autosomal recessive anonychia [Nat Genet. (2006), 38(11), 1245~7], neural tube defects [N. Eng]. J.
Med (2007), 356(14), 1432—7], alpha—thalassemia (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 cience (2006), 26(20), 5383-5392], Beckwith—Wiedemann Syndrome tric and Developmental Pathology (2003), 6(4), 299-3 06] and Rett syndrome. tion of cell ing by the Wnt signaling pathway is critical for the formation of neuronal circuits. Wnt pathway modulates in neural tissue, among other things, axon pathfinding, dendritic development, and synaptic assembly. Through different receptors, Wnt pathway activates and/or regulates diverse signaling pathways and other processes that lead to local changes on the cytoskeleton or global cellular changes involving nuclear function. Recently, a link n neuronal activity, essential for the formation and refinement of neuronal connections, and Wnt signaling has been red. Indeed, neuronal activity regulates the e of various Wnt proteins and the zation of their receptors. Wnt pathway mediates synaptic structural s induced WO 40215 2012/055172 by neuronal activity or experience. Evidence suggests that dysfunction in Wnt signaling contributes to neurological disorders [Brain Research Reviews (2000), 33(1), 1—12; Oncogene (2006) 25(57), 7545-7553; Molecular Neurodegeneration (2008), 3, 9; Neurobiology of Disease (2010), 38(2), 148—153; Journal of Neuroa’evelopmental Disorders , 3(2), 162—174 and Cold Spring Harbor Perspectives in Biology February (2012), 4(2)].
SUMMARY OF THE INVENTION The present invention makes available s and reagents, involving contacting a cell with an agent, such as an aromatic compound, in a sufficient amount to antagonize Wnt activity, e. g., to reverse or control an aberrant growth state or correct a genetic disorder due to mutations in Wnt signaling components.
Some embodiments disclosed herein include Wnt inhibitors containing an indazolecarboxamide core. Other embodiments disclosed herein include ceutical itions and methods oftreatment using these compounds.
One ment disclosed herein includes a nd having the structure of a I: 0 / R4 NH R2 N/ In some embodiments of formula (1): R1, R2 and R4 are independently selected from the group consisting of H, C1_9 alkyl, halide, -N(R1°)2, —XR1°, CN, oer3 and -CF3; R3 is selected from the group consisting of carbocyclle6, heterocyclle6, arle6 and heteroarle6', with the proviso that when R3 is heteroaryl, the heteroaryl is not selected from the group consisting of isoquinoline, 1H—pyrrolo[2,3-c]pyridine and tetrazole; 2012/055172 R5 is selected from the group consisting of ~(C1_9 ncarbocyclle7, —(C1_9 alkyl)nheterocyclle7, -(C1-9 alkyl)narle7 and -(C1_9 alky1)nheteroarle7; with the proviso that R5 is not 4-pyridle7 when R1, R2 and R4 are H, R3 is selected from the group consisting of 3-pyridle6, 4-pyridle6, 2—pyridle6, phenle6, o NQLNHZ i“ 9 P | leR6, imidazoleR6, pyrimidineR6, oxazoleRG, N/ *9‘/No 9‘; Sgt?/ o N/ / CI N/ and N and R6 and R7 are both H. a , with the proviso that R5 is not —(CH2)(3-pyridyl)R7 when R1, R2 and R4 are H, R3 is selected from the group consisting of 3-pyridle6, 4—pyridle6 and thiazoleR6, and R6 and R7 are both H; with the proviso that R5 is not phenle7 when R1, R2 and R4 are H, R3 is 4- pyridle6 and R6 and R7 are both H; with the proviso that R3 is not 3-pyridle6 when R1, R2 and R4 are H, R5 is EQON/0N\ /ass LLL QR”X/0 selected from the group ting of phenle7, W9 (21,09,909 L32 Cl 191;,9*°" 19K ,99 7 o\ /o i9, and , 9 , 599F and R6 and R7 are both H; with the proviso that R3 is not oxazoleR6 when R1, R2 and R4 are H, R5 is selected from the group consisting of c“ and and R6 is H; , , With the proviso that R3 is not thiazoleR6 when R1, R2 and R4 are H, R5 is selected from the group ting of and \/, and R6 is H; each R6 is 1-5 substituents each selected from the group consisting of H, C1_9 alkyl, halide, amino, 001:3, -CF3, -CN, —XR1°, {01-9 alkyl)ncarbocyclle8, -(C1-9 alkyl)nheterocyclle3, -(C1_9 alkyl)narle8, -(C1_9 alkyl)nheteroarle3, -C(=O)R“, - N(R10)C(=O)R”, -(C1_9 alkyl)nN(R10)2, —(C1_9 alkyl)nN(R10)SOzR11 and -S02R”; each R7 is 1—5 substituents each selected from the group consisting of H, C1_9 alkyl, , amino, -OCF3, -CF3, -CN, -XR10, -(C1_9 alkyl)ncarbocyclle9, —(c1_9 alky1)nheterocyclle9, -(C1.9 alkyl)narle9, {01-9 alkyl)nheteroarle9, -C(=O)R”, - N(R1°)C(=O)R”, -(C1_9 alkyl)nN(R10)z, -(c1_9 alkyl)nN(R10)SOgR11 and -SOZR11; each R8 is 1-5 substituents each selected from the group consisting of H, C1_3 alkyl, halide, amino, ocrg, -CF3 —CN, -XR12, —C(=O)R13, -N(R12)C(=O)R13, -(C1_9 alkyl)nN(R12)2, -(C1-9 nN(R12)SOgRl3 and -SOZR13; each R9 is 1—5 substituents each selected from the group consisting of H, C1_3 alkyl, halide, amino, -OCF3, —cr3 -CN, -XR12, R13, -N(R12)C(=O)R13, -(C1_9 alkyl)nN(R12)2, -(C1_9 alkyl)nN(R12)SOZR13 and —s02R13; each R10 is independently selected from the group consisting ofH, C1_9 alkyl, -(C1_ 9 alkyl)nN(R14)2, —(c1_9 alkyl)ncarbocyclle8, -(C1_9 alkyl)nheterocyclle8, {01-9 alkyl)narle8 and —(C1_9 alky1)nheteroarle8; each R11 is independently ed from the group consisting of C1_9 alkyl, - N(R14)2, {01-9 alkyl)ncarbocyclle8, —(cl_9 alkyl)nheterocyclle8, —(c1_9 alkyl)narle8 and -(C1_9 alkyl)nheteroarle8; each R12 is independently selected from the group consisting of H, C1.9 alkyl, —(C1_ 9 alkyl)nN(R14)2, -(C1_9 alkyl)ncarbocyclyl, -(C1_9 alky1)nheterocyclyl, ~(C1_9 alkyl)naryl and -(C1_9 alkyl)nheteroaryl; each R13 is ndently ed from the group consisting of C1_9 alkyl, — N(R14)2, -(C1_9 alkyl)ncarbocyclyl, -(C1_9 alkyl)nheterocyclyl, —(C1_9 alkyl)naryl and —(c1_9 alkyl)nheteroaryl; each R14 is independently selected from the group consisting of H, C1-3 alkyl, carbocyclyl and aryl; 2012/055172 each X is ed from the group consisting of a bond, and -S-; and eachnis 0 or 1.
Some embodiments include stereoisomers and pharmaceutically acceptable salts of a compound of general formula (I).
Some embodiments include pro-drugs of a compound of general formula (I).
Some embodiments of the t invention include pharmaceutical compositions comprising a compound of general formula (I) or in a pharmaceutically acceptable carrier, diluent, or excipient.
Other embodiments disclosed herein include methods of inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins by administering to a subject affected by a disorder or disease in which aberrant Wnt signaling is ated, such as cancer and other diseases associated with abnormal angiogenesis, ar proliferation, cell cycling and mutations in Wnt signaling components, a nd according to formula (1). Accordingly, the compounds and compositions provided herein can be used to treat , to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation and correct a genetic disorder due to mutations in Wnt signaling components. Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, pulmonary is, rheumatoid arthritis, derma, mycotic and viral infections, osteochondrodysplasia, Alzheimer’s disease, lung disease, osteoarthritis, polyposis coli, osteoporosis—pseudoglioma syndrome, familial exudative retinopathy, retinal angiogenesis, early coronary disease, tetra-ameliasyndrome, Mullerian-duct regression and zation, SERKAL syndrome, diabetes mellitus type 2, nn syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto—onycho-dermal sia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader— Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.
Some embodiments of the present invention e methods to e a compound of general formula (I).
It is to be tood 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 Compositions and methods for inhibiting one or more members of the Wnt pathway, including one or more Wnt proteins would be of tremendous benefit.
Certain embodiments provide such compositions and methods.
Some embodiments relate to a method for treating a disease including, but not limited to, cancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderrna, mycotic and viral infections, bone and cartilage diseases, Alzheimer’s disease, lung disease, osteoarthritis, polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma me, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Mullerian- duct regression and zation, SERKAL syndrome, type II diabetes, Fuhimann syndrome, Al-Awadi/Raas—Rothschjld/Schinzel phocomelia syndrome, odonto-onycho- dermal dysplasia, obesity, split—hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal ive anonychia, neural tube defects, alpha-thalassemia (ATRX) me, fragile X syndrome, ICF syndrome, an's syndrome, Prader-Willi syndrome, Beckwith— Wiedemann Syndrome, Norrie disease and Rett syndrome.
In some embodiments, pharmaceutical compositions are provided that are effective for treatment of a disease of an , e.g., a mammal, caused by the ogical activation or mutations of the Wnt pathway. The composition includes a pharmaceutically able carrier and a Wnt y inhibitor as described .
Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly tood by one of ordinary skill in the art to which this sure belongs. All patents, ations, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
In this specification and in the claims, the following terms 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, ethyl, n—propyl, isopropyl, n—butyl, yl, sec-butyl and pentyl. Alkyl groups can either be unsubstituted or tuted with one or more substituents, e. g., halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group. Alkyl groups can be saturated or unsaturated (e.g., containing -C=C- or -CEC- subunits), at one or several positions. Typically, alkyl groups will comprise l to 9 carbon atoms, preferably 1 to 6, more preferably 1 to 4, and most preferably 1 to 2 carbon atoms.
As used herein, “carbocyclyl” means a cyclic ring system containing only carbon atoms in the ring system backbone, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls may include le fused rings. Carbocyclyls may have any degree of saturation ed that at least one ring in the ring system is not aromatic. Carbocyclyl groups can either be unsubstituted or substituted with one or more tuents, e.g., alkyl, halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the ion, with a protecting group. Typically, carbocyclyl groups will comprise 3 to 10 carbon atoms, preferably 3 to 6.
As used herein, “lower alkyl” means a subset of alkyl having 1 to 3 carbon atoms, and thus is a hydrocarbon substituent, which is linear, or branched.
Examples of lower alkyl e methyl, ethyl, 11-propyl and isopropyl. se, radicals using the terminology “lower” refer to radicals preferably with l to about 3 carbons in the alkyl portion of the radical.
As used herein, “amido” means a H-CON— or CON—, carbocyclyl—CON-, aryl-CON—, aryl~CON— or cyclyl-CON group wherein the alkyl, carbocyclyl, aryl or heterocyclyl group is as herein described.
As used , “aryl” means an aromatic radical having a single-ring (e.g., phenyl) or multiple sed rings (e.g., yl or anthryl) with only carbon atoms present in the ring ne. Aryl groups can either be unsubstituted or substituted with one or more substituents, e.g., alkyl, amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents. A preferred carbocyclic aryl is phenyl.
As used herein, the term “heteroaryl” means an aromatic radical having one or more heteroatom(s) (e.g., N, O, or S) in the ring backbone and may include a single ring (e.g., pyridine) or multiple sed rings (e.g., quinoline). Heteroalyl groups can either be unsubstituted or substituted with one or more substituents, e.g., amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, adiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3 idinyl, quinazolinyl, quinolinyl, thieno[2,3- c]pyridinyl, pyrazolo[3,4—b]pyridinyl, pyrazolo[3,4—c]pyridinyl, pyrazolo[4,3-c]pyridine, lo[4,3—b]pyridinyl, tetrazolyl, and others.
In these definitions it is y contemplated that substitution on the aryl and heteroaryl rings is within the scope of certain embodiments. Where tution 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. Though many substituents will be useful, preferred substituents include those commonly found in aryl compounds, such as alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo, haloalkyl, mercapto and the like.
As used , “amide” includes both RNR’CO— (in the case of R = alkyl, alkaminocarbonyl-) and RCONR’- (in the case ofR = alkyl, alkyl carbonylamino-).
As used herein, the term “ester” includes both ROCO- (in the case of R = alkyl, alkoxycarbonyl-) and RCOO- (in the case ofR = alkyl, alkylcarbonyloxy-).
As used herein, "acyl" means an H—CO- or alkyl-CO-, carbocyclyl- CO-, aryl-CO—, heteroaryl-CO— or heterocyclyl-CO- group wherein the alkyl, carbocyclyl, aryl or heterocyclyl group is as herein described. Preferred acyls contain a lower alkyl.
Exemplary alkyl acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, t—butylacetyl, butanoyl and palmitoyl.
As used herein, "halo”, “halide” or “halogen” is a chloro, bromo, fluoro or iodo atom radical. Chloro, bromo and fluoro are preferred halides. Most preferred halide is fluorine.
As used herein, "haloalkyl" means a hydrocarbon substituent, which is linear or ed or cyclic alkyl, alkenyl or alkynyl substituted with , bromo, fluoro or iodo atom(s). Most preferred of these are fluoroalkyls, wherein one or more of the hydrogen atoms have been substituted by fluoro. Preferred haloalkyls are of l to about 3 carbons in length, more preferred haloalkyls are 1 to about 2 carbons, and most preferred are 1 carbon in length. The d n will recognize then that as used herein, lkylene" means a diradical variant of haloalkyl, such diradicals may act as spacers n radicals, other atoms, or between the parent ring and r functional group.
As used herein, “heterocyclyl” means a cyclic ring system sing at least one heteroatom in the ring system backbone. Heterocyclyls may include multiple fused rings. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. Heterocyclyls may be substituted or unsubstituted with one or more substituents, e.g., alkyl, halide, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, y, carbonyl, benzyloxy, aryl, heteroaryl, and other substituents, and are attached to other groups via any available valence, preferably any available carbon or nitrogen. More preferred heterocycles are of 5-7 s. In six membered clic heterocycles, the heteroatom(s) are selected from one up to three of O, N or S, and wherein when the heterocycle is five membered, preferably it has one or tw0 heteroatoms selected from O, N, or S. Examples of heterocyclyl include azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, 1,4,2—dithiazolyl, 1,3—benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, oindolyl, dihydropyridinyl, 1,3—dioxanyl, 1,4-dioxanyl, oxolanyl, isoindolinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, yl, thiazinyl, thiinyl, thiazolidinyl, azolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl, rpholinyl, and others.
As used herein, “substituted amino” means an amino l which is substituted by one or two alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl groups, wherein the alkyl, aryl, heteroaryl or heterocyclyl are defined as above.
As used herein, “substituted thiol” means RS— group wherein R is an alkyl, an aryl, heteroaryl or a heterocyclyl group, wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are defined as above.
As used herein, “sulfonyl” means an alkylSOz, arylSOz, heteroarylSOz, carbocyclylSOz, or heterocyclyl—$02 group wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl are defined as above.
As used herein, ”sulfamido" means an alkyl-N-S(O)2N—, aryl-NS(O)2N-, heteroaryl—NS(O)2N—, yclyl—NS(O)2N or heterocyclyl-NS(O)2N— group wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl group is as herein described.
As used herein, "sulfonamido" means an alkyl—S(O)2N-, aryl-S(O)2N-, heteroaryl-S(O)2N-, carbocyclyl-S(O)2N- or heterocyclyl-S(O)2N— group wherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl group is as herein described.
As used herein, o" means an alkyl-NCON-, aryl—NCON—, heteroaryl—NCON- , carbocyclyl-NCON— or heterocyclyl-NCON— group wherein the alkyl, yclyl, aryl, heteroaryl or heterocyclyl group is as herein described.
As used herein, when two groups are indicated to be “linked” or “bonded” to form a “ring,” it is to be understood that a bond is formed between the two groups and may involve replacement of a hydrogen atom on one or both groups with the bond, y g a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring. The skilled artisan will recognize that such rings can and are readily formed by routine chemical reactions, and it is within the pulview of the skilled artisan to both envision such rings and the methods of their formations. Preferred are rings having from 3-7 members, more preferably 5 or 6 members. As used herein the term “ring” or “rings” when formed by the ation oftwo radicals refers to heterocyclic, yclic, aryl, or heteroaryl rings.
The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical ures, even when kinetically; the artisan recognizes that such ures are only a very small portion of a sample of such compound(s). Such compounds are clearly contemplated within the scope of this invention, though such resonance forms or tautomers may not be explicitly represented herein.
The compounds provided herein may encompass various chemical forms. The compounds also encompasses diastereomers as well as optical isomers, e.g. mixtures of enantiomers including racemic mixtures, as well as individual omers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Separation of the individual isomers or selective synthesis of the dual s is accomplished by application of various s which are well known to practitioners in the art. Unless ise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.
The term “administration” or “administering” refers to a method of giving a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian, where the method is, e. g., orally, subcutaneously, intravenously, intranasally, topically, ermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, ly, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, leurally, via wound irrigation, intrabuccally, intra-abdominally, articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonaly cavities, intraspinally, intrasynovially, intrathoracically, Via thoracostomy irrigation, epidurally, ympanically, isternally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic devices. The preferred method of administration can vary depending on various factors, e. g, the components of the pharmaceutical composition, the site of the disease, the disease involved, and the severity of the disease.
A “diagnostic” as used herein is a compound, method, system, or device that assists in the identification and terization of a health or disease state.
The diagnostic can be used in standard assays as is known in the art.
The term “mammal” is used in its usual biological sense. Thus, it specifically includes humans, , , dogs, and cats, but also includes many other species.
The term aceutically acceptable carrier” or “pharmaceutically acceptable ent” es any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and tion delaying agents and the like which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art.
Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. In addition, various nts such as are commonly used in the art may be included. These and other such compounds are bed in the ture, e. g. in the Merck Index, Merck & Company, Rahway, NJ.
Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds) (2010); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 12th Ed. The McGraw—Hill Companies.
The term “pharmaceutically able salt” refers to salts that retain the biological effectiveness and properties of the compounds of the preferred embodiments and, which are not biologically or otherwise undesirable. In many cases, the compounds of the preferred embodiments are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and WO 40215 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, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived e, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and ry amines, tuted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and lamine. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., hed September 11, 1987 porated by nce herein).
“Solvate” refers to the compound formed by the interaction of a solvent and a Wnt y tor, a metabolite, or salt thereof. Suitable es are pharmaceutically acceptable solvates including hydrates.
“Subject” as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non—human primate or a bird, e. g. , a chicken, as well as any other vertebrate or invertebrate.
By “therapeutically ive amoun ” or “pharmaceutically effective ” is one 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.
“Therapeutically effective amount” is also intended to include one or more of the nds of formula (I) in combination with one or more other agents that are effective to inhibit Wnt related diseases and/or conditions. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and y, Advances in Enzyme Regulation (1984), 22, 27-55, occurs when the effect of the nds when administered in combination is greater than the additive effect of the compounds when stered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. It will be appreciated that different concentrations may be employed for prophylaxis than for ent of an active disease. This amount can further depend upon the t’s , weight, sex, age and medical history.
A therapeutic effect relieves, to some extent, one or more of the symptoms of the disease, and includes curing a disease. g” means that the symptoms of active disease are eliminated. However, certain long—term or permanent effects of the disease may exist even after a cure is obtained (such as extensive tissue damage).
“Treat,” “treatment,” 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 y suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of ms, postponing or preventing the further development of a disorder and/or reducing the severity of symptoms that will or are expected to develop.
Compounds The compounds and compositions described herein can be used as anti—proliferative agents, e.g., anti-cancer and anti-angiogenesis agents, and as inhibitors of the Wnt signaling pathway, e.g., for ng diseases or disorders ated with aberrant Wnt signaling. In addition, the compounds can be used as inhibitors of one or more kinases, kinase receptors, or kinase complexes. Such compounds and itions are also useful for controlling cellular proliferation, differentiation, and/or apoptosis.
Some embodiments of the present ion include compounds, salts, ceutically acceptable salts or pro-drug thereof of formula (I): O / R4 NH R2 N In some embodiments of formula 1, R1, R2 and R4 are independently selected from the group consisting of H, C1_9 alkyl, halide, -N(R10)2, -XR10, CN, -OCF3 and -CF3.
In some embodiments of formula I, R3 is selected from the group consisting of carbocyclle6, heterocyclle6, arle6 and heteroarle6.
In some embodiments of formula I, when R3 is heteroaryl, the aryl is not ed from the group consisting of isoquinoline, IH-pyrrolo[2,3— c]pyridine and tetrazole.
In some embodiments of formula I, R5 is selected from the group consisting of -(c1_9 alkyl)ncarbocyclle7, -(c1_9 alkyl)nhete1‘ocyclle7, —(c1_9 alkyl)narle7 and ~(C1_9 alkyl)nheteroarle7.
In some embodiments of formula I, R5 is not dle7 when R1, R2 and R4 are H, R3 is selected from the group consisting of 3—pyridle6, 4—pyridle6, 2- e6, phenle6, thiazoleR6, imidazoleRG, pyrimidineR6, oxazoleR6, N/ o n N/ Er NH2 F 6% /0 [ m a For QO \ w N / /N N/ rid N/ / o /N o l I N\ \ \ '16 H N \ UK; u \ Ls? l | N/ N/ CI N/ d N/ and R6 and R7 are both , , , In some embodiments of formula I, R5 is not (3-pyridyl)R7 when R1, R2 and R4 are H, R3 is selected from the group consisting of dle6, 4- pyridle6 and thiazoleR6, and R6 and R7 are both H.
In some embodiments of formula I, R5 is not phenle7 when R1, R2 and R4 are H, R3 is 4-pyridle6 and R6 and R7 are both H.
In some embodiments of formula I, R3 is not 3—pyridle6 when R1, R2 and R4 are H, R5 is selected from the group consisting of phenle7, 3 2 2 :01? 303% 0”” Mi7,00 if” r1: ct; cm Mg? m i; and Seng and R6 and R7 are both H.
In some embodiments of formula I, R3 is not oxazoleR6 when R1, R2 and R4 are H, R5 is selected from the group ting of c“ and R6 is H.
In some embodiments of formula I, R3 is not thiazoleR6 when R1, R2 R4 R5 \/ and are H, is selected from the group consisting of V©V and IDVNV, and R6 is H.
In some ments of formula I, each R6 is 1—5 substituents each selected from the group consisting of H, C1_9 alkyl, halide, amino, -OCF3, —CF3, -CN, - XRIO, —(c1_9 alkyl)ncarbocyclle8, {01-9 alkyl)nheterocyclle8, {01-9 alky1)narle8, —(c1_9 alkyl)nheteroarle8, -C(=O)R“, -N(R10)C(=O)R”, -(c1_9 alkyl)nN(R10)2, -(c1_9 alky1)nN(R10)SO;gR“ and -SOZR“.
In some embodiments of formula I, each R7 is 1—5 tuents each ed from the group consisting of H, C1-9 alkyl, halide, amino, -OCF3, -CF3, -CN, - XRIO, -(C1.9 ncarbocyclle9, -(C1_9 alkyl)nheterocyclle9, —(C1_9 alkyl)narle9, —(C1_9 alkyl)nheteroarle9, -C(=O)R“, -N(R1°)C(=O)R“, —(c1_9 alkyl)nN(R10)2, ~(C1_9 alkyl)nN(R10)SOZR“ and -SOZR“.
In some embodiments of formula I, each R8 is 1-5 substituents each selected from the group consisting of H, C1_3 alkyl, , amino, OCF3, -CF3 -CN, — XRIZ, —C(=O)R13, —N(R12)C(=O)Rl3, -(C1_9alkyl)nN(R12)2, -(C1_9 alkyl)nN(R12)SozR13 and -SOzR13.
In some embodiments of formula I, each R9 is 1-5 substituents each selected from the group consisting of H, C1_3 alkyl, halide, amino, ~0CF3, ~CF3 ~CN, - XRIZ, -C(=O)R13, )C(=O)Rl3, -(C1_9alkyl)nN(R12)2, —(c1_9 alkyl)nN(R12)SOZR13 and -SOZR13.
In some embodiments of formula I, each R10 is independently selected from the group consisting of H, C1.9 alkyl, -(C1.9 alkyl)nN(R14)2, —(C1.9 alkyl)ncarbocyclle8, -(C1-9 alky1)nheterocycly1R8, -(C1_9 alkyl)nary1R8 and —(C1_9 alkyl)nheteroarle8.
In some embodiments of a I, each R11 is independently selected from the group consisting of C1_9 alkyl, —N(R14)2, —(C1_9 alkyl)ncarbocyclle8, -(C1_9 alkyl)nheterocyclle8, —(C1_9 alkyl)narle8 and -(C1_9 alkyl)nheter0arle8.
In some embodiments of formula I, each R12 is independently selected fiom the group consisting of H, C1-9 alkyl, —(C1-9 alkyl)nN(R14)2, -(C1.9 alkyl)ncarbocyclyl, -(C1_9 alkyl)nheterocyclyl, -(C1_9 alkyl)naryl and ~(C1_9 nheteroary1.
In some embodiments of formula I, each R13 is independently selected from the group consisting of C1_9 alkyl, -N(R14)2, -(C1_9 alkyl)ncarbocyclyl, —(C1_9 alky1)nheterocyclyl, -(C1_9 alky1)naryl and —(C1_9 nheteroaryl.
In some ments of formula I, each R14 is independently selected from the group consisting ofH, C1_3 alkyl, carbocyclyl and aryl.
In some embodiments of formula I, each X is selected from the group consisting of a bond, —0— and -S-.
In some embodiments of fomiula I, each n is 0 or 1.
WO 40215 In some embodiments of fonnula I, X is O.
In some embodiments of formula I, R1, R2 and R4 are H.
Some embodiments of the present invention include compounds, salts, ceutically acceptable salts or pro-drug thereof of formula (Ia): 0 / In some embodiments of formula Ia, R3 is selected from the group consisting of arle6 and heteroarle6.
In some embodiments of formula Ia, When R3 is heteroaryl, the heteroaryl is not selected from the group consisting of isoquinoline, 1H-pyrrolo[2,3— c]pyridine and tetrazole.
In some ments of formula Ia, R5 is selected from the group consisting of ~carbocyc1le7, -heterocyclle7, ~arle7, -heter0arle7, and —(C1_2 alkyl)heteroarle7.
In some embodiments of formula Ia, R5 is not 4—pyridle7 when R3 is selected from the group consisting of dle6, 4-pyridle6, 2-pyridle6, phenle6, o HQLNHZ leR6, imidazoleR6, pyrimidineRfi, oxazoleRc", N/ 45% (r:o @1673/ o N/ / on N/ and N and R6 and R7 are both H.
, , In some embodiments of formula Ia, R5 is not —(CH2)(3-pyridyl)R7 when R3 is ed from the group consisting of 3-pyridle6, 4-pyridle6 and thiazoleR6, and R6 and R7 are both H.
In some ments of formula Ia, R5 is not phenle7 when R3 is 4- pyridle6 and R6 and R7 are both H.
In some embodiments of formula Ia, R3 is not 3-pyridle6 when R5 is U Dv selected from the group consisting of phenle7 3 W o 001$?‘0 r1“ 302qu ”1 CI o o cf em“’1 re43* Joe 55)n F and FeIf ,and R6 and R7 are both H.
In some embodiments of formula Ia, R3 is not oxazoleR6 when R5 is selected from the group consisting of C” and R6 is H.
In some embodiments of formula Ia, R3 is not thiazoleR6 when R5 is aDan ande/©\/N\/ 6- selected from the group consisting of ,and R is H.
In some ments of formula Ia, each R6is 1-2 substituents each selected from the group consisting of H, C1_3 alkyl, halide, amino, -OCF3, —CF3, —CN, — ORIO, -(C1_2 alkyl)heterocyclles, -heterocyclle8, -(C1_2 alkyl)arle8, —C(=O)R11, - N(R1°)C(=O)R“ and -(c1_2 a1kyl)N(R10)2.
In some embodiments of formula Ia, each R7 is 1-2 substituents each selected from the group consisting of H, C1_3 alkyl, halide, amino, -OCF3, -CF3, -CN, — ORIO, ~(C1-2 alkyl)heterocycly1R9, —heterocyclle9, —arle9, -(C1_2 alkyl)arle9, — C(=0)R“, -N(R1°)C(=0)R“, -N(R1°)2, -(C1_2 alky1)N(R10)2, —N(R10)SO2R“ and ~SO2R”.
In some embodiments of a Ia, each R8 is 1-2 tuents each selected from the group consisting of H, C1_3 alkyl, halide, amino, OCF3, -CF3 ~CN and - OR”.
In some embodiments of a Ia, each R9 is 1—2 substituents each selected from the group consisting of H, C1_3 alkyl, halide, amino, -OCF3, -CF3 MCN and - OR”.
In some embodiments of a Ia, each R10 is independently selected from the group consisting of H, C1_3 alkyl, -(C1-3 alkyl)N(R14)2 and -arle8.
In some embodiments of formula Ia, each R11 is independently selected from the group consisting of C1-3 alkyl, -N(R14)2, -carbocyclle8 and ~ heterocyclleg.
In some embodiments of formula Ia, each R12 is independently selected from the group consisting of H and C1_3 alkyl.
In some embodiments of formula Ia, each R14 is independently selected from the group consisting of H, C1_3 alkyl and yclyl.
In some embodiments of formula I or formula Ia, halide is fluorine.
In some embodiments of formula I or formula Ia, R3 is —arle6.
In some embodiments of formula I or formula Ia, R3 is oarle6.
In some embodiments of formula I or formula Ia, R5 is —arle7.
In some embodiments of formula I or formula Ia, R5 is —heteroarle7.
In some embodiments of formula I or formula Ia, R5 is — heterocyclle7.
In some embodiments of formula I or formula Ia, R3 is oarle6 and R5 is —heteroarle7.
In some embodiments of a I or formula Ia, R3 is —phenle6 and R5 is —heteroarle7.
In some embodiments of formula I or formula Ia, R3 is —heteroary1R6 and R5 is —phenle7.
In some embodiments of formula I or a Ia, R3 is idle6 and R5 is —3 -pyridle7.
In some embodiments of formula I or formula Ia, R3 is —3-pyridle6 and R5 is -pyridle7.
In some embodiments of formula I or formula Ia, R3 is —3—pyridle6 and R5 is -pyridazinle7.
In some embodiments of formula I or formula Ia, R3 is —3-pyridle6 and R5 is —pyrazinle7.
In some embodiments of formula I or formula Ia, R3 is ~3—pyridle6 and R5 is ~ pyrimidinle7.
In some embodiments of formula I or formula Ia, R3 is —3-pyridle6 and R5 is benzo[d][l,3]dioxolyl.
In some embodiments of formula I or formula Ia, R3 is —3—pyridle6 and R5 is 2,3-dihydrobenzo[b][1,4]dioxinyl.
In some ments of formula I or a Ia, the aryl is phenyl.
In some embodiments of formula I or formula Ia, when R3 is heteroaryl, the heteroaryl is 3-pyridyl.
In some embodiments of formula I or a Ia, when R5 is heteroaryl, the heteroaryl is 3-pyridyl.
In some embodiments of formula I or formula Ia, when R5 is heteroaryl, the heteroaryl is 5-pyrimidinyl.
] In some embodiments of formula I or formula Ia, when R5 is heteroaryl, the heteroaryl is 4-pyridazinyl.
In some embodiments of formula I or formula Ia, when R5 is heteroaryl, the heteroaryl is lyl.
In some ments of formula I or formula Ia, when R5 is aryl, the heteroaryl is benzo[d][1,3]dioxolyl.
] In some embodiments of formula I or formula Ia, when R5 is heteroaryl, the heteroaryl is 2,3-dihydrobenzo [b][l,4]dioxinyl.
In some ments of formula I or formula Ia, R6 is a heterocyclyl.
For example, the heterocyclyl can be selected from the group consisting of morpholinyl, piperazinyl, dinyl, ydropyranyl, azetidinyl and pyrrolidinyl. In n embodiments, R6 is morpholinyl. In another embodiment, R6 is piperazinyl. In another embodiment, R6 is piperidinyl. In another embodiment, R6 is pyrrolidinyl.
In some embodiments of formula I or formula Ia, R7 is a heterocyclyl.
For example, the heterocyclyl can be selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, azetidinyl and pyrrolidinyl. In certain embodiments, R7 is morpholinyl. In another embodiment, R7 is piperazinyl. In another embodiment, R7 is piperidinyl. In another embodiment, R7 is pyrrolidinyl. In another ment, R7 is azetidinyl.
In some embodiments of formula I or formula Ia, R10 is a carbocyclyl.
For example, the carbocyclyl can be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R10 is cyclopropyl. In r embodiment, R10 is cyclobutyl. In another embodiment, R10 is cyclopentyl. In another embodiment, R10 is cyclohexyl.
In some embodiments of formula I or formula Ia, R11 is a heterocyclyl.
For example, the cyclyl can be selected from the group consisting of morpholinyl, piperazinyl, dinyl, tetrahydropyranyl, azetidinyl and pyrrolidinyl. In certain embodiments, R11 is morpholinyl. In another embodiment, R11 is zinyl. In another embodiment, R11 is piperidinyl. In another embodiment, R11 is pyrrolidinyl. In another embodiment, R11 is azetidinyl.
In some embodiments of a I or formula Ia, R11 is a carbocyclyl.
For example, the yclyl can be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R11 is cyclopropyl. In another embodiment, R11 is utyl. In another embodiment, R11 is cyclopentyl. In another embodiment, R11 is cyclohexyl.
In some embodiments of a I or formula Ia, R12 is a carbocyclyl.
For example, the yclyl can be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R12 is cyclopropyl. In r embodiment, R12 is cyclobutyl. In another ment, R12 is cyclopentyl. In another embodiment, R12 is cyclohexyl.
In some embodiments of formula I or formula Ia, R13 is a heterocyclyl.
For e, the heterocyclyl can be selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, azetidinyl and pyrrolidinyl. In certain embodiments, R13 is morpholinyl. In r embodiment, R13 is piperazinyl. In another embodiment, R13 is piperidinyl. In another embodiment, R13 is pyrrolidinyl. In another embodiment, R13 is azetidinyl.
In some embodiments of formula I or fo1mula Ia, R13 is a carbocyclyl.
For example, the carbocyclyl can be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain ments, R13 is cyclopropyl. In another embodiment, R13 is cyclobutyl. In r embodiment, R13 is cyclopentyl. In another embodiment, R13 is cyclohexyl.
] In some embodiments of formula I or formula Ia, R6 is one substituent.
] In some embodiments of formula I or formula Ia, R6 is 1—2 substituents.
In some embodiments of a I, R6 is 1-3 substituents.
In some embodiments of formula I, R6 is 1-4 substituents.
In some embodiments of formula I or formula Ia, R6 is H.
In some embodiments of formula I or formula Ia, R6 is one substituent and the substituent is a halide.
] In some embodiments of formula I or formula Ia, R6 is one substituent and the substituent is —NH2.
In some embodiments of formula I or formula Ia, R6 is one substituent and the substituent is -OCF3.
In some embodiments of formula I or formula Ia, R6 is one substituent and the substituent is -OCH3.
In some embodiments of formula I or formula Ia, R6 is one tuent and the substituent is -CF3.
In some embodiments of f01mu1a I or formula Ia, R6 is one substituent and the substituent is —heterocyc1y1R8.
In some ments of formula I or formula Ia, R6 is one substituent and the substituent is —(CH2)heterocyclle8.
In some embodiments of formula I or formula Ia, R6 is one substituent and the substituent is —(CH2)pyrrolidinle8.
In some embodiments of formula I or formula Ia, R6 is one substituent and the tuent is —(CH2)pyrrolidinle8 Where R8 is two substituents and both tuents are halides.
In some embodiments of formula I or formula Ia, R6 is one substituent and the substituent is piperidinle8.
In some embodiments of formula I or formula Ia, R6 is one substituent and the tuent is —(CH2)phenle8.
In some embodiments of formula I or formula IaIR6 is one substituent and the substituent is — phenoxng.
In some ments of formula I or a Ia, R6 is one substituent and the substituent is 1“ In some embodiments of formula I or a Ia, R6 is one substituent and the substituent is )2.
In some embodiments of formula I or formula Ia, R6 is one substituent and the substituent is -N(R10)2 where each R10 is independently selected from C1_3 alkyl.
In some embodiments of formula I or formula Ia, R6 is one substituent and the substituent is —(CH2)N(R10)2.
In some embodiments of formula I or formula Ia, R6 is one substituent and the substituent is —(CH2)N(R10)2 where each R10 is independently selected from C1.3 alkyl.
In some embodiments of formula I or formula Ia, R6 is one substituent and the substituent is -N(R10)SOZR11.
] In some embodiments of formula I or formula Ia, R6 is one substituent and the substituent is -N(R10)C(=O)R“.
In some embodiments of formula I or formula Ia, R6 is one substituent and the substituent is -N(R10)C(=O)R11 where R11 is a cyclyl.
In some embodiments of formula I or formula Ia, R6 is one tuent and the substituent is -N(R10)C(=O)R11 where R11 is a carbocyclyl.
In some embodiments of formula I, R6 is two substituents and the substituents are e and —(C1_9 alkyl)nhete1‘ocyclle8.
In some embodiments of formula Ia, R6 is two substituents and the substituents are fluorine and -heterocyclle8.
In some ments of formula Ia, R6 is two substituents and the substituents are fluorine and —(C1.2 alkyl)heterocyclle8.
In some embodiments of formula I or formula Ia, R6 is one substituent and the substituent is select from the group consisting of JQOKEEEBCXC9, l Sm1WULFU U WE 1 HQ In some embodiments of formula I or formula Ia, R7 is one substituent.
In some embodiments of formula I or formula Ia, R7 is 1—2 substituents.
In some embodiments of formula I, R7 is 1-3 substituents.
In some embodiments of formula I, R7 is 1-4 substituents.
In some embodiments of fonnula I or formula Ia, R7 is one substituent and the substituent is a halide.
In some embodiments of formula I or formula Ia, R7 is one substituent ' and the substituent is ~NH2.
In some embodiments of a I or formula Ia, R7 is one substituent and the substituent is —-OH.
In some embodiments of formula I or formula Ia, R7 is one substituent and the substituent is -CF3.
In some embodiments of a I or formula Ia, R7 is one substituent and the substituent is ~CN.
WO 40215 In some ments of formula I, R7 is one substituent and the substituent is —XR10 where X is O and R10 is C1_3 alkyl.
In some embodiments of formula Ia, R7 is one tuent and the substituent is -OR10 and R10 is C1_3 alkyl.
In some embodiments of formula I or formula Ia, R7 is one substituent and the substituent is —phenle9.
In some embodiments of formula I or formula Ia, R7 is one substituent and the substituent is —(CH2)N(R10)2.
In some embodiments of formula I or formula Ia, R7 is one substituent and the substituent is —(CH2)N(R10)2 Where each R10 is independently selected from C1_3 alkyl.
In some embodiments of formula I or formula Ia, R7 is one substituent and the substituent is ~(CH2)heterocyclle9.
In some embodiments of f01mula I or formula Ia, R7 is one substituent and the tuent is —(CH2)pyrrolidinle9.
In some embodiments of formula I or formula Ia, R7 is one substituent and the substituent is —heterocyclle9.
In some embodiments of formula I or formula Ia, R7 is one substituent and the substituent is —— phenoxng.
In some embodiments of formula I or a Ia, R7 is one tuent and the substituent is —-(CH2)phenle9.
In some embodiments of formula I or formula Ia, R7 is one substituent and the substituent is —phenle9.
] In some ments of formula I or formula Ia, R7 is one substituent and the substituent is -N(R1°)C(=0)R“.
In some ments of formula I or formula Ia, R7 is one substituent and the substituent is —N(R10)C(=O)R11 Where R11 is a carbocyclyl.
In some embodiments of formula I or formula Ia, R7 is one substituent and the substituent is -N(R10)2.
In some embodiments of formula I or formula Ia, R7 is one substituent and the substituent is -C(=O)R11 where R11 is select from the group consisting of ~ heterocyclle8 and )2.
In some embodiments of formula I or formula Ia, R7 is one substituent and the substituent is -S02R11.
In some embodiments of formula I or formula Ia, R7 is one substituent and the substituent is -SO;R”; and R11 is C1_3 alkyl.
In some embodiments of formula I or formula Ia, R7 is two substituents and the substituents are C1_3 alkyl and ~heterocyclle9.
] In some embodiments of formula I or formula Ia, R7 is one substituent and the tuent is select from the group consisting of ] In some embodiments of formula I or formula Ia, R8 is one substituent.
] In some embodiments of formula I or formula Ia, R8 is 1—2 substituents.
In some embodiments of formula I, R8 is 1-3 substituents.
In some embodiments of formula I, R8 is 1-4 substituents.
In some embodiments of formula I or fomiula Ia, R8 is H.
In some embodiments of formula I or formula Ia, R8 is one substituent and the tuent is C13 alkyl.
In some embodiments of formula I or formula Ia, R8 is one substituent and the substituent is —OH.
In some embodiments of formula I or formula Ia, R8 is one substituent and the tuent is a halide.
In some embodiments of formula I or formula Ia, R8 is two substituents and the substituents are halides.
] In some embodiments of formula I, R8 is three substituents and the substituents are halides.
In some embodiments of formula I or formula Ia, R9 is one tuent.
In some ments of formula I or formula Ia, R9 is 1-2 substituents.
In some embodiments of formula I, R9 is 1—3 substituents.
In some ments of a I, R9 is 1-4 substituents.
In some embodiments of formula I or a Ia, R9 is H.
In some embodiments of formula I or formula Ia, R9 is one substituent and the substituent is C13 alkyl.
In some embodiments of formula I or formula Ia, R9 is one tuent and the substituent is —OH.
In some ments of formula I or formula Ia, R9 is one substituent and the substituent is a halide.
In some embodiments of formula I or formula Ia, R9 is two substituents and the substituents are halides.
In some embodiments of formula I or formula Ia, R8 is a -C1_3 alkyl.
For example, the -C1-3 alkyl can be selected from the group consisting of methyl, ethyl, n— propyl and isopropyl. In certain embodiments, R8 is methyl. In another embodiment, R8 is ethyl . 2012/055172 In some embodiments of formula I or formula Ia, R10 is a —C1_3 alkyl.
For example, the -C1-3 alkyl can be ed from the group consisting of methyl, ethyl, n- propyl and iso-propyl. In certain ments, R10 is methyl. In another embodiment, R10 is ethyl. In another embodiment, R10 is yl. In r embodiment, R10 is iso- propyl.
In some embodiments of formula I or formula Ia, R11 is a -C1_3 alkyl.
For example, the -C1-3 alkyl can be selected from the group consisting of methyl, ethyl, n— propyl and opyl. In certain embodiments, R11 is methyl. In another embodiment, R11 is ethyl. In rembodiment, R11 is yl. In another embodiment, R11 is iso- propyl.
In some embodiments of a I or formula Ia, R14 is a -C1_3 alkyl.
For example, the -C1-3 alkyl can be ed from the group consisting of methyl, ethyl, n- propyl and iso-propyl. In certain embodiments, R14 is methyl. In another embodiment, R14 is ethyl. In another embodiment, R14 is yl. In another embodiment, R14 is iso- propyl.
In some embodiments of formula I or formula Ia, R3 is —3-pyridle6 and R5 is —3 -pyridle7; R6 is one substituent consisting of -(C1_2 alkyl)N(R10)2; and R7 is one substituent consisting of -CF3; and each R10 is -C1_3 alkyl.
In some embodiments of formula I or formula Ia, R3 is ~3-pyridle6 and R5 is —3—pyridle7; R6 is one substituent consisting of -(C1-2 alkyl)heterocyclle8; R7 and R8 are both H; and the heterocycle is a 5—member ring.
In some embodiments of formula I or formula 121, R3 is —3-pyridle6 and R5 is —3-pyridle7; R6 is one substituent consisting of -(C1_2 alkyl)heterocycly1R8; R7 and R8 are both H; and the heterocycle is a 6-member ring.
In some embodiments of formula I or formula Ia, R3 is —3-pyridle6 and R5 is —3—pyridle7; R6 is one substituent ting of -(C1-2 alkyl)heterocyclle8; R7 is one substituent consisting of CN; R8 is H; and the heterocycle is a 5-member ring.
In some embodiments of formula I or formula Ia, R3 is —3-pyridle6 and R5 is —3-pyridle7; R6 is one substituent consisting of —(C1_2 alkyl)heterocyclle8; R7 is one substituent consisting of CN; R8 is H; and the heterocycle is a 6—member ring.
In some embodiments of formula I or fomiula Ia, R3 is idle6 and R5 is idle7; R6 is one substituent consisting of —(C1_2 alkyl)heterocyclle8; R7 is one substituent consisting of CF3; R8 is H; and the heterocycle is a er ring.
In some embodiments of fonnula I or formula Ia, R3 is —3-pyridle6 and R5 is —3-pyridle7; R6 is one substituent consisting of —(C1_2 alkyl)heterocyclle8; R7 is one tuent consisting of -heterocyclle8; each R8 is H; and the heterocycles are independently selected from a 5 or 6-member ring.
] In some embodiments of formula I or formula Ia, R3 is —3-pyridle6 and R5 is —3-pyridle7; R6 is one substituent consisting of —(C1_2 alkyl)N(R10)2; and R7 is one tuent consisting of -CN; and each R10 is -C1.3 alkyl.
In some embodiments of formula I or formula Ia, R3 is —3-pyridle6 and R5 is idle7; R6 is one substituent consisting of -(C1_2 alkyl)N(R10)2; and R7 is one substituent consisting of —(C1_2 alkyl)heterocyclle8; R8 is H; each R10 is -C1_3 alkyl; and the heterocycle is a 6—member ring.
In some embodiments of formula I or formula Ia, R3 is —3—pyridle6 and R5 is ~3-pyridle7; R6 is one substituent consisting of -(C1-2 alkyl)heterocyclle8; R7 is one substituent consisting of -heterocyclle8; each R8 is one substituent independently selected from H and —OH; and the cycles are independently selected from a 5 or 6- member ring.
In some embodiments of fonnula I or formula Ia, R3 is —3-pyridle6 and R5 is ~3-pyridle7; R6 is one substituent consisting of -(C1_2 alkyl)heterocyclle8; R7 is one substituent consisting of -C(=O)R“; R11 is -heterocyclle8; each R8 is H; and the heterocycles are independently selected from a 5 or er ring.
In some embodiments of formula I or formula Ia, R3 is —3-pyridle6 and R5 is —3-pyridle7; R6 is one substituent consisting of -(C1_2 alkyl)heterocyclle8; R7 is one substituent consisting of —heterocyclle8; each R8 is 1-3 substituents independently selected from H and F with the proviso that at least one substituent on one heterocycle is fluorine; and each heterocycle is a 5-member ring.
] In some embodiments of formula I or formula Ia, R3 is —3-pyridle6 and R5 is idy1R7; R6 is one tuent consisting of -(C1_2 alky1)heterocyc1le8; R7 2012/055172 is one substituent consisting of -C(=O)Ru; R11 is -NHR10; R10 is heterocyclleS; each R8 is H; and the heterocycles are independently selected from a 5 or er ring.
In some ments of formula I or formula Ia, R3 is —3-pyridle6 and R5 is —3 -pyridy1R7; R6 is one substituent consisting of —(C1_2 alkyl)heterocyclle8; R,7 is one tuent consisting of -SOZR11; R8 is H; R11 is —C1_3 alkyl; and the heterocycle is a 6-member ring.
In some embodiments of formula I or formula Ia, R3 is —3-pyridy1R6 and R5 is —3-pyridle7; R6 is one substituent consisting of -(C1_2 alkyl)heterocyclle8; R7 is H; R8 is 1-4 substituents independently selected from H and F with the proviso that at least one substituent is fluorine; and the heterocycle is a 5—member ring.
Illustrative compounds of Formula (I) are shown in Table 1.
Table 1.
WO 40215 PCT/U52012/055172 / \N (I) C\N/ o WO 40215 PCT/U52012/055172 WO 40215 PCT/U52012/055172 WO 40215 PCT/U52012/055172 WO 40215 PCT/U52012/055172 WO 40215 PCT/U82012/055172 100 101 103 104 106 107 109 110 112 113 WO 40215 PCT/U52012/055172 WO 40215 PCT/U82012/055172 WO 40215 PCT/U52012/055172 WO 40215 PCT/U82012/055172 WO 40215 PCT/U82012/055172 WO 40215 PCT/U82012/055172 WO 40215 PCT/U52012/055172 232 233 234 WO 40215 235 236 237 238 239 241 242 244 245 247 248 250 251 WO 40215 PCT/U82012/055172 253 254 255 257 258 260 261 263 264 265 266 267 268 269 270 WO 40215 PCT/U52012/055172 W0 40215 PCT/U82012/055172 O H /\N\© F FAQF /\N\© U /\NU 292 0\ 293 0 294 0 / / NH NH / NH l I I N\ N\ \ \/N \/N N] E E 0 n O H O IN! Q /\NU Q /\NU [N] /\NU 295 0 296 0 297 O /| NH /l NH /| N“ N\ N\ N\ \N \N \/N ° N ° 0 ° 0 ”L 0 0 C” 73 WAN” //\~ 73 V/km' ' //\~ 73 298 0 299 o 0 / l/ 300 NH NH /l NH “\{N ° H :10 //\~ U 301 302 303 o /| NH / \N 304 305 M: 306 q 0 / N: N\ l \/N N\ H J“ 307 308 309 310 311 312 WO 40215 PCT/U52012/055172 WO 40215 0 F 0 '0 ac / \ N N “oN / N 4’) 334 o d d 335 336 / N; o / N; I I NH N\ N\ \ \ N HIM NIN \/N \ )k / \N 339 T)“ 0 N; WO 40215 PCT/U52012/055172 HO “9 NW0 U / \ / \N 355 0 356 (I 0 357 NH G NH :{N N\ H N/ //\0 0 V PAC“F N / \ \b L” 358 / o 359 NH 360 / NH q I N\ N\ \N N M &Nd /\N \ 367 / o N; 368 o 369 o / / / N; NJ ”” N NJ \ \ \ N \ N fl 3’“ N m 0/ 0’ FF N\// U /\N Q / \N O / \N 370 o N; 371 0 NH/ 372 0 / / / N: N\ I l \ N\ N\ ,(N 5N §N H N N H H //\N/ //\/ ”\J //\/ [o] N\’/N ”WM \ 0 / N \ \ i / / \N N N NH NH 373 / Vi / / 0 374 0 0 375 / 1/ / NH NH W I 1 l N N\ N\ \ \ \/N N’N NN N H H WO 40215 PCT/U52012/055172 //\N/ Nu / / HO ”QM I / \N o U 376 377 0 NH/ 378 o & / / N: I 8 N\ N\ \N \IN E” E "Q N/ FflF / \N 379 380 381 0 / NH 382 383 384 N/ , N/ \ \ Vi / \N 385 386 387 0 / NH 388 389 390 / \N 391 392 393 / / NH WO 40215 PCT/U52012/055172 N/ N/ \N///\ FF \Nf\ PgF \ 394 395 C”\ U 396 C" 0 0 /! NH /l NH N\ N\ \ \N 397 399 400 402 #9 C /l NH INI/ \Nf \ CL w 403 405 o /l NH 406 408 409 411 WO 40215 PCT/U52012/055172 412 413 414 415 416 417 418 419 420 ”NJ \ N \N 421 422 C 423 / NH ‘\ \ ”"f \ 0 / \N 424 425 N / 426 / NH “NJ \ | ° \ \N \N 427 C” 428 \TJKNH g 429 VAN" O 0 O Q / NH /l NH /| NH N\I M N\ N N ”/N N/ “HI WO 40215 PCT/U52012/055172 430 431 432 433 / 434 435 436 437 438 439 440 441 442 443 444 / :N 445 446 447 WO 40215 PCT/U82012/055172 “O \ N / N 448 449 451 EN1 452 0 Q" 454 VAN“ @" 455 / NH (fiN) <1 / /"\ 457 o 458 / NH (ON) / \N 460 / 461 / NH 463 / 464 WO 40215 PCT/U82012/055172 WO 40215 PCT/U52012/055172 WO 40215 PCT/U82012/055172 WO 40215 523 524 526 527 529 530 532 533 535 536 538 539 541 542 WO 40215 544 / 545 546 / a o / NH / ‘ NH N \ | H N/ O 0Q 09 547 Cr 548 594 1in QM /1 ONH /] N\ N\ \N \N V/(‘LNH / /\ G1 :N 550 0 551 552 0 / NH / NH ”\I ”\I /N \/N N N H H O‘< > F 0‘< : Ck / \N CLO Q / \N 553 o N; 554 o / N; 555 / / N: N N\ \ N\] \N 5 :~ .( u H u U- i F / \ FAQ" \ 556 557 NH: C”\ 558 C” N\| O \ /| N/l "\ \ \ EN F 00 0© \ \ / ” 559 560 561 Q / 0 g” NH / ‘ NH N\ l \ N\ /N \ u ”x" 0 0© O/Ci [N] g” O \ \ 562 563 564 Win“ C" O 0 / / NH NH ‘ | N\ N\ N [N WO 40215 565 VAN” / / 566 568 569 571 572 574 575 577 578 580 581 WO 40215 PCT/U82012/055172 WO 40215 PCT/U52012/055172 (N1 /\~ 604 605 606 / / NH o o \ i / \N / \N 607 608 T N“ / 609 VJkNH / / NH EN / \N ()1! / \N 610 / 611 612 / o 0 / NH / NH N\ N\ \/N \/N E N 613 614 615 U / \N O / \N / 617 618 616 / o o ”/1 NH / NH “\l/N N\ H N EN] o ON “0”” 619 620 621 ON 0 o / NH /l NH N\ N\ \N \/N WO 40215 PCT/U52012/055172 WO 40215 WO 40215 PCT/U82012/055172 WO 40215 PCT/U52012/055172 WO 40215 PCT/U52012/055172 WO 40215 PCT/U52012/055172 WO 40215 PCT/U82012/055172 742 743 745 746 748 749 751 752 754 755 757 758 WO 40215 PCT/U82012/055172 WO 40215 781 782 784 785 787 788 790 791 793 794 796 797 WO 40215 o/\° \N/H\NH 799 Q / 800 802 803 805 806 808 809 811 812 814 815 817 818 WO 40215 PCT/U52012/055172 820 821 0 / NH 822 823 824 N/ N“ I 825 826 827 828 829 830 831 832 833 834 Ham/’0 F 0 V FAG: / \N / NH 835 836 / 837 o N\ / NH N l N/ \ Com ound re aration The starting materials used in ing the compounds of the invention are known, made by known methods, or are cially available. It will be apparent to the skilled artisan that methods for preparing precursors and functionality. related to the compounds claimed herein are generally described in the literature. The skilled n given the literature and this disclosure is well equipped to prepare any of the compounds.
It is recognized that the skilled artisan in the art of organic chemistry can readily carry out manipulations without fin‘ther direction, that is, it is well within the scope and ce of the skilled artisan to carry out these manipulations. These include ion of carbonyl compounds to their corresponding alcohols, ions, acylations, aromatic tutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. These manipulations are sed in standard texts such as March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 6th Ed., John Wiley & Sons (2007), Carey and Sundberg, Advanced Organic Chemistry 5th Ed., Springer (2007), Comprehensive Organic Transformations: A Guide to Functional Group Transformations, 2Ild Ed., John Wiley & Sons (1999) (incorporated herein by reference in its entirety) and the like.
The skilled artisan will y appreciate that n reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these lations can be found for example in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007), incorporated herein by reference in its entirety.
To further illustrate this invention, the following examples are ed. The es should not, of course, be construed as specifically ng the invention. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled n, armed with the present disclosure, and skill in the art is able to e and use the invention without exhaustive examples.
Trademarks used herein are examples only and reflect illustrative materials used at the time of the invention. The skilled artisan will recognize that variations in lot, cturing processes, and the like, are expected. Hence the examples, and the trademarks used in them are non—limiting, and they are not intended to be limiting, but are merely an illustration of how a d artisan may choose to perform one or more ofthe embodiments of the invention. (1H) nuclear magnetic resonance spectra (NMR) were measured in the indicated solvents on a Bruker NMR ometer (Avance TM DRX300, 300 MHz for 1H or Avance TM DRXSOO, 500 MHZ for 1H) or Varian NMR spectrometer (Mercury 400BB, 400 MHZ for 1H). Peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. The peak multiplicities are denoted as follows, 5, singlet; d, doublet; t, triplet; q, quartet; ABq, AB quartet; quin, quintet; sex, sextet; sep, septet; non, nonet; dd, doublet of doublets; d/ABq, doublet of AB quartet; dt, doublet of triplets; td, triplet of doublets; m, multiplet.
The following abbreviations have the indicated meanings: brine = saturated aqueous sodium chloride CDCl3 = deuterated chloroform DCE = dichloroethane DCM = dichloromethane DHP = opyran DIPEA = diisopropylethylamine DMF = methylformamide 6 = deuterated dimethylsulfoxide ESIMS = electron spray mass spectrometry EtOAc = ethyl acetate EtOH = ethanol h = hour HATU = 2-(1Hazabenzotriazoly1)-1,1,3,3—tetramethyluronium orophosphate HCl = hydrochloric acid HOAc = acetic acid H2804 = sulfuric acid iPrOH = opyl alcohol KOAc = potassium e K3PO4 = potassium phosphate LAH = lithium aluminum e mCPBA = meta-Chloroperoxybenzoic acid MeOH = methanol MgSO4 = magnesium sulfate min. = minute MW = microwave NaBH(OAc)3 = sodium triacetoxyborohydride NaHCO3 = sodium onate NaHSO3 = sodium bisulfite NaHSO4 = sodium bisulfate NaOH = sodium hydroxide NH4OH = ammonium hydroxide NMR = nuclear magnetic nce Pd/C = palladium(0) on carbon PdC12(dppf)2 = 1,1'~bis(diphenylphosphino)ferrocene]palladium(II) chloride Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0) 3)4 = tetrakis(triphenylphosphine)palladium(0) PPTS = pyridinium p-toluenesulfonate r.t. = room temperature satd. = saturated sol”. = solution Reflx. = heated to reflux TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography Tr-Cl = trityl chloride or nylmethyl chloride The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds provided herein. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. The skilled artisan is thoroughly equipped to prepare these compounds by those methods given the literature and this sure. The compound numberings used in the synthetic schemes depicted below are meant for those c schemes only, and should not be construed as or confused with same numberings in other ns of the application. Unless otherwise indicated, all variables are as defined above.
General procedures Compounds of Formula I of the t invention can be prepared as depicted in Scheme 1.
”W 0 O R4 N R4 N/ R4 N/ CO H2 <\,l‘| HNJ \0/ j:Q,l\ i \0/ \N NHOMe(Me)*HCl, \N F39 0 0 CF; \N 2 N/ imidazole, DMF, 65°C 2 N/ 12, DCM, r.t.
R2 N/ R R H H H R1 R1 R1 H III w DHP,PPTS DCM, reflux 0 \/< /| \ LAH \ KOAc,PdCIz(dppf)2 /N THF 0°C R2 \ N N ’ DMF,90°C,2h R2 R1 R1 O O VII VI R3—Br K3P04 Pd(PPh3)4 H20,90°C,3h 0 / 4 4 R R R4 002“ NH CHO RS—NH R3 R3 7' R3 \N AgNO3, NaOH, H2 \N HATU. DIPEA \N / Dioxane, rt, overnight / DMF, rt, overnight / R2 N R2 N R2 N R1 R1 R1 0 o 0 VIII IX X TFA, DCM, Et3SiH, rt, 3 h 0 / R4 NH R2 N/ Scheme 1 Scheme 1 describes a method for preparation of indazole—3- carboxamide derivatives (1) by first forming the Weinreb amide (III) of a 1H—indazole—3- carboxylic acid (11). The Weinreb amide (III) is reacted with (bis(trifluoroacetoxy)iodo)benzene to e the 5-iodo-1H-indazole—3-carboxylic acid (IV) followed by THP protection of the indazole nitrogen. The b amide of protected indazole V is reduced to aldehyde VI followed by reaction with bis(pinacolato)diboron to give the pinacol ester (VII). Suzuki ng with a variety of aromatic and nonaromatic bromides yields the R3 substituted indazole VIII. Oxidation of the aldehyde to the acid (IX) followed by HATU mediated coupling of a variety of amines and sequent ection produces the desired indazolecarboxamide tives (I).
] Compounds of Formula I of the present invention can also be prepared as depicted in Scheme 2.
R4 R R COZH c02H COZR Br Br \ HOAc, Br2 \ ROH, H2804 \ N/N 90°C, 16 h N/N reflux, Elli 2 2 2 N/N R R R H H R = Me, Et H R1 R1 R1 II XI XII DHP, PPTS DCM, reflux R4 N/H R4 R4 cozH 002R Br Br Br \ R —NH2 \ NaOH,H20 \ 90°C, 1 h 2 N/N HATU DIPEA R ’ R2 N/N R2 N/N DMF, rt, overnight R1 R1 R1 0 O XV 'XIV XIII Route: 2 Route: 1 ‘B—B’ R3—“OH” 1. id bi 2 h , KOAc, PdCIz(dppf)2,DMF, 90°C, KOAc, PdClZ(dppf)2 DMF, 900C, 2 h 2. R3_Bl' 3 ll , K3PO4, Pd(PPh3)4,H20, 900C, ,R5 o R4 NH TFA DCM \N Et3SiH, rt, 3 h / R2 N x I Scheme 2 ] Scheme 2 describes an alternative method for preparation of indazole- 3-carboxamide derivatives (1) by bromination of the indazole tion followed by esterification to form ester XII. The le nitrogen is THP protected and the ester is hydrolyzed to acid XIV. The acid is coupled with a variety of amines to produce amide XV Which is then coupled with a variety of c acids (Route 1) to give X.
Alternatively, XV can be converted to the boronate ester and then couple to a variety of bromides (Route 2) to yield X. Final deprotection of the indazole nitrogen yields the desired indazolecarboxamide derivatives (I).
PCT/U82012/055172 Compounds of Formula I of the present invention can also be prepared as depicted in Scheme 3.
R4 R4 R fig“COZH COZH COZR Br Br HOAc, Br2 fig ROH, st04 \ \N / / | 90°C, 16 h reflux 4h /\ / 2 N 2 N ’ R R R2 N H H H R1 R1 R=Me, Et R1 H XI X” Route: 1 Tr—Cl, DMF Tr—Cl, DCM Route. 2_ TEA, l't DIPEA, 11 R4 R4 COZH COZR Br Br R —NH25 \ NaOH, H20 \ N N 90°C 1 h HATU, DIPEA ’ R2 N/ R2 N’ DMF, rt, overnight \ \ R1 TI' R1 TI' XVIII XVII XVI Route: 4 Route: 3 R _B(0H)23 1. O‘B—B/Ofi0' ‘o ,KOAc, PdClz(dppf)2 DMF, 90°C, 2 h KOAc, PdClz(dppf)2 DMF, 900C, 2 h 2. R3—Br 3 h , K3PO4, Pd(PPh3)4, H20, 900C, o R R4 NH TFA, DCM, \N Et3SiH, rt, 3 h / R2 N Scheme 3 Scheme 3 describes another alternative method for preparation of indazole—3~carboxamide derivatives (I) by ation of the indazole 5—position followed by either Route 1: esterification to form ester XII, then trityl protection of the indazole en and then finally hydrolyzed of the ester to acid XVII; or Route 2: trityl protection of the le nitrogen directly to acid XVII. The acid is coupled with a variety of amines to produce amide XVIII which is then coupled with a variety of 2012/055172 boronic acids (Route 3) to give XIX. Alternatively, XVIII can be converted to the boronate ester and then couple to a variety of bromides (Route 4) to yield XIX. Final deprotection of the indazole nitrogen yields the desired indazolecarboxamide derivatives (1). rative Com ound Exam les Preparation of intermediate romopyridiny1)—1,l-dimethylurea (XXII) is depicted below in Scheme 4. 0 N Br HZN Br l \ /N C1 Pyridine. _ Y i l + N / / \l(l)/ 0°C-609C, overnight N XX XXI XXII Scheme 4 Step 1 ] 3-Aminobromo pyridine (XX) (1.0 g, 5.78 mmol) was dissolved in pyridine and cooled to 0°C before adding dimethyl carbamyl chloride (XXI) (0.683 g, 6.35 mmol). The reaction mixture was stirred at room temperature for 2 h and then heated overnight at 60°C under argon. The solution was cooled to room temperature, poured into ice water and extracted with EtOAc. The organic extract was dried over MgSO4, filtered and concentrated to a residue to afford 3—(5-bromopyridin—3 ,1—dimethylurea (XXII) as a brown solid, (1.24 g, 5.09 mmol, 88% yield). 1H NMR (DMSO-dg) 8 ppm 8.67—8.64 (m, 2H), 8.23 (d, J = 7.8 Hz, 1H), 2.93 (s, 6H); ESIMS found for CngoBrN3O m/z 245.05(M+H).
The following intermediates were prepared in accordance with the procedure described in the above Scheme 4.
N-(5-bromopyridinyl)morpholine—4-carboxamide (XXIII): Tan solid (0.82 g, 48%). 1H NMR (DMSO—d6) 3.43-3.45 (m, 4H), 3.60-3.62 (m, 4H), 8.21 (t, J: 2.0 Hz, 1H), 8.26 (d, J: 2.0 Hz, 1H), 8.62 (d, J: 2.2 Hz, 1H), 8.91 (s, 1H); ESIMS found for C10H12BrN302 m/z 286 (M+H).
XXIV N—(5-bromopyridinyl)cyclopropanecarboxamide (XXIV): Off white solid, (83% yield), 1H NMR(CDC13, 400 MHz) 8 ppm .39 (m, 3H), 7.54 (bs, 1H), 1.56-1.50 (m, 1H), 1.13—1.07 (m, 2H), 0.96—0.90 (In, 2H); ESIMS found for C9H9BrN20 m/z 240.85 (M+H).
Preparation of intermediate (XXVI) is depicted below in Scheme 5.
OHC Br I HCl N/ NaBH(OAc)3 WBr\N TEA, DCE XXV XXVI Scheme 5 Step 1 To a on of 5—bromonicotinaldehyde (XXV) (5.0 g, 26.9 mmol) in DCE (108 mL) was added dimethylamine-HCI (4.39 g, 53.8 mmol) and TEA (7.5 g, 53.8 mmol). The reaction was stirred at room temperature for 1 h. NaBH(OAc)3 was added and the reaction was stirred overnight at room temperature. The on was diluted with DCM and sat. aq. NaHC03. The organic layer was separated, washed with water, brine, dried and concentrated under vacuum to produce l-(5-bromopyridin—3-yl)-N,N— dimethylmethanamine (XXVI) as a brown liquid (92.6% yield). 1H NMR (CDCl3) 8 ppm 2.15 (s, 6H), 3.43 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=2Hz, 1H), 8.59 (d, J=3Hz, 1H); ESIMS found for cm, 113er m/z 215 (MB‘79+H) and 217 (MBr81+H). 2012/055172 The following intermediates were prepared in accordance with the procedure bed in the above Scheme 5. 0mgN \ XXVII 3-Bromo(pyrrolidin—1~ylmethyl)pyridine (XXVII): Golden liquid (1.35 g, 97% yield). 1H NMR dg) 1.68-1.71 (m, 4H), 2.42—2.44 (m, 4H), 3.60 (s, 2H), 7.96 (s, 1H), 8.48 (d, J=2Hz, 1H), 8.58 (d, J=3Hz, 1H); ESIMS found for C10H13BI'N2 M/Z 242 (M+H).
OWE"l / N XXVIII 3-Bromo(piperidin—1-ylmethy1)pyridine (XXVIII): Brown liquid (13.1 g, 94% yield). 1H NMR (DMSO-d6) 1.36—1.39 (m, 2H), 1.46—1.51 (m, 4H), 2.31— 2.32 (m, 4H), 3.46 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=2Hz, 1H), 8.58 (d, J=3Hz, 1H); ESIMS found for C11H15BrN2 m/z 257 (M+H). 0ycmN/ XXIX 4—((5-Bromopyridin—3-yl)methyl)morpholine (XXIX): Brown oil (1.02 g, 35.6% yield). ESIMS found for C10H13BerO m/z 258 (M+H). 1-((5-Bromopyridin—3-y1)methy1)methylpiperazine (XXX): Brown oil (0.93 g, 64% yield). 1H NMR (DMSO-ds) 2.14 (s, 3H), 2.27-2.37 (m, 8H), 3.49 (s, 2H), 7.95 (s, 1H), 8.47 (d, J=1.7Hz, 1H), 8.59 (d, J=2.2Hz, 1H); ESIMS found for C11H16BrN3 m/z 272 (M+H).
XXXI 1-(3—Bromofluorobenzyl)~4~methylpiperazine (XXXI): Light yellow oil (2.07 g, 68% yield). 1H NMR dg) 2.14 (s, 3H), 2.28-2.40 (m, 8H), 3.46 (s, 2H), 7.15-7.17 (m, 1H), 7.35 (s, 1H), 7.40-7.42 (m, 1H); ESIMS found for C12H16B1'FN2 m/Z 288 (M+H).
HO N XXXII romopyridin—3-yl)piperidin—4-ol (XXXII): Brown oil (2.15 g, 7.93mmol, 72.7% . 1H NMR (DMSO-dg) 1.34-1.41 (m, 2H), 1.67—1.71 (m, 2H), 2.03—2.07 (m, 2H), 2.62-2.64 (m, 2H), 3.42-3.46 (m, 1H), 3.47 (s, 2H), 4.55 (d, J=4.2Hz, 1H), 7.93-7.94 (m, 1H), 8.46 (d, z, 1H), 8.58 (d, J=2.2Hz, 1H); ESIMS found for C11H15BI‘N20 m/z 272 (M+H).
F Pow\ Br XXXIII 3—Bromo-5 -((3 ,3 -difluoropyrrolidin—1~yl)methyl)pyridine (XXXIII): Brown liquid (7.38 g, 26.64 mmol, 94.9% yield). 1H NMR (DMSO'dfi) 2.21-2.30 (m, 2H), 2.70 (t, J=7Hz, 2H), 2.89 (t, J=13Hz, 2H), 3.66 (s, 2H), 7.95-7.98 (m, 1H), 8.57 (d, J=1.7HZ, 1H), 8.61 (d, J=2.2HZ, 1H); ESIMS found for C10H11BrF2N2 m/z 276 (M+H).
Preparation of 3-benzyl—5—bromopyridine (XXXVI) is depicted below in Scheme 6.
©/\ZnBr V BI' Br Br \ / ‘ PdC12(dppf)2, CuI l N/ THF,50 C0 \ XXXIV XXXVI Scheme 6 To a solution of 3,5—dibromopyridine (XXXIV) (1.03 g, 4.36 mmol) in THF (7 mL) under argon was added CuI (50 mg, 0.26 mmol) and PdC12(dppf)2 (178 mg, 0.22 mmol). Benzylzinc(II) bromide (XXXV) (0.5M in THF) (13.09 mL, 6.55 mmol) was slowly added by syringe. The reaction was heated at 50°C over the weekend. The reaction was quenched with water and extracted with EtOAc. The EtOAc was ted, washed with water, brine, dried over MgSO4 and concentrated under vacuum. The residue was purified on a silica gel column (100% hexanes —+ 5:95 hexanes) to afford ylbromopyridine (XXXVI) (0.614 g, 2.47 mmol, 57% yield) as a light brown oil. 1H NMR (DMSO-d6) 5 ppm 3.98 (s, 2H), 7.19-7.23 (m, 1H), .32 (m, 4H), 7.92-7.93 (m, 1H), 8.51 (d, J=2Hz, 1H), 8.54 (d, J=3Hz, 1H); ESIMS found for BrN m/Z 248 (M+H).
Preparation of 3-bromo—5-phenoxypyridine (XXXIX) is depicted below in Scheme 7.
VIII Br B' 0 \ CsCO3 / NMP, 100°C mBr\ N N XXXVII XXXIX Scheme 7 $212.1 To a solution of 3,5-dibromopyridine (XXXVII) (1.00 g, 4.24 mmol) in NMP (11 mL) was added phenol (XXXVIII) (398 mg, 4.24 mmol) and CsC03 (1.38 g, 4.24 mmol). The reaction was heated at 100°C over the weekend. The reaction was then partitioned between Et20/water. The EtZO was separated, washed with 2X water, brine, dried over MgSO4 and concentrated under vacuum. The residue was purified on a silica gel column (100% hexanes —+ 2:98 EtOAc:hexanes) to afford 3-bromo-5— phenoxypyridine (XXXIX) (535 mg, 2.14 mmol, 50% yield) as a clear oil. 1H NMR (DMSO—d6) 6 ppm .15 (m, 2H), 7.23-7.26 (m, 1H), 7.43-7.46 (m, 2H), 7.69-7.70 (1n, 1H), 8.37 (d, J=3Hz, 1H), 8.49 (d, J=2Hz, 1H); ESIMS found for C11HgBrNO m/z 250 (M+H). ation of l—(5—bromopyridinyl)methylpiperazine (XL) is depicted below in Scheme 8.
HNCN— Br Br Br \ \r‘ON K2C03,DMF / I ‘ N/ 120°C, overni htg \ I XL Scheme 8 To a solution of 3,5-dibromopyridine II) (2.90 g, 12.24 mmol) in dry DMF (20 mL) was added l—methylpiperazine (2.987 mL, 26.93 mmol) and K2C03 (5.58 g, 40.39 mmol). The reaction was heated at 120°C overnight. An additional portion of 1-methylpiperazine (6 mL) was added and heating was continued for another 24 h. The reaction was poured into ice water and filtered. The filtrate was extracted with 66% MeOH/CHC13. The organic layer was dried over MgSO4, filtered and concentrated under vacuum to yield l-(5—bromopyridin—3—yl)—4-methylpiperazine (XL) as a brown viscous oil (2.49 g, 9.76 mmol, 79.8% . ESIMS found for C10H14BrN3 m/z 256 (M+H).
The following intermediate was prepared in accordance with the procedure described in the above Scheme 8.
(JBr/ romopyridin-3 -yl)morpholine (XLI): Yellow solid (1.12 g, 4.61 mmol, 64.9% yield). ESIMS found for C9H11BrN2O m/z 244.1 (M+H).
Preparation of 5-bromo-N-cyclohexylnicotinamide (XLIV) is depicted below in Scheme 9.
NI-I2 XLIII ”020 Br \ HATU, DIPEA ONO N/ NJKEj/B XLII Scheme 9 Step 1 To a solution of 5-bromonicotinic acid (XLII) (500 mg, 2.49 mmol) in DMF (8 mL) was added cyclohexanamine (XLIII) (247 mg, 2.49 mmol) and DIPEA (643 mg, 4.98 mmol). The reaction was cooled at 0°C before adding HATU (947 mg, 2.49 mmol). The on was warmed to room temperature and stirred for 4 hrs. The reaction was diluted with EtOAc, washed with 2x water, brine, dried over MgSO4 and concentrated under vacuum to yield crude 5-bromo~N-cyclohexylnicotinamide (XLIV).
The t was used without further purification. ESIMS found for C12H15BrN20 m/z 283 (M+H).
Preparation of 3-br0mo-5—(((2R,6S)—2,6-dimethylpiperidin—lyl )methyl)pyridine (XLVII) is depicted below in Scheme 10.
OHC Br Br \ NaBH4 H0 \ ‘ ‘ MeOH N/ / XXV XLV 1. 4M HCl/dioxane 2. 5002 Br Br N \ ch03 Cl \ l I / MeCN, 80°C / N N XLVII XLVI Scheme 10 ] To a solution of 5-bromonicotinaldehyde (XXV) (2.05 g, 11.0 mmol) in MeOH (85 mL) was added NaBH4 (832 mg, 21.99 mmol). The reaction was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NH4C1 (5 mL). The reaction was concentrated under vacuum and the residue was partitioned between saturated aqueous NH4Cl/EtOAc. The organic layer was separated, washed with water, brine, dried over MgSO4 and concentrated under vacuum to yield crude (5- yridin-3—yl)methanol (XLV) as a golden oil (1.54 g, 8.2 mmol, 74% yield). The product was used without further purification. ESIMS found for C6H6BrNO m/z 188 (M+H).
Step 2 (5-Bromopyridin—3-yl)methanol (XLV) (1.54 g, 8.2 mmol) was d with 4M HCl in dioxane (10 mL) at 0°C and then evaporated. The e was dissolved in SOClz (4 mL) and refluxed for 2 hrs. The SOClz was removed and the residue was triturated with hexane to produce HCl salt of 3—bromo(chloromethyl)pyridine (XLVI) as a brown solid (1.30 g, 5.4 mmol, 66% yield). The product was used without further purification. ESIMS found for C6H5BrClN m/z 206 (M+H).
Step 3 To a solution of 3-bromo—5—(chloromethyl)pyridine (XLVI) (1.17 g, 4.8 mmol) in MeCN (0.2 mL) and )-2,6—dimethy1piperidine (2.6 mL, 19.3 mmol) was added K2C03 (667 mg, 4.8 mmol). The reaction was refluxed for 5 hrs. TLC showed the presence of starting maten'al so additional (2S,6R)—2,6—dimethylpiperidine (2.0 mL, 14.8 mmol) was added and the reaction was refluxed for an additional 5 hrs. The solvent was removed and the residue was partitioned between EtOAc/water. The EtOAc was separated and washed with brine, dried over MgSO4 and concentrated under . The residue was purified on a silica gel column (100% hexanes —> 6:94 hexanes) to afford 3-bromo—5-(((2R,6S)—2,6-dimethylpiperidin—1-yl)methyl)pyridine (XLVII) as a clear oil (728 mg, 2.57 mmol, 53% yield). 1H NMR (DMSO-dg) 5 ppm 0.92 (d, J=8Hz, 6H), 1.21-1.32 (m, 3H), 1.52—1.55 (m, 2H), .63 (m, 1H), 2.42-2.46 (m, 2H), 3.73 (s, 2H), 7.97—7.98 (m, 1H), 8.50 (d, J=3Hz, 1H), 8.55-8.56 (m, 1H); ESIMS found for BI‘N2 m/Z 283 (M+H).
Preparation of intermediate 3‘—fluorobiphenyl—3 ~amine (L1) is depicted below in Scheme 11.
XLIX Br “(l/i) OZNU 3 OZN ”2“ 0H -H2Pd/C- K3P04, Pd(PPh3)4, H20, EtOH, rt, 5 h Dioxane, MW, 95°C, 2h XLVIII Scheme 11 Step 1 A 25 mL microwave vessel was charged with 1-bromonitrobenzene (XLVHI) (0.61 g, 3.0 mmol), 3-fluorophenylboronic acid (XLIX) (0.46 g, 3.3 mmol), ium phosphate tribasic (0.95 g, 4.5 mmol), 1,4-dioxane (15.0 mL), and water (3.0 mL). Tetrakis(tripheny1phosphine)palladium(0) (0.17 g, 0.15 mmol) was added, and the reaction was placed in a microwave reactor for 1 h at 95°C. An additional 3- fluorophenylboronic acid (0.20 g) and tetrakis(triphenylphosphine)palladium(0) (0.05 g) were added, and the reaction was heated for another 1 h at 95°C in a ave reactor.
The organic solvent was separated from the water and concentrated to a residue. The e was then purified by flash chromatography using a 25 g Thomson normal phase silica gel cartridge (100% hexanes —> 1:99 EtOAczhexanes) to afford 3'—flu0r0-3— nitrobiphenyl (L) (0.63 g, 2.91 mmol, 97% yield) as a white solid. 1H NMR (DMSO—d6) ppm 8.48 (t, J: 2.0 Hz, 1H), 8.26—8.24 (m, 1H), 8.20-8.18 (m, 1H), 7.78 (t, J=8Hz, 1H), 7.70—7.68 (m, 1H), 7.67-7.65 (m, 1H), 7.59-7.56 (m, 1H), .28 (m, 1H).
Step2 10% Palladium on carbon (0.095g) was added to a solution of 3'— fluoronitrobiphenyl (L) (0.63 g, 2.88 mmol) in EtOH (20.0 mL). The flask was evacuated and replaced with a en atmosphere. The solution was stirred at room temperature for 5 h under hydrogen. The st was filtered through a pad of Celite, and the t was removed under reduced pressure. The e was purified by flash chromatography using a 40 g Thomson no1rna1 phase silica gel cartridge (100% hexanes —> 15:85 EtOAczhexanes) to afford 3'-flu0robiphenyl-3—amine (LI) (0.34 g, 1.81 mmol, 63% yield) as a light yellow oil. 1H NMR (DMSO—d6) 6 ppm .44 (m, 1H), 7.40— 7.39 (m, 1H), 7.36—7.33 (m, 1H), 7.15—7.14(m, 1H), 7.10 (t, J=7.7Hz, 1H), 6.85-6.84 (m, 1H), 6.80-6.79 (m, 1H), 6.60-6.58 (m, 1H), 5.18 (s, 2H); ESIMS found for CleloFN m/z 188 (M+H).
Preparation of ediate 5—(3-fluorophenyl)pyridin-3—amine (LIII) is depicted below in Scheme 12.
XLIX Br Hows/Q \ HZN l 6H N/ K3P04, Pd(PPh3)4, H20, N/ DMF, MW, 180°C, 1 h LII LIII Scheme 12 Step 1 To a ave vial was added 3-aminobromopyridine (LII) (0.400 g, 2.31 mmol), ophenyl boronic acid (XLIX) (0.356 g, 2.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.133 g, 0.116 mmol), potassium phosphate (0.736 g, 3.47 mmol), water (1 mL), and DMF (5 mL). The reaction Vial was capped, purged with argon and heated under microwave irradiation for 1 h at 180°C. The solution was filtered through a pad of Celite and concentrated under vacuum. The residue was purified by column chromatography (4:6 EtOAczhexanes —> 7:3 EtOAczhexanes) to afford the 5—(3—fluorophenyl)pyridinamine (LIII) (0.360 g, 1.92 mmol, 83% yield) as a yellow—white solid. ESIMS found for C11H9FN2 m/z 189.1 (M+H).
Preparation of intermediate 5—((dimethylamino)methyl)pyridin—3— amine (LVII) is depicted below in Scheme 13.
OHC Br \ Br \ \ | (CH3)2NH*HCI,Et3N,NaBH(OAc)3 ' T I N/ DCE, rt, ght / XXV LIV , Xanthphos Pd2(dba)3, Xylene.MW 130°C,5h (OOME NH NH \T \ 2 \ TFA,rt,1h T \ i i N/ / LVII LVI Scheme 13 Step 1 5-Bromonicontinaldehyde (XXV) (5.01 g, 26.9 mmol) and dimethylamine hydrochloride (4.39 g, 53.8 mmol) were suspended in 1,2-dichloroethane (108 mL). ylamine (7.50 mL, 53.8 mmol) was added, and the reaction was stirred at room temperature for l h. Sodium triacetoxyborohydride (8.56 g, 40.4 mmol) was added, and the reaction was further stirred at room temperature overnight. The reaction was diluted with saturated sodium bicarbonate solution and DCM. The organic layer was separated, washed sequentially with water and brine, dried over MgSO4, filtered and concentrated to give 1-(5—bromopyridin—3-yl)-N,N—dimethylmethanamine (LIV) (1.19 g, 23.9 mmol, 89% yield) as a brown oil: 1H NMR (DMSO-dg) 8 ppm 8.59 (d, J =3Hz, 1H), 8.47 (d, J=2Hz, 1H), 7.94 (s, 1H), 3.43 (s, 2H), 2.15 (s, 6H); ESIMS found for CgHuBer m/z 215 (M+H).
Step 2 ] In a 25 mL microwave vessel, 1-(5-bromopyridinyl)—N,N- dimethylmethanamine (LIV) (1.27 g, 5.92 mmol), 4—methoxybenzylamine (LV) (0.77 mL, 5.92 mmol), cesium carbonate (2.70 g, 8.29 mmol) and xanthphos (0.17g, 0.30 rnmol) were suspended in xylenes (12.0 mL). The t was degassed, and tris(dibenzylideneacetone)dipalladium(0) (0.27 g, 0.30 mmol) was added. The vessel was sealed, and the reaction was heated to 130°C for 5 h in a microwave reactor. The solvent was ed away from the solid material and concentrated to a e. The residue was purified by silica gel chromatography using a 40 g n normal-phase silica gel cartridge (100% CHC13 —> 3:97 MeOH[7N NH3]:CHC13) to afford 5- thylamino)methyl)—N-(4—methoxybenzyl)pyridinamine (LVI) (0.68 g, 2.49 mmol, 42% yield) as a yellow solid. 1H NMR (DMSO-dg) 5 ppm 7.84 (d, J=3Hz, 1H), 7.64 (d, J=2Hz, 1H), 7.27 (d, J=lle, 2H), 6.88 (d, J=11Hz, 2H), 6.83—6.82 (m, 1H), 6.35 (t, J=8Hz, 1H), 4.20 (d, J=8Hz, 2H), 3.72 (s, 3H), 3.24 (s, 2H), 2.08 (s, 6H); ESIMS found for C16H21N3O m/z 272 (M+H). 5—((dimethylamino)methyl)~N~(4-methoxybenzyl)pyridin—3—amine (LVI) (0.15 g, 0.56 mmol) was dissolved in TFA (2.0 mL) and stirred at room temperature for 1 h. The TFA was removed, and the residue was treated with 7N ammonia in MeOH/chloroform mixture (7/93) to neutralize the TFA and concentrated again to a residue. The residue was purified by flash silica gel chromatography utilizing a 4 g Thomson norrnal—phase silica gel cartridge (100% CHCl3 —> 3:97 MeOH[7N NH3]:CHC13) to afford 5—((dimethylamino)methyl)pyridin-3—amine (LVII) (0.044 g, 0.29 mmol, 52% yield) as a brown oil. ESIMS found for CgH13N3 m/z 152 (M+H).
The following intermediate was prepared in accordance with the procedure described in the above Scheme 13.
HZN / .N ON\ LVIII ] 5-((4—Methylpiperazin—l—y1)methyl)pyridin—3-amine (LVIII): Dark yellow solid (138 mg, 0.67 mmol, 71% yield). ESIMS found for C11H18N4 m/z 207 (M+H).
Preparation of intermediate 6—(pyrrolidin—l-ylmethyl)pyridin-3 -a1nine (LXIII) is depicted below in Scheme 14. o2” o N \ 2 DIBAL,DCM, \ i ‘ / ~78°C to rt, 3h / N COzMe N CHO LIX LX 1 / Eth, NaBH(OAc)3 DCE, rt, overnight H N2 O N \ 2 \ i Pd/C-H2 I / N EtOH,rt,5h / N N N LXIII LXII Scheme 14 To a suspension of methyl 5-nitropicolinate (LIX) (1.282 g, 7.03 mmol) in DCM (25 mL) stirred at -78°C under argon was slowly added DIBAL (1M in e) (9.14 mL, 9.14 mmol). The solution was allowed to warm to room temperature over 3 h. An aqueous solution of potassium sodium tartrate was added, d further with water and DCM. The solution was stirred at room temperature for another 30 min before the organic layer was separated. The aqueous layer was extracted 2X DCM, combined with the organic layer, dried over MgSO4, d and evaporated under reduced pressure. The residue was d by column chromatography to produce 5- nitropicolinaldehyde (LX) as a brown oil (0.64 g, 4.2 mmol, 60% yield). 1H NMR (DMSO-d6) 5 ppm 8.17 (d, J=9Hz, 1H), 8.81 (dd, J=9sz J=2Hz, 1H), 9.56 (d, J=2Hz, 1H), 10.08 (s, 1H).
Step 2 ] Preparation of 5—nitro—2—(pyrrolidin-l-ylmethyl)pyridine (LXII) was performed following the procedure listed in Scheme 5, Step 1. Purple oil (041 g, 1.98 mmol, 86% yield). 1H NMR (DMSO-d6) 5 ppm 9.28 (d, J=3Hz, 1H), 8.56 (dd, J=11Hz, 3H2, 1H), 7.72 (d, J=11Hz, 1H), 3.85 (s, 2H), 2.53—2.50 (m, 4H), 1.75—1.70 (m, 4H).
Preparation of intermediate 6—(pyrrolidin-1—ylmethyl)pyridin-3 -amine (LXIII) was performed following the procedure listed in Scheme 11, Step 2. Dark brown oil (0.35 g, 1.97 mmol, quantitative). ESIMS found for C10H15N3 m/z 178 (M+H).
The following ediate was prepared in accordance with the procedure described in the above Scheme 14.
/ N0/ LXIV 6-((4-Methylpiperazin—1-yl)methyl)pyridin—3-amine (LXIV): Brown oil (120 mg, 0.58 mmol, 100% . ESIMS found for C11H13N4 m/z 207 (M+H).
Preparation of intermediate uorophenoxy)pyridin—3~amine (LXVIII) is depicted below in Scheme 15.
LXVI OZN \ pyridine / 120°C, overni htg ”Mmg/ N CI N o LXV LXVII Pd/C-H EtOH, €11, rt N O LXVIII Scheme 15 Step 1 ] A solution of r0—5—nitropyridine (LXV) (1.98 g, 12.5 mmol) and 3-fluorophenol (LXVI) (1.4 g, 12.5 mmol) in pyridine (20 mL) was heated at 120°C overnight under argon. The solution was cooled to room temperature and concentrated under vacuum. The residue was dissolved in EtOAc, washed with water, brine, dried over MgSO4 and evaporated. The residue was purified by silica gel column chromatography (100% hexane —> 2:98 EtOAc2hexane) to give 2-(3-fluor0phenoxy)nitropyridine (LXVII) as a yellow s oil (2.27 g, 9.7 mmol, 77% yield). 1H NMR dg) 5 ppm 7.11 (dd, J=8Hz, J=2Hz, 1H), 7.17 (dt, J=8Hz, J=6Hz, 1H), 7.23 (td, J=10Hz, J=2Hz, 1H), 7.31 (d, J=9Hz, 1H), 7.52 (q, J=9Hz, 1H), 8.64 (dd, J=9Hz, J=3Hz, 1H), 9.05 (d, J=3Hz, 1H); ESIMS found for C11H7FN203 m/z 234.9 (M+H).
Step 2 Preparation of intermediate 6—(3-fluorophenoxy)pyridin—3-amine I) was performed following the procedure listed in Scheme 11, Step 2. Black green Viscous oil (1.90 g, 9.3 mmol, 96% yield). 1H NMR (DMSO-dg) 5 ppm 5.18 (brs, 2H), 6.74-6.83 (m, 3H), 6.90 (dt, 1H), 7.09 (dd, J=9Hz, J=3Hz, 1H), 7.34 (q, J=7Hz, 1H), 7.57 (d, J=3Hz, 1H); ESIMS found for C11H9FN20 m/z 204.4 (M+).
The following intermediates were prepared in accordance with the procedure described in the above Scheme 15.
HZN F N O LXIX 6-(4—Flu01‘0phen0xy)pyridin~3~amine (LXIX): Dark brown oil (870 mg, 4.3 mmol, 100% yield). 1H NMR (DMSO—d6) 5 ppm 5.08 (brs, 2H), 6.75 (d, J=15Hz, 1H), 6.90-7.01 (m, 2H), 7.07 (dd, J=9Hz, J=3Hz, 1H), 7.16 (t, 9H2, 1H), 7.26-7.30 (m, 1H), 7.73 (d, J=3Hz, 1H); ESIMS found for C11H9FN20 m/z 204.9 (M+H).
H2NUU 6~(2-Fluorophenoxy)pyridin—3-amine (LXX): Dark brown oil (611 mg, 3.0 mmol, 91% yield). ESIMS found for C11H9FN20 m/z 204.9 (M+H).
Preparation of intermediate 6—phenylpyridin—3 -amine (LXXIV) is depicted below in Scheme 16.
LXXII B(OH)2 0 N O N 2 \ 2 \ i Pd(PPh3)4, K3PO4 N/ dioxane/HZO, 95 C0 / Br N LXXI LXXIII Pd/C-Hz EtOH, 6h, rt HZN \ LXXIV Scheme 16 Step 1 To a solution of 2-bromo—5—nitropyridine (LXXI) (302 mg, 1.49 mmol) in a mixture of dioxane (14 mL) and water (3 mL) was added phenylboronic acid (LXXII) (199 mg, 1.64 mmol), Pd(PPh3)4 (86 mg, 0.74 mmol) and K3PO4 (473 mg, 2.23 mmol). The reaction was microwaved at 95°C for 1h. The on was cooled and the organic phase was separated, dried over MgSO4 and evaporated under vacuum. The residue was d by silica gel column chromatography (100% hexane —> 5:95 EtOAczhexane) to give 5-nitro—2—phenylpyridine (LXXIII) as ite needles (254 mg, 1.27 mmol, 85% yield). ESIMS found for 202 m/z 200.9 (M+H).
Step 2 Preparation of intermediate 6-phenylpyridin-3—amine (LXXIV) was performed following the procedure listed in Scheme 11, Step 2. Black green s oil (211 mg, 1.24 mmol, 98% yield). 1H NMR (DMSO—dg) 8 ppm 5.45 (s, 2H), 6.99 (dd, J=11Hz, J=3Hz, 1H), 7.25-7.28 (m, 1H), 7.38-7.40 (m, 2H), 7.62 (d, J=11Hz, 1H0, 7.89- 7.91 (m, 1H), 8.02 (d, J=3Hz, 1H); ESIMS found for N2 m/z 171 (M+H).
The following intermediates were prepared in accordance with the procedure described in the above Scheme 16.
HZN \ / F LXXV 6-(3-Fluorophenyl)pyridinamine (LXXV): Brown oil (252 mg, 1.34 mmol, 98% yield). ESIMS found for C11H9FN2 m/z 189 (M+H).
H2N \ LXXVI luoropheny1)pyridin-3—amine (LXXVI): Deep purple oil (202 mg, 1.07 mmol, 98% yield). ESIMS found for C11H9FN2 m/z 189 (M+H).
Preparation of intermediate 5-benzylpyridin—3—amine (LXXX) is ed below in Scheme 17. o\a’ LXXVIII 02N Br 3 OZN \ \ | PdCI2(dppf)z, mm | / dioxane/HZO, 90°C N/ LXXVII LXXIX Pd/C-Hz EtOH, 6h, rt Scheme 17 To a solution of 3-bromo—5-nitropyridine (LXXVII) (295 mg, 1.45 mmol) in e (14 mL) was added 2-benzyl—4,4,5,5-tetramethyl—l,3,2-dioxaborolane (LXXVIII) (420 uL, 1.89 mmol), PdClg(dppf)2, (120 mg, 0.15 mmol) and 2M aqueous K3PO4 (2.2 mL, 4.36 mmol). The reaction was microwaved at 90°C for 2h. The reaction was cooled and the organic phase was separated, dried over MgSO4 and evaporated under vacuum. The residue was purified by silica gel column chromatography (100% hexane —> 6:94 EtOAczhexane) to give 3—benzyl—5—nitropyridine (LXXIX) as brown oil (117 mg, 0.54 mmol, 37% . 1H NMR (DMSO-d6) 5 ppm 4.16 (s, 2H), 7.21-7.25 (m, 1H), .33 (m, 4H), 8.45-8.46 (m, 1H), 8.93 (d, J=2Hz, 1H), 9.21 (d, J=3Hz, 1H); ESIMS found for N202 m/z 215 (M+H).
] Preparation of 5-benzylpyridin—3-amine (LXXX) was performed following the procedure listed in Scheme 11, Step 2. Black green viscous oil (139 mg, 0.75 mmol, 98% . ESIMS found for C12H12N2 m/z 185 (M+H).
Preparation of intermediate 2-(4-methylpiperazin—1—yl)pyridin—3~amine (LXXXIV) is depicted below in Scheme 18.
(\N/ ozN QLXXXII \ “N ozu \ \ I I Pd/C-Hz ‘ Cl N/ CsZC03, Xanthphos, Pd2(dba)3, f“ N/ MeOH, rt, 16 h (\N N/ Xylene, MW, 90°C, 2 h /Nd /”\J LXXXI LXXXHI LXXXIV Scheme 18 Step 1 To a microwave vial was added 2-chloronitropyridine (LXXXI) (1.00 g, 6.31 mmol), ylpiperazine (LXXXII) (0.758 g, 7.57 mmol), cesium carbonate (2.88 g, 8.83 mmol), Pd2(dba)3 (0.173 g, 0.189 mmol), xanthphos (0.109 g, 0.189 mmol), and dioxane (5 mL). The reaction vial was capped and purged with argon.
The solution into the reaction vial was heated under microwave irradiation for 2 h at 90°C. The solution was filtered through a pad of Celite and concentrated to a residue under vacuum. The residue was d by column chromatography (1 :99 MeOHzCHC13 —> 8:92 MeOHzCHClg) to afford 1-methyl-4—(3-nitro-pyridinyl)-piperazine (LXXXIII) (1.30 g, 5.85 mmol, 93% yield) as a brown oil.
To a stirring solution of 1-methyl(3-nitro-pyridin—2-yl)-piperazine (LXXXIII) (1.30 g, 5.85 mmol) in‘MeOH (15 mL) was added 10% Pd/C. The solution was purged with hydrogen. The on was stirred at room ature for 16 h under hydrogen. The solution was filtered through a pad of Celite and concentrated to a residue under . The residue was purified by column chromatography (100% CHC13 —> 2:98 MeOH[7N NH3]:CHC13) to afford 2-(4—methylpiperazinyl)pyridin—3~amine (LXXXIV) (0.466 g, 2.42 mmol, 52% yield) as a tan solid. ESIMS found for C10H16N4 m/z 192.4 (M+H).
The following intermediates were prepared in accordance with the procedure bed in the above Scheme 18.
H2N / LXXXV 6—(Pyrrolidiny1)pyridin—3-amine (LXXXV): Deep purple oil (1.43 g, 8.77 mmol, 100% yield). ESIMS found for C9H13N3 m/z 164 (M+H).
N/ NOK LXXXVI 6-(4—Methylpiperazin—1-y1)pyridin—3-amine (LXXXVI): Purple solid (598 mg, 3.11 mmol, 32% yield). ESIMS found for cmeN4 m/Z 193 (M+H).
LXXXVII holinopyridin-3—amine (LXXXVII): Purple solid (782 mg, 4.36 mmol, 95% yield). ESIMS found for C9H13N30 m/z 180 (M+H).
H2N / \N TNN\ LXXXVIII NZ-(2-(Dimethylamino)ethyl)—N2-methylpyridine-2,5-diamine (LXXXVIII): Deep purple oil (1.55 g, 7.98 mmol, 96% . ESIMS found for C10H13N4 m/z 195 (M+H).
Preparation of intermediate 1-(5-aminopyridinyl)piperidinol (XCI) is depicted below in Scheme 19.
HN<:>—OH LXXXIX OZN OZN \ \ I K2C03,DMF l N/ 85°C, overnight CI N/ O LXV XC Pd/C-H2 EtOH,6h,rt HZN \ Scheme 19 To a solution of 2-chloro—5—nitropyridine (LXV) (5.0 g, 31.5 mmol) in DMF (50 mL) was added piperidin-4—ol (LXXXIX) (3.5 g, 34.65 mmol) and K2C03 (8.7 g, 63.0 mmol). The reaction was headed at 85°C overnight. The solution was poured into ice water, stirred for 15 min and then d. The solid was washed with cold water and dried under vacuum to produce minopyridin-2—yl)piperidinol (XC) as a yellow solid (6.62 g, 29.67 mmol, 94.2% yield). 1H NMR (DMSO-dg) 5 ppm 1.34—1.42 (m, 2H), 1.77-1.83 (m, 2H), 3.40—3.56 (m, 2H), 3.76—3.83 (m, 1H), 4.12 (brd, 2H), 4.81 (d, J=4Hz, WO 40215 1H), 6.94 (d, J=10HZ, 1H), 8.17 (dd, J=10HZ, J=3HZ, 1H), 8.94 (d, J=3HZ, 1H); ESIMS found for C10H13N3O3 m/z 224.1 (M+H) Preparation of intermediate 1—(5-aminopyridinyl)piperidinol (XCI) was performed following the procedure listed in Scheme 11, Step 2. Dark brown oil (5.7 g, 29.5 mmol, 99.5% yield). 1H NMR (DMSO‘dé) 5 ppm 1.36 (tq, J=13Hz, J=4Hz, 2H), 1.72-1.76 (m, 2H), 2.79 (dt, J=13Hz, J=3Hz, 2H), 3.54—3.61 (m, 1H), 3.70— 3.78 (m, 2H), 4.49 (s, 2H), 4.61 (d, J=4Hz, 1H), 6.61 (d, J=9Hz, 1H), 6.88 (dd, J=9Hz, J=3Hz, 1H), 7.57 (d, J=3Hz, 1H); ESIMS found for N30 m/z 194.1 (M+H).
The following intermediates were prepared in accordance with the procedure described in the above Scheme 19.
XCII 6-(Piperidin—1-yl)pyridin—3-amine : Dark red Viscous oil (4.93 g, 27.81 mmol, 95.9% yield). 1H NMR (DMSO-ds) 5 ppm 1.48-1.71 (m, 8H), 3.42—3.53 (m, 2H), 4.48 (brs, 2H), 6.59 (d, J=9Hz, 1H), 6.89 (dd, J=9Hz, J=3Hz, 1H), 7.58 (d, J=3Hz, 1H); ESIMS found for C10H15N3 m/Z 178.0 (M+H).
HZN \ N/ “D XCIII ] 5-Methyl(pyrrolidin—1-yl)pyridinamine (XCIII): Dark blue viscous oil (2.06 g, 12.62 mmol, 100% yield). 1H NMR (DMSO-d6) 8 ppm 1.76-1.82 (m, 4H), 2.13 (s, 3H), 3.15-3.20 (m, 4H), 4.53 (brs, 2H), 6.74 (d, J=3.5Hz, 1H), 7.42 (d, J=2.7Hz, 1H); ESIMS found for C10H15N3 m/z 178.1 (M+H).
H2N \ XCIV 6—(Azetidin—l—yl)—5-methylpyridinamine (XCIV): Dark red solid (2.0 g, 11.29 mmol, 86.9% yield). 1H NMR (DMSO—d6) 5 ppm 2.11 (quin, J=7Hz, 2H), 3.76-3.87 (m, 4H), 4.50 (brs, 2H), 6.72 (d, J=2.5Hz, 1H), 7.38 (d, J=2.5Hz, 1H); ESIMS found for C9H13N3 m/z 164.4 (M+H). 6—(Azetidin—1-yl)pyridin~3-amine (XCV): Burgundy solid (1.45 g, 9.70 mmol, 99.3% yield). ESIMS found for C8H11N3 m/z 149.0 (M+H).
] Preparation of intermediate tert—butyl 4-(5-aminopyridin—2- yl)piperazine-1~carboxylate (XCVIII) is depicted below in Scheme 20. 02N HN N—Boc XCVI OzNfi / EtOH, 70°C, 16 h / N Cl N Nfi va XCVII km Pd/C—Hz EtOH, 6h, rt Scheme 20 Step 1 To a solution of 2—chloro-5~nitropyridine (LXV) (2.0 g, 12.6 mmol) in EtOH (20 mL) was added tert—butyl piperazine-l-carboxylate (XCVI) (7.05 g, 37.9 mmol). The on was headed at 70°C for 16 h. The on was concentrated under vacuum and then dissolved in EtOAc. The EtOAc was washed with 1 M NaOH, brine and then dried over MgSO4 to give tert—butyl 4-(5-nitropyridin—2-yl)piperazine—1— carboxylate (XCVII) as a yellow solid (4.94 g). ESIMS found for C14H20N4O4 m/z 309.0 (M+H).
Preparation of ediate tert—butyl 4—(5-aminopyridin—2- yl)piperazine—1—carboxylate (XCVIII) was performed following the procedure listed in Scheme 11, Step 2. Purple solid (990 mg, 3.56 mmol, quantitative). ESIMS found for C14H22N402 m/z 278.8 (M+H).
] Preparation of intermediate N—(3-aminopyridin—4-yl) cyclopropanecarboxamide (C11) is depicted below in Scheme 21.
NH2 0 c HNJE OzN OZN \ Cl/“W \ I l N/ pyridine N/ XCIX CI Pd/C-Hz EtOH, 6h, rt *1le HZN \ Scheme 21 Preparation of N—(3-nitropyridinyl)cyclopropanecarboxamide (CI) was med following the procedure listed in Scheme 4, Step 1. Orange solid (130 mg, 0.93 mmol, 13% yield). ESIMS found for C9H9N303 m/z 207.8 (M+H).
Preparation of intermediate N—(3 -aminopyridin—4-yl) cyclopropanecarboxamide (CII) was performed following the procedure listed in Scheme 11, Step 2. Dark grey solid (100 mg, 0.56 mmol, quantitative). ESIMS found for C9H11N3O m/z 178.3 (M+H). ation of intermediate nopyridinyl)(pyrrolidin-1— yl)methanone (CV) is depicted below in Scheme 22. 02” \ HATU, DIPEA / DMF, rt, 2h D N COZH CIII CIV o Pd/c-H2 EtOH, 6h, rt HZN \ CV 0 Scheme 22 $213 To a solution of 5-m'tropicolinic acid (CIII) (500 mg, 2.97 mmol) in DMF (15 mL) was added pyrrolidine (244 pl, 2.47 mmol) and DIPEA (1.03 mL, 5.95 mmol). The reaction was cooled at 0°C before adding HATU (1.13 g, 2.47 mmol). The reaction was warmed to room temperature and stirred for 2 hrs. The reaction was concentrated under vacuum and then dissolved in a mixture of water and 10% iPrOH/CHC13. The organic layer was separated and the aqueous phase was washed again with 10% CHClg. The combined organic phases were washed with brine, dried over MgSO4 and evaporated to yield (5~nitropyridin—2-yl)(pyrrolidin—1-yl)methanone (CIV) as a red solid (849 mg). ESIMS found for C10H11N303 m/z 222.1 (M+H).
Step 2 ] Preparation of intermediate (5-aminopyridin—2-yl)(pyrrolidin—1— yl)methanone (CV) was performed following the procedure listed in Scheme 11, Step 2.
Yellow solid (708 mg, 7.3 mmol, 96.4% yield). ESIMS found for C10H13N30 m/z 191.4 (M+H).
The following intermediate was prepared in accordance with the procedure described in the above Scheme 22.
HZN \ | H / N O )3 5—Amino—N-cyclopentylpicolinamide (CVI): Yellow solid (450 mg, 2.19 mmol, 93.7% yield). ESIMS found for C11H15N3O m/z 206.1 (M+H).
Preparation of intermediate 6-(methylsulfonyl)pyridin—3-amine (CIX) is depicted below in Scheme 23. 02” \ 02“ NaSMe \ 02" mCPBA \ I ‘ / THF/HZO i / DCM / / N Cl N SMe N 0A0 LXV CVII CVIlI Pd/C-H2 EtOH,6h,rt N oys<o Scheme 23 Step 1 ] To a solution of sodium thoxide in THF (53 mL) and H20 (20 mL) cooled to 0°C was added 2-chloronitropyridine (LXV) (5.09 g, 32.09 mmol). The reaction was warmed to room temperature and stirred for 2 hrs. The reaction was poured into ice water and d for 10 minutes, filtered, washed with water, dried under vacuum to yield 2-(methylthio)-5—nitropyridine (CVII) as a yellow solid (5.14 g, 30.20 mmol, 94.1%). 1H NMR (DMSO-d6) 6 ppm 2.62 (s, 3H), 7.57 (d, J=8.9Hz, 1H), 8.38 (d, J=8.9Hz, 1H), 9.22 (d, J=2.7Hz, 1H); ESIMS found for C6H6NZOZS m/z 171.1 (M+H).
Step 2 To a solution of 2—(methylthio)—5-nitropyridine (CVII) (502 mg, 2.95 mmol) in DCM (60 mL) was mCPBA (1.33 g, 5.90 mmol). The reaction was stirred at room temperature for 1 hr. Two additional portions of mCPBA (2 X 250 mg) were added at 1 hr intervals for a total reaction time of 4 hr. The reaction was poured into saturated aqueous NaHCOg. The c phase was separated and washed with water, brine and then dried over MgSO4. The solvent was removed under vacuum to produce crude 2- (methylsulfonyl)nitropyridine (CVIII) (854 mg) which was used without purification for step 3. ESIMS found for 04S m/z 203.0 (M+H).
Preparation of intermediate hylsulfonyl)pyridin~3~amine (CIX) was performed following the procedure listed in Scheme 11, Step 2. The crude product was used as is without purification. ESIMS found for C6H8N202S m/z 173.0 (M+H).
Preparation of intermediate (tetrahydro-2H-pyran—2-yl)-1H- indazole—3—carbaldehyde (CXIV) is depicted below in Scheme 24. n O / 0 / co H2 <\/IN HN\/>/ N N \ O O \ 0/ A 0/ I Jk | \N NHOMe(Me)*HCl, \N F30 0 0 CFs \N N/ imidazole, DMF, 65°C N/ 12, DCM, m. N/ H H H cx CXI CXJI DHP,PPTS DCM, reflux o N/ CHO \ I I 0 3N LAHo 3" N THF, 0 C N CXIV ob CXIII ob Scheme 24 Step 1 1H-indazole—3—carboxylic acid (CX) (100 g, 617 mmol) in DMF was treated with carbonyldiimidazole (110 g, 678 mol) at room temperature until the evolution of gas ceased (ca. 15 s). The reaction was heated to 60-65°C for 2 h and then d to cool to room ature. N,O-Dimethylhydroxylamine—HCl (66.2 g, 678 mmol) was added as a solid and the mixture was heated to 65°C for 3 h. The reaction was concentrated to a paste, taken up in DCM and washed subsequently with water and 2 N HCl. The t could be seen coming out of solution. The solid was filtered and rinsed separately with EtOAc. The EtOAc and DCM layers were separately washed with sodium bicarbonate followed by brine, dried over MgSO4 and concentrated under reduced pressure. The resulting solids were combined, triturated with 1:1 mixture of DCM-ether, filtered, and dried to produce N-methoxy-N-rnethyl-1H-indazole—3- carboxamide (CXI) as a white solid (100 g, 487 mmol, 79% yield). 1H NMR (DMSO-d6) 6 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 N302 m/z 206 (M+H).
Step_ 2 To N—methoxy—N—methyl-lH—indazolecarboxamide (CXI) (20 g, 97.4 mmol) in DCM (l L) was added (Bis(trifluoroacetoxy)iodo)benzene (46 g, 107 mmol) followed by portionwise addition of iodine (14.84 g, 58.5 rnmol) at room ature. After 1 h, saturated aqueous NaHSO3 (600 mL) was added and a solid began to precipitate which was filtered and rinsed with excess DCM. The filtrate was washed with bline, dried over MgSO4, concentrated and the ing solid was triturated with a minimal amount of DCM. The combined solids were dried under vacuum over KOH to produce 5~iodo-N-methoxy—N—methyl—lH—indazole—3-carboxamide (CXII) as a white solid (23.2 g, 70 mmol, 72% yield). 1H NMR (DMSO-dg) 5 ppm 3.45 (s, 3H), 3.77 (s, 3H), 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 C10H101N302 m/z 331 (M+H). §t_ep_§ A mixture of 5—iodo—N-methoxy-N—methyl—lH~indazole—3- carboxamide (CXII) (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 h. The solution was poured into a saturated aqueous 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 MeOHzDCM) to provide 5— iodo—N—methoxy—N-1nethy1-1—(tetrahydro—2H—pyranyl)— lH—indazole-3—carboxamide (CXIII) as a white Viscous oil (19.1 g, 46 mmol, 92% yield). 1H NMR (DMSO—d6) 6 ppm 1.28—1.84 (m, 6H), 3.43 (s, 3H), 3.60—4.04 (s, 5H), .08 (m, 1H), 7.45-7.87 (m, 2H), 8.39 (s, 1H); ESIMS found for C15H131N3O3 m/Z 416 (M+H).
Step4 Lithium aluminum hydride (160 mg, 4.21 mmol) was added in portions to a cooled (0°C) solution of 5-iodo-N—methoxy-N—methyl-1—(tetrahydro—2H— pyran—2-yl)-1H—indazolecarboxamide (CXIII) (1.46 g, 3.5 mmol) in THF. ng was continued at 0°C until the reaction was completed, approximately 30 min. The on was quenched by the slow addition of EtOAc at 0°C, and the whole mixture was poured into 0.4 N s . The organic layer was washed with brine, dried over MgSO4, concentrated, and purified on a silica gel column (100% EtOAc —> 3:97 MeOHIDCM) to give 5-iodo(tetrahydro-2H-pyran—2—yl)~1H—indazolecarbaldehyde (CXIV) as a white solid (0.90 g, 3.15 mmol, 72% yield). 1H NMR (DMSO-dG) 6 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), .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), .13 (s, 1H); ESTMS found for C13H13IN202 m/Z 357 (M+H).
Preparation of intermediate 5-bromo—1—(tetrahydro-2H—pyran—2-yl)— 1H—indazolecarboxylic acid (CXVIII) is depicted below in Scheme 25.
C02H step 1 COZH step 2 COZMe Br Br \ HOAc, Brz \ MeOH, H2S04 \ /N 90°C /N /N N a 16 h reflux 4h N ’ N H H H CX CXV CXVI p-toluenesulfonic acid, DHP, PPTS step 5 step 3 THF, 60 “C, 16 h DCM, reflux COZH COzMe Br Br \ NaOH, H20 \ N/ 90"C, 1 h N/N step 4 O O CXVHI CXVI] Scheme 25 Step 1 A suspension of indazolecarboxylic acid (CX) (1.0 g, 6.16 mmol) in glacial acetic acid (60 mL) was heated at 120°C to get a clear solution. The solution was cooled to 90°C. A solution of bromine (0.633 mL, 12.33 mmol) in glacial acetic acid (2 mL) was added slowly to the solution while heating at 90°C. The solution was further heated 16 h at 90°C. The solution was cooled to room temperature, poured into ice water and further d at room temperature for 15 min. The solids formed were filtered, washed with cold water and dried under vacuum at room temperature to get 5—bromo-1H~ indazolecarboxylic acid (CXV) as a white solid (1.30 g, 5.39 mmol, 87.5% yield). 1H NMR (DMSO-d6) 5 ppm 13.95 (s, 1H), 13.18 (br s, 1H), 8.21 (d, J: 1.2 Hz, 1H), 7.65 (d, J: 7.0 HZ, 1H), 7.56 (dd, J: 7.0, 1.2 Hz, 1H); ESIMS found for CgH4BI‘N202 m/z 242.0 (M+H).
Step 2 Concentrated sulfuric acid (1 mL) was added to a suspension of 5- bromo-lH-indazolecarboxylic acid (CXW (1.30 g, 5.39 mmol) in dry MeOH (50 mL) and heated to reflux for 4 h under argon. The on was cooled to room ature and the MeOH was evaporated under vacuum. The residue was ved in EtOAc and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated WO 40215 to afford methyl 5~bromo~1H-indazolecarboxylate (CXVI) as a white solid (1.35 g, .29 mmol, 98% yield). 1H NMR (DMSO-ds) 5 ppm 1413 (s, 1H), 8.21 (d, J: 1.6 Hz, 1H), 7.67 (d, J: 7.2 Hz, 1H), 7.59 (dd, J: 7.2, 1.2 Hz, 1H), 3.92 (s, 3H); ESIMS found for C9H7BrN202 m/z 256.0 (M+H).
Step 3 A sion of methyl 5-bromo-1H-indazole—3—carboxylate (CXVI) (1.35 g, 5.29 mmol), pyridinium p-toluenesulfonate (0.143 g, 0.56 mmol) and 3,4 dihydro—2H—pyran (1.02 mL, 11.90 mmol) in anhydrous dichloroethane (20 mL) was refluxed 5 h under argon. The suspension was turned into the clear solution. The solution was cooled and the excess solvent was evaporated under vacuum. The residue was dissolved in EtOAc and washed with dilute NaHC03 solution (satd. NaHC03 soln/HZO: 1:9). The organic layer was dried over , filtered and concentrated. The residue was purified by column chromatography (100% hexanes —> 5:95 EtOAczhexanes) to get methyl o(tetrahydro~2H~pyran~2~yl)-1H-indazolecarboxylate (CXVII) as a white solid (1.47 g, 4.34 mmol, 82% yield). 1H NMR (DMSO-d6) 5 ppm 8.22 (d, J = 1.4 Hz, 1H), 7.89 (d, J: 7.2 Hz, 1H), 7.68 (dd, J: 7.2, 1.6 Hz, 1H), ), 6.02 (dd, J: 8.0, 2.4 Hz, 1H), 3.94 (s, 3H), 3.88 (m, 1H), 3.79 (m, 1H), 2.37-2.31 (m, 1H), 2.05-1.96 (m, 2H), 1.77—1.73 (m, 1H). 1.60-1.58 (m, 2H); ESIMS found for C14H15BrN203 m/z 340.0 (M+H).
Step 4 2 N Aqueous NaOH solution (10 mL) was added to a suspension of methyl 5—bromo—1-(tetrahydro-2H-pyranyl)—1H-indazole—3-carboxylate (CXVII) (1.30 g, 3.83 mmol) in water (20 mL) and heated at 90°C for 1 h. The solution was cooled to room temperature, d with ice water and acidified to pH 3.0 with 10% s HCl.
The solids formed were filtered, washed with cold water and dried under vacuum at room temperature to get 5-bromo—1-(tetrahydro~2H—pyranyl)—lH-indazolecarboxylic acid (CXVIII) as a white solid (0.87 g, 2.68 mmol, 70% yield). ESIMS found for C13H13BrN203 m/z 326.0 (M+H).
Step 5 To a on of 5—bromo—1H—indazole—3—carboxylic acid (CXV) (59.8 g, 248 mmol) in THF (800 mL) under argon was added. 3,4 dihydro-2H—pyran (50.6 mL, 558 mmol) and p-TsOH (4.72 g, 24.8 mmol). The reaction was heated to reflux at 60°C for 16 h. An additional portion of p—TsOH (0.025 eq) and 3,4 dihydro—2H-pyran (0.56 eq) was added and the reflux continued for 5 h. The solution was concentrated under .
EtOAc was added to the residue and the suspension was filtered and dried under high vacuum overnight to produce 5-bromo(tetrahydro—2H—pyran—2-yl)-1H-indazole carboxylic acid (CXVIII) as a white solid (49.07 .g, 150.9 mmol, 60.8% yield). ESIMS found for BrN203 m/z 326.3 (M+H).
Preparation of ediate 5-bromo—1-trityl-1H-indazole—3-carboxylic acid (CXXI) is depicted below in Scheme 26.
COZH step 1 COzEt Br Br \N MeOH, st04 \N N/ reflux, 4h N/ H H CXV CXIX Tr—Cl DMF ’ Tr—Cl DCM Step 4 ’ 5 ept 2 TEA, rt DIPEA, rt c02H COzEt Br Bl' \ N OH H 0a a \ / 90°C 1121 /N N ’ N Tr step 3 Tr CXXI CXX Scheme 26 Step_ 1 Preparation of intermediate ethyl 5-bromo-lH—indazolecarboxylate (CXIX) was performed following the procedure listed in Scheme 25, Step 2. White solid. (3.60 g, 13.38 mmol, 64.5% yield). 1H NMR (DMSO-dfi) 5 ppm 1.37 (t, J=7Hz, 3H), 4.40 (q, J=7Hz, 2H), 7.57 (dd, J=9Hz, J=2Hz, 1H), 7.66 (d, J=9Hz, 1H), 8.20 (d, J=2Hz, 1H), 14.11 (brs, 1H); ESIMS found for C10H9B1'N202 m/z 269.0 (M+H).
Step 2 To a solution of ethyl o-1H-indazolecarboxylate (CXIX) and trityl chloride in DCM was slowly added DIPEA. The solution was stirred at room temperature overnight. The on was poured into water and stirred for 5 min. The organic layer was separated, dried over MgSO4 and concentrated under vacuum. The residue was ed by column chromatography using a ISCO 200RF system with a Si02 column (12 g) (100% hexanes —> 10:90 hexanes) to produce a white solid. (357 mg, 0.70 mmol, 69.8% yield). 1H NMR (DMSO-d6) 5 ppm 1.34 (t, J=7Hz, 3H), 4.38 (q, J=7Hz, 2H), 6.43 (d, J=9.5Hz, 1H), 7.11—7.14 (m, 6H), 7.31-7.35 (m, 10H), 8.23 (d, J=2Hz, 1H); ESIMS found for C29H23BrN202 m/z 511.0 (M+H).
Step 3 Preparation of intermediate otrityl-1H—indazole-3 —carboxylic acid (CXXI) by hydrolysis of ethyl 5-bromo—1~trityl—1H—indazole—3—carboxylate (CXX) can be performed following the procedure listed in Scheme 25, Step 3.
Step 4 Preparation of intermediate 5—bromotrityl—1H—indazole—3—carboxylic acid (CXXI) by tritylation of 5-b1'omo-lH—indazolecarboxylic acid (CXV) can be performed following the procedure listed in the Journal ofMedicinal Chemistry (2003), 46(25), 5458—5470.
Example 1 Preparation of 5-(5-(3,3-dimethylureido)pyridin—3-yl)-N-(pyridin yl)—1H—indazole—3~carboxamide (1) is depicted below in Scheme 27. o E $o T \ l / / ‘ CHO 0 0,3 N N\ \ XXII N”/ \N KOAc, PdClz(dppf)_ K3P04, Pd(PPh3).. / DMF, 90°C, 2 h H20, 90°C, 3h CXIV0 0 o CXXII CXXIII AgN03, NaOH, 1L1z Dioxane, rt overnight \TANH / \ cxxv \NiNH / 0 j N“ N I c02H \ N \ TFA, DCM, \ N/N EtasiH, rt, 3 h HATU, DIPEA N N/N O 0 1 CXXVI b”DMF, rt, overnight CXXIV 5 Scheme 27 Step 1-2 A solution of 5-iodo-l—(tetrahydro-2H—pyran—2—yl)-1H—indazole carbaldehyde (CXIV) (1.780 g, 5.0 mmol), bis(pinacolato)diboron (1.523 g, 6.0 mmol), KOAc (1.471 g, 15 mmol) and dry DMF (20 mL) was purged with argon. PdC12(dppf)2 (0.245 g, 0.3 mmol) was added to the reaction and purged again with argon. The solution was heated at 90°C for 2 h. Once TLC showed the disappearance of (CXIV), the solution was cooled to room temperature. To this on was added K3PO4 (1.592 g, 7.5 mmol), 3—(5—bromopyridin—3—yl)-1,1—dimethylurea (XXII) (1.220 g, 5.0 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol) and water (2 mL). The solution was purged with argon and heated at 90°C for 3 h. The solution was cooled to room ature and then concentrated under reduced pressure. The residue was dissolved in DCM and washed with water, dried over MgSO4, filtered and then ated under vacuum. The residue was purified on a silica gel column (100% DCM —> 2:98 MeOHzDCM) to give 3—(5-(3-formyl-1—(tetrahydro-2H— pyran—2-yl)-1H—indazolyl)pyridinyl)-1,l-dimethylurea I) as a brown viscous oil which solidified under vacuum at room temperature (354 mg, 0.90 mmol, 18% yield for 2 steps). 1H NMR (DMSO-dg) 8 ppm 10.22 (s, 1H), 8.76 (d, J = 1.6 Hz, 1H), 8.63 (s, 1H), 8.52 (d, J: 1.6 Hz, 1H), 8.36 (s, 1H), 8.24 (m, 1H), 8.05 (d, J: 7.2 Hz, 1H), 7.91 (dd, J: 7.2, 1.4 Hz, 1H), 6.13 (dd, J: 7.6, 2.0 Hz, 1H), 3.93 (m, 1H), 3.85 (m, 1H), 2.98 (s, 6H), 2.47—2.42 (m, 1H), 2.11—2.06 (m, 2H), 1.82—1.79 (m, 1H) 1.64 (m, 2H); ESIMS found for C21H23N503 m/Z 394.0(M+H).
Step 3 A on of sodium hydroxide (0.173 g, 4.33 mmol) in water (5 mL) was added to a solution of silver nitrate (0.367 g, 2.16 mmol) in water (5 mL) to give a brown precipitate. 3-(5-(3 -formyl—1~(tetrahydro—2H—pyran~2-yl)—lH—indazol-S—yl) pyridinyl)—1,1—dimethylurea (CXXIII) (0.340 g, 0.86 mmol) was dissolved in 1,4- dioxane (10 mL) and added to the reaction which was stirred overnight at room temperature. The solution was diluted with water and then extracted with diethyl ether.
The aqueous layer was separated and carefully brought to pH = 3 with aqueous HCl. The aqueous layer was then extracted with 10% iPrOH/chloroforrn. The combined organic layers were then dried (NaZSO4), filtered and concentrated to give 5—(5—(3,3— dimethylureido)pyridin-3 —yl)(tetrahydro-2H-pyran—2-yl)— 1 H—indazole-3 xylic acid (CXXIV) as a brownish white solid (246 mg, 0.60 mmol, 70% yield). 1H NMR GDMSO—d6) 5 ppm 13.26 (br. s, 1H), 8.87 (s, 1H), 8.63 (s, 1H), 8.41 (s, 1H), 8.34 (s, 1H), 8.03 (d, J:- 7.1 Hz, 1H), 7.86 (dd, J: 7.2, 1.3 HZ, 1H), 6.06 (dd, J: 8.0, 4.0 Hz, 1H), 3.92 (m, 1H), 3.80 (m, 1H), 2.98 (s, 6H), 2.42-2.39 (m, 1H), 2.03—2.02 (m, 2H), 1.79-1.77 (m, 1H) 1.61 (m, 2H); ESIMS found for N504 m/z M+H).
Step 4 HATU (0.190 g, 0.5 mmol) was added to a on of 5-(5-(3,3- dimethylureido)pyridin-3 -yl)(tetrahydro-2H—pyran—2-yl)-1H—indazole-3 —carboxylic acid (CXXIV) (0.39 g, 1.21 mmol) and diisopropylethylamine (0.174 mL, 1.0 mmol) in DMF stirred at room ature under argon. After stirring 5 min, the solution was added with 3—aminopyridine (CXXV) (0.047 g, 0.5 mmol). The solution was stirred overnight at room temperature under argon. The DMF was removed under reduced pressure, and the residue was treated with water, sonicated briefly and d. The solids were washed with cold water and dried at room temperature. The product was purified by column chromatography using a 4 g Thomson normal phase silica gel cartridge (100% DCM —> 5:95 MeOHzDCM) to afford 5-(5-(3,3—dimethy1u1‘eido)pyridin— 3 -yl)—N—(pyridin~3 —yl)—1 ahydro~2H—pyran-2—yl)-1H—indazolecarboxamide ) as an off white solid (323 mg, 0.67 mmol, 55% yield). 1H NMR (DMSO—d6) 5 ppm 10.56 (s, 1H), 9.06 (d, J: 2.0 Hz, 1H), 8.75 (d, J: 1.6 Hz, 1H), 8.64 (s, 1H), 8.53 (d, J: 1.6 Hz, 1H), 8.46 (s, 1H), 8.34-8.29 (m, 2H), 8.26 (1n, 1H), 8.03 (d, J: 7.0 Hz, 1H), 7.88 (dd, J: 7.0, 1.2 Hz, 1H), 7.43 (dd, J: 6.64, 3.84 Hz, 1H), 6.07 (dd, J= 8.0, 1.8 Hz, 1H), 3.98 (m, 1H), 3.82 (m, 1H), 2.98 (s, 6H), 2.63—2.60 (m, 1H), 2.11-2.06 (m, 2H), .81 (m, 1H) 1.52 (m, 2H); ESIMS found for C21H23N5O4 m/Z 410.0(M+H).
Steps TFA (5 mL) was added to a solution of 3,3— dimethylureido)pyridin—3 —yl)—N-(pyridin-3 -y1)— 1 -(tetrahydro-2H-pyran—2-y1)- 1H— indazole~3~carboxamide (CXXVI) (0.134 g, 0.27 mmol) and triethylsilane (0.110 mL, 0.69 mmol) in DCM (5 mL) and stirred 3 h at room ature. The solvent was removed under vacuum. The residue was treated with water, sonicated briefly to disperse the solids, basified to pH 9.0 with 5 N NH40H and sonicated again. The solids were filtered, washed with cold water and purified by column chromatography (100% DCM —> :95 MeOH[7N NH3]:DCM) to afford 5-(5-(3,3-dimethylureido)pyridin—3—yl)-N- (pyridin—3 H—indazole—3—carboxamide (1) as a white solid (35.8 mg, 0.09 mmol, 33% yield). 1H NMR (DMSO-d6) 5 ppm 13.99 (s, 1H), 10.69 (s, 1H), 9.08 (d, J: 1.2 Hz, 1H), 8.74 (d, J: 1.8 Hz, 1H), 8.63 (s, 1H), 8.51 (d, J: 1.5 Hz, 1H), 8.47 (s, 1H), 8.33-8.30 (m, 2H), 8.26 (m, 1H), 7.80 (s, 2H), 7.41 (dd, J= 6.6, 3.6 Hz, 1H), 2.98 (s, 6H); ESIMS found for C21H19N702 m/z 402.3(M+H).
The following compound was prepared in accordance with the procedure described in the above Example 1.
N—(5-Fluoropyridin—3 —yl)(pyridin—3 -yl)-1H—indazolecarboxamide Light tan solid. 1H NMR (DMSO-d6) 5 ppm 7.53 (dd, J=8Hz, J=5Hz, 1H), 7.82-7.86 (m, 2H), 8.13-8.15 (m, 1H), 8.31-8.34 (m, 2H), .48 (m, 1H), 8.60 (dd, J=5Hz, J=2Hz, 1H), 894 (d, J=2Hz, 1H), 8.99 (d, J=2Hz, 1H), 10.97 (s, 1H), 14.05 (s, 1H); ESIMS found for C13H12FN5O m/z 334 (M+1).
Example 2 Preparation of 5—(5 pyridin—3-yl)-N-(6-(trifluoromethyl)pyridin~ 3-yl)-lH-indazolecarboxamide (2) is depicted below in Scheme 28.
//\N 0” cxxrx col” HzN—QCFJB FUBOH ‘HM—’ HATU DIPEA N/N KOAc, PdClz(dppf)z N,“ DMF, rt, overnight DMF, 90"C, 2h cxvrno cxxvnro 0 cxxx TFA, DCM, Et3SiH, rt, 3 h CI:3 / \N / NH Scheme 28 Step 1 HATU (1.125 g, 2.96 mmol) was added to a solution of 5-bromo—1— (tetrahydro-2H—pyran—2-yl)—lH—indazole—3—carboxylic acid (CXVIII) (0.876 g, 2.69 mmol) and diisopropylethylamine (1.03 mL, 5.92 mmol) in DMF stirred at room temperature under argon. After ng 5 min, the solution was added with 5—amino—2- trifluoromethyl pyridine (CXXVII) (0.479 g, 2.96 mmol). The on was stirred 24 h at room temperature under argon. The DMF was removed under reduced pressure, and the residue was treated with water, sonicated briefly and filtered. The solids were washed with cold water and dried at room temperature. The product was purified by silica gel column chromatography (100% hexanes —> 7:93 EtOAczhexanes) to afford 5-bromo (tetrahydro—2H—pyran—2-yl)—N—(6-(trifluoromethyl)pyridin—3-yl)— 1 H-indazole-3 - amide (CXXVIII) as a white solid (1.17 g, 2.50 mmol, 93% yield). 1H NMR (DMSO'dG) 5 ppm 10.93 (s, 1H), 9.23 (d, J: 1.9 Hz, 1H), 8.60 (dd, J: 6.8, 1.4 Hz, 1H), 8.38 (d, J= 4.4 Hz, 1H), 7.95 (m, 2H), 7.70 (dd, J= 7.1, 1.5 Hz, 1H), ), 6.04 (dd, J= 8.1, 1.9 Hz, 1H), 3.98 (m, 1H), 3.82 (m, 1H), 2.59-2.54 (m, 1H), 2.08-2.03 (m, 2H), 1.81-1.77 (m, 1H). 1.66-1.61 (m, 2H); ESIMS found for BrF3N402 m/Z 470.0 (M+H). gen; A solution of 5—bromo—1-(tetrahydro-2H—pyranyl)—N—(6— (trifluoromethyl) pyridinyl)-1H—indazolecarboxamide (CXXVIII) (0.469 g, 1 mmol), o-pyridylboronic acid (CXXIX) (0.156 g, 1.1 mmol), potassium phosphate tribasic (0.318 g, 1.5 mmol) and water (degassed, 1 mL) in DMF (10 mL) was purged with argon. Tetrakis(triphenylphosphine)palladium(0) (0.034 g, 0.03 mmol) was added and the solution was purged again with argon. The reaction was heated to 90°C for 3 h when TLC showed disappearance of starting material. The solution was cooled to room temperature and excess solvent was removed under vacuum. The residue was treated with water, sonicated briefly and the solids formed were filtered. The solids were washed with cold water and dried under vacuum at room temperature which was purified by silica gel column chromatography (2:8 EtOAczhexanes —> 3:7 EtOAczhexanes) to afford 5-(5 pyridin—3 -yl)- l -(tetrahydro-2H-pyranyl)-N—(6-(trifluoromethyl) pyridin—3—yl)—1H—indazolecarboxan1ide (CXXX) as a white solid (427 mg, 0.88 mmol, 88% yield). 1H NMR (DMSO-dg) 6 ppm 10.95 (s, 1H), 9.25 (d, J: 1.8 Hz, 1H), 8.85 (m, 1H), 8.63 (d, J=1.8 Hz, 1H), 8.61 (d,J= 2.1 Hz, 1H), 8.53 (m, 1H), 8.16-8.13 (m, 1H), 8.08 (d, J: 7.1 Hz, 1H), 7.97—7.94 (m, 2H), 6.11 (dd, J: 8.1, 1.8 HZ, 1H), 4.01 (m, 1H), 3.88—3.83 (m, 1H), 2.63-2.60 (m, 1H), .07 (m, 2H), .80 (m, 1H). 1.69-1.65 (m, 2H); ESIMS found for C24H19F4N502 m/z 486.0 (M+H).
Step 3 TFA (10 mL) was added to a solution of 5-(5-fluoropyridin—3~yl)—1- (tetrahydro—2H—pyran—2-yl)—N—(6—(trifluoromethyl)pyridin-3 -yl)- l H—indazole-3 — carboxamide (CXXX) (0.420 g, 0.86 mmol) and triethylsilane (0.345 mL, 2.16 mmol) in DCM ( 10 mL) and stirred 5 h at room temperature. The solvent was removed under vacuum. The residue was treated with water, sonicated briefly to disperse the solids, basified to pH 9.0 with 5 N NH4OH and sonicated again. The solids were d, washed with cold water and air dried at room ature. The solids were suspended in DCMrMeOH (1:1) mixture and boiled to get a clear solution. The solution was cooled to room temperature. The solids formed were filtered washed with DCM and dried under vacuum at room temperature to get 5-(5-fluoropyridin—3—yl)—N—(6- (trifluoromethyl)pyridin—3 —yl)-1H—indazole—3—carboxamide (2) as a white solid (72.9 mg, 0.18 mmol, 21% yield). 1H NMR (DMSO-d5) 8 ppm 14.13 (br. s, 1H), 11.11 (s, 1H), 9.27 (d,J= 1.8 Hz, 1H), 8.84 (m, 1H), 8.63 (dd, J: 6.8, 1.8 Hz, 1H), 8.60 (d, J: 2.0 Hz, 1H), 8.53 (m, 1H), 8.14-8.11 (m, 1H), 7.94 (d, J = 6.9 Hz, 1H), 7.90—7.83 (m, 2H); ESIMS found for C19H11F4N50 m/z 402.30 (M+H).
The ing nd was prepared in accordance with the procedure described in the above Example 2. 5 -(Pyridin—3-yl)-N-(6-(trifluoromethy1)pyridin—3 -y1)- l H—indazole—3 — amide 3.
White solid (19% yield). 1H NMR (DMSO-ds) 5 ppm 14.03 (br. s, 1H), 11.10 (s, 1H), 9.27 (d, J: 1.8 Hz, 1H), 8.94 (d, J= 1.6 HZ, 1H), 8.63 (dd, J: 6.8, WO 40215 1.7 Hz, 1H), 8.60 (m, 1H), 8.48 (s, 1H), 8.15—8.13 (1n, 1H), 7.93 (d, J: 6.9 Hz, 1H), 7.85 (s, 2H), 7.54 (m, 1H); ESIMS found for C19H12F3N5O m/z 384.0 (M+H).
N—(1—Methy1—5-(trifluoromethyl)—1H—pyrazol—3~y1)-5—(py1'idin-3—y1)- 1H—indazolecarboxamide 37.
Light green solid (76.7 mg, 0.20 mmol, 48.4% yield). 1H NMR (DMSO-ds) 5 ppm 3.93 (s, 3H), 7.18 (s, 1H), 7.55 (dt, J=8Hz, J=3Hz, 1H), 7.81 (dd, J=15Hz, J=9Hz, 2H), 8.16 (d, J=8Hz, 1H), 8.45 (s, 1H), 8.61 (d, J=4Hz, 1H), 8.95 (s, 1H), 10.81 (s, 1H), 13.96 (s, 1H); ESIMS found for C13H13F3N60 m/z 387.1 (M+H). 5-(Pyridin-3 -y1)—N—(pyridin-3 -ylmethyl)—1H—indazolecarb0xamide White solid (54.5 mg, 0.17 mmol, 78% yield). 1H NMR (DMSO-ds) 5 ppm 4.53 (d, J=6Hz, 2H), 7.35 (dd, J=8Hz, J=5Hz, 1H), .52 (m, 1H), 7.74-7.78 (m, 3H), 8.09-8.11 (m, 1H), 8.41—8.42 (m, 1H), 8.45 (dd, J=5Hz, J=2Hz, 1H), 8.57 (dd, J=5Hz, J=2Hz, 1H), 8.59 (d, J=2Hz, 1H), 8.90 (d, J=2Hz, 1H), 9.16 (t, J=6Hz, 1H), 13.77 (s, 1H); ESIMS found for C19H15N50 m/z 330 (M+H). ] 5 —(Pyridin-3 —yl)—N—(4~(trifluoromethyl)pyridinyl)-1H-indazole-3 - carboxamide 48.
White solid (67 mg, 0.17 mmol, 62% yield). 1H NMR (DMSO—d6) 5 ppm 7.52 (dd, J=8Hz, J=5Hz, 1H), 7.83-7.87 (m, 3H), 8.12 (td, J=8Hz, J=2Hz, 1H), 8.41 (t, J=1Hz, 1H), 8.59 (dd, J=5Hz, J=2Hz, 1H), 8.75 (d, J=5Hz, 1H), 8.92 (d, J=3Hz, 1H), 9.08 (s, 1H), 10.21 (s, 1H), 14.06 (hrs, 1H); ESIMS found for C19H12F3N5O m/z 384.0 (M+H). 5-(Pyridin-3 —yl)—N—(6—(pyrrolidin—1~yl)pyridin-3 -yl)-1H—indazole-3 — carboxamide 53.
Beige solid (23.8 mg, 0.06 mmol, 44.5% . 1H NMR (DMSO-dg) 6 ppm 1.92—1.97 (m, 4H), 3.38 (t, J=7Hz, 4H), 6.46 (d, J=9Hz, 1H), 7.52 (dd, J=8Hz, J=5Hz, 1H), 7.80 (dq, J=9Hz, J=2Hz, 2H), 7.97 (dd, J=9Hz, J=3Hz, 1H), 8.12 (dd, J=8Hz, J=4Hz, 1H), 8.47 (s, 1H), 8.50 (d, J=3Hz, 1H), 8.59 (dd, J=5Hz, J=2Hz, 1H), 8.92 (d, J=2Hz, 1H), 10.22 (s, 1H), 13.86 (s, 1H); ESIMS found for C22H20N6O m/z 385.1 (M+H).
Maj» N—(4-(Cyclopropanecarboxamido)pytridinyl)—5—(pyridinyl)—1H- indazole—3—carboxamide 58.
White solid (32.7 mg, 0.08 mmol, 37.0% yield). 1H NMR (DMSO-ds) ppm 0.84-0.88 (m, 2H), 0.88-0.92 (m, 2H), 1.91—1.99 (m, 1H), 7.52 (dd, J=8Hz, J=5Hz, 1H), 7.73 (d, J=6Hz, 1H), 7.82 (dd, J=12Hz, J=9Hz, 2H), 8.12 (dt, J=9Hz, J=4Hz, 1H), 8.34 (d, J=6Hz, 1H), 8.44 (S, 1H), 8.59 (dd, J=5Hz, J=2Hz, 1H), 8.80 (s, 1H), 8.92 (d, J=2Hz, 1H), 10.03 (s, 1H), 10.31 (S, 1H), 13.98 (s, 1H); ESIMS found for C22H13N602 m/z 399.0 (M+H).
N—(6-(Cyclopentylcarbamoyl)pyridinyl)(pyridin~3—yl)—1H- indazolecarboxamide 181.
Light yellow solid (18 mg, 0.04 mmol, 16.6% yield). 1H NMR ds) 8 ppm 1.50—1.64 (m, 4H), 1.67—1.76 (m, 2H), 1.85-1.94 (m, 4H), 4.24 (quin, J=8Hz, 1H), 7.53 (dd, J=8Hz, J=5Hz, 1H), 7.84 (ABq, 2H), 8.03 (d, J=9Hz, 1H), 8.14 (d, J=8Hz, 1H), 8.45 (d, J=8Hz, 1H), 8.48 (s, 1H), 8.54 (dd, J=9Hz, J=2,5Hz, 1H), 8.60 (d, J=4Hz, 1H), 8.94 (d, J=2Hz, 1H), 9.16 (d, J=2Hz, 1H), 10.97 (s, 1H), 14.08 (brs, 1H); ESIMS found for C24H22N602 m/z 427.1 (M+H).
Example 3 ] Preparation of N,5-di(pyridinyl)—lH-indazolecarboxamide (4) is depicted below in Scheme 29.
WO 40215 CXXXI a“; U\ \ 0“ / / CHO l CHO 1 con: | / N N \ \N N \ \N AgNO3, NaOH, H2 \N N/ KOAc, PdClz(dppf)z N/ Dioxane, rt, overnight N’ DMF, 90°C, 2 h o o o CXIV cxxxn CXXXIII CXXV'II HATU, DIPEA DMF, rt, overnight / \N o o C/N/ / NH / NH | | N \ N \ \/N TFA, DCM, \/N u EtJSiI—I, rt, 3 h N 4 o CXXXIV Scheme 29 S_tep_1 5-Iodo(tetrahydro-2H-pyranyl)-1H-indazolecarbaldehyde (CXIV) (1.53 g, 4.30 mmol), pyridine—3—boronic acid (CXXXI) (0.58 g, 4.73 mmol), and potassium phosphate tribasic (1.37 g, 6.45 mmol) was dissolved in 1,4—dioxane (43.0 mL) and water (9.0 mL). Tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.4301 mmol) was added, and the reaction was heated to 95°C for 2.5 h. The solvent was removed, and the residue was partitioned between EtOAc and water. The organic phase was separated and washed sequentially with water and brine. The al was dried (MgSO4), concentrated, and purified by flash chromatography using a 40 g Thomson normal phase silica gel cartridge» (100% hexanes —> 1:1 EtOAczhexanes) to afford 5-(pyridin—3—y1) (tetrahydro—2H~pyran—2-yl)—1H—indazolecarbaldehyde (CXXXII) (0.62 g, 2.02 mmol, 47% yield) as a tan amorphous solid. 1H NMR (DMSO-ds) 5 ppm 10.23 (s, 1H), 8.95 (d, J: 2.3 Hz, 1H), 8.61 (dd, J: 4.8, 1.5 Hz, 1H), 8.39 (d, J: 0.98 Hz, 1H), 8.17-8.14 (m, 1H), 8.06 (d, J= 8.8 Hz, 1H), .93 (m, 1H), .60 (m, 1H), 6.13 (dd, J= 9.4, 2.4 Hz, 1H), 3.93-3.90 (m, 1H), 3.86-3.81 (m, 1H), 2.45-2.41 (m, 1H), 2.11-2.07 (m, 2H), .78 (m, 1H), 1.66-1.62 (m, 2H); ESTMS found for C18H17N302 m/z 308 (M+H).
Step 2 To a solution of silver nitrate (0.55 g, 3.25 mmol) in water (10 mL) was added a solution of sodium ide (0.26 g, 6.50 mmol) in water (5 mL) to give a brown precipitate. 5-(pyridin-3 -yl)—1—(tetrahydro-2H—pyran—2—yl)-1H-indazole-3 - carbaldehyde (CXXXII) (0.40 g, 1.30 mmol) dissolved in 1,4-dioxane (3 mL) was added to the reaction which was stirred at room temperature for 2 h. The reaction was then extracted with l ether. The s layer was separated and carefully brought to pH = 3 with 10% aqueous HCl. The aqueous layer was then extracted five times with iPrOH/chloroform (1/9). The combined organic layers were then dried (MgSO4) and concentrated to afford 5—(pyridin—3-yl)-1—(tetrahydro-2H-pyran—2—yl)—1H-indazole carboxylic acid (CXXXIII) (0.30 g, 0.93 mmol, 70% yield) as a white solid. 1H NMR (DMSO—ds) 8 ppm 13.28 (br, 1H), 8.93 (s, 1H), 8.60 (d, J: 4.1 HZ, 1H), 8.32 (d, J = 0.83 Hz, 1H), 8.14-8.12 (m, 1H), 8.00 (d, J: 8.8 Hz, 1H), 7.86 (dd, J: 8.8, 1.7 Hz, 1H), 7.52 (dd, J: 7.8, 4.7 Hz, 1H), 6.04 (dd, J = 9.3, 2.3 Hz, 1H), 3.92-3.90 (m, 1H), 3.83— 3.78 (m, 1H), 2.44-2.37 (m, 1H), 2.08-2.02 (m, 2H), .76 (m, 1H), 1.63—1.61 (m, 2H).
To a on of 5-(pyridin—3-yl)~1-(tetrahydro-2H-pyran—2—yl)—1H— le-3—carboxylic acid (CXXXIII) (0.39 g, 1.21 mmol) and 3-aminopyridine (CXXVII) (0.11 g, 1.21 mmol) in DMF (4.0 mL) was added N,N-diisopropylethylamine (0.42 mL, 1.21 mmol). The solution was cooled to 0°C before adding HATU (0.46 g, 1.21 mmol). The ice bath was removed, and the reaction warmed to room temperature and stirred for 2 h. The DMF was removed under reduced pressure, and the residue was partitioned between chloroform and water. The organic phase was separated and washed sequentially with water and brine, dried over MgSO4, filtered, and concentrated. The product was purified by column tography using a 25 g Thomson normal phase silica gel cartridge (100% CHCl3 —> 2:98 MeOH1CHC13) to afford N,5—di(pyridinyl)— 1—(tetrahydro-2H-pyran—2-yl)~1H—indazole—3 -carboxamide (CXXXIV) (0.36 g, 0.90 mmol, 75% yield) as an off-white solid. 1H NMR (DMSO-d5) 5 ppm 10.56 (s, 1H), 9.06 (d, J: 2.4 Hz, 1H), 8.94 (d, J: 2.3 Hz, 1H), 8.60 (dd, J= 4.8, 1.5 Hz, 1H), 8.47 (d, J = 1.1 Hz, 1H), .33 (m, 1H), .29 (m, 1H), 8.16-8.14 (m, 1H), 8.04 (d, J: 8.8 Hz, 1H), 7.90 (dd, J: 8.8, 1.8 Hz, 1H), 7.54-7.52 (m, 1H), 7.43-7.41 (m, 1H), 7.43—7.41 (m, 1H), 6.08—6.06 (m, 1H), 4.01-3.99 (m, 1H), 3.87-3.82 (m, 1H), 2.64-2.57 (m, 1H), 2.11-2.06 (m, 2H), .80 (m, 1H), 1.69-1.65 (m, 2H); ESIMS found for C23H21N502 m/z 400 (M+H).
Step4 ’TFA (5.0 mL) was added to a solution of N,5-di(pyridin—3—yl)—1- (tetrahydro-2H-pyranyl)-1H—indazole-3 -carboxamide (CXXXIV) (0.36 g, 0.90 mmol) and triethylsilane (0.29 mL, 1.81 mmol) in DCM (5.0 mL). The solution was stirred overnight at room temperature. An additional 5.0 mL of TFA was added, and the solution was again stirred overnight. The solvents were removed, and the residue was treated with 7 N ammonia in MeOH. The solvents were again removed, and the product was purified by flash chromatography using a 12 g Thomson normal phase silica gel cartridge (100% CHC13 —+ 5:95 MeOH[7N NH3]:CHCl3) to afford N,5—di(pyridin—3 -yl)-1H-indazole-3— carboxamide (4) (0.23 g, 0.73 mmol, 82% yield) as a white solid. 1H NMR (DMSO-d6) 5 ppm 14.00 (s, 1H), 10.69 (s, 1H), 9.08 (d, J: 2.0 Hz, 1H), 8.93 (d, J: 2.0 Hz, 1H), 8.60 (dd, J = 4.8, 1.3 Hz, 1H), 8.48-8.47 (m, 1H), 8.33-8.31 (m, 2H), 8.15-8.12 (m, 1H), 7.85- 7.81 (m, 2H), 7.54—7.51 (m, 1H), 7.41—7.39 (m, 1H); ESIMS found for C18H13N5O m/z 316 (M+H).
] The ing compounds were prepared in ance with the procedure described in the above Example 3.
N—(3'-Fluor0bipheny1-3~yl)—5-(pyridin—3~yl)-1H—indazole—3— carboxamide 5.
White solid (77 mg, 0.19 mmol, 69% yield). 1H NMR d6) 5 ppm 13.95 (s, 1H), 10.50 (s, 1H), 8.94 (d, J = 2.3 Hz, 1H), 8.59 (dd, J= 4.6, 1.5 Hz, 1H), 8.51 (d, J: 1.0 Hz, 1H), 8.31-8.30 (m, 1H), 8.15-8.13 (m, 1H), 7.99—7.97 (m, 1H), 7.83- 7.82 (m, 2H), 7.55—7.45 (m, 6H), 7.24—7.22 (m, 1H); ESIMS found for C25H17FN4O m/z 409 (M+H). 5-(Pyridin~3 —(pyridin—4—yl)- l H-indazolecarboxamide 6.
Off-white solid (52 mg, 0.16 mmol, 77% . 1H NMR (DMSO-dg) ppm 14.05 (br, 1H), 10.83 (s, 1H), 8.94 (d, J: 2.0 Hz, 1H), 8.60 (dd, J = 4.6, 1.2 Hz, 1H), .47 (m, 3H), 8.15-8.13 (m, 1H), 7.94 (dd, J: 5.0, 1.4 Hz, 2H), 7.86—7.82 (m, 2H), 7.54-7.52 (m, 1H); ESIMS found for C13H13N5O m/z 316 (M+H).
N—(5—((Dimethylamino)methyl)pyridin-3—yl)(pyridin—3 -yl)-1H- indazolecarboxamide 7.
Off-white solid (37 mg, 0.10 mmol, 47% yield). 1H NMR (DMSO—d6) ppm 14.00 (s, 1H), 10.68 (s, 1H), 8.94 (d, J: 2.0 Hz, 1H), 8.91 (d, J: 2.3 Hz, 1H), 8.60 (dd, J= 4.7, 1.2 Hz, 1H), 8.49—8.48 (m, 1H), 8.38—8.37 (m, 1H), 8.21 (d, J: 2.2 Hz, 1H), 8.16—8.13 (m, 1H), 7.85-7.81 (m, 2H), 7.52 (dd, J: 7.9, 4.9 Hz, 1H), 3.44 (s, 2H), 2.19 (s, 6H); ESIMS found for C21H20N6O m/z 373 (M+H). 5 —(Pyridin—3 -yl)-N-(6-(pyrrolidinylmethyl)pyridinyl)-1H- indazole—3-carboxamide 8.
Off-white solid (38 mg, 0.10 mmol, 77% yield). 1H NMR (DMSO-d6) ppm 13.99 (br, 1H), 10.64 (s, 1H), 8.96 (d, J: 2.5 Hz, 1H), 8.93 (d, J: 2.4 Hz, 1H), 8.59 (dd, J: 4.8, 1.5 Hz, 1H), 8.48 (d, J: 1.2 Hz, 1H), 8.27 (dd, J: 8.5, 2.5 Hz, 1H), 8.16—8.12 (m, 1H), 7.84—7.80 (m, 2H), 7.54—7.51 (m, 1H), 7.41 (d, J: 8.5 Hz, 1H), 2.37 (s, 2H), 2.50-2.47 (m, 4H), 1.72—1.70 (m, 4H); ESIMS found for C23H22N60 m/z 399 (M+H).
N—(5—(3-Fluorophenyl)pyridin—3 -(pyridin—3—yl)-1H-indazole-3 - carboxamide 9.
White solid (35 mg, 0.09 mmol, 47% . 1H NMR (DMSO—d6) 5 ppm 14.05 (br s, 1H), 10.79 (s, 1H), 9.13 (d, J: 2.0 Hz, 1H), 8.94 (d, J= 1.9 Hz, 1H), 8.68—8.65 (In, 2H), 8.60 (dd, J: 4.83, 4.83 Hz, 1H), 8.52-8.49 (m, 1H), 8.16-8.12 (m, 1H), 7.85—7.81 (m, 2H), .56 (m, 3H), 7.54-7.50 (m, 1H), 7.31—7.26 (m, 1H). ESIMS found for C24H16FN50 m/z 410.5 (M+H). 2012/055172 N—(2-(4—Methylpiperazin—1-yl)pyridin—3 -yl)-5 din—3 -yl)— l H— indazole-3—carboxamide 11.
White solid (11 mg, 0.03 mmol, 65% yield). 1H NMR (DMSO-dg) 5 ppm 14.10 (s, 1H), 9.63 (s, 1H), 8.93 (d, J: 2.1 Hz, 1H), 8.65-8.59 (m, 2H), 8.48 (s, 1H), 8.16-8.12 (m, 1H), 8.11-8.09 (m, 1H), 7.87-7.80 (m, 2H), 7.55—7.51 (m, 1H), 7.20-7.17 (m, 1H), 3.10-3.06 (m, 4H), 2.80-2.40 (m, 4H), 2.30 (s, 3H). ESIMS found for N7O m/z 414.0 (M+H).
N-(6—(4-Methylpiperazin— l -yl)pyridin-3 -yl)-5—(pyridin—3—yl)- l H- indazole—3-carboxamide 12.
White solid (31 mg, 0.07 mmol, 39% yield). 1H NMR (DMSO-ds) 5 ppm 13.86 (br s, 1H), 10.33 (s, 1H), 8.92 (d, J: 2.1 Hz, 1H), 8.60-8.58 (m, 2H), 8.46 (s, 1H), 8.14—8.11 (m, 1H), 8.10-8.02 (m, 1H), 7.83—7.78 (m, 2H), 7.54-7.50 (m, 1H), 6.86 (d, J: 9.1 Hz, 1H), 345-3 .42 (m, 4H), 2.42-2.39 (m, 4H), 2.21 (s, 3H). ESIMS found for C23H23N7O m/z 414.3 (M+H).
N—(Pyridazin—4—yl)-5~(pyridin—3—yl)-1H—indazolecarboxamide 14.
Off-White solid (50 mg, 0.16 mmol, 99% yield). 1H NMR (DMSO—ds) ppm 14.20-13.90 (br, 1H), 11.15 (s, 1H), 9.71-9.70 (m, 1H), 9.09-9.08 (m, 1H), 8.94 (d, J: 2.0 Hz, 1H), 8.61-8.60 (m, 1H), 8.47—8.46 (m, 1H), 8.25 (dd, J: 5.9, 2.8 Hz, 1H), .13 (m, 1H), 7.86-7.85 (m, 2H), 7.53 (dd, J: 7.8, 5.0 Hz, 1H); ESIMS found for C17H12N60 m/z 317 (M+H).
N—(6-((4—Methylpiperazin—1—yl)methyl)pyridin—3 -yl)—5 —(pyridin-3 -yl)- 1H-indazolecarboxamide 15.
White solid (42 mg, 0.10 mmol, 81% yield). 1H NMR (DMSO—d6) 8 ppm 13.97 (br, 1H), 10.65 (s, 1H), 8.97 (d, J= 2.4 Hz, 1H), 8.93 (d, J: 2.1 Hz, 1H), 8.59 (dd, J: 4.7, 1.5 Hz, 1H), 8.48-8.47 (m, 1H), 8.28 (dd, J: 8.5, 2.5 Hz, 1H), 8.15-8.12 (m, 1H), 7.85—7.81 (m, 2H), 7.54-7.51 (1n, 1H), 7.40 (d, J: 8.5 Hz, 1H), 3.55 (s, 2H), 2.42— 2.28 (m, 8H),2.15 (s, 3); ESIMS found for C24H25N7O m/z 428 (M+H).
Example 4 Preparation of 5—(5-fluoropyridin-3 -(pyridin-3 H—indazole- 3-carboxamide (13) is depicted below in Scheme 30.
/ \N CXXIX / I CXXV O F B \ \ 002” / \ NH H N I Br 2 Br N/ \N WAN \N —> N/ HATU, DIPEA N/ KOAc. 1>dC12(dppf)2 H DM'F, 0°C.”, 2 h H DMF, MW, 180“C, I h CXV cxxxv Scheme 30 Step 1 To a stirring solution of nopyridine (CXXV) (0.195 g, 0.2.07 mrnol) in DMF (10 mL) was added o-1H—indazole—3-carboxylic acid (CXV) (0.500 g, 0.2.07 mmol) and N,N-diisopropylethylamine (0.723 mL, 4.15 mmol). The on mixture was cooled to 0°C and added with HATU (0.787 g, 2.07 mmol). The reaction mixture was allowed to warm to room temperature and stirred for an additional 2 h. The on was concentrated under . The residue was purified by column chromatography (1:99 MeOH[7N NH3]:CHC13 —+ 4:96 MeOH[7N NH3]:CHC13) to afford 5-bromo-N-(pyridin—3—y1)-1H-indazole-3—carboxamide (CXXXV) (0.200 g, 0.63 mmol, 30% yield) as a white solid. ESIMS found for C13H9BrN4O m/z 318.0 (M+H).
Step 2 To a microwave vial was added 5-bromo—N-(pyridin—3-yl)-1H- indazolecarboxamide (CXXXV) (0.200 g, 0.63 mmol), 5-fluoropyridine—3-boronic acid (CXXIX) (0.098 g, 0.694 mmol), tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.032 mmol), potassium phosphate (0.201 g, 0.947 mmol), water (1 mL), and DMF (5 mL). The reaction vial was capped, purged with argon and heated under microwave irradiation for 1 h at 180°C. The solution was filtered through a pad of Celite and concentrated under vacuum. The crude product was purified by column chromatography (100% CHC13 —> 2:98 MeOH[7N NH3]: CHCl3) to afford 5—(5-fluoropyridin—3-yl)-N— (pyridin—3-y1)-1H—indazolecarboxamide (13) (4 mg, 0.01 mol, 2% yield) as a white solid. 1H NMR (DMSO—d6) 5 ppm 14.02 (br s, 1H), 10.70 (s, 1H), 9.08 (d, J= 2.5 Hz, 1H), 8.83 (t, J: 1.8 Hz, 1H), 8.60 (d, J: 2.7 Hz, 1H), 8.53-8.52 (m, 1H), 8.34—8.29 (m, 2H), 8.14-8.09 (m, 1H), 7.89-7.81 (m, 2H), 7.42-7.38 (m, 1H). ESIMS found for C13H12FN50 m/z 334.0 (M+H).
Example 5 Preparation of N-(pyridin—3—yl)(5-(trifluoromethyl)pyridin—3—y1)- 1H-indazolecarboxamide (16) is depicted below in Scheme 31.
CXXVH \N \N ma Q};<:::: 2:: Br\©:<N —N N/ HATU DIPEA KOAc PdCl2(dppf)z DMF, rt, overnight DMF, 90°C, 2 h CXVHI CXXXVC CXXXVIO CXXXVII F36 Br K3PO4, Pd (PPh3)4 H20, 90"C, 3 h TFA, DCM, Et3S'LH, rt, 3 h CXXXVIII Scheme 31 Step 1 Preparation of intermediate 5-bromo—N—(pyridin—3—yl)-l-(tetrahydro- 2H-pyranyl)-lH—indazole—3-carboxamide ) was performed following the ure listed in Scheme 19, Step 4. Light yellow solid (5.5 g, 13.7 mmol, 88% yield).
ESIMS found for C13H17BrN402 m/z 401.1 (M79B‘+H) and 403.1 (MSIB’+H).
Steps 2-3 Preparation of intermediate N-(pyridin—3-yl)-l-(tetrahydro-ZH—pyran— 2-yl)(5 —(trifluoromethyl)pyridin-3 -yl)-lH-indazole-3—carboxamide (CXXXVIII) was performed ing the procedure listed in Scheme 26, Steps 1-2. Tan solid (295 mg, 0.63 mmol, 84% yield). ESIMS found for C24H20F3N502 m/z 468.1 (M+H).
Step 4 Preparation of N—(pyridin—3-yl)-5—(5—(trifluoromethyl)pyridin—3—yl)- 1H—indazolecarboxamide (16) was perf01med following the procedure listed in Scheme 28, Step 4. White solid (95 mg, 0.25 mmol, 39.3% yield). 1H NMR (DMSO-ds) 5 ppm 7.40 (dd, J=2.2Hz, J=2Hz, 1H), 7.84 (d, J=6.7Hz, 1H), 7.93 (dd, J=l.5Hz, J=7Hz, 1H), 8.29-8.34 (m, 2H), 8.50 (s, 1H), 8.57 (s, 1H), 8.99 (s, 1H), 9.09 (d, J=2Hz, 1H), 9.25 (d, J=1.6Hz, 1H), 10.72 (hrs, 1H); ESIMS found for C19H12F3N5O m/z 383.9 (M+H).
The ing compounds were prepared in accordance with the procedure bed in the above e 5. 5~(5-((Dimethylamino)methyl)pyridiny1)—N—(6-(trifluoromethyl) pyridin—3-yl)-1H—indazolecarboxamide 26.
White solid (93 mg, 0.21 mmol, 78% yield). 1H NMR (DMSO—d6) 5 ppm 2.24 (s, 6H), 3.57 (s, 2H), 7.86 (Abq, J=8Hz, 2H), 7.93 (d, J=9Hz, 1H), 8.04 (brs, 1H), 8.50 (d, J=7Hz, 1H), 8.63 (dd, J=9Hz, J=2Hz, 1H), 8.85 (d, J=2Hz, 1H), 9.27 (d, J=2Hz, 1H), 11.11 (s, 1H), 14.11 (s, 1H); ESIMS found for C22H19F3N60 m/z 441.0 (M+H) N-(5—(3 —(Pyridin—3 -ylcarbamoyl)—lH—indazol-S-yl)pyridin—3—yl) morpholinecarboxamide 32.
White solid (132 mg, 0.30 mmol, 56% yield). 1H NMR (DMSO-dg) 5 ppm 3.49 (t, J=5Hz, 4H), 3.64 (t, J=5Hz, 4H), 7.40 (dd, J=8Hz, J=5Hz, 1H), 7.82 (d, J=1Hz, 1H), 8.26 (t, J=2Hz, 1H), 8.30—8.34 (m, 2H), 8.47 (s, 1H), 8.54 (d, J=2Hz, 1H), 8.72 (d, J=2HZ, 1H), 8.87 (S, 1H), 9.09 (d, 2H2, 1H), 10.71 (S, 1H), 14.01 (S, 1H); ESIMS found for C23H21N703 m/z 444.3 (M+H).
(Dimethylamino)methy1)pyridiny1)-N-(6-(2-fluorophen0xy) pyridin—3-y1)—1H—indazolecarb0xamide 36.
White solid (137 mg, 0.28 inmol, 53% yield). 1H NMR (DMSO-ds) 6 ppm 2.20 (s, 6H), 3.53 (s, 2H), 7.16 (d, J=9Hz, 1H), 7.22—7.40 (m, 4H), 7.82 (d/Abq, J=9Hz, J=1Hz, 2H), 8.00 (t, J=2Hz, 1H), 8.38 (dd, J=9Hz, J=3Hz, 1H), 8.47 (s, 1H), 8.49 (d, J=2Hz, 1H), 8.55 (d, J=3Hz, 1H), 8.83 (d, J=2Hz, 1H), 10.67 (s, 1H), 13.97 (brs, 1H); ESIMS found for C27H23FN602 m/z 383.1 (M+H). 5-(5—(Cyclopropanecarboxamido)pyridin—3-y1)-N—(6~(4- piperazin-l —y1)pyridin—3 —y1)-1H-indazole-3 -carb0xamide 38.
White solid (39 mg, 0.08 mmol, 61% yield). 1H NMR (DMSO-dé) 6 ppm 0.83—0.90 (m, 4H), 1.80-1.86 (m, 1H), 2.25 (brs, 3H), 2.45 (brs, 4H), 3.45 (brs, 4H), 6.86 (d, J=9Hz, 1H), 7.79 (d, J=1Hz, 1H), 8.04 (dd, J=9Hz, J=3Hz, 1H), 8.42 (t, J=2Hz, 1H), 8.46 (s, 1H), 8.60 (dd, J=10Hz, J=3Hz, 2H), 8.76 (d, J=2Hz, 1H), 10.34 (s, 1H), .56 (s, 1H), 13.90 (s, 1H); ESIMS found for C27H27N302 m/z 497.4 (M+H). 5-(5—(Cyclopropanecarboxamido)pyridin~3—yl)—N—(6-(trifluoromethyl) pyridin—3 —yl)- 1 H-indazole-3 —carboxamide 39.
White solid (128 mg, 0.27 mmol, 45% yield). 1H NMR (DMSO-d6) 6 ppm 0.82—0.90 (m, 4H), 1.80-1.86 (m, 1H), 7.84 (s, 2H0, 7.92 (d, J=9Hz, 1H), 8.43 (d, J=2Hz, 1H), 8.48 (s, 1H), 8.61-8.65 (m, 2H), 8.77 (d, J=2Hz, 1H), 9.27 (d, J=2Hz, 1H), .57 (s, 1H), 11.11 (s, 1H), 14.11 (s, 1H); ESIMS found for C23H17F3N602 m/z 467.1 (M+H).
(Dimethylamino)methyl)pyridin—3 —yl)-N—(pyridin-3 -yl)—1H— indazole-3 -carboxamide 40.
White solid (312 mg, 0.84 mmol, 77% yield). 1H NMR (DMSO-ds) 6 ppm 2.21 (s, 6H), 3.53 (s, 2H), 7.40 (dd, J=8Hz, J=5Hz, 1H), 7.83 , J=9Hz, J=2Hz, 2H), 8.01 (t, J=2Hz, 1H), 8.29—8.34 (m, 2H), 8.48 (dd, J=4Hz, J=1Hz, 1H), 8.83 (d, J=2Hz, 1H), 9.08 (d, J=3Hz, 1H), 10.70 (s, 1H), 13.99 (hrs, 1H); ESIMS found for C21H20N50 m/z 373.0 (M+H).
VJKNH Q”\ / NH 5-(5 -(Cyclopropanecarboxamido)pyridin-3 -y1)-N-(pyridin—3 -y1)— 1H- indazolecarboxamide 41.
White solid (148 mg, 0.37 mmol, 71% yield). 1H NMR (DMSO-ds) 8 ppm 0.83-0.90 (m, 4H), 1.80-1.87 (m, 1H), 7.40 (dd, J=8HZ, J=5Hz, 1H), 7.82 (d, J=1Hz, 1H), 8.29-8.34 (m, 2H), 8.43 (t, J=2HZ, 1H), 8.47 (s, 1H), 8.62 (d, J=2Hz, 1H), 8.76 (d, J=2Hz, 1H), 9.08 (d, J=2Hz, 1H), 10.57 (s, 1H), 10.70 (s, 1H), 14.01 (s, 1H); ESIMS found for C22H13N602 m/Z 399.0 (M+H).
N—(Pyridin-3 -y1)-5—(5 ~(pyrrolidiny1methyl)pyridin—3 —y1)— 1 H— indazole—3 ~carboxamide 43.
White solid (157 mg, 0.39 mmol, 76% yield). 1H NMR (DMSO—d6) 6 ppm 1.70-1.74 (m, 4H), 2.46—2.52 (m, 4H), 3.71 (s, 2H), 7.40 (dd, J=8Hz, J=5Hz, 1H), 7.83 (d/Abq, J=9Hz, J=2HZ, 2H), 8.02 (t, J=2HZ, 1H), 8.29—8.34 (m, 2H), 8.48 (s, 1H), 8.51 (d, J=2Hz, 1H), 8.82 (d, J=2Hz, 1H), 9.08 (d, J=2Hz, 1H), 10.70 (s, 1H), 14.00 (s, 1H); ESIMS found for C23H22N60 m/z 399.0 (M+H). thoxypyridin—3 -yl)—5 —(5-(pyrrolidin~1—y1methy1)pyridin—3 -y1)— 1H—indazolecarboxamide 44.
White solid (62 mg, 0.14 mmol, 39% . 1H NMR d6) 5 ppm 1.32 (t, J=7Hz, 3H), 1.70—1.74 (m, 4H), 2.47—2.52 (m, 4H), 3.71 (s, 2H), 4.29 (q, ' 139 J=7Hz, 2H), 6.81 (d, J=9Hz, 1H), 7.82 (d/Abq, J=9Hz, J=2Hz, 2H), 8.01 (t, J=2Hz, 1H), 8.16 (dd, J=9Hz, J=3Hz, 1H), 8.46 (s, 1H), 8.51 (d, J=2Hz, 1H), 8.63 (d, J=2Hz, 1H), 8.81 (d, J=2Hz, 1H), 10.51 (s, 1H), 13.94 (hrs, 1H); ESIMS found for C25H26N602 m/z 443.4 (M+H).
N—(6—Ethoxypyridin-3 -yl)(5—(piperidi11—1 -ylmethyl)pyridin—3 -yl)- 1H-indazole~3 —carboxamide 45.
White solid (98 mg, 0.21 mmol, 44% yield). 1H NMR ds) 8 ppm 1.32 (t, J=7Hz, 3H), 1.34—1.42 (m, 2H), 1.47-1.53 (m, 4H), 2.38 (brs, 4H), 3.56 (s, 2H), 4.29 (q, J=7HZ, 2H), 6.81 (d, J=9Hz, 1H), 7.81 (d/Abq, J=9Hz, J=2HZ, 2H), 7.99 (t, J=2Hz, 1H), 8.16 (dd, J=9Hz, J=3Hz, 1H), 8.46 (d, J=1Hz, 1H), 8.49 (d, J=2Hz, 1H), 8.63 (d, J=2Hz, 1H), 8.81 (d, J=2Hz, 1H), 10.51 (s, 1H), 13.92 (hrs, 1H); ESIMS found for C26H23N602 m/z 457.3 (M+H). 5 —(5~(Pipe1‘idin—1—ylmethyl)pyridin-3 -yl)-N-(pyridin-3 -yl) - 1 H— indazole-3—carboxamide 46.
White solid (126 mg, 0.31 mmol, 52% yield). 1H NMR (DMSO-d6) 8 ppm 1.36-1.42 (m, 2H), 1.48-1.55 (m, 4H), 2.39 (brs, 4H), 3.57 (s, 2H), 7.40 (dd, J=8Hz, J=5Hz, 1H), 7.83 (d/Abq, J=9Hz, J=2Hz, 2H), 7.99 (t, J=2Hz, 1H), 8.30-8.34 (m, 2H), 8.48 (d, J=1Hz, 1H), 8.49 (d, J=2Hz, 1H), 8.82 (d, J=2Hz, 1H), 9.08 (d, J=2Hz, 1H), .70 (s, 1H), 14.00 (hrs, 1H); ESIMS found for C24H24N60 m/z 413.0 (M+H). 5—(5—(Piperidin—1-ylmethyl)pyridin—3-yl)—N—(4-(t1'ifluoromethyl) pyridin-3 -y1)-1H-indazolecarboxamide 47.
White solid (150 mg, 0.31 mmol, 71% yield). 1H NMR (DMSO—dG) 8 ppm 1.34—1.42 (m, 2H), 1.46—1.53 (m, 4H), 2.37 (brs, 4H), 3.55 (s, 2H), 7.81-7.87 (m, 3H), 7.98 (s, 1H), 8.41 (s, 1H), 8.48 (d, J=2Hz, 1H), 8.75 (d, J=5Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.07 (s, 1H), 10.22 (s, 1H), 14.06 (hrs, 1H); ESIMS found for C25H23F3N60 m/z 481.0 (M+H). idin—3 -yl)(3 -(pyrrolidin—1-ylmethyl)phenyl)—lH—indazole—3 — amide 49.
Tan amorphous solid (53.4 mg, 0.13 11111101, 72% yield). 1H NMR dg) 8 ppm 1.70—1.71 (m, 4H), 2.47-2.49 (m, 4H), 3.67 (s, 2H), 7.31 (d, J=8Hz, 1H), 7.40 (dd, J=8Hz, J=5Hz, 1H), 7.44 (t, J=8Hz, 1H), 7.58—7.60 (m, 1H), 7.63—7.64 (m, 1H), 7.76—7.78 (m, 2H), 8.30-8.34 (m, 2H), 8.44 (s, 1H), 9.08 (d, J=2Hz, 1H), 10.68 (s, 1H), 13.93 (s, 1H); ESIMS found for C24H23N50 m/z 398 (M+H). henylpyridin—3 -yl)—5 —(5 -(pyr1‘olidinylmethyl)pyridin-3 —yl)— 1H-indazole—3—carboxamide 50.
Tan flaky solid (61.3 mg, 0.13 mmol, 74% . 1H NMR (DMSO- d6) 8 ppm 1.71-1.72 (m, 4H), 3.72 (s, 2H), 7.39—7.42 (m, 1H), 7.47-7.50 (m, 2H), 7.81~ 7.86 (m, 2H), 8.00 (d, J=9Hz, 1H), 8.02—8.03 (m, 1H), 8.08-8.10 (m, 2H), 8.45 (dd, J=9HZ, J=3Hz, 1H), 8.49-8.50 (m, 1H), 8.51 (d, J=2Hz, 1H), 8.83 (d, J=2Hz, 1H), 9.18 (d, J=3Hz, 1H), 10.81 (s, 1H), 14.03 (s, 1H); ESIMS found for C29H26N60 m/Z 475 (M+H).
N-(Pyridin—3-y1)-5—(6—(pyrrolidin—1-y1)pyridin—3 -y1)-1 H—indazole—3 - carboxamide 51.
Yellow solid (32 mg, 0.08 mmol, 37.8% yield). 1H NMR (DMSO-d6) ppm 1.94—2.01 (m, 4H), 3.42-3.48 (m, 4H), 6.57 (d, J=9Hz, 1H), 7.40 (dd, J=8Hz, J=5Hz, 1H), 7.72 (d, J=1Hz, 2H), 7.85 (dd, J=9Hz, J=3Hz, 1H), 8.29-8.34 (m, 3H), 8.43 (d, J=2Hz, 1H), 9.08 (d, J=2Hz, 1H), 10.63 (s, 1H), 13.87 (s, 1H); ESIMS found for C22H20N6O m/z 385.0 (M+H).
N-(6-Cyanopyridin—3 -yl)(5 -(pyrrolidiny1methyl)pyridin-3 -yl)— 1H-indazole—3-carboxamide 52.
Beige solid (52 mg, 0.12 mmol, 49.1% . 1H NMR (DMSO-ds) 6 ppm 1.70-1.75 (m, 4H), 3.31-3.36 (m, 4H), 7.85 (dq, J=9Hz, J=2Hz, 2H), 8.02 (s, 1H), 8.05 (d, J=9Hz, 1H), 8.47 (s, 1H), 8.52 (d, J=2Hz, 1H), 8.58 (dd, J=9Hz, J=3Hz, 1H), 8.82 (d, J=2Hz, 1H), 9.28 (d, J=2Hz, 1H), 11.18 (s, 1H), 14.13 (hrs, 1H); ESIMS found for C24H21N7O m/z 424.3 (M+H). 5-(6—Methoxypyridin—3 -yl)-N-(pyridin-3 -yl)- l H-indazole-3 - carboxamide 54.
White solid (79.7 mg, 0.23 mmol, 44.2% yield). 1H NMR (DMSO-ds) 8 ppm 3.91 (s, 3H), 6.95 (d, J=9Hz, 1H), 7.40 (dd, J=9Hz, J=5Hz, 1H), 7.78 (dd, , J=2Hz, 2H), 8.06 (dd, J=9Hz, J=3Hz, 1H), 8.29-8.34 (m, 2H), 8.39 (s, 1H), 8.51 (d, J=2Hz, 1H), 9.08 (d, J=3Hz, 1H), 10.67 (s, 1H), 13.91 (hrs, 1H); ESIMS found for C19H15N502 m/z 346.0 (M+H). 5-(5—Benzylpyridin—3 -yl)—N~(pyridin—3 —yl)- l H-indazole-3 —carboxamide Yellow solid (101.9 mg, 0.25 mmol, 76% yield).'1H NMR (DMSO'dG) ppm 4.09 (s, 2H), 7.19—7.23 (m, 1H), 7.30—7.35 (m, 4H), 7.39-7.41 (m, 1H), 7.78—7.82 (m, 2H), 7.99 (t, J=2Hz, 1H), .33 (m, 2H), 8.45 (s, 1H), 8.51 (d, J=2Hz, 1H), 8.76 (d, J=2Hz, 1H), 9.08 (d, J=2Hz, 1H), 10.69 (s, 1H), 14.00 (s, 1H); ESIMS found for C25H19N5O m/z 406 (M+H). henoxypyridin—3—y1)—N~(pyridin—3—y1)—1H-indazole-3— carboxamide 56.
White solid (73.6 mg, 0.18 mmol, 75% yield). 1H NMR dg) 5 ppm 7.17-7.18 (m, 2H), 7.22-7.23 (m, 1H), 7.38-7.41 (m, 1H), .47 (m, 2H), 7.72- 7.73 (m, 1H), 7.80-7.81 (m, 2H), 8.29-8.31 (m, 2H), 8.37-8.38 (m, 1H), 8.44-8.45 (m, 1H), 8.74 (d, J=2Hz, 1H), 9.06 (d, J=2Hz, 1H), 10.69 (s, 1H), 14.00 (s, 1H); ESIMS found for C24H17N502 m/Z 408 (M+H). 5-(5-(Pyrrolidin— 1 —y1methyl)pyridin-3 -y1)-N—(4-(triflu0romethyl) pyridin—3 —y1)-1H-indazolecarboxamide 57.
White solid (64 mg, 0.14 mmol, 35.2% yield). 1H NMR (DMSO—dg) 5 ppm 1.67-1.74 (m, 4H), 2.44-2.52 (m, 4H), 3.70 (s, 2H), 7.81-7.88 (m, 3H), 8.00 (d, J=2Hz, 1H), 8.41 (s, 1H), 8.50 (d, J=2Hz, 1H), 8.75 (d, J=5Hz, 1H), 8.81 (d, J=2Hz, 1H), 9.07 (s, 1H), 10.22 (s, 1H), 14.01 (hrs, 1H); ESIMS found for C24H21F3N60 m/z 467.3 (M+H). 5 -(5~(Cyc1ohexylcarbamoy1)pyridin—3 ~y1)—N—(py1‘idin—3 ~y1)-1H— indazole-3 xamide 59.
Light brown solid (117 mg, 0.27 mmol, 49.7% yield). 1H NMR (DMSO—d6) 5 ppm 1.10-1.21 (m, 1H), 1.28-1.39 (m, 4H), 1.63 (d, J=12Hz, 1H), 1.72- 1.78 (m, 2H), 1.86-1.91 (m, 2H), .87 (m, 1H), 7.41 (dd, J=8Hz, J=5Hz, 1H), 7.84 (d, J=8Hz, 1H), 7.91 (d, J=9Hz, 1H), 8.30-8.36 (m, 2H), 8.48 (t, J=2Hz, 1H), 8.55 (s, 1H), 8.59 (d, J=8Hz, 1H), 8.99 (d, J=2Hz, 1H), 9.04 (d, J=2Hz, 1H), 9.09 (d, J=2Hz, 1H), 10.72 (s, 1H), 14.04 (s, 1H); ESIMS found for C25H24N602 m/z 441.0 (M+H).
RN 1‘\ 5-(3-Fluoro—5-((4-methy1piperazin— 1 -y1)methy1)pheny1)—N—(4- (trifluoromethyl)pyridin~3-y1)-1H—indazolecarboxamide 60. p White solid (43 mg, 0.08 mmol, 76.3% yield). 1H NMR (DMSO-dg) 6 ppm 1.23 (s, 3H), 2.22—2.50 (m, 8H), 3.56 (s, 2H), 7.12 (d, J=9Hz, 1H), 7.42 (dd, J=8Hz, J=2Hz, 1H), 7.47 (s, 1H), 7.80 (d, J=1Hz, 2H), 7.85 (d, J=5Hz, 1H), 8.39 (s, 1H), 8.75 (d, J=5Hz, 1H), 9.08 (s, 1H), 10.22 (s, 1H), 14.02 031‘s, 1H); ESIMS found for C26H24F4N6O m/Z 513.3 (M+H). ] 5-(5 -((4—Methy1piperazin—1 -y1)methyl)pyridin—3 ~yl)—N-(pyridin—3-y1)— 1H—indazole—3-carb0xamide 61.
White solid (81.6 mg, 0.19 mmol, 55% yield). 1H NMR (DMSO-d6) 5 ppm 2.14 (s, 3H), 2.33-2.42 (m, 8H), 3.60 (s, 2H), 7.39-7.41 (m, 1H), 7.81-7.85 (m, 2H), 8.00-8.01 (m, 1H), .33 (m, 2H), 8.47-8.48 (m, 1H), 8.49 (d, J=2Hz, 1H), 8.82 (d, J=2Hz, 1H), 9.08 (d, J=3Hz, 1H), 10.74 (s, 1H), 14.00 (s, 1H); ESIMS found for C24H25N7O m/z 427.8 (M+H).
N—(6—Cyanopyridin-3 -y1)(5—(piperidin— 1 —y1methy1)pyridin—3 -y1)-1H- indazole—3-carb0xamide 62.
Off-White solid (42 mg, 0.10 mmol, 36.9% yield). 1H NMR (DMSO- d6) 5 ppm 1.36-1.42 (m, 2H), 1.47-1.54 (m, 4H), 2.38 (brs, 4H), 3.57 (s, 2H), 7.85 (d, J=1Hz, 2H), 8.00 (t, J=2Hz, 1H), 8.05 (d, J=9Hz, 1H), 8.47 (d, J=1Hz, 1H), 8.50 (d, J=2Hz, 1H), 8.58 (dd, J=9Hz, J=3Hz, 1H), 8.82 (d, J=2Hz, 1H), 9.28 (d, J=2Hz, 1H), 11.18 (s, 1H), 14.12 (brs, 1H); ESIMS found for C25H23N7O m/z 438.1 (M+H). 5-(5—(Piperidin- 1 hyl)pyridin—3 -y1)-N—(6-(triflu01‘omethyl) pyridin-3 -y1)—1H-indazole—3—carb0xamide 63.
White solid (78 mg, 0.16 mmol, 49% yield). 1H NMR dG) 5 ppm 1.35-1.44 (m, 2H), .57 (m, 4H), 2.40 (brs, 4H), 3.59 (brs, 2H), 7.85 (s, 2H), 7.93 (d, J=9Hz, 1H), 8.01 (s, 1H), 8.48 (s, 1H), 8.50 (s, 1H), 8.63 (d, J=8Hz, 1H), 8.83 (s, 1H), 9.27 (s, 1H), 11.11 (s, 1H), 14.11 (brs, 1H); ESIMS found for C25H23F3N60 m/z 481.1 (M+H). 5-(5-(Morpholinomethyl)pyridin—3 -y1)-N-(pyridin—3~y1)-1H-indazole— 3-Carboxamide 64.
White solid (77 mg, 0.19 mmol, 66% yield). 1H NMR (DMSO—d6) 5 ppm 2.41—2.43 (m, 4H), 3.58-3.60 (m, 4H), 3.61 (s, 2H), 7.39-7.41 (m, 1H), 7.81—7.85 (m, 2H), 8.02-8.03 (m, 1H), 8.31-8.33 (m, 2H), 8.47-8.48 (m, 1H), 8,51 (d, J=2Hz, 1H), 8.83 (d, J=2Hz, 1H), 9.08 (d, J=2Hz, 1H), 10.70 (s, 1H), 14.00 (s, 1H); ESIMS found for C23H22N602 m/z 415 (M+H).
N~(6~Phenylpyridin-3 —y1)(5-(piperidin— 1 —y1methy1)pyridin—3 —y1)— 1H-indazole-3 -Carb0xamide 65.
White solid (61.5 mg, 0.13 mmol, 68% yield). 1H NMR dg) 5 ppm 1.39—1.40 (m, 2H), 1.49-1.53 (m, 4H), 2.38—2.39 (m, 4H), 3.57 (s, 2H), 7.39-7.43 (m, 1H), 7.47—7.50 (m, 2H), 7.82—7.86 (m, 2H), 7.99-8.01 (m, 2H), 8.08—8.10 (m, 2H), 8.44 (dd, J=9Hz, J=3Hz, 1H), 8.50-8.51 (m, 2H), 8.83 (d, J=2Hz, 1H), 9.18 (d, J=3Hz, 1H), .81 (s, 1H), 14.02 (s, 1H); ESIMS found for C30H28N60 m/z 489 (M+H). 5-(5-Cyanopyridin—3 -yl)—N—(pyridin—3 -yl)-1H-indazolecarboxamide Beige solid (107 mg, 0.31 mmol, 66.7% yield). 1H NMR (DMSO-d6) 6 ppm 7.40 (dd, J=8Hz, J=4Hz, 1H), 7.84 (d, J=8Hz, 1H), 7.91 (dd, J=9Hz, J=2Hz, 1H), 8.30-8.34 (m, 2H), 8.57 (s, 1H), 8.72 (t, J=2Hz, 1H), 9.03 (d, J=2Hz, 1H), 9.09 (d, J=2Hz, 1H), 9.23 (d, J=2Hz, 1H), 10.72 (s, 1H), 14.06 (s, 1H); ESIMS found for C19H12N60 m/z 340.8 (M+H). 5 —(3-Fluoro—5-(piperidin—1-ylmethyl)phenyl)-N—(pyridin—3 —y1)-1 H- le-3~carboxamide 67.
Yellow solid (84 mg, 0.20 mmol, 66% . 1H NMR (DMSO—ds) 6 ppm 1.37-1.39 (m, 2H), 1.49—1.54 (m, 4H), 2.37—2.38 (m, 4H), 3.54 (s, 2H), 7.12-7.13 (m, 1H), 7.39—7.43 (m, 2H), 7.47-7.48 (m, 1H), 7.77-7.81 (m, 2H), 8.31-8.33 (m, 2H), 8.44- 8.45 (m, 1H), 9.08 (d, J=2Hz, 1H), 10.69 (s, 1H), 13.97 (s, 1H); ESIMS found for C25H24FN5O m/z 430 (M+H). ] 5-(5-(Morpholinomethyl)pyridinyl)-N-(6-(trifluoromethyl)pyridin— 3—yl)~1H-indazole-3—carboxamide 68.
White solid (72 mg, 0.15 mmol, 30.5% yield). 1H NMR (DMSO-d6) 6 ppm 2.43 (brs, 4H), 3.56-3.63 (m, 4H), 3.62 (s, 2H), 7.85 (Abq, J=9Hz, 2H), 7.93 (d, J=9Hz, 1H), 8.04 (s, 1H), 8.49 (s, 1H), 8.52 (d, J=1Hz, 1H), 8.63 (dd, J=9Hz, J=3Hz, 1H), 8.84 (d, J=2Hz, 1H), 9.27 (d, J=2Hz, 1H), 11.11 (s, 1H), 14.11 (hrs, 1H); ESIMS found for C24H21F3N602 m/z 483.3 (M+H).
N—(6-Morpholinopyridin—3 -yl)—5-(5 -(piperidin— 1 -ylmethyl)pyridin—3 - -indazolecarboxamide 69.
Light yellow solid (58 mg, 0.12 mmol, 36.4% yield). 1H NMR (DMSO-ds) 5 ppm 1.37-1.44 (m, 2H), 1.51 (quin, J=5Hz, 4H), 2.33—2.40 (m, 4H), 3.40 (t, J=5Hz, 4H), 3.56 (s, 2H), 3.71 (t, 5H2, 4H), 6.89 (d, J=9Hz, 1H), 7.78 (d, J=8Hz, 1H), 7.81 (d, J=9Hz, 1H), 7.97 (t, J=2Hz, 1H), 8.06 (dd, J=9Hz, J=2Hz, 1H), 8.46 (d, J=10Hz, 1H), 8.60 (d, J=2Hz, 1H), 8.79 (d, J=2Hz, 1H), 10.35 (s, 1H), 13.90 (hrs, 1H); ESIMS found for C23H31N702 m/z 498.0 (M+H).
N—(6—(4-Methylpiperazinyl)pyridin-3 -yl)-5—(5-(piperidin ylmethyl)pyridinyl)-lH-indazole—3—carboxamide 70.
Light yellow solid (37 mg, 0.07 mmol, 39.2% yield). 1H NMR (DMSO-d6) 5 ppm 1.37-1.44 (m, 2H), 1.51 (quin, J=5Hz, 4H), 2.22 (s, 3H), .42 (m, 8H), 3.44 (t, J=5Hz, 4H), 3.56 (s, 2H), 6.86 (d, J=9Hz, 1H), 7.79 (d, J=9HZ, 1H), 7.82 (d, J=10Hz, 1H), 7.98 (d, J=2Hz, 1H), 8.03 (dd, J=9Hz, J=3Hz, 1H), 8.48 (d, J=11Hz, 1H), 8.58 (d, J=3Hz, 1H), 8.81 (d, J=3Hz, 1H), 10.34 (s, 1H), 13.89 (hrs, 1H); ESIMS found for NgO m/z 511.5 (M+H). 5 -(5—(Piperidin—1-ylmethy1)pyridin—3 —y1)-N-(6-(pyrrolidin—1 -y1) pyridin—3 -yl)-1H-indazole-3 -carboxamide 71.
Tan solid (53.9 mg, 0.11 mmol, 53% yield). 1H NMR (DMSO-d6) 8 ppm 1.38-1.39 (m, 2H), 1.51—1.52 (m, 4H), 1.93—1.96 (m, 4H), 2.36—2.38 (m, 4H), 3.36— 3.39 (m, 4H), 3.56 (s, 2H), 6.46 (d, J=9Hz, 1H), 7.78-7.83 (m, 2H), 7.96 (dd, J=9HZ, J=3Hz, 1H), 7.98—7.99 (m, 1H), .47 (m, 2H), 8.49 (, d, J=3Hz, 1H), 8.80-8.81 (m, 1H), 10.23 (s, 1H), 13.87 (s, 1H); ESIMS found for C28H31N7O m/z 482 (M+H).
] N—(6-(3-Fluorophenyl)pyridin~3-yl)—5—(5-(piperidin—1-ylmethyl) n-3 -yl)—1H-indazole-3—carboxamide 72.
White solid (54.8 mg, 0.11 mmol, 64% yield). 1H NMR (DMSO-ds) 5 ppm 1.39-1.40 (m, 2H), .54 (m, 4H), 2.38—2.39 (m, 4H), 3.57 (s, 2H), 7.22—7.26 (m, 1H), 7.51-7.55 (m, 1H), 7.82-7.86 (m, 2H), 7.88-7.91 (m, 1H), 7.94—7.96 (m, 1H), 8.00— 8.01 (m, 1H), 8.06 (d, J=9Hz, 1H), 8.46 (dd, J=9Hz, J=3Hz, 1H), 8.50 (s, 2H), 8.82 (d, J=2Hz, 1H), 9.20 (d, J=2Hz, 1H), 10.86 (s, 1H), 14.03 (s, 1H); ESIMS found for C30H27FN6O m/z 507 (M+H).
N-(6-(4-Fluorophenyl)pyridin—3—yl)—5~(5—(piperidin—1-ylmethy1) pyridin-3 -y1)—1H-indazolecarboxamide 73.
White solid (50.8 mg, 0.10 mmol, 55% yield). 1H NMR (DMSO-d6) 8 ppm 1.39—1.40 (m, 2H), 1.49—1.53 (m, 4H), 2.36-2.39 (m, 4H), 3.57 (s, 2H), 7.29-7.32 (m, 2H), 7.82—7.86 (m, 2H), 7.98—8.01 (m, 2H), 8.12-8.15 (m, 2H), 8.43 (dd, J=9Hz, J=3Hz, 1H), 8.49 (s, 2H), 8.82 (d, J=2Hz, 1H), 9.17 (d, J=3Hz, 1H), 10.81 (s, 1H), 14.02 (s, 1H); ESIMS found for C30H27FN60 m/z 507 (M+H). (2-(Dimethylamino)ethyl)(methyl)amino)pyridin—3—yl)—5-(5— (piperidiny1methy1)pyridin—3-yl)—1H-indazolecarboxamide 74.
Light yellow solid (88.5 mg, 0.17 mmol, 61.7% yield). 1H NMR (DMSO-dg) 5 ppm 1.38-1.42 (m, 2H), 1.51 (quin, J=5Hz, 4H), 2.18 (s, 6H), 2.34-2.40 (m, 6H), 2.99 (s, 3H), 3.56 (s, 2H), 3.61 (t, J=7Hz, 2H), 6.61 (d, J=9HZ, 1H), 7.79 (d, J=9Hz, 1H), 7.81 (d, J=9Hz, 1H), 7.95 (dd, J=9Hz, J=3Hz,\1H), 7.98 (t, J=2Hz, 1H), 8.46 (s, 1H), 8.48 (d, J=2Hz, 2H), 8.81 (d, J=2Hz, 1H), 10.24 (s, 1H), 13.84 (hrs, 1H); ESIMS found for N30 m/z 513.5 (M+H). 5 -(5 -(Piperidin— 1 —ylmethyl)pyridin—3—yl)-N—(pyridaziny1) - 1 H- indazole—3-carboxamide 75.
White solid (53 mg, 0.13 mmol, 33.7% yield). 1H NMR (DMSO-ds) 5 ppm 1.36-1.43 (m, 2H), 1.47-1.54 (m, 4H), 2.33—2.42 (m, 4H), 3.57 (s, 2H), 7.85 (s, 2H), 8.00 (t, J=2Hz, 1H), 8.25 (dd, J=6Hz, J=3Hz, 1H), 8.47 (t, J=1HZ, 1H), 8.50 (d, J=2Hz, 1H), 8.82 (d, J=2Hz, 1H), 9.09 (d, J=6Hz, 1H), 9.71 (dd, J=3Hz, J=1Hz, 1H), 11.16 (s, 1H), 14.16 (hrs, 1H); ESIMS found for C23H23N7O m/z 414.1 (M+H). 5—(5 -(Piperidin-1 -ylmethyl)pyridin—3 -yl)-N-(pyridin-3 —ylmethyl)— 1H— indazolecarboxamide 76.
White solid (26.8 mg, 0.06 mmol, 27% yield). 1H NMR (DMSO-d6) 5 ppm 1.38-1.39 (m, 2H), 1.49-1.51 (m, 4H), 2.36—2.37 (m, 4H), 3.55 (s, 2H), 4.53 (d, J=6Hz, 2H), 7.35 (dd, J=8Hz, J=5Hz, 1H), 7.74-7.80 (m, 3H), 7.95-7.96 (m, 1H), 8.41- 8.42 (m, 1H), 8.45-8.46 (m, 1H), 8.48-8.49 (m, 1H), 8.58-8.59 (m, 1H), 8.78 (d, J=2Hz, 1H), 9.17 (t, J=6Hz, 1H), 13.77 (s, 1H); ESIMS found for C25H26N60 m/z 427 (M+H).
N—Cyclohexyl—5-(5—(piperidin—1-ylmethyl)pyridin-3 -yl)—1H—indazole— 3-carboxamide 77.
White solid (50.4 mg, 0.12 11111101, 72.5% yield). 1H NMR d6) ppm 1.12—1.47 (m, 7H), 1.50-1.53 (m, 4H), 1.60-1.63 (m, 1H), 1.73—1.75 (m, 2H), 1.83- 1.84 (m, 2H), .38 (m, 4H), 3.55 (s, 2H), 3.81-3.87 (m, 1H), 7.73-7.78 (m, 2H), 7.95-7.96 (m, 1H), 8.14 (d, J=8Hz, 1H), 8.41-8.42 (m, 1H), 8.47 (d, J=2HZ, 1H), 8.78 (d, J=2Hz, 1H), 13.67 (s, 1H); ESIMS found for C25H31N50 m/z 418 (M+H). zo [d] [1 ,3]dioxol-5—yl)-5—(5-(piperidi11—1 -y1methy1)pyridin-3 - y1)-1H-indazole-3—carb0xamide 78.
White solid (48.6 mg, 0.11 mmol, 22.1% yield). 1H NMR (DMSO-dg) 8 ppm 1.37—1.43 (m, 2H), 1.51 (quin, J=5Hz, 4H), 2.36-2.42 (m, 4H), 3.56 (s, 2H), 6.01 (s, 2H), 6.90 (d, J=9Hz, 1H), 7.37 (dd, J=9Hz, J=2Hz, 1H), 7.57 (d, J=2Hz, 1H), 7.91 (dd, J=9Hz, J=Hz, 1H), 7.82 (dd, J=9Hz, J=1Hz, 1H), 7.99 (t, J=2Hz, 1H), 8.47 (dd, J=12Hz, J=2Hz, 1H), 8.81 (d, J=2Hz, 1H), 10.34 (s, 1H), 13.89 (s, 1H); ESIMS found for C26H25N503 m/z 456.0 (M+H).
O//\O N—(2,3-Dihydrobenzo [b] [1 ,4]dioxin—6-y1)—5-(5—(piperidin—1 -y1methyl) pyridin—3—y1)-1H-indazole-3 -carboxamide 79.
White solid (98.4 mg, 0.21 mmol, 38.7% yield). 1H NMR (DMSO—d6) ppm .42 (m, 2H), 1.51 (quin, J=5Hz, 4H), 2.34-2.41 (m, 4H), 3.56 (s, 2H), 4.20— 4.27 (m, 4H), 6.82 (d, J=9Hz, 1H), 7.35 (dd, J=9Hz, J=3Hz, 1H), 7.51 (d, J=3Hz, 1H), 7.78 (dd, J=9Hz, J=1Hz, 1H), 7.81 (dd, J=9Hz, J=1Hz, 1H), 7.98 (t, J=2Hz, 1H), 8.47 (dd, J=12Hz, J=2Hz, 1H), 8.81 (d, J=2Hz, 1H), 10.26 (s, 1H), 13.87 (hrs, 1H); ESIMS found for C27H27N503 m/z 470.4 (M+H).
N—(5—Benzylpyridin-3 -y1)(5-(piperidin— 1—ylmethyl)pyridin-3 -y1)- azolecarboxamide 80.
] White solid (81.9 mg, 0.16 mmol, 59% yield). 1H NMR (DMSO-d6) 5 ppm 1.39—1.41 (m, 2H), 1.49—1.53 (m, 4H), 2.37-2.39 (m, 4H), 3.56 (s, 2H), 4.00 (s, 2H), 7.20-7.23 (m, 1H), 7.28-7.34 (m, 4H), 7.79-7.84 (m, 2H), 7.98-7.99 (m, 1H), 8.23-8.24 (m, 1H), 8.25 (d, J=2Hz, 1H), 8.45—8.46 (m, 1H), 8.49 (d, J=2Hz, 1H), 8.81 (d, J=2Hz, 1H), 8.89 (d, J=2Hz, 1H), 10.65 (s, 1H), 13.97 (s, 1H); ESIMS found for C31H30N60 m/z 503 (M+H). 5 -(5-(Pipen'din—1—ylmethyl)pyridin-3 —y1)-N-(pyrazin—2—yl)- 1H- indazole—3—carboxamide 81.
White solid (104 mg, 0.25 mmol, 41.7% yield). 1H NMR (DMSO-d6) ppm 1.35—1.42 (m, 2H), 1.51 (quin, J=5Hz, 4H), .42 (m, 4H), 3.57 (s, 2H), 7.83 (d, J=9Hz, 1H), 7.85 (d, J=9Hz, 1H), 8.00 (s, 1H), 8.45 (d, J=2Hz, 1H), 8.46 (s, 1H), 8.50 (s, 1H), 8.83 (d, J=2Hz, 1H), 9.50 (s, 1H), 10.36 (s, 1H), 14.11 (hrs, 1H); ESIMS found for C23H23N7O m/z 413.9 (M+H).
N—Phenyl-5 -(5-(piperidinylmethyl)pyridin—3-yl)— l H-indazole-3 - carboxamide 82.
] White solid (97.8 mg, 0.24 mmol, 81% yield). 1H NMR (DMSO-d6) 8 ppm 1.39—1.40 (m, 2H), 1.49-1.53 (m, 4H), 2.37-2.39 (m, 4H), 3.57 (s, 2H), 7.09-7.12 (m, 1H), 7.34-7.37 (m, 2H), 7.80 (d, J=9Hz, 1H), 7.83 (dd, J=9Hz, 2H2, 1H), 7.907.92 (m, 2H), 7.99-8.00 (m, 1H), 8.47-8.48 (m, 1H), 8.49 (d, J=2Hz, 1H), 8.81 (d, J=2Hz, 1H), .40 (s, 1H), 13.92 (s, 1H); ESIMS found for C25H25N5O m/z 412 (M+H). ] (4-Methylpiperazin— 1 -yl)(5—(5—(piperidin—1-ylmethyl)pyridin—3 -yl)-1H— lyl)methanone 83.
Light yellow amorphous solid (74.6 mg, 0.18 mmol, 93% yield). 1H NMR (DMSO-d6) 5 ppm 1.38—1.39 (m, 2H), 1.48-1.53 (m, 4H), 2.22 (s, 3H), 2.36—2.41 (m, 8H), 3.55 (s, 2H), 3.72-3.73 (m, 2H), 4.01—4.02 (m, 2H), 7.73 (d, J=9Hz, 1H), 7.79 (dd, J=9Hz, J=2Hz, 1H), 7.95-7.96 (m, 1H), 8.22 (d, J=1Hz, 1H), 8.46 (d, J=2Hz, 1H), 8.78 (d, J=2Hz, 1H), 13.64 (s, 1H); ESIMS found for C24H30N6O m/z 419 (M+H).
/ NH 5—(5—(((2R,6S)—2,6—Dimethylpiperidin- 1 —yl)methy1)pyridin—3 -y1)-N- (pyridin—3 -yl)—1H-indazole-3 -carboxamide 84.
Beige solid (76.5 mg, 0.17 mmol, 75.5% yield). 1H NMR (DMSO-dg) ppm 1.00 (d, J=6Hz, 6H), 1.21—1.35 (m, 3H), 1.55 (d, , 2H), 1.60-1.65 (m, 1H), 2.45-2.53 (m, 2H), 3.84 (s, 1H), 7.40 (dd, J=7Hz, 3H2, 1H), 7.79 (dd, J=9Hz, J=2Hz, 1H), 7.83 (dd, J=9Hz, J=1Hz, 1H), 8.04 (s, 1H), 8.29-8.35 (m, 2H), 8.46 (s, 1H), 8.60 (d, J=2Hz, 1H), 8.73 (d, J=2Hz, 1H), 9.08 (d, J=3Hz, 1H), 10.70 (s, 1H), 14.00 (hrs, 1H); ESIMS found for C26H23N60 m/z 441.3 (M+H).
N—(5-((Dimethylamino)methyl)pyridin~3 —yl)—5—(5 —(piperidin— 1 - ylmethyl)pyridin—3 -yl)-1H—indazole-3 xamide 86.
White solid (41.5 mg, 0.09 mmol, 72% yield). 1H NMR (DMSO-dg) 5 ppm 1.39-1.40 (m, 2H), 1.49—1.54 (m, 4H), 2.19 (s, 6H), 2.36—2.39 (m, 4H), 3.44 (s, 2H), 3.58 (s, 2H), 7.81 (d, J=9Hz, 1H), 7.85 (dd, J=9Hz, J=2Hz, 1H), 8.00—8.01 (m, 1H), 8.21 (d, J=2Hz, 1H), .38 (m, 1H), 8.49—8.50 (m, 2H), 8.83 (d, J=2Hz, 1H), 8.91 (d, J=2Hz, 1H), 10.69 (s, 1H), 14.01 (hrs, 1H); ESIMS found for C27H31N7O m/z 470 (M+H). 2012/055172 ] N—( 1 -Methylpiperidin—4-y1)-5 -(5-(piperidiny1methy1)py1‘idin—3 ~y1)- 1H—indazolecarboxamide 87.
White amorphous solid (18.2 mg, 0.04 mmol, 59.8% yield). 1H NMR (DMSO—dG) 5 ppm 1.39-1.40 (m, 2H), 1.49-1.53 (m, 4H), 1.66—1.75 (m, 4H), 1.95-2.00 (m, 2H), 2.18 (s, 3H), 2.37—2.38 (m, 4H), 2.77 (d, J=11Hz, 2H), 3.55 (s, 2H), 3.81-3.83 (m, 1H), 7.73-7.75 (m, 1H), 7.77-7.79 (m, 1H), 7.95-7.96 (m, 1H), 8.25 (d, J=8Hz, 1H), 8.41-8.42 (m, 1H), 8.47 (d, J=2Hz, 1H), 8.78 (d, J=2Hz, 1H), 13.70 (s, 1H); ESIMS found for C25H32N60 m/Z 433 (M+H).
N-(5~((Dimethylamino)methy1)pyridin—3 —y1)—5-(5-(pyrrolidin— 1 - ylmethy1)pyridinyl)-1H—indazole-3 -carboxamide 106.
White solid (39.4 mg, 0.09 mmol, 74% yield). 1H NMR dé) 8 ppm 1.71-1.73 (m, 4H), 2.49-2.50 (m, 4H), 2.18 (s, 6H), 3.43 (s, 2H), 3.71 (s, 2H), 7.81 (d, J=9Hz, 1H), 7.84 (ABq, J=9Hz, 1H), 8.02-8.03 (m, 1H), 8.21 (d, J=2Hz, 1H), 8.37- 8.38 (m, 1H), 8.48-8.49 (m, 1H), 8.51 (d, J=2Hz, 1H), 8.83 (d, J=2Hz, 1H), 8.91 (d, J=2Hz, 1H), 10.68 (s, 1H), 13.98 (s, 1H); ESIMS found for C26H29N7O m/z 456 (M+H).
] N-(5-((4-Methy1piperaziny1)methyl)pyridin—3 -y1)-5 ~(5~(piperidin— 1 - ylmethyl)pyridin—3 -yl)- l H—indazole—3—carboxamide 124.
N—(6—(Piperidin— l -yl)pyridin—3 ~yl)~5—(5—(piperidin— l -y1methyl)pyridin— 3—y1)-lH-indazole-3 -carboxa1nide 126.
Grey solid (92.7 mg, 0.19 mmol, 29.0% yield). 1H NMR (DMSO-d6) 5 ppm 1.48-1.64 (m, 12H), 2.32—2.43 (m, 4H), 3.48 (t, J=4.5Hz, 4H), 3.56 (s, 2H), 6.83 (d, J=9Hz, 1H), 7.80 (ABq, , 2H), 7.98 (s, 1H), 8.00 (d, J=2.4Hz, 1H), 8.47 (d, J=10Hz, 2H), 8.55 (d, J=2.5Hz, 1H), 8.81 (d, J=2Hz, 1H), 10.27 (s, 1H), 13.86 (s, 1H); ESIMS found for N7O m/z 496.5 (M+H).
N—(3-Fluorophenyl)-5—(5 ~(piperidin-1—y1methy1)pyridin—3 -y1)— 1 H- indazolecarboxamide 162.
White solid (176 mg, 0.41 mmol, 56.8% yield). 1H NMR (DMSO-d6) ppm 1.36—1.43 (m, 2H), 1.47—1,55 (m, 4H), 2.38 (bl‘S, 4H), 3.56 (s, 2H), 6.93 (dt, J=9Hz, J=3Hz, 1H), 7.39 (q, J=8Hz, 1H), 7.75 (dd, J=8Hz, J=1Hz, 1H), 7.82 (d/Abq, J=9Hz, J=1Hz, 2H), 7.89 (td, J=12Hz, J=2Hz, 1H), 7.99 (t, J=2Hz, 1H), 8.47 (s, 1H), 8.49 (d, J=2Hz, 1H), 8.82 (d, J=2Hz, 1H), 10.66 (s, 1H), 13.97 (brs, 1H); ESIMS found for C25H24FN50 m/z 430.0 (M+H). [0051 1] 5-(5 -(Piperidin-1 hyl)pyridin—3 —yl)—N—(tetrahyd1‘o-2H—pyran—4— yl)-1H—indazolecarboxamide 163.
Tan amorphous solid (88 mg, 0.21 mmol, 88% yield). 1H NMR (DMSO-ds) 6 ppm 1.39-1.40 (m, 2H), 1.49-1.53 (m, 4H), .76 (m, 4H), 2.37-2.38 (m, 4H), 3.39-3.42 (m, 2H), 3.56 (s, 2H), 3.88-3.90 (m, 2H), 4.05-4.10 (m, 1H), 7.74 (d, J=9Hz, 1H), 7.77—7.79 (m, 1H), 7.95-7.96 (m, 1H), 8.37 (d, J=8Hz, 1H), 8.41-8.42 (m, 1H), 8.47 (d, J=2Hz, 1H), 8.79 (d, J=2Hz, 1H), 13.72 (s, 1H); ESIMS found for C24H29N502 m/z 420 (M+H).
N—(S-Fluoropyridin—3 —yl)(5-(pipe1‘idin—1-ylmethyl)pyridin-3 -yl)-1H— indazole-3~carboxamide 168.
] White solid (286 mg, 0.66 mmol, 56% yield). 1H NMR (DMSO-dg) 5 ppm 1.39 (m, 2H), 1.49-1.53 (m, 4H), 2.38 (brs, 4H), 3.56 (s, 2H), 7.81-7.86 (m, 2H), 7.99 (s, 1H), 8.31-8.34 (m, 2H), 8.47 (s, 1H), 8.49 (d, J=l.3 Hz, 1H), 8.82 (d, J=l.7Hz, 1H), 8.99 (s, 1H), 10.97 (s, 1H), 14.07 (brs, 1H); ESIMS found for C24H23FN6O m/z 431.4 (M+H).
N—(6—(4-Hydroxypipe1‘idinyl)pyridin-3 -yl)-5 —(5 -(piperidin— l - ylmethyl)pyridin-3 —yl)- l H-indazolecarboxamide 1 69.
Off—white solid (33 mg, 0.06 mmol, 53.8% yield). 1H NMR (DMSO— d6) 6 ppm 1.32-1.43 (m, 4H), .57 (m, 4H), 1.74-1.83 (m, 2H), 2.33-2.44 (m, 4H), 3.04 (t, J=10Hz, 2H), 3.56 (s, 2H), 3.63—3.73 (m, 1H), 3.93-4.02 (m, 2H), 4.72 (s, 1H), 6.85 (d, J=9Hz, 1H), 7.80 (ABq, , 2H), 7.99 (d, J=7Hz, 2H), 8.47 (d, J=10Hz, 2H), 8.54 (s, 1H), 8.81 (s, 1H), 10.28 (s, 1H), 13.87 (s, 1H); ESIMS found for C29H33N702 m/z 512.3 (M+H). 5-(5—((4-Hydroxypiperidinyl)methyl)pyridin—3 -y1)-N-(6—(pyrrolidin- l -yl)pyridin-3 -yl)—1H—indazolecarboxamide 170.
] Off-white solid (125.4 mg, 0.25 mmol, 73.2% . 1H NMR (DMSO-d6) 5 ppm 1.93—1.96 (m, 4H), 2.09—2.12 (m, 2H), 2.70—2.72 (m, 2H), 3.37-3.39 (m, 4H), 3.46-3.47 (m, 1H), 3.58 (s, 1H), 4.52 (d, J=4Hz, 1H), 6.46 d, J=9Hz, 1H), 7.77- 7.82 (m, 2H), 7.95—7.98 (m, 2H), 8.44-8.48 (m, 2H), 8.49 (d, J=2.5Hz, 1H), 8.80 (d, J=2.1Hz, 1H), 10.20 (s, 1H), 13.85 (s, 1H); ESIMS found for C28H31N702 m/z 498 (M+H). ] ethy1—6—(py1*rolidin— 1 —y1)pyridin-3 —y1)—5-(5 -(piperidin-1 — ylmethyl)pyridin—3-y1)-1H-indazolecarboxamide 172.
Off-White solid (186 mg, 0.38 mmol, 72.2% yield). 1H NMR (DMSO- d6) 6 ppm 1.34-1.43 (m, 2H), 1.47-1.55 (m, 4H), 1.82—1.89 (m, 4H), 2.30 s, 3H), 2.33- 2.42 (m, 4H), 3.43 (t, J=6.6Hz, 4H), 3.56 (s, 2H), 7.81 (ABq, J=10Hz, 2H), 7.89 (d, J=2Hz, 1H), 7.98 (s, 1H), 8.38 (d, J=2Hz, 1H), 8.47 (d, J=8Hz, 2H), 8.81 (d, J=2Hz, 1H), .24 (s, 1H), 13.86 (s, 1H); ESIMS found for C29H33N7O m/z 496.4 (M+H). [0052 1] N—(6-(Azetidin—1-y1)methylpyridin—3-y1)(5 -(piperidin—1 - ylmethyl)pyridin—3-yl)-1H-indazolecarboxamide 1 73.
Off—white solid (184 mg, 0.38 mmol, 62.6% yield). 1H NMR (DMSO- d6) 8 ppm 1.35-1.43 (m, 2H), 1.47-1.54 (m, 4H), 2.16 (s, 3H), 2.22 (quin, J=7Hz, 2H), 2.34-2.42 (m, 4H), 3.56 (s, 2H), 4.00 (t, J=7Hz, 4H), 7.81 (ABq, J=10Hz, 2H), 7.85 (d, J=2Hz, 1H), 8.39 (d, J=2Hz, 1H), 8.47 (d, J=10Hz, 2H), 8.81 (d, J=2Hz, 1H), 10.24 (s, 1H), 13.87 (s, 1H); ESIMS found for C23H31N7O m/Z 482.0 (M+H).
N—(6-(Azetidin-l -yl)pyridin—3 -y1)-5—(5-(piperidin— l hyl)pyridin— 3—yl)-1H—indazole—3-carb0xamide 174.
White solid (14.9 mg, 0.03 mmol, 11.0% yield). 1H NMR (DMSO-d6) 8 ppm 1.36-1.43 (m, 2H), 1.47—1.54 (m, 4H), 2.32 (quin, J=7Hz, 2H), 2.35—2.42 (m, 4H), 3.56 (s, 2H), 3.92 (t, J=7Hz, 4H), 6.39 (d, J=9Hz, 1H), 7.77—7.83 (m, 2H), 7.98 (dd, J=9Hz, J=2Hz, 2H), 8.42-8.53 (m, 3H), 8.78-8.84 (m, 1H), 10.27 (s, 1H), 13.87 (s, 1H); ESIMS found for C27H29N7O m/z 468.0 (M+H).
N—(6-Meth0xypyridin—3 -yl)—5-(5-(piperidin— l -ylmethyl)pyridin—3 -yl)- 1H-indazolecarboxamide 175.
White solid (31.2 mg, 0.07 mmol, 25.8% yield). 1H NMR (DMSO—dg) 8 ppm 1.36-1.43 (m, 2H), .55 (m, 4H), 2.33—2.42 (m, 4H), 3.56 (s, 2H), 3.85 (s, 3H), 6.84 (d, J=9Hz, 1H), 7.81 (ABq, J=12Hz, 2H), 7.98 (s, 1H), 8.18 (dd, J=9Hz, J=2.7Hz, 1H), 8.47 (dd, J=10Hz, J=1Hz, 2H), 8.65 (d, z, 1H), 8.81 (d, J=2Hz, 1H), 10.50 (s, 1H), 13.91 (hrs, 1H); ESIMS found for C25H25N602 m/z 443.4 (M+H).
N—(2—Aminopyrimidin—5~y1)—5 —(5-(piperidinylmethyl)py1'idin—3 -yl)— 1H—indazole-3—carb0xamide 176.
Yellow solid (412 mg, 0.96 mmol, 52.5% yield). 1H NMR dg) ppm 1.37-1.43 (m, 2H), 1.47-1.54 (m, 4H), 2.35-2.41 (m, 4H), 3.56 (s, 2H), 6.49 (s, 2H), 7.81 (ABq, , 2H), 7.98 (s, 1H), 8.47 (dd, J=12Hz, J=2Hz, 2H), 8.63 (s, 1H), 8.81 (d, J=2Hz, 1H), 10.32 (s, 1H), 13.91 (s, 1H); ESIMS found for C23H24N30 m/z 429.3 (M+H).
N-(6-(Piperazin— 1 -yl)pyridin-3 -yl)—5—(5 —(piperidin-1 hyl)pyridin— 3 -yl)~1H-indazole-3 ~carb0xamide 177.
Tan solid (160 mg, 0.32 mmol, 28.5% yield). 1H NMR (DMSO-dé) 5 ppm 1.37—1.43 (m, 2H), 1.48—1.54 (m, 4H), 2.34—2.41 (111,411), 2.79 (t, J=5Hz, 4H), 3.36 (t, J=5Hz, 4H), 3.56 (s, 2H), 6.82 (d, J=9Hz, 1H), 7.81 (ABq, J=10Hz, 2H), 7.98 (s, 1H), 8.02 (dd, J=9Hz, J=2.7Hz, 1H), 8.47 (dd, J=9Hz, J=2Hz, 2H), 8.57 (d, J=2.5Hz, 1H), 8.81 (d, J=2Hz, 1H), 10.29 (s, 1H); ESIMS found for C23H32N30 m/z 497.1 (M+H). 2012/055172 N—(6-Hydroxypyridin—3—yl)(5-(piperidiny1methyl)pyridin—3-yl)— azolecarboxamide 178.
] Off-White solid (78.3 mg, 0.18 mmol, 52.4% yield). 1H NMR (DMSO— d6) 5 ppm 1.36-1.43 (m, 2H), 1.48—1.54 (m, 4H), 2.35-2.42 (m, 4H), 3.56 (s, 2H), 6.38 (d, J=10Hz, 1H), 7.80 (ABq, J=11Hz, 2H), 7.83 (dd, J=10Hz, J=3Hz, 1H), 7.97 (s, 1H), 8.04 (d, J=2.5Hz, 1H), 8.44 (s, 1H), 8.48 (d, J=2Hz, 1H), 8.80 (d, J=2Hz, 1H), 10.27 (s, 1H), 11.42 (hrs, 1H), 13.87 (bI‘S, 1H); ESIMS found for C24H24N602 m/z 429.1 (M+H). 5-(5—(Piperidin—1—ylmethyl)pyridin—3 -yl)-N—(6—(pyrrolidine carbonyl)pyridin—3-yl)—1H-indazole-3 -carboxa1nide 179.
Light yellow solid (61 mg, 0.12 mmol, 37.8% yield). 1H NMR (DMSO—ds) 5 ppm 1.37—1.43 (m, 2H), 1.48-1.55 (m, 4H), 1.82—1.90 (m, 4H), 2.38 (brs, 4H), 3.17 (d, J=5Hz, 2H), 3.51 (t, J=7Hz, 2H), 3.57 (s, 2H), 3.70 (t, J=7Hz, 2H), 7.79 (d, J=9Hz, 1H), 7.84 (Abq, J=11Hz, 2H), 8.00 (s, 1H), 8.46 (dd, J=9Hz, J=2.5Hz, 1H), 8.48 (dd, J=9Hz, J=2Hz, 2H), 8.82 (d, J=2Hz, 1H), 9.10 (d, J=2Hz, 1H), 10.91 (s, 1H), 14.05 (hrs, 1H); ESIMS found for C29H31N702 m/z 510.6 (M+H).
N—(6-(Cyclopentylcarbamoyl)pyridin-3 —yl)-5—(pyridin-3 -yl)~ 1 H- indazole—3-carboxamide 181.
Light yellow solid (18 mg, 0.04 mmol, 16.6% yield). 1H NMR (DMSO-ds) 6 ppm 1.50-1.64 (m, 4H), 1.67-1.76 (m, 2H), 1.85-1.94 (m, 4H), 4.24 (quin, J=8Hz, 1H), 7.53 (dd, J=8Hz, J=5Hz, 1H), 7.84 (ABq, 2H), 8.03 (d, J=9Hz, 1H), 8.14 (d, J=8Hz, 1H), 8.45 (d, J=8Hz, 1H), 8.48 (s, 1H), 8.54 (dd, J=9Hz, J=2,5Hz, 1H), 8.60 (d, J=4Hz, 1H), 8.94 (d, J=2HZ, 1H), 9.16 (d, J=2Hz, 1H), 10.97 (s, 1H), 14.08 (hrs, 1H); ESIMS found for C24H22N502 m/z 427.1 (M+H). 5~(5~Aminopyridin-3 -yl)-N—(6—(piperidin— 1 ~yl)pyridinyl)-1H— indazolecarboxamide 182.
] Off-white solid (23.4 mg, 0.06 mmol, 19.4% yield). 1H NMR (DMSO— d6) 5 ppm 1.51—1.63 (m, 6H), 3.47 (t, J=5Hz, 4H), 5.45 (s, 2H), 6.83 (d, , 1H), 7.24 (t, J=2Hz, 1H), 7.73 (dq, J=9Hz, J=2Hz, 2H), 7.94 (d, J=2.5Hz, 1H), 8.00 (dd, J=9Hz, J=2.5Hz, 1H), 8.08 (d, J=2Hz, 1H), 8.40 (s, 1H), 8.56 (d, J=2.5Hz, 1H), 10.27 (s, 1H), 13.84 (s, 1H); ESIMS found for C23H23N7O m/z 414.3 (M+H). 5-(5-((3,3-Difluoropyrrolidin—1-yl)methy1)pyridin—3~y1)-N-(6- (pyrrolidin— 1—y1)pyridin~3 ~y1)—1H-indazole-3 xamide 183.
Off—white solid (307 mg, 0.61 mmol, 39.6% yield). 1H NMR (DMSO— d6) 5 ppm 1.95 (t, J=6.5Hz, 4H), 2.28 (tt, J=13.5Hz, J=7Hz, 2H), 2.76 (t, J=7Hz, 2H), 2.94 (t, J=13.5Hz, 2H), 3.38 (t, J=6.5Hz, 4H), 3.77 (s, 2H), 6.46 (d, J=9Hz, 1H), 7.81 (dq, J=8.5Hz, J=1.5Hz, 2H), 7.97 (dd, J=9Hz, J=2.5Hz, 1H), 8.03 (s, 1H), 8.48 (s, 1H), 8.49 (d, J=2.5Hz, 1H), 8.52 (s, 1H), 8.84 (d, J=2Hz, 1H), 10.23 (s, 1H), 13.87 (s, 1H); ESIMS found for C27H27F2N7O m/z 504.0 (M+H). 1 84 N—(6-(Cyclopentylcarbamoyl)pyridin~3 —y1)—5—(5 —(piperidin— 1 - ylmethyl)py1‘idin—3—yl)-1H—indazolecarboxamide 184; ] White solid (3.2 mg, 0.01 mmol, 18.5% . 1H NMR (DMSO—d6) 5 ppm 1.36-1.43 (m, 2H), 1.43-1.64 (m, 8H), 1.64—1.76 (m, 2H), 1.82—1.93 (m, 2H), 2.38 (bl'S, 4H), 3.57 (s, 2H), 4.24 (quin, J=7Hz, 1H), 7.84 (ABq, J=10Hz, 2H), 8.00 (s, 1H), 8.03 (d, J=9Hz, 1H), 8.44 (d, J=8Hz, 1H), 8.48 (dd, J=8Hz, J=2Hz, 2H), 8.55 (dd, J=9Hz, J=2.5Hz, 1H), 8.82 (d, J=2.5Hz, 1H), 9.16 (d, J=2.5Hz, 1H), 10.98 (s, 1H), 14.06 (hrs, 1H); ESIMS found for C30H33N702 m/z 524.5 (M+H).
N—(6-(Methylsulfonyl)pyridin—3 -y1)-5 -(5-(piperidiny1methyl) pyridin—3 -y1)-1H-indazolecarb0xamide 185.
White solid (72 mg, 0.15 mmol, 56.4% yield). 1H NMR (DMSO—d6) 3 ppm 1.36—1.43 (m, 2H), 1.48-1.55 (m, 4H), 2.39 (brs, 4H), 3.27 (s, 3H), 3.57 (s, 2H), 7.85 (s, 2H), 8.00 (s, 1H), 8.08 (d, J=8.5Hz, 1H), 8.49 (dd, J=10Hz, J=1.5Hz, 2H), 8.83 (d, z, 1H), 9.26 (d, J=2.5Hz, 1H), 11.19 (s, 1H), 14.13 (brs, 1H); ESIMS found for N603S m/z 491.1 (M+H). {.1 7». 5 -Methy1piperazin—1-y1)pyridin—3 -y1)-N—(6-(pyrrolidin— 1 — y1)py1‘idin—3 ~yl)-1H—indazole—3—carboxamide 186.
Off—white solid (196 mg, 0.41 mmol, 47.8% yield). 1H NMR (DMSO- d6) 5 ppm 1.89-1.98 (m, 4H), 2.27 (brs, 3H), 3.25—3.42 (m, 12H), 6.45 (d, J=9Hz, 1H), 7.53 (s, 1H), 7.77 (q, J=8.5Hz, 2H), 7.96 (d, J=6.5Hz, 1H), 8.31 (d, J=5.5Hz, 2H), 8.43 (s, 1H), 8.48 (s, 1H), 10.21 (s, 1H), 13.83 (s, 1H); ESIMS found for C27H30NgO m/Z 483.4 (M+H). ] 5 —(5-M01pholinopyridin-3 —yl)-N—(6-(pyrrolidin—1—yl)pyridin—3 -yl)-1H- indazole-3 -carboxamide 187.
White solid (92 mg, 0.20 mmol, 43.5% yield). 1H NlVlR (DMSO-ds) 6 ppm 1.94 (t, J=6.5 Hz, 4H), 3.28 (t, z, 4H), 3.38 (t, J=6.5Hz, 4H), 3.78 (t, J=4.5Hz, 4H), 6.45 (d, J=9Hz, 1H), 7.55 (s, 1H), 7.77 (dq, J=8.5HZ, J=1.5HZ, 2H), 7.96 (dd, J=9Hz, J=2.5Hz 1H), 8.33 (dd, J=6.5Hz, J=3Hz, 2H), 8.44 (s, 1H), 8.49 (d, J=2.5Hz, 1H), 10.21 (s, 1H), 13.83 (s, 1H); ESIMS found for C26H27N702 m/z 470.5 (M+H). (3,3-Difluoropyrrolidin—1~yl)methyl)pyridinyl)-N-(pyridin—3- yl)—1H-indazolecarboxamide l 88.
White solid (209 mg, 0.48 mmol, 56.6% yield). 1H NMR (DMSO-dg) 6 ppm 2.23-2.32 (m, 2H), 2.76 (t, J=7Hz, 2H), 2.94 (t, J=13.5Hz, 2H), 3.77 (s, 2H), 7.40 (q, J=8Hz, 1H), 7.83 (dq, J=8Hz, J=2Hz, 2H), 8.04 (s, 1H), 8.31-8.34 (m, 2H), 8.49 (s, 1H), 8.53 (d, J=2Hz, 1H), 8.85 (d, J=2.5Hz, 1H), 9.08 (d, J=2Hz, 1H), 10.70 (s, 1H), 14.01 (hrs, 1H); ESIMS found for C23H20F2N60 m/Z 435.2 (M+H). [0055 1] N—(Pyridin-3 —yl)—5 —(5—(pyrrolidinyl)pyridi11—3 —y1)- l H—indazole—3 — carboxamide 189.
White solid (30 mg, 0.08 mmol, 26.0% yield). 1H NMR dg) 8 ppm 1.91—2.05 (m, 4H), 3.33-3.39 (m, 4H), 7.09 (s, 1H), 7.40 (q, J=8Hz, 1H), 7.79 (s, 2H), 7.96 (d, J=2.5Hz, 1H), 8.14 (s, 1H), 8.30—8.34 (m, 2H), 8.44 (s, 1H), 9.07 (d, J=2Hz, 1H), 10.68 (s, 1H), 13.97 (hrs, 1H); ESIMS found for C22H20N6O m/z 385.2 (M+H). 5 —(5 -((Dimethylamino)methyl)py1‘id'm—3 ~yl)-N-(6-(pyrrolidin~ 1 — yl)pyridinyl)— 1 H—indazole-3 -carboxamide 1 90.
White solid (142 mg, 0.32 mmol, 39.7% yield). 1H NMR (DMSO—d6) ppm 1.92-1.97 (m, 4H), 2.20 (s, 6H), 3.35-3.40 (m, 4H), 3.53 (s, 2H), 6.46 (d, J=9Hz, 1H), 7.80 (dq, J=9Hz, z, 2H), 7.97 (dd, J=9Hz, J=3Hz, 1H), 8.00 (s, 1H), 8.46- 8.50 (m, 3H), 8.82 (d, J=2.5HZ, 1H), 10.22 (s, 1H), 13.86 (hrs, 1H); ESIMS found for C25H27N7O m/z 442.4 (M-l—H).
Example 6 Preparation of N-(6—(2-fluorophenoxy)pyridin-3 -(pyridin—3-yl)— 1H—indazolecarboxamide (18) is depicted below in Scheme 32.
CXXXI ‘1’” \/ \ 0H / / COZMe 1 ‘ 602Me 1 COZH Br / N N \N N \ \ \N NaOH,H20 \N N/ Pd(PPh3)4, K3roJ N/ we, 1h N’ H10, DMF, 90°C 0 o o CXVII CXXXIX CXL Had—@749F7” HATU, DIPEA DMF, rt, overnight . :Qo / \N O o C/N / NH / NH I l N\ N\ \N TFA, DCM, \N / ‘— / H Et3SiH, rt, 3 h N 18 o CXLI Scheme 32 Step 1 To a solution of methyl 5-bromo—1—(tetrahydro—2H—pyran—2-yl)-1H— indazole—3—carboxylate (CXVII) (7.0 g, 20.6 mmol) in DMF (80 mL) and water (16 mL) was added K3PO4 (6.56 g, 30.9 mmol), pyridin—3—ylboronic acid (CXXXI) (2.79 g, 22.7 mmol), Pd(PPh3)4 (1.19 g, 1.03 mmol) and. The solution was purged with argon and heated at 90°C for 3 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The e was dissolved in DCM and washed with water, dried over MgSO4, filtered and then evaporated under vacuum. The e was purified on a silica gel column (100% DCM —> 1.52985 MeOHzDCM) to give methyl 5~(pyridin—3 -yl)—1 ahydro-2H-pyran—2-yl)-1H—indazole-3 -carboxylate (CXXXIX) as an orange oil which solidified at It (6.28 g, 18.6 mmol, 90% yield).
ESIMS found for C19H19N303 m/z 338.0 (M+H).
Step 2 ] Preparation of intermediate 5-(pyridinyl)-1—(tetrahydro-2H-pyran -indazolecarboxylic acid (CXL) was performed ing the procedure listed in Scheme 25, Step 4. White solid (900 mg, 2.78 mmol, 15% yield). ESIMS found for C18H17N3O3 m/z 324.1 (M+H).
Step; Preparation of intermediate N-(6-(2—fluorophenoxy)pyridin-3—yl) (pyridin-3 -yl)-l -(tetrahydro-2H-pyranyl)- l H—indazole—3-carboxamide (CXLI) was performed following the procedure listed in Scheme 28, Step 3. Off-white solid (207 mg, 0.41 mmol, 66% yield). 1H NMR (DMSO-ds) 5 ppm 1.60—1.69 (m, 2H), .87 (m, 1H), 2.03—2.13 (m, 2H), 2.56—2.65 (m, 1H), 3.84 (dt, J=11Hz, J=4Hz, 1H), 3.99 (t, J=11Hz, 1H), 6.07 (dd, J=10HZ, J=2Hz, 1H), 6.98 (dd, J=3HZ, J=2Hz, 1H), 7.03—7.08 (m, 2H), 7.14 (d, J=9Hz, 1H), 7.46 (t, J=7Hz, 1H), 7.61 (dd, J=8Hz, J=5Hz, 1H), 7.91 (dd, J=9Hz, J=2HZ, 1H), 8.05 (d, J=9Hz, 1H), 8.25 (d, J=8Hz, 1H), 8.37 (dd, J=9Hz, J=3Hz, 1H), 8.49 (s, 1H), 8.64 (dd, J=5Hz, J=2Hz, 1H), 8.66 (d, J=3Hz, 1H), 9.00 (d, J=2Hz, 1H), 10.59 (s, 1H); ESIMS found for C29H24FN503 m/z 509.2 (M+H).
Preparation of N—(6—(2~fluorophenoxy)pyridin-3—yl)—5-(pyridin—3-yl)— 1H—indazolecarboxamide (18) was performed following the procedure listed in Scheme 28, Step 4. White solid (128 mg, 0.30 mmol, 54.7% yield). 1H NMR (DMSO-dg) ppm 7.16 (d, J=9Hz, 1H), 7.23—7.39 (m, 4H), 7.52 (dd, J=8Hz, J=5Hz, 1H), 7.79-7.85 (m, 2H), 8.13 (td, J=8Hz, J=2Hz, 1H), 8.38 (dd, J=9Hz, J=3Hz, 1H), 8.46 (s, 1H), 8.56 (d, J=3Hz, 1H), 8.59 (dd, J=5Hz, J=1Hz, 1H), 8.93 (d, J=2Hz, 1H), 10.65 (s, 1H), 13.96 (brs, 1H); ESIMS found for C24H16FN502 m/z 426.0 (M+H).
The following compounds were prepared in ance with the procedure described in the above Example 6.
WO 40215 3-Fluorophenoxy)pyridin—3 —yl)—5 -(pyridin—3-yl)— l H—indazole-3 — carboxamide 19.
Off—white solid (148 mg, 0.35 mmol, 89.3% yield). 1H NMR (DMSO- d6) 5 ppm 6.98 (dd, J=8HZ, J=2Hz, 1H), 7.01-7.06 (m, 2H), 7.13 (d, J=9Hz, 1H), 7.44 (q, J=7Hz, 1H), 7.53 (dd, J=8Hz, J=5Hz, 1H), 780-7 .85 (m, 2H), 8.14 (td, J=6Hz, J=2Hz, 1H), 8.40 (dd, J=9Hz, J=3Hz, 1H), 8.47 (s, 1H), 8.60 (dd, J=5Hz, J=1Hz, 1H), 8.69 (d, J=3Hz, 1H), 8.93 (d, J=2Hz, 1H), 10.71 (s, 1H), 13.99 (s, 1H); ESIMS found for C24H16FN502 m/z 426.0 (M+H).
N-(6—(4—Fluorophenoxy)pyridin—3 —yl)—5—(pyridin-3 -yl)-1H-indazole—3 - carboxamide 20.
White solid (82 mg, 0.19 mmol, 91.8% yield). 1H NMR (DMSO-d6) 5 ppm 7.08 (d, J=9Hz, 1H), 7.15-7.21 (m, 2H), 7.22-7.27 (m, 2H), 7.67 (dd, J=8Hz, J=5Hz, 1H), 7.81-7.88 (m, 2H), 8.31 (d, J=8Hz, 1H), 8.36 (dd, J=9Hz, J=3Hz, 1H), 8.51 (s, 1H), 8.63 (d, J=3Hz, 1H), 8.66 (dd, J=5Hz, J=1Hz, 1H), 9.02 (d, 2Hz, 1H), 10.67 (s, 1H), 14.00 (s, 1H); ESIMS found for C24H16FN502 m/z 426.0 (M+H).
Example 7 Preparation of N-(6-carba1noylpyridin—3—yl)(5—(piperidin ylmethyl)pyridin—3-y1)-1H—indazolecarboxamide (180) is depicted below in Scheme H2S04, HOAc 85°C, 20 min Scheme 33 To a solution of N—(6—cyanopyridin—3-yl)(5—(piperidin ylmethyl)pyridin—3-yl)-1H-indazolecarboxamide (62) (200 mg, 0.45 mmol) in glacial acetic acid (2 mL) heated at 85°C was carefully added dropwise sulfuric acid (2 mL). The reaction was heated at 85°C for another 20 minutes before pouring into ice. The solution was basified with cold 5N NH4OH. The solids formed were d, washed with cold washed and dried under vacuum. The dry solid was suspended in DCM and a few drops of MeOH were added. The insoluble solids were filtered and ded. The filtrate was concentrated and suspended again in DCM, boiled for 15 minutes and filtered. The solid was dried under vacuum to give N—(6—carbamoylpyridin—3-yl)—5-(5-(piperidin—1- ylmethyl)pyridin—3-yl)-1H-indazolecarboxamide (180) as a white solid (192 mg, 0.42 mmol, 93.7% yield). 1H NMR d6) 6 ppm 1.36—1.42 (m, 2H), .55 (m, 4H), 2.38 (brs, 4H), 3.56 (s, 2H), 7.49 (s, 1H), 7.65 (d, J=9Hz, 1H), 7.80 (d, J=9Hz, 1H), 7.97 (s, 1H), 8.03 (s, 2H), 8.41 (s, 1H), 8.45 (d, J=2Hz, 1H), 8.54 (dd, J=9Hz, J=2.5Hz, 1H), 8.80 (d, J=2Hz, 1H), 9.15 (d, J=2Hz, 1H), 10.83 (brs, 1H); ESIMS found for C25H25N702 m/z 456.4 (M+H).
Administration and Pharmaceutical Compositions Some embodiments include phalmaceutical compositions comprising: (a) a safe and therapeutically effective amount of the indazole—3—carboxamide, or its corresponding enantiomer, diastereoisomer or tautomer, or pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier.
The compounds of this invention may also be usefiil in combination (administered together or sequentially) with other known agents. stration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, aneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro—otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, leurally, via wound irrigation, intrabuccally, intra—abdominally, articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, intracisternally, intravascularly, intraventricularly, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic devices. Oral and parenteral administrations are customary in treating the tions. nds of the invention intended for pharmaceutical use may be administered as crystalline or ous products. ceutically acceptable itions may e solid, semi-solid, liquid, solutions, colloidal, liposomes, emulsions, suspensions, xes, coacervates and aerosols. Dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, ts, lled release or the like. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, milling, grinding, supercritical fluid processing, vation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying, or evaporative drying. ave or radio frequency drying may be used for this purpose. The compounds can also be administered in sustained or controlled e dosage forms, including depot injections, osmotic pumps, pills (tablets and or capsules), ermal (including electrotransport) patches, implants and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
] The compounds can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like. The term ient" is used herein to describe any ingredient other than the compound(s) of the invention. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, um stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a—tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, ium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen ate, ium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, ium trisilicate, polyvinyl pyrrolidone, cellulose—based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene—block polymers, and wool fat. Cyclodextrins such as u-, [3, and y-cyclodextrin, or chemically modified derivatives such as yalkylcyclodextrins, including 2— and 3-hydroxypropyl-b-cyclodextrins, or other solubilized tives can also be advantageously used to enhance delivery of compounds of the formulae described . Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. The contemplated compositions may contain -100% active ingredient, in one embodiment 01—95%, in another embodiment 75- 85%, in a further embodiment 20-80%, Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins. 2005).
] In one preferred embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with the active ingredient, a diluent such as e, sucrose, ium phosphate, or the like; WO 40215 a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, , solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG’s, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which the two active ingredients are physically separated are also contemplated; e.g., capsules with'granules (or s in a capsule) of each drug; two-layer tablets; two—compartment gel caps, etc.
Enteric coated or delayed e oral dosage forms are also contemplated.
Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to fonn a solution, colloid, me, on, xes, coacervate or suspension. If desired, the pharmaceutical ition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, vents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, an monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).
In some embodiments, the unit dosage of compounds ofFonnula (I) is 0.25 mg/Kg to 50 mg/Kg in humans.
In some embodiments, the unit dosage of compounds of Formula (I) is 0.25 mg/Kg to 20 mg/Kg in humans.
In some embodiments, the unit dosage of nds of Formula (I) is 0.50 mg/Kg to 19 mg/Kg in humans.
In some embodiments, the unit dosage of compounds of Formula (I) is 0.75 mg/Kg to 18 mg/Kg in humans.
] In some embodiments, the unit dosage of compounds of Formula (I) is 1.0 mg/Kg to 17 mg/Kg in humans.
In some embodiments, the unit dosage of compounds of Formula (I) is 1.25 mg/Kg to 16 mg/Kg in humans.
In some embodiments, the unit dosage of compounds of Formula (I) is 1.50 mg/Kg to 15 mg/Kg in humans.
In some embodiments, the unit dosage of compounds of Formula (I) is 1.75 mg/Kg to 14 mg/Kg in humans.
In some embodiments, the unit dosage of compounds of Formula (I) is 2.0 mg/Kg to 13 mg/Kg in humans.
] In some embodiments, the unit dosage of compounds of Formula (I) is 3.0 mg/Kg to 12 mg/Kg in humans.
In some embodiments, the unit dosage of compounds of a (I) is 4.0 mg/Kg to 11 mg/Kg in humans.
In some embodiments, the unit dosage of compounds of F01mula (I) is .0 mg/Kg to 10 mg/Kg in humans.
In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
In some ments, the itions are provided in unit dosage forms suitable for twice a day administration of a precise dose.
In some embodiments, the compositions are provided in unit dosage forms suitable for three times a day administration of a precise dose.
Injectables can be ed in conventional forms, either as liquid solutions, colloid, liposomes, complexes, coacervate or suspensions, as emulsions, or in solid forms le for titution in liquid prior to injection. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.
However, percentages of active ingredient of 0.01% to 10% in solution are employable, and could be higher if the composition is a solid or suspension, which could be subsequently diluted to the above percentages.
In some embodiments, the composition will comprise 01-10% of the active agent in on.
In some embodiments, the ition will comprise 0.1-5% of the active agent in solution.
In some embodiments, the composition will comprise 0.1-4% of the active agent in solution.
In some embodiments, the composition Will comprise 0.15-3% of the active agent in solution.
In some embodiments, the composition will comprise 0.2—2% of the active agent in solution.
In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1~96 hours.
] In some ments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-72 hours.
In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-48 hours.
In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-24 hours.
In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous on over a period of 1-12 hours.
] In some embodiments, the compositions are provided in dosage forms le for continuous dosage by intravenous infusion over a period of 1-6 hours.
In some embodiments, these compositions can be administered by enous infusion to humans at doses of 5 mg/m2 to 300 mg/mz.
In some embodiments, these compositions can be stered by intravenous infusion to humans at doses of 5 mg/m2 to 200 mg/mz.
In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 5 mg/m2 to 100 mg/mz.
In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 10 mg/m2 to 50 mg/m2.
In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 50 mg/m2 to 200 mg/mz.
In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 75 mg/m2 to 175 mg/mz.
In some embodiments, these itions can be administered by intravenous infusion to humans at doses of 100 mg/m2 to 150 mg/mz.
In one preferred embodiment, the compositions can be administered to the respiratory tract (including nasal and pulmonary) e. g., through a nebulizer, metered- dose inhalers, er, mister, aerosol, dry powder inhaler, insufflator, liquid instillation or other suitable device or que.
In some embodiments, aerosols intended for delivery to the nasal mucosa are provided for inhalation through the nose. For l delivery to the nasal cavities, inhaled particle sizes of about 5 to about 100 microns are useful, with particle sizes of about 10 to about 60 microns being preferred. For nasal delivery, a larger inhaled particle size is desired to maximize impaction on the nasal mucosa and to minimize or prevent pulmonary deposition of the administered formulation. In some embodiments, aerosols ed for delivery to the lung are provided for inhalation through the nose or the mouth. For optimal ry to the lung, inhaled aerodynamic le sizes of equal or less than 10 um are useful, with an aerodynamic particle size of about 0.1 to 10 microns being preferred. Inhaled particles may be defined as liquid ts containing dissolved drug, liquid droplets containing suspended drug particles (in cases where the drug is insoluble in the suspending medium), dry particles of pure drug substance, drug substance incorporated with excipients, liposomes, emulsions, colloidal s, coacervates, aggregates of drug nanoparticles, or dry particles of a diluent which contain ed drug nanoparticles.
In some embodiments, compounds of Formula (I) disclosed herein intended for respiratory delivery (either systemic or local) can be administered as aqueous ations, as non-aqueous solutions or suspensions, as suspensions or solutions in halogenated hydrocarbon propellants with or without l, as a colloidal system, as emulsions, coacervates or as dry powders. Aqueous formulations may be lized by liquid nebulizers employing either hydraulic or ultrasonic atomization or by modified micropump systems (like the soft mist inhalers, the Aerodose® or the AERX® systems). Propellant-based systems may use suitable pressurized metered-dose inhalers (pMDIs). Dry s may use dry powder inhaler devices (DPIs), which are e of dispersing the drug substance effectively. A desired le size and distribution may be obtained by choosing an riate device.
WO 40215 In some embodiments, the compositions of Formula (I) disclosed herein can be administered to the ear by various methods. For example, a round window catheter (e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873) can be used. atively, formulations can be orated into a wick for use between the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) or absorbed to collagen sponge or other solid support (e. g., U.S. Pat. No. 4,164,559).
If desired, formulations of the invention can be incorporated into a gel ation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).
In some embodiments, compounds of Formula (I) disclosed herein intended for delivery to the ear can be stered Via an implanted pump and ry system through a needle ly into the middle or inner ear ea) or through a cochlear implant stylet electrode channel or alternative prepared drug deliveiy channel such as but not limited to a needle through temporal bone into the cochlea.
Other options include delivery via a pump through a thin film coated onto a multichannel electrode or ode with a specially imbedded drug delivery channel (pathways) carved into the thin film for this purpose. In other embodiments the acidic or basic solid gacyclidine can be delivered from the reservoir of an external or internal implanted pumping system.
Formulations of the invention also can be administered to the ear by intratympanic injection into the middle ear, inner ear, or cochlea (e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815).
Intratympanic injection of therapeutic agents is the technique of injecting a therapeutic agent behind the tympanic membrane into the middle and/or inner ear. In one embodiment, the formulations described herein are administered directly onto the round window membrane Via transtympanic injection. In another ment, the ion channel modulating agent acceptable formulations described herein are administered onto the round window ne via a non-transtympanic approach to the inner ear. In additional embodiments, the formulation described herein is stered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the crista fenestrae cochleae.
In some embodiments, the compounds of Fonnula (I) are ated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or ion enemas, containing conventional suppository bases such as cocoa butter or other ides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a e of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
Suppositories for rectal administration of the drug (either as a solution, colloid, suspension or a complex) can be prepared by mixing the drug with a suitable non—irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt or erode/dissolve in the rectum and e the drug.
Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene .
It is to be noted that concentrations and dosage values may also vary with the severity of the ion to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supelvising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or ce of the claimed compositions.
Solid compositions can be provided in various different types of dosage forms, depending on the physicochemical properties of the drug, the desired dissolution rate, cost considerations, and other criteria. In one of the embodiments, the solid composition is a single unit. This implies that one unit dose of the drug is comprised in a , physically shaped solid form or article. In other words, the solid composition is coherent, which is in contrast to a le unit dosage form, in which the units are rent.
Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed s, film—like units, foil—like units, wafers, lyophilized matrix units, and the like. In a preferred embodiment, the solid WO 40215 composition is a highly porous lyophilized form. Such lyophilizates, sometimes also called wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also enables the rapid dissolution of the active compound.
On the other hand, for some applications the solid composition may also be formed as a le unit dosage fonn as defined above. es of multiple units are powders, granules, microparticles, pellets, mini-tablets, beads, lyophilized powders, and the like. In one embodiment, the solid composition is a lyophilized powder.
Such a dispersed lyophilized system comprises a multitude of powder particles, and due to the lyophilization process used in the ion of the , each particle has an irregular, porous microstructure through which the powder is capable of absorbing water very rapidly, resulting in quick dissolution. Effervescent compositions are also contemplated to aid the quick sion and absorption of the compound.
] Another type of articulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water- soluble excipients which are coated with the drug, so that the drug is located at 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 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 cizer, or other excipients used in pharmaceutical coating compositions.
Also provided herein are kits. Typically, a kit includes one or more compounds or compositions as described herein. In certain embodiments, a kit can include one or more delivery systems, e.g., for delivering or administering a compound as provided above, and directions for use of the kit (e.g., ctions for ng a patient).
In another embodiment, the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with cancer. In another embodiment, the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with one or more of hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, bone and cartilage diseases, Alzheimer’s disease, lung disease, osteoarthritis, sis coli, bone y and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra—amelia, Miillerian-duct regression and Virilization, SERKAL me, type II diabetes, nn syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho—dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal sia, focal dermal hypoplasia, mal recessive anonychia, neural tube defects, alpha—thalassemia (ATRX) me, fragile X syndrome, ICF syndrome, an's syndrome, Prader-Willi syndrome, Beckwith—Wiedemann Syndrome, Norrie disease and Rett syndrome The actual dose of the active compounds of the present invention depends on the specific nd, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
Methods of Treatment The compounds and compositions provided herein can be used as inhibitors and/or modulators of one or more components of the Wnt pathway, which may include one or more Wnt proteins, and thus can be used to treat a variety of ers and diseases in which aberrant Wnt signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, and cell cycling.
Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or t angiogenesis, to reduce or inhibit cellular proliferation, to t a genetic disorder, and/or to treat a neurological condition/disorder/disease due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of s, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral ions, bone and cartilage diseases, neurological conditions/diseases such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), motor neurone disease, le sclerosis or autism, lung disease, osteoarthritis, polyposis coli, bone density and 2012/055172 vascular defects in the eye (Osteoporosis—pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Mullerian—duct sion and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, di/Raas-Rothschild/Schinzel phocomelia syndrome, —onycho—dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive hia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF me, Angelman's syndrome, Prader-Willi syndrome, th-Wiedemann Syndrome, Norrie disease and Rett me.
With respect to cancer, the Wnt pathway is known to be constitutively activated in a y of cancers including, for example, colon cancer, cellular carcinoma, lung cancer, ovarian cancer, prostate cancer cancer and leukemias , pancreatic such as CML, CLL and T-ALL. The tutive activation is due to constitutively active B—catenin, s due to its stabilization by interacting factors or inhibition of the degradation pathway. Accordingly, the compounds and compositions described herein may be used to treat these cancers in which the Wnt pathway is constitutively activated.
In certain embodiments, the cancer is chosen from hepatocellular carcinoma, colon , leukemia, lymphoma, sarcoma and ovarian cancer.
Other cancers can also be treated with the compounds and compositions described herein.
More particularly, cancers that may be treated by the compound, compositions and methods described herein include, but are not limited to, the following: 1) Breast cancers, including, for example ERJr breast cancer, ER" breast cancer, her2' breast cancer, her2+ breast cancer, stromal tumors such as fibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumors such as large duct papillomas; carcinomas of the breast including in situ (noninvasive) carcinoma that includes ductal oma in situ (including Paget’s disease) and lobular carcinoma in Situ, and invasive (infiltrating) carcinoma including, but not d to, invasive ductal carcinoma, invasive lobular carcinoma, medullary carcinoma, colloid (mucinous) carcinoma, tubular carcinoma, and invasive papillary oma; and miscellaneous malignant neoplasms.
Further examples of breast cancers can e luminal A, luminal B, basal A, basal B, and triple negative breast cancer, which is estrogen or negative (ER'), progesterone receptor negative, and her2 negative (her2). In some embodiments, the breast cancer may have a high risk pe score. 2) Cardiac s, including, for e sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma. 3) Lung cancers, including, for example, bronchogenic carcinoma, e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma, alveolar and iolar carcinoma; bronchial adenoma; sarcoma; lymphoma; omatous hamartoma; and mesothelioma. 4) Gastrointestinal cancer, ing, for example, cancers of the gus, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancers of the stomach, e. g., oma, lymphoma, and leiomyosarcoma; s of the pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, ibroma, and fibroma; cancers of the large bowel, e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma.
) Genitourinary tract s, including, for example, cancers of the kidney, e.g, adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia; cancers of the bladder and urethra, e.g., squamous cell carcinoma, tional cell carcinoma, and adenocarcinoma; cancers of the prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis, e.g., seminoma, teratoma, nal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, denoma, adenomatoid tumors, and lipoma. 6) Liver cancers, including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma, and hemangioma. 7) Bone cancers, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, ant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors. 8) Nervous system s, including, for example, cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthorna, and osteitis deformans; cancers of the meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma, glioma, moma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma. 9) Gynecological cancers, including, for example, cancers of the uterus, e.g., endometrial carcinoma; cancers of the , e.g., al carcinoma, and pre tumor cervical sia; cancers of the ovaries, e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumors, Sertoli Leydig cell , dysgerminoma, and malignant teratoma; cancers of the vulva, e.g., us cell carcinoma, intraepithelial carcinoma, adenocarcinoma, rcoma, and melanoma; cancers of the , e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopian tubes, e.g., carcinoma. 10) Hematologic cancers, including, for example, cancers of the blood, e. g., acute d leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin's lymphoma, non n's lymphoma (malignant lymphoma) and Waldenstrom's macroglobulinemia. 11) Skin s and skin ers, including, for example, malignant melanoma, basal cell carcinoma, us cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, a, dermatofibroma, keloids, and scleroderma. 12) Adrenal gland cancers, including, for example, neuroblastoma.
] Cancers may be solid tumors that may or may not be metastatic.
Cancers may also occur, as in leukemia, as a diffuse tissue. Thus, the term “tumor cell,” as provided herein, includes a cell afflicted by any one of the above identified disorders.
A method of treating cancer using a nd or composition as bed herein may be combined with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery (e.g., oophorectomy). In some embodiments, a compound or composition can be stered before, during, or after another anticancer agent or ent.
The compounds and compositions described herein can be used as anti-angiogenesis agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatments for cancer and other diseases associated with cellular eration mediated by protein kinases. Accordingly, provided herein is a method of treating cancer or preventing or reducing angiogenesis through kinase inhibition.
In on, and including 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, scleroderma, immunological disorders involving undesired proliferation of leukocytes, and osis and other smooth muscle disorders.
Furthermore, such compounds may be used to prevent de-differentiation of post-mitotic tissue and/or cells.
Diseases or disorders associated with uncontrolled or abnonnal cellular proliferation include, but are not d to, the ing: o a variety of cancers, including, but not limited to, oma, 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. o a e process which features abnormal cellular proliferation, e.g., benign prostatic hyperplasia, familial adenomatosis polyposis, neurofibromatosis, atherosclerosis, arthritis, ulonephritis, restenosis following angioplasty or vascular surgery, atory bowel disease, lantation rejection, endotoxic shock, and fungal infections. ic disorders such as skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; ulonephritis; hypertrophic scar ion; uterine fibrosis; renal fibrosis; cirrhosis of the liver, liver fibrosis; adhesions, such as those occurring in the abdomen, pelvis, spine or tendons; chronic obstructive ary disease; s following myocardial infarction; ary fibrosis; fibrosis and scarring associated with diffiise/interstitial lung disease; central nervous system fibrosis, such as fibrosis ing stroke; fibrosis associated with neuro—degenerative disorders such as Alzheimer's e or multiple sclerosis; fibrosis associated with erative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease and radiation fibrosis. 0 defective apoptosis-associated conditions, such as cancers (including but not limited to those types mentioned herein), viral ions (including but not limited to herpesvirus, poxvirus, Epstein—Barr virus, s Virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus erythematosus, rheumatoid tis, derma, autoimmune mediated glomerulonephritis, atory bowel disease and autoimmune diabetes mellitus), neurodegenerative ers (including but not limited to Alzheimer’s disease, lung disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteroporosis and tis), aspirin—sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain. 0 genetic diseases due to mutations in Wnt signaling components, such as polyposis coli, bone y and vascular defects in the eye (Osteoporosis— pseudoglioma Syndrome, OPPG), familial exudative retinopathy, retinal angiogenesis, early coronary disease, tetra—amelia, Mullerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith—Wiedemann Syndrome, Norrie disease and Rett syndrome.
Furthermore, the nds and compositions described herein can be used to treat neurological conditions, disorders and/or es caused by dysfiinction in the Wnt signaling pathway. Non-limiting examples of neurological conditions/disorders/diseases which can be treated with the compounds and compositions ed herein include Alzheimer's disease, aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attention deficit hyperactivity disorder, auditory processing er, autism, alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, cephalic er, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, al vasculitis, cervical spinal stenosis, Charcot—Marie-Tooth disease, Chiari mation, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin—Lowry syndrome, complex regional pain syndrome, compression neuropathy, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, tive trauma disorder, Cushing’s me, cytomegalic inclusion body disease (CIBD), Dandy-Walker syndrome, Dawson disease, De r's syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phase syndrome, dementia, dermatomyositis, developmental xia, diabetic neuropathy, diffuse sclerosis, Dravet syndrome, onomia, dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome, alitis, encephalocele, encephalotrigeminal angiomatosis, encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor, Fabry's disease, Fahr's syndrome, familial spastic paralysis, febrile seizure, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville's syndrome, Gaucher’s disease, Gerstmann's me, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, gray matter heterotopia, Guillain—Barré syndrome, HTLV-l associated myelopathy, Hallervorden-Spatz disease, hemifacial Spasm, hereditary spastic paraplegia, heredopathia ca uritiformis, herpes zoster oticus, herpes zoster, Hirayama syndrome, holoprosencephaly, Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile Refsum disease, infantile spasms, inflammatory myopathy, ranial cyst, intracranial hypertension, Joubert syndrome, Karak me, Kearns- Sayre syndrome, Kennedy disease, Kinsbourne syndrome, Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease, Lambert-Eaton myasthenic me, Landau-Kleffner syndrome, lateral medullary (Wallenberg) syndrome, Leigh's disease, Lennox-Gastaut syndrome, Nyhan syndrome, leukodystrophy, Lewy body dementia, cephaly, -in syndrome, Lou Gehrig's disease, lumbar disc disease, lumbar spinal stenosis, Lyme disease, Machado-Joseph disease (Spinocerebellar ataxia type 3), macrencephaly, sia, megalencephaly, Melkersson—Rosenthal syndrome, Menieres disease, itis, Menkes disease, etachromatic leukodystrophy, ephaly, micropsia, Miller Fisher syndrome, misophonia, mitochondrial myopathy, Mobius me, monomelic ophy, motor neurone disease, motor skills disorder, Moyamoya disease, mucopolysaccharidoses, multi—infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, c encephalomyelitis, myasthenia graVis, myelinoclastic diffuse sclerosis, myoclonic Encephalopathy of infants, myoclonus, hy, myotubular myopathy, myotonia congenital, narcolepsy, neurofibromatosis, eptic malignant syndrome, lupus erythematosus, neuromyotonia, neuronal ceroid lipofuscinosis, Niemann—Pick disease, ivan—McLeod syndrome, tal gia, occult Spinal Dysraphism Sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension, palinopsia, paresthesia, Parkinson's disease, paramyotonia Congenita, paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralyses, peripheral athy, photic sneeze reflex, phytanic acid storage disease, Pick's disease, crogyria (PMG), polymyositis, porencephaly, post—polio syndrome, postherpetic neuralgia (PHN), postural hypotension, -Willi syndrome, primary lateral sis, prion diseases, progressive hemifacial atrophy, progressive multifocal ncephalopathy, progressive supranuclear palsy, pseudotumor cerebri, Ramsay Hunt syndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome type III, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsum disease, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, ic movement disorder, Romberg syndrome, Saint Vitus dance, Sandhoff disease, phrenia, Schilder's disease, schizencephaly, sensory integration dysfunction, septo-optic dysplasia, Shy-Drager syndrome, Sjogren's syndrome, snatiation, Sotos syndrome, spasticity, spina bifida, spinal cord tumors, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson-Olszewsld syndrome, Stiff-person syndrome, stroke, Sturge—Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, am's , syncope, hesia, syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardive dysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus, tethered spinal cord syndrome, Thomsen disease, thoracic outlet syndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxic encephalopathy, transient ischemic attack, issible spongiform alopathies, transverse myelitis, tremor, trigeminal neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis, sis, Von Hippel—Lindau disease (VHL), Viliuisk Encephalomyelitis (VE), Wallenberg’s me, Werdnig, Hoffman disease, west syndrome, Williams syndrome, Wilson's disease and Zellweger syndrome.
The compounds and itions may also be useful in the inhibition of the development of invasive cancer, tumor angiogenesis and metastasis.
In some embodiment, the ion provides a method for treating a disease or disorder associated with aberrant cellular eration by administering to a patient in need of such treatment an effective amount of one or more of the compounds of Formula (I), in combination (simultaneously or sequentially) with at least one other agent.
In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In some embodiments, the method of treats a disorder or disease in which nt Wnt signaling is implicated in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharrnaceutically acceptable salt thereof.
In some embodiments, the disorder or disease is cancer.
] In some embodiments, the disorder or disease is diabetic retinopathy.
In some embodiments, the disorder or disease is pulmonary fibrosis.
In some ments, the disorder or disease is rheumatoid arthritis.
In some embodiments, the disorder or disease is scleroderrna.
In some embodiments, the disorder or disease is a mycotic or Viral infection.
In some embodiments, the disorder or disease is a bone or age disease.
In some embodiments, the disorder or disease is rthritis.
In some embodiments, the er or e is lung disease.
In some embodiments, the disorder or disease is a genetic disease caused by mutations in Wnt signaling components, wherein the genetic disease is selected from: polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative retinopathy, retinal angiogenesis, early coronary disease, tetra-amelia me, Mullerian—duct regression and Virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, diRaas-Rothschild/Schinzel elia syndrome, odonto-onycho-dermal dysplasia, y, split—hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha—thalassemia (ATRX) syndrome, fragile X me, ICF syndrome, Angelman syndrome, Prader- Willi syndrome, Beckwith—Wiedemann Syndrome, Norrie e and Rett syndrome.
In some embodiments, the patient is a human.
In some embodiments, the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian .
In some embodiments, the cancer is chosen from: lung cancer — non— small cell, lung cancer - small cell, multiple myeloma, nasopharyngeal , neuroblastoma, arcoma, penile cancer, pituitary , prostate cancer, blastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer — basal and squamous cell, skin cancer — ma, small intestine cancer, stomach cancers, testicular cancer, thymus cancer, thyroid cancer, uterine a, vaginal cancer, vulvar cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma, gestational trophoblastic disease, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer oma and lymphoma), Ewing tumor, esophagus cancer, endometrial cancer, colorectal cancer, cervical cancer, brain or spinal cord tumor, bone metastasis, bone cancer, bladder cancer, bile duct cancer, anal cancer and adrenal cortical cancer.
In some embodiments, the cancer is hepatocellular carcinoma.
In some embodiments, the cancer is colon cancer.
In some embodiments, the cancer is breast .
In some embodiments, the cancer is pancreatic cancer.
In some embodiments, the cancer is chronic myelo id leukemia (CML).
In some embodiments, the cancer is chronic myelomonocytic leukemia.
In some embodiments, the cancer is chronic lymphocytic leukemia (CLL).
] In some embodiments, the cancer is acute myeloid ia.
In some embodiments, the cancer is acute lymphocytic leukemia.
In some embodiments, the cancer is n lymphoma.
] In some embodiments, the cancer is lymphoma.
] In some ments, the cancer is sarcoma.
In some embodiments, the cancer is ovarian cancer.
In some embodiments, the cancer is lung cancer — non-small cell.
In some embodiments, the cancer is lung cancer - small cell.
In some embodiments, the cancer is multiple myeloma.
] In some embodiments, the cancer is nasopharyngeal cancer.
In some embodiments, the cancer is neuroblastoma.
] In some embodiments, the cancer is osteosarcoma.
In some embodiments, the cancer is penile cancer.
In some embodiments, the cancer is pituitary tumors.
In some embodiments, the cancer is te cancer.
In some embodiments, the cancer is retinoblastoma.
In some embodiments, the cancer is rhabdomyosarcoma.
In some embodiments, the cancer is salivary gland cancer.
In some embodiments, the cancer is skin cancer — basal and squamous cell.
In some embodiments, the cancer is skin cancer — melanoma.
In some embodiments, the cancer is small intestine cancer.
In some ments, the cancer is stomach cancers.
In some embodiments, the cancer is testicular cancer.
] In some embodiments, the cancer is thymus .
In some embodiments, the cancer is thyroid cancer.
In some embodiments, the cancer is uterine sarcoma.
In some embodiments, the cancer is vaginal cancer.
] In some embodiments, the cancer is vulvar cancer.
] In some embodiments, the cancer is Wilms tumor.
In some embodiments, the cancer is laryngeal or hypopharyngeal cancer.
In some embodiments, the cancer is kidney cancer.
In some embodiments, the cancer is Kaposi sarcoma.
In some embodiments, the cancer is gestational trophoblastic disease.
WO 40215 In some embodiments, the cancer is gastrointestinal stromal tumor.
In some embodiments, the cancer is gastrointestinal carcinoid tumor.
In some embodiments, the cancer is gallbladder cancer.
In some embodiments, the cancer is eye cancer (melanoma and lymphoma).
In some embodiments, the cancer is Ewing tumor.
] In some embodiments, the cancer is esophagus cancer.
In some embodiments, the cancer is endometrial cancer.
In some embodiments, the cancer is colorectal cancer.
In some embodiments, the cancer is cervical cancer.
] In some embodiments, the cancer is brain or spinal cord tumor. ,[00716] In some embodiments, the cancer is bone metastasis.
In some embodiments, the cancer is bone cancer.
In some embodiments, the cancer is bladder cancer.
In some embodiments, the cancer is bile duct cancer.
In some embodiments, the cancer is anal cancer.
In some embodiments, the cancer is adrenal cortical cancer.
In some embodiments, the disorder or disease is a neurological condition, disorder or disease, wherein the neurological ion/disorder/disease is selected from: Alzheimer's disease, frontotemporal dementias, dementia with lewy , prion diseases, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, corticobasal degeneration, mutiple system atrophy, amyotrophic lateral sclerosis (ALS), inclusion body myositis, , degenerative myopathies, diabetic neuropathy, other metabolic neuropathies, endocrine neuropathies, orthostatic hypotension, multiple sclerosis and t-Marie-Tooth disease.
In some embodiments, the compound of Formula (I) inhibits one or more proteins in the Wnt pathway.
] In some embodiments, the nd of Formula (I) inhibits signaling induced by one or more Wnt proteins.
] In some ments, the Wnt proteins are chosen from: WNT], WNTZ, WNTZB, WNT3, WNT3A, WNT4. WNTSA, WNTSB, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNTIOA, WNTIOB, WNTll, and WNT16.
In some ments, the compound of Formula (I) ts a kinase activity.
In some embodiments, the method of treats a disease or disorder mediated by the Wnt pathway in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula (I) inhibits one or more Wnt proteins.
In some embodiments, the method of treats a disease or disorder mediated by kinase activity in a patient, the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of a (I), or a ceutically acceptable salt thereof.
In some embodiments, the disease or disorder comprises tumor growth, cell proliferation, or angio genesis.
In some embodiments, the method of ts the ty of a protein kinase receptor, the method comprises contacting the receptor with an ive amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
In some embodiments, the method treats a disease or disorder associated with aberrant cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt thereof.
In some embodiments, the method prevents or reduces angiogenesis in a t; the method comprises administering to the patient a eutically effective amount of a compound (or compounds) of Formula (I), or a pharmaceutically acceptable salt f.
In some embodiments, the method prevents or reduces al cellular eration in a patient; the method comprises administering to the patient a therapeutically effective amount of a compound (or compounds) of Formula (I), or a phannaceutically acceptable salt thereof.
In some embodiments, the method of treats a disease or disorder associated with aberrant cellular proliferation in a patient, the method comprising administering to the patient a pharmaceutical composition comprising one or more of the compounds of claim 1 in combination with a pharrnaceutically acceptable carrier and one or more other agents.
Moreover, the compounds and compositions, for e, as inhibitors of the CDKs, can modulate the level of cellular RNA and DNA synthesis and therefore are expected to be useful in the treatment of viral infections such as HIV, human papilloma virus, herpes virus, Epstein-Barr virus, irus, Sindbis virus, pox virus and the like.
Compounds and compositions described herein can inhibit the kinase ty of, for example, CDK/cyclin complexes, such as those active in the Go. or G.1 stage of the cell cycle, e. g., CDK2, CDK4, and/or CDK6 complexes.
Evaluation of Biological Activity The biological activity of the compounds described herein can be tested using any suitable assay known to those of skill in the art, e. g., or . For e, the activity of a compound may be tested using one or more of the test methods outlined below.
In one example, tumor cells may be screened for Wnt independent growth. In such a method, tumor cells of interest are contacted with a nd (i.e. inhibitor) of interest, and the proliferation of the cells, e.g. by uptake of tritiated thymidine, is monitored. In some embodiments, tumor cells may be isolated from a candidate patient who has been screened for the ce of a cancer that is associated with a on in the Wnt signaling pathway. Candidate cancers include, without limitation, those listed above.
In another example, one may utilize in vitro assays for Wnt ical activity, e.g. stabilization of nin and promoting growth of stem cells. Assays for ical activity of Wnt include stabilization of fi-catenin, which can be measured, for example, by serial dilutions of a candidate inhibitor composition. An exemplary assay for Wnt ical activity contacts a Wnt composition in the presence of a candidate inhibitor with cells, e.g. mouse L cells. The cells are cultured for a period of time sufficient to stabilize B-catenin, usually at least about 1 hour, and lysed. The cell lysate is resolved by SDS PAGE, then transferred to nitrocellulose and probed with dies specific for B-catenin.
In a r example, the activity of a candidate compound can be measured in a Xenopus secondary axis bioassay (Leyns, L. et al. Cell (1997), 88(6), 747- 756).
Example 7 Another screening assay for Wnt activity is described as follows.
Reporter cell lines can be generated by stably ucing cells of cancer cell lines (e.g., colon cancer) with a lentiviral construct that include a wnt-responsive promoter g expression of the firefly luciferase gene.
Lentiviral ucts can be made in which the SP5 promoter, a promoter having eight TCF/LEF binding sites derived from the SP5 er, is linked upstream of the firefly luciferase gene. The lentiviral constructs can also include a hygromycin resistance gene as a selectable . The SP5 promoter construct can be used to transduce SW480 cells, a colon cancer cell line having a mutated APC gene that generates a truncated APC protein, leading to de-regulated accumulation of nin. A control cell line can be generated using another lentiviral construct containing the luciferase gene under the control of the SV40 promoter which does not e B-catenin for activation.
Cultured SW480 cells bearing a er construct can be distributed at approximately 10,000 cells per well into 96 well or 384 well plates. Compounds from a small molecule compound library can then be added to the wells in half-log dilutions using a ten olar top concentration. A series of control wells for each cell type receive only buffer and compound solvent. Twenty-four to forty hours after the addition of compound, reporter activity for luciferase can be assayed, for example, by addition of the Glo luminescence reagent (Promega) and the Victor3 plate reader (Perkin Elmer). gs can be normalized to DMSO only treated cells, and ized activities can then be used in the IC50 calculations. Table 2 shows the activity of selected indazole-3 -carboxamide analogs.
Table 2.
Wnt inhibition Compound Wnt inhibition 1 2 5,000 nM 3 200 nM 4 160 nM 10,000 nM 6 270 nM 7 110 nM 8 130 nM 9 10,000 nM 11 10,000 nM 12 63 nM 13 1,250 nM 14 106 nM 15 37 nM 16 10,000 nM 18 122 nM 19 107 nM 20 118 nM 23 120 nM 26 210 nM 32 1,250 nM 36 275 nM 37 L 1,120 nM 38 l 120 nM 39 65 nM 40 ' 65 nM 41 67 nM 42 500 nM 43 63 nM 44 l 158 nM 45 110 nM 46 15 nM 47 71 nM 48 10,000 nM 49 57 nM 50 71 nM 51 26 nM 52 57 nM 53 63 nM 54 158 nM 55 44 11M 56 160 nM 57 10, 000 nM 58 71 nM 59 3,100 nM 60 10,000 nM 61 239 nM 62 16 nM 63 100 nM 64 6 nM 65 101 nM 66 10,000 nM 67 10,000 nM 68 48 nM 69 50 nM 70 41 nM 71 25 nM 72 215 nM 73 322 nM 74 65 nM 75 40 nM 76 F 850 nM 77 2,650 nM 78 239 nM 79 123 nM 80 158 nM 81 77-142 nM 82 j[ 143-188 M 83 25003400 11M 84 822-898 M 86 66 nM 87 2,440 11M 106 33 nM 124 67 nM 126 22 nM 162 l 426 nM 163 15,400 nM 168 l 66 113/1 169 49 nM 170 43 n\/I 172 60 11M 173 36 n\/I 174 48 nM 175 25 n\/I 176 30 nM 177 183 11M 178 297 nM 179 30 n\/I 180 13 11M 181 38 n\/I 182 35 nM 183 49 n\/I 184 40 nM 185 | 27 1131 186 460 nM 187 | 215 nM 188 9 nM | 189 L 85 1M 190 I 1,200 nM I The term “comprising” as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude onal, unrecited elements or method steps.

Claims (94)

WHAT IS CLAIMED IS:
1. A compound or pharmaceutically acceptable salt thereof having the structure of formula I: wherein: R1, R2 and R4 are independently selected from the group consisting of H, C1-9 alkyl, halide, )2, -XR10, CN, -OCF3 and -CF3; R3 is selected from the group ting of arylR6 pyridylR6, pyrimidylR6, pyridazinylR6, and pyrazinylR6; R5 is selected from the group consisting of -(C1-9 alkyl)ncarbocyclylR7, - piperazinylR7, -tetrahydropyranylR7, -pyrrolidinylR7, -piperidinylR7, -arylR7, and - heteroarylR7 with the proviso that R5 is not 4-pyridylR7 when R1, R2 and R4 are H, R3 is selected from the group consisting of 3-pyridylR6, 4-pyridylR6, 2-pyridylR6, R6, pyrimidineR6, , , , , , , , , and , and R6 and R7 are both H; with the proviso that R5 is not phenylR7 when R1, R2 and R4 are H, R3 is 4-pyridylR6 and R6 and R7 are both H; with the proviso that R3 is not dylR6 when R1, R2 and R4 are H, R5 is selected from the group consisting of phenylR7, , , , , , , , , , , and , and R6 and R7 are both each R6 is 1-5 tuents each selected from the group consisting of H, C1-9 alkyl, halide, amino, -OCF3, -CF3, -CN, -XR10, -(C1-9 alkyl)ncarbocyclylR8, -(C1-9 alkyl)nheterocyclylR8, -(C1-9 alkyl)arylR8, -(C1-9 nheteroarylR8, -C(=O)R11, - N(R10)C(=O)R11, -(C1-9 alkyl)nN(R10)2, -(C1-9 alkyl)nN(R10)SO2R11 and -SO2R11; each R7 is 1-5 substituents each selected from the group consisting of H, unsubstituted C1-9 alkyl, halide, amino, -OCF3, -CF3, -CN, -XR10, -(C1-9 alkyl)ncarbocyclylR9, -(C1-9 alkyl)nheterocyclylR9, -arylR9, -(C1-9 alkyl)nheteroarylR9, - C(=O)R11, -N(R10)C(=O)R11, -(C1-9 alkyl)nN(R10)2, and -(C1-9 alkyl)nN(R10)SO2R11; each R8 is 1-5 substituents each ed from the group consisting of H, C1-3 alkyl, halide, amino, OCF3, -CF3 -CN, -XR12, -C(=O)R13, -N(R12)C(=O)R13, -(C1-9 alkyl)nN(R12)2, -(C1-9 alkyl)nN(R12)SO2R13 and -SO2R13; each R9 is 1-5 substituents each selected from the group consisting of H, C1-3 alkyl, halide, amino, -OCF3, -CF3 -CN, -XR12, R13, -N(R12)C(=O)R13, -(C1-9 alkyl)nN(R12)2, -(C1-9 alkyl)nN(R12)SO2R13 and -SO2R13; each R10 is independently ed from the group ting of H, C1-9 alkyl, -(C1- 9 alkyl)nN(R14)2, -(C1-9 alkyl)ncarbocyclylR8, -(C1-9 alkyl)nheterocyclylR8, -(C1-9 alkyl)narylR8 and -(C1-9 alkyl)nheteroarylR8; each R11 is independently selected from the group consisting of C1-9 alkyl, -N(R14)2, -(C1-9 alkyl)ncarbocyclylR8, -(C1-9 alkyl)nheterocyclylR8, -(C1-9 alkyl)narylR8 and -(C1-9 alkyl)nheteroarylR8; each R12 is independently selected from the group consisting of H, C1-9 alkyl, -(C1- 9 alkyl)nN(R 2, -(C1-9 alkyl)ncarbocyclyl, -(C1-9 alkyl)nheterocyclyl, -(C1-9 alkyl)naryl and -(C1-9 alkyl)nheteroaryl; each R13 is ndently selected from the group consisting of C1-9 alkyl, -N(R14)2, -(C1-9 alkyl)ncarbocyclyl, -(C1-9 alkyl)nheterocyclyl, -(C1-9 alkyl)naryl and -(C1-9 alkyl)nheteroaryl; each R14 is independently selected from the group consisting of H, C1-3 alkyl, carbocyclyl and aryl; each X is selected from the group ting of -O- and -S-; and each n is 0 or 1.
2. The compound of claim 1 wherein n is 0.
3. The compound of claim 1 wherein n is 1.
4. The compound of claim 1 wherein X is O.
5. The compound of claim 1 wherein R1, R2 and R4 are H.
6. The compound of claim 1 n R3 is 3-pyridylR6.
7. The compound of claim 1 wherein R3 is 5-pyrimidinylR6.
8. The compound of claim 1 wherein R3 is 4-pyridazinylR6.
9. The compound of any one of claims 6-8 wherein R6 is one substituent and is selected from the group consisting of H and C(=O)R10.
10. The compound of claim 1 wherein R5 is oarylR7.
11. The compound of claim 10 wherein the heteroaryl is 3-pyridyl.
12. The compound of claim 10 wherein the heteroaryl is 5-pyrimidinyl.
13. The compound of claim 10 wherein the heteroaryl is 4-pyridazinyl.
14. The compound of claim 10 wherein R7 is one substituent and is selected from the group consisting of H, halide, -OCF3, -CF3, -(C1-9 alkyl)nheterocyclylR9, -(C1-9 alkyl)nN(R10)2, -(C1-9 alkyl)nN(R10)SO2R11 and -N(R10)C(=O)R11.
15. A compound of claim 1, or pharmaceutically acceptable salt thereof having the structure of formula Ia: wherein: R3 is selected from the group consisting of arylR6, pyridylR6, pyrimidinylR6, zinylR6, and pyrazinylR6; R5 is selected from the group consisting of -carbocyclylR7, -piperazinylR7, - tetrahydropyranylR7, -pyrrolidinylR7, -piperidinylR7, -arylR7, and -heteroarylR7; with the proviso that R5 is not 4-pyridylR7 when R3 is selected from the group consisting of 3-pyridylR6, 4-pyridylR6, 2-pyridylR6, phenylR6, pyrimidineR6, , , , , , , , , and , and R6 and R7 are both with the proviso that R5 is not phenylR7 when R3 is 4-pyridylR6 and R6 and R7 are both H; with the proviso that R3 is not 3-pyridylR6 when R5 is selected from the group consisting of phenylR7, , , , , , , , , , , , and , and R6 and R7 are both each R6 is 1-2 substituents each selected from the group consisting of H, C1-3 alkyl, , amino, -OCF3, -CF3, -CN, -OR10, -(C1-2 alkyl)heterocyclylR8, -heterocyclylR8, -(C1- 8, R11, -N(R10)C(=O)R11 and -(C 10) 2 alkyl)arylR 1-2 alkyl)N(R 2; each R7 is 1-2 substituents each selected from the group consisting of H, unsubstituted C1-3 alkyl, halide, amino, -OCF3, -CF3, -CN, -OR10, -(C1-2 alkyl)heterocyclylR9, -heterocyclylR9, 9, -C(=O)R11, )C(=O)R11, -N(R10)2, and -(C1-2 N(R10)2, -N(R10)SO2R11; each R8 is 1-2 substituents each selected from the group consisting of H, C1-3 alkyl, halide, amino, OCF3, -CF3 –CN and -OR12; each R9 is 1-2 tuents each selected from the group consisting of H, C1-3 alkyl, halide, amino, -OCF3, -CF3 –CN and -OR12; each R10 is independently selected from the group consisting of H, C1-3 alkyl, -(C1- 14) 8; 3 alkyl)N(R 2 and -arylR each R11 is independently selected from the group consisting of C1-3 alkyl, -N(R14)2, -carbocyclylR8 and -heterocyclylR8; each R12 is independently selected from the group consisting of H and C1-3 alkyl; each R14 is independently selected from the group consisting of H, C1-3 alkyl and carbocyclyl.
16. The compound of claim 1 having a structure selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
17. The compound of claim 16 having a structure ed from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
18. The compound of claim 16 having a ure selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
19. The compound of claim 16 having a structure ed from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
20. The compound of claim 16 having a structure ed from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
21. The nd of claim 16 having a structure selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
22. The nd of claim 16 having a structure selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
23. The compound of claim 16 having a structure ed from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
24. The nd of claim 16 having a structure selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
25. The compound of claim 1 having a structure ed from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , and .
26. The compound of claim 25 having a ure selected from the group consisting of: , , , , , , , , , , and .
27. The compound of claim 25 having a structure selected from the group consisting of: , , , , , , , , , and .
28. The nd of claim 25 having a structure selected from the group consisting of: , , , , , and .
29. The compound of claim 1 having a ure selected from the group consisting of: , , , , , , , , , , , , , and .
30. The compound of claim 29 having a structure selected from the group consisting of: , , and .
31. The compound of claim 29 having a structure selected from the group consisting of: , , and .
32. The compound of claim 29 having a structure selected from the group consisting of: , , and .
33. The compound of claim 29 having a structure selected from the group consisting of: and ,.
34. The compound of claim 29 having a structure selected from the group consisting of: , , and .
35. A pharmaceutical composition comprising a therapeutically effective amount of at least one nd according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically able excipient.
36. Use of at least one compound according to claim 1, or a pharmaceutically able salt thereof, in the preparation of a pharmaceutical composition for treating a disorder or disease in which aberrant Wnt signaling is implicated in a patient.
37. The use according to claim 36, wherein the disorder or disease is cancer.
38. The use according to claim 36, wherein the disorder or disease is ic retinopathy.
39. The use according to claim 36, wherein the er or disease is rheumatoid arthritis.
40. The use according to claim 36, wherein the er or disease is a mycotic or viral infection.
41. The use according to claim 36, wherein the disorder or disease is a bone or age disease.
42. The use according to claim 36, wherein the er or disease is a neurological ion, disorder or disease, wherein the neurological condition/disorder/disease is selected from: mer's disease, frontotemporal dementias, dementia with lewy bodies, prion diseases, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, corticobasal degeneration, mutiple system atrophy, ophic lateral sclerosis (ALS), inclusion body myositis, autism, degenerative myopathies, diabetic neuropathy, other metabolic neuropathies, endocrine neuropathies, orthostatic hypotension, le sis and Charcot-Marie-Tooth disease.
43. The use according to claim 36, wherein the disorder or disease is lung disease.
44. The use according to claim 36, wherein the disorder or disease is osteoarthritis.
45. The use according to claim 36, wherein the disorder or disease is a genetic e caused by mutations in Wnt signaling components, wherein the genetic e is selected from: polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Müllerian-duct regression and virilization, SERKAL syndrome, diabetes us type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.
46. The use according to claim 36, wherein the disorder or disease is a ic disorder, wherein the fibrotic disorder is selected from: skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver, liver fibrosis; adhesions, such as those occurring in the abdomen, pelvis, spine or tendons; c obstructive pulmonary disease; fibrosis following dial infarction; pulmonary fibrosis; fibrosis and scarring ated with diffuse/interstitial lung disease; central nervous system is, such as fibrosis ing stroke; fibrosis associated with neuro-degenerative disorders such as Alzheimer's Disease or multiple sclerosis; fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ic disease and radiation is.
47. The use according to claim 36, wherein the t is a human.
48. The use according to claim 37, wherein the cancer is chosen from: hepatocellular carcinoma, colon , breast cancer, pancreatic cancer, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, c lymphocytic leukemia (CLL), acute myeloid leukemia, acute cytic leukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian cancer.
49. The use according to claim 37, wherein the cancer is chosen from: lung cancer - non-small cell, lung cancer - small cell, multiple myeloma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer - basal and squamous cell, skin cancer – melanoma, small intestine cancer, stomach cancers, testicular cancer, thymus cancer, thyroid cancer, uterine a, vaginal cancer, vulvar cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma, ional trophoblastic disease, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma), Ewing tumor, esophagus cancer, endometrial , colorectal cancer, al cancer, brain or spinal cord tumor, bone metastasis, bone cancer, bladder cancer, bile duct cancer, anal cancer and adrenal al cancer.
50. The use according to claim 36, wherein the compound inhibits one or more ns in the Wnt pathway.
51. The use according to claim 50, wherein the nd inhibits signaling induced by one or more Wnt proteins.
52. The use according to claim 51, wherein the Wnt proteins are chosen from: WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4. WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16.
53. The use ing to claim 36, wherein the compound inhibits a kinase activity.
54. Use of at least one compound according to claim 1, or a ceutically acceptable salt thereof in the preparation of a ceutical composition for treating a disorder or e mediated by the Wnt pathway in a patient.
55. The use according to claim 54, wherein the compound inhibits one or more Wnt proteins.
56. Use of at least one compound according to claim 1, or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating a disorder or disease mediated by kinase activity in a patient.
57. The use according to claim 56, wherein the e or disorder comprises tumor growth, cell proliferation, or angiogenesis.
58. Use of at least one compound according to claim 1, or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for inhibiting the activity of a protein kinase receptor.
59. Use of at least one compound according to claim 1, or a pharmaceutically acceptable salt thereof in the preparation of a ceutical composition for treating a disease or disorder associated with aberrant cellular proliferation in a patient.
60. Use of at least one compound according to claim 1, or a ceutically acceptable salt thereof in the preparation of a pharmaceutical composition for ting or reducing angiogenesis in a patient.
61. Use of at least one compound according to claim 1, or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for preventing or reducing abnormal cellular proliferation in a patient.
62. Use of one or more of the compounds according to claim 1, or a pharmaceutically acceptable salt in combination with a pharmaceutically acceptable carrier and one or more other agents thereof in the preparation of a pharmaceutical composition for treating a disease or er associated with nt cellular proliferation in a patient.
63. A compound or pharmaceutically acceptable salt, thereof having the structure of Formula Ia: wherein: R3 is selected from the group consisting of 3-pyridylR6, 5-pyrimidinylR6, and 4- pyridazinylR6; R5 is selected from the group consisting of oarylR7; R6 is a substituent ed from the group consisting of -(C1-2 alkyl)heterocyclylR8 and -heterocyclylR8; R7 is 1-2 substituents each independently ed from the group consisting of H, C1-3 alkyl, halide, -NH2, -OCF3, -CF3, -CN, -OR10, -(C1-2 alkyl)heterocyclylR9, - cyclylR9, and -SO2R11; R8 is 1-2 substituents each independently selected from the group consisting of H, C1-3 alkyl, halide, and -OR12; each R9 is 1-2 substituents each independently selected from the group consisting of H, C1-3 alkyl, halide, amino, -OCF3, -CF3, –CN, and -OR12; R10 is selected from the group consisting of H and C1-3 alkyl; R11 is C1-3 alkyl; and each R12 is independently selected from the group consisting of H and C1-3 alkyl.
64. The compound of claim 63, wherein R3 is dylR6.
65. The compound of any one of the claims 63-64, wherein R6 is -(C1-2 heterocyclylR8.
66. The compound of any one of the claims 63-64, wherein R6 is - heterocyclylR8.
67. The compound of any one of the claims 63-66, wherein the R6 heterocyclylR8 is independently selected from the group consisting of azetidinylR8, pyrrolidinylR8, dinylR8, piperazinylR8, and morpholinylR8, wherein the R7 heterocyclylR9 is independently ed from the group consisting of azetidinylR9, idinylR9, piperidinylR9, piperazinylR9, and morpholinylR9.
68. The nd of any one of the claims 64, 65 and 67, wherein R6 is selected from the group consisting of -(C1-2 alkyl)piperidinylR8, -(C1-2 alkyl)pyrrolidinylR8, and -(C1-2 alkyl)morpholinylR8.
69. The compound of any one of the claims 64, 65 and 68, wherein R6 is selected from the group consisting of –CH2piperidinylR8, -CH2pyrrolidinylR8, and -CH2morpholinylR8.
70. The compound of any one of the claims 64-65 and 68-69, wherein R6 is – CH2piperidinylR8.
71. The compound of any one of the claims 64-65 and 68-69, wherein R6 is – CH2pyrrolidinylR8.
72. The compound of any one of the claims 64-65 and 68-69, wherein R6 is – CH2morpholinylR8.
73. The compound of any one of the claims 64-72, n R8 is 1-2 substituents each independently selected from the group consisting of H and F.
74. The compound of any one of the claims 64-73, wherein R5 is selected from the group consisting of -pyridylR7, -pyrimidinylR7, -pyridazinylR7, and - pyrazinylR7.
75. The compound of any one of the claims 64-74, wherein R5 is –3-pyridylR7.
76. The compound of any one of the claims 64-75, wherein R7 is selected from the group consisting of H, C1-3 alkyl, halide, -NH2, -CF3, -CN, -OR10, - heterocyclylR9, and -SO2R11.
77. The compound of any one of the claims 64-76, wherein R7 is selected from the group ting of H, methyl, F, -NH2, -CF3, -CN, -OMe, -OEt, -OiPr, -SO2Me, , , , , , , and .
78. The compound of any one of the claims 64-77, wherein R7 is selected from the group consisting of H, -NH2, -CF3, -CN, -OMe, -OEt, -OiPr, , , and .
79. The compound of claim 63, wherein the compound of Formula (Ia) has a structure selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , or a pharmaceutically acceptable salt thereof.
80. The nd of claim 1, wherein the compound of Formula (Ia) has a structure selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , and , or a pharmaceutically able salt thereof.
81. The compound of claim 63, or pharmaceutically acceptable salt thereof having the structure of Formula Ia: wherein: R3 is 3-pyridylR6; R5 is selected from the group consisting of pyridylR7, -pyrimidinylR7, and - pyridazinylR7; R6 is –CH2heterocyclylR8; R7 is 1-2 tuents each independently selected from the group consisting of H, F, methyl, -NH2, -CF3, -CN, -OMe, -SO2Me, , , , , , , and ; R8 is 1-2 substituents each independently selected from the group consisting of H and halide.
82. The compound of claim 81, wherein the R6 heterocyclylR8 is selected from the group consisting of azetidinylR8, pyrrolidinylR8, piperidinylR8, piperazinylR8, and morpholinylR8.
83. The compound of claim 81, wherein R6 is –CH2piperidinylR8.
84. The compound of any one of the claims 82-84, wherein R7 is ed from the group consisting of H, -CF3, -OMe, -CN, , , and .
85. The nd of any one of the claims 81-84, wherein R8 is H.
86. A ceutical composition comprising a eutically ive amount of a compound or pharmaceutically acceptable salt thereof having the structure of Formula Ia: wherein: R3 is selected from the group consisting of 3-pyridylR6, 5-pyrimidinylR6, and 4- pyridazinylR6; R5 is selected from the group consisting of -heteroarylR7; R6 is a substituent selected from the group consisting of -(C1-2 alkyl)heterocyclylR8 and -heterocyclylR8; R7 is 1-2 substituents each independently selected from the group consisting of H, C1-3 alkyl, halide, -NH2, -OCF3, -CF3, -CN, -OR10, -(C1-2 alkyl)heterocyclylR9, - heterocyclylR9, and -SO2R11; R8 is 1-2 substituents each independently selected from the group consisting of H, C1-3 alkyl, halide, and -OR12; each R9 is 1-2 substituents each independently selected from the group consisting of H, C1-3 alkyl, halide, amino, -OCF3, -CF3, –CN, and -OR12; R10 is selected from the group consisting of H and C1-3 alkyl; R11 is C1-3 alkyl; each R12 is independently selected from the group ting of H and C1-3 alkyl; a pharmaceutically acceptable excipient.
87. The pharmaceutical composition of claim 86, comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof having the structure of Formula Ia: wherein: R3 is 3-pyridylR6; R5 is ed from the group consisting of pyridylR7, -pyrimidinylR7, and - pyridazinylR7; R6 is –CH2heterocyclylR8; R7 is 1-2 substituents each independently selected from the group ting of H, F, methyl, -NH2, -CF3, -CN, -OMe, -OEt, -OiPr, -SO2Me, , , , , , , and ; R8 is 1-2 substituents each independently selected from the group consisting of H and halide; and a pharmaceutically able ent.
88. The pharmaceutical composition of claim 87, wherein the R6 heterocyclyl is independently selected from the group consisting of azetidinylR8, pyrrolidinylR8, piperidinylR8, piperazinylR8, and morpholinylR8.
89. The pharmaceutical composition of claim 87, wherein R6 is – CH2piperidinylR8.
90 The pharmaceutical composition of any one of the claims 87-89, wherein R7 is selected from the group consisting of H, -OMe, -OEt, -OiPr, -CF3, -CN, , , and .
91. The pharmaceutical composition of any one of the claims 87-90, wherein R8 is H.
92. The pharmaceutical ition of claim 87, wherein the compound of Formula (Ia) has a structure selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , and , or a pharmaceutically acceptable salt thereof.
93. The compound of claim 1, or ceutically acceptable salt thereof having the structure of:
94. A pharmaceutical composition comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof having the structure of: 291 291
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