SG182187A1 - 5-heteroaryl substituted indazoles as kinase inhibitors - Google Patents

5-heteroaryl substituted indazoles as kinase inhibitors Download PDF

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SG182187A1
SG182187A1 SG2012043113A SG2012043113A SG182187A1 SG 182187 A1 SG182187 A1 SG 182187A1 SG 2012043113 A SG2012043113 A SG 2012043113A SG 2012043113 A SG2012043113 A SG 2012043113A SG 182187 A1 SG182187 A1 SG 182187A1
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Singapore
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indazol
benzyl
triazol
carboxamide
indazole
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SG2012043113A
Inventor
Irini Akritopoulou-Zanze
Brian D Wakefield
Helmut Mack
Sean C Turner
Alan F Gasiecki
Vijaya J Gracias
Kathy Sarris
Douglas M Kalvin
Melissa J Michmerhuizen
Qi Shuai
Jyoti R Patel
Margaretha Bakker
Nicole Teusch
Peter J Kovar
Stevan W Djuric
Andrew J Long
Anil Vasudevan
Adrian Hobson
John Moore Nigel St
Lu Wang
Dawn George
Biqin Li
Kristine Frank
Eric T Johnson
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Abbott Gmbh & Co Kg
Abbott Lab
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Publication of SG182187A1 publication Critical patent/SG182187A1/en

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Abstract

5-HETEROARYL SUBSTITUTED INDAZOLES AS KINASE INHIBITORSAbstractThe present invention relates to compounds of formula (1) or pharmaceutical acceptable salts, wherein A, R1,R2, R3 and m, are defined in the description. The present invention relates also to methods of making said compounds, and compositions containing said compounds which are useful for inhibiting kinases such as Glycogen Synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus Kinases (JAK), Ala, PAK4, PLK, CK2, KDR, MK2, JNK I, aurora, pim I and nek 2.No suitable figure

Description

S-HETEROARYL, SUBSTITUTED INDAZOLES AS KINASE INHIBITORS
Techical Field
The present invention relates to S-substituted indazole comamning compounds, methods of making the compounds, compositions containing the compounds which are usefy) for inhibiting kinases such as Glycogen Synthase kinase 3 (GSK-3), Rho kinase (ROCK),
Janus Kinases (JAK), AKT, PAKA, PLE, CK2, KDR, MK2, JNK, aurora, pim 1 and nek 2.
Background of the invention
Protein kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine, serine, threonine, or histidine residue located on a protein substrate.
Protein kinases clearly play a role in normal cell growth. Many of the growth factor receptor proteins have intracellular domains that function as protein kinases and it is through this function that they effect signaling. The interaction of growth factors with their receptors is a necessary event in the normal regulation of cell growth, and the phosphorylation state of substrate proteins often is related to the modulation of cel] growth.
It is widely known that abnormal protein phosphorylation may be directly linked to certain disease states or may be a contributing factor in the onset of such diseases. As a result, protein kinases have become the targets of new pharmaceutical research (Cohen, P.
Nature Reviews Drug Discovery, 1:309-313, 2002). Various protein kinase inhibitors have been used clinically in the treatment of 2 wide varicty of diseases, such as cancer, chronic mflammatory diseases, diabetes and stroke.
The protein kinases are a large and diverse fami) y of enzymes that catalyze protein phosphorylation and play a key role in cellular signaling. Protein kinases may ¢xert positive or negative regulatory effects, depending upon their target protein. Protein kinases are involved in specific signaling pathways which regulate cell functions such as, but not limited to, metabolism, cell cycle progression, cell adhesion, vascular function, apoptosis, and angiogenesis. As a result, malfunctions of cellular signaling have been associated with many diseases, the most characterized of which include cancer and diabetes. The regulation of signal transduction by cytokines and the association of signal molecules with proto- oncogenes and tumor suppressor genes have been well documented. Similarly, the connection between diabetes, viral infections and the conditions related thereto has also been . associated with the regulation of protein kinases.
Because protein kinases regulate nearly every cellular process. including metabolism,
cell proliferation, cell differentiation, and cell survival, they are attractive targets for therapeutic intervention for various disease states. For example, cell-cycle contro! and angiogenesis, in which protein kinases play a pivotal role are cellular processes associated with numerous disease conditions such as, but not limited to, cancer, inflammatory diseases, abnormal angiogenesis and diseases related thereto. atherosclerosis, macular degeneration, diabetes, obesity, and pain.
The elucidation of the intricacy of protein kinase pathways and the complexity of the relationship and interaction among and between the various protein kinases and kinase pathways highlights the importance of developing pharmaceutical agents capable of acting as protein kinase modulators, regulators or inhibitors that have beneficial activity on multiple kinases or multiple kinase pathways,
It has therefore been suggested that duc to the complexity of intracellular signalin g cascades of protein kinase pathways, agents that affect multipie pathways sirmultaneousty may be required for meaningfui clinical activity. Although it has been suggested that a single agent that provides combinatorial cffects is an attractive notion, there is a need to identify and use single agents that target the right combination of multiple pathways that are clinically effective in a particular disease setting.
Glycogen synthase kinasc-3 (GSK-3) is a serine/threonine kinase encoded by two isoforms, GSK-3a and GSK-3p with molecular weights of 51 and 47 kDa, respectively.
These share 97% sequence similarity in their kinase catalytic domains. The GSK-3a isoform has an extended glycine-rich N-terminal tail. A minor splice variant of GSK-3 has been identified (expressed at ~15% of total) with a 13 amino acid insert within the kinase domain.
This variant had a reduced activity towards tau. GSK-3 is highly conserved throughout evolution, and found in all mammals thus far with high homology in the kinase domain. Both isoforms are ubiquitously expressed in mammalian tissues, mcluding the brain.
Pharmacological GSK-3 inhibitors are not able to selectively inhibit one of the isoforms.
GSK-3f plays an important role in the control of metabolism, differentiation and survival, It was initially identified as an enzyme able to phosphorylate and hence inhibit glycogen synthase. Subsequently, it was recognized that GSK-35 was identical to tay protein kinase I (TPK 1), an enzyme that phosphorylates tau protein in epitopes that are also found to be hyperphosphorylated in Alzheimer's disease and in several taupathies.
Interestingly, protein kinase B (AKT) phosphorylation of GSK-38 results in a loss of kinase activity, and it has been proposed that this inhibition may mediate some of the effects of neurotrophic factors. Moreover, phosphorylation of B-catenin (a protein involved in cell survival} by GSK-38, results in its degradation by an ubiquitinilation dependent proteasome pathway.
Therefore it appears that mhibition of GRE-3f activity may result in neurstrophic activity. There is evidence that lithi um, an uncompetitive inhibitor of GSK-3f, enhances neurttogenesis in some models and can also increase neuronal survival, through the induction of survival factors such as Bel-2 and the inhibition of the expression of proapoptotic factors such as P53 and Bax.
Further studies have shown that -amyloid increases G SK-30 activity and tau protein phosphorylation. Moreover. this hyperphosphorylation as well as the neurotoxic effects of f- amyloid are blocked by lithium chloride and by a GSK-3f antisense mRNA. These observations taken together suggest that GSK-3f3 may be the link betwesn the two major pathological processes in Alzheimer's disease: abnormal APP (Amyloid Precursor Protein) processing and tau protein hyperphosphorylation,
These experimental observations indicate that GSK-3f may find application in the prevention and treatment of the neuropathological consequences and the cognitive and attention deficits associated with Alzheimer's disease, as well as other acute and chronic neurodegenerative diseases. These include, but are not Hmited to Parkinson's discase, tauopathics (e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy) and other dementia including vascular dementia; acute stroke and other traumatic injuries; cerebrovascular accidents (e.g. age related macular degeneration); brain and spinal cord trauma; peripheral neuropathies: retinopathies and glaucoma.
GSK-3p may also have utility in the treatment of other diseases such as: non-insulin dependent diabetes and obesity; manic depressive illness; schizophrenia; alopecia; inflammation; cancers such as breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and several virus-induced tumors.
Rho kinases (ROCKs), the first Rho effectors fo be described, are serine/threonine kinases that are important in fundamental processes of cell migration, cell proliferation and cell survival. Abnormal activation of the Rho/ROCK pathway has been observed in Various disorders. Examples of disease states in which compounds of the present invention have potentially beneficial therapeutic effects due to their anti vasospasm activity includes cardiovascular diseases such as hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, cerebral vasospasm after subarachnoid bleeding, pulmonary hypertension and atherosclerosis. The muscle relaxing property is also beneficial for treating asthma, male erectile dysfunctions, female sexual dysfunction, and over-active bladder syndrome. Injury to the adult vertebrate brain and spinal cord activates
ROCKS, thereby inhibiting neurite growth and sprouting. Inhibition of ROCKS results in mduction of new axonal growth, axonal rewiring across lesions within the CNS, accelerated regeneration and enhanced functional recovery afier acute neuronal Injury m mammals {spinal-cord injury, traumatic brain injury). Inhibition of the Rho/ROCK pathway has also proved to be efficacious m other animal models of neurodegeneration like stroke, mflammatory and demyelinating diseases, Alzheimer's disease as wel] as the treatment of pain. Rho/ROCK pathway inhibitors therefore have potential for preventing neurodegeneration and stimulating neuroregeneration in various neurological disorders, including spinal-cord injury, Alzheimer's disease, stroke, multiple sclerosis, amyotrophic lateral sclerosis, as well as the treatment of pain. ROCK inhibitors have been shown to 13 possess anti-inflammatory properties. Thus, compounds of the invention can be used as treatment for neuroinflammatory diseases such as stroke, multiple sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and inflammatory pain, as well as other inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, iiritable bowel syndrome, Croim’s disease, psoriasis, ulcerative colitis,
Lupus, and inflammatory bowel disease. Since ROCK mhibitors reduce cell proliferation and oo cell migration, they could be useful in treating cancer and tumor metastasis. Further more, there 1s evidence suggesting that ROCK inhibitors suppress cytoskeletal rearrangement upon virus invasion, thus they also have potential therapeutic value in anti-viral and anti-bacterial applications. ROCK inhibitors are also useful for the treatment of insulin resistance and diabetes. Further, ROCK inhibitors have been shown to ameliorate progression of cystic fibrosis (Abstract $02.3, 8th World Congress on Inflammation. Copenhagen, Denmark, June 16-20, 2007).
In addition, Rho-associated coiled-coil forming protein kinases (ROCK)-1 and -2. have been shown to enhance myosin light chain (MLC) phosphorylation by inhibiting MLC phosphatase as well as phosphorylating MLC. This results in the regulation of actin-myosin contraction. Recent reports have demonstrated that inhibition of ROCK results in disruption : of inflammatory cell chemotaxis as welf as inhibition of smooth muscle contraction in models of pulmonary inflammation associated with asthma. Therefore, the inhibitors of the
Rho/ROCK pathway should be useful for the treatment of asthma.
The Janus kinases (JAKs) are an mnportant family of intracellular protein tyrosine kinases (PTKs), with 4 mammalian members, JAKL, JAK2, JAKS, and TVER2, as well as homologs in chicken, fish, and Drosophila. The JAKs play critical roles in several important intracellular signaling pathways, including the eponymous JAK/STAT pathway, central to the mediation of cytokine signaling. It is this pivotal role in cytokine signaling that underpins the notion that specific JAK inhibitors may be therapeutically deployed in situations where cytokine activity results in disease. important examples of this include autoimmune diseases such as rheumatoid arthritis and psoriasis, myeloproliferative syndromes such as, leukemias, lymphomas, and cardiovascular diseases. 16 JAKZ, a member of the Janus kinase (JAK) family of protein tyrosine kinages (FTES), 1s an important intracellular mediator of cytokine signaling. Mutations of the JAK? gene are associated with hematologic cancers, and aberrant JAK activity is also associated with a number of immune diseases, including rheumatoid arthritis.
Aurora kinases are a family of multigene mitotic serine-threonine kinases that functions as a class of novel oncogenes. These kinases comprise aurora-A, aurora-B, and aurora-B members. These are hyperactivated and/or over-expressed in several solid tumors including but not limited to breast, ovary, prostate, pancreas, and colorectal cancers. In particular aurora-A is a centrosome kinase, and its localization depends on the cell cycle and plays an important role cell cycle progression and cell proliferation. Aurora-A is located in the 20q13 chromosome region that is frequently amplified in several different types of malignant tumors such as colorectal, breast and bladder cancers. Inhibition of aurora kinase activity could help to reduce cell proliferation, tumor growth and potentially tumorigenesis.
Accordingly, there remains a need for the development of methods comprising the use of a single agent drug capable of targeting specific sets of kinases or kinase pathways. In particular such methods affect the right combination of multiple targets thereby achieving clinical efficacy.
Summary Of The Invention
In the principle embodiment, the present invention provides compounds of Formula (1),
Ri
A SN
Ram” N
Ra 1,
or a pharmaceutically acceptable salt thereof, wherein
Aas (Ris (Ri {Rik (Riv) (Ry)
Moly a =i ss lm aN Rf pr Fr re) / owe yok 7 N Bd Sn Bi Hl Ht WE
Negi 5 Noy 3 iN; y {> 3 “nN 5 {5 {ily {iil} {iv {vi
Fads (Rui {Ruila (File
TY HN N-F, N-IN
LS] 3 ng a
N / a
YY y 4; s LN 3 A 5 {vi} {vii} (viii) {ix)
Nihil (os (Foal (Roa
TR ne: N= N-HN
XY Se Sd cy ~ MN & 3 4 ’ Le 5 ? (x) {xi} (xii) (xiii) (Rav) (Rule {Rws) (Ryvitkd
Co Mion “eon
S N I =x =N ; Noy Ay 5 NEN 5 (xiv) {xv) {xvi) {xvii}
Ride (Rosle (Rade {Ryxida
SCH TS Ty
LS ; 7 : “7 : NE {xviii} {xix) (xx) (xxi) a (lk
No 0 ; { 5 : or 4 5 : :
GC Ss {xxii} (xxii)
Ry 1s hydrogen, alkyi, aryl, heterocycle, heteroaryl, R,RiN-, RRgN-C{O)- or
RRgN-S(0)s-;
R; 18 hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, heterocyclecarbony! or ReRN-alkyl-C(O)-;
Rais alkyl, alkoxy, aryl, cyano, cycloalkyl, halogen, haloalkyl, heteroaryl, nitro, or
RgRpN-;
Rais alkyl, alkoxvallkyl, aryl, cycloalkyl, heteroaryl, heterocycle, heterocyclealkyl,
RR; N- or RR N-alkyl-;
Rs is alkyl, aryl, or heteroaryl;
Rs 1s alkyl, alkoxyalkyl, RjRiN-allkeyl-, aryl, cycloalkyl or heteroaryl;
R- is alkyl, aryl or heteroaryl:
R. and R;, are each independently hydrogen, alikyl, arylaliey], cyecloalioyl, 3 cycloalkylalkyl, heteroarylalkyl, Ry-C(O)-, or Rs-5(0%-
Re and Rg are each independently hydrogen, alkyl or heteroaryl;
Re. and Ry are each independently hydrogen, alkyl, arylallevl, heteroarylallyi,
Ro-C(O)-, or Rop-5(0 a;
Re and Ry are each depen dently hydrogen, alkyl, or atkvlcarbonyl: i0 Ry and Ry are each mdependently hydrogen, alicyl, aryl, arylalkyl, eycloal kvl, heteroaryl, or heterocycle;
Rs, Ri, Rai Riv. Ro, Rui, Rusia Russ, Ri Rao Riv Rit, Rist, Rocio Row, Ris, Ravi: Rocwiin Rugs
Ras Rais Rit a0d Roi are each independently alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylaliyl, aryl(hydroxy)alkyl, aryloxyalkyl, arylcarbonyl, arylthioalkyl, carboxy, carboxyalkyl, cyanoalkyl, cycloalkyl, cycioalicylaliyl, cycloalkylcarbonyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealiyl, heterocyclecarbonyl, hydroxyalkyl, trialkylsitylalicyl, HaNC(O)-alkyl, Z,ZoN-, LaZpNalkyl,
ZZNC(O)- or Z.ZNS(O)s- wherein Riv Rows Rais and Rij may occur at any open valence on compounds (xiv), (xv), (xvi) or (xvii);
Z, and Zy, are cach independently hydrogen, alkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, HoNC(O)-, HoNalkylC(O)-, HoNC(O)-aleyl, dialkyINC(O}- or dialkyINC(O}-alkyl-;
Zand Zg4 are each mdependently hydrogen, alkyf, alkoxyalkyl, aryl, arylalkyl, aryl(hydroxyjalicyl, cycloallovi, cycloalkylalkvi, heteroarylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl, HoNC(O3-alkyl-, dialkyINC(O)-alkyl-, dialkyIN-alkyl-, or
CHZ 7x
Ze 1s aryl or heteroaryl;
Zr is heteroarylalleyl, heterocyclealkyl, or ZyZyN-alkyi-; mis 0, 1 or2; 36 ais 0 orl; bis, 1, 0r2; cis 0, 1. 2 or 3; and dis0, 1,2 Jord
Also provided are pharmaceutically acceptable compositions comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically suitable carrier.
The object of the present invention is to provide compounds that are useful for the preventive of or treatment of diseases caused by abnormal protein kinase activity. In addition, the invention also provides pharmaceutically effective compositions of the compounds of the present invention that are useful for the prevention of or treatment of said diseases,
The present invention also relates to a pharmaceutical composition which COMIPIISES at least one S-substituted indazole compound of the formula (1) which TAY exist as a pharmaceutically acceptable salt or prodrug thereof, in the presence or absence of pharmaceutically acceptable carriers, dragees, adjuvants or other auxiliary substances.
The compounds of the present invention have inhibitory activity against GSK-3,
ROCK-1, ROCK-2, JAKZ as well as other kinases and are useful for the inhibition of such kmases. Certain compounds of the present invention are selective toward one or more kinases and may be useful for the selective inhibition of such kinases. Accordingly, the compounds of the present invention are useful as an active ingredient for the preparation of a composition, which enables preventive and/or therapeutic treatment of a disease caused by abnormal GSK-3 activity and more particularly, of neurodegenerative diseases such as
Alzheimer's disease. In addition, the compounds of the present invention are also useful as an active ingredient for the preparation of a composition for preventive and/or therapeutic treatment of neurodegencrative discases such as Parkinson's disease, tauopathics (e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear palsy) and other dementia including vascular dementia; acute stroke and other traumatic injuries; cerebrovascular accidents (c.g. age related macular degeneration); brain and spinal cord trauma; peripheral neuropathies; retinopathies and glaucoma: and other diseases such as non-insulin dependent diabetes (such as diabetes type TI) and obesity: manic depressive illness; schizophrenia; alopecia; cancers such as breast cancer, non-small ceil tung carcinoma, thyroid cancer, T or B-cell Jeukemia and several virus-induced tumors.
Detailed Description of the Invention
Compounds of the present invention have the formula (1) as described above, More particularly, compounds of formula {1} can include, but are not limited to, compounds wherein A is (ii), (iii), (iv), (vii), (x). (xiv), (xv), (xvi), (xvii), (xviii), (xix), (xx). (xxi), (xxii), or {xx1it).
In another embodiment of the present invention there is disclosed a compound of formula (I). wherein A is (ii), (Riko [Fo
N. AN (ii): > Ris hydrogen, aryl, heteroaryl, heterocycle, R,RiN- or RRgN-C{O)-; R; is hydrogen, alkoxycarbonyl, heterocyclecarbonyl, alkylcarbonyl, or ReRN-alkyl-C(O)-; Ry is alkyl, alkoxyalkyl, aryl, cycloalkyl, heterocycle, heterocyclealioyl, RGREN-, or RyRy N-alkyl-; Rs ig alkyl, aryl, or heteroaryl: R, and R, arc cach independently hydrogen, arylalkyl, cycloalicylalkyl, Re-C(0)-, or Rs-5(0%-; 1, and Ry are each independently hydrogen or heteroaryl, R, and Ry are each independently hydrogen ar alkyl, R; and Ry, are cach independently hydrogen, alkyl, aryl. cycloalkyl, or heterocycle; Ry; is alkyl, alkoxyalkyl, alkoxycarbonyl, aryl, arylalkyl, aryl(hydroxy)alkyl, aryloxyalkyl, arylcarbonyl, alkoxycarbonylalkyl, arylthioalkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyi, cycloalkyicarbonyl, halogen, heteroaryl, heteroarylalkyl, heterocyele, heterocyciealkyl, heterocyelecarbonyl, hydroxyalkyl, trialkeyisilylalkyl, ZZ N-. £,ZxNalkyl-, or 7,7 ,NC{O)-:
Zy and Zy, are cach independently hydrogen, alkyl, or HoNalkylC(O)-; Z, and 74 are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, cycloalicyl, cycloalkylafkyl, heteroarylalkyl, heterocyclealkyl, hydroxyalkyl, or dialkyIN-alkyl-: mis 0; and bis 0, 1, or 2.
In another embodiment of the present mention, there is disclosed a compound of formula (1), wherein A is (iii}, (Rie oo
On
N . (iif)
R; 1s hydrogen or R,RyN- R; Is hydrogen; R. is R;RiN-alkyl-; R, and R, are each independently hydrogen or R4-C{O}-; R; and R,. are each alkyl; Ry is alkoxycarbonylalkyl, alkyl, arylalkyl, cyanoalkyl, heterocyclealkyl, or HoNC( O)-alkyl- cis 0, 1, 0r 2; and m is 0.
In another embodiment of the present mvention, there is disciosed a compound of formula (1), wherein A is (iv), (Riv)
MN
(iv)
R; is hydrogen or R.RuN-; Ry is hydrogen; R, and R,, are each hydrogen; R;, is aryl, arylalicyl, heterocycle, heterocyelealkyl, Z,Z Nalky!l or Z.Z4NS(O),-; Z, and Zy are each independently hydrogen or alkyl; 7. and Zg are each alkyl: cis 0, 1. or 2: and m is 0.
In another embodiment of the present invention. there is disclosed & compound of formula {1}, wherein A is (vii), (Ride [5 0 (vii)
R; 1s hydrogen, alkyl, or RRM: Ry 18 hydrogen: RB, and Ry, are each hydrogen: Ry, is alkyl, alkoxycarbonyl, aryl, arylalkyl, cycloalkyl, hewerocyelealkyl, heterocyclecarbonyl, hydroxyalkyl, or Z,Z4NC(O)-; Z, and Zy are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl(bydroxy)alkyl, cycloalkyl, cycloalkylalkyl, hetercarylalkyl, heterocycle. heterocyclealkyl, hydroxyalkyl, or CHZ.Zs, Z. is aryl or heteroarvi, Zs is heteroarylalkyl, heterocyclealikyl, or Z,Z;N-alkyl-; bis 1; and m is 0.
In another embodiment of the present invention, there is disclosed a compound of formula (I), wherein A 1s {x), iy (>
Ss (x) :
E18 hydrogen; R; is hvdrogen, BR, 1s alkyl, aryl, or Z2,Z,N-: Z., and Z;, are each independently hydrogen, alkyl, arvi, or arvialkyl; bis 1 or 2; and m 1s 0.
In another embodiment of the present invention, there is disclosed a compound of formula {I}, wherein A is (x1v).
NY 5s
STN
{xiv}
R, is hydrogen; R; is hydrogen; Ry is Z.ZuN-; Z, and Z;, are each independently hydrogen or cycloalkyl; c 1s 1; and m 15 0.
In another embodiment of the present invention, there is disclosed a compound of formula (I), wherein A is (xv),
Tey “3
NEN
(xv)
Ry 15 hydrogen or R,RyN-; Rs is hydrogen; R, and Rj, arc each hydrogen; Ry. is
Z2ZoN-1 Z, and Zi are each independently hydrogen, alkoxycarbonylalkyl. aryl, arylalkyl. or cycloalkyl; dig Oor 1: and mis
In another embodiment of the present invention, there is disclosed a compound of formula (1), wherein A is (xvi),
Forder “3
Pl {xvi}
R: is hydrogen; Ry is hydrogen; Ry, is ZuZ N=: 7, and Zy, arc each independently hydrogen or cycloalkyl: d is 1; and mis 0.
In another embodiment of the present invention, there is disclosed a compound of formula (1), wherein A is (xvii),
Pos (A (xvii) 13 Ry is hydrogen; R; is hydrogen; Ruy; is aryl or Z,,ZyN-; Z, and Z,, arc each independently hydrogen, alkyl. alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, or
HoNC(O)-alikyl-; dis Gor 1; and m is 0.
In another embodiment of the present invention, there is disclosed a compound of formula (I), wherein A is (xviii), (Raviitke
TY
NZS
{xviii}
Ry 18 RoReN-; R; is hydrogen; R, and Ry, are cach hydrogen; ¢ is 0; and m is 0.
In another embodiment of the present invention, there is disclosed a compound of formula (1), wherein A is (xix).
Forde Ng, 3H
NF
{xix} :
Ti
Ry is RyRpN-; Ry is hydrogen; R, and Ry, are each independently hydrogen; ¢ is 0; and mis 0.
In another embodiment of the present invention, there is disclosed a compound of formula (1), whersin A is {xx},
Ly
Es =
N
(xx
Ry is RyRpMN-; Ry is hydrogen; Ry is RjRyIN-alkyl-; BR, and Ry, are each hydrogen or
R4-C(O); R, and Ry, are independently alkyl; Ry is Z.ZuN- or heterocycle; 7, and 7, are independently hydrogen or alkyl; ¢is 0 or |; and m is 0. 34] In another embodiment of the present invention, there is disclosed 2 compound of formula (I), wherein A is (xxi).
NS
CH
(xxi)
Bis RyRN-; Ro ig hydrogen; R, and Ry, are each hydrogen; Ry; is alkoxy; d is 1; and mis. :
In another embodiment of the present invention, there is disclosed a compound of formula (I), wherein A is {xxii}, {Roxie
Ex 0 (xxi)
R18 RyRpN-; Ris hydrogen; R, is RiRiN-alky!-; R, and R,, are each independently hydrogen or Rs-C(O)-; R; and Ry are cach alkyl; c 1s 0 and m is 0.
In another embodiment of the present invention, there is disclosed a compound of formula (I), wherein A is (xxiii), fl i {3 (xxiii)
Rp i8 RRpN-; Ry is hydrogen; R, and Ry, arc cach hydrogen; ¢ 1s 0; and m is 0.
Specific embodiments contemplated as part of the invention include, buf are not limited to, compounds of formula (1), for example: 5-(1-benzyl-18-1,2, 3-friazol-5 -yD)-1H-indazole compound with S5-(1-benzyl-1H- 1.2, 3~triazol-d-yi).] B-indazole, 5-(1H-1,2 3-triazol-5-y 1-1 H-indazole;
S-{1-benzyl-1H-1,2,3-tri azol-4-y1}-1H-indazole: 5-[1-(2-methylbenzyl)- 18-1 A3-triazol-4-y I-11 H-indazole.
Se 1-03-methylbenzyl)-1H-1 Ay 3-triazol-4-y 1 | H-indazole, 5-[1-{4-methytbenzyh)-1H-1 22, 3-triazob-4-yl]- 1H -indazole; 5-[1-(3-methoxybenzyl}- 1-1 ,2,3-triazol-4-yl]-1H-indazole: 3-[1-(2-fluorobenzyl}-1H -1.2,3~triazol-4-yl}-1H-indazole; 5-[1-(3-fluorobenzyl)-1 H-1,2.3-triazol-4-y1}- 1H ~-indazole; is 5-[1-(4-fluorobenzyl}- 1H-1 2, 3-triazol-4-y1]-1 H-indazole; 5-[1-(2-chlorobenzyl)-1 H-1,2,3-triazol-4-y1}-1H-indazole: 5-[1-(3-chlorobenzyt)-1H-1 :2,3-triazol-4-yi]-1H nd azole; 5-[1-(4-chiorobenzy!)-1H-1.2 3-triazo] -4-ylj-1H-indazole: 5-[1-(2-bromobenzyl}-1 H-1 .2.3-triazol-d-yi]-1 H-indazole; 5-[1-{2-nitrobenzyl)-1H-1 .2.3-triazol-4-y[]-1H -indazole; 5-{1-(3-nitrobenzyl)-1H-1,2.3-tri azol-4-yl]-1H-indazole: 5-{1-(4-nitrobenzy)-1H-1 2. 3-triazoi-4-y1]-1H-indazole: 2-{[4-(1H-indazol-5-y1)-1H-1 22,3-triazol-1-ylimethyl t benzonitrile; 3-{[4-(1H-indazol-5-y1)-1H-1.2,3-triazol-] -yiimethyl} benzonitrile: 4-{[4~{1H-indazol-5-yI}-1H-1,2 3-triazol- 1 -ylImethyl} benzonitrile; 3-11 -[2-(wifluoromethylbenzyl]- IH-1 2, 3-triazol-4-y] {-1H-indazole: 5-1 -[3-(wrifluoromethyl)benzyl]- 11-1 12, 3ntriazol-4-yit-1H-indazole: 5-01 -[4-(wifluoromethyl)benzyl]-1H-1 2.3-triazol-4-y1}-1H-indazole:
S-{1 -{ 3-{trifluoromethoxy Ybenzyl]-1H-1 .2,3-triazol-4-y11-1H-indazolc:
S5-41.14-( trifluoromethoxy)benzy!]-1H-1 2. 3-triazol-4-yl}- 1H-indazole; 5-[1-(d-tert-butylbenzyl)-1H-1 2, 3-triazol-4-y1]-1 H-indazole; methyl 3-{[4-(1H-indazol-3-y])-1H-1 2, 3-triazol-1-yl methyl} benzoate; methyl 4- {[4-(1 Hendazol-5-y1}-1H-1,2, 3~triazol-1 -yllmethyl benzoate: 5-[1-(2 4-dimethylbenzy])-1H-1.2 3-tri azoi-4-yl}-1H-indazole;
5-[1-(3,5-dimethylbenzyl)-1H-1 Z,3-triazol-4-y1}-1H-indazole: 5-[1-(2,3-dichlorobenzyl)-1H-1 2,3-triazol-4-yl]- 1 H-indazole; 5-[1-(2.4-dichlorobenzyl)- 1H-1 2, 3-thazol-4-yl}-1H-indazole: 5-[1-(2.5-dichlorobenzyly-1H-1,2, 3-1 azol-4-yl1-1H-indazole; 5-[1-(3,5-dichlorobenzyl}-1H-1 2, 3-triazol-4-y11-1H-indazole; 5-41 -[2.4-bis(trifluoromethylybenzyl]-1H-1 2. 3-triazol-4-yl} -1H-indazole:
N-cyciohexyl-6-( 1H-in dazol-5-yhimidazo[2,1-b] [1.3]thiazol-3-amine;
N-cyclohexyl-2-(1H-in dazol-5-yhimidazo[ 1,2-alpyridin-3-amine:
N-cyciohexyl-2-(1 H-mdazol-5-ylimidazo[1.2-alpyrazin-3-amine:
H 3-[i-benzyl-4-(4-fluoropheny!- 1 H-imidazol-5 -yl}-TH-indazole;
N= {3-[4-(4-fluorophenyi)-5-( 1H -indazol-5-y1)-1H-imidazol-] -yijpropyl L-N,N- dimethylamine;
N-cyclohexyl-2-( 1H-indazol-3-y1)imidazof1 2-ajpyrimidin-3-amine; 5-[4-(4-fluorophenyl)-1-(1 -phenylethyl}-1H-inidazol-5 -yl}-1H-indazole; 2-(1H -indazol-5-y1)-N-isopropylimi dazof1.2-a}pyrimidin-3-amine; 4-(1H-indazol-5-y1}-N-phenyi- ,3-thiazol-2-amine; 5+(2-methyl-1,3-thiazol-4-yI)-1 H-indazole,
N-cthyl-4-(1H-indazol-5-y1)-1 .3-thiazol-2-amine:
N-benzyl-4-(1H~indazol-5-yi}-1 3-thiazol-2-amine; 4-(1H-indazol-5-y1)-1 .3-thiazol-2-amine; 4-(1H-indazol-5-y1}-N-(2-phenylethyl}- I 3-thiazol-2-amine;
N-benzyi-2-(1H -indazol-5-ylyimidazo] 1,2-a]pyrimidin-3 -amine;
N-butyl-2-(1H -indazol-5-yl)imidazo[ 1,2-alpyrimidin-3-amine;
N-(4-chloropheny!)-2-(1H -indazol-5-yDimidazo| 1 »2-ajpyrimidin-3-amine; 2-(JH-indazol-5-y1)-N-( 4-methoxyphenyimidazo[ 1.2-a|pyrimidin-3 -aming; 2-(1H-indazol-5-yl}imidazo[ ! 2-a pyrimidine; methyl N-{2-{1H-indazol-5-yl}imidazo[ 1 .2-ajpyridin-3-y!]glycinate;
N-benzyl-2-(1H-indazol-3-yhimidazo [1.2-a]pyridin-3-amine:
N-{4-chloropheny!}-2-(1 H-indazol-5-yl)imidazo[ 1 -2-alpyridin-3-amine; 2-+(1 H-indazol-5-y1}-N-(4-methoxypheny! Yimidaza[ I,2-a]pyridin-3-amine; tert-butyl 4-[4-(4-fluorophenyl )-5-(1 B-indazol-5-yI)-1H-imidazol-1 -yl]piperidine-1- carboxylate; 3,5-bis(1-benzyl-1H-1 2, 3-triazol-4-y1}- 1 H-indazole: 5-(1-benzyl-1H-1 2, 3-triazol-4-y1)-3-phenyl-1H-indazole,
S-(1-benzyl-1H-1,2,3-triazol-4-y1)-1 H-indazol-3-amine;
S(1-benzyl-1H-1 2, 3-triazol-dwyl)-1-[(1-m ethylipiperidin-4-yljcarbonyl]- [H-indazp!- 3-amine;
IN[5-(1-benzyl-1H- 23 razol-d-yl-1 B-indazol-3-yl1-2-methoxyacetamide;
N-[5-(1-benzyl- 15-12 3-triazo] ~4-yl-1H-indazol-3-y1]-N NV -dimethylglycinamide:
Ne[5-(1-benzyl-1H-1,2,3-tri azol-4-yl)-1H-indazo!-3-y] Jbutanamide: 5-{4-(4-fluorophenyl)-1 -piperidin-4-yl-1 H-imidazol-5 -ylj-1H-indazole; 5-{4-(4-fluorophenyl)-1 -[2-(1-meth yipyrrolidin-2-yhethyl]- 1 H-imidazol-5-yl1-1H- indazale: 5 {4-{4-fluorophenyl}- ~{3-{d-methyipiperazin.] -yhpropyl}-1 H-imidazol-5 ~ylte TH mdazoie; ethyl 5-(1 H-indazol-3-yhisoxazole-3-carboxylate; 5-(1H-indazol-5 -vi)-N-methylisoxazole-3-carboxamide; 3-(3-benzylisoxazol-5-yl)-1H-indazole:
N-[5-(1-benzyl-1H-1.2 3-triazol -4-yl)-1H-indazol-3-ylTbenzamide: 3-(3-propylisoxazol-5-y1)- 1H-indazole;
N-benzyl-4-{1H-indazol -5-yI}-5-phenyl-1 3-thiazol-2-amine; 4-(1H-indazol-5-yl}-N,5-diphenyi-1,3-thi azol-2-amine; 5-(1-benzyl-S-cyclopropyi-1H-1,2.3 ri azol-4-yl)-1H-indazole: 5-{1-benzyl-4-cyclopropyl-1H-1.2. 3-triazo -5-yh-1H-indazole; : 2-(1H-indazol-5-y])-3 -phenylimidazo{1,2-alpyrimidine: 5-11 -(tetrahydro-2H-pyran-4-ylmethyl)- LH-1.2 3-triazol-4-yi}-1H-indazole: 3-[3-(piperidin-[-ylcarbonyl}isoxazol-5 -yl]-1H-indazole; 5-(1H-ndazol-5-y1}-N -phenylisoxazole-3-carboxamide:
N-cyclohexyl-3-(1H-indazol-5 -yDisoxazole-3-carboxamide; 5-[3-(piperidin-1-ylmethyl)isoxazol-3 -yl]-1H-indazole; [5-(1 H-mdazol-5-yl)isoxazol-3-y!Jmethanol: 5-1 H-indazol-5-y1)-N~(2-methoxyethyljisoxazole-3-carboxamide: 5-(1-benzyl-5-phenyl-1H-1 »2,3-triazol-4-yl)-1H-indazole; 5-(4-benzyl-1H-1.2,3-triazol-1-y1)-1 H-indazole: 5-(1-benzyl-3-cyclopropyl-1H-1 A,3-rlazol-4-yl)- 1 H-indazol-3-amine; 5-(1-benzyl-d-cyclopropyl-1H-1 2. 3-trtazol-5-y1)- 1 H-indazol-3-amine; 3-(3~1sobutylisoxazol-5-y1}-1H-indazol-3 -amine, 3-(3-benzylisoxazol-3-yl)-1H-indazol-3-amine: i5
N-{2-[4-{4-fluorophenyl)-5-(1 H-indazol-5-y1)-1 H-imidazol-1 -yllethyl }-N,N- dimethylamine; 5-[4-(4-fluorophenyl)-1-(3-morpholin ~4-yipropyl)-1H-imidazoi-5-y1]-1H-indazolc: 5-{4-{4-flusrophenyl}- 1-(3-pyrrolidin-1 -ylpropyl }-1H-imidazol-S-yii-1 E-indazole; 5-{4-(4-fluorophenyi}~ 1-2 -{4~-methyipiperidin- | ~yhethyll-1H-imidazol-5-y1}-1H- mdazole; 5-1-1 -benzylpiperidin-4-y1)-4-(4-flucrophenyl}- 1H-imidazol-5-y1}-1H-indazole; 3-[4-(4-fluorophenyl)-1 -(Z-morpholin-4-ylethyl)-1 H-imidazol-5-y1}-1H-indazole; 5-[1-(1-benzylpyirolidin-3-y])-4-( 4-fluorophenyl}-1H-imi dazol-5-ylj-1H-indazolc: 16 2-{4-[4~{4-fluoropheny!}-5.( i H-indazo! ~5-yI}-1H-imidazol-1-ylpiperidin-1 ~yi-2- oxocthanel; 5~(1-benzyl-5-phenyi-1H-1,2 3-tri azol-4-yl)-1H-indazol-3-amine; 2-[1-(1H-indazol-5-y1}-1H-1,2,3-tri azol-4-yilpropan-2-ol;
S-{4-(methoxymethyl}-1H-1.2.3-triazoi-] -yl}-1H-indazole; [5 I-[1-(1H-indazol-5-y1)1H-1 2, 3-triazol-4-yil-1-phenylethanol;
S-(4-propyl-1H-1,2,3-triazol-1 ~yb)-1H-indazole; 1-[1-(1H-indazol-5-y1)-1H-1 »2,3-triazol-4-yljpropan-2-o!l: 3-[1-(1H-indazol-5-y])-1H-] .2,3-triazol-4-yllpropan-1-ol;
I-{[1-(1H-indazol-5-y}-1H-1.2.3 -triazol-4-ylimethyl }-1H-1 .2,3-benzotriazole; 5~{4-{(phenylthio)methyl]-1H-1.2 3-triazol 1 -yl-1 H-indazole;
S-{4-cyclopropyi-1H-1.2,3~triazoi- 1 -yI}-1H-mdazole; 5-{4-(2-phenylethyl)-1H-1.2,3-triazol-1 -yl]-1H-indazole; 5-t4-(cyclohexylimethyl)-1H-1.2,3-triazo]-1 -yl}-1H-indazole;
S-(4-cyclopentyl-1H-1,2,3-triazol-1 -yI)-1H-indazole; 1-[1-(1H-indazol-5-yD-1H-1 2.3-triazol-4-yl]cyciohexanol; 3-l4-{phenoxymethyl)-1H-1.2.3-triazal- 1 ~-yl]-1H-indazole;
S-{4-[(1.1 -dioxidothiomorpholin-4-ylmethyl]-1H-1,2 3-triazol-] -yl}-1H-indazole; 3-{4-(3-phenylpropyl)-1H-1.2 3-riazol-| -yi]-1H-indazole; {1-benzyl-4-(1H-indazol-5-yi)-1H-1.2,3-triazol-3 -yl(phenyl)methanone;
N,N-diethyl-N-{[1-(1H-indazol-5 yi 1H-1,2,3tri azol-4-yl methyl} amine; ethyl N-[2-(1] -indazol-5-yl)imidazo[ | 2-a]pyrimidin-3-y1}-beta-alaninate: 5-{1-benzyl-5-methyl-1H-1.2, 3-11 azol-4-yi)-1H-indazole; 5~(1-benzy!-5-methyl-1H-1.2,3-tri azol-4-yl}-1H-indazol-3-amine;
N[2+( 1 H-indazol-5-yljimidazo! 1 2-a]pytimidin-3-yl]-B-alaninamide,
5-{1-benzyl-5-iodo-1H-1,2.3 -triazoi-4-y1)-1H-indzzol-3-amin e:
N-{3-[4-(3-amino-1H -indazol-3-yl}-1-benzyl-1H-] 2,3riazol-5-yl phenyl | “N'-(3- methylphenylurea;
S-(1H-mdazol-5-y13-N-¢ L-isopropoxyethyllisoxazole-3-carboxamide: >-[3-(morpholin-4-yi carbonyl isoxazol-5-yl]-1H ~indazole; 5+( tH-indazol-5-y1-N-( S-morpholin-4-yipropylisoxazole-3 -carboxamide;
N-{2-(1H-imidazol-4-yl ethyl J-5-(1H-indazol-3~-yhisoxazo le-3-carboxamide: {(3R)-1-{[5-(1H-indazol-5-y]}isoxazo!-3 ~yllcarbonyl}piperidin-3-ol; 1-{[5-(1H-indazo!-3 -yhisoxazol-3-yljcarbonyl } piperidin e-3-carboxamide; 2e[2-(4-{[5-(1 H-indazol-5 -ylhsoxazol-3 -yljcarbonylpiperazin- 1 -ylhethoxyJethanol; 5-{3-{{4-methyl-1,4-diazepan-1 -yDearbonyl]isoxazol-5-y1}-1H-indazole:
N-(3-hvdroxypropyl)-5-( 1 H-indazol-5 -yhisoxazole-3-carboxamide:
N-[(1R}-2-hydroxy-1-ph enylethyl]-5+(1 H-indazol-5-yl)isoxazole-3-carboxamide;
N-[3-(1H-imidazol-1 -yhpropyl}-5-(1 H-indazol-5-yljisoxazole-3-carboxamide; 5-{1H-indazol-5~y1}-N- [3-(2-oxopyrrolidin-1 -ylpropyllisoxazole-3-carboxamide:
N- {2-f4-(aminosulfonyljphenylethyl }-5-(1H-indazol-3-yl Jisoxazole-3-carboxamide: [1-benzyl-4-(] H-indazol-5-y1)-1H-1 2, 3-triazol-5-y1}(3 -chlorophenylymethanone; [1-benzyl-4-(1H-indazol-5~y1)-1H-1 2,3-triazol-5-y1)( cyclopropylmethanone: 5-[5-cyclopropyl-1 -ttetrahydro-2H-pyran-4-ylmethyl)- 1H-1,2 3-triazoi-4-y1}-1H- indazole; oo
N= {[1-benzyl-4-(1 Hind azol-5-yl)-1H-1 2,3-triazol-5-yl methyl tglycinamide; (4-fluoropheny!)[4-(1H-indazol-5-y1)- 1 ~(ictrabydro-2H-pyran-4-yimethyl)- 1H-1.23- triazol-5-ylJmethanone; (4-chlorophenyl)[4-(1 H-indazol-5-yl)-1-(tetrahydro-7H -pyran-4-vimethyl)-1{3-1,2.3- triazol-5-yl}methanonc; (3-chlorophenyl)[4-(1 H-indazol-5-v1}-1 ~(tetrahydro-2H-pyran-4-ylmethy!)-1 H-1,2,3- tnazol-5-yljmethanone; (2-chlorophenyl [4 1H-indazol-5-y1}-1 ~(tetrahydro-2H-pyran-4-ylmethyl)- iH-1,2,3- triazol-5-ylJmethanone; cyclopentyl{4-(1H-indazol-3 -vD-1-(tetrahvdro-211 ~pyran-4-ylmethyl}- 11-12 3- razol-3-yljmethanone;
I-benzyl-4-(1H-indazol-5 -y1}-1H-1,2 3-triazoie-3 ~carboxylic acid; 3-{5-(4-fluorophenyi}-1 =f df trifluoromethylbenzyi]-1 H-1,2,3-triazol-4-v1 1 H- indazol-3-amine:
5-{1-benzy!-5-(4-fluorophenyl)-1H-1 2,3-triazol-4-y1}- 1 H-indazol-3-amine; [4-(1H-indazol-5-y1)-1 -(tetrahydro-2H-pyran-4-ylmethy! F1H-1,2,3-triazol-5- vil tetrahydro-2H-pyran-d-yDmethanone: 5-[1-benzyl-5-(2-methylphenyl)- 1 H-1.2, utr] azol-4-yll-1H-indazole; 5-{1-benzyl-5-[(4-methyipiperazin-] -yhycarbonyIl-1H-1.2 3-ri azol-d-yli-1H- indazole;
I-{{1-benzyl-4-(1H-indazo!-5-y1)-1H-1,2,3-rriazo I-5-yl]jcarbouyl! piperidin-4-ol:
T-acetyl-5-1 S-(4-fluorophenyl}-1-(tetrahydro-2H-pyran-4-vimethyl)-1 H- 1,2,3-triazol- 4-y11-1H-indazole;
I-benzyl-d-(1H-indazol-5-yI +N. N-dimeth yi-1H-1.2 3triazole-S-carbox amide:
N,I-dibenzyi-4-(1 H-indazol-5-yI}-1H-1.2 3-tri azole-5-carboxamide;
N-~(Z-hydroxy-2-phenylethyl)-5- 1H ~indazol-5-y1)-N-methyliscxazole-3-carboxam; de;
N-[(18}-2-hydroxy-1 -phenylethyl}-5-(1H-indazol-5-y1)isoxazole-3 -carboxamide;
N-benzyl-N-(2-hydroxyethyl}-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide; 5-[1-benzyl-5-(2-methylphenyl)-1H-1.2_3-tr azol-4-yl}-3-methyl-1H-indazole: 5-[1-benzyl-5-(2-methyiphenyl)-1H-1 2,3-triazol-4-yi]-1 H-indazol-3-amine; 2-{2-[1-(1H-indazol-5-y1}-1H-1,2.3 -triazol-4-yijethyl}-1H-isoindole-1 S{Z2H)-dione; 5-{4-{(24-dichiorophenoxy)methyl]-1H-1.2 3-iriazol-1 -yl}-1H-indazole; 5-{4-[(2.6-dichlorophenoxy)methyi]-1H-1,23-iriazol-1 -yl}-1H-indazole; 5-{5-(4-fluorophenyi)-] ~(tetrahydro-2H-pyran-4-ylmethyl)-1H-1 2. 3-riazol-4-yl]-1H- indazole; i-{{1-(1H-indazol-5-y1)-1H-1 -2.3-triazol-4-yImethyl}-1H-indazole: 3-[I-benzyl-5-(piperidin-1 ~ylcarbonyl}-11-1.2, 3-triazol -4-yl]-1H-indazole; 5-[5-(2-methylphenyl)-1 ~(tetrahydro-2H-pyran-4-ylmethyl)- 1H-1.2,3-triazol-4-yl1]-
IH-indazole; 5-[5-(2-methylpheny[)-1-(tetrahydro-2H -pyran-4-yvimethvl)-1H-1 2,3-triazol-4-yl1-
IH-1ndazol-3-amine; 3-[1-benzyl-S-(morpholin-4-ylcarbonyl)- 1H-1 2, 3-triazol-4-y1]-1H-indazole: 5-[1-benzyl-5-(d-methoxyphenyl)-1H-1 ,2,3-triazol-4-yl}-1H-indazoi-3-amine;
N-[(18)-1 -benzyl-2-hydroxyethyl]-5-( 1H-ndazol-5-ylisoxazole-3-carboxamide:
N-[(18,2R)-2-hydroxy-2,3-dihydro-1H-inden-1 -vI]-5-(1H-indazol-3-yl)isoxazole-3- carboxamide; 5-{3-f (3-phenylmorpholin-4-yl)carbonyl Jisoxazol -5-v1}-1H-indazole;
N-benzyl-5+( 1H-mdazol-5-yl)isoxazole-3-carboxamide; ig
((18)-2-{[5-(1H~indazol-5-yl}isoxazol-3 -yl]earbonyl}-6.7-dimethoxy-1,2,3 4- tetrahydroisoquinotin-1-ylimethanol;
N-[(IR}-3-hydroxy-1 -phenylpropyl}-5-( 1H -indazol-5-yi)isoxazole-3-carboxamide:
N-f(1S)-3-hydroxy-1 -phenylpropyl}-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide: 3 N-2,3-dihydro-1 H-inden-1 -yl-5-(1H-indazol-5-y1isoxazale-2 -carboxamide;
N-2,3-dihydro-1H-inden-2-y1-5-(1 H-indazol-5-yl)isoxazoie-3 carboxamide; 5-(1H-ndazol-5-y1)-N-(1 -phenyipropyDisoxazole-3-carboxamide; 5-{1-benzyl-5-[ 3-(dimethylamino)pheny1]-1H-1 23-triazol-4-vlt-1H-indazol-3- amine; 5-{1-benzyl-5-[4-(dimethylamino Jphenyl]-18-1,2 3-triazol-4-yl} - 1 H-indazol- 3- amine;
N-{3-[4-(3-amino- 1 H-indazol-5-y])-1 -benzyl-1H-1,2,3-triazol-5- yliphenyl} acetamide;
N-{4-[4-(3-amino-1 H-indazol-5-y1}-1-benzyl-1H-1,2 3-triazol-5- yliphenyl}acetamide; 5-{1-benzyl-5-[3-( 1H-pyrazol- -yhphenyl}-18-1.2,3-iriazo] -4-vi}-1H-indazol-3- amine; 5-[}-benzyl-5-(1-methyl-1 Hepyrazol-4-y[}-1H-1 2. 3-triazol-4-y1}- 1 H-indazol-3- ‘amine; 3-[4-(3-amino-1H-indazol-5-yl)-1 -benzyl-1H-1,2, 3 ri azol-5-ylj-N-phenyibenzamide: 3-[4~(3-amino-1H-indazol-5 -yh-1-benzyl-1H-1,2,3-triazo}-5 -vl]-N-benzylbenzamide; 5-[1-benzyl-5-(1-methyl-1 H-indol-3-y1)-1H-~1,2.3 ~triazol-4-yI]-1H-indazol-3-amine; 3-[I-benzyl-5-(3-methoxyphenyl)-1H-1 22, 3-triazol-4-yl1-1H-indazol-3 -anmne; 5-11-benzyi-S-( 3-morpholin-4-ylpheny!}-1H-1.2.3-iriazo] -4-yl]-1H-indazol-3-amine, 5-[3-(1 :3-dihydro-2H-isoindol-2-yicarbonyl)isoxazol-5-y1]- 1H-indazole; 5-{3-[(4-methyl-2-phenylpiperazin- 1 -ylcarbonyljisoxazol-5-y1}-1H-indazole ;
I-{[}-benzyl-4-(1H-indazol-5-yD)-1H-1 -2.3-triazol-5-yi]carbonyl } piperidin-4-amine:
N-{5-(1-benzyl-5-phenyl- 11-1 2, 3-triazol-4-yl)-1 H-indazol-3-yl]benzamide;
N-[{5-(i-benzyl-5-phenyl-1H-1 22,3-triazol-d-yi)-1 H-indazol-3-yllbenzenesulfonamide:
N-[5-(1-benzyl-5-phenyi-1H-1 »2.3-triazol-4-yl)-1 H-indazol-3-y1]-N'-(4- methoxyphenyl urea;
N-[5-(1-benzyl-5-phenyi- 1H-1 -2,3-triazol-4-yl}-1H-indazol-3-y1Ibutanamide:
N-[5-(1-benzyl-5-phenyl-1H-1.2, 3-triazo I-4-yl)-1H-indazol-3-yI]-2- methylpropanamide;
N-[5~(I-benzyl-5-phenyl-1H-1,2,3-triazol-4-y1)-1 H-indazol-3- vljeyclopropanecarboxamide:
N-[1-benzoyl-5-(1-benzyl-S-cyclopropyl-15-1,2. 3-45 azol-4-yh-1H-mdazol-3- vi]benzamide,
N-[5-(1-benzyl-5-cyclopropyl- 1 F-1.2 3-triazol ~4yl}-1H-indazol-3-y1]-3~ fluorobenzamide;
N-[5~(] -benzyl-5-cyciopropyl-1H-1.2.3 -triazol-4-yi}-1H-indazol-3-viJhenzamide:
N-benzyl-5-(1-benzyl-S-cyclopropyl-1H-1.2,3-tri azol-4-yl)-1H-indazol-3-amine;
N-[(IR)-1-benzyl-2-hydroxyethyl]-5-( 1 H-indazol-5 -yDisoxazole-3-carboxamide:
S-{1-benzyl-1H-pyrazol-d-v1)-1 H-indazole:
MN-[(1R}-3-hydroxy- I-phenylpropyl]-5-(3-methyi-1H-ind azol-5-ylhsoxazole-3- carboxamide; 3-[4-(3-amino-1H-indazol-5-y!)- | -benzyl-1H-1,2, 3-triazol-5-yi]phenol: 3-[4-(3-amino-1H-indazol-5-y1)-1 -benzyl-1H-1,2,3-triazol-5-yljbenzamide; 5-{1-benzyl-5-[4-(methylsuifonyl phenyl 1H-1.2. 3 tri azol-4-yl}-1H-indazol-3- amine;
N-[5-{1-benzyl-5-cyclopropyl-1H-1.2.3 ~triazol-4-y1}-1H-indazol-3-y11-2- chiorobenzamide;
N-[5~(1-benzyl-3-cyclopropyl-1H-1,2.3 -triazol-4-yl)-1H-indazol-3-y1]-4- chlorobenzamide;
N-[5-(1-benzyl-5-cvelopropyi-111-1.2.3 -triazol-4-y1}-1H-indazol-3- yiethanesulfonamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3 -triazol-4-y1)-1H-indazol-3- yllbenzenesnlfonamide;
N-[5-(1-benzyl-5-cyclopropyi-1H-1,2 3-tri azol-4-yl}-1H-indazol-3-v1]-2- chlorobenzenesulfonamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2.3 -triazol-4-y1)-1H-indazol-3-y1}-3- chlorobenzenesulfonamide;
N-{5-(1-benzyl-5-cyclopropyl-1H-1,2,3 -triazol-4-y1)-1H-indazol-3-yl}.4- chiorobenzenesulfonamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2.3 ~triazol-4-yi)-1H-indazol-3-y1]-2.5- dimethylfuran-3-sulfonamide; 5-(1-benzyl-5-cyclopropyl-1H-1 wn 3triazol-d-yl)-N-(2 -chiorobenzyl}-1H-indazol-3- amine;
5-{1-benzyl-5-cyclopropyl-1H-1 +2,3-triazol-4-y1}-N~(3-chlorobenzyl)-1 H-indazol-3- amine;
N-p5-(1-benzyl-5-cyclopropyl-1H-1,2.3 ~t11az0l-4-y}-1H-indazol-3-y1]-3- chlorobenzamide; 3 N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3 ~triazol-4-yl}-1H-indazol-3-y1}-2-furamide; 5-{I-benzyl-5-cyclopropyl-1H-1 2, 3-miazol-4-yi)-N-ethyl-1H-indazol-3-amine: 5-(1-benzyl-5-cyclopropyl-1H-1 2, 31118201 4-y Ej N-( 4-chlorobenzyl)-1H-indazol-3- amine; 5-{1-benzyl-3-cyclopropyl-1H-1.2, 3-11 az01-4-y[}-N-(3-furyimethyl)- 1 H-indazol-3- amine;
N-[5-(1-benzyi-5-cyclopropyl-1H-1,2.3 -triazol-4-y »-1H-indazol-3-yi]-N'-[ 5-methyl- 2-{trifluoromethyl}-3-furyl jurea;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2.3 -triazol-4-yl)-1H-indazol-3-y1}-3-furamide; 5-(1H-indazol-5-y[}-N-[(1S}-1-ph enylpropyllisoxazole-3-carboxamide: 5-(1H-indazol-5-y)-N-[(1R}-1 -phenylpropyllisoxazole-3-carboxamide: 5-(1-benzyl-1H-pyrazol-4-vl}-1H-indazol-3 -amine; i-benzyl-4-(1H-mndazol-5-y1-N-[( 25 tetrahydrofuran-2-yimethyll-1H-1.2 3-triazole-
S-carboxamide; 1-benzyl-4-{ 1H-indazol-5-y1)-N-( 2-isopropoxyethyl)-1H-1.2 3-triazole-3- carboxamide;
I-benzyl-4-(1 H-indazol-5-y13-N-[(2R)-tetrahydrofuran-2 -yimethyl]-1H-1,2, 3-triazole-
S-carboxamide;
I-benzyl-4-(11-indazol-5-y1)}-N-( tetrahydrofuran-3-ylmethyl)-1H-1,2 3-triszole-5- carboxamide;
I-benzyl-N-cyclopentyl-4-(1H-indazol-5-y1)-1H-1 2. 3-triazole-3 ~carboxamide;
I-benzyl-N-(cyclopentyimethyl)-4-( 1H -indazoi-5-yl}-1H-1.2,3-triazole-5- carboxamide;
I-benzyl-N-ethyl-4-(] H-indazol-5-yl)-N-methyi-1H-1,2 3-tri azole-3-carboxamide; ] ~benzyl-4-(1H-indazol-5-y1)-N-isopropyl-N -methyl-1H-1,2,3-triazole-5- carboxamide;
I-benzyi-4-(1 H-indazol-5-y1)-N-(2-methoxyethyl}-N-methyl-1 H-1.2 3-triazole-3- carboxarnide; 1 ~benzyl-4-(1H-indazol-5-yl)-N-phenyl-1 H-1.2.3-triazole-5-carboxamide:; 1 -benzyl-N-(4-chlorophenyl)-4-{ 1H-indazol-35-yl)-1H-1 .2.3~triazole-5-carboxamide;
I-benzyl-4-(1H-indazol-5~y1)-N-(2-morpholin-4-ylethy!}- 1H-1,2.3-triazole-5- carboxamide; l-benzyl-N-[2-(dimethylamine ethyl]-4-( 1 H-indazo]-5 ~yD-Nemethyl-1H-1,2 3- trizzole-S-carboxamide; l-benzyl-N-(2-hydroxyethyl}-4-( 1 H-mdazol-5-yh-Nepropyl-1H-1.2 3«irazoic-5- carboxamide;
I-benzyl-N-[3-(dimethylaminojpropy}-4-(} H-in dazol-5-yl)-N-methyi-1H-1,2,3- triazole-3-carboxamide;
I-benzyl-N-[2-(diethylamine ethyl ]-4-( 1 Hendazol-5-y-N-methyl- 1H-1.2 3-triazole-
Secarboxamide;
MN, F-dibenzyl-N-ethyl-4-(1H-indazol-5-y1}-1H-1,2.3 -triazole-5-carboxamide;
N,1-dibenzyl-N-(2-hydroxyethyl}-4-( | H-indazol-5-y1}-1H-1.2, 3-friazole-5- carboxamide; (3R)-1-{[1-benzyl-4-(1H-indazol-5-yi}- 1 H-1 2. 3-tr1azol-5-yljcarbonyl piperidin-3-ol; 1-{[1-benzyl-4-(1H-indazol-5-y{}-1FH-1,2,3-ri azol-3-yl carbonyl} piperidine-4- carboxamide; 5-{1-benzyl-5-[( 2,6-dimethytmorphofin-4-yljcarbonyl]-1H-1 2. 3-triazol-4-yl}-1H- indazole;
S-{5-[(4-acetylpiperazin-1-ylcarbonyl]-1-benzyl-1H-1 ,2.3-triazol-4-y1}-1H-indazole; 5-{}-benzyl-5-{(4-phenylpiperazin-1-yhecarbonyl]- 1H-1,2.3-triazo -4-y]}-1H- mdazole;
I-benzyl-N-[{ 1R)-1 -(hydroxymethyl)-2-methylpropyl]-4-( 1 H-indazol-3 -yi-1H-1,2.3- triazole-S-carboxamide;
I-benzyl-N-[(18)-1 -(hydroxymethyl}-2-methylpropy!}-4-(1 H-indazol-5-y[}-1H-1,2.3- triazole-5-carboxamide;
I-benzyl-N-[3-(1H-imidazol-1-yDpropyi]-4-( 1H-indazol-5 -yI}-1H-1,2,3-trjazole-5- carboxamide;
N-[5-(1-benzyl-3-cyclopropy!-1H-1.2 3-tri azol-4-y1)-1H-indazol-3-y1]-N'-cthylurea;
N-[3-(1-benzyi-5-cyclopropyl-1H-1,2 3-triazol-4-y1)-1H-in dazol-3-yl}-N'-phenylurea;
N-benzyl-N'-[5-(1 -benzyl-5-cyclopropyl-1H-1 .2,3~r1iazol-d-yi)-1H-indazol-3-yljurea;
N-[3-(i-benzyl-S-cyclopropyl-1H-1,2 3-triazol-4-y1)-1 H-indazol-3 -yl-N'-(2- chlorophenyl urea;
N-[5<(1-benzyl-5-cyclopropyl-1H-1,2.3 ~triazol-4-yl)-1H-indazol-3-yI]-N'-(3- chlorophenyljures;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2.3-tri azol-4-yl)-1H-indazol-3-y1}-N'-{4- chlorophenylurea;
N-[5-(1-benzyl-5-iado~1H-1.2 3-triazol-d-y[}- 1H -indazol-3-yi}benzamide; 3-[4-(3-amino-1H-indazol-5-y1)- 1 H-pyrazol-1 -ylipropanenitrile; 2-[4~(3-amino- | H-indazol-5-y1)-1 H-pyrazol-] ~ylJacetamide: methyl 3-[4-(3-amino- 1 H-indazoi-5-y1)-1 He-pyrazol-1-yljpropancate; 3-[4-(3~amino-1H-indazol-5-y1}- 1 H-pyrazol-1 -vllpropanamide; [4~(3-ammo-1H-indazol-5-y1)-1 H-pyrazol- ~yliacetonitrile; 4-(3-amino-1H-indazol-3-y1)-N,N-dimethyl- 1 H-imidazole-1 sulfonamide;
S-pyrazin-Z-yl-1H-indazol-3-amine; 5-thien-2-yl- 1 H-indazol-3-amine; 5-(Z-ammepyrimidin-4-y1)-1H-indazeol-3-amine: 5-(2-methoxypyridin-3-yl)-1H-indazol-3-amine;
S-imidazo{1,2-a]pyridin-3-yl-1 H-indazol-2 -amine;
N*N’-dimethyl-N'-[5-(1H-1,2 3-triazol -4-yl}-1H-indazo!-3-y1}glycinamide; 5-(1H-pyrazol-5-yl}-1H-indazol-3-amine; 5-{(4-methyl-1H-imidazo!-5-yl)-1 H-indazol-3-amine; 5-(1H-imidazol-4-y1)-1H-indazol-3-amine;
NN dimethyl-N'- {5-[1-(3-methylbenzyl-1H-1,2, 3 tri azol-4-yl1-1H-indazol-3- yliglycinamide; 5-(1-benzyl-1H-imidazol-4-yl)- 1 H-indazol-3-amine:
N'-{5-[1-(4-tert-butylbenzyl)-1H-1 2,3-triazol-4-yl}-1H-indazol-3-yl }-N* N° dimethylglycinamide;
N° N-dimsthyl-N'- {5-[1-(2-piperidin-1 -ylethy])-1 H-1.2.3-triazol-4-y1}- 1 H-indazol-3- yl}glycinamide;
N'IN"-dimethyl-N'- {5-1 <2-morpholin-4-ylethyl}- 1H-1 2,3-triazot-4-yi1-1H-indazol- 3-yl}glycinamide;
NI (5- {1-]2-(3 S-dimethylisoxazol-4-ylethyl]-1H-1 2.3-triazol-4-yl} -1H-indazol-3- yI-N*N’-dimethylelycinamide ;
N(5-{1-[2-(3 S-dimethyl-1H-pyrazol-4-yhethyl]- 1TH-1.2, 3-tr] azol-4-vl}-1H-indazol- 3-yD-NEN *~dimethylglycinamide: 2-{4-{3-[(N,N-dimethylglycyljamino|- | H-indazol-5 “yl -1H-1.2,3-triazol-1-y1)-2- methylpropanoic acid; ethyl (4-{ 3-{(N.N-dimethylglycyljamino]-1H-indazol-3 -yl}-1H-1,2,3-triazol-1-
vlacetate;
NY N*-dimethyl-N'-(5- { I-[{trimethylsily] ymethyl}-1H-1,2 3-triazol-4-y1}~1H-indazol-
I-yDelycinamide;
WN [5-(3-Furyl)-| H-indazol-3-y1 N° N dimethyl glycinamide: 3 NY N*-dimethyi-N Ls IH-pyrazol-5-y1}-1H-indazol-3-y1] glvcinamide;
N° N*-dimethyl-N (3 -pyrimidin-3-yl-1 B-indazol-3 ~yhglycinamide; nN! -[5-(2,1,3-benzoxadiazol-3-yI)-1 H-indazol-3 YN N? ~dimnethylglveinamide;
NN -dimethyl-N' ~[5-{1H-pyrazol-4-yi)-1 H-indazol-3-yl]glycinamide:
NY N-dimethyl-N Lf 5-(1-m ethyl-1H-pyrazol-4.y[}-1H-in dazol-3-vlglveinamide:
N'-[5-(3,5-dimethyl-1 H-pyrazol-4-yl)- | H-indazol-3-y1]-N" WN -dimethylglycinamide:
N'- {5-2 ~(¢imethylamino ypyrimidin-S-y1]-1 H-indazol-3-y1} NN dimethylgiycinamide;
N’N*-dimethyl-N' -[5-(2-morpholin-4-ylpyrimidin-5-yI}-1H-indazol-3- vllglycinamide; 13 N° N’-dimethyl-N'-{5-[1 -(2-morphotin-4-ylethyl)- 1H-pyrazol-4-yi]-1 H-indazol-3- vi} glycinamide;
N'-{5-(1-benzyl-5-cyclopropyl- 15-1 2,3-triazol-4-yI}-1 H-indazol-3-yl]-N* N* dimethylglyeinamide;
N' -[5-(1-benzyl- 1H-pyrazol-4-yl)-1 H-indazol-3-y1}-N* N’-dimethy! glycinamide;
N 15-0 ~benzyl-1H-1,2 3-triazol-4-y1)- 1 H-indazol-3 -yl]-N"-methylglycinamide;
N-[5-(1-benzy!-1H-1.2,3-triazol-4~y]}-1 H-indazol ~3-y1}-2-pyrrolidin-1-ylacetamide:
N-[ 3-(1-benzyl-1H-12 3-triazol-4-y!}-1H-indazol-3 -yI]-N"-cyclopentyiglycinamide;
NL[5-¢1 -benzyl-1H-1.2.3-triazol-4-v1)-1 H-indazol-3 -yI}-N *-cyclopropylglyeinamide:
N'-[5-(1-benzyl-1H-1,2.3 triazol-4-y1)-1 H-indazol-3-yl}-N"-tetrahydro-2H-pyran-4- ylglycinamide;
N-[5-(1-benzyi-1H-1.2,3-triazol-4-v1)-1 H-indezol-3-y11-2-(3-hydroxypyrrolidin-1- yhacetamide;
N-[5-{1-benzyl-1H-1.2.3 -triazol-4-yi)-1 H-indazol-3-y11-2-( 3-hydroxypiperidin-i- yhacetamide;
N'-[5-(1-benzyl-1H-1,2,3-triazol-d-yl}-1 H-indazol-3-yl]-N* WN -dimethvl-beta- alaninamide;
N-[5-(1-benzyl-1H-1,2,3-triazol-4-y1)-1 H-indazol-3-yl]-2-morphalin-4-ylacetamide;
N-[5-(1-benzy!-1H-1.2.3-tr azoi-4-yl)-1H~indazol-3-yi}-2-(4-meth ylpiperazin-1- vhacetamide;
N-[3-{1-benzyl-1H-1,2 3-triazol-4-y1)-1 H-indazol-3-y1}-2-( 3-oxopiperazin-1- vhacetamide;
N-I5-(1-benzyl-1H- 1.2,3-trazol-4-y1}- 1 H-indazol-3-yI]-IN *-isopropylglycinammide;
N51 -benzyl-1H-1.2.3-triazol-4-v])-1 Heindazol-3 yi -cvelohexylglyein amide:
N-[5-(1-benzyl-1H-1,2,3-triazol-4-yi}- 1H-indazoi-3 ~yllacetamide;
N'-f5-(1-benzyl-1H-1,2.3-triazol-4-y1)- 1 Heindazo 1-3-y1}-N"-cyclobutylglycinamide:
N-[5-(1-benzyi-1H-12 3-triazol-4-yi)-1H-indazol-3 -y]-N'-propylurea,
N-[5-(i-benzyl-1H-1.2 3-triazol-4-yi}- 1 H-indazol-3-y] jethanesulfonamide: 5-(1-benzyl-1H-1,2, 3-trigzol-4-yI}-N-(cyclopropylmethyl)- 1 H-indazol-3-aminc. 19 IefSe(1-benzyl-1H-1.2, 3-triazol-4-y1)-1 H-indazol -2 ~yH-N'-ethylurea;
I-{5-(1-benzyl-1H-1,2,3-triazol-4-yi}- 1H -indazol-3-ylipyrrolidin-2-one,
N-[5-(1-benzyi-1H-1.2 3-triazol-4-yi)-1H-indazol-3-yl}-4- {dimethylamino)butanamide;
N-3.,4-dihydro-1H-isochromen-4-yl-5-(1 H-mdazol-5-yisoxazole-3-carboxamide;
N-{cyclohexyimethyl)-5-(1H-indazol-5-yl)isoxazole-3-carboxamide;
N-(3-chlorobenzyl)-S-(1H-indazol-5-yl)isoxazole-3-carboxamide; 5-(1 H-mdazo!-5-yl)}-N-(2-methoxybenzyl isoxazole-3-carboxamide; 5-(1H-indazol-5-y1}-N-[2-( trifluoromethylbenzyllisoxazole-3-carboxamide: 3-(1H-indazol-5-yl}-N-[3-(trifluoromethyl benzyl Jisoxazole-3-carboxamide; 5-{1H-indazol -5-y1}-N-[4-(trifluoromethyDbenzyl lisoxazole-3-carboxamide; 5-(1H-mdazol-5-yl}-N-(pyridin-2-ylmethylisoxazole-3-carboxamide: 5~(1H-indazol-5-y1}-N-(pyridin-3-ylm ethylnsoxazole-3-carboxamide; 5-(1H-indazol-3-yI}-N-(pyridin-4-yimethyl)isoxazole-3-carboxamide;
N-(2-chlorobenzyl)-5-(1H-indazol-5-ylisoxazole-3-carboxamide:
N-(4-chlorobenzyl}-3-(1H-indazol-3-yl)isoxazole-3-carboxamide: 5-(1H-indazol-5-y1}-N-(1-phenyl-2-piperidin-1-viethyisoxazol e-3-carboxamide;
N-{2-(1H-imidazol-1-yl}-1-phenylethy!]-5-( 1 H-indazol-5-y1jisoxazole-3- carboxamide; 5-{1H-mndazol-5-yl}+N-(2-morpholin-4-yi-1 -phenylethybisoxazole-3-carboxamide; 5-(1H-indazol-5-yl}-N-[2~(4-methylpiperazin-1 -yl)-1 -phenylethvi}isoxazole-3- carboxamide; 5-(1H-indazol-5-yl)-N-{1-phenyl-2-pyrrolidin- | -vlethyl)isoxazole-3-carboxamide; tert-butyl 2-({]5-(1H-indazol-5-ylisoxazol-3-yl Jearbonyl}amino)-2- phenylethyicarbamate;
>-(1H-indazol-5-y1}-N-(1-naphthylmethyi lisoxazole-3-carboxamide: 5-+(1 H-indazol-5-y1)-N~(2-phenylethyl)isoxazole-3-carboxamide; 5-{1H-indazol-5-y1}-N-(2-pyridin-2-ylethylisoxazole-3-carbox amide:
S-(1H-mdazol-5-y1)-N-(2-pyridin-3-ylethyllisoxazole-3-carboxamide: 5-(1H-mdazol-5-y1}-N-{2-pyri din-d-ylethyl)isoxazole-3-carboxamide;
N-[2-(Z-chlorophenylyethyl]-5-( 1H-in dazol-5-yl)isoxazole-3-carboxamide;
N-[2-(3-chlorophenyljethyl]-5-(1H-imdazol-5-ylisoxazole-3-carboxamide:
N-[2-(4-chlorophenyljethyl}-5-() H-indazol-5-yl}isoxazole-3-carbozamide;
N-benzyl-N-ethyl-5-(1H-indazol-5-ylYisoxazole-3-carboxami de; 5-(1H-indazol-5-yl J-N-methyl-N-(J-naphthylmethy!Yisoxazole-3-carboxamide: 5-(1H-mdazol-5-y1}-N-methyl-N-(Z-phenylethyljisoxazole-3 -carboxamide; 53-(1Handazol-5-y1-N-methyl-N-(2-pyridin-2 -ylethyl)isoxazole-3-carboxamide; 5~(1H-indazol-5-y]}-N-[(1R)}-1 -phenylethyijisoxazole-3-carboxamide: 5-(1H-indazol-5-yl}-N-1,2,3,4-tetrahydronaphthalen-1 -ylisoxazole-3-carboxamide; 5-(1H-indazol-5-y1}-N-[( 1 8)-1-(1-naphthyliethyl jisoxazole-3-carbox ammde;
S-(1H-indazol-5-yb}-N-[(I1R}-1-(1-n aphthyljethyl}isoxazole-3-carboxamide;
N-{3«(dimethylamino)-1-ph enylpropyl]-5-(1H-indazol-5-yl}isox azole-3-carboxamide;
N+(2,3~dihydro-1,4-benzodioxin-S-yimethyl)-5-( 1 H-indazeol-5-vl)isoxazole-3- carboxamide;
N-(3,4-dihydro-2H-1 S-benzodioxepin-6-ylmethy!)-35-(1H-indazol-3 -yl)isoxazole-3- carboxamide; 5-{(1H-indazol-5-y[}-N-{(1-methyl-1 H-indol-4-ylymethyljisoxazole-3-carboxamide: 5-{3-[(3-phenyipyrrolidin-] -yl)carbonyllisoxazol-5-y1}-1H-indazole; 5-{3-[(2-phenylpyrrolidin-I-ylcarbonyl Jisoxazol-5-yI -1H-indazole; 5-{3-{(2-phenylpiperidin-1 -ybcarbonyllisoxazol-5-yt}-1H-indazole; 5-(1H-indazol-5-y[}-N-[(18)-1 -phenylethyijisoxazole-3-carboxamide;
S-{1H-indazol-5-y1)-N-[(IR)}-1 -(4-methyiphenylethyllisoxazole-3-carbox amide; 5-(1H-indazol-5-y1)-N-[{18)-1-(4-methylph enyljethyllisoxazole-3-carboxamide;
N-[(1R,28)-2-hydroxy-2,3-dihydro- {| H-inden-1 -yli-5-(1H-indazol-5-yl)isoxazole-3- carboxamide;
N-{(1R,2R}-2-hydroxy-2,3-dihvdro-1H-inden-1 -y1]-5-(1H-indazol-5-vhisoxazole-3- carboxamide;
N-[(1R}-1-(4-bromophenylethyi]-5-( | H-indazol-5 ~yhisoxazole-3-carboxamide;
N-[(15}-1-(4-bromophenyl)ethyi]-5-(1H-indazol-5 -ylyisoxazole-3-carboxamide;
N-[(1R)-1-(4-chlorophenyljethy]]-5-( 1H-indazol-5-yl)isoxazole-3-carboxamide:
N-[(18}~1-(4-chloropheny])ethyl]-5-(] H-indazol-5-yl}isoxazole-3-carboxamide;
S3-{1H-mdazol-5-y1}-N-{(18)1 ~(Z-naphthyliethy!Jisoxazole-3-carboxamide:
M-[1-(4-ethoxyphenyl}-2-hydroxyethyl |-5-( | H-indazel-3-vljisoxazale-3- carboxamide;
N-[Z-hydroxy-1-(4-isepropyiphenyl ethyl }-5-(1H-indazol-5 -ylisoxazole-3- carboxamide;
N-[1-(3.4-dimethyiph enyl}-2-hydroxyvethyl]-5-(1 H-indazol-5-yhisoxazole-3- carboxamide;
N-[2-hydroxy-1-{2-methoxyphenyljethy]-5-( 1 H-indarol-3-yljisoxazole-3- carboxamide;
N-[2-hydroxy-1-(4-methylphenyDethyl]-5-(1 H-indazol-5-yl)isoxazole-3- carboxamide; 5-(1H-indazol-5-y1}-N-{( 1R}-1 -(2-methoxyphenylethyl Jisoxazole-3-carboxamide:
N-[(15}-1-(3,4-difluorophenyl)ethyl]-5-( 1 H-indazol-5-yl)isoxazole-3-carboxamide: 5-(1H-indazol-5-y1}-N-{{1R }-]-(3-methoxyph enylethylJisoxazole-3-carboxamide:; 5-(1H-indazol-5-y1)-N-{{ 1R)-1-[3-( triffuoromethylphenyllethyl}isoxazole-3- carboxamide;
N-[1-(2,3-dihydro-1,4-benzodioxin-6-yljethyt}-5-( 1H-ind azol-3-yljisoxazole-3- carboxamide;
N-[1-(3,5-dichlorophenyl}-2-hydroxyethyl}-5-( 1H -indazol-5-yl)isoxazole-3- carboxamide; tert-butyl 5-(1-benzyl-1H-1,2,3-triazol-4-y1}-3-[( {[6-(triflucromethyl}pyridin-2- vl]amino}carbonylyamino}-1H-indazole-] -carboxylate; 5-(1-benzyl-1H-1.2,3-triazol-4-yD-1-{(1 -methylpiperidin-2-yl)carbonyl]- 1 H-indazol-
J-amine; 5-(1-benzyl-1H-1,2.3-trtazol-4-y1)-1-[{dimeth ylaminojacetyl]-1H-indazol-3-amine: terr-butyl 3-amino-3-(1-benzyl-1 4-1 ,2,3-triazol-4-y1}-1 H-indazole-1 carboxylate;
N-{5+(1-benzyl-1H-1.2,3-triazoi-4-yl}- 1 H-indazo!-3-y1}-2-piperidin-1-ylacetamide;
N-[5-(1-benzyl-1H-1.2,3~triazol-4-y1)-1 H-indazol-3 -vl]-2-morpholin-4-vlacetamide; and
No[5-(1-benzyi-1H-1.23 ~triazol-4-y1)-1H-indazol-2-y]]-1 -methylpiperidine-2- carboxamide,
All patents, patent applications, and literature references cited in the specification are herem incorporated by reference in their entirety. In the case of mcongsistencies, the present disclosure, including definitions, will prevail.
Ag used throughout this specification and the appended claims, the following terms have the following meanings:
The term: "alkenyl!" as used herein. means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, Z-propenvl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl., 5- 1 hexenyl, Z-heptenyl, 2-methyl-1 -heptenyl, and 3-decenyl,
The term "alkoxy" as used hercin, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexvyloxy.
The terro "alkoxyalkoxy" as used herein, means an atkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein.
Representative examples of elkoxyalkoxy clude, but are not limited lo, tert-butoxymethoxy, 2-cthoxyethoxy, 2-methoxyethoxy, and methoxymethoxy,
The term "alkoxyalkoxyalkyl" as used herein, means an alkoxyalkoxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, 48 defined herein. Representative examples of alkoxyalkoxyalkyl include, but are not limited to, tert-butoxymethoxymethyl, ethoxymethoxymethyl, ( Z-methoxyethoxy)methyl, and 2-(2- methoxyethoxy)etlyl.
The term "alkoxyalkyl" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an allcylene group, as defined herein.
Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
The term "alkoxycarbonyl" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
Representative examples of alkoxvearbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
The term "alkoxycarbonylalkyl” as used herein, means an alkoxycarbonyl! group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of alkoxycarbonyfalkyl include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and 2-tert-butoxycarbonylethyl.
The term "alkyl" as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl. n-propyl, isc-propyl, n-butyl, sec-butyl, iso-butyl, ter-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, J-methylhexyl, 2,2-dimethyipentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
The term "alkyicarbonyl" as used herein, means an allyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein,
Representative examples of alkylcarbony! include, but are not Hmited to, acetyl, l-oxopropyl, 16 2.2-dimethyl-1-oxopropyl, 1-oxobutyl, and -oxopentyl.
The term "alkylcarbonylallcyl” as used herein, means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkylene group. as defined herein. Representative examples of allcylcarbonylalky! include, but arc not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl. 13 The term "alkyicarbonyloxy™ as used herein. means an alkylearbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, cthylcarbonyloxy, and tert-butvicarbonyloxy.
The term "alkylene" means a divalent group derived from a straight or branched chain hydrocarbon of from 1 fo 10 carbon atoms. Representative examples of alkylene include, but are not himited to, ~CH,-, -CH(CH:)-, -C(CBi)o-, -CH,CHo-, ~CH,CHLCIT,-, ~CHCH2CHCHy-, and -CH,CH(CH;)CH,-.
The term “alkylene-NR,-" 25 used herein, means an alkylene group, as defined herein, appended to the parent molecular moiety through a ~NRg- group, as defined herein.
The term "alkylsulfinyl" as used herein, means an afkyi group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein.
Representative examples of allyisulfiny! include, but are not limited to, methylsulfiny! and ethylsulfinyi,
The term "alkylsulfinylalkyl” as used herein, means an allcylsulfinyl group, as defined herein, appended to the parent molecular moiety through an aflcylene group, as defined herein. Representative examples of alkylsulfinylalkyl include, but are not limited to, methylsulfinylmethyl and ethylsulfinylmethyl.
The term "alkylsulfonyl" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
Representative examples of alikylsulfonyl include, but are not limited to. methylsulfonyl and ethylsulfonyl.
The term "alkylsulfomylalkyl” as used herein, means an allcylsulfony] group, as defined herein, appended to the parent molecular moiety through an alkylene group, ag defined herein. Representative examples of alkylsulfonylalky! include, but are not fimited to, methyisulfonylmethyl and ethylsuifonylmethyi.
The term "alkylthio" as used herein, means an alkyl group, as defined herein, appended to the parent molecular motety through a sulfur atom. Representative examples of alkylthio mclude, but arc not limited to, methylthio, ethyithio, teri-butylthic, and hexyithio.
The term "alkylthioalkyl” as used herein, means an alkylthio group. as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
Representative examples of allylthioalky! include, but are not limited to, methylthiomethyl and 2-(ethylthio)ethyl.
The term "alkyny!" as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, I- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl,
The term "aryl," as used herein, means phenyl, a bicyclic aryl or a tricyclic aryl. The bicyclic aryl is naphthyl, or a phenyl fused to a cycloalkyl, or a phenyl fused to a cycloalkenyl, or a phenyl fused to a monocyclic heteroaryl ring as defined herein, or 2 phenyl fused to a monocyclic heterocycle as defined herein, The bicyclic aryl of the present invention must be attached to the parent motecular moiety through any available carbon atom contained within the phenyl ring. Representative examples of the bicyclic aryl include, but are not limited to, 2.3-dihydro-1,4-benzodioxin-3-vl, 2,3~dihydro-1.4-benzodioxin-6-vyl, 3.4- dihydro-2H-1 .2-benzodioxepin-6-yl, dihydroindenyl, indenyl, indol-4-yl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl. The tricyclic aryl is anthracene or phenanthrene, or a bicyclic aryl fused to a cycloalkyl, or a bicyclic aryl fused to 2 cycloalkenyl, or a bicyclic aryl fused to a phenyl. The tricyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the tricyclic aryl.
Representative examples of tricyclic aryl ring include. but are not limited to, azuienyl, dihydroanthracenyl, fluorenyl, and tetrahydrophenanthrenyvl.
The ary] groups of this invention are optionally substituted with 1,2, 3,4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylearbonyl, alkylearbonylalicyl,
alkylcarbonyloxy, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alicylsulfonylalkyt, alkylthio, alkylthioalkyl, alkynyl, aryl*NC{O)-, aryl *NHC(OINH-, carboxy, carboxvalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkyl, heteroaryl, hydroxy, hydroxyalkyl, mercapte, morpholine, nitro, 7,7, N-, or { L:ZNycarbonyl. Aryl® is optional substituted with 1, 2 or 3 substituents independently selected from atkyl, hale, cyano or nitro.
Zy and Z, are cach independently sclected from hydrogen. alkyl or alkylcarbonyl.
The term "aryloxy" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of aryloxy clude, but are not limited te, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy. 4- methyiphenoxy, and 3,5-dimethoxyphenoxy.
The term "aryloxyalky?!" as used herein, means an aryloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
Representative examples of aryloxyalky! include, but are not limited to, 2-phenoxyethyl, 3- naphth-2-yloxypropyl and 3-bromophenoxymethyl.
The term "arylalkyl" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative exampies of arylalkyl mclude, but are not limited to, benzyl, 2-phenylethyl, 3-phenyipropyl. and 2-naphth-2-ylethyl.
The term "aryl(hydroxy)alkyl” as used herein, means an aryl group. as defined herein, appended to the parent molecular moiety through an alkylene group bearing one hydroxy group, as defined herein. Representative examples of aryl(bydroxy)alkyl include. but are not limited to, 2-phenylethanol-2-yl and 2-hydroxy-2-phenylethany!.
The term "arylcarbonyl" as used herein, means an ary! group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
Representative examples of arylearbonyl include, but are not limited to. benzoyl and naphthoyl.
The term "arylthio" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of arylthie include, but are not limited to, phenylihio and 2-naphthylthio.
The term "arylthioalky!" as used herein. means an arylthio group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
Representative examples of arylthicalkyl include, but are not limited to, phenylthiomethyl, 2- naphth-2-ylthioethy!, and S-phenylthiomethyl,
The term "azido" as used herein, means a -N- group.
The term “azidoalkyl” as used herein, means an azido group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
The term "carbonyl" as used herein, means a -C(O)- group.
The term "carboxy" as used herein, means a -CO,H group.
A The term "carboxyalkv]™ as used herein, means a carboxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
Representative examples of carboxyallkyl include, but are not limited to, carboxymethyl, 2- carboxyethyl. and 3-carboxypropyl.
The term "cyano" as used herein, means a -CN group. 1G The term "cyanoalkyl” as used herein, means a cyano group, as defined herein, appended io the parent molecular moiety through an alkylene group, as defined herein.
Representative examples of cvanoalkyl include, but are not limited to. cyanomethyl, 2- cyanoethyl, and 3-cyanopropyl.
The term "cycloalkenyl" as used herein, means a monocyclic or bicyclic ring system, containing from 3 to 10 carbons and containing af lcast one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of monocyclic ring systems include, but are not limited to, 2-cyclohexen-1-yl, 3-cyclohexen-1-yi, 2,4 cyclohexadien-1-yl and 3-cyclopenten-1-yl. Bicyclic ring systems are exemplified by a monocyclic cycloalkenyl ring system which is fused to another monocyclic cyclealkyl ring as defined herein, a monocyclic aryl ring as defined herein, a monocyclic heterocycle as defined herein or a monceyclic heteroaryl as defined herein. The bicvelic ring systems of the present invention must be appended to the parent molecular moiety through an available carbon atom within the cycloalkenyl ring. Representative examples of bicyelic ring systems include, but are not himited to, 4,5-dihydro-benzo[ 1,2, 5Joxadiazole, 3a, 4. 5. 6, 7, Ta-hexahydro-1H- dndenmyl, 1,2, 3,4, 5, 6-hexahydro-pentalenyl, 1.2, 3,4, 4a, 5, 6, Ba-octahydro-pentalenyl,
The term "cvcloalky!™ as used herein, means a monocychic, bicyclic, or spirocyclic ring system, Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to § carbon atoms. Examples of monocyelic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl groups of the present invention are exemplified by a monocyclic cycloalkyl ring fused to another monocyclic cycloalkyl ring, or a monocyclic cycloalkyl ring fused cycloalkenyl, or a monocyclic cycloalkyl ring fused to a phenyl ring, or a monocyclic cycloalkyl ring fused to a monocyclic heteroaryl ring as defined herein, or a monocyclic cycloalkyl ring fused to a monocyclic heterocycle as defined herein. The bicyclic cycloalkyl ring systems of the present invention must be appended to the parent molecular moiety through an available carbon atom within the monocycloalkyl ring,
The cycloalkyl groups of the present invention are optionally substituted with 1, 2. 3. or 4 substituents selected from alkenyl, alkoxy, alkonyalloxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, allyl, aikylearbonyl, alkcylearbonyloxy, alkyisulfonyl, alkylthio, alkylthioalkyl, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, oxo, Z,Z,N-, or ( ZaZ N)carbonyl,
The term “cycloalkylalkyl,” as used herein, means a cycloalkyl group appended to the parent molecular moiety through an allyl group, as defined herein, 1G The term "cycloalkylearbony!” as used herein. means cycloalkyl group, as defined herem, appended to the parent molecular moiety through a carbonyl group, as defined herein.
Representative exampies of cycloalkylearbony! include, but are not limited to, cyclopropylcarbonyl, 2-cyelobutylcarbonyl, and cyclohexylcarbonyl.
The term "formyl" as used herein, means a -C(O)H group.
The term "formylalkyl" as used herein, means a formyl group, as defined herein, appended to the parent molecular moiety through an allcylene group, as defined herein,
Representative examples of formylalkyl include, but are not limited to, formyhmethy! and 2- formylethyl.
The term "halo" or "halogen" as used herein, means -ClI, -Br, -l or -F.
The term "haloalkoxy" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
Representative examples of haloalkoxy include, but are not Himited to, chloromethoxy, 2- fluoroethoxy, trifluoromethoxy, and pentaflucroethoxy.
The term "haloalkyl" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.
Representative examples of haloalky! include. but are not limited to, chloromethyl, 2- flucroethyl, trifluoromethyl, pentafluorocthyl, and 2-chloro-3-fluoropentyl.
The term "hefercaryl," as used herein, means a monocyclic heteroaryl or a bicyclic heteroaryl. The monocyclic heteroaryl is a 5 or 6 membered ring containing at least one heteroatom independently selected from O, N, or S. The 5 membered ring contains two double bonds may contain. one, two, three or four heteroatoms. The 6 membered ring contains three double bonds may contain one, two, three or four heteroatoms. The Soré membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl, Representative examples of monocyche heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyi, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyi, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of 2 monocyclic heteroaryl fused to a monocyclic aryl ring as defined herein, a monocyclic cycloalkyl ring as defined herein, a monocyclic cycloalkenyl ring as defined herein, another monocyclic heteroaryl or a monocyclic heterocycle ring as defined herein. The bicyclic heteroaryl ring systems of the present invention must be appended to the parent molecular moiety through an available carbon atorn within the heteroaryl ring. The bicyclic heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the bicyclic heteroaryl. Representative examples of bicyclic heteroaryl include, but are not limited to, benzofuranyl, benzoxadiazolyl, 1,3- benzothiazolyi, benzimidazolyl, benzodioxolyl, benzothiophenyi, chromenyl, cinnolinyl, furopyridine, indolyl, indazolyt, isoindolyl, isoquinotinyl, naphthyridinyl, oxazolopyridine, quinotinyl, thienopyridine and thienopyridinyl.
The heteroaryl groups of the present invention are optionally substituted with 1. 2,3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, atkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alicylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthicalkyl. alkynyl, benzyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalicyt, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, Ly ZoN-, or (Zs ZaN)carbonyl. Heteroaryl groups of the present invention that are substituted may be present as tautomers. The present invention encompasses all tautomers including non-aromatic tautomers.
The term “hetercarylalkyl,” as used herein, means & heteroaryl group appended to the parent molecular moiety through an alkyl group, as defined herein,
The term "heterocycle" or “heterocyclic” as used herein, refers to a monocyclic, bicyclic, tricyclic or a spirocyelic ring system that contains af least one heteroatom. The monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The 3 or 4 membered ring contains ] heteroatom selected from the group consisting of O, N and 8. The 5 membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of 0, Nand S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S.
The monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, L3-dioxolanyl, [,3-dithiolanyl, 1, 3-dithiany], mmidazolinyl, nmidazolidinyl, isothiazolinyl. isothiazolidinyl, 1soxazolinyl, isoxazolidinyl, isoindoline-13-dione, morpholinyl, oxadiazolinyi, oxadiazolidinyl, oxazolinyl, oxazotidinyd, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyi, pyrrolinyl, pyrrohidinyl, tetrahydrofuranyl, tetrahydrotiienyl, thiadiazolinyl, thi adiazolidinyl, thiazolinyl, thiazolidinyi, thiomorpholinyl, 1,1 -dioxidothiomorpholiny! (thismorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle of the present mvention is defined as a monocyclic heterocycle fused to a phenyl group, a cycloalkylgroup as defined herein, & cycloalkenyl group as defined herein, another monocyclic heterocycle group as defined herein, or a spirocyelic ring wherein one carbon atom of the monocyclic heterocycle is bridged by two ends of an alkylene chain. The bicyelic heterocycle of the present invention is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclic ring. Representative examples of bicyelic heterocycle include, but are not Hmited te. 1,3-benzodioxolyl, 1.3-benzodithiolyl, 2.3-dihydro-1.4- benzodioxinyl, 2,3~dihydro-1-benzofuranyl, 2.3-dihydro-1 -benzothienyl, 3,4-dihydro-1F- isochromen-4-yl, 2,3~dihydro-1H-indolvl, succinmimidyl, and 1.2.3, 4-tetrahydroquinoliny!,
The tricyclic heterocycle is a bicyclic heterocycle fused to a phenyl, or a bicyclic heterocycle fused to a cycloalkyl, or a bicyclic heterocycle fused to a cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle, The tricyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any mitrogen atom contained within the tricyclic heterocycle. Representative examples of tricyclic heterocycle include, but are not limited to, 2,3,4,44.9 9a-hexahydro-1H-carbazol yi, 52,0,7,8,9.9a- hexahydrodibenzo[b,d furanyl, and 32.,6.7,8.9 9a-hexahydrodibenzo[b,d]thienyl.
The heterocycles of this invention are optionally substituted with 1, 2.0r 3 substituents independently selected from alkenyl, alkoxy. alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, atkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alikcyicarbonyl, alkylcarbonyialicyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, aryl, benzyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloatkoxy, haloalkyl, halegen, hydroxy, hydroxyalkyl, hydroxyalkylcarbonyl, hydroxyalkoxyalkyl, mercapto, oxo, Z;Z,N-, or (Z:Z4Nycarbonyl.
The term “heterocyelealkyl,” as used herein, means a heterocycle group appended to the parent molecular moiety through an alky] group, as defined herein.
The term "heterocyclecarbonyl” as used herein, means a heterocycle, as defined herein, appended to the parent molecular moiety through a carbony! group, as defined herein. 3s
The term "hydroxy" as used herein, means an -OH group.
The term "hydroxyalkyl” as nsed herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alleylene group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, S-hydroxypropyl, 2.5-dihydroxypentyl, and 2-cthyl-4- hydroxyheptyl.
The term “hydroxyalkyicarbony!” as used herein, means a hydroxyalkyl group, ag defined herein, as appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples include, but are not limited fo, Z-hydroxyacetyl, and
HD) 4-hydroxybutanoyl.
The term "hydroxvatkoxyalky!" as used herein, means a hydroxvalkoxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of hydroxyalkoxyalkyi include, but are not limited to, (2-hydroxy-ethoxy)-ethyl, and (3-hydroxyl-propoxyl)-ethyl, i5 The term "hydroxy-protecting group” or "O-protecting group” means a substituent that protects hydroxyl groups against undesirable reactions during synthetic procedures.
Examples of hydroxy-protecting groups include, but are not limited te, substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl. 2- (trimethylsityl)-ethoxymethyl, benzyl, and triphenylmethyt; tetrahydropyrany| ethers; substituted ethyl ethers, for example, 2,2 2-trichloroethy] and t-butyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsiiv! and t-butyldiphenylsilyl; cyclic acetals and ketals, for example, methylene acetal, acetonide and benzylidene acetal; cyclic ortho esters, for example, methoxymethylene; cyclic carbonates; and cyclic boronates, Commonly used hydroxy-protecting groups are disclosed in T.W, Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New Yori (1999),
The term "mercapto” as used herein, means a -SH STOup.
The term "nitrogen protecting group” as used herein, means those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Preferred nitrogen protecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl {Chbz), formyl, phenylsulfonyl, tert-butoxyearbonyl {Boc), tert-butylacetyl, tr fluoroacetyl, and triphenyimethyi (trity!).
The term "nitro" as used herein, means a -NO; group.
The term "trialkylsilyl" as used herein. means three independently selected allel groups, as defined herein, appended to the parent molecular moiety through a silicon atom.
Representative examples of trialkylsilyl include, but are not limited to, trimethylsilyl, iriethylsilyl, t-butyldimethylsiiyl and trisopropylsilyl.
The term "triatkylsitylatkyl" as used herein, means a trialkylsily] group, as defined herein, appended to the parent molecular through an alkylene group, as defined herein,
Representative examples of trialkylsilylalky! include, but are not limited to, trimethylsilylmethyl, Z~mimethylsilylethyl, and 2-t-butyldimethylsilylethyl,
The term "Z,Z;N" as used herein, means two groups, Z, and Zp, which are appended to the parent molecular moiety through a nitrogen atom. 7, and 2; are each independently hydrogen, alkoxycarbonyl, alley. alieyloarbonyl, aryl, arylalkyl and formyl. In certain instances within the present mvention, Z) and 7, taken together with the nitrogen atom to which they are attached form a heterocyclic ting. Representative examples of 7, 7,N include, but are not limited to, amino, methylamine, acetylamino, acetylmethylamino, phenylaming, benzylamine, azetidinyl, pyrrolidiny! and piperidiny!.
The term " ZsZN" a5 used herein, means fwo groups. Zs and Zs, which are appended to the parent molecular moiety through a nitrogen atom. Zs and Zs are cach independently hydrogen, alkyl, aryl and arylalkyl. Representative examples of ZaZ,N include, but are not limited to, amino, methylamino, phenylamino and benzylamine.
The term "( Z3Z;N)carbonyl" as used herein, means a NZ27. group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
Representative examples of (Za ZyNjcarbonyl include, but are not limited to, aminocarbonyl, {methylamino)carbonyl, (dimethylamino carbonyl, and {ethylmethylamine carbonyl,
The term "oxo" as used hersin, means a =O moiety.
The term "sulfinyl" as used herein, means a -S(0)- group.
The term "sulfonyl!" as used herein, means a ~502- group.
The term “sulfonamide” as used herein means a -SO, NH, group.
The term "tautomer" as used herein means a proton shift from one atom of a compound to another atom of the same compound wherein two or more structurally distingt compounds are in equilibrium with each other.
Compounds of the present invention may exist as stereoisomers wherein, asymmetric or chiral centers are present. These stereoisomers are "R"™ or "§" depending on the configuration of substituents around the chiral carbon atom. The terms "R" and "S" used herein are configurations as defined in TUPAC 1974 Recommendations for Section E,
Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The present invention contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the present imvention may be prepared synthetically from commercially available starting materials that contain asymmetric ar chiral centers or by preparation of racemic mIKtures followed by resolution which is well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary; or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
The compounds and processes of the present mvention will be better understood by reference to the following Exaraples, which are intended as an illustration of and not a limitation upon the scope of the invention. Further, all citations herein are incorporated by reference.
Compound names are assigned by using Name Pro namin g software, which is provided by ACD/Labs. Alternatively, compound names are assigned using AUTONOM naming software, which is provided by MDL Information Systems GmbH (formerly known as Beilstein Informationssysteme) of Frankfurt, Germany, and is part of the CHEMDRAW®
ULTRA v. 6.0.2 software suite and ISIS Draw v. 2.5. Also, compound names are assigned using Struct=Name naming algorithm, which ig part of the CHEMDRAW® ULTRA v. 9.0.7 software suite.
Abbreviations
Abbreviations which have been used in the descriptions of the Schemes and the
Examples that follow are: DMT for N N-dimethylformamide, DMSO for dmethyl sulfoxide,
EtOAc for ethyl acetate, CHC: for chloroform, CHL, for dichloromethane, CH.CN for acetonitrile, THF for tetrahydrofuran, HATU for O~(7-azabenzotriazol-1 -y DN, N, NUNC - tetramethyluronium hexafluorophosphate, EDC or EDC] for 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochioride, LC/MS for liquid chromatography/mass spectroscopy,
NH OAc for ammonium acetate, NaBH(OAc). for sodium triacetoxyborohydride. PBS for bovine serum albumin, PRS for phosphate buffered saline, TMS for trimethylsilyl, MW for microwave, DMAP for 4-(dimethylamino)pyridine, dppf for 1,1" bis(diphenylphosphino)ferrocene, TFA for trifluoroacetic acid, BINAP for 2.2'- bis(diphenyiphosphino)-1,1 -binaphyl, TBAF for tetrabutylammonium fluoride, Tween for polyoxoethylenesorbitan monolaurate HPLC for high pressure liquid chromatography, DME for 1,2-dimethoxyethane, Boc for teri-butoxycarbonyl, BSA for bovine serum albumin, DTT for dithiothreitol, ATP for adenosine triphosphate, EDTA for cthylenediaminetetraacetic acid,
HPMC for hydroxypropylmethyloeliniose, T™B for33° 55 ““tetramethvlbenzidine and
HEPES for 4-{Z-hydroxyethyl}-1-piperazineethanesulfonic acid.
Preparation of Compounds of the Present Invention
The compounds and processes of the present invention will be better understood in connection with the following svithetic Schemes and Examples that illustrate 2 means by which the compounds of the present invention can be prepared,
Scheme
R, R,
Kas A x = N Pd catalyst ~F N 1 Rz 2 R;
As shown in Scheme 1, compounds of formula 2 which are representative of compounds of formula (1), may be made accordingly. Compounds of formula 1. wherein R, and R; are as defined in formula (1), and X; is iodo, bromo or chloro, and which may be obtained from commercial sources or may be synthesized according to methods known in the literature, when treated with reagent A-M;, wherein A is defined in formula (1) and M; is ~51(R,); or ~B{OR,). wherein R, is alkyl or aryl, and Ry is hydrogen, alkyl, aryl or the two
Ry groups together with the boron atom to which they are attached form a 1,3-dioxeborolane, in the presence of a palladium catalyst will provide compounds of formula 2. Such reactions between compounds of formula 1 and compounds of formula A-Sn(R,):, commonly known as Stille couplings, utilize a palladium catalyst such as, but not limited to, tetrakis(iriphenyiphosphine)palladium( ay, dichlorobis(triphenylphosphineipalladium(I), tris(dibenzylidineacetone )dipaliadium or palladium diacetate, in the presence or absence of a ligand such as ri 2-furyl)yphesphine or triphenylarsine in a solvent such as toluene or DMF at a temperature from about 25 °C fo about 150 °C. In addition, Lil), Cu(D), or Mn(I1) salts may be added to improve reactivity or specificity. Reactions between compounds of formula 1 and compounds of formula A-B(ORy}2, commonly known ag Suzuki couplings utilize palladium catalysts such as, but not limited to, tetrakis(mphenyiphosphine)palladium(0), dichlorobis(triphenylphosphine)paliadium(Tr), tris( dibenzylidineacetone)dipalladium or palladium diacetate, A pailadivm ligand may be added such as 2- (dicyclohexylphosphino biphenyl, tri-t-butyiphosphine, or tris(2-furyl phosphine and a base such as, but not limited to, aqueous KiPOy. cesium carbonate, potassium carbonate or
NayCOs in solvents such as toluene, dimethoxvethane, dioxane, water or DMF at a temperature from about 25 °C to about 150 °C. The reaction may also be achieved with heating in a microwave reactor oven,
Although many organo stannanes are commercially available or described in the literature, it is also possible to prepare additional stannanes from A-halides or A-trifiates by treatment with a hexa-alkyldistannane of formula ({R,):8n); in the presence of Pd{PhsP),.
Similarly, in the absence of commercially available organoboron reagents, A~B(OR,), may be prepared from the corresponding halides or triflates (A-halo or A-triflate) via metal exchange with an organolithium followed by the addition of the alicyt borate.
Scheme 2
R, R,
ZZ N EE — La y 1 Re 2 Ry
Compounds of formula 2, wherein Ri and R; are as defined in formula (TNand A is a heteroaryl ring linked to the parent moiety through a nitrogen atom may be prepared as iliustrated in Scheme 2. The treatment of compounds of formula 1 with a reagent of formula
A-H, wherein the H is a hydrogen on a nitrogen atom contained within the heteroaryl ring A, in the presence of a base such as, but not limited fo, sodium t-butoxide or cesium carbonate and a metal catalyst such as, but not limited to, copper metal, Cul or palladium diacetate and optionally with a ligand such as, but not limited to, BINAP, or tri-tertbutylphosphine will provide compounds of formula 2
Scheme 3
Ry Ri
Cd Ay
Ris C + To — { eee ’ { ”
NOs, i oN = 3 4 8p, g HA
As previously mentioned in Scheme 1, compounds of formula (I) may be synthesized utilizing Stille couplings as described in Scheme 3. Compounds of formula 3, wherein Rj; is defined in formula (1), when treated with compounds of formula 4, wherein R; is defined in formula (1) and Py is & nitrogen protecting group such as, but not limited to, tert-
butyloxycarbonyl or acetyl, in the presence of dich lorobis(riphenyiphosphine palladium 1M) and (thiophene-2-carbonyloxy)copper m toluene under heated conditions will provide compounds of formula 5. Compounds of formula 2 when treated with conditions known io remove the protecting group such ag hydrochloric acid or rifluoroacetic acid in & solvent such as acetic acid or dioxane when the protecting group is tert-butyloxycarbonyl or sodjum hydroxide, fithium hydroxide, or potassium hydroxide in an aqueous mixture of THF, isopropanol, or dioxane when the protecting group is acetyl will provide compounds of formula 6 which are representative of compounds of formula (1) wherein A is (ii).
Scheme 4 be BU. SniMa SnBu, oN Ris k
Wr” or 0” dioxane snes
BusSnN(EHC(O)OMe heat N 0 ZL 8 3
Compounds of formula 3 utilized in Scheme 3 to generate compounds of formula (1) may be prepared as outlined in Scheme 4. Compounds of formula 7, which are obtained from commercial sources or may be prepared according to methods known fo one skilled in the art, when treated with either 1,1, ~tributyl-N, N-dimethylstannamine or methyl ethyl(tributylstanny])carbamate will provide compounds of formula 8. Alkynes of formula 8 when heated in the presence of compounds of formula 9, wherein Rj; is defined in formula (1) and Ns is an azide, will provide compounds of formula 3.
Scheme § 1. ==TMS iY ob RE am Ms “CO 85°C, ON “rr CuSO, Cu N ) BY
N 2, TBAF, THF N N ig a1 i2
As outlined in Scheme 5, compounds of formula [2 which are representative of compounds of formula (1), wherein A is (11) may be prepared accordingly. Compounds of formula 10 wherein R; 1s defined in formula (I) and X; is iodo, bromo, chloro, or triflate, when treated with TMS acetylene in the presence of copper iodide, dichlorobis(triphenylphosphine jpalladiumIr) and triethylamine followed by treatment with tetrabutylammonium fluoride or potassium hydroxide will provide compounds of formula 1 1.
The reaction may be done in a solvent such as, but not limited to, DMF at ambient temperature or under heated conditions. Compounds of formula 11 when treated with RC, sodium azide, copper sulfate, and metallic copper under heated conditions in 2 solvent such as dioxane, will provide compounds of formula 12 which are representative of compounds of formula (1) wherein A is {ii}.
Scherne 6 1) TMS 5 Ri,
Z cul Sn 'o Na N }
Xs . CN PACIL(PPha), SRE 2 CN or Nay NL. CN MN H
Eta XY Cu.80 N AS 27g 2) TBAF F Cu wire Fe heat 1 14 is
Ris, Ri,
MN v NH VC NH “N 4 Boc,O N Ser
N | ON 1 i 20 oO 0
A
! 1 } Rs Cl 18 2) TFA pyr, CHCl,
Ri, R o
MN ify
Ce EE
MN = \ No Ry
N N Re nS | N on ZN = Re 19 H
Alternatively, compounds of formula 15 when treated wiih TMS-acetylene in the presence of copper iodide, dichlorobis(triphenylphosphine palladium) and tricthylamine foliowed by treatment with tetrabutylammoniom fluoride or potassium hydroxide will provide compounds of formula 14. The reaction may be done in a solvent such as, but not limited to, DMF at ambient temperature or under heated conditions. Compounds of formula 14, when treated with compounds of formula 9, wherein Rj; 1s defined in formula (ID, or sodium azide, copper sulfate and metallic copper under heated conditions wil} provide compounds of formula 15. Compounds of formula 15. when heated in the presence of hydrazine in ethanol, will provide compounds of formula 16. Compounds of formula 16 when treated with di-tert-butyldicarbonate and a catalytic amount of DMAP in a solvent such as THF or acetonitrile will provide compounds of formula 17. Compounds of formula 17 when treated with compounds of formula 18 in the presence of a base such as. but not limited to, pyridine in a solvent such ag dichloromethane followed by treatment with trifluoroacetic acid will provide compounds of formula 19. Compounds of formula 16 when treated with a carboxylic acid using carboxylic acid-amine coupbing conditions known to one ski ted in the > art will provide compounds of formula 19A. Standard carboxylic acid amine coupling conditions include adding a coupling reagent such as, but not limited to, I-(3- dimethylaminopropyl)-3-ethylcarbodiimi de hydrochloride (EDCI), 1 3dicyclohexylcarbodiimide (BCC), Bis( 2-ox0-3-oxazolidinylphosphinic chloride {BOPCIY. O~(7-azabenzotriazol-1 ~yD-NN,N' N* -tetramethyluronium hexafluorophosphate (HATU) or G-benzotriszol-1 VINNY IN ietrameth yiuronium tetrafluoroborate (FBT) with or without an auxiliary reagent such as, but not limited to, I-hydroxy-7-azabenzotriazole (HOAT) or I-hvdroxybenzotriazole hydrate (HOBT) in a solvent such as. but not limited to, dichloromethane,
Scheme 7
N
Kin Aco0, KOAG, Xin mn y z 70°C To NaN;, CuSO,
I / ————— : NH, TT = N Na,CO, 20 No I~ 21 22
Me
NaN Ay \
ZN
O
Compounds of formula 24 which are representative of compounds of formula (I) may be prepared accordingly. Compounds of formulz 20, wherein X, is halo or triflate, when treated with the compound of formula 21, acetic anhydride and a base such as, but not limited to, potassium acetate under heated conditions wil] provide compounds of formula 22,
Compounds of formula 42 when treated with sodium azide, copper sulfate, a base such as sodium carbonate and compounds of formula 23, wherein Ry; 1s defined in formula (hy and are either available from commercial sources or may be prepared by one skilied in the art, will provide compounds of formula 24.
Scheme R
R, i] TN R. 1 ii Ny rn 23 Ra ; g
TN — I TN
NF PACH Pha), SAAN 2) TRA ; ul :
Boc Foc 25 Et,N 27 © 5.
Ri, N ‘
Mr mn N’ \ Ry
MN. Toy nN Sy
NT ~, aA ! of | TN
I N i ~FN pr ~N fd 29 H 30
As outlined in Scheme &, compounds of formula 29 and 30, which are representative of compounds of formula (I), may be prepared accordingly. Compounds of formula 25, wherein R, is defined in formula (I} and X, is hale or triflate, when treated with compounds of formula 23, copper iodide, dichlorobis(triphenyiphosphine)paliadium(il ) and triethylamine in DMF at ambient temperature or under heated conditions wil] provide compounds of formula 27. Compounds of formula 27 when treated with compounds of formula 9, under heated conditions, and either neat or in a solvent such as, but not limited to, dioxane, will 0 provide compounds of formula 29 and 30.
Scheme 9 1) NH;OH HCI, NaOH Rui
Ry ~cHO 2) Chioramine-T 3H,0 N R, en . 3) CuB0y, Cu wire O eh 31 4) a R. N 3 ZN
AN 32 In
N
“N 11
Compounds of formula 32 which are representative of compounds of formula (1), wherein A is (vii), and R, and Ryii are defined in formula (1). may be prepared accordingly.
Aldehydes of formula 31, wherein Ris 1s defined in formula (1) which may be obtained from commercial sources, when treated with hydroxylamine hvdrochloride and aqueous sodium hydroxide will provide an oxime intermediate which when oxidized with Chloramine T trihydrate, followed by treatment with copper sulfate and copper wire and compounds of formula 11 will provide compounds of formula 32,
Scheme 10
Cl 0 r H 0 R, [we tN oy
NPN ( OG ~~ “Ps a { : IN rein & ll J JN ——
En oo a “hf
HH H
33 34
Sp SU.
NS ee SAA ~~ ee
N | N
FN . N
H 36 : 25 TO Py
Z3~NH Zg™=-NH
Q R 1) )- NH; p= N = 1 3 sg 1 \ =
Br ® N | = N 36A N 2) deprotection N 38
Compounds of formula 38 which are representative of compounds of formula (1) wherein A is (x), are prepared accordingly. Compounds of formuia 33. wherein R, is defined in formula (1) which may be obtained from commercial sources or prepared by one skilled in the art, when treated with N,O-dimethylthydroxylamine using acid coupling conditions known to one skilled in the art will provide compounds of formula 34. Standard carboxylic acid- arnine coupling conditions include adding a coupling reagent such as, but not limited to, 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1.3- dicyclohexylcarbodiimide (BCC), bis(2~0x0-3-oxazolidiny \phosphinic chloride (BOPCI), O- (7-azabenzotri azol-1-yl)-N,N,N" N’-tetramethyfuronium hexafluorophosphate (HATU) or O- benzotriazol-1-yl-N,N.N* N’-tetramethyluronium tetrafTuoroborate { TRTU) with or without an auxiliary reagent such as, but not limited to, i-hydroxy-7-azabenzotriazole (HOAT) or 1- hydroxybenzotriazole hydrate (HOBT) in a solvent such as, but not limited to, dichloromethane, Compounds of formula 34 when treated with a Grignard reagent such as benzylmagnesiun bromide in a solvent such as tetrahydrofuran below ambient temperature will provide compounds of formula 33. Compounds of formula 35 when treated with a proteciing group reagent such as. but not limited to, di-rerr-butyldicarbonate and a cata vii amount of DMAP in a solvent such as THF or acetonitrile will provide compounds of formula 36. Compounds of formula 36 when treated with pyridinium tribromide in a solvent such as, but not limited to, THF with or without the use of heat will provide compounds of formula 36A, Compounds of formula 36A when treated with compounds of formula 37 with or without the use of heat followed by treating the product with conditions that will remove the nitrogen protecting group will provide compounds of formula 48. Commonly used nitrogen-protecting groups as well as methods to remove them are disclosed in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,
New York (1999).
Scheme 11
NH ) a | 0 5 3 N SY 2, 1 ~
Yo ——— | N av 2) deprotection ZN \ H 36 Pr 46
Compounds of formula 36, wherein R; is defined in formula ( 1} and P; is a nitrogen protecting group, when treated with compounds of formula 39 under heated conditions followed by treating the product with conditions known to one skilled in the art that will remove a nitrogen protecting group or as outlined in the literature, will provide compounds of formula 40 which are representative of compounds of formula (I) wherein A is (xvi).
Scheme 12
OE
Ry R. a 2 Ri
RON Boc,O RPS 43 rt pyr HBr,
Nee No — Noe = N ouinP N BACH, (PPh), N THF 41 ae a Fou 44 ois
A
0 Ry” TNH 3
Br 2° ge | A
SR ee NT Frey
LAN EIOH | N
N ZN
H
As outlined in Scheme 12, compounds of formula 47 which are representative of compounds of formula (1), wherein A is (x) may be prepared accordingly. Compounds of formula 41, wherein R, is defined in formula (1), when treated with di~tert-butyldicarbonate and a catalytic amount of DMAP in a solvent such as THF or acetonitrile will provide compounds of formula 42. Treatment of compounds of formula 42 with tributyl(1- :
ethoxyvinyl)stannane and dichlorobis(triphenylphosphine)palladium(Tr) will provide compounds of formula 44. Compounds of formula 44 when treated with pyridinium tribromide in THF will provide compounds of formula 45. Compounds of formula 45 when treated with compounds of formula 46 in a solvent such as, but not limited to, ethanol, wherein Ry is defined in formula (I), will provide compounds of formula 47.
Scheme 13
Toi. s0, N -
OMG. i wg, ¢ 1 ad rr 8 5 N ~~ SA,
FN SNH, “FN
H Ry’ H 48 50 81
As shown in Scheme 13, compounds of formula 51 which are representative of compounds of formula (1), wherein A is {Iv}, may be prepared accordingly. Compounds of formula 48, wherein R, is defined in formula (I), and which are either available through commercial sources or may be prepared according to literature procedures or as outlined herein, when heated in the presence of both compounds of formula 49 and compounds of formula 30, both of which are either commercially available or may be prepared by one skilled in the art using procedures described in the literature, wil] provide compounds of formula 51,
Scheme 14 oN
R. r 1) a J dL
Or LOO A Sc(OTf), X— 1" =
NL Bug | SN —_— TT a NSA § 2 DF Sy 2) CEN"-Z, 55 A 52 48 54 = H
X=CH, N.S
Y = CH, N, bond
As outlined in Scheme 14, compounds of formula 35 which are representative of compounds of fornmula (1) wherein A is (xiv), (xv), (xvi) or {xvii}, may be prepared accordingly. Compounds of formula (52), wherein R, is defined in formula {I}, when treated with butyilithium followed by treatment with DMF followed by an acidic work up will provide compounds of formula 48, Compounds of formula 48 when treated with compounds of formula 53, wherein X is ~CH-, -N-or-8-, ¥ iy —CH-, “N-org bend, and scandium wi{triflate) followed by treatment with compounds of formula 54, wherein Za 1s define in formula (1) will provide compounds of formula 535.
Scheme 15
Rude, } R.q 7 R,
NC
“, Ry ey y Tn,
WN en | “Nn
LE nN ’ i : nN
H H
11 £8
As outlined in Scheme 135, compounds of formula 36, which are representative of 3 compounds of formula {IY wherein A is (vii) may be prepared accordingly. Compounds of formula (11), wherein RB; is defined in formula (1), when treated with a reagent such as. but not limited to, ethyl 2-chioro-2-(hydroxyimino acetate with a bage such as, but not limited to, triethylamine will provide compounds of formula 56. The reaction may be performed in a solvent such as but limited to toluene and may require the use of heat.
Scheme 16
R. 2 RNa (8) No Ri
N ee BN
N TEA N My i Cui ,
Boc N 27 28 H
Ag outlined in Scheme 16, compounds of formula 29 which are representative of compounds of formula (1) wherein A is (if) may be prepared accordingly. Compounds of formuia (27), wherein R, is defined in formula (I), when treated with a compound of formula 9, RaC(O)Cl er ICL, Cul, and triethylamine in a solvent such as, but not limited to, tetrahydrofuran will provide compounds of formuta 29. The reaction may be performed at ambient temperature or with the use of heat,
Scheme 17 3 Ri £ 1 Rs
Br N ammonium formate Si nme SO ju formic acid N 45 J OtBu 57
As outlined in Scheme 17, compounds of formula 27 which are representative of compound of formula (1), wherein A is {vi}, may be prepared accordingly. Compounds of formula 45, wherein R, is defined in forrauia (1), when treated with ammonium, formate and formic acid will provide compound of formula 57.
Scheme 18 1 ¥ hf
H SA CHz-NO, 2 i ny “ — Te Lo
Say Sp
Bt 48 28
As outlined in Scheme 18, compounds of formula 58 which are representative of compounds of formula (1). wherein A ig {vii}, may be prepared accordingly. Compounds of formula 48, wherein Ry is defined in formula {1}. when treated with nitromethane wilj provide compaotnds of formula 38 ( Organic Preparations and Procedures International, 2001, 33, 381. 386).
Scheme 19
AF ze
SN
I A qr 58 78 Ri
Nz
N N
H i 48 §0
As outlined in Scheme 19, compounds of formula 60 which are representative of compounds of formula (I), wherein A is (vi), may be prepared accordingly. Compounds of formula 48, wherein R | is defined in formula (1), when treated with I-(isocyanomethyl sulfonyl)-4-methylbenzene, 29, and a suitable base such as, but not limited to, potassium carbonate in a solvent such as methanol or tetrahydrofuran and subsequently treated with a suitable acid such as hydrochloric acid wil} provide compounds of formula 60.
Scheme 20
Ne.
Si
Q Ry Q Ri NN 7 N Ry ll = 62 0
FN N N
H H H
33 6&1 62
As outlined in Scheme 20), compound of formula 63 which are representative of compounds of formula (1), wherein A is (vi), may be prepared accordingly. Compounds of formula 33, wherein Rt is defined in formula (I}, when treated with a suitable chlorinating agent such as thionyl chloride wil provide compounds of formula 61. Compounds of formula §1, when treated with 2-(trimethylsilyl)-2H-1,2,3-trazole, 62, in a solvent such as sulfolane will provide compound of formula 63.
Scheme 21
OCH, ) 1 oR an 1 od 1500 “0c; ST Pe J “ [_] NN 1 i Woo ON TL “
ZN Fg ZN 51 H 64 H 66 H
As outlined in Scheme 21, compounds of formula 66 which are representative of compounds of formula (I). wherein A is (ix), may be prepared accordingly. Compounds of formula 61, wherein R 1 18 defined in formula {1}, when treated with hydrazine in a suitable solvent such as tetrahydrofuran will provide compounds of formula 4. Compounds of formula 64, when treated with trimethylorthoformate, 63, in the presence of a catalytic amount of p-toluene sulfonic acid in a solvent such as tetrahydrofuran will provide compounds of formula 66.
Scheme 22
Add NH, (R,0).B CN» ACN Schemes AOS
Tr Pd-catalys: Tr ZZ y 67 £8 G9
As outlined in Scherne 22, compounds of formula 69 which are representative of compounds of formula (D). wherein A is as defined in formula (I) can be made accordingly.
Compounds of formula 67, wherein R, is hydrogen, alkyl, aryl or the two Ry groups together with the boron atom to which they are attached form a [,3-dioxeborolane, in the presence of a pafladium catalyst using the Suzuki reaction conditions described in Scheme 1 in the presence of a heteroaryl iodide (A-T) provide compounds of formula 68. Compounds of formula 68 are transformed to compounds of formula 69 upon treatment with hydrazine as described in Scheme 6.
Scheme 23
RCO H, iz 2 M
TY A {8 Me,
TL 2) Bog,O ALY KoCO, [Tw oT THF ZN 70 a 9 7 I.
Hi 0
A Lo eS. N Nap
TEN Ee we ~ gems 73 24 H
As outlined in Scheme 23, compounds of formula 74 which, are representative of compounds of formula (1), wherein R; and Ry are as defined for formula (I) are prepared starting with compounds of formula 70, wherein X1 18 iodo, bromo, or chloro. Treatment of compounds of formula 70 first with hydrazine and then with di-tert-butyldicarbonate as described in Scheme 6 furnishes compounds of formula 71. Compounds of formula 71 upon reaction with acid chlorides of formula 18 in the presence of a base such ag potassium carbonate in tetrahydrofuran at ambient temperature over 2 to 8 hours provide compounds of formula 72. Alternatively, compounds of formula 72 can be made from compounds of formula 71 using the conditions described in Scheme 6. Compounds of formula 72 are reacted with {trimethylsilyl)acetylene under the conditions described in Schemes 5 and 6 to give compounds of formula 73. Compounds of formula 74 are obtained from compounds of formula 73 upon treatment with Rii-Ns in aqueous t-butanol in the presence of copper(Il) sulfate and sodium { R}-2-((8)-1.2-dihydroxyethyl)-4-hydroxy-5-0x0-2,5-dihydrofuran-3- olate at 40-80 °C over 1 to 6 hours.
Scheme 24 ll “dl
Br Raq A Ra
Cr A-BIOR,), Tr
N N
75 SY 76
As outlined in Scheme 24, compounds of formula 76, which are representative of compounds of formula (1). wherein A and Ry are as defined for formula (I) are obtained from compounds of formula 75. Compounds of formula 73 can be treated with A-B(OR,),
wherein A is defined ag for formula {I) and R, is hydrogen, alkyl, aryl or the two Ry groups together with the boron atom fo which they are attached form a 1.3-dioxoborolane, in the presence of a palladium catalyst using the Suzuki reaction conditions described in Scheme 1 10 give compounds of formula 76.
Scheme 25
Ney
R; SnBu; he CN Scheme 3 TY “CN Scheme 8 y=( 2
Ri Ney LL Ry CL i 78 78 8
H
N= NA
Wh ) Ry
Ri @ N il IN
H
80
As outlined in Scheme 25, compounds of formula 80, which are representative of compounds of formula (I), wherein Ry; and R,, are as defined for formula (1) are prepared accordingly. Compounds of formula 77 and 78 reacted under Stille coupling conditions described in Scheme 3 supply compounds of formula 79. Compounds of formula 79 when reacted as described in Scheme 6 provide compounds of formula 80.
Scheme 26 3
A Pak 1) R, COC iA ~ yy Ny ie A Sy 4 iv
Po] CON
Ny 2) TEA UL ) H st W g nA
A 1
RINGO Ry H
I | MN
SE
H
&3 0.0
HIS
ReSO.CH 4 Rs — RR 1D = N
H
84
HIN- 2
R.CHO NN { ———— | N
ZN
[i 85
As outlined in Scheme 26, compounds of formulas 82, 83. 84, and 85, which are representative of compounds of formula (1), wherein A, Ra, Rs, R, and R; are as defined for > formuta (1), are prepared from compounds of formula 81, Compounds of formula 81 can be treated with an acid chloride, 18, in solvent such as tetrahydrofuran in the presence of a bage such as potassium carbonate or triethylamine to give compounds of formula 82. An alternative solvent is dichloromethane and an alternative base is pyridine. The acid chlorides can be prepared from the corresponding carboxylic acidg by treatment with oxalyl chioride with a catalvtic amount of NN-dimethylformamide. To prepare compounds of formula 83, compounds of formula 8] can be treated with RjNCO in heated pyridine. Compounds of formula 84 are prepared from compounds of formula 81 by treatment with RsS0:Cl in pyridine at or near room temperature. Compounds of formula 85 are also prepared from compounds of formula 81 in a reductive amination reaction with R,CHO in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride and acetic acid in a solvent such as I.2-dichloroethane at or near room temperature and subsequent treatment with trifluoroacetic acid in dichloromethane to remove the t-butoxycarbonyl protecting group.
Scheme 27 o 0 and A iar,
Aran HNR TI
Tr N er oo wn
H 87 " 86 87
As outlined in Scheme 27, compounds of formula 87, wherein A, Rj and Ry are defined for formula (1), can be prepared from compounds of formula 86. Compounds of formula 86 are prepared as described for compounds of formula 82 in Scheme 26.
Compounds of formula 86 can then be heated in the presence of an amine, HNRR,, and a base such as triethylamine in a solvent such as acetonitrile to give compounds of formula 87.
Alternatively, heterocycles such as pyrrolidine, piperidine, piperazine, and morpholine can be substituted for the amine,
Scheme 28
Ri Ze Rs “Or “Or
O SF N oO SAF N (Ray Rz {Rahn Rz 88 89
As outlined in Scheme 28. compounds of formula 89, wherein A. Ri, Ro, Ram, Z, and Z arc as defined for formula (I), can be prepared form compound of formula 88.
Compounds of formula 88 can be prepared as described in Schemes1-4, 7-9, 22, 24. and 26.
During the preparation of compounds of formula 88, the carboxylic acid moiety pendant on A can be protected as an ester and subsequently hydrolyzed to expose the carboxylic acid by methods known to one skilled in the art of organic synthesis. Compounds of formula &8 when treated with an amine (HNZ.Z,) using carboxvlic acid-amine coupling conditions known to one skilled in the art will provide compounds of formula 89. Standard carboxylic acid amine coupling conditions include adding a coupling reagent such as, but not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1,3dicyclohexylcarbodiimide (DCC), bis(2-ox0-3 -oxazolidinyljphosphinic chloride (BOPCI),
O-(7-azabenzotriazol-1-yI}-N N,N" N “stetramethyluronium hexafluorophosphate (HATU) or
O-benzotriazol-1-y1-N,NN"N’ -tetramethyturenium tetrafluoroborate (TBTU) optionally in the presence of a base such as triethylamine or disopropylethylamine with or without an auxiliary reagent such as, but not limited 10, -hydroxy-7-azabenzotriazole (HOAT)or 1- hydroxybenzotriazole hydrate (HOBT) in a solvent such as, but net timited to, dichloromethane or MN N-dimethylformamide.
EXAMPLES
The compounds and processes of the invention will be better understood by reference to the following examples, which are intended as an Hlustration of and not a limitation upon the scope of the invention. 0 Example
S5-(I-benzyl-1H-1.23 -triazol-5-y1}-1H-indazole compound with 5-(1-benzyl-1H-1.2 3-triazol- 4-yiy-1H-indazole
Example 1A tert-Butyl 5-iode-1H-indazole-1 -carboxylate
To an ice bath cooled solution of 4-iodo-2-methylanitine (20 g, 83.24 mmol} in chloroform (250 mL) was added dropwise a solution of acetic anhydride (21.2 g, 208.1] mmol} in chloroform (50 mL), Upon completion of the addition, the mixture was stirred at room temperature for 1 hour. Potassium acetate (2.3 g, 24.97 mmol) and isoamylnitrite (22.3 mL, 166.48 mmol) were added and the mixture was heated at 70 °C for 20 hours. The mixture was cooled and quenched with saturated aqueous NaliCOs to pH 7. The mixture was extracted with dichloromethane, and the organics were dried over sodium sulfate and filtered.
The solvent was evaporated under reduced pressure, The crude solid was washed with methanol, dissolved in tetrahydrofuran (200 mL) and treaied with a warm solution of KOH (60 g) in water (200 mL). The mixture was stirred for 15 minutes and was treated with 6N
HCI to pH 1. The layers were separated, the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure, The crude solid was dissolved in dichloromethane (500 mL) and triethylamine (23 mL, 166.48 mmol), and di-ierr- butyldicarbonate (23.6 g, 108.2 mmol) and a catalytic amount of dimethylaminopyridine (~ 5 mg) were added. The mixture was stirred at room temperature for 2 hours, diluted with water, extracted with dichloromethane, and dried with sodium sulfate and filtered. The solvent was evaporated under reduced pressure fo afford the title compound. MS (ESI) m/z 344.9 (M=H)".
Example 1B tert-Butyl S-({trimethylsilylethynyl)-] H-indazole-1-carboxylate
Example 1A (10.81 g, 31.4 mmol), dichlorobis( triphenylphosphine)paliadium(i) (1.1 2. 1.57 mmol}. and copper (1) iodide (365 mg, 1.92 mmol} were combined in tricthylamine (70 mL) under an inert atmosphere. Trimethyisiiyl acetylene (5.0 mL, 36.0 mmol) was added and the mixture was stirred at 60 °C overnight. The solvent was removed under reduced pressure and the resulting residue was dissolved in methylene chloride and washed with 1 N hydrochloric acid, The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-40% ethy] acetate in hexanes to afford the title compound. MS (ESI+) m/z 215.0 (M-99)".
Example 1C 5-Ethynyl-1H-indazole
Example IB (7.93 g, 25.2 mmol) was dissolved in methanol (150 mL). A solution of i N potassium hydroxide (50 mL) was added, and the mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting slurry was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure to afford the title compound. 'H NMR {300 MHz, DMSO-d, 8 ppm 13.24 (5, 1 H) 8.10 (s, ]
H) 7.95 (s, 1 H) 7.55 (d, /=8.82 Hz, | H) 7.39 (dd, /=8.48, 1.36 Hz, 1 H) 4.03 (s, | H).
Example 1D 5-(1-benzyl-1H-1,2 3-triazol-3 -yl)-1H-indazole compound with 5-(1-benzyl-1H-1.2.3-triazol- 4-yl}-1H-indazole
Into a microwave vial were added 100.0 mg {0.70 mmol} of Example 1C and 94 mg (0.70 mmol) of benzyl azide. The mixture was heated at 160 °C for 20 minutes using microwave irradiation (CEM-Discover, 100 Watts, | minute ramp time). The mixture was dissalved in ethyl acetate and purified by silica gel chromatography eluting with 75% ethyl acetate in hexane to afford the title compounds. 'H NMR (300 MHz, DMSO-ds) 8 ppm 13.28 (s, 1H) 13.12 (s. 1 H) 8.61 {s, TH) 823 (5, 1 H) 8.13 (s, 1 H)B.11 (s, 1 HY 7.94 (5,1 36 H)7.82-7.89(m, 2H) 7.56 - 7.70 (m, ZH} 720-744 (m, OH) 6.97 - 7.02 {(m, 2 H) 5.69 (s, 2H) 5.65(s, 2H). MS (CD m/z 276 (M+H)".
Example 2
5-(1H-1,2,3-triazol-5-y1)-1H-indazole
Into a microwave vial were added 100.0 mg (0.70 mmol} of Example 1C, 81 mg (0.7 mmol) of trimethylsilyl azide, Cul {4 mg), and dimethy formamide/methanol {(Iml., 6:1).
The mixture was heated at 160 °C for 20 minutes using microwave irradiation {CEM-
Discover, 100 Watts, 1 minuie ramp time). The mixture was dissolved in ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous
MgSO, filtered and concentrated under reduced pressure, and purified by silica gel chromatography eluting with 80% ethyl acetate in hexanes to afford the 6itfe compound. 'H
NMR. (300 MHz, DMSO-dg) oppm 13.16 (s, 1 HY 8.3] (s, TE} 8.25 (5, 1 HH 8.13 (5, 1 H) 0 787(d, J=8.82 He, 1 H) 7.62 (d, J=8.82 Hz, I H). MS (Ci) m/z 186 {M+HY.
Example 3 5-(1-benzyl-1H-1.2,3-triazol -4-yI}-1H-indazole 13 Example 3A fert-Butyl 5-iodo-1H-indazole-1 ~carboxylate
To an ice bath cooled solution of 4-i0do-2-methylaniline (20 g. 83.24 mmol) in chloroform (250 mL) was added dropwise with an addition funne! a solution of acetic anhydride (21.2 g, 208.11 mmol} in chloroform (50 mL). Upon completion of the addition, the mixture was stirred at room temperature for 1 hour, Potassium acetate (2.5 2. 24.97 mmal} and isoamylnitrite (22.3 mL, 166.48 mmol) were added, and the mixture was heated at 70°C for 20 hour. The mixture was then cooled and quenched with saturated aqueous
NaHCO; te pH 7. The mixture was extracted with dichloromethane. dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude solid was washed with methanol, dissolved in tetrahydrofuran (200 mL) and treated with a warm solution of KOH (60 gin water (200 mL). The mixture was stirred for 15 minutes and was treated with 6N HCl to pH 1. The layers were separated, the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The crude material was dissolved in dichloromethane (500 mi.) and triethylamine (23 ml, 166.4% mmol), and di-zerr-butyldicarbonate (23.6 g, 108.2 mmol), and a catalytic amount of dunethylaminopyridine (~ 5 mg) were added. The mixture was stirred at room temperature for 2 hours, quenched with water, extracted with dichloromethane, and dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure to afford the title compound. MS (ESI+) m/z 344.9 (M+H)
Example 3B fert-Butyl S-({trimethylsilyljethynyl)-1H-indazole-] carboxylate 3 Example 3A, (10.81 g, 31 4 mmol}, dichlorobis(triphenylphosphine)palladium(i) (1.1 g, 1.57 mmol), and copper (1) iodide {365 mg, 1.92 mmol) were combined in tricthylamine (70 mL) under an inert atmosphere. Trimethylsilyl acetylene (5.0 mL, 36.0 mmol} was added and the mixture was stirred at 60 °C overnight. The solvent was removed under reduced pressure and the resulting residue was dissolved in methylene chloride and washed with 1 N hydrochloric acid. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. MS (ESI m/z 215.0 (M-GGY"
Example 3C 5-Ethynyl-1H-indazole
Example 3B (7.93 g. 25.2 mmol) was dissolved in methanol (150 mL). A solution of 1 N potassium hydroxide (50 mL) was added and the mixture was stirred at ambient temperature for | hour. The solvent was removed under reduced pressure, and the resulting slurry was dissofved in ethy! acetate and washed with water and brine. The organic laver was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure io afford the title compound. 'H NMR (300 MHz, DMSO-ds) 8 ppm 13.24 (s, I HY) R.10(s, 1
H) 7.95 (s, 1 H) 7.55 (d, /~8.82 Hz, | H) 7.39 (dd, /=8.48, 1.36 Hz, 1 H) 4.03 (s, 1 H).
Example 3D
S-(1-benzyl-1H-1.2,3-triazol-4-y1)-1 H-indazole
Example 3C (40 mg, 0.28 mmol), benzyl azide (37 mg, 0.28 mmol}, CuSO, (14 mg, 0.056 mmol) and Cu wire (14 mg) were combined in rerr-butano! (0.5 mL) and water (0.3 mL) and heated in a CEM-Discover microwave for 10 minutes at 125°C and 100 Watts, To the mixture was added 1M HCI and water, the product was extracted with dichloromethane, and purified by silica gel chromatography (50% ethyl acetate in hexanes) to afford the title compound. 'H NMR (400 MHz, DMSO-ds) & ppm 13.10 (s, | H) 8.60 {s, 1 H) 8.23 (5, 1 H} 8.11(s, 1 H) 7.85 (d. }=8.59, 1.53 Hz, | H} 7.55 (d, I=8.59 Hz, 1 H) 7.26 - 7.45 {m, 5 H) 5.63 (s, 2 H). MS (ESI+) m/z 276.0 (M-+H)".
Example 4 5-[1-(Z-methylbenzyi)-1H-1 A 3-riazol-4-yil-1H-indarple
Into a 5 mb CEM Microwave reaction tube which contained a Teflon-coated micro. flea stirring bar were added 17.6 mg (0.124 mmol) of Example 3C, 300 ul aqueous solution containing 7.80 mg (0.118 mmol) of sodium azide; followed by 15.79 ul. (0. 118 mmol; 21.80 mg 0.95 equivalents) of 2-methyl-benzyl bromide (added neat). To the suspension were then added 300 pl. of rers-butanol; 25 mg of copper wire; and finally 50 nL of I N aqueous copper sulfate pentahydrate solution. The microwave reaction vessel was then capped and heated with stirring for 10 minutes at 125 °C at 100 Watts power on a CEM-
Discover microwave, After cooling to ambient temperature, the mixture was diluted with 0.25 N aqueous HCI and the aqueous suspension was extracted with dichloromethane. The organic layer was washed with distilied water: saturated aqueous NaCl; and then dried over anhydrous sodium sulfate and filtered. The dried solution wag diluted with acetonitrile; and the soluble organic material was then filtered thru a glass wool plug which was overlaid with additional anhydrous sodium sulfate. An aliquot of the filtrate was then removed for subsequent LC/MS analysis. Those solutions that contained the desired triazole product were then evaporated in-vacuo and then redissolved in 1.50 ml of 1:1 DMSO/methanol. The solution of the crude triazole product was then purified by reverse-phase HPLC using an acetonitrile/water 0.1% TFA gradient elution method to afford the title compound. "H NMR {500 MHz, DMSO-ds/D»0) 8 ppm 2.37 (5, 3 H) 5.66 (s,2 H) 7.16 - 7.34 (m, 4 H) 7.63 (4, 4=8.54 Hz, 1 H) 7.87 (d, }=8.70, 1.37 Hz, | H) 8.14 (s, 1 H) 8.25 (s, 1 H) 8.49 (5, 1 Hy. MS (ESI) m/z 289.9 (M-+H)".
Exampie 35 5+ 1-(3-methylbenzyl)-1H-1 12,3-triazol-4-vI}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methylbenzylbromide with 3-methyl-benzy! bromide. "FH NMR (500 MHz,
DMS0-ds/D20) 8 ppm 8.58 (5, 1 H) 8.25 {s, TH) 8.14 (5, 1 H) 7.87 (d. J=8.85, 1.53 Hz, 1 H) 7.64(d, }=8.54 Hz. 1 H) 7.30 (t, J=7.63Hz 1 H) 7.14 - 7.24 (m, 3 H)5.60(s,2H)2.31(s, 3
Ff). MS (ESI) m/z 289.8 (M+H)".
Example 6
S-[1-(4-methylbenzyl)-1 H-1 12, 3-triazol-4-yl]-1H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyibenzylbromide with 4~-methyl-benzyl bromide 'H NMR (560 MHz,
DMBO0-ds/Dy0) & ppm 8.55 (s, 1 H) 8.24 (5, 1H) 8.14 (5, 1 H) 7.86 (d, 1=8.54, 1.53 Hz. 1H) 7.63(d,J=885Hz, 1H) 7.25- 7.33 (m. 2 HY 7.08 - 7.24 (m, 2 FH) 5.59 (s, 2 Hy 2.00 {5.3 H).
MS (ES) m/z 290.1 (M+H)".
Example 7
S-{1-(3-methoxybenzyl)-1H-1 .2,3-triazol-4-y[}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 3-methoxylbenzylbromide. 'H NMR (500 MHz,
DMSO-dg/13,0) & ppm 8.59 (s, 1 H) 8.25 (s, TH) 8.14 (5, 1 H) 7.87 {d,}=8.54, 1.53 Hz, | Hj 7.04 (d, J=8.85 Hz, 1 H) 7.33 (t, J=7.93 Hz, 1 H) 6.89 -7.00 (m, 3 H) 5.62 (s, 2 F)3.76 (s, 3
Hj. MS (ESI+) m/z 306.1 (M+H)".
Example § 5-[1-(2-fluorobenzyl)-1H-1 ,2,3-triazol-4-yI]-1H-indazele
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 2-fluorobenzylbromide. 'H NMR (500 MHz,
DMSO-dyD,0) 8 ppm 8.57 (8, TH) 825s, IH) 8.12-8.17 (m, 1 H) 7.87 (d, J=8.54, 1.53
Hz, 1H) 7.64 (d, }=8.54 Hz, | H) 7.41 - 7.49 (m, J=7.32, 7.32 Hz, 2 H) 7.22 - 7.33 (mn,
J=7.02 Hz, 2H) 5.71 (s. 2H). MS (ESI) m/z 293.9 (M~+H)".
Example 9 5-[1-(3-fluorobenzyl)-1H-1 +2, 3-triazol-4-yl}- 1 H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 3-flusrobenzylbromide. 'H NMR. (5060 MHz,
DMSO-de/D20) 8 ppm 8.61 (5, 1 H) 8.25 (s, THY 8.15(s, 1 Hy 7.87 (d, J=8.85, 1.53 Hz. 1 H) 7.64(d, J=8.54 Hz, 1 H) 7.41 - 7.51 (m, TH) 7.15 - 7.28 (m, 3 HF) 5.6% (5, 2 H). MS (ESI+) m/z293.8 (M+H)"
Example 10 5-[1-(4-fluorobenzy])-1H-1 2, 3-triazol~-4-yl]-1H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting Z-methyl-benzyl bromide with 4-fluorobenzylbromide. 'H NMR (500 MHz,
DMSO0-ds/D,0) 6 ppm 8.58 (5, 1 HYB.24 (5,1 HD) 8.34 (5, 1 Hy 7.46 (d, J=8.85, 1.53 Hz, 1 1) 7.64 (d, J=8.85 Hz, 1 H) 7.46 (d, J=8.85, 5.49 He, 2 HY 7.24 (1, J=9.00 tz, 0 Hy 5.64 (5,2 H).
MS (ESH)Ym/z 293.9 (MAH
Example 11 5-[1-(2-chiorebenzyl)-1H-1 -2,34riazol-d-y1]-1 H-indazole
The title compound was prepared according to the procedure outlined in Example 4, i0 substituting Z-methyi-benzy! bromide with Z-chlorobenzylbromide. H NME {500 MHz,
BMSO-ds/12,0) 5 ppm 8.56 (s, 1 HY) 826s, 1 H) 8.14 (5, | H) 7.88 (d, }=8.54, 1.53 Hz, 1 H) 7.64 (d, J=8.54 Hz, 1 H) 7.55 (d, J=7.63. 1.53 Hz, 1 HY 732-748 (m, 3H) 5.76 (s, 2 H).
MS (EST) m/z 309.8 (M+H)".
Example 12 5-[1-(3-chlorobenzy-1H-1 .2,3-triazol-4-y1]-1 H-indazole
The title compound was prepared according to the procedure outlined in Exampie 4, substituting 2-methyl-benzyl bromide with 3-chlorobenzylbromide. 'H NMR (500 MHz,
DMS0-d¢/D20) 5 ppm 8.62 (s, 1 FH) 8.26 (s, 1 HI) 8.15 (s, 1 H) 7.87 (d, 7=8.54, 1.53 Hz. 1 H) 7.64 (d, }=8.54 Hz, 1 H) 7.40 - 7.49 (m, J=7.63 Hz, 3 H) 7.35 (d, }=6.41 Hz, | H}3.67(s, 2
H). MS (ESI+) m/z 309.8 (M+H)",
Example 13 5-[i-(4-chlorobenzyl)-1H-1 2, 3-triazol-4-y1}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting Z-methyl-benzy} bromide with 4-chlorobenzylbromide. 'H NMR (560 MHz,
DMBSO-d#/D10) & ppm 8.58 (s, 1 Hy 824 (5, TH) 8.15 (s. 1 H) 7.86 (d, J=8.54, 1.53 Hz, 1 H) 7.64 (d, J=8.85 Hz, 1 H) 7.45- 7.52 (m, 2H) 7.38 - 744 (m, 2 H) 5.65 (s, 2H). MS (ESI) m/z 307.7 (M-HY.
Example 14 5-[1-(Z-bromobenzyl)-1H-1 .2,3-triazol-4-yi}- 1 H-indazole
The title compound was prepared according to the procedure outlined in Example 4,
substituting 2-methyi-benzy! bromide with Z-bromobenzylbromide. 'H NMR {500 MHz,
DMSO-ds/90) 8 ppm 8.55 (s. 1 H) 8.26 (s. F814 (s, 1 H) 7.88 (d. I=8.54. 1.53 Hz, 1 H) 1.72(d, J=7.93 Hz, 1 H) 7.64 (d, J=8.54 Hz, TH) 741-750 (m, 1 H) 7.27 - 7.40 {m, 2 H) 5.74 {s, 2H}. MS (ESF) m/z 353.5 (MH) :
Example 15 5-{1-(Z-nitrobenzyl}-1H-1,2. 3-triazol-4-yl}-1H-indazole the title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzy] bromide with Z-nitrobenzylbromide. "HNMR {500 MHz,
Ho DMSO-ds/D00) 8 ppm 8.57 (5, 1 H) 8.27 (5, THY B12 - 8.22 6m, 2 HI) 7.98 {a, J=8.54, 1.53
Hz, THY 775-783 (m, 1 H) 7.60 - 7.72 {m, 2H) 7.27 {d, }=7.63 Hz, 1 H) 6.02 (5,2 H). MS (ESI) m/z 320.8 (M+H)".
Example 16
S-[1-(3-nitrobenzy!)-1H-1 2, 3-rtazol-4-y1}- 1 H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 3-nitrobenzylbromide. 'H NMR (500 MHz,
DMSO0-ds/D20} 6 ppm 8.65 (3, 1 H) 8.21 - 8.28 (m, 3H) 8.15(s, 1 H} 7.80 - 7.91 (m, 2 H) 7.73 (.J=778 Hz, 1 H) 7.65 (d. }=8.54 Hz, 1 H} 5.83 (s, 2 H). MS (ESI+) m/z 320 8 (MHD
Example 17 3-[ 1-(4-nitrobenzyi}-1H-1 .2.3-triazol-4-y1}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzy] bromide with 4-nitrobenzylbromide. 'H NMR (500 MHz,
DMSO-d¢/DyO) 8 ppm 8.64 (5, 1 HY 8.22 - 8.31 (m, 3H) 8.15 (s, | H) 7.8% (4, 3=8.70. 1.37
Hz, 1 H) 7.57 - 7.68 (m, 3 H) 5.83 (5, 2 Hy. MS (EST+) m/z 320.7 (M+H)".
Example 18 2-{[4-(1H-indazol-5-y1}- 1 F-1.2 3-triazol-1 -ylimethy!} benzonitrile
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 2-cyanobenzylbromide. I NMR (500 MHz,
DMSO-ds/D20) 8 ppm 8.61 (5.1 H) 8.26 (s, 1H)8.13(s, 1 H) 7.93 (d, }=7.63 Hz, | FH) 7.88
(d, J=8.54, 1.53 Hz, 1 H) 7.72 - 7.80 (m, I H) 7.57 - 7.68 (m, 2 H) 7.53 (d, }=7.93 Hz, 1 H) 5.86 (8,2 H). MS (BSI+) m/z 300.9 (M+H)".
Example 19 3 3-{{4( 1H-indazol-5-y1}-1H-1.2 3-triazol-] -yllinethyl! benzonitrile
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzy! bromide with 3-cyanobenzyTbromide. 'H NMR (500 MHz,
DMSO0-ds/D:0) 6 ppm 8.63 (5. TH}B.26 (s. H)B.15(s, | HY 7.85-7.93 (m, 211) 7.83 (d,
F=T63 He, 1 HY 7.72 (4, 38.04 Hz, 1 Hy 7.36 - 7.68 (m. 2 Hj 5.74 (s. 2H). MS (ESI) mz
Ho 300.9 (vr)
Example 20 4-{[4-(1H-1ndazol-5-yI}- 1 8-1 2.3-triazol-1-yl methyl} benzonitrile
The title compound was prepared according to the procedure outlined in Exampie 4, substituting 2-methyl-benzyl bromide with 4-cyanobenzylbromide. 'H NMR (300 MHz,
DMSG-d¢/D>0) 8 ppm 8.62 (s. 1H) 8.26 (s, 1 FI) 8.15 (s, 1 H) 7.82 -7.93 (m, J=8.24 Hz 3
H) 7.65(d, I=8.54 Hz, 1 H) 7.54 (d, }=8.24 Hz, 2 H) 5.78 (5, 2 H). MS (ESI) m/z 360.7 (M+HY",
Example 21 3-41-02 trifluorornethylybenzyl]-1H-1.2, 3-triazol] -4-yl}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 2-riflueromethylbenzylbromide. 'H NMR {500
MHz, DMS0-ds/D,0) 8 ppm §.56 (s, 1 H) 8.27 (5, 1 H) 8.15 (s, 1 H) 7.89 (d, 1=8.85, 1.53
Hz, 1H)7.85(d, J=793 Hz 1 H) 7.72 (t, J=7.63 Hz, 1 H) 7.55 - 7.68 (m, 2 H) 7.33 (d,
J=7.93 Hz, 1 H) 5.85 (s, 2 H). MS (ESI) m/z 300.7 (M+H)",
Example 22 3-{1 -{3-(trifluoromethyl)benzyl 1H-1.2,3-triazol-4-y1}-1 H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 3-trifluoromethylbenzylbromide. 'H NMR (500
MHz, DMSO-d¢/D,0) § ppm %.65 (s. LH}8.25(s, 1H} 8.14 (s, | H) 7.87 (d, 1=8.70, 1.37
Hz, 1H) 7.77 (s, 1 HY 7.71 - 7.76 {(m, 1H) 7.61 - 7.65 (m. 3 H) 5.78 {s. 2H). MS (ESI) m/z
344.0 (M+H)".
Example 23
S-t-l4( triffuoromethyl benzyl} 1 Fi-1 a 3-triazold.yli-1 Heindazole
The title compound was prepared according to the procedure outlined in Example 4, substituting Z-methyl-benzyl bromide with a-trifluoromethylbenzylbromide. "I NMR (500
MHz, DMS0-ds/D20) 8 ppm §.63 (s, TH}YB25 (5, 1H) 8.14 (s, 1 H) 7.87 (d, J=8.54 Hz, | H)
TT8{d, J=7.93 Hz, 2 H) 7.63 (d, J=8.54 Hz, 1 H) 7.58 (d, J=7.93 Hz, 2 HYS78 (5, 2 H). MS (ESI) m/z 344.2 (Mi+H)"
Example 24 5-{1-B3~(trifluoromethox yobenzylj-1H-1 od, 3-triazol-4-y1}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 3-trifluoromethoxybenzylbromide. HNMR {500
MHz, DMSO0-d5/D>0) 8 ppm 8.64 (s, 1HY825 (s, 1H) 8.14 (s, 1 H) 7.87 (d, J=8.54 Hz, 1 H) 1.64 (d, J=8.54 Iz, 1 H) 7.56 (t, I=8.24 Hz, 1 FI) 7.31 - 7.45 {(m, 3H) 5.73 (s, 2 H). MS (ESI+) m/z 359.9 (M+H)".
Example 25 5-11 [4~(irifluoromethoxy ybenzyl]- LH-1,2 3-triazol-4-y] t-1H-1ndazole
The title compound wag prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 4-trifluoromethoxybenzylbromide. 'H NMR {500
MHz, DMSO-dg/D,0) 6 ppm 8.61 (s, 1 H) 8.25 (5, 1 H)8.14(s, 1 H) 7.87 (d, J=8.70, 1.37
Hz, 1 H) 7.63 (d, J=8.54 Bz, | H} 7.52 (d, J=8.85 Hz, 2 H) 7.40 {(d,1=824 Hz, 2 H) 5.70 (s,2
Hj. MS (ESI+) m/z 359.9 (M+H)"
Example 26 5-1 -(4-tert-butylbenzyi)- 1 H-1 2,3-triazol-4-y1}-1H-indazoje
The titie compound was prepared according to the procedure outlined in Example 4, 36 substituting 2-methyl-benzyl bromide with 4-tert-butytbenzylbromide. 'H NMR (500 MHz,
DMSO0-ds/D,0) 8 ppm 8.58 (s, TH) 824 (5, 1H) 8.13 (s. 1H) 7.86 (d, J=8.85, 1.53 Hz, 1 H) 7.63 (d, J=8.54 Hz, 1 H) 7.42 (d, }=8.04 Hz, 2H} 7.32(d, J=8.24 Hz, 2 H) 3.60 (s, 2H) 1.26 (s. 9 Hy. MS (ESI+) m/z 332.1 (M+H)". 6d
Example 27 methyl 3«{[4~-(1H-induazo BS-yD-TH-1.2 3triaznl-1- viimethyl} benzoate
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 3-carbomethoxybenzylbromide, '"H NMR (500
MHz, DMSO-dy/D,0) § ppm 8.62 (5, 1 H) 8.25 (s, | HY814¢(s, 1 Hy 7.92 - 7.00 (m, 2 HH) 7.87 (d, 1=8.54, 1.53 Hz, | H) 7.68 (d, 27.63 Hz, | H) 7.63 (d, }=8.54 Hz, 1 H} 7.5% (x, #763 Hz, | H) 5.75 (5. 2 H)3.86 (5,3 H). MS (BSH) m/z 333.9 (M+H)"
HY Example 28 methyl 4- [4-(1H-indazol-5-y1}-1H-1 2. 3-triazol-1-yljm ethyl} benzoate
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 4-carbomethoxybenzylbromide, *H NMR (500
MHz, DMSO-ds/D.0) § ppm 8.62 (s, 1 H) 825 (s, 1 H) 8.14 (s, 1 H) 7.99 {d, }=8.24 Hz, 2 H) 7.87 (d,1=%.85 fz, 1 H} 7.63 (d, I=8.54 Hz, 1 H) 7.49 (d, J=8.24 Hz. 2 FH} 5.76 (s, 211) 3.85 (s, 3 FH). MS (EST+) m/z 333.9 (M+)
Example 29 5-11 2,4-dimethylbenzyl)-1H-1 2, 3-triazol-4-yI]-1H-indazale
The title compound wag prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzy! bromide with 2,4-dimethylbenzylchloride. ‘H NMR (500 MHz,
BMSO-ds/D,0) 8 ppm 8.43 (s, 1H) 8.24 (s, 1 H)&.13 (s, 1 H) 7.86 (d, J=8.54 Hz, 1 Hy 7.62 (d, J=8.54 Hz, 1 H) 7.12 (d, J=7.93 Hz. 1 H} 7.07 {(s, TH) 7.04 (d, J=7.63 Hz, 1 H) 5.60 (s, 2
Hy2.3245, 3 H) 2.26 {s,3 H). MS (ESI+) m/z 304.0 (M+HY",
Example 30 5-11 ~(3,5-dimethylbenzyl)- | H-1 .2,3-triazol-4-y1}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 3.5-dimethylbenzylbromide. 'H NMR (500 MHz,
DMSO-d,/D20) 8 ppm §.56 (s. 1H) 8.24 (5, 1 FI} 8.13 (s, 1 H) 7.87 (d, J=8.54 Hz, 1H) 7.63 (d,J=8.54 Hz, 1 H) 6.95 - 7.01 (m, 3 H) 5.35 (s, 2 H} 2.26 (8,6 H). MS (ESI+) m/z 304.2 (M+HY
Example 31 5-[1-(2,3-dichlorobenzyl)-1H-1 .2,3-triazol-4-y1]- 1 H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 2,3-dichlorobenzyichloride. 'H NMR {500 MHz,
DMSO-de/D:0) 8 ppm 8.59 (5, 1 FT) 8.26 (s, 1 EL) 8.14 (5, 1 H) 7.88 (dl. J=8.70, 1.37 Hz. I FH) 7.69 (d. J=8.09, 1.37 Hz, 1 H) 7.63 (d, J=8.54 Hz, | H) 7.44 (1, )=7.78 Hz, 1 FH} 7.31 (d,
J=7.78, 1.07 Hz, 1 H) 5.81 (5, 2 }). MS (ESI) m/z 343.8 (MH).
Example 32 id 5-{1-{Z.4-dichlorobenzyl)-1H-1.2, 3-triazo] -4-yil-1H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzy! bromide with 2,4-dichlorobenzyichloride. 'H NMR {500 MHz,
DMSO-ds/D20) 6 ppm 8.56 (5, 1 H) 8.25 (5, 1 HY 8.13 (s. 1H) 7.87 (d, J=8.54 Hz, 1 Hy7.72 (d, J=2.14 Hz, 1 H) 7.63 (d, }=8.54 Hz. 1 H) 7.50 (d, }=8.39, 1.98 Hz, 1 H) 7.40 (d, }=8.24
Hz, 1 H)5.74(s, 2 H). MS (ESI) m/z 341.8 (M-H),
Example 33 5-[1-(2,5-dichlorobenzyl)-1H-1 12. 3-triazol-4-yil-1H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 2.5-dichlorobenzyichioride. 'H NMR (500 MHz,
DMSO-ds/D20) 8 ppm 8.59 {s, 1 H) 8.26 (s, TH} 8.14 (s, 1 H) 7.88 (d, J=8.85 Hz, 1 H) 7.63 (d, J=8.85 Hz, 1 Hy 7.56 - 7.61 (m. | H) 7.49 - 7.55 (m, 1 HY 7.47 (d, J=2.44 Hz, 1 FI) 5.75 (s, 2H). MS (ESH) m/z 343.8 (M+H),
Example 34 5-[1-(3.5-dichlorobenzyh-1H-1 ,2,3-trtazol-4-yi]- 1 H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyl-benzyl bromide with 3,5-dichlorobenzylchloride. '"H NMR {500 MHz,
DMS0-d/D>0) 8 ppm 8.64 (s, 1 H) 8.26 (s, 1 H) 8.15(s, 1 H) 7.87 (d, J=8.85 Hz, 1 H) 7.57 -7.71(m, 2H) 7.44 (d, J=1.53 Hz, 2 F) 5.69 {s, 2 H). MS (ESI+) m/z 344.1 (M~H)".
Example 35 5-{1-[2.4-bis(trifluoromethylb enzyl]-1H-1.2.3-riazol-4-y1} - 1 H-indazole
The title compound was prepared according to the procedure outlined in Example 4, substituting 2-methyi-benzyl bromide with 2,4-bisttrifluoromethy bromide. 'H NMR (560
MHz, BMSQ-ds/D,0) § ppm 8.62 (s, 1 HY 8.27 (5, 1 H} 8.07 - 8.1% {m, 3 H} 7.85 (d, J=8.70, 1.37 Hz, 1 HY 7.64 (d, }=8.54 Hz, | HY 749 (d, J=7.93 Hz, 1 H) 5.96 (8, 2H) ME (ESI+) m/z 411.7 (M+HY,
Example 36
N-cyelohexyl-6-(1 H-indazol-5-yl)imidazo|2, 1-b}{1.3]thiazol-5-amine 1 Example 364A 1H-indazole-5-carbaldehyde
To a solution of 5-bromoindazole (3g 25.38 mmol) in tetrahydrofuran (100 mL) cooled at -50 °C under argon was added dropwise & solution of 1.6 M n-butyllithium in hexanes (40 ml, 63.44 mmol). Dimethylformamide (3.9 mL, 50.75 mmol} was added. and the mixture was allowed to warm to room temperature and stirred for 15 minutes. The mixture was then quenched with water, extracted with ethy] acetate, preabsorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10-30% ethyl acetate in hexanes to afford the title compound. 'H NMR (500 MHz, DMSO-dg) & ppm 10.03 (5,
H) 8.45 (s, 1 H) 8.35 (s, 1 H) 7.85 (dd, /=8.70, 1.37 Hz, 1 H) 7.69 {d, J=8.54 Hz, 1 ¥1).
Example 36B
N-cyclohexyl-6-(1 B-indazol-5-yl)imidazo[2, 1-b][1,3}thiazol-5-amine
Example 364 (50 mg, 0.34 mmol} and 2-aminothiazole (28 mg, 0.34 mmol) were combined with scandium triflate {8 mg, 0.017 mmol) in anhydrous methanol (1 ml) ina 4 mL vial. The vial was sealed and shaken at ambient temperature for 30 minutes. Cyclohexy! 1socyanide (42 mL, 0.34 mmol} was added, and the mixture was shaken for 2 days at room temperature. The mixture wag purified by reverse-phase HPLC using an acetonitrile/water 0.1% TFA gradient elution method to afford the title compound as the TFA salt. 'H NMR (500 MHz, DMSO-ds) 8 ppm 13.12 (s. TH)832(s, 1 H) 8.13 (s, 1 H) 8.05 (d, 7=%.85, 1.22
Hz 1 H)7.92(d, J=4.27 Hz, 1H) 7.60 (d, J=8.54 Hz, 1 H) 7.37 (d, J=3.66 Hz, 1 H) 4.89 (s, 1
HY2.78-2.94(m, 1 H) 1.73 - 1.83 (m. 2 H) 1.58 - 1.68 (m. 2 FH) 145 -1.53 (m, 1 H) 1.16 - 1.29 (m, 2H) 1.04 - 1.14 (m, 3 H). MS (ESI) m/z 338.1 (M+H)",
Example 37
N-cyclohexyl-2-{ 1H-mdazol-5-ylimidazo[ L.2-alpyridin-3-amine
The title compound was prepared according to the procedure outlined in Example 36B, substituting 2-aminothiazole with Z-aminopyridine. "H NMR (500 MHz, DMSO- de) Sppm 13.04 (5. 1 HY 8.57 (5, TH) B23 -8.39 (m. 2 11) 8.1 (s, 1 HY 7.57 (d, I=8.54 Hz. 1
H) 7.46 (d, }=885 Hz, 1 H) 7.12 - 7.2] (m. I H) 6.88 (1, 7=6.71 Hz, 1 H) 4.78 (d. J=5.%0 Hz,
LHP278-2.91 (m, 1 H)1.69-1.77 {m, J=10.98 Hz, 2 HY 1.57 - 1.67 {m, 2H) 1.45 - 1.53 (m, TH} 121-134 (m, 2H) 1.01 - 1.16 {m, 3 H). MS (ESI+) m/z 332.1 (M-+HY"
Example 38
N-cyclohexyl-2-(1 H-indazol-5-yimidazo[ 1 2 -4}pyrazin-3-amine
The title compound wag prepared according to the procedure outlined in Example 368, substituting 2-aminothiazole with 2~amimopyrazine. 'H NMR (500 MHz, DMSQ- ds) ppm 13.12 (5. 1 H) 8.90 (d,J=1.22 Hz, | H) 8.61 (s, 1 H)8.37(d, 1=4.58. 1.53 Hz, 1 H) 8.29(d, J=8.70, 1.37 Hz, 1 H) 8.15 (5, 1 H) 7.85 (d, }=4.58 Hz, I H) 7.62 (d, }=8.85 Hz, 1 Hj} 5.05(d, 6.71 Hz, 1 H) 2.81 - 2.99 (mn, 1H) 1.70 - 1.77 (m, 1=10.68 Hz, 2H) 1.58 - 1.67 (m,
ZH) 147s, THY 1.24 - 1.38 (m, 2H) 1.00- 1.16 (m, 3 H). MS (ESI) m/z 333.1 (M+H)',
Example 39 5-1 -benzyl-4-{4-fluorophenyl)-| H-imidazo!-5-y1}-1H-indazole into a 20 mL scintillation vial was added 50.0 mg (0.34 mmol} of Example 36A. To the solid was added a 2.0 mL dimethylformamide solution containing 0.46 mmol (49 mg) of benzylamine and 50 mg of powdered activated 4A molecular sieves. The vial was then capped and heated at 60 °C for 4 hours on an orbital shaker. The vial was allowed to coof to ambient temperature; and was uncapped. To the suspension was added 37 mg (0.23 mmol) of anhydrous potassium carbonate followed by 66 mg (0.23 mmol) o-(p-toluenesulfonyl)-4- fluorobenzylisonitrile. The vial was then capped and heated overnight at 60 °C on a shaker.
The vial was removed from the shaker; allowed to cool to ambient temperature; and the resulting suspension was filtered, The filtrate was evaporated under reduced pressure at medium heat on a Savant Speed Vac. The crude residues were redissolved in 1:1
DMSO/methano! and purified by reverse-phase HPLC using an acetonitrile/water TEA gradient etution method 16 afford the title compound as the TFA salt, 'H NMR (300 MHz,
DMSO-ds) 8 ppm 9.01 (5. 1 H) 8.12 (s, 1H} 7.76 (s, 1 H) 7.60 (d. J=8 48 Hz, 21) 732.-7.45
(m, 2 H) 7.09 - 7.30 (m, 6 H) 6.96 (d, J=6.61, 2 88 Hz, 2H} 5.23 (s, 2H). MS (DCH nv/z 369 (M+).
Example 40
N-{3-[4-(4-1] uorophenyi}-5-(1H-indazol-5 “yi 1H-imidazo}-] -vlpropyl} -N.M-dimethylamine
The title compound was prepared as a TFA salt according to the procedure outlined in
Example 30 substituting benzylamine with NUN -dimethylpropane-1,3-diamine. "HNMR (300 MHz, DMSO-dy) & ppm 9.49 (s, 1 H) 8.88 (s, 1 1H} 8.19 (8, TF) 7.94 (s, 1 FI} 7.73 {d,
J=8.81 Hz, 1 H) 7.20. 7 44 (m, 3 H} 7.07 (1, J=8.98 Hz, 2 HY 4.01 ((, J1=7.12 Hz, 2 H} 2.89. 3.04(m, J=10.51 Hy, 2 H) 2.68 (5,2 H) 2.67 (s, 3 HY LB7-2.02 (m, 2 H}). MS {DCT m/z 364 (M+)
Example 41
N-cyclohexyl-2-(1H-in dazol-5-yl}imidazof L.2-a}pyrimidin-3-amine
The title compound was prepared as a TFA salt according to the procedure outlined in
Example 36B substituting pyrimidin-2-amine for thiazol-2-amine. 'H NMR (500 MHz,
DMSO-ds) 8 ppm 13.21 - 13.4] (m. 1H) 9.07 (d, 3=5.80 Hz, | H) 8.85 (d, 7=3.05 Hz. | H)
B.51(s, 1H) 824 (s, 1 H) 8.14 (d, }=8.70, 1.37 Hz, 1 H) 7.73 (d. J=8.83 Hz, 1 H) 7.47 - 7.54 (m, 1 H} 5.25 - 5.41 (m, ]=2.75 Hz, 1 HY 281-291 (m, J=10.53,10.53 Hz, 1 H) 1.74 - 1.83 200 (m 2H} 1.56- 1.66 (m, 2H} 1.43 - 1.50 (m, 1 H)1.24(q, }=11.09 Hz, 2 H) 1.06 1.14 (m, 3
Hj. MS (ESI+) m/z 333.1 (M+R),
Example 42
S-[4-(4-fluorophenyl)-1-(1 ~phienylethy|)- IH-imidazol-5-y1]-1H-indazole
The title compound was prepared according to the procedure outlined in Example 39 substituting I-phenylethanamine for benzylamine. 'H NMR (300 MHz, CDCl;) 8 prem 8.04 (s. 1 H)7.75-7.84 (m, 1 H) 7.35 - 7.55 (m, 4H) 7.20-7.31 (m, 5 H} 6.76 - 7.01 (m, 4 H) 3.094q, =7.12 Hz, 1H) 1.82 (d, 3H). MS (DCD m/z 383 (M+H)".
Example 43 2-(1 B-indazol-5-y1)-N-isopropylimidazo] .2-alpyrimidin-3-amine
Example 36A (42 mg, 0.287 mmol) and 2-aminopyrimidine (27 mg, 0.284 mmol) were combined with scandium triflate (7 mg, 0.014 mmol} in anhydrous methanol (2 mL) in a 4 ml vial. The vial was sealed and shaken at ambient temperature for 30 minutes,
Isopropyl isocyanide (27 mL, 0.286 mmol} was added and the mixture was shaken at arnbienf temperature overnight, followed by 40 °C for 2 hours, The mixture was absorbed on silica gel and purified using silica ge! chromatography eluting using a gradient of 0-5% methanol in dichloromethane to afford the title compound. "HNMR (300 MHz, DMSG-ds) & ppm 13.08 (s, 1 H) 8.75 (d, 1=6.95, 1.86 Haz, I H) 8.60 (s, 1 H) 8.31 (d, J=8.82. 1 36 Hz, 1H) 8.20 (d,
F=475 Hz, 1H) 8.14 (5. 1 H) 7.60 (d, J=8.82 Hz, 1 H) 7.03 (d, J=6.7%, 4.07 Hz, 1 H) 6.54 id.
F=4.75 Hz, 1 H) 4.86 (d, J=5.09 Hz, 1 H) 1.05 (d, J=6.10 Hz, 6 1). MS (ESI+) m/z 293.0 (M+HY 1
Example 44 4-(1 H-indazol-5-y1}-N-ph enyl-1,3-thiazol-2 -amine
Example 444A teri-Butyl 5-bromo-1H-indazole-1 ~carboxylate 5-Bromoeindazoie (4.40 2, 22.3 mmol) and a catalytic amount of dimethylaminopyridine {(~50 mg) were dissolved in dichloromethane (100 mb). Di-terr-butyl dicarbonate (5 43 g, 24.9 mmol) was added, and the mixture was stirred at ambient temperature overnight. The mixture was absorbed on sifica gel and purified by silica gel chromatography cluting with a gradient of 0-40%, ethyl acetate in hexanes to afford the title compound. MS (ESF) m/z 297.2 (M+H)",
Example 44R rert-Butyl 5-acetyl-1H-indazole-1 ~carboxyliate
Example 44A (5.12 g, 17.2 mmol}, tributyl (1 -ethoxyvinyl} tin (7.0 mL, 20.7 mrnol), and dichiorobis(triphenylphosphine)palladium(IT) (672 mg, 0.957 mmol) were combined mn toluene (85 mL). Nitrogen was bubbled into the mixture for 5 minutes, and the mixture was heated to 100 °C in a sealed tube overnight. The mixture was absorbed on silica gel and purified by silica ge! chromatography eluting with a gradient of 0-40% ethyl! acetate in hexanes to afford the ttle compound. MS (ESI+) m/z 283.0 (M+Nay"
Example 44C tert-Butyl 5-(2-bromoacetyl)-1H-indazole-] -carboxylaie
Example 44B (1.60 ¢, 6.15 mmol) and pyridinium tribromide (1.98 g, 6.19 mmo!) were combined in tetrahydrofuran and heated to 40 °C for 2 hours. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 40% ethyl acetate in hexanes to afford the title compound. MS (ESI) m/z 360.9 (M+Na)
Example 44D 4-(1 H-indazol-5-y1)-N-phenyl-] ,3-thiazol-2-amine
Example 44C (71 mg, 0.208 mmol) and I-phenyi-2-thiourea (33mg, 0.217 mmol) were combined in ethanol (300 mL}in a4 mb vial. The vial wae shaken at 80°C overnight. 1 The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of methanol in dichloromethane ((-3%) to afford the title compound. 'H
NMR. (400 MHz, DMSO-dg) 8 ppm 13.08 (s, 1 H) 10.23 (5, 1H) 832 (5, 1 H)y8.14 4s, 1 1) 7.93 (d, J=8.59, 1.53 Hz, 1 H} 7.75 {d, 3=8.75, 1.07 Hz, 1H) 7.58 (d, J=8.90 Hz, 1 H) 7.36 (d,
J=8.59, 7.36 Hz, 1 H) 7.25 (8, 1H)6.92-7.02 (m, 1 HI). MS (ESI+} m/z 292.9 (M+).
Example 45 5-(2-methyl-1 ,3-thiazol-4-y1}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 44D substituting I-phenyl-2-thiourea with thicacetamide, I NMR (300 MHz, DMSO- ds) 8 ppm 13.10 (s. 1 FH) B34 (s, 1 HY 8.12 (5, 1 H) 7.94 (d, }=8.82, 1.70 Hz. 1 HY 785 (5, 1
H) 7.57 (d. 1=8.82 Hz, } H) 2.73 (5,3 HI). MS (ESF) m/z 215.9 (MH).
Example 46
N-ethyl-4-(1H-indazo}-5 -yb-1.3-thiazol-2-amine
The title compound was prepared according to the procedure outlined in Example 44D substituting I-phenyl-2-thicurea with othylthiourea. 'H NMR (306 MHz, DMSO- ds) 8 ppm 13.04 (5, 1 B) 8.21 (s, 1H) 8.09 (s, 1 H) 7.83 (d, J=8.65, 1.53 Hz. 1 H) 7.58 (¢,
J=5.43 Hz, 1 H) 7.51 (d, J=8.82 Hz, 1 H) 6.96 (s, 1 H)3.22 - 3.34 (m, 2H) 1.21 (t, i=7.29
Hz, 3 H). MS (ESI) m/z 244.9 (M+H)",
Example 47
N-benzyl-4-(1 H-indazol-5-y1-1,3-thiazol-2 -aniine
The title compound was prepared according to the procedure outlined in Example
44D substituting 1-phenyl-2-thiourea with l-benzyl-2-thicurea. 'H NMR (400 MHz, DMSO- ds) & ppm 13.02 (s, 1 HI) 8.21 (s, 1 Hy 8.12 (t J=5.83 Hz, 1 H) ROK (5. 1 HY 7.83 (d, J=8.96, 1.53 Hz, 1 H) 7.50 (d, J=§.90 Hz, | HY 7.39-7.45 (im. 2 H) 7.35 (1, }=7.52 Hz, 2H) 7.26 (1,
J=T21 He, TH) 6.97 (s, 1 HY 4.54 (4, J=5.83 Hz, 1H). MS (EST+) m/z 306.9 (MH).
Example 48 4-(IH-indazol-5-yl)-1,3-thiazol-2-amine
The title compound was prepared according to the procedure outlined in Example 4410 substituting 1-phenyl-2-thiourea with thiourca, 'H NMR (300 MHz, DMSO-d) 6 DI 16 13.03 6s, 1 HY 8.17 (5, 1 FD 8.07 {s, LH) 7.81 (d, 3=8.82, 1.36 Hz 1 H) 7.50 (d, J=8.82 Hz,
FH) 7.01 (s, 2H) 6.92 (5, 1 H). MS (ESI) m/z 216.9 (M-+H)"
Example 49 4-(1H-mndazol-5-y1)-N-( 2-phenylethyl}-1 3-thiazol-2-amine
The title compound was prepared according to the procedure outlined in Example 44D substituting 1-phenyl-2-thiourea with l-phenethylthiourea. 11 NMR (300 MHz,
DMSO-ds) & ppm 13.03 (s. 1 H) 8.23 (s, 1H) 8.09 (5, 1 FT) 7.85 (d, J=8.65, 1.53 Hz, 1H)
T71(t, J=5.43 Hz, 1 H) 7.51 (d. }=8.82 Hz, TH) 7267.36 (m, 4 H) 7.18 - 7.26 {m. 1 H) 6.97 (s, 1 H) 3.47 - 3.59 (m, 1 H) 2.94 (t, J=7.44 Hz, 1 H). MS (ESI) m/z 321.0 (MH).
Example 50
N-benzyl-2-(1H-indazol-3-y|)imi dazo[1.2-ajpyrimidin-3-amine
The title compound was prepared according to the procedure outlined in Example 43 substituting benzylisocyanide for 1sopropy! isocyanide. 'H NMR (300 MHz, DMSO- de) Sppm 13.10(s, 1 H) 8.50 - 8.58 {m, 2H) 8.39 (d. }=4.07. 2.03 Hz, 1 Hj) 8.25 (d, J=8.81, 1.36 Hz, | HY 8.13 (s, 1 H) 7.61 (d. J=8.81 Hz, 1 H) 7.24 (5,5 H) 6.92 (d, }=6.78, 4.07 Hz, 1
H) 5.44 (1, }=6.27 Hz, 1 H) 4.13 (d, J=6.10 Hz, 2 H). MS (ESI) m/z 341.0 (M+H)".
Example 51
N-butyl-2-(1H-indazol-5-ylYimidazo[ 1.2 -aJpyrimidin-3-amine
The title compound was prepared according to the procedure outlined in Example 43 substituting butylisocyanide for isopropyl isocvanide. 'H NMR (300 MHz, DMSO-d,) 0 ppm 13.09 (s. 1 H) 8.70 (d, J=6.78, 2.03 Hz, | H) 8.35 (s, 1 H) 8.44 (d, 1=4.07, 2.03 Hz I H) 8.25
(d, J=8.82, 1.36 Hz, 1 H) 8.14 (5, 1 H) 7.61 (d, J=8.82 Hz, 1 H) 7.03 (d, J=6.78, 4.07 Hz, 1 H) 4.90 (t, }=5.93 Hz, 1 H) 2.96 (s, 2 H) 1.40 (8, 2H) 1.34 (5, 2HY 0.82 (1. }=720 Hz 3 H) M8 (ESI) m/z 307.0 (M~+H)"
Example 52
N-{(4-chlorophenyl)-2-(] H-indazol-5-ylyimidazo[ 1 Z-apyrimidin-3-amine
The title compound was prepared accordmg to the procedure outlined in Example 43 substituting 4-chlorophenylisocyanide for isopropyl isocyanide. "HNMR {500 MHz,
DMSO-dg) 8 ppm 13.12 (5. | H) 8.5% (dd, /=4.12, 1.98 Hz, | HY 8.46 (d, J=15.87 Hz, 2 H
B40 (dd, /=6.71, 1.83 Hz, 1 8.06 - 8.16 (m, 2 HY 7.58 (d, /=%.85 Hz, I H) 7.18 (d, J=8 85
Hz, 2H) 7.05 (dd, J=6.71,3.97 Hz, 1 H) 6.57 (d, /=B.85 Hz, 2 HI}. MS (ESI) m/z 361.0 (M~+HY".
Exarnple 53 2«1H-indazol-5-y1}-N ~(4-methoxyphenylyimidazo[1,2 -apyrimidin-3-amine
The title compound was prepared according to the procedure outlined in Example 43 substituting 4-methoxyphenylisocyanide for isopropyl isocyanide. 'H NMR (500 MHz,
DMSO-ds) 8 ppm 13.10 (s, 1 H) 8.56 (dd, ./~3.97. 2.14 Hz, 1H} 8.47 (s, 1 H) 8.36 (dd,
J=6.56, 1.98 Hz, 1 H) 8.15 (dd, ./=8.70, 1.37 Hz, 1 H) 8.10 (s, 1 H) 7.99 (s, 1 H) 7.57 (d,
J=R.54Hz, 1 H) 7.03 (dd, J=6.71. 4.27 Hz, 1H} 6.76 (d, /=8.85 Hz, 2 H) 6.50 (d,./=8.85 Hz, 2H) 3.63 (s, 3H). MS (ESIH+) m/z 357.4 (M+H)",
Example 54 2-(1H-indazol-5-yljimidazo[ 1 2-alpyrimidine
The title compound was prepared according to the procedure outlined in Example 44D substituting 2-aminopyrimidine for I-phenyt-2-thiourea. 'H NMR {300 MHz, DMSO- ds) 6 ppm 13.13 (5, 1 H) 8.96 (dd, J=6.78, 2.03 Hy. I H) 8.51 (dd, /=4.41, 2.03 Hz. 1 H) 8.42 (s, 1 H}836 (s, 1 H) 8.15 (5, 1 H) 8.01 (dd. J=B.82, 1.70 Hz, 1 H) 7.62 (d, ./=58 48 Hz, 1 H) 7.04 (dd, J=6.61, 4.24 Hz, 1 H). MS (ESi+) m/z 236.1 (M+H)"
Example 55 methyl N-[2-(1B-indazo!-3-y] yimidazo[1,2-a]pyridin-3-yl]glycinate
The title compound was prepared as a TFA salt according to the procedure outlined in
Example 36B substituting Z-aminopyridine for 2-aminothiazole and methyl Z-isocyanoacstate for cyclohexyl isocyanide. 'H NMR (400 MBz, DMSO-ds) 8 ppm 13.41 {s, 1 HY 8.90 (d.
J=6.75 Hz, 1 H) 8.38 (3, 1 H) 8.27 (s, 1 FI} 7.84 = 7.98 (m, 3 HY 7.77 (d, 8.90 Hz, | H} 7.55 (td, J=6.75, I 23 Hz, 1 H) 5.95 - 6.06 (m. 1 H) 3.87 (d, J=4.60 Hz. 2 HY 3.57 (s. 3H) MS (EST+) m/z 340.1 (MH).
Example 56
N-benzyl-2-(1 H-indazol-5-ylyimidazo! { 2~a]pyridin-3-amine
The title compound was prepared accordin 8 to the procedure outlined in Example 36B substituting Z-aminopyridine for 2-aminothiazoie and benzyl isocyvanide for cyclohexyl isocyanide. The final product precipitated out of solution and was isolated after filiration. 'H
NMR (400 MHz, DMSQ-dg) d ppm 13.04 (s, 1 H) 8.49 (5. 1 H) 8.16 - 8.27 {(m, 2 H) 8.09 (g, 1
H) 7.58 (d, J=8.80 Hz, 1 H) 7.44 {d, J=890 Hz, 1 H) 7.19 - 7.35 (m, 5 H) 7.13 (ddd, J=8.98, 6.67, 0.92 Hz, 1 H) 6.80 (1d, J=6.75,0.92 Hz, 1 H) 5.32 (t, J=6.14 Hz, 1 H)4.12 (d, }=6.14
He 2 H). MS (ESI+) m/z 322.1 (M+)
Example 57
N-{4-chlorophenyl)-2-(1 H-indazol-S-ylyimidazo[1 2-alpyridin-3-amine
The title compound was prepared according fo the procedure outlined in Example 36B substituting 2-aminopyridine for 2-aminothiazole and I-chioro-4-isocyanobenzene for cyclohexyl isocyanide. 'H NMR (400 MHz, DMSO-d) 8 ppm 13.06 (s, 1 H) 8.39 (s, 2 H) 8.85 - 8.14 (m, 2 H) 7.94 (d, }=6.75 Hz, 1 H) 7.62 (d. }=8.90 Hz, | H} 7.55 (d, J=8.59 Hz, 1
H)Y728-734(m. 1H) 7.17 (d, J=8.90 Hz, 2 IT) 6.88 - 6.96 (m, J=6.75, 6.75 Hz, 1 H) 6.53 (d, J=8.59 Hz, 2 H}, MS (ESI) m/z 360.0 (M+H)".
Example 58 2-(1H-indazol-5-y1}-N-( 4-methoxypheny!)imidazo[ 1.2-ajpyridin-3-amine
The title compound was prepared according to the procedure outlined in Example 36B substituting 2-aminopyridine for 2-aminothiazole and I-isocyano-4-methoxybenzene for cyclohexyl isocyanide. '"H NMR (400 MHz, DMSO-d;) § ppm 13.04 (s, 1 HY 8.44 (s, 1 H) 8.14 (d, J=8.90, 1.23 Hz, 1 IT) 8.06 (s, 1 H) 7.87 - 7.96 (m, 2 H) 7.59 (d, J=8.90 Hz, 1 H) 7.54 {d, J=8.5% Hz, 1 H) 7.24 - 7.33 (tm, 1 H) 6.86 - 6.93 (m, J=6.75, 6.75 Hz, 1 HY 6.75 (d. 1=9.2]
Hz, 2 H) 6.47 (d. J=09.21 Hz, 2 H) 3.63 (s, 3 H). MS (ESE) m/z 356.1 (M+H)".
Example 59 tert-butyl 4-[4-(4-fluoropheny)-5.¢1 Heindazol-5-y1)-1 Heimidazol-1 ~ylipiperidine-- carboxylate
The title compound was prepared according to the procedure outlined in Example 39 substituting tert-butyl 4-aminopiperidine-1 -carboxylate for benzylamine. 'H NMR {400
MHz, DMSO-ds} & ppm 13.32 (s, TH) 8.14 (s, 1 HH) 8.01 (6, 1H) 7.79 (s. 1 H) 7.6% (d, J=8.59
Hz, 2H) 7.24 7.39 (m, 2 H) 6.97 (1, J=8.90 Hz, 2 H} 391-405 (mm 2H) 3.71 - 3.84 {m,
Fy2.53-260 fm. 2H} 1.76 - 194 (im, dH) 135.7140 {m, 9H). MS (BC miz 467
HO (MEY
Example 60 3,5-bis(1-benzyl-1H-1 2.3~trtazol-4-y1}- 1 Fl-indazole
I3 Example 60A tert-Butyl 5-bromo-3-iodo- 1 H-indezole. I-carboxylate
To a solution of 5-bromeindazole {10 g, 50.75 mmol) in dimethylformamide (00 mL) was added KOH (10 8. 177.63 mmol). Overa period of 2 hours, iodine (20g, 78.80 mmol) was added. The mixture was treated with a solution of Na:S:05 (20 g) in water (200 mL), extracted with ethyl acetate, washed with brine, dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure. The solid wag dissolved in dichloromethane (350 mL) and treated with di-tert-butyl dicarbonate (14.4 g, 65.98 mmol} and dimethylaminopyridine (10 mg, 0.08 mmol). The mixture was stirred for 20 minutes at
Too temperature and passed directly through 2 bed of silica gel to afford the titie compound.
MS (DCI/NH;3) m/z 422.9 (M+H)".
Example 60R tert-butyl 3-bromo-3-phenyl-1H-indazole-1-carboxylate and tert-butyl 5-bromo-3-jodo-1FH- indazole-1 -carboxylate
To a solution of Example 60A (2.1 8, 3 mmol) ia toluene (10 mL) was added
Pd{PPhs), (173 mg, 0.15 mmol), a solution of NaxCOs (1.1 g, 10 mmol) in water (3 ml}, and a solution of phenyl boronic acid {671 mg, 5.5 mmol) in methanol (3 mL). The mixture was stirred at room temperature for 5 days, quenched with water, extracted with ethyl acetate and purified by silica gel chromatography eluting with 5% ethyl acetate / hexanes to afford the title compounds as a mixture, 'H NMR (500 MHz, DMSO-dg) 8 ppm 8.28 (d, ./=1.53 Hz, 1
H) 8.12 (d, 78.85 112, 1 H) 7.97 - 8.04 (m, 3H) 7.80 . 7.86 (m, 2H) 7.75 (d. J=1 83 Hz.
BY 754-763 (m, 3H) 1.68 {s, 9H) 1.64 (5, 9 FH). MS (EST m/z 373.9 (M+H)
Example 600 tert-Butyl 3,5-bis(( trimethylsilyl jethynyl)-1H-indazole-1 -carboxylate and tert-butyl 5-bromo- 3 -((trimethylsilyDethynyl)- TH-indazole-1 ~carboxylate
Example 60B (1 ¢, 2.55 mmol), dichlerobis(triphenyiphosphin ¢)palladivm(Ii} (29 my, 16 0.13 mmol, triethylamine (1.78 m1.. 12.75 mmol), trimethylsilyl acetylene (0.432 mL, 3.06 mizol}, and Cul (24 mg, 0.13 mmol} were combined in dimethylformamide (10 mL) and stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed with wafer, and purified by silica gel chromatography to afford the title compounds. 'H
NMR (500 MHz, DMSO-d) 8 ppm 8.10 (d, J=8.85 Hz, 1 1) 8.07 (d, /=8.85 Hz, 1 H) 7.97 {d,/~1.83 Hz, 1H) 7.84 (s. 1H) 7.82 (dd, J=8.85, 1.83 Hz, 1H} 7.71 (dd, /=8.54, 1.53 Hz, 1
HY 1.65 (s, 18 11) 0.33 (d, /=0.92 Hz, 18 H).
Example 60D tert-butyl 3.5-diethynyl-1H-indazole-1-carboxyiate and tert-butyl 5-bromo-3-ethynyl-1H- indazole-] -carboxylate
To a solution of Example 60C (350 mg, 0.85 mmol) in tetrahydrofuran (SmL) was added a 1M solution of TBAF in tetrahydrofuran (2 mL 2 mmol}. After 10 minutes, the solvent was evaporated under reduced pressure and the crude mixture was purified by silica gel chromatography cluting with 5% ethyl acetate in hexanes to afford the title compounds.
HNMR {500 MHz, DMSO-d) § ppm 8.12 (d, J=7.93 Hz, | H) 8.07 (d, /~8.85 Hz. 1 1) 8.01 (d, /~1.53 Hz, 1 H) 7.90 {s, 1 H) 7.83 (dd, ./=8.85, 1.83 Hz, 1H) 7.74 (dd, /=% 85, 1.53
Hz, 1 HY4.91 (s, | H) 4.90 (s. TH) 4.20 (5, 1 H) 1.66 (s,9 H) 1.65 (s, 9 H),
Example 60F 3.5-bis(1-benzyl-1H-1 2.3-triazol-4-y]}- 1 H-indazole
The title compound was prepared according to the procedure outlined in Example 30 substituting Example 60D for Example 3C, 'H NMR (500 MHz, DMSO-d) 8 ppm 13.35 {s,
TH)876(s, 1 H) 8.71 (s, 1 H} 8.70 (s, 1 H) 7.92 (d, F=8.61, 1.28 Hz, 1 H) 7.64 (d, J=§.79
Hz, 1 H) 7.38 - 7.43 (m, 8 H) 7.33 - 7.37 (m, 2 F1) 5.73 (5, 2 H) 5.66 (5, 2 Hj. MS (ESI+) m/z 433.2 (M+H)".
Example 61 5-{1-benzyl-1H-1,2 3-11 azoi~4-yl}-3-phenyl-1H-indazole
Example 61A fert-Buty] 3-phenyl-5-({trimethvisi lyhethynyh-1H-indazole-1-carboxylate and tert-butyl 5- bromo-3-phenyi-1H-indazole- | carboxylate
Example 60B (1 g, 2.55 mmol}, dicilorobis(triphenylphosphine pal iadium( Hy (89mg, 0.13 mmol), triethylamine {1.78 mL, 12.75 mmol), trimethylsilyl acetylene (0.432 mL, 3.06 mmol), and Cul (24 mg, 0.13 mmol) were combined in dimethylformamide (10 ml} and stirred at room temperature for 20 hours, The mixture was diluted with ethyl acetate and purified by silica gel chromatography to afford the title compound. 'H NMR (500 MHz,
DMSO-ds) & ppm 8.26 (4. J=1.53 Hz, 1 H) 809 - 8.19 (m, 3 H) 7.96 - 8.03 (m, 4 H) 7.83 (dd,
J=8.85, 1.83 Hz, 1 H} 7.72 (dd, /=8.85, 1.33 Hz, 1 H) 7.50 - 7.65 (m, 6 H) 1.68 (s, 18 H) 0.26 -0.27 (m, 9 1).
Example 61B feri-Butyl 5-ethynyl-3-phenyl-1H-indazole-] -carboxylate and tert-butyl 5-brome-3-phenyl-
IH-indazole-1~carboxyiate
The title compound was prepared according to the procedure outlined in Example 60D substituting Example 61A for Example 60C. "H NMR (500 MHz, DMSO-d) 8 ppm 8.28 (d,/=1.53 Hz, 1 H) 8.21 (s. 1 H) 8.16 (d, /=8.54 Hy, 1 H)8.12(d, /~8.85 Hz, 1 H) 7.97 -8.05(m. 4H) 7.83 (dd, J=8.85, 1.83 Hz, 1 H) 7.75 (dd, /=8.85, 1.53 Hz, 1 H) 7.53 - 7.64 (m, 6 H) 427 (5, 1 H} 1.68 (s, © H) 1.68 (s, 9 H).
Example 61C 5-(1-benzyl-1H- 1.2, 3-triazol-4-y1}-3-phenyl-1 H-indazole
The title compound was prepared according to the procedure outlined in Example 3D substituting Example 618 for Example 3C. 'H NMR (500 MHz, DMSO-d) 8 ppm 13.38 {s, 1H) 8.77 (3,1 H) 8.52 (5, 1 H) 8.06 (d.J=7.33 Hz, 2 H) 7.98 (d. }=8.79 Hy, | H) 7.69 (d,
J=8.79 Hz, 1 H) 7.53 - 7.61 (m, }=7.51, 7.5 Hz, 2H) 7.33 - 7.48 (m, 6 H) 5.68 (s, 2 H) MS
(ESI) m/z 352.0 (M+H)".
Example 62
S+(1-benzyl-1H-1.2 3.4m azol-4-y1)-1 H-indarol-3-araine
Example 62A 2-Fluoro-5-((trimethylsilylyethynybenzonitriie 5-Bromo-2-fluorobenzonitrile (5.01 g, 25.0 mmol), dichlorobis(tripheny phosphine palladium 1) (652 mg. 0.929 mmol), and copper (1) iodide (413mg, 2.17 mmot) were combined in tricthylamine (15 mi} under an atmosphere of nitrogen. Trimethylsilyl acetylene (4.2 mL, 25.7 mmo!) was added and the mixture wag heated to 100°C. The mixture solidified and was monitored by LC/MS. After completion, the mixture was diluted with methylene chloride and washed with | N HCL The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (5-45%) to afford the title compound. ‘H NMR. (300
MHz, DMSO-ds) & ppm 8.09 (dd, ./=6.10,2.03 Hz, 1 H) 7.77 - 7.97 (my, 1 H) 7.54 (1, J=9 15
Hz, 111) 0.15 - 0.32 (m, © Hj.
Example 62B 5-Ethynyl-2-fluorobenzoniirile
Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 70 mL) was added to a solution of Exampie 62A (5.05g,23.2 mmol) in tetrahydrofuran (50 mL) and allowed fo stir for 20 minutes. The mixture was dilufed with methylene chloride and washed with water.
The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-409, ethyl acetate in hexanes to afford the title compound. 'H
NMR (300 MHz, DMSO-dg) 8 ppm 8.13 (dd, J=6.27, 220 Hz, 1 H) 7.82 - 7.95 (mm, 1 H) 7.56 {t, /=8.99 Hz, 1 H) 4.40 (s, 1 H).
Example 62C 5«(1-Benzyi-1H-1 »2,3-triazol-4-y1)-2-fluorobenzonitrile
Example 62B (1.68 g, 11.6 mmel} was dissolved in ferr-butano! {14 mL). Benzyl azide (2.14 g, 15.8 mmol) was added and the mixture was transferred to 14 microwave vialg (1.0 mL each). Water (0.5 mL), a small piece of copper wire, and a 1 M solution of copper
(II} sulfate (0.5 mL) were added to each microwave vial and the vials were heated in a CEM-
Discover microwave at 125 °C using 160 Watts for 10 minutes each. The vials Were recombined, diluted with ethyl acetate, and washed with water and brine. The organic material was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-30% ethyl acetate in hexanes to afford the title compound. 'H NMR (300
MHz, DMSO-d) 8 ppm 8.73 (5, 1 H)833-844(m, 1 H)8.19-832 (m, 1 H) 7.56 - 7.70 (m, 1 H)7.28-747 (m, 5 HY 5.68 (3, 2 H).
Example 62D 1G o-(1-benzyl-1H-1,2,3-riazol-4-y1)- 1 H-indazol-3-ami ne
Hydrazine hydrate (18 mL) was added to Example 62C (1.93 ¢, 6.94 mmokL} m ethanol (16 mL). The mixture was heated to 95 °C overnight. The mixture was diluted with ethyl acetate and washed with water. Some of the product precipitated in the separatory funnel and was filtered to afford the title compound. The cthy! acetate layer was concentrated under reduced pressure and the resulting solid was triturated with methanol to afford additional title compound. 'H NMR (300 MHz, DMSO-dg) 8 ppm 1143 (s, 1 H) 8.42 (s, 1H)Y821(s, 1 H) 7.67 (d, J=8.82, 1.70 Hz, 1 H) 7.38 (s, 5 H) 7.26 (d, I=8 48 Hz, 1 H) 2.64 (5, 2 H) 5.38 (5, 2 H). MS (ESIH) m/z 291.0 (M-+H)".
Example 63 5-(1-benzyl-1H-1 22. 3-triazol-4-y1)-1-[( ] -methylpiperidin-4-yl)carbonyl]- 1H-indazol-3-amine
Example 62D (44 mg, 0.152 mmol), b-methylpiperdine-4-carboxylic acid bydrochioride (27 mg, 0.150 mmol), and HATU (61 mg, 0.160 mmol) were combined in tetrahydrofuran (2 mL). Diisopropylethylamine {116 mL, 0.631 mmol) was added and the mixture was heated to 90 °C for 30 minutes. The mixture was diluted with methylene chloride and washed with | N sodium hydroxide. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-15% methanol in dichloromethane to afford the titie compound. 'H NMR. (300 MHz, DMSO-d) § ppm 8.58 (s, 1H) 8.47 (5,1 H) .26 (d, J=8 48 Hz, 1 H) 7.97 (d, J=8.48, 1.70 Hz. | H) 7.38 (s, 5 H) 658(s,2H)5.67 (5.2 H)3.35-347 (m, 1 H) 2.95 (d, J=11.19 Hz, 2 H) 2.28 (s,3H)2.03- 220m, 2H) 1.92(s, 2H) 1.77 (5. 2 H). MS (ESI) m/z 416.2 (M+H)".
Example 64
N-[5-(1-benzyl-1H-1,2,34ri azol-4-vi)-1H-indazol-3 -yi-2-methoxvacetamide
Example 64A teri-Buty] 3-amino-5-(1 -benzyl-1H-1.2 3-triazo! ~d-yh-1H-indazole-1 ~carboxylate
Example 62D (1.80 g. 6.20 mmol) was suspended in methylene chioride (100 ml.) with a catalytic amount of dimethylaminopyridine. A solution of di-ferr-butyl dicarbonate (1.36 g, 6.23 mmol) in methylene chloride {50 ml.) was added dropwise over | hour. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 6-5% methanol in dichloromethane to afford the title compound. MS (ESI+; m/z 391.1 (M+H)Y,
Example 64R
N-[5-(1-benzyl-1H-1,2,3-#ri azol-4-yi)-1 H-indazol-3-y1]-2-methoxyacetamide
Example 64A (45 mg, 0.115 mmol) was dissolved in methylene chloride (1.5 mL} and pyridine (0.5 mL). Methoxy acetyl chloride (18 ul, 0.197 mmol) was added and the mixture was stirred at ambient temperature for 2 hours. The solvents were removed using a warm stream of nitrogen, the mixture was injected on a silica gel cofumn, and the product was purified by silica gel chromatography eluting with a gradient of (-5% methanol in dichloromethane to afford tert-butyl 5-(1 -benzyl-1H-1,2,3-triazol-4-y1)-3-(2- methoxyacetamido)-1H-indazole-1 -carboxylate (58 mg). The intermediate was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (1 mL) and stirred at ambient temperature overnight. The solvents were removed under reduced pressure, and the mixture was purified by preparative HPLC on a C8 column using a gradient of 10% to 100% acetonitrife/water containing 0.1% trifluoroacetic acid io afford the title compound. "H NMR {300 MHz,
DMSO-ds) 6 ppm 12.79 (s, 1 H} 10.16 (s, 1 H) 8.59 (5, 1 H) 820s, 1 1) 7.83 (g, J=8.635, 1.53 Hz, 1 H) 7.51 (d, J=8.82 Hz, 1 H) 7.37 (s, 5 H) 5.64 (5,2 H)4.12 {s, 2 H) 3.42 (s, 3 Fi),
MS (EST+) m/z 363.0 (M-+H)",
Example 65
N [5-1 -benzyl-1 H-1,2 3-tri azol-4-v1}-1 H-indazol-3 yl -dimethylglycinamide
Example 644A (81 mg, 0.207 mmol} was dissolved in methylene chloride (2 mL) and pyridine (0.5 mL). Dimethylaminoacetylchloride hydrochloride, 80% (120 mg, 0.607 mmol)
was added in three portions over 2 hours and the mixture was stirred at ambient temperature overnight. Trifluoreacetic acid (2 mL) was added and the mixture was stirred for 3 hours.
The mixture was diluted with methylene chloride and washed with 1 N sodium hydroxide,
The organic layer was absorbed on silica gel and purified using silica gel chromatography eluting with a gradient of $-15% methanol in dichloromethane to afford the title compound. "H NMR (300 MHz, DMSO-d;) § ppm 12.77 (8, 1 H) 10.05 (s, | H) 8.58 (s, 1 H) 8.24 (¢. 1
H) 7.82(d, J=8.65, 1.53 Hz, | H) 7.50 (d, J=8.82 Hz, 1 14) 7.30 - 7.44 {m, 5H) 5.64 (s. 2 1D) 3.36 -3.20(m, 2H) 2.34 (5, 6 H). MS (ESI+) m/z 376.1 {M+HY".
Example 66
N-[5-(1-benzyl-1H-1.2.3 Ariazol-4-y])-1H-indazol-3 -yljbutanamide
Example 64A (76 mg, 0.195 mmol) was dissolved in methylene chloride (2 mL) and pyridine (0.2 mL). Butyry! chloride (26 ul, 8.250 mmol) was added and the mixture was stirred at ambient temperature for 2 hours, Trifluoroacctic acid (1 mL} was added and the mixture was stirred for 3 hours. The mixture was diluted with methylene chloride and washed with water, The organic layer was absorbed on silica gel and purified using silica gel chromatography eluting with a gradient of 1-8% methane] in dichloromethane to afford the title compound. '"H NMR. (300 MHz, DMSO-d) & ppm 12.76 (s, 1 H) 10.30 (8, 1 H) 8.37 (s,
FH) 8.23 (5,1 H) 7.81 (d, I=8.82 Hz, 1 H) 7.49 (d, ]=8.82 Hz, 1 H) 737 (s. 5H) 5.64 (s, 2
HY2.39(t, 1=7.29 Hyg 2 HY) 1.67 (5, 2 H) 0.97 (1, J=7 46 Hz, 3H). MS (ESI) m/z 361.1 (M+H)".
Example 67 5-[4-(4-fluorophenyl)-] -piperidin-4-yl-] H-imidazoi-5-yi]-1H-indazole
The title compound was prepared according to the procedure outlined in Example 39 substituting piperidin-4-amine for benzylamine. ‘H NMR (300 MHz, DMSO-d,) 8 ppm 13.28 (s, 1 H) 8.14 (5,1 H) 7.94 (s., TH) 7.78 (s, 1 HY 7.63 - 7.72 (m, 2H) 721-743 (m, 2
H) 6.90- 7.04 (m, 2 H) 4.14 (d,7=5.59, 1.86 Hz, 1 H) 3.53 -3.74 {(m, J=5.76 Hz, | H) 2.94 (d, J=12.21 Hz, 2H) 2.21 - 2.35 (m,2H)1.74- 1.88 (m, 3 H). MS (DCT) m/z 362 (MH),
Example 68 3-{4-(4-fluorophenyl)-1 -[2+(1 ~methylpyrrolidin-2-yljethyl]- 1H-tmidazol-5-y1} -1H-indazole
The title compound was prepared according to the procedure outlined in Example 39 substituting 2-( I-methylpyrrolidin-2-yl)ethanamine for benzylamine. "H NMR {300 MHz,
DMSO-dg) & ppm 13.30 (s, I HY 8.14 (s, 1 H) 7.86 (5, 1 H) 7.82 (s. 1 H) 7.68 {d, F=8 4% Hz, 1
H)7.24-7.47 (m, 3 H) 6.92 - 7.08 (m, 2 H) 3.83 (t, J=7.80 Hz, 2 HY2.71- 2.93 (m., 1 Hy 1.88 “2.61 (m, 3H) 1.74 - 1.88 (m, | £3) 1.00 - 1.83 (m, 7 HY. MS (DCT mdz 390 (MH)
Example 69 5-{4-(4-flucrophenyl)-1 ~[3-{4-methvipiperazin-1 -ylpropyll-1H-imidazol-5 -yl}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 39 substituting 3-{4d-methyipiperazin- -yljpropan-1-amine for benzylamine. 'H NMR (300
Ho MHz, DMSG-dg) 6 ppm 13.36 (s, 1 H) 8.13 (s, 1 H) 7.81 (5. 2H} 7.67 (d, }=8.48 Hz. 1 H)
TIL -TA5 (mm, 2 HY 7.027 (d, J=84%, 136 Hz, | H)6.87- 7.66 (m, 2H) 3.72 - 3.9] (m, 2 H) 192-221 (m, 10H) 1.91 -2.20 {s. 3H) 1.51 - 1.66 (m, 2 H}). MS (ESky m/z 419 (M+H)',
Example 70 ethyl 5-1 H-indazol-5-y1 Jisoxazole-3-carboxyiate
Example 3C (1.83 g, 12.9 mmol) was dissolved in toluene (60 mL) and triethylamine (2.2 mL) and warmed to 90°C. Ethyl 2-chloro-2-(hydroxyimino)acetate (1.89 g, 12.5 mmol) was dissolved in toluene (15 mL) and was added dropwise over 30 minutes. Following the addition, the mixture was diluted with ethy! acetate and washed with 1 N hydrochloric acid.
The organic layer was concentrated under reduced pressure and the resulting residue was friturated with methanol to afford the title compound. 'H NMR (300 MHz, DMSO-d) 8 ppm 13.38 (s, 1 H) 8.43 (s, 1 H) 8.23 (s, 1 H) 7.92 (d, }=8.82. 1.36 Hz, 1 H) 7.70 (d, J=8 82 Hz, 1
H) 7.44 (s, 1 Hy 4.41 (q, J=7.12 Hz, 2H) 1.35 (t, J=7.12 Hz. 3 H). MS (EST) m/z 257.9 (MAH
Exampie 71 5-{1 H-indazol-5-y1)-N-methylisoxazole-3-carboxamide
Example 71A 5-(1H-indazol-5 -ylyisoxazole-3-carboxylic acid
Example 70 (1.5G g, 5.83 mmol) was dissolved in tetrahydrofuran (100 mL), methano! (10 mL), and water (10 mL). Potassium hydroxide (680 mg, 12.1 mmol) was added, and the mixture was stirred at ambient temperature for 2 hours, The solvents were removed under reduced pressure, and the resulting residue wag triturated with a mixture of
N hydrochloric acid and methane! to provide a solid that was filtered to afford the title compound. 'H NMR (300 MHz, DMSO-d) & ppm 13.37 (5, 1 HY 8.3% (5, 1 H) 8.02 {s. 1 Hy 7.90 (dd, /=8.81, 1.36 Hz, | H)7.69(d, /=8.82 Hz. | HY 7.30 (s, 1 8H),
Example 71B 3-{1H-indazol-5-y1)-N-methylisoxazole-3-carboxami de
Example 714A (46 mg, 0.201 mmol), HAT (88 mg, 0.231 mmel), and diisopropylethylamine (133 ul, 0.764 mmol) were combined in tetrabydrofuran (2 mb}
Monomethylamine (40% solution in water (50 ul.) was added, and the reaction was stirred at 50°C for 2 hours. The mixture was diluted with methylene chloride and washed with | N sodium hydroxide, N hydrochloric acid, and brine. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 16-50% ethyl acetate in hexanes to afford the title compound. 'H NMR. (300 MHz, DMSO-ds) 8 ppm 1336(s, 1H)8T2 (q, 7=4.30 Hz, 1 H) 8.39 (s. 1 Hy 823 (5,1 H) 7.80 (d, J=8.65, 1.53 Hz, 1
H) 7.69 (d, 78.82 Hz, 1 H) 7.28 (s, 1 H) 2.80 (d, J=4.75 Hz, 3 H). MS (ESI+) m/z 243 0 (M+H)".
Example 72 3-(3-benzylisoxazol-5-yi)-1H-indazole
Phenytacetaldehyde (90+ %) (266 mg, 2.38 mmol) was dissolved in teri-butanol (1 mL) and water (1 mL). Hydroxylamine hydrochloride (79 mg. 1.14 mmol) was added followed by a 6N solution of sodium hydroxide (19 ul, 21.7 mmol). The mixture was stirred for 30 minutes. Chioramine-T trihydrate (308 mg, 1.09 mmol) was added slowly over 3 minutes followed by the addition of copper (II) sulfate and = small piece of copper wire,
Example 3C (154 mg, 1.08 mmol} was added and the mixture was stirred at 50 °C for 2 hours then ambient temperature overnight. The mixture was diluted with methylene chloride and washed with water, The organic layer was absorbed on silica gel and purified by silica gel chromatography cluting with a gradient of | 0-50% ethyl acetate in hexanes to afford the tie compound, 'H NMR {300 MHz, DMSG-ds) & ppm 13.31 {(s, 1 H) 8.28 (s, I HY 818 (s, 1H) 7.79 (dd, /=8.65, 1.53 Hz, 1 H) 7.64 (d, /=8 81 Hz, | H)7.13-7.46 (m, 5 H) 6.83 (s. 1 H) 4.04 (s, 2 H). MS (ESI+) m/z 275.7 (M+),
Example 73
N-[5-(1-benzyl-1H-1,2,3-tri azol-4-yl}-1H-~indazol-3-y1[benzamide
Example 64A (72 mg, 0.184 mmol) was dissolved in methylene chloride (2 mL) and pyridine (0.2 mL). Benzoyl chloride (36 ul, 6.310 mmol} was added, and the mixture was stirred at ambient temperature for 2 hours, Trifluoroacetic acid (1 mL) was added and the mixture was stirred for 3 hours. The mixture was difuted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified using silica gel chromatography eluting with a gradient of 1-8% methanol in dichloromethane to afford the title compound. 'H NMR (300 MHz, DMSO-dy) 8 ppm L288 {s, 1H) 10.81 (s, 1 HY 8.63 (, i PHE16(s, | H) 8.06 - 8.13 {m, 2H) 788 {d. J=8.42. 1.36 Hz, 1 Hy 7.59 - 7.64 {m, J=7.12
Hz, TH) 7.51 - 7.59 (m, 3 H) 7.31 - 7.42 (m. 5 FH) 5.63 (5, 2H). MS (ESI) m/z 395.1 (M+H)".
Example 74 5+(3-propylisoxazol-5-y1}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 72 substituting butyraldehyde for phenylacetaldehyde. 'H NMR (300 MHz, DMSO-ds) 6 ppm 13.31 (s, 1 H) 8.28 (s, 1 H) 8.20 (8, TH) 7.76 - 7.85 (m, 1 H) 7.63 - 7.70 (m, 1 H) 6.88 (s, 1
HY2.63(t, 3746 Hz, 2H) 1.61 - 1.79 (m. 2 HY 0.96 (t, J=7.20 Hz 3 H). MS (ESI+) m/z 228.0 (MH)
Example 75
N-benzyl-4-(1H-indazoi-5 ~vh-3-phenyl-1,3-thiazo]-2-amine
Exampic 75A 1H-indazole-5-carboxylic acid
The title compound was prepared according to the procedure outlined in Example 3A, substituting methyl 4-amine-3-methylbenzoate for 4-10do-2-methylaniline. During the final workup, addition of 6 N HCI until pH é resulted in the formation of a solid, which was filtered, washed twice with water and dried in vacuo to afford the title compound. 'H NMR. (3006 MHz, DMSO-ds) 8 ppm 13.32 (s, TH} 12.83 (5, 1 H) 8.46 (s. 1 H) 8.24 (s, 1H) 7.92 (dd, J=8.82, 1.70 Hz, 1 H) 7.60 (d../=8.82 Hz 1 H),
Example 75B
N-Methoxy-N-methyl-1H-indazole-3-carbox amide
To a suspension of Example 754 {1.6 g, 10 mmol) and N,O-dimethythydroxylamine (1.1 g, 1] mmol} in dichloromethane (40 mL) and dimethyiformamide (18 mL) was added triethylamine (1.67 mL, 12 mmol) and EDC (2.1 g. 11 mmol}, and the mixture was stirred at room temperature for 24 hours. The solvents were evaporated under reduced pressure, and the resulting residue was diluted with ethyl acetate and washed with water. The organic layer wus dried over sodium sulfate and purified by silica gel column chromatography in ethyl acetate to afford the ttle compound. MS (ESI) m/z 206.0 (M+)
Example 75C
I-{1H-indazol-5-y1)-2 -phenyiethanone
A solution of Example 75B (900 mg, 4.39 mmol) in tetrahydrofuran {10 mL) was cooled under argon with an ice bath and treated with a 2M solution of benzyl magnesium chloride in tetrahydrofuran (6.6 mL, 13.16 mmol). The reaction was stirred overnight at room temperature followed by the addition of one more equivalent of benzyl magnesium chloride. The mixture was heated at 70 °C for 9 hours. One more equivalent of benzylmagnesium chioride was added, and the reaction was heated at 70°C for another 90 minutes and was allowed to cool to room temperature. Aqueous saturated ammonium chloride was added, and the product was extracted with ethyl acetate and purified by silica gel column chromatography using 30% ethyl acetate in hexanes to afford the title compound.
MS (ESI+) m/z 237.1 (M+).
Example 75D terf-Butyl 5~(2-phenylacetyl)-1H-indazole-1 ~carboxviate
To a suspension of Example 75C (236 mg, | mmol} in dichloromethane (2 mL) was added di-tert-buty! dicarbonate (327 mg, 1.5 mmol) and a pinch of dimethylaminopyridine (~2 mg). The mixture was stirred for 15 minutes, and passed through a bed of silica gel and eluted with dichlormethane. The solvent was evaporated under reduced pressure to afford the title compound. MS (ESI+) m/z 337.0 (MH),
Example 73E : 2-Bromo-1-(1 H-indazol-5-y1}-2-phenvicthanone
To a solution of Example 75D (336 mg, I mmol) in tetrahydrofuran (20 mL) heated at
40°C with an oi! bath was added dropwise with an addition fimnel a solution of pyridinium tribromide (352 mg, 1.1 mmol) in tetrahydrofuran (20 mL) over 10 minutes. The reaction mixture was heated for an extra 2 hours, and was cooled, filtered, and the filtrate Was evaporated to afford the tle compound, MS (ESI-ym/z 212.9 (M-HY.
Example 75F
N-benzyl-4-(1H-indazol-3 -yi)}-5-phenvl-1 3-thiazol-2-amine
A vial containing Example 75E (50 mg, 0.16 mmol) and I-benzylthiourea (26 me, 0.16 mmol) in ethane! (1 mL} was capped and heated in » heater shaker at 80 °C for 2 hours, 16 The solution of the crude product was purified by reverse-phase HPLC usIng an acctonitrile/water 0.1% TFA gradient elution method to afford the title compound as a TFA salt. "HNMR (400 MHz, DMSO-dg) 8 ppm 12.99 (8, 1H) 833 - 8.37 (m, 1 H) 8.01 (s, | H) 7.92-7.99(m, 1 H) 7.82 (s, 1 H} 7.60 - 7.67 (tm, J=7.83, 7.83 Hz, 1H) 731-745 (m, 5H) 707 -7.30 (om, 5 HY 4.53 (d, J=4.60 Hz, 2 H). MS (ESI+)Y m/z 383.0 (M-+H)".
Example 76 4-(1H -indazol-5-yl}-N,5-diphenyl- 1,3-thiazol-2-amine
The title compound was prepared as a TRA salt according to the procedure outlined in
Example 75F substituting i-phenyithioures for I-benzylthiourea. 'H NMR (400 MHz,
DMSO-d) 6 ppm 13.09 (5. 1 H) 10.29 (s, I H) 8.05 (d, }=0.92 Hz, 1 H) 7.89 (d, }=1.53, 0.92
Hz, 1 H) 7.69 (d, J=8.59, 1.23 Hz, 2 H) 7.47 (dt, }=8.59, 0.92 Hz, 1 H) 740-744 (m, 1 H) 7.26737 (m, TH) 6.94 - 702 (m. J=7.36, 7.36 Hz, 1 H). MS (ESI+) m/z 369.0 (M+H)",
Example 77 5-(1-benzyl-5-cyclopropyl-1H-1 .2,3-triazo)-4-y1)-1H-indazole
Example 77A tert-butyl 5-( cyclopropylethynyl)-1H-indazole-1 -carboxyiate
Example 44A (2.31 g, 7.77 mmol), cyclopropyl acetylene (620 mg, 9.37 mmol), dichiorobis(triphenyiphosphine palladium) (170 mg, 0.242 amo), and copper (I) iodide (92 mg, 0.483 mmol) were combined in triethylamine (16 mL) under an inert atmosphere of nitrogen. The mixture was heated to 100 °C in a sealed tube for 4 hours, The mixture was diluted with methylene chloride and washed with 1 N hydrochleric acid, The organic layer was absorbed onto silica gel and purified by silica gel chromatography cluting with a gradient of 5-50% ethyl acetate in hexanes to afford the title compound. MS (ESI) m/z 283.0 (M+HY".
Example 77B 5-(1-benzyl-5-cyclopropyl-1B-] 2,3-triazol-4-y1}-1H-indazole
Example 774A (145 mg, 0.51 mmol) and benzyl azide (82 mg, 0.62 mmol} were heated neat in a CEM-Discover microwave at 150°C and 15¢ Watts, for 10 minutes. The crude mixture was dissolved in dichloromethane and purified by silica pel column chromatography using 50% cthy! acetate in hexanes as the eluent. 'H NMR (400 MHz, DMSC-dg) 8 pom
P302(s, THY 8.11 (d. J=5.52 He, 2H) 7.7% (d, 3=8.59. 1.53 Hz, 1 H) 7.60 (d, J=8.59 Hz, 1
H) 7.26 - 7.45 (m. 5 H) 5.60 (5,2 H) 1.78 - 1.92 (m, 1 H) 0.98 - 1.09 (m, 2H) 0.31 - 0.45 (m, 2H). MS (EST) m/z 316.0 (M+HY",
Example 78 5-(1-benzyl-4-cyclopropyl-11-1 22, 3-tr1azol-5-y1)-1H-indazole
The title compound was isolated as a by-product according to the procedure outlined in Example 77B. 'H NMR (500 MHz, DMSO-d,) 8 ppm 13.29 (s, 1 H) 8.14 (s, 1 H) 7.80 (s,
LH) 7.65 (d, 3=8.85 Hz, 1 H) 7.29 (d, J=8.54, 1.53 Hz, 1 H) 7.21 - 7.27 {m, 3 H) 6.93 (d.
J=7.48,1.98 Hz, 2 H) 5.49 (8, 2H) 1.70 - 1.80 (m, 1 H} 0.81 -0.92 (m, 4 H). MS (EST+) m/z 316.0 (M+H)".
Example 79 2-(1H-indazol-5-y1)-3 -phenylimidazol 1 2-a]pyrimidine
A vial containing Example 75E (80 mg, 0.25 mmol) and pyrimidin-2-amine {23 mg, 0.25 mmol) in ethanol {1 mL) was capped and heated in a heater shaker at 86 °C for 21 hours,
The solution of the crude product was purified by reverse-phase HPLC using an acetomtrile/water 0.1% TFA gradient elution method to afford the title compound. 'H NMR (400 MHz, DMSO-d) 8 ppm 8.69 (dd, /=4.30. 1.84 Hz, 1 H) §.59 (dd, J=6.75, 1.84 Hz, 1 H) 8.07 (s,1 HY8.02¢(s, 1 H) 746 - 7.65 (m, 7H) 7.16 {dd, /=6.75, 3.99 Hz, 1 H). MS (ESi+) m/z 312.0 (M+H)".
Example 80
S-f1-{tetrahydro-2H pyran-d-ylmethy}-1H-1,2 3-tri azoi-4-yl}-1H-indazole
Example BOA 4-{azidomethyljtetrahydro- 21 -pyTan 4-(lodomethyljtetrahydro-2H-pyran (4.76 ¢, 21.1 mmol) was dissolved in dimethyl sulfoxide (25 mL). Sodium azide (2.70 g, 41.5 mmol) was added and the mixture was stirred at ambient temperature overnight. The resultin g slurry was diluted with diethyl ether and washed with water. The organic layer was concentrated under reduced pressure to afford the 1&0 itle compound. The product was used directly in subsequent reactions without characterization,
Example 80B 5-17 -{tetrahydro-2H-pyran-4-ylmethyl)- 1H-1.2 3-triazol-4-y1}-1 H-indazole
Example 80A (122 mg, 0.864 mmol) and Example 3C (150 mg, 4.619 mmol} were combined in a microwave vial with teri-butanol (1 mL) and water (I mL). A small piece of copper wire followed by copper(ll) sulfate (5 mg, 0.02 mmol) was added, and the vial wag stirred in a microwave (CEM-Discover) at 125°C at 100 W for 10 minutes. The mixture was diluted with methylene chloride and washed with | N hydrochloric acid. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 0-3% methanol in dichloromethane to afford the fitle compound. 'H NMR (300 MHz,
DMSO-ds) 8 ppm 13.11 (s. 1 H) 8.53 (s, 1 H)§.22 (s, TH) 8.12 (s, 1 H) 7.85 fd, J=8.48, 1.36
Hz, 1 H) 7.60 (d, }=8 82 Hz, 1 H)4.32(d, }=7.12 Hz. 2 H) 3.85(d, 1=11.70, 2.54 Hz. 2 Eh 321-336(m, 2H) 2.14 {8, 1H) 1.47 (5, 2H) 1.30 (5. 2 H). MS (ESI+) m/z 284.0 (M+H)".
Example 81 3-[3-(piperidin-1 -ylearbonyl)isoxazol-3-v1]-1H -indazole
Example 81A 5 ~(1H-indazol-5-yl)isoxazole-3-carboxylic acid
Example 70 (1.50 g, 5.83 mmol) was dissolved in tetrahydrofuran (100 mL), methano! (10 mL), and water (10 mL). Potassium hydroxide (680 mg, 12.1 mmol) was added and the mixture was stirred af ambient temperature for 2 hours. The solvents were ge removed under reduced pressure. and the resulting residue was triturated with a mixture of i
N hydrochloric acid and methanol] to provide a solid that was filtered to afford the title compound. 'H NMR (300 MHz, DMSO-d & ppm 13.36 (s, 1 HY 8.41 (5, 1 Hy 8.23 (s. 7H) 7.91 (dd, J=8.82, 1.70 Hz, 1 H) 7.70 (d,./=8.82 Hz, } Hy 7.36 (5, | iH).
Example 81B 5-[3-(piperidin-1 -yicarbonyl Yisoxazo! ~5-yil-1H-indazole
Example §1A (110 mg, 0.480 mmol), piperidine (55 ul, 0.556 mmol), and HATD (101 mg, 0.266 mmol) were combined in dimethylformamide ml)
Diisopropylethylamine (133 ui, 0.764 mmol) was added and the reaction was stirred af 45 °C for 2 hours. The mixture was diluted with ethyl acetate and washed with | N sodium hydroxide, | N hydrochloric acid, water (3 times), and brine. The organic layer was absorbed on silica gel and purified by silica pel chromatography eluting with a gradient of 0-59 methanol in dichloromethane to afford the title compound. 'H NMR {300 MHz, DMSO- do) 8 ppm 13.37 (5, 1 H) 8.34 - £40 (m, 1 Hj} 8.21 - 8.25 (m, | H)7.84-791 (m, 1 H) 7.66 - 7.72 (m, 1 Hy 7.20 (s, 1 FI) 3.59 - 3.69 (m, 2H) 3.48 - 3.58 (m, 2 H) 1.47 - 1.72 (m, 6 H).
MS (ESI+) m/z 297.0 (M+H)".
Example 82 5-(1H-indarol-5 ~yl)-N-phenylisoxazole-3-carbox amide
The title compound was prepared according to the procedure outlined in Example 81R
Substituting aniline for piperidine. 'H NMR (500 MHz, DMSO-ds) & ppm 13.40 {s, 1TH) 10.74 (s, 1 H) 8.44 (5, 1 H) 8.25 {s, 1 H) 7.93 (d, }=8.85, 1.52 Hz, 1 H) 7.82 (d, }=7.63 Hz, 2
H) 7.72(d, }=8.85 Hz, 1 H) 7.44 (8, LH} 735-742 (m, 2 H) 7.16 (t, J=732 Hz, | H). MS (BSI) m/z 304.9 (M+H)".
Example 83
N-cyclohexyl-5-(1 H-mdazol-5-yl}isoxazole-3-carboxarmi de
Example 81A (53 mg, 0.231 mmol), cyclohexyiamine (29 ul, 0.253 mmol), and
HATU (101 mg, 0.266 mmol) were combined in dimethyl formamide {2 mL).
Diisopropylethylamine (133 ul, 0.764 mmol) was added, and the reaction was stirred at 435 °C for 2 hours. The mixture was diluted with ethyl acetate and washed with 1 N sodium hydroxide, 1 N hydrochioric acid, water (3 times), and brine. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0-5%, methanol in dichloromethane to afford the title compound, 'H NMR (300 Milz, DMSO- de) © ppen 13.36 (5, 1 H) 8.58 {(d, J=8.14 Hz, THYE38 (5, | HH} 8.22 (5. 1 Hy 7.88 (d. J=8.81,
L70 He, TH} 7.69 (d, 1=8.81 Hz, 1 H} 7.08 (8, 1H) 3.69 - 3.86 (m, 1 H} 1.77 {s, 4 Hy 1.60 (d, J=1221 Hz 1H) 1.20 - 1.46 (m, 4 H) 1.06 - 1.26 (m, 1 Hy. MS(ESI®) m/z 311.0 (M+H)".
Example 84
S-[3-(piperidin-] -vimethyhisoxazoh-5-y1]-1H-indazole
Example 818 (22 mg, 0.0742 mmol} was dissolved 1n tetrahydrofuran (2.5 mL) under an inert atmosphere of nitrogen. Lithium aluminum hydride (1.0 M solution in tetrahydrofuran) (250 ul) was added and the mixture was heated to 70 °C for 20 minutes.
Methanol was added, and the mixture was absorbed an silica gel and purified by silica gel chromatography eluting with a gradient of methanol in dichloromethane {0-7%) to afford the title compound. 'H NMR (400 MHz, DMSO-ds) 8 ppm 13.30 (5, 1 H) 8.31 {5,1 H) 8.20 (5. 1
H) 7.84 (d, J=8.59, 1.53 Hz, I H) 7.66 (d. J=8.59 Hz, 1 H) 6.92 (s, 1 H) 3.54 (s,2 Hy 2.32 - 2.46 (on, 2H) 1.47 - 1.59 (m, 4 H) 1.33 - 1 46 (m, 2 H). MS (ESI+) m/z 283 0 (M-+H)".
Example 85 [5-(1H-indazol-5-yl)isoxazol-3-y jmethanol
Example 70 (84 mg, 0.366 mmol) was dissolved in tetrahydrofuran (8 mL). Lithium aluminum hydride (1.0 M solution in tetrahydrofuran) (3.0 mL) was added in 1.0 mL porticns over 2 hours. After the final addition, the mixture was stirred for an additional 30 minutes.
The mixture was diluted with methylene chloride and washed with water and the organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0-20% methanol in dichloromethane to afford the title compound. "H NMR (400
MHz, DMSO-ds) 8 ppm 13.31 (s, 1 H) 8.31 (s, 1H) 8.21 (s, 1 H) 7.83 (4, J=8.59, 1.53 Hz, 1
H)7.67(d, I=8.90 Hz, 1 H) 6.93 (s, | HY 5.51 (s, 1 H) 4.36 (d, }=2.45 Hz, 1 Hj. MS (ESI) m/z 215.9 (M+H)"
Example 86 5-(1H-indazol-5-y1)-N-(2-m ethoxyethyl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 81RB substituting 2-methoxyethy! amine for piperidine. 'H NMR (300 MHz, DMSO-ds) 8 ppm 13.36 (s, 1 Hy 8.74 (+. }=4.92 Hz, 1 H) 8.39 (s. 1H) 8.25 (5,1 H) 7.80 (d, J=R8.65, 1.53 fz, 1
BH} 7.69 (d, I=882 Hz, 1 H) 7.30 (gs, 1 FI} 3.38 - 3.53 (mi, 4 H) 3.28 (s, 2 FH). MS (ESI+) m/z 287.0 (M+HY
Example 87 5-(1-benzyl-5-phenyl-1B-1 vey 3-triazof-4-y1}-1H-indazole
Example 874A
I-{5-iodo- 1 H-indazol-| ~yhethanone 4-lodo-2-methylaniline (30.2 2. 130 mmol) was dissolved in chioroform (300 mL) and cooled to 5°C. Acetic anbtydride (35 mL, 343 mmol} was added dropwise, and the mixture was allowed to warm to ambient temperature. Potassium acetate (4.21 £, 42.9 mmol) and isoamylnitrite (37 mL, 277 mmol} were added, and the mixture was heated to 70°C overnight. The mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The solvents were removed under reduced pressure and the resulting residue was triturated with methanol 10 afford the title compound. 'H NMR (300 MHz, DMSO-ds) 8 ppm 8.41 (s, 1 H) 8.33 (s, 1 H) 8.05 - 8.21 (m, 1 H} 7.90 (dd,
J=8.48, 170 Hz, 1 H) 2.71 {s, 3 HD),
Example 87B 1-Benzyl-5 -phenyl-4-{tributylstannyl)-1H-1.2, 3-iriazole
Phenylethynyitri-n-butyltin (8.25 g. 21.1 mmol) and benzyl azide (2.3 ml, 18.4 mmol} were combined and heated to 150°C overnight. The mixture was purified by silica gel chromatography chuting with a gradient of 5-40% ethy! acetate in hexancs to afford the ttle compound. MS (ESI+) m/z 526.3 (M~H)".
Example 87C 1-(5-(1-Benzyl-5-phenyl-1H-1,2 3-triazol ~4-yl}j~1H-indazol-1-yl)ethanone
Example 87A (139 mg, 0.486 mmol), Example 878 (284 mg. 0.342 mmel), dichlorobis(triphenylphosphine)palladium(I1) {40 mg, 0.057 mmol} and copper thiophene-2- carboxylate (167 mg, 0.876 mmol) were combined in toluene {1.5 mL) m a microwave vial under an inert atmosphere of nitrogen. The vial was heated in a microwave (CEM-Discover)
to 150 °C at 125 Watts for 20 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. MS (ES) m/z 394.1 (M+),
Example 87D 5-(1-benzyl-5-phenyl-1H-1 2, 3-triazol-4-y1)-1 H-indazole
Example 87C (95 mg, 6.242 mmol) wag dissolved in tetrahydrofuran (2.0 mL), methanol (1.0 mL) and water (1.8 mL), and potassium hydroxide (64 mg, 1.14 mmol) was added. The mixture was stirred for 2 hours, and diluted with cthy! acetate and washed with 160 water, The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0-59, methanol in dichloromethane fo afford the title compound. 'H NMR (306 MHz, DMSO-d) Gppm 13.08 (5, 1 H) 8.00 (s, 1H) 7.79 (5, 1
H) 744-7356 (m, 5H) 724-736 {m, 5 H)6.95-7.03 (m, 2 H) 5.49 (5, 2H). MS (ESI+) m/z 252.1 (M+H)".
Example 88 5-{4-benzyl-1H-1,2,3-triazol- -yh-1H-indazole
Example 7A (969 mg, 3.39 mmol), 3-phenyl-1 -propyne (392 mg, 3.37 mmol), sodium azide (278 mg, 4.28 mmol), sodium ascorbate (68 mg, 3.43 mmol), sodium carbonate (75 mg, 4.708 mmol), and L-proline (78 mg, 8.98 mmol) were combmed in a 1:1 mixture of . dimethyl sulfoxide and water (1G mL). Copper(IT) sulfate pentahydrate (46 mg, 0.184 mmol} was added and the mixture was stirred at 65°C for 3 hours. 6N Sodium hydroxide (1 mL) was added, and the mixture was stirred for 30 minutes to deprotect the indazole. The mixture was diluted with ethyl acetate and washed with 1 N hydrochloric acid. The organic ayer wag concentrated under reduced pressure, and the resulting residue wag triturated with methanol
The remaining solids were absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0-59 methanol in dichloromethane to afford the title compound. '"H NMR (300 MHz, DMSO-d4) & ppm 13.35 (s, 1 H) 8.58 (5, 1 H) 8.17 - 8.27 (m, 1 H) 7.86 (d, 3=8.82,2.03 Hz, 1 H) 7.67 - 7.77 (m, 1 1) 7.27 - 7.36 (m, 2 H) 718-727 (m, 1 Hy 4.10 (s, 1 H). MS (ESI) m/z 276.0 (M+H)*,
Example 89 5-1 -benzyl-5-cyclopropyi- 1H-1.2 3-triazol-4-y]). IH~indazol-3-amine
Example 89A 5-(Cyclopropylethynyl}-2-flusrobenzoni trile 5-Bromo-2-fluorobenzonitrile (3.06 g, 15.3 nmol), dichiorobis(triphenyipbosphine)palladinm() (478 mg, 0.681 mmol), and copper(l) iodide (165mg 0.866 mmol} were combined in triethylamine (15 ml} under an inert atmosphere of nitrogen. Cyclopropylacetylene (1.8 mL) was added, and the mixture was heated to 60°C until it turned to a black solid. The mixture was diluted with methvlene chloride and washed with 1 N hydrochloric acid. The organic laver was absorbed on silica gel and purified by silica gel chromatography eluting with 4 gradient of 5-40% ethyl acetate in hexanes to afford the title compound, MS (ESI) m/z 319.0 ¢ MAH)
Example 89R 5-(1-benzyl-S-cyclopropyl-1H-1 2, 3-triazol-4-y1)-1H-indazol-3-amine
Example 89A (211 mg, 1.14 mmol) and benzyl azide (143 ul, 1.14 mmol} were combined in 2 microwave (CEM-Discover) vial and heated to 160°C using 100 Watts for 26 minutes. The mixture was absorbed on silica gel and purified by silica get chromatography eluting with a gradient of 20-60% ethyl acetate in hexanes to afford a mixture of inseparable triazole regiomers. The mixture of regiomers were treated with hydrazine hydrate {3.0 mL) and ethanol (3.0 mL) and heated to 96 °C for 1 hour, The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica get chromatography cluting with a gradient of 1-6% methanol in dichloromethane to afford the title compound. 'H NMR. (300 MHz, DMSO-d) 8 ppm 11.43 {s, 1H) 8.07 ¢s, 111) 7.63 (d, J=8.65. 1.53 Hz, 1 H) 7.32 - 7.45 (m, 3H) 7.24 - 7.32 (m, 3 H)
S.68(s, 2H) 5.40 (s, 2 H) 1.60- 1.83 {m, 1H} 0.98 - 1.08 (m, 2 H)G32-06.42 (m, 2 11). MS (ESTH)ym/z 331.0 (M+H)",
Example 00 -(I-benzyl-4-cyclopropyi-1H-1,2,3 ~triazol-5-y1)-1H-indazol-3-amine
The title compound was isolated as a by-product accordmg to the procedure outfined in Exampie 89B. 'H NMR {300 MHz, DMSO-d) § ppm 11.62 {(s, 1 H) 7.79 (s, 1 H) 7.32 (d.
J=8.48 Hz, 1 H) 7.20 - 7.27 (m, 3 H) 7.15 (d, J=8.65, 1.53 Hz, | Hj 6.93 (d. 1=7.12, 2.37 Hz, 2H) 549 (s, 2H) 5.45 (5,2 HY 1.71 - 1.82 (m, 1 H) 0.80 - 0.89 (m. 4 H}. MS (ESI) m/z 3301 (MH
Example 91
S~(3-tsobutylisoxazol-5-yI)- 1 H-indazel? ~ANine
Example 914 2-fluore-5-(3-isobutylisoxazol-5-yl benzonitrile
The title compound wag prepared according to the procedure outlined in Example 72 substituting 1sovaleraldehyde for phenylacetaldehyde and Example 628 for Example 3C. 'H
NMR (360 MHz, DMSO-d) 8 ppm 8.47 (dd, .J=6.10, 2.03 Hz, | Hy819-829(m, 1 HY 7.71 (4, 7=8.99 Hz. i H)7.08 (s, 1 F) 2.56 (d, =7.12 Hz, 2H) 186 - 2.10 (m, | Hy 0.94 (d, J=6.7%
Hz, ¢ H).
Example 91IB 5~(3-isobutylisoxazol-5-y1}-1H-indazal-3 -amine 13 To Example 91A (75 mg, 0.307 mmol} was added hydrazine hydrate (1.5 mL) in cthanel (1.6 mL). The mixture was heated to 70°C overnight in a sealed vial The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0-5% methanol in dichloromethane to afford the title compound. 'H NMR (300 MHz, DMSC-dg) § ppm 11.67 (s, 1 HY 8.26 (s. | H} 7.66 (dd, /=8.82, 1.70 Hz, | H) 7.32 (d /=8.48 Hz. I H) 6.67 (s, 1 H) 5.56 (5, 2 H) 2.51 - 2.58 (m, 2H} 1.89 -2.11 (m, 1 H) 0.95 (d,.J=6.44 Hz, 6 H).
MS (ESI+) m/z 257.0 (M+H)".
Example 92 3-(3-benzylisoxaral-S -y1)-1H-indazol-3-aminc
Example 92A 5-(3-benzylisoxazol-3-yl I-2-fluorobenzonitrile
The title compound was prepared according to the procedure outlined in Example 72 substituting Example 62B for Example 3C. The crude product was used in the next step without further purification ar characterization,
Example 92R
3-(3-benzylisoxazol-5-yi)- 1H-indazol-3-amine
To Example 924 (65 mg, 0.234 mmol) was added hydrazine hydrate (1.5 mL) in ethanol (1.0 mL). The mixture was heated fo 70 °C overnight in a scaled vial. The mixture was dituted with methylene chiovide and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of (-20%, methanol in dichloromethane to afford the i ¢ compound. 'H NMR (300 MHz, DMSO- ds} 6 ppm 11.67 (s, 1 H) 8.26 (5.1 H) 7.66 (d, I=8.82. 1.70 Hz, 1 H) 7.32 (d, }=8.4% Hz, 1 H) 6.67 (s, 1 H) 5.56 (s. 2 H) 245 - 2.57 (on 2 HY 1.97 - 2.08 tm. 110) 0.95 (d, J=6.44 Hz, 6 H),
MS (EST) m/z 291.0 (MH) 1G
Example 63
N- {2-[4-(4-fluorophenyl)-5-( [H-indazo!-5-y1}- 1 H-imidazol-1 ~yllethyl L-N,N -dimethylamine
The title compound was prepared according to the procedure outlined in Example 39 substituting 2-dimethylaminoethylamine for benzylamine. 'H NMR (500 MHz, ¢) 8 ppm
I3.28(s, 1 HY 8.14 (s, 1 HY 7.78 - 7.87 (m, 2 H) 7.68 (d, J=8.54 Hz, 1 H) 7.33 - 7.41 (m, 2 H) 7.28 (d, J=8.54, 1.53 Hz. 1 HY 6.95 -7.05 (m, 2 H) 3.86 (t, J=6.56 Hz, 2 H) 2.31 (1, J=6.71
Hz, 2 H) 2.00 (s, 6 H).
Example 94 3-{4-(4-fluorophenyl)-1-(3 -morpholin-4-ylpropyl)-1 H-imidazo I-5-y1}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 39 substituting 3-morpholinopropylamine for benzylamine. 'H NMR (500 MHz, DMSO-d, /
D0) 8 ppm 13.28 (5, 1 H) 8.14 (s, TH}7.79- 7.87 (m, 2 H) 7.68 (d, J=8.24 Hz, 1 H) 7.34 . 742 (m, 2H) 7.28 (d, J=8.54, 1.53 Hz, 1H) 6.92 - 7.03 (mm, 2 H) 3.77 - 3.89 (m, 2H) 3.24 - 330(m 4 H)Y2.10 (4, 16.56 He, 2H) 1.960-2.05(m. 4H) 1.54 - 1.66 (m. 2 H). MS (ESH+) m/z 406.1 (M+H)".
Example 95 3-[4-(4-fluorophenyl)-1-(3-pyrrolidin-1 -vlpropyl}-1H -imidazol-5-y1]-1H-indazole
The title compound was prepared according 10 the procedure outlined jn Example 39 substituting 3-pyrrolidinopropylamine for benzylamine. '"H NMR (500 MHz, DMSO-d; / 0,0) 6 ppm 8.13 (d, 1=0.92 Hz, 1 H) 7.79 - 7.85 (m, 2 H) 7.68 (d, J=8.534 Hz, 1 H) 7.38 (4,
J=8.85, 5.49 Hz, 2 H) 7.27 (4, J=8.54, 1.53 Hz, 1 H) 6.99 {t, J=9.00 Hz, 2 H) 3.82 - 3.90 (m,
2H)2.21 (1, J=6.7] Hz, 2 H) 2.08 - 2.18 (m, 4 H) 1.56 - 1.65 (m, 2 H) 1.44 - 1.53 (m, 4 H).
ME (ESI+) m/z 390.2 (M+H)".
Example 96 3 5-1 4-{4-fluorophenyl)-1 ~{2-(4-methylpiperidin. | -yhiethyl]-] H-imidazol-5-vii-1 Heindazole
The title compound was prepared according to the procedure outlined in Example 39 substituting 2-(4-methylpiperidin-1-yI)ethanamine for benzylamine, 'H NMR. (500 MHz,
DMSO-ds / 20} 8 ppm 13.29 (s, TH) 8.14 (s, 1 H) 7.83 (s, | HY 7.81 (s, TH) 7.67 (d,
JS=8.54 Bz, 1H) 7.32 - 7.40 (m, 2 H} 7.28 (dd, J=8.54, 1.53 Hz. 1 H}Y6.93 - 7.04 (m, 2 1 0 3.85 (i.J=6.56 Hz, 2 HY 2.60 (d, /=11.60 Hz. 2 H} 2.37 {t./=6.56 Hz, 2H) 1.71 - 1.85 {m, 2
Hy 1.45(d, /~1129 Hz, 2H) 1.15 - 1.30 {m, 1 H) 0.95 - 1.07 (m, 2 FH) 0.83 (d, v=6.71 Hz, 3
H) MS (ESH) m/z 404.1 (M~H)",
Example 97 5-111 -benzylpiperidin-d-yly-4-( 4~Tluorophenyl}-1H-imidazol -3-yl]-1H-indazole
The title compound was prepared according to the procedure outiined in Example 39 substituting 4-amino-N-benzylpiperidine for benzylamine. "H NMR (500 MHz, DMSO-d, /
D0) 6 ppm 13.32 (s, 1 H) 8.14 (5, 1H) 8.02 (5, 1 H) 7.78 (s, 1H) 7.69 (d, 5=8.54 Hz, | H) 707-740 (m. 8 1) 6.97 (1, J=R.85 Hz, 2H} 3.50 - 3.63 (m, 1 H) 3.40 (5, 2 H) 2.82 (d,
I=11 90 Hz, 2H) 1.90 - 2.05 (m, 2 H) 1.72 - 1.89 (m, 4 Hy. MS (ESI+) m/z 452.2 (M+H)™.
Example 98 5+[4-(4-fluoropheny!)-1 ~(Z-morphotin-4-ylethyl}- 1H -imidazol-5-yl]-1H-indazole
The title compound was prepared according to the procedure outlined in Example 39 substituting 2-morpholinoethylamine for benzylamine, 'H NMR (5300 Mtlz, DMSO-d, /
D200) 8 ppm 13.27 (5,1 HY 8.14 (s, 1 H) 7.86 (s, 1 H) 7.81 (s, 1 H) 7.67 (d, }=8.54 Hz, 1 Hj 7.33-7.42(m, 2H) 7.29 (d, J=8.54 Hz, 1 H) 6.95 - 7.06 (m, 2 4) 3.87 {t, J=6.41 Hz, 2 H) 3.42 - 3.51 (m, 4 H) 2.40 (1, J=6.56 Hz, 2H} 2.21 (d. 1=3.97 Hz, 4 H). MS (ESI) m/z 392] (M+)",
Example 99 5-[1-(1-benzyipyrroli din-3-yl J-4-(4-fluorophenyi}-1H-imidazol-% -yl}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 39 substituting 3-pyrrlidinobenzyiamine for benzylamine. 'H NMR (500 MHz, DMSO-d; /
D0) 8 ppm 13.29 (5, 1 HY 8.13 (5, 1 FY 8.03 (s., 1H} 7.76 (s, 1 H) 7.67 (d, 3=8.54 Hz, 1 H) 7.29 7.38 (m, 6 H) 7.20 - 7.28 (m, 2 2) 6.98 {(t. 79.00 Hz, 2H) 4.25 - 4.34 (m, 1 BH) 2.53 . 3.69 (m, 2H} 2.89 - 2.97 (m, 1 H) 2.824 (4, J=0.76,3.05 He, 1 H) 2.53 (d. }=10.07, 6.7] Hz, |!
HYZUA7-234(m 2H) 1.92 - 2.03 (m, | Hy MS (ESF) m/z 438.7 (MH),
Example 100
Exampic 100 has been removed and is not part of this document, . :
Example 107 2-{4-14-(4-fluorophenyl)}-3-( 1 H-ind azol-5-yl}-1 H-imidazol-1 -yi]pipenidin-1-yi}-2-oxoethanol
The title compound was prepared according to the procedure outlined in Example 30 substituting 1-(4-aminopiperidin-1 -y1}-2-hydroxyethanone for benzylamine. 'H NMR (300
MHz, DMSO-d; / D»0) 8 ppm 13.27 (5, 1TH)B.14 (5, 1 F1) 7.99 (5, 1 H) 7.87 (s, 1 H} 7.69 (d,
J=848 Hz, 1 H)7.25-7.39 (m, 4 Hj 6.91 - 7.03 (m, 2 H) 4.48 (1, J=5.43 Hz, 1 H)Y4.34-4.44 (m. 1 H) 4.07 (t, }=5.59 Hz, 1 H) 3.79 - 3.9] (m, 1 H)3.64 - 3.77 (m, 1 H) 2.85 (m, 1H) 2.77 - 2.90 (m, 5 H). MS (DCI) m/z 420 (M+H)"
Example 102 3-(1-benzy}-S-phenyl-1H-1,2 3-triazol -4-yl}-1H-indazol-3-amine
Example 102A
S-(1-Benzyl-5-phenyl-1H-1 2. 3-triazol-4-y1)-2-fluorobenzonitrile
Example 878 (415 mg, 0.792 mmol), S-bromo-2-flucrobenzonitrile (158 mg, 0.790 mmol), dichiorobis(triphenylphosphinepalladium(Ir) (52 mg. 0.074 mmol}, and copper thiophene-2-carboxylate (226 mg, 1.19 mmol) were combined in toluene (ZmLyina microwave vial under an inert atmosphere of nitrogen. The vial was heated in a microwave (CEM-Discover} to 150°C at 125 Watts for 20 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexanes (5-40%) to afford the title compound. MS (ESI+) m/z 355.1 (M-+HY.
Example 102B 5-(1-benzyi-5-phenyl-1H.1 2,3-tazol-4-y1-1Heindazol-3-amine
Example 102A (120 mg. 0.339 mmol) was treated with hydrazine hydrate (1.0 mL} in ethanol (1.0 mL) and heated fo 60°C overnight, The mixture was diluted with methviene chioride and washed with water. The organic layer was absorbed on silica gel und purified by silica gel chromatography eluting with a gradient of 0-5%, methanol in dichloromethane to afford the title compound. 'H NMR (300 MHz, DMSO-d) § ppm 11.40 (s, 1 H) 8.06 {s, I
BH) 742-755 (m, 3H) 7.23 - 733 (m, 5 H) 7.02 - 7.10 (m, 2 H) 6.94-7.02 (m, 2 H) 5.49 (s, 2H} 5.34 (, 2H), MS (BST+) m/z 367 1 (MAE
Example 103
Io 2-1-0 H-indazol-5-yl)-]1 H-] 2. 3-triazol-4-ylipropan-2-o]
The title compound wag prepared according to the procedure outlined in Example 88 substituting Z-methyl-3-butyn-2-ol for 3-phenyl-1-propyne except that the crude reaction mixture was quenched with 2 mL of 1 N aqueous NaOH; and stirred for 1.5 hours at ambient temperature. The suspension was then dried by heated forced nitrogen gas evaporation prior fo extraction. 'H NMR {500 MHz, DMSO-d, / D0) 6 ppm 8.51 (s, 1 H)8.22-820 (m, 2 H) 7.88 (d, J=9.00, 1.9% Hz, 1 H) 7.77 {d, }=8.85 Hz, | 0) 1.57 (5,6 H). MS (ESI) m/z 244.0 (MH),
Example 104
S-{4-(methoxymethyl)-1H-1 22,3-tr1azol-1-y1]- 1 H-indazole
The title compound wag prepared according to the procedure outlined in Example 8% substituting methyl propargyl ether for 3-phenyl-1-propyne. ‘H NMR (500 MHz, DMSO-d, /
D0) 8 ppm R73 (5, 1 H) 8.23 - 8.29 (m, J=1.83 Hz, 2 H) 7.88 (d, I=8.85, 2.14 Hz, 1 HY 7.78 (d, J=9.15 Hz, 1 H) 4.57 (8,2 H}335(s, 3 H). MS (ES) m/z 230.0 (M+HY".
Example 105 [1 LH-indazol-5-y1)-1H-1.2.3 -triazol-4-yi}-1 -phenylethano]
The title compound was prepared according to the procedure outlined in Example 88 substituting 2-pheny!-3-butyn-2-ol for 3-phenyi-T-propyne. *H NMR (500 MHz, DMSO-d, /
D0) 8 ppm 8.52 (5, 1 H) 8.21 - 8.28 (m, 2 H) 7.87 (d, }=8.85, 2.14 Hz, 1H) 7.76 (d, }=9.15
Hz 1H)7.51-757 (om. 2 H) 7.34 (1, J=7.78 Hz, 2 HY 7.24 (t, 17.32 Hz, 1 FH} 1.92 (s, 3 H).
MS (ESI) m/z 306.0 (M+H)".
Example 106
S«{(4-propyl-1H-1,2.3-triazol-1 -y1}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 88 substituting {-pentyne for S-phenvi-1-propyne. "H NMR. (500 MHz, DMSO-d; / D,0) § ppm 850(s, 1 H)820-830(m, 2 H) 7.87 (d, =0.00, 1.98 Hz, 1 FI) 7.77 (d. J=8.85 Hz, 1 Hy 2.7) (L.J=7.48 Hz, 2H) 1.64 - 1.78 (m, 2 H) 0.97 (t, }=7.32 Hz, 3 H). MS (ESI+ym/z 228.0 (M-+H)".
Example 107
FG F-[1-{1H-mdazol-5-y1)-1H-1 Zo d-triazol-d-ylipropan-2-ol
The title compound was prepared according to the procedure outlined in Example 88 substituting pent-4-yn-2-al for 3-phenyl-i-propyne. 'B NMR (300 MHz, DMSO-d, / 1,0) § ppm 8.49 (s, 1H) 8.26 - 8.33 (m, 2 H) 7.88 (dd, J=9.00, 1.98 Hz, 1 H) 7.74 - 7.82 (rm, 1 I) 3.95-4.08(m, 1 H) 2.74 - 2.89 (m, 2 H) 1.16 (d, /=6.10 Hz, 3 H). MS (ESI+ym/z 244 ¢ (M+H)"
Example 108 3-[1-(1H-indazol-5-y1}-1H-1 .2,3-triazol-4-ylpropan-1-ol
The title compound was prepared according to the procedure outlined in Example 88 substituting 4-pentyn-1-of for 3-phenyl-1-propyne. 'H NMR (500 MHz, DMSO-ds / D0) 8 ppm 8.50 (s, 1 H) 8.28 (s, 1 H) 8.23 (d, J=1.83 Hz, TH} 7.83-791 (mn, 1H) 7.74- 7.82 {m, ]
H) 4.50 (t,/=6.41 Hz, 1 H} 3.51 (1, J=6.41 Hz, 2 BH) 2.77 (, J=7.63 Hz, 2 H) 1.80 - 1.90 (m, 2
H)MS (EST+) m/z 244.0 (M+H)",
Example 109
I-{{I-(1H-indazol-5-yl}-1H-1.2.3 -triazol-4-ylimethyl}-1H-1,2 3-benzotriazole
The title compound was prepared according to the procedure outlined in Example 88 substituting i-propargyl-11-benzotriazole for 3-phenyl-T-propyne. 'H NMR (560 MHz,
DMSO-ds / D0) 8 ppm 8.91 (5, 1 H) 8.21 - 8.20 {m, 2H) 8.07 (d, J=8.54 Hz, | H) 7.99 (d,
J=854Hz, 1 H)7.84 (d, 1=9.00, 1.98 Hz, TH) 772-781 (m. 1 H) 7.57 - 7.65 (m, ! H) 7.41 -7.52(m, 1 H) 6.16 (s, 2H). MS (ESE) m/z 315.0 (M-HY"
Example 110
Se {4-[(phenylthioymethyil-1 H-1,2.3-tviazol-1-y1 «1H -indazole
The title compound was prepared according io the procedure outlined im Example 88 substituting phenyl propargyl sulfide for 3-phenyl-T-propyne. 'H NMR {500 MHz, DMSO- ds / D0) 8 ppm 8.59 (5, 1 Hy 8.26 (s, 1 HY 821 (d, F100 Hz, 1 Hy 780- 7.86 (em. 1 11) 7.72 = 7.79 ¢m, I H) 7.43 (d, J=8.39, 1.37 Hz, 2 Hy 7.35 (4, J=7.78 Hz, 2 H) 7.22 {t, }=7.32 Hz, 1
H) 4.38 (s, 2 H), MS (ESI+) m/z 308.3 (M+H)"
Example 111
S-{4-cyclopropyl-1H-1.2 3-triazoi-| -yl}- 1 H-indazole
The title compound was prepared according to the procedure outlined in Example #8 substituting cyclopropyiacetylene for 3-phenyl-t-propyne. 'H NMR {500 MHz, DMSO-d, /
D0) & ppm 8.46 (5, 1 H) 8.25 (s, 1 HY 8.20 (d, 1=1.53 Hz, 1 H) 7.84 (d. 1=9.00, 1 98 Hz,
H) 7.76 (d, 1=8.85 Hz, 1 H) 1.97 - 2.14 (m, 1 H)0.93- 1.06 (m, 2H)0.77 - 0.9] (m, 2 H).
MS (ESI) m/z 226.0 (M+H)",
Example 112 5-{4-(2-phenylethyl}-1H-1.2. 3-triazol- 1 -yl}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 88 substituting I-phenyi-1-butyne for 3-phenyl-1-propyne. The product was a 1:1 mixture of starting material and title compound. ‘FH NMR (500 MHz, DMSO-d; / DO) 8 ppm 8.48 {s, 1
Hj 8.25(s, 1 H) 8.21 (d, J=1.53 Hz, 1 HY 8.06 (s, 1 H) 7.81 - 7.89 (m, 1H) 7.73 - 7.80 (m, 1
H) 7.61 (dd../=8.85, 1.53 Hz, 1 H) 7.45 (d, /=8.54 Ho, | H) 725-736 (m, 4H) 7.17 - 7.25 (m, 1 H)3.04 (5,4 H). MS (ESI m/z 296.1 (M+H)",
Example 113 3-[4-(cyclohexyimethyl)-1H-] .2,3-triazol-1-y1}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 88 substituting 3-cyclohexyl-] -propyne for 3-phenyl-1-propyne. 'H NMR (500 MHz, DMSO-d, /Dy0) 8 ppm 8.49 (5, 1 HY 821-829 (m, 2 H) 7.8% (d. 1=9.00, 1.98 Hz, | I) 7.77 (d, J=8.85
Hz, 1 H)2.61 (d, J=6.71 Hz, 2 H) 1.54-1.77(m. 6 H) 1.08 - 1.30 (m, 3H) 6.91 - 1.05 (m, 2
H). MS (ESI+) m/z 282.2 (M+H)"
Example 114 5-(4-cyclopentyl-1H-1,2 3-triazol-] -vi}1H-indazole
The title compound was prepared according to the procedure outlined in Example 88 substituting cyclopentylacetyiene for 3-phenyl-l-propyne. 'H NMR {500 MHz, DMSO-d, /
D0) ppm B52 (s, 1H) R19 - 830 {m. 2 H} 7.88 (d, }=9.00, 1 98 Hz, 1 H) 7.77 (d, }=8.85
Hz. THY3.13-3.27(m, 1 H) 1.98 - 2.15 (m, 2H) 1.57 - 1.84 (m, 6 FH). MS (ES1+y m/z 254.0 (M+HY"
Example 113 i) t-[1-(1H-indazol-5-yi)-1H-1 Lpd-triazol-d-vijevelohexano]
The title compound was prepared according to the procedure outlined in Example 88 substituting l-ethynyl-1-cyclohexanol for 3-phenyl-1-propyne. 'H NMR (500 MHz, DMSC- ds / 020) & ppm 8.52 (5. 1 H) 8.21 - 8.30 (m, /=1.53 Hz, 2 H) 7.89 (dd. J/=6.00, 1.98 Hz, 1 H)
T77(d, J=8.85 Hz, 1 HY 2.16 - 2.46 (m, 1 H)1.92-2.05(m, 2H) 1.77- 1.86 (m, 2H) 161 - 1s L77(m, 2H) 1.51 - 1.59 (m, PH) 1.42 - 1.51 (m, 2 H) 1.28 - 1.40 (m,./=6.92, 2.90 Hz, 1
H)MS (EST+) m/z 284.0 ( M+H),
Exampie 116 5-[4-(phenoxymethy!)-1H-1 2p 3-triazol-1-y11-1H-indazole
The title compound was prepared accordin g to the procedure outlined in Example 88 substituting phenyl propargy! ether for 3-phenyl-T-propyne. 'H NMR {500 MHz, DMSQ-d, /
D200) 8 ppm 8.87 (5, 1 H) 8.22 - 834 (m, 2 H} 7.89 (d, ]=8.85, 1.83 Hz, | H) 7.79 (d, J=9.15
Hz, 1H) 7.29 - 7.41 (m, 2 H) 7.09 (d, J=7.63 Hz, 2 H) 6.99 (t, ]=7.32 Hz, 1 H} 5.25 (s, 2 H).
MS (ESI+) m/z 292.0 (M+H),
Example 117
S5-{4-[(1,1 -dioxidothiomorpholin-4-yl methyl ]-1H-] -2,3-triazol-1-y1}-1H-indazole
The tile compound was prepared according to the procedure outlined in Example 88 substituting N-propargyl thiomorpholine-sulfone for 3-phenyl-1-propyne. 'H NMR (300
MHz, DMSO-d; / D,0) § ppm 8.81 (s, 1 H) 8.24 - 8.36 (m, 2 H} 7.89 (d, J=9.00, 1.98 Hz, 1
H) 7.80 (d, J=9.13 Hz, 1 H) 4.38 (8,2 H) 3.30 - 3.56 (m, }=39.36 Hz, 8 H). MS (ESI+) m/z 332.9 (M+H)".
Example 118 5-[4-(3-phenyipropyl)-1H.1 +2, 3-triazol-1-y1}-1 H-indazole
The title compound was prepared according to the procedure outlined in Example 88 substituting I-phenyl- -peniyne for 3-phenyt-1-propyne. 'H NMR {500 MHz, DMSO-d, /
DOS ppm 8.52 (s, 1 HY 8.26 (5. 1 Ep 8.23(d, J=1.53 Hz, 1 H) 787 (d, }=9.00, 1.98 Hz,
H) 7.76 (d. J=9.15 Hz, 1 H) 7.31 (4, F732 Hz, 2H) 7.23 - 7.28 (m, 2 H) 7.20 (1, }=7.32 Hz, 1
H)2.74 (4, =7.63 Hz, 2H) 2.65-2.72(m, 2H) 1.95. 2.05 (m, 2H). MS (ESI+) m/z 304.2 (M+H)".
Example 119 [1-benzyl-4-(1H-indazol-5 -yD-1H-1.2.3-triazo} -5-ylJ(phenyimethanone
Example 1194 teri-Butyl 5-ethynyl-1H-indazole-1 ~carboxylate
To a solution of Example 3C (230 mg, 1.62 mmol) in dichloromethane (10 mL) was added di-tert-butyl dicarbonate (459 mg, 2.1 mmol) and a pinch of dimethylaminopyridine (~3 mg), and the mixture was stirred fro 30 minutes at room temperature, Water was added, and the product was extracted with dichloromethane, dried over sodium sulfate, filtered, and the solvent wag evaporated under reduced pressure to afford the title compound. MS (ESI) m/z265.0 (M+Na)".
Example 1198 [1-benzyl-4-(1H-indazol-5-y1)-1H-1 +2,3-triazol-5-yl] (phenyl methanone
A vial under argon containing Example 119A (90 mg, 0.37 mmol), benzyi azide {0.047 mL, 0.37 mmol), tetrahydrofuran (3 mL}, triethylamine (0.062 mL, 0.44 minwl), Cul (71 mg, 0.37 mmol) and benzoyl chloride (0.059 ml, 0.5] mmol) was capped and shaken for 16 hours. The solvents were evaporated, and the product was purified by silica ge! column chromatography in 5-30% ethyl acetate in hexanes. The crude material was treated with TFA {0.5 mL) in dichloromethane {1 mL} and purified by reverse-phase HPLC using an acetonitrile/water 0.1% TFA gradient elution method to afford the title compound. 'H NMR (500 MHz, DMSO-ds / D,0) 8 ppm 13.08 (s. 1 H) 7.98 (s, 1 H) 7.77 {s, 1 H) 7.54 (d, J=8.24, 1.22 Hz, 2H) 7.43 - 7.48 (m. | H) 733-740 (m, 2H) 7.22 - 7.30 (m, 5H) 7.17 - 7.21 (m, 2
H) 5.74 (s, 2 Hy, MS (ESI+) m/z 380.1 (M+),
Example 120
N,N-diethyl-N-{[1 ~{(1H-indazol-5-y1)-1H-1 2, 3-triazol-4-yljmethyl amine
The title cormpound wag prepared according to the procedure outlined in Example 8% substituting 1 I-diethylpropargylamine for S-phenyl-1-propyne. 'H NMR {300 Miz,
DMSO-d) 8 ppm 8.98 (5, 1 MH) 8.30 (d, =1 36 Hz, TH) 827 (s. 1 H) 7.85 - 7.93 (ra, 1 HD 775-783 (m, 1 H) 4.33 (d, J=4.07 Hz, 2H) 3.11 - 3.23 (m. 4H) 131 (1, }=7.12 Hz, 6 H).
MS (ESI+) m/z 271.0 (M+H)".
Example 121 i ethyl N-J2~(1H-in dazol-5-y1yimidazol | Z-alpyrimidin-3 -vl|-beta-alaninate
The title compound was prepared according to the procedure outlined in Example 43 substituting ethyl isocyanopropionate for isopropyl isocyanide. 'H NMR (300 MHz, DMSO- ds) 8 ppm 13.09 (s. 1 H) 8.71 (d, J=6.7%, 2.03 Hz, 1 H) 8.54 (5,1 Hy 8.46 (¢, J=4.24, 1.87 Ha, 1H) 8.23 (d, =8.82. 136 Hz, 1 H) 8.14 (s, 1H) 7.61 (d. J=8.82 Hz. 1 H) 7.03 (d, }=6.78, 407Hz 1 H)5.03 {t, J=5.93 Hz, 1 H) 3.96 (g, J=7.12 Hz, 2 H) 3.23 (q. J=6.22 Hz, 2 H) 2.47 = 2.55(m, 2H) 1.08 (t, I=7.12 Hz, 3H). MS (ESI) m/z 351.1 (M+H)".
Example 122 541 -benzyl-5-methyl-1H-1 2.3-triazol-4-yl}- 1 H-indazole
Example 1224 1-B enzyl-5-methyl-4-( tributylstannyl)-1H-1,2, 3-triazole
Tributyl(1-propynyhiin (3.87 ¢, 11.8 mmol) and benzyl azide (2.2 mL, 17.6 mmol) were combined and heated to 150 °C overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5-409; cthyl acetate in hexanes to afford the title compound. MS (ESI) m/z 464.2 (M+H)",
Example 1228
I-(5-(1 -Benzyl-3-methyl-1 H-1 2. 3-triazol-4-y1)- 1H-indazol-1 -vl}ethanone
Example 87A (235 mg, 0.821 mmol), Example 1224 (380 mg, 0.522 mmol), dichlorobis(triphenylphosphine palladiumIr) (60 mg, 0.085 mmot}, and copper thiophene-2- carboxylate (323 mg, 1.23 mmol) were combined it toluene (2.0 mL) in a microwave vial under an inert atmosphere of nitrogen. The vial was heated in a microwave (CEM-Discover)
to 150°C at 125 Watts for 20 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-40% cthyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 332.0 (M+EH)"
Example 122C 3-(1-benzyl-5-methyi-1H-1 2.3-triazol-d-y1y. | H-indazoie
Example 122B (109 mg, 0.379 mmol} was dissolved in tetrahydrofuran (3.0 mL) and water (0.5 mL), and potassium hydroxide (53 mg, 0.945 mmol) was added. The mixture was stirred for 2 hours, diluted with ethyl acetate, and washed with water. The organic layer was 1 absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0- 5% methanol in dichloromethane to afford the title compound. 'H NMR (300 MHz, DMSO- ds) 8 ppm 13.13 (5,1 H) 8.12 (5, 1 HY801 (s, 1 K)7.71 - 7.78 (me, 1H) 7.59-7.66 (m, 1 FH) 731-745 (m,3H)7.23-7.00 {m, 2 H) 5.65 (5,2 H) 2.43 (5, 3 H). MS (ESI) m/z 290.1 (M+H)".
Example 123 5-(1-benzyl-5-methyl-1F-1 -2.3-triazol-4-y1}- 1 H-indazol-3-amine
Example 123A 5-(1-Benzyl-5-methyl-1H-1 2, 3-triazol-4-y1}-2-fluorobenzonitrile
Example 1224 (415 mg, 0.792 mmol), 5-bromo-2-fluorobenzonitrile (158 mg, 0.79¢ mmaol), dichlorobis(triphenyiphosphine palladium) (52 mg, 0.074 mmol), and copper thiophene-2-carboxylate {226 mg, 1.19 mmol) were combined in toluene (2 mL} in a microwave vial under an inert atmosphere of nitrogen. The vial was heated in a microwave (CEM-Discover) at 150°C at 125 Watts for 20 minutes. The mixture was absorbed on sifica gel and purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 293.0 (M+H)".
Example 123B 5-(1-benzyl-5-metiryl-1H-1 2. 3-triazol-4-y1)-1H-indazol-3-amine
Example 123A (120 mg, 0.339 mmol) was treated with hydrazine hydrate (1.0mL) in ethanol (1.0 mL) and heated 10 60 °C overnight. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica ge! chromatography eluting with a gradient of methanol in dichloromethane {0-5%) to afford the tile compound. 'H NMR (300 MHz, DMEO-ds} 8 ppm 11.43 (5, 1 HY 7.98 (s, 1
FH} 7.60 {d, }=8.65, 1.53 Hz, 1 HD 727-744 (ra, 4 BY 7.01 - 7.07 (m, 2H} 5.65 (3,2 H) 5.4] (8, 2H) 241 (5, 3H). MS (ESE) m/z 305.1 (M+R),
Example 124
N24 LH -indazol-5-ylimidazo[1 wea Jryrimidin-3-yi}- B-alaninamide
Example 127 ¢42 mg. {120 mmol) and a solution of 7 N ammenis in methanol {1.0 mL) were combined and heated to 60°C overnight. The mixture was absorbed on silica gel and purified by silica gel chromatography chuting with 2 gradient of methanol in dichloromethane (1 7%) to afford the title compound. 'H NMR (300 MHz, DMSO- de) & ppm 13.09 (s, 1 H} 8.76 (d, J=6.78, 2.03 Hz, 1 H) 8.56 {s, 1 H) 8.45 (d, 7=4.07, 2.03 Hz, 1H) 8.24 (d, J=8.82, 1.36 Hz, 1 H) 8.15 (s, 1 H) 7.61 (d, J=R 4% Hz, 1H} 7.32 (5, 1 H) 7.03 {d, 7=6.78, 4.07 Hz, 1 H} 6.85 (s, 1 H) 4.93 {t. J=6.10 Hz, 1 H)3.11- 3.23 (m, 2 Hy 2.32 (1,
J=6.78 Hz, 2 H). MS (ESI) m/z 322.0 (M+H)",
Example 125 5-(1-benzyl-5-iodo-1H-1 2, 3-triazol-d-yl)- 1H -indazol-3-amine
Example 1254 5-(1-Benzyl-5-iodo~1H-1.2 3-iriazo]-4- yh-2-fluorobenzonitrile
A mixture of Example 62B (200 mg, 1.38 mmol}, benzyl azide (0.176 mL, 1.38 mmol), tetrahydrofuran (12 mL}, triethylamine (0.230, 1.56 mmol), Caf (263 mg, 1.38 mmol) and ICH(0.069 ml, 1.38 mmol) under argon was stirred ai room temperature for 24 hours.
The solvent wag evaporated and the crude mixture was dissolved in dichloromethane, loaded directly onto a silica gel column and eluted with ethyl acetate / hexanes (10-20%) to afford the title compound. MS (ESI) m/z 404.9 (M+H)"
Example 1235B 5-(1-benzyl-5-iodo-1H-1,2.3-triazol -4-y1}-1H-indazo!-3-amine
Example 1254 (50 mg, 0.12 minol) and hydrazine monohydrate (1mL) in ethanol (1 mL} were heated at 95 °C for 2 hours. Water was added, and the solid was collected by filtration and further purified by reverse-phase HPLC using an acctonitrile/water 0.1% TFA gradient elution method to afford the title compound as a TFA salt, ‘H NMR {500 MHz,
DMSO0-ds) 6 ppm 12.07 (5, 1 H) 8.30 (s, 1H) 7.83 (d. }=8.85, 1.53 Hz, 1 H) 7.44 (d, 1=8.54
Hz, TH) 7.38 - 7.43 (m, F130 730 Hz, 2H 7.30. 7.37 (m, THY 7.23-727 {m. J=7.02
Hz ZH) 5.74 (s, 2 Hy 4.00 (5. 2 Hj MS (ESI) m/z 417.0 (M+HY,
Example 126
N-{3-f4-(3-amino-1 H-indazol-5-yl)-1 ~benzyl-1H-1 +2, 3-triazol-5-yllphenyl FN methylphenyliurea
Example 126A 1-(3-(1-Benzyl-4-( 3-cyano-4-fluorophenyl)- 11-1 .2,3-triazol-5-yvliph enyl)-3-m-tolylurea
A vial under argon contaming Example 125A (94 mg, 0.23 mmol), 1-(3-(4,4,5,5- tetramethyl-1 .3.2-dioxaborolan-2-ylphenyl)-3-m-tolylurea (prepared according to a procedure described in W02004/1 13304) (990 mg, 0.26 ramol), PdClydppf dichloromethane (19 mg, 0.02 mmo!) potassium carbonate (64 mg, 0.46 mmol}, DME (2 mL) and water (0.2 mL) was capped and heated in a heater shaker at 80°C for 90 minutes. The solvents were evaporated and the product was extracted with methanol / dichloromethane. Silica gel column chromatography using 10% ethyl acetate in hexanes afforded the title compound. 200 MS (ESM) m/z 503.2 (M+H)".
Example 126B
N-{3-[4-(3-amino-1H-indazol-5 -y}-1-benzyl-1H-1 2, 3-triazol-5-yljphenyl} “N'-(3- methylphenylurea
Example 126A (25 mg, 0.05 mmol) and hydrazine monohydrate (6.5mL) in ethanol {2 mL) were heated at 8G °C for I hour. The crude mixture was loaded onto a silica gel column and eluted with a gradient of 0-5% methanol in dichioromethane to afford the title compound. '"H NMR (500 MHz, DMSO0-ds) 8 ppm 11.40 (5, 1 H) 8.79 (8, 1H) 8.63 (s, 1 H) 8.12 (5,1 H) 7.57(d, }=8.24,1.22 Hz, 1 H) 7.43 (1, J=1.83 Hz, 1 H) 7.38 (1, J=7.93 Hz, 1 H)7.23-734 (m,4H)7.08-7.22(m, 4 H) 7.03 (d. }=6.71 Hz, 2 H) 6.88 (d, 7=7.63 Hz, 1 H) 6.78 (d,
F=732 Hz, 1 HY 3.50 (5, 2 H) 5.36 (s, 2H) 2.26 (s, 3 H). MS (ESI) m/z 5153 {M+HY
Example 127 5-(1 H-indazol-5-y1}-N-(2-isopropoxyethyllisoxazole-3-carboxamide in a 20 mL vial 2 solution of 81 A (37 mg, 0.18 mmol) dissolved in dimethyiformamide (0.8 mL) was added, followed by the addition of HATU (61 mg, 0.18 mmol) dissolved in dimethylformamide (0.8 mb). Then a solution of 2- isopropoxyethanamine (20 mg, 0.20 mmol) dissolved in dimethylformamide (0.9 mL) was added followed by diisopropylethylamine (42 mg, 0.36 mmol) dissolved in dimethyiformamide (0.8 mL]. The mixture was then shaken at 40 °C for three hours. The crude reaction mixture was filtered through a Si-carbonate cartridge (6 mL. 2 g) supplied by
Silieyele Chemical Division with methanol, checked with LC/MS, and concentrated fo dryness. The residue was dissolved in 1] DMSO/methanol and purified by reverse phase
HPLC (Agilent, 5%-100% TEA /water gradient, 8 minute run). 'H NMR (300 MHz, DMSO- ds /D>0) & ppm 8.38 - 8.43 (m, 1 H) 8.22 +830 (m. 1H) 7.90 (d, 1 BY7.73(d, 1 €) 7.21 - 7.29 (m, 1H) 3.56 - 3.65 (m, 1 I) 3.52 (tL, 2H) 3.43(,2H)1.10(d, 6 H}. MS (ESI) m/z 315 (M+H)".
Exampic 128 5-[3 -(morphelin-4-ylcarbonyliisoxazol-3 -yl]-1H-indazole
The title compound was prepared according io the procedure outlined in Example 127 substituting morpholine for Z-isopropexyethanamine. 'H NMR (300 MHz, DMSO-
As/D>0) 8 ppm 8.36 - §.43 (m, 1 H) 8.22 - 8.20 (m, 1H) 7.89 (d, 1 H) 7.72 (d, 1 Hy 7.11 - 7.22(m, 1 H) 3.68 - 3.72 (m. 4 H) 3.61 -3.6% (m, 4 H). MS (ESI+) m/z 209 (M+H)".
Example 129 23 5-(1H-indazol-5-y1)-N-(2 -morpholin-4-yipropyl)isoxazole-3-carboxamide
The title compound was prepared as a TFA salt according to the procedure outlined in
Example 127 substituting 3-morpholinopropan-1-amine for 2-isopropoxyethanamine. 'H
NMR (300 MHz, DMSO-64/D20) ppm 8.37 - 8.46 (m, 1 H) 8.20 - 8.31 (m, 1 H} 7.91 (d, 1
H)7.73 (d, 1 H) 7.17 - 7.36 (m, 1 H) 3.98 - 4.08 (m, 2H) 3.57 3.73 (m, 2H) 342-351 (m, 300 2H)335-3.41(m,2H)3.14-3.22 (m. 2H)3.01 -3.14 (m, 2H) 1.88 - 2.06 (m, 2H). MS (ESI+) m/z 356 (M+H)",
Example 130
N-[2-(1H -imidazol-4-yl)ethyl]-5-( IH-indazol-5-yljisoxazole-3-carboxarni de
The title compound was prepared according to the procedure outlined in Example 127 substituting 7-(1 H-imidazol-4-vhethanemine for I-isopropoxyethanamine. 'H NMR {360
MHz, DMSO-d4/D,0) 8 ppm 8.90 - 8.97 {m, | H) 8.34 - § 46 (m, 1 Hy 820-832 (m, 1 ID 7.90{d, 1H) 7.72(d, I H) 7.38 - 7.49 (me, 1 H) 7.14 7.28 (m, 1 H) 3.57 (6, ZH} 2.96 (1. 2 H).
MS (ESI+) m/z 323 (M+H)'.
Example 131 0 {(3R)1-{[5-(1H-mdazol-5-y1)i s0xazoi-3-yljcarbonyl | piperidin-3-ol
The title compound was prepared according to the procedure outlined in Example 127 substituting (R}-piperidin-3-o! hydrochloride for 2-isopropoxyethanamine. 'H NMR (300
MHz, DMSG-d¢/D,0) 8 ppm §.34 - 8.45 (m, 1H) 819-830 (m, 1 H) 7.80 {¢. 1 H) 7.72 (d,
PH) 7.13 (d, 1 H) 4.03 - 4.19 (m. | FE 3.64 -3.72 (m, 1 H) 3.54 - 3.62 (m, 1 H)3.34-3.44 (m, 1H)3.20-3.32 (m, I H}2.99-3.10 (m, 1 HY 1.67 - 2.03 (m, 2H) 1.36 - 1.61 (m, 2 FI).
MS (ESI+) m/z 313 (M+H).
Example 132
I-{[5-(1 H-indazol-5-yl}isoxazol-3-yljcarbonyi ¢piperidine-3-carboxamide
The title compound was prepared according wo the procedure outlined in Example 127 substituting piperidine~3-carboxamide for 2-isopropoxyethanamine. 'H NMR (300 MHz,
DMSO-de/D20) 8 ppm 8.36 - 8.45 (m, 1H) 8.22 -8.32 (m, 1 H) 7.90 (d, 1 HY 7.72 (d, 1 HI) 707-723 (m, | HY 4.27 - 4.56 (m, 1 H)3.91-4.05(m, 1 H)3.09-337 (m, 1 H)2.85-3.04 (m, 1 H)2.31-2.45 (m, 1 H} 1.89 -2.05 (m, 1H) 1.73 - 1.86 (m, 1 FN) 1.60 - 1.72 (m, TH) 1.36-155(m. 1 H). MS (ESI-) mz 338 (M-H).
Example 133 2-[2-(4-415-(1H -indazo!-5-yl)isoxazol-3-yl carbonyl! piperazin-1-yljethoxy]ethanol
The title compound was prepared as a TFA salt according to the procedure outlined in
Example 127 substituting 2-(Z-(piperazin-1-yl)ethoxy)ethanol for 2-isopropoxyethananine. 'H NMR (300 MHz, DMSO-d4#/D,0) 8 ppm 8.39 - 8.48 (m, 1 FH) 8.19 -8.32 (m, 1 H) 7.92 (4,
VEY 794d, 1H) 7.17 - 727 (m, 1 H) 4.49 - 4.60 (m, I H}3.94-4.01 (m. 1 1) 3.76 - 3.81 (m, 4 H}3.56- 3.63 (m, 2H) 3.51 - 3.56 (m.2H)3.33-343 (m, 3 H)3.13-3.23 {m, 1 H)
2.65 - 2.75 (m, 2 H). MS (ESI+) m/z 386 (M+H)".
Example 134
Se {3-[(4-methyl-1 d-diazepan-] -vhicarbonyl isoxazol-5 -ylb-1H-indazole 3 The title compound was prepared as 2 TFA salt according to the procedure outlined in
Example 127 substituting I-methy!-1.4-diazepane for 2-tsopropoxyethanarmine. 'H NMR (300 MHz, DMSO-ds/D,G) & PPM 8.38 - 8.46 (m, 1 H) 8.22 -8.37 {(m, 1 H) 7.85 - 7.98 (m,
B)7.75(d 1 HD) 7.22(d, 1 FD) 4.07 - 4.19 (m, TH) 3.69 - 3.77 (m, 2 H} 3.59 - 3.67 {m, 1 Hj 3.44 - 3.59 (m, 1 H)3.35 - 3.44 (m, 1 H)324-335(m, 2 Hy 2.84. 2.05 {m, 3 Hj 2.66 -2.74 0 (my TF) 2.06 - 2.26 (m, 2 H). MS (EST) miz 326 (MH)
Example 133
N-(3-hydroxypropyl}-5-(1H -indazol-3-yisoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 127 substituting 3-aminopropan-1-of for 2-isopropoxyethanamine. 'H NMR (300 MHz, DMSO- ds/D>0} 5 ppm 8.36 - 8.45 (m, 1 H} 8.20 - 8.30 (m, I H) 7.84 - 7.94 (m, 1 H} 7.71 (d. 1 Hj 7.18 -7.28 (m, 1 HY 3.48 (t, 2 H) 3.35 (t, 2H) 1.64 - 1.78 (m, 2 H). MS {(ESH) m/z 387 (MH).
Example 136
N-[(1R)-2-hydroxy-I-pheny] ethyl]-5-(1H-indazol-5-vi)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 127 substituting (R)-2-amino-2-phenylethano! for 2-1sopropoxyethanamine. 'H NMR (300 MHz,
DMSO-de/D20) 8 ppm 9.11 (d, 1 H) £.37 - 8.46 (m, 1H) 8.23 -8.28 (m, 1 H) 7.91 (d. HY 7.73(d, 1 H) 740-745 (m, 2H) 732-735(m, 2H) 7.23 - 732 (m. 2H)Y5.05-5.13 (m, 1
H) 3.66 - 3.72 (m, 2 H), MS (EST+) m/z 349 (MAH),
Example 137
N-[3-(1H-imidazol-1-ylypropy1]-5-(1 H-indazol-5-yl}isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 127 substituting 3-(1H-imidazol-1 -ylipropan-1-amine for 2-isopropoxyethanamine. H NMR (300 MHz, DMSO-ds/D20) 8 ppm 9.02 - 9.10 (m, 1H) 8.40 - 8.44 (m, 1 H)8.25- 8.29 (m, 1
H) 787-795 (m, 1H) 7.71 - 7.82 (m, 2 H) 7.61 -7.69 (m, 1 H) 7.2¢- 7.29 (m, 1 HY 4.28 (1,
ZHY335(, 2H) 206-219 (m, 2 HF). MS (ESI+) m/z 337 (M+H)™.
Example 138
S-(1H-indazol-5-y1)-MN-3 “(Z-oxopyrrolidin. ly! Jpropyilisoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 127 substituting [-(3-aminopropypyrrolidin-2-one for 2-isopropoxyethanamine. 'H NMR (300
MHz, DMSO-ds/D»0) 8 ppm 8.38 - 8.43 (fm, I H)8.24 - 8.30 (m, | H) 7.47 - 7.93 (m. 1H) 734d, THY 7.22 - 7.26 (m, 1 H) 3.39 (tL. 2H}3.21-3.30(m. 4 H) 2.26 {t.2H)1.90-2.00 (m. 2H) 1.70 - 1.79 (m, 2 H). MS (ESH) m/z 354 (MF
Example 139
N- {2-4 ammosulfonylphenyljethyl} -3-(1H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 127 substituting 4-(2-aminoethy] Ibenzenesulfonamide for 2-isopropoxyethanamine, 'H NMR
IS (300 MAz, DMSO-ds/D,0) 8 ppm 8.37 - 8.42 (m, I H) 8.24 ~ 8.29 (m, 1 H) 7.86 -7.93 (m, 1
HY 7.70 - 7.80 (m, 3 H) 7.47 (d, 2H) 7.20-7.24 (mm, 1 H) 3.57 (t. 2H} 2.96 (t, 2 H)., MS (ESI+) m/z 412 (M+H)".
Example 140 [{-benzyl-4-(18-indazol-5 -yD-18-1,2 3-triazol. 3-y1)(3 -chlorophenyl methanone
The title compound was prepared according to the procedure outlined in Example 1198 substituting 3-chlorobenzoyl chloride for benzoyl chloride. 'H NMR (500 MHz,
DMSO-de) 8 ppm 13.09 (s. 1 H) 7.99 (8, 1H)7.77(s, 1H) 7.38 - 7.5] (m.4 H) 728-737 {(m, 3H) 7.20- 7.27 (m, 4 H) 5.78 {s. 2H). MS (ESI+) m/z 414.1 (M+HY
Example 141 [1-benzyl-4-(1 H-indazol-5-y1)-1H-1.2.2 ~triazol-5-y1J{cyclopropymethanone
The title compound was prepared according to the procedure outlinsd in Example 119B substituting cyclopropanccarbony! chloride for benzoyl chloride. "H NMR (500 MHz,
DMSO-de) 8 ppm 13.26 (s. TH) 8.18 (5, 1 H) 8.08 (s. | H) 7.61 - 7.70 (m, 2 H) 7.29 - 7.40 (m, 3 H) 7.24 (d, J=7.02 Hz, 2 H) 5.79 (5, 2H) 1.86-2.00 (m. 1 FH) 0.98 - 1.12 (m, 2 H) 0.77 -0.93 (m, 2 H). MS (ESI+) m/z 344.1 (M~H)",
Io
Example 142 5-[S-cyclopropyl-1 ~{tetrahydro-2H-pyran-<4-ylmethyl}- 1H-1.2 3-triazol-4-y1]-1H-indazole
Example 1424 3 5-Cyclopropyl-1 ~{(tetrahydro-2 H-pyran-4-yl Jymethyl)-4-(tributylstanmy] 1H-1,2,3triazole
Cyclopropyl acetylene (142 mg, 2.15 mmol) was added to BIL I -tributyf-N,N- dimethylstannanamine (716 mg, 2.14 mmol) in hexane (3.0 mL} and stirred in a seated vial at 70°C for 2 hours. The mixture was cooled to ambient temperature, and the vial was stirred unsealed for 10 minutes. Example 80A (455 mg, 3.722 mime) was added, and the vial was 16 resealed and heated to 130°C overni ght. The mixture was purified by silica gel chromatography eluting with a gradient of ethy! acetate in hexanes (5-509%) to afford the title compound. MS (ESI+) m/z 498.3 (M+H)"
Example 142RB
F-(5-(5-Cyclopropyl-1-(( tetrahydro-2H-pyran-4-yl)methyl}-] H-1.2,3-triazol-4-y1)-1H- mdazol-1-yljethanone
Example 142A (220 mg. 0.444 mmol), Example 87A {128 mg, 0.447 mmol), dichlorobis(triphenylphosphine)patladium(ir (33 mg, 0.047 mmol), and copper thiophene-2- carboxylate (127 mg, 0.666 mmol} were combined in toluene (2.0 mL) in a 4 mL vial under an inert atmosphere of nitrogen. The vial was sealed and heated 150 °C for 20 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-70% ethyl acetate in hexanes to afford the title compound. MS (ESI) m/z 366.0 (M-+H)",
Example 142C 5-[5-cyclopropyl-1 -(tetrahydro-2H-pyran ~4-ylmethy!)-1H-1,2.3-triazo! -4-y1]-1H-indazole
Example 142B (46 mg, 0.126 mmol} was dissolved in tetrahydrofuran (2.0 mL) and water (0.5 mL.) and potassium hydroxide (80 mg, 1.43 mmol) was added. The mixture was stirred for 2 hours, and was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography cluting with a gradient of 0-8% methanol in dichloromethane to afford the title compound. 'H NMR (300 MHz, CDCls) 8 ppm 8.19 {8, 1 H) 7.96 (d, I=8.82 Hz, 1 H) 7.61 (d, 17.80 Hz, 1 H) > 7.25- 7.28 (m, 1 H)4.34 (d, J=6 44 Hz, 2 H) 4.02 (d, J=11.36, 3.56 Hz. ? H) 3.421, J=11.53
Hz, 2 H)2.33- 2.46 (m. 1 H) 1.81 - 1.95 (m, 1 HY) 1.59~ 1.76 (m, 2 H) 1.43 - 1.58 (m, 2 H) 23-128 (m, 1H) 1.10 - 1.20 (m, 2H) 0.47 - 0.62 (m, ZH). MS (ESI) m/z 324.1 (M-+HY"
Example 143
NLA -benzyld.( IH-mndazol-5-y1)-141.2 3-triazol-5 -yijmethyl} glycinamide
Example 1434 2-({1-Benzyl-d tributylstannyl)-1H-1.2.3 ~triazol-5-yDmethylisoindoline. | J-dione 1 N-Propargylphthalimide (2.35 gmg, 12.7 mmol} was added to 1,1, ] -tributyl-N N- dimethylstannanamine (423mg, 12.7 mmol) in hexane (3.0 mL) and stirred in a sealed via at 70°C for 2 hours. The mixture was cooled to ambient temperature and the vial was stirred unsealed for 10 minutes. Benzyl azide (2.0 mL, 16.0 mmol} was added and the vial wag resealed and heated to 130 °C overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 10-50%, ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 609.3 (M+H)".
Example 143B 2-({4-(1-Acetyl-1 H-indazol-5-y1)-1-benzyl-1H-1 .2,3-triazol-3 -ylymethyt)isoindoline-1.3- dione
Example 143A (567 mg, 0.934 mmol), Example §7A (268 mg, 0.934 mmol), dichlorobis(triphenylphosphine)palladium(il) {67 mg, 0.095 mmol), and copper thiophene-2- carboxylate (268 mg, 1.4] mmol) were combined in toluene {2.5 mL) in a microwave vial under an inert atmosphere of nitrogen. The vial was heated in a microwave (CEM-Discover) 23 10 130°C at 125 Watts for 20 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of | 0-50% ethyl acetate in hexanes 0 afford the title compound. MS (ESI+) m/z 477.2 (M+H)".
Example 143C (1-Benzyl-4-(1H-indazol-5 ~yh-1H-1 «2.3-triazol-5-yDmethanamine
Example 1438 (140 mg, 0.294 mmol) was treated with hydrazine hydrate (0.7 mL) in ethanol (0.7 mL) and stirred at ambient temperature overnight. The mixture wag absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 1-69 methanol in dichloromethane to afford the title compound. MS (ESI+) m/z 305.0 (M-+H)"
Example 143D
NL {[1-benzyl-4-( 1H-indazol-5-y1)-1H-1,2 3-triazol-5 ~ylImethyl! glycinamide
Example 143C (66 mg, 0.217 mmol), N-(tert-butoxycarbonyl)-glycine {39 mg, 0.223 mio), and HATU (85 mg, 0.274 mmol} were combined in methylene chloride (2.5 mL).
Diisopropylethylamine (156 ul, 0.865 mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of G-6% methanol in dichloromethane to afford tert-butyl 2-((1-benzyl-4-( | H-indazo 5-y1)-1H-1,2 3-triazol-5 -yhmethylamino)-2- oxoethylcarbamate. This carbamate was dissolved in tetrahydrofuran (2mlYyand 0.5 ml ofa
Isolation of 1 N hydrochloric acid in diethyl ether was added and the mixture was stirred for 20 minutes at room temperature. The solvents were removed under reduced pressure, and diethyl ether was added to the mixture and stirred at room temperature overnight. The solvent was decanted, and the resulting residue was dried under a stream of nitrogen to afford the title compound as a hydrochloride salt. 'H NMR (300 MHz, DMSO-ds) § ppm 13.21 {(s. 1H)9.02(t J=5.09 Hz, Hj 8.11-8.16 (m, 2 FH) 8.06 (s, 2 H) 7.75 - 7.82 (m, 1 H) 7.64 (d,
J=8.82 Hz, 1 H) 7.30 - 7.45 (m, 3 H)7.23-731 (m, 2H) 5.72 (8,2 H)4.57(d, I=5.09 Hz, 2
H)3.41(q. J=5.76 Hz, 2 H). MS (ESI+) m/z 362 1 (M+H)".
Example 144 {(4-fluorophenyl)[4-(] H-indazol-5-yI)-1 ~(tetrahydro-2H-pyran-4-ylmethyl)- 1H-1.2,3-triazol-
S-ylimethanone
The title compound was prepared according to the procedure outlined in Example 119B substituting 4-fluorobenzoyl chloride for benzoyl chloride and Example 80A for benzyl azide. 'H NMR {300 MHz, DMSO-d) 8 ppm 13.10 (8, TH)800 (5, 1H} 7.72 - 7.80 {m, 3
H)738-7.44 (m, 1 H)7.30-736 (m, 1 BH) 7.09- 7.19 (m, 2H} 4.41 (d, J=7.12 Hz, 2 1) 3.80 (d, J=11.36, 2.54 Hz, 2 H)3.14-326(m, 2 H)2.04-2.15 (m, 1H) 1.38 - 1.49 (m, 2 Hj 1.19 - 1.35 (m, 2 H). MS (ESI+) m/z 406.1 (M+H)",
Example 145 {(4-chlorophenyl)4-(1H ~indazol-5-yl)-1 -(tetrahvdro-2H -pyran-d-yimethyl)-1H-1.2 3-triazol- 5-ylJmethanone
The title compound was prepared according to the procedure outlined in Example 119B substituting 4-chiorobenzoyl chloride for benzoyl chloride and Example 8GA for benzyl azide. 'H NMR (300 MHz, DMSO-d) 8 ppm 13.10 (5, 1 H) 8.00 (s, 1 H)7.77 (5, 1 H) 7.6% : (d, =8.48 Hz, 2H) 7.26 - 7.45 (m, 4 H)y4.42(d, }=712 Hz, 2 1) 3.81 (d. J=11.1 9,2.71 Hz, 2
H}3.14-327 (m, 2H) 2.03 - 2.19 (m, 1 HY L38- 1.51 (tm, 2H) 1.22 1.36 (m, 2 Hj. MS (ESI) m/z 422.1 (MH),
Example 146 (3-chiorophenyl){4-(1H -indazol-5-yl}-1-(tetrahydro-2H -pyran-4-ylmethyl)-1H-1,2 3 -triazol-
S-yllmethanone
The title compound was prepared according to the procedure outlined in Example 1G 119B substituting 3-chlorobenzoy! chloride for benzoyl chloride and Example BOA for benzyl azide. "H NMR (300 MHz, DMSO-ds) 8 ppm 13.04 (5, 1 H)795(s, 1H) 7.64 (5, 1 H) 7.48 - 7.54 (m, T HY 7.29 - 7.35 (m, 1 11) 7.22 - 7.2% (m, 1H) 7.13- 7.22 (m, 3 H) 4.58 (4, ]=7.12
Hz 2H) 3.86 (d, J=11.53, 2.37 Hz 2 H) 3.20 - 3.30 (m, 2H 211-224 (m, 1H) 1.45-1.54 (m, 2H} 1.33 - 1.44 (m, 2 H). MS (ESF) m/z 422.1 (M+H)".
Example 147 (2-chlorophenyl){4-(1 H-indazol-5-y1}-1-(tetrahydro-2H -pyran-4-yimethyl)-1H-1,2 3-triazoi- 5-ylJmethanone
The title compound was prepared according to the procedure outlined in Example 1198 substituting 2-chiorobenzoyl chloride for benzoyl chloride and Example 80A for benzyl azide. "H NMR (300 MHz, DMSO-ds) 8 ppm 13.08 (s, 1 HY7.99 (s, 1H) 7.75 (5, 1 H) 7.66 (t. J=1.86 Hz, | H) 7.56 (d, ]=7.80 Hz, 1 Hy 747-7353 (m, 1 H)7.36- 7.42 (m, 1 HY 7.23 - 7.34 (m, 2 Hy 4.45 (d, J=6.78 Hz. 2 HY3.82(d, J=11.19, 2.37 Hz, 2 HI} 3.18 - 3.29 (m. 2 H) 209-223 (m, 1 HY 1.41 - 1.53 (mu 2 H) 1.28 - 1.38 (mn, 2 H), MS (ESF) m/z 422.1 (MEH.
Example 148 cyclopentyl[4-(1H-indazol-5 ~yi)~1 ~(tetrahydro-2H-pyran-4-yimethyl}- 1H-1.2,3-triazol-5- ylimethanone
The title compound was prepared according to the procedure outlined in Example 1198 substituting cyclopentanecarbonyl chloride for benzoyl chloride and Example 80A for benzyl azide. 'H NMR (300 MHz, DMSO-ds) 8 ppm 13.27 (s, 1 H) 8.18 (s, 1 H) 7.95 (5, 1
H) 7.68 (d, J=8.48 Hz, 1 H) 7.52 (¢, J=8.48. 1.70 Hz, 1H) 4.47 (d, }=7.12 Hz, 2 H) 3.85 (d,
F=11.53,2.37Hz, 2H) 3.18 - 3.30 (m, 2H)3.02- 3.14 (m, I H)2.00-2.17(m, 1H) 1.19 - 1.76 (m, 12 H). MS (ESI+) m/z 380.1 (M+H)".
Example 149
I-benzyl-4-(1H-indazol-5-y1}-1H-1 <.3-triazole-5-carboxylic acid
Example 149A
Methyl 1 -benzyl-4-(tributylstannyl}-1H-] .2,3-triazole-5-carboxylate
Methyi propialate (5.75 g, 68.4 mmol} was added to methyl
HY ethyl{tributylstannyl carbamate (26.9 g, 68.6 mmol) in a large sealed tube. The mixture was heated to 70 °C overnight. The mixture was cooled to ambient temperature and the vial was stirred unsealed for 10 minutes. Benzyl azide (10.2 mL. 81.6 mmol} was added, and the vial was rescaled and heated to 130°C overnight. The mixture was purified by silica gef chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 508.3 {M-HH)".
Example 1498
Methyl 4-(1-acetyl-1 H-indazol-3-y1}-1-benzyl-1H-1 -2,3-triazole-3-carboxylate
Example 149A (7.17 g, 14.1 mmol), Example 87A (4.02 g, 14.1 mmol), dichlorobis(triphenylphosphine jpalladium(TT) (1.01 mg, 1.44 mmol), and copper thiophene-2- carboxylate (4.07 mg, 21.3 mmol} were cornbined in toluene (55 mL) in a large scaled tube under an inert atmosphere of nitrogen. The tube was sealed and heated at 150 °C for 30 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography cluting with a gradient of 10-50% ethyl acetate in hexanes to afford the title compound. MS (ESH)ym/z 376.1 (M+H)
Example 149C
I-benzyl-4-( 1 H-indazol-5-y1}-1H-1 2 3-rriazole-3 carboxylic acid
Example 1498 (3.40 mg, 9.06 mmol) was dissolved in tetrahydrofuran (100 mL), methanol (10 mL), and water (10 mL), and potassium hydroxide (1.63 g. 29.1 mmol) was added. The mixture was stirred for 3 hours, was diluted with ethyl acetate and washed with 1
N hydrochloric acid, washed with brine, and the combined organic layers were dried over sodium sulfate. After filtration, the solvents were removed under reduced pressure to afford the title compound. *H NMR (300 MHz, DMSO-d,) 8 ppm 13.16 (s, 1 HY 8.11 - 8.18 (m, 2
H)7.66-7.76 (m, 1 H) 7.54 - 7.62 (m, 1 H)7.31-7.43 (m, 3H) 7.22 -7.20 (m, 2 H) 5.93 (s., 2H). MS (ESF) m/z 320.0 (M+H)*,
Example 150 5~{5-(4-fucrophenyl)-1 ~{4-{trifluorom cthylibenzyl]-1H-1 wn d-triazol-d-ylte1 Heundazol-3. anne
Example 150A
I-{Azidomethvi}-4-( trifluoromethyilbenzene
Sodium azide (2.30 g, 35.4 mmol} was added to a solution of 4. {trifluoromethylibenzyl bromide (4.26 g, 17.8 mmol) dissolved in dimethy! sulfoxide (15 ml} and stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure to afford the title compound, The crude product was used in the next step without further characterization.
Example 1508 5-(4-F fuoropheny!j-4-(tributylstannyl)-1 -( A-(triffuoromethyl)benzyl)-1H-1.2 3-triazole 4-Fluorophenyl acetylene (524 mg, 4.36 mmol) was added to 1, i-tributyl-N,N- dimethylstannanamine (146g, 4.37 mmol), and the mixture was stirred in a sealed vial at 30 °C for 30 minutes. The mixture was cooled to ambient temperature, and the vial was stirred unsealed for 10 minutes. Example 150A (1.28 g, 6.30 mmol) was added and the vial wag resealed and heated to 130 °C overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5-35% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 612.3 (M+H)".
Example 150C 2-Fluoro-5-(5«(4-fluorophenyl)- 1 ~(4-(trifluoromethyl)benzyl)-1H-1 2, 3-triazol-4- vhbenzonitrile
Example 150B (485 mg, 0.795 mmol}, 5-bromeo-2-fluorehenzonitrile (i43 mg, 0.715 mmol), dichlorobis(triphenylphosphine)palladium(11) {49 mg, 0.070 mmol), and copper thiophene-2-carboxylate {205 mg, 1.08 mmol) were combined in toluene (2.0 mL) ina 4 mL vial under an inert atmosphere of nitrogen. The vial was sealed and heated at 150°C for 30 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10-50% othyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 441.2 (M+H)",
Example 1500 5-{5-(4-fi uorophenylj-1-[4- trifluoromethyl benzyl 1H-1,2,3-tr1az0 l-4-y1}~1H-indazol-3- amine
Example 150C was treated with hydrazine hydrate (1.0 mL} in ethanol (1.0 mk}, and the reaction mixture was stirred and heated to 65°C for 3 hours. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica ge! chromatography eluting with a gradient of (0-69 methanol in dichloromethane to afford the fitle compound. 'H NMR (300 MHz, DMEO-ds) 8 ppm 11 42 (5, 1 H)8.04 (s, 1 H) 7.67 (d, J=%.14 Hz, 2H) 7.26 - 7.41 (m4 H) 7.22 (d, }=8.48 Hz, 2 H} 7.03715 (m, 2H) 5.62 (s, 2 H) 3.36 (s, 2 H). MS (ESF) m/z 453.1 (MH)
Example 131 >-[1-benzyl-5 ~(4-fluorophenyl)-1H-1 +2, 3-triazol-4-y1}-1 H-indazol-3 -amine
Example 151A
I-Benzyl-5-(4-] uorophenyl)-4-{tributylstannyi)- IH-1,2,3 triazole 4-Fluorophenyl acetylene (325 mg, 4.37 mmol} was added to LL -tributyl-N,N- dimethyistannanamine (1.46 ¢, 4.37 mmol), and the mixture was stirred in a sealed vial at 50 °C for 2 hours. The mixture was cooled to ambient temperature, and the vial was stirred unsealed for 10 minutes. Benzyl azide (850 ul, 6.80 mmol) was added, and the vial was rescaled and heated to 130 °C overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5-35% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 544 4 (M-+HY
Example 151B 541 -Benzyl-5-(4-fluorophenyl)- H-1.2,3-riazp]-4-yi }-2-fluorobenzonitrile
Example 151A (361 mg, .666 mmol), 3-bromoe-2-flucrobenzonitrile (119 mg, 0.595 mmol), dichlorobis(triphenylphosphine patladium(Il ) {45 mg, 0.064 mmot), and copper thiophene-2-carboxylate (193 mg, 1.01 mmol) were combined in toluene (20midinad mL vial under an inert atmosphere of nitrogen. The vial was sealed and heated 150°C for 30 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes (0 afford the title compound. MS (ESI) m/z 373.0 (M~+H)" & Example 1510 5-[F-benzyl-5-(4-fi uorophenyl}-1H-| 2, 3riazol-4-yl]-| H-indazol-3-amine
Example 151B (135 mg, 0.363 mmol) was treated with hydrazine hydrate (1.0 ml} in ethanol (1.0 mL) and stirred and heated to 65°C for 3 hours, The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0-6%, methanol in dichloromethane to afford the title compound. 'H NMR (300 MHz, DMSO-d;) 6 ppm 11.40 {(s, 1 H) 8.02 (5,1 H) 7.24 - 7.38 {m, 7H) 7.03 - 7.14 (m, 2 8) 6.98 (d, J=7.29, 2.20 Hz, 2 Hj) 5.50 (s,2H)535 (5,2 HY. MS (ESI) m/z 385 1 (M+HY".
Example 1352 [4-(1 H-indazol-5-yl)-1- tetrahydro-2H-pyran-4-yimethyl)- IH-123 -triazol-5-yl){tetrahydro- 2H-pyran-4-y|}methanone
The title compound wag prepared according to the procedure outlined in Example 1198 substituting Example 80A for benzy! azide and tetrahydro-2H-pyran-4-carbony! chioride for benzoyl chioride. 'H NMR (300 MHz, DMSO-d) 5 ppm 13.30 (s, 1 Hy $18 (s,
TH) 8.00 (s, 1H) 7.69 (d, J=8.48 Hz, 1 H) 7.53 (d. J=8.65, 1.53 Hz, 1 H) 4.48 (d, J=7.12 He, 2H)3.79-3.90 (m, 2 Hy3.62-3.74 (m, 2 H)3.18-330(m, 2 HY2.76 - 2.88 (m, 1 1) 2.64 - 2.76 (m, 2 HY2.00-2.17 (m, 1H} 1.20 - 1 58 (m, 8 HY. MS (EST+) m/z 396.0 {(M-+H)",
Example 153 5-{I-benzyi-5 -(2-methylphenyl)-1H-1 2,3~triazol-d-yl]- 1 H-indazole
Example 153A 1-Benzyl-3 -0-tolyl-4-{tributylstannyl)-] H-1.2, 3-iriazole 2-Ethynyl toluene (456 ul, 3.62 mmol) was added to L11-tributyl-N,N- dimethylstannanamine (1.21 g, 3.62 mmol), and the mixture was stirred in a sealed vial at 70 °C for 3 hours. The mixture was cooled to ambient temperature, and the vial was stirred unsealed for 10 minutes. Benzyl azide (678% ul, 5.42 mmot} was added, and the vial was reseated and heated to 130°C overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5-45% ethyl acetate in hexanes io afford the utle compound. MS (EST+) m/z 5390.8 (M+H) 3 Example 153R i-(5~(1-Benzyl-5-o-tolyvi-1H-1 2. 3-triazol-4-vD)- 1 H-indazal-| -vlethanene
Example 153A (119mg, 0.221 mmot), Example 87A (63 mg. 0.221 mmol}, dichlorobis(triphenyiphosphine)palladium( II) (16 mg, 0.023 ramol), and copper thiophene-2- carboxylate (65 mg, 0.341 mmol} were combined in toluene (2.0 mL) in 2 4 mL vial under an ert atmosphere of nitrogen. The vial was sealed and heated at 150°C for 20 minutes. The mixture was absorbed on silica gel and purified by sitica gel chromatography eluting with a gradient 5-45% of ethyl acetate in hexanes fo afford the title compound. MS (ESH) m/z 408.7 (M+HY".
Example 153C 5-[1-benzyl-5-(2 -methylphenyl)-1H-1 .2,3-triazol-4-y1]-1H-indazole
Example 153B (42 mg, 0.103 mmol) was dissolved in tetrahydrofuran (2.0 mL) and water (0.3 mL), and potassium hydroxide (48 mg, 0.856 mmol} was added. The mixture was stirred for 1 hour, was diluted with methylene chloride and washed with water, The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 1-6% methanol in dichloromethane te afford the title compound. 'H NMR (300
MHz, DMSO-dy) 8 ppm 13.07 (s, TH) 7.97 (s, 1 H) 7.73 (s, | H) 7.44 - 7.53 (m, 3 H) 7.39 (t,
J=6.95 Hz, | H) 7.28 - 7.35 (m, 2H) 7.21 - 7.29 (m, 3 H) 6.86 - 6.95 (m, 2 7} 5.28 - 5.45 (im, 2H) 1.5% (2, 3H). MS (EST+) m/z 366.1 (M+H)".
Example 154 5-11 -benzyl-5-[(4-methylpiperazin- L-ylcarbonyi]-1H-1 -2,3-riazol-4-y1}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 81B substituting Example 149C for Example 81A and 1 -methyl piperazine for piperidine and tetrahydrofuran for dimethylformamide. 'H NMR (300 MHz, DMSO-d) & ppm 13.20 (s,
H)8.16 (s, 1 HY 7.96 (s, | H) 7.57 - 7.60 (m, 2H) 7.31 - 744 (m, 3 1) 7.23 - 7.30 {m, 2 H) 5.36 -5.83(m, 2 H) 3.40 - 3.65 (m, F=4.75 Hz, 2 H) 2.38 - 2.49 (m, 2H) 2.10 - 2.22 (m, 2 H)
L&I (s, 3H) 1.40 (t, }=4.92 Hz, 2 HY. MS (EST+) m/z 402.2 (MH).
Example 135 1-{[1-benzyl-4-(1H-indazol-5-yl}-1H-1 -2,3-triazol-3-yljcarbonyl} piperidin-4-gl
The title compound was prepared according to the procedure outlined in Example 818 substituting Example 149C for Example 81A and 4-hydroxy piperidine for piperidine and tetrahydrofuran for dimethylformamide. 'H NMR (300 MHz, DMSC-ds) 8 ppm 13.15 - 13.24 (m, 1 H) 8.16 (s, 1 H) 7.97 (s, | H} 7.55 - 7.68 (m, 2 H) 7.32 - 7.43 (m, 3H) 723-730 {m, 2H} 35.41 - 5.83 (mn, J=65.10 Hz, 2 HY 4.58 (d. J=3.39 Hz, 1 H) 3.74 - 3.91 (m, I H) 3.37 = 348 (m, ZH) 2.66 - 2.79 (m, § HY 2.25 - 2.47 fm, TH) 1.54 168 (m, 1 HY 1.20 - 1.36 (rn, 14 PHY 6.74 - 0.90 (m, 1 H) 0.40 - 0.60 (m, | Hy. MS (BSI+) m/z 403] (M-+HY"
Example 156 [-acetyl-5-[5- 4-fluorophenyl)-1-(tetra hydro-2H-pyran-4-vimethyi)- LH-1,2,3-triazol-4-y1}-
Til-indazole
Example 156A 5-(4-Fluorophenyl)-1-(( tetrahydro-2H-pyran-4-ylymethyl}-4-( tributylstannyl)-1H-1.2,3- triazole 4-Fluorepheny! acetylene (440 ul, 3.88 mmol} was added to L1,1-tributyl-N,N- dimethylstannanamine {1.30 g. 3.89 mmol), and the mixture was stirred in a sealed vial at 50 °C for 40 minutes. The mixture was cooled to ambient temperature, and the vial wag stirred unsealed for 10 minutes. Example 80A (710 uL, 5.6% mmol) was added and the vial was rescaled and heated to 130°C overnj ght. The mixture was purified by silica gel chromatography eiuting with a gradient of 5-50% ethy! acetate in hexanes to afford the title compound. MS ( ESE) m/z 552.4 (M+H)",
Example 1568 l-acetyl-5-[5-(4-fluoropheny])-1 ~(tetrahydro-2H-pyran-4-ylmethy!)- H-1,2,3-triazol-4-yI}- 1H-indazole
Example 156A (433 mg, 0.787 mmol), Example 87A (205 mg, 0.717 mmol), dicklorobis(triphenylphosphine)palladium(ii) {35 mg, 0.078 mmol), and copper thiophene-2- carboxylate (224 mg, 1.17 rumol} were combined in toluene {2.0 mL) in a 4 mL vial under an inert atmosphere of nitrogen. The vial was sealed and heated to 150°C for 20 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-45% cthyl acetate in hexanes, and was tritarated with methanol to afford the title compound. 'H NMR. (300 MHz, DMB0-ds) & ppm 8.40 - 8.48 (m, J=0.68 Hz, H) 8.25 (d, J=B.82 Hz, 1 H} 7.82 - 7.91 {m, | H)7.73 (d,J=8.48, 1.70 Hz, 1 H} 7.50 - 7.60 {m, 2 1) 738-749 (m, 2M 4.13¢d, J=7.12 Hz. 2 H)3.76 (d, }=11.36, 254 Hz, 2 HY 3.10 - 3.25 {m,
ZHY270(s, 3H) 1.86- 2.08 (m. 1 H) 1.37 (d, J=12.55, 1.70 Hz, 2 HH} 1.03 - 1.23 {m, 2 H).
ME (ESI) m/z 420.2 (M+H)",
Example 157
HO -benzyl-4-(1H-indazol-5-y1 1 N, N-din ethyl-1H-1,2,3-triazole- 5-carboxamide
The title compound was prepared according to the procedure outlined in Example 81B substituting Example 149C for Example 81A and dimethylamine for piperidine and tetrahydrofuran for dimethylformamide. 'H NMR (300 MHz, DMSO-ds) 6 ppm 13.19 {s, 1
H)8.15(s, | H) 7.96 (t, }=1.19 Hz, 1 H) 7.62 (d, J=1.36 Hz, 2 H) 7.33 - 7.44 (m, 3 H} 7.24 - 7.33(m, 2H) 5.59 (s,2 FI} 2.92 (s, 3 H)2.21 (s, 3H). MS (ESI) m/z 347.1 (M+HY".
Example 158
N,1-dibenzyl-4-(1H-indazol-5-y}-1H-1.2.3 -triazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 81B substituting Example 149C for Exampic 1A and benzyl amine for piperidine and tetrahydrofuran for dimethylformamide. 'H NMR (300 MHz. DMSO-ds) 8 ppm 13.15 (3, 1
H) 9.35 (t, J=6.10 Hz, 1 HY 8.0] (d, J=12.55 Hz. 2 H) 7.68 (d, J=8.82, 1.36 Hz, 1 H) 7.53 (d,
J=8.82 Hz, t H) 7.17 - 7.41 (m, 10 H) 5.66 (s,2 H) 4.41 (d, }=6.10 Hz, 2 H). MS (ESI) m/z 409.1 (M+Hy'.
Example 139
N-(2-hydroxy-2-phenylethyl})-3-( 1 B-indazol ~5-y1)-N-methylisoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 818 substituting DL -alpha-{ methylaminomethylYbenzy! alcohol for piperidine. "H NMR (300
MHz, DMSO-d) 8 ppm 13.01 (5, TH) 8.29 (5, 1 HY 8.17 (5, 1 H) 7.73 - 7.85 (m, 1 BH) 7.62 - 7.72{m, 1 H} 7.16 - 7.43 (m, 3 H) 6.86 (5,1 H) 5.17 (d, J=4.39 Hz, 1 H) 4.89 (8, 1 FH) 3.71 (d,
J=5.49 Hz, 2H) 3.10 (s. 3 H). MS (ESI) m/z 363.1 (M+R). i21
Example 160
N-[(18)-2-hydroxy-1 -phenylethyl]-5-(1 H-indazol-5-yDisoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 818 substituting (5}-2-amino-Z-phenylethano! for piperidine. 'H NMR (300 MHz, DMSO. de) 8 ppm 13.37 (5. 1H) 9.05 (d. J=B.14 Hz, 1 HI) 8.40 (5. THY 8.23 (s, 1 H) 7.809 (4d. J=8.65, 1.53 Hz, 1 H) 7.70 (d, J=8.82 Hz, 1H) 7.20 - 7.46 (m. 6 H) 5.02 - 5.13 (m, 1 H) 4.98 (i
J=5.59 Hz, 1 H) 3.61 - 3.82 (m, 2 H}. MS (ESI+) m/z 349.0 (M+HY
Example 16] 0 N-benzyl-N-{ 2-hydroxyethyl)-5-( Heindazol-3-yDisoxazole-3 -carboxamide
The title compound was prepared according to the procedure outlined in Example R1B substituting 2-(benzylamino)ethano! for piperidine. "H NMR (300 MHz, DMSO-ds) 6 ppm 13.37 (s, 1 H) 9.05 (d, 1=8.48 Hz, 1 H) 8.40 (s, 1 1) 8.23 (5, 1H) 7.89 (d, }=8.65, 1.53 Hz, I
HY 7.70 (d, I=8.82 Hz, 1 HY722-745(m, 6 HY5.02-5.14 (m, 1 HY 4.98 (1, J=5.76 Hz, | Hy) 3.61381 (m, 2H). MS (ESI+) m/z 349.0 (M+H)",
Example 162 51 -benzyl-5-(2-methylphenyi)- 1H-1 2,3-triazol-4-yl]-3-methyl- 1H-mndazole
Example 1624
I-(5-Bromo-3-methyl-1H-indazol-1 ~ylhethanone 5-Bromo-3-methyl-1H-indazole (838 mg, 3.97 mmol) was dissolved in methylene chioride (15 mL) and ditsopropylethylamine (0.7 mL} Acetic anhydride (500 ul. 529 mmol) was added and the mixture wag stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate, washed with 1 N sodium hydroxide followed by 1 N hydrochioric acid and then brine. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to afford the title compound. MS {ESI+)y m/z 252.7 (MHD
Example 162R
I-(5-(1 -Benzyl-5-o-tolyl-1H-1 12: 3-triazol-4-yl)-3-methyl-1 H-indazol-1-yDethanone
Example 153A (436 mg, 0.808 mmol), Example 162A (203 mg, 0.810 mmol}, dichlorobis(triphenyiphosphine)palladium(I) (56 mg, 0.080 mmol}, and copper thiophene-2-
carboxylate (239 mg, 1.25 mmol) were combined in toluene (2.0 mL) in a 4 mL vial under an inert atmosphere of nitrogen. The vial was scaled and heated 150°C for 30 minutes, The mixture was absorbed on silica gel and purified by silica gel chromatography chuling with a gradient of 16-50% ethyl acetate in hexanes to afford the title compound. MS (BESi+) m/z 422.6 (M+HY
Example 1620 5-[1-benzyl-5-(2 -methylphenyl)-1H-1 +2,3-triazol-4-y1]-3-methyl- H-indazole
Example 162B (202 mg, 0.54% mmol} was dissolved in tetrahydrofuran (5.0 ml), methanol (0.5 mb} and water (0.3 mb} and potassium hydroxide (133 mg, 2.37 mmol) was added. The mixture was stirred for 1 hour and then wag diluted with methylene chloride and washed with water, The organic fayer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 30-80% ethyl acetate in hexanes to afford the title compound. 'H NMR (300 MHz, DMSO-ds) 8 ppm 12.63 (8, 1 HY 7.70 (s, 1 H) 744-7352 (m, 1 H)7.38-7.43 (m, 1 H) 7.29 - 7.38 (m, 4 H) 7.22 - 7.29 (m, 3 H) 6.89 - 6.96 (im, J=6.44, 3.05 Hz, 2 H) 5.30 - 5.4% (m, 2 H) 2.32 (5, 3 H) 1.58 {s, 3 H). MS (ESI+} m/z 380.1 (M+H).
Example 163 5-[1-benzyl-5-(2 -methylphenyi)-1H-1 22, 3-triazol-d-y]- 14 -indazol-3-amine
Example 163A 5-(1-Benzy! ~5-0-tolyl-1 H-1.2.3-triazol-4-y1)-2-fluorobenzonitriie
Example 153A (430 mg, 0.834 mmol), 5-brome-2-fluorobenzonitrile {167 mg, 0.835 mirol), dichlorobis(triphenytphosphine)palladiumi I) (56 mg, 0.080 mmol), and copper thiophene-2-carboxyiate {242 mg, 1.27 mmol} were combined in toluene (Z.0mL} in a 4 mL vial under an inert atmosphere of nitrogen. The vial was sealed and heated at 150°C for 30 minutes. The mixture wag absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes to afford the titte compound. MS (ESI+) m/z 369.2 (M+H)".
Example 1638 5-1 “benzyl-5-(2-methylphenyl)-1H-1,2 3-triazol-4-yI]- [H-indazol-3-amine
Example 163A (202 mg, 0.548 mmol) was treated with hydrazine hydrate {1.0 mL) in ethanol (1.0 mL) and stirred and heated to 60 °C overnight. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 35-85% ethyl acetate in hexanes to afford the title compound. 'H NMR (300 MHz, DMSO-dg) & ppm 11.38 (5, IT HO
BIT(s, TH)741-74%(m 1H) 733-740 (mn, J=6.95,695 He. L HY 7.28 - 7.32 (mm, 2 ID) 7.21 -7.28 (m, 3H) 7.00 - 7.06 (m, 1 H) 6.86 - 6.05 (m, 3 H) 3.27 - 5.44 (m, 4 H) 1.58(s, 3
H). MS (ESI) m/z 381.1 (M+H)"
Example 164 2-42-[1-{1H-indazol-5-y])- 18-1.2,3-triazol-4-yllethyl}- 1 H-isoindole- | S{2H)-dione
The title compound was prepared according to the procedure outlined in Example 88 substituting 2-(but-3-ynylisoindolime-1.3-dione for 3-phenyl-1-propyne. The crude product was subjected fo 25% TFA / dichloromethane and purified by reverse-phase FPLC using an acetomtrile/water 0.1% TFA gradient elution method to afford the title compound. 'H NMR
I5 (400 MHz, DMSO-dg) 8 ppm 13.33 (s, 1 Hy 8.65(s, 1 H} 8.22 (s, 1 H) 8.18 (d, J=1.53 Hz. 1
B) 7.78 - 7.90 (m, SH) 7.71 - 7.75 (m. 1 H) 3.92 (t.J=7.21 Hz, 2 H) 3.08 (t, J=7.21 Hz, 2 H).
MS (EST+) m/z 359.0 (M+H)",
Example 165 5-{4-[(2.,4-dichlorophencxyymethyl]-15-1,2_3-triazol-1 -yl}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 8&8 substituting 2,4-dichloro-] -(prop-2-ynyloxyibenzene for 3-phenyl-1-propyne. The crude product was subjected to 25% TFA / dichloromethane and was purified by reverse-phase
HPLC using an acetonitrile/water 0.1% TEA gradient elution method to afford the title compound. 'H NMR (400 MHz, DMSO-ds) 6 ppm 13.36 (5. 1 FI) 8.93 (s, 1 11) 8.28 (d.
J=1.55 Hz, 1 H) 823 (s, 1 H} 7.88 (d, J=8.90, 1.84 Hz, | FH) 7.76 (d, J=8.90 Hz, 1 H) 7.59 (d,
J=2.46 Hz, 1 H) 7.39 - 7.49 (m, 2H) 5.37 (5. 2 H). MS (EST+) m/z 359.9 (M+H)".
Example 166 5-{4-{(2,6-dichlorophenoxymethyi]-1H-1,2 3-triazol-1 ~yl}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 88 substituting 1.3 -dichloro-2-(prop-2-ynyloxy)benzene for 3-phenyl-1-propyne. The crude product was subjected to 25% TFA / dichloromethane and purified by reverse-phase HPLC using an acetonitrile/water 0.1% TEA gradient elution method to afford the title compound. "H NMR (500 MHz, DMSO-d) & ppm 13.39 (5, THY B97 (5, 1 H) 8.29 (d. }=1.53 Hz, 1 H) 8.24 (5, 1 H) 7.89 (d, }=9.00, 1.98 Hz, I H) 7.76 (4, J=8.85 Hz, | H) 7.51 - 7.55 {m, 2H) 7.19 - 7.26 (m, J=8.24, 8 24 Hz, | H) 5.22 {5,2 HH} MS (ESF) m/z 359.9 (MH)
Example 167 3-[5-(4-fluorephenyl)-i-{ tetrahydre-2H -pyran-4-yImethyl}-1H-1 2.3-triazol-4-yl]-1H- indazole
Example 1568 (16% mg, (401 mmol) was dissolved in tetrahydrofuran (5.0 mi), methanol (0.5 ml} and water (0.5 mL) and potassium hydroxide (138 mg, 2.46 mmol) was added. The mixture was stirred for 1 hour, and was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 0-7% methano! in dichloromethane to afford the tile compound. "HNMR (300 MHz, DMSO-d, & ppm 13.08 (s, 1 H) 8.02 (s, | H) 7.77 (s, 1
H)7.50- 7.58 (m, 2 H) 7.37 - 7.49 (im, 4 Hy 4.11 (d, J=7.12 Hz, 2 H) 3.76 {(d, J=11.53,2.71
Hz, 2TH) 3.11 -3.24 (m, 2 HI) 1.88 - 2.03 (m, 1 H) 1.30- 1.43 (m. }=12.72. 1.86 Hz, 2 H) 1.04 - 1.22 (m, 2 H). MS (ESI+) m/z 378.1 (M=~)".
Example 168 1-{{]-(1H-indazol-5-yI1H-1 2,3-triazol-4-yl|methyl} -1H-indazole
Exampie 168A }-{Prop-2-vnyl}-1H-indazole
Indazole (530 mg. 4.49 mmol) was dissolved i dimethylformamide (4 mL). Sodium hydride (60% suspension in mineral oil, 231 mg, 3.78 mmol) was added slowly, and the mixture was stirred for 10 minutes. Propargy! bromide (80% wit in toluene, 5.0 mL) was added, and the mixture was stirred at ambient temperature overnight. The mixture was diluted with ethyl! acetate, washed excessively with water, absorbed on silica gel, and purified by silica gel chromatography eluting with a gradient of 5-30% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 157.1 (M~+H)".
Example 168B 1-{[1-(1H-indazol-5-y1)-1H-1 2,3-triazol-4-ylimethylt -1 H-indazole
The title compound was prepared according to the procedure outlined in Example 88 substituting Example 168A for 3-phenyl-l-propyne, 'H NMR (300 MHz, DMSO-d) § ppm 13.36 (s, LH) 8.78 (5, 1 H) 8.22 (4, J=2.03, 0.68 Hz, 1 HY 8.20 (s, 1 H3 8.10 (d, J=1.02 Hz, 1
HY 780-787 (m, 2 By 7.75 - 7.80 (on, 1H 7.68 - 7.74 ¢m, 1 HY 7.39 - 7.46 (m, IH) 7.03 - 719 Gm 1H) 5.81 (s, 2 HY), MS (EST) m/z 316.0 (M+H)
Example 169 5-{1-benzyi-5-(piperidin-1 -yicarbonyly-1H-1.2 3 azol-4-yl}-1H-indazole
The title compound was prepared according wo the procedure outlined in Example 81B substituting Exemple 149C for Example 814 and tetrahydrofuran for dimethylformamide. "HNMR (300 MHz, DMSC-dg) 8 ppm 13.20 (s, 1 HY 8.16 (s, 1 H) 7.95 - 8.00 {m, }=1.02 Hz, 1H) 7.62 -7.68 (m, 1 H) 7.57 - 7.63 (mn, 1 Hy 7.31 -7.44 (m, 3H) 7.24 - 7.30 fm, 2 H)5.36- 5.84 (m, F=69.17 Hz, 2 11) 3.43 - 3.59 (m, 2H) 2.43 - 2.59 (m, 2H) 1.17 - 1.46 (m, J=39.67
Hz, 4 H) 0.49 - 0.65 (m. 2 H). MS (ESI+) m/z 387.1 (M+H)",
Example 170 3-[3-(2-methyiphenyl)-1-(tetrahydro -2H-pyran-4-yimethyvi)-1H-1 .2,3-riazol-4-y1]-1H- indazole
Example 170A 1-(( Tetrabydro-2H-pyran-4-y Dmethyl)-5-0-tolyl-4-(trib utylstannyl)-1H-1,2 3-triazole 2-Ethyny! toluene (376 mg, 4.57 mmol) was added to 1,1,1-tributyl-N,N- dimethylistannanamine (1.53 g. 4.58 mmol), and the mixture stirred in a sealed vial at 70 °C for 2 hours. The mixture was cooled to ambient temperature, and the vial was stirred unsealed for 10 minutes. Example 80A (648 mg, 4.5% mmol) was added and the via] Was rescaled and heated to 130 °C overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5-50% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 548 4 (M+H)",
Example 170B
I-(5-(1-{(Tetrahvdro-2H ~pyran-4-ylymethyl)-5-o-tolyl-1Fi-1,2. 3-triazol ~4-yl}-1H-indazol-]- yhethanone
Example 170A (432 mg, 0.791 mmol}, Example 87A (222 mg, (.776 mmol),
dichlorobis(triphenylphosphine)palladiumI) (58 mg, 0.083 mmol), and copper thiophene-2- carboxylate (231 mg, 1.21 mmol) were combined in toluene (2.0 mL) in a 4 mL vial under an mnert atmosphere of nitrogen. The vial was sealed and heated at 150°C for 20 minutes. The mixiure was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 20-70% ethyl acetate in hexanes to afford the title compound. MS (EST+) m/z 416.2 (M+).
Example 170C
S-[5+(Z-methylphenyD-1- tetrahyydro-2H-pyran-d-yimethy! 1-12, 3 triazol-d-y 11-1 H-
HO indazole
Example 1708 (184 mg, 0.443 mmol) was dissolved in tetrahydrofuran (3.0 mi), methanol (0.3 mL), and water (0.3 mL) and potassium hydroxide (140 mg, 2.50 mmol) was added. The mixture was stirred for 3 hours, and was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gei chromatography eluting with a gradient of 35-100% ethyl acetate in hexanes to afford the title compound. 'H NMR (300 MHz, DMSC-ds) 8 ppm 13.08 (8, 1H) 7.98 (5,1 H) 7.68 - 7.74 (mm, J=1.02, 1.02 Hz, 1 H) 7.49 - 7.56 (m. 1 H} 7.45 - 7.49 (m, 3 Hy 741 - 7.45 (m, 3=7.46 Hz, 2H} 4.10 (d, J=13.73, 6.95 Hz, 1 H) 3.89 (d,J=13.90, 7.80 Hz. 1 HY 3.77 (d, J=10.51. 2.73
Hz, 2H)3.10-3.24 (m, 2 H) 1.92 (5,3 H) 1.88 - 1.98 (m, | H) 1.26 - 1.43 {m, 2 H) 1.04 - 200 1.21 {m, 2 H). MS (ESI+) m/z 374.1 {M +H)".
Example 171 5-[5-(2-methylphenyl)-1 ~(tetrehydro-2H-pyran-4-ylmethy!)- 1H-1.2,3-triazol-4-y1]-1H- indazol-3-amine 23
Example 171A 2-Fluoro-5-(1-( (tetrahydro-2H-pyran-4-ylymethyl)-5 ~o-tolyl-1H-1,2,3-triazo] 4. yhbenzonitrile
Example 170A (411 mg, 0.752 mmol), 3-brome-2-fluorobenzonitrile (151 mg, 0.755 mmol), dichlorobis(triphenylphosphine ypailadium(Ir) {32 mg, 0.074 mmol), and copper thiophene-2-carboxylate (223 mg, 1.17 mmol) were combined in toluene (2.0 mL) in a 4 m1, vial under an inert atmosphere of nitrogen. The vial was sealed and heated 150°C for 30 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 10-50% cthyl acetate in hexanes to afford the title compound. MS (ESI) m/z 377.6 (M+H)",
Example 1718 5 -[5-(2-methyiphenyl)-1 ~{ tetrahydro-2H-pyran-4-yimethyl)- tH-1,2,31r azol-4-yl]-1H- indazol-3-aminc
Example 171A (175 mg, 0.465 mmol) was treated with hydrazine hydrate (2.0 mL} in ethanol (2.0 mL}, and the mixture was stirred and heated to 65 °C for 2 hours. The mixture was diluted with methviene chloride and washed with water. The organic layer was absorbed
I on silica gel and purified by silica gel chromatography eluting with a gradient of 1-89, methanol in dichicromethane to afford the title compound. ‘H NMR (360 MHz, DMSO- de) 8 ppm 11.39 (5, 1 H) 8.08 (s, 1 H) 7.45 - 7.55 (m, 1 H) 7.37 - 7.45 (m, 3 H) 7.01 - 7.08 (m, J=8.48 Hz, 1 H) 6.89 - 6.97 (m, 1 H) 5.34 (s, 2 H) 4.09 (d, J=13.73, 6.95 Hz, 1 H) 3.89 (d, }=13.73, 7.63 Hz, 1 H) 3.70 - 3.81 (m, 2 H) 3.08 - 3.04 (m, 2H) 1.91 (s, 3H) 1.84 - 1.99 (my, 1H) 1.22 - 1.41 (m, 2H) 1.04 - 1.20 (m, 2 H). MS (EST+) m/z 389.1 (MH).
Example 172 5-[1-benzyl-5-(morphol in-4-ylearbonyl}-1H-1 -2,3-triazol-4-y1]-1H-indazole
The title compound was prepared according to the procedure outlined in Example R1B substituting Example 149C for Example 81A, morpholine for piperidine, and tetrahydrofuran for dimethylformamide. 'H NMR (300 MHz, DMSO0-ds) 8 ppm 13.22 (3, 1 H) 8.18 (s, 1 H) 7.95 -8.03 (m, 1 H) 7.64 - 7.70 (m. 1 H)7.57- 7.64 (m, | H)7.33-745(m.3H)7.24- 731 (m, 2H) 5.76 (s, 1 H) 5.52 (s, 1 H)3.33-3.50(m, 4 H) 2.6] - 2.74 (m, 2H) 2.45 2.59 (m, 2
H). MS (EST+) m/z 389.1 {M+H)"
Example 173 5-1 -benzyl-5-(4-methoxyphenyl}- 1 H-1 »2.3-riazol-4-y1]-1H-indazol-3-amine
A vial under argon containing Example 1258 (50 mg, 0.12 mmol), 4- methoxyphenylboronic acid (20 mg, 0.13 mmol), PACly(dppf) dichloromethane (10 mg, 0.01 mmol) and potassium carbonate (33 mg, 0.24 mmol) in DME (2 mL) and water (0.2 mL} was capped and heated at 80°C in a heater shaker for 48 hours. The solvent was evaporated under reduced pressure, and the product was purified by reverse-phase HPLC using an acetonitrile/water 0.1% TEA gradient elution method to afford the titie compound. 'H NMR
{400 MHz, DMSO-d) 6 ppm 11.85 (s, 1 H) 8.18 (s, 1 H) 7.26 - 7.34 (m, 3 Hy 7.19725 (m,
ZHYT16-719(m, 2 H) 7.02 (t. }=8.13 Hz, 4 Hy 547 (5, 2H) 3.80 (s,3 H). MS (ESM) m/z 397.1 (MH),
Example 174
N-[(1S}-1-benzyl-2 -hydroxyethyl]-5-(1H -indazol-5-y1)i soxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 81R substituting (8)-(-}-2-amino-3-phenyl- I-propanol for piperidine. 1] NMR (300 MHz,
DMSO-ds) & ppm 13.36 (6. 1H} 8.47 ¢d, J=8.87 Hz. 1 HY838(s. 1 H) 8.22 (s, | HY 7.87 4d,
Ho F=8.82, 1.70 Hz, 1 H) 7.69 (d, 1=8.82 Hz, ] Hy 723-731 tm, 317.22 (5. THY 7.12 - 7.21 (m, I H)y4.90 (t, J=5.59 Hy, | HY 4.67 - 428 (m, 1 FH) 3.40 - 3.58 (m, 2H) 2.890 - 3.00 (m, 1
H)2.75- 2.86 (m, 1 HI). MS (ESF) m/z 363.0 (M+),
Example 1735
N-[(18,2R)-2 -hydroxy-2,3-dihydro-1H-inden- Loyi}-5-(1H-indazol-5 -yhisoxazole-3- carboxamide
The title compound wag prepared according to the procedure outlined in Example 81B substituting (15.2R)-(-)-cis-I-amino-2-indano] for piperidine. 'H NMR (300 MHz, DMSO- de) 8 ppm 13.38 (s, 1 I) 8.42 (s, 1 H) $.24 (s, 1H) 8.16 (d, }=R.48 Hz, 1TH) 7.91 (d, 1=8.82, 1.70Hz, 1H) 7.71 {d, J=848 Hz, 1 HY 7.45 (s, 1 H)}7.16 - 7.32 (m, 4 HY5.36-547 (m, 2 1) 4.50 -4.61 (m, 1 H) 3.14 (d, J=15.43, 5.26 Hz, | H)2.90 (d, 3-16.28, 1.7¢ Hz, 1 H). MS (ESI) m/z 361.0 (M-+H)",
Example 176 5-03 3-phenylmorpholin-4-ylicarbonylisoxazol-5-y) i-1H-indazote
The title compound wag prepared according to the procedure outlined in Example 818 substituting 3-phenylmorpholine hydrochloride for piperidine. 'H NMR {300 MHz, DMSO- ds) S ppm 13.38 (5, 1 H) 8.32 - 8.46 (m, 1H) 824 (s, 1 H) 7.81 - 7.96 (m, 1 H) 7.70 (d,
S=8.82 Hz, 1 H) 7.37 - 7.55 (m, 4 H) 7.26 - 7.37 (m, 2 H}5.34-571 (m, 1 Hy 4.51 (d,
J=1322Hz H) 3.78 - 4.39 (m, 3 H) 3.50 {t,/=11.36 Hz, 1 H) 3.33 - 3.41 {m, 1 H). MS (ESI) m/z 375.0 (M+H)"
Example 177
N-benzyl-5+( LH-indazol-5-ylisoxazole-3-carbox amide
The title compound was prepared according to the procedure outlined in Example 81B substituting benzylamine for piperidine. 'H NMR (300 MHz, Div S0-ds} & pom 13.36 {s,]
H)935(t J=6.27 Hz, 1 H) 8.40 (5. 1 H) 8.23 (s. 1H) 7.89 (d, J=8.82. 1.70 Hz, 1 H) 7.69 (d,
F=8.82 Hz, | H)7.33- 7.40 (m, 4 FH) 7.32 (s, 1 H} 7.22 - 7.30 (m, 1 Hy 4.48 (d, J=6.10 Hz 2
H). MS (ESI+) m/z 310.0 {(M+Hy".
Example 178
Io (15)-2-115-7) H-indazol-5-yl)isoxazol-3-yljearbonyl i-6,7-dimethoxy-1,2,3 4 tetrahydroisoquinolin-1 -yDmethanol
The title compound wag prepared according to the procedure outlined in Example 81B substituting (S}( 6,7-dimethoxy-1 2.3,4-tetrahydroisoquinolin- I-yhmethanol for piperidine,
MS (ESI) m/z 435.1 (M~+H)".
Example 179
N-[(1R}-3-hydroxy-1 -phenylpropyl]-5-(1 H-indazol-5-yhisoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 81B substituting ( R)-3-amino-3-phenylpropano] for piperidine. 'H NMR (300 MHz, DMSO- do) 8 ppm 13.37 (5, 1 H) 9.24 (d, J=8.48 Hz, 1 H) 8.39 (s, 1 Hy 8.23 {s, 1H) 7.88 (d, }=8 82.
L70 Hz, 1 B) 7.69 (d, I=8 82 Hz, 1 H) 7.38 - 7.46 (mm. 2H) 7.34 (t, }=7 46 Hz, 2H) 7.19- 730m, 2 H) 5.09- 527 (m, 1 H) 4.62 (t, 1=4.92 Hz, THY3.37-3.52 {m. 2H}2.00-216 (m, 1 H) 1.84 -2.00 (m, TH). MS (ESI+) m/z 363 | (M+).
Example 180
N-[(18)-3-hydroxy-1 -phenylpropyik-5-(1H-indazol-5 -yDisoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example §1B substituting ( S)-3-amino-3-phenylpropanol for piperidine. 'H NMR (300 MHz, DMSO- ds) & ppm 13.36 (s, 1 H) 8.24 (d, =8.14 Hz. 1 H) 8.39 (s, 1 Hy 8.22 (s, 1H) 7.88 (d, J=8.63, 1.53Hz 1H) 7.69 (d, J=8.81 He, 1 H) 7.37 - 7.45 (m, 2H) 7.29 - 7.37 (m, 2 Hy7.15-7.29 (m, 2 HF) 5.08 ~ 5.30 (m, | H) 4.55 - 4.68 (m, | Hy337-351(m, 2 H)2.00-2.14(m, 1 H)
LES - 1.99 (m, 1 H). MS (ESI+) m/z 363.0 (M+H)",
Example 181
N-2,3-dihydro-1H-inden-1 ~yi-5-(1H ~indazol-5-yliisoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example BIR substituting 1-aminoindane for piperidine, 'H NMR (300 MHz, DMSO-dg) 8 ppm 13.37 is, 1
OHY9I3(d, F814 Hz 1H) 839(s, 1 HD) B23 (5. 1 HI) 7.89 {d. J=8.82, 1.36 Hz, 1 H) 7.70 (d.
J=8.82 Hz IH} 7.35 (5, 1 H) 7.15 - 7.32 (m, 4 H) 5.55 {(g, }=7.91 Hz, 1 H)2.95-3.08 (m,
H)2.76-294 (mm, 1 H)2.37- 2.49 fm, | H)Z2.0T-2.05 (m, 1H). MS (ESI) m/z 345.0 (MH) i Example 182
N-2.3-dihydro-1 H-inden-2-y1-5-(1H-in dazol-5-yhisoxazole-3-carboxamide
The title compound wag prepared according to the procedure outlined in Example 81B substituting 2-aminoindane for piperidine. 'H NMR (300 MHz, DMSO-ds) & ppm 13.37 (s, 1
H) 9.08 (d, 3=7.46 Hz, 1 H) 8.39 (s, 1 H)8.23¢s, 1 H) 7.89 (d, =8.82. 1.70 Hz, 1 H) 7.69 (d,
J=R82Hz 1 HY 7.31 (s, 1H) 7.10 - 7.08 (m, 4 Hy 4.63 - 4.79 (m, 1 H) 3.24 (d, J=15.77, 7.63
Hz, 2H) 2.96 - 3.08 (m, 2 H). MS (ESH) m/z 345.0 (M+H)"
Example 183 5-(1H-indazol-5-y1)-N-( 1 -phenylpropyliisox azole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 81B substituting alpha-ethylbenzylamine for piperidine. 'H NMR (300 MHz, DMSO-ds) 8 ppm 1336 (s, 1 HY 9.18 (d, J=8.82 Hz. 1 H) 8.38 (s, 1 H)822 (s, 1 H) 7.88 (d. }=8.82, 1.36 Hz, 1
H) 7.69 (d, }=8.48 Hz, 1 H) 7.39 - 7.48 (m, 2 FH) 7.34 (1, }=7.29 Hz, 2 H)7.19- 7.29 (m, 2 H) 484-500 (m, 1 HY 1.60-2.04 {m, 2H) 0.91 (t, J=7.29 Hz, 3 H}. MS (ESI+) m/z 347.1 (MH)
Example 184 5-41 -benzyl-5-[3-(dimethylamino)phenyl}-I H-1.2,3-triazol-4-y1}-1H-indazol-3-amine
The title compound was prepared as a TEA salt according to the procedure outlined in
Example 173 substituting 3-(dimethylamine)phenylboronic acid for 4-methoxyphenylboronic acid. 'H NMR (500 MHz, DMSO-d) 8 ppm 11.52 (s. THY 8.17 (s, 1 H) 7.22 - 7.35 (m, 4 H) 7.08 -7.15(m, 2H) 7.03 (d, }=6.71 Hz, 2 H) 6.82 (d, J=8.39, 2.20 Hz, ] H)648-6.34 (m, 2
H) 5.47 (5, 2 H) 2.78 (s, 6 H). MS (ESI) m/z 410.2 (M~H)".
Example 185 5-{1 -benzyl-5-[4-(dimethylamino pheny!]- 1H-1,2,3-triazol-4-y1}-1H-indazol-2 -8Imine
The title compound was prepared as a TFA salt according to the procedure outlined in
Example 173 substituting A-{dimethylamine jphenyiboronic acid for 4-methoxyphenylboronic acid. "HNMR (500 MHz, DMSO-ds) 8 ppm 11.65 (8, HY 8.17 (s, 1 I) 7.23 = 7.38 (m, 3 Fl) 712-716 (m, 2H) 7.01 - 7.09 (m, 4 H) 6.74 - 6.78 (m, 2 H) 5.45 (5, 2 H} 2.95 (s, 6 H). MS (ESI+ym/z 410.2 (M+H)".
Example 186 i N= 3-[4-(3-amino-1 H-mdazol-5-y1}-1-benzyl- 1H-1 2, 3-triazol-5-yl|phenyl tacetamide
The title compound was prepared according to the procedure outlined in Example 173 substituting 3-acetamidophenylboronic acid for 4-methoxyphenylboronic acid. 'H NMR (500 MHz, DMSO-ds) 8 ppm 10.05 (5, 1H)8.14 (s, 1 H) 7.69 (d, =8.54 Hz, 1H) 7.54 (s, 1
H}7.41(t, }=793 Hz, 1 H) 7.24 - 7.32 (m, 3H) 7.08 - 7.16 (m, 2 H) 6.93 - 7.04 {m, 3 H) 5.48 (5.2H)2.01 (5,3 H). MS (ESIt) m/z 424.2 (M~+H)",
Example 187
N-{4-14-{3-amino-1 H-indazol-5-yi}-1-benzyl-1H-1 .2,3-triazol-3-ylphenyl } acetamide
The title compound was prepared according to the procedure outlined in Example 173 substituting 4-acetamidophenylboronic acid for 4-methoxyphenylboronic acid. "H NMR {500 MHz, DMSO-ds) & ppm 10.14 (5, ] H) 8.07 (s, 1 H} 7.66 (d, J=$.85 Hz, 2 H)7.24-7.32 (m, 3E) 7.18 - 7.22 (mm, 2H) 7.04 - 7.11 (m, 2H) 6.98 - 7.02 (m, 2 H) 5.48 (s,2H)535¢s,2 1) 2.04- 2.10 (m, 3 H). MS (ESI) m/z 424.1 (M+H)Y".
Example 188 5-1 1-benzyl-5-[3-(1H-pyrazol-1 -yhphenyl]-1H-1 2. 3-triazol-4-y[} -1H-indazol-3-amine
The title compound was prepared accordmg to the procedure outlined in Example 173 substituting 3-(1H-pyrazol-} ~yDphenylboronic acid for 4-methoxyphenylboronic acid. 'H
NMR (500 MHz, DMSO-d) 8 ppm 11.40 (s. 1 H) 8.45 (d, J=2.75 Hz, | H) 8.09 (s, 1 H) 7.99 (d.J=8.24, 1.53 Hz, 1 H) 7.80 - 7.85 (m. 1H) 7.74 (d,J=1.83 Hz, 1 H) 7.56 (t, J=7.93 Hz. 1
H) 720-730 (m, 3H) 7.06 - 7.16 (m, 3H) 6.98 - 7.04 (m, 2 H) 6.53 - 6.54 {m, 1 H) 5.55 (s, 2H) 5.35 (s, 2H). MS (BESI+) m/z 4332 (M+HY".
Example 189 3-[1-benzyl-5-(1 ~methyl-1H ~pyrazol-4-y1-1H-1 2,3-triazol-4-y1}-1H-indazo}-3-amine
The title compound was prepared according wo the procedure outlined in Example 173 substituting t-methyl-1H-pyrazol-4-y boronic acid for 4-methox ypbenylboronic acid, 'H
NMR (360 MHz, DMSO0-dg) 8 ppm 11.78 (5.1 Hy 8.11 (s, THY 7.87 (5, 1 H} 743 (s, 1 Hy 727-741 (m, 4 H) 7.24 (d, }=% 54 Hz, IH) 7.05- 7.11 (m, J=7.00 Hz, 2 H) 5.54 (5, 2 H) 3.86 (s, 3 H). MS (ESI*) m/z 370.9 (M-+H)".
Example 190 3-T4-(G-amino-1 H-indazol-5-y]}- ~benzyl-1F-1,7, 34 azol-5-yli-N-phenylbenzamide
The title compound was prepared according to the procedure outlined in Example 173 substituting 3-(phenylcarbamoyl)phenylboronic acid for 4-methoxyphenylboronic acid. 'H
NMR (500 MHz, DMSO-d) Sppm 11.41 (s,1 HY 10.22 (8. TH)8.07-8.12(m, 2 H} 7.95 (5,
VH) 7.73 (d, 1=7.63 Hz, 2 H) 7.60 (t, J=7.78 Hz, 1 H) 7.43 (d, J=7.63 Hz, | H) 7.32 - 7.36 (m,2H)7.21-7.30 (m, 3 H) 7.05 - 7.15 (m, 3 H) 7.00 (d, J=6.71 Hz, 2H) 5.54 (5,2 H} 5.36 {s, 2 H). MS (ESI+) m/z 486.2 (M+H)".
Example 19] 3-{4-(3-amino-] H-indazol-5-y1)-1 -benzyl-1H-1,2.3 ~triazol-5-yl1}-N-benzylbenzamide
The title compound was prepared according to the procedure outlined in Example 173 substituting 3-(benzylearbamoyl)phenylboronic acid for 4-methoxyphenyiboronic acid. 'H
NMR (500 MHz, DMSO-ds) 6 ppm 11.41 (5, 1 I) 9.04 (t, J=5.95 Hz, 1 H) 8.07 (s, 1 H) 8.01 (d, J=7.93 Hz, 1 H) 7.85 (5, | H) 7.56 (t, J=7.78 Hz, 1 H) 7.41 (d, }=7.63 Hz, 1 H) 7.21 - 7.35 (mm, 8H) 7.01-7.11 {m, 2 H) 6.96 (d, }=7.32,2.14 Hz, 2H) 5.52 (s, 2H) 5.35(s, 2 H) 4.45 (d, J=5.80 Hz, 2H). MS (ESI) m/z 500.2 (M+H)".
Example 192 5-[1-benzyl-5-(1-methyl-1 H-indol-5-yi}-1H-1.2, 3-triazo}-4-y1}- 1H-indazol-3-amine
The title compound was prepared as a TFA salt according to the procedure outhined in
Example 173 substituting F-methyl-1H-indol-5-yiboronic acid for 4-methoxyphenylboronic acid. "HNMR (500 MHz, DMSO-d, § ppm 11.35 (s, TH) 8.14 (s, 1 H} 7.54 (d, J=8.54 Hz, 1H) 7.50 (d, }=1.53 Hz, 1 H) 7.42 (d, J=3.05Hz, 1 1) 724 - 7.33 {m, 3H) 6.97-7.05(m, 5
H) 6.44 (d, J=2.75 Hz, 1 H) 5.46 (8. 2H) 5.33 (5.2 H) 3.83 (5. 3 H). MS (ESI+) m/z 420.1
(M+H)",
Example 193 5-1 ~benzyl-5-(3-methoxyphenyt}-1H-1 2. 3-triazol-d-yii- 1 H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example 173 substituting 3-methoxyphenylborenic acid for 4-methoxyphenylboronic acid. 'H NMR (500
MHz, DMSO-dg) 8 ppm 11.40 (s, TH) 8.08 (5, 1 1) 7.34 - 7.40 (m, I H) 7.24 - 7.32 (m, 3 H) 7.03711 (m, 3H) 6.98 - 7.02 (m, 2H) 6.80 - 6.85 (m, 2 FI) 5.49 (s, 2H) 5.35 (5, 2 H) 3.66 {8,3 H). MS (ESI=) m/z 397.1 {MH
Example 194 5-[1-benzyl-5-(3 -morpholin-4-ylph enyl)-1H-1,2 3-tr azol-4-yl}-1H-indazel-3-amine
A vial under argon containing Example 1258 (35 mg, 0.09 mmol}, 3- morpholinophenylboronic acid (21 mg, 0.09 mmol), PACLy(dppf) dichloromethane (7 mg, 0.009 mmol) and potassium carbonate (24 mg, 0.18 mmol) in DME (I mL} and water (0.1 mL) was capped and heated at 80 °C in a heater shaker for 3 days. The solvent was evaporated under reduced pressure, and the product was purified by reverse-phase HPLC using an acetonitrile/water 0.1% TFA gradient elution method to afford the title compound as a TFA salt. 'H NMR (500 MHz, DMSO-ds) & ppm 11.52 (s, TH) 8.14 (s, 1 H) 7.26 - 7.34 (m, 4H)6.98-7.12 (m, 5 H) 6.67 -6.75 (m, 2 H) 5.47 ($s, 2H) 3.57 3.73 (m, 4 H) 2.97 - 3.03 (m, 4 H). MS (ESI+) m/z 452.2 (M+H)Y".
Example 195 >-13-(1.3-dibydro-2H-isoindol-2-ylearbonyljisoxazol-5-y1]-1 Hoindazole
The title compound was prepared according to the procedure outlined in Example 81B substituting isoindoline for piperidine. 'H NMR (300 MHz, DMSO-dy) 8 ppm 13.38 {s, 1 H) 8.43 (s, 1H) 8.25 (5, 1 H} 7.93 (d. J=8.82, 1.36 Hz, 1 H) 7.71 (d, J=8.48 Hz, 1 4) 7.30 - 7.47 (mn, 5 H) 5.18 (s, 2 H) 4.92 (s. 2H). MS (ESI) m/z 331.0 (M+)
Example 196 5-{3-[(4-methyl-2-phen vipiperazin-1 -ylearbonylfisoxazol-5-yl i~1H-indazole
The title compound wag prepared according to the procedure outlined in Example 81R substituting L-methyl-3-phenylpiperazine for piperidine. 'H NMR {300 MHz, DMSO-
ds) ppm 13.12 (5, 1 H) 8.28 - 8.36 (m, 1 H) 8.18 (s, 1 H) 7.83 (d, J=879, 1.46 Hz, 1 H) 7.67 (d, J=8.79 Hz, 1 H) 7.48 (d, }=7.69 Hz, 2H) 7.30 - 740 (m, 2H) 7.21 - 7.20 {m, | BH) 7.14 (s,
PE) 5.56 «5.73 (m, }=5.86 Hz. | H}3.9%- 4.19 (m, J=8.42 Hz, 1 H)3.38-3.47 (m. 1 HI) 305-321 (m, 1=7.69 Hz, 1 H) 2.80 (d. =11.72 Hz, 1 H) 2.4] (d, 7=12.08, 4.3¢ Hz, 1 H) 224s, 3H) 2.02 - 2.16 (m, | H). MS (ESI+) m/z 388.1 (M+H)",
Example 197 i-{[1-benzyl-4-( 1H.in dazol-S-y1)-1H-1 2. 3-triazol-5-yljcarbonyl } piperidin-4-amine
Example 1974 teri-Butyl I-(1-benzyl-4-(1H-ind azol-5-y1y-1H-1 -2,3-triazole-5-carbonylypiperidin-4- ylcarbamate
The title compound was prepared according to the procedure outlined in Example 81R substituting Example 149C for Example 81B and 4-Boc-aminopiperidine for piperidine. MS (ESI) m/z 502.3 (M+H)",
Example 1978
I-{[1-benzyl-4-(1 H-mdazol-5-91)-1H-1 2 3-triazol-5 -ylicarbonyl} piperidin-d-amine
Example 197A (101 mg. 0.201 mmol) was dissolved in 4 M hydrochloric acid in dioxane (4 mL) and methanol (1 mL) and stirred at ambient temperature for 2 hours. The solvents were removed under reduced pressure to afford the title compound as an HC salt. ‘HNMR (300 MHz, DMSO-ds) 8 ppm 8.18 (5, | H) 7.92 - 8.08 (m, J=1.36 Hz, 3 H) 7.53 - 7.70 (m, 2 H) 7.24 - 7.47 (mm, 5 H) 5.40 - 5.73 (m, J=3.39 Hz, 2 H) 4.34 - 4.63 (m, [ HY3.44- 3.53 (m, J=3.39 Hz, 1 H) 2.95 -3.17 (m, 2H) 2.76 - 2.94 (m, J=11.02, 11.02 Hz, 1 H) 1.87 - 2.03(m, J~11.87 Hz, 1 H} 1.30 - 1.52 (m, J=10.85 Hz, 2 H) 0.66 - 0.9] (m. J=10.17 Hz, 1 H).
MS (EST) m/z 402.2 (M+H)".
Example 198
N-{5-(1-benzyl-5-phenyl-1H-1 .2,3-triazol-4-y1}-1 H-indazol -3-y!}benzamide
Example 1984 tert-butyl 3-amino-5-(1 -benzyl-5-phenyl-1H-1.2,3 tr azol-4-y1)-1H-indazole-1 ~carboxylate
Example 102B (200 mg, 0.55 mmol) and N,N-dimethylpyridin-4-amine (5 mg, 0.04 mmol) were dissolved in methylene chloride. The mixture was stirred at room temperature while a solution of di-tert-butyl dicarbonate (120 mg, 0.55 mmol} in 5 mL methylene chloride was added dropwise. The reaction mixture was allowed to stir at room temperature for 8 hours, was concentrated under vacuum, dissolved in methylene chloride {10 mL) and washed with dilute aqueous HC solution (1 N, 10 mL) and saturated MaHCO: agueous solution (10 mL). The organic layer was concentrated and purified by reverse phase-HPLC (CH.CN/ H,0
INH4OAC) to afford the title compound. 'H NMR (300 MHz, DMSO-d) & ppm 8.29 (5, 2
H), 743-759 (m, 3H), 7.03 - 7.38 {m, 6 H), 6.98 (d, J=7.17, 2.39 Hz, 2H}, 6.38 (5, 2 H), 5.52(s, 2H). 1.55 (5, 9 H}. MS (ES) m/z 467 (M+H)' [0
Exampie 198B
N-[5-(1-benzyl-5-phenyi-1 H-1 2 3-triazol-4-yi-1 H-indazol-3-ylbenzamide
Example 198A (37.5 mg, 0.08 mmol) and pyridine { 12.7 mg, 0.16 mmol} were dissolved in methylene chloride (Z2'mL}. The mixture was allowed to stir at room temperature,
Benzoyl chloride (14 mg, 0.1 mmol) was added to the mixture. The reaction mixture was allowed to stir at room temperature overnight, concentrated under vacuum and purified by reverse phase-HPLC (CHZCN/ HO /NHaOAC) to afford the Boc-protected precursor. The precursor was treated with 1:1 TFA / dichloromethane (2 mL) for 1 hour and was concentrated under vacuum to afford the title compound as a TFA salt. 'H NMR {300 MHz,
DMSO-d) 8 ppm 12.84 (5. 1 H), 10.70 (s, 1 H), 8.01 (d, 7=6.99 Hz, 2 H), 7.87 (x, | H), 7.50 - 7.69 (m, 3 H), 7.36 - 7.48 (m, 5 H), 7.18 - 7.35 (m, 5 H), 6.92 - 7.03 (m. 2 Hj, 5.48 (s, 2 H).
MS (EST) m/z 471 (M+H)".
Example 199
N-[3-(1-benzy!-3 -phenyl-1H-1 2, 3-triazol-4-y1)-1 H-indazol-3 -vijbenzenesulfonamide
The title compound was prepared according to the procedure outlined in Example 198B substituting benzenesulfonyi chioride for benzoyl chloride. 'H NMR. (300 MHz,
DMSO-ds) 8 ppm 12.69 (s. 1 H}, 10.61 (s, 1 H), 7.99 (5, 1 H), 7.70 «7.76 (m, 2 H, 7.45 - 7.62(m, 6 H), 7.24 - 7.36 (m, 7 H}. 6.99 (d, 1=6.99, 2.21 Hz, 2 H), 5.50 (5,2 H). MS (ESI+) m/z 507 (M+)
Example 200
N-{5-(1 -benzyl-3-pheny!-1H-1 :2,3-triazol-4-y1)- 1 H-indazal-3 -v1] -N'~{4-methoxyphenyures
Example 198A (25 mg, 0.54 mmol} was dissoived in dioxane (ZmLyand I-
Isocyanato-4-methoxybenzene! 24 mg, 0.16 mmol) was added to the solution. The reaction
Mixture was stirred at 86 °C for 17 hours, concentrated, and purified by reverse phase-HPLC (CHRON HO /W HaOAcC) to afford the Boc-protected precursor, The Precursor was treated with 1:1 TEA / dichloromethane (2 mL} for 1 hour and concentrated under vacuum to afford the title compound as a TFA salt. 'H NMR (300 MHz, DMSO-d) 8 ppm 12.54 (s, 1 HY, 9.51 (s,1 H), 9.42 (5, 1 H}, 828 (s, 1 H), 7.45 - 7.51 {m, 3H), 7.36 - 7.42 (mm, 2 H}, 7.24 - 7.35 (ra, 7H), 6.98 (d. I=7.1 7.439 Hz, 2H), 6.87 - 6.94 (m. 2H), 5.50 (s, 2 H), 3.74 (5. 3
Hy MS (ESI+H)Y m/z 516 (M+H)"
Example 201
N-I5-(1 -benzyl-5-phenyi-1H-1 2,3 riazol-4-yl)- 1 H-indazol-3 -vl]butanamide
The title compound wag prepared as a TFA salt according to the procedure outlined in
Example 198B substituting butyryl chloride for benzoyl chloride. 'H NMR (300 MHz.
DMSO-ds) 8 ppm 10.77 - 10.84 (m, 1 H), 8.07 (s, 1 H), 7.97 (d, J=8.82 Hz, 1 H), 7.64 {d,
J=8.82, 1.47 Hz, 1 H), 7.43 - 7.57 {m, 3H), 7.22 - 7.38 {m, 5H), 6.91 - 7.06 (m, 2 H}, 5.50 (5, 2H), 233 ¢t, 1=7.17 Hz, 2H), 1.54 - 1.60 (m, 2 H), 0.91 (t, }=7.35 Hz, 3 H). MS (ESI+) m/z 437 (M+H)".
Example 267
N-[5+(] -benzyl-5-phenyl-1H-1 2 3-triazol-4-y1)-1 H-indazol-3-y1]-2 -methylpropanamide
The title compound was prepared according to the procedure outlined in Example 198B substituting isobutyry! chloride for benzoyl chloride. 'H NMR {300 MHz, DMSO- ds) & ppm 12.66 (s, 1 H), 10.12 (s. 1H), 7.80 (s, 1 H), 742 - 7.55 (m, 4H), 7.33 - 7.39 {m, 1
HY, 722-7232 (m, 5 H), 6.97 (d. 1=6.99, 2.57 Hz, 2H), 5.48 (s, 1 HY), 2.59 - 2.69 {m, 1 FH},
LOT (d, J=6.99 Hz, 6 H). MS (ESI+) m/z 437 (M+H)™.
Example 203
Ne[S(1 -benzyl-5-phenyi-1H-1,2.3-tri azol-4-yl}-1 H-indazol-3-yl]cyclopropan ecarboxamide 36 The title compound was prepared according to the procedure outlined in Example 1988 substituting cyclopropanecarbonyl chloride for benzoyl chloride. "HI NMR {300 MHz,
DMSO-ds) 8 ppm 10.45 - 10.64 (s, 1 H), 7.91 (5, 1 H), 7.43 - 7.55 (m, 3H), 7.31743 (m, 2
H). 7.23730 (m, 5H), 6.97 (d, J=7.17, 2.39 Hz, 2 H). 5.48 (8, 2H), 1.77-1.91 (m, 1 H),
0.69 - 0.87 (m, 4 H). MS (ESI+) m/z 435 (M+),
Example 204
N-{i-benzoyl-5-(1 ~benzyl-3-cyclopropyl-18-1,2, 3m azol-4.yh)-1H-indazol-3-yl ben zamide
Example 89B ( 33mg, 0.1 mmol} was dissolved in tetrahydrofuran ( 0.6 mL) in a
CEM microwave tube. Benzoyl chioride (28 mg, 0.2 mmol) was added and the mixture was heated at 120°C for 15 minutes in the CEM-Discover microwave. The reaction mixture was cooled io room temperature, and concentrated. the residue was purified by reverse phase-
HPLC (CH:ON/ HO /NHLO AC) to afford the title compound. 'H NMR (300 MHz, DMSO- do) 8 ppm 11.35 (5, 1 H), 8.55 (d, J=8.82 Hz, | H}, 8.36 (s, 1 H), 8.17 (d, J=8.64, 1.65 Hz, 1
H), 8.00 (d, }=7.54, 2.39 Hz, 4 H), 7.51 - 7.72 (m, 6 H), 7.26 - 7.45 (m, 5 H), 5.71 (s,2 H), 176 - 1.87 (m, TH), 1.11 (d, J=6.62 fiz, 2 H), 0.44 (d, J=4.41 Hz, 2 H)., MS (ES) m/z 539 {(M-+HY™
Example 205
N-[5-{1-benzyl-5 -cyclopropyl-1H-1,2.3 -triazol-4-yl)-1 H-indazol-3-yi]-3-fluorobenzamide
Example 2054 tert-Butyt 3-amino-5-(1 -benzyl-S-cyclopropyl-1H-1 »2,3-triazol-4-y1)-1H-indazole- | - carboxviate
The title compound was prepared according to the procedure outlined in Example 198A substituting Example $98 for Example 102A. 'H NMR (300 MHz, DMSO-d) & rpm 8.26 (s, 1 H), 7.96 - 8.07 (m, | H), 7.86 - 7.95 (m, 1 H), 7.35 - 7.46 {m, 3H), 7.28 - 7.35 (m, 2H), 6.35- 6.47 (m, 2H), 5.70 (5, 2H), 1.72 - 1.84 (mn. 1 H), 1.60 (8,9 H), 0.99- 1.10 (d,
J=1.84 Hz 2H), 0.38 (d,J=3.68 Hz, 2 HB), MS (ESI+} m/z 431 {M+HY"
Example 205B
N-[5-(1-benzy]-3 -cyclopropyl-1H-1,2 3-triazol-4-y1)-1 H-indazol-3-y1]-3-fluorobenzamide
Example 205A (25 mg, 0.058 mmol) and pyridine (9.2 mg, 0.116 mmol} were dissolved in methylene chloride (1 mb). The mixture was allowed to stir at TOM temperature, and 3-fluorobenzoy! chloride (11.1 mg, 0.58 mmol} was added to the mixture. The reaction mixture was allowed to stir at room temperature overnight, and was concentrated and purified by reverse phase-HPLC (CH;CN/ HoO /NH40AR) to afford the Boc-protected precursor. The precursor was treated with 1:1 TFA / dichloromethane (2 mL) for 1 hour and concentrated under vacuum to afford the title compound as a TPA galt. "1 NMR (300 MHz, DMSO- ds) 8 ppm 10.58 (s, 1 H), 7.75 (5, ! H), 7.51 -7.60 (m. 1 FH), 7.46 (d, 4=8.82, 1.47 He, 1 H), 75-728 mn, 2HY, 700d, J=2.21 By, H}, 6.88 - 7.05 (m, 6 193, 531 (5. 2H). 1.35 - 1.47 2 (m =515 Hz, 1 HY, 0.68 (d, }=8.27. 1.65 Hz, 2 H),0.03 (d. 7=5.52 Hz. 2 1). MS (ESI) m/z 453 (M+H)'.
Example 206
N-[5.(1 -benzyl-S-cyclopropyl-1H-1,2 3-tri azol-4-y1-1H-indazol-3-yl benzamide
The title compound was prepared according to the procedure outlined in Example 2058 substituting benzovy! chloride for 3-fluorobenzoyl chloride. 'H NMR (300 MHz,
DMSO-d) 6 ppm 12.89 (s, 1 H), 10.83 (s, 1H), 8.02 - 8.15 (m, 3 H), 7.83 (d. J=8.82, 1.47
Hz, 1H), 7.50 - 7.66 (in, 4 H), 7.24 - 7.43 {o. 5 HY, 5.67 (5, 2H), 1.77 (m. 1 Hy, 099-110 (m, 2H), 0.39 (m, 2 H). MS (ESM) m/z 435 (M+H)".
Example 207
N-benzyl-5-(1 -benzyl-5-cyclopropyl-1H-1.2 3-11 azol-4-yl}-1H-indazol-3-amine
To a solution of Example 89B (18.3 mg, $0.05 mmol) in dimethylformamide (2 mL) was added acetic acid {15 mg, 0.25 mmol} and benzaldehyde (6.4 mg. 0.06 mmol). The reaction mixture was stirred at room temperature overnight. Sodium triacetoxyborohydride (NaBH(OAc)s, 32 mg, 0.15 mmol) was added to the mixture. The reaction was stirred at room temperature for 3 hours, concentrated and purified by reverse phase-HPLC (CH, CN/
Ho0 /NH4OAC) to afford the title compound. 'H NMR, (300 MHz, DMSO-d;) 8 ppm 13.09 (8, 1H}, 9.24 (5, 1 H), 8.02 - 8.10 (mm, 3H), 7.84 - 7.90 (m, 1 HB). 7.49 - 7.67 {m, 4 H), 7.25 - 7.45 (m, 5 H), 5.70 (s. 2 H), 3.30 (5, 27H). 188-195 (m, 1 H), 1.01 - 1.09 (mm. 2 H), 0.43 (d, 1=4.04 Hz, 2 H). MS (ESI) m/z 42] (M+H)Y".
Example 208
N-[(1R)-] -benzyl-2-hydroxyethyl]-5-(1H -indazol-5-yl}isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 81B substituting (R)-(=}-2-amino-3-phenyl- 1 -propano! (37 mg, 0.245 mmel) for piperidine. 'H
NMR (306 MHz, DMSO-ds) 8 ppm 13.36 (s. 1H) 8.46 (d, J=8.82 Hz, 1 I) 8.37 (s. 11822
(s, 1 H) 7.87 (dd, /=8.82, 1.36 Hz 1H) 7.69 (d, J=8.82 Hz. | H) 7.12 - 7.35 (m. 6 H) 4.89 {t,
S=5.59 Hz, 1 H)4.13 - 4.25 (m, 1H) 3.40 - 3.58 (m, 2 H) 2.90 - 2.69 (m, 1H) 2.74 - 2.87 (rn,
LH). MS (ESH) m/z 363.0 (M+EY
Example 209 5-(1-benzyl-1 H-pyrazol-4-y])-1H-indazole
Example 2004 -(5-Brome-1H-indazol-1 -ylethanone 4-Bromo-2-methylaniline (25.0 2, 134 mmol) was dissolved in chloroform (250 mL), and the mixture was cooled to 5 °C. Acetic anhydride (35 ml, 343 mmol} was added dropwise, and the mixture was allowed to warm to ambient temperature. Potassium acetate (3.57 g, 40.4 mmol) and isoamylnitrite (35 mL, 262 mmol) were added, and the mixture wag heated at 70°C overnight. The mixture was neutralized with saturated sodium bicarbonate and extracted with methylene chloride. The combined organic layers were concentrated under reduced pressure, and the resulting residue was triturated with methano! to afford the title compound. 'H NMR (300 MHz, DMSO-ds) & ppm 8.45 {s, 1 H) 8.26 (d../~R8 82 Hz, 1
H) 8.17 (d, J=1.70 Hz, 1 H) 7.77 (dd, /=8.82, 2.03 Hz, 1 H) 2.72 (s, 3 H).
Exampie 2098
S-(1-benzyl-1H-pyrazol-4-y[}-1 H-indazole
Example 209A (425 mg, 1.78 mmol), i-benzyl-4-(4,4,5,5-tetramethyl- 1 3.2 dioxaborolan-2-yl}-1H-pyrazole (508 mg, 1.79 mmol), dichlorobis(triphenyiphosphine)palladium(Tr) (133 mg, 6.189 mmot), and potassium carbonate (742 mg, 5.37 mmol) were combined in a sealed vial with dioxane (10 mL} and water (1 mL) under and inert atmosphere of nitrogen, and the mixture was heated to 110°C overnight. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 45-90% ethyl acetate in hexanes to afford the title compound. 'H NMR (300 MHz, DMSO-d,) ppm 13.00 (s, 1 H) 8.25 (s, | H} 8.02 (s, FH) 7.92 (5, 2H) 7.55 - 7.61 (m, 1 H) 7.48 - 7.54 (m, 1 H) 7.25 - 7.40 (m, 5 H) 5.35 (5, 2 H). MS (ESI+) m/z 274.9 (M+H)".
Example 210
N-f{1 R)-3-hydroxy-1 -phenylpropyi]-5 -(3-methyl-1H-indazol-3 -yisoxazoie-3-carboxamide
Example 2104 tere-Buiyl 5 ~bromo-3-methy] -1H-mdazole- -carboxviate >~Bromo-3-methyl-1H-indazoie (3.11 g, 24.2 mmol) and catalytic dimethylaminopyridine {(~30 mg) were dissolved in methylene chloride (100 mL). Di-rers. butyl dicarbonate (5.9 g, 27.0 mmol) was added, and the mixture was stirred at ambient temperature for 3 hours. The solvent was removed under reduced pressure, and the resulting 1 residue was diluted with ethyl acetate and washed with 1 W sodium hydroxide {twice), 0.1 N hydrochloric acid, and brine The organic layer was dried over sodium sulfate and filtered.
The filtrate was concentrated under reduced pressure to afford the title compound. MS (ESI+y m/z 210.8 (M-Boc)™.
Example 210B fert-Butyl 3-methyl-3 ~((trimethyisilyl)ethymyl)- 1H-indazole-] -carboxylate
Example 210A (7.55 £, 24.3 mmol), dichiorobis(triphenyiphosphine)paliadium(Ir) (870 mg, 1.24 mmol), and coppex( 1} iodide (250 mg, 1.31 mmol) were combined in triethylamine (60 mL} under an inert atmosphere of nitrogen. Trimethylsilyl acetylene (4.0 mL, 28.0 mmol) was added, and the mixture was heated at 60 °C overnight. The mixture was diluted with methylene chloride and washed with 0.1 M hydrochloric acid. The organic layer was absorbed onto silica gel and purified by silica gai chromatography eluting with a gradient of 10-40% ethv! acetate in hexanes to afford the title compound. MS (ESI) m/z 228.9 {M-
Boe)".
Example 210C 5-Ethynyi-3-m ethyl-1H-indazole
Example 210B (7.26 g, 22.1 mmol) was dissolved in methano} (170 mL). A solution of 1 N potassium hydroxide (435 mL) was added, and the mixture was stirred ar ambient temperature overnight. The solvent was removed under reduced pressure, and the resulting residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. MS (ESI+) m/z 157.1 (M+H)Y"
Example 2100 ethyl 5-(3-methyl-] H-indazol-5-yl)isoxazole-3-carboxylate
Example 2100 (411 mg, 2.63 mimnol} was dissolved in toluene {15 mL) and triethylamine (478 ul) and warmed to 90°C. Ethy! chloroozimidoacetate {480 mg, 3.17 mmol) dissolved in toluene (15 mL) was added slowly dropwise over 30 minutes, Following the addition, the mixture was diluted with ethyl acetate and washed with | N hydrochloric acid. The organic layer was concentrated under reduced pressure and the resulting residue was triturated with methanol to afford the title compound. MS (ESI) m/z 271.9 (MH).
Example 210F 5-(3-methyl-] H-indazol-5-yl)isoxazole-3-carboxylic acid
Example 210D (325 mg, 1.20 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (1 mL), and water {1 mL) and potassium hydroxide (150 mg, 2.67 mmol} was added. The mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with ethyl acetaic and washed with 1 N hydrochloric acid. The product precipitated in the separatory funnel and was filtered to afford the title compound. MS (ESI+) m/z 243.9 {(M-+H)",
Example 210F
N-[(1R}-3-hydroxy-1 -phenylpropyl]-5-(3 -methyi-1H-indazol-5 -yDisoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 81B substituting Example 210E for Example 81A and (R}-3-amino-3-phenylpropan-1 -ol for piperidine. 'H NMR (300 MHz, DMSO-d,) § ppm 12.93 (5, TH) 8.45 (¢, J=8.&2 Hz, 1H) 8.33 (s, TH) 7.84 (d, J=8.82. 1.70 Hz, 1 H} 7.59 (d, 79.16 Hz, 1 H} 721-729 (m, 5H) 7.13 25-721 (m, I H) 4.89 (1, ]=5.59 Hz, TH) 4.10 - 4.26 (m, 1 H) 3.42 . 3.56 {m, 2 H)y2.88-3.00 (m, 1H) 2.75-2.87 (m, 1 H) 2.55 (8. 3 Hi. MS (ESI+) m/z 377.1 (M-+H)".
Example 211 3-[4-(3-amino-1H-indazol-3 -yI}-1-benzyl-1H-1 2,3-triazol-5-yl phenol
A vial under argon containing Example 125B (35 mg, 0.09 mmol), 3- hydroxyphenylboronic acid (12 mg, 0.09 mmol), PdCly(dppfy-dichioromethane (7 mg, 0.009 mmol) and potassium carbonate (24 mg. 0.18 mmol) in DME (1 mL} and water (0.1 ml.) was capped and heated at 80°C in a heater shaker for 3 days. The solvent was evaporated and the product was purified by reverse-phase HPLC using an acetonitrile/water 0.1% TFA gradien: elution method to afford the title compound. 'H NMR (500 MHz, DMSO-dg) 8 ppm 11.40 (5,
PHY 9.68 (s, THY 8.00 (5,1 H) 7.24 - 7.25 (mM. 5B) 6.98 - 7.13 (m, 3 H) 6.48 (d, J=8.09, 1.98
Hz, 1 HY 6.73 {5,1 H) 6.60 - 6.66 (m, JH) 5.47 (5, 2 HY 5.35 (5, 2 HY. MS (ES) myz 383.1 (M+HY.
Example 212 3-[4-(3-amino-1 H-indazol-5-y1)-1-benzyi-1H-1 -2,3-triazol-5-y1]benzamide
The title compound was prepared according © the procedure outlined in Example 173 substituting -carbamoyiphenylboronic acid for 4-methoxyphenylboronic acid. 'H NMR {500 MHz, DMSO-dg) 8 ppm 11.41 (s, 1 HY 8.07 (s, 1 H) 7.97 - 8.03 (m, 2H) 7.83 - 7.87 (m. 1H) 7.53 (t, }=7.78 Hz, | H) 7.45 {s, 1H) 7.38 {d, J=7.63 Hz, | H) 7.23 - 7.30 (m, 3 H) 7.00 - 7.10 (m, 2 H) 6.96 (d, J=7.48, 1.0% Hz, ZH} 5.51 (5,2 FI 5.35 {s, 2 H). MS (ESI+) m/z 410.1 (M+H)".
Example 213 5-{1 -benzyl-5-[4-(methylsulfonyl)phenyl}- 1H-1.2 3-triazol-4-y1}-1H-indazo!-3 -amine
The title compound was prepared according to the procedure outlined in Example 173 substituting 4-( methylsuifonyl}phenylboronic acid for 4-methoxyphenylboronic acid. 'H
NMR (500 MHz, DMSO-d) 8 ppm 11.44 (5, 1 11) 7.94 - 8 03 (m, 3 H} 7.58 (d, J=8.54 Hz, 2
H)722-730(m,3H)7.04 - 7.13 {m, 2 H) 6.98 (d, J=7.48, 1.98 Hz, » H) 5.56 (5,2 H) 5.37 (s, 2H) 3.28 (s, 3 H). MS (EST) m/z 445.2 (M-+H)",
Example 214
N-[5+1 ~benzyl-S-cyclopropyl-1H-1 2. 3-triazol-4-y1)-1 H-indazol-3-yi}-2-chiorobenzamide
The title compound was prepared according to the procedure outlined in Example 205B substituting 2-chlorebenzoyl chloride for 3-fluorobenzoyl chioride. 'H NMR (300
MHz, DMSO-ds) 6 ppm 10.94 {s, 1H), 824 (s, 1 H), 7.85 (d, J=8.82, 1.47 Hz, | H), 7.65 (d,
J=6.99, 1.84 Hz, 1H), 7.43 - 7.61 (m, 4H), 7.26 - 7.42 (m, § H), 5.68 (8, 2H) 1.71 -1.83 (mu 1H), 104-112 (m, 2 H), 0.37 - 0.45 (m, 2 H). MS (ESIH) m/z 469 (M+H)",
Example 215
N-[5-(1 ~benzyl-3-cyclopropyl-1 H-1.2 3-triazol-4-y1)-1H -indazol-3-yl]-4-chlorobenzamide
The title compound was prepared according to the procedure outlined in Example 205B substituting 4-chlorobenzoyl chloride for 3-fluorobenzoy! chloride. 'H NMR (360
MHz, DMSO-ds) 8 ppm 10.53 (5, TH), 7.65 7.71 {m. 3 Fl). 7.42(d, J=8.82, 1.47 Hz. I Hj,
TAB -7.24 (m, 2 HY, 712-748 (m, 1H), 6.93 - 7.02 (m. 3H), 6.87 - 6.92 {m, 3 H}, 5.27 (s,
ZHYI30-144(m, 1H), 050-067 (m, 2H}, -0.07- 0.04 (m, 2 HY. MS (ESI) m/z 469 (M+H).
Example 216
N-{5-{ 1 -benzyl -5-cyclopropyl-1H-1,2.3 “71870 - dey] Fl-mdazol-3-yliethanesulfonamide 14 The ntle compound was prepared according to the procedure outlined in Example 205B substituting ethanesulfony! chloride for 3-fluorobenzoyl chloride. 'H NMR. (300 MHz,
DMSO-ds) 8 ppm 10.19 (s, 1 H), 8.15 {s, 1H), 7.82 (d, }=8.64, 1.65 Hz, 1 H), 7.53 (d, }=8.22
Hz, TH), 7.35-745 (m, 3H), 727 - 7.35 (m, 2 H), 5.69 (s, 2 H), 3.30 {q. 7=7.35 Hz, 2 1), 174-187 (m, 1 H), 1.27 - 1.36 (m3 H), 1.02 - 1.12 (m, 2 H), 0.34 - 0.44 (m, 2H). MS 13 (BSH) m/z 423 (M+H)".
Example 217
N-[5-(1 -benzyl-S-cyclopropyl-1H-1,2.3 ~triazol-4-yi}-1H -indazol-3-yi}benzenesulfonamide
The title compound was prepared according to the procedure outlined in Example 205B substituting benzenesulfonyl chioride for 3-fluorobenzoyl chloride. 'H NMR (300
MHz, DMSO-ds) 8 ppm 12.75 {s, 1H), 10.69 (s, 1 H), 8.02 {s, 1H). 7.71 - 7.83 (m, 3H), 7.43 - 7.60 (m, 4 H), 7.34 - 7.43 (m, 3H}, 7.27 - 7.34 (m, 2 H), 5.69 (5, 2H), 1.69 - 1.83 {m,
LH), 0.99 - 1.11 (m, 2 H), 0.31 - 0.45 (m, 2 H). MS (ESI+) m/z 471 (M+H)",
Example 218
N-[5-(1-benzyl-5 -cyclopropyl-1H-1 2, 3triazol-4-yI)-1Hondazol-3 ~yl}-2- chlorobenzenesulfonamide
The title compound was prepared according to the procedure outlined in Example 205B substituting 2-chlorobenzene-1 -sulfonyl chloride for 3-fluorobenzoyl chioride, 'H
NMR (300 MHz, DMS0-ds) 8 ppm 12.36 (5, 1 11), 10.60 {s, 1H), 7.67 (5.1 H), 7.62 (d,
J=791, 1.65 Hz, 1 H), 7.40 (d, J=8.82, 1.47 Hz, 1 H), 7.14 - 7.27 {m, 2 H), 7.00 - 7.12 {m, 4
H), 6.96 - 7.00 (m, 1 H), 6.90 - 6.95 {(m, 2H), 531 (5,2H), 1.29. 1.44 (m, 1H), 061-074 (m, 2 H), -0.05- 0.05 (m, 2 H). MS (EST+) m/z 505 (M41)
Example 219
N-[5-(1 ~benzyl-S-cyclopropyl-1H-1 ply I-ATIaZO ey) ] H-indazol-3-yi]-3- chlorobenzenesulfonamide
The title cornpound was prepared as an HOE gale according to the procedure outlined in Example 205B substituting 3-chlorohenzene-]| sulfonyl chloride for 3-fluorobenzoy! chloride. 'H NMR (300 MHz, DMS0-ds) ppm 12.84 (5, 1 H), 10.86 {s, LH), 8.00 (s, 1 H), 7.82(s, 1 H), 7.72 (d, }=7.72 Hz, 1 HJ), 7.64 (d, I=1.84 Hz, 1 H), 7.57 (d, J=7.72 Hz, 1 H}. 7.50 (d. J=8.82 Hz, 1 H), 7.34 - 7.45 (m, 3 H), 7.28 - 7.34 (m, 2 H), 5.69 (5. 2H), 1.71 - 1.83 {m. 1TH). 1.06 (m, 2 H), 037 (m, 2 HY. MS (ESI+y m/z 505 OM+H)" fg
Example 220
N-[5{I-benzyi-3 -cyclopropyl-1H-1 2,3-triazol-4-y1)-1H-indazol-3 ~yi]-4~ chlorobenzenesulfonamide
The title compound was prepared as an HCI salt according to the procedure outlined 13 in Example 2058 substituting 4-chlorobenzene-1-sulfony| chloride for 3-fluorobenzoy! chloride. 'H NMR (300 MHz, DMSO0-ds) 8 ppm 12.80 (5, 1 H), 10.79 {s, 1 H), 8.00 ¢s, 1 H, 7.73 - 783 (m, 3 H), 7.56 - 7.64 (m, 2 H), 7.49 (d, }=8.82 Hz, 1 H), 7.34 - 7.45 {m, 3 H), 7.28 = 7.34 (m, 2H), 3.69 (5, 2H), 1.71 - 1.86 (m, 1 H),0.99 - 1.12 (m, 2H), 0.31 - 0.43 (m, 2 H).
MS (ESI) m/z 505 (M+HY"
Example 221
N-{5-(1 ~benzyl-5-cyclopropyl-1H-1,2,3-tri azol-4-yl}-1H-indazol-3-yl]-2.5 -dimethylfuran-3- sulfonamide
The title compound was prepared as an HCI salt according to the procedure outlined in Example 2058 substituting 2.5-dimethylfuran-3-sulfony) chloride for 3-fluorobenzoyi chloride. "H NMR {300 MHz, DMSC-ds) 8 ppm 12.82 (s, 1H), 10.48 (s. 1 H), 8.00 (s, I H), 7.78 (d, J=8.64, 1.65 Hz, | H), 7.50 (d, J=9.19 Hz, 1 H), 7.34 - 745 (m, 3 Hj), 7.28 - 7.33 (m, 2H), 6.20 (s, 1 H), 5.69 (s, 2 H), 2.1] (8,6 FH), 1.71 - 1.84 (m0, 1 H), 1.01 - 1.1] (m, 2 H), 0.32-0.41 (m, 2 H). MS (ESI) m/z 489 (M+H)".
Example 222 3-(1-benzyl-5-cyclopropyl-1H-1 12,3-triazol-4-y1)-N-(2-chlorobenzyl}-1H-indazo)-3-amine
The title compound was prepared according to the procedure outlined in Example 207 substituting Z-chlorobenzaldehvde for benzaldehyde. "H NMR (300 MHz, DMSO-d;) 8 ppm
L1.55 (s, 1 H), 8.20 (s, 1 H), 7.69 (4. J=8.46, 1.47 Hz, 1 H). 7.49 (d, =8.82 Hz, 1 H), 7.34 - 7.46 (m, 4 HY, 7.23 - 733 (m. 5 H} 5.69 (5, 2H), 4.56 (5,2 1), 1.72 1.83 (m, I H} 069.
LOS {m, 2 7), 0.35 - 0.42 (m, 2H}. MS (ESI) m/z 455 (MH)
Example 223 3-(1-benzyl-5-cyclopropyl-1H-1 2,3-triazol-4-y1)-N-( 3-chiorobenzyl}-1H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example 207 substituting 3-chiorobenzaldehyde for benzaldehyde. 'H NMR (300 MHz, DMSG-d;) § ppm
Wo 11530, THY 8.15(s, 1 HY, 7.59.7 77 (m, 1H), 7.25 - 7.48 (m, 10 H), 5.68 {s, 2 HJ}, 4.46 (5, 2H) 171 - 1.80 (m, 1 HD, 1.04 (s. 2H), 0.38 (s, 2H).
Example 224
N-[3-(3 ~benzyl-5-cyclopropyl-1H-1 2, 3-trtazol-4-yl)-i H-indazol-3-y11-3-chlorobenzamide
The title compound was prepared according 1o the procedure outlined in Example 203B substituting 3-chlorobenzoyl chloride for 3-fluorobenzoyl chloride. "H NMR (300
MHz, BMSO0-ds) 8 ppm 10.99 (s, 1 H), 8.12(s, 2 H), 8.03 (d, J=7.72 Hz, 1H), 7.83 (d,
F=6.46 Hz, 1 H), 7.68 (s, 1 H), 7.58 (t,J=8.09 Hz, 2H), 7.33 - 7.44 {m, 3 H), 7.25 - 7.33 (mm,
ZH). 568 (s, 2H), 1.72 - 1 86 (Mm, 1H). 0.99-1.12(m, 2 H), 0.34 - 0.45 (m; 2H). MS (ESI+) m/z 470 (MH).
Exampie 225
N-[5-(1 -benzyl-5-cyclopropyl-1H-1 22, 3-triazol-4-yf)-1H -indazol-3-y1]-2-furamide
The title compound was prepared accordmg to the procedure outlined in Example 205B substituting furan-2-carbonyl chloride for 3-flvorobenzoyl chloride. 'H NMR (300
MHz, DMSO-ds) 8 ppm 10.36 (s, 1 H), 7.71 (s, 1 H), 7.42 (d, 3=8.82, 1.47 Hz, 1H), 7.15 (d,
F=8.82 Hz, 1 H), 7.06 (d, J=3.31 Hz, ] H), 6.93 - 7.03 (m, 3 H), 6.86 - 6.93 (m, 2H), 6.31 ¢d,
J=349, 1.65 Hz, 1 H), 5.28 (s, 1 H), 1.31 - 1.45 (m, 1 H), 0.59 - 0.7] (m, 2 H), -0.05 - 0.05 (m, 2 H). MS (ESi+) m/z 425 (M+H)".
Example 226 3-(1-benzyl-3-cyclopropyl-1H-1 .2,3-triazol-4-y1)-N-ethyl-1 H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example 207 substituting acetaldehyde for benzaldehyde. 'H NMR (300 MHz, DMSO-d, 8 ppm 8.56 (s, 1H), 830-842 (m, | HY, 790-817 (m. 2 HY, 720-745 (m.5 H)., 570s, 2 HF), 1.78 - 1.95 (m, ZH), 1.67 (5, 1 HJ), 1.06 (m, 3 H), 0.95 (m, 2 H), 029-048 (m, 2 Hj). MS (ESI) m/z 359 (MH)
Example 227 5-(1-benzyl-5 -cyclopropyl-1H-1,2,3 -triazol-4-y1)-N-(4-chlorobenzyl)-1 H-indazo!-3-amine
The title compound was prepared according to the procedure outlined in Example 207 substituting 4-chlorobenzaldehyde for benzaldehyde, "IT NMR {300 MHz, DMS0-dg) 5 ppm 10.01 ¢s, 1H), 9.05 (5. 1H}, 8.25833 fm, | H), 8.09 (d, J=8 46 Hz 1 H), 7.84 -7.97 (m, 2
H). 757-773 (m, 2 1), 7.06 - 7.51 (mo, 6 H), 5.70 (3, 2H), 1.71 - 1.84 (m, 1 H),097-1.15 (m, 2 H), 0.36 - 0.47 (mm, 2 Hj. MS (ESI+) m/z 455 (MHF).
Example 228 5-(1-benzyl-3 -cyclopropyi-1H-1,2.3 -triazol-4-y1}-N-(3 ~furylmethyl)-18 -indazol-3-amine
The title compound was prepared according to the procedure outlined in Example 207 substituting furan-3-carbaidehyde for benzaldehyde. 'H NMR (300 MHz, DMBG-dg) 8 ppm 8.21 (s, 1H), 7.90 (s, 1 H), 7.71 - 7.82 (m, 1 H), 7.55 - 1.68 (m, 2 H), 7.24 - 7.51 {m, 6 H), 5.68 (s, 2H), 433 (5,2 Hj, 1.67 - 1.85 (m, 1 H), 095-113 (m, 2 H) 0.30 - 0.42 (m, 2 1).
MS (ESH) m/z 411 (M+H)".
Example 229
N-[5-(1-benzyl -5~cyclopropyl-1H-1,2, 3x azol-4-yl)-1 H-indazol-3 VIJ-N'-[5-methy]-2- (trifluoromethy] »3-furyllurea
Example 205A (30 mg, 0.07 mmol) was dissolved in dioxane {2 mL) and 3- isocyanato-S-methyl-2-(triftuoromethyl furan (40mg, 0.21 mmol} was added to the solution,
The reaction mixture was stirred at 80°C for 12 hours, concentrated and purified by reverse phase-HPLC (CH:.ON/ H,0 /NH4OAc) to afford the Boc-protected precursor. The precursor was dissolved in methanol and treated with excess HCI in dioxane (4 M, 0.5 mmol). The reaction was allowed to stir for 5 hours and concentrated under vacuum to afford the title compound as an HCl salt, 'H NMR (300 MHz, DMSO0-d;) 8 ppm 12.73 (s, 1 H), 10.19 (s, 1
H), 8.40 {s, 1 H), 7.83 (d, J=8.82, 147 Hz, 1 H), 7.64 - 7.75 (m, 1 H), 7.49 (d, J=8.82 Hz, 1
H), 735-745 (m, 3H). 7.27 - 7.35 (m, 2H). 5.69 (5, 2 H), 2.33 (5,3H), 1.73-1.84 (m, 1
H), 1.02 1.11 (m, 2 H), 0.35 - 0.43 (m, 2 H). MS (ESI+) m/z 522 (M+H)".
Example 230
M501 -benzyl-S-cyolopropyl-1H.1 Lod-triazol-d-yii-1 Heindazol-3 -vil-3-faramide
The title compound was prepared as an HCI salt according to the procedure outlined in Example 2058 substitutin ¢ furan-3-carbony! chioride for 3-fluorobenzoyl chloride. 'H
NMR (300 MHz, DMSO-ds) 8 ppm 10.64 (s, 1 FH), 846 (s, 1 H), 8.13 {s, 1 HY. 7.74 - 7.84 (m,
SHY T52-758 (ny THY, 7.33 - 7 46 (m, 3H}, 7.24 7.33 (m, 3 H) 7.06 (s, 1 H), 5.68 (5. 2
H), 1.70 - 1.86 {m, 1 H), 0.99 - 1.00 {m, 2H), 0.33 - 0.44 (m, 2 H). MS (ESI+) m/z 425
Ho (Mey
Example 231 5-(1H-indazol-3 -yI-N-[{15}-1 -phenyipropvljisoxazoie-3 carboxamide
The title compound was prepared according to the procedure outlined in Example 81B 13 substituting (S)-(-)-] -phenylpropyl amine for pi peridine. 'H NMR (300 MHz, DMSO- ds) 6 ppm 13.37 {s, 1 H) 9.20 (d, J=8.48 Hz, 1 H) 8.39 (s, 1 H}8.23 (s, 1 H) 7.88 (d, }=8.81,
L706 Hz, 1 H) 7.69 (d, 1=8 81 Hz, 1 H) 7.38 - 7.49 (m, 2 H) 7.18 -7.38 (m, 4 H) 4.83 - 5.00 (m, 1 H)1.73-1.97 fm. 2 H) 0.86 - 0.97 (m, 3 H). MS (ESI) m/z 347.0 (M+H)",
Example 232 3-{1H -indazol-5-ylj-N-|{ 1R}-1 -phenylpropyllisoxazole-3-carboxamide
The title compound was prepared according to the procedure outhned in Example 81B substituting (R)-( --1-phenvipropy! amine for piperidine. "H NMR {300 MHz, DMSO- de) 8 ppm 13.37 {s, 1 H) 9.20 (d, J=8.48 Hz, | H) 8.39 (s, H) 8.23 (s, 1 H) 7.88 (d, J=K.65, 153 Hz 1H) 7.69 (d, 3=8.81 Hz, 1 H) 7.39 - 7.48 (m.2H) 7.18 - 7.38 (m, 4 H) 4.85 -4.99 (m, 1 H) 1.74 - 1.97 {m, 2 H) 0.9% (t, J=7.29 Hz, 3 H). MS {ESI+) m/z 347.0 {(M+H)".
Example 233
S5-(1-benzyl-1 H-pyrazol-4-yl)-1H-indazol-3-amine 36
Example 2334 5-(1-Benzyl-1 H-pyrazol-4-yl1)-2 -fluorobenzonitrile 5-Bromo-2-fluorobenzonitrile (484 mg, 2.42 mmol}, 1-benzyl-4-(4,4.5 D-tetramethyi-
1.3,2-dioxaborolan-2-y1)- 1H-pyrazole (736 mg, 2.59 mmol), dichlorobis(triphenylphosphine palladium) (174 mg, 0.248 mmol), and potassium carbonate (1.36 g. 9.84 mmel) were combined in a sealed vial with dioxane (10 mL) and water (1 ml) under an inert atmosphere of nitrogen, and the mixture was heated to 110°C 3 overnight. The mixture was diluted with methylene chioride and waghed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography cluting with a gradient of 10-50% ethyl acetate in hexanes to afford the tite compound. MS ¢ ESE) m/z 290.0 (M+H)",
Example 2338 5-(1-benzyi-1H-pyrazol -4-yD)-1H-mdazo!-3-amine
Example 233A (591 mg. 2.13 mmol) was treated with hydrazine hydrate (4.0 mL) in ethanol (3.0 mL) and was stirred and heated to 70°C overnight. The mixture was dituted with methylene chloride and washed with water. The organic layer was concentrated under reduced pressure, and the resulting residue was triturated with methanol to afford the title compound. 'H NMR. (300 MHz, DMSO-dg) 8 ppm 11.32 (s, 1 Hy 8.10 (s, 1 H) 7.85 (s, 1 H} 7.80 (s. 1 H) 7.44 (d, J=8 48. 1 70 Hz, TH) 725-741 (m, 5 H) 7.21 (d, I=8.82 tz, 1 H) 5.33 (8.2 H)524-530 (m, 2 H). MS (ESI) m/z 290.0 (M+H)",
Example 234
I-benzyl-4-(1H-indazol-3 “YD-N-[(2S)-tetrahydrofuran-2-ylmethyl]-1 H-1,2,3riazole-5- carboxamide
Into a 20 mL vial, a solution of Example 149C (51 mg, 0.16 mmol) dissolved in dimethylformarmide (0.5 mb} was added, followed by the addition of (S)-(+)- tetrahydrofurfurylamine (18.2 mg, 8.18 mmol) dissolved in dimethyiformamide (0.9 mij. A solution of HATU (68 mg, 0.18mmol} dissolved in dimethylformamide (0.5 mL) was added followed by a solution of diisopropylethylamine (0.087 ml, 0.5 mmol) dissolved in dimethylformamide (0.5 mL). The mixture was shaken at 50 °C overnight. The reaction wag filtered through a Si-Carbonate cartridge (6 mlL-1g) supplied by Silicycle Chernical Division, and the filtrate was transferred to 20 mL vials. The reaction was checked by LC/MS and concentrated to dryness, The residue was dissofved in 1:1 DMSO/methano! and purified by reverse phase HPLC (Agitent, $%-100%, TFA/water gradient, 8 minute run). 'H NMR (300
MHz, DMSO-d,/1,0) 8 ppm 135-154 (m, 1 FH) 1.64 - 1.06 (m, 3H) 3.17 - 3.26 {m, 1 H)
332-338(m, 1 H)3.50-3.77 (m, 2 H)3.81- 4.00 (m, 1 H}5.58-5.74 (m,2H)7.21-7.41 (m, 5 H) 7.54 - 7.66 (m, 1 H) 7.68 - 7.84 (m, 1 H) 8.01 - 8.19 (m, 2 H), MS (ESI) m/z 401 (M-HY.
Example 235 l-benzyl-4-(1 H-indazol-5-yT3-N-( 2-1sopropoxyethyl)-1H-1.2,3-triazole-5-carbox amide
The title compound was prepared according to the procedure outlined in Example 234 substituting Z-aminocthylisopropy! ether for (S)-{+)-tetrahydrofurfurylamine. "H NMR (300
MHz, DMSQ-dy/D20) 6 ppm 0.98 (d. 6 HY33%-3.45 (m, 4H) 3.45 - 3.57 (m, 1 H) 561 -
Wo 574m 2H) 7.25 7.46 (m, SH) 7.57 - 7.65 (m, LH) 7.68 - 7.80 (m, 1 H)%.04-8.13 {m, 2
H). MS (ESI+) m/z 405 (M+R)
Example 236
I-benzyi-4-(] H-indazol -5-yD-N-[(2R }-tetrabydrofuran-2-ylmethy!]- TH-1.2,3-triazole-5-
Is carboxamide
The title compound was prepared according to the procedure outlined in Example 234 substituting (R)-( --tetrahydrofurfurylamine for (S)-(t)tetrabydrofurfurylamine, 'H NMR (300 MHz, DMSO-dys/D,0) & ppm 1.34 - 1.60 (m, 1 H} 1.65 - 1.94 (m, 3 H}3.16-3.26 (m, 1
H}3.33-3.39(m. 1 H)3.51-3.77 (m, 2H) 3.78 - 4.00 (mm, 1 H) 5.60 - 5.73 {m, 2H} 7.26 - 7.45(m, 5 H) 7.56 - 7.68 (m, 1 Hy 7.71 -7.79 (im, 1 H) 8.01 - 8.15 (nm, 2 Hy. MS (ESI) m/z 401 (M-HY,
Example 237
I-benzyi-4-(1H-indazol-5 -yD-N-( tetrahydrofuran-3-yimethyl)-111-1,2.3-triazole-5- carboxamide
The title compound was prepared according to the procedure outlined in Example 234 substituting 3-aminomethyltetrahydrofuran for (S)-(+)-tetrahydrofurfurvlamine. "H NMR (300 MHz, DMSO-d¢/D>0) 6 ppm 1.36 - 1.59 (m, 1 H) 1.67 - 2.00 (m, | H) 219-245 (m, 1
Hy3.01-3.23(m, 2H)3.45-3.77 (m, 2 H)545-614(m. 2H) 7.16 - 7.44 (m, § H) 7.50 - 7.84 (m, 2 H) 7.96- 8.25 (m, 2 HJ. MS (ESI+) m/z 403 (M+H)",
Example 238
I-benzyl-N-cyclopentyi-4-( 1 H-indazol-5 -yh-1H-1,2 3-triazole-5-carboxamide
The title compound was prepared according to the procedure outlined in Example 234 substituting cvclopentylamine for (5)-(+)-tetrahydrofurfurylamine. 'H NMR {300 MHz,
DMS0-de/D20) 8 ppm 1.19 - 1.63 (m, 6 23 1.71 - 1.90 (mm, 2H) 3.99437 (m, 1H) 5.52. 5.77 (m, 2HY7.22-745(m, SH} 7.55 - 7.93 (m, 2H} 7.95 - 820 (m, 2H). MS (ESI) mz 385 (M-HY.
Example 230 ] ~benzyl-N-(cyclopentyimethyl)-d-(] H-indazol-5-yl)- 1 H-1,2 3-triazole-5-carbox amide
The title compound was prepared according to the procedure outlined in Example 234 iO substituting aminomethylcyclopentane for Sp{Ti-tetrahydrofurfuryviamine. 'H NMR. (3040
MHz, DMSO-ds/D,0) 6 ppm 1.02 - 1 28 (mn, 2H) 1.34- 1.73 {m, 6 H) 1.83 - 2.17 (my, TH) 303-317 (m2 H) 5.51 - 5.86 (m. 2 Hy 720-742 (m, 5 H)7.52- 7.81 (m, 2 H) 7.93 -8.19 (m, 2 H}. MS (ESI+) m/z 401 (M+H)".
Example 240
I-benzyi-N-cthyl-4-(1H-indazol-5 yl}-N-methyl-1H-1,2,3-triazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 234 substituting N-methylethylamine hydrochloride for { S)-(-)-tetrahydrofurfurylamine, 'H
NMR (300 MHz, DMSO-d¢/D20) & Ppa 0.33 - 0.56 (m, 1 H) 0.90 - 1.14 (m, 2 H)2.15-2.25 200 (m, 2 H)2.58-2.69 (m, 1 H) 2.82 - 3.0] {m, 1 H}3.35-3.52(m, 1 H) 540-567 (am, ZH) 7.14 -748 (m, 5H) 7.56 - 7.79 (m, 2 H) 7.90 - 8.24 (m, 2H). MS (ESI+) m/z 36] {(M+H)",
Example 241
I-benzyl-4-(1H-indazol-5-vi J-N-1sopropyl-N-methyl-1H-1 .2,3-{riazole-5-carboxamide
The title compound was prepared according to the procedure outlined in Example 234 substituting methylisopropylamine for (S)-(+)-tetrahydrofurfurylamine. 'H NMR {300 MHz,
DMSO-ds/D20) § ppm 0.22 - 0.51 (m, 2 Hy 0.84 - 1.09 (m, 4 H) 1.96 - 2.13 (m, 2 H)2.74 - 2.87(m, 1 H) 4.44 - 4,92 (m, | H) 5.43 - 5.67 (m, 2H) 7.20 7.44 (m, 5H) 7.51 - 7.73 (m, 2
H) 7.84 - 8.14 (m. 2 H). MS (ESI) m/z 375 (MAH).
Example 242
I-benzyl-4-(] H-mdazol-5-y[}-N-(2-methoxvethyl N-methyl 1H-1,2 3-triazole-5- carboxamide
The title compound was prepared according to the procedure outlined in Example 234 substituting N-{2-methoxvethyl methylamine for (8)«( titetrahydrofurfurvlamine, 'H NMR. (300 MHz, DMBO-de/D,0) 8 ppm 2.25 - 2.40 {(m, 2H) 2.74 - 3.06 {m. 4 H)3.406- 3.75 (m, 3
Hy 538-573 (m, 2 H) 7.1% - 7.45 (mn, 5 HY 7.53 7.74 {m. 2 Hy 785-819 (m, 2 H). MS (ESI+ym/z 391 (M-+H)".
Example 243
I-benzyi-4-(1H-indazol-5 -yi-N-phenyi-1H-1 2, 3-triazole-5-carbox amide
The title compound wag prepared according to the procedure outlined in Example 234
IG substituting aniline for (5 )-(+)-tetrahydrofurfurylamine. HNMR (300 MHz, DMEQO- de/D3,0) 6 ppm 5.65 - 5.79 (m, 2H)Y7.04 -7.55 (mm, ICH) 754-784 (m, 2) 7.95.82] {1n, 2H). MS (ESH) m/z 395 (Vi+H)",
Example 244
I-benzyl-N-( 4-chiorophenyl}-4-(1 H-indazol-5-yI}-1H-1 -2,3-triazole-5-carboxamide
The title compound was prepared according to the procedure outlined in Example 234 substituting 4-chloroaniline for (S}-(+)-tetrahydrofurfurylamine. 'H NMR (300 MHz,
DMS0-d¢/D;0) 8 ppm 5.70 - 5.74 (m, 2H) 725-742 (m, 7 H)7.43-7.52 (m, 2 H) 7.54 - 7.66 (m, 1 HY 7.68 ~ 7.77 (m, 1 H) 8.03 -8.15(m, 2H). MS (ESI-) m/z 427 (M-HY
Example 245
I-benzyl-4-(1H-indazol-5 ~y)-N-(2-morpholin -4-yiethyl}~1H-1.2 3uriazole-5 -carboxamide
The title compound was prepared according to the procedure outlined in Example 234 substituting N-( 3-aminopropylymorpholine for (S)-(F)-tetrahydrofurfuryiamine. "HNMR (300 MHz, DMB0-ds/D,0) 8 ppm 2.94 - 3.13 {m, 6 H) 3.46 -3.61 (m, 2 HY3.63-3.79 (m, 4
H)5.61- 588 (m, 2H) 7.19 - 7.46 (m, 5 H) 7.56 - 7.88 (m, 2 H) 7.88 - 8.30 (m, 2 H). MS (ESI-) m/z 430 (M-HY
Example 246 1-benzy! -N-[2-(dimethylamino)ethy!]-4-( I H-indazol-5-y1)-N-methyl-1 H-1.23-triazole-5- carboxamide
The title compound was prepared as a TFA salt according to the procedure outlined in
Example 234 substituting NN N-trimethylethylenediamine for (S)-(+)-
tetrahydrofurfurylamine, 'H NMR (300 MHz, DMSO0-d¢/D,0) 8 ppm 2.28 - 2.42 (m, 3 H) 273-300 (m, 6 H}3.07-3.19(m, 2 H) 3.56 - 3.80 (m, 2 H)5.55-568 (m, 2 Hy 724-747 (mm, 5 H) 7.56 - 7.7% (mm, 2H) 7.01 -8.02 {m, 1H 810-817 {m, I H). MS (ESI+) m/z 404 (MH),
Example 247
I-benzyl-N-(2 -hydrox vethyl)-4-(1H-i ndazol-5-y1)-N -propyl-TH-1 .2.3-triazole-5-carboxramide
The title compound was prepared according to the procedure outlined in Example 234 substituting 2-(propylamine ethane! for ({ Sh-(+)-tetrahydrofurfurylamine. "HNMR (300
Ho MHz, DMSO-dg/D0) ppm 0.22 - 0.39 (m, 1 BY 0.80 - LO6 (mm, SHY 1.50 - 1.75 {m, 1 H) 265-278 (m, 1 Hy 2.80 -2.04 (m, 1 H)2.97-3.09 (m, TH) 3.37. 3.50 (m, 1 H)3.51-2363 {m, 1H} 3.61-3.73 (m, | H) 539-574 (m, 2 H)7.20-7.44 (m, 5 H) 7.30 - 785 (m, 2 H) 7.86 - 8.25 (m, 2 11). MS (ESI) m/z 405 (M+H)”, 13 Example 248
I-benzyl-N-[3 -(dimethylamino propyl ]-4-( IH-indazo}-3 -VD-N-methyl-1F-1 2 3-111 azole-5- carboxamide
The title compound wag prepared as a TFA salt according to the procedure outiined in
Example 234 substitutin g N.N.N-trimethyl-1,3-propanediamine for (S)-(+)- tetrahydrofurfurylamine, "H NMR {300 MHz, DMSO-d¢/D.0) & ppm 8.06 - 8.23 (m, | HH 785-805(m, 1 H)7.57.7.73 (mM. 2HY7.19- 7.48 (mm, 5H)5.41-574 (m, 2H) 3.36-3.45 {m, 2 H} 2.88 - 3.10 (m, 3H) 2.60 - 2.86 (m, 5 H) 224.242 (m, 4 HY1.73-1.91 (m, 1 Hy.
MS (EST+) m/z 418 (M+H)",
Example 249
I-benzyl-N-[2- diethylaminoyethyl}-d-¢ IH-indazol-5-y1)-N -methyl-1H-1.2,3-triazole-5- carboxamide
The title compound was prepared as a TFA salt according to the procedure outlined in
Example 234 substituting N.N-diethyl-N-methylethy] enediamine for (S)-(+)- tetrahydrofurfurylamine. ‘fy NMR (300 MHz, DMSO-dg/D,0) § ppm 7.82 - 8.24 (m, 2 H) 7.56 7.76 (m, 2 HY 7.15 - 7.49 (m, 5H) 5.54-3.71 (mM, 2H) 3.60-377 (Mm, 2H) 3.20-3.24 (m, 2 HY3.13- 3.18% (m, 2H)3.03-3.11 (m, 2H} 232-244 (m, 3 H) 0.63 - 141 (m, 6 H).
MS (ESI+) m/z 432 (M+H)".
Example 250
N.I-dibenzyl-N-ethyl~4-( 1 H-indazo| -5-yl-10-1,2, 34riazole-5-carboxan de
The title compound wag prepared according to the procedure outlined in Example 234 substituting MN-ethylbenzylamine for { S)-(+tetrahydroturfurylamine. 'H NMR (300 MHz,
DBMS0-ds/D0) 8 ppm 7.81 - 8.20 (mM. 2H} 749-771 (m, 2 Hy 7.24 - 7 51 {m, 9H) 6.39. 738 (m, 2H) 541-574 (m, 2 H)4.53-4.84(m 1 H)23.82-400 (m, 1H} 337-354 ¢m, 1
HYZ.61- 2.78 (mm. 1 H) 0.91 - 1.08 (m. I H)027-045 (m.2 FH). MS (BSH m/z 437 (M+). id
Example 251
N, 1-dibenzyl-N-(2 -hydroxyethyl}-4-(1 H-indazol-5-yt)-1H-1 .2,3-triazole-5-carboxamide
The title compound was prepared according to the procedure outlined in Example 234 substituting N-benzylethanolamine for (S)-(4 tetrahydrofurfurylamine. MS (ESI) m/z 453 (M+H)"
Example 252 (3R)-1-{] 1-benzyl-4-( H-indazol-5-y1)- 1H-1.2, 3-triazol-5 -ylicarbonyl} piperidin-3-o
The title compound was prepared according to the procedure outlined in Example 234 substituting (R)-()-3-hydroxypiperidine hydrochloride for { S)-(t)-tetrahydrofurfurylamine. "H NMR (300 MHz, DMSC-dy/D»0) § ppm 7.83 -8.22 (m, 2 H) 7.51 - 7.78 (m, 2H; 7.23. 7.45 (m, 5H) 5.46 - 5.75 (m, 2H) 3.80 - 4.31 (m, 1 H)340-3.68 (m, 1 H)2.58-3.15 {m, 2
H)2.19-2.49 (m, 1 H)0.31-2.14 (m, 4 FH). MS (ESF) m/z 403 (M+H)".
Example 253 1-{[1-benzyl-4-( IH-indazol-5-y1)-1H-1 2,3-triazol-5-yljcarbony! {piperidine-4-carboxamide
The title compound was prepared according to the procedure outlined in Example 234 substituting isonipecotamide for (S}-(+)-tetrahydrofurfurylamine. '"H NMR (300 MHz,
DMSO-ds/D3,0) 8 ppm 7.86 - 8.24 (m, 2H) 7.53 - 7.70 (m. 2 H) 7.22 - 7.46 (m, 5 H) 5.42 - 577(m 2H) 4.19- 4.48 {m, 1H} 2.65-3.10 (m, 2 H)227-247 (m, 1 HY 2.05 - 2.24 {m, !
H)1.65-1.89(m.1H)1.29-155 (ra, 1 H) 0.98 - 1.27 (m, | H) 0.52 - 0.87 (m, 1 H). MS (ESI+) m/z 430 (M~+H)".
Example 254 5-{1-benzyl-5 [email protected] ycarbonyl]- TH-1.2,3-triazol-4-y] 1-1 H.indazole
The title compound was prepared according to the procedure outlined in Example 234 substituting L.6-dimethylmorpholine for (SH{)-tetrahydrofurfurytamine. 'H NMR (300
MHz, DMSO-d/Dy0) 8 ppm 7.87 - 8.27 (m, 2 HY 7.50 - 7.76 (rm, 2H) 7.12 - 7.45 (m, 5 1D 346-568 (m, 2 H) 4.16 - 4.43 (m, 1 H) 2.61 - 2.98 (m, 1 H)236-241¢m, 2H) 1.77 - 2.13 {m, 1H) 0.86- 1.39 (m, 3 4) 0.38 - 0.93 (mw, 3 HY). MS (ESI+) m/z 417 {(M+HY",
Example 2535 5-{5-[{4-acetylpiperazin- i -yhearbonyl]-1 ~benzyl-1H-1 v2,3-triazol-4-vl- 1 H-indazole
The title compound was prepared according to the procedure outlined in Example 234 substituting l-acetylpiperazine for { S}-(+)-tetrahvdrofurfurylamine. 'H NMR (300 MHz,
DMSO-ds/D0) 8 ppm 7.89 - 8.4] (m, 2H) 7.55 - 7.86 (m. 2 H)7.07- 7.51 (m, 5 H) 5.44 . 5.82(m, 2 H)3.46-3.70 (m, 3 HY335-349¢(m,2H)2.57- 2.93 (m0, 3H) 1.61 -2.03 (m, 3 15H). MS (ESI) m/z 430 (M+H)",
Example 256 5-11 -benzyl-5-[(4-phenyipiperazin- Lyljcarbonyl]-111-1.2, 3-tri azol-4-yl}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 234 substituting | -phenylpiperazine for (S)-(+)-tetrahydrofurfurylamine. "H NMR (300 MHz,
DMSO0-ds/D20) 6 ppm 7.79 - 8.38 (m, 2H) 7.53 - 7.73 (m, 2 H) 722-746 {m, 5H) 7.05 - 7.19 (m, 2 H) 6.64 - 6.79 (m, 3 H} 554-568 (m, 2H) 3.50. 3.90 {(m,2H}2.93-315(m, 2
H)2.62-2.89 (m, 2H) 2.19 - 2.43 (m, 2H). MS (ESI-) m/z 462 (M-Hy.
Example 257
I-benzyl-N-[(1R)-1 -(hydroxymethyl)-2-methylpropyl] -4-(1H-indazol-5-y1)-1H-1 2,3 triazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 234 substituting (R}-(+)-2-amino-3-methyl-1 -butanol for ( S)-(+}-tetrahydrofurfurylamine. 'H
NMR (300 MHz, DMSO-ds/D10) 8 ppm 7.95 - 8.31 (m, 2H) 7.52 - 7.96 (m, 2 FH) 7.18 - 7.46 (m, 5H) 5.42 - 5.86 (m, 2 H) 3.68 ~3.94 (mn, 1 H)3.38-3.50 (m, 2H) 1.49 - 2.08 (m, 1 H) 0.50 - 1.20 (m, 6 H). MS (ESI+) m/z 405 (M+H)",
Example 258
I-benzyl-N-[(18}-1 (hydroxymethyl }-2-methylpropyl]-4-( tH-mndazol-5-y1}-1H-1,2 3-triazoie-
S-carboxamide
The title compound was prepared according © the procedure outlined in Example 234 substituting (S)(~}-2-amino-3-methyl- I -butano) for (S)-(+)-tetrahydrofurfurylamine. 'H
NMR (300 MHz, DMSO-d4/1,0) & ppm 7.94 - 8.36 (m, 2 H) 7.52 « 7.84 (m, 2 H} 7.18.75] {m, 5H) 5.57 - 5.76 (m, 2 H) 3.75 - 3.94 (m, | Hy 335-354 (m, 2H) 1.70- 1.94 (m, 1 H} 0.54 - 1.09 (m, 6 H). MS (ESI) m/z 405 (M+H)',
Example 259 l-benzyl-N-[3~(1H-imidazol- L-yhpropyi]-4-(1 H-mdazol-5-yD-1H-1.2 3-triazcle-5- carboxamide
The title compound was prepared according to the procedure outlined in Example 234 substituting 1-(3-aminopropyl)imidazole for (5)-(+}tetrahydrofurfurylamine, 'H NMR (300
MHz, DMSO-d¢/D;0) 8 ppm 8.57 - 8.85 (m. | H}7.92-8.16 (m, 2 H) 7.60 - 7.80 {m, 2 H)
TAT-T755(m, 2H) 7.19 - 740 (tn. 5 H) 5.54 - 5.75 (mM. 2H) 3.83-421 (m, 2 H)3.19-3.2¢ (m, 2 H) 1.79 - 2.06 (m, 2 H). MS (ESH) m/z 427 (M+H)",
Example 260
N-[5-(1-benzyl-5-cyclopropyl-1H-1 -2,3-triazol-4-y1)-1H-indazol-3-y1}-N"-ethyiurea
The title compound was prepared as a hydrochloric acid salt according to the procedure outlined in Example 229 substitutin g 1socyanatocthane for 3-isocyanato-5-methyl- 2-(triflnoromethyfuran. 'H NMR (300 MHz, DMSO-d) 8 ppm 12.38 (s, 1 H), 9.47 (5, 1
H), 8.38 (s, 1H), 7.85 - 7.97 (mn, 1 H), 7.78 (d, J=8.82, 1.47 Hz, 1 H), 7.34 - 7.50 {m, 4 H), 724-733(m, 2H), 5.69 (s, 2 Hy 307-329 (mm, 2 13, 1.70 - 1.83 (m, 1 HY), 1.12 (1, 3=7.17
Hz, 3H), 1.00 - 1.08 (m, 2 H), 0.37 (d, J=3.68 Hz 2 H). MS (ESI+) m/z 402 (M+H)".
Example 261
N-~{5-(1-benzyl-5-cyclopropyi-1H-1 2,3-triazol-4-yi)-1 H-indazol-3-yl}-N'-phenylurea
The title compound was prepared as a hydrochloric acid salt according to the procedure outlined in Example 229 substituting isocyanatobenzene for 3-1socyanato-5- methyl-2-(triffuoromethylfuran. 'H NMR (300 MHz, DMSO-dg) 8 ppm 12.47 - 12.78 fm. 1
H), 9.64 (s, 1 H), 8.39 (s. 1 H), 7.70 - 7.95 (m, 1 H), 7.45 - 7.60 (m., 3 H), 7.27 - 7.45 {m, 7
H), 7.02 (m, 1H), 5.69 (5. 2H), 1.79 (m, 1 H), 1.07 (m, 2 1), 0.40 (m, 2 H). MS (BSI+) m/z 450 (MHD).
Example 267 3 N-benzyl-N'-[5-(1 -benzyl-5 ~cyclopropyl-1H-1.2 3.414 azol-4-yl}-1H-indaro}-3 -yilurea
The title compound was prepared as a hydrochloric acid salt according to the procedure outlined in Example 229 substituting (tsocyanatomethyl)benzene for 3-isocyanato-
S-methyl-2-{trifluoromethy furan. 41 NMR (300 MHz, DM 5O-ds) 8 ppm 12.42 (5, 1 FI, 9.61 (8, TH), 837 (5, T H), 823-833 (om, 1H), 7.79 (d, J=8.82, 1.47 Haz, | H), 7.36 - 7.50 (m, 4H) 7.28 - 7.36 (m, 6 HE 720-727 (m, 1 H), 5.69 (5, 2 FH}, 4.45 (d, I=5.88 Hz, 2 1),
L65-1.79(t. 1=8.27, 8.27 Hz, 1 H}, 0.99 - 1.08 (m, 2 H), 0.30 - 0.43 {m, 2 Hy. MS (ESI+) m/z 464 (M-+H)",
Example 263
N-[5-(1 -benzyl-5-cyclopropyl-1H-1 -2,3-triazol-4-y1)-1H-indazol.3 ~y1}-N'-(2~ chlorophenyijurea
The title compound was prepared as a hydrochloric acid salt according to the procedure outlined in Example 229 substituting 1-chloro-2-isacyanatobenzene for 3- isocyanato-3-methyl-2(trifluoromethyl) furan. "H NMR (300 MHz, DMSO-ds) 8 ppm 12.74 200 (8, 1H), 10.235, 1 H). 8.44 (3, 1 H), 8.34 (d, J=8.09 Hz, 1 H), 7.83 (d, J=8.82, 1.47 Hz. 1 H), 7.46 -7.55(m, 2 H), 7.35 - 7.45 (m, 3H), 7.28 - 7.35 (m, 3 H), 7.03 -7.12 (m, 1 H), 5.70 (s, 2H), 1.70 1.86 (m, 1 H), 1.00-1.12 (m, 2H), 6.33 - 0.45 (m, 2 H). MS (ESIH) m/z 484 (M+).
Example 264
N-[5-(1-benzyi-3 -cyciopropyl-1H-1 2, 3~tr1az0]-4-y])-1 H-indazol-3-y1]-N-(3- chiorophenyDurea
The title compound was prepared as a hydrochloric acid salt according to the procedure outlined in Example 229 substitutin g 1-chloro-3-isacyanatobenzene for 3- 180Cyanato-5-methyl-2-( trifluoromethyl)furan, 'H NMR (300 MHz, DMSO0-ds) 6 ppm 12.66 (s, 1H). 10.02 (s, 1 H), 9.71 (5, 1 H). 8.22. 8.48 (m, 1 H), 7.71 - 7.9 (m, 2 H), 7.51 (d,
J=8.46 Hz, 1 H), 7.37- 7.46 (m, 2 H}, 7.26 - 7.37 (m, SH), 7.02 - 7.1] (m, 1 H), 5.69 (s, 2
Hj, 1.73- 1.89 (m, 1 H), 0.99 - 1.11 {m, 2H}, 0.33 - 0.48 (m, 2 H). MS (ESI+) m/z 484
(M+H)".
Example 265
N-[5(}-benzyi-5 -cyelopropyl-1H-1,2 3-triazo) 4. yp 1B-indazol-3-yi]- {4 chiorophenylures
The title compound was prepared as a hydrochloric acid salt according to the procedure outlined in Example 229 substituting I-chloro-4-isocyanatobenzene for 3. isocyanato-3-methyl-2-(trifluoromethy! furan, 'H NMR (300 MHz, DMSC-dg) 8 ppm 12.65 (8. 1 HJ. 9.96 (¢, 1 FH), 9.68 (5, 1 BL, 837s, 1 HY, 7.81 (d, J=8.82. 1.47 Hz, 1 H), 7.53 - 7.60
HO (m, 2H), 7.50 (d, J=8.82 Hz, | H), 7.39 - 7.44 (m, 1H), 7.33 - 7.40 (m, 4 H), 7.27 - 732 im, 2H), 5.69 (s. 2H), 1.71 - 1.87 Om, TH) 1.00- 1.12 (m, 2 H), 034-044 (m, 2 1). MS (ESI+) m/z 484 (M+F)",
Example 266 1s N-[5-(1-benzyl-5-iodo-1H-1 2, 3-triazol-4-y])-1H-indazol-3 -vijbenzamide
Example 266A tert-butyl 3-amino-5-(] -benzyl-5-iodo-1H-1,2 3-triazo 4-y-1H-indazole- carboxylate
The title compound was prepared according to the procedure outlined m Example 198A substituting Example 125B for Example 102B. The product was used directly in subsequent reactions without characterization.
Example 266B
N-[5-(1-benzyl-3-iodo-1F1-1.2_3-tri azol-4-yi)-1 H-indazol-3-yIJbenzamide
The title compound was prepared as a TFA salt according to the procedure outlined in
Example 205B substituting Example 266A for Example 205A, 'H NMR {300 MHz, DMSO- de) 6 ppm 12.97 {s, 1 H). 10.89 (s. 1H), 828 (s, 1H), 8.05-8.14 (m, 2 H), 7.88 (d, J=8 82, 1.47 Hz, 1 H), 7.58 - 7.67 (m, 2 H), 7.54 (t, 3=7.35 Hz, 2 H), 7.20 = 7.45 {m, 3 H), 7.23 (d,
F=6.9% Hz, 2 H), 5.73 (s, 2 H). MS (ESI+) m/z 521 (M~H)".
Example 267 3-[4-(3-amino-1H -indazol-3-yi)-1H-pyrazol- 1 -yl]propanenitrile
Example 267A 3-(4-{44.5 S-tetramethyl-1.3 <~dioxaborolan-2-y]}-1 H-pyrazol-1-vlipropanenitrile
To a solution of 4-(4.4.5,5-tetramethyl-1.3,2-dioxaborolan-2-y1). BE-pyrazole (5.00 g, 25.8 mmol) in acetonitrile {50 mL} was added acrylonitrile (3.4 mk, 57 mmol) followed by 3 1,&-dtazabicyclo[3 4.0lundec-7-ene (1.94 mL. 120 mmol). After about 2 hours, the reaction mixture was concentrated under reduced pressure. The crude material was then dissolved in a minimal amount of dichloromethane and purified via silica gel chromatography eluting with a gradient of 10-50% ethy! acetate in heptane to afford the title compound. 'H NMR {400
MHz, DM80-ds) 8 ppm 8.03 (5, 1 HY, 7.64 (5, 1H), 4401, I= 6.4 Hz, 2H), 3.06 i=6.4
Hz 2H), 1.26 (s, 12H). MS (ESI+) m/z 2473 (M+H)".
Example 2678 3-[4-{3-amino-1H-indazol-5 -yl}-1H-pyrazol-1 -yl}propanenitrile
To a microwave vial was added S-bromo-1H-indazol-3-amine (6.14 g, 0.66 mmol), tetrakis(triphenylphosphine)palladium(0) (0.076 g, 0.066 mmol}, and sodium carbonate (0.147 g, 1.39 mmol) followed by a solution of Example 267A (0.212 £, 0.858 mmol) in 1,2- dimethoxyethane (2.50 mL} and then water (1.25 mL}. The mixture was heated in a CEM microwave at about 150 °C for about 20 minutes (275 psi maximum pressure, about 2 minutes ramp, 200 maximum watts) and then the mixture was concentrated under reduced pressure. Methanol {20 mL} was added and the resulting mixture was stirred for about I hour. The insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure onto silica gel and purified via silica gel chromatography eluting with a stepwise gradient of dichloromethane/methanol/ ammonium hydroxide (99¢:9:1 to 985:13.5:1 50 980:18:2) to afford a solid. This solid was dissolved in a minimum amount of hot acetonitrile (~2 mL), filtered to remove minor amount of ingolubles, while washing with methanol (<0.5 mL}, and left to sit at ambient temperature. The resul ting solid that formed overnight was collected by filtration, while washing with additional acetonitrile, and dried in 4 vacuum oven at about 60 °C for about 2 hours to afford the title compound. ‘H NMR {400
MHz, DMSO-dg} & ppm 11.35 (s, TH), 8.10 (s, 1H), 7.86 (s. 1H), 7.84 (s. 1H), 7.44 (dd, J = 8.54, 1.26 Hz, 1H), 7.23 (d. J =8.62 Hz, 1H), 5.32 (s, 2H), 4.42 (1, 1 = 6.36 Hz, 2H), 3.10 (1. ] = 6.43 Hz, 2H). MS (ESI+) m/z 253.2 (M+H)".
Example 268 2-{4-(3-armino-1H-indazol-5 ~yI-1H-pyrazol-1-yljacetamide
Example 268A 2-(4-(4.4,5 5-tetramethy]-1 .3.2-diexaborolan-2-y1)- 1H -pyrazol-1-yhacetamide
A suspension of 4-(4.4.5.5-tetramethyl-1,3,2~dioxaborolan-2-y1)-1H-pyrazole (2.00 g, 10.3 mmol), Z-bromoacetamide {2.14 g, 15.5 mmo!), and potassium carbonate (2.14 og, 15.5 mmol) in acetone (60 mL) was heated at about 50 °C for ahout 3.5 days. The reaction mixture was then cooled to ambient temperature, filtered through diatomaceous carth, while washing with additional acetone, and then concentrated under reduced pressure. The crude material was then dissolved in 2 minimal amount of dichloromethane and purified via silica gel chromatography eluting with a gradient of 80-100% ethyl acetate in heptane to afford the title compound. "H NMR (400 MHz, DMSO-d) & ppm 7.88 (s, TH). 7.57 (s. TH), 7.46 (s, 1H), 7.24 (s, 1H), 4.77 (s, 2H), 1.26 (s, 12H). MS (ESI) m/z 252.2 (M+H)".
Example 268B 2-[4-(3-amino-1H-indazol-5 ~y1)-1H-pyrazol-1-yl]acetamide
The title compound was prepared according to the procedure outlined in Example 2678 substituting Example 268A for Example 267A and heating at about 120 °C for about 10 minutes. 'H NMR (400 MHz, DMSO-dg) 6 ppm 11.32 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 777 (s. 1H), 7.48 (s, 1H), 745 (d. J = 8.6 Hz, 1H), 7.26 (s, TH), 7.22 (d, I = 8.7 Hz, 1H), 5.28 {s, 2H), 4.78 (s, 2H). MS (ESI) m/z 257.2 (M+H)"
Example 269 methyl 3-[4-(3-amino-1H-indazol-5 -yI)-1H-pyrazol-1 -ylipropanoate
Example 269A methyl 3-(4-(4,4.5.3 ~tetramethyl-1 ,3,2-dioxaborolan-2-y1)-1 Hepyrazol-1-yl)propanoate
The title compound was prepared according to the procedure outlined in Example 267A substituting methyl acrylate for acrylonitrile. 'H NMR (400 MHz, DMSQ-ds) 8 ppm 7.91 (8, 1H), 7.57 (s, 1H), 4.35 (t, ] = 6.73 Hz, 2H), 2.87 (t, 1 = 6.75 Hz. 2H}, 3.59 (5, 3H),
1.24 (s, 12H). MS (ESI+) m/z 281.2 (M+H)",
Example 269B methyl 3-{4-(3-aming- | Heindazol-5-y1)-1H-pyrazol-1 ~ylipropanoate
The title compound wag prepared according to the procedure outlined in Example 2678 substituting Example 269A for Example 267A and Beating at about 120 °C for about 20 minutes. 'H NMR (400 MHz, DMSG-ds) & ppm 11.32 {s. 1H), 8.00 (s. 1H), 7.85 (s, 1H), 7.76 (s. 1H), 7.42 (d, J = 8.50 Hz, TH), 7.21 (d, I= 8.61 Hz, 1H), 5.28 (8. 2H), 437 (1, = 6.71 Hz, 2H), 3.61 (5, 3H), 2.97 {t, J = 0.69 Hz, 2H}. MS (ESH} m/z 286.2 (M+H)Y io
Example 276 3-{4-(3-amino- IH-indazol-5-y1)-1H-pyrazol-] -vljpropanamide
Example 270A 3-(4-(4,4.5,5-tetramethyl- 1.3,2-dioxaborolan-2-y1)-1H -pyrazol-1-ylipropanamide
The title compound was prepared according to the procedure outlined in Example 267A substituting acrylamide for acrylonitrile (0.72 ¢, 53%). 'H NMR (400 MHz, DMSO- de) d ppm 7.84 (s, 1H), 7.56 (s, TH}, 7.37 (3, 1H), 6.88 (s, 1H), 4.301, J = 6.80 Hz, 2H), 2.60 (L.J=6.79 Hz, 2H), 1.24 (s, 12H). MS (ESI+) m/z 266.2 (M+HY)
Example 270B 3-[4-(3-amino-1H -indazol-5-yl}-1H-pyrazol-1 -vl]propanamide
The title compound was prepared according to the procedure outlined in Example 267B substituting Example 270A for Example 267A and heating ar about 120 °C for about 15 minutes (0.056 g, 22%). 'H NMR (400 MHz, DMSO-ds) 8 ppm 11.32 (s, 1H), 7.94 (d, J = 0.53 Hz, 1H), 7.84 (s, 1H), 7.75 (d.J/= 0.54 Hz, 1H), 7.42 (ma, 2H), 7.20 (d, J = 8.26 Hz,
TH), 6.89 (s, 1H), 5.27 (s, 2H), 4.32 (t..J = 6.89 Hz, 2H), 2.65 (1,7 = 6.89 Hz, 2H). MS (ESI+)ym/z 271.6 (M-+H)",
Example 27]
[4-(3-amino-1H-indazol-5-y[}-1 H-pyrazol-i-vljacetonitrile
Example 2714 2-(4(44 5 S-tetramethyl-1,3,2-dioxaborol an-2-yl)-1H-pyrazol-1-yDacetonitrile
The title compound was prepared according fo the procedure outlined in Example 268A substituting 2-bromaacetoniwile for 2-bromoacetamide. 'H NMR (400 MHz, DMSO- ds) & ppm 7.99 (s, 1H), 7.66 (s, 1H). 5.45 (5, 2H), 1.25 (s, 12H). 1¢
Example 271B tert-butyl 3-(bis( tert-butoxycarbonylaming)-5-bromo- 1 Hin dazole-1-carboxylate
To 5-brome-1H-indazol-3-amine (2.00 g, 9.43 mmol) in tetrahydrofuran (20 ml) was added 4-(dimethylamino)pyridine (0.230 g, 1.886 mmol) and di-terr-butyl dicarbonate (6.18 15g, 283 mmol). The reaction was heated at 50 °C for about 2 hours, cooled to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in, diethy! ether (100 mL.) and then washed sequentially with 1 N hydrochloric acid 2x25ml), IN sodium hydroxide (2 x 25 mL) and brine (25 mL). The organic layer was then dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried in a vacuum oven at about 60 °C to afford the title compound. 'H NMR (400 MHz, DMSO-d) 8.05 (d, 1 = 8.95
Hz, 1H), 7.99 (d, J = 1.00 Hz, 1H}. 7.81 (dd, J = 8.94, 1 89 Hz, TH), 1.65 (5, 9H), 1.40 (s, 18H). MS (ESI+) m/z 512.2 (M+H)".
Example 271C tert-butyl 3-(bis( tert-butoxycarbonyl)aming)-5-( F-{cyanomethy!)-1H -pyrazol-4-vl}-1H- indazole-1-carboxylate
A vial was charged with Example 271A (0.682 g. 2.93 mmol), Example 271B (125g, 2.44 mmol), cesium carbonate {1.99 g, 6.10 mmol}, 1 4-dioxane (12.5 mL) and water (2.50 mL) Aftera vacuum/nitrogen purge through a septa, tris(dibenzylideneacetone)dipalladium( 0) (0.112 g, 0.122 mmol} and tri-z-butylphosphonium tetrafluoroborate (0.085 g, 0.29 mmol} were added and a cap was put on the vial after flushing with nitrogen. Afier about 6 hours at ambient temperature, the reaction was partitioned between saturated aqueous sodium bicarbonate and dichloromethane {50 mL cach). The layers were separated and the aqueous layer was extracted with additional dichloromethane (2 x 50 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude oil was dissolved in 2 minimal amount of dichloromethane and purified via silica gel chromatography eluting with a gradient of 20-60% ethyl acetate in heptane to afford the title compound. 'H NMR (400 MHz, DMSO-dg) & ppm 8.43 (5, TH), 8.19 (5, 1H), 8.08 {d, j= 9.22 Hz, 1H). 7.93 (m, 2H), 5.53 (8, 2H}, 1.67 (s, 9H), 1.39 (5, 18H). MS (ESI+) m/z 539.3 (M-+HY".
Example 2710 [4-(3~amino-1 H-indazol-5-v}-1H-pyrazol-1 -vljacetonitrile
To a solution of feri-butyi 3-(bis{tert-butoxycarbonyl jamino)-5-¢ I-{cyanomethyl)-1H- pyrazol-4-yi\-1H-indazole-] -carboxylate (0.30 g, 0.557 mmol) in dichloromethane (4.0 mi.) was added trifluoroacetic acid (2.0 mL). After about 45 minutes, the reaction was slowly quenched with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (3 x 23 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude solid. A white precipitate that was suspended in both the initial aqueous layer and the brine layer was filtered and added to the crude solid. The resulting solid was triturated with dichloromethane/methanoi (19:1). The remaining solid was collected by vacuum filtration and dried in a vacuum oven at about 70 °C to afford the title compound. 'H NMR (400 MHz,
DMSO-ds} 8 ppin 11.37 (s. 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.89 (s, UH) 749-741 (m, 1H), 7.24 (d, J = 8.71 Hz, 1H), 5.52 (s, ZH), 5.31 (5, 2H). MS (ESI) m/z 239.1 (M+H)",
Example 272 4-(3-amino-1H-indazol-5-y1)-IN N-dimethyl-1H-imidazole- 1 -sulfonamide 3-Cyano-4-fluorophenylboronic acid (0.083 g, 0.503 mmol), 4-iodo-N,N-dimethyi- 1H-imidazole-1-sulfonamide {0.167 g, 0.5354 mmol), sodium carbonate (0.128 g 1.208 mmol) and tetrakis(iriphenylphosphine palladium 0) (0.035 g, 0.030 mmol) were combined in dimethoxyethane (4 mL) and water (1.5mL). The reaction mixture was heated in a microwave (CEM-Discover) at about 150 °C for about 25 minutes. The organic layer was separated and the solvent was removed under reduced pressure. To the residue was added ethanol (0.7 mL) and hydrazine monohydrate {1 mL). The reaction mixture was heated at about 80 °C for about 20 hours. The reaction mixture was partitioned between water £5 mb) and dichloromethane {100 mL). The organic layer was separated and concentrated under reduced pressure. The residue was purified by reverse phase HPLC usin g acetonitrile/water {0.05 M ammonium acetate) gradient clution method to afford the ile compound. 'H NMR (400 MHz, DMSO-ds) 8 ppm 11.42 (s, 1H). 825 (s, 1H), 8.21 (d../ = 1.36 Hz, IH), 7.92 (d,J = 1.37 Hz, 1H), 7.74 (dd, J = 8.66, 1.58 Hz, IH}, 7.23 (d, J = 8.68 Hz, 1H). 5.35 {s, 2H), 2.87 (s, 6H). MS (ESI) m/z 307.2 (M+H)".
H) Example 273
S-pyrazin-2-yl-1H-indazol-3-amine
The title compound was prepared accordin g to the procedure outlined in Example 272 substituting 2-iodopyrazine for 4-iodo-N,N~dimethyl-1H-imidazole- | -sulfonamide. "H NMR (400 MHz, DMSO-ds) 6 ppm 11.61 (s, 1H). 9.18 (d, 1H, J = 1.6), 8.66 (dd, 1H, J = 17,243, 8.59(d, 1H, J=1.0),851 (d, 1H, J = 2.5), 8.04 (dd, IH, J = 1.8, 8.8), 7.35 (d, 1H, 1=92), 5.54 (s, 2H). MS (ESI+) m/z 212.2 (M-+H)",
Example 274
S-thien-2-yi-1H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example 272 substituting 2-iodothiophene for 4-todo-N,N-dimethyl-1H-imidazole-1-sul fonamide. 'H
NMR (400 MHz, DMSO-d; ) & ppm 11.47 (s, 1H), 7.99 (d, 1H, I= 1.4), 7.55 (dd. 1H. ] = 1.8, 8.8), 743 (dd. 1H, T= 1.0, 5.1), 7.35 (dd, IH, 1 =1.1,3.6), 7.26 (d, 1H, J = 8.0), 7.10 (dd, 1H, J =3.5,51).542(d, 2H, J = 8.8). MS (ESI+) m/z 216.1 (M+H)",
Example 275 3-(2-aminopyrimidin-4-y1)-1H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example 272 substituting S-iodopyrimidin-2-amine for 4-1odo-N,N-dimethyl-1H-imidazole- 1 -sul fopamide. "HNMR (400 MHz, DMSO-ds) 6 ppm 11.40 (s, 1H), £.53 (, 2H), 7.91 (dd, 1H, 1 = 0.7, 1.5). 7.47 (dd, IH. T= 1.8, 8.6), 7.28 (dd, 1H, ] = 0.7, 8.7), 6.64 (s, 2H), 5.36 (s, 2H). 1H NMR (400 MHz, DMSO-d; ) 8 ppm 11.41 (s, 1H), 8.53 (s, 2H), 7.92 (m, 1H), 7.47 (dd, J = 8.66, 1.74 Hz, 1H), 7.28 (dd, J = 8.63, 0.65 Hz, 1H}, 6.64 (s, 2H), 5.36 (3, 2H}. MS (ESI) m/z i64
227.2 (M+H)™.
Example 276 5-(2-methoxypyridin-3 ~yh-1H-indazol-3-armine
The title compound was prepared according to the procadure outlined in Example 272 substituting 3-iodo-Z-methoxypyridine for 4-iodo-N,N-dimethyl-1H-imidazole-] sulfonamide. 'H NMR (400 MHz, DMSO-d; } § pp 11.43 (s, 1H), 8.14 (dd, 1H, J = 1.9, 3.0), 7.86 (s, 1H), 7.71 (dd, IH, J=2.0,7.2), 7.42 (dd, TH, J=1787. 726 1H. = 5.6), 7.09(dd, IH. 1=5.0,7.3), 2.38 (s, 2H), 3.89 (s, 3H). MS (ESF) miz 241.2 {M+HY"
Example 277
S-imidazof 1 Z-alpyridin-3-yl-1H-indazol-3 ~ginine
The title compound was prepared according to the procedure outlined in Example 272 substituting 3-bromoimidazof 1. 2-ajpyridine for 4-iodo-N,N-dimethyl-1 H-imi dazole-1- sulfonamide. 'H NMR {400 MHz. DMSO0-ds) 8 ppm 8.52 (dt, 1H, J = 1.2, 7.0%, 7.99 (dd, 1H,
I=07,1.7), 7.68 (s, 1H), 7.65 (dt, 2H,J=1.2, 9.0), 7.46 (dd, 1H, J = 1 8, 8.6), 7.39 (dd, TH,
J=08, 8.6), 7.28 (ddd, 1H, J = 1.2,6.6,9.2),6.96 (1d, 1H, J = 1.3,6.7), 5.47 (s. 2H). MS (ESI) m/z 250.2 (M+H)",
Example 27%
NY N-dimethyl-N' -[5-(1H-1,2,3-triazol-4-y1)-1H -ndazol-3-yl]glveinamide
Example 65 (257 mg, 0.685 mmol) was dissolved in ethanol (153ml). The reaction mixture was hydrogenated in an H-Cube apparatus with palladium hydroxide (20%) on carbon at about 80 °C and about 60 psi for about 8 hours. The solvent was removed under reduced pressure and the resiue was purified by reverse phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound. 'H NMR (400 MHz, DMSO-d) § ppm 8.16-8.37 (m, 1H), 7.10-7.4¢ (bs, 2H), 7.00-7.34 (bs, 2H), 6.87-7.04 (bs, 2H), 3.33-3.34 (m, 2H). MS (ESIH+) m/z 286.2 {(M+H)".
Example 279 3-(1H-pyrazol-3-yl}-1 H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example 272 substituting 5 sodo-1H-pyrazele for 4-10do-IN.N-dimethyl-1H-imidazole-1 -sulfonamide. 'H
NMR (400 MHz, DMS0-d;) 6 ppm 7.87-7.94 (m, 3H), 7.60-7.63 (m, 1H). 7.48 (dd, J = 8.53, 1.62 Hz, 1H). 7.19-7.32 (m, 2H), 525-528 (m, 2H). MS (ESI) m/z 200.1 (M+H)"
Example 280
S5-(4-methyl- 1 H-imidazo! -5-yh-1H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example 272 substituting 5-10do-4-methyl-1H-imidazole for 4-10de-N.N-dimethyi-1 H-mmidazole-1- sulfonamide. "FH NMR (400 MHz, DMSO-d) & ppm 7.85 (s, 1H), 7.52 (d, 2H, I = 6.6), 7.22 (m. TH), 5.3 2 (bs, 2H). 2.37 (s, 3H). MS (ESI+) m/z 214.1 (MEY
Example 281 5-(1H-imidazol-4-y1)-1H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example 272 substituting 4-iodo-1H-imidazole for 4-10do-N.N-dimethyl-1H-imidazole-1 sulfonamide. 'H
NMR (400 MHz, DBMSO-ds) & ppm 8.07 (5, TH), 7.66 (s, 1H), 7.63 (d, 1H, ] = 8.6), 7.37 (s,
TH), 7.20 (d, 1H, 1 =8.8), 5.2% (s. 2H). MS (ESI+) m/z 200.1 (M+H)",
Example 282
NN dimethyl-N'- {5-1 -(3-methylbenzyl)-1H-1,2,3-triazol-4-y1]- 1 H-indazol-3. vl} glycinamide
Example 282A 5-bromo- IH-indazo!-3-amine
The title compound was prepared according to the procedure outlined in Example 62D substituting 5-bromo-2-fluorobenzonitrile for Example 62C. 'H NMR (400 MHz,
DMSO-dy) 6 ppm 11.55 (s, 1H), 7.92 (d,J=1%7 Hg, TH), 7.30 (dd. J = 8.79, 1.89 Hz, 1 H), 7.19 (d, J =8.78 Hz, 1H). 5.41 (s, 2H),
Example 282B tert-butyl 3-amino-5-bremo-1 H-indazole-] carboxylate
The title compound wag prepared according to the procedure outlined in Example
64A substituting Example 282A for Example 62D. '"H NMR {400 MHz, DMSO-d; § ppm 8.12(d. J=1.93 Hz, IH), 7.95-7.81 (m, 1H), 7.65 (dd, J = 8.85, 1.96 Hz, 1H). 6.39 (d, J = 4.44 Hz, TH), 1.58 (m, 9H)
Example 282C tert-butyl 5-bromo-3-( 2-(dimeth ylaminejacetamido)- 1 H-indazole-] ~carboxylate
To a mixture of Example 2828 {24.43 g, 78 mmol), potassium carbonate (81 g. 587 menol} and 2+ dimethylamino acetyl chloride hydrochloride (43.3 8. 274 mmol) was added tetrahydrofuran (200 mL). The reaction mixture was surred at room temperature for about 2 hours. The reaction mixture was filtered and the filirate was washed with water (50 nL),
The organic layer was separated and the aqueous layer was extracted with dichloromethane (3 x 100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol in dichloromethane (5%) to afford the title compound, "H NMR (400 MHz, DMSO-d;) 8 ppm 10.72 {s, 1H), 8.19¢d, 1H, J =] 6), 8.03 (d, IF, 1 = 9.0), 7.76 (dd, 11, J = 2.0, 9.0}, 3.22 (s, 2H), 2.32 (s, 6H), 1.63 (s, OH).
Example 282 D tert-butyl 342-{dim ethylaminojacetamido)-3-{(trimethyisilyDethynyl)- I H-indazole-1- carboxylate
To a mixture of Example 282C (2.56 g, 6.44 mmol}, bis{triphenylphosphine)palladium( 11) chloride (0.225 g, 0.321 mmol}, and copper(1) iodide (0.073 g, 0.383 mmol) was added triethylamine (20 mL, 144 mmol) followed by ethynyltrimethyisilane (0.760 €, 7.73 mmol). The reaction mixture was heated at about 60 °C for about 3 hours. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate in dichloromethane (10%) to give the title compound. 'H NMR {400 MHz, DMSO-ds) 8 ppm 10.69 (s, 1H), 8.08 (s, 1H), 8.04 (d, 1H. J=9.0), 7.62 (d, 1H, J = 8.8), 3.21 (s, 2H), 2.30 (s, OH}, 1.61 (s, OH), 0.23 (s, 9H),
Example 282EF 2-{dimethylamino )-N-{ S-ethynyl-1H-indazal-3 -yllacetamide
To Example 2820 (0.303 g, 6.731 mmol} in methanol (5 mL) was added aqueous potassium hydroxide (1.46 mi, 1.46 mmol, 1.0 solution). The reaction mixture was stirred at room temperature for about 1 hour. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (80 mL). The organic layer was separated and washed with water (10 mL) and brine (10 mL}, dried over magnesium suifate, filtered and concentrated under reduced pressure tn afford the title compound. "H NMR (400 MHz, 16 DMSO-dg) 6 ppm 12.89 (s, 1H), 10.14 (s, 1H), 8.00 (4, PHL F=12.1), 7.44 (s, 2H), 7.38 (d,
TH, J = 8.6), 4.02 (s, 1H), 3.17 {s, 2H), 2.33 (s, 6F).
Example 282F
WN N*-dimethy] -N'- 5-[1-(3-methylbenzyD-1H-1 22, 3-triazol-4-yl}-1H-indazol-3- vliglycinamide
To a suspension of Example 282E (0.16 g, 0.660 mmol} in tert-butano! (1.2 mL) was added 1 -(azidomethyl)-3-methylbenzene (0.098 g, 0.667 mmol), then water {(1.2mL). A solution of sodium ( R)-2-({S)- 1.2-dihydroxyethyl)-4-hydroxy-5-0x0-2.5-dihydrofuran-3-olate {0.057 mL. 0.066 mmol, 1.6 M in water) and an aqueous solution of copper (11) sulfate pentahydrate (0.019 ml, 6.6 pmol, 0.34M) was added. The reaction mixture was heated at about 60 °C for about 2 hours. The solvent was removed under reduced pressure and the residue was purified by reverse phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound. 'H NMR (400 MHz, DMSO- ds} & ppm 12.77 (s, 1H), 10.05 (s, 1H), 8.56 (s, 1H), 8.24 (s, 1H), 7.82 (d, 1H, J = 8.6}, 7.50 (d, IH, J=818), 7.28 (1, 1H, J = 7.6), 7.16 (m, 4H), 5.59 (s, 2H), 3.18 {s. ZH), 2.34 (s, 6H), 2.30 (s, 3H). MS (ESI) m/z 390.3 (M+),
Example 283 5-(1-benzyl-1H -imidazol-4-yI}-1H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example 272 substituting 1-benzyl-4-iodo-1H-imidazole for 4-iodo-N,N-dimethyl- | H-imidazole-1- sulfonamide. 'H NMR {400 MHz, DMSO-d;) 8 ppm 11.29 (s, IH), 8.67 (s, 1H), 7.79 {s, tH), 7.61 (d, 1H, J = 8.6), 7.46 (s, 1H), 7.36 (m, 581), 7.17 (d, 1H, J = 8.8), 5.28 {s, 2H), 53.22
(8, 2H). MS (ESI+) m/z 290.2 (M+H}".
Example 284
Ng S-[I-(4-tert-burytbenzyi)-1H-1,2.3 ~triazol-4-yl|-1 B-indazol-3-yl FRE NE dimethylgiveinamide
The title compound was prepared according to the procedure outlined in Example 282F substituting I-{azidomethyl}-4-tert-butylbenzene for | -(azidomethyl}-3-methylbenzene. 'H
NMR (400 MHz, DMSO-d, 6 ppm 12.88 (5, 1H), 10.05 (s. 1H), 8.57 (s, 1H), 8.23 (s. 1H),
TEI, TH, J=8.8), 7.50 {d, 1H, 1 = BB). 7.41 (d, 2H, F=18.2), 7.30 (d. 2H, J = 8.2), 3.18 (5, tO 2H), 2.34 (s, 6H), 1.26 (s, 9H), MS (ESi+) m/z 432.2 (M+HY
Example 285
NN -dimethy}-N'- {5-[] ~(2-piperidin-1-ylethyl)-1H- | 2,3-triazol-4-y1]-1H-indazol-3- yliglyeinamide
The title compound was prepared according to the procedure outlined in Example 282F substituting 1-( 2-azidoethyl)piperidine for t-(azidomethyl)-3-methylbenzene. 9 NMR (400 MHz, DMSO-dg) 6 ppm 12.91 (s, 1H), 10.07 (s, 1H), 8.47 (s, TH), 8.22 (5, 1H), 7.80 (dd, 1H, J = 1.2, 8.7), 7.52 {d, IHL J = 8.8), 4.49 (t, 211. J = 6.4), 3.19 (s, 23, 2.76 (t, 2H, ] = 6.4), 2.41 (s, 4H), 2.35 (s, 6H), 1.69 (s, 3H), 1.47 (m, 4H), 1.37 (dd, 2H, J = 5.2, 10.23. MS (BSI) m/z 395.3 (M-HY
Example 286
NON dimethyl-N'-(5-[12-morpholin-4-ylethyl}- 1 H-1,2,3-triazol 4-y1]- 1H. indayopa. vl}glveinamide 235 The title compound was prepared according to the procedure outlined in Example 282F substituting 4-(2-azidoethylymorpholine for I-(azidomethy!)-3-methylbenzene. 'H
NMR (400 MHz. DMSO-ds) & ppm 12.83 (s, 151), 10.07 (s, 1H), 8.49 (5, 1H), 8.23 (s, IFT), 7.81(dd, 1H. J=13.8.7), 7.52 (d, IH, J=88),4.53 (1, 2H, J = 6.3), 3.55 (m, 4H), 3.19 (s, 2H), 2.80 (t, 2H, 1 = 6.3), 2.45 (m, 4H), 2.35 (s, 6H). MS (ES) m/z 397.3 (M-HY.
Example 287
Nl 5-{1-[2-(3,5 -dimethylisoxazol-4-y1)ethyl J-1H-1,2,3-triazo! -“4-vli-1H-indazol-3 -y13-
N° N’-dimethylelycimamide
The title compound was prepared according to the procedure outlined in Example
282F substituting 4-(2-azidoethyl}-3,5-dimethylisoxazole for 1-(azidomethyl)-3- methylbenzene, 'H NMR (400 MHz, DMSO-d) 8 prm 12.90 (s, 1H), 10.07 (s, 1H), 8.44 {s, 1H), 8.21 (s, 1H), 7.78 (dd, 1H, J = L387), 752d 1H, I= 8.8), 4.51 (t, 2H, I = 6.7). 3.19 {s, 2H}, 2.93 (1, 2H, ] = 6.7), 2.35 (s, 6H} 2.08 (d, 6H, J = 4.3). MS (EST m/z 4067.2 {Mi-HY,
Example 288
N51] -[2-(3.5-dimethyl-1 H-pyrazol-4-yiiethyl]-1H-1 2, 3-tr1azol-4-ylit-1 H-indazgl-3-yI)-
NN -dimethy glycinamide
The title compound was prepared according to the procedure outlined in Example 0 Z82F substituting 4-(2-azidoethyl}-3.5-dimethyl-1H-pyrazole for 1-{azidomethyl}-3- methylbenzene. 'H NMR (400 MHz, DMSO-ds) 6 ppm 12.85 (s, 1H), 10.06 (s, 1H), 8.37 (s, 1H), 821 (s, 1H), 7.78 (d, 1H, ] = BE). 7.51(d, 1H, 1=8.8), 4.42 (t. 2H, J = 6.9), 3.19 (s, 2H), 289 (1, 2H, 1 = 7.0), 2.35 (5, 6H), 1.97 (5, 6H). MS (ESI) m/z 406.2 (M-HY. 153 Example 289 2-{4- 3-[(N.N-dimethylglycy!jamino]-1H -indazol-5-y1}-1H-1.2,3-triazol-1 -y1)-2- methylpropanoic acid
The title compound was prepared according to the procedure outlined in Example
Z82F substituting 2-azido-2-methylpropanoic acid for I-(azidomethyl)-3-methylbenzene. 'H
NMR {400 MHz, DMSO-ds) 6 ppm 12.77 (s, 1H). 10.03 (s, TH), 8.47 (s, 1H), 8.22 (s, 1H), 7.85 (dd, 1H, J=109, 8.7), 7.49 (d, TH, I= 8.6), 3.21 (s, 2H), 2.36 (s. 6H), 1.77 (s, 6H). MS (ESE) m/z 370.2 (M-HY,
Example 290 ethyl (4- 3-[(N.N-dimethyiglycyljamino]-1H-indazo}-5-y] t-1H-1,2 3-triazol-1-yl)acetate
The title compound was prepared according to the procedure outlined in Example 282F substituting ethyl 2-azidoacetate for I-(azidomethy!)-3-methylbenzene. 11 NMR. (400
MHz, DMSO-d) 8 ppm 12.87 (s, IH), 10.08 (s, 1H), 8.51 (s, 1H). 8.26 (s, 1H), 7.82 (dd, 1H,
J=1.4,8.7), 7.53 (d, 1H, J = 8.8), 5.44 (s, 2H), 4.21 (q, 2H, J = 7.0), 3.19 (5, 2H), 2.35 (s, 6H), 1.24 ¢t, 3H, J = 7.1). MS (ESI+H) mvz 372.2 (M-+HY.
Example 291
N * N’-dimethyl-N h(5- {i -[{trimethylsilyhmethyl}-1H-1.2.3 ~triazol-4-y1!-1H-indazol-3~ vhglycinamide
The title compound was prepared according to the procedure outlined in Example 282F substituting (azidomethy)trimethylsilanc for I-(azidomethyl}-3-methylbenzene. 'H
NME (460 MHz, DMSO-ds) 8 ppm 13.04 (5, TH), 10.20 (s, 1H), 8.46 (s, THY, 8.36 (s, 1H), 7.94 (dd, TH, J =1.3,8.7), 7.65 (d, LHL J = 8.8), 4.18 (s, 211), 2.33 (8, 2H}, 2.49 (5, 6H), 0.25 {m, 9H). MS (ESI) m/z 372.7 (M-+H)",
Example 202
N' -[5-(3-furyl)-1 H-indazol-3-y1]-N * N'-dimethyl glycinamide
The title compound was prepared according to the procedure outhned in Example 16 233A substituting Example 282C for S-bromo-Z-fluorobenzeonitrile and furan-3-ylboronic acid for | “bonzyl-4-(4.4.5,5-tetramethyi-1,3 2-dioxaborolan-2-yl)- | H-pyrazole. "H NMR (600 MHz, DMSO-ds) § ppm 12.70 (s, 1H), 9.98 (s, IH), 8.08 (8, 1H). 7.90 (5, 1H), 7.72 (t, 1H, J =1.6}, 7.59 (dd, 1H, J = 14,87), 745d, 1H, I= 8.8). 6.87 (s, 1H), 3.17 (s, 2H}, 2.33 {s, 6H). MS (ESI+) m/z 285.2 (M+H)".
Example 293
N’N’-dimethyl-N' -[5-(1H-pyrazol-5-y1}-1 H-indazol-3-vl]glycinamide
The title compound was prepared according to the procedure outlined in Example 233A substituting Example 282C for S-bromo-2-fluorobenzonitrile and IH-pyrazol-5- ylboronic acid for I-benzyl-4-(4,4,5 S-teframethyl-1.3,2-dioxaborolan-2-y1)- 1 H-pyrazole. 'H
NMR (400 MHz, DMSO-dg) & ppm 12.68 (s, TH). 10.01 (5, 1H), 8.12 (s, TH), 7.80 (d, 1H, J = 9.0), 7.69 (s, 1H), 746 (d, 1H, ] = 8.6), 6.60 (d, IH, J=2.0), 3.17 (d, 2H, J = 6.4), 2.34 (s, 6H}. MS (ESI+) m/z 285.2 (M+H)Y",
Example 204
N° N’-dimethyl-N'-( 5-pyrimidin-5-yl-1 H-indazol-3-ylglycinamide
The title compound was prepared according to the procedure outlined in Exampic 233A substituting Example 282C for 5-bromo-2-fluorobenzonitrile and pyrimidin-5- yiboronic acid for I-benzyl-4-(4,4,5 5-tetramethyl- 1 3.2-dioxaborolan-2-y1)-1H-pyrazole. H
NMR (600 MHz. DMSO0-ds) 6 ppm 12.87 (s, 1H), 10.11 (s, 1H), 9.16 (s, 1H} 9.09 (5, ZH), 8.16 (s, 1H), 7.75 (dd, 1H, J = 1.5, 8.8), 760 (d, 1H. I= 8.8), 3.18 (5, 2H), 2.33 (s, 6H). MS (ESI+) m/z 297.2 (M-+H)", i71
Example 295
N! -[5-(2,1,3-benzoxadi azol-5-yI)-1 H-indazol-3-y13-N2 N* -timethylglveinamide
The title cornpound wag prepared according to the procedure outlined in Example 233A substituting Example 2820 for S-brome-2-fluorobenzonitrile and benzofc][1,2,5}oxadiazol-5-yIboronic acid for !-benzy] def 4.4.5 S-tetramethyl-1,3,2. dioxaboralan-2-y1)-1 H-pyrazolc. "H NMR {600 MHz, DMSG-ds) 8 ppm 12.87 (s, 1H), 10.15 {s, TH}, 8.29 (s, 1H), 8.21 (s. IH). 8.16 (d, 1H, J = 9.4), 7.99 (dd, 1H, J = 1.1,9.4), 7.85 (m, 1H), 7.59 (d, 1H. } = 8.8), 3.10 {s, 2H}, 2.34 (s, 6H). MS (ESI+) m/z 337.2 (MH),
H} Example 296
NY N’dimethyl-N 5 -(1H-pyrazol-4-yl)-1 H-indazol-3-vljglycinamide
The title compound was prepared according to the procedure outlined in Example 233A substituting Example 282C for S-bromo-2-flusrobenzonitrile and 4-(4,45 5. tetramethyl-1 .3.2-dioxaborolan-2-y1)-1 H-pyrazole for | “benzyl-4-{4,4.5 »S-tetramethyl-1,3,2. dioxaborotan-2-y{)-1H-pyrazole. 'H NMR {600 MHz, DMSO-ds) 8 ppm 12.62 {s, 1H), 9.94 {s, 1H), 7.95 (s, 2H), 7.87 {s, 1H), 7.58 (d, 1H. 1 = 8.8), 7.42(d, IH, = 8.8}, 3.16 (s, 2H), 2.34 (s. 6H). MS (ESI+) m/z 285.2 (M+HY"
Example 297
N° N"-dimethyl-N Lr 5-(1-methy!- 1H-pyrazol “A-yl)- 1H-indazel-3 ~yllglyeinamide
The title compound was prepared according to the procedure outlined in Example 233A Substituting Example 282C for 5-brome-2-fluorobenzonitrile and I-methyl-4-(4.4.5 5. tetramethyl-1,3.2 -dioxaborolan-2-y1)-1H -pyrazole or | -benzyl-4-(4.4.5 5 terramethyi- 1 3,2 dioxaborolan-2-y1)-1H-pyrazole. '"H NMR {600 MHz, DMSO-d) 8 ppm 12.64 (5, 1H), 9.08 (8, 1H), 8.04 (s, IH), 7.86 (s, 1H), 7.76 (s, TH), 7.55 (dd, 1H, 1= 16, 8.6), 7.43 (4, 1H, I= 8.8), 3.87 (5, 3H), 3.17 (s. 2H}, 2.35 (s, 6H). MS (ESI+) m/z 299.2 (M+H}",
Example 298
N15 -(3,5-dimethyl-1H -pyrazol-4-yI)- 1H -indazol-3-y1] “N° N*-dimethyl glycinamide
The title compound was prepared according to the procedure outlined in Example 233A substituting Example 282C for S-bromo-2-fluorobenzonitrile and 3,5-dimethyl-4- (44,5,5-tetramethyl-1,32-dioxaborolan-2-y1)- H-pyrazole for I-benzyl-4-(4.4.5 5. tetramethy!-1.3.2-dioxaborolan-2-yl)-1H-pyrazole. 'H NMR (600 MHz, DMS0-ds) 8 ppm 12.63 (s, 1H), 10.02 (5, 1H), 7.63 (s, 1H), 7.46 (m, 1H), 7.27 (dd, IH, J = 1.6, 8.6), 3.16 {s, )
2H), 2.32 (s, 6H), 2.18 {s, 6H). MS (ESI+) m/z 323.2 (M+H)".
Example 299
NE {5-12 <(dimeth yiamino jpyrimidin-5-yi [1H indazol-3-yl1 AN dimeth viglyeinarnide
The title compound was prepared according to the procedure outlined in Exampie 233A substituting Exampie 282C for 5-bromo-2-fluorobenzonitrile and N.N-dimethyl-5- (4.4.5.5 tetramethyl-1,3,2-dioxaborolan-2-y1pyrimidin-2-amine for F-benzyl-4-(4,4.5.5. tetramethyl-} 3,2-dioxaborolan-2-y1)-1H-pyrazoic. 'H NMR (600 Miz, DMSO-d) 8 Dyin 12.72 (s. 1H), 10.03 (s. TH}, 8.62 (5, 2H), 7.91 (s, TH), 7.58 (dd, 1H. f= 16, 8.6), 751 (d,
IH, T= 85), 3.16 (s, 8H), 2.33 (s, 6H). MS (ESI) m/z 340.2 (M+HY"
Example 360
N* N -dim ethyl-N' [5-02 -morpholin-4-yipyrimidin-5-yi)-1 H-indazol-3-ylglycinamide
The title compound was prepared according to the procedure outlined in Example 5 233A substituting Example 282C for S-bromo-2-fluorobenzonitrile and 4-(5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2 -yDpyrimidin-2-vyl ymorpholine for 1 -benzyl-4-(4,4.5.5- tetramethyl-1 »3,2-dioxaberolan-2-yl)-1H-pyrazole, "HNMR (600 MHz, DMS0O-ds) & ppm 12.74 (s, 1H), 10.03 (s, 1H), 8.67 {s. 2H), 7.94 (s, 1H), 7.60 (dd, 1H. J= 1.8, 8.8). 7.52 {d, 1H, I= 8.5), 3.74 (m, 4H), 3.67 (m, 4H), 3.17 (s, 2H), 2.33 (s, 6H). MS (EST+) m/z 382.2 (MH)
Example 301
NN *-dimethyl-N'- 15-{1-02 -morpholin-4-ylethyl}-1 H-pyrazol-4-y1)-1H-indazol-3- vl}ielycinamide
The title compound was prepared according to the procedure outlined in Example 233A substituting Example 282C for S-bromo-2-fluorobenzonitrile and 4-(2-(4-(4,4.5,5- tetramethyl-1.3.2 -dioxaborotan-2-y])-1 H-pyrazoi-1 -yDethylimorpholine for | -benzyl-4- (4.4.5 5-tetramethyl-1 .3.2-dioxaborolan-2-y1)-1 H-pyrazole. 'H NMR (600 MHz, DMSO0-dy) & ppm 12.63 (s, 1H), 9.96 (s, 1H], 8.09 (s, 1H}, 7.85 {s, 1H), 7.77 (s, 1H), 7.54 (dd, 1H, J = 300 1.5.8.8), 7.43 (d, 1H, J= 8.5), 424 (t, 2H, I = 6.6), 3.34 (m, 4H), 3.16 {s, 2H), 2.73 (t, 2H, ] = 6.6), 2.41 (s, 4H), 2.34 (s, 6H). MS (ESI+) m/z 398 3 (M-+H)".
Example 302
N51 -benzyl-S-cyelopropyl-1H-1,2 3-triazol-4-y1)-IH-indasol- 3-115 1.
dimethylglycinamide
Example 3024
I-benzyl-S-cyclopropyl-4-( tributylstannyli-11-1,2 3-triazole
The title compound was prepared according to the procedure outlined in Example 122.4 substituting toluene for hexane and {azidomethyl)benzene for Example 8A. The crude product was used in the next step without purification, 16
Example 3028 5-(1-benzyl-5-cyclopropyl-1H-1.2.3-triazo] -4-vi}-2-fluorcbenzonitrile
The title compound was prepared according to the procedure outlined in Example 1428 substituting Example302A for Example 142A and 2-fluoro-5-iodobenzonitrite for 8TA.
MS (ESI+) mz 319.2 (M+)
Example 302C 5-(1-benzyl-5-cyclopropyl-1H-1 2:3tr1azol-d-y-1H-indazol-3-amine
The title compound was prepared according to the procedure outlined in Example 62D substituting Example 3028 for Example 62C. MS (ESI-) m/z 299.2 (M-HY,
Example 362D tert-butyl 3-amino-5-(1 ~benzyl-3-cyclepropyl-1H-1 2. 3-triazol-4-v1)-1H-indazole-1- carboxylate
The title compound was prepared according to the procedure outlined in Example 604A substituting Example 302C for Example 62D.
Example 302E
N'-[5-(1-benzy!-5-cyclopropyl-1H-] -2,3-triazol-4-y1)-1H-indazol-3-y1]-N* NZ dimethviglycinamide
The title compound was prepared according to the procedure outlined in Example 64B substituting Example 302D for Example 64A and dimethylaminoacetylchloride hydrochioride for methoxy acetyl chloride. 'H NMR {400 MHz, DMSO-d) § ppm 12.76 {s, 1H), 10.06 (s, 1H), 8.18 (s, 1H), 7.79 (d, TH, I= 88), 7.50 (d, 1H, I = 8.8), 7.34 (m, SH), 5.68 (s, 2H), 3.16 (s, 2H}, 2.32 (s, 6H), 1.76 (m, 1H), 1.05 (q, 2H. 1 = 6.1). 0.39 (q, 2H, J = 5.45 MS (ESI) m/z 416.3 (MH). MS (EST) m/z 416.3 (M+5y
Example 303
N'-{5+(1-benzyl-1 H-pyrazol-4-yl)-1 H-indazol-3-y1]-N° N"-dimethylglycinamide
Example 303A
J-amino-5-(1 -benzyl-1H-pyrazol-4-yl-indazole-1 ~carboxylic acid tert-butyl ester
The title compound was prepared according to the procedure outlined in Example 604A substituting Example 233B for Example 62D (0.925 g, 100%). 'H NMR (400 MHz,
DMSO-de) 6 ppm 8.19 (s, 1H), 8.04 {s, 1H), 7.90-7.95 (m, 1H). 7.87 (s, 1H), 7.74 (d. T= 1.6
Hz, 1H), 7.28-7.36 (m, 5 H), 6.27 (s, 2H), 5.37 (s, 2H), 1.58 (3, 9H), MS (ESE) m/z 390 (MH).
Example 303B
N'-[5-(1-benzyl-1H-pyrazol-d-y1)-1 H-indazol-3-y1]-N* N*-dimethylglycinamide
A suspension of 2-( dimethylamino acetic acid (32 mg, 0.308 mmol) and oxaly!
C20 chloride {0.31 mL, 6.61 mmol} in dichloromethane (5 mb.) and dimethylformamide (2 drops) was stirred at ambient temperature for about | hour then concentrated under reduced pressure. ‘The residue was suspended in tetrahydrofuran (3 mL) and added to a suspension of
Example 303A (40 mg, 0.103 mmol) and potassium carbonate {43 mg, 0.308 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at ambient temperature for shout minutes then rifluoroacetic acid {4 mL) was added and the reaction mixture was heated at abeut 60 °C for about 20 hows. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. diluted with dichloromethane (20 mL) and washed with 15% aqueous sodium hydroxide solution (20mL). The organic extract was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude 30 material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt, ‘H NMR (400 MHz, DMSO-ds) 8 ppm 9.97 (s, 11), 8.21 (s, 1H), 7.853 (s, JH), 7.82 (s, 1H), 7.56 (d, J = 8.7 Hz, 1H), 743 (d, I = 8.6 Hz, 1H), 7.32-7.40 (m, 2H), 7.25-7.32 (m, 3H), 5.35 (5, 2H),
3.16 (s, 2H), 2.33 (s, 6H), 1.91 (s, 3H}. MS (ESI) m/z 375 (M+H)".
Example 304
N'-[5-(1-benzyl 1H-1,2, 3otri 2z01-4-yl)-1H-indazol-3 yl }-N -methyiglycinamide
The title compound was prepared according to the procedure outlined in Example 303B substituting 2( tert-butoxycarbonyl( methylamine acetic acid for 2- (dimethylaminojacetic acid and Example 64A for Example 303A. 'H NMR (406 MHz,
DMSO-ds} 6 ppm 8.56 (s, 11), 8.28 {s, LF), 7.78-7 88 (1m, 1H), 7.45-7.56 {m, TH}, 7.28-7.43 (5H. m}. 5.64 (2H, 8). 2.37 (s, ZH). 1.89 (s, 3H). MS (ESM) m/z 362 (M+H). 14
Hxample 305
N-[5-(1-benzyl-1H-1 J2yd-triazol-4-v1}-1H-indazol-3 -yli-2-pyrrolidin-1-ylacetamide
Example 305A tert-butyl 5-(1-benzyl-1H-1,2,3-tri azol-4-y1)-3-( i-bromoacetamido)-1H-indazole- 1 - carboxviate
To a suspension of Example 64A (500 mg, 1.28 mmol) in tetrahydrofuran {12 mL) was added diisopropylethylamine (6.22 mL. 1.28 mmol}. The reaction mixture was stirred at ambient temperature for about 15 minutes then 2-bromoacety! chloride (0.11 mL, 1.2 mmol) was added. The reaction mixture was stirred at ambient temperature for about 16 hours then additional Z-bromoacetyl chloride (0.11 mL, 1.2 mmol) was added. The reaction mixture was stirred for an additional 15 minutes then concentrated under reduced pressure to provide the title compound as a brown solid. Thig material was used without further purification.
Example 305B
N-[5-(1-benzyi-1H1-1 -2,3-trtazol-4-vi)-1H-indazol-3 ~y1]-2~pyrrolidin-1-yiacetamide
To a solution of Example 3054 {44 mg, 0.086 mmol) and diisopropylethylamine (0.015 mL, 0.086 mmol) in acetonitrile {1 mi) was added pyrrolidine (0.021 m1. 0.25 mmol} and the reaction mixture was heated at about 60 °C for about 15 minutes. The reaction mixture was cooled to ambient temperature and trifluoroacetic acid (I mL} was added. The reaction mixture was heated at about 60 °C for about 48 hours. The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane (20 mi} and washed with
15% aqueous sodium hydroxide solution (20 mL}. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC using aceionitrile/water {0.05 M ammonium acetate} gradient elution method to afford the title compound. 'H NMR {400 MHz, DMSO. dg) 8 ppm §.58 (5, FH), 8.24 (s, THY, 7.81 (d, T= 8.7 Hz, 1H). 7.50 (d, } = 8.7 Haz, IF}, 7.27- 7.45 (m, 5H), 5.64 (s, 2H), 3.35 (s, ZH), 2.65 (s, 4H), 1.76 (5, 4H), MS (ESI+) m/z 402 (M-+H])",
Example 306 16 N = 5-(I-benzyl-1H-1.23 -triazol-4-yli-1H-indazo l-3-y1-N"-cyclopentylelycinamide
The title compound was prepared according to the procedure outlined in Example 305B substituting cyclopentanamine for pyrrolidine (0.004 g, 12%). "HNMR (400 MHz,
DMB0-ds) 6 ppm 8.56 (5, 1H), 8.31 (s, 1H), 7.73-7.86 (d, J=8.8 Hz, 1H), 7.49 (d,J=87
Hz, 1H), 7.29.7 45 (m, SH}, 5.64 (s, 2H), 3.37 (s, 2H), 2.99-3.14 (m, 1H), 1.60-1.80 {m, 45), 1.30-1.50 (m, 4H). MS (ESHY m/z 416 (M+H)Y",
Example 307
N51 -benzyl-1H-1,2 3-triazol ~4-yl)-1H-indazol-3 yi]-N -cyclopropylglycinamide
To a solution of Example 305A {100 mg, 0.196 mmol) and diisopropylethyiamine 200 (0.034 mL, 0.19 mmol} in acetonitrile (1 mL) was added cyclopropanamine (11 mg, 0.15 mmol) and the reaction mixture was heated at about 60 °C for about | hour. The reaction mixture was cooled to ambient temperature and hydrochloric acid {4 N in dioxane, | mL} was added. The reaction mixture was stirred at ambient temperature for about 16 hours. The reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient chition method to afford the title compound as the acetate salt. 'H NMR (400 MHz,
DMSO-de) 6 ppm 10.18 (5, 1H). 8.28 (5, 1H), 8.56 (s. IH), 7.81 (d, } = 8.6 Hz, 1H), 7.49 (d.J = 8.7 Hz, 1H), 7.30-7.45 (m, SH). 5.64 (s, 2H), 3.45 (s, 2H), 2.18-2.26 (m, 1H), 1.89 (s. 3H), 0.37-06.45 (m, 2H), 0.29-0.37 {oL 2H). MS (ESF) m/z 388 {M+H)".
Example 308
N' -[5-(1-benzyl-1H-1,2 3 -triazol-4-y[)-1H -indazol-3-y1]-N’-tetrabydro-2H-pyran 4. viglycinamide
The title compound was prepared as the acetate salt according to the procedure outlined in Example 307 substituting tetrahydro-2H-pyran-4-amine for cyclopropanamine. 'H NMR {400 MHz, DMSG-dg) 8 ppm 8.56 (s. 1H} 8.31 (5, 1H), 7.81 (d, I= 8.7 Hz, 1H), 150d, T= 87 Hz, 1H), 7.31.7.45 {m, 5H}, 5.64 (5, 2H), 3.84 (4, J = 11.2 Hz, 21}, 3.43 (&,
ZH), 330 J=108 Hz ZED), 2.62-2.74 (mm, 1H), 1.88 (8, 3H), 1.75-1.85 (m, 2H), 1.24-1 30 (mm, 2H). MS (ESI+) m/z 432 (M+),
Example 309
MN-[5-{1-benzyl-1H-] 22 3-triuzol-d-y1i-1H-indazo] ~3¥l-2-{3-bydroxypyrrolidin.| - 19 viacetamide
The title compound wag prepared as the diacetate salt according to the procedure outlined in Example 307 substituting pyrrolidin-3-o! for cyclopropanarmine. 'H NMR (400
MHz, DMSO-dg) & ppm 10.09 (s. 1H), 8.22 (s, 1H), 8.58 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H). 7.50(d, J =8.7 Hz, 1H), 7.28-7.45 (m, 5H), 5.64 (s, 2H), 4.16-4.26 (m. 1H), 3.34 (5, 2M), 2.97-2.93 (m, 2H), 2.52-2.65 (m, 2H), 1.98-2.13 (m, 1H), 1.87 (s, 6H), 1.56-1.69 (m, 1H).
MS (ESI+) m/z 418 (M+HY",
Example 310
N-[3-(1-benzyl-1¥1-1 .2,3~triazol-4-y1}-1 H-mdazol-3-y1]-2-(3 ~hydroxypiperidin-]- vhacetamide
The title compound was prepared as the acetate salt according to the procedure outlined in Example 307 substituting piperidin-3-ol for cyclopropanamine. 'H NMR {400
MHz, DMSO-dg) 8 ppm 10.05 (s, TH}, 8.56 (s, 1H), 823 (5, 1H). 7.82 (d, J = 8.7 Hz, 1H), 7.50(d, 1 = 8.7 Hz, 1H), 7.29-7.44 (m, 5H), 5.64 (s, 2H), 3.55-3.67 (mn. 1H}, 3.20 (s, 2H), 2.77-2.88 (m, 1H), 2.60-2.70 (m, 1H), 2.22-2.35 (m, 1H), 2.12-2.23 (m, TH), 1.88 (5, 3H), 1.66-1.78 {m, 2H), 1.43-1.59 (m, 1H). 1.13-1.27 (m, IH). MS (ESI) m/z 432 (M+H)",
Example 311
N'-[5 ~(I-benzyl-1H-1,2,3-tr azol-4-y1)-1H-indazol-3 -yII-N* Ndimethyl-beta-alaninami de
The title compound was prepared as the acetate salt accordin ¢ to the procedure outlined in Example 307 substituting dimethylamine for cvclopropanamine. "H NMR (460
MHz, DMSO-ds) § ppm 10.48 (s, TH), 8.54 (s, 1H), 8.26 {s, 1H), 7.80 {d, J = 8.7 Hz, 1H), 7.48 (d, J =8.7 Hz, 1H), 7.30-7 44 (m, 58), 5.64 (s, 2H), 2.60 (d, }=6.1 Hz, 2H), 2.54 (d, ] =
6.3 Hz, 2H), 2.21 (5, 6H), 1.90 {s. 3H). MS (EST+) m/z 390 (M+H)",
Example 312
N-[5-(1-benzyl 1H 1,2 3-tri azoi-d-v 1} {H-indazol-2-y1] -Z-merpholin-4-ylacetamide & The title compound was prepared according to the procedure outlined in Example 307 substituting morpholine for cyclopropanamine. 'H NMR (400 MHz, DMSO-ds) 8 ppm 10.10 (5, TH), 8.57 (s, 1H), 8.23 (s, 1H), 7.81 (d. J=8.7 Hz, 1H), 7.50 (d, J} =8.7 Hz, 1H), 7.29- 7.46 (m, 5H), 5.64 (5, 2H). 3.59-3.7] {m, 4H}, 3.22-3.28 (m. 2H), 2.54 -2 64 {m, 4H). MS (ESI+ym/z 418 (MH)
Example 313
N-[5-(1-benzyl-1H-1,2, 3-triazol] -4-yt)-1H-indazol-3-y1]-2-( 4-methylpiperazin- i - yljacetamide
The title compound was prepared as the diacetate sait according to the procedure outlined in Example 307 substituting |-methylpiperazine for cyclopropanamine. 'H NMR (400 MHz, DMSO-d) 8 ppm 8.57 (s, 1H), 8.25 (s, 1H), 7.81 {(d. J=87 Hz 1H), 7.50 (d. ] = 8.7 Hz, 1H}, 7.32-7.43 (m, SH), 5.64 (s, 2H), 3.22 (s, 2H), 2.53-2.63 (m, 4H), 2.31-2.45 (m, 4H), 2.17 (s, 3H), 1.85 (s, 6 H). MS (ESI+) m/z 431 (M+H)". | Example 314
N-[5-(1-benzyl-1H-1 2, 3-triazol-4-y1)-1H-indazol-3 ~yl]-2-(3~oxopiperazin-1- yliacetamide
The title compound was prepared according to the procedure outlined in Example 307 substituting piperazine-2-one for cyclopropanamine. 'H NMR (400 MHz, DMSG-ds) 8 ppm 10.21 (s, 1H), 8.57 (s, 1H), 8.22 (s, 1H), 7.81 ¢d, I = 8.7 Fz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.31 — 7.46 (m, 5H), 5.64 (s, 2H), 3.36 {s, 2H), 3.24 (5, 2), 3.17 (s, 2H), 2.78 (5. 2H). MS (ESI) mz 431 (M+H)".
Example 315
N'-[5(1 -benzyl-1H-1,2,3 ~triazol-4-yI}-1H-indazol-3 -yI-N*-isopropylelycinamide
The titie compound was prepared as the acetate salt according to the procedure ouflined in Example 307 substituting propan-2-amine for cyclopropanamine. 'H NMR (400
MHz, DMSO-ds} 8 ppm 8.56 {(s 1H), 8.31 (s, 1H), 7.81 (d, 1 =8.7Hz, 1H), 7.49 (d. J = 8.7
Hz, 1H), 7.31-7.44 (m, SH), 5.64 (s, 2H), 3.39 (s, ZH), 2.73-2.86 {m, IH), 1.90 (s, 3H), 1.04 (d, J = 6.1 Hz, 6H). MS (ESI) m/z 390 (M+H})
Exampie 314
N'-[5-(1 -benzyl-1H-1,2,3-irtazol-4-v1)-1 H-indazo! -3-y11-N* cyclohexyl glvcinamide
Fhe title compound was prepared as the acetate salt according to the procedure outlined in Example 307 substituting cyclohexanamine for cyclopropanamine. ‘H NMR {400
MHz, DMSO-ds) § ppm 8.55 (s, 1H), 8.31 (5, IED, 7.81 (d. J = 8.7 Hz, 1H), 749 (4, J~ 8.7
Hz, 1H), 7.30-7.44 (m, 5H), 5.64 (s, 2H). 3.40 (s. 2H}. 1.90 {s, 3H}, 1.80-1.88 (m, ZH), 1.63-
Ho 1.73 {m, 2H), 1.50-1.60 (m, 1H), 1.02-1.29 (ma, SH). MS (ESI) m/z 430 (M+H)
Example 317
N-[5-(1-benzyl-1H-1 2:3-triazol-4-yl}-1H -indazol-3-yljacetamide
To a mixture of Example 64A (20 mg, 0.051 mmo!) and diisopropylethylaming (0.063 ml, 0.35 mmol} in tetrahydrofuran (1.5 mL) was added acetyl chloride (0.013 mL, 0.17 mmol} and the reaction mixture was stirred at ambient temperature for about 1.5 hours.
Hydrochloric acid (4 N in dioxane, 1.5 mL} was added and the mixture stirred at ambient temperature for about 16 hours. The solvent was removed under reduced pressure and the crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt, "H NMR (400 MHz, DMSO0-ds) 8 ppm 10.35 (s, 1H), 8.57 (s, 1H), 8.22 (s, 1H), 7.8] (d, J = 8.7 He, 1H), 748 (d, J = 8.7 Hz, HH), 7.33-7.42 (m, 5H), 5.64 (s, 2H), 2.13 (s, 3H). MS (ESI-) m/z 331 (M-TH).
Example 318
NL34(1 -benzyl-1H-1,2,3-triazol-4-y1)-1H ~indazol-3-y1]-N-cyclob utytelyveinamide
The title compound was prepared according to the procedure outlined in Example 307 substituting cyclobutanamine for cyclopropanamine. 'H NMR (400 MHz, DMSO-dg) & ppm 8.36 (s, 1H), 8.29 (5. 1H), 7.81 (d, 1 = 8.7 Hz, 1H), 7.49 (d, I = £.7 Ho. 1H), 7.31-7.45 (m,
SH), 5.64 (s, 2H), 3.31 (s, 2H), 2.01-2.20 (m, 2H), 1.48-1.83 {m, SH). MS (ESI+) m/z 402 {MH
Example 316
N-[5-(1-benzyl-1H-1,2, 3-11 azol-4-y1)-1 H-indazol-3-y1]-N'-propylurea
To a solution of Example 644 (75 mg, §.19 mmol) in pyridine (2 mL) was added 1- isocyanatopropane (16 mg, 0.19 mmol} and the reaction mixture was stirred at ambient temperature for about 3 hours. Additional isocyanate {0.1 mL) was added and the mixture was heated af about 80 °C for about 16 hours. The reaction mixture was cooled to ambient iernperature and water (5 ml) was added. The resulting precipitate was collected by filtration then treated with hydrochloric acid (4 N solution in dioxane, 3 mL) and stirred at room temperature for about 4.5 hours. Diethyl ether (5 mL) was added and the precipitate collected by filiration. The crude material was purified by reverse-phase HPLC using acetonitrile/water {0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 'H NMR (400 MHz, DMSO-dg) & ppm 5.34 (s. 1H), 8.50 (s, 1H), 8.42 (5, 1H), 7.80 (d, ] = 8.7 Hz, IH), 738 (d, I = 8.7 Hz, 1H), 7.31-7.48 {m, 5H). 5.65 (s, 2H), 3.18 (dd, 1 = 6.6, 12.7 Hz, 2H), 1.51 (dd, F= 7.1, 14.3 Hz, 2H), 0.91 (t, =7.3 Hz, 3H). MS (ESI+) m/z 376 (M+HY.
Example 320
No[5-+(1-benzyl-1H-1,2 3-iri azot-4-y1)-1H-indazol-3-yl]ethanesul fonamide
To a solution of Example 64A (75 mg, 0.19 mmol} in pyridine (2 mL) was added ethanesulfony! chloride (25 mg, 0.19 mmol) and the reaction mixture was stirred at room temperature for about 3 hours. Additional sulfonyl chloride (25 mg, 0.19 mmol} was added and the reaction mixture was stirred for about 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in dichioromethane (10 mL) and washed with 1 N agueous hydrochloric acid {10 mL). The organic portion was separated, dried under reduced pressure, and treated with hydrochioric acid (4 N in dioxane, 3 ml) and stirred at room temperature for about 12 hours. The reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. '"H NMR (400 MHz, DMSO-ds) & ppm 16.12 (s. 1H}, 8.61 (s, 1H), 8.24 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.09-7.48 (m, 5H), 5.64 (8. 2H), 3.29 (d. J = 9.2 Hz, 2H), 1.31 (t, J=7.3 Hz, 3H). MS (ESI) m/z 383 (M+H)Y
Example 321 5-(1-benzyl-1H-1,2,3-tri azok4-yl}-N-(cyclopropylmethyl)- IH-indazol-3-amine
A mixture of Example 644 (100 mg, (.256 mmol), cyelopropanecarbaldehy de {0.057 ml, 0.76 mmol), sodium triacetoxyborohydride (163 mg, 0.76 mmol) and acetic acid (0.044 mL, 0.76 mmol} in 1,2-dichlorocthane (5 mL) was stirred af ambient ternperature for about 2.5 hours. Hydrochloric acid (4 Nin dioxane. 4 mL.) was added and the reaction mixture was stirred for about 16 hours, The precipitate was collected by filtration, rinsing with ether (10 mi). The solid was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (0.1 mL) and the reaction mixtare was stirred at room temperature for about 2 hours.
The reaction mixture was neutralized by the addition of 15%, aqueous sodium hydroxide solution (about 15 mL) and the organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 'H NMR (400 MHz, DMSO-dg) 8 ppm 11.43 (s, 1H), §.4] (s, 1H}, 8.28 (5, 1H), 7.68 (d, 1 = 8.7 Hz, 1H), 7.32-7 45 {m, 5H), 7.26 (d, 1 = 8.6 Hz, 1H), 6.08 (t. J=35.7 Hz, 1H), 5.64 (s, 2H), 3.12{,1=6.2Hz 2 H), 1.04- 1.22 (m, 1H), 0.35-0.53 (m, 2H), 0.17-0.32 {m, 2H). MS (ESI+) m/z 345 (M+HY,
Example 322
N-[5-(1-benzyl-1H-1 23-triazol-4-y1)- 1 H-indazol-3 -yl]-N'-ethyiurea
The title compound was prepared according to the procedure outlined in Example 319 substituting isocvanatoethane for l-1socyanatopropane. 'H NMR {400 MHz, DMSO-ds) & ppm 9.32 (s, 1H), 8.49 (s, 1H), 8.42 {s, 1H), 7.81 (d. 1 = 8.7 Hz, IH), 7.70 (d, J = 8.7 Hz.
TH), 7.31-7.49 (m, 5H), 5.65 (s, 2H). 3.23(d, J = 6.9 Hz, 2H), 1.12 (1,7 = 7.1 Hz, 3 H). MS (ESI) m/z 362 (M+H)".
Example 323 1-[5-(1-benzyl-1H-1 2, 3-triazol-4-y1)- 1 H-indazol-2 “ylipyrrolidin-2-one
A suspension of Example 64A (200 mg, 0.51 mmol) and diisopropylethylamine (0.089 mL, 0.51 mmol) in tetrahydrofuran (5 mL} was stirred for about 15 minutes at ambient temperature then 4-bromobutanoy! chioride (0.059 ml, 0.51 mmol) was added. The reaction mixture was stirred for about 16 hours. The precipitate was removed by filtration and the filtrate concentrated under reduced pressure. The residue was taken up in acetonitrile (5 mL)
and treated with diisopropylethiylamine (0.089 mL, 0.51 mmol) and heated at about 60 °C for about 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with hydrochloric acid {4 N ir dioxane, 5 mL} and the reaction mixture stirred at room temperature for about 2 hours, The reaction mixture was concentrated under reduced pressure and the crude matertal was purified by reverse-phase HPLC using acetonitrile/water {0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt, "FH NMR {400 MHz, DMSO-dg) 6 ppm 12.84 (s, 1H), 8.56 (s, 1H}, 8.49 (5. IH), 7.84 (d. J = 8.6 Hz, IH), 7.51 (d, 1 = 8.7 Ho,
TEE), 7.26.7 46 (m, 5H), 5.64 (8, 2H), 3.96 (1. } = 6.0 Hy, 2H) 2.56 (6, 1 = 7.9 Hz, 2H, 205 2.12 (m, 2H). MS (ESI) m/z 359 (M-+H)",
Example 324
N-[5-(1-benzyl-1H-1,2 3-tri azol-4-yli-1 H-indazol-3-y1]-4-( dimethylamino )butanamide
The title compound was prepared as the diacetate salt accordmg fo the procedure
I5 ouilined in Example 303B substituting 4-(dimethylamino)butanoic acid for 2- (dirnethylamino)acetic acid and substituting Example 64A for Example 303A. 'H NMR (400
MHz, DMSO-ds) 8 ppm 10.34 (s, 1H), 8.53 (s, 1H), 8.22 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.30-7.4] (m, SH), 5.62 (s, 2H), 2.4] {t. J=7.2 Hz 2H), 2.28 {t, J= 6.8 Hz, 2H), 2.14 (s, 6H), 1.84 (s, 6H), 1.74-1.77 (m, 2H). MS (ESI) m/z 462 (M-HY
Example 325
N-3,4-dihydro-1 H-isochromen-4-yi-5-(111 ~ndazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 818 substituting 3. 4-dihydro-1H-isochromen-4-amine for piperidine. 'H NMR (300 MHz,
DMSO-ds) 8 ppm 13.4 (brs, 1 HY, 9.02(d, 1 H), 8.4 (m, 1H), 8.22 (m, 1 H), 7.75 (m, 2 H), 7.2-7.4 (m, 5 H), 5.24 (m, 1 H), 4.75 (m, 2 H), 4.02 (m, 1 H), 3.8 {m, I H). MS m/z (ESi+) 361 (M+H)",
Example 326
N-(cyclohexyimethy])-3 -(1H-indazol-5-y1}i soxazole-3-carboxamide 5-1 B-Indazol-S-yl)isoxazole-3-carboxylic acid (35 mg, 0.15 mmol, Example 71A), was dissolved in N N-dimethylformamide {0.8 mL) followed by the addition of HATU (60 mg, G.15 mmol) dissolved in N,N-dimethylformamide (0.8 mL}. Then a solution of 1-
cyclohexylmethanamine (17 mg, 8.17 mmol), dissolved in N, N-dimethviformamide (0.8mL} was added, followed by diisopropylethylamine (56 nL,0..31 mmol} dissolved in NN- dimethylformamide (0.8 mL). The resulting mixture was shaken for 3 hours at 40 °C. The reaction was filtered, checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 dimethyl sulfoxide/methano! and purified by reverse phase HPLC (Phenomenex® Luna®@ CB(2) 5 um 100A AXTAT™ column {30 mm > 75 mm), 50 mi/min, 10-100% acetonitrile/0.1% trifluoroacetic acid in water) to provide the title product. 'H
NMR (500 MHz, DMS0-ds/D,0) 8 ppm 0.91 - 0.97 {m, 2H), 1121.27 (m, 4 H), 1.61 -
L75(m, SHY, 3.08 - 3.16 (m, 2H), 722. 724 fm, LHL 7.71 - 7.75 (m, 1 HY, 7.87 - 7.90 {m,
TH)LR23-827m, H} 838-841 (m, 1H). MS (ESI+) m/z 325 (M+H)", (ESi-) m/z 323 (M-HY.
Example 327
N-(3-chlorobenzyl}-5-(1 H-indazol-5-yl}isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326 except 1-(3-chlorophenyl)methanamine was substituted for 1-cyclohexylmethanamine, 'H
NMR (500 MHz, DMSO-de/D,0) § ppm 4.47 - 4.52 (m, 2 H), 7.27 - 7.29 (m, 1 H), 7.30 - 7.42(m, 4H), 7.72 - 7.75 (m, 1 H), 7.89 - 7.93 (m, | H), 8.25 - 28 (m. 1H), 841-842 (in, 1H). MS (ESF) m/z 353 (M+H)"; (ESL) m/z 351 (M-H)" 26
Example 328 5~(1H-indazol-5-y1)-N-{2 -methoxybenzylyisoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326 except I-(2-methoxyphenylimethanamine was substituted for I-cyclohexylmethanamine. 'H
NMR (500 MHz, DMSO-ds/D20) 8 ppm 3.82 - 3.86 {m, 3 H), 4.45 - 4.50 (m, 2 Hj, 6.92 - 6.97 (m, 1 H), 7.01 - 7.04 {m, 1 H), 7.19 - 7.24 (m, | H), 7.26 - 7.31 (m, 2H), 7.69 - 7.77 (m, 1H), 7.88- 7.93 (m, 1 H}, 8.24 - 8.28 (m, 1 Hj, 838-844 (m, 1 H). M8 (EST+) m/z 349 (M+H)"; (ESI-) vz 347 (M-HY.
Example 329 5-(1H-indazol-3-y1}-N-[2 (tri fluoromethylbenzyllisoxazole-3-carboxanmi de
The title compound was prepared using the procedure described in Exampe 326 excent I-[2-(zrifluoromethylypheny! jmethanamine was substituted for 1-
cyclohexylmethanamine., 'H NMR. (500 MHz, DMBO-ds/D:0) 6 ppm 4.66 - 4.73 (m, 2 FD), 729-733 (m, 1 H), 749 - 7.60 (m, 2 H). 7.67 - 7.79 (m, 3H), 7.91 - 7.94 (m, 1 H), 8.26 -
B.28(m, 1 H), 8.41 - 8.45 (m, 1 H). MS (ESI) m/z 387 (M+H)"; (BSI) m/z 385 (M-H)".
Example 330
S~(1H-indazol-5-y1)-N-[3-(wrifluoromethyl benzyl Jisoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326 except 1-[3-(trifluoromethy phenyl jmethanamine was substituted for 1- cyelohexylmethanamine. 'H NMR {500 MHz, DMSO-ds/D,0} § ppm 4.57 - 4.61 (m, 2 FH), 728-731 (m, 1H), 759-777 (m, 5 HJ, 7.90 - 7.94 (m, | H), 827 - 8.28 (m, | FH), 8.40 - 8.43 (m, 1 H). MS (ESI) m/z 385 (M-H).
Example 331 3-(1H-indazol-5-y! J-N-[4-(trifluoromethy!)benzylfisoxazoic-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326 except | -[4-(trifluoromethy! phenyl jmethanamine was substituted for 1- cyclohexylmethanamine. 'H NMR (500 MHz, DMSO-ds/D;0) 6 ppm 4.55 - 4.60 (5, 2 H), 7.27-7.30 (m. 1 HY, 7.54 - 7.59 (m, 2 H), 7.70 - 7.76 (m, 3 H), 7.88 - 7.94 (m, 1 H), 8.24 - 8.28 (m, 1 H}, 8.40 - 8.44 (m, 1 H). MS (ESE) m/z 387 (M+H)'; (BSI-) m/z 385 (M-Hy".
Example 332 5-(1H-indazol-5-y1}-N-(pyri din-2-yimethyl}isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326 except I-pyridin-2-ylmethanamine was substituted for I-cyclohexyimethanamine. '"H NMR {560 MHz, DMSO0-ds/D;O0) 8 ppm 4.74 - 4.84 (5.2 H),7.30-7.34 (m, 1 H), 7.68 - 7.81 (m, 3
H), 7.89 -7.97 (m. ] H), 8.22 - 8.33 (m, 2 H), 8.40 - 8.45 (m, 1 H), 8.67 ~ 8.76 (m, 1 H). MS (ESI) m/z 320 (M=~H)"; (ESI-) m/z 318 (M-H)".
Example 333 5-( 1 H-indazol-5-y1)-N~(pyridin-3-yImethylyisoxazole-3-carbox amide
The title compound was prepared using the procedure described in Exampe 326 except I-pyridin-3-yimethanamine was substituted for l-cyclohexylmethanamine. 'H NMR (500 MHz, DMBO-ds/Dy0) 8 ppm 4.61 - 4.68 (8. 2H), 7.27 -7.31 (m, 1 H), 7.70 - 7.75 (m, 1
H), 7.83 - 7.94 (m, 2 H), 8.24 - 8.28 {m, I H), 8.31 -8.37 (m, 1 H}, 8.40 -8.44 (m, 1 H), 8.69 -8.74 (m, 1 H), 8.77 - 8.82 {m, 1 H). MS (ESI) nz 320 (MH); (ESI-) m/z 318 (M-HY,
Example 334 5-(1 H-indazol-5-y1)-N-(pyridin-4-yim cthylyisoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326 except I-pynidn-4-yimethanamine was substituted for I-cyclohexylmethanamine. 'H NMR (500 MHz, DMSO-d,/D.0) 8 ppm 473 «480 (5, 7H) 730-733 {m, 1H}, 7.73 - 7.78 (m, 16 HM), 7.89-7.97 (m, 3 FI), 8.25 - R30 {m, 1H), 8.40 - 8.46 (m, | H), 8.76 - 8.83 (m, 2 H), MS (ESE) m/z 318 (M-HY.
Example 335
N-~(2-chlerobenzyl}-3-( 1H -indazol-5-yl)isoxazole-3-carboxamide
The title compound wag prepared using the procedure described in Exampe 326 except 1-(2-chlorophenymethanamine was substituted for I-cyclohexyimethanamine. 'H
NMR (500 MHz, DMSO-ds/D,0) 6 ppm 4.54 - 4.58 (s,2H),7.27-732 (m, | H), 733-742 (m, 3H), 7.47 - 7.49 (m, | H), 7.71 7.77 (m, 1 H). 7.88 - 7.9% {m, I H), 824-827 (m, 1
H), 841-844 (m, | H). MS (ESF) m/z 353 (M+H)", (ESI-y mvz 351(M-HY,
Example 336
N-(4-chlorobenzyl)-5-(1H-indazol-5-yljisoxanole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326 except I-(4-chlorophenyymethanamine was substituted for I-cyclohexyimethanamine, Hi
NMR (500 MHz, DMSO-dy/D20) 8 ppm 4.42 - 4.49 {(m, 2H), 7.22- 7.31 (m, | H), 7.34 - 7.49 (m, 4 H), 7.70 - 7.76 (m, | H), 7.84 -792 (m, 1 H), 8.17 - 8.30 (m, 1 H), 8.35 - 8.47 (im,
TH). MS (ESI-) m/z 351 (M-HY
Example 337 5-(1H-indazol-3-yl}-N-(1 -phenyl-2-piperidin- -viethyl}isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 81B substituting I-phenyl-2-piperidin-1-ylethanamine for piperidine. 'H NMR {300 MHz,
DMSO-ds) 8 ppm 13.4 (brs, | H), 9.12(d, 1 H), 84 (5, 1 HY, 8.22 (5, 1 H), 7.9 (d, 1 Hy, 7.7
(d, 1H}, 7.2-7.4 (m, 6 H), 5.2 {m, 1 FH), 32 (m, 2 H), 2.3 (m, 4H), 1.2-1.4 (m, 6 H). MS (ESI) m/z 416 (M+H),
Example 338
A N-[2-{IH-imidazol-1 ~y1)-1 -phenylethy!]-5-( 1 H-indazol-3 -yljisoxazole-3-carboxamide
The title compound wags prepared according to the procedure outlined in Example 1B substituting 2-(1H-imidazol-1 ~yI}-1-phenyiethanamine for piperidine. "FH NMR {300 MHz,
DMSO-ds) 8 ppm 13.4 (brs, | Hy. 95(d TH), 8.4 (s. 1 H), 822 (8, VEL 7.78 fm, 1 FD), 7.50 (2H), 7.72(d, 2H), 7.2-74 (m. 5 HY 6.85 (s, 1H), 5.44 (m1, 1 H), 4.44 {m, ZH} MS 16 (BSI) m/z 399 (M+H)".
Example 339 5-18 -indazol-5-y1)-N-(2-morpholin-4-yi- -phenylethylyisoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example §1B 13 substituting 2-morpholin-4-yl-1 -phenylethanamine for piperidine. "H NMR (300 MHz,
DMSO-ds) 6 ppm 13.4 (brs, 1 HY. 9.2 (d, 1H), 84s, 1 H), 822 (s, TH), 7.9(d, 1 H), 7.7 (d,
PH), 7.2-7.4 (m, 6 H), 5.2 {m, 1H), 3.6 (m, 4 H), 3.4 (m, 2 H), 2.4 (m, 4 H). MS (ESI+) m/z 418 (M+H)".
Example 340 5+{1H-in dazol-5-y1}-N-f2 (4-methylpiperazin-] -vI)-1-ph enylethylhsoxazole-3-carboxarnide
The title compound was prepared according to the procedure outlined in Example 81B substituting 2-( 4-methylpiperazin-1 -y1}-I-phenylethanamine for piperidine. 'H NMR (300
MHz, DMSO-ds) 8 ppm 13.6 (brs, 1 H), 9.14 (d. 1H), 8.4 (s, 1 H), 8.22 (s, 1H} 7.9(d,1
HLTA 1H). 72-74 (m, 6 H), 5.2 (m, 1 H), 3.2 (m, 2 H),24(m 4H), 22 (m, 4 Hy 2.1 (m, 3 Hj). MS (ESI) m/z 432 (M-+H)"
Example 341 5-(1H-indazol-5-y[}-N-(} -phenyl-2-pyrrolidin-1 -yiethyl}isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 1B substituting 1-phenyl-2-pyrrolidin-1-ylethanamine for piperidine. 'H NMR (300 MHz,
BMSO-di) 8 ppm 13.4 (brs, 1 FH). 9.14 (d, 1 H), 8.4 (5, 1 H), 8.22(s, 1 H), 7.9(d, 1 H), 7.7 (d, 1H), 7.2-7.4 (m, 6 H), 5.18 {(m, 1 H),32(m, 2H), 2.4 (m, 4 H), 1.8 (m, 3 H#). MS (ESI+)
m/z 402.5 (M+H)".
Example 342 tert-butyl 2-({[5-(1 H-inda zol-S-yhisoxazol-3-yljcarbonyl amine ri-phenylethyicarbamate
The title compound was prepared according to the procedure outlined in Example 81B substituting tesr-butyl 2-amino-2-phenylethylcarbamate for piperidine. 'H NMR (300 MHz,
DMSO-ds) 6 ppm 13.4 (brs, 1 H), 9.14 (d, TH). 84(s, 1 H), 822 (5.1 H), 7.0 {(d, 1H}, 7.7 (d, 1H), 7.2-7.4 (m. 6 FH), 7.00 (+, 1 H), 5.18 (m, 1 H), 3.2 (m, 2H), 1.4 (s, 9 Hy. MS (ESI) m/z 449 (M+H)"
Example 343 5-(1H-mdazol-5-yI)-N-(1 -naphthyimethyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 328 except 1-(1-naphthylymethanamine was substituted for t-cyclohexylmethanamine. 'H NMR (500 Miz, DMSO-4,/D,0) 8 ppm 4.93 -4.99 (m, 2H), 7.28 - 7.32 (m, 1 HY}, 7.48 - 7.66 (mn, 4H), 7.70 - 7.76 (m, 1 H). 7.86 - 7.92 (m, 2H), 7.96 - 8.00 (m. 1 H), 8.18 - 8.23 {m, 1 H}, 8.24 - 827 (m, 1 H), 8.38 - 8.44 (m, 1 HY). MS (ESI) m/z 367 {M-HY)".
Example 344
S-(1H-indazol-5-y1)-N-(2-phenylethyl)isoxazole-3 carboxamide
The title compound was prepared using the procedure described in Exampe 326 except Z-phenylethanamine was substituted for l-cyclohexylmethanamine. 'H NMR (500
MHz, DMSO-de/D20) 8 ppm 2.84 - 2.92 (t, 2H),347-3.57(t, 2H), 7.18 - 7.35 (m, 6 H), 7.69-7.77(m, 1 H), 7.86 - 7.91 (in, 1 H), 8.22-829(m, 1 H). 837 -8.44 (m, 1 H), MS (ESI) miz 333 (MHD; ( ESky m/z 331 (M-H)
Example 345 5-(1H-indazol-5-y[}-N-(2-pyridin-2 ~ylethylyisoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326 except 2-pyridin-2-ylethanamine was substituted for l-cyclohexylmethanamine. 'H NMR (500 MHz, DMSO-d¢/D>0) § ppm 3.22 - 3.29 (G2H), 371-375 (4, 2H), 7.14- 7.26 (m, 1
F), 7.70 - 7.75 (m, 1 H), 7.81 - 7.94 (m, 3 H), 823-829 (m, 1 H), 8.35 -§.44 (rm, 2 H}, 8.7]
- 8.83 (m, | H). M8 (ESI) m/z 334 (MH) (ESI) m/z 332 (M-H)".
Example 346
S~(1H-indazol-5-y{}-1.{ 2-pyridin-3-ylethy isoxazole 3-carbox araide
The title compound was prepared using the procedure described in Exampe 326 except 2-pyridin-3-ylethanamine was substituted for 1-cyclohexylmethanamine. 'H NMR (500 MHz, DMSG-ds/D,0) 8 ppm 3.01 - 3.13 (t, 2 H), 3.55 - 3.70 (t, 2H), 7.14 - 7.26 (m,
H). 770-777 6m, 1 HY, 7.84 - 7.05 (m, 2H), 8.25 -8.26 (m, 1 H). 836-845 (m, 2 H), 2.69 ~ 875 (m, THY, 8.77 - 8.84 (mm, THY. MS (ESF mz 334 {MTEY (BSL) m/z 332 (M-HY.
Example 347 51H -indazol-5-y[}-N-(2-pyridin -4-ylethyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326 except 2-pyridin-4-ylethanamine was substituted for I-cyclohexylmethanamine, 'H NMR (500 MHz, DMSO-do/D,0) 8 ppm 3.12 - 3.23 (t. 2H). 3.67-3.71 (4, 2H), 7.20- 7.21 (m, I
H), 7.69-7.76 (m, 1 FD), 7.86 - 7.9] {(m. 3H), 825-827 (m. H), 838-841 (m, 1 H), 8.70 - 8.77 {m, 2 H). MS (ESI) m/z 334 (M+H)", (ESE) m/z 332 (M-H)
Example 348
N-2-2-chlorophenyhethyl}-3-(1 H-indazal-5-yDisoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326 except 2-(2-chlorophenyl)ethanamine was substituted for I-cyclohexylmethanamine. 'H
NMR. (500 MHz, DMSO-ds/D20) 8 ppm 2.99 - 3.05 (L2H), 354-3612 H), 7.21 -7.23 {m, 1H}, 7.26 - 7.33 (m, 2 H), 735-740 (m, 1 H), 741 - 7.47 (m. TH}, 7.70 - 7.75 (m,
HY, 7.87-7.93 (m, | H), 823-831 (m, 1H), 8.37 - 8.44 (m. 1 Hy. MS (ESi+) m/z 367 (M+H)"; (ESI-) m/z 365 {M-Hy.
Example 349
N-[Z-(3-chioro phenyllethyl]-5-(1H-indazol-5 -ylisoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326 except 2-(3-chiorophenyl)ethanamine was substituted for l-cyclohexylmethanamine. 'H
NMR (500 Miz, DMSO-ds/I3,0) § ppm 2.89 (t. 2H). 3.54 (t, 2H), 7.19 - 7.47 (m, 5 H), 769-777 (m, 1 H), 7.86 - 7.94 (m, 1H), 8.22- 8.29 (m, 1 FH), 8.38 - 8.42 (m, 1 H). MS
(ESI-) m/z 365 (M-HY.
Example 350
N-{2-(4-chiorophenyllethyl]-5-( 1 H-indazol-3 ~yiisoxezole-3-carboxamide
The title compound was prepared usin g the procedure described in Exampe 326 except 2-(4-chlorophenyl)ethanamine was substituted for I-cyclohexyimethanamine, 'H
NMR (500 MHz, DMSO-d¢/D»0) 8 ppm 2.86 (t, 2H), 3.50 (1, 2H), 7.17 - 7.04 {m, 1 H), 7.27 =A (m, 4H), 7.71-7.76 (m, 1 H), 7.85 - 7.01 {m, 1H), 8.21 -8.29 (m, ] FI). 8.34 - “44 (m, 1 H). MS (BSI) m/z 365 (M-HY. iG
Example 351
N-benzyl-N-ethyl-5-(1H-indazol-5 -ylnsoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326 except N-benzyl-N-cthylamine was substituted for I-cyclohexylmethanamine. 11 NMR (500
MHz, DMSO-d¢/D,0) 8 ppm 1.06 - 1.19 (m, 3 H), 3.37349 (m, 2 H), 4.69 - 4.76 (m. 2 H). 7.21 -7.28(m, 1 H), 7.28 - 7.49 (m, 5 H), 7.69 - 7.78 (m, 1H), 7.83 - 7.97 (m, 1 I), 8.24 - 8.32 (m, | H), 836-846 (m, | H). MS (ESI+) m/z 347 (M+); (ESI) m/z 345 {(M-Hy.
Example 352 5-(1 H-indazol-5-yI}-N-methyl-N~(1 -naphthyimethyl)isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326 except N-methyl-N-(1-naphthylmethyl)amine was substituted for 1-cyclohexylmethanamine. 'H NMR (500 MHz, DMSC-d/D;0) 8 ppm 3.04 - 3.11 (m, 3 H), 520-535(m, 2H), 7.20 - 7.31 (m 1H), 7.33 - 7.66 (m, 4 HY, 7.66 - 7.77 (m, 1H), 7.81 - 8.18 (m, 4 H), 8.20 - 8.28 {m, 1H). B31-845(m, | H). MS (ESI) m/z 383 (M+H)"; (ESI) m/z 381 {M-HY.
Example 353 >-(1H-indazol-5-y1)-N-methyl-N-(2 -phenylethylisoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326 except N-methyl-N-(2-phenylethy]amine was substituted for 1-cyclohexylmethanamine, 'H
NMR (500 MHz, DMSO-dy/D,0) 8 ppm 2.86 - 2.97 (m, 2 H), 3.06 - 3.13 (m, 3 Hj, 3.76 - : 3.74 (m, 2 H), 6.64 - 739 (m, 6 H), 7.69 - 7.92 {(m, 2H}, 8.24 - 8.44 (m, 2 H)., MS (ESI+) m/z 347 (M+H)"; (ESI-) m/z 345 (M-Hy.
Example 354 5-(1H-indazol-5-y1)-N-methyl-N-(2-pyridin-2-ylethyDisoxazole-3-carboxarmide
The title compound was prepared using the procedure described in Exampe 326 except Nemethyl-A-( Z-pyridin-2-ylethylamine was substituted for 1- cyciohexylmethanamine. 'H NMR. (500 MHz, DMSC-dy/D>0) 8 ppm 5.07 - 3.22 (m, 3 FH), 3.26-339(m, 2H), 3.92 - 4.04 (m. 2H), 6.85 - 7.14 {m, ] H). 7.65 - 8.05 (m, 4 H), 8.23 - 8.56 (m, 3 H). 8.65 - 8.86 (m, 1 FI). MS (ESI) m/z 348 (MH); (ESI) m/z 346 (MH. 1 Exampie 355 5-(1H-indazol-5-y[}-N-{(1R)-1 -phenylethyl}isoxazole-3-carboxamide
The title compound was prepared using the procedure described in Exampe 326 except (1R)-1-phenylethanamine was substituted for L-cyclohexylmethanamine. '"H NMR (500 MHz, DMSO-ds/D,0) 8 ppm 1.49 - 1.54 (m, 3H), 5.12 - 5.20 (m, 1 H), 7.23 - 7.29 (m, 2H), 7.33-746(m, 4H), 7.71 -7.75 (m, 1H), 7.87- 7.91 (m, 1 H), £22 - 8.2% {m, 1H), 8.37 - 842 (m, I H). MS (ESI) m/z 333 (M+H)"; (ESE) m/z 331 (M-HY"
Example 356 5-(1H-indazo}-5-y1}-N-1,2.3 A-tetrahydronaphthalen-1-ylisoxazole-3 carboxamide 26 The title compound was prepared using the procedure described in Exampe 326 except 1,2,3,4-tetrahydronaphthalen-1-amine wag substituted for I~cyclohexylmethanamine, "HNMR (500 MHz, DMSO-ds/D;0) & ppm 1.72 - 2.09 (m, 4 H), 2.68 - 2.85 (m, 2 H), 5.19 - 3.260 (m, 1 H), 7.12 - 7.24 (m, 4 H), 7.20 735 (m, 1H), 7.69-7.77 (m, 1 H), 7.86 - 7.92 {m,
TH) 8.25-830 (m, ] H), 8.38 - 8.43 {m, I H). MS (ESI) m/z 357 (M-Hy".
Example 357 5-(1H-indazol-5-y1}-N-[(18}-1 -(I-naphthyl)ethyllisoxazole-3-carbox amide
The title compound was prepared according to the procedure outlined in Example 81B substituting (1.5)-1-( I-naphthyljethanamine for piperidine. 'H NMR (300 MHz, DMSO-d) 8 ppm 134 (brs 1H), 04 (d 1 H). 8.4 (5,1 H), 8.25 (5,1 H), 8.22 (brs. 1 H), 7.95 (d. 1 H). 7.85 (m, 2 H), 7.65 (m, 2B), 7.5 (m, 3H), 7.3 (s, 1 H), 5.9 (m, 1 H), 1.65 (d, 3 H). MS (ESI+) m/z 382.9 (M+H)".
Example 358 5-{1H-indazol-5-y}-N-{{ IR} 1-( L-naphthylethyllisoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example RIB substituting (1R)-1-(1 -naphthy!jethanamine for piperidine. 'H MME (300 MHz, DMSO-ds} 6 ppm 134 (brs 1H), 94d 1H), 84 (s. 1H), 8.25(s, 1 HI), 8.22 (brs, 1 Hj, 7.95 (d, 1 H), 7.65 (rm, 2 H), 7.65 (m, 2 H), 7.5 (m, 3 HY, 7.3 (5, TH), 5.9 (m, 1 H), 1.65 (d, 3 H). MS (ESI+) m/z 382.9 (M+),
Example 339 i N-[3-{dimethylamino)-] -phen yipropyl]-5-(1 H-indazol-3-yhisoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 81B substituting N° MN -dimethyi-1 -phenylpropane-1,3-diamine for piperidine. 'H NMR (300
MHz, DMSO-ds) & ppm 13.4 (brs, | H), 0.4 (d, 1 H), 8.4 (s, 1 H), 8.25 (8, LH). 7.92 (m, 1
H), 7.7 (m, 1 H), 7.3-7.5 (m, 6 H), 5.15 (m, 1H), 3.2 (m, 2 H), 7.75 (s, 6 H), 2.35 (m, 1 FH), 205 (m, 1 H). MS (ESI) m/z 390 (M+H)".
Exampie 360
N-(2,3-dihydro- L,4-benzodioxin-5-ylmethyl)-5-(] H-indazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 81B substituting 1-(2.3-dihydro-1 4-benzodioxin-5-yymethanamine for piperidine. 'H NMR (300
MHz, DMSO-ds) 8 ppm 13.4 (brs, 1 H),924(t, 1H), 84 (5,1 H), 825 (s, 1 H), 7.92 (d, 1
H), 7.7(d, 1 H), 7.24 (s. 1 H), 6.9 (m, 3 H),44(d,2H),43(d, 2H). 4.25 (d, 2 H). MS (ESi+y m/z 377 (M-+H)™.
Example 361
N-(3.4-dihydro-2H-1,3 -benzodioxepin-6-yimethyi)-5-(1 H-indazol-5-yhisoxazole-3- carboxamide
The title compound was prepared according to the procedure outlined in Example 81B substituting 1-(34-dihydro-2/4-1,5-benzodioxepin-6-ylimethanamine for piperidine. 'H
NMR (300 MHz, DMSO-ds) ppm 13.4 (brs, 1H), 9.2 (1, 1H), 8.4 (s, 1 H), 8.25 (s. 1 FI), 7.92(d, 1H), 7.7 (d, 1 H), 7.24 (5, 1 H}, 6.9 (m, 3H), 4.42 (d, 2H), 4.15 (m, 4 H), 2.2 (m, 2
H). MS (ESI+) m/z 391 (M+H)".
Example 362 5-(1H-indazol-5-y1}-N-[{] -methyl-1H-indol-4-y1imeth vllisoxazole-3-carboxamide
The title compound was prepared according to the procedure outlined in Example 81B substituting ( }-methyl-1H-indol-4-y methylamine for piperidine, 'H NMR {300 MHz,
DMSO-d) 6 ppm 13.4 (brs, 1 H), 924(t, 1H), 8.4 (s, 1 HI), 8.25 {(s, THD, 7.92 (d, 1 1D. 7.7 (d, 1H), 7.38 (m, 3 H), 7.18 (m, | HY, 7.0(d, TH). 6.6 (s, 1 H), 4.7 (d, ZH), 3.8 (s. 3H). MS (EST+) m/z 372 (MH)
Example 363 3-13-(3-phenylpyrrolidim-1 -vhicarbony!]isoxazol-3 ~yli-1H-indazole
The title compound was prepared according to the procedure outlined in Example 81B substituting 3-phenylpyrrolidine for piperidine. "H NMR (300 MHz, DMSO-ds) 8 ppm 13.4 (brs, 1 H),84 (m, 1 HD), 8.25 (s, 1H), 7.92(d, 1 Hy, 7.8 (d, 1 HY, 7.24 (m, 6 H), 4.4 (m, | H), 3.4(m, 2H), 24 (m, 2 H), 2.0 (m, 2 H). MS (ESI+} m/z 359 (M+H)"
Example 364 5-{3-[(2-phenylpyrroiidin-] -yhecarbonyllisoxazol-3 -yl}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 81B substituting 2-phenylpyrrolidine for piperidine. 'H NMR (300 MHz, DMSO-d) § ppm 13.4 (brs, 1H), 8&4 (m, 1 H), 8.25 (s, 1H), 7.92{d, 1 H), 7.8 (d, 1 H). 7.24 (m, 6 B), 5.6 (m, 0.3
H), 5.2 (m, 0.7 H), 4.0 (m, 2H), 1.8-2.0 (m, 4 H). MS (ESI+) m/z 2390 (M+HY.
Example 365 5-{3-[(2-phenytpiperidin-1 -yhcarbonyilisox azol-5-yl}-1H-indazole
The title compound was prepared according to the procedure outlined in Example 81B substituting 2-phenvipiperidine for piperidine. 'H NMR (300 MHz, DMSO-d, & ppm 13.4 (brs. 1H), 84 (m, 1 H), 8.25 (s, 1H), 7.92(d, 1 H), 7.8 (d. 1 H). 7.24 {m, 6 H), 5.6 (m, 0.3
H), 5.2 (m, 0.7H), 4.0 (m, 2 H). 1.82.0 (m, 6 HY. MS (ESI+) m/z 373 (M+H)".
Example 366 5~(1H-indazol-5-y1)-N-f{1 S)-1-phenylethyllisoxazole-3 carboxamide
S5-( 1H-Indazol-5-yllisoxazole-3-carboxyiic acid (36 mg, 0.16 mmol, Example 71A), was dissolved in N.N-dimethylformamide (1.0 ml} followed by the addition of HATU (60 mg, 0.16 mmol) dissolved in N.N-dimethylformamide (0.5 mL). Then a solution of (8)-1- phenylethanamine (22 mg, 0.18 mmol), dissolved in N, N-dimethylformamide (0.6 ml.) was added, followed by diisopropylethvlamine (36 uL.0.32 mmol) dissolved in HNN dimethyiformamide {0.2 mL). The resulting mixture was shaken for 3 hours at 40 °C. The reaction was filtered, checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 dimethy! sulfoxide/methano! and purified by reverse phase HPLC {Phenomenex® Luna® C82) 5 um 100A AXIAT™ column (30 mm x 75 mm), 30 mL/min, 10-100% acetonitrile/0.1% trifluoroacetic acid in water} to provide the title product. 'H
NMR (300 Miz, DMBO-de/D>0) & ppm 1.50 (d. 3 FE), 5.06 - 522 fm, 1 H), 723-729 (m, 2 16H), 734-738 (m, 2 HY, 740-745 (m, 2H), 7.76 - 7.75 {m, 1 Hj, 7.87 - 7.92 (m, 1 H), 8.25 = 8.27 (m, 1 H), 8.39 - 8.41 (m, } H), 928 ¢d, 1 7). MS (ESI) m/z 333 (M+H)" (ESI) m/z 331 (M-Hy.
Example 367 5-(1B-indazol-5-y1)-N- [(1R)-1-( 4-methylphenylethyljisoxazole-3-carboxamide
The title compound was prepared using the procedure deseriped in Example 366 except (1R)-1( 4-methylphenylethanamine was substituted for (S)-1 -phenylethanarnine, 'H
NMR (300 MIz, DMSO-d/D20) 8 ppm 1.49 (d,3H),2.25-231 (mm, 3 H), 5.09 - 5.18 (m,
PH), 7.14 - 7.08 (m, 2H), 7.23 - 7.24 (m, 1 H), 7.28 - 7.32 (m. 2H), 7.70 - 7.75 (m, 1 H), 7.86-792(m, I HL 822-820 (m, 1H), 837-842 (m, 1H), 9.19 (d, 1 H), MS (ESI+) myz 347 (MH); (ESI-) 345 (M-HY".
Example 368 5-(1H-indazol-5-y])-N -[(1S)-1-¢ 4-methylphenylethy!]i soxazole-3-carboxarnide
The title compound was prepared using the procedure descriped in Example 366 except { 1S}-1-(4-methylphenyljethanamine was substituted for (S)-1 ~phenylethanamine. ‘H
NMR. (500 MHz, DMSO0-ds/D20) 8 ppm 1.48 (d, 3H), 2.26 -230 (m, 3 H), 505-523 (m,
TH), 7.15 - 7.17 (m, 2 HI), 7.22 = 7.25 (m, 1H), 728-732 (m, 2 H), 7.67 - 7.79 (m, 1 Hj, 7.86 -7.93 (m, 1 H), 8.22 - 8.30 (m, 1H), 838-84] (m, 1 HY, 921(d 1H). MS (ESI-) m/z 345(M-H).
Example 369
N-[(1 R.28)-2-hydroxy-2,5-dihydro-1H-inden- [-y1]-5-( 1FI-i ndazol-5-yl}isoxazole-3-
carboxamide
The title compound was prepared using the procedure descriped in Example 366 except (1R.25)-1-aminotndan-2-0 was substituted for (5)-1-phenylethanamine. 'H NMR (500 MHz, DMSO-dy/D20)} 6 ppm 2.89 22.96 (m, 1H), 2.13 - 3.7; {m, 1 H}. 4.55 - 4.61 {m,
THE540-547(m, 1H) 721-734 (m, 4H), 739-742 (m, 1 HB), 7.72 - 7.77 {m, 1 Hj, 751-795 (m, 1 H), 8.25. 8.29 {m, 1 H), 8.42 - 8.45 (m, 1 H). MS (ESI-) m/z 359 (M-H)".
Example 370
Ia[{ IR.ZR)-2-hydroxy-2 3-dihydro-1H-inden. ] VIS H-indazol-5-y isoxazole. 3. 16 carboxamide
The title compound was prepared using the procedure descriped in Example 366 except (1R.2R)-1-aminoindan-2-o0! was substituted for (8)-1-phenylethanamine. 'H NMR (300 MHz, DMSO-de/D20) § ppm 2.72 - 2.83 (m, 1 H), 3.13 - 3.30 (m, | H), 4.44 - 4.53 (m,
TH). 524-532 (m, 1H), 7.10- 7.18 (m, 1H), 7.20 - 7.27 (m, 3 H), 7.30 - 7.33 (m, 1 H), 772-778 (m, 1 H), 7.91 - 7.93 (m, TH), 8.24 - 8.29 (m, 1 H), 8.41 - 8.45 (m, 1 H), 9.17 (d, tH). MS (ESI-) m/z 359 (M-HY".
Example 371
N-[{1R)-1~{4-bromopheny! Jethyl]-5-(1H-i ndazol-5-yl)isoxazole-3-carboxamide
The title compound wag prepared using the procedure deseriped in Example 366 oxcept (1K)-1-(4-bromophenyl)ethanamine was substituted for (S)-1-ph enylethanamine. 'H
NMR (500 MHz, DMS0-ds/D20} & ppm 1.50 (d, 3 H), 508-518 (m, 1 H), 7.21 - 7.27 {m, 1H), 7.36 - 7.41 (m, 2H), 7.50 - 7.59 (m, 2H), 7.70 - 7.76 (m, 1 H}), 7.86 -7.93 (m, | H), 823-829 (m, | H), 8.38 - 8.41 (m, 1 H},932(d, 1 H). MS (ESI) m/z 411 (M+HY
Example 372
N-[(18)-1 ~(4-bromophenyljethyl]-5-(1 H-indazol -S-yl)isoxazole-3-carboxamide
The title compound was prepared using the procedure descriped in Example 366 except ( 18)-1-(4-bromophenyllethanamine was substituted for (S)-1 ~phenylethanamine. ‘I
NMR (500 MHz, DMSO-dy/D20) 6 ppm 1.49 (d, 3 FH), 5.09 - 5.19 (m, 1 H), 7.23 - 7.25 {(m, 1H). 7.37-740 (m, 2H), 7.53 - 7.57 tm, 2H), 7.71 - 7.75 (m, 1 H), 7.87 - 7.92 (m, 1H),
B25-827(m. 1 H), 838-841 (m, IH), 9.32(d, 1 H}. MS (ESI) negative jon 409 (M-HY.
Example 373
N-[{IR)-1 -(4-chlorophenyljethyl}-5-(1 H-indazol-S-yvhisoxazole-3 ~carboxamide
The title compound was prepared using the procedure descriped in Example 366 except (1R-1 «(4-chlorophenyljethanamine was substituted for {8)-1 -phenylethanamine. 'H
NMR (500 MHz, DMSO-de/D20) 8 ppm 1.50 (d, 3 HL 500-521 4m, 1H), 7.22 - 7.26 (mm.
TH), 738-747 (m, 4 H), 7.70 - 7.75 (m. 1H), 7.87 - 7.92 (m, 1 H), 8.20 - 8.28 (m, | H). 838-841 (m, I H), 9.33 (d, 1 H). MS (ESI-) m/z 365 (M-H)".
Example 374
N-{(15)-1-(4-chioroph enyljethyl]-5-(1 H-indazol-5-yhisoxazole-3-carboxamide
The title compound was prepared using the procedure descriped in Example 366 except (15)-1-(4-chiorophenyl)ethanamine was substituted for (S)-1 -phenylethanamine, 'H
NMR. (500 MHz, DMSO-de/D20) 8 ppm 1.49 (d, 3H), 512-519 (m. 1 H). 7.23 - 7.25 (m,
TH), 739-747 (m, 4H), 7.71 - 7.74 (m, 1 H), 7.87791 (m. | H), 825-827 (m, 1 H), 837-843(m, 1H), 9.32 (d, 1 FH). MS (ESI-) m/z 365 (M-Hy
Example 373 3-(1H-indazo}-5-y1}-N-[(1 S31 2-naphthyljethyl}isoxazole-3-carboxamide
The title compound was prepared using the procedure descriped in Example 366 except (18-1 -(2-naphthyl)ethanamine was substituted for (S)-1-phenylethanamine. “H NMR (500 MHz, DMSO-ds/D20) 8 ppm 1.61 (d. 3H), 530-538 (m, 1 H), 7.25 - 726 (m, 1 H), 7.48 - 7.55 (m, 2H), 7.60 - 7.63 {m, 1H), 7.72 - 7.75 (m, 1 H), 7.88 - 7.95 (m, 5 H), 8.25 - 8.28 (m, 1 H}, 8.39 - 8.43 (mm, 1H), 9.39 (d, | H), MS (ESI-) m/z 381 (M.-H,
Example 376
N-[1-{4-ethoxyph enyl)-2-hydroxyethyl]-5-(1 H-indazol-5-yl)isoxazole-3-carboxami de
The title compound was prepared using the procedure descriped in Example 366 except Z-amino-2-(4-ethoxyphenyl)ethanot was substituted for (S)-1 -phenylethanamine. 'H
NMR (500 MHz, DMSO-ds/320) § ppm 1.32 (t, 3 H), 3.62 -3.67 (m, 1 H), 3.70 - 3.73 (m, I 30H), 3.96-4.06 (m, 2 H), 4.98 - 5.06 (m, 1 H), 6.87 - 6.9] (m, 2H), 7.23 - 7.36 (m, 3 H), 7.70 = 7.75 (m, 1 H), 7.88 - 7.9] (m, IH), 825-827 (m, 1 H), 839-842 (m, 1 H). MS {ESI-) m/z 391 (M-HY.
Exampic 377
N-[2-hydroxy-1-( 4-1sopropylphenyliethyll-3 ~(1H-indazol-5-y1)isoxazole-3-carbox amide
The title compound was prepared using the procedure descriped in Example 366 except 2-amino-2-(4-isopropylphenyl ethanol was substituted for (S)-1-phenylethanamine, "HNMR (500 MHz, DMSO-ds/D20) 6 ppm 1.18 (d, 6 ET), 2.81 - 2.91 (m, 1 Hj, 3.65-3.70 (m, J Hy. 3.72 - 3.74 (m, 1 H), 5.01 - 5.00 (m, 1 H), 7.20 - 7.28 (m, 3 H), 7.20 - 7.35 (m, 2
B), 7.72 - 780 (m, 1 H), 7.87 - 7.95 (m, | H), 8.24 - 829 (m, 1 H), 8.38 - 8.44 {m, 1 H). MS (ESI-) m/z 389 (M-HY,
HY Examnle 378
N-f1-(3 A-dimethylphenyl)-2-hydroxyethyl]-5-( 1H-indazol-5-yl)isoxazole-3-carboxarmide
The title compound was prepared using the procedure descriped in Example 366 except 2-amino-2-(3 4-dimethylphenyljethano! was substituted for (S)-1-phenyiethanamine. "H NMR (500 MHz, DMSO-de/D20) & ppm 2.30 (d, 6 H), 3.56 -3.63 (m, 1 H). 3.65 - 3.73 (m, 1H), 532-542 (m, 1 1), 7.06 - 7.08 (m, 2H), 7.23 - 7.28 (m, 2 H), 7.69 - 7.76 (mm, 1
H), 7.87 - 7.95 (m, 1 H), 8.25 - §.28 {m. 1H), 8.39843 (m, 1 1). MS (ESI~y m/z 375 (M-
Hy.
Example 379
N-[2-hydroxy-1 ~(2-methoxyphenyl)ethyl}-3-(1 H-indazol-5-ylisoxazole-3-carhoxamide
The title compound was prepared using the procedure descriped in Example 366 except 2-amino-2-{2-methoxyphenyl)ethano] was substituted for (S)-1-phenylethanamine. 'H
NMR (500 MHz, DMSO-do/D20) & ppm 3.60 - 3.66 (mn, 2 H), 3.84 - 3.8% (m, 3 H), 5.37 - 5.48 (m, 1 H). 6.95 (1, 1 H), 7.00 - 7.06 (m. TH), 7.24 - 7.31 (m, 2H), 7.32 - 7.36 {m, I Hj, 771-797 (m, 1 H), 7.85 - 7.97 (m, 1H). 8.24 - 8.28 (m, 1 H), 8.40 - 8.45 (m, 1H). MS (ESI) m/z 379 (M+); negative ion 377 (M-H Vy.
Example 380
N-[2-hydroxy-1-( 4-methyliphenyljethyl}-54 1 H-indazol-5 ~yl}Yisoxazole-3-carboxamide
The title compound was prepared using the procedure descriped in Example 366 except 2-amino-2-(4-methylphenyl)ethano was substituted for (S)-1-phenylethanamine. ‘H
NMR (500 MHz, DMSO-d/D20)} § ppm 2.26 - 2.32 (m, 3 H), 3.65 - 3.70 (m, 1 H}, 3.72 - 3.75 (m, 1 H), 5.01 - 5.08 (m, LH), 7.10 - 7.21 (mm, 2H), 7.25 7.35 (m, 3 H), 7.70 - 7.77 {m,
1H), 7.86 - 7.95 (m, 1 H), 8.26 - 8.28 (ra, 1 H), 8.39 - 8.46 (m, 1 H). MS (ESI) m/z 363 (M+H); (ESI-) m/z 361 (M-HJ.
Example 381 5-(1H-indazol-5-y1}-N-[{ 1R)-] -( Z-methoxyphenylethyljisoxazole-3~carboxamide
The title compound was prepared using the procedure descriped in Example 366 except (1R)-1-(2-methoxyphenyljethanamine was substituted for (S)-] -phenyiethanamine. "HNMR (500 Miz, DMSO-de/D20} & ppm 1.43 (d, 3 HY. 3.82 -3.86 (m. 3H), 5.41 - 5.50 (m, 1H}, 6.95 (x, 1H), 7.00. 7.05 (m, THY, 7.23.72%9(m, 2 HY. 735-739 (m, 1 HY, 7.71 - 7.76 (m, 1H). 7.88 - 7.92 (m, | H), 825-827 (m, | H), 8.37 - 8.43 (m, 1 H). MS (ESI) m/z 363 (MH); (ESI) mv/z 361 (M-H)
Example 382
N-[(18)-1 -(3.4-difluorophenyl ethyl ]-5-(1 H-indazol-5 -yhisoxazole-3-carboxamide 13 The title compound was prepared using the procedure descriped in Example 366 except (18}-1-(3,4-difluorophenyljethanamine was substituted for (8}-1-phenylethanamine, "H NMR (500 MFiz, DMSO-d/D20) & ppm 1.50 (d, 3 H), 509-524 (m, 1H), 7.21 - 7.30 (m, 2H), 7.35 - 7.44 (m, 1 H), 7.44 - 7.53 (m, I H}, 7.68 « 7.82 (m. 1 H), 7.86 - 7.94 (m, 1
H) 8.26 - 8.27 (m, 1 H), 8.39 - 8.42 (m, 1 H). MS (ESI) m/z 367 (M-HY".
Example 383 5-(1H-indazol-5-y[}-N-[(1R)-1 -(3-methoxyphenylethyljisoxazole-3-carboxami de
The title compound was prepared using the procedure deseriped in Example 366 except (1R)-1-(3-methoxyphenyljethanamine was substituted for {S)-1-phenylethanamine. "HNMR (500 MHz, DMSO-de/D20) & ppm 1.50 (d, 3 H), 3.75 - 3.77 (m,3 FH), 501-519 (m, 1H), 6.80 - 6.87 (m, 1 H), 6.97 - 7.02 {mL 2H), 721-732 (m, 2H), 7.70 - 7.75 {(m, 1
H), 7.87-7.95 (m, 1 H), 822 - 8.31 (m, | H), 8.37 - 8.43 (m, 1 H). MS (ESI) m/z 361 (M-
Hy.
Example 384 5-(1H-indazol-5-y])-N- {(IR}-1-{3-(trifluorometh vliphenyliiethyi} isoxazole-3-carboxamide
The title compound was prepared using the procedure descriped in Example 366 except (1R)-1-[3-(irifluoromethyl)pheny!lethanamine was substituted for (S)-1-
phenylethanamine. 'H NMR (500 MHz, DMSO0-d¢/B20) § ppm 1.54 {d. 3H), 522-3529 (m. TH). 7.23 - 7.27 (m. 1 H), 7.58 - 7.69 (m, 2 H), 7.71 - 7.75 {m. 2H), 7.77 - 7.83 (m, 1
Hj, 787-792 (m, 1 Hy, 8.24 - 8.00 {(m, 1H), 8.38 - 842 (m1. 1 H). MS (ESE) m/z 399 (M-
Hy.
Exampic 385
N-11-(2,3-dihvdro-1 4-benzodioxin-6-yljethyl]-5-(1 H-ndazol-5-yl)isoxazole-3-carboxamide
The title compound was prepared using the procedure descriped in Example 366 except 1-(2,3-dihydro-1 A-benzodioxin-6-yhethanamine was substituted for (S)-1- 1 phenylethanamine., 'H NMR (500 Miz, DMSO-do/D20 § ppm 1.46 {d. 3H), 4.18 - 4.05 (m, 4 Hj, 5.01 - 5.10 (m, 1 H), 6.80 - 6.95 (rm, 3 Hy, 7.22 - 7.24 (m, 1 HD, 7.70 - 7.74 (m, 1
H), 7.87-791 (m, 1 H), 8.26 - 8.27 {m, 1 H), 8.39 - 8.41 (m, 1 H). MS (ESI-) m/z 389 (M-
Hy.
IS Example 386
N-{1-(3 »5-dichorophenyl}-2-hydroxyethyl]-5-¢ tH-indazol-5-yhisoxazole-3-carboxamide
The title compound was prepared using the procedure descriped in Example 366 except Z-amino-2-(3,5-dichlorophenyl ethanol was substituted for (8)-1 -phenylethanamine. '"H NMR (500 MHz, DMSO-ds/D20) 8 ppm 3.68 - 3.72 (m, 1 H),3.76 - 3.78 (m, 1 H), 5.02 - 200 330(m, 1H), 7.26 -729 (m, 1 H), 7.47 -7.52 (m, 3 HY), 7.72 - 7.75 (m, 1 H), 7.89 - 7.93 (m,
TH) 825-828 (m, 1 H), 8.39. 8.44 {m, 1 H). MS (ESI-)mv/z 415 (M-HY.
Example 387 tert-butyl 5-(1-benzyl-15-1 2, 3-triazol-4-y1)-3-[( { [O-{triftucromethylypyridin-2- yilamino j carbony!)amino]- 1 H-indazole-] carboxylate
A solution of triphosgens in dichloromethane was cooled to 0 °C under nitrogen,
Then a mixture of tristhylamine (0.426 mL, 3.07 mmol) and Example 64A (150 mg, 0.384 mmol) in dichloromethane (2 mL) was slowly added dropwise. The resultant mixture was stirred at room temperature for 1 hour. Then b-(trifluoromethyljpyridin-2-amine (62.3 mg, 0.384 mmol) was added followed by stirring overnight at room temperature. The precipitate was filtered off and washed with dichloromethane and water. The product was dried under vacuum to provide the title compound. MS m/z 579.3 (M+H)"
Example 388
S-( 1-benzyl-1H-1,2,3-triazol-d-y)- | -[{1 -methylpiperidin-2-yicarbonyl]- LH-indazol-3-amine
I-Methylpiperidine-3-carboxylic acid hydrochloride was combined with a mixture of dimethylformamide and dichloromethane under nitrogen and stirred for 15 minutes. Then carbonyldiimidazole was added portionwise. The resultant solution was stirred at room temperature for 1 hour. Then Example 62 was added followed by stirring at 60 °C for 2 hours and then at room temperature overnight. The reaction mixture was poured into ice water and brine was added. The cold solution was decanted, and the residue was taken Tne 16 dichloromethane and washed with water (ZX). The organic layer was dried with magnesium sulfate, and the volatiles were removed under reduced pressure. The decanted solution Was extracted with ethyl acetate (3X). The combined organic layers were washed with brine (2X), dried with magnesium sulfate. and concentrated. The residue was taken into a small amount of acetone and then dropped into distilled water. A precipitate was collected by filtration, washed with water, and dried to provide the title compound. MS m/z 579 3 (M+H)".
Example 389 5-(1-benzyl-1H-1 2,3-triazol-4-y])-1 -[(dimethylaminojacetyl]-1 H-indazol-3 -amine 2-(Dimethylamino)acetic acid was dissolved in dimethyiformamide and pyridine under nitrogen at room temperature over 13 minutes. Carbonyidiimidazole was added portionwise. The resultant mixture was stirred at room temperature for I hour. Then
Example 62 was added, and the mixture was stirred overnight at room temperature. The volatile material was removed under reduced pressure, and the remainder was added to ice water. Sodium chloride was added and thick oil came out of the cool solution. The solution was decanted. The residue was washed with water (3X) and then dried. From the decanted solution, a precipitate came out overnight of the water/dimethylformamide mixture. This proved to be starting material which wag filtered off and discarded. The product residue was crystallized in dichioromethane, collected by filtration, rinsed with a small quantity of dichloromethane and ether. The product was dried te provide the title compound. MS m/z 376.3 (M+H)",
Example 390 terg-butyl 3-amino-5-(1 -benzyl-1H-1 2, 3-tr1azol-4-y1)-1 H-indazole-1 carboxylate
Example 62 was suspended in dichloromethane along with a catalytic amount of dimethylaminopyridine. A solution of di-tert-buty! dicarbonate in dichloromethane {166 ml) was added over | hour. The reaction mixture was stirred for approximately 40 hours. Silica gel was added, and the mixture was concentrated. This silica mixture was added to a silica gel column and the material was eluted first with dichloromethane and then with 1% methanol/dichloromethane and lastly with 2% methanol/dichioromethane. The fractions containing the desired product were combined and concentrated to provide the title compound. MS m/z 391.3 (M+H i
Example 391
N-[5-(1-benzyi-1H-1 2,3-triazol-4-y[}-1H -indazol-3-yl]-2-piperidin-] -ylacetamide 2-(Piperidin-1-yDacetic acid was combined with dimethylformamide and pyridine,
The mixture was stirred for 15 minutes at room temperature, and then carbonyldiimidazole was added portionwise. Stirring was continued at room temperature for | hour, and then
Example 644 was added followed by continued stirring for 24 hours. The reaction mixture was warmed to 60 °C for 14 hours. A small amount of the title compound was obtained. MS m/z 416.3 (ME)
Exampie 392
N-[5-(1-benzyl-1H-1,2, 3-1 az0l-4-yl)-1H-indazol-3-y1]-2 -morphehin-4-ylacetamide 2-Morpholinoacetic acid was combined with dimethylformamide and pyridine. The mixture was stirred for 15 minutes at room temperature, and then carbonyldiimidazole was added portionwise. Stirring was continued at room temperature for 1 hour, and then Example 064A was added followed by continued stirring for 28 hours. The reaction mixture was warmed to 60 °C for 4 hours and then SUITING Was continued overnight at room temperature.
The reaction mixture was warmed again to 60 °C for 7 hours. A small amount of the title compound was obtained, MS m/z 418.3 (M+HY"
Example 393
N-[5-~(1-benzyl-1H-1.2 3-tri azol-4-yl)-1H-indazol-3-yl]-1 -methylpiperidine-2-carboxamide
I-Methylpiperidine-3-carboxylic acid hydrochloride was combined with dimethylformamide and pyridine. The mixture was stirred for 15 minutes at room ternperature, and then carbonyldiimidazole was added portionwise, String was continued af room temperature for 1 hour, and then Example 644A was added followed by continued stirring for 28 hours. The reaction mixture was warmed to 60 °C for 4.25 hours and then stirring was continued overnight at room temperature. The reaction mixture was warmed aga to 60 °C for 7 hours. A small amount of the title compound was obtained, MS m/z 416.3 (M=+H)",
Biological Data
ROCK-2 Inhibitory Assay
The compounds of formula (1) were tested for their ability to inhibit N-terminal Hisé- tagged recombinant human ROCK-2 residues 1 1-552 expressed by baculovirus in S£21 cells (Upstate). In 384-well v-bottom polypropylene plates (Axygen), 1 nM (final concentration} in 10 ul recombinant N-terminal His6-tagged recombinant human ROCK-2 residues 11-552 expressed by baculovirus in S21 cells (Upstate) was mixed with 2 uM (final concentration) in 10 ul biotinylated peptide substrate (biotin-Aha-KEAKEKRQEQIAKRRRLSSLR ASTSKSGGSOK (SEQ ID NO: 1) (Genemed), and various concentration of inhibitor (2% DMSO final} in reaction buffer (25 mM HEPES, pH 7.5, 0.5 mM DTT, 10 mM MgClz, 100 uM Na VO, 0.073 mg/ml Triton X- 100), and the reaction was mitiated by addition of 5 uM unlabelled ATP containing 0.01 uCi [*P1-ATP (Perkin Elmer). The reaction was quenched after 1 hour by the addition of 50 ul stop buffer (50 mM EDTA, 2M Nac! final concentration). 80 ul of the stopped reactions were transferred to 384-well streptavidin-coated FlashPlates (Perkin Elmer), incubated 10 minutes at room temperature, washed 3 times with 0.05% Tween-20/PRS using an ELX-405 23 automated plate washer (BioTek), and counted on a TopCount Scintillation Plate Reader (Packard).
ROCK-1 Inhibitory Assay
The compounds of formula (I) were tested for their ability to inhibit N-terminal Hisé- tagged, recombinant, human ROCK-1 amino acids 17-535 expressed by baculovirus in S21 celts (Upstate). In 384-well v-bottom polypropylene plates (Axygen), 2 nM (final concentration) in 10 ul recombinant N-terminal His6-tagged, recombinant, human ROCK-1 - amino acids 17-535 expressed by baculovirus in S21 cells (Upstate) in reaction buffer wes : mixed with 2 uM (final concentration) biotinylated peptide substrate
(biotin-Aha-VRRLRRLTAREAA (SEQ ID NG: 2) (Genemed), and various concentration of mhibitor (2% DMSO final) in 10 ul reaction buffer (25 mM HEPES, pH 7.5, 6.5 mM DTT, 10 mM MgCl, 100 uM NasV0,, 0.075 mg/ml Triton X-100), and the reaction was initiated by addition of 5 uM uniabelled ATP containing ¢.01 uli [VPLATP (Perkin Elmer). The reaction was quenched after | hour by the addition of 50 ul stop buffer (30 mM EDTA, 2M
NaCl final concentration). 80 ul. of the stopped reactions were transferred to 384-well streptavidin-coated FlashPlates (Perkin Elmer), incubated 10 minutes at room temperature, washed 3 times with 0.05% Tween-20/PRS using an ELX-4035 automated plate washer {BioTek), and counted on a TopCount Scintillation Plate Reader (Packard).
USK inhibitory Assay
The compounds of formula (1) were tested for their ability to inhibit N-terminal Hig6- tagged GSK-3 expressed by baculovirus in Sf21 cells (Upstate). In 384-well v-botiom polypropylene plates {(Axygen}, 10 ul recombinant N-terminal His-tagged GSK3 expressed by baculovirus in S£21 cells {Upstate} was mixed with 10 ui biotinylated peptide substrate (biotin-ahx-YRRAAVPPSPSLSRHSSPHQS(p)EDEEE (SEQ ID NO: 3)), 2 uM final concentration (Genemed), and various concentration of inhibitor (2% DMSO final) in reaction buffer (20 mM HEPES, PH7.5 ImM DTT, 10 mM MgCl, 100 uM MNaV(,, 0.075 mg/ml Triton X-100}, and the reaction was initiated by addition of 20 ui [PPLATP, 5 uM final concentration, 2 mCi/umol (Perkin Elmer). The reaction was quenched after 1 hour by the addition of 30 uj stop buffer (36 mM EDTA, 2M NaCl final concentration). 80 pL of the stopped reactions were transferred to 384-well streptavidin-coated FlashPlates (Perkin
Elmer), incubated 10 minutes at room temperature, washed 3 times with 0.05% Tween- 20/PBS using an ELX-405 automated plate washer (BioTek), and counted on a TopCount
Scintillation Plate Reader (Packard).
Human GSK-30 Inhibitory Assay
Compounds were tested for their ability to mhibit human Glycogen Synthase kinase-3 beta (hGSK-30) to phosphorylate biotin-YRRAAVPPSPSLSRHSSPHQ(pS)EDEEE,
Compounds were incubated with 0.5uci® P-ATP, 10 uM ATP, 0.01250 hGSK-3p (Upstate cell signaling solutions) and uM substrate (biotin-YRRAAVPPSPSLSRHSSPHQ(pS)EDEEE (SEQ ID NO: 3)) in 50 mM HEPES, 10 mM MgCl, 100 uM NazVOy, 1 mM DTT, 0.0075% Triton, 2% DMSO {total volume 50 ul)
for 30 minutes at room temperature. The incubation was stopped by addition of an equal volume of 100 mM EDTA, 4 M NaCl. 80 ul of this mixture was added to streptavidin- coated Flashplates (PerkinElmer). Following a wash step, *P incorporation was quantified on ‘a MicroBeta microplate liquid scintillation ceunter (PerkinElmer). 1050s were determined by 2 fitting a sigmoidal dose-response curve to the counts obtained at the different concentrations in GraphPad Prism.
Human GSK-3a Inhibitory Assay
Compounds were tested for their ability to inhibit human Glycogen Synthase kinase-3 alpha (hGSK-30) 0.5 nM final concentration of to phosphorylate biotin-YRRAAVPPSPSLSRHSSPHO(pS)EDEEE (SEQ ID NO: 3). Compounds were incubated with 0.5 Ci “P-ATP, 10 M ATP, 0.01250 hGSK-3 (Upstate cell signaling solutions) and 2 uM substrate (biotin-Y RRAAVPPSPSLSRH SSPHQ(PS)EDEEE) in 50 mM
HEPES, 10 mM MgClo, 100 uM Nas VO, 1 mM DTT, 0.0075% Triton, 2% DMSO (total volume 50 pL) for 30 minutes at room temperature. The incubation was stepped by addition of an equal volume of 100 mM EDT A, 4M NaCly. 80 pL of this mixture was added to streptavidin-coated Flashplates {PerkinElmer}. Following a wash step, °P mcorporation was quantified on a MicroBeta microplate hquid scintillation counter (PerkinElmer). 1050s were determined by fitting a sigmoidal dose-response curve to the counts obtained at the different concentrations in GraphPad Prism.
JAK?Z Inhibition Assay
Jak? kinase activity was assayed by a homogenous time-resolved fluorescence (HTRF) in vitro kinase assay ( Mathis, G., HTREF(R) T: echnology. I Biome! Screen, 1999. 46): p. 309-314), Specifically, 10 uL C-terminal His6-tagged, recombinant, human JAK, amino acids 808-end, expressed by baculovirus in SE] cells (Upstate) was mixed with 10 ul inhibitor (various concentrations, 2% final DMSO) and 10 ul of ATP (3 uM final concentration) in reaction buffer (56 mM HEPES, pH 7.5, 10 mM MgCl, 2 mM MnCl, 0.1% BSA and I mM DTT, 40 xL final volume). The reaction was initiated by addition of 10 ul of Bio-PDK peptide (Brotin-Ahx-KTFCGTPEYLAPEV RREPRILSEEEQEMFRDEDYIADWC (SEQ ID NO: 4), 0.5 uM final concentration) in a black 384-wel] piate (Packard). After 60 minutes mcubation at room temperature, the reaction was quenched by addition 60 pL stop/revelation buffer to give 30 mM EDTA, 1 ug/ml streptavidin-APC ( Prozyme), 50 ng/m) anti-phogphotyresine mAb PT66-K Europium Cryptate, 30 mM HEPES, pH 7.5, 120 mM KF, 0.005% Tween-20, 0.05% BSA). The quenched reaction was allowed to stand at rcom temperature for 1 hour and then read in a time-resolved fluorescence detector (Envision, Perkin Elmer) at 615 nm and 665 nm simultaneously. The ratio between the signal of 615 nm and 665 nm was used in the calculation of the Css.
Methods - B-catenin Ieporter-vene assay
Compounds were tested for their ability to modulate B-catenin-modulated gene transcription in a LEF/TCE(T-cell factor) reporter gene assay. §Y-5Y5Y human neuroblastoma cells were transiently transfected with 80 ng/well TOPFLASH plasmid {Upstate cell signaling solutions) containing two sets of three copies of the TCF binding site upstream of the Thymidine kinase minimal promoter and firefly Luciferase open reading frame or with 80 ng/well FOPFLASH plasmid (Upstate cell signaling solutions) containing three copies of a mutated TCE binding site upstream of the Thymidine kinase minimal promoter and firefly Luciferase open reading frame. In addition, all cells were transiently transfected with the 20 ng/well pRL-TK plasmid (Promega) containing the herpes simplex virus thymidine kinase promoter to provide low to moderate levels of Renilla Luciferase expression. Transfection medium was exchanged for serum-free medium containing the test substance and incubated for 24 hours at 37 °C. The incubation was stopped and quantified using the Dual Glo Luciferase Assay (Promega) as indicated and quantified on a Pherastar reader (BMG).
Firefly Luciferase activity was normalized for Renilla Luciferase activity per well.
Subsequently, the normalised TOPFLASH response was compared to the normalised
FOPFLASH response, thus giving the LEF/TCF specific signal. The maximal response is the maximal ratio between the normalised TOPFLASH and FOPFLASH signals. Sigmoidal dose-response curves were fitted using Graphpad Prism.
Murine Asthma Model of acute asthma
Female Balb/c mice were purchased from Taconic and housed at Abbott Bigresearch
Center. Animals were utilized at 8-12 weeks of age. All protocols were approved by the
Institutional Animal Care and Use Committee (IACUC). Dexamethasone (Dex), and ovalbumin (OVA) were purchased from Sigma. Endotoxin was removed from ovalbumin using DetoxiGel (Pierce) according to manufacturer's protocol and the final material contained less than 0.1 EUfmg protein. Alum Imject was purchased from Pierce.
Animals were sensitized to OVA on day 0 and 7 with an Lp. injection of 8 ug OVA in
Z mg alum, On days 14 and 16, animals received intranasal challenge of 0.3 ug OVA in 50 3 ulsterile PBS. Animals were dosed Lp. with a representative compound of formula (1) {dissolved with 0.5% HMPC, 0.02% Tween 80 in water) twice per day at doses of 3, 10, and 30 mg/kg/dose beginning the afternoon of day 13. The final dose of compound was administered 30 minutes prior to measurement of arway hyperresponsiveness {AHR
Dexamethasone was administered orally once a day on days 13-17 at a dose of 3 mg/kg. All endpoints were analyzed on day 17, 24 hours after the second OVA challenge. AHR was assessed using unconscious restrained whole body plethysmography | Briefly, a surgical plane of anesthesia was induced with an ip. injection of ketamine and xylazine. A tracheal canula was surgically inserted between the third and fourth tracheal rings. Spontaneous breathing was prevented by an intravenous (i.v.) jugular vein injection of pancuronium bromide. Animals were placed in a whole body plethysmograph {Buxco} and mechanical ly ventilated with 0.2 ml room air at 150 breaths per minute with a volume-controlled ventilator (Harvard Apparatus). Pressure in the lung and flow within the plethysmograph were measured using transducers, and lung resistance was calculated as pressure/flow using
Biosystem Xa software, Baseline resistance as well as resistance following challenge with methacholine (3, 10 or 30 mg/ml) that was delivered with an inline ultrasonic-nebulizer were measured. Upon completion of pulmonary function testing, the lungs were | avaged 4 times with 0.5 ml sterile PRS. Lavage fluid wes analyzed for JL-13, AMCase, MucSac and cellufar infiitrates. The efficacy of the test compound was tested at doses of 3,10 and 30 mg/ko bid (6,20, 60 mg/kg/day). Challenge with OVA caused an increase in lung resistance to 6.90 cm
H,O/mlfsec vs, 4.65 cm HoO/ml/sec in animals challenged with PRS. Treatment of mice with the test compound significantly inhibited {(p=0.601) methacholine-induced airways resistance down to 4.55 cm H-0/mb/sec and 4.77 em H,0/mi/sec at doses ranging between 1 and 100 mg/kg. The preferred compounds require a dose of less than 50 mg/kg to exhibit said response. The most preferred compounds require a dose of less than 30 mg/kg to exhibit said response. This inhibition was equivalent to measurements taken in the PBS challenged group (4.65 cm H,O/ml/sec) and to treatment of 3 mg/kg dexamethasone (4.76 cm
HoO/ml/sec). 1L-13 measurement: 11-13 concentrations in the bronchoalveolar lavage fluid (BAL)
were measured by ELISA (R & D Systems) according to manufacturer’s instructions, IL-13 concentrations in the BAL fluid were significantly induced to 102.5 pg/ml in OVA challenged mice as compared io levels below detection in the PRS challenged group. This induction was signi ficanily inhibited (p<0.05) by 60% after administration of the test compounds administration at the 30 mg/kg dose. There was no significant inhibition at the 3 mg/kg or 10 mg/kg dose groups.
AMCase measurement: Acidic mammalian chitinase (AMCage) activity was determined in a 1:10 dilution of BAL fluid with 0.01% ESA, 30 mM sodium citrate, 60 mM sodium phosphate, pld 5.2 in the presence of RO uM 4-methylombellifery] B-DN N- 1 diacetylchitobioside. Reactions were incubated for 15 minutes at room temperature and quenched by addition of 100 ul of | M glycine/NaOH pH 10.6. Product formation was determined by fluorescence emission at 460 nm using excitation at 385 nm on a Fiuoroskan
Ascent fluorometer, AMCage activity was induced to 28 5U in OVA challenged animals compared to 2.17U in the PBS challenged animals. This mduction was significantly inhibited (p<0.01)in the 30 mg'kg group by 35% after test compounds were administered.
MUCSAC measurement: Concentrations of the mucin gene MUCSAC were quantitated by ELISA format. Briefly, BAL samples are diluted 1:2 in buffer (29% BSA in
PBS) and plated onto high protein binding 96-wel] plates (Costar) and dried. After a series of washes, a 1:100 dilution of biotinylated MUC5AC antibody (Clone 43M, LabV 18100} was added for | hour. Plates are washed and a 1:3000 dilution of streptavidin-HRP (Southern
Biotech) was added to the plate for 15 minutes. Plates were then developed using a TMB substrate (Sigma) for 30 minutes. The reaction was stopped using 1M H;SO; and then read in a spectrophotometer at OD 450mm. Levels of MUCSAC were reduced by greater than 50% after administration of test compounds.
Determination of Antinociceptive Effect: Models for Neuropathic Pain ee sleet Models for Neuropathic Pain
Spinal Nerve (1.5/1.6) Ligation Model of Neuropathic Pain. As previously described in detail by Kim and Chung (Kim S. H.; Chung JM. An experimental mode! for peripheral neuropathy produced by segmental spinal nerve ligation in the rat, Pain 1992, 50, 355-3 63), a l.5 cmincision was made dorsal to the lumbosacral plexus, In anesthetized rats, the paraspinal muscles (left side) were separated from the spinous processes, the 15 and Lg spinal nerves isolated, and tightly ligated with 3-0 silk threads, Following hemostasis, the wound was sutured and coated with antibiotic ointment. The rats were allowed to recover and then placed in a cage with soft bedding for 14 days before behavioral testing for mechanical allodynia.
Sciatic Nerve Ligation Model of Neuropathic Pain, As previously described in detail by Bennett and Xie (Bennett G. J: Xie Y-K. A peripheral moncneuropathy in rat that produces disorders of pain sensation like those seen Inman. Pain 1988, 33, 87-107) in anesthetized rats, a 1.5 om incision was made 0.5cm below the pelvis and the biceps femoris and the gluteous superficialis (right side} were separated. The sciatic nerve was exposed, isolated, and four loose ligatures (5-0 chromic catgut) with 1 mm spacing were placed around it. The rats were allowed to recover and then placed in a cage with soft bedding for 14 days before behavioral testing for mechanical allodynia as described above. in addition. animals 16 were also tested for cold allodynia by dipping their hind paw in a cold-water bath (4.5°C) and determining the paw withdrawal latency.
Selected analogs of compounds of formula (1), dosed cither i.p. or p.o. demonstrated greater than 30% inhibition of tactile allodynia in the Chung and Bennett models of neuropathic pain described herein at doses ranging from 1-150 mg/kg,
In summary, a representative compound of formula (1) in a mouse mode! of acute asthma was effective in inhibiting airway resistance in a dose range between 1 and 100 mg/kg. High dose (30 mg/kg) treatment also inhibited 11-13 induction as well as AMCase activity and MUCSAC levels in the BAL fluid,
Representative compounds of formule (1) in rat models of neuwopathic pain were effective as demonstrated by a greater than 30% inhibition of taciile allodynia at doses ranging from 1-150 mg/kg.
The compounds of formula ( F) were found to inhibit human ROCK-2, N-terminal His- tagged GSK-3f, human GSK-38, Hi s6-tagped. recombinant, human JAK? and Firefly
Luciferase exhibiting an 1Cs, of about 1.0 1M to about 10 1M, preferably about 100 nM to about 1.0 uM. More preferably, compounds of fornmula {I) were found to inhibit human
ROCK-2, N-terminal His-tagged GSK-38, human GSK-3p, Hist-tagged, recombinant. human JAK2 and F irefly Luciferase exhibiting an 1Cs; of about 10 nM 0 about 100 nM, and most preferably less than 10 nM.
In addition, certain compounds of formula (I} exhibited inhibition of human ROCK? with a selectivity of greater than 10 fold against a panel of 50 kinase targets, Certain compounds of formula (1) exhibited inhibition of human GSK-3f with a selectivity of greater than 10 fold against a panel of 50 kinase targets. Certain compounds of formula (1) exhibited inhibition of His6-tagged, recombinant, human JAK? with a selectivity of greater than 10 fold against a panel of 50 kinase targets.
Methods of Administration
The present invention also provides pharmaceutical compostitons that comprise compounds of the present invention. The pharmaceutical compositions comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenierally, mtracisternally, intravaginally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term "parenterally," as used herein, refers to modes of administration that mciude intravenous. intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
The term "pharmaceutically acceptable carrier,” as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to. lactose, glucose and sucrose: starches such as, but not Himited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl! cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocos butter and
Suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oi} and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to. ethyl oleate and ethyl Jaurate: agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water: isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the Judgment of the formulator.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile mjectable solutions or dispersions just prior to use. Exarnples of suitable aqueous and Nonaquecus carriers, diluents, solvents or vehicles include water, ethanol, polyols {such as glycerol, propylene glycol, polyethylene glycol and the like), vegetabie oils (such ag olive oil), injectable organic esters (such as ethyl oleate) and suitable mixtures thereof Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants,
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of MICTOOIZanisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben,
J0 chlorebutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the mjectable pharmaceutical form can be brought about by the inclusion of agents, which delay absorption such as aluminum monostearate and gelatin,
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutancous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form, Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglveolide, Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug refease can be controlled. Exampies of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissues,
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile mjectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable carrier or excipient, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose,
mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinyipyrrolidone, sucrose and acacia; ¢f humectants such ag glycerol; d) disintegrating agents such as agar-agar, calcium carbonate. potato or tapioca starch. alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; ¢) wetting agents such as cetyl alcoho! and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and 1) lubricants such as tale, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof in the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such carriers as lactose or milk sugar as well as high molecular weight polyethylene glycols and the fike.
The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of & composition such that they release the active Ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and WAXES.
The active compounds can also be in nricro-encapsulated form, if appropriate, with one or more of the above-mentioned carriers.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl! alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrabydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated 1sostearyl alcohols, polyoxyethylene sorbiio! and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof,
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixin g the compounds of this invention with suitable non-irritating carriers or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lameliar hydrated Hquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present mvention, stabilizers, preservatives, excipients and the like. The preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together,
Methods to form liposomes are known in the art. See, for example, Prescott, Bd.
Methods in Cell Biclogy, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
Dosage forms for topical administration of 4 compound of this invention inciude powders, sprays, ointments and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants, which may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemptated as being within the scope of this invention.
Actual dosage levels of active mgredients in the pharmaceutical compositions of thig invention can be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration, The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated.
When used in the above or other treatments, a therapeutically effective amount of ane of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form. The phrase "therapeutically effective amount” of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. Tt will be understood, however, that the total daily usage of the compounds and compositions of the present mvention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health. sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed: and like factors well known in the medical arts.
The term "pharmaceutically acceptable salt,” as used herein, means salts derived from morganic or orgamic acids, The salts can be prepared in sity during the final isolation and purification of compounds of Formula (I) or separately by reacting the free base of a compound of Formula (I) with an inorganic or organic acid, Representative acid addition salts include, but are not limited to, acetate, adipate, alginaic, citrate, aspartate, benzoate, benzenesulfonate, bisul fate, butyrate, camphorate. camphorsulfonate, digluconate. glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, kydroiodide, 2-hydroxyethansul fonate {1sethionate), lactate, maleate, fumarate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, (L) tartrate, {D) tartrate, (DL) tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, and undecanoate.
The term “pharmaceutically acceptable prodrug” or "prodrug, "as used herein, represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical Judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like. Prodrogs of the present invention may be rapidly transformed in vivo to compounds of Formula (13, for example, by hydroivsis in blood.
The present invention contemplates compounds of Formula (I) formed by synthetic means or formed by in vivo biotransformation,
The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others, are equivalent to the unsolvated forms for the purposes of the invention,
The total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.003 to about 30 mg/kg/day. For purposes of oral administration, more preferable doses can be in the range of from about 0.01 to about 10 mg/kg/day. If desired, the effective daily dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submuitiples thereof to make up the daily dose.
Protein kinases can be classified into broad groups based upon the identity of the amino acid(s) that they target (serine/threonine, tyrosine, lysine, and histidine). For example, tyrosine kinases inchude receptor tyrosme kinases {RTKs), such as growth factors and non- receptor tyrosine kinases, such as the sre kinase family. There are also dual-specific protein kinases that target both tyrosine and serine/threonine, such as cyclin dependent kinases (CDKs) and mitogen-activated protein kinases (MAPKs),
The protein fyrosine kinases {PTKs) compose a large family of kinases that regulate cell to cell signals involved in growth, differentiation, adhesion. motility, and death (Pearson,
M. etal, In Protein Tyrosine Kinases, Fabbro, D., McCormick, F., Eds.; Humana Press Inc. 2006: pp 1-29). Members of the tyrosine kinase include, but are not limited fo, Yes, BMX,
Syk. EphAl, FGFR3, RYK, MUSK, JAK and EGFR. Tyrosine kinascs are distinguished mie two classes, i.¢., the receptor type and non-receptor type tyrosine kinases, Interestingly, the entire family of tyrosine kinases consists of at least 90 characterized kinases with at least 38 receptor type and at least 32 honreceptor type kinases comprising at least 30 total subfamilies. Tyrosine kinases have been implicated in a number of diseases in humans, including diabetes and cancer (Pearson, M. et al., In Protein Tyrosine Kinases; Fabbro, D..
McCormick, F., Eds.; Humana Press Inc., 2006: pp 1-29). Tyrosine kinases are often involved in most forms of human malignancies and have been linked to a wide variety of congenital syndromes (Robertson of al., Trends Gener. 16:265.271. 2000).
The non-receptor tyrosine kinases represent 4 group of intracellular enzymes that lack extracelhufar and transmembrane sequences. Currently, over 32 families of not-recepior tyrosine kinases have been identified (Robinson et al, Oncogene 19, 5548-5557, 2000).
Representative examples include Sre, Bik, Csk, ZAP70 and Kak families. In particular, the
Sre family of non-receptor tyrosine kinase family is the largest, consisting of Src, Vas, Fyn, 3¢ Lyn, Lek, Blk, Hek, Fer and Yrk protein tyrosine kinases. The Src family of kinases have been linked to oncogenesis, cell proliferation and tumor progression. Many of the protein tyrosine kinases have been found to be involved in cellular signaling pathways involved in various pathological conditions including but not limited to cancer and hyperproliferative disorders and immune disorders.
The cyclin dependent kinases CDK fepresent a group of intracellular enzymes that control progression through the cell cycle and have essential roles in cell proliferation (Cohen, P. Nature Reviews Drug Discovery 1, 309.315. 2002). Representative examples of
CDEs include, but are not limited to. cyclin dependent kinase 2 (CDK2Y, eyelin dependent kinase 7 (CDK7), cyclin dependent kinase 6 (CDK) and cell division contra! 7 profein (CDC2). CDKs have been implicated in the regulation of transitions between different phases of the cell cycle, such ag the progression from a quiescent stage in G1 (the gap between mitosis and the onset of DNA replication for a new round of cel} division) to S (the period of active DNA synthesis), or the progression from (2 te M phase, in which active mitosis and cell division occur (Rowell et al. Critical Reviews in Immunology 2603), 189- 212,2006). CDK complexes are formed through association of a regulatory evelin subunit (e.g. cyclin A, B1,B2, D1, D2. D3, and EY and a catalytic kinase subunit (c.g, cde2 (CDK),
CDK2, CDE4, CDKS, and CDK6). CDKs display an absolute dependence on the cyclin subunit in order fo phosphorylate their target substrates, and different kinase/cychn pairs function to regulate progression through specific portions of the cell cycle, F urthermore,
CDKs have been implicated in various disease states, including but not limited to, those displaying the cancer phenotype, various neoplastic disorders and in neurological disorders (Pallas ct al. Current Medicinal Chemistry: Central Nervous System Agents 5(2), 101-1089, 2003),
The mitogen activated protein (MAP) kinases participate in the transduction of si nals to the nucleus of the cell in response to cxtracellular stimuli. Representative examples of
MAP kinases include, but are not limited to, mitogen activated protein kinase 3 {MAPK3), mitogen-sctivated protein kinase | (ERK2), mitogen-activated protein kinase 7 (MAPK), mitogen-activated protein kinase & (JNK 1), mitogen-activated protein kinase 14 (p38 aipha), 5 mitogen-activated protein kinase 10 (MAPK 10), INK3 aipha protein kinase, stress-activated protein kinase JINK2 and mitogen-activated protein kinase 14 (MAPK14). MAP kinases are a family of proline-directed serine/threonine kinases that mediate signal transduction from extracellular receptors or heath shock, or UV radiation (Barr et al, Trends in
Pharmacological Sciences 27(103, 525-330, 2006). MAP kinases activate through the phosphorylation of threonine and tyrosine by dual-specificity protein kinases, including tyrosine kinases such as growth factors. Cell proliferation and differentiation have been shown to be under the regulatory control of multiple MAP kinase cascades (Sridhar et al.
Pharmaceutical Research, 17:11 1345-1353, 2000). As such, the MAP kinase pathway plays critical roles in a number of disease states, for example, defects in activities of MAP ldnases have been shown to lead to aberrant cell proliferation and carcinogenesis {Qi et al., Journal of
Cell Science 1 18(16), 3569-3572, 2005). Moreover, MAP kinase activity has also been implicated in insulin resistance assoc ated with type-2 diabetes (Fujishiro et al. Recent
Research Developments in Physiology 1{Pt. 23, 801-812, 2003).
The p90 ribosomal $6 kinases (Ral) are serine/threonine kinases which function in mitogen-activated cell growth and proliferation, differentiation, and cell survival. Examples of members of the Rsk family of kinases include, but are not hmited to, ribosomal protein $6 kinase, 90 kDa, polypeptide 2 (Rsk3), ribosomal protein S6 kinase. 90 klia, polypeptide 6 (Rsk4}, ribosomal protein 56 kinase, 90 kDa, polypeptide 3 (Rsk) and ribosomal protein $6 kinase, 90 kDa, polypeptide | (Rsk1/p90Rsk). The Rsk family members are activated by extracellular signal-related kinases and phosphoinositide-dependent protein kinase 1 (Frodin and Gammeltoft, Mol. Cell Endocrinol. 151, 65-77, 1999). Under basal conditions, RSE kinases are localized in the cytoplasm of cells and upon stimulation by mitogens, the activated (phosphorylated by extracellular-related kinase) RSK transiently translocates to the plasma membrane where they become fully activated. The fully activated RSK phosphorylates substrates that are involved in cell growth, proliferation, differentiation, and cell survival (Clark et al. Cancer Research 65, 3108-31 16, 2005). RSK si gnaling pathways have also been associated with the modulation of the cell cycle (Gross et al., J. Biol. Chem. 276, 46099-46103, 2001 J. Current data suggests that small molecules that inhibit Rsk may be useful therapeutic agents for the prevention and treatment of cancer and flammatory diseases.
Members of the checkpoint protein kinase family (CHK) are serine/threonine kinases that play an important role in cef! cycle progression. Examples of members of the checkpoint family include, but are not limited to, CHK and CHK. Checkpoints kinases are control systems that coordinate cell cycle progression by influencin 2 the formation, activation and subsequent inactivation of the cyclin-dependent kinases, Checkpoints kinases prevent cel] cycle progression at inappropriate times, maintain the metabolic balance of cells while the cell is arrested, and in some instances can induce apoptosis {programmed celi death) when the requirements of the checkpoint have not been met (Nurse, Cell, 91, RO5-867, 1997;
Hartwell ef al, Science, 266, 1821-1828, 1994). Members of the checkpoint family of kinases have been implicated in cell proliferative disorders, cancer phenotypes and other diseases related to DNA damage and repair (Kumagai and Dunphy Cell Cycle, 5, 1265-1268 (2000); Xiao et al., Molecular Cancer Therapeutics 5, 1935-1943, 2006).
Aurora kinases are 2 family of multigene mitotic serine-threonine kinases that functions as a clags of novel oncogenes. These kinases comprise aurora-A and aurora-R members. Aurora kinases are hyperactivated and/or over-expressed in several solid tumors mcluding but not lirnited to, breast. bvary, prostate, pancreas, and colorectal cancers. In particular avrora-A is a centrosome kinase that plays an important role call cycle progression and cell proliferation. Aurora-A ig located in the 20q13 chromosome region that is frequently amplified in several different types of malignant tumors such as colorectal, breast and bladder cancers. There is iso a high correlation between aurora-A and high histo-prognostic grade aneuploidy, making the kinase a potential prognostic vehicle. Inhibition of aurora kinase activity may reduce cell proliferation, tumor growth and potentially tumorigenesis. A detailed description of aurora kinase function is reviewed in Journal of Cell Science, 119, 3664-3675, 2006.
The Rho-associated coiled-coil-containing protein serine/threonine kinases ROCK] and ROCK-2 are thought io play a major role in cytoskeletal dynamics by serving as downstream effectors of the Rho/Rac family of cytokine-and growth factor-activated small
GTPases. ROCKS phosphorylate various substrates, including, but not limited fo, myosin light chain phosphatase, myosin light chain, ezrin-radixin-moesin proteins and LIM (for
Linii, Isil and Mec3) kinases. ROCKS alse medi ate the formation of actin stress fibers and focal adhesions in various cell types. ROCKs have an important role in cell migration by enhancing cell contractility and are required for tail retraction of monocytes and cancer ceils.
ROCK inhibitors have also been shown to reduce tumor-cell dissemination in vive, Recent experiments have defined new functions of ROCK in cells, including centrosome positioning and celi-size regulation, which might contribute to various physiological and pathological states (Mueller et al, Nanure Reviews Drug Discovery 4, 387-398, 2005). The
ROCK family members are attractive intervention targets for a variety of pathologies including cancer and cardiovascular disease. ROCK inhibitors can be useful therapeutic agents for hypertension, angina pectoris, and asthma. Furthermore, Rho is expected to play a role in peripheral circulation disorders, arteriosclerosis, inflammation, and autoimmune disease and as such, is a useful target for therapy (Shimokawa et al, 4 rieriosclerosis,
Thrombosis, and Vascular Biology, 25, 1767-1775, 2003),
The limited success of pharmacaotherapeutic approaches in spinal-cord injury is based to a large extent on the inability of injured nerve fibers in the white matter of the human spinal cord to regrow and re-establish synaptic contacts with their disconnected partner neurons. A hostile micro-environment, characterized by the presence of a large variety of molecular neurite-growth inhibitors at the iesion site, in the scar tissue and on CNS myelin,
accounts for this irreversible arrest of neurite-growth. In tissue culture, these inhibitors of neurite growth often induce very dramatic responses, including the collapse of the formation and withdrawal of the neurite. Scar tissue in the human brain and spinal cord is 2 strong and persistent barrier for any regenerative neurite growth and ROCK inhibitors might help injured fibers to grow or sprout beyond this regeneration-inhibiting tissue, A variety of evidence indicates that injury to brain and spinal cord results in g strongly activated RhoA~ROCK. pathway. Due to the persistent presence of the neurite growth inhibitors at or around the lesion site and in CNS myelin, such activation could potentially persist for a long time, making ROCK ishibition an atiractve goal not only for acute and sub-acute treatment, but also for chronic treatment of spinal-cord injury. Inhibition of ROCK oy two different small- molecule ROCK inhibitors (Y-27632 and fasudil) stimulated or accelerated functional recovery in different mouse and rat spinal-cord-injury models when given locally or systemically immediately after infury as a single dose or over several weeks (Dergham, Pet al. Rho signaling pathway targeted to promote spinal cord repair. J, Neurosci. 22, 6570-6577, 2002: Hara, M. et al. Protein kinase inhibition by fasudil hydrochloride promotes neurological recovery after spinal cord injury in rats. J. Neurosurg. Spine 93, 94-101, 2000.;
Fournier, A. E. et al. ROCK inhibition enhances axonal regeneration in the injured CNS. J.
Neurosci. 23, 1416-1423, 2003: Sung, J. K. etal A possible role of Rho A/Rho-kinase in experimental spinal cord injury in rat. Brain Res. 959, 26-38, 2003; Tanaka, H. et al,
Cytoplasmic p2HCipt/WAF1) enhances axonal regeneration and functional recovery after spinal cord injury in rats, Neuroscience 127, 155-164, 2004). Tn these studies, ROCK inhibition not only enhanced nerve-fiber growth beyond the lesion site. but was also neuroprotective and decreased tissue damage and cavity formation. On the basis of these rodent studies, ROCK inhibitors, which possess neuroprotective and neuroregeneration- stimulating activities, could offer significant benefit for spinally injured patients. In addition, they could normalize spinal blood flow due to their vasodilatory effects, thereby further enhancing tissue preservation,
Pathologically, Alzheimer's disease is characterized at the microscopic level by intraceliular neurofibrillary tangles and extracellular amyloid aggregates. Neurofibrillary tangles contain aberrantly phosphorylated tau protein, a microtubule-associated protein and substrate for ROCK, whereas the amyloid aggregates are formed primarily by toxic 42- amino-acid long amyloid-B (AB) peptides. 1t was recently shown (Zhou, Y. et al.
Nonsteroidal anti-inflammatory drugs can lower amyloidogenic AB42 by mhibiting Rho.
Science 302, 1215-1217. 2003) that in cells secreting A472 and in transgenic PDAPP MICE producing large amounts of AB42, some NSAIDs lowered AB42 by inhibiting the RhoA—
ROCK pathway. The ROCK inhibitor Y-27637 was effective in lowering AR42 levels both in cell culture and in PDAPP fransgenic mice after intra-cerebroventricular injection.
Activation of Rho by geranylgeranylpyrophosphate, a lipid required for the membrane attachment of Rho, increased AP42 levels; this increase was completely prevented by Y- 27632. The ROCK inhibitor Y-27632 used in animal Alzheimer’s disease models was efficient in lowering the amount of the toxic AB42 levels, but had no effect on total AB levels and this effect of Rho or ROCK inhibitors is at lcast one mechanism by which NSAIDs reduce AP4Z levels. In addition wo many other therapeutic interventions, these inhibitors have the well-documented advantage of stimulating regenerative growth of neuritis and it is therefore possible that the hibition of this pathway could result in repair of the amyloid- damaged neural circuitry,
Most important in disease pathogenesis is the migration of leukocytes beyond the brain endothelium into the CNS and the inflammatory cascade stimulated by these cells, which finally results in demyelination of CNS fiber tracts and in neurite damage and loss.
Leukocytes require active RhoA and ROCK for their journey beyond brain endothelium, because their trans-endothelial migration was prevented by the ROCK inhibitor Y-2763294,
Neuroprotective activities of the ROCK. inhibitors fasudil and hydroxy-fasudil are not restricted to spinal-cord injury models, but have also been reported in cerebral multi-infarct models in gerbils and rats (Toshima Y, Satoh S, Tkegaki I, Asano T. A new model of cerebral microthrombosis in rats and the neuroprotective effect of a Rho-kinase inhibitor,
Stroke 31, 2245-2250, 2000; Satoh, S. et al. Pharmacological profile of hydroxy fasudii as a selective ROCK inhibitor on ischemic brain damage. Life Sci, 69, 1441-1453, 2001;
Kitaoka, V. et al. Involvement of RhoA and possible neuroprotective effect of fasudil, a
ROCK inhibitor, in NMDA-induced REUrotoxicity in the rat retina. Brain Res. | 018, 111-118, 2004). In rodent strake models, several regeneration inhibitors, such as the ROCK activating
NgR1I complex and one of its ligands, NOGO-A, have been neutralized 24 hours or even 1 week after induction of a cerebral stroke and mmproved functional recovery has been observed (Lee, JK, Kim, J. E., Sivula, M. & Strittmatter, S. M. Nogo receptor antagonism promotes stroke recovery by enhancmg axonal plasticity. J. Neurosci. 24, 6209-6217, 2004; Wiessner,
C. et al. Anti-Nogo-A antibody infusion 24 hours after experimental stroke improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats. J. Cereb. Blood Flowhetab. 23. 154-165, 2003), Blocking ROCK is therefore a feasible neuroregenerative strategy; furthermore. such a sirategy has the advantage that the therapeutic treatment window for the use of these inhibitors might be larger than for thrombolytic or neuroprotective stroke treatment options.
Neuronal injuries in the peripheral nervous system or m the CNS of humans can lead to a chronic pain state known as neuropathic pain. Inflammatory mediators such ag lysophosphatidic acid (LFA) which is produced in response to injury has recently been shown 0 be involved in initiation of neuropathic pain in a mouse model of peripheral nerve injury (Inoue. M. et al. Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling. Nature Med. 10, 12-718, 2004). LPA is present at lesion sites in the PNES and
CNS, and exerts its function by binding to Geprotein-coupled TPA receptors which results in 16 activation of the RhoA-ROCK pathway. The ROCK inhibitor Y-27637 prevented the initiation of neuropathic pain after nerve injury or LPA injection, whereas another ROCK inhibitor, H-1152, relieved neuropathic pain in an L5 spinal-nerve-transection model (Tatsumi, S. et al. Involvernent of Rho-kinase in inflammatory and neuropathic pain through phosphorylation of myristoylated alanine-rich C-kinase substrate {MARCKS). Neuroscience 131, 491-498, 2005). The results of these studies indicate that ROCK is a potential drug target responsible for the induction and also maintenance of persistent pain states,
Moreover, Schueller et al. (Abstract 121 6, 8th World Congress on inflammation,
Copenhagen, Denmark, June 16-20, 2007) have demonstrated that SLx-211 9. an orally bioavailable, potent and highly selective inhibitor of ROCK. 2 reduces atherogenesis in the presence of dramatically elevated lipid levels in groups of 8 ApoE knockout mice, indicaticating that selective inhibition of ROCK 2 has the potential to limit atherosclerosis,
The 70 kDa ribosomal 86 kinase (p70S6K) 15 activated by numerous mitogens, growth factors and hormones. Activation of p70S6K occurs through phosphorylation at a number of sites and the primary target of the activated kinase is the 40S ribosomal protein 86, a major component of the machinery involved in protein synthesis in mammalian cells. In addition, p70S6K activation has been implicated in cell cycle control, neuronal cell differentiation, regulation of cell motility and a cellular response that is important in tumor metastases, immunity and tissue repair. Modulation of p70Sé6 kinase activity may also have therapeutic implications in disorders such as cancer, inflammation, and various neuropathies.
A detailed discussion of p7056K kinases can be found in Prog. Cell Cycle Res. 1,21-32, 1995, and Immunol. Cell Biol. 78, 447.51, 2000.
Glycogen synthase kinase 3 (GSK-3) is a ubiquitousty expressed constitutively active serine/threonine kinase that phosphorylates cellular substrates and thereby regulates a wide variety of cellular functions, including development, metabolism, gene transcription, proiein translation, cytoskeletal organization, cell cycle regulation, and apoptosis. GSK-3 was initially described as 2 key enzyme mvolved in glycogen metabolism, but is now known to regulate a diverse array of cell functions, Two forms of the enzyme, GEK-3~1 and GSK- 3+7, have been previously identified. The activity of GSK-3+/ is negatively regulated by protein kinase B/Akt and by the Wnt signaling pathway. Small molecules inhibitors of GSK- 3 may, therefore, have several therapeutic uses, including the treatment and prevention of neurodegenerative diseases and stimulation of neurogeneration in various neurological disorders (Gartner et al. J. Cell Science, 2006, 1 19, 3927-3934. Zhou et al. Neuron, 2004, 42, ¥97-912), type IT diabetes, bipolar disorders, stroke, cancer, osteoarthritis, osteoporosis, tO rheumatoid arthritis (Cuzzocres et al, (Hnical fmmunology, 2006, 120, 37-67) and chronic inflammatory disease. General review: Kockeritz et al., Current Drug Targers, 7, 1377- 1388, 2006. Review of neurological applications: Curren: Drug Targers, 7(11}, 1389-1397 and 1399-1409, 2006.
Protein kinases have become attractive targets for the treatment of cancers {Fabbro et al, Pharmacology & Therapeutics 93:79-98, 2002). It has been proposed that the involvement of protein kinases in the development of human malignancies may occur by: (1) genomic rearrangements (e.g., BCR-ABL in chronic myelogenous leukemia), (2) mutations leading to constitutively active kinase activity, such as acute myelogenous leukemia and gastrointestinal tumors, (3) deregulation of kinase activity by activation of oncogenes or loss of tumor suppressor functions, such as in cancers with oncogenic RAS, (4) deregulation of kinase activity by over-expression, as in the cage of EGFR and (5) ectopic expression of growth factors that can contribute io the development and maintenance of the neoplastic phenotype (Fabbro et al., Pharmacology & Ti herapeurics 93:79-98, 2002).
Certain cancers are associated with angiogenesis. Angiogenesis is the growth of new capillary blood vessels from pre-existing vasculature (Risau, W., Nature 386:671-674. 1997).
It has been shown that protein kinases can contribute to the development and maintenance of the neoplastic phenotype (Fabbro et al, Pharmacology & Therapeutics 93:79-98, 2002). For example, VEGF A-D and their four receptors have been implicated in phenotypes that involve neovascualrization and enhanced vascular permeability, such as tumor angiogenesis and lymphangiogenesis (Matter, A... Drug Discov. Today 6:1005-1023, 2001).
It has been recognized that a single agent approach that specifically targets one kinase or one kinase pathway may be inadequate fo treat diseases and disorders, in particular cancer, for several reasons, Models have suggested that 5 to 7 mutations are necessary for the progression of a normal cell to & malignant one. Furthermore, it is widely recognized that cancer is the result of alterations in multiple pathways, in particular protein kinase pathways that are associated with processes such as cel] growth, proliferation, apoptosis, moti fity, or mvasion, In a majority of cancers, common feature is the simultaneous overexpression and/or hyper-activation of a variety of protein kinases, such as receptor and non-receptor kinases, serine/threonine kinases, P13 kinases and cell cycle associated kinases, In fact, several of these kinases, either alone or in conjunction with other kinases, have been implicated in a number of processes important for cell survival, proliferation, growth and malignant transformation, motility and invasion leading to metastasis and an gI0genests or
I¢ inflammation, and diseases, disorders, and conditions associated therewith.
Accordmgly, blocking one target kinase may not be clinically sufficient because there are multiple target kinases that affect the progression of a condition, disease, or disorder. In addition, biocking one target kinase may not be clinically sufficient because redundant kinase-mediated pathways and alternative onco geme or inflammatory mechanisms may 13 compensate for the blocked target kinase. Moreover, the use of a single agent can also increase the chances that resistance to that agent will develop.
Cardiovascular disease accounts for nearly one quarter of total annual deaths worldwide. Vascular disorders such as atherosclerosis and restenosis result from dysregulated growth of the vessel walls and the restriction of blood flow io vital organs.
Various kinase pathways, e.g. JNK, are activaied by atherogenic stimuli and regulated through local cytokine and growth factor production in vascular cells (Yang et al, Immunity 9:575, 1998). Ischemia and ischemia coupled with reperfusion in the heart, kidney or brain result in cell death and scar formation, which can ultimately lead to congestive heart failure, renal failure or cerebral dysfumection. In organ transplantation, reperfusion of previously ischemic donor organs results in acute leukocyte-mediated tissue inj ury and delay of graft function. Ischemia and reperfusion pathways are mediated by various kinases. For example, the JNK. pathway has been linked to leukocyie-mediated tissue damage (Li et al., Mol. Cell,
Biol. 16:3947-5954, 1996), Finally, enhanced apoptosis in cardiac tissues has also been linked to kinase activity (Pombo et al., J. Biol Chem. 269:26546-26551, 1994).

Claims (1)

  1. What is claimed is
    1. A compound of formula (1) A b, es Ref? TN Fz 3 (1, or & pharmaceutically acceptable salt thereof, wherein Ag (Fila Risky (Fale (Rise (Roh N: Tg [Fy j ES nN 3 MEN
    ‘ . nN < . N Bd / Ww / 5h Noy , Now 3 {e ' {3 ; 4 ’ a) (ii) (iif) (iv) (v) SF Ral (Rui (Fila a Tn N-I, Nr SIA EE Na 7 & 3 Lt 3 LP 5 (vi) (vif) (viii) (ix) Rds (Riko {Ryda (Re hh pn N-lq N-+ LYE NG Ee! | 5h 0 ; lg ; CN ; , (x) (xi) (xii) (xiii) (Rave {Rav (Ri) {Ryviie . CO Toor Tes 57ON Soy Ny : Sy ; {xiv} (xv) {xvi} {xvii} (Ryviiide: (Reis N (Rue {Ryda ST CH TH Su LL , Ne ) SE 3 SN 5 {xviii {xix} {xx} {xxi} ull i
    WN . 0 : [3 o [3+ 0 8 (xxi) {axif) R; is hydrogen, alkyl, aryl, heterocycle, heteroaryl, R,RyN-, RRgN-C({O}- or
    ReRaN-8(0),-; R218 hydrogen, alkyl, alkoxycarbonyl, alkylcarbonyl, arvicarbonyl, heterocyelecarbonyl or ReRN-alkyl~C(0)-; Rais alkyl, alkoxy, aryl, cyano, cycloalicyl, halogen, haloalkyl, heteroaryl, nitro, or RoRpN- Ra 1s alkyl, alkoxvalicyt, aryl, cycloalkyl, heteroaryl, heterocycle, heterocyclealkyl, EjRiN- or R;RiN-alkyl-; Rs is allcyl, aryl, or heteroaryl; Re 1s aticy!, alkoxyalkyl, RiRyN-alkeyl-, aryl, cycloalkyl or heteroaryl; R= is alieyl, ary] or heteroaryl; Ra and Ry, are each independently hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, R~C(O)-, or Rs-3{0),-; Rc and Ry are each independently hydrogen, alicyl or heteroaryl; Re and Ry are each independently hydrogen, alkyl, arylalkyl, heteroarylalkyl, Rs-C(O)-, or R5-8(0)-; Rg and R; are each independently hydrogen, alicyl, or alkylcarbonyl; Rj and Ry, are each mdependently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heterocycle; Ri, Rit, Rist, Riv, Ry, Rui Ris, Ruin, Ris, Ra, Ruse Riis Riis, Ricivs Rigy, Ricuiys Riu Ravi, Ruins Rix, Rui, Riis, and Roi are each mdependently alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyi, aryl, arylalkyl, aryl(hydroxy)aliyl, aryloxyalkyl, arylcarbonyl, arylhioalkyl, carboxy, carboxyalkyl, cyanoalkyi, cycloalkyl, eyeloalicylalkyl, cycloalkylearbonyl, halogen, heteroaryl, heteroarylalky!, heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, trialkyisitylalkyl, HONC(O alkyl, Z,ZuN-. ZoZoNalkyi, ZZNC(O)- or LoZNS{O)p- wherein Ry, R,,. Rai, and Ruy; may oceur at any open valence on compounds (xiv), (xv}, (xvi) or (xvii); Za and Zy are each independently hydrogen, alkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, HaNC(O)-, HaNalkylC(O)-, HoNC(O)-alkyl, dialkyINC(O)- or dialkyINC(O}-alkyl-; 3g Ze and Zg are each independently hydrogen, allyl, alkoxyalkyl, aryl, arylalkyl, aryl(hydroxyjalkyl, cycloalkyl, cycloalkylalkyl, heteroary] alkyl, heterocycle. heterocyclealkyl, hydroxyalkyl, HyNC( O)-alkyl-, dialkyINC(O)-alkyt-, dialkyIN-alkyl-, or
    CHZ.7;, Ze 15 aryl or heteroaryl;
    Zr 1s heteroarylalkyl, heteracyclealkyl, or Za ZoNwalkyl-; mis @, 1or2; swwlorl: bis, 1, or; cis, 1, 2 or 3: and dis 0, 1,2, 3or4. 2 The compound according to claim 1, wherein Acts (in), (iit), (Gv). (vii), (x0, (xiv), (xv), Covi), (xvii), (vit), (xix), xx), Cox) (xxaid, 16 or (xxiii).
    3. The compound according to claim 2, wherein A ig (11) i) No (il); Riis hydrogen, aryl. heteroaryl, heterocycle, R,ReN-, or ReRgN-C(O)-; Ry is hydrogen, alkoxycarbonyl, heterocyclecarbonyl, alicylcarbonyl, or ReReN-alkyl-C(0)-; Ra 1s alkyl, alkoxyalkyl, aryl, cycloalkyl, heterocycle, heterocyclealkyl, RiRyN- or RjRyN-alkyi-; Rs 1s alkyl, aryl or heteroaryl:
    R. and Ry, are cach independently hydrogen, arylalicyl, cycloalkylalkyl, Re-C(O)- or Rs-S(0),-;
    R. and Ry are each independently hydrogen or heteroaryl;
    R. and Ry are each independently hydrogen or alkyl; R; and Ry are each independently hydrogen, alkyl, aryl, cycloalkyl, or heterocycle; Rii 1s alkyl, alkoxyalkyl, alkoxycarbonyl, aryl, arylalkyl, aryl(hydroxy)alkyl, aryloxyalkyl, arylcarbonyl, alkoxycarbanylalkyl. arylthioalkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylearbonyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyciecarbonyl, hydroxyalkyl, malkylsilylalkyl, Z,Z.N-, ZoZpNallyl- or Z.Z NC(O)- Z, and Z,, are each independently hydrogen, alkyl or HyNalkylC(O)-;
    Zc and Zg are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclealicyl, hydroxvalky! or dialkyIN- ably; mis 0; and bis, I,0r2.
    4. The compound according to claim 3, wherein R; is hydrogen, heterocycle, RR N-, or RR gN-C(O Rj 1s hydrogen, alkoxycarbonyl or RR N-alkyi-Cr Oy, Ry 1s alkyl, alkoxyalkyl, aryl, cycloalkyl, heterocyele. heterocyclealkyl, RiRyN- or RR N-alkyl-; Rs 1s alkyl, aryl or heteroaryl; R, and Ry, are each independently hydrogen, arylalkyl, cycloalkytalkyl, R4-C(O) or Rs-S(0)p- R; and Ry, are each independently hydrogen, alkyl, aryl cycloalkyl! or heterocycle: Ri; is alkyl, alkoxyallyl, alkoxycarbonylalky, aryl, arylalkyl, aryloxyalkyl, arylcarbonyl, arylthioalkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, halogen, heteroaryl, heteroarylalkyl, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, trialkylsitylallkyl, ZoLoNalkyl-, or Z,Z4NC(O)- Zand Zy, are each independently hydrogen or alkyl; Ze and Z4 are each independently hydrogen, alkyl, alkoxyalkyl, aryl. arylalkyl, cycloalkylalicyl or heterocyclealkyl; m is 8; and bish, I or2. 23
    5. The method according to claim 3, wherein Ry 18 hydrogen or R,RuN-; Rs is hydrogen; Ra 1s alkyl, alkoxyalkyl or aryl; Rs 1s alkyl or arvi;
    R. and Ry are each independently hydrogen, arylalkyl, Ry4-C(O)- or Rs-S(0),m: Rij is alleyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl or halogen; bis 1 or2; and mis 0.
    6. The method according to claim 3, wherein Ri is hydrogen, aryl, heteroaryl or R,RyN-, wherein the heteroaryl is triazole substituted with arylalkyl; Ry is alkoxyalkyl, alkyl, aryl, or RR N-; Es 1s alkyl, aryl, or heteroaryl;
    R. and Ry, are each independently hydrogen, arylalkyl, Ra-C(O)-, or Rs-85(0h R; and Ry are alkyl; Ri; is allyl, alkoxyalkyl, aryl, arylalkyl, aryl(hydroxyalkyl, aryloxyalkyl, aryicarbonyl, arylthicalicyl, carboxy, cycloalkyl, cycioallcylalicy], cycloalkylcarbonvl, halogen, heteroaryl, heteroarylatkyi, heterocyciealioyl, heterocyclecarbonyl, hydroxyaliyl, ZaZpNalleyl or LoZ NCO); Zo and Zy, are each independently hydrogen or HyNaliy!-C(O)-;
    Z. and Zy are each independently hydrogen, alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, or heterocyelealkyl; bis [ or 2; and mis 0.
    7. The compound according to claim 2. wherein A is (iif) a [on (111), R; 15 hydrogen or R,R,N-; Ry is hydrogen; R, and Ry, are each hydrogen; Ry; 1s arylallcyl; mis {; and cis l.
    8. The compound according to claim 2, wherein A is (iii) - (fide [Re N
    (nt); Rj is hydrogen or R\RpN-: Ry 1s hydrogen, Rg is RyRy M-alkyl-; Ry and Ry, are each independently hvdrogen, or Fa-C(O)-; R; and R;, are alkyl: Riii is alkoxycarbonylalkyl, alkyl, arylalkyl, cyanoalkyl, heterocyclealkyl, or HyNC(O)-alkyl-; cis 0, Vor 2; and 16 m is 0.
    9. The compound according to claim 2, wherein A is (iv) (Riv) & N (iv); Ry is hydrogen or R.RyN-: R; is hydrogen;
    R. and R,, are each hydrogen; Riv 1s alkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl or ZaZpNalleyl or ZZgNS(0)z-; Zq and Zp, are each independently hydrogen or alkyl; Ze and Zg are cach alkyl; cis 0, or 1; and mis 0,
    10. The compound according to claim 2, wherein A is (vil) (ie LR (vil); Ry 1s hydrogen,~NR,R,, or alkyl; Ry 18 hydrogen;
    R. and Ry are each hydrogen; Rui 18 alkyl, alkoxycarbonyl, aryl, arylalkyl, cycloalkyl, heterocyelealkyl, heterocyclecarbonyl, hydroxyalkyl or Z,Z4NC( Oh Ze and Z; are each mdependently hydrogen, alkyl, alkoxyalkyl, aryl, arylaficv], aryi(hydroxy alkyl, cycloalkyl, cycloalkylalkyl, heteroarvialioyt, heterocycle, heterocyciealkyl, hydroxyalkyl, er CHZ.Zy: Ze 18 aryl or heteroaryl; Zr 18 heteroarvialiyl, heterocyelealkyl, or Ly doN-alkyi-: bis 1: and mis
    I. The compound according to claim 2, wherein A is (vii) igs Lx (vii) R; is hydrogen, alkyl. or R,RyN-: Rj is hydrogen;
    R. and Ry, are each hydrogen; Ry; 18 alkyl, alkoxycarbonyl, arylalkyl, cycloalkyl, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl or Ze ZgNC(O)-; Ze and Zy are cach independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl(hydroxyalkyl, cycloalkyl, heteroarylalleyl, heterocycicatkyl or hydroxyalkyl; bis 1; and mis 0.
    12. The method according to claim 2, wherein A is {vii) (Reidy {x 0 (vii): Ry is hydrogen or RaRyN-; Ry 1s hydrogen;
    Rq and Ry, are hydrogen; Rui is alkyl or arylalkyl; bis I; and mig G
    13. The compound according to claim 2, wherein A is (x) (Ryn Ey iS xh Ry 1s hydrogen; Ry: is hydrogen; Ry is alkyl, aryl or Z,7,N-; Z, and Z,, are cach independently hydrogen, alkyl, aryl or arylalkyl; bis I or 2; and mis 0.
    14. The compound according to claim 2, wherein A is (xiv) The ES Ss N (avy; Rj is hydrogen; Ry is hydrogen; Riv 18 ZaZiN-; Zy and 7, are each independently hydrogen or cycioalloyl; cis 1; and mis §,
    15. The compound according to claim 2, wherein A is (xv) Tey “ SEN (xv);
    R) 18 hydrogen or RaRpN-; Ry 1s hydrogen; Ra and Ry, are hydrogen; Fo 18 2,70 N=: Za and Zy, are each mndependently hydrogen, allkoxycarbonylalleyl, aryl, arylalkyl or cycloalkyl; dig 0 or 1; and mis @, 0 ia The compound according to claim 2, wherein A is (xvi) ole EN “5 Neg Ay (xvi); Ry is hydrogen; Ry is hydrogen; Ryvi 18 Z,ZuN-; Za and Zy, are cach independently hydrogen or cycloalkyl; dis 1; and mis §,
    17. The compound according to claim 2. wherein A is (xvii) TE oN Ay (xvii); Rj is hydrogen; R: is hydrogen; Riv 18 Z,ZuN- or aryl; Zy and 7, are each independently hydrogen, alkyl, alkoxycarbonylalleyl, aryl, arylalkyl, cycloalicyl, or HoNC(G)-alkyl; dis 0 or 1; and mis (0.
    18. The compound according to claim 2, wherein A is {xviii} {Ryviile ST Nw {xvii}; Ry 1s RaRpN-; Ro is hydrogen; R, and Ry are each hydrogen; cis 0. and mis 0.
    19. The compound according fe claim 2, wherein A ig (xix) (Rix) Br “NP (xix); R; is RyRyN-; R; is hydrogen;
    R. and Ry, are each hydrogen; c 18 {: and mis ¢.
    20. The compound according to claim 2, wherein A is (xx) {Rax)e EE nN (xx); Rj 18 RaRpN-; Ry 1s hydrogen; Ra is RiRyN-alkyi-; 23 R. and Ry, are each independently hydrogen or Ra-C(O)-; R; and Ry are independently alkyi; Ry 18 Z.ZpM- or heterocycle; Za and 7 are each independently hydrogen or alley!
    cisfor 1; and mis 0. 21 The compound according to claim 2, wherein A is ( XXi) (Roath CH nN (xx1); By is RyRy N=; Rs 15 hydrogen; Ry and R;, are each hydrogen; Rui 15 alkoxy; dis I: and mig §. 22, The compound according to claim 2, wherein ALS (xxii) (Rie Cx 0 (xxii); Rj is RyRyuN-; R; is hydrogen; Ry is RjRyN-atkyl-;
    R. and Ry, are each independently hydrogen or R4-C{O)-; Rj and Ry, are each independently alkyl; cis 0; and mis ¢.
    23. The compound according to claim 2, wherein A is (xxiii) hie Rn {3 (xxiily; Ry 1s RyReN-; Ry is hydrogen;
    R. and Ry, are each hydrogen; cis (0; and m is 0. 5024 The compound of claim 1, that is 5-{1-benzyl-1H-1,2.3-triazol-5-y1}-1 H-indazole compound with 3-(1-benzyl-1H-
    1.2 3-triazol-4-yl}-1H-indazole; 5-(1H-1,2,3-trtazol-5-y1)- 1 H-indazole: 5-(1-benzyl-1H-1,2,3-triazol-4-vI)-1 Hoindazole: 5-01-{2-methylbenzyl}-1H-1 2, 3-triazol-4-yi}-1H-indazole; 5-[1-(3-methylbenzyl)-1H-1,2,3-triazol-4-y1]-1 H-mdazole, 3-{1-(4-methylbenzyl)-1H-1.2 3-triazol-4-yl}- 1 H-indazole: 5-[1-(3-methoxybenzyl)- 1H-1,2,3-triazol-4-y1]-1 H-indazole; 5-f1-(2-fluorobenzyl)-1H-1 .2,3-triazol-4-y1}-1H-indazole; 13 5-[1-(3-flucrobenzyl)-1H-1,2,3-triazol-4-y1)-1 H-indazole; 5-[1-(4-fluorobenzyl}-1H-1 ,2,3-riazol-4-y1}-1H-indazole; 5-[1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-y11-1H-in dazole; >-{1-{3-chlorobenzyl)-1H-1 .2.3-tr1azol-4-y1}-1H-indazole: 5-[1-(4-chiorobenzyh)-1H-1 ,2.3-triazol-4-y1]-1H-indazole, 5-[1-(2-bromobenzyl)-1H-1 »2.3-triazol-4-y1}-1H-indazole; S-1+(2-nitrobenzyl)-1H-1,2,3-tr1 azol-4-yl]-1H-indazole; 5-[1-(3-nitrobenzyl)-1H-1.2 3-triazol-4-y]]-1 H-indazole; 3-[1-(4-nitrobenzyl)-1H-1.2 3-triazol-4-y[]-1 H-indazole; 2-{[4-(1H-indazol-5-y1)-1H-1.2 3-triazol-1 -ylimethyl} benzonitrile; 3-{{4-(1H~ndazol-5-y1)-1H-1,2, 3-triazol-1 -ytimethyl} benzonitrile; 4-{[4-(1H-indazol-5-y1}-1H-1.2.3-triazol-1 -ylimethyl} benzonitrile; 5-{1-[2-(trifluoromethylbenzyl}-1 H-1 2 3-triazol-4-yl}- 1H-indazole; 5-{1-[3~(irifluoromethyh)benzyl]-1H-1 12, 3-triazol-4-yl}-1H-indazole; 5- {1 4-(trifluoromethyl)benzy]]-1H-1 .2,3-triazol-4-yl}~1H-indazole: 5-{1-[3-{trifluoromethoxyibenzyl]-1H-1 .2.3-tr1azol-4-yl}~1H-indazole; 5-{1-{4-(mifluoromethoxy)benzyll-1H- -2.3-triazol-4~y1}-1H-indazole; S-[I~{4-tert-butylbenzyl)-1H-1 ,2.3-triazol-4-y1}-1H-indazole; methyl 3-{{4-(1H-indazol-5-yI}-1H-1.2.3-triazol-1 -vimethyl} benzoate; methyl 4- {[4-(1H-indazol-5-y-1H-1.2, 3-triazol-1 -yljmethyi benzoate;
    5-[1-(2 A-dimethylbenzyl)-1H-1 .2.3-triazol-4-yl1]- 1H-indazole; 5-[1-(3,5-dimethylbenzyl}-1H-1 v2 3-triazol-4-y1]- 1 H-indazole; 5-11-(2 3-dichlorobenzy)-1H-1,2.3-trj azol-4-yl}-1H-indazole: 5el1-{2 d-dichlorobenzyl}- 1-1 2, 3-triazol-d-yI]- 1 H-indazole: 5-[1-{2,5-dichlorobenzy])-1H-1 2.3-triazol-4-yii-1 H-indazole; 5-[1-(3.5-dichlorobenzyi}-1H-] .2.3-triazol-4-y1]- 1 H-indazole;
    5-1-2. 4-bis{trifluoromethylbenzyl - 1H-1.2, 3-11 azol-4-yl}-1H-indazole; Necyclohexyl-6-(1 H-indazol-5-yl)imidazo[2,1-b]{1 JA]thiazel-5-amine; Necyclohexyi-2(1 B-indazol-5-ylyimidazo{1.2-a|pyridin-3-amine:
    i0 N-cyclohexyl-2-1H-indazol-5-ylyimidazo[ 1 2-afpyrazin-3-amine; 5-[1-benzyl-4-(4-fluorophenyl)-1 H-imidazel-5-y1]-1H-indazole; N-{3-[4-(4-flucropheny)-5-( 1 H-indazol-5 -yh-1H-tmidazol-1-yljpropyl -N N-
    dimethylamine;
    N-cyciohexyl-2-( 1 H-indazol-3 -ylyimidazof | ,2-a|pyrimidin-3-amine;
    5-[4-(4-fluorophenyl}-1-(1-pheny] ethyl)-1H-imidazol-5-y1}-1H-indazole: 2-(1H-indazol-5-y1)-N-isopropylimidazo| 1 2-a]pyrimidin-3-amine; 4-{ 1H-mdazol-5-y[}-N-phenyl- ,3-thiazol-2-amine; 5-(2-methyl-1,3-thiazol-4-yl)-1H-indazole; N-ethyl-4-(1H-indazol-3-y1)-1,3-thiazol-2-amine;
    N-benzyl-4-(1H-indazol-5-y1)- 1 S-thiazol-2-amine; 4-(1H-indazol-5-yl)-1,3-thiazol-2-amine: 4-(1H-indazol-5-y1)-N-(2-phenylethyl}-1 J-thiazol-2-amine;
    N-benzyl-2-(1 H-indazol-5-yhimidazo[1,2-a]pyrimidin-2 -amine; N-butyl-2-{TH-indazo!-5-yDimidazo[ 1 2-alpyrimidin-2-amine;
    N-(4-chloropheny!}-2-(1H-indazol-5 -yDimidazo[1,2-alpyrimidin-3-amine: 2-1 H-indazol-5-y1}-N-(4-methoxypheny!imidazof 1,2-alpyrimidin-3-amine; 2-(1H-indazol-5-yl}imidazo[ 1,2-a pyrimidine; methyl N-[2-(1H-indazol-3 -yi)imidazo[1,2-aJpyridin-3-yi] glycinate;
    N-benzyl-2-(1H-indazol-5-y] Jyimidazo[1,2-ajpyridin-3-amine;
    N-(4-chjoropheny!)-2-(1H-in dazol-5-ylyimidazo[ 1,2-a]pyridin-3-amine:
    2-{1 H-indazol-5-y1)-N-(4-methoxyphenyl)imidazo[ 1.2-a]pyridin-3-amine; tert-butyl 4-[4-(4-flusropheny!}-5-(1 H-indazo!-5-y1)-1H-imidazol- | -vi]piperidine-1- carboxylate; 3,5-bis(1-benzyl-1H-1,2 3-riazol-4-yl}-1 H-indazole;
    5-(1-benzyl-1H-1 :2,3~triazol-4-y1)-3-phenyl- 1H-mdazole;
    S-{1-benzyl-1H-1 2, 3-triazoi-d-yi)-1 H-indazol-3-amine;
    5-(1-benzyl-1H-1 2, d-triazol-4-y1-1-[{ I -meth yipiperidin-4-ylicarbonylj-1H-indazol 3-amine;
    Nu[5-(I-benzyl-1H-1 2.3-triazol-4-yi)-1 H-mdazol-3-vi1-2 -methoxyacetamide; N51 -benzyl-1H-1.2,3-triazo]-4-yl)- LH-indazol-3-y1]-N, NV dimethyiglycinamide: IN-{5-(1-benzyl-1H-1.2 3-1] azol-4-yl)-1 H-indazol-3-ylbutanamide: 5-[4-{4-fluorophenyl)-1 -prperidin-4-yi-1H-imidazol-5 ~yl}-1H-indazole;
    5 {4-{4-fluorophenyl)-1-[2-( 1 -methyipyrrolidin.? ~yhethyl]- H-imidazol-5-v{1-1H- indazole; 5-{4-(4-fluorophenyl)-1 | 3-(4-methylpiperazin-] ~yhpropyl}-1 H-imidazol-5-y13-1H- indazoie; ethyl 5-(1H-indazol-5 -yhisoxazole-3-carboxylate; 5-{1H-indazol-5 ~y1}-N-methylisoxazoie-3-carboxami de; 3-(3-benzylisoxazol-5-yl)-1H-indazole; N-[5-(1-benzyl-1H-1,2,3-4ri azol-4-yl)-1 H-indazo!-3-yljbenzamide; 5-(3-propylisoxazol-5-y1)-1 H-indazole; N-benzyl-4-(1H -indazol-5-y1}-5-phenyl-1,3-thi azol-2-amine; 4-(1H-indazol-5-yl)-N,5-diph enyl-1,3-thiazol-2-amine: 5-(1-benzyl-5-cyclopropyl-1H-1 ,2.3-triazol-4-y1}-1H-indazole: 5-(1-benzyl-4-cyclopropyl-1H-1,2, 3tri azol-5-yI}-1H-indazole; 2-(1 H-indazol-5-yi}-3-phenyiimidazof I, Z-a]pyrimidine; 5-1 -(tetrahydro-2H-pyran-4-ylmethyl}- IH-1,2,3-triazol-4-yl}-1 H-indazole; 5-{3-(piperidin-1-ylcarbonyl)isoxazol-5 ~yl}-1H-indazole; 5-(1H-indazol-5-y1j-N-phenylisoxazole-3-carbox amide; N-cyclohexyl-5-(1H-indazol-5 -ylisoxazole-3 carboxamide; 5-[3-(piperidin-1 -ylmethyl}isoxazol-5-y1]-1 H-indazole; {5-(1H-indazol-5-yhisoxazol -3-ylimethanol; 5-{1H-indazol-5 -¥1)-N-(2-methoxyethyl)isoxazol e-3-carboxamide; 5-{1-benzyl-3-phenyl-111-1,2 3-ri azol-4-y1)-1H-indazole; S-(4-benzyl-1H-1,2.3-triazol-1 -yl}-1H-indazole: 5-(1-benzyl-5-cyclopropyl-1H-1 2,3~tr1azol-4-y1}-1H-in dazol-3-amine: 5-(1-benzyl-4-cyclopropyl-1H-1,2.3-iri azol-5-yl)~1H-indazol-3-aminc; 5-(3-1sobutylisoxazol-5-yl)-] H-indazol-3-amine;
    5-(3-benzylisoxazol-5-y1)-1H -indazol-3-amine; N-{2-[4-(4-fluorophenyl)-5-( 1 H-indazol-5-y1)-1 H-imidazol-1 -ylethyl}-N N- dimethylamine; S-l4-(4-fluoropheny))-1-(3 -morpholin-4-yipropyi- 1 H-imi dazel-5-y11-1H-indazole; 5-[4-(4-fiuorophenyl)-1-(3-pyrrolidin-1 ~ylpropyl}-1H-imidazol-5-yI]-1 H-indazole, 5-{4-(4-fluorophenyl)-1 ~|2-(4-methylpiperidin- | -ybethyl}-1H-imidazol-5-y1}-1 H- indazole: 5-1-1 -benzylpiperidin-4-yl}-4-(4-fluoropheny }1H-imidazol-3-y1]-1H-indazole: 5] 4-{4-fluorophenyl)-1-(2 ~morpholin-4-viethvl}-1 H-imidazol ~5-vi}-1H-indazole; HO S-[1-(T-benzylpyrrolidin.2 -ylj-d-(4-fluorophenyl)-1 H-imidazoi-5-yi}-1H-indazoie, 2-{4-[4-(4-fluorophenyl}-5-( H-indazol-5-yI}-1H-imidazol- 1 -yl]piperidin-1-yi}-2- oxocthanol; 5-(1-benzyi-5-phenyl-1H-1 2, 3-triazot-d-yl)-1 H-indazol-3-amine; 2-[1-(1H-indazol-5-y)-1H-1 2, 3-triazol-4-ylipropan-2-ol; S-{d-(methoxymethyl}-1H-1.2.3-triazol-1 -yl}-1H-indazole; 1-[1-(1H-indazol-3-yI}-1H-1 +2, 3-triazol-4-yi}-1-phenylethanol; S-(4-propyl-1H-1,2,3-triazol-1-y1)-1H-indazole; I-[1-(1H-indazol-5-y1)-1¥-1 +2. 3-triazol-4-ylipropan-2-ol; 3-[1-(1H-indazol-5-yi}-1H-1 .2,3-triazol-4-yl]propan-1-of; 1-{[1 { IH-indazol-5-y1)-1H-1,2.34riazo -4-yilmethyl}-1H-1,2.3 -benzotriazole; 5-{4-{(phenylthioymethyl]-1H-1.2 3-triazol-1 -yl}-1H-indazole; 5-(4-cyclopropyl-1H-1,2.3-triazol-1 ~y)-1H-~indazole; 5-{4-(2-phenylethyl)-1H-1,2,3-triazol-1 -yl}-1H-indazole; 5-[4-(cyclobexylmethyD-1T1-1.2 3-triazol-1 ~yl]-1H-ndazole; 5-(4-cyclopentyl-1H-1.2,3-triazo0l-1 -yh-1H-indazole; 1-[}-{1H-indazol-5-y[)-1H-1 »2,3-triazol-4-yl]cyclohexanoc!: 5-{4-(phenoxymethyl}-1H-1,2.3-triazol-1 -ylj-1H-indazole; 5-{4-[(1,1 -dioxidothiomorphotin-4-ylmethyl]-1H-1,2 3-triazol-1 -yl}-1H-indazole; 5-14-(3-phenylpropyi}-1H-1,2,3-triazoi-1 -yl}j-1H-indazole; [1-benzyl-4-(111-indazol-3-y1)-1H-1.2 3-triazol -5-yl(phenyDmethanone:
    N.N-diethyi-N-{[1-(1H-indazol-3-y])-1H-1 »2.3-triazol-4-yljmethyl famine; ethyl N-I2-(1H-indazol-3-yl)imi dazo[1,2-alpyrimid n-3-yl]-beta-ataninate; 5-(1-benzyl-5-methyl-1H-1.2,3-triazol-4-y1)- 1 H-indazole: S-(1-benzyl-3-methyl-1H-1.2,3 -triazol-4-yl}-1H-indazol-3-amine;
    N- [2-(1H-indazol-5-y1)imidazo[ 1 2-a}pyrimidin-3-yl]-B-alaninamide;
    5-(1-benzyl-5-iodo-11-1.2.3 ~tniazol-4-y1)-1H-indazol-3-amine:
    Ne {3-[4-(G-aming-1 H-indazol-5-y1)-1-benzyl- 198-12 3-triazal-5 -yi]phenyl} -Mw(3- methyiphenyl ures;
    S-(1H-mdazol-3-y1 J-N-(Z-1sopropoxyethyDisoxazole-3-carboxamide: 3-[3-(morpholin-4-ylearbonyl)isoxazel-5 -yl}-1H~indazole; 5-{1H-mndazo}-5-y1)-N-(3 ~morpholin-4-yIpropylisoxazole-3-carboxamide; N-[2-(1H ~imidazol-4-yl)ethyl}-5+(1H-i ndazol-5-yi)isoxazol e-J-carboxamide; (R)-1-{[5<(1B-indazol-3-yDisoxazol-3 ~vHearbonyl i piperidin-3-cl;
    19 1-{I5-(1H-indazol-3 -yijsoxazol-3-yljcarbonyl ipiperidine-3-carboxamide: 2-[2~(4-{[5-(1H-indazol-5-y])isoxazol-3 ~yljcarbonyl}piperazin-1 -yhethoxylethanol; 3-{3-{(4-methyl-1,4-diazepan-1 -yDearbonyljisoxazol-5-y1t-11 -indazole; N-(3-hydroxypropyl)-5-(1 H-mdazol-5-yljisoxazole-3-carboxamide; N-[(1R}-2-hydroxy-1 -phenylethyl}-5-(1H-indazol-5 -yDisoxazole-3-carboxamide:
    N-[3-(1H-tmidazol-1-yl)propyi}-5-(1 H-mdazol-5-ylisoxazole-3 -carboxamide; 5-{1H-indazoi-5-y1}-N-I3 ~(2-oxopyrrolidin-1 -yDpropyllisoxazole-3-carboxamide:
    N-{ 2-[4-(aminosulfonyliphenyljethyl }-5-(1H-indazol-5~-yDisoxazol e-3-carboxamide; [ 1-benzyl-4-(1H-indazol-5-y1)-1H-1.2,3-tri azoi-5-y1j( 3-chlorophenylymethanone; [1-benzyl-4-(1H-indazol-5-y1)- 1 H-1 23-11 azol-3-yl|(cyclopropyhmethanone: S-[5-cyclopropyi-1 ~(tetrahydro-2H-pyran-4-ylmethy!}- 1H-1,2.3-triazol4-y1j-1H- indazale; N-{[1 -benzyl-4-(1H-indazol-5-y1)-1 H-1 2 3-triazol-5-yijmethyl} glycinamide ; (4-fluoropheny!}[4-(1H-indazol-5 -yl)-1-{teirahydro-2H -pyran-4-yimethyl}-1H-1,2 3- triazol-5-yl]methanone; 23 (4-chlorophenyl)l4-(1H-indazol-5 -yl)~1 -(tetrabydro-2H-pyran-4-ylmethyl)- iH-1,2,3- triazol-3-yllmethanone: (3-chlorophenyl)[4-( 1 H-indazol-5-y1)-1 -(tetrahydro-2H-pyran-4-yimethyl)-1 H-1,2.3- triazol-5-yiimethanone; (2-chiorophenyl}{4-(1H-indazol-5-y1}-1 ~(tetrahydro-2H -pyran-4-vimethy-1H-1.2.13- triazol-5-yl]methanone; cyclopentyl[4-(1H-indazol-5-yi}-1 ~(tetrahydro-2H-pyran -4-ylmethyl}-1H-1,2,3- triazol-5-yijmethanone; I-benzyl-4-(1H-indazo]-5-y1)-1H-1 2, 3~triazole-5-carboxylic acid;
    5-{5~(4-fluorophenyl)-] -[4-{trifluoromethy!)benzyi]-1 H-1,2,3-triazol-4-y1} -1H- indazol-3-amine; 5-[1-benzyl-5-(4-fluoroph enyl}-1H-1,7 3-tri azol-d-yl]-1H-indazol-3-amine: [4-(1H-indazol-5-y]}-1 ~{tetrahydro-ZH-pyran-4-yim ethyl)-1H-1,2,3-triazol-5- yj(tetrahydro-2H-pyran-4-ylmethanonc: 5-{1-benzyl-5-(2 -methylphenyly-1H-1.2 J3-triazol-4-yi]-1 H-indazole; 5-41 -benzyl-5-[(4-methylpiperazin- I-yDearbonyli-1H-1,2.3-tri azoi-d-yli-iH.
    Indazole; I-{[1-benzyl-4-(1 H-indazol-5-y13-1H-1 2.3 ~triazol-S-yijcarbonyl i pi peridin-4-ol; L-acetyl-5-[5-(4-fluoropheny!)- | -(tetrahydro-2H-pyran-4-yimeth yvh-1-1,2, 3-mriazol- 4-yl}-1H-indazole; i-benzyl-4-(1H-indazol-5 =yD-N.N-dimethyl-1H-1 2, 3~triazole-5-carbox amide: N, I-dibenzyl-4-(1 H-indazol-5-y1)-1H-1 :2,3-triazole-5-carboxamide; N-(Z2-hydroxy-2 -phenylethyl}-5-(1H-in dazol-5-yl)-N-methylisoxazole-3-carboxamide: N-[(18)-2-hydroxy-1 -phenyiethyll-5-(1 H-indazol-5-y!)isoxazole-3 ~carboxamide; N-benzyl-N-(2 -hydroxyethyl)-5-(1 H-indazol-3-yl)isoxazole-3-carboxamide: S-[1-benzyl-5-(2 -methylphenyi)-1H-1 :2.3-triazol-4-y1]-3-methyl-1H-indazole; 5-1 -benzyl-5-(2-methylphenyl)- 1H-1.2,3-triazol-4-y1]-1 H-indazeol-3-amine: 2-{2-11-(1 H-indazol-5-y[}-1H-1.2,3-tri azol-4-yilethyl!-1H-isoindole-1 S{2H)-dione: 5- {4-[(2,4-dichlorophenoxy)methyl}- 1 H-1 ,2.3-triazol-1-y1}-] H-indazole; 5- {4-{(2,6-dichlorophenoxy)methyl-1 H-1,2,3-triazol-1-y]}- 1 H-i ndazole; 3-[5~(4-fluorophenyl)-1 ~(tetrahydro-2H-pyran-4-ylmethyi)-1 H-1,2,3-triazol-4-y1}-1H- indazole; V-{[1-(1H-indazol-5-y1}-1F1-1.2.3tri azol-4-ylimethyl}-1H-indazole: 5-[1-benzyl-5-(piperidin-I -ylearbonyl)-1H-1 2, 3-triazol-4-yl}-1H-indazole; 5-[5-(2-methylphenyl)-] ~(tetrahydro-2H-pyran-4-ylmethyl)-1 H-1.2,3-triazol-4-y1]- 1H-indazole; 5-[5-(2-methylphenyl)-1 (tetrahydro-2H ~pyran-4-yvimethyl)-1H-1.2.3 -triazol-4-yl]- 1H-indazol-3-amine; 5-[1-benzyl-5-( morpholin-4-ylcarbonyl)- 1 H-} 2. 3-triazol-4-yi]-1 H-indazofie; 5-1 -benzy!-5-(4-methoxyphenyl)-1 H-1.2.3-triazol-4-y1]-1 H-iridazol-3 -amine; N-[(18)-1 -benzyl-2-hydroxyethyl]-5-(] H-indazol-S-yi}isoxazole-3-carbox amide; N-[(18.2R)-2-hydroxy-2,3-di hydro-1H-inden-] -yl]-5-(1H-indazol-5 -yl)isoxazole-3- carboxamide;
    5-f 3-{(3-phenylmorpholin-4-yl)carbonyljisoxazol-5-yl +-1H-indazole; N-benzyl-5-(1 H-indazol-5-yl)isoxazole-3-carbox amide: {(18)-2-{[5-(1 H-indazol-5 -yinsoxazol-3-yvilcarbonyl : -6.7-dimethoxy-1,2.3 4- tetraliydroisoquinolin-1-yl methanol; N-[{1R}-3-hydroxy-1 -phenylpropyl]-5-( 1H -indazol-5-yljisoxazole-3-carbox amide; Ne[(18}-3-hydroxy-1 -phenyipropyl}-5-(1 H-indazol-5-yDisoxazole-3-carboxami de: N-2,3-dibrydro-1H-inden-1 -yi-5-(15 -indazol-5-yl)isoxazole-3-carboxamide;
    N-2.3-dihvdro-1H-ind en-2-yi-5-(1H-indazol-5-y1}isoxazole-3-carbox amide; S-(1H-ndazol-5-yI}-N-(] -phenylpropyDisoxazole-3-carboxamide: iG 5-41 -benzyl-5-[3-(dimethylamino jphenyi]- 18-1.2 3-mriazol-4-yli-1H-indazol-3- amine; 5-{1 -benzyl-5-[4-(dimethylamino phenyl]- HEL-1.2, 3-triazol-4-y1} - | H-indazol-3- amine; N-{3-{4-(3-amino-1H -indazol-5-y1)-1-benzyl-1H-1.2.3-tri azol-5- yliphenyt} acetamide; N-{4-[4-(3-amino-] H-indazol-5-yl}-1-benzyl-1H-1.2,3-triazol-5- yllphenyl} acetamide; 3~{1-benzyl-5-[3-(1H-pyrazol-1 -yi phenyl j-1H-1,2,3-triazol-4-yl 1 H-indazol-3- amine; 3-[1-benzyl-5-(1-methyl-1H -pyrazol-4-y1y-1H-1,2 3 tri azol-4-yl]-1H-indazo!-3- amine; 3-[4-(3-amino- | H-indazol-5-yl)- -benzyl-1H-1,2,3-triazol-5-y1}-N -phenylbenzamide: 3-[4-(3-amino-1H-indazol-5-yl)-1 -benzyl-1H-1 2,3-triazol-5-y1]-N-benzylbenzamide: 5-[1-benzy!-5-(1-methyl-1 H-indol-5-y1}-1H-1.2.3 -triazol-d-y1}-1H-indazol-3-amine: S-[1-benzyl-5-(3-methoxyphenyl)-1H-1,2, 3-1 az0l-4-y1]-1H-indazol-3-amine; 5-[1-benzyl-3 ~(3-morpholin-4-ylphenyl)-1H-1 2, 3-triazol-4-y13-1H-indazol-3-am ine; 5-[3-(1 3-dihydro-2H-isoindol-2-ylcarbonylisoxazol- 5-v1 - iH-indazole; 5-{3-[(4-methyl-2-phenyipiperazin-1 -yhearbonyllisexazol-5-yl}-1 H-indazole; I-{[1-benzyl-4-(1H-indazol-5-y)-1H-1 »2,3-triazol-S-yl]carbonyl } piperidin-4-amine; N-[5-(1-benzyl-5-phenyl-1H-1 2.3-triazol-4-yl)-1 H-indazol-3-yl]benzamide: N-[5-(1-benzyl-5-phenyl-1H-1 2. 3-triazol-4-yh-1H -indazol-3-yiJbenzenesutfonamide: N-[5-(1-benzy!-5-phenyl-1H-1 :2,3-triazol-4y]}- 1H -indazol-3-y1]-N'~(4- methoxyphenylurea; N-{5-(1-benzyl-5-phenvl-1H-1,2. 3-triazol -4-y1)-1H-indazol-3-yiJbutanamide;
    N-[S-(1-benzyl-5-phenyi-1H-1 2,3-triazol-4-yl)-1 H-indazol-3-yI]-2- methylpropanamide; N-[5-(1-benzyl-5-phenyl-1H-1.2 3-triazol -4-yi}-1H-mdazol-3- ylleyclopropanecarboxamide: N-[1-benzoyi-5-(1 ~benzyl-S-cyclopropyi-1H-1,2 3-tri azol-4-y1}-1H-indazol-3- yllbenzamide; N-[5-{1-benzyl-5 ~cyclopropyl-1H-1,2 3-triazo} ~4-y1)-1H-indazo}-3-y1}-3- fluorobenzamide; N-[5-( 1-benzyi-5 -~cyclopropyi-1H-1.2 3~riazo Ldeyy-1H-indazol-2 -ylibenzamide; IN-benzyl-5-(1 -benzyl-3-cyclepropyl-1H -1,2,3-triazol-4-yi)-1H-indazol-3-amin e; N-{{1R}-1-benzy)-2 -hydroxyethyl}-3-(1H-indazol -5-yhisoxazole-3-carboxamide: 3-(1-benzyl-1H-pyrazol-4-y)- iB-indazole; N-{(1R}-3-hydroxy-} -phenylpropyl}-5-(3-methyi-1H-in dazol-3-yl)isoxazole-3- carboxamide;
    3-{4-(3-amino- 1 H-indazol-5 -yb-1-benzyl-1H-1 .2,3-triazol-5-ylphenol; 3-[4-(3-amino- 1 H-indazol-5-y)-1 -benzyl-1H-1,2 3-tri azol-5-yl]benzamide; 5-{1-benzyl-5-[4-( methylsulfonylphenyll-1H-1 2, 3-triazol-4-y1}-1H-indazo}-3-
    anne; N-[5-(1-benzyl-5-cyclopropyl-1H-1.2,3 ~triazol-4-yl)-1H-indazol-3-yl]-2- chlorobenzamide; N-{5-(1-benzyl-5-cyclopropyl-11-1,2.3 -triazol-4-v1)-1H-indazol-3 -yi-4- chlorobenzamide; N-{5-(1-benzyl-5-cyclopropyl-1H-1 .2,3-triazol-4-y1)-1H-indazol-3- vljethanesulfonamide: N-[53-(1-benzyl-5-cyciopropyl-1H-1 2 317i azol-4-v1)-1H-indazol-3- ylIbenzenesuifonamide; N-[5-(1-benzyl-3-cyclopropyl-1H-1 .2.3-triazol-4-v1-1H-indazol-3 -yl}-2- chlorobenzenesulfonamide; N-[5-(1-benzy!-5-cyclopropyl-1H-1 .2,3-triazol-4-y1)-1H-indazoi-3 -yl}-3- chlorobenzenesulfonamide: N-[5-(1-benzyl-3-cyciopropyl-1H-1.2.3 ~triazol-4-y1}-1H-indazol-3 -vl}-4- chlorobenzenesulfonamide; N-[5-(1-benzyl-5-cyclopropyl-1H-1 san 3-triazol-4-y1i-1H-indazoi-3 ~yi}-2,5- dimethylfuran-3-sulfonamide:
    5-(1-benzyl-5-cyclopropyi-1H-1 ,2,3-triazol-4-y1)-N-(2~chlorobenzyl}- 1H-indazol-3- amine;
    5-{1-benzyl-5-cyclopropyi-1Fi-1 2 3-triazo dey 1)-N-(3 ~chlerobenzyl)-1H-indazol-3- BITHTIC,
    N-[5-(1-benzyl-5-cyelopropyi-1H-1 23-triazol-4-yi)-1 Heindazol-3-yl}-3-
    chlorobenzamide;
    N-[5-(T-benzyl-5-cyclopropyl-1H-1,2.3 -triezol-4-yl)-1H-indazol-3-y1}-2-furamide;
    5+{1-benzyl-5-cyclopropyi-1H-1 2, 3-triazol-d-yl)-Noethyl-1H-indazol-3-amine:
    5-{ I-benzyi-5-cyclopropyl-11-1.2. 311 azol-d-yl}-N-(4-chiorobenzy 1 H-indazol-3-
    amine; 5-(1-benzyl-S-cyclopropyl-1H-1.2.3-1ri azol-4-yl}-N-(3-furylmetnyl)- 1 H-indazoi-3-
    ang; N-[5-(1-benzyl-S-cyclopropyl-1H-1,2,3-tri azol-4-y1}-1H-indazol-3 =y1]-N'-[ 5-methyl- 2-(trifluoromethyl)-3-furylJurea;
    N-[5-(I-benzyl-3-cyclopropyi-1H-1.2.3 -triazol-4-yl}-1H-~indazol-3-y1]-3-furamide: 5-( 1H-indazol-5-y1}-N-[(18)-1 -phenylpropyllisoxazole-3-carboxamide: 5+(1d-mdazol-5-y1)-N-[(1R)}-1 -phenylpropyllisoxazole-3-carbox amide; 5-(1-benzyl-1H-pyrazol-4-y13-1H-indazol-3-amine: 1-benzyl-4-( 1H-indazol-3 -Y1-N-[(28)-tetrahydrofuran-2-ylmethyl]- 1H-1.2 3-triazole-
    S-carboxamide;
    I-benzy!-4-(1H-indazol-5-y[}-N( 2-tsopropoxyethyl)-1H-1.2 3-triazole-5- carboxamide; I-benzy!-4-(1H-indazol-5 -YD)-N-[(2R )-tetrahydrofuran-2-yimethyl]- 1H-1,2,3-triazole- S-carboxamide; I-benzyl-d-(1 H-indazol-5-yl)-N-(tetrahydrofuran-3-ylmethvl 3-1H-1,2 3-miazole-5- carboxamide; I-benzyl-N-cyclopentyl-4-( 1 H-indazol-5 ~yD-1H-1,2.3-triazole-5-carboxamide; I-benzyl-N-(cyclopentylmethyl)-4-( 1 H-indazol-5 ~yD-1H-1.2 3-4riazole-3- carboxamide; [-benzyl-N-gthyl-4-(1H-in dazol-5-v1)-N-methyl-1H-1.2 3-triazole-5 -carboxamide; I-benzyi-4-(1 H-indazol-5-y1)-N-isopropy!-N-methy!- 1 H-1 2, 3-triazole-3- carboxamide; 1-benzyl-4-(1H-indazol-5-y1)-N-(2 -methoxyethyl}-N-methyl-1H-1,2.3-triazole-5- carboxamide;
    1-benzyl-d-{1H-indazol-5 =y1}-N-phenyl-1H-1 +2,3-triazole-5-catboxamide; i -benzyl-N-(4-chlorophenyl)-4-{ IH-indazol-5-y)-1H-1,7 3 ~triazole-5-carboxamide: I-benzyl-4-(1 B-indazol-5-y1)-N-(2 -morpholin-4-ylethyl}-1H-1.2, 3-trazole-5- carboxamide; F-benzyl-N-[2-( dimethylamine ethy!]-4-( 1 H-indazo ~5-yI-N-methyl-1H-1,2,3- triazole-5-carboxamide: 1 -benzyl-N-(2-hydroxyethyl).4-( IH-mdazol-5-y1)-Nopropyl-1H-1 dy 3-triazole-5- carboxamide; I-benzyl-N-[3 ~(dimethv] ammo ypropyl-4-( | H-indazol-5 “yI-Nemethyl-151-1.2 3. triazole-5-carboxamide; I-benzyl-N-{2-(di ethylamine)ethyl}-4-¢ TH-indazol-5-y])-N -methyi-1H-1,2 3-triazole- S-carboxamide; N,I-dibenzyl-N-ethyl-4-(] H-indazol-5-y1)-1H-1 «2, 3-triazole-3-carboxamide; N,i ~Gibenzyl-N-(2-hydroxyethyl)-4-(1 H-indazol-5-yI)-1H-1 ,2,3-triazole-5- carboxamide: (3R)-1-{[1-benzyl-4-( 1H-indazo)-5 -vI}-1H-1.2, 3-41 azol-5-yljcarbonyl }piperidin-3-ol ; [-{[1-benzyl-4-(1 H-indazol-5-vI)-1H-1 -2,3-triazol-5-yl]carbonyl i piperidine-4- carboxamide; 5-11-benzyl-5 -[(2,6~dimethyimorpholin-4-y! Jearbonyl]-1H-1 2,3-triazol-4-yl} 1H. indazole; 5-{5-[(4-acetylpiperazin-] -ylycarbony!]-1-benzyl-1H-1 2. 3-triazol-4-yl}-] H-indazole; 5-{1-benzyl-3-f {(4-phenylpiperazin-1 -ylhycarbonyl}-1H-1,2 3 ~triazol-4-yl}-1H- indazole; L-benzyl-N-[(1R)-1 ~(bydroxymethyl)-2-methyipropy!]-4-( 1H-indazol-5-yi}-1H-1,2 3. triazole-5-carboxamide: l-benzyl-N-[(18)-1 -(hydroxymethyl)-2-methyipropyi]-4-(1 H-indazol-5-y[)-1H-1 2.3 triazole-5-carboxamide; i-benzyl-N-[3-(1H-imidazol-] -yDpropyl]-4-(1H-indazo]-3 ~yi)-1H-1.2 3-triazole-5- carboxamide;
    N-[5-(1-benzy! -5-cyclopropyl-1H-1,2,3-tri azol-4-v1)-1H-indazol-3 ~yvi}-N'-cthylurea; N-[54(1 -benzyl-3-cyclopropyl-1H-1 .2,3-triazol-4-y1)-1H-indazo]-3 -yil-N'-phenylurea: N-benzyl-N'-[5-(1-benzyl ~3-cyclopropyl-1H-1,2,3-triazol ~4-yl}-1H-indazol-3-ylJurea; N-[5-(1 ~benzyl-5-cyclopropyl-1H-1 .2,3-triazol-4-y1)-1H-indazol-3 -yH-N-(2-
    chlorophenylyurea;
    N-[5-(1 -benzyi-5-cyclopropyl-1H-1,2,3 ~triazol-4-y1)-1H-indazal-3 ~ylj-N( 3. chlorophenylurea:
    N-{5-{1-benzy] -s-cyclopropyl-1H-1,2,3 -triazol-4-y1-1H-indazal-2 Sy IN (4 chlorophenylyurea;
    N-[5-(I-benzyl-5-iodo-1H-1,2.3 ~triazot-d-yl).1 H-indazol-3-yljbenzamide: 3-[4-(3-amino- 1 H-in dazol-5-yI)- 1 H-pyrazoi-1 -yljpropanenitrile; 2-[4-{3-amino-1H-indazol ~S-yl}- 1 Hpyrazal-| -yijacetamide; methyl 3-[4-(3-amino-1H-in dazol-5-y1}-1H-pyrazol-] ~yijpropanoate; 3-[4-(3-amino-1 H-mdazol-3-y1}-1 Hpyrazol- -vl]propanamide;
    [4-(3-amine-1H-indazol -3-y1-1H-pyrazol-1-yl|acctoniti le; 4-(3-amino-1 H-indazo! ~3-y1-N,N-dimethyi- 1 H-tmidazole-1 -sulfonamide; S-pyrazin-2-yl-1H -indazol-3-amine; 5-thien-2-yl-1H-indazo! ~3-amine; 5-(Z-aminopyrimidin-4-y|}- 1 H-indazol-3 ~gImine; 3-(2-methoxypyridin-3-y1)-1 H-indazol-3-amine: S-imidazol1 2-alpyridin-3-yl-1 H-indazol-3-amine ; N° N*-dimethy!-N'-[5-(1H-] 2,3-triazol-4-y1)-1H-indazol-3-yl]glycinamide: 5-(1H-pyrazol-5-y1}-1H-in dazol-3-amine: S-(4-methyl-1 H-imidazol-5-y1)-1 H-indazol-3-amine; 28 5~(1H-imidazol-4-y[)-1 H-indazol-3-amine: NN -dimethyl-N'- {5] 1 ~(3-methylbenzyl}-1H-1.2.3-triazol-d-y1}- | H-indazol-3. vitalycinamide; 5-(I-benzyl-1 H-imidazol-4-y1)-1H -indazol-3-amine; N'-{5-[1-(4-tert-butylbenzyl)-1H-1 2.3-triazol-4-yl}-1 H-indazol-3-y1 }-N? N2- dimethylglycinamide: N N-dimethyl-N'- {5/1 “(2-piperidin-1-yiethyl}-1H-1,2,3-triazol4-y11-1H-indazol-3. yltglycinamide; N° N-dimethyl-N'- {5[1 ~(2-morpholin-d-yiethyl}-1H-] ,2.3-triazol-4-yl}-1H-indazol- 3-y1}glycinamide; NL(5-{1 2-(3 S-dimethylisoxazol-4-yl)etayl]- 1H-1,2 3-triazol-4-y1 } -1H-indazel-3- y1}-N° N’-dimethylglycinamide: N 5-1 1-[2-(3,5-dirnethy]-1 H-pyrazol-4.ylethyl]- 1H-1 2, 3-triazol-4-y1}. 1 H-indazol- 3-y1)-N’ N’-dimethylglycinamide: 2-(4- {3-[(NN -dimethylglveyl Yamino]-1 H-indazol-5-y1}-1H-1.2 3-triazol-1 “yi methylpropanoic acid; ethyl (4-{3-[(N N-dimethylglyeyDamine]- 1 B-indazol-5 sy -TH-1,2 3-triazoi-1- vljacetate; NN dimethyl (52 (1 “{imethylsilylymethyl}-1H-1,2,3-riazol-4-y1}-1Heindazol- 3-yhelycinamide; N's -(3-furyl)-1H-indazol-3 yII-N* N-dimethyl glveinamide;
    N*.N’-dimethyl-N' ~{3-(1H-pyrazol-5-y1)-1H-ind azol-3-yl|glycinamide; N° N “dimethyl -N.( S-pyrimidin-5-y1-1H-indazo!-3 ~yhglycinamide; nN ~[5-(2.1.3-henzox adiazol-5-y])-1H -indazol-3-y1}-N ‘ N'-dimethylglveinamide, 1G KN -dimethyi-N ! -{5-(1H-pyrazol-d-yi)-] H-indazol-3-yl]glycinamide; NN *-dimethyl-N' -[5-(1-methyl-1B-pyrazol-4 -¥1)-1H-indazol-3-yi] glycinamide; N'“[5-(3,5-dimethyl-1 H-pyrazol-d-yl}-1 H-indazol-3-y1}-N N’-dimethy] glycinamide; N'-{5-[2+ dimethylarmino )pyrimi din-5-y1]-1H-indazol-3-y1' -N? N= dimethylglycinamide; NEN “-dimethyl-N' -[5-(2-morpholin-4-ylpyrimidin-5 -y1)-1H-indazol-3- vilglycinamide; N° N*-dimethyl-N L {5-[1-{2 ~-morpholin-4-ylethyl)-1 H-pyrazol-4-y]-1H-indazol-3- vi} glycinamide; N'[5-(1 -benzyl-S-cyclopropyi-1H-1 2,3-triazol-d-yi- 1H -indazol-3-y1]-N’ N°- dimethylglyeinamide; N51 -benzyl-1H-pyrazol-4-yl)-1 H-indazol-3-y13-N’ IN “-dimethylglycinamide; N'{5-(1-benzyl-1H-1 2,3-triazol-4-yl)-1H-indazol-3-y1}-N"-methyi glycinamide; N-[5-(1-benzyl-1H-1 2,3-triazol-4-yl}- 1 H-indazol-3 -yif-2-pyrrolidin-1-ylacetami de; N51 ~benzyl-1H-1,2 3-tri azol-4-yl-1H-indazol-3-y11.N" -cyclopentylglycinamide;
    NT5.1 -benzyl-1H-1,2 3-triazol-d-y1}- 1 H-indazol-2 ~y1] N’-cyclopropyl glycinamide; NLT5-(3 -benzyl-1H-1,2,3-tri azol-4-yl)-1H-indazol-3 -yI]-N"-tetrahydro-2H -pyran-4. viglycinamide: N-[5-(1-benzyl-1H-1 2. 3-trlazol-4-yl}-1 H-indazol-3-y1}-2-( 3-hydroxypyrrolidin-1- yDacetamide; N-[5-(1-benzyi-1H-1.2,3-triazol-4-y 1-1 H ~-indazol-3-y1]-2-( 3-hydroxypiperidin-1- vhacetamide; N'I5(1-benzyl-1H-1,2,3 -triazol-4-y1)-1H-indazol-3-y1}]-N' N -dimethyl-beia- alaninamide; N-[5-(1-benzyl-1H-1 .2,3-triazol-4-yi)-1 H-indazol-3 -yl}-2-morpholin-4-yiacetamide:
    N-[5-(1-benzyl-1H-1.2.3-triazol-4-yl)- 1 H-indazol-3-yl]-2-(4-methylpiperazin-1- vijacetamide;
    N-[5-{1-benzyl-1H-1.2 3-triazol ~-vl1H-ndazol-3-y1]-2+( 3-oxopiperazin-1- vhacetarnide;
    N'[5(T-benzyl-1H-1,2, 3-4riazol-4-yl)-1 Hrindazol-3-yI1-N"-isopropylglycinamide: N53 -benzyl-1H-1.2,3-triazol-4-yi)-1 H-indazol-3-yI}-N"-cyclohexylglycinamide: N-[5-(1-benzyl-1H-1,2,3-triazol-4-y|}- 1 H-indazol-3 -yljacetamide;
    N' 4 5-(1-benzyl-1H-1,2, 3-triazol-4-yl)- H-indazol-3-y1}-N*-cvelobutylglycinamide; N-[5-{1-benzyl-1H~1.2 3-triazol “dey 1TH indazol-3 -yI}-Npropylurea:
    N-[5-(1-benzyi-1H-1 2.3-triazol-d-yl)-1B-indazol-3-yijcthanesulfonami de: 5-1-benzyl-1H-1,2,3-triazol-4-y1}-N-{ cyclopropylmethyl)-1H-indazot-3-amine; N-{5-(1-benzyl-1H-1.2,3-triazol-4-y1)- 1 H-indazo] ~3-vl]-N'-cthylurea; 1-{5-(1-benzyl-1H-1,2,3-triazol-4-yl)-1 H-indazol-3-yllpyrrolidin-2-one; N-[5-(1-benzvi-1H-1,2,3 tri az0l-4-yl)-1H-indazol-3-y1]-4-
    {dimethylaminoYoutanamide;
    N-3 4-dihydro-1H-isochromen-4-y[-54 1 H-indazol-5 -ylyisoxazole-3-carboxamide; N-{cyclohexyimethyl)-3-(1H -indazol-5-yl)isoxazole-3-carbox amide; N-(3-chlorobenzyl)-5-( 1 H-mdazol-3-yl)isoxazole-3-carboxamide; S-(1H-indazol-3-y1}-N-{2-methox ybenzyl)isoxazole-3-carboxamide;
    5-{1H-indazol-5-yb)-N-{2-(tri fluoromethylbenzyljisoxazole-3-carboxamide; 5-(1H-ndazol-5-v1)-N-[ 3-(trifluorom ethyDbenzyllisoxazole-3-carboxamide: 5~(1H-mdazol-3-y1}-N-[4-(iri fluoromethyl)benzylJisoxazole-3-carboxamide: 5-(1H-mdazol-5-y1)-N-(pyri din-Z-ylmethyl}isoxazole-3-carboxamide;
    5(1 H-indazol-5-y1)-N-(pyridin-3-yimethyl}isoxazole-3-carboxamide:
    5-(1H-indazol-3-y1}-N-(pyridin-4-ylmeth yl)isoxazole-3-carboxamide: N-{Z-chlorobenzyl}-5-(1H-indazol-5 ~yl}isoxazote-3-carboxamide: Ne{4-chlorobenzyi)-5-(114 -indazol-5-ylisoxazole-3-carboxamide: 3-(1H-indazol-5-yl}-N-(i-phenyl-2-piperidin- | -ylethyl)isoxazole-3-carboxamide: N-[2-(1H-imidazol-1-y1}-1-phenylethyl]-5-( | H-indazol-5-yisoxazole-3-
    carboxamide; 3-(1H-mmdazol-5-y1)-N-(2~-morpholin-4-y]-1 -phenylethyl)isoxazole-3-carboxamide; 5-(1H -indazol-5-yl)-N-{2-(4-methylpiperazin-1 -y1}-1-phenylethyllisoxazole-3-
    carboxamide; 5-(1H-indazol-5-y1)-N-(1-phenyl-2-pyrrolidin-1 -ylethyl)isoxazole-3-carboxamide;
    tert-buiyl 2-( {{5-(1H-indazol-5.y)isoxazol-3 -yljearbonyl}amino)-2- phenyiethylcarbamate;
    5-(1H-indazol-5-yi}-N-(1 -naphthylmethyDiscxazole-3-¢ arboxamide; 5-(1H-indazol-5-yi}-M -(2-phenylethyllisoxazole-3-carboxamide;
    3 5-{1H-indazol-5-y1)-N-({ Z-pyridin-2Z-ylethyltisoxazole-2 ~carboxamide: 5-(1H -indazol-3-yl}-N-(2-pyri din-3-ylethyl}isoxazole-3-carboxamide; 5-1 H-indazol-5-y1)-N-(2-pyridin-4-ylethyl)isoxazole-3 ~carboxamide; N-[2-(2-chlorophenyliethyl]-5-(1 H-mdazol-5-yl)isoxazole-3-carboxamide: MN-[2(3~chlorop henyhethyll-5-( 1 H-indazol -S-yInsoxazole-J-carboxamide:
    N-[2«4-chloraph enylethyl]-5(1 E-mdazol-5-ylyisoxazole-3-carbox arnids; N-benzyl-N-ethyl-5-(1H- ndazol-5-yilisoxazole-3 -carboxamide; 5-{1H-indazol-5-yi}-N-m ethyl-N-(1 -naphthylmethyisoxazole-3 -carboxamide; 5~(1H-indazol-5-yl)-N ~methyl-N-(2-phenylethy!}isoxazole-3-carbox amide; 5-(1H-indazol-5 -ylj-N-methyl-N-(2-pyridin-2 -“ylethylisoxazole-3-carbox amide;
    5-1 H-mdazol-5-y1)-N-[(1R)-1 -phenylethyllisoxazole-3-carboxamide; S-(1H-indazol-5-yl}-N-1 .2,3,4-tetraliydronaphthalen-1 -vlisoxazole-3-carboxamide; 5-{1H-indazol-5-y1}-N-[(18)-1 (1 -naphthyljethyllisoxazole-3-carboxamide; S-(1H-mdazol-5-y1)-N-{{ IR )-1(1 -naphthyliethyllisoxazole-3-carboxamide: N-[3-(dimethylamino)-1 -phenylpropyi}-3-(1 H-indazol-5-yl)isoxazole-3-carboxamid e;
    N-(2,3-dihydro-1 A-benzodioxin-S-yimethyl)-5-( I H-indazol-5-y1Yisoxazole-3- carboxamide; N-(3,4-dihydro-2H-1 »2-benzodioxepin-6-yimethy1)-5-( 1 H-indazol-5-yl)isoxazole-3- carboxamide; 5-(1H-mdazol-5-y1}-N-[(1 -methyl-1H -indol-4-ylymethyl Jisoxazole-3-carhoxamide: 23 5~{3-[(3-phenyipyrrelidin-1 -yhearbonyllisoxazol-5-y1}-1H-indazole: 3-{3-[(2-phenyipyrrolidin-1 -yl)carbonyliisoxazol-5-yl1-1 H-indazole; 5-{3-[{2-phenylpiperidin-1 -vhearbonyl]isoxazol-5-y[} ~1H-indazole; 5-(1B-indazol-5-y1)-N-[(1S)-] -phenylethyifisox azole-3-carboxamide; 5-(1H-indazol-5-y[}-N-[{ IR} -(4-methylphenyl)ethyllisoxazole-3 ~carboxamide; 5-(1-mdazol-5-y1)-N-[(18)-] ~{4-methyiphenylethyllisoxazole-3-carboxami de: N-[{1IR.2 S)-2-hydroxy-2, 3~dihydro-1H-inden-1 ~y1}-5-(1H-indazol-5-yl}isoxazole-3- carboxamide; N-[(1R,2R)-2-hydroxy-2.3-dihvdro-1H-inden-1 ~y1}-5-{1H-indazol-5-y)isoxazole-3- carboxamide;
    N-[(IR)-1+ 4-bromophenyliethyi]-5-(1 H-indazol-5-yl)isoxazole-3-carboxamide; N-f(18)-1 ~{(4-bromophenylethy! }-5-(1H-indazol-5 ~yDisoxazole-3-carboxamide; N-[(IR}-1+(4-chicrophenylethy! 1-5-1 H-indazol-3 ~yhisoxazole-3-carboxamide; N-[{18)-I-(4-chiorophenyljethyl }-5-(1H-indazo I-S-yDisoxazole-3-carboxamide; 5-(1H-mndazol-5-y1)-N-[(18}] (Z-naphthyl Jethyllisoxazole-3-carbosamide; N-[1-(4-ethoxyphenyl}-2-hydroxyethyl]-5-(1 H-indazol-3-yhisoxazole-3- carboxamide; N-[2-hydroxy-1-(4-isepropyiph enylethyl}-5-(1H-indazol-5-yhisoxazole-3- carboxamide; Nel 1-03 4-dimethyiph enyly-2-hydroxyethyll-5-(1H -indazol-3-vljisoxazole-3- carboxamide; N-{2-hydroxy-1-(2-methoxyphenylethyl]-5-(1H -indazol-5-yl}isoxazole-3- carboxamide; N-[2-hvdroxy-1 ~{4-methylphenyl)ethyl]-5-(1 H-indazol-5-yhisoxazole-3- carboxamide; 5-(1H-indazol-5-y[)-N-[{1R)-1 ~(2-methoxyphenylethylJisoxazole-3-carboxamide; N-[(18}-1 -(3 A-difluorophenyl)ethyl}-5-¢ 111 -indazol-5-y] Nsoxazole-3-carboxamide: 5~(1H-indazol-5-y1)-N-[(1R)-1 ~(3-methoxyphenyl)ethylJisoxazole-3-carboxamide: 5-{1H-indazol-5-y1}-N-{(1R}- | -[ 3~(tri fluoromethylyphenyi ethyl} isoxazole-3- carboxamide; N-[1-(2,3-dihydro-] 4-benzodioxin-6-ylyethyl]-5-(1H -indazol-5-ylisoxazole-3- carboxamide, N-T1-(3,5-di chlorophenyl)-2-hydroxyethyl]-5-(1 H-mdazol-3-ylisoxazole-3- carboxamide; terr-butyl 5-(1-benzyl-1H-1.2 347i azol-4-yH-3-f( {{6-(tri fluoromethylpyridin-2. yllamino}carbonylamino]-1 H-indazole- 1 -carboxylate; 5-(1-benzyl-1H-1,2,3-iriazol-4-y1}-1-[(1-m ethylpiperidin-2-yi)carbonyl]-1 H-indazol- J-amine; S-(1-benzyl-1H-1.2,3-triazol-4 ~y1)-1-[{dimethyl amino)jacetyl]-1 H-indazol-3-amine; tert-butyl 3-amino-5-(1-benzyl-14-1,2,3-triazol -4-y1)-1H-indazole-1-carboxylate; N-[5-(I-benzyl-1H-1.2.3-triazol-4-yl)- 1 H-indazol-3 ~yl}-2-piperidin-1-ylacetamide; N-[5-(1-benzyl-1H-1,2 3-triazol-4-y1}-1 H-indazol-3 -yl1-2Z-morpholin-4-ylacetamide; or N-[5-(1-benzyl-1H-1 2 3-triazol-4-y1)-1H-indazol-3 -y1}-1-methylpineridine-2-
    carboxamide. 25, A pharmaceutical composition comprising a therapeutically effective amount of 2 compound of formula (1) according to claim 1, in combination with a pharmaceutically suitable carrier.
    26. A method of inhibiting Glycogen Synthase kinase 3 (GSK-3), Rho kinase (ROCK), fanus Kinases (JAK), AKT, PAKA, PLE, CKZ, KDR, MKZ2, JNK, auroras, pim | and nek 2 comprising administering a therapeutically effective amount of a compound of Formula (1) according to claim 1.
    27. A method of inhibiting GSK-3 kinase comprising administering a therapeutically effective amount of a compound of Formula (1}, according to claim 4, wherein the the inhibition of GSK-3 kinase is useful for the ireatment or prevention of diseases or disorders regulated by GSK-3 kinase in 2 human in need thereof,
    28. The method according to Claim 27, wherein the inkibition of GSK-3 kinase is useful for stimulation of neuroregencration and the treatment and prevention of neurodegenerative diseases, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, multiple sclerosis, cognitive and attention deficits associated with Alzheimer's disease. acute and chronic neurodegenerative diseases, dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma.
    29. The method accord to Claim 28, wherein the acute and chronic neuradegenerative diseases are Parkinson's disease and tauopathies,
    30. The method according to Claim 29. wherein the tautopathies are frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, and progressive supranuclear palsy.
    31. The method according to Claim 28, wherein the dementia i$ vascular dementia.
    32. The method according to Claim 28, wherein the cerebrovascular accident is age related oo macular degeneration.
    33. The method according to Claim 27, wherein the inhibition of GSK-3 kinase is useful for the treatment non-insukin dependent diabetes and obesity, manic depressive illness, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis. and osteoporosis.
    34. The method according to Claim 33, wherein the cancer is breast cancer, non-small cell hung carcinoma, thyroid cancer, T or B-cell leukemia, and virus-induced tumors.
    35. A method of inhibiting GSK-3 kinase comprising administering a therapeutically effective amount of a compound of Formule (1), according to claim 8, wherein the imhibition of GBK-3 kinase is useful for the treatment or prevention of diseases or disorders regulated by GSK-3 kinase in a human in need thereof
    36. The method according to Claim 38, wherein the inhibition of GSK-3 kinase ig useful for stimulation of heuroregencration and the treatment and prevention of neurodegenerative diseases, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, multiple sclerosis, cognitive and attention deficits associated with Alzheimer's disease, acute and chronic neurodegencrative diseases, dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma,
    37. The method accord to Claim 36, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathies.
    38. The method according to Claim 37, wherein the tautopathies are frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, and progressive supranuclear palsy,
    39. The method according to Claim 36, wherein the dementia is vascular dementia,
    40. The method according to Claim 36, wherein the cerebrovascular accident is age related macular degeneration.
    41. The method according to Claim 35, wherein the inhibition of GSK-3 kinase is useful for the treatment non-insulin dependent diabetes and obesity, manic depressive illness,
    schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis, and osteoporosis.
    42. The method according to Claim 41, wherein the cancer is breast cancer, non-small cel] lung carcinoma, thyroid cancer, T or B-cell leukemia, and virus-induced tumors,
    43. A method of inhibiting GSK-3 kinase comprising administering a therapeutically effective amount of a compound of Formula (1), according to claim 9, wherein the the inhibition of GSK-3 kinase is useful for the treatment or prevention of diseases or disorders regulated by GSK-3 kinase in 2 human in need thereof, 19
    44. The method according to Claim 43, wherein the inhibition of GSK.3 kinase is useful for stimulation of neuroregencration and the treatment and prevention of neurodegenerative discases, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, multiple sclerosis, cognitive and attention deficits associated with Alzheimer's discase, acute and chronic neurodegenerative discases, dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma.
    45. The method accord to Claim 44, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathies.
    46. The method according to Claim 45, wherein the tautopathies are frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, and progressive supranuclear palsy.
    47. The method according to Claim 44, wherein the dementia is vascular dementia.
    48. The method according to Claim 44, wherein the cerebrovascular accident is age related macular degeneration,
    49. The method according to Claim 43, wherein the inhibition of GSK-3 kinase is useful for the treatment non-insulin dependent diabetes and obesity, manic depressive illness, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis, and Osteoporosis.
    50. The method according to Claim 49, wherein the cancer is breast cancer, non-small cell fung carcinoma, thyroid cancer, T or B-cell leukemia, and virus-induced tumors,
    51. A method of inhibiting GSK-3 kinase comprising administering a therapeutically effective amount of a compound of Formula (I), according to claim 11, wherein the the > inhibition of GSK-3 kinase is useful for the treatment or prevention of diseases or disorders regulated by GSK-3 kinase in a human in need thereof,
    52. The method according to Claim 51, wherein the inhibition of GSK-3 kinase is useful for stimulation of neuroregeneration and the treatment and prevention of neurodegenerative diseases, inflammatory and demyelinating diseases. Alzheimer's disease, stroke, multiple sclerosis, cognitive and attention deficits associated with Alzheimer's disease, acute and chronic neurodegenerative diseases, dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma.
    53. The method accord to Claim 52, wherein the acute and chronic neurodegencrative diseases are Parkinson's disease and tauopathies.
    54. The method according to Claim 53, wherein the tautopathics are frontotemporoparictal dementia, corticobasal degeneration, Pick's disease, and progressive supranuclear palsy.
    55. The method according to Claim 52, wherein the dementia 18 vascular dementia.
    56. The method according to Claim 52, wherein the cerebrovascular accident is age related macular degeneration.
    57. The method according to Claim 51, wherein the inhibition of GSK-3 kinase is useful for the treatment non-insulin dependent diabetes and obesity, manic depressive illness, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis, and Osteoporosis. 36
    58. The method according to Claim 57, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and virus-induced tumors.
    59. A method of inhibiting GSK-3 kinase comprising administering a therapeutically effective amount of a compound of Formula (1), according to claim 14, wherein the the inhibition of GSK-3 kinase is useful for the treatment or prevention of diseases or disorders regulated by GSK-3 kinase in a human in need thereof,
    60. The method according to Claim 59, wherein the mhibition of GSK-3 kinase is useful for stimulation of neuroregeneration and the treatment and prevention of neurodegencrative diseases, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, multiple sclerosis, cognitive and attention def; cits associated with Alzheimer's disease, acute and chronic neurodegenerative diseases, dementia, acute stroke and other traumatic injuries, [0 cerebrovascular accidents, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma.
    61. The method accord to Claim 68, wherein the acute and chronic neurodegenerative discases are Parkinson's disease and tauopathies.
    62. The method according to Claim 61, wherein the tautopathics are frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, and progressive Supranuclear palsy.
    63. The method according to Claim 60, wherein the dementia is vascular dementia.
    64. The method according to Claim 60, wherein the cerebrovascular accident is age related macular degeneration.
    65. The method according to Claim 59, wherein the inhibition of GSK-3 kinase 1s useful for the treatment non-insulin dependent diabetes and obesity, manic depressive i ness, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis, and osteoporosis.
    66. The method according to Claim 65, wherein the cancer 18 breast cancer, non-small cel] lung carcinoma, thyroid cancer, T or B-cell leukemia, and virus-induced tumors.
    67. A method of inhibiting GSK-3 kinase comprising administering a therapeutically effective amount of a compound of Formula (1), according to claim 15, wherein the the inhibition of GSK-3 kinase is useful for the treatment or prevention of diseases or disorders regulated by GSK-3 kinase in a human in need thereof.
    68. The method according to Claim 67, wherein the inhibition of GSK-3 kinase is useful for stimulation of neuroregeneration and the treatment and prevention of neurodegenerative diseases, inflammatory and demyelinating diseases, Alzheimer s disease, stroke, multiple sclerosis, cognitive and attention deficits associated with Alzheimer's discase, acute and chronic neurodegenerative dj scases. dementia, acute stroke and other traumatic mjuries, cerebrovascular accidents, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma. 69 The method accord to Claim 68, wherein the acute and chronic neurodegencrative diseases are Parkinson's disease and tauopathies.
    70. The method according to Claim 69, wherein the tautopathies are frontotemporoparictal dementia, corticobasal degeneration, Pick's disease, and progressive supranuclear palsy.
    71. The method according to Claim 68. wherein the dementia is vascular dementia.
    72. The method according to Claim 68, wherein the cerebrovascular accident is age related macular degeneration.
    73. The method according to Claim 67, wherein the inhibition of GSK-3 kinase is useful for the treatment non-insulin dependent diabetes and obesity, manic depressive iliness, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis, and osteoporosis.
    74. The method according to Claim 73, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and virus-induced tumors.
    75. A method of inhibiting GSK-3 kinase comprising administering a therapeutically effective amount of a compound of Formula (1), according to claim 16, wherein the the inhibition of GSK-3 kinase is useful for the treatment or prevention of diseases or disorders regulated by GSK-3 kinase in a human in need thereof.
    76. The method according to Claim 75, wherein the inhibition of GSK-3 kinase 1s useful for stimulation of neuroregeneration and the treatment and prevention of neurodegenerative diseases, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, multiple sclerosis, cognitive and attention deficits associated with Alzheimer's disease, acute and chronic neurodegenerative diseases, dementia. acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord trauma, peripheral neuropathies, > retinopathies and glaucoma,
    77. The method accord to Claim 76, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathies. 1G 78. The method according to Claim 77, wherein the tautopathies are frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, and progressive supranuclear palsy.
    79. The method according to Claim 76, wherein the dementia is vascular dementia.
    80. The method according to Claim 76, wherein the cerebrovascular accident is age related macular degeneration.
    81. The method according to Claim 75, wherein the inhibition of GSK-3 kinase is useful for the treatment non-insulin dependent diabetes and obesity, manic depressive illness, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis, and osteoporosis,
    82. The method according to Claim 81, wherein the cancer 1s breast cancer, non-small cel lung carcinoma, thyroid cancer, T or B-cell leukemia, and virus-induced tumors,
    83. A method of whibiting GSK-3 kinase comprising administering a therapeutically effective amount of a compound of Formula (I), according to claim 17, wherein the the inhibition of GSK-3 kinase is useful for the treatment or prevention of diseases or disorders regulated by GSK-3 kinase in a human in need thereof.
    84. The method according to Claim 83, wherein the inhibition of GSK-3 kinase is useful for stimulation of neuroregeneration and the treatment and prevention of neurodegenerative diseases, inflammatory and demyelinating diseases, Alzheimer s discase, stroke, nultiple sclerosis, cognitive and attention deficits associated with Alzheimer's disease, acute and chronic neurodegenerative diseases, dementia, acute stroke and other traumatic injuries,
    cerebrovascular accidents, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma.
    85. The method accord to Claim 84, wherein the acute and chronic neurcdegenerative diseases are Parkinson's disease and tauopathies.
    86. The method according to Claim 85, wherein the tautopathies are frontoternporoparictal dementia, corticobasal degeneration. Pick's disease. and progressive supranuciear palsy.
    87. The method according to Claim 84, wherein the dementia is vascular dementia.
    88. The method according to Claim 84, wherein the cerebrovascular accident is age related macular degeneration.
    89. The method according to Claim 83, wherein the inhibition of GSK-3 kinase is useful for the treatment non-insulin dependent diabetes and obesity, manic depressive illness, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis, and OSLEOpPOTosis.
    90. The method according to Claim 89, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-call leukemia, and virus-induced tumors.
    91. A method of inhibiting GSK.-3 kinase comprising administering a therapeutically effective amount of a compound of Formula {I}. according to claim 18, wherein the the inhibition of GSK-3 kinase is useful for the treatment or prevention of diseases or disorders regulated by GSK-3 kinase in a human in need thereof.
    92. The method according to Claim 91, wherein the inhibition of GSK-3 kinase is useful for stimulation of neuroregeneration and the treatment and prevention of neurodegenerative diseases, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, multiple sclerosis, cognitive and attention deficits associated with Alzheimer's disease, acute and chronic neurodegencrative diseases, dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma.
    93. The method accord to Claim 92, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathies.
    94. The method according to Claim 93, wherein the tautopathies are fromtotemporoparietal dementia, corticobagal degeneration, Pick's disease, and progressive supranuclear palsy.
    95. The method according to Claim 92, wherein the dementia is vascular dementia.
    96. The method according to Claim 92. wherein the cerebrovascular accident i age related 16 macular degeneration.
    G7. The method according to Claim 91, wherein the inhibition of GSK-3 kinase is useful for the treatment non-~insulin dependent diabetes and obesity, manic depressive iliness, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis, and ostesporosis.
    98. The method according to Claim 97, wherein the cancer is breast cancer. non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and virus-induced tumors,
    99. A method of inhibiting GSK-3 kinase comprising administering a therapeutically effective amount of a compound of Formula (1), according to claim 19, wherein the the inhibition of GSK-3 kinase is usefu] for the treatment or prevention of diseases or disorders regulated by GSK-3 kinase in a human in need thereof,
    100. The method according to Claim 99, wherein the inhibition of GSK-3 kinase is useful for stimulation of neuroregeneration and the treatment and prevention of neurodegenerative diseases, mflammatory and demyelinating diseases, Alzheimer's disease, stroke, multiple sclerosis, cognitive and attention deficits associated with Alzheimer's disease, acute and chronic neurodegenerative diseases, dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma.
    101. The method accord to Claim 106, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathies.
    102. The method according to Claim 101, wherein the tautopathies are frontotemporoparictal dementia, corticobasal degeneration, Pick's disease, and progressive supranuclear palsy.
    103. The method according to Claim 100. wherein the dementia is vascular dementia.
    104. The method according to Claim 106, wherein the cerebrovascular accident is ape related macular degeneration.
    185. The method according to Claim 99. wherein the mhibition of GSK-3 kinase is useful for the treatment non-msulin dependent diabetes and obesity, manic depressive illness, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis, and osteoporosis.
    106. The method according to Claim 105, wherein the cancer 1s breast cancer, non-smalj cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and virus-induced tumors.
    107. A method of inhibiting GSK-3 kinase comprising administering a therapeutically effective amount of a compound of Formula (I). according to claim 28, wherein the the inhibition of GSK-3 kinase is useful for the treatment or prevention of diseases or disorders regulated by GSK-3 kinase in a human in need thereof.
    108. The method according to Claim 197, wherein the inhibition of GSK-3 kinase 18 useful for stimulation of neuroregeneration and the treatment and prevention of neurodegenerative diseases, inflammatory and demyelinating diseases, Alzheimer's discase, stroke, multiple sclerosis, cognitive and attention deficits associated with Alzheimer's disease, acute and chronic neurodegenerative diseases, dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma.
    109. The method accord to Claim 108, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathies.
    110. The method according to Claim 109, wherein the tautopathies are frontotemporoparietal dementia, corticobasal degeneration, Picks discase, and progressive supranuclear palsy.
    111. The method according to Claim 108, wherein the dementia is vascular dementia,
    112. The method according to Claim 188, wherein the cerebrovascular accident ig age related macular degeneration.
    113. The method according to Claim 187. wherein the inhibition of GSK-3 kinase is useful for the treatment non-insulin dependent diabetes and obesity, manic depressive illness, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis, and osteoporosis.
    114. The method according fo Claim 113, wherein the cancer ig breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cali leukemia, and virus-induced tumors,
    115. A method of inhibiting GSK-3 kinase comprising administering a therapeutically effective amount of a compound of Formula (1}, according to claim 21, wherein the the inhibition of GSK-3 kinase is useful for the treatment or prevention of diseases or disorders regulated by GSK-3 kinase in a human in need thereof.
    116. The method according to Claim 115, wherein the inhibition of GSK.-3 kinase is useful for stimulation of neuroregeneration and the treatment and prevention of neurodegenerative diseases, mflammatory and demyelinating diseases, Alzheimer's disease, stroke, multiple sclerosis, cognitive and attention deficits associated with Alzheimer's disease. acute and chronic neurodegenerative discases, dementia, acute stroke and other traumatic juries, cerebrovascular accidents, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma. 23
    117. The method accord to Claim 116, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathies.
    118. The method according to Claim 117. wherein the tautopathies are frontotemporoparietal dementia, corticobasal degeneration, Pick's disease. and progressive supranuclear palsy.
    119. The method according to Claim 1 16, wherein the dementia is vascular dementia,
    120. The method according to Claim 116, wherein the cerebrovascular accident is age related macular degeneration.
    121. The method according to Claim 115, wherein the hibition of GSK-3 kinase is useful for the treatment non-insulin dependent diabetes and obesity, manic depressive illness, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis, and osteoporosis.
    122. The method according to Claim 121, wherein the cancer is breast cancer, non-small cel] lung carcinoma, thyroid cancer, T or B-cell leukemia, and virus-induced tumors,
    123. A method of mnhibiting GSK-3 kinase comprising administering a therapeutical by effective amount of a compound of Formula (1), according to claim 22, wherein the the inhibition of GSK-3 kinase is useful for the treatment or prevention of diseases or disorders regulated by GSK.-3 kinase in a human in need thereof.
    124. The method according to Claim 123, wherein the inhibition of GSK-3 kinase is useful for stimulation of neuroregeneration and the treatment and prevention of neurodegenerative diseases, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, multiple sclerosis, cognitive and attention deficits associated with Alzheimer's disease, acute and chronic neurodegenerative diseases, dementia, acute stroke and other traumatic mjuries, cerebrovascular accidents, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma.
    125. The method accord to Claim 124, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathies.
    126. The method according to Claim 125, wherein the tautopathics are frontotemporoparictal dementia, corticobasal degeneration, Pick's disease, and progressive supranuclear palsy.
    127. The method according to Claim 124, wherein the dementia is vascular dementia.
    128. The method according to Claim 124, wherein the cerebrovascular accident is age related macular degeneration.
    129. The method according to Claim 123, wherein the inhibition of GSK-3 kinase is useful for the treatment non-insulin dependent diabetes and obesity, manic depressive iliness, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis, and osteoporosis.
    130. The method according to Claim 129, wherein the cancer is breast cancer, non-small cell 3 lung carcinoma, thyroid cancer, T or B-cell leukemia, and virus-induced tumors,
    131. A method of inhibiting GSK-3 kinase comprising administering a therapeutical by effective amount of a compound of Formula (1), according to clarm 23, wherein the the inhibition of GSK.-3 kinase is useful for the treatment or prevention of diseases or disorders regulated by GSK-2 kinase in a human in need thereof
    132. The method according to Claim 131, wherein the inhibition of GSK-3 kinase is useful for stimulation of neuroregeneration and the treatment and prevention of ncurodegenerative diseases, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, multiple sclerosis, cognitive and attention deficits associated with Alzheimer's disease, acute and chronic neurodegenerative diseases, dementia, acute stroke and other traumatic mjuries, cerebrovascular accidents, brain and spinal cord frauma, peripheral neuropathies, tetinopathies and glaucoma.
    133. The method accord to Claim 132, wherein the acute and chronic neurodegencrative diseases are Parkinson's disease and tauopathies.
    134. The method according to Claim 133, wherein the tautopathies are frontotemporoparictal dementia, corticobasal degeneration, Picks disease, and progressive supranuciear palsy.
    135. The method according to Claim 132, wherein the dementia is vascular dementia,
    136. The method according to Claim 132, wherein the cerebrovascular accident 1s age refated macular degeneration.
    137. The method according to Claim 131, wherein the inhibition of GSK-3 kinase is useful for the treatment non-insulin dependent diabetes and obesity, manic depressive iliness, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis, and osteoporosis.
    138. The method according to Claim 137, wherein the cancer 1s breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cel] leukemia, and virus-induced tumors.
    139. A method of inhibiting JAK kinase comprising administering a therapeutically effactive amount of a compound of Formula (1), accordin gto claim 1 wherein the inhibition of JAK kinase is useful for the treatment or prevention of diseases or disorders regulated by JAK kinases in a human in need thereof
    146. The method according to Claim 139, wherein the mhibition of JAK kinase is useful for 16 the treatment of autoimmune diseases, myeloproliferative syndromes and cardiovascular diseases associated with abnormal activity of JAK kinases comprises administering to a mammalian organism in need thereof an effective amount of a compound according to claim
    5.
    141. The method according to Claim £48, wherein the myeloproliferative syndromes are leukemias, lymphomas or cancer.
    142. The method according to Claim 141, wherein the cancer 1s hematologic cancer.
    143. The method according to Claim 146, wherein the autoimmune diseases are rheumatoid arthritis and psoriasis. 144, The method according to Claim 139, wherein the mhibition of JAK kinase is useful for the treatment of autoimmune diseases, myeloproliferative syndromes and cardiovascular diseases associated with abnormal activity of JAK kinases comprises administering to a mammalian organism in need thereof an effective amount of a compound according to claim
    8.
    145. The method according to Claim 144, wherein the myeloproliferative syndromes are leukemias, lymphomas or cancer.
    146. The method according to Claim 145, wherein the cancer 1s hematologic cancer.
    147. The method according to Claim 144, wherein the autoimmune diseases are rheumatoid arthritis and psoriasis.
    148. The method according to Claim 139, wherein the inhibition of JAK kinase is useful for the treatment of autoimmune diseases, myeloproliferative syndromes and cardiovascular diseases associated with abnormal activity of JAK kinases comprises administering to a mammalian organism in need thereof an effective amount of a compound according to claim
    12.
    149. The method according to Claim 148, wherein the myeloproliferative syndromes are leukemias, lymphomas or cancer.
    150. The method according to Claim 149, wherein the cancer 1s hematologic cancer,
    151. The method according to Claim 148, wherein the autoimmune diseases are rheumatoid arthritis and psoriasis.
    152. A method of inhibiting ROCK kinase comprising administering a therapeutically effective amount of a compound of Formula (1), according to claim 3, wherein the inhibition of ROCK kinase is useful for the treatment of neurodegeneration, inflammatory and 26 demyelinating diseases, Alzheimer's disease, stroke, pulmonary inflammation associated with asthma, asthma, for accelerated regeneration and enhanced functional recovery after spinal-cord injury, for multiple sclerosis, pain, hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, cerebral vasospasm after subarachnoid bleeding, pulmonary hypertension, atherosclerosis, male erectile dysfunctions, female sexual dysfunction, over-active bladder syndrome, induction of new axonal growth, axonal rewiring across lesions within the CNS, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, rheumatoid arthritis, osteoarthritis, irritable bowel syndrome, Crohn's disease, psoriasis, ulcerative colitis, Lupus, cancer and tumor metastasis, anti-viral and anti-bacterial applications, insulin resistance, di abetes, cystic fibrosis, angina pectoris, and arteriosclerosis.
    153. A method of inhibiting ROCK kinase comprising administering a therapeuti cally effective amount of a compound of Formula (I), according to claim 6, wherein the inhibition of ROCK kinase 1s useful! for the treatment of neurodegeneration, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, pulmonary inflammation associated with asthma, asthma, for accelerated regeneration and enhanced functional recovery after spinal-cord injury, for multiple sclerosis, pain, hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, cerebral vasospasm after subarachnoid bleeding, pulmonary hypertension, atherosclerosis, male erectile dysfunctions, female sexual dysfunction, over-active bladder syndrome, induction of new axonal growth, axonal rewiring across lesions within the CNS, amyotrephic lateral sclerosis, Huntington's disease, Parkinson's disease, rheumatoid arthritis, osteoarthritis, irritable bowel syndrome, Crohn's disease, psoriasis, ulcerative colitis, Lupus, cancer and tumor metastasis, anti-viral and anti-bacterial applications, insulin resistance, diabetes, cystic fibrosis, angina pectoris, and arteriosclerosis.
    154. A method of inhibiting ROCK kinase comprising administering a therapeutically effective amount of a compound of Formula (1), according to claim 7, wherein the inhibition of ROCK kinase is useful for the treatment of neurodegeneration, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, pulmonary inflammation associated with asthma, asthma, for accelerated regeneration and enhanced functional recovery after spinal-cord injury, for multiple sclerosis, pain, hypertension, chronic and con gestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, cerebral vasospasm after subarachnoid bleeding, pulmonary hypertension, atherosclerosis, male erectile dysfunctions, female sexual dysfunction, over-active bladder syndrome, induction of new axonal growth, axonal rewiring across lesions within the CNS, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, rheumatoid arthritis, osteoarthritis, irritable bowel syndrome, Crohn's disease, psoriasis, ulcerative colitis, Lupus, cancer and tumor metastasis, anti-viral and anti-bacteriaj applications, insulin resistance, diabetes, cystic fibrosis, angina pectoris, and arteriosclerosis.
    155. A method of inhibiting ROCK kinase comprising administering a therapeutically effective amount of a compound of Formula (I), according to claim 16, wherein the inhibition of ROCK kinase is useful for the treatment of neurodegeneration, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, pulmonary inflammation associated with asthma, asthma, for accelerated regeneration and enhanced functional recovery after spinal-cord injury, for multiple sclerosis, pain, hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, cerebral vasospasm after subarachnoid bieeding, pulmonary hypertension, atherosclerosis, male erectile dystunctions, female sexual dysfunction, over-active bladder syndrome, induction of new axonal growth, axonal rewiring across lesions within the CNS, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, rheumatoid arthritis, osteoarthritis, irritable bowel syndrome, Croho's disease, psoriasis. ulcerative colitis, Lupus, cancer and tumor metastasis, anti-viral and anti-bacterial applications, insulin resistance, diabetes. cystic fibrosis, angina pectoris, and arteriosclerosis.
    156. A method of inhibiting ROCK kinase comprising administering a therapeutically 0 effective amount of a compound of Formula {I}, according to claim 13, wherein the inhibition of ROCK kinase is useful for the treatment of neurodegeneration, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, pulmonary inflammation associated with asthma, asthma, for accelerated regeneration and enhanced functional recovery afer spinal-cord injury, for multiple sclerosis, pain, hypertension, chronic and congestive heart 13 failure, cardiac hypertrophy, restenosis, chronic renal failure, cerebral vasospasm after subarachnoid bleeding, pulmonary hypertension, atherosclerosis, male erectile dysfunctions, female sexual dysfunction, over-active bladder syndrome, induction of new axonat growth, axonal rewiring across lesions within the CNS, amyotrophic lateral sclerosis, Huntington's discase, Parkinson's disease, rheumatoid arthritis, osteoarthritis, irritable bowel syndrome, Crohn's disease, psoriasis, ulcerative colitis, Lupus, cancer and tumor metastasis, anti-viral and anti-bacterial applications, insulin resistance, diabetes, cystic fibrosis, angina pectoris, and arteriosclerosis.
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RU2009149696A (en) 2011-07-20
AU2008262038A1 (en) 2008-12-18
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KR20100032886A (en) 2010-03-26
MX2009013213A (en) 2010-03-30
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BRPI0811065A2 (en) 2014-12-02
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CA2689117A1 (en) 2008-12-18
RU2487873C2 (en) 2013-07-20

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