KR20100032886A - 5-heteroaryl substituted indazoles as kinase inhibitors - Google Patents

Abstract

The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts, wherein A, R, R, Rand 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), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

Description

5-Heteroaryl substituted indazoles as kinase inhibitors}

The present invention relates to 5-substituted indazole-containing compounds, methods for preparing the compounds and kinases such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4 , PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2, relates to a composition containing the compound.

Protein kinases are a class of enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine, serine, threonine or histidine residues located on protein substrates. Protein kinases apparently play a role in normal cell growth. Many growth factor receptor proteins have intracellular domains that act as protein kinases through this function that they act on signaling. The interaction of growth factors with their receptors is an essential event in the normal regulation of cell growth, and the phosphorylation status of matrix proteins is often associated with the regulation of cell growth.

It is well known that abnormal protein phosphorylation may be directly related to a particular disease state or may be a contributing factor in the onset of such disease. As a result, protein kinases have been the target of new pharmaceutical research (Cohen, P. Nature Reviews Drug Discovery, 1: 309-315, 2002). Various protein kinase inhibitors have been used clinically in the treatment of various kinds of diseases such as cancer, chronic inflammatory diseases, diabetes and stroke.

Protein kinases are a huge and diverse class of enzymes that catalyze protein phosphorylation and play an important role in intercellular signaling. Protein kinases can exert positive or negative regulatory effects depending on their target protein. Protein kinases are involved in specific signaling pathways that regulate cell function, such as, but not limited to, metabolism, cell cycle progression, cell adhesion, vascular function, apoptosis, and angiogenesis. As a result, dysfunction of cell signaling has been associated with a number of diseases, the most characterized of which include cancer and diabetes. The regulation of signal transduction by cytokines and the binding of signal molecules to prototumor and tumor suppressor genes have been well documented. Similarly, the relationship between diabetes, viral infections and the conditions associated with it has also been associated with the regulation of protein kinases.

Because protein kinases regulate almost all cellular processes, including metabolism, cell proliferation, cell differentiation and cell survival, they are interesting targets for the therapeutic intervention of various disease states. For example, cell cycle regulation and angiogenesis, in which protein kinases play a central role, include, but are not limited to, a number of disease states, including, but not limited to, cancer, inflammatory diseases, abnormal angiogenesis and related diseases, atherosclerosis, It is a cellular process associated with macular degeneration, diabetes, obesity and pain.

The description of the complexity of the protein kinase pathway and the complexity of the associations and interactions between the various protein kinases and kinase pathways is provided in the context of a number of kinases or agents that can act as protein kinase modulators, modulators or inhibitors with advantageous activity against multiple kinase pathways. Emphasis is placed on the development of pharmaceutical preparations.

Thus, because of the complexity of the intracellular signaling cascade of protein kinase pathways, it has been suggested that agents acting on multiple pathways simultaneously may be required for important clinical activity. While it has been suggested that a single agent that provides a combinatorial effect is an interesting view, there is a need to identify and use a single agent that targets the correct combination of multiple pathways that are clinically effective for a particular disease setting.

Glycogen synthase kinase-3 (GSK-3) is a serine / threonine kinase encoded by two isoforms, GSK-3α and GSK-3β having molecular weights of 51 and 47 kDa, respectively. They share 97% sequence similarity within the kinase catalytic domain. GSK-3α isoforms have extended glycine-rich N-terminal tails. Minor splice variants of GSK-3β were found to have 13 amino acid inserts in the kinase domain (expressed in about 15% of the total). This variant has reduced activity against tau. GSK-3 is highly conserved during evolution and is highly homologous in the kinase domain and has been found in all mammals to date. Both isotypes are ubiquitously expressed in mammalian tissues including the brain. Pharmacological GSK-3 inhibitors cannot selectively inhibit one of the isoforms.

GSK-3β plays an important role in the regulation of metabolism, differentiation and survival. It was initially identified as an enzyme that can phosphorylate glycogen synthase. It was subsequently recognized that GSK-3β is the same as tau protein kinase 1 (TPK1), an enzyme that phosphorylates tau proteins in epitopes that have also been found to be hyperphosphorylated in Alzheimer's disease and some tauopathy.

Interestingly, it has been suggested that protein kinase B (AKT) phosphorylation of GSK-3β results in a loss of kinase activity, and this inhibition may mediate some of the effects of neurotrophic factors. In addition, phosphorylation of β-catenin (protein involved in cell survival) by GSK-3β results in its degradation by the ubiquitinilation dependent proteasome pathway.

Thus, it is believed that inhibition of GSK-3β activity can result in neurotrophic activity. Lithium, a noncompetitive inhibitor of GSK-3β, enhances neurogenesis in some models, and also induces the induction of survival factors such as Bc1-2 and the expression of apoptosis-proapoptotic factors such as P53 and Bax. There is evidence that inhibition can increase neuronal survival.

Further studies have revealed that β-amyloid increases GSK-3β activity and tau protein phosphorylation. In addition, these hyperphosphorylation and neurotoxic effects of β-amyloid are blocked by lithium chloride and GSK-3β antisense mRNA. Together these observations suggest that GSK-3β may be the link between two major pathological processes in Alzheimer's disease: abnormal APP (amyloid precursor protein) processing and tau protein hyperphosphorylation.

These experimental observations indicate that GSK-3β may be applied to the prevention and treatment of neuropathological prognosis and cognitive and attention deficits associated with Alzheimer's disease and other acute and chronic neurodegenerative diseases. These include Parkinson's disease, tau disease (eg, frontotemporopariental dementia, corticobsal degeneration, Pick's disease, progressive nuclear palsy) and other dementia including vascular dementia; Acute stroke and other traumatic injuries; Cerebrovascular accidents (eg age related macular degeneration); Brain and spinal cord trauma; Peripheral neuropathy; Including but not limited to retinopathy and glaucoma.

GSK-3β may also be used to treat non-insulin dependent diabetes and obesity; Mood swings; Schizophrenia; Alopecia; Inflammation: May be useful for the treatment of other diseases such as breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and some virus-induced tumors.

Rho kinase (ROCK), the first Rho effector described, is a serine / threonine kinase that is important in the basic process 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 the compounds of the invention have potentially beneficial therapeutic effects due to their antivascular spasms activity include cardiovascular diseases such as hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, After subarachnoid hemorrhage, cerebrovascular spasm, pulmonary hypertension and atherosclerosis. Muscle relaxation is also advantageous for treating asthma, male erectile dysfunction, female sexual dysfunction, and overactive bladder syndrome. Damage to the adult vertebrate brain and spinal cord activates ROCK, thereby inhibiting neurite growth and germination. Inhibition of ROCK results in the induction of new axon growth, axonal rewiring that crosses lesions within the CNS, accelerated regeneration and improved function recovery after acute neuronal injury (spinal cord injury, traumatic brain injury) in mammals do. Inhibition of the Rho / ROCK pathway has also been proven effective in treating pain and other neurodegenerative animal models such as stroke, inflammatory and demyelinating diseases, Alzheimer's disease. Thus, Rho / ROCK pathway inhibitors have the potential to prevent neurodegeneration and to inhibit neurodegeneration in various neurological disorders including spinal cord injury, Alzheimer's disease, stroke, multiple sclerosis, amyotrophic lateral sclerosis and to treat pain. Have ROCK inhibitors have been shown to contain anti-inflammatory properties. Accordingly, the compounds of the present invention can be used for neuroinflammatory diseases such as stroke, multiple sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis and inflammatory pain and other inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, irritability It can be used for the treatment of bowel syndrome, Crohn's disease, psoriasis, ulcerative colitis, lupus and inflammatory bowel disease. Because ROCK inhibitors reduce cell proliferation and cell migration, they can be useful for treating cancer and tumor metastasis. In addition, there is evidence suggesting that ROCK inhibitors inhibit cytoskeletal rearrangements upon virus invasion, and therefore they also have strong therapeutic value in antiviral and antimicrobial applications. ROCK inhibitors are also useful for the treatment of insulin resistance and diabetes. In addition, ROCK inhibitors have been shown to reduce the progression of cystic fibrosis (Abstract S02.3, 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 not only inhibit myosin light chain (MLC) phosphatase but also enhance MLC phosphorylation by phosphorylating MLC. This induces actin-myosin contraction regulation. Recent reports have demonstrated that inhibition of ROCK induces inhibition of smooth muscle contraction as well as destruction of inflammatory cell chemotaxis in asthma-related lung inflammation models. Therefore, inhibitors of the Rho / ROCK pathway should be useful for treating asthma.

Janus kinases (JAK) are an important class of intracellular protein tyrosine kinases (PTKs) with homologs in four mammalian members, JAKl, JAK2, JAK3 and TYK2, as well as chickens, fish and fruit flies. JAK plays an important role in many important intracellular signaling pathways, including the progenitor JAK / STAT pathway, which is central to cytokine signaling mediation. This plays a pivotal role in cytokine signaling in support of the view that certain JAK inhibitors can be therapeutically deployed in situations where cytokine activity causes disease. Important examples thereof include autoimmune diseases such as rheumatoid arthritis and psoriasis, myeloproliferative syndromes such as leukemia, lymphoma and cardiovascular disease.

JAK2, a member of the Janus kinase (JAK) family of protein tyrosine kinases (PTKs), is an important intracellular mediator of cytokine signaling. Mutations in the JAK2 gene are associated with hematological cancers, and abnormal JAK activity is also associated with a number of immune diseases, including rheumatoid arthritis.

Aurora kinases are a class of multigenic mitotic serine-threonine kinases that function as novel tumor gene classes. These kinases include Aurora-A, Aurora-B and Aurora-B members. These are overactivated and / or overexpressed in many solid tumors, including but not limited to breast cancer, ovarian cancer, prostate cancer, pancreatic cancer and colorectal cancer. In particular, Aurora-A is a centroid kinase whose ubiquity is dependent on the cell cycle and plays an important role in cell cycle progression and cell proliferation. Aurora-A is located in the 20ql3 chromosome region which is often amplified in many different forms of malignant tumors such as colorectal cancer, breast cancer and bladder cancer. Inhibition of aurora kinase activity can help reduce cell proliferation, tumor growth and potentially tumorigenesis.

Accordingly, there is a need to develop a method that involves the use of a single agent drug that can target a kinase or a specific set of kinase pathways. In particular, this method affects the correct combination of multiple targets, thereby achieving clinical efficacy.

Summary of the Invention

In a major embodiment, the present invention provides a compound of formula 1 or a pharmaceutically acceptable salt thereof.

In Chemical Formula 1,

A is

이고;

ego;

R ₁ is hydrogen, alkyl, aryl, heterocycle, heteroaryl, R _a R _b N-, R _c R _d NC (O)-or R _c R _d NS (O) _2- ;

R ₂ is hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, heterocyclecarbonyl or R _e R _f N-alkyl-C (O) —;

R ₃ is alkyl, alkoxy, aryl, cyano, cycloalkyl, halogen, haloalkyl, heteroaryl, nitro or R _g R _h N—;

R ₄ is alkyl, alkoxyalkyl, aryl, cycloalkyl, heteroaryl, heterocycle, heterocyclealkyl, R _j R _k N- or R _j R _k N-alkyl-;

R ₅ is alkyl, aryl or heteroaryl;

R ₆ is alkyl, alkoxyalkyl, R _j R _k N-alkyl-, aryl, cycloalkyl or heteroaryl;

R ₇ is alkyl, aryl or heteroaryl;

R _a and R _b are each independently hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, R ₄ -C (O)-or R ₅ -S (O) _2- ;

R _c and R _d are each independently hydrogen, alkyl or heteroaryl;

R _e and R _f are each independently hydrogen, alkyl, arylalkyl, heteroarylalkyl, R ₆ -C (O)-or R ₇ -S (O) _2- ;

R _g and R _h are each independently hydrogen, alkyl or alkylcarbonyl;

R _j and R _k are each independently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heterocycle;

R _i , R _ii , R _iii , R _iv , R _v , R _vi , R _vii , R _viii , R _ix , R _x , R _xi , R _xii , R _xiii , R _xiv , R _xv , R _xvi , R _xvii , R _xviii , R _xix , R _xx , R _xxi , R _xxii and R _xxiii are each independently alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, aryl (hydroxy) alkyl, Aryloxyalkyl, arylcarbonyl, arylthioalkyl, carboxy, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, hetero Cycliccarbonyl, hydroxyalkyl, trialkylsilylalkyl, H ₂ NC (O) -alkyl, Z _a Z _b N-, Z _a Z _b N alkyl, Z _c Z _d NC (O)-or Z _c Z _d NS (O) _2- , where R _xiv , R _xv , R _xvi and R _xvii are May occur at any open valence on the compound of formula (xiv), (xv), (xvi) or (xvii);

Z _a and Z _b are each independently hydrogen, alkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, H ₂ NC (O)-, H ₂ NalkylC (O)-, H ₂ NC (O) -Alkyl, dialkylNC (O)-or dialkylNC (O) -alkyl-;

Z _c and Z _d are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl (hydroxy) alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl, H ₂ NC (O) -alkyl-, dialkylNC (O) -alkyl-, dialkylN-alkyl- or CHZ _e Z _f ;

Z _e is aryl or heteroaryl;

Z _f is heteroarylalkyl, heterocyclealkyl or Z ₁ Z ₂ N-alkyl-;

m is 0, 1 or 2;

a is O or l;

b is 0, 1 or 2;

c is 0, 1, 2 or 3;

d is 0, 1, 2, 3 or 4.

Also provided are pharmaceutically acceptable compositions comprising a therapeutically effective amount of a compound of Formula 1 together with a pharmaceutically suitable carrier.

It is an object of the present invention to provide compounds useful for the prevention or treatment of diseases induced by abnormal protein kinase activity. In addition, the present invention also provides pharmaceutically effective compositions of the compounds of the present invention useful for the prophylaxis or treatment of such diseases.

The present invention also provides a 5-substituted indazole compound of Formula 1 which may be present as a pharmaceutically acceptable salt or prodrug thereof in the presence or absence of a pharmaceutically acceptable carrier, dragee, adjuvant or other auxiliary substance. It relates to a pharmaceutical composition comprising the above.

The compounds of the present invention have inhibitory activity against GSK-3, ROCK-1, ROCK-2, JAK2 and other kinases and are useful for the inhibition of such kinases. Certain compounds of the invention are selective for one or more kinases and may be useful for the selective inhibition of such kinases. Accordingly, the compounds of the present invention are active ingredients for the preparation of compositions which allow prophylactic and / or therapeutic treatment of diseases induced by abnormal GSK-3 activity, more particularly neurodegenerative diseases such as Alzheimer's disease. It is useful as. In addition, the compounds of the present invention may include neurodegenerative diseases such as Parkinson's disease, tauopathy (eg, anterior temporal parietal lobe dementia, cortical basal ganglia degeneration, pick disease, advanced nuclear palsy) and other dementia including vascular dementia; Acute stroke and other traumatic injuries; Cerebrovascular accidents (eg age related macular degeneration); Brain and spinal cord trauma; Peripheral neuropathy; Retinopathy and glaucoma; And other diseases such as non-insulin dependent diabetes mellitus (eg type 2 diabetes) and obesity; Mood swings; Schizophrenia; Alopecia; It is also useful as an active ingredient for preparing compositions for the prophylactic and / or therapeutic treatment of cancers such as breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and many virus-induced tumors.

The compound of the present invention has the formula (1) as described above. More particularly, compounds of formula (1) are those in which A is formula (ii), (iii), (iv), (vii), (x), (xiv), (xv), (xvi), (xvii), (xviii) , (xix), (xx), (xxi), (xxii) or (xxiii), may be included, but is not limited thereto.

In another embodiment of the invention, A is formula (ii);

R ₁ is hydrogen, aryl, heteroaryl, heterocycle, R _a R _b N— or R _c R _d NC (O) —; R ₂ is hydrogen, alkoxycarbonyl, heterocyclecarbonyl, alkylcarbonyl or R _e R _f N-alkyl-C (O) —; R ₄ is alkyl, alkoxyalkyl, aryl, cycloalkyl, heterocycle, heterocyclealkyl, R _j R _k N- or R _j R _k N-alkyl-; R ₅ is alkyl, aryl or heteroaryl; R _a and R _b are each independently hydrogen, arylalkyl, cycloalkylalkyl, R ₄ -C (0)-or R ₅ -S (O) _2- ; R _c and R _d are each independently hydrogen or heteroaryl, R _e and R _f are each independently hydrogen or alkyl, and R _j and R _k are each independently hydrogen, alkyl, aryl, cycloalkyl or heterocycle ; R _ii is alkyl, alkoxyalkyl, alkoxycarbonyl, aryl, arylalkyl, aryl (hydroxy) alkyl, aryloxyalkyl, arylcarbonyl, alkoxycarbonylalkyl, arylthioalkyl, carboxy, carboxyalkyl, cycloalkyl, cyclo Alkylalkyl, cycloalkylcarbonyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, trialkylsilylalkyl, Z _a Z _b N-, Z _a Z _b N Alkyl- or Z _c Z _d NC (0)-; Z _a and Z _b are each independently hydrogen, alkyl or H ₂ NalkylC (O) —; Z _c and Z _d are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclealkyl, hydroxyalkyl or dialkylN-alkyl-; m is 0; Described are compounds of formula 1 wherein b is 0, 1 or 2.

In another embodiment of the invention, A is formula (iii),

R ₁ is hydrogen or R _a R _b N-; R ₂ is hydrogen; R ₄ is R _j R _k N-alkyl-; R _a and R _b are each independently hydrogen or R ₄ -C (O) —; R _j And R _k are each alkyl; R _iii is alkoxycarbonylalkyl, alkyl, arylalkyl, cyanoalkyl, heterocyclealkyl or H ₂ NC (O) -alkyl-; c is 0, 1 or 2; Described are compounds of formula (1) wherein m is zero.

In another embodiment of the invention, A is formula (iv),

R ₁ is hydrogen or R _a R _b N-; R ₂ is hydrogen; R _a and R _b are each hydrogen; R _iv is aryl, arylalkyl, heterocycle, heterocyclealkyl, Z _a Z _b Nalkyl or Z _c Z _d NS (O) _2- ; Z _a and Z _b are each independently hydrogen or alkyl; Z _c and Z _d are each alkyl; c is 0, 1 or 2; Described are compounds of formula (1) wherein m is zero.

In another embodiment of the invention, A is formula (vii),

R ₁ is hydrogen, alkyl or R _a R _b N; R ₂ is hydrogen; R _a and R _b are each hydrogen; R _vii is alkyl, alkoxycarbonyl, aryl, arylalkyl, cycloalkyl, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl or Z _c Z _d NC (O) —; Z _c and Z _d are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl (hydroxy) alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl or CHZ _e Z _f ; Z _e is aryl or heteroaryl, Z _f is heteroarylalkyl, heterocyclealkyl or Z ₁ Z ₂ N-alkyl-; b is 1; Described are compounds of formula (1) wherein m is zero.

In another embodiment of the invention, A is formula (x),

R ₁ is hydrogen; R ₂ is hydrogen; R _x is alkyl, aryl or Z _a Z _b N-; Z _a and Z _b are each independently hydrogen, alkyl, aryl or arylalkyl; b is 1 or 2; Described are compounds of formula (1) wherein m is zero.

In another embodiment of the invention, A is formula (xiv),

R ₁ is hydrogen; R ₂ is hydrogen; R _xiv is Z _a Z _b N-; Z _a and Z _b are each independently hydrogen or cycloalkyl; c is 1; Described are compounds of formula (1) wherein m is zero.

In another embodiment of the invention, A is formula (xv),

R ₁ is hydrogen or R _a R _b N-; R ₂ is hydrogen; R _a and R _b are each hydrogen; R _xv is Z _a Z _b N-; Z _a and Z _b are each independently hydrogen, alkoxycarbonylalkyl, aryl, arylalkyl or cycloalkyl; d is 0 or 1; Described are compounds of formula (1) wherein m is zero.

In another embodiment of the invention, A is formula (xvi),

R ₁ is hydrogen; R ₂ is hydrogen; R _xvi is Z _a Z _b N-; Z _a and Z _b are each independently hydrogen or cycloalkyl; d is 1; Described are compounds of formula (1) wherein m is zero.

In another embodiment of the invention, A is formula (xvii),

R ₁ is hydrogen; R ₂ is hydrogen; R _xvii is aryl or Z _a Z _b N-; Z _a and Z _b are each independently hydrogen, alkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl or H ₂ NC (O) -alkyl-; d is 0 or 1; Described are compounds of formula (1) wherein m is zero.

In another embodiment of the invention, A is formula (xviii),

R ₁ is R _a R _b N-; R ₂ is hydrogen; R _a and R _b are each hydrogen; c is 0; Described are compounds of formula (1) wherein m is zero.

In another embodiment of the invention, A is formula (xix),

R ₁ is R _a R _b N-; R ₂ is hydrogen; R _a and R _b are each independently hydrogen; c is 0; Described are compounds of formula (1) wherein m is zero.

In another embodiment of the invention, A is formula (xx),

R ₁ is R _a R _b N-; R ₂ is hydrogen; R ₄ is R _j R _k N-alkyl-; R _a and R _b are each hydrogen or R ₄ -C (O) —; R _j and R _k are independently alkyl; R _xx is Z _a Z _b N- or heterocycle; Z _a and Z _b are independently hydrogen or alkyl; c is 0 or 1; Described are compounds of formula (1) wherein m is zero.

In another embodiment of the invention, A is of formula (xxi),

R ₁ is R _a R _b N-; R ₂ is hydrogen; R _a and R _b are each hydrogen; R _xxi is alkoxy; d is 1; Described are compounds of formula (1) wherein m is O.

In another embodiment of the invention, A is formula (xxii),

R ₁ is R _a R _b N-; R ₂ is hydrogen; R ₄ is R _j R _k N-alkyl-; R _a and R _b are each independently hydrogen or R ₄ -C (O) —; R _j and R _k are each alkyl; c is 0; Described are compounds of formula (1) wherein m is zero.

In another embodiment of the invention, A is formula (xxiii),

R ₁ is R _a R _b N-; R ₂ is hydrogen; R _a and R _b are each hydrogen; c is 0; Described are compounds of formula (1) wherein m is zero.

Particular embodiments contemplated as part of the present invention include, but are not limited to, compounds of Formula 1, for example:

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole and 5- (1-benzyl-1H-1,2,3-triazol-5-yl) -1H-indazole;

5- (1H-1,2,3-triazol-5-yl) -1H-indazole;

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole;

5- [1- (2-methylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (3-methylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (4-methylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (3-methoxybenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (2-fluorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (3-fluorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (4-fluorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (2-chlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (3-chlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (4-chlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (2-bromobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (2-nitrobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (3-nitrobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (4-nitrobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

2-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} benzonitrile;

3-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} benzonitrile;

4-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} benzonitrile;

5- {1- [2- (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;

5- {1- [3- (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;

5- {1- [4- (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;

5- {1- [3- (trifluoromethoxy) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;

5- {1- [4- (trifluoromethoxy) benzyl] -1 H-1,2,3-triazol-4-yl} -1 H-indazole;

5- [1- (4-tert-butylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

Methyl 3-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} benzoate;

Methyl 4-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} benzoate;

5- [1- (2,4-dimethylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (3,5-dimethylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (2,3-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (2,4-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (2,5-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1- (3,5-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- {1- [2,4-bis (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;

N-cyclohexyl-6- (1H-indazol-5-yl) imidazo [2,1-b] [1,3] thiazol-5-amine;

N-cyclohexyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyridin-3-amine;

N-cyclohexyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrazin-3-amine;

5- [1-benzyl-4- (4-fluorophenyl) -1H-imidazol-5-yl] -1H-indazole;

N- {3- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] propyl} -N, N-dimethylamine;

N-cyclohexyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine;

5- [4- (4-fluorophenyl) -1- (1-phenylethyl) -1H-imidazol-5-yl] -1H-indazole;

2- (1H-indazol-5-yl) -N-isopropylimidazo [1,2-a] pyrimidin-3-amine;

4- (1H-indazol-5-yl) -N-phenyl-1,3-thiazol-2-amine;

5- (2-methyl-1,3-thiazol-4-yl) -1H-indazole;

N-ethyl-4- (1H-indazol-5-yl) -1,3-thiazol-2-amine;

N-benzyl-4- (1H-indazol-5-yl) -1,3-thiazol-2-amine;

4- (1H-indazol-5-yl) -1,3-thiazol-2-amine;

4- (1H-indazol-5-yl) -N- (2-phenylethyl) -1,3-thiazol-2-amine;

N-benzyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine;

N-butyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine;

N- (4-chlorophenyl) -2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine;

2- (1H-indazol-5-yl) -N- (4-methoxyphenyl) imidazo [1,2-a] pyrimidin-3-amine;

2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidine;

Methyl N- [2- (1H-indazol-5-yl) imidazo [1,2-a] pyridin-3-yl] glycinate;

N-benzyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyridin-3-amine;

N- (4-chlorophenyl) -2- (1H-indazol-5-yl) imidazo [1,2-a] pyridin-3-amine;

2- (1H-indazol-5-yl) -N- (4-methoxyphenyl) imidazo [1,2-a] pyridin-3-amine;

Tert-butyl 4- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] piperidine-1-carboxylate;

3,5-bis (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole;

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -3-phenyl-1H-indazole;

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine;

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1-[(1-methylpiperidin-4-yl) carbonyl] -1 H-indazol-3-amine ;

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-methoxyacetamide;

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ^2, N ² - dimethyl-glycine amide;

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] butanamide;

5- [4- (4-fluorophenyl) -1-piperidin-4-yl-1H-imidazol-5-yl] -1H-indazole;

5- {4- (4-fluorophenyl) -1- [2- (1-methylpyrrolidin-2-yl) ethyl] -1H-imidazol-5-yl} -1H-indazole;

5- {4- (4-fluorophenyl) -1- [3- (4-methylpiperazin-1-yl) propyl] -1H-imidazol-5-yl} -1H-indazole;

Ethyl 5- (1H-indazol-5-yl) isoxazole-3-carboxylate;

5- (1H-indazol-5-yl) -N-methylisoxazole-3-carboxamide;

5- (3-benzylisoxazol-5-yl) -1H-indazole;

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide;

5- (3-propylisoxazol-5-yl) -1H-indazole;

N-benzyl-4- (1H-indazol-5-yl) -5-phenyl-1,3-thiazol-2-amine;

4- (1H-indazol-5-yl) -N, 5-diphenyl-1,3-thiazol-2-amine;

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazole;

5- (1-benzyl-4-cyclopropyl-1H-1,2,3-triazol-5-yl) -1H-indazole;

2- (1H-indazol-5-yl) -3-phenylimidazo [1,2-a] pyrimidine;

5- [1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [3- (piperidin-1-ylcarbonyl) isoxazol-5-yl] -1H-indazole;

5- (1H-indazol-5-yl) -N-phenylisoxazole-3-carboxamide;

N-cyclohexyl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

5- [3- (piperidin-1-ylmethyl) isoxazol-5-yl] -1H-indazole;

[5- (1H-indazol-5-yl) isoxazol-3-yl] methanol;

5- (1H-indazol-5-yl) -N- (2-methoxyethyl) isoxazole-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-yl) -1H-indazole;

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine;

5- (1-benzyl-4-cyclopropyl-1H-1,2,3-triazol-5-yl) -1H-indazol-3-amine;

5- (3-isobutylisoxazol-5-yl) -1H-indazol-3-amine;

5- (3-benzylisoxazol-5-yl) -1H-indazol-3-amine;

N- {2- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] ethyl} -N, N-dimethylamine;

5- [4- (4-fluorophenyl) -1- (3-morpholin-4-ylpropyl) -1H-imidazol-5-yl] -1H-indazole;

5- [4- (4-fluorophenyl) -1- (3-pyrrolidin-1-ylpropyl) -1H-imidazol-5-yl] -1H-indazole;

5- {4- (4-fluorophenyl) -1- [2- (4-methylpiperidin-1-yl) ethyl] -1H-imidazol-5-yl} -1H-indazole;

5- [1- (1-benzylpiperidin-4-yl) -4- (4-fluorophenyl) -1H-imidazol-5-yl] -1H-indazole;

5- [4- (4-fluorophenyl) -1- (2-morpholin-4-ylethyl) -1H-imidazol-5-yl] -1H-indazole;

5- [1- (1-benzylpyrrolidin-3-yl) -4- (4-fluorophenyl) -1H-imidazol-5-yl] -1H-indazole;

2- {4- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] piperidin-1-yl} -2-oxo ethanol;

5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine;

2- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] propan-2-ol;

5- [4- (methoxymethyl) -1H-1,2,3-triazol-1-yl] -1H-indazole;

1- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] -1-phenylethanol;

5- (4-propyl-1H-1,2,3-triazol-1-yl) -1H-indazole;

1- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] propan-2-ol;

3- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] propan-1-ol;

1-{[1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] methyl} -1H-1,2,3-benzotriazole;

5- {4-[(phenylthio) methyl] -1H-1,2,3-triazol-1-yl} -1H-indazole;

5- (4-cyclopropyl-1H-1,2,3-triazol-1-yl) -1H-indazole;

5- [4- (2-phenylethyl) -1H-1,2,3-triazol-1-yl] -1H-indazole;

5- [4- (cyclohexylmethyl) -1H-1,2,3-triazol-1-yl] -1H-indazole;

5- (4-cyclopentyl-1H-1,2,3-triazol-1-yl) -1H-indazole;

1- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] cyclohexanol;

5- [4- (phenoxymethyl) -1H-1,2,3-triazol-1-yl] -1H-indazole;

5- {4-[(1,1-dioxydothiomorpholin-4-yl) methyl] -1H-1,2,3-triazol-1-yl} -1H-indazole;

5- [4- (3-phenylpropyl) -1H-1,2,3-triazol-1-yl] -1H-indazole;

[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] (phenyl) methanone;

N, N-diethyl-N-{[1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] methyl} amine;

Ethyl N- [2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-yl] -β-alanineate;

5- (1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl) -1H-indazole;

5- (1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine;

N ^3- [2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-yl] -β-alaninamide;

5- (1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine;

N- {3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] phenyl} -N '-(3 -Methylphenyl) urea;

5- (1H-indazol-5-yl) -N- (2-isopropoxyethyl) isoxazole-3-carboxamide;

5- [3- (morpholin-4-ylcarbonyl) isoxazol-5-yl] -1H-indazole;

5- (1H-indazol-5-yl) -N- (3-morpholin-4-ylpropyl) isoxazole-3-carboxamide;

N- [2- (1H-imidazol-4-yl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

(3R) -1-{[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} piperidin-3-ol;

1-{[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} piperidine-3-carboxamide;

2- [2- (4-{[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} piperazin-1-yl) ethoxy] ethanol;

5- {3-[(4-methyl-1,4-diazepan-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole;

N- (3-hydroxypropyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N-[(1R) -2-hydroxy-1-phenylethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N- [3- (1H-imidazol-1-yl) propyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- [3- (2-oxopyrrolidin-1-yl) propyl] isoxazole-3-carboxamide;

N- {2- [4- (aminosulfonyl) phenyl] ethyl} -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] (3-chlorophenyl) methanone;

[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] (cyclopropyl) methanone;

5- [5-cyclopropyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

N ¹ -{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] methyl} glycinamide;

(4-fluorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5- General] metanon;

(4-chlorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl ] Methanone;

(3-chlorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl ] Methanone;

(2-chlorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl ] Methanone;

Cyclopentyl [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl] methanone;

1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxylic acid;

5- {5- (4-fluorophenyl) -1- [4- (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3- Amines;

5- [1-benzyl-5- (4-fluorophenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine;

[4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl] (tetrahydro-2H -Pyran-4-yl) methanone;

5- [1-benzyl-5- (2-methylphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- {1-benzyl-5-[(4-methylpiperazin-1-yl) carbonyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;

1-{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] carbonyl} piperidin-4-ol;

1-acetyl-5- [5- (4-fluorophenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H -Indazole;

1-benzyl-4- (1H-indazol-5-yl) -N, N-dimethyl-1H-1,2,3-triazole-5-carboxamide;

N, 1-dibenzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide;

N- (2-hydroxy-2-phenylethyl) -5- (1H-indazol-5-yl) -N-methylisoxazole-3-carboxamide;

N-[(1S) -2-hydroxy-1-phenylethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N-benzyl-N- (2-hydroxyethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

5- [1-benzyl-5- (2-methylphenyl) -1H-1,2,3-triazol-4-yl] -3-methyl-1H-indazole;

5- [1-benzyl-5- (2-methylphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine;

2- {2- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] ethyl} -1H-isoindole-1,3 (2H) -dione ;

5- {4-[(2,4-dichlorophenoxy) methyl] -1 H-1,2,3-triazol-1-yl} -1 H-indazole;

5- {4-[(2,6-dichlorophenoxy) methyl] -1H-1,2,3-triazol-1-yl} -1H-indazole;

5- [5- (4-fluorophenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

1-{[1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] methyl} -1H-indazole;

5- [1-benzyl-5- (piperidin-1-ylcarbonyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [5- (2-methylphenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [5- (2-methylphenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3- Amines;

5- [1-benzyl-5- (morpholin-4-ylcarbonyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;

5- [1-benzyl-5- (4-methoxyphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine;

N-[(1S) -1-benzyl-2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N-[(1S, 2R) -2-hydroxy-2,3-dihydro-1H-inden-1-yl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide ;

5- {3-[(3-phenylmorpholin-4-yl) carbonyl] isoxazol-5-yl} -1H-indazole;

N-benzyl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

((1S) -2-{[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} -6,7-dimethoxy-1,2,3,4-tetrahydroiso Quinolin-1-yl) methanol;

N-[(1R) -3-hydroxy-1-phenylpropyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N-[(1S) -3-hydroxy-1-phenylpropyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N-2,3-dihydro-1H-inden-1-yl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N-2,3-dihydro-1H-inden-2-yl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- (1-phenylpropyl) isoxazole-3-carboxamide;

5- {1-benzyl-5- [3- (dimethylamino) phenyl] -1 H-1,2,3-triazol-4-yl} -1 H-indazol-3-amine;

5- {1-benzyl-5- [4- (dimethylamino) phenyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3-amine;

N- {3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] phenyl} acetamide;

N- {4- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] phenyl} acetamide;

5- {1-benzyl-5- [3- (1H-pyrazol-1-yl) phenyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3-amine;

5- [1-benzyl-5- (1-methyl-1H-pyrazol-4-yl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine;

3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] -N-phenylbenzamide;

3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] -N-benzylbenzamide;

5- [1-benzyl-5- (1-methyl-1H-indol-5-yl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine;

5- [1-benzyl-5- (3-methoxyphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine;

5- [1-benzyl-5- (3-morpholin-4-ylphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine;

5- [3- (1,3-dihydro-2H-isoindol-2-ylcarbonyl) isoxazol-5-yl] -1H-indazole;

5- {3-[(4-methyl-2-phenylpiperazin-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole;

1-{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] carbonyl} piperidin-4-amine;

N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide;

N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzenesulfonamide;

N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N '-(4-methoxyphenyl) Urea;

N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] butanamide;

N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-methylpropanamide;

N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] cyclopropanecarboxamide;

N- [1-benzoyl-5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -3-fluorobenzamide;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide;

N-benzyl-5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine;

N-[(1R) -1-benzyl-2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

5- (1-benzyl-1H-pyrazol-4-yl) -1H-indazole;

N-[(1R) -3-hydroxy-1-phenylpropyl] -5- (3-methyl-1H-indazol-5-yl) isoxazole-3-carboxamide;

3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] phenol;

3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] benzamide;

5- {1-benzyl-5- [4- (methylsulfonyl) phenyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3-amine;

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-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -4-chlorobenzamide;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] ethanesulfonamide;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzenesulfonamide;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-chlorobenzenesulfonamide;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -3-chlorobenzenesulfonamide;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -4-chlorobenzenesulfonamide;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2,5-dimethylfuran-3- Sulfonamides;

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N- (2-chlorobenzyl) -1H-indazol-3-amine;

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N- (3-chlorobenzyl) -1H-indazol-3-amine;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -3-chlorobenzamide;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-puramide;

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N-ethyl-1H-indazol-3-amine;

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N- (4-chlorobenzyl) -1H-indazol-3-amine;

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N- (3-furylmethyl) -1H-indazol-3-amine;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N '-[5-methyl-2 -(Trifluoromethyl) -3-furyl] urea;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -3-puramide;

5- (1H-indazol-5-yl) -N-[(1S) -1-phenylpropyl] isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N-[(1R) -1-phenylpropyl] isoxazole-3-carboxamide;

5- (1-benzyl-1H-pyrazol-4-yl) -1H-indazol-3-amine;

1-benzyl-4- (1H-indazol-5-yl) -N-[(2S) -tetrahydrofuran-2-ylmethyl] -1H-1,2,3-triazole-5-carboxamide ;

1-benzyl-4- (1H-indazol-5-yl) -N- (2-isopropoxyethyl) -1H-1,2,3-triazole-5-carboxamide;

1-benzyl-4- (1H-indazol-5-yl) -N-[(2R) -tetrahydrofuran-2-ylmethyl] -1H-1,2,3-triazole-5-carboxamide ;

1-benzyl-4- (1H-indazol-5-yl) -N- (tetrahydrofuran-3-ylmethyl) -1H-1,2,3-triazole-5-carboxamide;

1-benzyl-N-cyclopentyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide;

1-benzyl-N- (cyclopentylmethyl) -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide;

1-benzyl-N-ethyl-4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide;

1-benzyl-4- (1H-indazol-5-yl) -N-isopropyl-N-methyl-1H-1,2,3-triazole-5-carboxamide;

1-benzyl-4- (1H-indazol-5-yl) -N- (2-methoxyethyl) -N-methyl-1H-1,2,3-triazole-5-carboxamide;

1-benzyl-4- (1H-indazol-5-yl) -N-phenyl-1H-1,2,3-triazole-5-carboxamide;

1-benzyl-N- (4-chlorophenyl) -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide;

1-benzyl-4- (1H-indazol-5-yl) -N- (2-morpholin-4-ylethyl) -1H-1,2,3-triazole-5-carboxamide;

1-benzyl-N- [2- (dimethylamino) ethyl] -4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide;

1-benzyl-N- (2-hydroxyethyl) -4- (1H-indazol-5-yl) -N-propyl-1H-1,2,3-triazole-5-carboxamide;

1-benzyl-N- [3- (dimethylamino) propyl] -4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide;

1-benzyl-N- [2- (diethylamino) ethyl] -4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide ;

N, 1-dibenzyl-N-ethyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-carboxamide;

N, 1-dibenzyl-N- (2-hydroxyethyl) -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide;

(3R) -1-{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] carbonyl} piperidin-3-ol ;

1-{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] carbonyl} piperidine-4-carboxamide;

5- {1-benzyl-5-[(2,6-dimethylmorpholin-4-yl) carbonyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;

5- {5-[(4-acetylpiperazin-1-yl) carbonyl] -1-benzyl-1H-1,2,3-triazol-4-yl} -1H-indazole;

5- {1-benzyl-5-[(4-phenylpiperazin-1-yl) carbonyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;

1-benzyl-N-[(1R) -1- (hydroxymethyl) -2-methylpropyl] -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5 Carboxamide;

1-benzyl-N-[(1S) -1- (hydroxymethyl) -2-methylpropyl] -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5 Carboxamide;

1-benzyl-N- [3- (1H-imidazol-1-yl) propyl] -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carbox amides;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N'-ethylurea;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N'-phenylurea;

N-benzyl-N '-[5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] urea;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N '-(2-chlorophenyl) Urea;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N '-(3-chlorophenyl) Urea;

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N '-(4-chlorophenyl) Urea;

N- [5- (1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide;

3- [4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] propanenitrile;

2- [4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] acetamide;

Methyl 3- [4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] propanoate;

3- [4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] propanamide;

[4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] acetonitrile;

4- (3-amino-1 H-indazol-5-yl) -N, N-dimethyl-1 H-imidazole-1-sulfonamide;

5-pyrazin-2-yl-1H-indazol-3-amine;

5-thien-2-yl-1H-indazol-3-amine;

5- (2-aminopyrimidin-4-yl) -1H-indazol-3-amine;

5- (2-methoxypyridin-3-yl) -1 H-indazol-3-amine;

5-imidazo [1,2-a] pyridin-3-yl-1H-indazol-3-amine;

N ² , N ² -dimethyl-N ^1- [5- (1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] glycinamide;

5- (1H-pyrazol-5-yl) -1H-indazol-3-amine;

5- (4-methyl-1H-imidazol-5-yl) -1H-indazol-3-amine;

5- (1H-imidazol-4-yl) -1H-indazol-3-amine;

N ^2, N ² - dimethyl ^{-N 1 - {5- [1- (} 3- methyl-benzyl) -1H-1,2,3- triazol-4-yl] -1H- indazol-3-yl} glycine amides;

5- (1-benzyl-1H-imidazol-4-yl) -1H-indazol-3-amine;

^{N 1 - {5- [1- (} 4-3 -tert-butylbenzyl) -1H-1,2,3- triazol-4-yl] -1H- indazol-3-yl} -N ^2, N ² Dimethylglycineamide;

N ^2, N ² - dimethyl ^{-N 1 - {5- [1- (} 2- piperidin-1-yl-ethyl) -1H-1,2,3- triazol-4-yl] -1H- indazole -3-yl} glycineamide;

N ^2, N ² - dimethyl ^{-N 1 - {5- [1- (} 2- morpholin-4-yl-ethyl) -1H-1,2,3- triazol-4-yl] -1H- indazole- 3-yl} glycineamide;

^{N 1 - (5- {1- [} 2- (3,5- dimethyl-4-yl in) ethyl] -1H-1,2,3- triazol-4-yl} -1H- indazol- 3-yl) -N ² , N ² -dimethylglycinamide;

^{N 1 - (5- {1- [} 2- (3,5- dimethyl -1H- pyrazol-4-yl) ethyl] -1H-1,2,3- triazol-4-yl} -1H- indazol Zol-3-yl) -N ² , N ² -dimethylglycinamide;

2- (4- {3-[(N, N-dimethylglycyl) amino] -1H-indazol-5-yl} -1H-1,2,3-triazol-1-yl) -2-methyl Propanoic acid;

Ethyl (4- {3-[(N, N-dimethylglycyl) amino] -1H-indazol-5-yl} -1H-1,2,3-triazol-1-yl) acetate;

N ² , N ² -dimethyl-N ^1- (5- {1-[(trimethylsilyl) methyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3-yl) Glycinamide;

N ^1- [5- (3-furyl) -1H-indazol-3-yl] -N ² , N ² -dimethylglycinamide;

N ² , N ² -dimethyl-N ^1- [5- (1H-pyrazol-5-yl) -1H-indazol-3-yl] glycinamide;

N ² , N ² -dimethyl-N ^1- (5-pyrimidin-5-yl-1H-indazol-3-yl) glycinamide;

N ^1- [5- (2,1,3-benzoxadiazol-5-yl) -1H-indazol-3-yl] -N ² , N ² -dimethylglycinamide;

N ² , N ² -dimethyl-N ^1- [5- (1H-pyrazol-4-yl) -1H-indazol-3-yl] glycinamide;

N ^2, N ² - dimethyl -N ¹ - [5- (1- methyl -1H- pyrazol-4-yl) -1H- indazol-3-yl] glycine amide;

N ^1- [5- (3,5-dimethyl-1H-pyrazol-4-yl) -1H-indazol-3-yl] -N ² , N ² -dimethylglycinamide;

N ^1- {5- [2- (dimethylamino) pyrimidin-5-yl] -1H-indazol-3-yl} -N ² , N ² -dimethylglycinamide;

N ² , N ² -dimethyl-N ^1- [5- (2-morpholin-4-ylpyrimidin-5-yl) -1H-indazol-3-yl] glycinamide;

N ^2, N ² - dimethyl ^{-N 1 - {5- [1- (} 2- morpholin-4-ylethyl) -1H- pyrazol-4-yl] -1H- indazol-3-yl} glycine amide ;

N ¹ - [5- (1- benzyl-5-cyclopropyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ^2, N ² - dimethyl glycine amides;

N ¹ - [5- (1- benzyl -1H- pyrazol-4-yl) -1H- indazol-3-yl] -N ^2, N ² - dimethyl-glycine amide;

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ² - methyl glycine amide;

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-pyrrolidin-1-ylacetamide;

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ² - cyclopentyl-glycine amide;

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ² - cyclopropyl-glycine amide;

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ² - tetrahydro -2H- pyran-4-yl Glycinamide;

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2- (3-hydroxypyrrolidin-1-yl Acetamide;

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2- (3-hydroxypiperidin-1-yl Acetamide;

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ^3, N ³ - dimethyl -β- alanine amide;

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-morpholin-4-ylacetamide;

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2- (4-methylpiperazin-1-yl) acet amides;

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2- (3-oxopiperazin-1-yl) acet amides;

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ² - isopropyl-glycine amide;

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ² - cyclohexyl-glycine amide;

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] acetamide;

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ² - cyclobutyl glycine amide;

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N'-propylurea;

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] ethanesulfonamide;

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -N- (cyclopropylmethyl) -1H-indazol-3-amine;

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N'-ethylurea;

1- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] pyrrolidin-2-one;

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -4- (dimethylamino) butanamide;

N-3,4-dihydro-1H-isochromen-4-yl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N- (cyclohexylmethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N- (3-chlorobenzyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- (2-methoxybenzyl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- [2- (trifluoromethyl) benzyl] isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- [3- (trifluoromethyl) benzyl] isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- [4- (trifluoromethyl) benzyl] isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- (pyridin-2-ylmethyl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- (pyridin-3-ylmethyl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- (pyridin-4-ylmethyl) isoxazole-3-carboxamide;

N- (2-chlorobenzyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N- (4-chlorobenzyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- (1-phenyl-2-piperidin-1-ylethyl) isoxazole-3-carboxamide;

N- [2- (1H-imidazol-1-yl) -1-phenylethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- (2-morpholin-4-yl-1-phenylethyl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- [2- (4-methylpiperazin-1-yl) -1-phenylethyl] isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- (1-phenyl-2-pyrrolidin-1-ylethyl) isoxazole-3-carboxamide;

Tert-butyl 2-({[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} amino) -2-phenylethylcarbamate;

5- (1H-indazol-5-yl) -N- (1-naphthylmethyl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- (2-phenylethyl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- (2-pyridin-2-ylethyl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- (2-pyridin-3-ylethyl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N- (2-pyridin-4-ylethyl) isoxazole-3-carboxamide;

N- [2- (2-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N- [2- (3-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N- [2- (4-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N-benzyl-N-ethyl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N-methyl-N- (1-naphthylmethyl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N-methyl-N- (2-phenylethyl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N-methyl-N- (2-pyridin-2-ylethyl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N-[(1R) -1-phenylethyl] isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N-1,2,3,4-tetrahydronaphthalen-1-ylisoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N-[(1S) -1- (1-naphthyl) ethyl] isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N-[(1R) -1- (1-naphthyl) ethyl] isoxazole-3-carboxamide;

N- [3- (dimethylamino) -1-phenylpropyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N- (2,3-dihydro-1,4-benzodioxin-5-ylmethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N- (3,4-dihydro-2H-1,5-benzodioxepin-6-ylmethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N-[(1-methyl-1H-indol-4-yl) methyl] isoxazole-3-carboxamide;

5- {3-[(3-phenylpyrrolidin-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole;

5- {3-[(2-phenylpyrrolidin-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole;

5- {3-[(2-phenylpiperidin-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole;

5- (1H-indazol-5-yl) -N-[(1S) -1-phenylethyl] isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N-[(1R) -1- (4-methylphenyl) ethyl] isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N-[(1S) -1- (4-methylphenyl) ethyl] isoxazole-3-carboxamide;

N-[(1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide ;

N-[(1R, 2R) -2-hydroxy-2,3-dihydro-1H-inden-1-yl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide ;

N-[(1R) -1- (4-bromophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N-[(1S) -1- (4-bromophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N-[(1R) -1- (4-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N-[(1S) -1- (4-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N-[(1S) -1- (2-naphthyl) ethyl] isoxazole-3-carboxamide;

N- [1- (4-ethoxyphenyl) -2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N- [2-hydroxy-1- (4-isopropylphenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N- [1- (3,4-dimethylphenyl) -2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N- [2-hydroxy-1- (2-methoxyphenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

N- [2-hydroxy-1- (4-methylphenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N-[(1R) -1- (2-methoxyphenyl) ethyl] isoxazole-3-carboxamide;

N-[(1S) -1- (3,4-difluorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N-[(1R) -1- (3-methoxyphenyl) ethyl] isoxazole-3-carboxamide;

5- (1H-indazol-5-yl) -N-{(1R) -1- [3- (trifluoromethyl) phenyl] ethyl} isoxazole-3-carboxamide;

N- [1- (2,3-dihydro-1,4-benzodioxin-6-yl) ethyl] -5- (1H-indazol-5-yl) isoxazole-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-yl) -3-[({[6- (trifluoromethyl) pyridin-2-yl] amino} carbo Yl) amino] -1 H-indazole-1-carboxylate;

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1-[(1-methylpiperidin-2-yl) carbonyl] -1H-indazol-3-amine ;

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1-[(dimethylamino) acetyl] -1H-indazol-3-amine;

Level 3-Butyl 3-amino-5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-1-carboxylate;

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-piperidin-1-ylacetamide;

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-morpholin-4-ylacetamide; And

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -1-methylpiperidine-2-carboxamide

All patents, patent applications, and references cited herein are hereby incorporated by reference in their entirety. In case of inconsistency, the present specification, including definitions, will control.

As used throughout this specification and the appended claims, the following terms have the following meanings:

As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon of 2 to 10 carbon atoms containing one or more carbon-carbon double bonds formed by the removal of two hydrogens. Examples of representative alkenyl are ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-hep Tenyl and 3-decenyl, including but not limited to.

The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative alkoxy examples include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy.

The term "alkoxyalkoxy" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein. Representative alkoxyalkoxy examples include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 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, as defined herein. Examples of representative alkoxyalkoxyalkyls include, but are not limited to, tert-butoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy) methyl and 2- (2-methoxyethoxy) ethyl Do not.

The term "alkoxyalkyl" as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative alkoxyalkyl examples 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 alkoxycarbonyls 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. Examples of representative alkoxycarbonylalkyls include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl and 2-3-butoxycarbonylethyl.

As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon of 1 to 10 carbon atoms. Examples of representative alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, secondary-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3 -Methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

The term "alkylcarbonyl" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Examples of representative alkylcarbonyls include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl.

The term "alkylcarbonylalkyl" as used herein, means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Examples of representative alkylcarbonylalkyls include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl and 3-oxopentyl.

The term "alkylcarbonyloxy" as used herein, means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative alkylcarbonyloxy examples include, but are not limited to, acetyloxy, ethylcarbonyloxy and tert-butylcarbonyloxy.

The term "alkylene" means a divalent group derived from straight or branched chain hydrocarbons having 1 to 10 carbon atoms. Examples of representative alkylenes are -CH _2- , -CH (CH ₃ )-, -C (CH ₃ ) _2- , -CH ₂ CH _2- , -CH ₂ CH ₂ CH ₂ CH, and -CH ₂ CH ₂ CH ₂ CH ₂ -and —CH ₂ CH (CH ₃ ) CH ₂ —, including but not limited to.

The term "alkylene-NR _g- " as used herein, means an alkylene group, as defined herein, appended to the parent molecular moiety through the -NR _g -group, as defined herein.

The term "alkylsulfinyl" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein. Representative alkylsulfinyl examples include, but are not limited to, methylsulfinyl and ethylsulfinyl.

The term "alkylsulfinylalkyl" as used herein, means an alkylsulfinyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Examples of representative alkylsulfinylalkyls 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. Examples of representative alkylsulfonyls include, but are not limited to, methylsulfonyl and ethylsulfonyl.

The term "alkylsulfonylalkyl" as used herein, means an alkylsulfonyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Examples of representative alkylsulfonylalkyls include, but are not limited to, methylsulfonylmethyl and ethylsulfonylmethyl.

The term "alkylthio" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Examples of representative alkylthios include, but are not limited to, methylthio, ethylthio, tert-butylthio and hexylthio.

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. Examples of representative alkylthioalkyls include, but are not limited to, methylthiomethyl and 2- (ethylthio) ethyl.

As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon group of 2 to 10 carbon atoms containing one or more carbon-carbon triple bonds. Representative alkynyl examples include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl and 1-butynyl.

As used herein, the term "aryl" means phenyl, acyclic aryl or tricyclic aryl. Bicyclic aryl is naphthyl, phenyl fused to cycloalkyl or phenyl fused to cycloalkenyl, or phenyl fused to a monocyclic heteroaryl ring as defined herein, or monocysine as defined herein. Phenyl fused to a click heterocycle. Bicyclic aryls of the invention must be attached to the parent molecular moiety through the available carbon atoms contained in the phenyl ring. Examples of representative bicyclic aryls are 2,3-dihydro-1,4-benzodioxin-5-yl, 2,3-dihydro-1,4-benzodioxin-6-yl, 3,4- Dihydro-2H-1,5-benzodioxepin-6-yl, dihydroindenyl, indenyl, indol-4-yl, naphthyl, dihydronaphthalenyl and tetrahydronaphthalenyl It is not limited. Tricyclic aryl is anthracene or phenanthrene, or bicyclic aryl fused to cycloalkyl, or bicyclic aryl fused to cycloalkenyl, or bicyclic aryl fused to phenyl. Tricyclic aryl is attached to the parent molecular moiety through any carbon atom contained in tricyclic aryl. Examples of representative tricyclic aryl rings include, but are not limited to, azulenyl, dihydroanthracenyl, fluorenyl and tetrahydrophenanthrenyl.

The aryl groups of the present invention are alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfinyl, Alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, aryl ^* NC (O)-, aryl ^* NHC (O) NH-, carboxy, carboxyalkyl, cyano, cya Noalkyl, formyl, formylalkyl, halogen, haloalkyl, heteroaryl, hydroxy, hydroxyalkyl, mercapto, morpholino, nitro, Z ₁ Z ₂ N- and (Z ₃ Z ₄ N) carbonyl Optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Aryl ^* is optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, halo, cyano or nitro. Z ₁ And Z ₂ are each independently selected from hydrogen, alkyl or alkylcarbonyl.

As used herein, the term "aryloxy" refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative aryloxy examples include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy and 3,5-dimethoxyphenoxy.

The term "aryloxyalkyl" as used herein, means an aryloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Examples of representative aryloxyalkyls 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. Examples of representative arylalkyls include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl 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 comprising one hydroxy group, as defined herein. do. Examples of representative aryl (hydroxy) alkyls include, but are not limited to, 2-phenylethanol-2-yl and 2-hydroxy-2-phenylethanyl.

The term "arylcarbonyl" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Examples of representative arylcarbonyls 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. Examples of representative arylthios include, but are not limited to, phenylthio and 2-naphthylthio.

The term "arylthioalkyl" as used herein, means an arylthio group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative arylthioalkyl examples include, but are not limited to, phenylthiomethyl, 2-naphth-2-ylthioethyl and 5-phenylthiomethyl.

The term "azido" as used herein, means a -N ₃ 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.

As used herein, the term "carbonyl" refers to the group -C (O)-.

The term "carboxy" as used herein, means a -CO ₂ H group.

The term "carboxyalkyl" as used herein, means a carboxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Examples of representative carboxyalkyls include, but are not limited to, carboxymethyl, 2-carboxyethyl and 3-carboxypropyl.

As used herein, the term "cyano" refers to a -CN group.

The term "cyanoalkyl" as used herein, means a cyano group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Examples of representative cyanoalkyls include, but are not limited to, cyanomethyl, 2-cyanoethyl and 3-cyanopropyl.

As used herein, the term “cycloalkenyl” refers to a monocyclic or bicyclic ring system having 3 to 10 carbon atoms containing one or more carbon-carbon double bonds formed by the removal of two hydrogens. Examples of representative monocyclic ring systems include 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yl and 3-cyclopenten-1-yl This is not restrictive. Bicyclic ring systems include monocyclic cycloalkenyl ring systems fused to another monocyclic cycloalkyl ring as defined herein, a monocyclic aryl ring as defined herein, as defined herein Such as monocyclic heterocycles or monocyclic heteroaryls as defined herein. The bicyclic ring system of the present invention must be attached to the parent molecular moiety through available carbon atoms in the cycloalkenyl ring. Examples of representative bicyclic ring systems are 4,5-dihydro-benzo [1,2,5] oxadiazoles, 3a, 4,5,6,7,7a-hexahydro-1H-indenyl, 1, 2,3,4,5,6-hexahydro-pentalenyl, 1,2,3,4,4a, 5,6,8a-octahydro-pentalenyl.

As used herein, the term "cycloalkyl" refers to a monocyclic, bicyclic or spirocyclic ring system. Monocyclic ring systems are exemplified by saturated cyclic hydrocarbon groups having 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The bicyclic cycloalkyl group of the invention is a monocyclic cycloalkyl ring fused to another monocyclic cycloalkyl ring, or a monocyclic cycloalkyl ring fused to cycloalkenyl, or a mono fused to a phenyl ring To a cyclic cycloalkyl ring, or to a monocyclic cycloalkyl ring fused to a monocyclic heteroaryl ring as defined herein or to a monocyclic cycloalkyl ring fused to a monocyclic heterocycle as defined herein Is illustrated. Bicyclic cycloalkyl ring systems of the invention must be attached to the parent molecular moiety through available carbon atoms in the monocycloalkyl ring.

Cycloalkyl groups of the invention are alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl , Carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, oxo, Z ₁ Z ₂ N- And 1, 2, 3 or 4 substituents selected from (Z ₃ Z ₄ N) carbonyl.

As used herein, the term "cycloalkylalkyl" refers to a cycloalkyl group attached to the parent molecular moiety through an alkyl group as defined herein.

As used herein, the term “cycloalkylcarbonyl” refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative cycloalkylcarbonyl examples include, but are not limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl, and cyclohexylcarbonyl.

As used herein, the term "formyl" refers to the group -C (O) H.

As used herein, the term “formylalkyl” refers to a formyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Examples of representative formylalkyl include, but are not limited to, formylmethyl and 2-formylethyl.

As used herein, the term "halo" or "halogen" means -Cl, -Br, -I or -F.

As used herein, the term "haloalkoxy" means one or more halogen as defined herein, attached to the parent molecular moiety through an alkoxy group as defined herein. Representative haloalkoxy examples include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy and pentafluoroethoxy.

As used herein, the term "haloalkyl" means one or more halogen as defined herein, attached to the parent molecular moiety through an alkylene group as defined herein. Representative haloalkyl examples include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

As used herein, the term “heteroaryl” refers to monocyclic heteroaryl or bicyclic heteroaryl. Monocyclic heteroaryl is a 5 or 6 membered ring containing one or more heteroatoms independently selected from O, N or S. The five-membered ring contains two double bonds and may contain one, two, three or four heteroatoms. The six-membered ring contains three double bonds and may contain one, two, three or four heteroatoms. 5 or 6 membered heteroaryl is attached to the parent molecular moiety via any carbon atom or any nitrogen atom contained within heteroaryl. Examples of representative monocyclic heteroaryls are furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, Tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl. Bicyclic heteroaryl is a monocyclic heteroaryl fused to a monocyclic aryl ring as defined herein, a monocyclic cycloalkyl ring as defined herein, a monocyclic cycloal as defined herein A kenyl ring, another monocyclic heteroaryl or monocyclic heterocycle ring as defined herein. Bicyclic heteroaryl ring systems of the present invention must be attached to the parent molecular moiety through available carbon atoms in the heteroaryl ring. Bicyclic heteroaryl is attached to the parent molecular moiety via any carbon atom or any nitrogen atom contained within the bicyclic heteroaryl. Examples of representative bicyclic heteroaryls are benzofuranyl, benzoxadiazolyl, 1,3-benzothiazolyl, benzimidazolyl, benzodioxolyl, benzothiophenyl, chromenyl, cinnolinyl, furopyridine, indole Reels, indazolyl, isoindolinyl, isoquinolinyl, naphthyridinyl, oxazolopyridine, quinolinyl, thienopyridine and thienopyridinyl.

Heteroaryl groups of the present invention are alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, Alkylthioalkyl, alkynyl, benzyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, Z ₁ Z ₂ N- And Optionally substituted with 1, 2, 3 or 4 substituents independently selected from (Z ₃ Z ₄ N) carbonyl. Substituted heteroaryl groups of the invention may exist as tautomers. The present invention includes all tautomers, including non-aromatic tautomers.

As used herein, the term “heteroarylalkyl” refers to a heteroaryl group attached to the parent molecular moiety through an alkyl group as defined herein.

As used herein, the term “heterocycle” or “heterocyclic” means a monocyclic, bicyclic, tricyclic or spirocyclic ring system containing one or more heteroatoms. Monocyclic heterocycles are 3, 4, 5, 6 or 7 membered rings containing one or more heteroatoms independently selected from the group consisting of O, N and S. The three or four membered ring contains one heteroatom selected from the group consisting of O, N and S. 5-membered rings contain 0 or 1 double bonds and 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains 0, 1 or 2 double bonds and 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S. Monocyclic heterocycles are attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Examples of representative monocyclic heterocycles are azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1, 3-dithianil, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, isoindolin-1,3-dione, morpholinyl, oxa Diazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetra Hydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxydothiomorpholinyl (thiomorpholine sulfone), thiopyranyl and tri Thianyl, but is not limited thereto. The bicyclic heterocycles of the present invention are monocyclic heterocycles fused to phenyl groups, cycloalkyl groups as defined herein, cycloalkenyl groups as defined herein, another as defined herein A monocyclic heterocycle group, or one carbon atom of a monocyclic heterocycle, is defined as a spirocyclic ring bridged by two ends of an alkylene chain. Bicyclic heterocycles of the invention are attached to the parent molecular moiety via any carbon atom or any nitrogen atom contained in the heterocyclic ring. Examples of representative bicyclic heterocycles include 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxyyl, 2,3-dihydro-1- Benzofuranyl, 2,3-dihydro-1-benzothienyl, 3,4-dihydro-1H-isochromen-4-yl, 2,3-dihydro-1H-indolyl, succinimidyl and 1,2,3,4-tetrahydroquinolinyl, including but not limited to. Tricyclic heterocycles are fused to bicyclic heterocycles fused to phenyl, or bicyclic heterocycles fused to cycloalkyl, or bicyclic heterocycles fused to cycloalkenyl, or monocyclic heterocycles. Bicyclic heterocycle. Tricyclic heterocycles are attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the tricyclic heterocycle. Examples of representative tricyclic heterocycles are 2,3,4,4a, 9,9a-hexahydro-1H-carbazolyl, 5a, 6,7,8,9,9a-hexahydrodibenzo [b, d] Furanyl and 5a, 6,7,8,9,9a-hexahydrodibenzo [b, d] thienyl.

Heterocycles of the invention are alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkyl Thioalkyl, alkynyl, aryl, benzyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, hydroxyalkylcarbonyl, hydroxyalkoxyalkyl , Mercapto, oxo, Z ₁ Z ₂ N- And Optionally substituted with 1, 2 or 3 substituents independently selected from (Z ₃ Z ₄ N) carbonyl.

As used herein, the term “heterocyclealkyl” refers to a heterocycle group bonded to the parent molecular moiety through an alkyl group as defined herein.

As used herein, the term “heterocyclecarbonyl” refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.

As used herein, the term "hydroxy" refers to an -OH group.

As used herein, the term “hydroxyalkyl” refers to one or more hydroxy groups, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative hydroxyalkyl examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl and 2-ethyl-4-hydroxyheptyl.

The term "hydroxyalkylcarbonyl" as used herein, means a hydroxyalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples include, but are not limited to, 2-hydroxyacetyl and 4-hydroxybutanyl.

The term "hydroxyalkoxyalkyl" as used herein, means a hydroxyalkoxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Examples of representative hydroxyalkoxyalkyls include, but are not limited to, (2-hydroxy-ethoxy) -ethyl and (3-hydroxyl-propoxy) -ethyl.

The term "hydroxy-protecting group" or "O-protecting group" refers to a substituent that protects the hydroxyl group from undesirable reactions during the course of the synthesis. Examples of hydroxy protecting groups include substituted methyl ethers such as methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl) -ethoxymethyl, benzyl and triphenylmethyl; Tetrahydropyranyl ethers; Substituted ethyl ethers such as 2,2,2-trichloroethyl and tert-butyl; Silyl ethers such as trimethylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl; Cyclic acetals and ketals such as methylene acetal, acetonide and benzylidene acetal; Cyclic ortho esters such as methoxymethylene; Cyclic carbonates; And cyclic boronates. Commonly used hydroxy protecting groups are described in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).

The term "mercapto" as used herein, means a -SH group.

As used herein, the term "nitrogen protecting group" refers to groups that are intended to protect the amino group from undesirable reactions during the synthesis process. Preferred nitrogen protecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, tert-butoxycarbonyl (Boc), tert-butylacetyl, trifluoroacetyl and triphenyl Methyl (trityl).

As used herein, the term "nitro" refers to a -NO ₂ group.

As used herein, the term “trialkylsilyl” refers to three independently selected alkyl groups as defined herein, bonded to the parent molecular moiety through a silicon atom. Representative trialkylsilyl examples include, but are not limited to, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and triisopropylsilyl.

The term "trialkylsilylalkyl" as used herein, means a trialkylsilyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Examples of representative trialkylsilylalkyls include, but are not limited to, trimethylsilylmethyl, 2-trimethylsilylethyl and 2-3-butyldimethylsilylethyl.

The term "Z ₁ Z ₂ N" as used herein refers to two groups Z ₁ and Z ₂ bonded to the parent molecular moiety through a nitrogen atom. Z ₁ and Z ₂ are each independently hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl. In certain examples of the invention, Z ₁ and Z ₂ together with the nitrogen atom to which they are attached form a heterocyclic ring. Representative examples of Z ₁ Z ₂ N include, but are not limited to, amino, methylamino, acetylamino, acetylmethylamino, phenylamino, benzylamino, azetidinyl, pyrrolidinyl and piperidinyl.

The term "Z ₃ Z ₄ N" as used herein refers to two groups Z ₃ bonded to the parent molecular moiety through a nitrogen atom. And Z ₄ . Z ₃ and Z ₄ are each independently hydrogen, alkyl, aryl and arylalkyl. Representative examples of Z ₃ Z ₄ N include, but are not limited to, amino, methylamino, phenylamino and benzylamino.

The term "(Z ₃ Z ₄ N) carbonyl" as used herein, means an NZ ₃ Z ₄ group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Examples of representative (Z ₃ Z ₄ N) carbonyl include, but are not limited to, aminocarbonyl, (methylamino) carbonyl, (dimethylamino) carbonyl and (ethylmethylamino) carbonyl.

The term "oxo" as used herein, means a = 0 moiety.

The term "sulfinyl" as used herein, means a -S (O)-group.

The term "sulfonyl" as used herein, means a -SO ₂ -group.

As used herein, the term "sulfonamide" refers to the group -SO ₂ NH ₂ .

As used herein, the term “tautomer” refers to proton transfer from one atom of a compound to another atom of the same compound, wherein two or more structurally distinct compounds are in equilibrium with each other.

The compounds of the present invention may exist as stereoisomers in which asymmetric or chiral centers exist. These stereoisomers are "R" or "S" depending on the arrangement of substituents around the chiral carbon atom. As used herein, the terms “R” and “S” are described in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The present invention contemplates various stereoisomers and mixtures thereof, which are specifically included within the scope of the present invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds of the present invention can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers or after preparation of racemic mixtures, by separation well known to those skilled in the art. These separation methods include (1) binding of a mixture of enantiomers to a chiral adjuvant, recrystallization or chromatographic separation of the resulting mixture of diastereomers, and glass or (2) optical enantiomers from optically pure product aids. Illustrated by direct separation of a mixture of isomers on a chiral chromatography column.

The compounds and methods of the present invention can be further understood with reference to the following examples, which by way of example do not limit the scope of the invention. In addition, all citations herein are incorporated by reference.

Compound names are assigned using Name Pro naming software provided by ACD / Labs. Alternatively, compound names are designated using AUTONOM naming software, provided by MDL Information Systems GmbH (formerly known as Beilstein Informationssysteme) in Frankfurt, Germany, and the CHEMDRAW ^R ULTRA v.6.0.2 software suite and ISIS Draw It is part of v.2.5. In addition, compound names are specified using the Struct = Name naming logarithm, which is described in CHEMDRAW ^R ULTRA v. It is part of the 9.0.7 software suite.

Abbreviation

The abbreviations used in the following schemes and in the description of the examples are as follows:

DMF: N, N-dimethylformamide, DMSO: dimethyl sulfoxide, EtOAc: ethyl acetate, CHCl ₃ : chloroform, CH ₂ Cl ₂ : dichloromethane, CH ₃ CN: acetonitrile, THF: tetrahydrofuran, HATU: O -(7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, EDC or EDCI: 1- (3-dimethylaminopropyl) -3-ethyl Carbodiimide hydrochloride, LC / MS: liquid chromatography / mass spectrometer, NH ₄ OAc: ammonium acetate, NaBH (OAc) ₃ : sodium triacetoxyborohydride, PBS: bovine serum albumin, PBS: phosphate buffered saline , TMS: trimethylsilyl, MW: microwave, DMAP: 4- (dimethylamino) pyridine, dppf: 1,1'-bis (diphenylphosphino) ferrocene, TFA: trifluoroacetic acid, BINAP: 2,2'- Bis (diphenylphosphino) -1,1'-binafil, TBAF: tetrabutylammonium fluoride, Tween: polyoxoethylene sorbitan monolau Late, HPLC: high pressure liquid chromatography, DME: 1,2-dimethoxyethane, Boc: tert-butoxycarbonyl, BSA: bovine serum albumin, DTT: dithiothritol, ATP: adenosine triphosphate, EDTA: Ethylenediaminetetraacetic acid, HPMC: hydroxypropylmethylcellulose, TMB: 3,3 ', 5,5'-tetramethylbenzidine and HEPES: 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid.

Preparation of Compounds of the Invention

The compounds and methods of the present invention will be better understood with reference to the following synthetic schemes and examples illustrating how the compounds of the present invention may be prepared.

Scheme 1

As shown in Scheme 1, a compound of Formula 2, which is a representative compound of Formula 1, may thus be prepared. R ₁ And wherein R ₂ is as defined in formula 1, X ₁ is iodo, bromo or chloro, and the compound of formula 1 which may be obtained from a conventional source or synthesized according to methods known in the literature, is palladium Treatment with reagent AM ₁ in the presence of a catalyst provides a compound of formula 2 wherein A is as defined in Formula 1 and M ₁ is -Sn (R _z ) ₃ or —B (OR _y ) ₂ , wherein R _z is alkyl or aryl, R _y is hydrogen, alkyl, aryl or both R _y groups together with the boron atoms to which they are attached form 1,3-dioxoborolane )to be. The reaction of a compound of Formula 1 with a compound of Formula A-Sn (R _z ) ₃ , commonly known as Still coupling, is carried out in a solvent such as toluene or DMF at a temperature of about 25 to about 150 ° C. Palladium catalysts such as, but not limited to, the presence or absence of ligands such as tri (2-furyl) phosphine or triphenylarcin, for example, tetrakis (triphenylphosphine) palladium (0), dichlorobis (Triphenylphosphine) palladium (II), tris (dibenzylidineacetone) dipalladium or palladium diacetate is used. In addition, Li (I), Cu (I) or Mn (II) salts may be added to enhance the reactivity or specificity. The reaction between a compound of Formula 1 and a compound of Formula AB (OR _y ) ₂ , commonly known as Suzuki coupling, is a palladium catalyst, such as, but not limited to, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), tris (dibenzylideneacetone) dipalladium or palladium diacetate are used. Palladium ligands such as 2- (dicyclohexylphosphino) biphenyl, tri-tert-butylphosphine or tris (2-furyl) phosphine and solvents at temperatures of about 25 to about 150 ° C. For example, toluene, dimethoxyethane, dioxane, water or bases in DMF, such as, but not limited to, aqueous K ₃ PO ₄ , cesium carbonate, potassium carbonate or Na ₂ CO ₃ can be added. The reaction can also be accomplished by heating in a microwave reactor oven.

Although many organic stannanes are commercially available or described in the literature, A- halides or A are treated with hexa-alkyldistananes of the formula ((R _z ) ₃ Sn) ₂ in the presence of Pd (Ph ₃ P) ₄ . It is also possible to prepare additional stannans from the treeplates. Similarly, in the absence of commercially available organoboron reagents, AB (OR _y ) ₂ is converted to the corresponding halide or triflate (A-halo or A-triflate) via metal exchange using organolithium, followed by addition of alkyl borate. Can be prepared from.

Scheme 2

Compounds of Formula 2 wherein R ₁ and R ₂ are as defined in Formula 1 and A is a heteroaryl ring bonded to the parent moiety through a nitrogen atom can be prepared as illustrated in Scheme 2. In the presence of a base such as but not limited to sodium tert-butoxide or cesium carbonate and a metal catalyst such as, but not limited to, copper metal, CuI or palladium diacetate, optionally a ligand, eg For example, but not limited to, BINAP or tri-tert-butylphosphine may be used to treat a compound of Formula 1 with a reagent of Formula AH, wherein H is hydrogen on a nitrogen atom contained in heteroaryl ring A Provides the compound of 2.

Scheme 3

As already mentioned in Scheme 1, the compound of Formula 1 may be synthesized using steel coupling as described in Scheme 3. Compounds of formula (3), wherein R _ii is defined in formula (1), wherein R ₁ is in the presence of dichlorobis (triphenylphosphine) palladium (II) and (thiophene-2-carbonyloxy) copper in toluene under heating conditions A compound of Formula 5 is provided upon treatment with a compound of Formula 4, as defined in Formula 1, wherein P ₁ is a nitrogen protecting group such as, but not limited to, tert-butyloxycarbonyl or acetyl. Compounds of formula (5) are prepared in a solvent such as acetic acid or dioxane when the protecting group is tert-butyloxycarbonyl or sodium hydroxide, lithium hydroxide or potassium hydroxide, and in an aqueous mixture of THF, isopropanol or dioxane when the protecting group is acetyl. Provided is a compound of Formula 6, wherein A is a representative compound of Formula 1 wherein A is formula (ii) upon treatment with known conditions to remove a protecting group such as hydrochloric acid or trifluoroacetic acid.

Scheme 4

The compound of formula 3 used in Scheme 3 to produce the compound of formula 1 may be prepared as outlined in Scheme 4. Compounds of formula (7) which can be obtained from conventional sources or can be prepared according to methods known to those skilled in the art can be prepared using 1,1,1-tributyl-N, N-dimethylstanamine or methyl ethyl (tributylstannyl). Treatment with carbamate provides a compound of formula 8. Alkynes of Formula 8 provide compounds of Formula 3 when heated in the presence of a compound of Formula 9 wherein R _ii is as defined in Formula 1 and N ₃ is an azide.

Scheme 5

As outlined in Scheme 5, a compound of Formula 12, wherein A is a representative compound of Formula 1, wherein Formula (ii) can be prepared accordingly. Compounds of formula 10 wherein R ₁ is as defined in Formula 1 and X ₁ is iodo, bromo, chloro or triflate are selected from the group consisting of copper iodide, dichlorobis (triphenylphosphine) palladium (II) and triethylamine Treatment with TMS acetylene in the presence, followed by treatment with tetrabutylammonium fluoride or potassium hydroxide provides a compound of formula 11. The reaction can be carried out in a solvent such as, but not limited to, DMF at ambient temperature or under heating conditions. The compound of formula 11 is a representative compound of formula 1 wherein A is a formula (ii) when treated with R _ii -Cl, sodium azide, copper sulfate and metallic copper under heating conditions in a solvent such as dioxane To provide.

Scheme 6

Alternatively, the compound of formula 13 is treated with TMS-acetylene in the presence of copper iodide, dichlorobis (triphenylphosphine) palladium (II) and triethylamine, and then treated with tetrabutylammonium fluoride or potassium hydroxide to To provide a compound. The reaction can be carried out in a solvent such as, but not limited to, DMF at ambient temperature or under heating conditions. The compound of formula 14 provides a compound of formula 15 when R _ii is treated with a compound of formula 9 as defined in formula 1, or with sodium azide, copper sulfate and metallic copper under heating intervening. Compound 15 provides compound 16 when heated in the presence of hydrazine in ethanol. The compound of formula 16 provides a compound of formula 17 upon treatment with di-tert-butyldicarbonate and a catalytic amount of DMAP in a solvent such as THF or acetonitrile. Compounds of formula 17 are treated with a compound of formula 18 in the presence of a pyridine in a solvent such as, for example, but not limited to, a trifluoroacetic acid to provide. The compound of formula 16 provides a compound of formula 19A upon treatment with carboxylic acid using carboxylic acid-amine coupling conditions known to those skilled in the art. Standard carboxylic acid amine coupling conditions include, but are not limited to, coupling reagents such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), l, 3-dicyclohexylka Bodyimide (DCC), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOPCl), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'- Tetramethyluronium hexafluorophosphate (HATU) or O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU) is a solvent, for example Presence or absence of auxiliary reagents in dichloromethane, such as, but not limited to, 1-hydroxy-7-azabenzotriazole (HOAT) or 1-hydroxybenzotriazole hydrate (HOBT) Addition under the following.

Scheme 7

Compounds of Formula 24, which are representative compounds of Formula 1, can thus be prepared. Compounds of formula 20, wherein X ₁ is halo or triflate, provide compounds of formula 22 upon treatment of the compounds of formula 21 with acetic anhydride and a base such as, but not limited to, potassium acetate under heating intervening. The compound of formula 22 is a compound of formula 23 wherein sodium azide, copper sulfate, bases such as sodium carbonate and R _ii are as defined in formula 1 and are commercially available from conventional sources or may be prepared by one skilled in the art. The treatment provides a compound of formula 24.

Scheme 8

As outlined in Scheme 8, compounds of Formula 29 and 30, which are representative compounds of Formula 1, can thus be prepared. Compounds of formula 25 wherein R ₁ is as defined in formula 1 and X ₁ is halo or triflate are compounds of formula 23, copper iodide, dichlorobis (triphenylphosphine) palladium in DMF at ambient temperature or under heating conditions Treatment with (II) and triethylamine affords the compound of formula 27. Compounds of formula 27, under heating conditions, are pure or provide a compound of formulas 29 and 30 upon treatment with a compound of formula 9 in a solvent such as, but not limited to.

Scheme 9

A is formula (vii) and R ₁ And compounds of Formula 32, wherein R _vii is a representative compound of Formula 1 as defined in Formula 1, can thus be prepared. The aldehyde of Formula 31, wherein R _vii is defined in Formula 1, which can be obtained from a conventional source, provides an oxime intermediate upon treatment with hydroxylamine hydrochloride and aqueous sodium hydroxide, which is oxidized to chloramine T trihydrate. And then treated with copper sulfate and copper wire and the compound of formula 11 to give the compound of formula 32.

Scheme 10

Thus, a compound of Formula 38 is prepared, wherein A is a representative compound of Formula 1 wherein Formula (x). Compounds of formula 33, wherein R ₁ is defined in formula 1, which may be obtained from conventional sources or prepared by one of ordinary skill in the art, may be prepared using N, using acid coupling conditions known to those skilled in the art. Upon treatment with, O-dimethylhydroxylamine, the compound of formula 34 is provided. Standard carboxylic acid amine coupling conditions include, but are not limited to, coupling reagents such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), l, 3-dicyclohexylka Bodyimide (DCC), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOPCl), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'- Tetramethyluronium hexafluorophosphate (HATU) or O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU) is a solvent, for example Presence or absence of auxiliary reagents in dichloromethane, such as, but not limited to, 1-hydroxy-7-azabenzotriazole (HOAT) or 1-hydroxybenzotriazole hydrate (HOBT) Addition under the following. The compound of formula 34 provides a compound of formula 35 upon treatment with a Grignard reagent such as benzyl magnesium bromide in a solvent such as tetrahydrofuran below ambient temperature. The compound of formula 35 provides a compound of formula 36 upon treatment with a protecting group reagent such as, but not limited to, di-tert-butyldicarbonate and a catalytic amount of DMAP in a solvent such as THF or acetonitrile do. The compound of formula 36 is treated with pyridinium tribromide in a solvent, such as, but not limited to, with or without heat to provide a compound of formula 36A. Compounds of formula 36A are treated with compounds of formula 37 with or without heat and the product is then subjected to conditions that remove nitrogen protecting groups to provide compounds of formula 38. Commonly used nitrogen-protecting groups and methods for removing them are described in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).

Scheme 11

Compounds of formula 36, wherein R ₁ is as defined in formula 1 and P ₁ is a nitrogen protecting group are treated with a compound of formula 39 under heating conditions, and then the product is known to those skilled in the art to remove the nitrogen protecting group. Conditions or as outlined in the literature to provide a compound of formula 40 wherein A is a representative compound of formula 1 wherein formula (xvii).

Scheme 12

As outlined in Scheme 12, a compound of Formula 47 may be prepared, wherein Formula 1 wherein A is Formula (x) is a representative compound. The compound of formula 41, wherein R ₁ is defined in formula 1, provides a compound of formula 42 upon treatment with di-tert-butyldicarbonate and a catalytic amount of DMAP in a solvent such as THF or acetonitrile. The compound of formula 42 is treated with tributyl (1-ethoxyvinyl) stannan and dichlorobis (triphenylphosphine) palladium (II) to give the compound of formula 44. Compounds of formula 44 are treated with pyridinium tribromide in THF to provide compounds of formula 45. The compound of formula 45 provides a compound of formula 47 upon treatment with a compound of formula 46 as defined in formula 1 wherein R _x in a solvent, such as, but not limited to, formula (1).

Scheme 13

As shown in Scheme 13, a compound of Formula 51 can be prepared, wherein A is a representative compound of Formula 1 wherein Formula (iv). Compounds of Formula 48, wherein R ₁ is as defined in Formula 1 and are available from conventional sources or can be prepared according to literature procedures or as outlined herein, are all commercially available or according to the procedures described in the literature. Heating in the presence of both a compound of formula 49 and a compound of formula 50, which may be prepared by one skilled in the art, provides a compound of formula 51.

Scheme 14

As outlined in Scheme 14, a compound of Formula 55 can be prepared, wherein A is a representative compound of Formula 1 wherein Formulas (xiv), (xv), (xvi) or (xvii). The compound of formula 52, wherein R ₁ is defined in formula 1, is treated with butyllithium followed by DMF followed by acidic post-treatment to provide the compound of formula 48. Compound 48 is treated with a compound of Formula 53 wherein X is -CH-, -N- or -S- and Y is -CH-, -N- or a bond and scandium tri (triplate), followed by Z _a Is treated with a compound of formula 54 as defined in formula 1 to provide a compound of formula 55.

Scheme 15

As outlined in Scheme 15, a compound of Formula 56 can be prepared, wherein A is a representative compound of Formula 1 wherein Formula (vii). Compounds of Formula 11 wherein R ₁ is defined in Formula ₁ may be combined with a base, such as, but not limited to, a reagent such as, but not limited to, ethyl 2-chloro-2- ( Upon treatment with hydroxyimino) acetate, the compound of formula 56 is provided. The reaction can be carried out in a solvent, for example but not limited to toluene, and may require the use of heat.

Scheme 16

As outlined in Scheme 16, a compound of Formula 29 can be prepared, wherein A is a representative compound of Formula 1 wherein Formula (ii). Compounds of formula 27, wherein R ₁ is as defined in formula 1, are compounds of formula 9, R _ii C (O) Cl or ICl, CuI, and a solvent, such as, but not limited to, tree in tetrahydrofuran Treatment with ethylamine gives a compound of formula 29. The reaction can be carried out at ambient temperature or using heat.

Scheme 17

As outlined in Scheme 17, a compound of Formula 57 can be prepared, wherein A is a representative compound of Formula 1 wherein Formula (vi). The compound of formula 45, wherein R ₁ is defined in formula 1, is treated with ammonium formate and formic acid to provide the compound of formula 57.

Scheme 18

As outlined in Scheme 18, a compound of Formula 58 can be prepared, wherein A is a representative compound of Formula 1 wherein Formula (vii). Treatment of a compound of Formula 48 with nitromethane, wherein R ₁ is defined in Formula 1, provides a compound of Formula 58 (Organic Preparations and Procedures International, 2001, 33, 381-386).

Scheme 19

As outlined in Scheme 19, a compound of Formula 60, wherein A is a representative compound of Formula 1, wherein Formula (vi) can be prepared accordingly. Compounds of formula 48, wherein R ₁ is defined in formula 1, are formulated as 1- (isocyanomethylsulfonyl) -4-methylbenzene in formula 59 and a suitable base in a solvent such as methanol or tetrahydrofuran, such as For example, but not limited to, treatment with potassium carbonate followed by treatment with a suitable acid, such as hydrochloric acid, provides a compound of formula 60.

Scheme 20

As outlined in Scheme 20, a compound of Formula 63, wherein A is a representative compound of Formula 1, wherein Formula (vi) can be prepared accordingly. The compound of formula 33, wherein R ₁ is defined in formula 1, is treated with a suitable chlorinating agent, for example thionyl chloride, to provide a compound of formula 61. Treatment of a compound of formula 61 with 2- (trimethylsilyl) -2H-1,2,3-triazole of formula 62 in a solvent, such as sulfolane, provides the compound of formula 63.

Scheme 21

As outlined in Scheme 21, a compound of Formula 66, wherein A is a representative compound of Formula 1 wherein Formula (ix), may be prepared. The compound of formula 61, wherein R ₁ is defined in formula 1, is treated with hydrazine in a suitable solvent such as tetrahydrofuran to provide the compound of formula 64. Treatment of a compound of formula 64 with trimethylorthoformate of formula 65 in the presence of a catalytic amount of p-toluene sulfonic acid in a solvent such as tetrahydrofuran provides the compound of formula 66.

Scheme 22

As outlined in Scheme 22, a compound of Formula 69 may be prepared, wherein A is a representative compound of Formula 1 as defined in Formula 1. Compounds of formula 67 wherein R _y is hydrogen, alkyl, aryl or two R _y groups together with the boron atoms to which they are attached form a 1,3-dioxoborolane in the presence of a palladium catalyst (AI) Suzuki reaction conditions described in Scheme 1 in the presence of) provide compounds of formula 68. The compound of formula 68 is transformed into a compound of formula 69 upon treatment with hydrazine as described in Scheme 6.

Scheme 23

As outlined in Scheme 23, a compound of Formula 74 wherein R _ii and R ₄ are representative of Formula 1 as defined in Formula 1 starts with a compound of Formula 70 wherein X ₁ is iodo, bromo or chloro Are manufactured. The compound of formula 70 is first treated with hydrazine and then with di-tert-butyldicarbonate as described in Scheme 6 to give the compound of formula 71. The compound of formula 71 provides a compound of formula 72 upon reaction with an acid chloride of formula 18 in the presence of a base, such as potassium carbonate, in tetrahydrofuran at ambient temperature for 2 to 8 hours. Alternatively, the compound of formula 72 can be prepared from the compound of formula 71 using the conditions described in Scheme 6. The compound of formula 72 is reacted with (trimethylsilyl) acetylene under the conditions described in Schemes 5 and 6 to give the compound of formula 73. The compound of formula 74 is composed of copper (II) sulfate and sodium (R) -2-((S) -1,2-dihydroxyethyl) -4-hydroxy-5-oxo for 1-6 hours at 40-80 ° C. Obtained from compounds of formula 73 upon treatment with R _ii -N ₃ in aqueous tert-butanol in the presence of -2,5-dihydrofuran-3-oleate.

Scheme 24

As outlined in Scheme 24, a compound of Formula 76 is obtained from a compound of Formula 75, wherein A and R ₄ are representative compounds of Formula 1 as defined in Formula 1. Compounds of formula 75 in the presence of a palladium catalyst, using the Suzuki reaction conditions described in Scheme 1, wherein A is as defined in formula 1, R _y is hydrogen, alkyl, aryl or two R _y groups are boron The compound of formula 76 can be obtained by treatment with AB (OR _y ) ₂ , which together with the atom form 1,3-dioxoborolane.

Scheme 25

As outlined in Scheme 25, a compound of Formula 80 is thus prepared, wherein R _ii and R ₄ are representative compounds of Formula 1 as defined in Formula 1. Compounds 77 and 78 are reacted under the steel coupling conditions described in Scheme 3 to provide compounds of formula 79. Reacting the compound of Formula 79 as described in Scheme 6 provides a compound of Formula 80.

Scheme 26

As outlined in Scheme 26, compounds of Formulas 82, 83, 84, and 85, wherein A, R ₄ , R ₅ , R _a and R _j are representative compounds of Formula 1 as defined in Formula 1, are compounds of Formula 81 Is prepared from. The compound of formula 81 can be treated with the acid chloride of formula 18 in a solvent such as tetrahydrofuran in the presence of a base such as potassium carbonate or triethylamine to afford the compound of formula 82. Alternative solvent is dichloromethane and alternative base is pyridine. Acid chlorides can be prepared from the corresponding carboxylic acids by treatment with oxalyl chloride with catalytic amounts of N, N-dimethylformamide. To prepare the compound of formula 83, the compound of formula 81 can be treated with R _j NCO in heated pyridine. Compounds of formula 84 are prepared from compounds of formula 81 by treatment with R ₅ SO ₂ Cl in pyridine at or near room temperature. The compound of formula 85 may also be added to R _a at or near room temperature in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride and acetic acid in a solvent such as 1,2-dichloroethane. Reductive amination reaction using CHO, followed by treatment with trifluoroacetic acid in dichloromethane and removal of the tert-butoxycarbonyl protecting group is prepared from the compound of formula 81.

Scheme 27

As outlined in Scheme 27, compounds of Formula 87, wherein A, R _j and R _k are defined in 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. The compound of formula 86 may then be heated in the presence of a amine, HNR _j R _k and a base such as triethylamine in a solvent such as acetonitrile to afford the compound of formula 87. Alternatively, heterocycles such as pyrrolidine, piperidine, piperazine and morpholine can replace amines.

Scheme 28

As outlined in Scheme 28, a compound of Formula 89 may be prepared from a compound of Formula 88, wherein A, R ₁ , R ₂ , R ₃ , m, Z _c and Z _d are defined for Formula 1. Compounds of formula 88 may be prepared as described in Schemes 1-4, 7-9, 22, 24, and 26. During the preparation of the compound of formula 88, the carboxylic acid residues pendant on A can be protected as esters and then hydrolyzed to expose the carboxylic acid by methods known to those skilled in the art of organic synthesis. Compounds of formula 88 are treated with amines (HNZ _c Z _d ) using carboxylic acid-amine coupling conditions known to those skilled in the art to provide compounds of formula 89. Standard carboxylic acid amine coupling conditions include, but are not limited to, coupling reagents such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), l, 3-dicyclohexylka Bodyimide (DCC), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOPCl), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'- Tetramethyluronium hexafluorophosphate (HATU) or O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU) is a solvent, for example Auxiliary reagents in, but not limited to, dichloromethane or N, N-dimethylformamide, such as, but not limited to, 1-hydroxy-7-azabenzotriazole (HOAT) or 1-hydroxybenzotriazole Adding in the presence or absence of a hydrate (HOBT), optionally in the presence of a base such as triethylamine or diisopropylethylamine All.

Example

The compounds and methods of the present invention will be better understood by reference to the following examples, which are intended to illustrate the invention and are not intended to limit the scope of the invention.

Example 1

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole and 5- (1-benzyl-1H-1,2,3-triazol-5-yl) -1H-indazole compound

Example 1A

Tert-Butyl 5-iodo-1H-indazole-1-carboxylate

A solution of acetic anhydride (21.2 g, 208.11 mmol) in chloroform (50 mL) was added dropwise to an ice bath cooling solution of 4-iodo-2-methylaniline (20 g, 83.24 mmol) in chloroform (250 mL). After the addition was complete, the mixture was stirred at rt for 1 h. Potassium acetate (2.5 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 NaHCO ₃ to pH 7. The mixture was extracted with dichloromethane, and the organic layer was 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 treated with a warm solution of KOH (60 g) in water (200 mL). The mixture was stirred for 15 minutes and 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 solid was dissolved in dichloromethane (500 mL) and triethylamine (23 mL, 166.48 mmol) and di-tert-butyldicarbonate (23.6 g, 108.2 mmol) and catalytic amount of dimethylaminopyridine (about 5 mg) were added. . The mixture was stirred at rt for 2 h, diluted with water, extracted with dichloromethane, 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 1B

Tert-butyl 5-((trimethylsilyl) ethynyl) -1H-indazole-1-carboxylate

Triethylamine (70 mL) of the compound of Example 1A (10.81 g, 31.4 mmol), dichlorobis (triphenylphosphine) palladium (II) (1.1 g, 1.57 mmol) and copper iodide (I) (365 mg, 1.92 mmol) In 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 1N 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-99) ⁺ .

Example 1C

5-ethynyl-1H-indazole

The compound of Example 1B (7.93 g, 25.2 mmol) was dissolved in methanol (150 mL). A solution of 1N potassium hydroxide (50 mL) was added, and the mixture was stirred at room 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, filtered and the solvent was removed under reduced pressure to afford the title compound.

Example 1D

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole and 5- (1-benzyl-1H-1,2,3-triazol-5-yl) -1H-indazole compound

To the microwave vial were added 100.0 mg (0.70 mmol) of the compound 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 W, 1 minute ramp time). The mixture was dissolved in ethyl acetate and purified by silica gel chromatography eluting with 75% ethyl acetate in hexanes to afford the title compound.

Example 2

5- (1H-1,2,3-triazol-5-yl) -1H-indazole

To the microwave vial were added 100.0 mg (0.70 mmol) of the compound of Example 1C, 81 mg (0.7 mmol) of trimethylsilyl azide, CuI (4 mg) and dimethylformamide / methanol (1 mL, 9: 1). The mixture was heated at 160 ° C. for 20 minutes using microwave irradiation (CEM-Discover, 100 W, 1 minute 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 ₄ , filtered, concentrated under reduced pressure and purified by silica gel chromatography eluting with 80% ethyl acetate in hexane to afford the title compound.

Example 3

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole

Example 3A

Tert-Butyl 5-iodo-1H-indazole-1-carboxylate

To an ice bath cooling solution of 4-iodo-2-methylaniline (20 g, 83.24 mmol) in chloroform (250 mL) was added dropwise a solution of acetic anhydride (21.2 g, 208.11 mmol) in chloroform (50 mL) with an addition funnel. After the addition was complete, the mixture was stirred for 1 hour at room temperature. Potassium acetate (2.5 g, 24.97 mmol) and isoamylnitrite (22.3 mL, 166.48 mmol) were added and the mixture was heated at 70 ° C for 20 h. The mixture was then cooled and then quenched with saturated aqueous NaHCO ₃ to 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 g) in water (200 mL). The mixture was stirred for 15 minutes and treated with 6N HCl to pH 1. The layers were separated, the organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude material was dissolved in dichloromethane (500 mL) and triethylamine (23 mL, 166.48 mmol) and di-tert-butyldicarbonate (23.6 g, 108.2 mmol) and catalytic amount of dimethylaminopyridine (about 5 mg) were added. . The mixture was stirred at rt for 2 h, quenched with water, extracted with dichloromethane, 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

Tert-butyl 5-((trimethylsilyl) ethynyl) -1H-indazole-1-carboxylate

Triethylamine (70 mL) of the compound of Example 3A (10.81 g, 31.4 mmol), dichlorobis (triphenylphosphine) palladium (II) (1.1 g, 1.57 mmol) and copper iodide (I) (365 mg, 1.92 mmol) ) 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 1N 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-99) < + >.

Example 3C

5-ethynyl-1H-indazole

The compound of Example 3B (7.93 g, 25.2 mmol) was dissolved in methanol (150 mL). 1N potassium hydroxide (50 mL) solution 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, filtered and the solvent removed under reduced pressure to afford the title compound.

Example 3D

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole

Example 3C compound (40 mg, 0.28 mmol), benzyl azide (37 mg, 0.28 mmol), CuSO ₄ (14 mg, 0.056 mmol) and Cu wire (14 mg) were added to tert-butanol (0.5 mL) and water (0.5 mL). ) And heated at 125 ° C. and 100 W for 10 minutes with CEM-Discover microwave. To the mixture was added 1M HCl and water and the product was extracted with dichloromethane and purified by silica gel chromatography (50% ethyl acetate in hexane) to afford the title compound.

Example 4

5- [1- (2-methylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

A 300 uL aqueous solution containing 17.6 mg (0.124 mmol) of the compound of Example 3C, 7.80 mg (0.118 mmol) of sodium azide in a 5 mL CEM microwave reaction tube containing a Teflon coated microplexer stirring bar; Then 15.79 uL (0.118 mmol; 21.80 mg, 0.95 equiv) of 2-methyl-benzyl bromide (added neatly) were added. Then 300 μL of tert-butanol in suspension; 25 mg of copper wire; And finally 50 µL of an aqueous 1N copper sulfate pentahydrate solution was added. The microwave reaction vessel was then covered and heated on CEM-Discover microwave at 100W power at 125 ° C. for 10 minutes with stirring. After cooling to ambient temperature, the mixture is diluted with 0.25N aqueous HCl; The aqueous suspension was extracted with dichloromethane. The organic layer was washed with distilled water and saturated aqueous NaCl, dried over anhydrous sodium sulfate and filtered. The dried solution was diluted with acetonitrile and then the soluble organics were filtered through a glass wool plug loaded with additional anhydrous sodium sulfate. An aliquot of the filtrate was then removed for subsequent LC / MS analysis. The solution containing the desired triazole product was then evaporated under vacuum and then redissolved in 1.50 mL of 1: 1 DMSO / methanol. The solution of crude triazole product was then purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution method to afford the title compound.

Example 5

5- [1- (3-methylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methylbenzylbromide with 3-methyl-benzyl bromide.

Example 6

5- [1- (4-methylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methylbenzylbromide with 4-methyl-benzyl bromide.

Example 7

5- [1- (3-methoxybenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 3-methoxylbenzylbromide.

Example 8

5- [1- (2-fluorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 2-fluorobenzylbromide.

Example 9

5- [1- (3-fluorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 3-fluorobenzylbromide.

Example 10

5- [1- (4-fluorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 4-fluorobenzylbromide.

Example 11

5- [1- (2-chlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 2-chlorobenzylbromide.

Example 12

5- [1- (3-chlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 3-chlorobenzylbromide.

Example 13

5- [1- (4-chlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 4-chlorobenzylbromide.

Example 14

5- [1- (2-bromobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 2-bromobenzylbromide.

Example 15

5- [1- (2-nitrobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 2-nitrobenzylbromide.

Example 16

5- [1- (3-nitrobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 3-nitrobenzylbromide.

Example 17

5- [1- (4-nitrobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 4-nitrobenzylbromide.

Example 18

2-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} benzonitrile

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 2-cyanobenzylbromide.

Example 19

3-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} benzonitrile

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 3-cyanobenzylbromide.

Example 20

4-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} benzonitrile

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 4-cyanobenzylbromide.

Example 21

5- {1- [2- (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 2-trifluoromethylbenzylbromide.

Example 22

5- {1- [3- (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 3-trifluoromethylbenzylbromide.

Example 23

5- {1- [4- (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 4-trifluoromethylbenzylbromide.

Example 24

5- {1- [3- (trifluoromethoxy) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 3-trifluoromethoxybenzylbromide.

Example 25

5- {1- [4- (trifluoromethoxy) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 4-trifluoromethoxybenzylbromide.

Example 26

5- [1- (4-tert-butylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 4-tert-butylbenzylbromide.

Example 27

Methyl 3-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} benzoate

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 3-carbomethoxybenzylbromide.

Example 28

Methyl 4-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} benzoate

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 4-carbomethoxybenzylbromide.

Example 29

5- [1- (2,4-dimethylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 2,4-dimethylbenzylchloride.

Example 30

5- [1- (3,5-dimethylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 3,5-dimethylbenzylbromide.

Example 31

5- [1- (2,3-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 2,3-dichlorobenzylchloride.

Example 32

5- [1- (2,4-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 2,4-dichlorobenzylchloride.

Example 33

5- [1- (2,5-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 2,5-dichlorobenzylchloride.

Example 34

5- [1- (3,5-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 3,5-dichlorobenzylchloride.

Example 35

5- {1- [2,4-bis (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 4 by replacing 2-methyl-benzyl bromide with 2,4-bis (trifluoromethyl) bromide.

Example 36

N-cyclohexyl-6- (1H-indazol-5-yl) imidazo [2,1-b] [1,3] thiazol-5-amine

Example 36A

1H-indazol-5-carbaldehyde

To a solution of 5-bromoindazole (5 g, 25.38 mmol) in tetrahydrofuran (100 mL) cooled at −50 ° C. under argon was added dropwise a 1.6 M n-butyllithium solution in hexane (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 ethyl acetate, preabsorbed on silica gel and purified by silica gel chromatography eluting with a 10-30% ethyl acetate gradient in hexanes to afford the title compound.

Example 36B

N-cyclohexyl-6- (1H-indazol-5-yl) imidazo [2,1-b] [1,3] thiazol-5-amine

Compounds of Example 36A (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) in a 4 mL vial. The vial was sealed and shaken at ambient temperature for 30 minutes. Cyclohexyl isocyanide (42 mL, 0.34 mmol) was added and the mixture was shaken for 2 days at room temperature. The mixture was purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution method to afford the title compound as a TFA salt.

Example 37

N-cyclohexyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyridin-3-amine

The title compound was prepared following the procedure outlined in Example 36B by replacing 2-aminothiazole with 2-aminopyridine.

Example 38

N-cyclohexyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrazin-3-amine

The title compound was prepared following the procedure outlined in Example 36B by replacing 2-aminothiazole with 2-aminopyrazine.

Example 39

5- [1-benzyl-4- (4-fluorophenyl) -1H-imidazol-5-yl] -1H-indazole

50.0 mg (0.34 mmol) of the compound of Example 36A were added to a 20 mL flash vial. To the solid was added 2.0 mL of a dimethylformamide solution containing 0.46 mmol (49 mg) of benzylamine and 50 mg of powdered activated 4 ′ molecular sieve. The vial was then capped and heated at 60 ° C. for 4 hours in an orbital shaker. The vial was cooled to ambient temperature and the lid opened. To the suspension was added 32 mg (0.23 mmol) of anhydrous potassium carbonate followed by 66 mg (0.23 mmol) of α- (p-toluenesulfonyl) -4-fluorobenzylisonitrile. The vial was then capped and heated at 60 ° C. overnight in a shaker. The vial was removed from the shaker, cooled to ambient temperature and the resulting suspension was filtered. The filtrate was evaporated under reduced pressure at medium heating temperature with a Savant Speed Vac. The crude residue was redissolved in 1: 1 DMSO / methanol and purified by reverse phase HPLC using an acetonitrile / water TFA gradient elution method to afford the title compound as a TFA salt.

Example 40

N- {3- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] propyl} -N, N-dimethylamine

The title compound was prepared as a TFA salt by following the procedure outlined in Example 39 by replacing benzylamine with N ¹ , N ¹ -dimethylpropane-1,3-diamine.

Example 41

N-cyclohexyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine

The title compound was prepared as a TFA salt following the procedure outlined in Example 36B by substituting thiazol-2-amine with pyrimidin-2-amine.

Example 42

5- [4- (4-fluorophenyl) -1- (1-phenylethyl) -1H-imidazol-5-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 39 by replacing benzylamine with 1-phenylethanamine.

Example 43

2- (1H-indazol-5-yl) -N-isopropylimidazo [1,2-a] pyrimidin-3-amine

The compound of 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 ambient temperature overnight and then shaken at 40 ° C. for 2 hours. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a 0-5% methanol gradient in dichloromethane to afford the title compound.

Example 44

4- (1H-indazol-5-yl) -N-phenyl-1,3-thiazol-2-amine

Example 44A

Tert-Butyl 5-bromo-1H-indazol-1-carboxylate

5-bromoindazole (4.40 g, 22.3 mmol) and a catalytic amount of dimethylaminopyridine (about 50 mg) were dissolved in dichloromethane (100 mL). Di-tert-butyl dicarbonate (5.43 g, 24.9 mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was taken up on silica gel and purified by silica gel chromatography eluting with a 0-40% ethyl acetate gradient in hexanes to afford the title compound. MS (ESI +) m / z 297.2 (M + H) ⁺ .

Example 44B

Tert-butyl 5-acetyl-1H-indazole-1-carboxylate

Example 44A compound (5.12 g, 17.2 mmol), tributyl (1-ethoxyvinyl) tin (7.0 mL, 20.7 mmol) and dichlorobis (triphenylphosphine) palladium (II) (672 mg, 0.957 mmol) It mix | blended in toluene (85 mL). Nitrogen was bubbled into the mixture for 5 minutes and the mixture was heated to 100 ° C. overnight in a sealed tube. The mixture was taken up on silica gel and purified by silica gel chromatography eluting with a gradient of 0-40% ethyl acetate in hexanes to afford the title compound. MS (ESI +) m / z 283.0 (M + Na) ⁺ .

Example 44C

Tert-butyl 5- (2-bromoacetyl) -1H-indazole-1-carboxylate

The compound of Example 44B (1.60 g, 6.15 mmol) and pyridinium tribromide (1.98 g, 6.19 mmol) were combined in tetrahydrofuran and heated to 40 ° C. for 2 hours. The mixture was taken up on silica gel and purified by silica gel chromatography eluting with a gradient of 0-40% ethyl acetate in hexanes to afford the title compound. MS (ESI +) m / z 360.9 (M + Na) ⁺ .

Example 44D

4- (1H-indazol-5-yl) -N-phenyl-1,3-thiazol-2-amine

Compounds of Example 44C (71 mg, 0.208 mmol) and 1-phenyl-2-thiourea (33 mg, 0.217 mmol) were combined in ethanol (300 mL) in a 4 mL vial. The vial was shaken at 80 ° C. overnight. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a methanol (0-5%) gradient in dichloromethane to afford the title compound.

Example 45

5- (2-methyl-1,3-thiazol-4-yl) -1H-indazole

The title compound was prepared following the procedure outlined in Example 44D, replacing 1-phenyl-2-thiourea with thioacetamide.

Example 46

N-ethyl-4- (1H-indazol-5-yl) -1,3-thiazol-2-amine

The title compound was prepared following the procedure outlined in Example 44D by replacing 1-phenyl-2-thiourea with ethylthiourea.

Example 47

N-benzyl-4- (1H-imidazol-5-yl) -1,3-thiazol-2-amine

The title compound was prepared following the procedure outlined in Example 44D, replacing 1-phenyl-2-thiourea with 1-benzyl-2-thiourea.

Example 48

4- (1H-indazol-5-yl) -1,3-thiazol-2-amine

The title compound was prepared following the procedure outlined in Example 44D, replacing 1-phenyl-2-thiourea with thiourea.

Example 49

4- (1H-indazol-5-yl) -N- (2-phenylethyl) -1,3-thiazol-2-amine

The title compound was prepared following the procedure outlined in Example 44D, replacing 1-phenyl-2-thiourea with 1-phenethylthiourea.

Example 50

N-benzyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine

The title compound was prepared following the procedure outlined in Example 43, replacing isopropyl isocyanide with benzylisocyanide.

Example 51

N-butyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine

The title compound was prepared according to the procedure outlined in Example 43, replacing isopropyl isocyanide with butyl isocyanide.

Example 52

N- (4-chlorophenyl) -2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine

The title compound was prepared following the procedure outlined in Example 43 by substituting isopropyl isocyanide with 4-chlorophenylisocyanide.

Example 53

2- (1H-indazol-5-yl) -N- (4-methoxyphenyl) imidazo [1,2-a] pyrimidin-3-amine

The title compound was prepared according to the procedure outlined in Example 43, replacing isopropyl isocyanide with 4-methoxyphenylisocyanide.

Example 54

2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidine

The title compound was prepared following the procedure outlined in Example 44D, replacing 1-phenyl-2-thiourea with 2-aminopyrimidine.

Example 55

Methyl N- [2- (1H-indazol-5-yl) imidazo [1,2-a] pyridin-3-yl] glycinate

The title compound was prepared as a TFA salt according to the procedure outlined in Example 36B by replacing 2-aminothiazole with 2-aminopyridine and cyclohexyl isocyanide with methyl 2-isocyanoacetate.

Example 56

N-benzyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyridin-3-amine

The title compound was prepared following the procedure outlined in Example 36B, replacing 2-aminothiazole with 2-aminopyridine and cyclohexyl isocyanide with benzyl isocyanide. The final product was precipitated out of solution and separated after filtration.

Example 57

N- (4-chlorophenyl) -2- (1H-indazol-5-yl) imidazo [1,2-a] pyridin-3-amine

The title compound was prepared following the procedure outlined in Example 36B, replacing 2-aminothiazole with 2-aminopyridine and cyclohexyl isocyanide with 1-chloro-4-isocyanobenzene.

Example 58

2- (1H-indazol-5-yl) -N- (4-methoxyphenyl) imidazo [1,2-a] pyridin-3-amine

The title compound was prepared following the procedure outlined in Example 36B by replacing 2-aminothiazole with 2-aminopyridine and cyclohexyl isocyanide with 1-isocyano-4-methoxybenzene.

Example 59

Tert-butyl 4- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] piperidine-1-carboxylate

The title compound was prepared following the procedure outlined in Example 39 by replacing benzylamine with tert-butyl 4-aminopiperidine-1-carboxylate.

Example 60

3,5-bis (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole

Example 6 OA

Tert-Butyl 5-bromo-3-iodo-1H-indazole-1-carboxylate

KOH (10 g, 177.63 mmol) was added to a solution of 5-bromoindazole (10 g, 50.75 mmol) in dimethylformamide (100 mL). For 2 hours iodine (20 g, 78.80 mmol) was added. The mixture was treated with a solution of Na ₂ S ₂ O ₅ (20 g) in water (200 ml), extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The solid was 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 room temperature and passed directly through a silica gel bed to afford the title compound. MS (DCI / NH ₃ ) m / z 422.9 (M + H) ⁺ .

Example 6OB

Tert-butyl 5-bromo-3-phenyl-1H-indazole-1-carboxylate and tert-butyl 5-bromo-3-iodo-1H-indazole-1-carboxylate

To a solution of Example 6OA (2.1 g, 5 mmol) in toluene (10 ml), Pd (PPh ₃ ) ₄ (173 mg, 0.15 mmol), a solution of Na ₂ CO ₃ (1.1 g, 10 mmol) in water (5 mL) and methanol (3 mL) Was added a solution of phenyl boronic acid (671 mg, 5.5 mmol). The mixture was stirred at rt 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 compound as a mixture.

Example 6 OC

Tert-butyl 3,5-bis ((trimethylsilyl) ethynyl) -1H-indazol-1-carboxylate and tert-butyl 5-bromo-3-((trimethylsilyl) ethynyl) -1H- Indazole-1-carboxylate

Example 6OB (1 g, 2.55 mmol), dichlorobis (triphenylphosphine) palladium (II) (89 mg, 0.13 mmol), triethylamine (1.78 mL, 12.75 mmol), trimethylsilyl acetylene (0.432 mL, 3.06 mmol) And CuI (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 water and purified by silica gel chromatography to afford the title compound.

Example 6 OD

Tert-butyl 3,5-diethynyl-1H-indazol-1-carboxylate and tert-butyl 5-bromo-3-ethynyl-1H-indazole-1-carboxylate

To a solution of Example 6OC (350 mg, 0.85 mmol) in tetrahydrofuran (5 mL) was added a TBAF 1M solution (2 mL, 2 mmol) in tetrahydrofuran. After 10 minutes, the solvent was evaporated under reduced pressure and the crude mixture was purified by silica gel chromatography eluting with 5% ethyl acetate in hexanes to afford the title compound.

Example 6 OE

3,5-bis (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole

The title compound was prepared following the procedure outlined in Example 3D, substituting Example 3C for Example 60D.

Example 61

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -3-phenyl-1H-indazole

Example 61A

Tert-butyl 3-phenyl-5-((trimethylsilyl) ethynyl) -1H-indazole-1-carboxylate and tert-butyl 5-bromo-3-phenyl-1H-indazol-1-carboxyl Rate

Example 6OB (1 g, 2.55 mmol), dichlorobis (triphenylphosphine) palladium (II) (89 mg, 0.13 mmol), triethylamine (1.78 mL, 12.75 mmol), trimethylsilyl acetylene (0.432 mL, 3.06 mmol) And CuI (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.

Example 61B

Tert-butyl 5-ethynyl-3-phenyl-1H-indazol-1-carboxylate and tert-butyl 5-bromo-3-phenyl-1H-indazole-1-carboxylate

The title compound was prepared following the procedure outlined in Example 60D, replacing Example 60C with Example 61A.

Example 61C

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -3-phenyl-1H-indazole

The title compound was prepared following the procedure outlined in Example 3D, replacing Example 3C with Example 61B.

Example 62

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine

Example 62A

2-fluoro-5-((trimethylsilyl) ethynyl) benzonitrile

5-bromo-2-fluorobenzonitrile (5.01 g, 25.0 mmol), dichlorobis (triphenylphosphine) palladium (II) (652 mg, 0.929 mmol) and copper iodide (I) (413 mg, 2.17 mmol) It mix | blended in triethylamine (15 mL) under nitrogen atmosphere. Trimethylsilyl acetylene (4.2 mL, 29.7 mmol) was added and the mixture was heated to 100 ° C. The mixture was solidified and monitored by LC / MS. After completion, the mixture was diluted with methylene chloride and washed with 1N HCl. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of ethyl acetate (5 to 45%) in hexanes to afford the title compound.

Example 62B

5-ethynyl-2-fluorobenzonitrile

Tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran, 70 mL) was added to a solution of Example 62A (5.05 g, 23.2 mmol) in tetrahydrofuran (50 mL) and stirred for 20 minutes. 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 5-40% ethyl acetate in hexanes to afford the title compound.

Example 62C

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -2-fluorobenzonitrile

Example 62B (1.68 g, 11.6 mmol) was dissolved in tert-butanol (14 mL). Benzyl azide (2.14 g, 15.8 mmol) was added and the mixture was transferred to 14 microwave vials (1.0 mL each). Water (0.5 mL), a small piece of copper wire, and a copper (II) sulfate 1M solution (0.5 mL) were added to each microwave vial, and the vials were heated with CEM-Discover microwave using 100 W at 125 ° C. for 10 minutes each. . The vials were combined, 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 5-50% ethyl acetate in hexanes to afford the title compound.

Example 62D

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine

Hydrazine hydrate (18 mL) was added to Example 62C (1.93 g, 6.94 mmol) in ethanol (10 mL). The mixture was heated to 95 ° C. overnight. The mixture was diluted with ethyl acetate and washed with water. A portion of the product was precipitated in a separatory funnel and filtered to afford the title compound. The ethyl acetate layer was concentrated under reduced pressure and the resulting solid was triturated with methanol to afford additional title compound.

Example 63

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1-[(1-methylpiperidin-4-yl) carbonyl] -1 H-indazol-3-amine

Example 62D (44 mg, 0.152 mmol), 1-methylpiperidine-4-carboxylic acid hydrochloride (27 mg, 0.150 mmol) and HATU (61 mg, 0.160 mmol) were combined in tetrahydrofuran (2 mL). Diisopropylethylamine (110 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 1N 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 title compound.

Example 64

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-methoxyacetamide

Example 64A

Tert-butyl 3-amino-5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-1-carboxylate

Example 62D (1.80 g, 6.20 mmol) was suspended in methylene chloride (100 mL) with a catalytic amount of dimethylaminopyridine. A solution of di-tert-butyl dicarbonate (1.36 g, 6.23 mmol) in methylene chloride (50 mL) was added dropwise over 1 hour. The mixture 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. MS (ESI +) m / z 391.1 (M + H) ⁺ .

Example 64B

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -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 solvent is removed using a warm nitrogen stream, the mixture is poured onto a silica gel column and the product is purified by silica gel chromatography eluting with a gradient of 0-5% methanol in dichloromethane to tert-butyl 5- ( 1-benzyl-1H-1,2,3-triazol-4-yl) -3- (2-methoxyacetamido) -1H-indazole-1-carboxylate (58 mg) was obtained. The intermediate was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (1 mL) and stirred overnight at ambient temperature. The solvent was removed under reduced pressure and the mixture was purified by preparative HPLC on C8 column using a gradient of 10-100% acetonitrile / water containing 0.1% trifluoroacetic acid to afford the title compound.

Example 65

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ^2, N ² - dimethyl glycine amide

Example 64A (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. Trifluoroacetic acid (2 mL) was added and the mixture was stirred for 3 hours. The mixture was diluted with methylene chloride and washed with 1N sodium hydroxide. The organic layer was absorbed on silica gel and purified using silica gel chromatography eluting with a gradient of 5-15% in dichloromethane to afford the title compound.

Example 66

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] butanamide

Example 64A (76 mg, 0.195 mmol) was dissolved in methylene chloride (2 mL) and pyridine (0.2 mL). Butyryl chloride (26 uL, 0.250 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 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 1-8% methanol in dichloromethane to afford the title compound.

Example 67

5- [4- (4-fluorophenyl) -1-piperidin-4-yl-1H-imidazol-5-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 39 by replacing benzylamine with piperidin-4-amine.

Example 68

5- {4- (4-fluorophenyl) -1- [2- (1-methylpyrrolidin-2-yl) ethyl] -1H-imidazol-5-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 39 by replacing benzylamine with 2- (1-methylpyrrolidin-2-yl) ethanamine.

Example 69

5- {4- (4-fluorophenyl) -1- [3- (4-methylpiperazin-1-yl) propyl] -1H-imidazol-5-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 39 by replacing benzylamine with 3- (4-methylpiperazin-1-yl) propan-1-amine.

Example 70

Ethyl 5- (1H-indazol-5-yl) isoxazole-3-carboxylate

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 added dropwise for 30 minutes. After addition, the mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid. The organic layer was concentrated under reduced pressure and the resulting residue was triturated with methanol to afford the title compound.

Example 71

5- (1H-indazol-5-yl) -N-methylisoxazole-3-carboxamide

Example 71A

5- (1H-indazol-5-yl) isoxazole-3-carboxylic acid

Example 70 (1.50 g, 5.83 mmol) was dissolved in tetrahydrofuran (100 mL), methanol (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 solvent was removed under reduced pressure and the resulting residue was triturated with a mixture of 1N hydrochloric acid and methanol to give a solid, which was filtered to afford the title compound.

Example 71B

5- (1H-indazol-5-yl) -N-methylisoxazole-3-carboxamide

Example 71A (46 mg, 0.201 mmol), HATU (88 mg, 0.231 mmol) and diisopropylethylamine (133 uL, 0.764 mmol) were combined in tetrahydrofuran (2 mL). Monomethylamine (40% solution in water) (50 uL) was added and the reaction stirred at 50 ° C. for 2 hours. The mixture was diluted with methylene chloride and washed with 1N sodium hydroxide, 1N hydrochloric acid and brine. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes to afford the title compound.

Example 72

5- (3-benzylisoxazol-5-yl) -1H-indazole

Phenylacetaldehyde (90 +%) (266 mg, 2.38 mmol) was dissolved in tert-butanol (1 mL) and water (1 mL). Hydroxylamine hydrochloride (79 mg, 1.14 mmol) was added, followed by 6N solution of sodium hydroxide (19 uL, 31.7 mmol). The mixture was stirred for 30 minutes. Chloramine-T trihydrate (308 mg, 1.09 mmol) was added slowly over 5 minutes, followed by copper (II) sulfate and a 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 at 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 eluting with a gradient of 10-50% ethyl acetate in hexanes to afford the title compound.

Example 73

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide

Example 64A (72 mg, 0.184 mmol) was dissolved in methylene chloride (2 mL) and pyridine (0.2 mL). Benzoyl chloride (36 uL, 0.310 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 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 1-8% methanol in dichloromethane to afford the title compound.

Example 74

5- (3-propylisoxazol-5-yl) -1H-indazole

The title compound was prepared following the procedure outlined in Example 72 by substituting butylacetaldehyde with butyraldehyde.

Example 75

N-benzyl-4- (1H-indazol-5-yl) -5-phenyl-1,3-thiazol-2-amine

Example 75A

1H-indazol-5-carboxylic acid

The title compound was prepared following the procedure outlined in Example 3A by replacing 4-iodo-2-methylaniline with methyl 4-amino-3-methylbenzoate. During the final workup, 6N HCl was added until pH 6 to form a solid, which was filtered, washed twice with water and dried in vacuo to afford the title compound.

Example 75B

N-methoxy-N-methyl-1H-indazol-5-carboxamide

Triethylamine (1.67 mL, 12 mmol) and a suspension of Example 75A (1.6 g, 10 mmol) and N, O-dimethylhydroxylamine (1.1 g, 11 mmol) in dichloromethane (40 ml) and dimethylformamide (10 ml) and EDC (2.1 g, 11 mmol) was added and the mixture was stirred at rt for 24 h. The solvent was evaporated under reduced pressure and the resulting residue was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and purified by silica gel column chromatography in ethyl acetate to afford the title compound. MS (ESI +) m / z 206.0 (M + H) ⁺ .

Example 75C

1- (1H-indazol-5-yl) -2-phenylethanone

A solution of Example 75B (900 mg, 4.39 mmol) in tetrahydrofuran (10 mL) was cooled under an argon in an ice bath and treated with a 2M solution of benzyl magnesium chloride (6.6 mL, 13.16 mmol) in tetrahydrofuran. The reaction was stirred at rt overnight and at least one equivalent of benzyl magnesium chloride was added. The mixture was heated at 70 ° C. for 9 hours. At least one equivalent of benzylmagnesium chloride was added and the reaction heated at 70 ° C. for an additional 90 minutes and cooled 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 + H) ⁺ .

Example 75D

Tert-butyl 5- (2-phenylacetyl) -1H-indazole-1-carboxylate

To a suspension of Example 75C (236 mg, 1 mmol) in dichloromethane (2 ml) was added di-tert-butyl dicarbonate (327 mg, 1.5 mmol) and some dimethylaminopyridine (about 2 mg). The mixture was stirred for 15 minutes, passed through a silica gel bed and eluted with dichloromethane. The solvent was evaporated under reduced pressure to afford the title compound. MS (ESI +) m / z 337.0 (M + H) ⁺ .

Example 75E

2-bromo-1- (1H-indazol-5-yl) -2-phenylethanone

A solution of pyridinium tribromide (352 mg, 1.1 mmol) in tetrahydrofuran (20 mL) using a dropping funnel in a solution of Example 75D (336 mg, 1 mmol) in tetrahydrofuran (20 mL) heated in an oil bath at 40 ° C. Added dropwise for 10 minutes. The reaction mixture was heated for an additional 2 hours, cooled, filtered and the filtrate was evaporated to afford the title compound. MS (ESI-) m / z 212.9 (M ⁻ H) ⁻ .

Example 75F

N-benzyl-4- (1H-indazol-5-yl) -5-phenyl-1,3-thiazol-2-amine

Vials containing Example 75E (50 mg, 0.16 mmol) and 1-benzylthiourea (26 mg, 0.16 mmol) in ethanol (1 mL) were covered with a lid and heated at 80 ° C. for 2 hours in a heater shaker. The crude product solution was purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution method to afford the title compound as a TFA salt.

Example 76

4- (1H-indazol-5-yl) -N, 5-diphenyl-1,3-thiazol-2-amine

The title compound was prepared as a TFA salt following the procedure outlined in Example 75F by substituting 1-benzylthiourea with 1-phenylthiourea.

Example 77

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazole

Example 77A

Tert-butyl 5- (cyclopropylethynyl) -1H-indazole-1-carboxylate

Example 44A (2.31 g, 7.77 mmol), cyclopropyl acetylene (620 mg, 9.37 mmol), dichlorobis (triphenylphosphine) palladium (II) (170 mg, 0.242 mmol) and copper iodide (I) (92 mg, 0.483 mmol ) Was combined in triethylamine (10 mL) under an inert atmosphere of nitrogen. The mixture was heated to 100 ° C. for 4 hours in a sealed tube. The mixture was diluted with methylene chloride and washed with 1N hydrochloric acid. The organic layer was absorbed on silica gel and 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 283.0 (M + H) ⁺ .

Example 77B

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazole

Example 77A (145 mg, 0.51 mmol) and benzyl azide (82 mg, 0.62 mmol) were purely heated with CEM-Discover microwave at 150 ° C. and 150 W for 10 minutes. The crude mixture was dissolved in dichloromethane and purified by silica gel column chromatography using 50% ethyl acetate in hexane as eluent.

Example 78

5- (1-benzyl-4-cyclopropyl-1H-1,2,3-triazol-5-yl) -1H-indazole

The title compound was isolated as a byproduct following the procedure outlined in Example 77B.

Example 79

2- (1H-indazol-5-yl) -3-phenylimidazo [1,2-a] pyrimidine

Vials containing Example 75E (80 mg, 0.25 mmol) and pyrimidin-2-amine (23 mg, 0.25 mmol) in ethanol (1 mL) were capped and heated at 80 ° C. for 21 hours on a heater shaker. The solution of the crude product was purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution method to afford the title compound.

Example 80

5- [1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

Example 8 OA

4- (azidomethyl) tetrahydro-2H-pyran

4- (iodomethyl) tetrahydro-2H-pyran (4.76 g, 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 resulting slurry was diluted with diethyl ether and washed with water. The organic layer was concentrated under reduced pressure to afford the title compound. The product was used directly in the next reaction without characterization.

Example 80B

5- [1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

Example 8OA (122 mg, 0.864 mmol) and Example 3C (150 mg, 0.619 mmol) were combined in a microwave vial with tert-butanol (1 mL) and water (1 mL). Following a small piece of copper wire, copper (II) sulfate (5 mg, 0.02 mmol) was added and the vial was stirred in microwave (CEM-Discover) for 10 minutes at 125 ° C. and 100 W. The mixture was diluted with methylene chloride and washed with 1N hydrochloric acid. 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.

Example 81

5- [3- (piperidin-1-ylcarbonyl) isoxazol-5-yl] -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), methanol (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 solvent was removed under reduced pressure and the resulting residue was triturated with a mixture of 1N hydrochloric acid and methanol to give a solid, which was filtered to afford the title compound.

Example 81B

5- [3- (piperidin-1-ylcarbonyl) isoxazol-5-yl] -1H-indazole

Example 81A (110 mg, 0.480 mmol), piperidine (55 uL, 0.556 mmol) and HATU (101 mg, 0.266 mmol) were combined in dimethylformamide (2 mL). Diisopropylethylamine (133 uL, 0.764 mmol) was added and the reaction stirred at 45 ° C. for 2 hours. The mixture was diluted with ethyl acetate and washed with 1N sodium hydroxide, 1N hydrochloric acid, water (3 times) and brine. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient in 0-5% methanol in dichloromethane to afford the title compound.

Example 82

5- (1H-indazol-5-yl) -N-phenylisoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with aniline.

Example 83

N-cyclohexyl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide

Example 81A (53 mg, 0.231 mmol), cyclohexylamine (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 stirred at 45 ° C. for 2 hours. The mixture was diluted with ethyl acetate and washed with 1N sodium hydroxide, 1N hydrochloric 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.

Example 84

5- [3- (piperidin-1-ylmethyl) isoxazol-5-yl] -1H-indazole

Example 81B (22 mg, 0.0742 mmol) was dissolved in 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 taken up on silica gel and purified by silica gel chromatography eluting with a gradient of methanol (0-7%) in dichloromethane to afford the title compound.

Example 85

[5- (1H-imidazol-5-yl) isoxazol-3-yl] methanol

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 portions over 2 hours. After the final addition, the mixture was stirred for an additional 30 minutes. The mixture was diluted with methylene chloride, 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.

Example 86

5- (1H-indazol-5-yl) -N- (2-methoxyethyl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by substituting piperidine with 2-methoxyethyl amine.

Example 87

5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazole

Example 87A

1- (5-iodo-1H-indazol-1-yl) ethanone

4-iodo-2-methylaniline (30.2 g, 130 mmol) was dissolved in chloroform (300 mL) and 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 (4.21 g, 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 solvent was removed under reduced pressure and the resulting residue was triturated with methanol to afford the title compound.

Example 87B

1-benzyl-5-phenyl-4- (tributylstannyl) -1H-1,2,3-triazole

Phenylethynyltri-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 eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. MS (ESI +) m / z 526.3 (M + H) ⁺ .

Example 87C

1- (5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-1-yl) ethanone

Example 87A (139 mg, 0.486 mmol), Example 87B (284 mg, 0.542 mmol), dichlorobis (triphenylphosphine) palladium (II) (40 mg, 0.057 mmol) and copper thiophene-2-carboxylate (167 mg, 0.876 mmol) was combined in toluene (1.5 mL) in a microwave vial under an inert atmosphere of nitrogen. The vial was heated to 150 ° C. in microwave (CEM-Discover) at 125 W 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 (ESI +) m / z 394.1 (M + H) ⁺ .

Example 87D

5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazole

Example 87C (95 mg, 0.242 mmol) was dissolved in tetrahydrofuran (2.0 mL), methanol (1.0 mL) and water (1.0 mL), and potassium hydroxide (64 mg, 1.14 mmol) was added. The mixture was stirred for 2 hours, diluted with ethyl acetate 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.

Example 88

5- (4-benzyl-1H-1,2,3-triazol-1-yl) -1H-indazole

Example 87A (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, 0.708 mmol) and L-proline (78 mg, 8.98 mmol) were combined in a 1: 1 mixture of dimethyl sulfoxide and water (10 mL). Copper (II) 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 1N hydrochloric acid. The organic layer was concentrated under reduced pressure, and the resulting residue was polished with methanol. The remaining solid 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.

Example 89

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine

Example 89A

5- (cyclopropylethynyl) -2-fluorobenzonitrile

5-bromo-2-fluorobenzonitrile (3.06 g, 15.3 mmol), dichlorobis (triphenylphosphine) palladium (II) (478 mg, 0.681 mmol) and copper iodide (I) (165 mg, 0.866 mmol) It was compounded in triethylamine (15 mL) under an inert atmosphere of nitrogen. Cyclopropylacetylene (1.8 mL) was added and the mixture heated to 60 ° C. until it turned a black solid. The mixture was diluted with methylene chloride and washed with 1N hydrochloric acid. The organic layer 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 319.0 (M + H) ⁺ .

Example 89B

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine

Example 89A (211 mg, 1.14 mmol) and benzyl azide (143 uL, 1.14 mmol) were combined in a microwave (CEM-Discover) vial and heated to 160 ° C. using 100 W for 26 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 20-60% ethyl acetate in hexanes to give a mixture of inseparable triazole resins. The mixture of rheomers was treated with hydrazine hydrate (3.0 mL) and ethanol (3.0 mL) and heated to 90 ° 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 gel chromatography eluting with a gradient of 1-6% methanol in dichloromethane to afford the title compound.

Example 90

5- (1-benzyl-4-cyclopropyl-1H-1,2,3-triazol-5-yl) -1H-indazol-3-amine

The title compound was isolated as a byproduct following the procedure outlined in Example 89B.

Example 91

5- (3-isobutylisoxazol-5-yl) -1H-indazol-3-amine

Example 91A

2-fluoro-5- (3-isobutylisoxazol-5-yl) benzonitrile

The title compound was prepared according to the procedure outlined in Example 72 by substituting phenylacetaldehyde for isovaleraldehyde and Example 3C for Example 62B.

Example 91B

5- (3-isobutylisoxazol-5-yl) -1H-indazol-3-amine

Example 91A (75 mg, 0.307 mmol) was added hydrazine hydrate (1.5 mL) in ethanol (1.0 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.

Example 92

5- (3-benzylisoxazol-5-yl) -1H-indazol-3-amine

Example 92A

5- (3-benzylisoxazol-5-yl) -2-fluorobenzonitrile

The title compound was prepared following the procedure outlined in Example 72, substituting Example 62C for Example 3C. The crude product was used for next step without further purification or characterization.

Example 92B

5- (3-benzylisoxazol-5-yl) -1H-indazol-3-amine

To 92A (65 mg, 0.234 mmol) hydrazine hydrate (1.5 mL) in ethanol (1.0 mL) was added. 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 0-20% methanol in dichloromethane to afford the title compound.

Example 93

N- {2- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] ethyl} -N, N-dimethylamine

The title compound was prepared following the procedure outlined in Example 39 by replacing benzylamine with 2-dimethylaminoethylamine.

Example 94

5- [4- (4-fluorophenyl) -1- (3-morpholin-4-ylpropyl) -1H-imidazol-5-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 39 by replacing benzylamine with 3-morpholinopropylamine.

Example 95

5- [4- (4-fluorophenyl) -1- (3-pyrrolidin-1-ylpropyl) -1H-imidazol-5-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 39 by replacing benzylamine with 3-pyrrolidinopropylamine.

Example 96

5- {4- (4-fluorophenyl) -1- [2- (4-methylpiperidin-1-yl) ethyl] -1H-imidazol-5-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 39 by substituting benzylamine with 2- (4-methylpiperidin-1-yl) ethanamine.

Example 97

5- [1- (1-benzylpiperidin-4-yl) -4- (4-fluorophenyl) -1H-imidazol-5-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 39 by replacing benzylamine with 4-amino-N-benzylpiperidine.

Example 98

5- [4- (4-fluorophenyl) -1- (2-morpholin-4-ylethyl) -1H-imidazol-5-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 39 by replacing benzylamine with 2-morpholinoethylamine.

Example 99

5- [1- (1-benzylpyrrolidin-3-yl) -4- (4-fluorophenyl) -1H-imidazol-5-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 39 by replacing benzylamine with 3-pyrrolidinobenzylamine.

Example 100

Example 100 has been removed, which is not part of the present application.

Example 101

2- {4- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] piperidin-1-yl} -2-oxo ethanol

The title compound was prepared following the procedure outlined in Example 39 by replacing benzylamine with 1- (4-aminopiperidin-1-yl) -2-hydroxyethanone.

Example 102

5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine

Example 102A

5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -2-fluorobenzonitrile

Example 87B (415 mg, 0.792 mmol), 5-bromo-2-fluorobenzonitrile (158 mg, 0.790 mmol), dichlorobis (triphenylphosphine) palladium (II) (52 mg, 0.074 mmol) and copper thiophene 2-carboxylate (226 mg, 1.19 mmol) was combined in toluene (2 mL) in a microwave vial under an inert atmosphere of nitrogen. The vial was heated to 150 ° C. in microwave (CEM-Discover) at 125 W for 20 minutes. The mixture was purified by silica gel chromatography eluting with a gradient of ethyl acetate (5-40%) in hexanes to afford the title compound. MS (ESI +) m / z 355.1 (M + H) ⁺ .

Example 102B

5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine

Example 102A (120 mg, 0.339 mmol) was treated with hydrazine hydrate (1.0 mL) in ethanol (1.0 mL) 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 0-5% methanol in dichloromethane to afford the title compound.

Example 103

2- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] propan-2-ol

The title compound was prepared by replacing 3-phenyl-1-propyne with 2-methyl-3-butyn-2-ol, except that the crude reaction mixture was quenched with 2 mL of 1N aqueous NaOH and stirred at ambient temperature for 1.5 hours. Prepared according to the procedure outlined in 88. The suspension was then dried by heated forced nitrogen gas evaporation prior to extraction.

Example 104

5- [4- (methoxymethyl) -1H-1,2,3-triazol-1-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propyne with methyl propargyl ether.

Example 105

1- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] -1-phenylethanol

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propyne with 2-phenyl-3-butyn-2-ol.

Example 106

5- (4-propyl-1H-1,2,3-triazol-1-yl) -1H-indazole

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propyne with 1-pentine.

Example 107

1- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] propan-2-ol

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propyne with pent-4-yn-2-ol.

Example 108

3- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] propan-1-ol

The title compound was prepared following the procedure outlined in Example 88, replacing 3-phenyl-1-propene with 4-pentyn-1-ol.

Example 109

1-{[1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] methyl} -1H-1,2,3-benzotriazole

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propyne with 1-propargyl-1H-benzotriazole.

Example 110

5- {4-[(phenylthio) methyl] -1H-1,2,3-triazol-1-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propene with phenyl propargyl sulfide.

Example 111

5- (4-cyclopropyl-1H-1,2,3-triazol-1-yl) -1H-indazole

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propene with cyclopropylacetylene.

Example 112

5- [4- (2-phenylethyl) -1H-1,2,3-triazol-1-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 88, replacing 3-phenyl-1-propyne with 1-phenyl-1-butyne. The product was a 1: 1 mixture of starting material and title compound.

Example 113

5- [4- (cyclohexylmethyl) -1H-1,2,3-triazol-1-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propyne with 3-cyclohexyl-1-propyne.

Example 114

5- (4-cyclopentyl-1H-1,2,3-triazol-1-yl) -1H-indazole

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propene with cyclopentylacetylene.

Example 115

1- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] cyclohexanol

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propyne with 1-ethynyl-1-cyclohexanol.

Example 116

5- [4- (phenoxymethyl) -1H-1,2,3-triazol-1-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propine with phenyl propargyl ether.

Example 117

5- {4-[(1,1-dioxydothiomorpholin-4-yl) methyl] -1H-1,2,3-triazol-1-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propine with N-propargyl thiomorpholine-sulfone.

Example 118

5- [4- (3-phenylpropyl) -1H-1,2,3-triazol-1-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propyne with 1-phenyl-1-pentine.

Example 119

[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] (phenyl) methanone

Example 119A

Tert-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 some dimethylaminopyridine (about 3 mg) and the mixture was stirred at room temperature. Stir for 30 minutes. Water was added, the product was extracted with dichloromethane, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to afford the title compound. MS (ESI +) m / z 265.0 (M + Na) ⁺ .

Example 119B

[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] (phenyl) methanone

Example 119A (90 mg, 0.37 mmol), benzyl azide (0.047 mL, 0.37 mmol), tetrahydrofuran (3 mL), triethylamine (0.062 mL, 0.44 mmol), CuI (71 mg, 0.37 mmol) and benzoyl chloride ( Vials under argon containing 0.059 mL, 0.51 mmol) were capped and shaken for 16 hours. The solvent was evaporated and the product was purified by silica gel 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 acetonitrile / water 0.1% TFA gradient elution method to afford the title compound.

Example 120

N, N-diethyl-N-{[1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] methyl} amine

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propyne with 1,1-diethylpropargylamine.

Example 121

Ethyl N- [2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-yl] -β-alanineate

The title compound was prepared following the procedure outlined in Example 43 by substituting isopropyl isocyanide with ethyl isocyanopropionate.

Example 122

5- (1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl) -1H-indazole

Example 122A

1-benzyl-5-methyl-4- (tributylstannyl) -1H-1,2,3-triazole

Tributyl (1-propynyl) tin (3.87 g, 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 5-40% ethyl acetate in hexanes to afford the title compound. MS (ESI +) m / z 464.2 (M + H) ⁺ .

Example 122B

1- (5- (1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl) -1H-indazol-1-yl) ethanone

Example 87A (235 mg, 0.821 mmol), Example 122A (380 mg, 0.822 mmol), dichlorobis (triphenylphosphine) palladium (II) (60 mg, 0.085 mmol) and copper thiophene-2-carboxylate (325 mg, 1.23 mmol) were combined in toluene (2.0 mL) in a microwave vial under an inert atmosphere of nitrogen. The vial was heated to 150 ° C. in microwave (CEM-Discover) at 125 W 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 (ESI +) m / z 332.2 (M + H) ⁺ .

Example 122C

5- (1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl) -1H-indazole

Example 122B (109 mg, 0.329 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 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.

Example 123

5- (1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine

Example 123A

5- (1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl) -2-fluorobenzonitrile

Example 122A (415 mg, 0.792 mmol), 5-bromo-2-fluorobenzonitrile (158 mg, 0.790 mmol), dichlorobis (triphenylphosphine) palladium (II) (52 mg, 0.074 mmol) and copper thiophene 2-carboxylate (226 mg, 1.19 mmol) was combined in toluene (2 mL) in a microwave vial under an inert atmosphere of nitrogen. The vial was heated in microwave (CEM-Discover) at 150 ° C. and 125 W 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 (ESI +) m / z 293.0 (M + H) ⁺ .

Example 123B

5- (1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine

Example 123A (120 mg, 0.339 mmol) was treated with hydrazine hydrate (1.0 mL) in ethanol (1.0 mL) 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 methanol (0-5%) in dichloromethane to afford the title compound.

Example 124

N ^3- [2- (1H-indazol-5-yl) imidazo [1,2-α] pyrimidin-3-yl] -β-alanineamide

Example 121 (42 mg, 0.120 mmol) and a solution of 7N ammonia 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 eluting with a gradient of methanol (1-7%) in dichloromethane to afford the title compound.

Example 125

5- (1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine

Example 125A

5- (1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl) -2-fluorobenzonitrile

Example 62B under argon (200 mg, 1.38 mmol), benzyl azide (0.176 mL, 1.38 mmol), tetrahydrofuran (12 mL), triethylamine (0.230, 1.56 mmol), CuI (263 mg, 1.38 mmol) and ICl ( 0.069 mL, 1.38 mmol) was stirred at rt for 24 h. The solvent was evaporated, the crude mixture was dissolved in dichloromethane, dropped 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 125B

5- (1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine

Example 125A (50 mg, 0.12 mmol) and hydrazine monohydrate (1 mL) in ethanol (1 mL) were heated at 95 ° C. for 2 hours. Water was added, the solid was collected by filtration and further purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution method to afford the title compound as a TFA salt.

Example 126

N- {3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] phenyl} -N '-(3 -Methylphenyl) urea

Example 126A

1- (3- (1-benzyl-4- (3-cyano-4-fluorophenyl) -1H-1,2,3-triazol-5-yl) phenyl) -3-m-tolylurea

Example 125A (94 mg, 0.23 mmol), 1- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -3-m-tolyl Urea (prepared according to the procedure described in WO2004 / 113304) (990 mg, 0.26 mmol), PdCl ₂ dppf dichloromethane (19 mg, 0.02 mmol), potassium carbonate (64 mg, 0.46 mmol), DME (2 mL ) And a vial under argon containing water (0.2 mL) was capped and heated in a heater shaker at 80 ° C. for 90 minutes. The solvent was evaporated and the product extracted with methanol / dichloromethane. Silica gel column chromatography using 10% ethyl acetate in hexanes gave the title compound. MS (ESI +) m / z 503.2 (M + H) ⁺ .

Example 126B

N- {3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] phenyl} -N '-(3 -Methylphenyl) urea

Example 126A (25 mg, 0.05 mmol) and hydrazine monohydrate (0.5 mL) in ethanol (2 mL) were heated at 80 ° C. for 1 h. The crude mixture was dropped on a silica gel column and eluted with a gradient of 0-5% methanol in dichloromethane to afford the title compound.

Example 127

5- (1H-indazol-5-yl) -N- (2-isopropoxyethyl) isoxazole-3-carboxamide

To a 20 mL vial was added a solution of Example 81A (37 mg, 0.18 mmol) dissolved in dimethylformamide (0.8 mL), followed by HATU (61 mg, 0.18 mmol) dissolved in dimethylformamide (0.8 mL). Then, a solution of 2-isopropoxytanamine (20 mg, 0.20 mmol) dissolved in dimethylformamide (0.9 mL) was added, followed by diisopropylethylamine (42 mg, dissolved in 0.8 mL). 0.36 mmol) was added. The mixture was then shaken at 40 ° C. for 3 hours. The crude reaction mixture was filtered through Si-carbonate cartridge (6 mL, 2 g) supplied by Silica Chemical Division using methanol, checked by LC / MS and concentrated to dryness. The residue was dissolved in 1: 1 DMSO / methanol and purified by reverse phase HPLC (Agilent, 5% to 100% TFA / water gradient, 8 min run).

Example 128

5- [3- (morpholin-4-ylcarbonyl) isoxazol-5-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 127, replacing 2-isopropoxytanamine with morpholine.

Example 129

5- (1H-indazol-5-yl) -N- (3-morpholin-4-ylpropyl) isoxazole-3-carboxamide

The title compound was prepared as a TFA salt by following the procedure outlined in Example 127 by replacing 2-isopropoxytanamine with 3-morpholinopropane-1-amine.

Example 130

N- [2- (1H-imidazol-4-yl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 127 by replacing 2-isopropoxyethanamine with 2- (1H-imidazol-4-yl) ethanamine.

Example 131

(3R) -1-{[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} piperidin-3-ol

The title compound was prepared following the procedure outlined in Example 127 by substituting 2-isopropoxytanamine with (R) -piperidin-3-ol hydrochloride.

Example 132

1-{[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} piperidine-3-carboxamide

The title compound was prepared following the procedure outlined in Example 127, replacing 2-isopropoxytanamine with piperidine-3-carboxamide.

Example 133

2- [2- (4-{[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} piperazin-1-yl) ethoxy] ethanol

The title compound was prepared as a TFA salt following the procedure outlined in Example 127 by substituting 2-isopropoxyethanamine with 2- (2- (piperazin-1-yl) ethoxy) ethanol.

Example 134

5- {3-[(4-methyl-l, 4-diazepan-1-yl) carbonyl] isoxazol-5-yl} -1 H-indazole

The title compound was prepared as a TFA salt following the procedure outlined in Example 127 by substituting 2-isopropoxytanamine with 1-methyl-1,4-diazepane.

Example 135

N- (3-hydroxypropyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 127, replacing 2-isopropoxyethanamine with 3-aminopropan-1-ol.

Example 136

N-[(1R) -2-hydroxy-1-phenylethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 127, replacing 2-isopropoxyethanamine with (R) -2-amino-2-phenylethanol.

Example 137

N- [3- (1H-imidazol-1-yl) propyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 127, replacing 2-isopropoxytanamine with 3- (1H-imidazol-1-yl) propan-1-amine.

Example 138

5- (1H-indazol-5-yl) -N- [3- (2-oxopyrrolidin-1-yl) propyl] isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 127, replacing 2-isopropoxyethanamine with 1- (3-aminopropyl) pyrrolidin-2-one.

Example 139

N- {2- [4- (aminosulfonyl) phenyl] ethyl} -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 127, replacing 2-isopropoxyethanamine with 4- (2-aminoethyl) benzenesulfonamide.

Example 140

[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] (3-chlorophenyl) methanone

The title compound was prepared following the procedure outlined in Example 119B, replacing benzoyl chloride with 3-chlorobenzoyl chloride.

Example 141

[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] (cyclopropyl) methanone

The title compound was prepared following the procedure outlined in Example 119B by replacing benzoyl chloride with cyclopropanecarbonyl chloride.

Example 142

5- [5-cyclopropyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

Example 142A

5-cyclopropyl-1-((tetrahydro-2H-pyran-4-yl) methyl) -4- (tributylstannyl) -1H-1,2,3-triazole

Cyclopropyl acetylene (142 mg, 2.15 mmol) was added to 1,1,1-tributyl-N, N-dimethylstannanamine (716 mg, 2.14 mmol) in hexane (3.0 mL) and at 70 ° C. in a sealed vial. Stir for 2 hours. The mixture was cooled to ambient temperature and the vial was sealed unsealed for 10 minutes. Example 8 OA (455 mg, 3.22 mmol) was added and the vial was resealed and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of ethyl acetate (5-50%) in hexanes to afford the title compound. MS (ESI +) m / z 498.3 (M + H) ⁺ .

Example 142B

1- (5- (5-cyclopropyl-1-((tetrahydro-2H-pyran-4-yl) methyl) -1H-1,2,3-triazol-4-yl) -1H-indazole- Ethanol

Example 142A (220 mg, 0.444 mmol), Example 87A (128 mg, 0.447 mmol), dichlorobis (triphenylphosphine) palladium (II) (33 mg, 0.047 mmol) and copper thiophene-2-carboxylate (127 mg, 0.666 mmol) was combined in toluene (2.0 mL) in 4 mL vials under an inert atmosphere of nitrogen. The vial was sealed and heated at 150 ° C. for 20 minutes. The mixture was taken up 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-ylmethyl) -1H-1,2,3-triazol-4-yl] -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, 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 0-8% methanol in dichloromethane to afford the title compound.

Example 143

N ¹ -{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] methyl} glycinamide

Example 143A

2-((1-benzyl-4- (tributylstannyl) -1H-1,2,3-triazol-5-yl) methyl) isoindoline-1,3-dione

N-propargylphthalimide (2.35 g mg, 12.7 mmol) was added to 1,1,1-tributyl-N, N-dimethylstannanamine (4.23 mg, 12.7 mmol) in hexane (3.0 mL), Stir at 70 ° C. for 2 hours in a sealed vial. The mixture was cooled to ambient temperature and the vial was sealed unsealed for 10 minutes. Benzyl azide (2.0 mL, 16.0 mmol) was added and the vial was 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-1H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl) methyl) isoindolin-1,3- Dion

Example 143A (567 mg, 0.934 mmol), Example 87A (268 mg, 0.934 mmol), dichlorobis (triphenylphosphine) palladium (II) (67 mg, 0.095 mmol) and copper thiophene-2-carboxylate (268 mg, 1.41 mmol) were combined in toluene (2.5 mL) in a microwave vial under an inert atmosphere of nitrogen. The vial was heated to 150 ° C. with microwave (CEM-Discover) at 125 W for 20 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 to afford the title compound. MS (ESI +) m / z 477.2 (M + H) ⁺ .

Example 143C

(1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl) methanamine

Example 143B (140 mg, 0.294 mmol) was treated with hydrazine hydrate (0.7 mL) in ethanol (0.7 mL) and stirred overnight at ambient temperature. The mixture was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 1-6% methanol in dichloromethane to afford the title compound. MS (ESI +) m / z 305.0 (M + H) ⁺ .

Example 143D

N '-{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] methyl} glycinamide

Example 143C (66 mg, 0.217 mmol), N- (tert-butoxycarbonyl) -glycine (39 mg, 0.223 mmol) and HATU (85 mg, 0.224 mmol) were combined in methylene chloride (2.5 mL). Diisopropylethylamine (150 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 0-6% methanol in dichloromethane to tert-butyl 2-((1-benzyl-4- (lΗ-indazole-5) -Yl) -1H-1,2,3-triazol-5-yl) methylamino) -2-oxoethylcarbamate was obtained. This carbamate was dissolved in tetrahydrofuran (2 mL), a 0.5 mL solution of 1N hydrochloric acid in diethyl ether was added, and the mixture was stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure, diethyl ether was added to the mixture and stirred at rt overnight. The solvent was decanted off and the resulting residue was dried under a stream of nitrogen to afford the title compound as a hydrochloride salt.

Example 144

(4-fluorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5- Japan] Metanon

The title compound was prepared following the procedure outlined in Example 119B by replacing benzoyl chloride with 4-fluorobenzoyl chloride and benzyl azide with Example 80A.

Example 145

(4-chlorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl ] Metanon

The title compound was prepared following the procedure outlined in Example 119B, replacing benzoyl chloride with 4-chlorobenzoyl chloride and benzyl azide with Example 80A.

Example 146

(3-chlorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl ] Metanon

The title compound was prepared following the procedure outlined in Example 119B by replacing benzoyl chloride with 3-chlorobenzoyl chloride and benzyl azide with Example 80A.

Example 147

(2-chlorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl ] Metanon

The title compound was prepared following the procedure outlined in Example 119B by replacing benzoyl chloride with 2-chlorobenzoyl chloride and benzyl azide with Example 80A.

Example 148

Cyclopentyl [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl] methanone

The title compound was prepared following the procedure outlined in Example 119B by replacing benzoyl chloride with cyclopentanecarbonyl chloride and benzyl azide with Example 80A.

Example 149

1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxylic acid

Example 149A

Methyl 1-benzyl-4- (tributylstannyl) -1H-1,2,3-triazole-5-carboxylate

Methyl propiolate (5.75 g, 68.4 mmol) was added to methyl 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 sealed unsealed for 10 minutes. Benzyl azide (10.2 mL, 81.6 mmol) was added and the vial was resealed and heated to 130 ° C. overnight. The mixture was 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 508.3 (M + H) ⁺ .

Example 149B

Methyl 4- (1-acetyl-1H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazole-5-carboxylate

Example 149A (7.17 g, 14.1 mmol), Example 87A (4.02 g, 14.1 mmol), dichlorobis (triphenylphosphine) palladium (II) (1.01 mg, 1.44 mmol) and copper thiophene-2-carboxylate (4.07 mg, 21.3 mmol) was combined in toluene (55 mL) under inert atmosphere of nitrogen in a large sealed tube. 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 eluting with a gradient of 10-50% ethyl acetate in hexanes to afford the title compound. MS (ESI < + >) m / z 376.1 (M + H) ⁺ .

Example 149C

1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxylic acid

Example 149B (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, diluted with ethyl acetate, washed with 1N hydrochloric acid, washed with brine and the combined organic layers were dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure to afford the title compound.

Example 150

5- {5- (4-fluorophenyl) -1- [4- (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3- Amine

Example 150A

1- (azidomethyl) -4- (trifluoromethyl) benzene

Sodium azide (2.30 g, 35.4 mmol) was added to a solution of 4- (trifluoromethyl) benzyl bromide (4.26 g, 17.8 mmol) dissolved in dimethyl sulfoxide (15 mL) and stirred overnight at ambient temperature. 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 150B

5- (4-fluorophenyl) -4- (tributylstannyl) -1- (4- (trifluoromethyl) benzyl) -1H-1,2,3-triazole

4-fluorophenyl acetylene (524 mg, 4.36 mmol) was added to 1,1,1-tributyl-N, N-dimethylstannanamine (1.46 g, 4.37 mmol) and the mixture was added at 50 ° C. in a sealed vial. Stir for 30 minutes. The mixture was cooled to ambient temperature and the vial was sealed unsealed for 10 minutes. Example 150A (1.28 g, 6.30 mmol) was added and the vial was 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-yl) benzonitrile

Example 150B (485 mg, 0.795 mmol), 5-bromo-2-fluorobenzonitrile (143 mg, 0.715 mmol), dichlorobis (triphenylphosphine) palladium (II) (49 mg, 0.070 mmol) and copper thiophene 2-carboxylate (205 mg, 1.08 mmol) was combined in toluene (2.0 mL) 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 was absorbed on silica gel and 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 441.2 (M + H) ⁺ .

Example 150D

5- {5- (4-fluorophenyl) -1- [4- (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3- Amine

Example 150C was treated with hydrazine hydrate (1.0 mL) in ethanol (1.0 mL) and the reaction mixture was stirred and heated to 65 ° C. for 3 h. 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.

Example 151

5- [1-benzyl-5- (4-fluorophenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine

Example 151A

1-benzyl-5- (4-fluorophenyl) -4- (tributylstannyl) -1H-1,2,3-triazole

4-fluorophenyl acetylene (525 mg, 4.37 mmol) was added to 1,1,1-tributyl-N, N-dimethylstannanamine (1.46 g, 4.37 mmol) and the mixture was added at 50 ° C. in a sealed vial. Stir for 2 hours. The mixture was cooled to ambient temperature and the vial was sealed unsealed for 10 minutes. Benzyl azide (850 uL, 6.80 mmol) was added and the vial was 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 544.4 (M + H) ⁺ .

Example 151B

5- (1-benzyl-5- (4-fluorophenyl) -1H-1,2,3-triazol-4-yl) -2-fluorobenzonitrile

Example 151A (361 mg, 0.666 mmol), 5-bromo-2-fluorobenzonitrile (119 mg, 0.595 mmol), dichlorobis (triphenylphosphine) palladium (II) (45 mg, 0.064 mmol) and copper thiophene 2-carboxylate (193 mg, 1.01 mmol) was 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 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 to afford the title compound. MS (ESI +) m / z 373.0 (M + H) ⁺ .

Example 151C

5- [1-benzyl-5- (4-fluorophenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine

Example 151B (135 mg, 0.363 mmol) was treated with hydrazine hydrate (1.0 mL) in ethanol (1.0 mL), stirred and heated to 65 ° C. for 3 h. 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.

Example 152

[4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl] (tetrahydro-2H Pyran-4-yl) methanone

The title compound was prepared following the procedure outlined in Example 119B by replacing benzyl azide with Example 80A and benzoyl chloride with tetrahydro-2H-pyran-4-carbonyl chloride.

Example 153

5- [1-benzyl-5- (2-methylphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

Example 153A

1-benzyl-5-o-tolyl-4- (tributylstannyl) -1H-1,2,3-triazole

2-ethynyl toluene (456 uL, 3.62 mmol) was added to l, l, 1-tributyl-N, N-dimethylstannanamine (1.21 g, 3.62 mmol) and the mixture was added at 70 ° C. in a sealed vial at 3 ° C. Stir for hours. The mixture was cooled to ambient temperature and the vial was sealed unsealed for 10 minutes. Benzyl azide (678 uL, 5.42 mmol) was added and the vial was resealed and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5 to 45% ethyl acetate in hexanes to afford the title compound. MS (ESI +) m / z 539.8 (M + H) ⁺ .

Example 153B

1- (5- (1-benzyl-5-o-tolyl-1H-1,2,3-triazol-4-yl) -1H-indazol-1-yl) ethanone

Example 153A (119 mg, 0.221 mmol), Example 87A (63 mg, 0.221 mmol), dichlorobis (triphenylphosphine) palladium (II) (16 mg, 0.023 mmol) and copper thiophene-2-carboxylate (65 mg, 0.341 mmol) was combined in toluene (2.0 mL) in a 4 mL vial under an inert atmosphere of nitrogen. The vial was sealed and heated at 15O < 0 > C for 20 minutes. The mixture was taken up on silica gel and purified by silica gel chromatography eluting with a gradient of 5-45% ethyl acetate in hexanes to afford the title compound. MS (ESI +) m / z 408.7 (M + H) ⁺ .

Example 153C

5- [1-benzyl-5- (2-methylphenyl) -1H-1,2,3-triazol-4-yl] -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, 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 to afford the title compound.

Example 154

5- {1-benzyl-5-[(4-methylpiperazin-1-yl) carbonyl] -1H-1,2,3-triazol-4-yl} -1H-indazole

The title compound was prepared according to the procedure outlined in Example 81B, replacing Example 81A with Example 149C, piperidine with 1-methyl piperazine and dimethylformamide with tetrahydrofuran.

Example 155

1-{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] carbonyl} piperidin-4-ol

The title compound was prepared according to the procedure outlined in Example 81B, replacing Example 81A with Example 149C, piperidine with 4-hydroxy piperidine, and dimethylformamide with tetrahydrofuran.

Example 156

1-acetyl-5- [5- (4-fluorophenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H -Indazole

Example 156A

5- (4-fluorophenyl) -1-((tetrahydro-2H-pyran-4-yl) methyl) -4- (tributylstannyl) -1H-1,2,3-triazole

4-fluorophenyl acetylene (440 uL, 3.88 mmol) was added to 1,1,1-tributyl-N, N-dimethylstannanamine (1.30 g, 3.89 mmol) and the mixture was added at 50 ° C. in a sealed vial. Stir for 40 minutes. The mixture was cooled to ambient temperature and the vial was sealed unsealed for 10 minutes. Example 80A (710 uL, 5.68 mmol) was added and the vial was resealed 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 552.4 (M + H) ⁺ .

Example 156B

1-acetyl-5- [5- (4-fluorophenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H -Indazole

Example 156A (433 mg, 0.787 mmol), Example 87A (205 mg, 0.717 mmol), dichlorobis (triphenylphosphine) palladium (II) (55 mg, 0.078 mmol) and copper thiophene-2-carboxylate (224 mg, 1.17 mmol) was 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, purified by silica gel chromatography eluting with a gradient of 5-45% ethyl acetate in hexanes, and triturated with methanol to afford the title compound.

Example 157

1-benzyl-4- (1H-indazol-5-yl) -N, N-dimethyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined in Example 81B, replacing Example 81A with Example 149A, piperidine with dimethylamine, and dimethylformamide with tetrahydrofuran.

Example 158

N, 1-dibenzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide

The title compound was prepared according to the procedure outlined in Example 81B, replacing Example 81A with Example 149C, piperidine with benzyl amine, and dimethylformamide with tetrahydrofuran.

Example 159

N- (2-hydroxy-2-phenylethyl) -5- (1H-indazol-5-yl) -N-methylisoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with DL-α- (methylaminomethyl) benzyl alcohol.

Example 160

N-[(1S) -2-hydroxy-1-phenylethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by substituting piperidine for (S) -2-amino-2-phenylethanol.

Example 161

N-benzyl-N- (2-hydroxyethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with 2- (benzylamino) ethanol.

Example 162

5- [1-benzyl-5- (2-methylphenyl) -1H-1,2,3-triazol-4-yl] -3-methyl-1H-indazole

Example 162A

1- (5-bromo-3-methyl-1H-indazol-1-yl) ethanone

5-bromo-3-methyl-1H-indazole (838 mg, 3.97 mmol) was dissolved in methylene chloride (15 mL) and diisopropylethylamine (0.7 mL). Acetic anhydride (500 uL, 5.29 mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate and washed with 1N sodium hydroxide followed by 1N hydrochloric 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 +) m / z 252.7 (M + H) ⁺ .

Example 162B

1- (5- (1-benzyl-5-o-tolyl-1H-1,2,3-triazol-4-yl) -3-methyl-1H-indazol-1-yl) ethanone

Example 153A (436 mg, 0.808 mmol), Example 162A (205 mg, 0.810 mmol), dichlorobis (triphenylphosphine) palladium (II) (56 mg, 0.080 mmol) and copper thiophene-2-carboxylate (239 mg, 1.25 mmol) was combined in toluene (2.0 mL) in a 4 mL vial under an inert atmosphere of nitrogen. The vias were sealed and heated at 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 to afford the title compound. MS (ESI +) m / z 422.6 (M + H) ⁺ .

Example 162C

5- [1-benzyl-5- (2-methylphenyl) -1H-1,2,3-triazol-4-yl] -3-methyl-1H-indazole

Example 162B (202 mg, 0.548 mmol) was dissolved in tetrahydrofuran (5.0 mL), methanol (0.5 mL) and water (0.5 mL), and potassium hydroxide (133 mg, 2.37 mmol) was added. The mixture was stirred for 1 h, then 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 30-80% ethyl acetate in hexanes to afford the title compound.

Example 163

5- [1-benzyl-5- (2-methylphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine

Example 163A

5- (1-benzyl-5-o-tolyl-1H-1,2,3-triazol-4-yl) -2-fluorobenzonitrile

Example 153A (450 mg, 0.834 mmol), 5-bromo-2-fluorobenzonitrile (167 mg, 0.835 mmol), dichlorobis (triphenylphosphine) palladium (II) (56 mg, 0.080 mmol) and copper thiophene 2-carboxylate (242 mg, 1.27 mmol) was combined in toluene (2.0 mL) 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 was absorbed on silica gel and 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 369.2 (M + H) ⁺ .

Example 163B

5- [1-benzyl-5- (2-methylphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine

Example 163A (202 mg, 0.548 mmol) was treated with hydrazine hydrate (1.0 mL) in ethanol (1.0 mL), 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 to 85% ethyl acetate in hexanes to afford the title compound.

Example 164

2- {2- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] ethyl} -1H-isoindole-1,3 (2H) -dione

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propyne with 2- (but-3-ynyl) isoindolin-1,3-dione. The crude product was applied to 25% TFA / dichloromethane and purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution method to afford the title compound.

Example 165

5- {4-[(2,4-dichlorophenoxy) methyl] -1H-1,2,3-triazol-1-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propyne with 2,4-dichloro-1- (prop-2-ynyloxy) benzene. The crude product was applied to 25% TFA / dichloromethane and purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution method to afford the title compound.

Example 166

5- {4-[(2,6-dichlorophenoxy) methyl] -1H-1,2,3-triazol-1-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 88 by replacing 3-phenyl-1-propyne with 1,3-dichloro-2- (prop-2-ynyloxy) benzene. The crude product was applied to 25% TFA / dichloromethane and purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution method to afford the title compound.

Example 167

5- [5- (4-fluorophenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

Example 156B (168 mg, 0.401 mmol) was dissolved in tetrahydrofuran (5.0 mL), 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, 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% methanol in dichloromethane to afford the title compound.

Example 168

1-{[1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] methyl} -1H-indazole

Example 168A

1- (prop-2-ynyl) -1H-indazole

Indazole (530 mg, 4.49 mmol) was dissolved in dimethylformamide (4 mL). Sodium hydride (60% suspension in mineral oil, 231 mg, 5.78 mmol) was added slowly and the mixture was stirred for 10 minutes. Propargyl bromide (80% by weight 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-yl) -1H-1,2,3-triazol-4-yl] methyl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 88, replacing 3-phenyl-propene with Example 168A.

Example 169

5- [1-benzyl-5- (piperidin-1-ylcarbonyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 81B, replacing Example 81A with Example 149C and dimethylformamide with tetrahydrofuran.

Example 170

5- [5- (2-methylphenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

Example 170A

1-((tetrahydro-2H-pyran-4-yl) methyl) -5-o-tolyl-4- (tributylstannyl) -1H-1,2,3-triazole

2-ethynyl toluene (576 mg, 4.57 mmol) was added to 1,1,1-tributyl-N, N-dimethylstannanamine (1.53 g, 4.58 mmol) and the mixture was added at 70 ° C. in a sealed vial. Stir for hours. The mixture was cooled to ambient temperature and the vial was sealed unsealed for 10 minutes. Example 80A (648 mg, 4.59 mmol) was added and the vial was resealed 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

1- (5- (1-((tetrahydro-2H-pyran-4-yl) methyl) -5-o-tolyl-1H-1,2,3-triazol-4-yl) -1H-indazole -1-yl) ethanone

Example 170A (432 mg, 0.791 mmol), Example 87A (222 mg, 0.776 mmol), dichlorobis (triphenylphosphine) palladium (II) (58 mg, 0.083 mmol) and copper thiophene-2-carboxylate (231 mg, 1.21 mmol) was combined in toluene (2.0 mL) in a 4 mL vial under an inert 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 silica gel chromatography eluting with a gradient of 20-70% ethyl acetate in hexanes to afford the title compound. MS (ESI +) m / z 416.2 (M + H) ⁺ .

Example 170C

5- [5- (2-methylphenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

Example 170B (184 mg, 0.443 mmol) was dissolved in tetrahydrofuran (3.0 mL), 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, 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 35-100% ethyl acetate in hexane to afford the title compound.

Example 171

5- [5- (2-methylphenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3- Amine

Example 171A

2-fluoro-5- (1-((tetrahydro-2H-pyran-4-yl) methyl) -5-o-tolyl-1H-1,2,3-triazol-4-yl) benzonitrile

Example 170A (411 mg, 0.752 mmol), 5-bromo-2-fluorobenzonitrile (151 mg, 0.755 mmol), dichlorobis (triphenylphosphine) palladium (II) (52 mg, 0.074 mmol) and copper thiophene 2-carboxylate (223 mg, 1.17 mmol) was combined in toluene (2.0 mL) 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 was absorbed on silica gel and 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 377.6 (M + H) ⁺ .

Example 171B

5- [5- (2-methylphenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3- Amine

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 h. 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 1-8% methanol in dichloromethane to afford the title compound.

Example 172

5- [1-benzyl-5- (morpholin-4-ylcarbonyl) -1H-1,2,3-triazol-4-yl] -1H-indazole

The title compound was prepared according to the procedure outlined in Example 81B by substituting Example 81A for Example 149C, piperidine for morpholine, and dimethylformamide with tetrahydrofuran.

Example 173

5- [1-benzyl-5- (4-methoxyphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine

Example 125B (50 mg, 0.12 mmol), 4-methoxyphenylboronic acid (20 mg, 0.13 mmol), PdCl ₂ (dppf) dichloromethane (10 mg, 0.01 mmol) and carbonic acid in DME (2 mL) and water (0.2 mL) A vial under argon containing potassium (33 mg, 0.24 mmol) was capped and heated at 80 ° C. for 48 hours in a heater shaker. The solvent was evaporated under reduced pressure and the product was purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution method to afford the title compound.

Example 174

N-[(1S) -1-benzyl-2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with (S)-(-)-2-amino-3-phenyl-1-propanol.

Example 175

N-[(lS, 2R) -2-hydroxy-2,3-dihydro-1H-inden-1-yl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with (1S, 2R)-(-)-cis-1-amino-2-indanol.

Example 176

5- {3-[(3-phenylmorpholin-4-yl) carbonyl] isoxazol-5-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 81B by substituting piperidine with 3-phenylmorpholine hydrochloride.

Example 177

N-benzyl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with benzylamine.

Example 178

((1S) -2-{[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} -6,7-dimethoxy-1,2,3,4-tetrahydroiso Quinolin-1-yl) methanol

The title compound was prepared according to the procedure outlined in Example 81B by replacing piperidine with (S)-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) methanol did. MS (ESI +) m / z 435.1 (M + H) ⁺ .

Example 179

N-[(1R) -3-hydroxy-1-phenylpropyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by substituting piperidine for (R) -3-amino-3-phenylpropanol.

Example 180

N-[(1S) -3-hydroxy-1-phenylpropyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with (S) -3-amino-3-phenylpropanol.

Example 181

N-2,3-dihydro-1H-inden-1-yl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with 1-aminoindane.

Example 182

N-2,3-dihydro-1H-inden-2-yl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with 2-aminoindane.

Example 183

5- (1H-indazol-5-yl) -N- (1-phenylpropyl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by substituting piperidine for α-ethylbenzylamine.

Example 184

5- {1-benzyl-5- [3- (dimethylamino) phenyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3-amine

The title compound was prepared as a TFA salt by following the procedure outlined in Example 173 by replacing 4-methoxyphenylboronic acid with 3- (dimethylamino) phenylboronic acid.

Example 185

5- {1-benzyl-5- [4- (dimethylamino) phenyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3-amine

The title compound was prepared as a TFA salt following the procedure outlined in Example 173 by replacing 4-methoxyphenylboronic acid with 4- (dimethylamino) phenylboronic acid.

Example 186

N- {3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] phenyl} acetamide

The title compound was prepared following the procedure outlined in Example 173, replacing 4-methoxyphenylboronic acid with 3-acetamidophenylboronic acid.

Example 187

N- {4- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] phenyl} acetamide

The title compound was prepared following the procedure outlined in Example 173 by substituting 4-methoxyphenylboronic acid with 4-acetamidophenylboronic acid.

Example 188

5- {1-benzyl-5- [3- (1H-pyrazol-1-yl) phenyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 173 by replacing 4-methoxyphenylboronic acid with 3- (1H-pyrazol-1-yl) phenylboronic acid.

Example 189

5- [1-benzyl-5- (1-methyl-1H-pyrazol-4-yl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 173 by replacing 4-methoxyphenylboronic acid with 1-methyl-1H-pyrazol-4-ylboronic acid.

Example 190

3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] -N-phenylbenzamide

The title compound was prepared according to the procedure outlined in Example 173, replacing 4-methoxyphenylboronic acid with 3- (phenylcarbamoyl) phenylboronic acid.

Example 191

3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] -N-benzylbenzamide

The title compound was prepared following the procedure outlined in Example 173 by replacing 4-methoxyphenylboronic acid with 3- (benzylcarbamoyl) phenylboronic acid.

Example 192

5- [1-benzyl-5- (1-methyl-1H-indol-5-yl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine

The title compound was prepared as a TFA salt by following the procedure outlined in Example 173 by replacing 4-methoxyphenylboronic acid with 1-methyl-1H-indol-5-ylboronic acid.

Example 193

5- [1-benzyl-5- (3-methoxyphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 173 by replacing 4-methoxyphenylboronic acid with 3-methoxyphenylboronic acid.

Example 194

5- [1-benzyl-5- (3-morpholin-4-ylphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine

Example 125B (35 mg, 0.09 mmol), 3-morpholinophenylboronic acid (21 mg, 0.09 mmol), PdCl ₂ (dppf) -dichloromethane (7 mg, 0.009 mmol) in DME (1 mL) and water (0.1 mL) And a vial under argon containing potassium carbonate (24 mg, 0.18 mmol) was covered and heated at 80 ° C. for 3 days in a heater shaker. The solvent was evaporated under reduced pressure and the product was purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution method to give the title compound as a TFA salt.

Example 195

5- [3- (1,3-dihydro-2H-isoindol-2-ylcarbonyl) isoxazol-5-yl] -1H-indazole

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with isoindolin.

Example 196

5- {3-[(4-methyl-2-phenylpiperazin-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with 1-methyl-3-phenylpiperazine.

Example 197

1-{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] carbonyl} piperidin-4-amine

Example 197A

Tert-butyl 1- (1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-carbonyl) piperidin-4-ylcarbamate

The title compound was prepared following the procedure outlined in Example 81B by substituting Example 81B for Example 149C and piperidine for 4-Boc-aminopiperidine. MS (ESI < + >) m / z 502.3 (M + H) ⁺ .

Example 197B

1-{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] carbonyl} piperidin-4-amine

Example 197A (101 mg, 0.201 mmol) was dissolved in 4M hydrochloric acid in dioxane (4 mL) and methanol (1 mL) and stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure to afford the title compound as an HCl salt.

Example 198

N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide

Example 198A

Tert-butyl 3-amino-5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-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. A solution of di-tert-butyl dicarbonate (120 mg, 0.55 mmol) in 5 mL methylene chloride was added dropwise while stirring the mixture at room temperature. The reaction mixture was stirred at rt for 8 h, concentrated in vacuo, dissolved in methylene chloride (10 mL) and washed with dilute aqueous HCl solution (1N, 10 mL) and saturated aqueous NaHCO ₃ (10 mL). The organic layer was concentrated and purified by reverse phase-HPLC (CH ₃ CN / H ₂ O / NH ₄ OAc) to afford the title compound.

Example 198B

N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide

Example 198A (37.5 mg, 0.08 mmol) and pyridine (12.7 mg, 0.16 mmol) were dissolved in methylene chloride (2 mL). The mixture was stirred at room temperature. Benzoyl chloride (14 mg, 0.1 mmol) was added to the mixture. The reaction mixture was stirred at rt overnight, concentrated in vacuo and purified by reverse phase-HPLC (CH ₃ CN / H ₂ O / NH ₄ OAc) to give Boc-protected precursors. The precursor was treated with 1: 1 TFA / dichloromethane (2 mL) for 1 hour and concentrated in vacuo to afford the title compound as a TFA salt.

Example 199

N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzenesulfonamide

The title compound was prepared following the procedure outlined in Example 198B by replacing benzoyl chloride with benzenesulfonyl chloride.

Example 200

N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N '-(4-methoxyphenyl) Urea

Example 198A (25 mg, 0.54 mmol) was dissolved in dioxane (2 mL) and 1-isocyanato-4-methoxybenzene (24 mg, 0.16 mmol) was added to the solution. The reaction mixture was stirred at 80 ° C. for 12 h, concentrated and purified by reverse phase-HPLC (CH ₃ CN / H ₂ O / NH ₄ OAc) to afford Boc-protected precursors. The precursor was treated with 1: 1 TFA / dichloromethane (2 mL) for 1 hour and concentrated in vacuo to afford the title compound as a TFA salt.

Example 201

N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] butanamide

The title compound was prepared following the procedure outlined in Example 198B by replacing benzoyl chloride with butyryl chloride.

Example 202

N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-methylpropanamide

The title compound was prepared following the procedure outlined in Example 198B by replacing benzoyl chloride with isobutyryl chloride.

Example 203

N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] cyclopropanecarboxamide

The title compound was prepared following the procedure outlined in Example 198B by replacing benzoyl chloride with cyclopropanecarbonyl chloride.

Example 204

N- [1-benzoyl-5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide

Example 89B (33 mg, 0.1 mmol) was dissolved in tetrahydrofuran (0.6 mL) in a CEM microwave tube. Benzoyl chloride (28 mg, 0.2 mmol) was added and the mixture was heated with CEM-Discover microwave at 120 ° C. for 15 minutes. The reaction mixture was cooled to rt and concentrated. The residue was purified by reverse phase-HPLC (CH ₃ CN / H ₂ O / NH ₄ OAc) to afford the title compound.

Example 205

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -3-fluorobenzamide

Example 205A

Tert-butyl 3-amino-5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazole-1-carboxylate

The title compound was prepared following the procedure outlined in Example 198A, replacing Example 102A with Example 89B.

Example 205B

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -3-fluorobenzamide

Example 205A (25 mg, 0.058 mmol) and pyridine (9.2 mg, 0.116 mmol) were dissolved in methylene chloride (1 mL). The mixture was stirred at rt and 3-fluorobenzoyl chloride (11.1 mg, 0.58 mmol) was added to the mixture. The reaction mixture was stirred at rt overnight, concentrated and purified by reverse phase-HPLC (CH ₃ CN / H ₂ O / NH ₄ OAc) to give Boc-protected precursors. The precursor was treated with 1: 1 TFA / dichloromethane (2 mL) for 1 hour and concentrated in vacuo to afford the title compound as a TFA salt.

Example 206

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide

The title compound was prepared following the procedure outlined in Example 205B by replacing 3-fluorobenzoyl chloride with benzoyl chloride.

Example 207

N-benzyl-5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-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 rt overnight. Sodium triacetoxyborohydride (NaBH (OAc) ₃ , 32 mg, 0.15 mmol) was added to the mixture. The reaction was stirred at rt for 3 h, concentrated and purified by reverse phase-HPLC (CH ₃ CN / H ₂ O / NH ₄ OAc) to afford the title compound.

Example 208

N-[(1R) -1-benzyl-2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with (R)-(+)-2-amino-3-phenyl-1-propanol (37 mg, 0.245 mmol).

Example 209

5- (1-benzyl-1H-pyrazol-4-yl) -1H-indazole

Example 209A

1- (5-bromo-1H-indazol-1-yl) ethanone

4-bromo-2-methylaniline (25.0 g, 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 (3.97 g, 40.4 mmol) and isoamylnitrite (35 mL, 262 mmol) were added and the mixture was 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 methanol to afford the title compound.

Example 209B

5- (1-benzyl-1H-pyrazol-4-yl) -1H-indazole

Example 209A (425 mg, 1.78 mmol), 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (508 mg , 1.79 mmol), dichlorobis (triphenylphosphine) palladium (II) (133 mg, 0.189 mmol) and potassium carbonate (742 mg, 5.37 mmol) with dioxane (10 mL) and water (1 mL) under an inert atmosphere of nitrogen. Formulated in a sealed vial 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 hexane to afford the title compound.

Example 210

N-[(1R) -3-hydroxy-1-phenylpropyl] -5- (3-methyl-1H-indazol-5-yl) isoxazole-3-carboxamide

Example 210A

Tert-butyl 5-bromo-3-methyl-1H-indazole-1-carboxylate

5-bromo-3-methyl-1H-indazole (5.11 g, 24.2 mmol) and catalytic dimethylaminopyridine (about 30 mg) were dissolved in methylene chloride (100 mL). Di-tert-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 residue was diluted with ethyl acetate and washed with 1N sodium hydroxide (twice), 0.1N 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 +) m / z 210.8 (M-Boc) ⁺ .

Example 210B

Tert-butyl 3-methyl-5-((trimethylsilyl) ethynyl) -1H-indazole-1-carboxylate

Example 210A (7.55 g, 24.3 mmol), dichlorobis (triphenylphosphine) palladium (II) (870 mg, 1.24 mmol) and copper iodide (I) (250 mg, 1.31 mmol) were treated with triethylamine under an inert atmosphere of nitrogen. It mix | blended in (60 mL). Trimethylsilyl acetylene (4.0 mL, 28.9 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 on silica gel and purified by silica gel chromatography eluting with a gradient of 10-40% ethyl acetate in hexanes to afford the title compound. MS (ESI +) m / z 228.9 (M-Boc) ⁺ .

Example 210C

5-ethynyl-3-methyl-1H-indazole

Example 210B (7.26 g, 22.1 mmol) was dissolved in methanol (170 mL). 1N potassium hydroxide (45 mL) solution was added and the mixture was stirred at 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) ⁺ .

Example 210D

Ethyl 5- (3-methyl-1H-indazol-5-yl) isoxazole-3-carboxylate

Example 210C (411 mg, 2.63 mmol) was dissolved in toluene (15 mL) and triethylamine (478 uL) and warmed to 90 ° C. Ethyl chlorooxymidoacetate (480 mg, 3.17 mmol) dissolved in toluene (15 mL) was slowly added dropwise over 30 minutes. After addition, the mixture was diluted with ethyl acetate and washed with 1N 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 (M + H) ⁺ .

Example 210E

5- (3-Methyl-1H-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 acetate and washed with 1N hydrochloric acid. The product was precipitated in a separatory funnel and filtered to afford the title compound. MS (ESI +) m / z 243.9 (M + H) ⁺ .

Example 210F

N-[(1R) -3-hydroxy-1-phenylpropyl] -5- (3-methyl-1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B, replacing Example 81A with Example 210E and piperidine with (R) -3-amino-3-phenylpropan-1-ol.

Example 211

3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] phenol

Example 125B (35 mg, 0.09 mmol), 3-hydroxyphenylboronic acid (12 mg, 0.09 mmol), PdCl ₂ (dppf) dichloromethane (7 mg, 0.009 mmol) in DME (1 mL) and water (0.1 mL) and A vial under argon containing potassium carbonate (24 mg, 0.18 mmol) was capped and heated in a heater shaker at 80 ° C. for 3 days. The solvent was evaporated and the product was purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution method to afford the title compound.

Example 212

3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] benzamide

The title compound was prepared following the procedure outlined in Example 173, replacing 4-methoxyphenylboronic acid with 3-carbamoylphenylboronic acid.

Example 213

5- {1-benzyl-5- [4- (methylsulfonyl) phenyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 173 by replacing 4-methoxyphenylboronic acid with 4- (methylsulfonyl) phenylboronic acid.

Example 214

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-chlorobenzamide

The title compound was prepared following the procedure outlined in Example 205B by replacing 3-fluorobenzoyl chloride with 2-chlorobenzoyl chloride.

Example 215

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -4-chlorobenzamide

The title compound was prepared following the procedure outlined in Example 205B by replacing 3-fluorobenzoyl chloride with 4-chlorobenzoyl chloride.

Example 216

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] ethanesulfonamide

The title compound was prepared following the procedure outlined in Example 205B by replacing 3-fluorobenzoyl chloride with ethanesulfonyl chloride.

Example 217

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzenesulfonamide

The title compound was prepared following the procedure outlined in Example 205B by replacing 3-fluorobenzoyl chloride with benzenesulfonyl chloride.

Example 218

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-chlorobenzenesulfonamide

The title compound was prepared following the procedure outlined in Example 205B by replacing 3-fluorobenzoyl chloride with 2-chlorobenzene-1-sulfonyl chloride.

Example 219

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -3-chlorobenzenesulfonamide

The title compound was prepared as HCl salt following the procedure outlined in Example 205B by replacing 3-fluorobenzoyl chloride with 3-chlorobenzene-1-sulfonyl chloride.

Example 220

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -4-chlorobenzenesulfonamide

The title compound was prepared following the procedure outlined in Example 205B by replacing 3-fluorobenzoyl chloride with 4-chlorobenzene-1-sulfonyl chloride.

Example 221

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2,5-dimethylfuran-3- Sulfonamide

The title compound was prepared as HCl salt following the procedure outlined in Example 205B by replacing 3-fluorobenzoyl chloride with 2,5-dimethylfuran-3-sulfonyl chloride.

Example 222

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N- (2-chlorobenzyl) -1H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 207 with 2-chlorobenzaldehyde substitution of benzaldehyde.

Example 223

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N- (3-chlorobenzyl) -1H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 207 by replacing benzaldehyde with 3-chlorobenzaldehyde.

Example 224

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -3-chlorobenzamide

The title compound was prepared following the procedure outlined in Example 205B by replacing 3-fluorobenzoyl chloride with 3-chlorobenzoyl chloride.

Example 225

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-puramide

The title compound was prepared following the procedure outlined in Example 205B by replacing 3-fluorobenzoyl chloride with furan-2-carbonyl chloride.

Example 226

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N-ethyl-1H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 207 with benzaldehyde substitution of acetaldehyde.

Example 227

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N- (4-chlorobenzyl) -1H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 207 with 4-chlorobenzaldehyde substitution of benzaldehyde.

Example 228

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N- (3-furylmethyl) -1H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 207 by replacing benzaldehyde with furan-3-carbaldehyde.

Example 229

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N '-[5-methyl-2 -(Trifluoromethyl) -3-furyl] urea

Example 205A (30 mg, 0.07 mmol) was dissolved in dioxane (2 mL) and 3-isocyanato-5-methyl-2- (trifluoromethyl) furan (40 mg, 0.21 mmol) was added to the solution. did. The reaction mixture was stirred at 80 ° C. for 12 h, concentrated and purified by reverse phase-HPLC (CH ₃ CN / H ₂ O / NH ₄ OAc) to afford Boc-protected precursors. The precursor was dissolved in methanol and treated with excess HCl (4M, 0.5 mmol) in dioxane. The reaction was stirred for 5 hours and concentrated in vacuo to afford the title compound as the HCl salt.

Example 230

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -3-puramide

The title compound was prepared as an HCl salt by following 3-fluorobenzoyl chloride with furan-3-carbonyl chloride following the procedure outlined in Example 205B.

Example 231

5- (1H-indazol-5-yl) -N-[(1S) -1-phenylpropyl] isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by substituting piperidine for (S)-(-)-1-phenylpropyl amine.

Example 232

5- (1H-indazol-5-yl) -N-[(1R) -1-phenylpropyl] isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with (R)-(-)-1-phenylpropyl amine.

Example 233

5- (1-benzyl-1H-pyrazol-4-yl) -1H-indazol-3-amine

Example 233A

5- (1-benzyl-1H-pyrazol-4-yl) -2-fluorobenzonitrile

5-bromo-2-fluorobenzonitrile (484 mg, 2.42 mmol), 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) -1H-pyrazole (736 mg, 2.59 mmol), dichlorobis (triphenylphosphine) palladium (II) (174 mg, 0.248 mmol) and potassium carbonate (1.36 g, 9.84 mmol) were converted to dioxane ( 10 mL) and water (1 mL) were combined in a sealed vial 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 10-50% ethyl acetate in hexanes to afford the title compound. MS (ESI +) m / z 290.0 (M + H) ⁺ .

Example 233B

5- (1-benzyl-1H-pyrazol-4-yl) -1H-indazol-3-amine

Example 233A (591 mg, 2.13 mmol) was treated with hydrazine hydrate (4.0 mL) in ethanol (3.0 mL), stirred and heated to 70 ° C. overnight. The mixture was diluted 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.

Example 234

1-benzyl-4- (1H-indazol-5-yl) -N-[(2S) -tetrahydrofuran-2-ylmethyl] -1H-1,2,3-triazole-5-carboxamide

To a 20 mL vial was added a solution of Example 149C (51 mg, 0.16 mmol) dissolved in dimethylformamide (0.5 mL), followed by (S)-(+)-tetra dissolved in dimethylformamide (0.9 mL). Hydrofurfurylamine (18.2 mg, 0.18 mmol) was added. A solution of HATU (68 mg, 0.18 mmol) 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 was filtered through a Si-carbonate cartridge (6 mL-1 g) supplied by Silica Chemical Division and the filtrate was transferred to a 20 mL vial. The reaction was checked by LC / MS and concentrated to dryness. The residue was dissolved in 1: 1 DMSO / methanol and purified by reverse phase HPLC (Agilent, 5% to 100% TFA / water gradient, 8 min run).

Example 235

1-benzyl-4- (1H-indazol-5-yl) -N- (2-isopropoxyethyl) -1H-1,2,3-triazole-5-carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with 2-aminoethylisopropyl ether.

Example 236

1-benzyl-4- (1H-indazol-5-yl) -N-[(2R) -tetrahydrofuran-2-ylmethyl] -1H-1,2,3-triazole-5-carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with (R)-(-)-tetrahydrofurfurylamine.

Example 237

1-benzyl-4- (1H-indazol-5-yl) -N- (tetrahydrofuran-3-ylmethyl) -1H-1,2,3-triazole-5-carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with 3-aminomethyltetrahydrofuran.

Example 238

1-benzyl-N-cyclopentyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with cyclopentylamine.

Example 239

1-benzyl-N- (cyclopentylmethyl) -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with aminomethylcyclopentane.

Example 240

1-benzyl-N-ethyl-4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with N-methylethylamine hydrochloride.

Example 241

1-benzyl-4- (1H-indazol-5-yl) -N-isopropyl-N-methyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with methylisopropylamine.

Example 242

1-benzyl-4- (1H-indazol-5-yl) -N- (2-methoxyethyl) -N-methyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with N- (2-methoxyethyl) methylamine.

Example 243

1-benzyl-4- (1H-indazol-5-yl) -N-phenyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with aniline.

Example 244

1-benzyl-N- (4-chlorophenyl) -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with 4-chloroaniline.

Example 245

1-benzyl-4- (1H-indazol-5-yl) -N- (2-morpholin-4-ylethyl) -1H-1,2,3-triazole-5-carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with N- (3-aminopropyl) morpholine.

Example 246

1-benzyl-N- [2- (dimethylamino) ethyl] -4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with N, N, N-trimethylethylenediamine.

Example 247

1-benzyl-N- (2-hydroxyethyl) -4- (1H-indazol-5-yl) -N-propyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with 2- (propylamino) ethanol.

Example 248

1-benzyl-N- [3- (dimethylamino) propyl] -4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with N, N, N-trimethyl-1,3-propanediamine.

Example 249

1-benzyl-N- [2- (diethylamino) ethyl] -4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide

The title compound was prepared as a salt of TFA following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with N, N-diethyl-N-methylethylenediamine.

Example 250

N, 1-dibenzyl-N-ethyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with N-ethylbenzylamine.

Example 251

N, 1-dibenzyl-N- (2-hydroxyethyl) -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with N-benzylethanolamine. MS (ESI < + >) m / z 453 (M + H) ⁺ .

Example 252

(3R) -1-{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] carbonyl} piperidin-3-ol

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with (R)-(+)-3-hydroxypiperidine hydrochloride.

Example 253

1-{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] carbonyl} piperidine-4-carboxamide

The title compound was prepared according to the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with isonifecotamide.

Example 254

5- {1-benzyl-5-[(2,6-dimethylmorpholin-4-yl) carbonyl] -1H-1,2,3-triazol-4-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with 2,6-dimethylmorpholine.

Example 255

5- {5-[(4-acetylpiperazin-1-yl) carbonyl] -1-benzyl-1H-1,2,3-triazol-4-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with 1-acetylpiperazine.

Example 256

5- {1-benzyl-5-[(4-phenylpiperazin-1-yl) carbonyl] -1H-1,2,3-triazol-4-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with 1-phenylpiperazine.

Example 257

1-benzyl-N-[(1R) -1- (hydroxymethyl) -2-methylpropyl] -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5 Carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with (R)-(+)-2-amino-3-methyl-1-butanol. .

Example 258

1-benzyl-N-[(1S) -1- (hydroxymethyl) -2-methylpropyl] -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5 Carboxamide

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with (S)-(-)-2-amino-3-methyl-1-butanol. .

Example 259

1-benzyl-N- [3- (1H-imidazol-1-yl) propyl] -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carbox amides

The title compound was prepared following the procedure outlined in Example 234 by substituting (S)-(+)-tetrahydrofurfurylamine with 1- (3-aminopropyl) imidazole.

Example 260

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N'-ethylurea

The title compound was prepared as a hydrochloride salt according to the procedure outlined in Example 229 by substituting 3-isocyanato-5-methyl-2- (trifluoromethyl) furan with isocyanatoethane.

Example 261

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N'-phenylurea

The title compound was prepared as a hydrochloride salt according to the procedure outlined in Example 229 by substituting 3-isocyanato-5-methyl-2- (trifluoromethyl) furan with isocyanatobenzene.

Example 262

N-benzyl-N '-[5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] urea

The title compound was prepared as a hydrochloric acid salt following the procedure outlined in Example 229 by replacing 3-isocyanato-5-methyl-2- (trifluoromethyl) furan with (isocyanatomethyl) benzene.

Example 263

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N '-(2-chlorophenyl) Urea

The title compound was prepared as hydrochloric acid salt according to the procedure outlined in Example 229, replacing 3-isocyanato-5-methyl-2- (trifluoromethyl) furan with 1-chloro-2-isocyanatobenzene. Manufactured.

Example 264

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N '-(3-chlorophenyl) Urea

The title compound was prepared as a hydrochloride salt according to the procedure outlined in Example 229, replacing 3-isocyanato-5-methyl-2- (trifluoromethyl) furan with 1-chloro-3-isocyanatobenzene. Manufactured.

Example 265

N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N '-(4-chlorophenyl) Urea

The title compound was prepared as hydrochloric acid salt according to the procedure outlined in Example 229, replacing 3-isocyanato-5-methyl-2- (trifluoromethyl) furan with 1-chloro-4-isocyanatobenzene. Manufactured.

Example 266

N- [5- (1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide

Example 266A

Tert-butyl 3-amino-5- (1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl) -1H-indazole-1-carboxylate

The title compound was prepared following the procedure outlined in Example 198A, replacing Example 102B with Example 125B. The product was used for the next step without characterization.

Example 266B

N- [5- (1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide

The title compound was prepared as a TFA salt by following the procedure outlined in Example 205B by substituting Example 205A for Example 205A.

Example 267

3- [4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] propanenitrile

Example 267A

3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propanenitrile

To a solution of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (5.00 g, 25.8 mmol) in acetonitrile (50 mL) Acrylonitrile (3.4 mL, 52 mmol) was added followed by l, 8-diazabicyclo [5.4.0] undec-7-ene (1.94 mL, 12.9 mmol). After about 2 hours, the reaction mixture was concentrated under reduced pressure. The crude material was then dissolved in a minimum amount of dichloromethane and purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in heptane to afford the title compound.

Example 267B

3- [4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] propanenitrile

In a microwave vial 5-bromo-1H-indazol-3-amine (0.14 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 g, 0.858 mmol) in 1,2-dimethoxyethane (2.50 mL) followed by water (1.25 mL). The mixture was heated with CEM microwave at about 150 ° C. for about 20 minutes (275 psi max pressure, about 2 min ramp, max 200 w), then the mixture was concentrated under reduced pressure. Methanol (20 mL) was added and the resulting mixture was stirred for about 1 hour. Insoluble matter was removed by filtration. The filtrate was concentrated on silica gel under reduced pressure and purified via silica gel chromatography eluting with a stepwise gradient of dichloromethane / methanol / ammonium hydroxide ((990: 9: 1 to 985: 13.5: 1.5 to 980: 18: 2). This solid was dissolved in a minimum amount of hot acetonitrile (about 2 mL), filtered and washed with methanol (<0.5 mL) while removing the minimum amount of insoluble material and left at ambient temperature. The resulting solid was collected by filtration and washed with additional acetonitrile and dried at about 60 ° C. in a vacuum oven for about 2 hours to afford the title compound.

Example 268

2- [4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] acetamide

Example 268A

2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) acetamide

4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (2.00 g, 10.3 mmol) in 2-acetone (60 mL), 2-bro A suspension of moacetamide (2.14 g, 15.5 mmol) and potassium carbonate (2.14 g, 15.5 mmol) was heated at about 50 ° C. for about 3.5 days. The reaction mixture was then cooled to ambient temperature, washed with additional acetone while filtration through diatomaceous earth, and then concentrated under reduced pressure. The crude material was then dissolved in a minimal amount of dichloromethane and purified by silica gel chromatography eluting with a gradient of 80-100% ethyl acetate in heptane to afford the title compound.

Example 268B

2- [4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] acetamide

The title compound was prepared following the procedure outlined in Example 267B by replacing Example 267A with Example 268A and heating at about 120 ° C. for about 10 minutes.

Example 269

Methyl 3- [4- (3-amino-1 H-indazol-5-yl) -1H-pyrazol-1-yl] propanoate

Example 269A

Methyl 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propanoate

The title compound was prepared following the procedure outlined in Example 267A by replacing acrylonitrile with methyl acrylate.

Example 269B

Methyl 3- [4- (3-amino-1 H-indazol-5-yl) -1H-pyrazol-1-yl] propanoate

The title compound was prepared following the procedure outlined in Example 267B by substituting Example 267A for Example 269A and heating at about 120 ° C. for about 20 minutes.

Example 270

3- [4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] propanamide

Example 270A

3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propanamide

The title compound was prepared following the procedure outlined in Example 267A by replacing acrylonitrile with acrylamide.

Example 270B

3- [4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] propanamide

The title compound was prepared following the procedure outlined in Example 267B by replacing Example 267A with Example 270A and heating at about 120 ° C. for about 15 minutes (0.056 g, 22%).

Example 271

[4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] acetonitrile

Example 271A

2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) acetonitrile

The title compound was prepared following the procedure outlined in Example 268A, replacing 2-bromoacetamide with 2-bromoacetonitrile.

Example 271B

Tert-butyl 3- (bis (tert-butoxycarbonyl) amino) -5-bromo-1H-indazole-1-carboxylate

4- (dimethylamino) pyridine (0.230 g, 1.886 mmol) and di-tert-butyl di in 5-bromo-1H-indazol-3-amine (2.00 g, 9.43 mmol) in tetrahydrofuran (20 mL) Carbonate (6.18 g, 28.3 mmol) was added. 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 diethyl ether (100 mL) and washed sequentially with 1N hydrochloric acid (2 × 25 mL), 1N sodium hydroxide (2 × 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.

Example 271C

Tert-butyl 3- (bis (tert-butoxycarbonyl) amino) -5- (1- (cyanomethyl) -1H-pyrazol-4-yl) -1H-indazol-1-carboxylate

Example 271A (0.682 g, 2.93 mmol), Example 271B (1.25 g, 2.44 mmol), cesium carbonate (1.99 g, 6.10 mmol), 1,4-dioxane (12.5 mL) and water (2.50 mL) in the vial Was charged. After vacuum / nitrogen purging through septa, tris (dibenzylideneacetone) dipalladium (0) (0.112 g, 0.122 mmol) and tri-tert-butylphosphonium tetrafluoroborate (0.085 g, 0.29 mmol) ) Was added, and the vial was capped after flushing with nitrogen. After about 6 hours at ambient temperature, the reaction was partitioned between saturated aqueous sodium bicarbonate and dichloromethane (50 ml each). 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 a minimal amount of dichloromethane and purified by silica gel chromatography eluting with a gradient of 20-60% ethyl acetate in heptane to afford the title compound.

Example 271D

[4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] acetonitrile

Tert-butyl 3- (bis (tert-butoxycarbonyl) amino) -5- (1- (cyanomethyl) -1H-pyrazol-4-yl) -1H- in dichloromethane (4.0 mL) Trifluoroacetic acid (2.0 mL) was added to a solution of indazole-1-carboxylate (0.30 g, 0.557 mmol). After about 45 minutes, the reaction was slowly quenched with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (3 x 25 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a crude solid. The white precipitate 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 / methanol (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.

Example 272

4- (3-amino-1 H-indazol-5-yl) -N, N-dimethyl-1 H-imidazole-1-sulfonamide

3-cyano-4-fluorophenylboronic acid (0.083 g, 0.503 mmol), 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide (0.167 g, 0.554 mmol), sodium carbonate ( 0.128 g, 1.208 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.035 g, 0.030 mmol) were combined in dimethoxyethane (4 mL) and water (1.5 mL). The reaction mixture was heated with microwave (CEM-Discover) at about 150 ° C. for about 25 minutes. The organic layer was separated and the solvent was removed under reduced pressure. Ethanol (0.7 mL) and hydrazine monohydrate (1 mL) were added to the residue. The reaction mixture was heated at about 80 ° C for about 20 minutes. The reaction mixture was partitioned between water (5 mL) and dichloromethane (100 mL). The organic layer was separated and concentrated under reduced pressure. The residue was purified by reverse phase HPLC using acetonitrile / water ((0.05M ammonium acetate) gradient elution method to afford the title compound.

Example 273

5-pyrazin-2-yl-1H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 272 by replacing 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide with 2-iodopyrazine.

Example 274

5-thien-2-yl-1H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 272 by replacing 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide with 2-iodothiophene.

Example 275

5- (2-aminopyrimidin-4-yl) -1H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 272 by replacing 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide with 5-iodopyrimidin-2-amine.

Example 276

5- (2-methoxypyridin-3-yl) -1 H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 272 by replacing 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide with 3-iodo-2-methoxypyridine.

Example 277

5-imidazo [1,2-a] pyridin-3-yl-1H-indazol-3-amine

The title compound was prepared according to the procedure outlined in Example 272 by replacing 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide with 3-bromoimidazo [1,2-a] pyridine. Manufactured.

Example 278

N ² , N ² -dimethyl-N ^1- [5- (1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] glycinamide

Example 65 (257 mg, 0.685 mmol) was dissolved in ethanol (15 mL). The reaction mixture was hydrogenated in an H-cube apparatus with palladium hydroxide on carbon (20%) at about 80 ° C. and about 60 psi for about 8 hours. The solvent was removed under reduced pressure and the residue was purified by reverse phase HPLC using an acetonitrile / water (0.05 M ammonium acetate) gradient elution method to afford the title compound.

Example 279

5- (1H-pyrazol-5-yl) -1H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 272 by replacing 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide with 5-iodo-1H-pyrazole.

Example 280

5- (4-Methyl-1H-imidazol-5-yl) -1H-indazol-3-amine

The title compound was prepared according to the procedure outlined in Example 272 by replacing 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide with 5-iodo-4-methyl-1H-imidazole. did.

Example 281

5- (1H-imidazol-4-yl) -1H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 272 by replacing 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide with 4-iodo-1H-imidazole.

Example 282

N ^2, N ² - dimethyl ^{-N 1 - {5- [1- (} 3- methyl-benzyl)) - 1H-1,2,3- triazol-4-yl] -1H- indazol-3-yl} Glycinamide

Example 282A

5-Bromo-1H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 62D by replacing Example 62C with 5-bromo-2-fluorobenzonitrile.

Example 282B

Tert-butyl 3-amino-5-bromo-1H-indazole-1-carboxylate

The title compound was prepared following the procedure outlined in Example 64A, substituting Example 282A for Example 62D.

Example 282C

Tert-Butyl 5-bromo-3- (2- (dimethylamino) acetamido) -1H-indazol-1-carboxylate

Tetrahydrofuran (200 mL) was added to a mixture of Example 282B (24.43 g, 78 mmol), potassium carbonate (81 g, 587 mmol) and 2- (dimethylamino) acetyl chloride hydrochloride (43.3 g, 274 mmol). The reaction mixture was stirred at rt for about 2 h. The reaction mixture was filtered and the filtrate was washed with water (50 mL). 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 (5%) in dichloromethane to afford the title compound.

Example 282D

Tert-Butyl 3- (2- (dimethylamino) acetamido) -5-((trimethylsilyl) ethynyl) -1H-indazole-1-carboxylate

Example 282C (2.56 g, 6.44 mmol), bis (triphenylphosphine) palladium (II) chloride (0.225 g, 0.321 mmol) and copper iodide (I) (0.073 g, 0.383 mmol) in a mixture of triethylamine ( 20 mL, 144 mmol) and then ethynyltrimethylsilane (0.760 g, 7.73 mmol) were added. 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 (10%) in dichloromethane to afford the title compound.

Example 282E

2- (dimethylamino) -N- (5-ethynyl-1H-indazol-3-yl) acetamide

To Example 282D (0.303 g, 0.731 mmol) in methanol (5 mL) was added aqueous potassium hydroxide (1.46 mL, 1.46 mmol, 1.0N solution). The reaction mixture was stirred at rt for about 1 h. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (80 mL). The organic layer was separated, washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound.

Example 282F

N ^2, N ² - dimethyl ^{-N 1 - {5- [1- (} 3- methyl-benzyl) -1H-1,2,3- triazol-4-yl] -1H- indazol-3-yl} glycine amides

To a suspension of Example 282E (0.16 g, 0.660 mmol) in tert-butanol (1.2 mL) was added 1- (azidomethyl) -3-methylbenzene (0.098 g, 0.667 mmol) followed by water (1.2 mL). Added. Sodium (R) -2-((S) -1,2-dihydroxyethyl) -4-hydroxy-5-oxo-2,5-dihydrofuran-3-oleate (0.057 mL, 0.066 mmol, A solution of 1.6 M) in water and an aqueous copper (II) sulphate pentahydrate (0.019 mL, 6.6 mmol, 0.34 M) were 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 an acetonitrile / water (0.05 M ammonium acetate) gradient elution method to afford the title compound.

Example 283

5- (1-benzyl-1H-imidazol-4-yl) -1H-indazol-3-amine

The title compound was prepared according to the procedure outlined in Example 272 by replacing 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide with 1-benzyl-4-iodo-1H-imidazole. did.

Example 284

^{N 1 - {5- [1- (} 4-3 -tert-butylbenzyl) -1H-1,2,3- triazol-4-yl] -1H- indazol-3-yl} -N ^2, N ² -Dimethylglycineamide

The title compound was prepared according to the procedure outlined in Example 282F with 1- (azidomethyl) -3-methylbenzene as 1- (azidomethyl) -4-tert-butylbenzene.

Example 285

N ^2, N ² - dimethyl ^{-N 1 - {5- [1- (} 2- piperidin-1-yl-ethyl) -1H-1,2,3- triazol-4-yl] -1H- indazole -3-yl} glycineamide

The title compound was prepared following the procedure outlined in Example 282F by replacing 1- (azidomethyl) -3-methylbenzene with 1- (2-azidoethyl) piperidine.

Example 286

N ^2, N ² - dimethyl ^{-N 1 - {5- [1- (} 2- morpholin-4-yl-ethyl) -1H-1,2,3- triazol-4-yl] -1H- indazole- 3-yl} glycineamide

The title compound was prepared following the procedure outlined in Example 282F by replacing 1- (azidomethyl) -3-methylbenzene with 4- (2-azidoethyl) morpholine.

Example 287

^{N 1 - (5- {1- [} 2- (3,5- dimethyl-4-yl in) ethyl] -1H-1,2,3- triazol-4-yl} -1H- indazol- 3-yl) -N ² , N ² -dimethylglycinamide

The title compound was prepared following the procedure outlined in Example 282F by replacing 1- (azidomethyl) -3-methylbenzene with 4- (2-azidoethyl) -3,5-dimethylisoxazole.

Example 288

^{N 1 - (5- {1- [} 2- (3,5- dimethyl -1H- pyrazol-4-yl) ethyl] -1H-1,2,3- triazol-4-yl} -1H- indazol Zol-3-yl) -N ² , N ² -dimethylglycinamide

The title compound was prepared following the procedure outlined in Example 282F by replacing 1- (azidomethyl) -3-methylbenzene with 4- (2-azidoethyl) -3,5-dimethyl-1H-pyrazole.

Example 289

2- (4- {3-[(N, N-dimethylglycyl) amino] -1H-indazol-5-yl} -1H-1,2,3-triazol-1-yl) -2-methyl Propanoic acid

The title compound was prepared following the procedure outlined in Example 282F, replacing 1- (azidomethyl) -3-methylbenzene with 2-azido-2-methylpropanoic acid.

Example 290

Ethyl (4- {3-[(N, N-dimethylglycyl) amino] -1H-indazol-5-yl} -1H-1,2,3-triazol-1-yl) acetate

The title compound was prepared following the procedure outlined in Example 282F, replacing 1- (azidomethyl) -3-methylbenzene with ethyl 2-azidoacetate.

Example 291

N ² , N ² -dimethyl-N ^1- (5- {1-[(trimethylsilyl) methyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3-yl) Glycinamide

The title compound was prepared following the procedure outlined in Example 282F, replacing 1- (azidomethyl) -3-methylbenzene with (azidomethyl) trimethylsilane.

Example 292

N ^1- [5- (3-furyl) -1 H-indazol-3-yl] -N ² , N ² -dimethylglycinamide

The title compound was 5-bromo-2-fluorobenzonitrile in Example 282C, 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Il) -1H-pyrazole was prepared following the procedure outlined in Example 233A by substituting furan-3-ylboronic acid.

Example 293

N ² , N ² -dimethyl-N ^1- [5- (1H-pyrazol-5-yl) -1H-indazol-3-yl] glycinamide

The title compound was 5-bromo-2-fluorobenzonitrile in Example 282C, 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Il) -1H-pyrazole was prepared following the procedure outlined in Example 233A by substituting 1H-pyrazole-5-ylboronic acid.

Example 294

N ² , N ² -dimethyl-N ^1- (5-pyrimidin-5-yl-1H-indazol-3-yl) glycinamide

The title compound was 5-bromo-2-fluorobenzonitrile in Example 282C, 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Yl) -1H-pyrazole was prepared following the procedure outlined in Example 233A by substituting pyrimidine-5-ylboronic acid.

Example 295

N ^1- [5- (2,1,3-benzoxadiazol-5-yl) -1H-indazol-3-yl] -N ² , N ² -dimethylglycinamide

The title compound was 5-bromo-2-fluorobenzonitrile in Example 282C, 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Il) -1H-pyrazole was prepared following the procedure outlined in Example 233A by substituting benzo [c] [1,2,5] oxadiazole-5-ylboronic acid.

Example 296

N ² , N ² -dimethyl-N ^1- [5- (1H-pyrazol-4-yl) -1H-indazol-3-yl] glycinamide

The title compound was 5-bromo-2-fluorobenzonitrile in Example 282C, 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Il) -1H-pyrazole is outlined in Example 233A by substituting 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole It was prepared according to the procedure.

Example 297

N ^2, N ² - dimethyl -N ¹ - [5- (1- methyl -1H- pyrazol-4-yl) -1H- indazol-3-yl] glycine amide

The title compound was 5-bromo-2-fluorobenzonitrile in Example 282C, 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Yl) -1H-pyrazole by substituted with 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole Prepared according to the procedure outlined in Example 233A.

Example 298

N ^1- [5- (3,5-dimethyl-1H-pyrazol-4-yl) -1H-indazol-3-yl] -N ² , N ² -dimethylglycinamide

The title compound was 5-bromo-2-fluorobenzonitrile in Example 282C, 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Yl) -1H-pyrazole with 3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole Prepared according to the procedure outlined in Example 233A.

Example 299

N ^1- {5- [2- (dimethylamino) pyrimidin-5-yl] -1H-indazol-3-yl} -N ² , N ² -dimethylglycinamide

The title compound was 5-bromo-2-fluorobenzonitrile in Example 282C, 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Yl) -1H-pyrazole to N, N-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2-amine Prepared according to the procedure outlined in Example 233A.

Example 300

N ² , N ² -dimethyl-N ^1- [5- (2-morpholin-4-ylpyrimidin-5-yl) -1H-indazol-3-yl] glycinamide

The title compound was 5-bromo-2-fluorobenzonitrile in Example 282C, 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Yl) -1H-pyrazole 4- (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2-yl) morpholine Prepared according to the procedure outlined in Example 233A.

Example 301

N ^2, N ² - dimethyl ^{-N 1 - {5- [1- (} 2- morpholin-4-ylethyl) -1H- pyrazol-4-yl] -1H- indazol-3-yl} glycine amide

The title compound was 5-bromo-2-fluorobenzonitrile in Example 282C, 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Yl) -1H-pyrazole to 4- (2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole- Prepared according to the procedure outlined in Example 233A by substitution with 1-yl) ethyl) morpholine.

Example 302

N ¹ - [5- (1- benzyl-5-cyclopropyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ^2, N ² - dimethyl glycine amides

Example 302A

1-benzyl-5-cyclopropyl-4- (tributylstannyl) -1H-1,2,3-triazole

The title compound was prepared following the procedure outlined in Example 142A, replacing hexane with toluene and Example 80A with (azidomethyl) benzene. The crude product was used for next step without purification.

Example 302B

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -2-fluorobenzonitrile

The title compound was prepared following the procedure outlined in Example 142B, replacing Example 142A with Example 302A and Example 87A with 2-fluoro-5-iodobenzonitrile. MS (ESI &lt; + &gt;) m / z 319.2 (M + H) ⁺ .

Example 302C

5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine

The title compound was prepared following the procedure outlined in Example 62D, substituting Example 302B for Example 62C. MS (ESI-) m / z 299.2 (MH) ⁻ .

Example 302D

Tert-butyl 3-amino-5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazole-1-carboxylate

The title compound was prepared following the procedure outlined in Example 64A, replacing Example 62D with Example 302C.

Example 302E

N ¹ - [5- (1- benzyl-5-cyclopropyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ^2, N ² - dimethyl glycine amides

The title compound was prepared according to the procedure outlined in Example 64B, replacing Example 64A with Example 302D and methoxy acetyl chloride with dimethylaminoacetylchloride hydrochloride.

Example 303

N ¹ - [5- (1- benzyl -1H- pyrazol-4-yl) -1H- indazol-3-yl] -N ^2, N ² - dimethyl glycine amide

Example 303A

3-Amino-5- (1-benzyl-1H-pyrazol-4-yl) -indazol-1-carboxylic acid tert-butyl ester

The title compound was prepared following the procedure outlined in Example 64A, replacing Example 62D with Example 233B.

Example 303B

N ¹ - [5- (1- benzyl -1H- pyrazol-4-yl) -1H- indazol-3-yl] -N ^2, N ² - dimethyl glycine amide

A suspension of 2- (dimethylamino) acetic acid (32 mg, 0.308 mmol) and oxalyl chloride (0.31 mL, 0.61 mmol) in dichloromethane (5 mL) and dimethylformamide (2 drops) was stirred at ambient temperature for about 1 hour. Then it was 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 about 30 minutes, then trifluoroacetic acid (4 mL) was added and the reaction mixture was heated at about 60 ° C. for about 20 minutes. The reaction mixture was cooled to ambient temperature, concentrated under reduced pressure, diluted with dichloromethane (20 mL) and washed with 15% aqueous sodium hydroxide solution (20 mL). The organic extract 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 acetate salt.

Example 304

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ² - methyl glycine amide

The title compound was prepared according to the procedure outlined in Example 303B, replacing 2- (dimethylamino) acetic acid with 2- (tert-butoxycarbonyl (methyl) amino) acetic acid, and Example 303A with Example 64A. .

Example 305

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-pyrrolidin-1-ylacetamide

Example 305A

Tert-butyl 5- (1-benzyl-1H-1,2,3-triazol-4-yl) -3- (2-bromoacetamido) -1H-indazole-1-carboxylate

To a suspension of Example 64A (500 mg, 1.28 mmol) in tetrahydrofuran (12 mL) was added diisopropylethylamine (0.22 mL, 1.28 mmol). The reaction mixture was stirred at ambient temperature for about 15 minutes, then 2-bromoacetyl chloride (0.11 mL, 1.2 mmol) was added. The reaction mixture was stirred at ambient temperature for about 16 hours, then additional 2-bromoacetyl chloride (0.11 mL, 1.2 mmol) was added. The reaction mixture was stirred for an additional 15 minutes and then concentrated under reduced pressure to give the title compound as a brown solid. This material was used without further purification.

Example 305B

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-pyrrolidin-1-ylacetamide

Pyrrolidine (0.021 mL, 0.25 mmol) is added to a solution of Example 305A (44 mg, 0.086 mmol) and diisopropylethylamine (0.015 mL, 0.086 mmol) in acetonitrile (1 mL) and the reaction mixture is about 60 Heated at about 15 minutes. The reaction mixture was cooled to ambient temperature and trifluoroacetic acid (1 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 mL) 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 acetonitrile / water (0.05 M ammonium acetate) gradient elution method to afford the title compound.

Example 306

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ² - cyclopentyl-glycine amide

The title compound was prepared following the procedure outlined in Example 305B by replacing pyrrolidine with cyclopentanamine (0.004 g, 12%).

Example 307

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ² - cyclopropyl glycine amide

To a solution of Example 305A (100 mg, 0.196 mmol) and diisopropylethylamine (0.034 mL, 0.19 mmol) in acetonitrile (1 mL) was added cyclopropanamine (11 mg, 0.19 mmol) and the reaction mixture was brought to about 60 ° C. Heated for about 1 hour. The reaction mixture was cooled to ambient temperature and hydrochloric acid (4N in dioxane, 1 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 an acetonitrile / water (0.05 M ammonium acetate) gradient elution method to give the title compound as acetate salt.

Example 308

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ² - tetrahydro -2H- pyran-4-yl Glycinamide

The title compound was prepared as an acetate salt following the procedure outlined in Example 307 by replacing cyclopropanamine with tetrahydro-2H-pyran-4-amine.

Example 309

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2- (3-hydroxypyrrolidin-1-yl Acetamide

The title compound was prepared as a diacetate salt following the procedure outlined in Example 307 by replacing cyclopropanamine with pyrrolidin-3-ol.

Example 310

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2- (3-hydroxypiperidin-1-yl Acetamide

The title compound was prepared as an acetate salt following the procedure outlined in Example 307 by substituting cyclopropanamine with piperidin-3-ol.

Example 311

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ^3, N ³ - dimethyl -β- alaninamide

The title compound was prepared as an acetate salt following the procedure outlined in Example 307 by substituting cyclopropanamine with dimethylamine.

Example 312

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-morpholin-4-ylacetamide

The title compound was prepared following the procedure outlined in Example 307, replacing cyclopropanamine with morpholine.

Example 313

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2- (4-methylpiperazin-1-yl) acet amides

The title compound was prepared as a diacetate salt following the procedure outlined in Example 307 by substituting cyclopropanamine with 1-methylpiperazine.

Example 314

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2- (3-oxopiperazin-1-yl) acet amides

The title compound was prepared following the procedure outlined in Example 307 by replacing cyclopropanamine with piperazin-2-one.

Example 315

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ² - isopropyl-glycine amide

The title compound was prepared as an acetate salt following the procedure outlined in Example 307 by replacing cyclopropanamine with propan-2-amine.

Example 316

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ² - cyclohexyl-glycine amide

The title compound was prepared as an acetate salt following the procedure outlined in Example 307 by replacing cyclopropanamine with cyclohexaneamine.

Example 317

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] acetamide

To a mixture of Example 64A (20 mg, 0.051 mmol) and diisopropylethylamine (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 Stir at temperature for about 1.5 hours. Hydrochloric acid (4N in dioxane, 1.5 mL) was added and the mixture was 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 an acetonitrile / water (0.05 M ammonium acetate) gradient elution method to give the title compound as acetate salt.

Example 318

N ¹ - [5- (1- benzyl -1H-1,2,3- triazol-4-yl) -1H- indazol-3-yl] -N ² - cyclobutyl glycine amide

The title compound was prepared following the procedure outlined in Example 307 by replacing cyclopropanamine with cyclobutanamine.

Example 319

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N'-propylurea

To a solution of Example 64A (75 mg, 0.19 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 at about 80 ° C. for about 16 hours. The reaction mixture was cooled to ambient temperature and water (5 mL) was added. The resulting precipitate was collected by filtration, then treated with hydrochloric acid (4N solution in dioxane, 3 mL) and stirred at room temperature for about 4.5 hours. Diethyl ether (5 mL) was added and the precipitate was collected by filtration. 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 acetate salt.

Example 320

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] ethanesulfonamide

To a solution of Example 64A (75 mg, 0.19 mmol) in pyridine (2 mL) was added ethanesulfonyl 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 was dissolved in dichloromethane (10 mL) and washed with 1N aqueous hydrochloric acid (10 mL). The organic portion was separated, dried under reduced pressure, treated with hydrochloric acid (4N in dioxane, 5 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 an acetonitrile / water (0.05 M ammonium acetate) gradient elution method to give the title compound as acetate salt.

Example 321

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -N- (cyclopropylmethyl) -1H-indazol-3-amine

Example 64A (100 mg, 0.256 mmol), cyclopropanecarbaldehyde (0.057 mL, 0.76 mmol), sodium triacetoxyborohydride (163 mg, 0.76 mmol) and acetic acid (0.044 mL) in 1,2-dichloroethane (5 mL) , 0.76 mmol) was stirred at ambient temperature for about 2.5 hours. Hydrochloric acid (4N in dioxane, 4 mL) was added and the reaction mixture was stirred for about 16 hours. The precipitate was collected by filtration and washed with ether (10 mL). The solid was dissolved in dichloromethane (10 mL), treated with trifluoroacetic acid (0.1 mL) and the reaction mixture was stirred at rt for about 2 h. The reaction mixture was neutralized by addition of 15% aqueous sodium hydroxide solution (about 15 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 acetonitrile / water (0.05 M ammonium acetate) gradient elution method to afford the title compound as acetate salt.

Example 322

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N'-ethylurea

The title compound was prepared following the procedure outlined in Example 319, replacing 1-isocyanatopropane with isocyanatoethane.

Example 323

1- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] pyrrolidin-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 at ambient temperature for about 15 minutes and then 4-bromobutanoyl chloride (0.059 mL, 0.51 mmol) was added. The reaction mixture was stirred for about 16 hours. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in acetonitrile (5 mL), treated with diisopropylethylamine (0.089 mL, 0.51 mmol) and heated at about 60 ° C. for about 16 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was treated with hydrochloric acid (4N in dioxane, 5 mL) and the reaction mixture was stirred at room temperature for about 2 hours. The reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse phase HPLC using an acetonitrile / water (0.05 M ammonium acetate) gradient elution method to give the title compound as acetate salt.

Example 324

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -4- (dimethylamino) butanamide

The title compound was prepared as a diacetate salt following the procedure outlined in Example 303B, replacing 2- (dimethylamino) acetic acid with 4- (dimethylamino) butanoic acid and Example 303A by Example 64A.

Example 325

N-3,4-dihydro-1H-isochromen-4-yl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by substituting piperidine for 3,4-dihydro-1H-isochromen-4-amine.

Example 326

N- (cyclohexylmethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

5- (1H-indazol-5-yl) isoxazole-3-carboxylic acid (35 mg, 0.15 mmol, Example 71A) was dissolved in N, N-dimethylformamide (0.8 mL) and then N, N-dimethyl HATU (60 mg, 0.15 mmol) dissolved in formamide (0.8 mL) was added. Then, a solution of 1-cyclohexylmethaneamine (17 mg, 0.17 mmol) dissolved in N, N-dimethylformamide (0.8 mL) was added, followed by di-soluble in N, N-dimethylformamide (0.8 mL). Isopropylethylamine (56 μL, 0.31 mmol) was added. The resulting mixture was shaken at 40 ° C. for 3 hours. The reaction was filtered, checked by LC / MS and concentrated to dryness. The residue was dissolved in 1: 1 dimethyl sulfoxide / methanol and reversed phase HPLC (Phenomenex® Luna® C8 (2) 5 μm 100 μs AXIA ™ column (30 mm × 75 mm), 50 mL / min, 0.1% trifluoro in acetonitrile / water Roacetic acid 10-100%) to give the title compound.

Example 327

N- (3-chlorobenzyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 1- (3-chlorophenyl) methanamine.

Example 328

5- (1H-indazol-5-yl) -N- (2-methoxybenzyl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 1- (2-methoxyphenyl) methanamine.

Example 329

5- (1H-indazol-5-yl) -N- [2- (trifluoromethyl) benzyl] isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 1- [2- (trifluoromethyl) phenyl] methanamine.

Example 330

5- (1H-indazol-5-yl) -N- [3- (trifluoromethyl) benzyl] isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 1- [3- (trifluoromethyl) phenyl] methanamine.

Example 331

5- (1H-indazol-5-yl) -N- [4- (trifluoromethyl) benzyl] isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 1- [4- (trifluoromethyl) phenyl] methanamine.

Example 332

5- (1H-indazol-5-yl) -N- (pyridin-2-ylmethyl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 1-pyridin-2-ylmethanamine.

Example 333

5- (1H-indazol-5-yl) -N- (pyridin-3-ylmethyl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 1-pyridin-3-ylmethanamine.

Example 334

5- (1H-indazol-5-yl) -N- (pyridin-4-ylmethyl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 1-pyridin-4-ylmethanamine.

Example 335

N- (2-chlorobenzyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 1- (2-chlorophenyl) methanamine.

Example 336

N- (4-chlorobenzyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 1- (4-chlorophenyl) methanamine.

Example 337

5- (1H-indazol-5-yl) -N- (1-phenyl-2-piperidin-1-ylethyl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with 1-phenyl-2-piperidin-1-ylethanamine.

Example 338

N- [2- (1H-imidazol-1-yl) -1-phenylethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by substituting piperidine for 2- (1H-imidazol-1-yl) -1-phenylethanamine.

Example 339

5- (1H-indazol-5-yl) -N- (2-morpholin-4-yl-1-phenylethyl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with 2-morpholin-4-yl-1-phenylethanamine.

Example 340

5- (1H-indazol-5-yl) -N- [2- (4-methylpiperazin-1-yl) -1-phenylethyl] isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by substituting piperidine for 2- (4-methylpiperazin-1-yl) -1-phenylethanamine.

Example 341

5- (1H-indazol-5-yl) -N- (1-phenyl-2-pyrrolidin-1-ylethyl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by substituting piperidine for 1-phenyl-2-pyrrolidin-1-ylethanamine.

Example 342

Tert-butyl 2-({[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} amino) -2-phenylethylcarbamate

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with tert-butyl 2-amino-2-phenylethanecarbamate.

Example 343

5- (1H-indazol-5-yl) -N- (1-naphthylmethyl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 1- (1-naphthyl) methanamine.

Example 344

5- (1H-indazol-5-yl) -N- (2-phenylethyl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 2-phenylethanamine.

Example 345

5- (1H-indazol-5-yl) -N- (2-pyridin-2-ylethyl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 2-pyridin-2-yletanamine.

Example 346

5- (1H-indazol-5-yl) -N- (2-pyridin-3-ylethyl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 2-pyridin-3-yleethanamine.

Example 347

5- (1H-indazol-5-yl) -N- (2-pyridin-4-ylethyl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 2-pyridin-4-yleethanamine.

Example 348

N- [2- (2-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 2- (2-chlorophenyl) ethanamine.

Example 349

N- [2- (3-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 2- (3-chlorophenyl) ethanamine.

Example 350

N- [2- (4-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 2- (4-chlorophenyl) ethanamine.

Example 351

N-benzyl-N-ethyl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with N-benzyl-N-ethylamine.

Example 352

5- (1H-indazol-5-yl) -N-methyl-N- (1-naphthylmethyl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with N-methyl-N- (1-naphthylmethyl) amine.

Example 353

5- (1H-indazol-5-yl) -N-methyl-N- (2-phenylethyl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with N-methyl-N- (2-phenylethyl) amine.

Example 354

5- (1H-indazol-5-yl) -N-methyl-N- (2-pyridin-2-ylethyl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with N-methyl-N- (2-pyridin-2-ylethyl) amine.

Example 355

5- (1H-indazol-5-yl) -N-[(1R) -1-phenylethyl] isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with (1R) -1-phenylethanamine.

Example 356

5- (1H-indazol-5-yl) -N-1,2,3,4-tetrahydronaphthalen-1-ylisoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 326 except for replacing 1-cyclohexylmethanamine with 1,2,3,4-tetrahydronaphthalen-1-amine.

Example 357

5- (1H-indazol-5-yl) -N-[(1S) -1- (1-naphthyl) ethyl] isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with (1S) -1- (1-naphthyl) ethanamine.

Example 358

5- (1H-indazol-5-yl) -N-[(1R) -1- (1-naphthyl) ethyl] isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by substituting piperidine for (1R) -1- (1-naphthyl) ethanamine.

Example 359

N- [3- (dimethylamino) -1-phenylpropyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with N ³ , N ³ -dimethyl-1-phenylpropane-1,3-diamine.

Example 360

N- (2,3-dihydro-l, 4-benzodioxin-5-ylmethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with 1- (2,3-dihydro-1,4-benzodioxin-5-yl) methanamine.

Example 361

N- (3,4-dihydro-2H-1,5-benzodioxepin-6-ylmethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by replacing piperidine with 1- (3,4-dihydro-2H-1,5-benzodioxepin-6-yl) methanamine.

Example 362

5- (1H-indazol-5-yl) -N-[(1-methyl-1H-indol-4-yl) methyl] isoxazole-3-carboxamide

The title compound was prepared following the procedure outlined in Example 81B by substituting piperidine for (1-methyl-1H-indol-4-yl) methanamine.

Example 363

5- {3-[(3-phenylpyrrolidin-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 81B by substituting piperidine for 3-phenylpyrrolidine.

Example 364

5- {3-[(2-phenylpyrrolidin-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 81B by substituting piperidine for 2-phenylpyrrolidine.

Example 365

5- {3-[(2-phenylpiperidin-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole

The title compound was prepared following the procedure outlined in Example 81B by substituting piperidine for 2-phenylpiperidine.

Example 366

5- (1H-indazol-5-yl) -N-[(1S) -1-phenylethyl] isoxazole-3-carboxamide

5- (1H-indazol-5-yl) isoxazole-3-carboxylic acid (36 mg, 0.16 mmol, Example 71A) was dissolved in N, N-dimethylformamide (1.0 mL) and then N, N-dimethyl HATU (60 mg, 0.16 mmol) dissolved in formamide (0.5 mL) was added. Then, a solution of (S) -1-phenylethanamine (22 mg, 0.18 mmol) dissolved in N, N-dimethylformamide (0.6 mL) was added and then added to N, N-dimethylformamide (0.2 mL). Dissolved diisopropylethylamine (56 μL, 0.32 mmol) was added. The resulting mixture was shaken at 40 ° C. for 3 hours. The reaction was filtered, checked by LC / MS and concentrated to dryness. The residue was dissolved in 1: 1 dimethyl sulfoxide / methanol and reversed phase HPLC (Phenomenex® Luna® C8 (2) 5 μm 100 μs AXIA ™ column (30 mm × 75 mm), 50 mL / min, 0.1% trifluoro in acetonitrile / water Roacetic acid 10-100%) to give the title product.

Example 367

5- (1H-indazol-5-yl) -Ν-[(1R) -1- (4-methylphenyl) ethyl] isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with (1R) -1- (4-methylphenyl) ethanamine.

Example 368

5- (1H-indazol-5-yl) -N-[(1S) -1- (4-methylphenyl) ethyl] isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with (1S) -1- (4-methylphenyl) ethanamine.

Example 369

N-[(lR, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with (1R, 2S) -1-aminoindan-2-ol.

Example 370

N-[(1R, 2R) -2-hydroxy-2,3-dihydro-1H-inden-1-yl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with (1R, 2R) -1-aminoindan-2-ol.

Example 371

N-[(1R) -1- (4-bromophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366, except for replacing (S) -1-phenylethanamine with (1R) -1- (4-bromophenyl) ethanamine.

Example 372

N-[(1S) -1- (4-bromophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with (1S) -1- (4-bromophenyl) ethanamine.

Example 373

N-[(1R) -1- (4-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with (1R) -1- (4-chlorophenyl) ethanamine.

Example 374

N-[(1S) -1- (4-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with (1S) -1- (4-chlorophenyl) ethanamine.

Example 375

5- (1H-indazol-5-yl) -N-[(1S) -1- (2-naphthyl) ethyl] isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with (1S) -1- (2-naphthyl) ethanamine.

Example 376

N- [1- (4-ethoxyphenyl) -2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with 2-amino-2- (4-ethoxyphenyl) ethanol.

Example 377

N- [2-hydroxy-1- (4-isopropylphenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with 2-amino-2- (4-isopropylphenyl) ethanol.

Example 378

N- [1- (3,4-dimethylphenyl) -2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with 2-amino-2- (3,4-dimethylphenyl) ethanol.

Example 379

N- [2-hydroxy-1- (2-methoxyphenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with 2-amino-2- (3-methoxyphenyl) ethanol.

Example 380

N- [2-hydroxy-1- (4-methylphenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with 2-amino-2- (4-methoxyphenyl) ethanol.

Example 381

5- (1H-indazol-5-yl) -N-[(1R) -1- (2-methoxyphenyl) ethyl] isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with (1R) -1- (2-methoxyphenyl) ethanamine.

Example 382

N-[(1S) -1- (3,4-difluorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with (1S) -1- (3,4-difluorophenyl) ethanamine.

Example 383

5- (1H-indazol-5-yl) -N-[(1R) -1- (3-methoxyphenyl) ethyl] isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with (1R) -1- (3-methoxyphenyl) ethanamine.

Example 384

5- (1H-indazol-5-yl) -N-{(1R) -1- [3- (trifluoromethyl) phenyl] ethyl} isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with (1R) -1- [3- (trifluoromethyl) phenyl] ethanamine.

Example 385

N- [1- (2,3-dihydro-l, 4-benzodioxin-6-yl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound followed the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with 1- (2,3-dihydro-1,4-benzodioxin-6-yl) ethanamine. Prepared using.

Example 386

N- [1- (3,5-dichlorophenyl) -2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366 except for replacing (S) -1-phenylethanamine with 2-amino-2- (3,5-dichlorophenyl) ethanol.

Example 387

Tert-butyl 5- (1-benzyl-1H-1,2,3-triazol-4-yl) -3-[({[6- (trifluoromethyl) pyridin-2-yl] amino} carbo Yl) amino] -1H-indazole-1-carboxylate

The solution of triphosgene in dichloromethane was cooled to 0 ° C. under nitrogen. Then a mixture of triethylamine (0.426 mL, 3.07 mmol) and Example 64A (150 mg, 0.384 mmol) in dichloromethane (2 mL) was added slowly dropwise. The resulting mixture was stirred at rt for 1 h. 6- (trifluoromethyl) pyridin-2-amine (62.3 mg, 0.384 mmol) was then added and stirred overnight at room temperature. The precipitate was filtered off and washed with dichloromethane and water. The product was dried under vacuum to give the title compound. MS m / z 579.3 (M + H) ⁺ .

Example 388

5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1-[(1-methylpiperidin-2-yl) carbonyl] -1H-indazol-3-amine

1-Methylpiperidine-3-carboxylic acid hydrochloride was combined under nitrogen with a mixture of dimethylformamide and dichloromethane and stirred for 15 minutes. Subsequently, carbonyldiimidazole was added dropwise. The resulting solution was stirred at rt for 1 h. Example 62 was then added, followed by stirring at 60 ° C. for 2 hours and then overnight at room temperature. The reaction mixture was poured into ice water and brine was added. The cold solution was decanted off and the residue was taken up in dichloromethane and washed with water (2X). The organic layer was dried over 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 over magnesium sulfate and concentrated. The residue was taken up in a small amount of acetone and then added dropwise to distilled water. The 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-yl) -1-[(dimethylamino) acetyl] -1H-indazol-3-amine

2- (dimethylamino) acetic acid was dissolved in dimethylformamide and pyridine for 15 minutes at room temperature under nitrogen. Carbonyldiimidazole was added dropwise into fractions. The resulting mixture was stirred at rt for 1 h. Example 62 was then added and the mixture was stirred at rt overnight. The volatiles were removed under reduced pressure and the residue was added to ice water. Sodium chloride was added and a dark oil resulted from the cold solution. The solution was decanted. The residue was washed with water (3X) and then dried. From the decanted solution, a precipitate formed from the water / dimethylformamide mixture overnight. This demonstrates that the starting material is filtered off and decanted. The product residue was crystallized in dichloromethane, collected by filtration and washed with a small amount of dichloromethane and ether. The product was dried to give the title compound. MS m / z 376.3 (M + H) ⁺ .

Example 390

Tert-butyl 3-amino-5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-1-carboxylate

Example 62 was suspended in dichloromethane with a catalytic amount of dimethylaminopyridine. A solution of di-tert-butyl dicarbonate in dichloromethane (160 mL) was added for 1 hour. The reaction mixture was stirred for about 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 first eluted with dichloromethane, then eluted with 1% methanol / dichloromethane and finally eluted with 2% methanol / dichloromethane. Fractions containing the desired product were combined and concentrated to provide the title compound. MS m / z 391.3 (M + H) ⁺ .

Example 391

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-piperidin-1-ylacetamide

2- (piperidin-1-yl) acetic acid was combined with dimethylformamide and pyridine. The mixture was stirred at room temperature for 15 minutes and then carbonyldiimidazole was added dropwise into fractions. Stirring was continued for 1 hour at room temperature, then Example 64A was added and then stirring was continued 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 (M + H) ⁺ .

Example 392

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-morpholin-4-ylacetamide

2-morpholinoacetic acid was combined with dimethylformamide and pyridine. The mixture was stirred at room temperature for 15 minutes and then carbonyldiimidazole was added dropwise into fractions. Stirring was continued for 1 hour at room temperature, then Example 64A was added and then stirring was continued for 28 hours. The reaction mixture was allowed to warm to 60 ° C. for 4 hours and then continued to stir overnight at room temperature. The reaction mixture was again warmed to 60 ° C. for 7 hours. A small amount of the title compound was obtained. MS m / z 418.3 (M + H) ⁺ .

Example 393

N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -1-methylpiperidine-2-carboxamide

1-methylpiperidine-3-carboxylic acid hydrochloride was combined with dimethylformamide and pyridine. The mixture was stirred at room temperature for 15 minutes and then carbonyldiimidazole was added dropwise into fractions. Stirring was continued for 1 hour at room temperature, then Example 64A was added and then stirring was continued for 28 hours. The reaction mixture was allowed to warm to 60 ° C. for 4.25 h and then continued to stir overnight at room temperature. The reaction mixture was again warmed 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 Suppression Test

Compounds of formula 1 were tested for their ability to inhibit N-terminal His6-labeled recombinant human ROCK-2 residues 11-552 expressed by baculovirus in Sf21 cells (Upstate). In 384-well v-based polypropylene plates (Axygen), 1 nM of 10 ul of recombinant N-terminal His6-labeled recombinant human ROCK-2 residues 11-552 (final) expressed by baculovirus in Sf21 cells (Upstate) (final) Concentration) to 2 μM (final concentration) in 10 μl biotinylated peptide substrate (Biotin-Aha-KEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK (SEQ ID NO: 1)) (Genemed) and reaction buffer (25 mM HEPES, pH 7.5, 0.5 mM DTT, 10 mM MgCl). ₂ , 100 uM Na ₃ VO ₄ , 0.075 mg / ml Triton X-100), mixed with various concentrations of inhibitors (2% DMSO final) and the reaction was 5 uM containing 0.01 uCi [ ³³ P] -ATP (Perkin Elmer) Unlabeled ATP was initiated by addition. The reaction was quenched after 1 hour with the addition of 50ul stop buffer (50mM EDTA, 2M NaCl final concentration). 80 uL of suspended reaction was transferred to 384-well streptavidin coated FlashPlates (Perkin Elmer), incubated for 10 minutes at room temperature, and 0.05% Tween- using ELX-405 automated plate washer (BioTek). Wash three times with 20 / PBS and count on a TopCount Scintillation Plate Reader (Packard).

ROCK-1 Suppression Test

Compounds of formula 1 were tested for their ability to inhibit N-terminal His6-labeled recombinant human ROCK-1 amino acids 17-535 expressed by baculovirus in Sf21 cells (Upstate). In 384-well v-based polypropylene plates (Axygen), in 10 ul of recombinant N-terminal His6-labeled recombinant human ROCK-1 amino acids 17-535 expressed by baculovirus in Sf21 cells (Upstate) in reaction buffer 2 nM (final concentration) to 2 uM (final concentration) of biotinylated peptide substrate (Biotin-Aha-VRRLRRLTAREAA (SEQ ID NO: 2)) (Genemed) and 10 μl of reaction buffer (25 mM HEPES, pH 7.5, 0.5 mM DTT, 10 mM) MgCl ₂ , 100 uM Na ₃ VO ₄ , 0.075 mg / ml Triton X-100), mixed with various concentrations of inhibitors (2% DMSO final), and the reaction was contained 0.01uCi [ ³³ P] -ATP (Perkin Elmer). It was initiated by the addition of 5 uM of unlabeled ATP. The reaction was quenched after 1 hour with the addition of 50ul stop buffer (50mM EDTA, 2M NaCl final concentration). 80 uL of stationary reaction was transferred to 384-well streptavidin coated flashplate (Perkin Elmer), incubated for 10 minutes at room temperature, and 0.05% Tween-20 / PBS using ELX-405 automated plate washer (BioTek) Washed three times with and counted on a top count flash plate reader (Packard).

GSK Suppression Assay

Compounds of formula 1 were tested for their ability to inhibit N-terminal His6-labeled GSK-3 expressed by baculovirus in Sf21 cells (Upstate). In 384-well v-based polypropylene plates (Axygen), 10 ul of recombinant N-terminal His6-labeled GSK3 expressed by baculovirus in Sf21 cells (Upstate) was converted to 10 ul of biotinylated peptide substrate (Biotin-ahx- YRRAAVPPSPSLSRHSSPHQS (p) EDEEE (SEQ ID NO: 3)), 2 uM final concentration (Genemed) and reaction buffer (25 mM HEPES, pH 7.5, 0.5 mM DTT, 10 mM MgCl ₂ , 100 uM Na ₃ VO ₄ , 0.075 mg / ml Triton X- 100) was mixed with various concentrations of inhibitors (2% DMSO final) and the reaction was initiated by addition of 20 [mu] l [ ³³ P] -ATP, 5 uM final concentration, 2 mCi / μmol (Perkin Elmer). The reaction was quenched after 1 hour with the addition of 50ul stop buffer (50mM EDTA, 2M NaCl final concentration). 80 uL of stationary reaction was transferred to 384-well streptavidin coated flashplate (Perkin Elmer), incubated for 10 minutes at room temperature, and 0.05% Tween-20 / PBS using ELX-405 automated plate washer (BioTek) Washed three times with and counted on a top count flash plate reader (Packard).

Human GSK-3β Inhibition Assay

Compounds were tested for their ability to phosphorylate biotin-YRRAAVPPSPSLSRHSSPHQ (pS) EDEEE by inhibiting human glycogen synthase kinase-3 beta (hGSK-3β). Compounds were prepared in 0.5 μCi ³³ P-ATP, 10 μM ATP, 0.0125 U hGSK-3β (Upstate Cell Signaling Solution) and 50 mM HEPES, 10 mM MgCl ₂ , 100 μM Na ₃ VO ₄ , 1 mM DTT, 0.0075% Triton, 2% DMSO (Total Incubated for 30 minutes at room temperature with lμM substrate (Biotin-YRRAAVPPSPSLSRHSSPHQ (pS) EDEEE (SEQ ID NO: 3)) in 50μL). An equal volume of 100 mM EDTA, 4M NaCl ₂ was added to stop the culture. 80 μL of this mixture was added to streptavidin coated flashplates (PerkinElmer). Following the wash step, ³³ P introduction was quantified on a Microβ microplate liquid scintillation counter (PerkinElmer). IC50 was determined by fitting sigmoidal dose-response curves to counts obtained at different concentrations in GraphPad Prism.

Human GSK-3α Inhibition Assay

Compounds were tested for their ability to phosphorylate biotin-YRRAAVPPSPSLSRHSSPHQ (pS) EDEEE (SEQ ID NO: 3) by inhibiting human glycogen synthase kinase-3 alpha (hGSK-3α) 0.5 nM final concentration. Compounds were prepared in 0.5 μCi ³³ P-ATP, 10M ATP, 0.0125U hGSK-3 (Upstate Cell Signaling Solution) and 50mM HEPES, 10mM MgCl ₂ , 100uM Na ₃ VO ₄ , 1mM DTT, 0.0075% Triton, 2% DMSO (Total Incubated for 30 minutes at room temperature with 2 μM substrate (Biotin-YRRAAVPPSPSLSRHSSPHQ (pS) EDEEE) in 50 μL volume. An equal volume of 100 mM EDTA, 4M NaCl ₂ was added to stop the culture. 80 μL of this mixture was added to streptavidin coated flashplates (PerkinElmer). Following the washing step, ³³ P introduction was quantified on a MicroBeta microplate liquid scintillation counter (PerkinElmer). IC50 was determined by fitting sigmoidal dose-response curves to counts obtained at different concentrations in GraphPad Prism.

JAK2 suppression test

Jak2 kinase activity was assayed by a homogenous time-resolved fluorescence (HTRF) in vitro kinase assay (Mathis, G., HTRF (R) Technology. J Biomol Screen, 1999. 4 (6): p.309-314). Specifically, 10 μL of C-terminal His6-labeled recombinant human JAK2, amino acid 808-terminus, expressed with baculovirus in Sf21 cells (Upstate) was added to the reaction buffer (50 mM HEPES, pH 7.5, 10 mM MgCl ₂ , 2 mM MnCl ₂ , Mix with 10ul inhibitor (various concentrations, 2% final DMSO) and 10ul ATP (5µm final concentration) in 0.1% BSA and 1mM DTT, 40μL final volume. The reaction was initiated by adding 10 ul of Bio-PDK peptide (Biotin-Ahx-KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC (SEQ ID NO: 4), 0.5 μm final concentration) in Black 384-well plate. After 60 min incubation at room temperature, the reaction was quenched with the addition of 60 μL stop / exposure buffer to 30 mM EDTA, 1 μg / ml streptavidin-APC (Prozyme), 50 ng / ml anti-phosphotyrosine mAb PT66-K europium cryptate , 30 mM HEPES, pH 7.5, 120 mM BKF, 0.005% Tween-20, 0.05% BSA). The quenched reaction was allowed to stand at room temperature for 1 hour and then read simultaneously at 615 nm and 665 nm with a time-resolved fluorescence detector (Envision, Perkin Elmer). The ratio between signals 615 nm and 665 nm was used for the calculation of IC ₅₀ .

Method- β-catenin transporter-gene assay

Compounds were tested for their ability to modulate β-catenin regulated gene transcription in the LEF / TCF (T-cell factor) transporter gene assay. SY-SY5Y human neuroblastoma cells are either 80ng / well TOPFLASH plasmid (Upstate cell signaling solution) or thymidine kinase containing two sets of three copies of thymidine kinase minimal promoter and three copies of the TCF binding site upstream of the half-duplicate luciferase open reading frame. The cells were transiently infected with an 80 ng / well FOPFLASH plasmid (Upstate cell signaling solution) containing three copies of the mutant TCF binding site upstream of the minimal promoter and half-diluted luciferase open reading frame. In addition, all cells were transiently transfected with 20 ng / well pR1-TK plasmid (Promega) containing a simple herpes virus thymidine kinase promoter to provide low to moderate levels of Renilla Liciferase expression. . Transfection medium was changed to serum free medium containing test substance and incubated at 37 ° C. for 24 hours. Cultures were stopped and quantified using the Dual Glo Luciferase Assay (Promega) as directed and quantified on a Pherastar reader (BMG).

Firefly luciferase activity was normalized to Renilla luciferase activity per well. The normalized TOPFLASH response was then compared to the normalized FOPFLASH response to obtain a LEF / TCF specific signal. The maximum response is the maximum ratio between normalized TOPFLASH and FOPFLASH signals. Sigmoidal dose-response curves were fitted using Graphpad Prism.

Mouse Asthma Model of Acute Asthma

Female Balb / c mice were purchased from Taconic and housed in the Abbott Bioresearch Center. Animals were used at 8-12 weeks of age. All protocols were approved by the Institutional Animal Care and Use Committee (IACUC). Dexamethasone (Dex) and egg white albumin (OVA) were purchased from Sigma. Endotoxins were removed from egg white albumin using a final material containing deoxygel (Pierce) and less than 0.1 EU / 1 mg protein according to the manufacturer's protocol. Alum Imject was purchased from Pierce.

Animals were sensitive to OVA with intraperitoneal injection of 8 μg OVA in 2 mg Alum on days 0 and 7. On days 14 and 16, animals received intranasal inoculation of 0.3 μg OVA in 50 μl of sterile PBS. Animals were given intraperitoneally with a representative compound of formula 1 (0.5% HMPC, dissolved in 0.02% Tween 80 in water) twice daily, starting at 13 pm and starting at 3, 10, and 30 mg / kg / dose. . Final compound doses were administered 30 minutes prior to airway hyperresponsiveness (AHR) measurements. Dexamethasone was administered orally at a dose of 3 mg / kg once daily on days 13-17. All endpoints were analyzed 24 hours after the second OVA inoculation on day 17. AHR was assessed using unconscious restrained whole body plethysmography. Briefly, surgical anesthesia was induced by intraperitoneal injection of ketamine and xylazine. A tracheal cannula was surgically inserted between the third and fourth tracheal cartilage rings. Intravenous (iv) jugular infusion of pancuronium bromide inhibited spontaneous breathing. Animals were placed on a systemic volumetric recorder (Buxco) and mechanically oxygenated using 0.2 ml room air at 150 breaths per minute with a volume-controlled ventilator (Harvard Apparatus). Lung pressure and flow in the volumetric recorder were measured using transducers and lung resistance was calculated as pressure / flow using BioSystem Xa software. Baseline resistance and resistance following inoculation with methacholine (3, 10 or 30 mg / ml) delivered to an in-line ultra nebulizer were measured. Upon completion of the lung function test, the lungs were washed four times with 0.5 ml sterile PBS. Washes were analyzed for IL-13, AMCase, Muc5ac and cellular infiltrates. The efficacy of the test compound was tested at doses of 3, 10 and 30 mg / kg bid (6, 20, 60 mg / kg / day). Of OVA immunization increased the lung resistance with 6.90cm H ₂ O / ml / sec for the 4.65cm H ₂ O / ml / sec in animals inoculated with PBS. Treatment of mice with test compounds significantly inhibited methacholine induced airway resistance down to 4.55 cm H ₂ 0 / ml / sec and 4.77 cm H ₂ 0 / ml / sec at doses ranging from 1 to 100 mg / kg (p < 0.001). Preferred compounds require a dosage of less than 50 mg / kg to exhibit the above reaction. Most preferred compounds require a dosage of less than 30 mg / kg to achieve the above reaction. This inhibition rate was comparable to the measurements taken in the PBS inoculated group (4.65 cm H ₂ O / ml / sec) and the measurements of 3 mg / kg dexamethasone (4.76 cm H ₂ O / ml / sec).

IL-13 Measurements: IL-13 concentrations in bronchoalveolar lavage fluid (BAL) were measured by ELISA (R & D Systems) according to manufacturer's instructions. IL-13 concentration in BAL fluid was significantly induced at 102.5 pg / ml in OVA inoculated mice compared to sub-detection levels in PBS inoculated groups. This induction was significantly inhibited (p <0.05) up to 60% after the test compound administration at the 30 mg / kg dose. There was no significant inhibition in the 3 mg / kg or 10 mg / kg dose group.

AMCase Determination: Acidic mammalian chitinase (AMCase) activity was determined to be 0.01% BSA, 30 mM sodium citrate, 60 mM sodium phosphate, pH in the presence of 80 uM of 4-methylumbelliferyl β-DN, N'-diacetylchitobioside. Measured with 1:10 dilution of BAL fluid using 5.2. The reaction was incubated at room temperature for 15 minutes and quenched by addition of 100 uL of 1M glycine / NaOH pH 10.6. Product formation was measured by fluorescence emission at 460 nm using excitation at 385 nm on a Fluoroskan Ascent fluorometer. AMCase activity was induced at 28.5 U in OVA inoculated animals compared to 2.17 U in PBS inoculated animals. This induction was significantly suppressed (p <0.01) by 35% after test compound administration in the 30 mg / kg group.

MUC5AC Measurement: The concentration of the mucin gene MUC5AC was quantified in ELISA format. Briefly, BAL samples were diluted 1: 2 in buffer (2% BSA in PBS), plated on high protein binding 96-well plates (Costar) and dried. After one series of washes, a 1: 100 dilution of biotinylated MUC5AC antibody (clone 45M, Lab Vision) was added for 1 hour. The plate was washed and a 1: 3000 dilution of streptavidin-HRP (Southern Biotech) was added to the plate for 15 minutes. The plate was then developed for 30 minutes using TMB substrate (Sigma). The reaction was stopped using 1M H ₂ SO ₄ and then read spectrophotometrically at OD 450 nm. The level of MUC5AC was even lower than 50% after test compound administration.

Determining Antipain Effects: Neuropathic Pain Model

Spinal nerve (L5 / L6) ligation model of neuropathic pain.

As described in detail above by Kim SH; Chung JM An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat.Pain 1992, 50, 355-363) I have done neuritis. In anesthetized rats, spinal lateral muscles (left) were separated from spinous processes, L5 and L6 vertebral nerves were separated and tightly ligated with 3 to 0 silk treads. After hemostasis, the wound was closed and covered with antibiotic ointment. Rats were recovered and placed in cages with soft bedding for 14 days prior to behavioral tests for mechanical allodynia.

Sciatic nerve ligation model of neuropathic pain. Bennett and Xie (Bennett GJ; Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.Pain 1988, 33, 87-107), as described in detail above, in anesthetized rats. , 1.5 cm incision was made on the pelvis 0.5 cm or less, and the biceps femoral and the shallow gluteous superficialis (right) were separated. The sciatic nerve was exposed, separated and four loose ligations (5-0 chromium joists) spaced 1 mm apart. Rats were recovered and placed in cages with soft bedding for 14 days prior to behavioral tests for mechanical allodynia as described above. In addition, animals were also tested for cold allodynia by immersing their hind legs in a cold water bath (4.5 ° C.) and measuring paw withdrawal latency.

Selected analogues of the compound of formula 1 administered intraperitoneally or parenterally were administered in the Chung and Bennett model of neuropathic pain described herein at doses ranging from 1 to 150 mg / kg. Excess% inhibition was demonstrated.

In summary, the representative compound of formula 1 in the mouse model of acute asthma was effective at inhibiting airway resistance in the dosage range of 1-100 mg / kg. High dose (30 mg / kg) treatment also inhibited IL-13 induction as well as AMCase activity and MUC5AC levels in BAL fluid.

Representative compounds of formula 1 in rat models of neuropathic pain were effective as evidenced by greater than 30% inhibition of tactile allodynia at doses ranging from 1 to 150 mg / kg.

Compounds of formula (I) exhibiting an IC _{50 of} from about 1.0 μM to about 10 μM, preferably from about 100 nM to about 1.0 μM, may comprise human ROCK-2, N-terminal His-labeled GSK-3β, human GSK-3β, His6-label Recombinant human JAK2 and fireflies have been found to inhibit luciferase. More preferably, the compound of formula 1, which exhibits an IC ₅₀ of about 10 nM to about 100 nM, most preferably less than 10 nM, comprises human ROCK-2, an N-terminal His-labeled GSK-3β, human GSK-3β, His6- Labeled recombinant human JAK2 and fireflies have been shown to inhibit luciferase.

In addition, certain compounds of Formula 1 exhibited inhibition of human ROCK-2 with more than 10-fold selectivity for a panel of 50 kinase targets. Certain compounds of formula 1 exhibited inhibition of human GSK-3β with more than 10-fold selectivity for a panel of 50 kinase targets. Certain compounds of formula 1 exhibited inhibition of His6-labeled recombinant human JAK2 with more than 10-fold selectivity for a panel of 50 kinase targets.

Dosing method

The invention also provides pharmaceutical compositions comprising the compounds of the invention. Pharmaceutical compositions comprise a compound of the invention formulated with one or more pharmaceutically acceptable non-toxic carriers.

The pharmaceutical compositions of the present invention can be administered to humans and other mammals orally, rectally, parenterally, intravaginally, vaginally, topically (eg as powders, ointments or drops), buccally, or as oral or nasal sprays. Can be. As used herein, the term “parenteral” means a mode of administration, including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

As used herein, the term "pharmaceutically acceptable carrier" means any kind of nontoxic inert solid, semisolid or liquid filler, diluent, encapsulating material or formulation aid. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars such as, but not limited to, lactose, glucose and sucrose; Starch such as, but not limited 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, cocoa butter and suppository waxes; Oils such as but not limited to peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; Glycols such as propylene glycol; Esters such as, but not limited to, ethyl oleate and ethyl laurate; Agar; Buffers 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 nontoxic suitable lubricants, such as, but not limited to, sodium lauryl sulfate and magnesium stearate, and, at the discretion of the formulator, are colorants, mold release agents, coating agents, sweeteners, flavoring agents. And fragrances, preservatives and antioxidants may be present in the compositions.

Pharmaceutical compositions of the present invention for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions immediately prior to use. . Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols such as glycerol, propylene glycol, polyethylene glycol, etc., vegetable oils such as olive oil, injectable organic esters such as ethyl ole Ate) and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating 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 auxiliaries such as preservatives, wetting agents, emulsifiers and dispersants. Inhibition of the activity of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical formulations can be induced by including agents that delay absorption, such as aluminum monostearate and gelatin.

In some cases, to prolong the action of the drug, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug also depends on its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered drug form is achieved by dissolving or suspending the drug in an oil vehicle.

Injectable depot formulations are prepared by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples 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 suitable for body tissue.

Injectable formulations may be sterilized by filtration through a bacterial retention filter or by the introduction of a sterile agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media immediately prior to use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is one or more inert, pharmaceutically acceptable carriers or excipients such as sodium citrate, dicalcium phosphate and / or a) fillers or extenders such as starch, lactose, Sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants, such as glycerol; d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retardants such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) humectants such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; And i) lubricants such as talc, 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 a buffer.

Solid compositions of a similar form can also be used as fillers in soft and hard filled gelatin capsules using the above-mentioned carriers, such as lactose or lactose as well as high molecular weight polyethylene glycols and the like.

Solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared using coatings and shells such as enteric skin and other coatings well known in the pharmaceutical formulating art. They may optionally contain an opacifying agent and may also be in the form of a composition in which they release only the active ingredient (s) or preferentially release to certain parts of the intestine, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

The active compound may also be present in microencapsulated form with one or more of the carriers described above where appropriate.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms are inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl Alcohols, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl Fatty acid esters of alcohols, polyethylene glycol and sorbitan and mixtures thereof.

In addition to inert diluents, oral compositions may also include auxiliaries such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and fragrances.

Suspensions, in addition to the active compounds, include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth And mixtures thereof.

Compositions for rectal or vaginal administration are preferably suitable non-irritating carriers or carriers, for example cocoa, which are solid at room temperature but liquid at body temperature and thus melt in the rectum or vaginal cavity to release the active compound. Suppositories that can be prepared by mixing with butter, polyethylene glycol or suppository waxes.

The compounds of the present invention may also be administered in liposome form. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolayer or multilayer hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The compositions of the present invention in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidyl choline (lecithin) used separately or together.

Methods for forming liposomes are known in the art (Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq).

Dosage formulations for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers or propellants that may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

The actual dosage level of the active ingredient in the pharmaceutical compositions of the invention can be altered to obtain an amount of active compound (s) effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. The choice of dosage level depends on the activity of the particular compound, the route of administration, the severity of the condition to be treated and the condition and previous history of the patient to be treated.

When used in these or other therapies, a therapeutically effective amount of one of the compounds of the invention may be used in its pure form or, if present, in the form of a pharmaceutically acceptable salt, ester or prodrug. The phrase “therapeutically effective amount” of a compound of the present invention means an amount of the compound sufficient to treat the disorder at a reasonable benefit / risk ratio applicable to all medical treatments. However, it is understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. Specific therapeutically effective dosage levels for any particular patient include the disorder to be treated and the severity of that disorder; The 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; Duration of treatment; Drugs used in combination or coincidental with the specific compound employed; And similar factors well known in the medical arts.

As used herein, the term “pharmaceutically acceptable salts” means salts derived from inorganic or organic acids. Salts can be prepared in situ during the final separation and purification of the compound of formula 1 or separately by reacting the free base of the compound of formula 1 with an inorganic or organic acid. Representative acid addition salts include acetates, adipates, alginates, citrate, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, camphorsulfonates, digluconates, glycerophosphates, hemisulfates, Heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, fumarate, methanesulfonate, nicotine Nate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, (L) tartrate, (D ) Tartrate, (DL) tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonei And including undecanoate, but are not limited to.

As used herein, the term “pharmaceutically acceptable prodrug” or “prodrug” is intended to be used in contact with tissues of humans and lower animals without reasonable toxicity, irritation, allergic reactions, and the like within reasonable medical judgment. It means a prodrug of a compound of the present invention that is suitable. The prodrugs of the invention can be rapidly converted in vivo to the compound of formula 1, for example by hydrolysis in blood.

The present invention contemplates a compound of Formula 1 that is formed by synthetic means or formed by in vivo biotransformation.

The compounds of the present invention may exist in unsolvated forms and in solvated forms, including hydrated forms such as semi-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 present invention.

The total daily dose of a compound of the invention administered to a human or lower animal may range from about 0.003 to about 30 mg / kg / day. For oral administration purposes, more preferred dosages may range from about 0.01 to about 10 mg / kg / day. If desired, an effective daily dose may be divided into multiple doses depending on the purpose of administration, and consequently, a single dosage composition may contain such amounts or submultiples thereof constituting the daily dose.

Protein kinases can be classified into a broad group based on the nature of the amino acid (s) they target (serine / threonine, tyrosine, lysine and histidine). For example, tyrosine kinases include receptor tyrosine kinases (RTKs) (such as growth factors) and nonreceptor tyrosine kinases (such as the src kinase class). There are also dual specific protein kinases that target both tyrosine and serine / threonine, such as cyclin dependent kinase (CDK) and mitogen activating protein kinase (MAPK).

Protein tyrosine kinases (PTKs) constitute a major class of kinases that regulate cell-to-cell signaling involved in growth, differentiation, adhesion, locomotion and death. Pearson, M. et al., In Protein Tyrosine Kinases; Fabbro, D., McCormick, F., Eds .; Humana Press Inc., 2006; pp 1-29]. Members of tyrosine kinases include, but are not limited to, Yes, BMX, Syk, EphA1, FGFR3, RYK, MUSK, JAK1 and EGFR. Tyrosine kinases are divided into two classes, receptor type and non-receptor type tyrosine kinases. Interestingly, the entire class of tyrosine kinases consists of at least 90 specialized kinases with at least 58 receptor types and at least 32 non-receptor kinases comprising a total of at least 30 subclasses. Tyrosine kinases have been implicated in a number of human diseases, 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 associated with most forms of human malignancies and have been linked to various congenital syndromes. Robertson et al., Trends Genet. 16: 265-271, 2000.

Non-receptor tyrosine kinases represent a group of intracellular enzymes lacking extracellular and transmembrane sequences. Currently, more than 32 non-receptor tyrosine kinase classes have been identified (Robin et al., Oncogene 19, 5548-5557, 2000). Representative examples include the Sre, Btk, Csk, ZAP70 and Kak classes. In particular, the Src class of the non-receptor tyrosine kinase class is the largest class consisting of Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk protein tyrosine kinases. The Src kinase class is associated with tumorigenesis, cell proliferation and tumor progression. Many protein tyrosine kinases have been found to be involved in cell signaling pathways involved in many pathological conditions, including but not limited to cancer and hyperproliferative disorders and immune disorders.

Cyclin dependent kinase CDKs represent a group of intracellular enzymes that regulate progression through the cell cycle and play a substantial role in cell proliferation (Cohen, P. Nature Reviews Drug Discovery 1, 309-315, 2002). Representative examples of CDKs include, but are not limited to, cyclin dependent kinase 2 (CDK2), cyclin dependent kinase 7 (CDK7), cyclin dependent kinase 6 (CDK6) and cell differentiation control 2 protein (CDC2). CDK regulates transition between different phases of the cell cycle, eg, from the stationary phase of G1 (the gap between somatic division and the onset of DNA replication for a new cycle of cell differentiation) to the S phase (period of active DNA synthesis). Progression, or progression from the G2 phase to the M phase, where active somatic and cell differentiation occurs. Rowell et al. Critical Reviews in Immunology 26 (3), 189-212, 2006]. CDK complexes bind the regulatory cyclin subunits (eg, cyclin A, B1, B2, D1, D2, D3, and E) and catalytic kinase subunits (eg, cdc2 (CDK1), CDK2, CDK4, CDK5, and CDK6) Is formed through. CDKs display an absolute dependence on cyclin subunits for phosphorylating their target substrates and exhibit different kinase / cycline pair functions that regulate progression through specific portions of the cell cycle. In addition, CDKs are involved in a variety of disease states, including but not limited to cancer phenotypes, various neoplastic disorders and neurological disorders. Pallas et al. Current Medicinal Chemistry: Central Nervous System Agents 5 (2), 101-109, 2005].

Mitogen activating protein (MAP) kinases are involved in signal transduction of the cell nucleus in response to extracellular stimuli. Representative examples of MAP kinases include, but are not limited to, mitogen activating protein kinase 3 (MAPK3), mitogen activating protein kinase 1 (ERK2), mitogen activating protein kinase 7 (MAPK7), mitogen activating protein kinase 8 ( JNK1), mitogen activating protein kinase 14 (p38 a), mitogen activating protein kinase 10 (MAPK 10), JNK3 a protein kinase, stress activating protein kinase JNK2 and mitogen activating protein kinase 14 (MAPK14). MAP kinases are a class of proline-derived serine / threonine kinases that mediate signal transduction from extracellular receptor or heat shock, or UV irradiation. Barr et al., Trends in Pharmacological Sciences 27 (10), 525-530, 2006 ]. MAP kinases are activated through phosphorylation of threonine and tyrosine by bispecific protein kinases, including tyrosine kinases such as growth factors. Cell proliferation and differentiation has been found 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 an important role in many disease states, for example, a lack of MAP kinase activity has been shown to induce aberrant cell proliferation and carcinogenesis. Qi et al., Journal of Cell Science 118 (16), 3569-3572, 2005]. Moreover, MAP kinase activity has been linked to insulin resistance associated with type 2 diabetes. Fujishiro et al. Recent Research Developments in Physiology 1 (Pt. 2), 801-812, 2003].

p90 ribosomal S6 kinase (Rsk) is a serine / threonine kinase that acts on mitogen activation cell growth and proliferation, differentiation and cell survival. Examples of members of the Rsk kinase class include, but are not limited to, ribosomal protein S6 kinase, 90 kDa, polypeptide 2 (Rsk3), ribosomal protein S6 kinase, 90 kDa, polypeptide 6 (Rsk4), ribosomal protein S6 kinase, 90 kDa, Polypeptide 3 (Rsk2) and ribosomal protein S6 kinase, 90 kDa, polypeptide 1 (Rsk1 / p90Rsk). Rsk family members are activated by extracellular signal-related kinases and phosphinositide dependent protein kinases 1 [Frodin and Gammeltoft, Mol. Cell. Endocrinol. 151, 65-77, 1999]. Under basal conditions, RSK kinases are localized in the cytoplasm of the cell and upon stimulation with mitogen, activated (phosphorylated by extracellular related kinases) RSKs are temporarily translocated to the plasma membrane where they are fully activated. Fully activated RSK phosphorylates substrates involved in cell growth, proliferation, differentiation and cell survival. Clark et al. Cancer Research 65, 3108-3116, 2005]. RSK signaling pathways are involved in the regulation of the cell cycle. Gross et al., J. Biol. Chem. 276, 46099-46103, 2001]. Current data suggest that small molecules that inhibit Rsk may be useful therapeutics for the treatment and prevention of cancer and inflammatory diseases.

Members of the checkpoint protein kinase class (CHK) are serine / threonine kinases that play an important role in cell cycle progression. Examples of members of the checkpoint class include, but are not limited to, CHK1 and CHK2. Checkpoint kinases are regulatory systems that cooperate with cell cycle progression by affecting the formation, activation and subsequent inactivation of cyclin dependent kinases. Checkpoint kinases can interfere with cell cycle progression at inappropriate points, capture cells while maintaining their metabolic balance, and in some cases induce apoptosis (programmed cell death) when the checkpoint requirements are not met See Nurse, Cell, 91, 865-867, 1997; Hartwell et al., Science, 266, 1821-1828, 1994]. Members of the checkpoint kinase family are involved in cell proliferative disorders, cancer phenotypes and other diseases related to DNA damage and repair (Kumagai and Dunphy Cell Cycle, 5, 1265-1268 (2006); Xiao et al., Molecular Cancer Therapeutics 5, 1935-1943, 2006].

Aurora kinases are a family of multigene mitotic serine-threonine kinases that act as novel oncogene classes. These kinases include Aurora-A and Aurora-B members. Aurora kinases are overactivated and / or overexpressed in some solid tumors, including but not limited to breast cancer, ovarian cancer, prostate cancer, pancreatic cancer and colorectal cancer. In particular, Aurora-A is a centrosome kinase that plays an important role in cell cycle progression and cell proliferation. Aurora-A is located in the 20q13 chromosome region which is frequently amplified in several different malignant tumor types such as colorectal cancer, breast cancer and bladder cancer. In addition, there is a high correlation between Aurora-A and a diploid of high histo-prognostic grade, which makes kinases a potential prognostic vehicle. Inhibition of aurora kinase activity can reduce cell proliferation, tumor growth and potentially tumorigenesis. A detailed description of aurora kinase function is reviewed in the Journal of Cell Science, 119, 3664-3675, 2006.

Rho-linked Coiled Coil-Containing Proteins Serine / Threonine Kinases ROCK-1 and ROCK-2 play an important role in cytoskeleton kinetics by acting as downstream agonists of the RHo / Rac class of cytokine- and growth factor-activated small GTPases I think. ROCK phosphorylates a variety of substrates including, but not limited to, myosin light chain phosphatase, myosin light chain, ezrin-radicin-moesin protein, and LIM (for Linl1, Is11, and Mec3) kinases. Also mediates the formation of actin stress fibers and local attachment in various cell types ROCK plays an important role in cell migration by enhancing cell contraction and is required for tail retraction of monocytes and cancer cells. ROCK inhibitors have also been found to reduce tumor cell transmission in vivo Recent studies have shown that ROCK in cells, including centrolocalization and cell size regulation, may contribute to various physiological and pathological conditions. New actions have been defined (Mueller et al, Nature Reviews Drug Discovery 4, 387-398, 2005.) Members of the ROCK class are cancer and cardiovascular diseases ROCK inhibitors may be useful therapeutic agents for hypertension, angina and asthma In addition, Rho plays an important role in peripheral circulation disorders, arteriosclerosis, inflammation and autoimmune diseases, It is considered a useful target by itself (see Shimokawa et al, Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 1767-1775, 2005).

The limited success of drug treatment methods in spinal cord injury is largely based on the impaired nerve fibers in the white matter of the human spinal cord failing to regrow and reestablish synaptic connections with their disconnected partner neurons. The hostile microenvironment characterized by the presence of various molecular neurite-growth inhibitors in the scar tissue and on the CNS myelin, at the site of the lesion, is involved in the inevitable inhibition of neurite growth. In tissue culture, these inhibitors of neurite growth often induce very pronounced responses, including the formation of neurite and disruption of atrophy. Scar tissue in the human brain and spinal cord is a strong and persistent barrier for any regenerative neural growth and ROCK inhibitors can help damaged fibers grow or germinate beyond such regenerative inhibitory tissue. Various evidence indicates that damage to the brain and spinal cord results in a strongly activated RhoA-ROCK pathway. Due to the continued presence of neurite growth inhibitors at or around the lesion site and in the CNS myelin, this activation potentially persists for a long time, making ROCK inhibition an attractive target for chronic treatment of spinal cord injury as well as acute and subacute treatment. can do. Inhibition of two different small molecule ROCK inhibitors (Y-27632 and fasudil) stimulated or promoted functional recovery in different mouse and rat spinal cord injury models when given either locally or systemic immediately after injury or over weeks as a single dose [ See Dergham, P. et al. "Promote spinal cord repair by targeting the Rho signaling pathway". J. Neurosci. 22, 6570-6577, 2002; Hara, M. et al. "Inhibition of protein kinase 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 improves axon regeneration in the damaged CNS". J. Neurosci. 23, 1416-1423, 2003; Sung, J. K. et al. "Possible Role of RhoA / Rho-Kinase in Rat Spinal Cord Injury". Brain Res. 959, 29-38, 2003; Tanaka, H. et al. "Cytoplasmic p21 (Cipl / WAFl) improves axon regeneration and functional recovery after spinal cord injury in rats". Neuroscience 127, 155-164, 2004]. In these studies, ROCK inhibition not only improved nerve fiber growth beyond the lesion site, but was also neuroprotective and reduced tissue damage and steel formation. Based on these rodent studies, ROCK inhibitors possessing neuroprotective and neuroregeneration-stimulating activity can provide significant benefits in spinal cord injured patients. In addition, they can further enhance tissue protection by normalizing spinal cord blood flow due to their vasodilating effects.

Pathologically, Alzheimer's disease is characterized at the microscopic level by intracellular neurofibrillary tangles and extracellular amyloid aggregates. Neurofibrillary knots contain abnormally phosphorylated tau proteins, microtubule bound proteins and substrates for ROCK, while amyloid aggregates are mainly formed by toxic 42-amino acid long chain amyloid-β (Aβ) peptides. Some NSAIDs have recently been shown to lower Aβ42 by inhibiting the RhoA-ROCK pathway in cells secreting Aβ42 and transgenic PDAPP mice producing large amounts of Aβ42. Zhou, Y. et al. "Nonsteroidal anti-inflammatory drugs can inhibit Rho, lowering amyloidogenic Aβ 42". Science 302, 1215-1217, 2003]. ROCK inhibitor Y-27632 is effective at lowering Aβ42 levels in both cell culture and PDAPP transgenic mice after intra-cerebroventricular injection. Activation of Rho by geranylgeranylpyrophosphate, a lipid required for membrane attachment of Rho, increased Aβ42 levels, which was completely prevented by Y-27632. ROCK inhibitor Y-27632 used in animal Alzheimer's disease models is effective in lowering the amount of toxic Aβ42 levels but has no effect on overall Aβ levels, and these effects of Rho or ROCK inhibitors are one or more of which NSAIDs reduce Aβ42 levels. It is a mechanism. In addition to many other therapeutic interventions, these inhibitors have well-reported advantages of stimulating regenerative growth of neuritis, and therefore it is possible to restore amyloid damaged neuronal circulation by inhibition of this pathway.

Most important in disease pathogenesis is that white blood cells in the brain endothelium migrate to the CNS and inflammatory cascades stimulated by these cells, eventually leading to demyelination and neurite damage and loss of the CNS fibrous canal. Leukocytes require active RhoA and ROCK for their navigation to brain endothelial because their endothelial migration is prevented by the ROCK inhibitor Y-2763294.

The neuroprotective activity of the ROCK inhibitor fasudil and hydroxy-fasudil is not limited to spinal cord injury models, but has also been reported in cerebral infarct models in Gerbils and rats. Toshima Y, Satoh S, Ikegaki I, Asano T. " Neuroprotective Effects of Rho-Kinase Inhibitors and New Models of Brain Microthrombosis in Rats ". Stroke 31, 2245-2250, 2000; Satoh, S. et al. "Pharmaceutical profile of hydroxy fasudil as a selective ROCK inhibitor in ischemic brain injury". Life Sci. 69, 1441-1453, 2001; Kitaoka, Y. et al. "Relevance of RhoA and possible neuroprotective effects of fasudil, a ROCK inhibitor, in NMDA induced neurotoxicity of rat retina". Brain Res. L018, 111-118, 2004]. In the rodent stroke model, some regenerative inhibitors, such as the ROCK-activated NgR1 complex and one of its ligands, NOGO-A, were neutralized within 24 hours or even 1 week after induction of brain stroke, and improved functional recovery was reported. , JK, Kim, JE, Sivula, M. & Strittmatter, SM "Nogo receptor antagonism promotes stroke recovery by enhancing axon formation". J. Neurosci. 24, 6209-6217, 2004; Wiessner, C. et al. "Anti-Nogo-A antibody injection 24 hours after laboratory stroke improved behavioral results and cortical spinal cord formation in normal and spontaneous hypertensive rats". J. Cereb. Blood FlowMetab. 23, 154-165, 2003]. Thus, blocking ROCK is an appropriate neuronal regeneration strategy, and in addition, this strategy has the advantage that the therapeutic range of treatment with these inhibitors may be wider than for thrombotic or neuroprotective stroke treatment options.

Neuronal damage in the human peripheral nervous system or CNS can lead to a chronic pain condition known as neuropathic pain. Inflammatory mediators such as lysophosphatidic acid (LPA) produced in response to injury have been shown to be involved in the initiation of neuropathic pain in a mouse model of peripheral nerve injury. Inoue, M. et al. "Onset of neuropathic pain requires riophosphatidic acid receptor signaling". Nature Med. 10, 712-718, 2004. LPA is present at the lesion sites of the PNS and CNS and exhibits its function by binding to G-protein bound LPA receptors that result in activation of the RhoA-ROCK pathway. ROCK inhibitor Y-27632 prevents the onset of neuropathic pain after nerve injury or LPA injection, while another ROCK inhibitor, H-1152, relaxes neuropathic pain in the L5 spinal cord-nerve transsection model. Tatsumi, S. et al. "Relevance of Rho-kinase in inflammation and neuropathic pain through phosphorylation of myristoylated alanine rich C-kinase substrate (MARCKS)". Neuroscience 131, 491-498, 2005]. These findings indicate that ROCK is a potential drug target involved in the induction and maintenance of persistent pain states.

Moreover, Schueller et al., Abstract 1216, 8th World Congress on Inflammation, Copenhagen, Denmark, June 16-20, 2007, are oral and bioavailable, potent and highly selective inhibitors of ROCK 2. Phosphorus SLx-2119 demonstrated a reduction in atherosclerosis in the presence of significantly elevated lipid levels in a group of 8 ApoE knockout mice, indicating that inhibition of ROCK 2 has the effect of inhibiting atherosclerosis.

70 kDa ribosomal S6 kinase (p70S6K) is activated by a number of mitogens, growth factors and hormones. Activation of p70S6K, which occurs through phosphorylation at multiple sites and major targets of activated kinases, is 40S ribosomal protein S6, a major component of the mechanism involved in protein synthesis in mammalian cells. In addition, p70S6K activation is involved in cell cycle regulation, neuronal cell differentiation, regulation of cell motility and cellular responses important for tumor metastasis, immunity and tissue repair. Modulation of p70S6 kinase activity will also have therapeutic effects on disorders such as cancer, inflammation and various neuropathies. A detailed discussion of p70S6K 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 uniquely expressed structurally active serine / threonine kinase that phosphorylates cell substrates and thereby modulates various cellular functions, and these functions include development, metabolism, gene transcription, protein translation, cellular Skeletal composition, cell cycle regulation and apoptosis are included. GSK-3 was initially described as a major enzyme involved in glycogen metabolism, but is now known to modulate various arrangements of cellular function. Two types of enzymes, GSK-3 + f and GSK-3 + f, were previously identified. The activity of GSK-3 + f is negatively regulated by protein kinase B / Akt and Wnt signaling pathways. Thus, small molecule inhibitors of GSK-3 are useful for the treatment and prevention of neurodegenerative diseases and for various neurological disorders [Gartner et al. J. Cell Science, 2006, 119, 3927-3934. Zhou et al. Neuron, 2004, 42, 897-912], type 2 diabetes, bipolar disorder, stroke, cancer, osteoarthritis, osteoporosis, rheumatoid arthritis [Cuzzocrea et al. Clinical Immunology, 2006, 120, 57-67] and several therapeutic uses, including stimulation of neurogenicity in chronic inflammatory diseases. General review: Kockeritz et al., Current Drug Targets, 7, 1377-1388, 2006 Review of neurological applications: Current Drug Targets, 7 (11), 1389-1397 and 1399-1409, 2006].

Protein kinases have become attractive targets for the treatment of cancer (Fabbro et al., Pharmacology & Therapeutics 93: 79-98, 2002). The relevance of protein kinases in the development of human malignancies may include (1) genomic rearrangements (eg BCR-ABL in chronic myeloid leukemia), and (2) mutations that structurally induce active kinase activity, such as acute myeloid leukemia. And gastrointestinal tumors, (3) deregulation of kinase activity or loss of tumor inhibitor function by activation of oncogenes, for example in cancers with myogenic RAS, and (4) kinase activity by overexpression as in EGFR. It has been proposed to be caused by deregulation and ectopic expression of growth factors that may contribute to the development and maintenance of tumorous phenotypes (Fabbro et al., Pharmacology & Therapeutics 93: 79-98, 2002].

Certain cancers are associated with angiogenesis. Angiogenesis is the growth of new capillary vessels from an existing vascular system (Risau, W., Nature 386: 671-674, 1997). Protein kinases have been found to contribute to the development and maintenance of neovascular phenotypes (Fabbro et al., Pharmacology & Therapeutics 93: 79-98, 2002). For example, VEGF A-D and its four receptors are associated with phenotypes involving neovascularization and enhanced vascular permeability, such as tumor neovascular and lymphocyte neovascularization. Matter, A., Drug Discov. Today 6: 1005-1023, 2001.

It is recognized that a single agent method that specifically targets one kinase or one kinase pathway may be inappropriate for treating diseases and disorders, particularly cancer, for several reasons. The model suggested that 5-7 mutations are required for normal cells to progress to malignant cells. In addition, it is widely recognized that cancer is the result of mutations in protein kinase pathways that are involved in multiple pathways, particularly processes such as cell growth, proliferation, apoptosis, locomotion or invasion. In most cancers, a general feature is the simultaneous overexpression and / or overactivation of various protein kinases, such as receptor and nonreceptor kinases, serine / threonine kinases, PI3 kinases and cell cycle related kinases. Indeed, some of these kinases, alone or in combination with other kinases, are involved in many processes important for cell survival, proliferation, growth and malignant transformation, migration and invasion, metastasis and angiogenesis or inflammation, and associated diseases, disorders And state.

Thus, blocking of one target kinase may be clinically insufficient because there are multiple target kinases that affect the progression of the condition, disease or disorder. In addition, blocking of one target kinase may be clinically insufficient because it can compensate for abundant kinase mediated pathways and target kinases blocked by alternative oncogenes or inflammatory mechanisms. Moreover, the use of a single agent may also increase the chance of developing resistance to that agent.

Cardiovascular disease accounts for about one quarter of the world's total annual deaths. Vascular diseases such as atherosclerosis and restenosis result from dysregulated growth of the vascular wall and restriction of blood flow to vital organs. Various kinase pathways, such as JNK, are activated by atherogenic stimulators and regulated through local cytokine and growth factor production in vascular cells (Yang et al, Immunity 9: 575, 1998). Ischemia and ischemia combined with reperfusion in the heart, kidney or brain lead to cell death and scar formation, which can ultimately lead to congestive heart failure, kidney failure or brain dysfunction. In organ transplantation, reperfusion of previous ischemic donor organs results in acute leukocyte mediated tissue damage and delay in graft function. Ischemic and reperfusion pathways are mediated by various kinases. For example, the JNK pathway is associated with leukocyte mediated tissue damage. Li et al., Mol. Cell. Biol. 16: 5947-5954, 1996. Finally, enhanced apoptosis in cardiac tissue is also associated with kinase activity. Pombo et al., J. Biol. Chem. 269: 26546-26551, 1994].

Claims (156)

A compound of formula 1 or a pharmaceutically acceptable salt thereof.
Formula 1

A is

ego;
R ₁ is hydrogen, alkyl, aryl, heterocycle, heteroaryl, R _a R _b N-, R _c R _d NC (O)-or R _c R _d NS (O) _2- ;
R ₂ is hydrogen, alkyl, alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, heterocyclecarbonyl or R _e R _f N-alkyl-C (O) —;
R ₃ is alkyl, alkoxy, aryl, cyano, cycloalkyl, halogen, haloalkyl, heteroaryl, nitro or R _g R _h N—;
R ₄ is alkyl, alkoxyalkyl, aryl, cycloalkyl, heteroaryl, heterocycle, heterocyclealkyl, R _j R _k N- or R _j R _k N-alkyl-;
R ₅ is alkyl, aryl or heteroaryl;
R ₆ is alkyl, alkoxyalkyl, R _j R _k N-alkyl-, aryl, cycloalkyl or heteroaryl;
R ₇ is alkyl, aryl or heteroaryl;
R _a and R _b are each independently hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, R ₄ -C (O)-or R ₅ -S (O) _2- ;
R _c and R _d are each independently hydrogen, alkyl or heteroaryl;
R _e and R _f are each independently hydrogen, alkyl, arylalkyl, heteroarylalkyl, R ₆ -C (O)-or R ₇ -S (O) _2- ;
R _g and R _h are each independently hydrogen, alkyl or alkylcarbonyl;
R _j and R _k are each independently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heterocycle;
R _i , R _ii , R _iii , R _iv , R _v , R _vi , R _vii , R _viii , R _ix , R _x , R _xi , R _xii , R _xiii , R _xiv , R _xv , R _xvi , R _xvii , R _xviii , R _xix , R _xx , R _xxi , R _xxii and R _xxiii are each independently alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, aryl (hydroxy) alkyl, Aryloxyalkyl, arylcarbonyl, arylthioalkyl, carboxy, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, hetero Cycliccarbonyl, hydroxyalkyl, trialkylsilylalkyl, H ₂ NC (O) -alkyl, Z _a Z _b N-, Z _a Z _b N alkyl, Z _c Z _d NC (O)-or Z _c Z _d NS (O) _2- , where R _xiv , R _xv , R _xvi and R _xvii are May occur at any open valence on the compound of formula (xiv), (xv), (xvi) or (xvii);
Z _a and Z _b are each independently hydrogen, alkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, H ₂ NC (O)-, H ₂ NalkylC (O)-, H ₂ NC (O) -Alkyl, dialkylNC (O)-or dialkylNC (O) -alkyl-;
Z _c and Z _d are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl (hydroxy) alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl, H ₂ NC (O) -alkyl-, dialkylNC (O) -alkyl-, dialkylN-alkyl- or CHZ _e Z _f ;
Z _e is aryl or heteroaryl;
Z _f is heteroarylalkyl, heterocyclealkyl or Z ₁ Z ₂ N-alkyl-;
m is 0, 1 or 2;
a is O or l;
b is 0, 1 or 2;
c is 0, 1, 2 or 3;
d is 0, 1, 2, 3 or 4. The method according to claim 1, wherein A is formula (ii), (iii), (iv), (vii), (x), (xiv), (xv), (xvi), (xvii), (xviii), ( xix), (xx), (xxi), (xxii) or (xxiii). The method of claim 2,
A is formula (ii);

R ₁ is hydrogen, aryl, heteroaryl, heterocycle, R _a R _b N— or R _c R _d NC (O) —;
R ₂ is hydrogen, alkoxycarbonyl, heterocyclecarbonyl, alkylcarbonyl or R _e R _f N-alkyl-C (O) —;
R ₄ is alkyl, alkoxyalkyl, aryl, cycloalkyl, heterocycle, heterocyclealkyl, R _j R _k N- or R _j R _k N-alkyl-;
R ₅ is alkyl, aryl or heteroaryl;
R _a and R _b are each independently hydrogen, arylalkyl, cycloalkylalkyl, R ₄ -C (0)-or R ₅ -S (O) _2- ;
R _c and R _d are each independently hydrogen or heteroaryl;
R _e and R _f are each independently hydrogen or alkyl;
R _j and R _k are each independently hydrogen, alkyl, aryl, cycloalkyl or heterocycle;
R _ii is alkyl, alkoxyalkyl, alkoxycarbonyl, aryl, arylalkyl, aryl (hydroxy) alkyl, aryloxyalkyl, arylcarbonyl, alkoxycarbonylalkyl, arylthioalkyl, carboxy, carboxyalkyl, cycloalkyl, cyclo Alkylalkyl, cycloalkylcarbonyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, trialkylsilylalkyl, Z _a Z _b N-, Z _a Z _b N Alkyl- or Z _c Z _d NC (0)-;
Z _a and Z _b are each independently hydrogen, alkyl or H ₂ NalkylC (O) —;
Z _c and Z _d are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclealkyl, hydroxyalkyl or dialkylN-alkyl-;
m is 0;
b is 0, 1 or 2; The method of claim 3,
R ₁ is hydrogen, heterocycle, R _a R _b N- or R _c R _d NC (O)-;
R ₂ is hydrogen, alkoxycarbonyl or R _e R _f N-alkyl-C (O) —;
R ₄ is alkyl, alkoxyalkyl, aryl, cycloalkyl, heterocycle, heterocyclealkyl, R _j R _k N- or R _j R _k N-alkyl-;
R ₅ is alkyl, aryl or heteroaryl;
R _a and R _b are each independently hydrogen, arylalkyl, cycloalkylalkyl, R ₄ -C (0)-or R ₅ -S (O) _2- ;
R _j and R _k are each independently hydrogen, alkyl, aryl, cycloalkyl or heterocycle;
R _ii is alkyl, alkoxyalkyl, alkoxycarbonylalkyl, aryl, arylalkyl, aryloxyalkyl, arylcarbonyl, arylthioalkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, halogen, hetero Aryl, heteroarylalkyl, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, trialkylsilylalkyl, Z _a Z _b Nalkyl- or Z _c Z _d NC (0)-;
Z _a and Z _b are each independently hydrogen or alkyl;
Z _c and Z _d are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, cycloalkyl or heterocyclealkyl;
m is 0;
b is 0, 1 or 2; The method of claim 3,
R ₁ is hydrogen or R _a R _b N-;
R ₂ is hydrogen;
R ₄ is alkyl, alkoxyalkyl or aryl;
R ₅ is alkyl or aryl;
R _a and R _b are each independently hydrogen, arylalkyl, R ₄ -C (0)-or R ₅ -S (O) _2- ;
R _ii is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl or halogen;
b is 1 or 2;
m is zero. The method of claim 3,
R ₁ is hydrogen, aryl, heteroaryl or R _a R _b N-, wherein heteroaryl is triazole substituted with arylalkyl;
R ₄ is alkoxyalkyl, alkyl, aryl or R _j R _k N—;
R ₅ is alkyl, aryl or heteroaryl;
R _a and R _b are each independently hydrogen, arylalkyl, R ₄ -C (0)-or R ₅ -S (O) _2- ;
R _j and R _k are alkyl;
R _ii is alkyl, alkoxyalkyl, aryl, arylalkyl, aryl (hydroxy) alkyl, aryloxyalkyl, arylcarbonyl, arylthioalkyl, carboxy, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, halogen, heteroaryl , Heteroarylalkyl, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl, Z _a Z _b Nalkyl or Z _c Z _d NC (0)-;
Z _a and Z _b are each independently hydrogen or H ₂ Nalkyl-C (O) —;
Z _c and Z _d are each independently hydrogen, alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl or heterocyclealkyl;
b is 1 or 2;
m is zero. The method of claim 2,
A is formula (iii),

R ₁ is hydrogen or R _a R _b N-;
R ₂ is hydrogen;
R _a and R _b are each hydrogen;
R _iii is arylalkyl;
m is 0;
c is 1; The method of claim 2,
A is formula (iii),

R ₁ is hydrogen or R _a R _b N-;
R ₂ is hydrogen;
R ₄ is R _j R _k N-alkyl-;
R _a and R _b are each independently hydrogen or R ₄ -C (O) —;
R _j And R _k is alkyl;
R _iii is alkoxycarbonylalkyl, alkyl, arylalkyl, cyanoalkyl, heterocyclealkyl or H ₂ NC (O) -alkyl-;
c is 0, 1 or 2;
m is 0. The method of claim 2,
A is formula (iv);

R ₁ is hydrogen or R _a R _b N-;
R ₂ is hydrogen;
R _a and R _b are each hydrogen;
R _iv is alkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, Z _a Z _b Nalkyl or Z _c Z _d NS (O) _2- ;
Z _a and Z _b are each independently hydrogen or alkyl;
Z _c and Z _d are each alkyl;
c is 0 or 1;
m is 0. The method of claim 2,
A is formula (vii),

R ₁ is hydrogen, —NR _a R _b or alkyl;
R ₂ is hydrogen;
R _a and R _b are each hydrogen;
R _vii is alkyl, alkoxycarbonyl, aryl, arylalkyl, cycloalkyl, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl or Z _c Z _d NC (O) —;
Z _c and Z _d are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl (hydroxy) alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl or CHZ _e Z _f ;
Z _e is aryl or heteroaryl;
Z _f is heteroarylalkyl, heterocyclealkyl or Z ₁ Z ₂ N-alkyl-;
b is 1;
m is 0. The method of claim 2,
A is formula (vii),

R ₁ is hydrogen, alkyl or R _a R _b N-;
R ₂ is hydrogen;
R _a and R _b are each hydrogen;
R _vii is alkyl, alkoxycarbonyl, arylalkyl, cycloalkyl, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl or Z _c Z _d NC (O) —;
Z _c and Z _d are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl (hydroxy) alkyl, cycloalkyl, heteroarylalkyl, heterocyclealkyl or hydroxyalkyl;
b is 1;
m is 0. The method of claim 2,
A is formula (vii),

R ₁ is hydrogen or R _a R _b N-;
R ₂ is hydrogen;
R _a and R _b are hydrogen;
R _vii is alkyl or arylalkyl;
b is 1;
m is zero. The method of claim 2,
A is of the formula (x),

R ₁ is hydrogen;
R ₂ is hydrogen;
R _x is alkyl, aryl or Z _a Z _b N-;
Z _a and Z _b are each independently hydrogen, alkyl, aryl or arylalkyl;
b is 1 or 2;
m is 0. The method of claim 2,
A is of formula (xiv),

R ₁ is hydrogen;
R ₂ is hydrogen;
R _xiv is Z _a Z _b N-;
Z _a and Z _b are each independently hydrogen or cycloalkyl;
c is 1;
m is 0. The method of claim 2,
A is of the formula (xv),

R ₁ is hydrogen or R _a R _b N-;
R ₂ is hydrogen;
R _a and R _b are hydrogen;
R _xv is Z _a Z _b N-;
Z _a and Z _b are each independently hydrogen, alkoxycarbonylalkyl, aryl, arylalkyl or cycloalkyl;
d is 0 or 1;
m is 0. The method of claim 2,
A is formula (xvi);

R ₁ is hydrogen;
R ₂ is hydrogen;
R _xvi is Z _a Z _b N-;
Z _a and Z _b are each independently hydrogen or cycloalkyl;
d is 1;
m is 0. The method of claim 2,
A is formula (xvii);

R ₁ is hydrogen;
R ₂ is hydrogen;
R _xvii is Z _a Z _b N- or aryl;
Z _a and Z _b are each independently hydrogen, alkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl or H ₂ NC (O) -alkyl-;
d is 0 or 1;
m is 0. The method of claim 2,
A is formula (xviii);

R ₁ is R _a R _b N-;
R ₂ is hydrogen;
R _a and R _b are each hydrogen;
c is 0;
m is 0. The method of claim 2,
A is formula (xix);

R ₁ is R _a R _b N-;
R ₂ is hydrogen;
R _a and R _b are each hydrogen;
c is 0;
m is 0. The method of claim 2,
A is formula (xx);

R ₁ is R _a R _b N-;
R ₂ is hydrogen;
R ₄ is R _j R _k N-alkyl-;
R _a and R _b are each independently hydrogen or R ₄ -C (O) —;
R _j and R _k are independently alkyl;
R _xx is Z _a Z _b N- or heterocycle;
Z _a and Z _b are each independently hydrogen or alkyl;
c is 0 or 1;
m is 0. The method of claim 2,
A is formula (xxi);

R ₁ is R _a R _b N-;
R ₂ is hydrogen;
R _a and R _b are each hydrogen;
R _xxi is alkoxy;
d is 1;
m is O. The method of claim 2,
A is formula (xxii);

R ₁ is R _a R _b N-;
R ₂ is hydrogen;
R ₄ is R _j R _k N-alkyl-;
R _a and R _b are each independently hydrogen or R ₄ -C (O) —;
R _j and R _k are each independently alkyl;
c is 0;
m is 0. The method of claim 2,
A is formula (xxiii);

R ₁ is R _a R _b N-;
R ₂ is hydrogen;
R _a and R _b are each hydrogen;
c is 0;
m is 0. The method of claim 1,
5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole and 5- (1-benzyl-1H-1,2,3-triazol-5-yl) -1H-indazole;
5- (1H-1,2,3-triazol-5-yl) -1H-indazole;
5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole;
5- [1- (2-methylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (3-methylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (4-methylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (3-methoxybenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (2-fluorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (3-fluorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (4-fluorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (2-chlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (3-chlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (4-chlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (2-bromobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (2-nitrobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (3-nitrobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (4-nitrobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
2-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} benzonitrile;
3-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} benzonitrile;
4-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} benzonitrile;
5- {1- [2- (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;
5- {1- [3- (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;
5- {1- [4- (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;
5- {1- [3- (trifluoromethoxy) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;
5- {1- [4- (trifluoromethoxy) benzyl] -1 H-1,2,3-triazol-4-yl} -1 H-indazole;
5- [1- (4-tert-butylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
Methyl 3-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} benzoate;
Methyl 4-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} benzoate;
5- [1- (2,4-dimethylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (3,5-dimethylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (2,3-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (2,4-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (2,5-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (3,5-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- {1- [2,4-bis (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;
N-cyclohexyl-6- (1H-indazol-5-yl) imidazo [2,1-b] [1,3] thiazol-5-amine;
N-cyclohexyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyridin-3-amine;
N-cyclohexyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrazin-3-amine;
5- [1-benzyl-4- (4-fluorophenyl) -1H-imidazol-5-yl] -1H-indazole;
N- {3- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] propyl} -N, N-dimethylamine;
N-cyclohexyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine;
5- [4- (4-fluorophenyl) -1- (1-phenylethyl) -1H-imidazol-5-yl] -1H-indazole;
2- (1H-indazol-5-yl) -N-isopropylimidazo [1,2-a] pyrimidin-3-amine;
4- (1H-indazol-5-yl) -N-phenyl-1,3-thiazol-2-amine;
5- (2-methyl-1,3-thiazol-4-yl) -1H-indazole;
N-ethyl-4- (1H-indazol-5-yl) -1,3-thiazol-2-amine;
N-benzyl-4- (1H-indazol-5-yl) -1,3-thiazol-2-amine;
4- (1H-indazol-5-yl) -1,3-thiazol-2-amine;
4- (1H-indazol-5-yl) -N- (2-phenylethyl) -1,3-thiazol-2-amine;
N-benzyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine;
N-butyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine;
N- (4-chlorophenyl) -2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine;
2- (1H-indazol-5-yl) -N- (4-methoxyphenyl) imidazo [1,2-a] pyrimidin-3-amine;
2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidine;
Methyl N- [2- (1H-indazol-5-yl) imidazo [1,2-a] pyridin-3-yl] glycinate;
N-benzyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyridin-3-amine;
N- (4-chlorophenyl) -2- (1H-indazol-5-yl) imidazo [1,2-a] pyridin-3-amine;
2- (1H-indazol-5-yl) -N- (4-methoxyphenyl) imidazo [1,2-a] pyridin-3-amine;
Tert-butyl 4- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] piperidine-1-carboxylate;
3,5-bis (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole;
5- (1-benzyl-1H-1,2,3-triazol-4-yl) -3-phenyl-1H-indazole;
5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine;
5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1-[(1-methylpiperidin-4-yl) carbonyl] -1 H-indazol-3-amine ;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-methoxyacetamide;
N^One-[5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N², N²Dimethylglycineamide;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] butanamide;
5- [4- (4-fluorophenyl) -1-piperidin-4-yl-1H-imidazol-5-yl] -1H-indazole;
5- {4- (4-fluorophenyl) -1- [2- (1-methylpyrrolidin-2-yl) ethyl] -1H-imidazol-5-yl} -1H-indazole;
5- {4- (4-fluorophenyl) -1- [3- (4-methylpiperazin-1-yl) propyl] -1H-imidazol-5-yl} -1H-indazole;
Ethyl 5- (1H-indazol-5-yl) isoxazole-3-carboxylate;
5- (1H-indazol-5-yl) -N-methylisoxazole-3-carboxamide;
5- (3-benzylisoxazol-5-yl) -1H-indazole;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide;
5- (3-propylisoxazol-5-yl) -1H-indazole;
N-benzyl-4- (1H-indazol-5-yl) -5-phenyl-1,3-thiazol-2-amine;
4- (1H-indazol-5-yl) -N, 5-diphenyl-1,3-thiazol-2-amine;
5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazole;
5- (1-benzyl-4-cyclopropyl-1H-1,2,3-triazol-5-yl) -1H-indazole;
2- (1H-indazol-5-yl) -3-phenylimidazo [1,2-a] pyrimidine;
5- [1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [3- (piperidin-1-ylcarbonyl) isoxazol-5-yl] -1H-indazole;
5- (1H-indazol-5-yl) -N-phenylisoxazole-3-carboxamide;
N-cyclohexyl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- [3- (piperidin-1-ylmethyl) isoxazol-5-yl] -1H-indazole;
[5- (1H-indazol-5-yl) isoxazol-3-yl] methanol;
5- (1H-indazol-5-yl) -N- (2-methoxyethyl) isoxazole-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-yl) -1H-indazole;
5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine;
5- (1-benzyl-4-cyclopropyl-1H-1,2,3-triazol-5-yl) -1H-indazol-3-amine;
5- (3-isobutylisoxazol-5-yl) -1H-indazol-3-amine;
5- (3-benzylisoxazol-5-yl) -1H-indazol-3-amine;
N- {2- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] ethyl} -N, N-dimethylamine;
5- [4- (4-fluorophenyl) -1- (3-morpholin-4-ylpropyl) -1H-imidazol-5-yl] -1H-indazole;
5- [4- (4-fluorophenyl) -1- (3-pyrrolidin-1-ylpropyl) -1H-imidazol-5-yl] -1H-indazole;
5- {4- (4-fluorophenyl) -1- [2- (4-methylpiperidin-1-yl) ethyl] -1H-imidazol-5-yl} -1H-indazole;
5- [1- (1-benzylpiperidin-4-yl) -4- (4-fluorophenyl) -1H-imidazol-5-yl] -1H-indazole;
5- [4- (4-fluorophenyl) -1- (2-morpholin-4-ylethyl) -1H-imidazol-5-yl] -1H-indazole;
5- [1- (1-benzylpyrrolidin-3-yl) -4- (4-fluorophenyl) -1H-imidazol-5-yl] -1H-indazole;
2- {4- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] piperidin-1-yl} -2-oxo ethanol;
5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine;
2- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] propan-2-ol;
5- [4- (methoxymethyl) -1H-1,2,3-triazol-1-yl] -1H-indazole;
1- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] -1-phenylethanol;
5- (4-propyl-1H-1,2,3-triazol-1-yl) -1H-indazole;
1- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] propan-2-ol;
3- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] propan-1-ol;
1-{[1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] methyl} -1H-1,2,3-benzotriazole;
5- {4-[(phenylthio) methyl] -1H-1,2,3-triazol-1-yl} -1H-indazole;
5- (4-cyclopropyl-1H-1,2,3-triazol-1-yl) -1H-indazole;
5- [4- (2-phenylethyl) -1H-1,2,3-triazol-1-yl] -1H-indazole;
5- [4- (cyclohexylmethyl) -1H-1,2,3-triazol-1-yl] -1H-indazole;
5- (4-cyclopentyl-1H-1,2,3-triazol-1-yl) -1H-indazole;
1- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] cyclohexanol;
5- [4- (phenoxymethyl) -1H-1,2,3-triazol-1-yl] -1H-indazole;
5- {4-[(1,1-dioxydothiomorpholin-4-yl) methyl] -1H-1,2,3-triazol-1-yl} -1H-indazole;
5- [4- (3-phenylpropyl) -1H-1,2,3-triazol-1-yl] -1H-indazole;
[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] (phenyl) methanone;
N, N-diethyl-N-{[1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] methyl} amine;
Ethyl N- [2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-yl] -β-alanineate;
5- (1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl) -1H-indazole;
5- (1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine;
N³-[2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-yl] -β-alanineamide;
5- (1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine;
N- {3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] phenyl} -N '-(3 -Methylphenyl) urea;
5- (1H-indazol-5-yl) -N- (2-isopropoxyethyl) isoxazole-3-carboxamide;
5- [3- (morpholin-4-ylcarbonyl) isoxazol-5-yl] -1H-indazole;
5- (1H-indazol-5-yl) -N- (3-morpholin-4-ylpropyl) isoxazole-3-carboxamide;
N- [2- (1H-imidazol-4-yl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
(3R) -1-{[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} piperidin-3-ol;
1-{[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} piperidine-3-carboxamide;
2- [2- (4-{[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} piperazin-1-yl) ethoxy] ethanol;
5- {3-[(4-methyl-1,4-diazepan-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole;
N- (3-hydroxypropyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-[(1R) -2-hydroxy-1-phenylethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- [3- (1H-imidazol-1-yl) propyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- [3- (2-oxopyrrolidin-1-yl) propyl] isoxazole-3-carboxamide;
N- {2- [4- (aminosulfonyl) phenyl] ethyl} -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] (3-chlorophenyl) methanone;
[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] (cyclopropyl) methanone;
5- [5-cyclopropyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
N^One-{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] methyl} glycinamide;
(4-fluorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5- General] metanon;
(4-chlorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl ] Methanone;
(3-chlorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl ] Methanone;
(2-chlorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl ] Methanone;
Cyclopentyl [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl] methanone;
1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxylic acid;
5- {5- (4-fluorophenyl) -1- [4- (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3- Amines;
5- [1-benzyl-5- (4-fluorophenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine;
[4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl] (tetrahydro-2H -Pyran-4-yl) methanone;
5- [1-benzyl-5- (2-methylphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- {1-benzyl-5-[(4-methylpiperazin-1-yl) carbonyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;
1-{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] carbonyl} piperidin-4-ol;
1-acetyl-5- [5- (4-fluorophenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H -Indazole;
1-benzyl-4- (1H-indazol-5-yl) -N, N-dimethyl-1H-1,2,3-triazole-5-carboxamide;
N, 1-dibenzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide;
N- (2-hydroxy-2-phenylethyl) -5- (1H-indazol-5-yl) -N-methylisoxazole-3-carboxamide;
N-[(1S) -2-hydroxy-1-phenylethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-benzyl-N- (2-hydroxyethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- [1-benzyl-5- (2-methylphenyl) -1H-1,2,3-triazol-4-yl] -3-methyl-1H-indazole;
5- [1-benzyl-5- (2-methylphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine;
2- {2- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] ethyl} -1H-isoindole-1,3 (2H) -dione ;
5- {4-[(2,4-dichlorophenoxy) methyl] -1 H-1,2,3-triazol-1-yl} -1 H-indazole;
5- {4-[(2,6-dichlorophenoxy) methyl] -1H-1,2,3-triazol-1-yl} -1H-indazole;
5- [5- (4-fluorophenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
1-{[1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] methyl} -1H-indazole;
5- [1-benzyl-5- (piperidin-1-ylcarbonyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [5- (2-methylphenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [5- (2-methylphenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3- Amines;
5- [1-benzyl-5- (morpholin-4-ylcarbonyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1-benzyl-5- (4-methoxyphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine;
N-[(1S) -1-benzyl-2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-[(1S, 2R) -2-hydroxy-2,3-dihydro-1H-inden-1-yl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide ;
5- {3-[(3-phenylmorpholin-4-yl) carbonyl] isoxazol-5-yl} -1H-indazole;
N-benzyl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
((1S) -2-{[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} -6,7-dimethoxy-1,2,3,4-tetrahydroiso Quinolin-1-yl) methanol;
N-[(1R) -3-hydroxy-1-phenylpropyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-[(1S) -3-hydroxy-1-phenylpropyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-2,3-dihydro-1H-inden-1-yl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-2,3-dihydro-1H-inden-2-yl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (1-phenylpropyl) isoxazole-3-carboxamide;
5- {1-benzyl-5- [3- (dimethylamino) phenyl] -1 H-1,2,3-triazol-4-yl} -1 H-indazol-3-amine;
5- {1-benzyl-5- [4- (dimethylamino) phenyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3-amine;
N- {3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] phenyl} acetamide;
N- {4- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] phenyl} acetamide;
5- {1-benzyl-5- [3- (1H-pyrazol-1-yl) phenyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3-amine;
5- [1-benzyl-5- (1-methyl-1H-pyrazol-4-yl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine;
3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] -N-phenylbenzamide;
3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] -N-benzylbenzamide;
5- [1-benzyl-5- (1-methyl-1H-indol-5-yl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine;
5- [1-benzyl-5- (3-methoxyphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine;
5- [1-benzyl-5- (3-morpholin-4-ylphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine;
5- [3- (1,3-dihydro-2H-isoindol-2-ylcarbonyl) isoxazol-5-yl] -1H-indazole;
5- {3-[(4-methyl-2-phenylpiperazin-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole;
1-{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] carbonyl} piperidin-4-amine;
N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide;
N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzenesulfonamide;
N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N '-(4-methoxyphenyl) Urea;
N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] butanamide;
N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-methylpropanamide;
N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] cyclopropanecarboxamide;
N- [1-benzoyl-5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -3-fluorobenzamide;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide;
N-benzyl-5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine;
N-[(1R) -1-benzyl-2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1-benzyl-1H-pyrazol-4-yl) -1H-indazole;
N-[(1R) -3-hydroxy-1-phenylpropyl] -5- (3-methyl-1H-indazol-5-yl) isoxazole-3-carboxamide;
3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] phenol;
3- [4- (3-amino-1 H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] benzamide;
5- {1-benzyl-5- [4- (methylsulfonyl) phenyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3-amine;
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-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -4-chlorobenzamide;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] ethanesulfonamide;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzenesulfonamide;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-chlorobenzenesulfonamide;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -3-chlorobenzenesulfonamide;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -4-chlorobenzenesulfonamide;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2,5-dimethylfuran-3- Sulfonamides;
5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N- (2-chlorobenzyl) -1H-indazol-3-amine;
5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N- (3-chlorobenzyl) -1H-indazol-3-amine;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -3-chlorobenzamide;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-puramide;
5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N-ethyl-1H-indazol-3-amine;
5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N- (4-chlorobenzyl) -1H-indazol-3-amine;
5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N- (3-furylmethyl) -1H-indazol-3-amine;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N '-[5-methyl-2 -(Trifluoromethyl) -3-furyl] urea;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -3-puramide;
5- (1H-indazol-5-yl) -N-[(1S) -1-phenylpropyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1R) -1-phenylpropyl] isoxazole-3-carboxamide;
5- (1-benzyl-1H-pyrazol-4-yl) -1H-indazol-3-amine;
1-benzyl-4- (1H-indazol-5-yl) -N-[(2S) -tetrahydrofuran-2-ylmethyl] -1H-1,2,3-triazole-5-carboxamide ;
1-benzyl-4- (1H-indazol-5-yl) -N- (2-isopropoxyethyl) -1H-1,2,3-triazole-5-carboxamide;
1-benzyl-4- (1H-indazol-5-yl) -N-[(2R) -tetrahydrofuran-2-ylmethyl] -1H-1,2,3-triazole-5-carboxamide ;
1-benzyl-4- (1H-indazol-5-yl) -N- (tetrahydrofuran-3-ylmethyl) -1H-1,2,3-triazole-5-carboxamide;
1-benzyl-N-cyclopentyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide;
1-benzyl-N- (cyclopentylmethyl) -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide;
1-benzyl-N-ethyl-4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide;
1-benzyl-4- (1H-indazol-5-yl) -N-isopropyl-N-methyl-1H-1,2,3-triazole-5-carboxamide;
1-benzyl-4- (1H-indazol-5-yl) -N- (2-methoxyethyl) -N-methyl-1H-1,2,3-triazole-5-carboxamide;
1-benzyl-4- (1H-indazol-5-yl) -N-phenyl-1H-1,2,3-triazole-5-carboxamide;
1-benzyl-N- (4-chlorophenyl) -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide;
1-benzyl-4- (1H-indazol-5-yl) -N- (2-morpholin-4-ylethyl) -1H-1,2,3-triazole-5-carboxamide;
1-benzyl-N- [2- (dimethylamino) ethyl] -4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide;
1-benzyl-N- (2-hydroxyethyl) -4- (1H-indazol-5-yl) -N-propyl-1H-1,2,3-triazole-5-carboxamide;
1-benzyl-N- [3- (dimethylamino) propyl] -4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide;
1-benzyl-N- [2- (diethylamino) ethyl] -4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide ;
N, 1-dibenzyl-N-ethyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-carboxamide;
N, 1-dibenzyl-N- (2-hydroxyethyl) -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide;
(3R) -1-{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] carbonyl} piperidin-3-ol ;
1-{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] carbonyl} piperidine-4-carboxamide;
5- {1-benzyl-5-[(2,6-dimethylmorpholin-4-yl) carbonyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;
5- {5-[(4-acetylpiperazin-1-yl) carbonyl] -1-benzyl-1H-1,2,3-triazol-4-yl} -1H-indazole;
5- {1-benzyl-5-[(4-phenylpiperazin-1-yl) carbonyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;
1-benzyl-N-[(1R) -1- (hydroxymethyl) -2-methylpropyl] -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5 Carboxamide;
1-benzyl-N-[(1S) -1- (hydroxymethyl) -2-methylpropyl] -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5 Carboxamide;
1-benzyl-N- [3- (1H-imidazol-1-yl) propyl] -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carbox amides;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N'-ethylurea;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N'-phenylurea;
N-benzyl-N '-[5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] urea;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N '-(2-chlorophenyl) Urea;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N '-(3-chlorophenyl) Urea;
N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N '-(4-chlorophenyl) Urea;
N- [5- (1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide;
3- [4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] propanenitrile;
2- [4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] acetamide;
Methyl 3- [4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] propanoate;
3- [4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] propanamide;
[4- (3-amino-1 H-indazol-5-yl) -1 H-pyrazol-1-yl] acetonitrile;
4- (3-amino-1 H-indazol-5-yl) -N, N-dimethyl-1 H-imidazole-1-sulfonamide;
5-pyrazin-2-yl-1H-indazol-3-amine;
5-thien-2-yl-1H-indazol-3-amine;
5- (2-aminopyrimidin-4-yl) -1H-indazol-3-amine;
5- (2-methoxypyridin-3-yl) -1 H-indazol-3-amine;
5-imidazo [1,2-a] pyridin-3-yl-1H-indazol-3-amine;
N², N²-Dimethyl-N^One-[5- (1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] glycinamide;
5- (1H-pyrazol-5-yl) -1H-indazol-3-amine;
5- (4-methyl-1H-imidazol-5-yl) -1H-indazol-3-amine;
5- (1H-imidazol-4-yl) -1H-indazol-3-amine;
N², N²-Dimethyl-N^One-{5- [1- (3-methylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-yl} glycinamide;
5- (1-benzyl-1H-imidazol-4-yl) -1H-indazol-3-amine;
N^One-{5- [1- (4-tert-butylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-yl} -N², N²Dimethylglycineamide;
N², N²-Dimethyl-N^One-{5- [1- (2-piperidin-1-ylethyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-yl} glycinamide;
N², N²-Dimethyl-N^One-{5- [1- (2-morpholin-4-ylethyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-yl} glycinamide;
N^One-(5- {1- [2- (3,5-dimethylisoxazol-4-yl) ethyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3- Day) -N², N²Dimethylglycineamide;
N^One-(5- {1- [2- (3,5-dimethyl-1H-pyrazol-4-yl) ethyl] -1H-1,2,3-triazol-4-yl} -1H-indazole- 3-day) -N², N²Dimethylglycineamide;
2- (4- {3-[(N, N-dimethylglycyl) amino] -1H-indazol-5-yl} -1H-1,2,3-triazol-1-yl) -2-methyl Propanoic acid;
Ethyl (4- {3-[(N, N-dimethylglycyl) amino] -1H-indazol-5-yl} -1H-1,2,3-triazol-1-yl) acetate;
N², N²-Dimethyl-N^One-(5- {1-[(trimethylsilyl) methyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3-yl) glycinamide;
N^One-[5- (3-furyl) -1 H-indazol-3-yl] -N², N²Dimethylglycineamide;
N², N²-Dimethyl-N^One-[5- (1H-pyrazol-5-yl) -1H-indazol-3-yl] glycinamide;
N², N²-Dimethyl-N^One-(5-pyrimidin-5-yl-1H-indazol-3-yl) glycineamide;
N^One-[5- (2,1,3-benzoxadiazol-5-yl) -1H-indazol-3-yl] -N², N²Dimethylglycineamide;
N², N²-Dimethyl-N^One-[5- (1H-pyrazol-4-yl) -1H-indazol-3-yl] glycinamide;
N², N²-Dimethyl-N^One-[5- (1-methyl-1H-pyrazol-4-yl) -1H-indazol-3-yl] glycinamide;
N^One-[5- (3,5-dimethyl-1H-pyrazol-4-yl) -1H-indazol-3-yl] -N², N²Dimethylglycineamide;
N^One-{5- [2- (dimethylamino) pyrimidin-5-yl] -1H-indazol-3-yl} -N², N²Dimethylglycineamide;
N², N²-Dimethyl-N^One-[5- (2-morpholin-4-ylpyrimidin-5-yl) -1H-indazol-3-yl] glycinamide;
N², N²-Dimethyl-N^One-{5- [1- (2-morpholin-4-ylethyl) -1H-pyrazol-4-yl] -1H-indazol-3-yl} glycinamide;
N^One-[5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N², N²Dimethylglycineamide;
N^One-[5- (1-benzyl-1H-pyrazol-4-yl) -1H-indazol-3-yl] -N², N²Dimethylglycineamide;
N^One-[5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N²Methylglycineamide;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-pyrrolidin-1-ylacetamide;
N^One-[5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N²Cyclopentylglycineamide;
N^One-[5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N²Cyclopropylglycineamide;
N^One-[5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N²-Tetrahydro-2H-pyran-4-ylglycinamide;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2- (3-hydroxypyrrolidin-1-yl Acetamide;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2- (3-hydroxypiperidin-1-yl Acetamide;
N^One-[5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N³, N³-Dimethyl-β-alanineamide;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-morpholin-4-ylacetamide;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2- (4-methylpiperazin-1-yl) acet amides;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2- (3-oxopiperazin-1-yl) acet amides;
N^One-[5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N²Isopropylglycineamide;
N^One-[5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N²Cyclohexylglycineamide;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] acetamide;
N^One-[5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N²Cyclobutylglycineamide;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N'-propylurea;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] ethanesulfonamide;
5- (1-benzyl-1H-1,2,3-triazol-4-yl) -N- (cyclopropylmethyl) -1H-indazol-3-amine;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N'-ethylurea;
1- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] pyrrolidin-2-one;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -4- (dimethylamino) butanamide;
N-3,4-dihydro-1H-isochromen-4-yl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- (cyclohexylmethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- (3-chlorobenzyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (2-methoxybenzyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- [2- (trifluoromethyl) benzyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- [3- (trifluoromethyl) benzyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- [4- (trifluoromethyl) benzyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (pyridin-2-ylmethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (pyridin-3-ylmethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (pyridin-4-ylmethyl) isoxazole-3-carboxamide;
N- (2-chlorobenzyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- (4-chlorobenzyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (1-phenyl-2-piperidin-1-ylethyl) isoxazole-3-carboxamide;
N- [2- (1H-imidazol-1-yl) -1-phenylethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (2-morpholin-4-yl-1-phenylethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- [2- (4-methylpiperazin-1-yl) -1-phenylethyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (1-phenyl-2-pyrrolidin-1-ylethyl) isoxazole-3-carboxamide;
Tert-butyl 2-({[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} amino) -2-phenylethylcarbamate;
5- (1H-indazol-5-yl) -N- (1-naphthylmethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (2-phenylethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (2-pyridin-2-ylethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (2-pyridin-3-ylethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (2-pyridin-4-ylethyl) isoxazole-3-carboxamide;
N- [2- (2-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- [2- (3-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- [2- (4-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-benzyl-N-ethyl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-methyl-N- (1-naphthylmethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-methyl-N- (2-phenylethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-methyl-N- (2-pyridin-2-ylethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1R) -1-phenylethyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-1,2,3,4-tetrahydronaphthalen-1-ylisoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1S) -1- (1-naphthyl) ethyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1R) -1- (1-naphthyl) ethyl] isoxazole-3-carboxamide;
N- [3- (dimethylamino) -1-phenylpropyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- (2,3-dihydro-1,4-benzodioxin-5-ylmethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- (3,4-dihydro-2H-1,5-benzodioxepin-6-ylmethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1-methyl-1H-indol-4-yl) methyl] isoxazole-3-carboxamide;
5- {3-[(3-phenylpyrrolidin-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole;
5- {3-[(2-phenylpyrrolidin-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole;
5- {3-[(2-phenylpiperidin-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole;
5- (1H-indazol-5-yl) -N-[(1S) -1-phenylethyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1R) -1- (4-methylphenyl) ethyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1S) -1- (4-methylphenyl) ethyl] isoxazole-3-carboxamide;
N-[(1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide ;
N-[(1R, 2R) -2-hydroxy-2,3-dihydro-1H-inden-1-yl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide ;
N-[(1R) -1- (4-bromophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-[(1S) -1- (4-bromophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-[(1R) -1- (4-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-[(1S) -1- (4-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1S) -1- (2-naphthyl) ethyl] isoxazole-3-carboxamide;
N- [1- (4-ethoxyphenyl) -2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- [2-hydroxy-1- (4-isopropylphenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- [1- (3,4-dimethylphenyl) -2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- [2-hydroxy-1- (2-methoxyphenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- [2-hydroxy-1- (4-methylphenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1R) -1- (2-methoxyphenyl) ethyl] isoxazole-3-carboxamide;
N-[(1S) -1- (3,4-difluorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1R) -1- (3-methoxyphenyl) ethyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-{(1R) -1- [3- (trifluoromethyl) phenyl] ethyl} isoxazole-3-carboxamide;
N- [1- (2,3-dihydro-1,4-benzodioxin-6-yl) ethyl] -5- (1H-indazol-5-yl) isoxazole-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-yl) -3-[({[6- (trifluoromethyl) pyridin-2-yl] amino} carbo Yl) amino] -1 H-indazole-1-carboxylate;
5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1-[(1-methylpiperidin-2-yl) carbonyl] -1H-indazol-3-amine ;
5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1-[(dimethylamino) acetyl] -1H-indazol-3-amine;
Level 3-Butyl 3-amino-5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-1-carboxylate;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-piperidin-1-ylacetamide;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-morpholin-4-ylacetamide; or
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -1-methylpiperidine-2-carboxamide, compound. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula 1 according to claim 1 together with a pharmaceutically suitable carrier. Glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, comprising administering a therapeutically effective amount of a compound of formula 1 according to claim 1 , KDR, MK2, JNKl, aurora, pim 1 and nek 2 method of inhibition. Administering a therapeutically effective amount of a compound of formula 1 according to claim 4, wherein the inhibition of GSK-3 kinase is useful for the treatment or prevention of a disease or disorder regulated by GSK-3 kinase in a person in need thereof. Inhibition method of GSK-3 kinase. The method of claim 27, wherein the inhibition of GSK-3 kinase is a stimulus of neuroregeneration and neurodegenerative diseases, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, multiple sclerosis, cognitive and attention deficits associated with Alzheimer's disease, acute and chronic Useful methods for the treatment and prevention of neurodegenerative diseases, dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord injury, peripheral neuropathy, retinopathy and glaucoma. The method of claim 28, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathy. 30. The method of claim 29, wherein the tau disease is frontotemporopariental dementia, corticobasal degeneration, Pick's disease and progressive nucleus palsy. The method of claim 28, wherein the dementia is vascular dementia. The method of claim 28, wherein the cerebrovascular accident is age related macular degeneration. The method of claim 27, wherein the inhibition of GSK-3 kinase is useful for the treatment of non-insulin dependent diabetes and obesity, mood swings, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis. The method of claim 33, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and virus induced tumor. Administering a therapeutically effective amount of a compound of formula 1 according to claim 8, wherein the inhibition of GSK-3 kinase is useful for the treatment or prevention of a disease or disorder modulated by GSK-3 kinase in a person in need thereof. Inhibition method of GSK-3 kinase. 36. The method of claim 35, wherein the inhibition of GSK-3 kinase is a stimulus of neuronal regeneration and 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 Useful methods for the treatment and prevention of dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord injury, peripheral neuropathy, retinopathy and glaucoma. The method of claim 36, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathy. 38. The method of claim 37, wherein the tauopathy is anterior temporal parietal lobe dementia, cortical basal ganglia degeneration, pick disease, and advanced nuclear palsy. The method of claim 36, wherein the dementia is vascular dementia. 37. The method of claim 36, wherein the cerebrovascular accident is age related macular degeneration. 36. The method of claim 35, wherein the inhibition of GSK-3 kinase is useful for the treatment of non-insulin dependent diabetes and obesity, mood swings, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis. 42. The method of claim 41, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and virus induced tumor. A method comprising the administration of a therapeutically effective amount of a compound of formula 1 according to claim 9, wherein the inhibition of GSK-3 kinase is useful for the treatment or prevention of a disease or disorder regulated by GSK-3 kinase in a person in need thereof. Inhibition method of GSK-3 kinase. The method of claim 43, wherein the inhibition of GSK-3 kinase is a stimulus of neuronal regeneration and 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 Useful methods for the treatment and prevention of dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord injury, peripheral neuropathy, retinopathy and glaucoma. 45. The method of claim 44, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathy. 46. The method of claim 45, wherein the tau disease is anterior temporal parietal lobe dementia, cortical basal ganglia degeneration, pick disease, and advanced nuclear palsy. 45. The method of claim 44, wherein the dementia is vascular dementia. 45. The method of claim 44, wherein the cerebrovascular accident is age related macular degeneration. The method of claim 43, wherein the inhibition of GSK-3 kinase is useful for the treatment of non-insulin dependent diabetes and obesity, mood swings, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis. The method of claim 49, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and virus-induced tumor. Administering a therapeutically effective amount of a compound of formula 1 according to claim 11, wherein the inhibition of GSK-3 kinase is useful for the treatment or prevention of a disease or disorder regulated by GSK-3 kinase in a person in need thereof. Inhibition method of GSK-3 kinase. 52. The method of claim 51, wherein the inhibition of GSK-3 kinase is a stimulus of neuronal regeneration and 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 Useful methods for the treatment and prevention of dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord injury, peripheral neuropathy, retinopathy and glaucoma. The method of claim 52, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathy. 54. The method of claim 53, wherein the tau disease is anterior temporal parietal lobe dementia, cortical basal ganglia degeneration, pick disease, and advanced nuclear palsy. The method of claim 52, wherein the dementia is vascular dementia. The method of claim 52, wherein the cerebrovascular accident is age related macular degeneration. 52. The method of claim 51, wherein the inhibition of GSK-3 kinase is useful for the treatment of non-insulin dependent diabetes and obesity, mood swings, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis. 58. The method of claim 57, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and virus induced tumor. Administering a therapeutically effective amount of a compound of formula 1 according to claim 14, wherein the inhibition of GSK-3 kinase is useful for the treatment or prevention of a disease or disorder modulated by GSK-3 kinase in a person in need thereof. Inhibition method of GSK-3 kinase. 60. The method of claim 59, wherein the inhibition of GSK-3 kinase is a stimulus of neuronal regeneration and 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 Useful methods for the treatment and prevention of dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord injury, peripheral neuropathy, retinopathy and glaucoma. 61. The method of claim 60, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathy. 62. The method of claim 61, wherein the tau disease is anterior temporal parietal lobe dementia, cortical basal ganglia degeneration, pick disease, and advanced nuclear palsy. 61. The method of claim 60, wherein the dementia is vascular dementia. 61. The method of claim 60, wherein the cerebrovascular accident is age related macular degeneration. 60. The method of claim 59, wherein the inhibition of GSK-3 kinase is useful for the treatment of non-insulin dependent diabetes and obesity, mood swings, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis. 66. The method of claim 65, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and virus induced tumor. Comprising administering a therapeutically effective amount of a compound of formula 1 according to claim 15, wherein the inhibition of GSK-3 kinase is useful for the treatment or prevention of a disease or disorder regulated by GSK-3 kinase in a person in need thereof. Inhibition method of GSK-3 kinase. 68. The method of claim 67, wherein the inhibition of GSK-3 kinase is a stimulus of neuronal regeneration and 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 Useful methods for the treatment and prevention of dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord injury, peripheral neuropathy, retinopathy and glaucoma. The method of claim 68, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathy. 70. The method of claim 69, wherein the tau disease is anterior temporal parietal lobe dementia, cortical basal ganglia degeneration, pick disease, and advanced nuclear palsy. 69. The method of claim 68, wherein the dementia is vascular dementia. The method of claim 68, wherein the cerebrovascular accident is age related macular degeneration. The method of claim 67, wherein the inhibition of GSK-3 kinase is useful for the treatment of non-insulin dependent diabetes and obesity, mood swings, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis, and osteoporosis. The method of claim 73, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and a virus-induced tumor. Comprising administering a therapeutically effective amount of a compound of formula 1 according to claim 16, wherein the inhibition of GSK-3 kinase is useful for the treatment or prevention of a disease or disorder regulated by GSK-3 kinase in a person in need thereof. Inhibition method of GSK-3 kinase. 76. The method of claim 75, wherein the inhibition of GSK-3 kinase is a stimulus of neuronal regeneration and 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 Useful methods for the treatment and prevention of dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord injury, peripheral neuropathy, retinopathy and glaucoma. 77. The method of claim 76, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathy. 78. The method of claim 77, wherein the tau disease is anterior temporal parietal lobe dementia, cortical basal ganglia degeneration, pick disease, and advanced nuclear palsy. 77. The method of claim 76, wherein the dementia is vascular dementia. 77. The method of claim 76, wherein the cerebrovascular accident is age related macular degeneration. 76. The method of claim 75, wherein the inhibition of GSK-3 kinase is useful for the treatment of non-insulin dependent diabetes and obesity, mood swings, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis. 82. The method of claim 81, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and virus induced tumor. A method comprising the administration of a therapeutically effective amount of a compound of formula 1 according to claim 17, wherein the inhibition of GSK-3 kinase is useful for the treatment or prevention of a disease or disorder regulated by GSK-3 kinase in a person in need thereof. Inhibition method of GSK-3 kinase. 84. The method of claim 83, wherein the inhibition of GSK-3 kinase is a stimulus of neuronal regeneration and 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 Useful methods for the treatment and prevention of dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord injury, peripheral neuropathy, retinopathy and glaucoma. 85. The method of claim 84, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathy. 86. The method of claim 85, wherein the tau disease is anterior temporal parietal lobe dementia, cortical basal ganglia degeneration, pick disease, and advanced nuclear palsy. 85. The method of claim 84, wherein the dementia is vascular dementia. 85. The method of claim 84, wherein the cerebrovascular accident is age related macular degeneration. 84. The method of claim 83, wherein the inhibition of GSK-3 kinase is useful for the treatment of non-insulin dependent diabetes and obesity, mood swings, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis. 90. The method of claim 89, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and virus induced tumor. Comprising administering a therapeutically effective amount of a compound of formula 1 according to claim 18, wherein the inhibition of GSK-3 kinase is useful for the treatment or prevention of a disease or disorder regulated by GSK-3 kinase in a person in need thereof. Inhibition method of GSK-3 kinase. 92. The method according to claim 91, wherein the inhibition of GSK-3 kinase is a stimulus of neuronal regeneration and 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 Useful methods for the treatment and prevention of dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord injury, peripheral neuropathy, retinopathy and glaucoma. 93. The method of claim 92, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathy. 94. The method of claim 93, wherein the tau disease is anterior temporal parietal lobe dementia, cortical basal ganglia degeneration, pick disease, and advanced nuclear palsy. 93. The method of claim 92, wherein the dementia is vascular dementia. 93. The method of claim 92, wherein the cerebrovascular accident is age related macular degeneration. 92. The method of claim 91, wherein the inhibition of GSK-3 kinase is useful for the treatment of non-insulin dependent diabetes and obesity, mood swings, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis. 98. The method of claim 97, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and virus induced tumor. A method comprising the administration of a therapeutically effective amount of a compound of formula 1 according to claim 19, wherein the inhibition of GSK-3 kinase is useful for the treatment or prevention of a disease or disorder regulated by GSK-3 kinase in a person in need thereof. Inhibition method of GSK-3 kinase. The method of claim 99, wherein the inhibition of GSK-3 kinase is a stimulus of neuronal regeneration and 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 Useful methods for the treatment and prevention of dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord injury, peripheral neuropathy, retinopathy and glaucoma. 101. The method of claim 100, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathy. 102. The method of claim 101, wherein the tau disease is anterior temporal parietal lobe dementia, cortical basal ganglia degeneration, pick disease, and advanced nuclear palsy. 101. The method of claim 100, wherein the dementia is vascular dementia. 101. The method of claim 100, wherein the cerebrovascular accident is age related macular degeneration. The method of claim 99, wherein the inhibition of GSK-3 kinase is useful for the treatment of non-insulin dependent diabetes and obesity, mood swings, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis. 107. The method of claim 105, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and virus induced tumor. A method comprising the administration of a therapeutically effective amount of a compound of formula 1 according to claim 20, wherein the inhibition of GSK-3 kinase is useful for the treatment or prevention of a disease or disorder regulated by GSK-3 kinase in a person in need thereof. Inhibition method of GSK-3 kinase. 108. The method of claim 107, wherein the inhibition of GSK-3 kinase is a stimulus of neuronal regeneration and 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 Useful methods for the treatment and prevention of dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord injury, peripheral neuropathy, retinopathy and glaucoma. 109. The method of claim 108, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathy. 109. The method of claim 109, wherein the tau disease is anterior temporal parietal lobe dementia, cortical basal ganglia degeneration, pick disease, and advanced nuclear palsy. 109. The method of claim 108, wherein the dementia is vascular dementia. 109. The method of claim 108, wherein the cerebrovascular accident is age related macular degeneration. 108. The method of claim 107, wherein the inhibition of GSK-3 kinase is useful for the treatment of non-insulin dependent diabetes and obesity, mood swings, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis. 116. The method of claim 113, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and virus induced tumor. Administering a therapeutically effective amount of a compound of formula 1 according to claim 21, wherein the inhibition of GSK-3 kinase is useful for the treatment or prevention of a disease or disorder modulated by GSK-3 kinase in a person in need thereof. Inhibition method of GSK-3 kinase. 117. The method of claim 115, wherein the inhibition of GSK-3 kinase comprises stimulation of neuronal regeneration and 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 Useful methods for the treatment and prevention of dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord injury, peripheral neuropathy, retinopathy and glaucoma. 116. The method of claim 116, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathy. 118. The method of claim 117, wherein the tau disease is anterior temporal parietal lobe dementia, cortical basal ganglia degeneration, pick disease, and advanced nuclear palsy. 116. The method of claim 116, wherein the dementia is vascular dementia. 116. The method of claim 116, wherein the cerebrovascular accident is age related macular degeneration. 116. The method of claim 115, wherein the inhibition of GSK-3 kinase is useful in the treatment of non-insulin dependent diabetes and obesity, mood swings, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis. 124. The method of claim 121, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and virus induced tumor. Comprising administering a therapeutically effective amount of a compound of formula 1 according to claim 22, wherein the inhibition of GSK-3 kinase is useful for the treatment or prevention of a disease or disorder regulated by GSK-3 kinase in a person in need thereof. Inhibition method of GSK-3 kinase. 124. The method of claim 123, wherein the inhibition of GSK-3 kinase is a stimulus of neuronal regeneration and 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 Useful methods for the treatment and prevention of dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord injury, peripheral neuropathy, retinopathy and glaucoma. 124. The method of claim 124, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathy. 126. The method of claim 125, wherein the tau disease is anterior temporal parietal lobe dementia, cortical basal ganglia degeneration, pick disease, and advanced nuclear palsy. 124. The method of claim 124, wherein the dementia is vascular dementia. 124. The method of claim 124, wherein the cerebrovascular accident is age related macular degeneration. 123. The method of claim 123, wherein the inhibition of GSK-3 kinase is useful for the treatment of non-insulin dependent diabetes and obesity, mood swings, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis. 129. The method of claim 129, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and virus induced tumor. Administering a therapeutically effective amount of a compound of formula 1 according to claim 23, wherein the inhibition of GSK-3 kinase is useful for the treatment or prevention of a disease or disorder regulated by GSK-3 kinase in a person in need thereof. Inhibition method of GSK-3 kinase. 131. The method of claim 131, wherein the inhibition of GSK-3 kinase is a stimulus of neuronal regeneration and 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 Useful methods for the treatment and prevention of dementia, acute stroke and other traumatic injuries, cerebrovascular accidents, brain and spinal cord injury, peripheral neuropathy, retinopathy and glaucoma. 134. The method of claim 132, wherein the acute and chronic neurodegenerative diseases are Parkinson's disease and tauopathy. 138. The method of claim 133, wherein the tau disease is anterior temporal parietal lobe dementia, cortical basal ganglia degeneration, pick disease, and advanced nuclear palsy. 134. The method of claim 132, wherein the dementia is vascular dementia. 134. The method of claim 132, wherein the cerebrovascular accident is age related macular degeneration. 134. The method of claim 131, wherein the inhibition of GSK-3 kinase is useful for the treatment of non-insulin dependent diabetes and obesity, mood swings, schizophrenia, alopecia, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis. 138. The method of claim 137, wherein the cancer is breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and virus induced tumor. Inhibition of JAK kinase comprising administering a therapeutically effective amount of a compound of formula 1 according to claim 1, wherein the inhibition of JAK kinase is useful for the treatment or prevention of a disease or disorder regulated by JAK kinase in a person in need thereof. Way. 139. The method according to claim 139, wherein the inhibition of JAK kinase, comprising administering an effective amount of the compound according to claim 5 to a mammalian organism in need thereof, comprises an autoimmune disease associated with abnormal activity of JAK kinase, myeloproliferative syndrome and Useful method for the treatment of cardiovascular diseases. 141. The method of claim 140, wherein the myeloproliferative syndrome is leukemia, lymphoma or cancer. 142. The method of claim 141, wherein the cancer is blood cancer. 141. The method of claim 140, wherein the autoimmune disease is rheumatoid arthritis and psoriasis. 139. The method according to claim 139, wherein the inhibition of JAK kinase, comprising administering an effective amount of a compound according to claim 8 to a mammalian organism in need thereof, comprises an autoimmune disease associated with abnormal activity of JAK kinase, myeloproliferative syndrome and Useful method for the treatment of cardiovascular diseases. 145. The method of claim 144, wherein the myeloproliferative syndrome is leukemia, lymphoma or cancer. 145. The method of claim 145, wherein the cancer is blood cancer. 145. The method of claim 144, wherein the autoimmune disease is rheumatoid arthritis and psoriasis. 139. The method according to claim 139, wherein the inhibition of JAK kinase, comprising administering an effective amount of the compound according to claim 12 to a mammalian organism in need thereof, comprises an autoimmune disease associated with abnormal activity of JAK kinase, myeloproliferative syndrome and Useful method for the treatment of cardiovascular diseases. 148. The method of claim 148, wherein the myeloproliferative syndrome is leukemia, lymphoma or cancer. 149. The method of claim 149, wherein the cancer is blood cancer. 148. The method of claim 148, wherein the autoimmune disease is rheumatoid arthritis and psoriasis. Inhibition of ROCK kinase is neurodegenerative, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, lung inflammation associated with asthma, treatment of asthma, accelerated regeneration and improved recovery after spinal cord injury, multiple sclerosis, pain, hypertension, chronic and congestive Sexual heart failure, hypertrophy, restenosis, chronic renal failure, cerebrovascular spasms after subarachnoid hemorrhage, pulmonary hypertension, atherosclerosis, male erectile dysfunction, female sexual dysfunction, overactive bladder syndrome, induction of new axon growth, within the CNS Axonal rewiring across the lesions, 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, antiviral A therapeutically effective amount of Formula 1 according to claim 3 useful for sex and antimicrobial applications, insulin resistance, diabetes, cystic fibrosis, angina and atherosclerosis. A method of inhibiting ROCK kinase comprising administering a compound. Inhibition of ROCK kinase is neurodegenerative, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, lung inflammation associated with asthma, treatment of asthma, accelerated regeneration and improved recovery after spinal cord injury, multiple sclerosis, pain, hypertension, chronic and congestive Sexual heart failure, hypertrophy, restenosis, chronic renal failure, cerebrovascular spasms after subarachnoid hemorrhage, pulmonary hypertension, atherosclerosis, male erectile dysfunction, female sexual dysfunction, overactive bladder syndrome, induction of new axon growth, within the CNS Axon redistribution across lesions, 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, antiviral and antimicrobial applications Administering a therapeutically effective amount of a compound of formula 1 according to claim 6, useful for insulin resistance, diabetes, cystic fibrosis, angina and atherosclerosis Methods of Suppressing ROCK Kinases Including Filtration. Inhibition of ROCK kinase is neurodegenerative, inflammatory and demyelinating disease, Alzheimer's disease, stroke, lung inflammation associated with asthma, treatment of asthma, accelerated regeneration and improved function recovery after spinal cord injury, multiple sclerosis, pain, hypertension, chronic and congestion Sexual heart failure, hypertrophy, restenosis, chronic renal failure, cerebrovascular spasms after subarachnoid hemorrhage, pulmonary hypertension, atherosclerosis, male erectile dysfunction, female sexual dysfunction, overactive bladder syndrome, induction of new axon growth, within the CNS Axon redistribution across lesions, 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, antiviral and antimicrobial applications Administering a therapeutically effective amount of a compound of formula 1 according to claim 7, useful for insulin resistance, diabetes, cystic fibrosis, angina and atherosclerosis Methods of Suppressing ROCK Kinases Including Filtration. Inhibition of ROCK kinase is neurodegenerative, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, lung inflammation associated with asthma, treatment of asthma, accelerated regeneration and improved recovery after spinal cord injury, multiple sclerosis, pain, hypertension, chronic and congestive Sexual heart failure, hypertrophy, restenosis, chronic renal failure, cerebrovascular spasms after subarachnoid hemorrhage, pulmonary hypertension, atherosclerosis, male erectile dysfunction, female sexual dysfunction, overactive bladder syndrome, induction of new axon growth, within the CNS Axon redistribution across lesions, 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, antiviral and antimicrobial applications A therapeutically effective amount of a compound of formula 1 according to claim 10, useful for insulin resistance, diabetes, cystic fibrosis, angina and atherosclerosis Method of inhibiting ROCK kinase comprising a yeoham. Inhibition of ROCK kinase is neurodegenerative, inflammatory and demyelinating diseases, Alzheimer's disease, stroke, lung inflammation associated with asthma, treatment of asthma, accelerated regeneration and improved recovery after spinal cord injury, multiple sclerosis, pain, hypertension, chronic and congestive Sexual heart failure, hypertrophy, restenosis, chronic renal failure, cerebrovascular spasms after subarachnoid hemorrhage, pulmonary hypertension, atherosclerosis, male erectile dysfunction, female sexual dysfunction, overactive bladder syndrome, induction of new axon growth, within the CNS Axon redistribution across lesions, 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, antiviral and antimicrobial applications A therapeutically effective amount of a compound of formula 1 according to claim 13, useful for insulin resistance, diabetes, cystic fibrosis, angina and atherosclerosis Method of inhibiting ROCK kinase comprising a yeoham.