RU2487873C2 - 5-substituted indazole as kinase inhibitors - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I)

or pharmaceutically acceptable salts thereof wherein A, R₁, R₂, R₃ and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of 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.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

Description

Field of Invention

The present invention relates to 5-substituted indazole-containing compounds, methods for producing such compounds, compositions containing such compounds that are useful for inhibiting kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNKl, aurora, pim 1 and nek 2.

BACKGROUND OF THE INVENTION

Protein kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to tyrosine, serine, threonine or histidine residues located on a protein substrate. Obviously, protein kinases play a role in normal cell growth. Many growth factor receptor proteins contain intracellular domains that function as protein kinases, and it is through this function that they transmit signals. The interaction of growth factors with their receptors is a necessary event in the normal regulation of cell growth, and the state of phosphorylation of substrate proteins is often associated with modulation of cell growth.

It is well known that abnormal protein phosphorylation can be directly associated with some disease states or it can be a factor contributing to the onset of such diseases. As a result, protein kinases are the targets of new pharmaceutical research (Cohen, P. Nature Reviews Drug Discovery, 1: 309-315, 2002). Various protein kinase inhibitors are clinically used to treat a wide range of different diseases, such as cancer, chronic inflammatory diseases, diabetes and stroke.

Protein kinases are a large and diverse family of enzymes that catalyze protein phosphorylation and play a key role in cell signaling. Protein kinases can exhibit a positive or negative regulatory effect, depending on their target proteins. Protein kinases are involved in specific signaling pathways that regulate cellular functions, such as, but not limited to, metabolism, cell cycle development, cell adhesion, vascular function, apoptosis and angiogenesis. As a result, impaired cellular signaling activity is associated with many diseases, the most characteristic of which include cancer and diabetes. The regulation of signal transduction by cytokines and the association of signal molecules with proto-oncogenes and tumor suppressor genes have been sufficiently documented. Similarly, the link between diabetes, viral infections, and related conditions is also attributed to the regulation of protein kinases.

Since protein kinases regulate almost every cellular process, including metabolism, cell proliferation, cell differentiation, and cell survival, they are attractive targets for therapeutic intervention in various disease states. For example, cell cycle control and angiogenesis, where protein kinases play an important role, are cellular processes associated with various disease states, such as, but not limited to, cancer, inflammatory diseases, abnormal angiogenesis and related diseases, atherosclerosis, yellow degeneration spots, diabetes, obesity and pain.

Finding out the intricate pathways of protein kinases and the complexity of the relationships and interactions between different protein kinases and kinase pathways underscores the importance of developing pharmaceuticals that can act as modulators, regulators, or inhibitors of protein kinases that have beneficial activity on various kinases or different kinase pathways.

Therefore, it is assumed that due to the complexity of the intracellular signaling cascades of protein kinase pathways, agents that affect different pathways simultaneously may be necessary for significant clinical activity. Although it is believed that a single agent that provides combined effects is attractive, there is a need for identification and application of individual agents that target the desired combinations and various pathways that are clinically effective in a particular disease.

Glycogen synthase kinase-3 (GSK-3) is a serine / threonine kinase encoded by two isoforms, GSK-3α and GSK-3β, with a molecular weight of 51 and 47 kDa, respectively. They have 97% sequence similarity in their kinase catalytic domains. The GSK-3α isoform has an elongated glycine-enriched N-terminal tail. A minor GSK-3β splicing variant was identified (expressed at ~ 15% of the total) with an insertion of 13 amino acids in the kinase domain. This variant had reduced tau activity. GSK-3 has survived in many species during evolution, and is still present in all mammals with high homology in the kinase domain. Both isoforms are expressed in many mammalian tissues, including the brain. Pharmacological inhibitors of GSK-3 cannot selectively inhibit one of the isoforms.

GSK-3β plays an important role in controlling metabolism, differentiation and survival. It was originally identified as an enzyme capable of phosphorylating and therefore inhibiting glycogen synthase. Subsequently, GSK-3β was found to be identical to tau protein kinase 1 (TPK1), an enzyme that phosphorylates tau protein in epitopes that have also been found to be hyperphosphorylated in Alzheimer's disease and some taupathies.

Interestingly, phosphorylation of GSK-3β protein kinase B (AKT) leads to a loss of kinase activity, and it has been suggested that this inhibition may mediate some effects of neurotrophic factors. Moreover, the phosphorylation of β-catenin (a protein involved in cell survival) by GSK-3β leads to its destruction by a proteasome-dependent ubiquitinylation.

Therefore, it turned out that inhibition of GSK-3β activity can lead to neurotrophic activity. There is evidence that lithium, a non-competitive GSK-3β inhibitor, enhances neuritogenesis in some models and can also enhance nerve cell survival through the induction of survival factors such as Bcl-2 and the inhibition of the expression of proapoptotic factors such as P53 and Bax.

Further studies have shown that β-amyloid increases GSK-3β activity and tau protein phosphorylation. Moreover, this hyperphosphorylation as well as the neurotoxic effects of β-amyloid are blocked by lithium chloride and GSK-3β antisense mRNA. Taken together, these observations suggest that GSK-3β can be the link between the two main pathological processes in Alzheimer's disease: abnormal APP processing (amyloid precursor protein) and tau protein hyperphosphorylation.

These experimental observations show that GSK-3β can be used in the prevention and treatment of neuropathological consequences and cognitive and attention deficits associated with Alzheimer's disease, as well as other acute and chronic neurodegenerative diseases. These include, but are not limited to: Parkinson's disease, taupathy (eg, frontotemporal-parietal dementia, corticobasal degeneration, Peak disease, progressive supranuclear palsy) and other dementias, including vascular dementia; sharp blow and other traumatic lesions; cerebrovascular disorders (e.g. age-related macular degeneration); brain and spinal cord injury; peripheral neuropathies; retinopathy and glaucoma.

GSK-3β can also be used to treat other diseases, such as: insulin-independent diabetes and obesity; manic-depressive disease; schizophrenia; alopecia; inflammation cancers such as breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B cell leukemia, and some virus-induced tumors.

Rho kinases (ROCK), the first Rho effectors to be described, are serine / threonine kinases that play an important role in the fundamental processes of cell migration, cell proliferation and cell survival. Abnormal activation of the Rho / ROCK pathway has been observed in various disorders. Examples of disease states where the compounds of the present invention have potentially beneficial therapeutic effects due to their anti-vasospasmodic activity include cardiovascular diseases such as hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, spasm of the head vessels brain after subarachnoid hemorrhage, pulmonary hypertension and atherosclerosis. The muscle relaxation property is also useful for treating asthma, male erectile dysfunctions, female sexual dysfunctions, and hyperreactive bladder syndrome. Damage to the brain and spinal cord in an adult vertebrate activates ROCK, thereby inhibiting the growth and spread of neuritis. ROCK inhibition leads to the induction of new axon growth, axon propagation through lesions in the central nervous system, accelerated regeneration, and enhanced functional recovery after acute neural lesions in mammals (spinal cord injury, traumatic brain injury). It has also been confirmed that inhibition of the Rho / ROCK pathway is effective in other animal models of neurodegeneration, for example, stroke, inflammatory and demyelinating diseases, Alzheimer's disease, and also for the treatment of pain. Rho / ROCK pathway inhibitors therefore have the potential to prevent neurodegeneration and stimulate neuroregeneration in various neurological disorders, including spinal cord injury, Alzheimer's disease, stroke, multiple sclerosis, amyotrophic lateral sclerosis, and also for the treatment of pain. ROCK inhibitors have been shown to have anti-inflammatory properties. Thus, the compounds of the present invention can be used to treat neuroinflammatory diseases such as stroke, multiple sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis and inflammatory pain, as well as other inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, irritable bowel syndrome, Crohn's disease, psoriasis, ulcerative colitis, lupus erythematosus, and inflammatory bowel disease. Since ROCK inhibitors reduce cell proliferation and cell migration, they could be useful in treating cancer and tumor metastases. Moreover, if there is evidence that ROCK inhibitors suppress cytoskeletal rearrangement during viral invasion, thus they also have potential therapeutic value for use as antiviral and antibacterial agents. ROCK inhibitors are also useful for treating 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, it has been shown that Rho-associated helically-helix-forming protein kinases (ROCKs) -1 and -2 enhance myosin light chain phosphorylation (MLC) by inhibiting MLC phosphatase as well as MLC phosphorylation. This leads to regulation of actin-myosin reduction. Recent reports have shown that inhibition of ROCK interrupts inflammatory cellular chemotaxis, as well as inhibition of smooth muscle contraction in models of pulmonary inflammation associated with asthma. Therefore, Rho / ROCK pathway inhibitors should be useful in treating asthma.

Janus kinases (JAK) are an important family of intracellular tyrosine protein kinases (PTKs) with 4 members present in mammals, JAK1, JAK2, JAK3 and TYK2, also homologs in chicken, fish and Drosophila. JAKs play a critical role in several important intracellular signaling pathways, including the main JAK / STAT pathway, central to mediate cytokine signaling. It is this central role in cytokine signaling that reinforces the belief that specific JAK inhibitors can find wide therapeutic application in situations where cytokine activity leads to disease. Important examples include autoimmune diseases such as rheumatoid arthritis and psoriasis, myeloproliferative syndromes such as leukemia, lymphomas, and cardiovascular diseases.

JAK2, a member of the Janus kinase family (JAK) of tyrosine protein kinases (PTK), is an important intracellular mediator of cytokine signal transduction. Mutations of the JAK2 gene are associated with hematologic cancers, and aberrant JAK activity is also associated with various immune diseases, including rheumatoid arthritis.

Aurora kinases are a family of multigenic mitotic serine-threonine kinases that act as a class of new oncogenes. These kinases include aurora-A, aurora-B, and aurora-B as members. They are hyperactivated and / or overexpressed in some solid tumors, including, but not limited to, breast, ovarian, prostate, pancreas and colorectal cancer. In particular, aurora-A is a centrosomal kinase, and its localization depends on the cell cycle and plays an important role in the development of the cell cycle and cell proliferation. Aurora-A is located in the 20ql3 region of the chromosome, which is often amplified in some different types of malignant tumors, such as colorectal cancer, breast and bladder cancer. Inhibition of aurora kinase activity may help in reducing cell proliferation, tumor growth, and potentially oncogenesis.

Consequently, there remains a need for the development of methods involving the use of a drug based on one active substance capable of targeting several specific types of kinases or kinase pathways. In particular, such methods act on the desired combination of several targets, thereby achieving clinical efficacy.

SUMMARY OF THE INVENTION

In a general embodiment, the present invention provides compounds of formula (I)

or their pharmaceutically acceptable salts, where

A represents

R ₁ represents 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 represents hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, heterocyclecarbonyl or R _e R _f N-alkyl-C (O) -;

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

R ₄ represents alkyl, alkoxyalkyl, aryl, cycloalkyl, heteroaryl, heterocycle, heterocyclalkyl, R _j R _k N - or R _j R _k N-alkyl;

R ₅ represents alkyl, aryl or heteroaryl;

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

R ₇ represents alkyl, aryl or heteroaryl;

R _a and R _b each independently represent hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, R ₄ -C (O) - or R ₅ -S (O) ₂ -;

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

R _e and R _f each independently represent hydrogen, alkyl, arylalkyl, heteroarylalkyl, R ₆ —C (O) - or R ₇ —S (O) ₂ -;

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

R _j and R _k each independently represent 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, carboxy, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, halogen, heteroaryl, heteroarylalkyl, heterocycle geterotsiklalkil, heterocycle-hydroxyalkyl, trialkylsilylalkyl, H ₂ NC (O) _{-alkyl, Z a Z b N-, Z} a Z b Nalkil, Z _c Z _d NC (O) - or Z _c Z _d NS (O) ₂ -, where R _XiV , R _xv , R _XVi and R _XVii may be present by any open valency in compounds (xiv), (xv), (xvi) or (xvii);

Z _a and Z _b each independently represent hydrogen, alkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl, H ₂ NC (O) -, H ₂ N alkyl C (O) -, H ₂ NC (O) -alkyl, dialkyl NC ( O) - or dialkylNC (O) -alkyl-;

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

Z _e represents aryl or heteroaryl;

Z _f represents heteroarylalkyl, heterocycloalkyl or Z ₁ Z ₂ N-alkyl-;

m is 0, 1 or 2;

a is 0 or 1;

b is 0, 1 or 2;

c is 0, 1, 2 or 3; and

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

Also provided are pharmaceutically acceptable compositions comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier.

The aim of the present invention is the provision of compounds that are useful for the prevention or treatment of diseases caused by abnormal activity of protein kinase. In addition, the invention also provides pharmaceutically effective compositions of the compounds of the present invention, which are useful for the prevention or treatment of these diseases.

The present invention also relates to a pharmaceutical composition, which includes at least one 5-substituted indazole compound of formula (I), which may exist in the form of a pharmaceutically acceptable salt or prodrug thereof, in the presence or absence of pharmaceutically acceptable carriers, pills, adjuvants or other excipients.

The compounds of the present invention have inhibitory activity against GSK-3, ROCK-1, ROCK-2, JAK2, as well as other kinases, and are useful for inhibiting such kinases. Some compounds of the present invention are selective for one or more kinases and may be useful for selectively inhibiting such kinases. Therefore, the compounds of the present invention are useful as an active ingredient in the preparation of a composition that provides the possibility of prophylactic and / or therapeutic treatment of a disease caused by abnormal activity of GSK-3, and, more specifically, of neurodegenerative diseases such as Alzheimer's disease. In addition, the compounds of the present invention are also useful as an active ingredient for preparing a composition for the prophylactic and / or therapeutic treatment of neurodegenerative diseases such as Parkinson's disease, tauopathy (e.g., frontotemporal-parietal dementia, corticobasal degeneration, Peak's disease, progressive supranuclear palsy) and other dementias, including vascular dementia; sharp blow and other traumatic lesions; cerebrovascular disorders (e.g. age-related macular degeneration); trauma to the brain and spinal cord; peripheral neuropathies; retinopathy and glaucoma; and other diseases, such as insulin-independent diabetes (such as type II diabetes) and obesity; manic-depressive disease; schizophrenia; alopecia; cancers such as breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B cell leukemia, and some virus-induced tumors.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention have the formula (I) described above. More specifically, compounds of formula (I) may include, but are not limited to, compounds where A is (ii), (iii), (iv), (vii), (x), (xiv), (xv), (xvi), (xvii), (xviii), (xix), (xx), (xxi), (xxii) or (xxiii).

In another embodiment, a compound of formula (I) is disclosed wherein A is (ii),

R ₁ represents hydrogen, aryl, heteroaryl, heterocycle, R _a R _b N - or R _c R _d NC (O) -; R ₂ represents hydrogen, alkoxycarbonyl, heterocyclecarbonyl, alkylcarbonyl or R _e R _f N-alkyl-C (O) -; R ₄ represents alkyl, alkoxyalkyl, aryl, cycloalkyl, heterocycle, heterocycloalkyl, R _j R _k N- or R _j R _k N-alkyl-; R ₅ represents alkyl, aryl or heteroaryl; R _a and R _b each independently represent hydrogen, arylalkyl, cycloalkylalkyl, R ₄ -C (O) - or R ₅ -S (O) ₂ -; R _c and R _d each independently represent hydrogen or heteroaryl, R _e and R _f each independently represent hydrogen or alkyl, R _j and R _k each independently represent hydrogen, alkyl, aryl, cycloalkyl or heterocycle ; R _ii represents alkyl, alkoxyalkyl, alkoxycarbonyl, aryl, arylalkyl, aryl (hydroxy) alkyl, aryloxyalkyl, arylcarbonyl, alkoxycarbonylalkyl, arylthioalkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkylalkylalkylalkylalkylalkylalkylalkyl hydroxyalkyl, trialkylsilylalkyl, Z _a Z _b N-, Z _a Z _b N alkyl, or Z _c Z _d NC (O) -; Z _a and Z _b each independently represent hydrogen, alkyl or H ₂ N alkyl C (O) -; Z _c and Z _d each independently represent hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkyl, hydroxyalkyl or dialkyl N-alkyl-; m is 0; and b is 0, 1 or 2.

In another embodiment of the present invention, a compound of formula (I) is disclosed, wherein A is (iii),

R ₁ represents hydrogen or R _a R _b N-; R ₂ represents hydrogen; R ₄ represents R _j R _k N-alkyl-; R _a and R _b each independently represent hydrogen or R ₄ —C (O) -; R _j and R _k are each alkyl; R _iii represents alkoxycarbonylalkyl, alkyl, arylalkyl, cyanoalkyl, heterocycloalkyl or H ₂ NC (O) -alkyl-; c is 0, 1 or 2; and m has a value of 0.

In another embodiment of the present invention, a compound of formula (I) is disclosed, wherein A is (iv),

R ₁ represents hydrogen or R ₃ R _b N-; R ₂ represents hydrogen; R ₃ and R _b each represent hydrogen; R _iV represents aryl, arylalkyl, heterocycle, heterocyclalkyl, Z _a Z _b N alkyl or Z _c Z _d NS (O) ₂ -; Z _a and Z _b each independently represent hydrogen or alkyl; Z _c and Z _d each represent alkyl; c is 0, 1 or 2; and m has a value of 0.

In another embodiment of the present invention, a compound of formula (I) is disclosed, wherein A is (vii),

R ₁ represents hydrogen, alkyl or R _a R _b N; R ₂ represents hydrogen; R _a and R _b each represent hydrogen; R _Vii represents alkyl, alkoxycarbonyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, heterocyclecarbonyl, hydroxyalkyl or Z _c Z _d NC (O) -; Z _c and Z _d each independently represent hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl (hydroxy) alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycle, heterocyclalkyl, hydroxyalkyl or CHZ _e Z _f , Z _e represents aryl or heteroaryl, Z _f represents heteroarylalkyl, heterocycloalkyl or Z ₁ Z ₂ N-alkyl-; b is 1; and m has a value of 0.

In another embodiment of the present invention, a compound of formula (I) is disclosed, wherein A is (x),

R ₁ represents hydrogen; R ₂ represents hydrogen; R _x represents alkyl, aryl or Z _a Z _b N-; Z _a and Z _b each independently represent hydrogen, alkyl, aryl or arylalkyl; b is 1 or 2; and m has a value of 0.

In another embodiment of the present invention, a compound of formula (I) is disclosed, wherein A is (xiv),

R ₁ represents hydrogen; R ₂ represents hydrogen; R _XiV represents Z _a Z _b N-; Z _a and Z _b each independently represent hydrogen or cycloalkyl; c is 1; and m has a value of 0.

In another embodiment of the present invention, a compound of formula (I) is disclosed, wherein A is (xv),

(xv)

R ₁ represents hydrogen or R ₃ R _b N-; R ₂ represents hydrogen; R ₃ and R _b each represent hydrogen; R _xv represents Z _a Z _b N-; Z _a and Z _b each independently represent hydrogen, alkoxycarbonylalkyl, aryl, arylalkyl or cycloalkyl; d is 0 or 1; and m has a value of 0.

In another embodiment of the present invention, a compound of formula (I) is disclosed, wherein A is (xvi)

R ₁ represents hydrogen; R ₂ represents hydrogen; R _XVi represents Z _a Z _b N-; Z _a and Z _b each independently represent hydrogen or cycloalkyl; d is 1; and m has a value of 0.

In another embodiment of the present invention, a compound of formula (I) is disclosed, wherein A is (xvii)

R ₁ represents hydrogen; R ₂ represents hydrogen; R _XVii represents aryl or Z _a Z _b N-; Z _a and Z _b each independently represent hydrogen, alkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl or H ₂ NC (O) -alkyl-; d is 0 or 1; and m has a value of 0.

In another embodiment of the present invention, a compound of formula (I) is disclosed wherein A is (xviii)

R ₁ represents R _a R _b N-; R ₂ represents hydrogen; R _a and R _b each represent hydrogen; c is 0; and m has a value of 0.

In another embodiment of the present invention, a compound of formula (I) is disclosed, wherein A is (xix)

R ₁ represents R _a R _b N-; R ₂ represents hydrogen; R _a and R _b each independently represent hydrogen; c is 0; and m has a value of 0.

In another embodiment of the present invention, a compound of formula (I) is disclosed wherein A is (xx)

R ₁ represents R _a R _b N-; R ₂ represents hydrogen; R ₄ represents R _j R _k N-alkyl-; R _a and R _b each represent hydrogen or R ₄ —C (O) -; R _j and R _k independently represent alkyl; R _xx represents Z _a Z _b N - or a heterocycle; Z _a and Z _b independently represent hydrogen or alkyl; c is 0 or 1; and m has a value of 0.

In another embodiment of the present invention, a compound of formula (I) is disclosed wherein A is (xxi)

R ₁ represents R _a R _b N-; R ₂ represents hydrogen; R _a and R _b each represent hydrogen; R _XXi represents alkoxy; d is 1; and m has a value of 0.

In another embodiment of the present invention, a compound of formula (I) is disclosed, wherein A is (xxii)

R ₁ represents R _a R _b N-; R ₂ represents hydrogen; R ₄ represents R _j R _k N-alkyl-; R _a and R _b each independently represent hydrogen or R ₄ —C (O) -; R _j and R _k are each alkyl; c is 0 and m is 0.

In another embodiment of the present invention, a compound of formula (I) is disclosed wherein A is (xxiii)

R ₁ represents R _a R _b N-; R ₂ represents hydrogen; R _a and R _b each represent hydrogen; c is 0; and m has a value of 0.

Specific embodiments contemplated as part of the present invention include, but are not limited to, compounds of formula (I), for example:

5- (1-benzyl-1H-1,2,3-triazol-5-yl) -1H-indazole compound with 5- (1-benzyl-1H-1,2,3-triazol-4-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] -1H-1,2,3-triazol-4-yl} -1H-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-indazol-5-yl] -1H-indazole;

N- {3- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-indazol-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-indazol-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-indazol-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] -1H-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 -dimethylglycinamide;

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

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

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

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

5- [4- (4-fluorophenyl) -1- (3-pyrrolidin-1-ylpropyl) -1H-indazol-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-yl-ethyl) -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-oxoethanol;

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-dioxidothiomorpholin-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] beta-alaninate;

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-α] 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-1H-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-indazol-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} piperidin-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-indazol-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- (lΗ-indazol-5-yl) -1- (tetrahydro-2Η-pyran-4-ylmethyl) -lΗ-1,2,3-triazol-5-yl] methanone;

(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-amine;

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- sludge) 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-isoindol-1,3 (2H) -dione;

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

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-tetrahydroisoquinolin-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] -1H-1,2,3-triazol-4-yl} -1H-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-1H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] phenyl} acetamide;

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

5- {1-benzyl-5- [3- (1H-pyrazol-1-yl) phenyl] -lH-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-1H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] -N-phenylbenzamide;

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

3- [4- (3-amino-1H-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-sulfonamide;

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-furamide;

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-furamide;

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-yl-ethyl) -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-triazole-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-indazol-1-yl) propyl] -4 (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide;

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-1H-indazol-5-yl) -1H-pyrazol-1-yl] propannitrile;

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

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

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

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

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

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

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

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

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

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

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

N ¹ - (5- {1- [2- (3,5-dimethylisoxazol-4-yl) 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-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-methylpropanoic 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] glycinamide;

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-yl-pyrimidin-5-yl) -1H-indazol-3-yl] glycinamide;

N ² , N ² -dimethyl-N ¹ - {5- [1- (2-morpholin-4-yl-ethyl) -1H-pyrazol-4-yl] -1H-indazol-3-yl} glycinamide;

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

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

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

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

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

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

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 ¹ - [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-beta-alaninamide;

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

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

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

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

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

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 -cyclobutylglycinamide;

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-yl-ethyl) isoxazole-3-carboxamide;

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

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

5- (1H-indazol-5-yl) -N- (2-pyridin-4-yl-ethyl) 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-yl-ethyl) 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-yl-isoxazole-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} carbonyl) amino] -1H 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;

tert-butyl 3-amino-5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole-1-carboxylate;

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

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

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

All patents, patent applications and reference documents known from the literature that are referred to in the present description, are incorporated into this application by reference in their entirety. In case of inconsistencies, this disclosure, including definitions, will take precedence.

As they are used in the text of the present description and the attached claims, the following terms have the following meanings:

The term “alkenyl,” as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and containing at least one carbon-carbon double bond formed by the removal of two hydrogen atoms. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl and 3- decentralized.

The term “alkoxy,” as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy and 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 examples of alkoxyalkoxy 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. Representative examples of alkoxyalkoxyalkyl include, but are not limited to, tert-butoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy) methyl and 2- (2-methoxyethoxy) ethyl.

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 examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.

The term “alkoxycarbonyl,” as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxycarbonylalkyl,” as used herein, means an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of alkoxycarbonylalkyl include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl and 2-tert-butoxycarbonylethyl.

The term “alkyl,” as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 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. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxo-propyl, 2,2-dimethyl-1-oxo-propyl, 1-oxo-butyl and 1-oxo-pentyl.

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. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxo-propyl, 3,3-dimethyl-2-oxo-propyl, 3-oxo-butyl and 3-oxo-pentyl.

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

The term “alkylene” means a divalent group derived from a straight or branched chain hydrocarbon consisting of from 1 to 10 carbon atoms. Representative examples of alkylene include, but are not limited to, —CH ₂ -, —CH (CH ₃ ) -, —C (CH ₃ ) ₂ -, —CH ₂ CH ₂ -, —CH ₂ CH ₂ CH ₂ -, —CH ₂ CH ₂ CH ₂ CH ₂ - and -CH ₂ CH (CH ₃ ) CH ₂ -.

The term “alkylene-NR _g -”, as used herein, means an alkylene group, as defined herein, appended to the parent molecular moiety through an —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 examples of alkylsulfinyl 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. Representative examples of alkylsulfinylalkyl include, but are not limited to, methylsulfinylmethyl and ethylsulfinylmethyl.

The term “alkylsulfonyl,” as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl 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. Representative examples of alkylsulfonylalkyl 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. Representative examples of alkylthio 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. Representative examples of alkylthioalkyl include, but are not limited to, methylthiomethyl and 2- (ethylthio) ethyl.

The term “alkynyl,” as used herein, means a linear or branched hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl and 1-butynyl.

The term “aryl,” as used herein, means phenyl, bicyclic aryl, or tricyclic aryl. Bicyclic aryl is naphthyl or phenyl condensed with cycloalkyl, or phenyl condensed with cycloalkenyl, or phenyl condensed with a monocyclic heteroaryl ring as defined herein, or phenyl condensed with a monocyclic heterocycle as defined herein. The bicyclic aryl of the present invention should be attached to the parent molecular moiety through any available carbon atom contained in the phenyl ring. Representative examples of bicyclic aryl include, but are not limited to, 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. The tricyclic aryl is anthracene or phenanthrene, or a bicyclic aryl condensed with cycloalkyl, or a bicyclic aryl condensed with cycloalkenyl, or a bicyclic aryl condensed with phenyl. A tricyclic aryl is attached to the parent molecular moiety through any carbon atom contained in a tricyclic aryl. Representative examples of a tricyclic aryl ring include, but are not limited to, azulenyl, dihydroanthracenyl, fluorenyl, and tetrahydrophenanthrenyl.

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

The term “aryloxy,” as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of aryloxy 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. Representative examples of aryloxyalkyl include, but are not limited to, 2-phenoxyethyl, 3-naphth-2-yloxypropyl and 3-bromophenoxymethyl.

The term “arylalkyl,” as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-yl-ethyl.

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 containing one hydroxy, as defined herein. Representative examples of aryl (hydroxy) alkyl 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. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and naphthoyl.

The term “arylthio,” as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of arylthio 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 examples of arylthioalkyl include, but are not limited to, phenylthiomethyl, 2-naphth-2-ylthioethyl, and 5-phenylthiomethyl.

The term “azido,” as used herein, means an —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.

The term “carbonyl,” as used herein, means a —C (O) group.

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. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, and 3-carboxypropyl.

The term “cyano,” as used herein, means 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. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.

The term “cycloalkenyl,” as used herein, means a monocyclic or bicyclic ring system containing from 3 to 10 carbon atoms and containing at least one carbon-carbon double bond formed by the removal of two hydrogen atoms. Representative examples of monocyclic ring systems include, but are not limited to, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yl and 3-cyclopenten-1-yl. Bicyclic ring systems are, by way of example, a monocyclic cycloalkenyl ring system that is fused to another monocyclic cycloalkyl ring as defined herein, a monocyclic aryl ring as defined herein, a monocyclic heterocycle as defined herein, or a monocyclic heteroaryl in this application. The bicyclic ring systems of the present invention should be attached to the parent molecular moiety through an accessible carbon atom in the cycloalkenyl ring. Representative examples of bicyclic ring systems include, but are not limited to, 4,5-dihydro-benzo [1,2,5] oxadiazole, 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.

The term “cycloalkyl,” as used herein, means a monocyclic, bicyclic or spirocyclic ring system. Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The bicyclic cycloalkyl groups of the present invention are exemplified by a monocyclic cycloalkyl ring fused to another monocyclic cycloalkyl ring, or a monocyclic cycloalkyl ring fused to cycloalkenyl, or a monocyclic cycloalkyl ring fused to a phenyl ring, or a monocyclic fused to cycloalkyl a heteroaryl ring as defined herein or a monocyclic cycloalkyl a ring fused to a monocyclic heterocycle as defined herein. The bicyclic cycloalkyl ring systems of the present invention should be attached to the parent molecular moiety through an accessible carbon atom in the monocycloalkyl ring.

The cycloalkyl groups of the present invention are optionally substituted with 1, 2, 3 or 4 substituents selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxy sulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthio, alkylthio, alkylthio , formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, oxo, Z ₁ Z ₂ N- or (Z ₃ Z ₄ N) carbonyl.

The term “cycloalkylalkyl,” as used herein, means a cycloalkyl group attached to the parent molecular moiety through an alkyl group as defined herein.

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

The term “formyl,” as used herein, means a —C (O) H group.

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

The term “halo” or “halogen,” as used herein, means —Cl, —Br, —I, or —F.

The term “haloalkoxy,” as used herein, means at least one halogen atom as defined herein attached to the parent molecular moiety through an alkoxy group as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

The term “haloalkyl,” as used herein, means at least one halogen atom, as defined herein, attached to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heteroaryl,” as used herein, means monocyclic heteroaryl or bicyclic heteroaryl. A monocyclic heteroaryl is a 5 or 6 membered ring containing at least one heteroatom independently selected from O, N or S. The 5 membered ring contains two double bonds and may contain one, two, three or four heteroatoms. The 6 membered ring contains three double bonds and may contain one, two, three or four heteroatoms. A 5- or 6-membered heteroaryl is bonded to the parent molecular moiety through any carbon atom or any nitrogen atom contained in the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, indazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazylazole, thiazylazole. A bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a monocyclic aryl ring as defined herein, a monocyclic cycloalkyl ring as defined herein, a monocyclic cycloalkenyl ring as defined herein, another monocyclic heteroaryl or monocyclic heterocyclic ring. The bicyclic heteroaryl ring systems of the present invention should be attached to the parent molecular group through an accessible carbon atom in the heteroaryl ring. A bicyclic heteroaryl is bonded to the parent molecular moiety through any carbon atom or any nitrogen atom contained in the bicyclic heteroaryl. Representative examples of bicyclic heteroaryl include, but are not limited to, benzofuranyl, benzoxadiazolyl, 1,3-benzothiazolyl, benzimidazolyl, benzodioxolyl, benzothiophenyl, chromenyl, cinnolinyl, furopyridine, indolyl, indazinopyridinyl, isoquinopyridinyl, thioquinopyridinyl .

The heteroaryl groups of the present invention are optionally substituted with 1, 2, 3 or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxy sulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylalkyl, alkylalkyl, alkyl benzyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, Z ₁ Z ₂ N - or (Z ₃ Z ₄ N) carbonyl. Heteroaryl groups of the present invention that are substituted may be present as tautomers. The present invention covers all tautomers, including non-aromatic tautomers.

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

The term “heterocycle” or “heterocyclic,” as used herein, refers to a monocyclic, bicyclic, tricyclic or spirocyclic ring system that contains at least one heteroatom. A monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N and S. A 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5-membered ring does not contain at all or contains one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7-membered ring does not contains completely or contains one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. A monocyclic heterocycle is bound to the parent molecular moiety through any carbon atom or any nitrogen atom contained in a monocyclic heterocycle. Representative examples of a monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl , isoxazolinyl, isoxazolidinyl, isoindolin-1,3-dione, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl-tetra-tyrinyl di-tetra-tyrinyl di-tetra-tyrinyl di-tetra-tyrinyl di-tetra-di-di-tetra-di-di-tetra-di-di-tetra-di-di-tetra-di-di-di-tetra-di-di-tetra-di-di-di-arynyl-tetra-di-di-thinyl-di-tetra-di-di-tetra-di-tyne-di-tetra-di-di-thinyl-di-Tyridinyl-tetra-di-Tyridinyl-Tyridinyl-Tyrnidinyl-Tyridinyl-Tyridinyl-Tyridinyl Tyridinyl Tyridinyl Tyridinyl Tyridinyl Tyridinyl Tyridinyl Tyridinyl Tyrenediyl Tyrnidinyl Tyridinyl Tires iazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholinesulfone), thiopyranyl and tritianil. The bicyclic heterocycle of the present invention is defined as a monocyclic heterocycle fused to a phenyl group, a cycloalkyl group defined in this application, a cycloalkenyl group defined in this application, another monocyclic heterocyclic group defined in this application, or a spirocyclic ring, where one carbon atom is monocyclic the heterocycle is connected by forming the bridge with two ends of the alkylene chain. The bicyclic heterocycle of the present invention is linked to the parent molecular moiety through any carbon atom or any nitrogen atom contained in the heterocyclic ring. Representative examples of a bicyclic heterocycle include, but are not limited to, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro -1-benzothienyl, 3,4-dihydro-1H-isochromen-4-yl, 2,3-dihydro-1H-indolyl, succinimimidyl and 1,2,3,4-tetrahydroquinolinyl. A tricyclic heterocycle is a bicyclic heterocycle condensed with phenyl, or a bicyclic heterocycle condensed with cycloalkyl, or a bicyclic heterocycle condensed with cycloalkenyl, or a bicyclic heterocycle condensed with a monocyclic heterocycle. A tricyclic heterocycle is linked to the parent molecular group through any carbon atom or any nitrogen atom contained in a tricyclic heterocycle. Representative examples of a tricyclic heterocycle include, but are not limited to, 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.

The heterocycles of the present invention are optionally substituted with 1, 2 or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxyisulfonyl, alkyl, alkylcarbonyl, alkylcarbonyl, alkylthioalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkyl , carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, hydroxyalkylcarbonyl, hydroxyalkoxyalkyl, mercapto, oxo, Z ₁ Z ₂ N- or (Z ₃ Z ₄ N) carbonyl.

The term “heterocycloalkyl,” as used herein, means a heterocyclyl group attached to the parent molecular moiety through an alkyl group as defined herein.

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

The term “hydroxy,” as used herein, means an —OH group.

The term “hydroxyalkyl,” as used herein, means at least one hydroxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of hydroxyalkyl 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-hydroxybutanoyl.

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. Representative examples of hydroxyalkoxyalkyl include, but are not limited to, (2-hydroxy-ethoxy) ethyl and (3-hydroxy-propoxy) ethyl.

The term “hydroxy protecting group” or “O-protecting group” means a substituent that protects the hydroxyl groups from undesired reactions during synthetic procedures. Examples of hydroxy protecting groups include, but are not limited to, substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, benzyl and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2-trichloroethyl and tert-butyl; silyl ethers, for example trimethylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl; cyclic acetals and ketals, for example, methylene acetal, acetonide and benzylidene acetal; cyclic ortho esters, for example methoxymethylene; cyclic carbonates; and cyclic boronates. Traditionally used hydroxy protecting groups are disclosed in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).

The term “mercapto,” as used herein, means an —SH group.

The term "nitrogen protecting group", as used herein, means groups that are intended to protect an amino group from undesirable reactions during synthetic procedures. Preferred nitrogen protecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, tert-butoxycarbonyl (Boc), tert-butylacetyl, trifluoroacetyl and triphenylmethyl (trityl).

The term “nitro,” as used herein, means an —NO ₂ group.

The term “trialkylsilyl,” as used herein, means three independently selected alkyl groups, as defined herein, appended to the parent molecular moiety through a silicon atom. Representative examples of trialkylsilyl include, but are not limited to, trimethylsilyl, 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. Representative examples of trialkylsilylalkyl include, but are not limited to, trimethylsilylmethyl, 2-trimethylsilylethyl and 2-tert-butyldimethylsilylethyl.

The term “Z ₁ Z ₂ N”, as used herein, means two groups, Z ₁ and Z ₂ , which are attached to the parent molecular group through a nitrogen atom. Z ₁ and Z ₂ each independently represent hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl. In some cases, in the present invention, Z ₁ and Z ₂ taken together with the nitrogen atom to which they are bonded 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, means two groups, Z ₃ and Z ₄ , which are attached to the parent molecular group through a nitrogen atom. Z ₃ and Z ₄ each independently represent 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. Representative examples of (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 in this application means = O group.

The term "sulfinyl", as used in this application, means -S (O) - group.

The term “sulfonyl,” as used herein, means —SO ₂ —group.

The term “sulfonamide”, as used herein, means an —SO ₂ NH ₂ group.

The term "tautomer" as used in this application means a proton shift from one atom in a compound to another atom in the same compound, where two or more structurally different compounds are in equilibrium with each other.

The compounds of the present invention can exist as stereoisomers where asymmetric or chiral centers are present. These stereoisomers are “R” or “S” depending on the configuration of the substituents around the chiral carbon atom. The terms "R" and "S" as used in this application mean configurations defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The present invention provides for various stereoisomers and mixtures thereof, and they are specifically included in the scope of the present invention. Stereoisomers include enantiomers and diastereomers and mixtures of enantiomers or diastereomers. The individual stereoisomers of the compounds of the present invention can be obtained synthetically from commercially available starting materials that contain asymmetric or chiral centers, or by preparing racemic mixtures followed by resolution, as is well known to those skilled in the art. Such separation methods are, by way of example, (1) coupling a mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography, and isolating an optically pure product from the auxiliary; or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.

The compounds and methods of the present invention will be better understood by reference to the Examples below, which are intended to illustrate and not to limit the scope of the present invention. In addition, all references in this application are incorporated by reference.

Connection names are specified using the Name Pro naming program, which is supplied by ACD / Labs. Alternatively, compound names are listed using the AUTONOM naming program, which is supplied by MDL Information Systems GmbH (formerly known as Beilstein Informationssysteme), Frankfurt, Germany, and is part of the CHEMDRA W® ULTRA v software suite. 6.0.2 and ISIS Draw v. 2.5. Also, compound names are indicated using the naming algorithm Struct = Name, which is part of the CHEMDRA W® ULTRA v software suite. 9.0.7.

Abbreviations

The abbreviations used in the descriptions of the Schemes and in the Examples below are as follows: DMF for N, N-dimethylformamide, DMSO for dimethyl sulfoxide, EtOAc for ethyl acetate, CHCl ₃ for chloroform, CH ₂ Cl ₂ for dichloromethane, CH ₃ CN for acetonitrile , THF for tetrahydrofuran, HATU for O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, EDC or EDCI for 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, LC / MS for liquid chromatography / mass spectroscopy, NH ₄ OAc for ammonium acetate, NaBH (OAc) ₃ for sodium triacetoxyborohydride, PBS for sheep’s serum albumin, PBS for phosphate buffered saline, TMS for trimethylsilyl, MW for microwave irradiation, DMAP for 4- (dimethylamino) pyridine, dppf for 1,1'-bis (diphenylphosphino) ferrocene, TFA for trifluoroacetic acid, BINAP for 2,2'-bis (diphenylphosphino) -1,1'-binafil, TBAF for tetrabutylammonium fluoride, Tween for polyoxyethylene sorbitan monolaurate, HPLC for high performance liquid chromatography, DME for 1,2-dimethoxyethane, Boc for tert-butoxycarbonyl, BSA for bovine serum albumin, DTT for dithiothreitol, ATP for adenosint ifosfata, EDTA for ethylenediaminetetraacetic acid, HPMC for hydroxypropylmethylcellulose, TMB for 3,3 ', 5,5'-tetramethylbenzidine and HEPES for 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid.

Obtaining compounds of the present invention

The compounds and methods of the present invention will be better understood in connection with the Synthesis Schemes and Examples presented below, which illustrate the means by which the compounds of the present invention can be obtained.

Scheme 1

As shown in Scheme 1, compounds of formula 2, which are typical representatives of compounds of formula (I), can be prepared as follows. The compounds of formula 1, where R_one and R₂ defined in formula (I) and X_one represents iodine, bromine or chlorine, and which can be obtained from commercial sources or can be synthesized in accordance with methods known from the literature, when treated with reagent A-M_onewhere A has the meaning defined in formula (I), and M_onerepresents -Sn (R_z)₃ or -B (OR_y)₂where R_z represents alkyl or aryl and R_y represents hydrogen, alkyl, aryl, or two groups R_y together with the boron atom to which they are attached form 1,3-dioxoborolane, in the presence of a palladium catalyst, compounds of formula 2 will be provided. In such reactions between compounds of formula 1 and compounds of formula -Sn (R_z)₃commonly known as Stille combinations, a palladium catalyst is used, such as, but not limited to, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), tris (dibenzylideneacetone) dipalladium or palladium diacetate, in the presence of or in the absence of a ligand, such as tri (2-furyl) phosphine or triphenylarsine, in a solvent, such as toluene or DMF, at a temperature of from about 25 ° C to about 150 ° C. In addition, salts of Li (I), Cu (I) or Mn (II) can be added to improve reactivity or specificity. In reactions between compounds of formula 1 and compounds of formula -B (OR_y)₂commonly known as Suzuki bindings, palladium catalysts are used, such as, but not limited to, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), tris (dibenzylidine acetone) dipalladium or palladium diacetate. You can add a palladium ligand, such as 2- (dicyclohexylphosphino) biphenyl, tri-tert-butylphosphine or tris (2-furyl) phosphine, and a base such as, but not limited to, aqueous K₃PO_four, cesium carbonate, potassium carbonate or Na₂CO₃, in solvents such as toluene, dimethoxyethane, dioxane, water or DMF, at a temperature of from about 25 ° C to about 150 ° C. The reaction can also be carried out by heating in a microwave reactor.

Although many organostannans are commercially available or described in the literature, additional stannanes can also be obtained from A-halides or A-triflates by treatment with hexa-alkyl distannan of the formula ((R _z ) ₃ Sn) ₂ in the presence of Pd (Ph ₃ P) ₄ . Similarly, in the absence of commercially available organoboron reagents, -B (OR _y ) ₂ can be obtained from the corresponding halides or triflates (A-halogen or A-triflate) via metal exchange with an organolithium compound followed by alkyl borate.

Scheme 2

The compounds of formula 2, where R ₁ and R _{2 are} defined in formula (I), and A is a heteroaryl ring bonded to the parent group through a nitrogen atom, can be prepared as illustrated in Scheme 2. Treatment of compounds of formula I with a reagent of formula AH, where H represents hydrogen on the nitrogen atom contained in the heteroaryl ring A, 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, metallic copper, CuI or diacetate palladium, and optionally with a ligand, such as, but not limited to, BINAP or tri-tert-butylphosphine, will provide compounds of formula 2.

Scheme 3

As indicated above for Scheme 1, the compounds of formula (I) can be synthesized using the Stille coupling as described in Scheme 3. The compounds of formula 3, where R _ii has the meaning defined in formula (I), when treated with compounds of the formula 4, where R ₁ has the meaning defined in formula (I), and P ₁ represents a nitrogen protecting group, such as, but not limited to, tert-butyloxycarbonyl or acetyl, in the presence of dichlorobis (triphenylphosphine) palladium (II) and (thiophene-2-carbonyloxy) copper, in toluene, under heating, will provide Compound of Formula 5. Compounds of Formula 5, when processed under conditions known to be used to remove the protecting group, such as hydrochloric acid or trifluoroacetic acid in a solvent such as acetic acid or dioxane, when the protecting group is tert-butyloxycarbonyl, or sodium hydroxide, lithium hydroxide or potassium hydroxide in an aqueous mixture of THF, isopropanol or dioxane, when the protective group is acetyl, will provide compounds of formula 6, which are typical my representatives of the compounds of formula (I) where A represents (ii).

Scheme 4

The compounds of formula 3 used in Scheme 3 to obtain compounds of formula (I) can be obtained as shown in Scheme 4. Compounds of formula 7, which are obtained from commercial sources or which can be obtained in accordance with methods known to specialists in this field, when treating them with either 1,1,1-tributyl-N, N-dimethylstannamine or methyl ethyl (tributylstannyl) carbamate will provide compounds of formula 8. Alkines of formula 8, when heated in the presence of compounds of formula 9, where R _ii has the meaning defined in formula (I), and N ₃ is an azide, compounds of formula 3 will provide.

Scheme 5

As shown in Scheme 5, compounds of formula 12, which are typical representatives of compounds of formula (I), where A represents (ii), can be obtained as follows. The compounds of formula 10, where R ₁ has the meaning defined in formula (I) and X ₁ represents iodine, bromine, chlorine or triflate, when they are treated with TMS acetylene in the presence of copper iodide, dichlorobis (triphenylphosphine) palladium (II) and triethylamine , followed by treatment with tetrabutylammonium fluoride or potassium hydroxide, will provide compounds 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. Compounds of formula 11, when treated with R _ii -Cl, sodium azide, copper sulfate and metallic copper, under heating, in a solvent such as dioxane, will provide compounds of formula 12, which are typical representatives of compounds of formula (I), where A represents (ii).

Scheme 6

Alternatively, compounds of formula 13, when treated with TMS-acetylene in the presence of copper iodide, dichlorobis (triphenylphosphine) palladium (II) and triethylamine, followed by treatment with tetrabutylammonium fluoride or potassium hydroxide, will provide compounds of formula 14. The reaction can be carried out in a solvent such as , but not limited to, DMF, at ambient temperature or under heating. Compounds of formula 14, when treated with compounds of formula 9, where R _ii has the meaning defined in formula (I), or sodium azide, copper sulfate and metallic copper under heating conditions will provide compounds of formula 15. Compounds of formula 15, when heated in the presence of hydrazine in ethanol will provide compounds of formula 16. Compounds of formula 16, when treated with di-tert-butyl dicarbonate and a catalytic amount of DMAP in a solvent such as THF or acetonitrile, will provide compounds of formula 17. Compounds of form 17, when treated with compounds of formula 18 in the presence of a base such as, but not limited to, pyridine, in a solvent such as dichloromethane, followed by treatment with trifluoroacetic acid, will provide compounds of formula 19. Compounds of formula 16, when treated with a carboxylic acid with using the carboxylic acid-amine coupling conditions known to those skilled in the art, compounds of formula 19A will be provided. Standard carboxylic acid-amine coupling conditions include the addition of a coupling reagent such as, but not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1,3-dicyclohexylcarbodiimide (DCC), bis (2- oxo-3-oxazolidinyl) phosphinic acid (BOPCl), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), or O-benzotriazol-1-yl-N tetrafluoroborate , N, N ', N'-tetramethyluronium (TBTU), with or without an adjuvant, such as, but not limited to, 1-hydroxy-7-azabenzotriaz l (HOAT) or 1-hydroxybenzotriazole hydrate (HOBT), in a solvent such as, but not limited to, dichloromethane.

Scheme 7

Compounds of formula 24, which are representative of compounds of formula (I), may be prepared as follows. Compounds of formula 20, wherein X ₁ is halogen or triflate, when treated with a compound of formula 21, acetic anhydride and a base such as, but not limited to, potassium acetate, compounds of formula 22 will be provided under heating conditions. Compounds of formula 22 their treatment with sodium azide, copper sulfate, a base such as sodium carbonate, and the compounds of formula 23, where R _ii has the meaning defined in formula (I), and which are either available from commercial sources or can be obtained by specialists in this area, will provide compounds of formula 24.

Scheme 8

As shown in Scheme 8, compounds of formula 29 and 30, which are typical representatives of compounds of formula (I), can be obtained as follows. Compounds of formula 25, wherein R ₁ is as defined in formula (I) and X ₁ is halogen or triflate when treated with compounds of formula 23, copper iodide, dichlorbis (triphenylphosphine) palladium (II) and triethylamine in DMF, at ambient temperature or under heating conditions, compounds of formula 27 will provide. Compounds of formula 27, when treated with compounds of formula 9 under heating conditions and either without a solvent or in a solvent such as, but not limited to, dioxane, will provide compounds of the formula 29 and 30.

Scheme 9

Compounds of formula 32, which are typical representatives of compounds of formula (I), wherein A is (vii) and R ₁ and R _{Vii are} defined in formula (I), can be prepared as follows. Aldehydes of the formula 31, where R _vii has the meaning defined in formula (I), which can be obtained from commercial sources, when treated with hydroxylamine hydrochloride and an aqueous solution of sodium hydroxide, will provide an intermediate oxime compound which, when oxidized with Chloramine T trihydrate , followed by treatment with copper sulfate and a copper wire and compounds of formula 11, will provide compounds of formula 32.

Pattern 10

Compounds of formula 38, which are representative of compounds of formula (I), wherein A is (x), are prepared as follows. The compounds of formula 33, where R ₁ has the meaning defined in formula (I), which can be obtained from commercial sources or can be obtained by specialists in this field, when they are treated with N, O-dimethylhydroxylamine using acidic coupling conditions known to specialists in compounds of formula 34 will provide in this area. Standard conditions for the coupling of a carboxylic acid-amine include the addition of a binding reagent, such as, but not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodi hydrochloride amide (EDCI), 1,3-dicyclohexylcarbodiimide (DCC), bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (BOPCl), O- (7-azabenzotriazol-1-yl) -N, N, N 'hexafluorophosphate , N'-tetramethyluronium (HATU) or tetrafluoroborate O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium (TBTU), with or without an excipient such as, but not limited to, 1- hydroxy-7-azabenzotriazole (HOAT) or 1-hydroxybenzotriazole hydrate (HOBT), in a solvent such as, but not limited to, dichloromethane. Compounds of formula 34, when treated with a Grignard reagent such as benzyl magnesium bromide, in a solvent such as tetrahydrofuran, will provide compounds of formula 35 at ambient temperature. Compounds of formula 35, when treated with a reagent that is a protecting group, such as but not limited to, di-tert-butyl dicarbonate and a catalytic amount of DMAP in a solvent such as THF or acetonitrile will provide compounds of formula 36. Compounds of formula 36, when they are treated with tribromido pyridinium in a solvent such as, but not limited to, THF, with or without heating, will provide compounds of formula 36 A. Compounds of formula 36 A, when treated with compounds of formula 37 with or without heating, followed by treatment of the product, exposing it Compounds of Formula 38 will provide conditions that remove a nitrogen protecting group. Traditionally used nitrogen protecting groups and methods for their removal are disclosed 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 (I) and P ₁ is a nitrogen protecting group when they are treated with compounds of formula 39 under heating conditions, followed by treatment of the product, subjecting it to conditions that, like this It is known to those skilled in the art that the nitrogen protecting group is removed, or, as shown in the literature, will provide compounds of formula 40, which are typical representatives of compounds of formula (I), where A is (xvii).

Pattern 12

As shown in Scheme 12, compounds of formula 47, which are typical representatives of compounds of formula (I), where A is (x), can be obtained as follows. Compounds of formula 41, wherein R ₁ is as defined in formula (I), when treated with di-tert-butyl dicarbonate and a catalytic amount of DMAP in a solvent such as THF or acetonitrile, compounds of formula 42 will be provided. Treatment of compounds of formula 42 with tributyl ( 1-ethoxyvinyl) stannane and dichlorobis (triphenylphosphine) palladium (II) will provide compounds of formula 44. Compounds of formula 44, when treated with pyridinium tribromide in THF, will provide compounds of formula 45. Compounds of formula 45, when treated with compounds of form uly 46 in a solvent such as, but not limited to, ethanol, wherein R _x is as defined in formula (I), will provide compounds of formula 47.

Pattern 13

As shown in Scheme 13, compounds of formula 51, which are typical representatives of compounds of formula (I), where A is (iv), can be obtained as follows. The compounds of formula 48, where R ₁ has the meaning defined in formula (I), and which are either available through commercial sources, or can be obtained in accordance with the procedures described in the literature, or as shown in this application, when heated in the presence of compounds of formula 49, as well as compounds of formula 50, which are either commercially available or can be obtained by specialists in this field using the procedures described in the literature, will provide compounds of formula 51.

Scheme 14

As shown in Scheme 14, compounds of formula 55, which are typical representatives of compounds of formula (I), where A is (xiv), (xv), (xvi) or (xvii), can be obtained as follows. The compounds of formula (52), where R ₁ has the meaning defined in formula (I), when they are treated with butyllithium followed by treatment with DMF and then acid treatment, will provide compounds of formula 48. Compounds of formula 48, when treated with compounds of formula 51, where X is —CH—, —N— or —S—, Y is —CH—, —N— or a bond, and three (triflate) ohm scandium, followed by treatment with compounds of formula 54, where Z _{a is} defined in the formula (I) will provide compounds of formula 55.

Scheme 15

As shown in Scheme 15, compounds of formula 56, which are representative of compounds of formula (I), wherein A is (vii), can be prepared as follows. The compounds of formula (11), where R ₁ has the meaning defined in formula (I), when they are treated with a reagent, such as, but not limited to, ethyl 2-chloro-2- (hydroxyimino) acetate, with a base such as, but not limited to triethylamine, will provide compounds of formula 56. The reaction can be carried out in a solvent such as, but not limited to, toluene, and the use of heat may be required.

Pattern 16

As shown in Scheme 16, compounds of formula 29, which are typical representatives of compounds of formula (I), where A represents (ii), can be obtained as follows. The compounds of formula (27), where R ₁ has the meaning defined in formula (I), when they are treated with a compound of formula 9, R _ii C (O) Cl or ICl, CuI and triethylamine in a solvent, such as, but not limited to, tetrahydrofuran will provide compounds of formula 29. The reaction can be carried out at ambient temperature or using heat.

Scheme 17

As shown in Scheme 17, compounds of formula 57, which are typical representatives of compounds of formula (I), wherein A is (vi), can be prepared as follows. The compounds of formula 45, where R ₁ has the meaning defined in formula (I), when treated with ammonium formate and formic acid, will provide a compound of formula 57.

Scheme 18

As shown in Scheme 18, compounds of formula 58, which are typical representatives of compounds of formula (I), where A is (vii), can be obtained as follows. The compounds of formula 48, where R ₁ has the meaning defined in formula (I), when treated with nitromethane, will provide compounds of formula 58 (Organic Preparations and Procedures International, 2001, 33, 381-386).

Scheme 19

As shown in Scheme 19, compounds of formula 60, which are typical representatives of compounds of formula (I), wherein A is (vi), can be prepared as follows. The compounds of formula 48, where R ₁ has the meaning defined in formula (I), when they are treated with 1- (isocyanomethylsulfonyl) -4-methylbenzene, 59, and a suitable base, such as, but not limited to, potassium carbonate, in a solvent, such as methanol or tetrahydrofuran, and followed by treatment with a suitable acid, such as hydrochloric acid, will provide compounds of formula 60.

Scheme 20

As shown in Scheme 20, compounds of formula 63, which are typical representatives of compounds of formula (I), where A is (vi), can be prepared as follows. Compounds of formula 33, wherein R ₁ is as defined in formula (I), when treated with a suitable chlorinating agent such as thionyl chloride, compounds of formula 61 will be provided. Compounds of formula 61, when treated with 2- (trimethylsilyl) -2H-1 , 2,3-triazole, 62, in a solvent such as sulfolane, will provide a compound of formula 63.

Scheme 21

As shown in Scheme 21, compounds of formula 66, which are typical representatives of compounds of formula (I), where A is (ix), can be obtained as follows. Compounds of formula 61, where R ₁ is as defined in formula (I), when they are treated with hydrazine in a suitable solvent such as tetrahydrofuran, will provide compounds of formula 64. Compounds of formula 64, when treated with trimethyl orthoformate, 65, in the presence of a catalytic amount p-toluenesulfonic acid in a solvent such as tetrahydrofuran will provide compounds of formula 66.

Scheme 22

As shown in Scheme 22, compounds of formula 69, which are typical representatives of compounds of formula (I), wherein A is defined in formula (I), can be prepared as follows. Compounds of formula 67, wherein R _y is hydrogen, alkyl, aryl, or two R _y groups, together with the boron atom to which they are bonded, form 1,3-dioxoborolan in the presence of a palladium catalyst using the Suzuki reaction conditions described in Scheme 1 in the presence of heteroaryl iodide (AI), compounds of formula 68 are provided. Compounds of formula 68 are converted to compounds of formula 69 by treatment with hydrazine as described in Scheme 6.

Scheme 23

As shown in Scheme 23, compounds of formula 74, which are typical representatives of compounds of formula (I), wherein R _ii and R ₄ are as defined for formula (I), are prepared starting from a compound of formula 70, where X ₁ is iodine , bromine or chlorine. Treatment of compounds of formula 70 first with hydrazine and then with di-tert-butyl dicarbonate as described in Scheme 6 gives compounds of formula 71. Compounds of formula 71, when reacted with acid chlorides of formula 18 in the presence of a base such as potassium carbonate, in tetrahydrofuran, at ambient temperature, compounds of formula 72 are provided for 2 to 8 hours. Alternatively, compounds of formula 72 can be prepared from compounds of formula 71 using the conditions described in Scheme 6. Compounds of formula 72 are subjected to reacting with (trimethylsilyl) acetylene under the conditions described in Schemes 5 and 6 to give compounds of formula 73. Compounds of formula 74 are prepared from compounds of formula 73 by treating R _ii -N ₃ in aqueous tert-butanol in the presence of copper sulfate (II ) and (R) -2 - ((S) -1,2-dihydroxyethyl) -4-hydroxy-5-oxo-2,5-dihydrofuran-3-sodium olate, at 40-80 ° C for a period of time from 1 up to 6 hours.

Scheme 24

As shown in Scheme 24, compounds of formula 76, which are representative of compounds of formula (I), wherein A and R _{4 are} defined for formula (I), are prepared from compounds of formula 75. Compounds of formula 75 can be treated with -B (OR _y ) ₂ where A has the meanings defined for formula (I), and R _y represents hydrogen, alkyl, aryl, or two R _y groups together with the boron atom to which they are attached form 1,3-dioxoborolan in the presence of a palladium catalyst using the Suzuki reaction conditions described in Scheme 1 to give a compound of the formula 76.

Pattern 25

As shown in Scheme 25, compounds of formula 80, which are representative of compounds of formula (I), wherein R _ii and R _{4 are} defined for formula (I), are prepared as follows. Compounds of formula 77 and 78 are coupled under the Still conditions of binding described in Scheme 3 to give compounds of formula 79. Compounds of formula 79, when reacted as described in Scheme 6, provide compounds of formula 80.

Scheme 26

As shown in Scheme 26, the compounds of formulas 82, 83 _. 84 and 85, which are typical representatives of compounds of formula (I), wherein A, R ₄ , R ₅ , R _a and R _j are as defined for formula (I), are prepared from compounds of formula 81. Compounds of formula 81 can be treated acid chloride, 18, in a solvent such as tetrahydrofuran, in the presence of a base such as potassium carbonate or triethylamine, to give compounds of formula 82. An alternative solvent is dichloromethane, and pyridine is an alternative base. Acid chlorides can be obtained from the corresponding carboxylic acids by treatment with oxalyl chloride with a catalytic amount of N, N-dimethylformamide. To obtain compounds of formula 83, compounds 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 treating R ₅ SO ₂ Cl in pyridine at or near room temperature. Compounds of formula 85 are also prepared from compounds of formula 81 in a reductive amination reaction with R _a CHO 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 at or near room temperature, and followed by treatment with trifluoroacetic acid in dichloromethane to remove the tert-butoxycarbonyl protecting group.

Scheme 27

As shown in Scheme 27, compounds of formula 87, where A, R _j and R _{k are} defined for formula (I), can be obtained from compounds of formula 86. Compounds of formula 86 are prepared as described for compounds of formula 82 in Scheme 26. Compounds of formula 86 it can then be heated in the presence of an amine, HNR _j R _k , and a base such as triethylamine in a solvent such as acetonitrile to give compounds of formula 87. Alternatively, the amine can be replaced by heterocycles such as pyrrolidine, piperidine, piperazine and morpholine.

Scheme 28

As shown in Scheme 28, compounds of formula 89, where A, R ₁ , R ₂ , R ₃ , m, Z _c and Z _{d are} defined for formula (I), can be obtained from compounds of formula 88. Compounds of formula 88 can be prepared as described in Schemes 1-4, 7-9, 22, 24 and 26. In the process of preparing compounds of formula 88, the carboxylic acid group as a side chain in A can be protected as an ester and then hydrolyzed, leaving the carboxylic acid open without protection, by methods known to those skilled in the art of organic synthesis. Compounds of formula 88, when treated with amine (HNZ _c Z _d ) using the carboxylic acid-amine coupling conditions known to those skilled in the art, will provide compounds of formula 89. Standard carboxylic acid-amine coupling conditions include the addition of a coupling reagent such as but not limited to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1,3-dicyclohexylcarbodiimide (DCC), bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (BOPCl), O- hexafluorophosphate (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetra amethyluronium (HATU) or tetrafluoroborate O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium (TBTU), optionally in the presence of a base such as triethylamine or diisopropylethylamine, with or without an excipient, such as but not limited to, 1-hydroxy-7-azabenzotriazole (HOAT) or 1-hydroxybenzotriazole hydrate (HOBT), in a solvent such as, but not limited to, dichloromethane or N, N-dimethylformamide.

EXAMPLES

The compounds and methods of the present invention will be better understood when referring to the examples below, which are intended to illustrate and not limit the scope of the present invention.

Example 1

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

Example 1A

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

To a solution of 4-iodo-2-methylaniline (20 g, 83.24 mmol) in chloroform (250 ml) cooled in an ice bath was added dropwise a solution of acetic anhydride (21.2 g, 208.11 mmol) in chloroform (50 ml ) Upon completion of the addition, the mixture was stirred at room temperature for 1 hour. Potassium acetate (2.5 g, 24.97 mmol) and isoamyl nitrite (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 phase 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-butyl dicarbonate (23.6 g, 108.2 mmol) and a catalytic amount of dimethylaminopyridine (~ 5 mg) were added. The mixture was stirred at room temperature for 2 hours, diluted with water, extracted with dichloromethane, dried with sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the title compound. MS (ESI +) m / z 344.9 (M + H) ⁺ .

Example 1B

tert-Butyl 5 - ((trimethylsilyl) ethynyl) -1H-indazole-1-carboxylate

The compound of Example 1A (10.81 g, 31.4 mmol), dichlorobis (triphenylphosphine) palladium (II) (1.1 g, 1.57 mmol) and copper (I) iodide (365 mg, 1.92 mmol) were combined in triethylamine (70 ml) in an inert atmosphere. Trimethylsilylacetylene (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 a 1N hydrochloric acid solution. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 5-40% ethyl acetate in hexane to elute to give the title compound. MS (ESI +) m / z 215.0 (M-99) ⁺ .

Example 1C

5-Ethinyl-1H-indazole

The compound of Example 1B (7.93 g, 25.2 mmol) was dissolved in methanol (150 ml). A 1N potassium hydroxide solution (50 ml) was added and the mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting suspension was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure to obtain the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.24 (s, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 7.55 (d, J = 8.82 Hz, 1H), 7.39 (dd, J = 8.48, 1.36 Hz, 1H), 4.03 (s, 1H).

Example 1D

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

100.0 mg (0.70 mmol) of the compound of Example 1C and 94 mg (0.70 mmol) of benzylazide were added to the microwave heating vessel. The mixture was heated at 160 ° C for 20 minutes using microwave irradiation (CEM-Discover, 100 watts, time to rise to a predetermined level of 1 minute). The mixture was dissolved in ethyl acetate and purified by silica gel chromatography using 75% ethyl acetate in hexane to elute to give the title compounds. H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.28 (s, 1H), 13.12 (s, 1H), 8.61 (s, 1H), 8.23 (s, 1H), 8.13 (s, 1H), 8.11 (s , 1H), 7.94 (s, 1H), 7.82-7.89 (m, 2H), 7.56-7.70 (m, 2H), 7.20-7.44 (m, 9H ), 6.97-7.02 (m, 2H), 5.69 (s, 2H), 5.65 (s, 2H). MS (CI) m / z 276 (M + H) ⁺ .

Example 2

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

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) were added to the microwave heating vessel. The mixture was heated at 160 ° C for 20 minutes using microwave irradiation (CEM-Discover, 100 watts, time to rise to a predetermined level of 1 minute). 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 and concentrated under reduced pressure and purified by silica gel chromatography using 80% ethyl acetate in hexane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.16 (s, 1H), 8.31 (s, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 7.87 (d, J = 8.82 Hz, 1H ), 7.62 (d, J = 8.82 Hz, 1H). MS (CI) m / z 186 (M + H) ⁺ .

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 a solution of 4-iodo-2-methylaniline (20 g, 83.24 mmol) in chloroform (250 ml) cooled in an ice bath was added dropwise through a dropping funnel a solution of acetic anhydride (21.2 g, 208.11 mmol) in chloroform (50 ml). Upon completion of the addition, the mixture was stirred at room temperature for 1 hour. Potassium acetate (2.5 g, 24.97 mmol) and isoamyl nitrite (22.3 ml, 166.48 mmol) were added and the mixture was heated at 70 ° C for 20 hours. The mixture was then cooled and 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 and 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-butyl dicarbonate (23.6 g, 108.2 mmol) and a catalytic amount of dimethylaminopyridine (~ 5 mg) were added. The mixture was stirred at room temperature for 2 hours, quenched with water, extracted with dichloromethane and dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure to obtain the title compound. MS (ESI +) m / z 344.9 (M + H) ⁺ .

Example 3B

tert-Butyl 5 - ((trimethylsilyl) ethynyl) -1H-indazole-1-carboxylate

The compound of Example 3A, (10.81 g, 31.4 mmol), dichlorobis (triphenylphosphine) palladium (II) (1.1 g, 1.57 mmol) and copper (I) iodide (365 mg, 1.92 mmol) combined in triethylamine (70 ml) in an inert atmosphere. Trimethylsilylacetylene (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 a 1N hydrochloric acid solution. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 5-40% ethyl acetate in hexane to elute to give the title compound. MS (ESI +) m / z 215.0 (M-99) ⁺ .

Example 3C

5-Ethinyl-1H-indazole

The compound of Example 3B (7.93 g, 25.2 mmol) was dissolved in methanol (150 ml). A 1N potassium hydroxide solution (50 ml) was added and the mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure, and the resulting suspension 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 obtain the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.24 (s, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 7.55 (d, J = 8.82 Hz, 1H), 7.39 (dd, J = 8.48, 1.36 Hz, 1H), 4.03 (s, 1H).

3D example

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

The compound of Example 3C (40 mg, 0.28 mmol), benzylazide (37 mg, 0.28 mmol), CuSO ₄ (14 mg, 0.056 mmol) and copper wire (14 mg) were combined in tert-butanol (0.5 ml ) and water (0.5 ml) and heated in a CEM-Discover microwave reactor for 10 minutes at 125 ° C and 100 watts. 1M HCl and water were added to the mixture, the product was extracted with dichloromethane and purified by silica gel chromatography (50% ethyl acetate in hexane) to obtain the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.10 (s, 1H), 8.60 (s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.85 (d, J = 8.59, 1, 53 Hz, 1H), 7.59 (d, J = 8.59 Hz, 1H), 7.26-7.49 (m, 5H), 5.65 (s, 2H). MS (ESI +) m / z 276.0 (M + H) ⁺ .

Example 4

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

17.6 mg (0.124 mmol) of the compound of Example 3C, 300 μl of an aqueous solution containing 7.80 mg (0.118 mmol) of azide was added to a 5 ml CEM Microwave reaction tube equipped with a Teflon-coated micro-flea rod stirrer. sodium; followed by 15.79 μl (0.118 mmol; 21.80 mg 0.95 equivalent) of 2-methyl-benzyl bromide (added without solvent). 300 μl of tert-butanol was then added to the suspension; 25 mg of copper wire; and finally 50 μl of a 1 N aqueous solution of copper sulfate pentahydrate. The microwave reaction vessel was then lidded and heated with stirring for 10 minutes at 125 ° C. at 100 watts in a CEM-Discover microwave device. After cooling to ambient temperature, the mixture was diluted with 0.25 N aqueous HCl; and the aqueous suspension was extracted with dichloromethane. The organic layer was washed with distilled water; saturated aqueous NaCl; and then dried over anhydrous sodium sulfate and filtered. The dried solution was diluted with acetonitrile; and the soluble organic matter was then filtered through a glass wool plug onto which an additional layer of anhydrous sodium sulfate was applied on top. An aliquot of the filtrate was then taken for subsequent LC / MS analysis. Those solutions that contained the desired triazole product were then evaporated in vacuo and then redissolved in 1.50 ml of a 1: 1 DMSO / methanol mixture. The solution of the crude triazole product was then purified by reverse phase HPLC using an acetonitrile / water 0.1% TFA gradient elution method to give the title compound. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 2.37 (s, 3H), 5.66 (s, 2H), 7.16-7.34 (m, 4H), 7.63 (d, J = 8.54 Hz, 1H), 7.87 (d, J = 8.70, 1.37 Hz, 1H), 8.14 (s, 1H), 8.25 (s, 1H), 8.49 (s, 1H). MS (ESI +) m / z 289.9 (M + H) ⁺ .

Example 5

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

The title compound was prepared according to the procedure described in Example 4, with the replacement of 2-methylbenzyl bromide with 3-methylbenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.58 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 8.85, 1.53 Hz, 1H), 7.64 (d, J = 8.54 Hz, 1H), 7.30 (t, J = 7.63 Hz, 1H), 7.14-7.24 (m, 3H), 5.60 (s, 2H) 2.31 (s, 3H). MS (ESI +) m / z 289.8 (M + H) ⁺ .

Example 6

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted with 4-methylbenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.55 (s, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 7.86 (d, J = 8.54, 1.53 Hz, 1H), 7.63 (d, J = 8.85 Hz, 1H), 7.25-7.33 (m, 2H), 7.18-7.24 (m, 2H), 5.59 (s, 2H), 2, 29 (s, 3H). MS (ESI +) m / z 290.1 (M + H) ⁺ .

Example 7

5- [1- (3-methoxybenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole The title compound was prepared according to the procedure for Example 4 with 2-methylbenzyl bromide 3 substituted -methoxybenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.59 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 8.54, 1.53 Hz, 1H), 7.64 (d, J = 8.85 Hz, 1H), 7.33 (t, J = 7.93 Hz, 1H), 6.89-7.00 (m, 3H), 5.62 (s, 2H) 3.76 (s, 3H). MS (ESI +) m / z 306.1 (M + H) ⁺ .

Example 8

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted with 2-fluorobenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.57 (s, 1H), 8.25 (s, 1H), 8.12-8.17 (m, 1H), 7.87 (d, J = 8.54, 1.53 Hz, 1H) 7.64 (d, J = 8.54 Hz, 1H), 7.41-7.49 (m, J = 7.32, 7.32 Hz, 2H), 7.22-7.33 (m , J = 7.02 Hz, 2H); 5.71 (s, 2H). MS (ESI +) m / z 293.9 (M + H) ⁺ .

Example 9

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

The title compound was prepared according to the procedure described in Example 4, with the substitution of 2-methylbenzyl bromide by 3-fluorobenzyl bromide. H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.61 (s, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 7.87 (d, J = 8.85, 1.53 Hz, 1H), 7.64 (d, J = 8.54 Hz, 1H), 7.41-7.51 (m, 1H), 7.15-7.28 (m, 3H), 5.68 (s, 2H). MS (ESI +) m / z 293.8 (M + H) ⁺ .

Example 10

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted with 4-fluorobenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.58 (s, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 7.86 (d, J = 8.85, 1.53 Hz, 1H), 7.64 (d, J = 8.85 Hz, 1H), 7.46 (d, J = 8.85, 5.49 Hz, 2H), 7.24 (t, J = 9.00 Hz, 2H), 5 64 (s, 2H). MS (ESI +) m / z 293.9 (M + H) ⁺ .

Example 11

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted with 2-chlorobenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.56 (s, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.88 (d, J = 8.54, 1.53 Hz, 1H), 7.64 (d, J = 8.54 Hz, 1H), 7.55 (d, J = 7.63, 1.53 Hz, 1H), 7.32-7.48 (m, 3H), 5.76 ( s, 2H). MS (ESI +) m / z 309.8 (M + H) ⁺ .

Example 12

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted with 3-chlorobenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.62 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.87 (d, J = 8.54, 1.53 Hz, 1H), 7.64 (d, J = 8.54 Hz, 1H), 7.40-7.49 (m, J = 7.63 Hz, 3H), 7.35 (d, J = 6.41 Hz, 1H), 5 67 (s, 2H). MS (ESI +) m / z 309.8 (M + H) ⁺ .

Example 13

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted with 4-chlorobenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.58 (s, 1H), 8.24 (s, 1H), 8.15 (s, 1H), 7.86 (d, J = 8.54, 1.53 Hz, 1H), 7.64 (d, J = 8.85 Hz, 1H), 7.45-7.52 (m, 2H), 7.38-7.44 (m, 2H), 5.65 (s, 2H). MS (ESI-) m / z 307.7 (MH) ^- .

Example 14

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted with 2-bromobenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.55 (s, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.88 (d, J = 8.54, 1.53 Hz, 1H), 7.72 (d, J = 7.93 Hz, 1H), 7.64 (d, J = 8.54 Hz, 1H), 7.41-7.50 (m, 1H), 7.27-7.40 ( m, 2H); 5.74 (s, 2H). MS (ESI +) m / z 353.5 (M + H) ⁺ .

Example 15

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted with 2-nitrobenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.57 (s, 1H), 8.27 (s, 1H), 8.12-8.22 (m, 2H), 7.88 (d, J = 8.54, 1.53 Hz, 1H) 7.75-7.83 (m, 1H), 7.60-7.72 (m, 2H), 7.27 (d, J = 7.63 Hz, 1H), 6.02 (s, 2H ) MS (ESI +) m / z 320.8 (M + H) ⁺ .

Example 16

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted with 3-nitrobenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.65 (s, 1H), 8.21-8.28 (m, 3H), 8.15 (s, 1H), 7.80-7.91 (m, 2H), 7.73 (t, J = 7.78 Hz, 1H), 7.65 (d, J = 8.54 Hz, 1H), 5.83 (s, 2H). MS (ESI +) m / z 320.8 (M + H) ⁺ .

Example 17

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted with 4-nitrobenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.64 (s, 1H), 8.22-8.31 (m, 3H), 8.15 (s, 1H), 7.88 (d, J = 8.70, 1.37 Hz, 1H) 7.57-7.68 (m, 3H); 5.83 (s, 2H). MS (ESI +) m / z 320.7 (M + H) ⁺ .

Example 18

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted with 2-cyanobenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.61 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.93 (d, J = 7.63 Hz, 1H), 7.88 (d, J = 8.54, 1.53 Hz, 1H), 7.72-7.80 (m, 1H), 7.57-7.68 (m, 2H), 7.53 (d, J = 7.93 Hz, 1H), 5.86 (s, 2H). MS (ESI +) m / z 300.9 (M + H) ⁺ .

Example 19

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

The title compound was prepared according to the procedure described in Example 4, with the replacement of 2-methylbenzyl bromide with 3-cyanobenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.63 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.85-7.93 (m, 2H), 7.83 (d, J = 7, 63 Hz, 1H), 7.72 (d, J = 8.24 Hz, 1H), 7.56-7.68 (m, 2H), 5.74 (s, 2H). MS (ESI +) m / z 300.9 (M + H) ⁺ .

Example 20

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted with 4-cyanobenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.62 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.82-7.93 (m, J = 8.24 Hz, 3H), 7.65 (d, J = 8.54 Hz, 1H), 7.54 (d, J = 8.24 Hz, 2H), 5.78 (s, 2H). MS (ESI +) m / z 300.7 (M + H) ⁺ .

Example 21

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted with 2-trifluoromethylbenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.56 (s, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 7.89 (d, J = 8.85, 1.53 Hz, 1H), 7.85 (d, J = 7.93 Hz, 1H), 7.72 (t, J = 7.63 Hz, 1H), 7.55-7.68 (m, 2H), 7.33 (d, J = 7.93 Hz, 1H); 5.85 (s, 2H). MS (ESI +) m / z 300.7 (M + H) ⁺ .

Example 22

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

The title compound was prepared according to the procedure described in Example 4, with the replacement of 2-methylbenzyl bromide with 3-trifluoromethylbenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.65 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 8.70, 1.37 Hz, 1H), 7.77 (s, 1H), 7.71-7.76 (m, 1H), 7.61-7.69 (m, 3H), 5.78 (s, 2H). MS (ESI +) m / z 344.0 (M + H) ⁺ .

Example 23

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

The title compound was prepared according to the procedure described in Example 4, with the substitution of 2-methylbenzyl bromide by 4-trifluoromethylbenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.63 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 8.54 Hz, 1H), 7.78 (d, J = 7.93 Hz, 2H), 7.63 (d, J = 8.54 Hz, 1H), 7.58 (d, J = 7.93 Hz, 2H), 5.78 (s, 2H). MS (ESI +) m / z 344.2 (M + H) ⁺ .

Example 24

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted by 3-trifluoromethoxybenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.64 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 8.54 Hz, 1H), 7.64 (d, J = 8.54 Hz, 1H), 7.56 (t, J = 8.24 Hz, 1H), 7.31-7.45 (m, 3H), 5.73 (s, 2H). MS (ESI +) m / z 359.9 (M + H) ⁺ .

Example 25

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

The title compound was prepared according to the procedure described in Example 4, with the replacement of 2-methylbenzyl bromide with 4-trifluoromethoxybenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.61 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 8.70, 1.37 Hz, 1H), 7.63 (d, J = 8.54 Hz, 1H), 7.52 (d, J = 8.85 Hz, 2H), 7.40 (d, J = 8.24 Hz, 2H), 5.70 (s , 2H). MS (ESI +) m / z 359.9 (M + H) ⁺ .

Example 26

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted with 4-tert-butylbenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.58 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.86 (d, J = 8.85, 1.53 Hz, 1H), 7.63 (d, J = 8.54 Hz, 1H), 7.42 (d, J = 8.24 Hz, 2H), 7.32 (d, J = 8.24 Hz, 2H), 5.60 (s , 2H); 1.26 (s, 9H). MS (ESI +) m / z 332.1 (M + H) ⁺ .

Example 27

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

The title compound was prepared according to the procedure described in Example 4, with the replacement of 2-methylbenzyl bromide by 3-carbomethoxybenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.62 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.92-7.99 (m, 2H), 7.87 (d, J = 8, 54, 1.53 Hz, 1H), 7.68 (d, J = 7.63 Hz, 1H), 7.63 (d, J = 8.54 Hz, 1H), 7.58 (t, J = 7.63 Hz, 1H), 5.75 (s, 2H), 3.86 (s, 3H). MS (ESI +) m / z 333.9 (M + H) ⁺ .

Example 28

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

The title compound was prepared according to the procedure described in Example 4, with the replacement of 2-methylbenzyl bromide by 4-carbomethoxybenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.62 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.99 (d, J = 8.24 Hz, 2H), 7.87 (d, J = 8.85 Hz, 1H), 7.63 (d, J = 8.54 Hz, 1H), 7.49 (d, J = 8.24 Hz, 2H), 5.76 (s, 2H), 3.85 (s, 3H). MS (ESI +) m / z 333.9 (M + H) ⁺ .

Example 29

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

The title compound was prepared according to the procedure described in Example 4 with substitution of 2-methylbenzyl bromide 2,4-dimethylbenzyl chloride. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.45 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.86 (d, J = 8.54 Hz, 1H), 7.62 (d, J = 8.54 Hz, 1H), 7.12 (d, J = 7.93 Hz, 1H), 7.07 (s, 1H), 7.04 (d, J = 7.63 Hz, 1H), 5.60 (s, 2H); 2.32 (s, 3H); 2.26 (s, 3H). MS (ESI +) m / z 304.0 (M + H) ⁺ .

Example 30

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

The title compound was prepared according to the procedure described in Example 4, with the replacement of 2-methylbenzyl bromide by 3,5-dimethylbenzyl bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.56 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.87 (d, J = 8.54 Hz, 1H), 7.63 (d, J = 8.54 Hz, 1H), 6.95-7.01 (m, 3H), 5.55 (s, 2H), 2.26 (s, 6H). MS (ESI +) m / z 304.2 (M + H) ⁺ .

Example 31

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted by 2,3-dichlorobenzyl chloride. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.59 (s, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.88 (d, J = 8.70, 1.37 Hz, 1H), 7.69 (d, J = 8.09, 1.37 Hz, 1H), 7.63 (d, J = 8.54 Hz, 1H), 7.44 (t, J = 7.78 Hz, 1H), 7 31 (d, J = 7.78, 1.07 Hz, 1H); 5.81 (s, 2H). MS (ESI +) m / z 343.8 (M + H) ⁺ .

Example 32

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted by 2,4-dichlorobenzyl chloride. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.56 (s, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 7.87 (d, J = 8.54 Hz, 1H), 7.72 (d, J = 2.14 Hz, 1H), 7.63 (d, J = 8.54 Hz, 1H), 7.50 (d, J = 8.39, 1.98 Hz, 1H), 7.40 (d , J = 8.24 Hz, 1H); 5.74 (s, 2H). MS (ESI-) m / z 341.8 (MH) ^- .

Example 33

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted by 2,5-dichlorobenzyl chloride. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.59 (s, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.88 (d, J = 8.85 Hz, 1H), 7.63 (d, J = 8.85 Hz, 1H), 7.56-7.61 (m, 1H), 7.49-7.55 (m, 1H), 7.47 (d, J = 2.44 Hz, 1H) 5.75 (s, 2H). MS (ESI +) m / z 343.8 (M + H) ⁺ .

Example 34

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted by 3,5-dichlorobenzyl chloride. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.64 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.87 (d, J = 8.85 Hz, 1H), 7.57-7.71 (m, 2H), 7.44 (d, J = 1.53 Hz, 2H), 5.69 (s, 2H). MS (ESI +) m / z 344.1 (M + H) ⁺ .

Example 35

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

The title compound was prepared according to the procedure described in Example 4, with 2-methylbenzyl bromide substituted by 2,4-bis (trifluoromethyl) bromide. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.62 (s, 1H), 8.27 (s, 1H), 8.07-8.18 (m, 3H), 7.89 (d, J = 8.70, 1.37 Hz, 1H) 7.64 (d, J = 8.54 Hz, 1H); 7.49 (d, J = 7.93 Hz, 1H); 5.96 (s, 2H). MS (ESI +) m / z 411.7 (M + H) ⁺ .

Example 36

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

Example 36A

1H-indazole-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 solution of 1.6 M n-butyllithium 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 was stirred for 15 minutes. The mixture was then quenched with water, extracted with ethyl acetate, pre-absorbed onto silica gel and purified by silica gel chromatography using a gradient of 10-30% ethyl acetate in hexane to elute to give the title compound. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 10.03 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 7.85 (dd, J = 8.70, 1.37 Hz, 1H), 7.69 (d, J = 8.54 Hz, 1H).

Example 36B

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

The compound 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 vessel. The vessel 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 an acetonitrile / water 0.1% TFA gradient elution method to give the title compound in the form of a TFA salt. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.12 (s, 1H), 8.32 (s, 1H), 8.13 (s, 1H), 8.05 (d, J = 8.85, 1.22 Hz, 1H), 7.92 (d, J = 4.27 Hz, 1H), 7.60 (d, J = 8.54 Hz, 1H), 7.37 (d, J = 3.66 Hz, 1H), 4.89 (s , 1H), 2.78-2.94 (m, 1H), 1.73-1.83 (m, 2H), 1.58-1.68 (m, 2H), 1.45-1.53 (m, 1H), 1.16-1.29 (m, 2H), 1.04-1.14 (m, 3H). MS (ESI +) m / z 338.1 (M + H) ⁺ .

Example 37

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

The title compound was prepared according to the procedure described in Example 36B with 2-aminothiazole substituted with 2-aminopyridine. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.04 (s, 1H), 8.57 (s, 1H), 8.23-8.39 (m, 2H), 8.11 (s, 1H), 7.57 (d, J = 8, 54 Hz, 1H), 7.46 (d, J = 8.85 Hz, 1H), 7.12-7.21 (m, 1H), 6.88 (t, J = 6.71 Hz, 1H) 4.78 (d, J = 5.80 Hz, 1H), 2.78-2.91 (m, 1H), 1.69-1.77 (m, J = 10.98 Hz, 2H), 1.57-1.67 (m, 2H), 1.45-1.53 (m, 1H), 1.21-1.34 (m, 2H), 1.01-1.16 (m, 3H ) MS (ESI +) m / z 332.1 (M + H) ⁺ .

Example 38

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

The title compound was prepared according to the procedure described in Example 36B with 2-aminothiazole substituted with 2-aminopyrazine. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.12 (s, 1H), 8.90 (d, J = 1.22 Hz, 1H), 8.61 (s, 1H), 8.37 (d, J = 4.58, 1.53 Hz , 1H), 8.29 (d, J = 8.70, 1.37 Hz, 1H), 8.15 (s, 1H), 7.85 (d, J = 4.58 Hz, 1H), 7 62 (d, J = 8.85 Hz, 1H), 5.05 (d, J = 6.71 Hz, 1H), 2.81-2.99 (m, 1H), 1.70-1, 77 (m, J = 10.68 Hz, 2H), 1.58-1.67 (m, 2H), 1.47 (s, 1H), 1.24-1.38 (m, 2H), 1 00-1.16 (m, 3H). MS (ESI +) m / z 333.1 (M + H) ⁺ .

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 was added to a 20 ml scintillation vessel. To this solid was added 2.0 ml of a solution of dimethylformamide containing 0.46 mmol (49 mg) of benzylamine and 50 mg of powdered activated 4Å molecular sieves. The vessel was then closed with a lid and heated at 60 ° C for 4 hours on an orbital shaker. The vessel was allowed to cool to ambient temperature; and the lid was opened. 32 mg (0.23 mmol) of anhydrous potassium carbonate was added to the suspension, followed by 66 mg (0.23 mmol) of α- (p-toluenesulfonyl) -4-fluorobenzylisonitrile. The vessel was then covered with a lid and heated overnight at 60 ° C on a shaker. The vessel was removed from the shaker; allowed to cool to ambient temperature; and the resulting suspension was filtered. The filtrate was evaporated under reduced pressure with moderate heating on a Savant Speed Vac. The crude residues were redissolved in a 1: 1 DMSO / methanol mixture and purified by reverse phase HPLC using gradient elution with the acetonitrile / water TFA method to give the title compound in the form of a TFA salt. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.01 (s, 1H), 8.12 (s, 1H), 7.76 (s, 1H), 7.60 (d, J = 8.48 Hz, 2H), 7.32-7.45 (m, 2H), 7.09-7.30 (m, 6H), 6.96 (d, J = 6.61, 2.88 Hz, 2H), 5.23 (s, 2H). MS (ECI) m / z 369 (M + H) ⁺ .

Example 40

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

The title compound was obtained in the form of a TFA salt in accordance with the procedure described in Example 39, with the substitution of benzylamine N ¹ , N ¹ -dimethylpropane-1,3-diamine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 9.49 (s, 1H), 8.88 (s, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.73 (d, J = 8.81 Hz, 1H ), 7.29-7.44 (m, 3H), 7.17 (t, J = 8.98 Hz, 2H), 4.01 (t, J = 7.12 Hz, 2H), 2.89 -3.04 (m, J = 10.51 Hz, 2H), 2.68 (s, 3H), 2.67 (s, 3H), 1.87-2.02 (m, 2H). MS (ECI) m / z 364 (M + H) ⁺ .

Example 41

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

The title compound was prepared in the form of a TFU salt according to the procedure described in Example 36B using pyrimidin-2-amine instead of thiazole-2-amine. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.21-13.41 (m, 1H), 9.07 (d, J = 5.80 Hz, 1H), 8.85 (d, J = 3.05 Hz, 1H), 8.51 (s , 1H), 8.24 (s, 1H), 8.14 (d, J = 8.70, 1.37 Hz, 1H), 7.73 (d, J = 8.85 Hz, 1H), 7 , 47-7.56 (m, 1H), 5.25-5.41 (m, J = 2.75 Hz, 1H), 2.81-2.91 (m, J = 10.53, 10, 53 Hz, 1H), 1.74-1.83 (m, 2H), 1.56-1.66 (m, 2H), 1.43-1.50 (m, 1H), 1.24 (q ., J = 1 1.09 Hz, 2H), 1.00-1.14 (m, 3H). MS (ESI +) m / z 333.1 (M + H) ⁺ .

Example 42

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

The title compound was prepared according to the procedure described in Example 39 using 1-phenylethanamine instead of benzylamine. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.04 (s, 1H), 7.75-7.84 (m, 1H), 7.35-7.55 (m, 4H), 7.20-7.31 (m, 5H), 6, 76-7.01 (m, 4H), 5.09 (q, J = 7.12 Hz, 1H), 1.82 (d, 3H). MS (ECI) m / z 383 (M + H) ⁺ .

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 vessel. The vessel was sealed and shaken at ambient temperature for 30 minutes. Isopropylisocyanide (27 ml, 0.286 mmol) was added and the mixture was shaken at ambient temperature overnight and then at 40 ° C for 2 hours. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 0-5% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.08 (s, 1H), 8.75 (d, J = 6.95, 1.86 Hz, 1H), 8.60 (s, 1H), 8.31 (d, J = 8.82, 1.36 Hz, 1H), 8.20 (d, J = 4.75 Hz, 1H), 8.14 (s, 1H), 7.60 (d, J = 8.82 Hz, 1H), 7 03 (d, J = 6.78, 4.07 Hz, 1H), 6.54 (d, J = 4.75 Hz, 1H), 4.86 (d, J = 5.09 Hz, 1H) 1.05 (d, J = 6.10 Hz, 6H). MS (ESI +) m / z 293.0 (M + H) ⁺ .

Example 44

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

Example 44A

tert-Butyl 5-bromo-1H-indazole-1-carboxylate

5-Bromoindazole (4.40 g, 22.3 mmol) and a catalytic amount of dimethylaminopyridine (~ 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 absorbed on silica gel and purified by silica gel chromatography using a gradient of 0-40% ethyl acetate in hexane to elute to give the title compound. MS (ESI +) m / z 297.2 (M + H) ⁺ .

Example 44B

tert-Butyl 5-acetyl-1H-indazole-1-carboxylate

The compound of Example 44A (5.12 g, 17.2 mmol), tributyl (1-ethoxyvinyl) tin (7.0 ml, 20.7 mmol) and dichlorbis (triphenylphosphine) palladium (II) (672 mg, 0.957 mmol) were combined in toluene (85 ml). Nitrogen was bubbled into the mixture for 5 minutes and the mixture was heated to 100 ° C in a sealed tube overnight. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 0-40% ethyl acetate in hexane to elute to give 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 absorbed on silica gel and purified by silica gel chromatography using a gradient of 0-40% ethyl acetate in hexane to elute to give 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

The compound 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 vessel. The vessel was shaken at 80 ° C. overnight. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of methanol in dichloromethane (0-5%) to elute to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.08 (s, 1H), 10.23 (s, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.93 (d, J = 8.59, 1, 53 Hz, 1H), 7.75 (d, J = 8.75, 1.07 Hz, 1H), 7.58 (d, J = 8.90 Hz, 1H), 7.36 (d, J = 8.59, 7.36 Hz, 1H), 7.25 (s, 1H), 6.92-7.02 (m, 1H). MS (ESI +) m / z 292.9 (M + H) ⁺ .

Example 45

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

The title compound was prepared according to the procedure described in Example 44D, with 1-phenyl-2-thiourea substituted with thioacetamide. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.10 (s, 1H), 8.34 (s, 1H), 8.12 (s, 1H), 7.94 (d, J = 8.82, 1.70 Hz, 1H), 7.85 (s, 1H), 7.57 (d, J = 8.82 Hz, 1H), 2.73 (s, 3H). MS (ESI +) m / z 215.9 (M + H) ⁺ .

Example 46

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

The title compound was prepared according to the procedure described in Example 44D, with 1-phenyl-2-thiourea substituted with ethylthiourea. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.04 (s, 1H), 8.21 (s, 1H), 8.09 (s, 1H), 7.83 (d, J = 8.65, 1.53 Hz, 1H), 7.58 (t, J = 5.43 Hz, 1H), 7.51 (d, J = 8.82 Hz, 1H), 6.96 (s, 1H), 3.22-3.34 (m, 2H) 1.21 (t, J = 7.29 Hz, 3H). MS (ESI +) m / z 244.9 (M + H) ⁺ .

Example 47

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

The title compound was prepared according to the procedure described in Example 44D, with 1-phenyl-2-thiourea substituted by 1-benzyl-2-thiourea. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.02 (s, 1H), 8.21 (s, 1H), 8.12 (t, J = 5.83 Hz, 1H), 8.08 (s, 1H), 7.83 (d, J = 8.90, 1.53 Hz, 1H), 7.50 (d, J = 8.90 Hz, 1H), 7.39-7.45 (m, 2H), 7.35 (t, J = 7.52 Hz, 2H), 7.26 (t, J = 7.21 Hz, 1H), 6.97 (s, 1H), 4.54 (d, J = 5.83 Hz, 1H). MS (ESI +) m / z 306.9 (M + H) ⁺ .

Example 48

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

The title compound was prepared according to the procedure described in Example 44D, with the replacement of 1-phenyl-2-thiourea with thiourea. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.03 (s, 1H), 8.17 (s, 1H), 8.07 (s, 1H), 7.81 (d, J = 8.82, 1.36 Hz, 1H), 7.50 (d, J = 8.82 Hz, 1H), 7.01 (s, 2H), 6.92 (s, 1H). MS (ESI +) m / z 216.9 (M + H) ⁺ .

Example 49

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

The title compound was prepared according to the procedure described in Example 44D with 1-phenyl-2-thiourea substituted by 1-phenethylthiourea. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.03 (s, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 7.85 (d, J = 8.65, 1.53 Hz, 1H), 7.71 (t, J = 5.43 Hz, 1H), 7.51 (d, J = 8.82 Hz, 1H), 7.26-7.36 (m, 4H), 7.18-7.26 ( m, 1H), 6.97 (s, 1H), 3.47-3.59 (m, 1H), 2.94 (t, J = 7.44 Hz, 1H). MS (ESI +) m / z 321.0 (M + H) ⁺ .

Example 50

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

The title compound was prepared according to the procedure described in Example 43 using benzyl isocyanide instead of isopropyl isocyanide. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.10 (s, 1H), 8.50-8.58 (m, 2H), 8.39 (d, J = 4.07, 2.03 Hz, 1H), 8.25 (d, J = 8.81, 1.36 Hz, 1H), 8.13 (s, 1H), 7.61 (d, J = 8.81 Hz, 1H), 7.24 (s, 5H), 6.92 ( d, J = 6.78, 4.07 Hz, 1H), 5.44 (t, J = 6.27 Hz, 1H), 4.13 (d, J = 6.10 Hz, 2H). MS (ESI +) m / z 341.0 (M + H) ⁺ .

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 described in Example 43 using butyl isocyanide instead of isopropyl isocyanide. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.09 (s, 1H), 8.70 (d, J = 6.78, 2.03 Hz, 1H), 8.55 (s, 1H), 8.44 (d, J = 4.07, 2.03 Hz, 1H), 8.25 (d, J = 8.82, 1.36 Hz, 1H), 8.14 (s, 1H), 7.61 (d, J = 8.82 Hz, 1H), 7.03 (d, J = 6.78, 4.07 Hz, 1H), 4.90 (t, J = 5.93 Hz, 1H), 2.96 (s, 2H), 1, 49 (s, 2H), 1.34 (s, 2H), 0.82 (t, J = 7.29 Hz, 3H). MS (ESI +) m / z 307.0 (M + H) ⁺ .

Example 52

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

The title compound was prepared according to the procedure described in Example 43 using 4-chlorophenyl isocyanide instead of isopropyl isocyanide. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.12 (s, 1H), 8.58 (dd, J = 4.12, 1.98 Hz, 1H), 8.46 (d, J = 15.87 Hz, 2H), 8.40 (dd , J = 6.71, 1.83 Hz, 1H), 8.06-8.16 (m, 2H), 7.58 (d, J = 8.85 Hz, 1H), 7.18 (d, J = 8.85 Hz, 2H), 7.05 (dd, J = 6.71, 3.97 Hz, 1H), 6.57 (d, J = 8.85 Hz, 2H). MS (ESI +) m / z 361.0 (M + H) ⁺ .

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 described in Example 43 using 4-methoxyphenyl isocyanide instead of isopropyl isocyanide. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.10 (s, 1H), 8.56 (dd, J = 3.97, 2.14 Hz, 1H), 8.47 (s, 1H), 8.36 (dd, J = 6.56, 1.98 Hz, 1H), 8.15 (dd, J = 8.70, 1.37 Hz, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.57 ( d, J = 8.54 Hz, 1H), 7.03 (dd, J = 6.71, 4.27 Hz, 1H), 6.76 (d, J = 8.85 Hz, 2H), 6, 50 (d, J = 8.85 Hz, 2H); 3.63 (s, 3H). MS (ESI +) m / z 357.4 (M + H) ⁺ .

Example 54

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

The title compound was prepared according to the procedure described in Example 44D using 2-aminopyrimidine instead of 1-phenyl-2-thiourea. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.13 (s, 1H), 8.96 (dd, J = 6.78, 2.03 Hz, 1H), 8.51 (dd, J = 4.41, 2.03 Hz, 1H), 8 42 (s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 8.01 (dd, J = 8.82, 1.70 Hz, 1H), 7.62 ( d, J = 8.48 Hz, 1H), 7.04 (dd, J = 6.61, 4.24 Hz, 1H). MS (ESI +) m / z 236.1 (M + H) ⁺ .

Example 55

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

The title compound was obtained in the form of a TFA salt in accordance with the procedure described in Example 36B using 2-aminopyridine instead of 2-aminothiazole and methyl 2-isocyanoacetate instead of cyclohexyl isocyanide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.41 (s, 1H), 8.90 (d, J = 6.75 Hz, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 7.84-7.98 (m, 3H), 7.77 (d, J = 8.90 Hz, 1H), 7.55 (td, J = 6.75, 1.23 Hz, 1H), 5.95-6.06 ( m, 1H), 3.87 (d, J = 4.60 Hz, 2H), 3.51 (s, 3H). MS (ESI +) m / z 340.1 (M + H) ⁺ .

Example 56

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

The title compound was prepared according to the procedure described in Example 36B using 2-aminopyridine instead of 2-aminothiazole and benzyl isocyanide instead of cyclohexyl isocyanide. The final product precipitated from the solution with the formation of a precipitate, and it was isolated after filtration. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.04 (s, 1H), 8.49 (s, 1H), 8.16-8.27 (m, 2H), 8.09 (s, 1H), 7.58 (d, J = 8, 90 Hz, 1H), 7.44 (d, J = 8.90 Hz, 1H), 7.19-7.35 (m, 5H), 7.13 (ddd, J = 8.98, 6.67 , 0.92 Hz, 1H), 6.80 (td, J = 6.75, 0.92 Hz, 1H), 5.32 (t, J = 6.14 Hz, 1H), 4.12 (d , J = 6.14 Hz, 2H). MS (ESI +) m / z 322.1 (M + H) ⁺ .

Example 57

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

The title compound was prepared according to the procedure described in Example 36B using 2-aminopyridine instead of 2-aminothiazole and 1-chloro-4-isocyanobenzene instead of cyclohexyl isocyanide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.06 (s, 1H), 8.39 (s, 2H), 8.05-8.14 (m, 2H), 7.94 (d, J = 6.75 Hz, 1H), 7.62 (d, J = 8.90 Hz, 1H), 7.55 (d, J = 8.59 Hz, 1H), 7.28-7.34 (m, 1H), 7.17 (d, J = 8.90 Hz, 2H), 6.88-6.96 (m, J = 6.75, 6.75 Hz, 1H), 6.53 (d, J = 8.59 Hz, 2H). MS (ESI +) m / z 360.0 (M + H) ⁺ .

Example 58

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

The title compound was prepared according to the procedure described in Example 36B using 2-aminopyridine instead of 2-aminothiazole and 1-isocyano-4-methoxybenzene instead of cyclohexyl isocyanide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.04 (s, 1H), 8.44 (s, 1H), 8.14 (d, J = 8.90, 1.23 Hz, 1H), 8.06 (s, 1H), 7.87 -7.96 (m, 2H), 7.59 (d, J = 8.90 Hz, 1H), 7.54 (d, J = 8.59 Hz, 1H), 7.24-7.33 ( m, 1H), 6.86-6.93 (m, J = 6.75, 6.75 Hz, 1H), 6.75 (d, J = 9.21 Hz, 2H), 6.47 (d , J = 9.21 Hz, 2H); 3.63 (s, 3H). MS (ESI +) m / z 356.1 (M + H) ⁺ .

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 according to the procedure described in Example 39 using tert-butyl 4-aminopiperidine-1-carboxylate instead of benzylamine. ¹ H NMR (400 MHz, DMSO-d ₅ ) δ ppm 13.32 (s, 1H), 8.14 (s, 1H), 8.01 (s, 1H), 7.79 (s, 1H), 7.68 (d, J = 8.59 Hz, 2H ), 7.24-7.39 (m, 2H), 6.97 (t, J = 8.90 Hz, 2H), 3.91-4.05 (m, 2H), 3.71-3, 84 (m, 1H), 2.53-2.69 (m, 2H), 1.76-1.94 (m, 4H), 1.35-1.40 (m, 9H). MS (DCI) m / z 462 (M + H) ⁺ .

Example 60

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

Example 60A

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

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

Example 60B

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 the compound of Example 60A (2.1 g, 5 mmol) in toluene (10 ml) was added 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 a solution of phenylboronic acid (671 mg, 5.5 mmol) in methanol (3 ml). The mixture was stirred at room temperature for 5 days, quenched with water, extracted with ethyl acetate and purified by silica gel chromatography using 5% ethyl acetate / hexane for elution to give the title compounds as a mixture. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.28 (d, J = 1.53 Hz, 1H), 8.12 (d, J = 8.85 Hz, 1H), 7.97-8.04 (m, 3H), 7.80-7 86 (m, 2H), 7.75 (d, J = 1.83 Hz, 1H), 7.54-7.63 (m, 3H), 1.68 (s, 9H), 1.64 ( s, 9H). MS (ESI +) m / z 373.9 (M + H) ⁺ .

Example 60C

tert-Butyl 3,5-bis ((trimethylsilyl) ethynyl) -1H-indazole-1-carboxylate and tert-butyl 5-bromo-3 - ((trimethylsilyl) ethynyl) -1H-indazole-1-carboxylate

The compound of Example 60B (1 g, 2.55 mmol), dichlorobis (triphenylphosphine) palladium (II) (89 mg, 0.13 mmol), triethylamine (1.78 ml, 12.75 mmol), trimethylsilylacetylene (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 give the title compounds. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.10 (d, J = 8.85 Hz, 1H), 8.07 (d, J = 8.85 Hz, 1H), 7.97 (d, J = 1.83 Hz, 1H), 7, 84 (s, 1H), 7.82 (dd, J = 8.85, 1.83 Hz, 1H), 7.71 (dd, J = 8.54, 1.53 Hz, 1H), 1.65 (s, 18H), 0.33 (d, J = 0.92 Hz, 18H).

Example 60D

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

To a solution of the compound of Example 60C (350 mg, 0.85 mmol) in tetrahydrofuran (5 ml) was added a solution of 1M TBAF in tetrahydrofuran (2 ml, 2 mmol). After 10 minutes, the solvent was evaporated under reduced pressure, and the crude mixture was purified by silica gel chromatography, eluting with 5% ethyl acetate in hexane, to give the title compounds. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.12 (d, J = 7.93 Hz, 1H), 8.07 (d, J = 8.85 Hz, 1H), 8.01 (d, J = 1.53 Hz, 1H), 7, 90 (s, 1H), 7.83 (dd, J = 8.85, 1.83 Hz, 1H), 7.74 (dd, J = 8.85, 1.53 Hz, 1H), 4.91 (s, 1H), 4.90 (s, 1H), 4.29 (s, 1H), 1.66 (s, 9H), 1.65 (s, 9H).

Example 60E

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

The title compound was prepared according to the procedure described in Example 3D using the compound of Example 60D instead of the compound of Example 3C. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.35 (s, 1H), 8.76 (s, 1H), 8.71 (s, 1H), 8.70 (s, 1H), 7.92 (d, J = 8.61, 1, 28 Hz, 1H), 7.64 (d, J = 8.79 Hz, 1H), 7.38-7.43 (m, 8H), 7.33-7.37 (m, 2H), 5, 73 (s, 2H); 5.66 (s, 2H). MS (ESI +) m / z 433.2 (M + H) ⁺ .

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-indazole-1-carboxylate

The compound of Example 60B (1 g, 2.55 mmol), dichlorobis (triphenylphosphine) palladium (II) (89 mg, 0.13 mmol), triethylamine (1.78 ml, 12.75 mmol), trimethylsilylacetylene (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 give the title compound. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.29 (d, J = 1.53 Hz, 1H), 8.09-8.19 (m, 3H), 7.96-8.03 (m, 4H), 7.83 (dd, J = 8.85, 1.83 Hz, 1H), 7.72 (dd, J = 8.85, 1.53 Hz, 1H), 7.50-7.65 (m, 6H), 1.68 (s , 18H); 0.26-0.27 (m, 9H).

Example 61B

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

The title compound was prepared according to the procedure described in Example 60D using the compound of Example 61A instead of the compound of Example 60C. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.28 (d, J = 1.53 Hz, 1H), 8.21 (s, 1H), 8.16 (d, J = 8.54 Hz, 1H), 8.12 (d, J = 8 , 85 Hz, 1H), 7.97-8.05 (m, 4H), 7.83 (dd, J = 8.85, 1.83 Hz, 1H), 7.75 (dd, J = 8, 85, 1.53 Hz, 1H), 7.53-7.64 (m, 6H), 4.27 (s, 1H), 1.68 (s, 9H), 1.68 (s, 9H).

Example 61C

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

The title compound was prepared according to the procedure described in Example 3D using the compound of Example 61B instead of the compound of Example 3C. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.38 (s, 1H), 8.77 (s, 1H), 8.52 (s, 1H), 8.06 (d, J = 7.33 Hz, 2H), 7.98 (d, J = 8.79 Hz, 1H), 7.69 (d, J = 8.79 Hz, 1H), 7.53-7.61 (m, J = 7.51, 7.51 Hz, 2H), 7 33-7.48 (m, 6H); 5.68 (s, 2H). MS (ESI +) m / z 352.0 (M + H) ⁺ .

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 (I) iodide (413 mg, 2.17 mmol) were combined in triethylamine (15 ml) under nitrogen. Trimethylsilylacetylene (4.2 ml, 29.7 mmol) was added and the mixture was heated to 100 ° C. The mixture was cured and the reaction was monitored by LC / MS. After completion of the reaction, the mixture was diluted with methylene chloride and washed with 1 N HCl. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of ethyl acetate in hexane (5-45%) to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.09 (dd, J = 6.10, 2.03 Hz, 1H), 7.77-7.97 (m, 1H), 7.54 (t, J = 9.15 Hz, 1H), 0 15-0.32 (m, 9H).

Example 62B

5-Ethinyl-2-fluorobenzonitrile

Tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran 70 ml) was added to a solution of the compound of Example 62A (5.05 g, 23.2 mmol) in tetrahydrofuran (50 ml) and allowed to stir 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 hexane to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.13 (dd, J = 6.27, 2.20 Hz, 1H), 7.82-7.95 (m, 1H), 7.56 (t, J = 8.99 Hz, 1H), 4 40 (s, 1H).

Example 62C

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

The compound of Example 62B (1.68 g, 11.6 mmol) was dissolved in tert-butanol (14 ml). Benzylazide (2.14 g, 15.8 mmol) was added and the mixture was transferred to 14 microwave vessels (1.0 ml each). Water (0.5 ml), a small piece of copper wire and 1 M copper (II) sulfate solution (0.5 ml) were added to each microwave vessel and the vessels were heated in a CEM-Discover microwave reactor at 125 ° C using a power of 100 watts for 10 minutes each. The contents of the vessels 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 using a gradient of 5-50% ethyl acetate in hexane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.73 (s, 1H), 8.33-8.44 (m, 1H), 8.19-8.32 (m, 1H), 7.56-7.70 (m, 1H), 7, 28-7.47 (m, 5H); 5.68 (s, 2H).

Example 62D

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

Hydrazine hydrate (18 ml) was added to the compound of 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 certain amount of product precipitated in a separatory funnel and was filtered to obtain the title compound. The ethyl acetate layer was concentrated under reduced pressure, and the resulting solid was triturated with methanol to give an additional amount of the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.43 (s, 1H), 8.42 (s, 1H), 8.21 (s, 1H), 7.67 (d, J = 8.82, 1.70 Hz, 1H), 7.38 (s, 5H), 7.26 (d, J = 8.48 Hz, 1H), 5.64 (s, 2H), 5.38 (s, 2H). MS (ESI +) m / z 291.0 (M + H) ⁺ .

Example 63

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

The compound of Example 62D (44 mg, 0.152 mmol), 1-methylpiperidin-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 1 N sodium hydroxide solution. The organic layer was absorbed on silica gel and purified by silica gel chromatography using a gradient of 5-15% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.58 (s, 1H), 8.47 (s, 1H), 8.26 (d, J = 8.48 Hz, 1H), 7.97 (d, J = 8.48, 1.70 Hz , 1H), 7.38 (s, 5H), 6.58 (s, 2H), 5.67 (s, 2H), 3.35-3.47 (m, 1H), 2.95 (d, J = 1.19 Hz, 2H), 2.28 (s, 3H), 2.03-2.20 (m, 2H), 1.92 (s, 2H), 1.77 (s, 2H) . MS (ESI +) m / z 416.2 (M + H) ⁺ .

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-indazole-1-carboxylate

The compound of 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 using a gradient of 0-5% methanol in dichloromethane to elute to give 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

The compound of Example 64A (45 mg, 0.115 mmol) was dissolved in methylene chloride (1.5 ml) and pyridine (0.5 ml). Methoxyacetyl chloride (18 μl, 0.197 mmol) was added and the mixture was stirred at ambient temperature for 2 hours. The solvents were removed using a warm nitrogen stream, the mixture was introduced into a column of silica gel, and the product was purified by chromatography on silica gel using a gradient of 0-5% methanol in dichloromethane to elute to give tert-butyl 5- (1-benzyl-1H-1 , 2,3-triazol-4-yl) -3- (2-methoxyacetamido) -1H-indazole-1-carboxylate (58 mg). The intermediate compound was dissolved in methylene chloride (2 ml) and trifluoroacetic acid (1 ml) and stirred at ambient temperature overnight. The solvents were removed under reduced pressure and the mixture was purified by preparative HPLC on a C8 column using a gradient of 10% to 100% acetonitrile / water containing 0.1% trifluoroacetic acid to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.79 (s, 1H), 10.16 (s, 1H), 8.59 (s, 1H), 8.20 (s, 1H), 7.83 (d, J = 8.65, 1, 53 Hz, 1H), 7.51 (d, J = 8.82 Hz, 1H), 7.37 (s, 5H), 5.64 (s, 2H), 4.12 (s, 2H), 3 42 (s, 3H). MS (ESI +) m / z 363.0 (M + H) ⁺ .

Example 65

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

The compound of Example 64A (81 mg, 0.207 mmol) was dissolved in methylene chloride (2 ml) and pyridine (0.5 ml). Dimethylaminoacetyl chloride 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 1 N sodium hydroxide solution. The organic layer was absorbed on silica gel and purified using silica gel chromatography using a gradient of 5-15% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.77 (s, 1H), 10.05 (s, 1H), 8.58 (s, 1H), 8.24 (s, 1H), 7.82 (d, J = 8.65, 1, 53 Hz, 1H), 7.50 (d, J = 8.82 Hz, 1H), 7.30-7.44 (m, 5H), 5.64 (s, 2H), 3.16-3, 20 (m, 2H); 2.34 (s, 6H). MS (ESI +) m / z 376.1 (M + H) ⁺ .

Example 66

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

The compound of Example 64A (76 mg, 0.195 mmol) was dissolved in methylene chloride (2 ml) and pyridine (0.2 ml). Butyryl chloride (26 μl, 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 using silica gel chromatography using a gradient of 1-8% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.70 (s, 1H), 10.30 (s, 1H), 8.57 (s, 1H), 8.23 (s, 1H), 7.81 (d, J = 8.82 Hz, 1H ), 7.49 (d, J = 8.82 Hz, 1H), 7.37 (s, 5H), 5.64 (s, 2H), 2.39 (t, J = 7.29 Hz, 2H ), 1.67 (s, 2H), 0.97 (t, J = 7.46 Hz, 3H). MS (ESI +) m / z 361.1 (M + H) ⁺ .

Example 67

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

The title compound was prepared according to the procedure described in Example 39 using piperidin-4-amine instead of benzylamine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.28 (s, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 7.78 (s, 1H), 7.63-7.72 (m, 2H), 7 21-7.43 (m, 2H), 6.90-7.04 (m, 2H), 4.14 (d, J = 5.59, 1.86 Hz, 1H), 3.53-3 74 (m, J = 5.76 Hz, 1H), 2.94 (d, J = 12.21 Hz, 2H), 2.21-2.35 (m, 2H), 1.74-1, 88 (m, 3H). MS (DCI) m / z 362 (M + H) ⁺ .

Example 68

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

The title compound was prepared according to the procedure described in Example 39 using 2- (1-methylpyrrolidin-2-yl) ethanamine instead of benzylamine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.30 (s, 1H), 8.14 (s, 1H), 7.86 (s, 1H), 7.82 (s, 1H), 7.68 (d, J = 8.48 Hz, 1H ), 7.24-7.47 (m, 3H), 6.92-7.08 (m, 2H), 3.83 (t, J = 7.80 Hz, 2H), 2.71-2, 93 (m, 1H), 1.88-2.01 (m, 3H), 1.74-1.88 (m, 1H), 1.00-1.83 (m, 7H). MS (DCI) m / z 390 (M + H) ⁺ .

Example 69

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

The title compound was prepared according to the procedure described in Example 39 using 3- (4-methylpiperazin-1-yl) propan-1-amine instead of benzylamine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.36 (s, 1H), 8.13 (s, 1H), 7.81 (s, 2H), 7.67 (d, J = 8.48 Hz, 1H), 7.32-7.45 (m, 2H), 7.27 (d, J = 8.48, 1.36 Hz, 1H), 6.87-7.06 (m, 2H), 3.72-3.91 (m, 2H ), 1.92-2.21 (m, 10H), 1.91-2.20 (s, 3H), 1.51-1.66 (m, 2H). MS (ESI +) m / z 419 (M + H) ⁺ .

Example 70

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

The compound of Example 3C (1.83 g, 12.9 mmol) was dissolved in toluene (60 ml) and triethylamine (2.2 ml) and heated to 90 ° C. Ethyl 2-chloro-2- (hydroxyimino) acetate (1.89 g, 12.5 mmol) was dissolved in toluene (15 ml) and added dropwise over 30 minutes. After addition, the mixture was diluted with ethyl acetate and washed with 1 N hydrochloric acid. The organic layer was concentrated under reduced pressure, and the resulting residue was triturated with methanol to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.38 (s, 1H), 8.43 (s, 1H), 8.23 (s, 1H), 7.92 (d, J = 8.82, 1.36 Hz, 1H), 7.70 (d, J = 8.82 Hz, 1H), 7.44 (s, 1H), 4.41 (q, J = 7.12 Hz, 2H), 1.35 (t, J = 7.12 Hz, 3H). MS (ESI +) m / z 257.9 (M + H) ⁺ .

Example 71

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

Example 71 A

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

The compound of 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 solvents were removed under reduced pressure, and the resulting residue was triturated with a mixture of 1 n hydrochloric acid and methanol to give a solid, which was filtered to obtain the title compound. ¹ H NMR (300 MHz, DMSO-d _d ) δ ppm 13.37 (s, 1H), 8.39 (s, 1H), 8.22 (s, 1H), 7.90 (dd, J = 8.81, 1.36 Hz, 1H), 7.69 (d, J = 8.82 Hz, 1H); 7.30 (s, 1H).

Example 71B

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

The compound of Example 71A (46 mg, 0.21 mmol), HATU (88 mg, 0.231 mmol) and diisopropylethylamine (133 μl, 0.764 mmol) were combined in tetrahydrofuran (2 ml). Monomethylamine (40% solution in water) (50 μl) was added and the reaction mixture was stirred at 50 ° C for 2 hours. The mixture was diluted with methylene chloride and washed with 1 N sodium hydroxide solution, 1 N hydrochloric acid solution and saturated saline. The organic layer was absorbed on silica gel and purified by silica gel chromatography using a gradient of 10-50% ethyl acetate in hexane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.36 (s, 1H), 8.72 (q, J = 4.30 Hz, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 7.89 (d, J = 8.65, 1.53 Hz, 1H), 7.69 (d, J = 8.82 Hz, 1H), 7.28 (s, 1H), 2.80 (d, J = 4.75 Hz, 3H). MS (ESI +) m / z 243.0 (M + H) ⁺ .

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 6 N sodium hydroxide solution (19 μl, 31.7 mmol). The mixture was stirred for 30 minutes. Chloramine-T trihydrate (308 mg, 1.09 mmol) was slowly added over 5 minutes, followed by the addition of copper (II) sulfate and a small piece of copper wire. The compound of Example 3C (154 mg, 1.08 mmol) was added and the mixture was stirred at 50 ° C for 2 hours, then 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 using a gradient of 10-50% ethyl acetate in hexane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.31 (s, 1H), 8.28 (s, 1H), 8.18 (s, 1H), 7.79 (dd, J = 8.65, 1.53 Hz, 1H), 7.64 (d, J = 8.81 Hz, 1H), 7.13-7.46 (m, 5H), 6.83 (s, 1H), 4.04 (s, 2H). MS (ESI +) m / z 275.7 (M + H) ⁺ .

Example 73

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

The compound of Example 64A (72 mg, 0.184 mmol) was dissolved in methylene chloride (2 ml) and pyridine (0.2 ml). Benzoyl chloride (36 μl, 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 using a gradient of 1-8% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.88 (s, 1H), 10.81 (s, 1H), 8.63 (s, 1H), 8.16 (s, 1H), 8.06-8.13 (m, 2H), 7 88 (d, J = 8.82, 1.36 Hz, 1H), 7.59-7.64 (m, J = 7.12 Hz, 1H), 7.51-7.59 (m, 3H ), 7.31-7.42 (m, 5H), 5.63 (s, 2H). MS (ESI +) m / z 395.1 (M + H) ⁺ .

Example 74

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

The title compound was prepared according to the procedure described in Example 72 using butraldehyde instead of phenylacetaldehyde. ¹ H NMR (300 MHz, DMSO-d _< j) δ ppm 13.31 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.76-7.85 (m, 1H), 7.63-7.70 (m, 1H), 6.88 (s, 1H), 2.63 (t, J = 7.46 Hz, 2H), 1.61-1.79 (m, 2H), 0.96 (t, J = 7 , 29 Hz, 3H). MS (ESI +) m / z 228.0 (M + H) ⁺ .

Example 75

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

Example 75A

1H-indazole-5-carboxylic acid

The title compound was prepared according to the procedure described in Example 3A using methyl 4-amino-3-methylbenzoate instead of 4-iodo-2-methylaniline. During the final treatment, the addition of a 6 N HCl solution until a pH of 6 was reached, and a solid formed, which was filtered, washed twice with water and dried in vacuo to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.32 (s, 1H), 12.83 (s, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 7.92 (dd, J = 8.82, 1, 70 Hz, 1H); 7.60 (d, J = 8.82 Hz, 1H).

Example 75B

N-Methoxy-N-methyl-1H-indazole-5-carboxamide

To a suspension of the compound 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) was added triethylamine (1.67 ml, 12 mmol) and EDC (2.1 g, 11 mmol) and the mixture was stirred at room temperature for 24 hours. The solvents were evaporated under reduced pressure, and the resulting residue was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and purified by silica gel column chromatography in ethyl acetate to obtain the title compound. MS (ESI +) m / z 206.0 (M + H) ⁺ .

Example 75C

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

A solution of the compound of Example 75B (900 mg, 4.39 mmol) in tetrahydrofuran (10 ml) was cooled under argon using an ice bath and treated with a 2M solution of benzyl magnesium chloride in tetrahydrofuran (6.6 ml, 13.16 mmol). The reaction mixture was stirred overnight at room temperature, followed by the addition of another equivalent of benzyl magnesium chloride. The mixture was heated at 70 ° C for 9 hours. Another equivalent of benzyl magnesium chloride was added and the reaction mixture was heated at 70 ° C for another 90 minutes and allowed to cool to room temperature. A saturated aqueous solution of ammonium chloride was added and the product was extracted with ethyl acetate and purified by silica gel column chromatography using 30% ethyl acetate in hexane to give 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 the compound of Example 75C (236 mg, 1 mmol) in dichloromethane (2 ml) was added di-tert-butyl dicarbonate (327 mg, 1.5 mmol) and a pinch of dimethylaminopyridine (~ 2 mg). The mixture was stirred for 15 minutes and passed through a pad of silica gel and eluted with dichloromethane. The solvent was evaporated under reduced pressure to obtain the title compound. MS (ESI +) m / z 337.0 (M + H) ⁺ .

Example 75E

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

To a solution of the compound of Example 75D (336 mg, 1 mmol) in tetrahydrofuran (20 ml), heated at 40 ° C in an oil bath, a solution of pyridinium tribromide (352 mg, 1.1 mmol) in tetrahydrofuran (20) was added dropwise through a funnel. ml) for 10 minutes. The reaction mixture was heated for another 2 hours and then cooled, filtered and the filtrate was evaporated to give the title compound. MS (ESI-) m / z 212.9 (MH). ^"

Example 75F

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

The vessel containing the compound of Example 75E (50 mg, 0.16 mmol) and 1-benzylthiourea (26 mg, 0.16 mmol) in ethanol (1 ml) was closed with a lid and heated in a heating device with shaking at 80 ° C for 2 hours. The crude product solution was purified by reverse phase HPLC using an acetonitrile / water gradient 0.1% TFA gradient elution method to give the title compound in the form of a TFA salt. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.99 (s, 1H), 8.33-8.37 (m, 1H), 8.01 (s, 1H), 7.92-7.99 (m, 1H), 7.82 (s, 1H), 7.60-7.67 (m, J = 7.83, 7.83 Hz, 1H), 7.31-7.45 (m, 5H), 7.17-7.30 (m, 5H), 4.53 (d, J = 4.60 Hz, 2H). MS (ESI +) m / z 383.0 (M + H) ⁺ .

Example 76

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

The title compound was prepared in the form of a TFA salt in accordance with the procedure described in Example 75F using 1-phenylthiourea instead of 1-benzylthiourea. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.09 (s, 1H), 10.29 (s, 1H), 8.05 (d, J = 0.92 Hz, 1H), 7.89 (d, J = 1.53, 0.92 Hz , 1H), 7.69 (d, J = 8.59, 1.23 Hz, 2H), 7.47 (dt, J = 8.59, 0.92 Hz, 1H), 7.40-7, 44 (m, 1H), 7.26-7.37 (m, 7H), 6.94-7.02 (m, J = 7.36, 7.36 Hz, 1H). MS (ESI +) m / z 369.0 (M + H) ⁺ .

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

The compound of Example 44A (2.31 g, 7.77 mmol), cyclopropylacetylene (620 mg, 9.37 mmol), dichlorobis (triphenylphosphine) palladium (II) (170 mg, 0.242 mmol) and copper (I) iodide (92 mg , 0.483 mmol) were combined in triethylamine (10 ml) under an inert nitrogen atmosphere. The mixture was heated to 100 ° C in a sealed tube for 4 hours. The mixture was diluted with methylene chloride and washed with 1 N hydrochloric acid. The organic layer was absorbed on silica gel and purified by silica gel chromatography using a gradient of 5-50% ethyl acetate in hexane to elute to give 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

The compound of Example 77A (145 mg, 0.51 mmol) and benzylazide (82 mg, 0.62 mmol) were heated without solvent in a CEM-Discover microwave reactor at 150 ° C. and 150 watts for 10 minutes. The crude mixture was dissolved in dichloromethane and purified by silica gel column chromatography using 50% ethyl acetate in hexane as the eluent. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.12 (s, 1H), 8.11 (d, J = 5.52 Hz, 2H), 7.79 (d, J = 8.59, 1.53 Hz, 1H), 7.60 (d , J = 8.59 Hz, 1H), 7.26-7.45 (m, 5H), 5.69 (s, 2H), 1.78-1.92 (m, 1H), 0.98- 1.09 (m, 2H); 0.31-0.45 (m, 2H). MS (ESI +) m / z 316.0 (M + H) ⁺ .

Example 78

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

The title compound was isolated as a by-product in accordance with the procedure described in Example 77B. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.29 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H), 7.65 (d, J = 8.85 Hz, 1H), 7.29 (d, J = 8.54, 1.53 Hz, 1H), 7.21-7.27 (m, 3H), 6.93 (d, J = 7.48, 1.98 Hz, 2H), 5.49 ( s, 2H), 1.70-1.80 (m, 1H), 0.81-0.92 (m, 4H). MS (ESI +) m / z 316.0 (M + H) ⁺ .

Example 79

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

The vessel containing the compound of Example 75E (80 mg, 0.25 mmol) and pyrimidin-2-amine (23 mg, 0.25 mmol) in ethanol (1 ml) was closed with a lid and heated in a heating device with shaking at 80 ° C within 21 hours. The crude product solution was purified by reverse phase HPLC using an acetonitrile / water 0.1% TFA gradient elution method to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.69 (dd, J = 4.30, 1.84 Hz, 1H), 8.59 (dd, J = 6.75, 1.84 Hz, 1H), 8.07 (s, 1H), 8 02 (s, 1H), 7.46-7.65 (m, 7H), 7.16 (dd, J = 6.75, 3.99 Hz, 1H). MS (ESI +) m / z 312.0 (M + H) ⁺ .

Example 80

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

Example 80A

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 suspension was diluted with diethyl ether and washed with water. The organic layer was concentrated under reduced pressure to obtain the title compound. The product was used directly in subsequent reactions without identification.

Example 80B

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

The compound of Example 80A (122 mg, 0.864 mmol) and the compound of Example 3C (150 mg, 0.619 mmol) were combined in a microwave vessel with tert-butanol (1 ml) and water (1 ml). A small piece of copper wire was added followed by copper (II) sulfate (5 mg, 0.02 mmol) and the contents of the vessel were mixed in a microwave device (CEM-Discover) at 125 ° C at 100 W for 10 minutes. The mixture was diluted with methylene chloride and washed with 1 N hydrochloric acid. The organic layer was absorbed on silica gel and purified by silica gel chromatography using a gradient of 0-5% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMS (M _J ) δ ppm 13.11 (s, 1H), 8.53 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.85 (d, J = 8.48, 1.36 Hz, 1H), 7.60 (d, J = 8.82 Hz, 1H), 4.32 (d, J = 7.12 Hz, 2H), 3.85 (d, J = 1 1.70, 2.54 Hz, 2H), 3.21-3.36 (m, 2H), 2.14 (s, 1H), 1, 47 (s, 2H), 1.30 (s, 2H). MS (ESI +) m / z 284.0 (M + H) ⁺ .

Example 81

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

Example 81A

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

The compound of 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 solvents were removed under reduced pressure, and the resulting residue was triturated with a mixture of 1 n hydrochloric acid and methanol to give a solid, which was filtered to obtain the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.36 (s, 1H), 8.41 (s, 1H), 8.23 (s, 1H), 7.91 (dd, J = 8.82, 1.70 Hz, 1H), 7.70 (d, J = 8.82 Hz, 1H); 7.36 (s, 1H).

Example 81B

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

The compound of Example 81A (110 mg, 0.480 mmol), piperidine (55 μl, 0.556 mmol) and HATU (101 mg, 0.266 mmol) were combined in dimethylformamide (2 ml). Diisopropylethylamine (133 μl, 0.764 mmol) was added and the reaction mixture was stirred at 45 ° C for 2 hours. The mixture was diluted with ethyl acetate and washed with 1 N sodium hydroxide solution, 1 N hydrochloric acid solution, water (3 times) and brine. The organic layer was absorbed on silica gel and purified by silica gel chromatography using a gradient of 0-5% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.37 (s, 1H), 8.34-8.40 (m, 1H), 8.21-8.25 (m, 1H), 7.84-7.91 (m, 1H), 7, 66-7.72 (m, 1H), 7.20 (s, 1H), 3.59-3.69 (m, 2H), 3.48-3.58 (m, 2H), 1.47- 1.72 (m, 6H). MS (ESI +) m / z 297.0 (M + H) ⁺ .

Example 82

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

The title compound was prepared according to the procedure described in Example 81B using aniline instead of piperidine. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.40 (s, 1H), 10.74 (s, 1H), 8.44 (s, 1H), 8.25 (s, 1H), 7.93 (d, J = 8.85, 1, 53 Hz, 1H), 7.82 (d, J = 7.63 Hz, 2H), 7.72 (d, J = 8.85 Hz, 1H), 7.44 (s, 1H), 7.35 -7.42 (m, 2H); 7.16 (t, J = 7.32 Hz, 1H). MS (ESI +) m / z 304.9 (M + H) ⁺ .

Example 83

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

The compound of Example 81A (53 mg, 0.231 mmol), cyclohexylamine (29 μl, 0.253 mmol) and HATU (101 mg, 0.266 mmol) were combined in dimethylformamide (2 ml). Diisopropylethylamine (133 μl, 0.764 mmol) was added and the reaction mixture was stirred at 45 ° C for 2 hours. The mixture was diluted with ethyl acetate and washed with 1 N sodium hydroxide solution, 1 N hydrochloric acid solution, water (3 times) and brine. The organic layer was absorbed on silica gel and purified by silica gel chromatography using a gradient of 0-5% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.36 (s, 1H), 8.58 (d, J = 8.14 Hz, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 7.88 (d, J = 8.81, 1.70 Hz, 1H), 7.69 (d, J = 8.81 Hz, 1H), 7.28 (s, 1H), 3.69-3.86 (m, 1H) 1.77 (s, 4H), 1.60 (d, J = 12.21 Hz, 1H), 1.20-1.46 (m, 4H), 1.06-1.20 (m, 1H ) MS (ESI +) m / z 311.0 (M + H) ⁺ .

Example 84

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

The compound of Example 81B (22 mg, 0.0742 mmol) was dissolved in tetrahydrofuran (2.5 ml) in an inert nitrogen atmosphere. Lithium aluminum hydride (1.0 M solution in tetrahydrofuran) (250 μl) was added and the mixture was heated to 70 ° C for 20 minutes. Methanol was added and the mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of methanol in dichloromethane (0-7%) to elute to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.30 (s, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 7.84 (d, J = 8.59, 1.53 Hz, 1H), 7.66 (d, J = 8.59 Hz, 1H), 6.92 (s, 1H), 3.54 (s, 2H), 2.32-2.46 (m, 2H), 1.47-1, 59 (m, 4H), 1.33-1.46 (m, 2H). MS (ESI +) m / z 283.0 (M + H) ⁺ .

Example 85

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

The compound of 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. Upon completion of the addition, the mixture was stirred for another 30 minutes. The mixture was diluted with methylene chloride and washed with water, and the organic layer was absorbed on silica gel and purified by silica gel chromatography using a gradient of 0-20% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.31 (s, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.83 (d, J = 8.59, 1.53 Hz, 1H), 7.67 (d, J = 8.90 Hz, 1H), 6.93 (s, 1H), 5.51 (s, 1H), 4.56 (d, J = 2.45 Hz, 1H). MS (ESI +) m / z 215.9 (M + H) ⁺ .

Example 86

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

The title compound was prepared according to the procedure described in Example 81B using 2-methoxyethylamine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.36 (s, 1H), 8.74 (t, J = 4.92 Hz, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 7.89 (d, J = 8.65, 1.53 Hz, 1H), 7.69 (d, J = 8.82 Hz, 1H), 7.30 (s, 1H), 3.38-3.53 (m, 4H) 3.28 (s, 3H). MS (ESI +) m / z 287.0 (M + H) ⁺ .

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 isoamyl nitrite (37 ml, 277 mmol) were added and the mixture was heated to 70 ° C. overnight. The mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The solvents were removed under reduced pressure and the resulting residue was triturated with methanol to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.41 (s, 1H), 8.33 (s, 1H), 8.05-8.21 (m, 1H), 7.90 (dd, J = 8.48, 1.70 Hz, 1H) 2.71 (s, 3H).

Example 87B

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

Phenylethynyl-tri-n-butyltin (8.25 g, 21.1 mmol) and benzylazide (2.3 ml, 18.4 mmol) were combined and heated to 150 ° C. overnight. The mixture was purified by silica gel chromatography using a gradient of 5-40% ethyl acetate in hexane to elute to give 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

The compound of Example 87A (139 mg, 0.486 mmol), the compound of 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) ) were combined in toluene (1.5 ml) in a microwave vessel under an inert atmosphere of nitrogen. The vessel was heated in a microwave device (CEM-Discover) to 150 ° C at 125 watts for 20 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 5-40% ethyl acetate in hexane to elute to give 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

The compound of 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 and diluted with ethyl acetate and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography using a gradient of 0-5% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.08 (s, 1H), 8.00 (s, 1H), 7.79 (s, 1H), 7.44-7.56 (m, 5H), 7.24-7.36 (m, 5H), 6.95-7.03 (m, 2H), 5.49 (s, 2H). MS (ESI +) m / z 252.1 (M + H) ⁺ .

Example 88

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

The compound of Example 87A (969 mg, 3.39 mmol), 3-phenyl-1-propine (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. A 6N sodium hydroxide solution (1 ml) was added and the mixture was stirred for 30 minutes to remove the protection from indazole. The mixture was diluted with ethyl acetate and washed with 1 N hydrochloric acid. The organic layer was concentrated under reduced pressure, and the resulting residue was triturated with methanol. The remaining solids were absorbed on silica gel and purified by silica gel chromatography using a gradient of 0-5% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.35 (s, 1H), 8.58 (s, 1H), 8.17-8.27 (m, 1H), 7.86 (d, J = 8.82, 2.03 Hz, 1H) 7.67-7.77 (m, 1H); 7.27-7.36 (m, 2H); 7.18-7.27 (m, 1H); 4.10 (s, 1H). MS (ESI +) m / z 276.0 (M + H) ⁺ .

Example 89

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

Example 89A

5- (cyclopropylethinyl) -2-fluorobenzonitrile

5-Bromo-2-fluorobenzonitrile (3.06 g, 15.3 mmol), dichlorobis (triphenylphosphine) palladium (II) (478 mg, 0.681 mmol) and copper (I) iodide (165 mg, 0.866 mmol) were combined in triethylamine (15 ml) in an inert atmosphere of nitrogen. Cyclopropylacetylene (1.8 ml) was added and the mixture was heated to 60 ° C until it turned into a black solid. The mixture was diluted with methylene chloride and washed with 1 N hydrochloric acid. The organic layer was absorbed on silica gel and purified by silica gel chromatography using a gradient of 5-40% ethyl acetate in hexane to elute to give 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

The compound of Example 89A (211 mg, 1.14 mmol) and benzylazide (143 μl, 1.14 mmol) were combined in a microwave (CEM-Discover) vessel and heated to 160 ° C. using a power of 100 watts for 26 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 20-60% ethyl acetate in hexane to elute to give a mixture of inseparable triazole regiomers. The regiomer mixture 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 using a gradient of 1-6% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.43 (s, 1H), 8.07 (s, 1H), 7.63 (d, J = 8.65, 1.53 Hz, 1H), 7.32-7.45 (m, 3H) 7.24-7.32 (m, 3H), 5.68 (s, 2H), 5.40 (s, 2H), 1.69-1.83 (m, 1H), 0.98-1 08 (m, 2H); 0.32-0.42 (m, 2H). MS (ESI +) m / z 331.1 (M + H) ⁺ .

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 by-product in accordance with the procedure described in Example 89B. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.62 (s, 1H), 7.79 (s, 1H), 7.32 (d, J = 8.48 Hz, 1H), 7.20-7.27 (m, 3H), 7.15 (d, J = 8.65, 1.53 Hz, 1H), 6.93 (d, J = 7.12, 2.37 Hz, 2H), 5.49 (s, 2H), 5.45 ( s, 2H), 1.71-1.82 (m, 1H), 0.80-0.89 (m, 4H). MS (ESI +) m / z 331.1 (M + H) ⁺ .

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 described in Example 72 using isovaleraldehyde instead of phenylacetaldehyde and using the compound of Example 62B instead of the compound of Example 3C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.47 (dd, J = 6.10, 2.03 Hz, 1H), 8.19-8.29 (m, 1H), 7.71 (t, J = 8.99 Hz, 1H), 7 08 (s, 1H), 2.56 (d, J = 7.12 Hz, 2H), 1.86-2.10 (m, 1H), 0.94 (d, J = 6.78 Hz, 6H).

Example 91B

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

To the compound of 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 vessel. 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 using a gradient of 0-5% methanol in dichloromethane to elute to give the title compound

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.67 (s, 1H), 8.26 (s, 1H), 7.66 (dd, J = 8.82, 1.70 Hz, 1H), 7.32 (d, J = 8.48 Hz , 1H), 6.67 (s, 1H), 5.56 (s, 2H), 2.51-2.58 (m, 2H), 1.89-2.11 (m, 1H), 0, 95 (d, J = 6.44 Hz, 6H). MS (ESI +) m / z 257.0 (M + H) ⁺ .

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 according to the procedure described in Example 72 using the compound of Example 62B instead of the compound of Example 3C. The crude product was used in the next step without further purification or determination of its characteristics.

Example 92B

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

To the compound of Example 92A (65 mg, 0.234 mmol) was added hydrazine hydrate (1.5 ml) in ethanol (1.0 ml). The mixture was heated to 70 ° C. overnight in a sealed vessel. 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 using a gradient of 0-20% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.67 (s, 1H), 8.26 (s, 1H), 7.66 (d, J = 8.82, 1.70 Hz, 1H), 7.32 (d, J = 8.48 Hz , 1H), 6.67 (s, 1H), 5.56 (s, 2H), 2.45-2.57 (m, 2H), 1.91-2.08 (m, 1H), 0, 95 (d, J = 6.44 Hz, 6H). MS (ESI +) m / z 291.0 (M + H) ⁺ .

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 according to the procedure described in Example 39 using 2-dimethylaminoethylamine instead of benzylamine. ¹ H NMR (500 MHz, s) δ ppm 13.28 (s, 1H), 8.14 (s, 1H), 7.78-7.87 (m, 2H), 7.68 (d, J = 8.54 Hz, 1H), 7.33 -7.41 (m, 2H), 7.28 (d, J = 8.54, 1.53 Hz, 1H), 6.95-7.05 (m, 2H), 3.86 (t, J = 6.56 Hz, 2H), 2.31 (t, J = 6.71 Hz, 2H), 2.00 (s, 6H).

Example 94

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

The title compound was prepared according to the procedure described in Example 39 using 3-morpholinopropylamine instead of benzylamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 13.28 (s, 1H), 8.14 (s, 1H), 7.79-7.87 (m, 2H), 7.68 (d, J = 8.24 Hz, 1H), 7.34 -7.42 (m, 2H), 7.28 (d, J = 8.54, 1.53 Hz, 1H), 6.92-7.03 (m, 2H), 3.77-3.89 (m, 2H), 3.24-3.30 (m, 4H), 2.10 (t, J = 6.56 Hz, 2H), 1.96-2.05 (m, 4H), 1, 54-1.66 (m, 2H). MS (ESI +) m / z 406.1 (M + H) ⁺ .

Example 95

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

The title compound was prepared according to the procedure described in Example 39 using 3-pyrrolidinopropylamine instead of benzylamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.13 (d, J = 0.92 Hz, 1H), 7.79-7.85 (m, 2H), 7.68 (d, J = 8.54 Hz, 1H), 7.38 (d , J = 8.85, 5.49 Hz, 2H), 7.27 (d, J = 8.54, 1.53 Hz, 1H), 6.99 (t, J = 9.00 Hz, 2H) 3.82-3.90 (m, 2H), 2.21 (t, J = 6.71 Hz, 2H), 2.08-2.18 (m, 4H), 1.56-1.65 (m, 2H), 1.44-1.53 (m, 4H). MS (ESI +) m / z 390.2 (M + H) ⁺ .

Example 96

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

The title compound was prepared according to the procedure described in Example 39 using 2- (4-methylpiperidin-1-yl) ethanamine instead of benzylamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 13.29 (s, 1H), 8.14 (s, 1H), 7.83 (s, 1H), 7.81 (s, 1H), 7.67 (d, J = 8.54 Hz, 1H ), 7.32-7.40 (m, 2H), 7.28 (dd, J = 8.54, 1.53 Hz, 1H), 6.93-7.04 (m, 2H), 3, 85 (t, J = 6.56 Hz, 2H), 2.60 (d, J = 1.60 Hz, 2H), 2.37 (t, J = 6.56 Hz, 2H), 1.71 -1.85 (m, 2H), 1.45 (d, J = 1.29 Hz, 2H), 1.15-1.30 (m, 1H), 0.95-1.07 (m, 2H), 0.83 (d, J = 6.71 Hz, 3H) MS (ESI +) m / z 404.1 (M + H) ⁺ .

Example 97

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

The title compound was prepared according to the procedure described in Example 39 using 4-amino-N-benzylpiperidine instead of benzylamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 13.32 (s, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.78 (s, 1H), 7.69 (d, J = 8.54 Hz, 1H ), 7.17-7.40 (m, 8H), 6.97 (t, J = 8.85 Hz, 2H), 3.50-3.63 (m, 1H), 3.40 (s, 2H), 2.82 (d, J = 1 1.90 Hz, 2H), 1.90-2.05 (m, 2H), 1.72-1.89 (m, 4H). MS (ESI +) m / z 452.2 (M + H) ⁺ .

Example 98

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

The title compound was prepared according to the procedure described in Example 39 using 2-morpholinoethylamine instead of benzylamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 13.27 (s, 1H), 8.14 (s, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.67 (d, J = 8.54 Hz, 1H ), 7.33-7.42 (m, 2H), 7.29 (d, J = 8.54 Hz, 1H), 6.95-7.06 (m, 2H), 3.87 (t, J = 6.41 Hz, 2H), 3.42-3.51 (m, 4H), 2.40 (t, J = 6.56 Hz, 2H), 2.21 (d, J = 3.97 Hz, 4H). MS (ESI +) m / z 392.1 (M + H) ⁺ .

Example 99

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

The title compound was prepared according to the procedure described in Example 39 using 3-pyrrolidinobenzylamine instead of benzylamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 13.29 (s, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.76 (s, 1H), 7.67 (d, J = 8.54 Hz, 1H ), 7.29-7.38 (m, 6H), 7.20-7.28 (m, 2H), 6.98 (t, J = 9.00 Hz, 2H), 4.25-4, 34 (m, 1H), 3.53-3.69 (m, 2H), 2.89-2.97 (m, 1H), 2.84 (d, J = 9.76, 3.05 Hz, 1H), 2.55 (d, J = 10.07, 6.71 Hz, 1H), 2.17-2.34 (m, 2H), 1.92-2.03 (m, 1H). MS (ESI +) m / z 438.1 (M + H) ⁺ .

Example 100

Example 100 is deleted and is not part of this document.

Example 101

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

The title compound was prepared according to the procedure described in Example 39 using 1- (4-aminopiperidin-1-yl) -2-hydroxyethanone instead of benzylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 13.27 (s, 1H), 8.14 (s, 1H), 7.99 (s, 1H), 7.81 (s, 1H), 7.69 (d, J = 8.48 Hz, 1H ), 7.25-7.39 (m, 4H), 6.91-7.03 (m, 2H), 4.48 (t, J = 5.43 Hz, 1H), 4.34-4, 44 (m, 1H), 4.07 (t, J = 5.59 Hz, 1H), 3.79-3.91 (m, 1H), 3.64-3.77 (m, 1H), 2 85 (m, 1H); 2.77-2.90 (m, 5H). MS (DCI) m / z 420 (M + H) ⁺ .

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

The compound of 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) were combined in toluene (2 ml) in a microwave vessel in an inert atmosphere of nitrogen. The vessel was heated in a microwave device (CEM-Discover) to 150 ° C at 125 watts for 20 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of ethyl acetate in hexane (5-40%) to elute 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

The compound of 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 using a gradient of 0-5% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.40 (s, 1H), 8.06 (s, 1H), 7.42-7.55 (m, 3H), 7.23-7.33 (m, 5H), 7.02-7, 10 (m, 2H), 6.94-7.02 (m, 2H), 5.49 (s, 2H), 5.34 (s, 2H). MS (ESI +) m / z 367.1 (M + H) ⁺ .

Example 103

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

The title compound was prepared according to the procedure described in Example 88 using 2-methyl-3-butyn-2-ol instead of 3-phenyl-1-propine, except that the crude reaction mixture was quenched with 2 ml 1 n aqueous NaOH solution; and stirred for 1.5 hours at ambient temperature. The suspension was then dried by evaporation using a stream of heated nitrogen gas before performing the extraction. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.51 (s, 1H), 8.22-8.29 (m, 2H), 7.88 (d, J = 9.00, 1.98 Hz, 1H), 7.77 (d, J = 8.85 Hz, 1H); 1.57 (s, 6H). MS (ESI +) m / z 244.0 (M + H) ⁺ .

Example 104

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

The title compound was prepared according to the procedure described in Example 88 using methylpropargyl ether instead of 3-phenyl-1-propine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.73 (s, 1H), 8.23-8.29 (m, J = 1.83 Hz, 2H), 7.88 (d, J = 8.85, 2.14 Hz, 1H), 7 78 (d, J = 9.15 Hz, 1H); 4.57 (s, 2H); 3.35 (s, 3H). MS (ESI +) m / z 230.0 (M + H) ⁺ .

Example 105

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

The title compound was prepared according to the procedure described in Example 88 using 2-phenyl-3-butyn-2-ol instead of 3-phenyl-1-propine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.52 (s, 1H), 8.21-8.28 (m, 2H), 7.87 (d, J = 8.85, 2.14 Hz, 1H), 7.76 (d, J = 9.15 Hz, 1H), 7.51-7.57 (m, 2H), 7.34 (t, J = 7.78 Hz, 2H), 7.24 (t, J = 7.32 Hz, 1H), 1.92 (s, 3H). MS (ESI +) m / z 306.0 (M + H) ⁺ .

Example 106

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

The title compound was prepared according to the procedure described in Example 88 using 1-pentin instead of 3-phenyl-1-propine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.50 (s, 1H), 8.20-8.30 (m, 2H), 7.87 (d, J = 9.00, 1.98 Hz, 1H), 7.77 (d, J = 8.85 Hz, 1H), 2.71 (t, J = 7.48 Hz, 2H), 1.64-1.78 (m, 2H), 0.97 (t, J = 7.32 Hz, 3H). MS (ESI +) m / z 228.0 (M + H) ⁺ .

Example 107

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

The title compound was prepared according to the procedure described in Example 88 using pent-4-in-2-ol instead of 3-phenyl-1-propine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.49 (s, 1H), 8.20-8.33 (m, 2H), 7.88 (dd, J = 9.00, 1.98 Hz, 1H), 7.74-7.82 ( m, 1H), 3.95-4.08 (m, 1H), 2.74-2.89 (m, 2H), 1.16 (d, J = 6.10 Hz, 3H). MS (ESI +) m / z 244.0 (M + H) ⁺ .

Example 108

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

The title compound was prepared according to the procedure described in Example 88 using 4-pentin-1-ol instead of 3-phenyl-1-propine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.50 (s, 1H), 8.28 (s, 1H), 8.23 (d, J = 1.83 Hz, 1H), 7.83-7.91 (m, 1H), 7.74 -7.82 (m, 1H), 4.50 (t, J = 6.41 Hz, 1H), 3.51 (t, J = 6.41 Hz, 2H), 2.77 (t, J = 7.63 Hz, 2H); 1.80-1.90 (m, 2H). MS (ESI +) m / z 244.0 (M + H) ⁺ .

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 according to the procedure described in Example 88 using 1-propargyl-1H-benzotriazole instead of 3-phenyl-1-propine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.91 (s, 1H), 8.21-8.29 (m, 2H), 8.07 (d, J = 8.54 Hz, 1H), 7.99 (d, J = 8.54 Hz , 1H), 7.84 (d, J = 9.00, 1.98 Hz, 1H), 7.72-7.81 (m, 1H), 7.57-7.65 (m, 1H), 7.41-7.52 (m, 1H); 6.16 (s, 2H). MS (ESI-) m / z 315.0 (MH) ^- .

Example 110

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

The title compound was prepared according to the procedure described in Example 88 using phenylpropargyl sulfide instead of 3-phenyl-1-propine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.59 (s, 1H), 8.26 (s, 1H), 8.21 (d, J = 1.22 Hz, 1H), 7.80-7.86 (m, 1H), 7.72 -7.79 (m, 1H), 7.43 (d, J = 8.39, 1.37 Hz, 2H), 7.35 (t, J = 7.78 Hz, 2H), 7.22 ( t, J = 7.32 Hz, 1H), 4.38 (s, 2H). MS (ESI +) m / z 308.3 (M + H) ⁺ .

Example 111

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

The title compound was prepared according to the procedure described in Example 88 using cyclopropylacetylene instead of 3-phenyl-1-propine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.46 (s, 1H), 8.25 (s, 1H), 8.20 (d, J = 1.53 Hz, 1H), 7.84 (d, J = 9.00, 1.98 Hz , 1H), 7.76 (d, J = 8.85 Hz, 1H), 1.97-2.14 (m, 1H), 0.93-1.06 (m, 2H), 0.77- 0.91 (m, 2H). MS (ESI +) m / z 226.0 (M + H) ⁺ .

Example 112

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

The title compound was prepared according to the procedure described in Example 88 using 1-phenyl-1-butine instead of 3-phenyl-1-propine. The product was a 1: 1 mixture of the starting material and the title compound. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.48 (s, 1H), 8.25 (s, 1H), 8.21 (d, J = 1.53 Hz, 1H), 8.06 (s, 1H), 7.81-7.89 (m, 1H), 7.73-7.80 (m, 1H), 7.61 (dd, J = 8.85, 1.53 Hz, 1H), 7.45 (d, J = 8.54 Hz, 1H), 7.25-7.36 (m, 4H), 7.17-7.25 (m, 1H), 3.04 (s, 4H). MS (ESI +) m / z 290.1 (M + H) ⁺ .

Example 113

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

The title compound was prepared according to the procedure described in Example 88 using 3-cyclohexyl-1-propine instead of 3-phenyl-1-propine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.49 (s, 1H), 8.21-8.29 (m, 2H), 7.88 (d, J = 9.00, 1.98 Hz, 1H), 7.77 (d, J = 8.85 Hz, 1H), 2.61 (d, J = 6.71 Hz, 2H), 1.54-1.77 (m, 6H), 1.08-1.30 (m, 3H), 0.91-1.05 (m, 2H). MS (ESI +) m / z 282.2 (M + H) ⁺ .

Example 114

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

The title compound was prepared according to the procedure described in Example 88 using cyclopentylacetylene instead of 3-phenyl-1-propine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.52 (s, 1H), 8.19-8.30 (m, 2H), 7.88 (d, J = 9.00, 1.98 Hz, 1H), 7.77 (d, J = 8.85 Hz, 1H), 3.13-3.27 (m, 1H), 1.98-2.15 (m, 2H), 1.57-1.84 (m, 6H). MS (ESI +) m / z 254.0 (M + H) ⁺ .

Example 115

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

The title compound was prepared according to the procedure described in Example 88 using 1-ethynyl-1-cyclohexanol instead of 3-phenyl-1-propine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.52 (s, 1H), 8.21-8.30 (m, J = 1.53 Hz, 2H), 7.89 (dd, J = 9.00, 1.98 Hz, 1H), 7 77 (d, J = 8.85 Hz, 1H), 2.16-2.46 (m, 1H), 1.92-2.05 (m, 2H), 1.77-1.86 (m , 2H), 1.61-1.77 (m, 2H), 1.51-1.59 (m, 1H), 1.42-1.51 (m, 2H), 1.28-1.40 (m, J = 9.92, 2.90 Hz, 1H). MS (ESI +) m / z 284.0 (M + H) ⁺ .

Example 116

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

The title compound was prepared according to the procedure described in Example 88 using phenylpropargyl ether instead of 3-phenyl-1-propine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.87 (s, 1H), 8.22-8.34 (m, 2H), 7.89 (d, J = 8.85, 1.83 Hz, 1H), 7.79 (d, J = 9.15 Hz, 1H), 7.29-7.41 (m, 2H), 7.09 (d, J = 7.63 Hz, 2H), 6.99 (t, J = 7.32 Hz, 1H), 5.25 (s, 2H). MS (ESI +) m / z 292.0 (M + H) ⁺ .

Example 117

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

The title compound was prepared according to the procedure described in Example 88 using N-propargylthiomorpholine sulfone instead of 3-phenyl-1-propine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.81 (s, 1H), 8.24-8.36 (m, 2H), 7.89 (d, J = 9.00, 1.98 Hz, 1H), 7.80 (d, J = 9.15 Hz, 1H), 4.38 (s, 2H), 3.30-3.56 (m, J = 39.36 Hz, 8H). MS (ESI +) m / z 332.9 (M + H) ⁺ .

Example 118

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

The title compound was prepared according to the procedure described in Example 88 using 1-phenyl-1-pentin instead of 3-phenyl-1-propine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.52 (s, 1H), 8.26 (s, 1H), 8.23 (d, J = 1.53 Hz, 1H), 7.87 (d, J = 9.00, 1.98 Hz , 1H), 7.76 (d, J = 9.15 Hz, 1H), 7.31 (t, J = 7.32 Hz, 2H), 7.23-7.28 (m, 2H), 7 , 20 (t, J = 7.32 Hz, 1H), 2.74 (t, J = 7.63 Hz, 2H), 2.65-2.72 (m, 2H), 1.95-2, 05 (m, 2H). MS (ESI +) m / z 304.2 (M + H) ⁺ .

Example 119

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

Example 119A

tert-Butyl 5-ethynyl-1H-indazole-1-carboxylate

To a solution of the compound of Example 3C (230 mg, 1.62 mmol) in dichloromethane (10 ml) was added di-tert-butyl dicarbonate (459 mg, 2.1 mmol) and a pinch of dimethylaminopyridine (~ 3 mg) and the mixture was stirred for 30 minutes at room temperature. Water was added and the product was extracted with dichloromethane, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to obtain 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

In an argon atmosphere, a vessel containing the compound of Example 119A (90 mg, 0.37 mmol), benzylazide (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 (0.059 ml, 0.51 mmol) were capped and shaken for 16 hours. The solvents were evaporated and the product was purified by silica gel column chromatography in 5-30% ethyl acetate in hexane. The crude material was treated with TFA (0.5 ml) in dichloromethane (1 ml) and purified by reverse phase HPLC using an acetonitrile / water gradient elution method of 0.1% TFA to give the title compound. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 13.08 (s, 1H), 7.98 (s, 1H), 7.77 (s, 1H), 7.54 (d, J = 8.24, 1.22 Hz, 2H), 7.43 -7.48 (m, 1H), 7.33-7.40 (m, 2H), 7.22-7.30 (m, 5H), 7.17-7.21 (m, 2H), 5 74 (s, 2H). MS (ESI +) m / z 380.1 (M + H) ⁺ .

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 according to the procedure described in Example 88 using 1,1-diethylpropargylamine instead of 3-phenyl-1-propine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.98 (s, 1H), 8.30 (d, J = 1.36 Hz, 1H), 8.27 (s, 1H), 7.85-7.93 (m, 1H), 7.75 -7.83 (m, 1H), 4.53 (d, J = 4.07 Hz, 2H), 3.11-3.23 (m, 4H), 1.31 (t, J = 7.12 Hz, 6H). MS (ESI +) m / z 271.0 (M + H) ⁺ .

Example 121

ethyl N- [2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-yl] beta-alaninate

The title compound was prepared according to the procedure described in Example 43 using ethyl isocyanopropionate instead of isopropyl isocyanide. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.09 (s, 1H), 8.71 (d, J = 6.78, 2.03 Hz, 1H), 8.54 (s, 1H), 8.46 (d, J = 4.24, 1.87 Hz, 1H), 8.23 (d, J = 8.82, 1.36 Hz, 1H), 8.14 (s, 1H), 7.61 (d, J = 8.82 Hz, 1H), 7.05 (d, J = 6.78, 4.07 Hz, 1H), 5.03 (t, J = 5.93 Hz, 1H), 3.96 (q, J = 7, 12 Hz, 2H), 3.23 (q, J = 6.22 Hz, 2H), 2.47-2.55 (m, 2H), 1.08 (t, J = 7.12 Hz, 3H ) MS (ESI +) m / z 351.1 (M + H) ⁺ .

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 benzylazide (2.2 ml, 17.6 mmol) were combined and heated to 150 ° C. overnight. The mixture was purified by silica gel chromatography using a gradient of 5-40% ethyl acetate in hexane to elute to give 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

The compound of Example 87A (235 mg, 0.821 mmol), the compound of 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 vessel under an inert nitrogen atmosphere. The vessel was heated in a microwave device (CEM-Discover) to 150 ° C at 125 watts for 20 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 5-40% ethyl acetate in hexane to elute to give 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

The compound of 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 using a gradient of 0-5% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.13 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.71-7.78 (m, 1H), 7.59-7.66 (m, 1H), 7.31-7.45 (m, 3H), 7.23-7.29 (m, 2H), 5.65 (s, 2H), 2.43 (s, 3H). MS (ESI +) m / z 290.1 (M + H) ⁺ .

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

The compound of Example 122A (415 mg, 0.792 mmol), 5-bromo-2-fluorobenzonitrile (158 mg, 0.790 mmol), dichlorbis (triphenylphosphine) palladium (II) (52 mg, 0.074 mmol) and copper thiophene-2-carboxylate (226 mg, 1.19 mmol) were combined in toluene (2 ml) in a microwave vessel in an inert atmosphere of nitrogen. The vessel was heated in a microwave device (CEM-Discover) at 150 ° C at 125 watts for 20 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 5-40% ethyl acetate in hexane to elute to give 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

The compound of 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 using a gradient of methanol in dichloromethane (0-5%) to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.43 (s, 1H), 7.98 (s, 1H), 7.60 (d, J = 8.65, 1.53 Hz, 1H), 7.27-7.44 (m, 4H) 7.21-7.27 (m, 2H); 5.65 (s, 2H); 5.41 (s, 2H); 2.41 (s, 3H). MS (ESI +) m / z 305.1 (M + H) ⁺ .

Example 124

N ³ - [2- (1H-indazol-5-yl) imidazo [1,2-α] pyrimidin-3-yl] -β-alanamide

The compound of Example 121 (42 mg, 0.120 mmol) and a 7 N solution of 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 using a gradient of methanol in dichloromethane (1-7%) to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.09 (s, 1H), 8.76 (d, J = 6.78, 2.03 Hz, 1H), 8.56 (s, 1H), 8.45 (d, J = 4.07, 2.03 Hz, 1H), 8.24 (d, J = 8.82, 1.36 Hz, 1H), 8.15 (s, 1H), 7.61 (d, J = 8.48 Hz, 1H), 7.32 (s, 1H), 7.03 (d, J = 6.78, 4.07 Hz, 1H), 6.85 (s, 1H), 4.93 (t, J = 6 , 10 Hz, 1H), 3.11-3.23 (m, 2H), 2.32 (t, J = 6.78 Hz, 2H). MS (ESI +) m / z 322.0 (M + H) ⁺ .

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

A mixture of the compound of Example 62B (200 mg, 1.38 mmol), benzylazide (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) under argon were stirred at room temperature for 24 hours. The solvent was evaporated and the crude mixture was dissolved in dichloromethane, loaded directly onto a silica gel column and eluted with ethyl acetate / hexane (10-20%) to give 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

The compound of 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 and the solid was collected by filtration and then purified by reverse phase HPLC using a gradient elution method with acetonitrile / water 0.1% TFA to give the title compound in the form of a TFA salt. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.07 (s, 1H), 8.30 (s, 1H), 7.83 (d, J = 8.85, 1.53 Hz, 1H), 7.44 (d, J = 8.54 Hz , 1H), 7.38-7.43 (m, J = 7.32, 7.32 Hz, 2H), 7.32-7.37 (m, 1H), 7.23-7.27 (m , J = 7.02 Hz, 2H), 5.74 (s, 2H), 4.00 (s, 2H). MS (ESI +) m / z 417.0 (M + H) ⁺ .

Example 126

N- {3- [4- (3-amino-1H-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

In an argon atmosphere, a vessel containing the compound of Example 125A (94 mg, 0.23 mmol), 1- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) - 3-m-tolylurea (obtained in accordance with 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 water (0.2 ml) were covered with a lid and heated in a heating device with shaking at 80 ° C for 90 minutes. The solvents were evaporated and the product was extracted with methanol / dichloromethane. Purification by silica gel column chromatography using 10% ethyl acetate in hexane afforded the title compound. MS (ESI +) m / z 503.2 (M + H) ⁺ .

Example 126B

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

The compound of Example 126A (25 mg, 0.05 mmol) and hydrazine monohydrate (0.5 ml) in ethanol (2 ml) were heated at 80 ° C. for 1 hour. The crude mixture was loaded onto a silica gel column and eluted using a gradient of 0-5% methanol in dichloromethane to give the title compound. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 11.40 (s, 1H), 8.79 (s, 1H), 8.63 (s, 1H), 8.12 (s, 1H), 7.57 (d, J = 8.24, 1, 22 Hz, 1H), 7.43 (t, J = 1.83 Hz, 1H), 7.38 (t, J = 7.93 Hz, 1H), 7.23-7.34 (m, 4H) , 7.08-7.22 (m, 4H), 7.03 (d, J = 6.71 Hz, 2H), 6.88 (d, J = 7.63 Hz, 1H), 6.78 ( d, J = 7.32 Hz, 1H), 5.50 (s, 2H), 5.36 (s, 2H), 2.26 (s, 3H). MS (ESI +) m / z 515.3 (M + H) ⁺ .

Example 127

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

A solution of the compound of Example 81A (37 mg, 0.18 mmol) dissolved in dimethylformamide (0.8 ml) was added to a 20-ml vessel, followed by the addition of HATU (61 mg, 0.18 mmol) dissolved in dimethylformamide (0, 8 ml). Then, a solution of 2-isopropoxyethanamine (20 mg, 0.20 mmol) dissolved in dimethylformamide (0.9 ml) was added, followed by diisopropylethylamine (42 mg, 0.36 mmol) dissolved in dimethylformamide (0.8 ml). The mixture was then shaken at 40 ° C for three hours. The crude reaction mixture was filtered through a Si-carbonate cartridge (6 ml, 2 g) supplied by Silicycle Chemical Division using methanol, monitored by LC / MS and concentrated to dryness. The residue was dissolved in a 1: 1 DMSO / methanol mixture and purified by reverse phase HPLC (Agilent, gradient 5% -100% TFA / water, over 8 minutes). ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.38-8.43 (m, 1H), 8.22-8.30 (m, 1H), 7.90 (d, 1H), 7.73 (d, 1H), 7.21-7, 29 (m, 1H), 3.56-3.65 (m, 1H), 3.52 (t, 2H), 3.43 (t, 2H), 1.10 (d, 6H). MS (ESI +) m / z 315 (M + H) ⁺ .

Example 128

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

The title compound was prepared according to the procedure described in Example 127 using morpholine instead of 2-isopropoxyethanamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.36-8.43 (m, 1H), 8.22-8.29 (m, 1H), 7.89 (d, 1H), 7.72 (d, 1H), 7.11-7, 22 (m, 1H), 3.68-3.72 (m, 4H), 3.61-3.68 (m, 4H). MS (ESI +) m / z 299 (M + H) ⁺ .

Example 129

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

The title compound was prepared in the form of a TFA salt in accordance with the procedure described in Example 127 using 3-morpholinopropan-1-amine instead of 2-isopropoxyethanamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.37-8.46 (m, 1H), 8.20-8.31 (m, 1H), 7.91 (d, 1H), 7.73 (d, 1H), 7.17-7, 36 (m, 1H), 3.98-4.08 (m, 2H), 3.57-3.73 (m, 2H), 3.42-3.51 (m, 2H), 3.35- 3.41 (m, 2H), 3.14-3.22 (m, 2H), 3.01-3.14 (m, 2H), 1.88-2.06 (m, 2H). MS (ESI +) m / z 356 (M + H) ⁺ .

Example 130

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

The title compound was prepared according to the procedure described in Example 127 using 2- (1H-imidazol-4-yl) ethanamine instead of 2-isopropoxyethanamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.90-8.97 (m, 1H), 8.34-8.46 (m, 1H), 8.20-8.32 (m, 1H), 7.90 (d, 1H), 7, 72 (d, 1H), 7.38-7.49 (m, 1H), 7.14-7.28 (m, 1H), 3.57 (t, 2H), 2.96 (t, 2H) . MS (ESI +) m / z 323 (M + H) ⁺ .

Example 131

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

The title compound was prepared according to the procedure described in Example 127 using (R) -piperidin-3-ol hydrochloride instead of 2-isopropoxyethanamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.34-8.45 (m, 1H), 8.19-8.30 (m, 1H), 7.89 (d, 1H), 7.72 (d, 1H), 7.13 (d, 1H), 4.03-4.19 (m, 1H), 3.64-3.72 (m, 1H), 3.54-3.62 (m, 1H), 3.34-3.44 ( m, 1H), 3.20-3.32 (m, 1H), 2.99-3.10 (m, 1H), 1.67-2.03 (m, 2H), 1.36-1, 61 (m, 2H). MS (ESI +) m / z 313 (M + H) ⁺ .

Example 132

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

The title compound was prepared according to the procedure described in Example 127 using piperidine-3-carboxamide instead of 2-isopropoxyethanamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.36-8.45 (m, 1H), 8.22-8.32 (m, 1H), 7.90 (d, 1H), 7.72 (d, 1H), 7.07-7, 23 (m, 1H), 4.27-4.56 (m, 1H), 3.91-4.05 (m, 1H), 3.09-3.37 (m, 1H), 2.85- 3.04 (m, 1H), 2.31-2.45 (m, 1H), 1.89-2.05 (m, 1H), 1.73-1.86 (m, 1H), 1, 60-1.72 (m, 1H); 1.36-1.55 (m, 1H). MS (ESI-) m / z 338 (MH) ^- .

Example 133

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

The title compound was obtained in the form of a TFA salt in accordance with the procedure described in Example 127 using 2- (2- (piperazin-1-yl) ethoxy) ethanol instead of 2-isopropoxyethanamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.39-8.48 (m, 1H), 8.19-8.32 (m, 1H), 7.92 (d, 1H), 7.74 (d, 1H), 7.17-7, 27 (m, 1H), 4.49-4.60 (m, 1H), 3.94-4.01 (m, 1H), 3.76-3.81 (m, 4H), 3.56- 3.63 (m, 2H), 3.51-3.56 (m, 2H), 3.33-3.43 (m, 3H), 3.13-3.23 (m, 1H), 2, 65-2.75 (m, 2H). MS (ESI +) m / z 386 (M + H) ⁺ .

Example 134

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

The title compound was obtained in the form of a TFA salt in accordance with the procedure described in Example 127 using 1-methyl-1,4-diazepane instead of 2-isopropoxyethanamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.38-8.46 (m, 1H), 8.22-8.32 (m, 1H), 7.85-7.98 (m, 1H), 7.75 (d, 1H), 7, 22 (d, 1H), 4.07-4.19 (m, 1H), 3.69-3.77 (m, 2H), 3.59-3.67 (m, 1H), 3.44- 3.59 (m, 1H), 3.35-3.44 (m, 1H), 3.24-3.35 (m, 2H), 2.84-2.95 (m, 3H), 2, 66-2.74 (m, 1H); 2.10-2.26 (m, 2H). MS (ESI +) m / z 326 (M + H) ⁺ .

Example 135

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

The title compound was prepared according to the procedure described in Example 127 using 3-aminopropan-1-ol instead of 2-isopropoxyethanamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.36-8.45 (m, 1H), 8.20-8.30 (m, 1H), 7.84-7.94 (m, 1H), 7.71 (d, 1H), 7, 18-7.28 (m, 1H), 3.48 (t, 2H), 3.35 (t, 2H), 1.64-1.78 (m, 2H). MS (ESI +) m / z 387 (M + H) ⁺ .

Example 136

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

The title compound was prepared according to the procedure described in Example 127 using (R) -2-amino-2-phenylethanol instead of 2-isopropoxyethanamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 9.11 (d, 1H), 8.37-8.46 (m, 1H), 8.23-8.28 (m, 1H), 7.91 (d, 1H), 7.73 (d, 1H), 7.40-7.45 (m, 2H), 7.32-7.39 (m, 2H), 7.23-7.32 (m, 2H), 5.05-5.13 ( m, 1H); 3.66-3.72 (m, 2H). MS (ESI +) m / z 349 (M + H) ⁺ .

Example 137

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

The title compound was prepared according to the procedure described in Example 127 using 3- (1H-indazol-1-yl) propan-1-amine instead of 2-isopropoxyethanamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 9.02-9.10 (m, 1H), 8.40-8.44 (m, 1H), 8.25-8.29 (m, 1H), 7.87-7.95 (m, 1H) ), 7.71-7.82 (m, 2H), 7.61-7.69 (m, 1H), 7.20-7.29 (m, 1H), 4.28 (t, 2H), 3.33 (t, 2H); 2.06-2.19 (m, 2H). MS (ESI +) m / z 337 (M + H) ⁺ .

Example 138

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

The title compound was prepared according to the procedure described in Example 127 using 1- (3-aminopropyl) pyrrolidin-2-one instead of 2-isopropoxyethanamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.38-8.43 (m, 1H), 8.24-8.30 (m, 1H), 7.87-7.93 (m, 1H), 7.73 (d, 1H), 7, 22-7.26 (m, 1H), 3.39 (t, 2H), 3.21-3.30 (m, 4H), 2.26 (t, 2H), 1.90-2.00 ( m, 2H), 1.70-1.79 (m, 2H). MS (ESI +) m / z 354 (M + H) ⁺ .

Example 139

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

The title compound was prepared according to the procedure described in Example 127 using 4- (2-aminoethyl) benzenesulfonamide instead of 2-isopropoxyethanamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.37-8.42 (m, 1H), 8.24-8.29 (m, 1H), 7.86-7.93 (m, 1H), 7.70-7.80 (m, 3H ), 7.47 (d, 2H), 7.20-7.24 (m, 1H), 3.57 (t, 2H), 2.96 (t, 2H). MS (ESI +) m / z 412 (M + H) ⁺ .

Example 140

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

The title compound was prepared according to the procedure described in Example 119B using 3-chlorobenzoyl chloride instead of benzoyl chloride. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.09 (s, 1H), 7.99 (s, 1H), 7.77 (s, 1H), 7.38-7.51 (m, 4H), 7.28-7.37 (m, 3H), 7.20-7.27 (m, 4H), 5.78 (s, 2H). MS (ESI +) m / z 414.1 (M + H) ⁺ .

Example 141

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

The title compound was prepared according to the procedure described in Example 119B using cyclopropanecarbonyl chloride instead of benzoyl chloride. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.26 (s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.61-7.70 (m, 2H), 7.29-7.40 (m, 3H), 7.24 (d, J = 7.02 Hz, 2H), 5.79 (s, 2H), 1.86-2.00 (m, 1H), 0.98-1.12 (m , 2H); 0.77-0.93 (m, 2H). MS (ESI +) m / z 344.1 (M + H) ⁺ .

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

Cyclopropylacetylene (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 stirred in a sealed vessel at 70 ° C for 2 hours. The mixture was cooled to ambient temperature and the contents of the vessel were mixed without sealing for 10 minutes. The compound of Example 80A (455 mg, 3.22 mmol) was added and the vessel was again sealed and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography using a gradient of ethyl acetate in hexane (5-50%) to elute to give 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-indazol-1-yl) ethanone

The compound of Example 142A (220 mg, 0.444 mmol), the compound of 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) ) were combined in toluene (2.0 ml) in a 4 ml vessel under an inert nitrogen atmosphere. The vessel was sealed and heated to 150 ° C for 20 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 5-70% ethyl acetate in hexane to elute to give 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

The compound of 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 using a gradient of 0-8% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.19 (s, 1H), 7.96 (d, J = 8.82 Hz, 1H), 7.61 (d, J = 7.80 Hz, 1H), 7.25-7.28 (m , 1H), 4.34 (d, J = 6.44 Hz, 2H), 4.02 (d, J = 1 1.36, 3.56 Hz, 2H), 3.42 (t, J = 1 1.53 Hz, 2H), 2.33-2.46 (m, 1H), 1.81-1.95 (m, 1H), 1.59-1.70 (m, 2H), 1.43 -1.58 (m, 2H), 1.23-1.28 (m, 1H), 1.10-1.20 (m, 2H), 0.47-0.62 (m, 2H). MS (ESI +) m / z 324.1 (M + H) ⁺ .

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) -lΗ-1,2,3-triazol-5-yl) methyl) isoindolin-1,3-dione

N-Propargylphthalimide (2.35 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) and stirred in a tightly closed vessel at 70 ° C for 2 hours. The mixture was cooled to ambient temperature and the contents of the vessel were mixed without sealing for 10 minutes. Benzylazide (2.0 ml, 16.0 mmol) was added and the vessel was again hermetically sealed and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography using a gradient of 10-50% ethyl acetate in hexane to elute to give 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-dione

The compound of Example 143A (567 mg, 0.934 mmol), the compound of 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 vessel under an inert nitrogen atmosphere. The vessel was heated in a microwave device (CEM-Discover) to 150 ° C at 125 watts for 20 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 10-50% ethyl acetate in hexane to elute to give 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

The compound of Example 143B (140 mg, 0.294 mmol) was treated with hydrazine hydrate (0.7 ml) in ethanol (0.7 ml) and stirred at ambient temperature overnight. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 1-6% methanol in dichloromethane to elute to give the title compound. MS (ESI +) m / z 305.0 (M + H) ⁺ .

Example 143D

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

The compound of Example 143C (66 mg, 0.217 mmol), N- (tert-butoxycarbonyl) glycine (39 mg, 0.223 mmol) and ΗATU (85 mg, 0.224 mmol) were combined in methylene chloride (2.5 ml). Diisopropylethylamine (150 μl, 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 using a gradient of 0-6% methanol in dichloromethane to elute to give tert-butyl 2 - ((1-benzyl-4- (lΗ-indazol-5-yl) -lΗ -1,2,3-triazol-5-yl) methylamino) -2-oxoethyl carbamate. This carbamate was dissolved in tetrahydrofuran (2 ml), and 0.5 ml of a solution of 1 n hydrochloric acid in diethyl ether was added, and the mixture was stirred for 20 minutes at room temperature. The solvents were removed under reduced pressure, and diethyl ether was added to the mixture, and stirred at room temperature overnight. The solvent was decanted and the resulting residue was dried under a stream of nitrogen to obtain the title compound in the form of a hydrochloride salt. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.21 (s, 1H), 9.02 (t, J = 5.09 Hz, 1H), 8.11-8.16 (m, 2H), 8.06 (s, 2H), 7.75 -7.82 (m, 1H), 7.64 (d, J = 8.82 Hz, 1H), 7.30-7.45 (m, 3H), 7.23-7.31 (m, 2H ), 5.72 (s, 2H), 4.57 (d, J = 5.09 Hz, 2H), 3.41 (q, J = 5.76 Hz, 2H). MS (ESI +) m / z 362.1 (M + H) ⁺ .

Example 144

(4-fluorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl} methanone

The title compound was prepared according to the procedure described in Example 119B using 4-fluorobenzoyl chloride instead of benzoyl chloride and using the compound of Example 80A instead of benzyl azide. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.10 (s, 1H), 8.00 (s, 1H), 7.72-7.80 (m, 3H), 7.38-7.44 (m, 1H), 7.30-7, 36 (m, 1H), 7.09-7.19 (m, 2H), 4.41 (d, J = 7.12 Hz, 2H) 3.80 (d, J = 1 1.36, 2, 54 Hz, 2H), 3.14-3.26 (m, 2H), 2.04-2.19 (m, 1H), 1.38-1.49 (m, 2H), 1.19-1 35 (m, 2H). MS (ESI +) m / z 406.1 (M + H) ⁺ .

Example 145

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

The title compound was prepared according to the procedure described in Example 119B using 4-chlorobenzoyl chloride instead of benzoyl chloride and using the compound of Example 80A instead of benzylazide. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.10 (s, 1H), 8.00 (s, 1H), 7.77 (s, 1H), 7.68 (d, J = 8.48 Hz, 2H), 7.29-7.45 (m, 4H), 4.42 (d, J = 7.12 Hz, 2H), 3.81 (d, J = 1 1.19, 2.71 Hz, 2H), 3.14-3.27 (m, 2H), 2.03-2.19 (m, 1H), 1.38-1.51 (m, 2H), 1.22-1.36 (m, 2H). MS (ESI +) m / z 422.1 (M + H) ⁺ .

Example 146

(3-chlorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl} methanone

The title compound was prepared according to the procedure described in Example 119B using 3-chlorobenzoyl chloride instead of benzoyl chloride and using the compound of Example 80A instead of benzyl azide. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.04 (s, 1H), 7.95 (s, 1H), 7.64 (s, 1H), 7.48-7.54 (m, 1H), 7.29-7.35 (m, 1H), 7.22-7.28 (m, 1H), 7.13-7.22 (m, 3H), 4.58 (d, J = 7.12 Hz, 2H), 3.86 (d , J = 1 1.53, 2.37 Hz, 2H), 3.20-3.30 (m, 2H), 2.11-2.24 (m, 1H), 1.45-1.54 ( m, 2H), 1.33-1.44 (m, 2H). MS (ESI +) m / z 422.1 (M + H) ⁺ .

Example 147

(2-Chlorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl} methanone

The title compound was prepared according to the procedure described in Example 119B using 2-chlorobenzoyl chloride instead of benzoyl chloride and using the compound of Example 80A instead of benzylazide. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.08 (s, 1H), 7.99 (s, 1H), 7.75 (s, 1H), 7.66 (t, J = 1.86 Hz, 1H), 7.56 (d, J = 7.80 Hz, 1H), 7.47-7.53 (m, 1H), 7.36-7.42 (m, 1H), 7.23-7.34 (m, 2H), 4, 45 (d, J = 6.78 Hz, 2H), 3.82 (d, J = 1 l, 19, 2.37 Hz, 2H), 3.18-3.29 (m, 2H), 2, 09-2.23 (m, 1H), 1.41-1.53 (m, 2H), 1.28-1.38 (m, 2H). MS (ESI +) m / z 422.1 (M + H) ⁺ .

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 according to the procedure described in Example 119B using cyclopentanecarbonyl chloride instead of benzoyl chloride and using the compound of Example 80A instead of benzyl azide. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.27 (s, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.68 (d, J = 8.48 Hz, 1H), 7.52 (d, J = 8.48, 1.70 Hz, 1H), 4.47 (d, J = 7.12 Hz, 2H), 3.85 (d, J = 1 1.53, 2.37 Hz, 2H), 3.18-3.30 (m, 2H), 3.02-3.14 (m, 1H), 2.00-2.17 (m, 1H), 1.19-1.76 (m, 12H) ) MS (ESI +) m / z 380.1 (M + H) ⁺ .

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 methylethyl (tributylstannyl) carbamate (26.9 g, 68.6 mmol) in a large hermetically sealed tube. The mixture was heated to 70 ° C. overnight. The mixture was cooled to ambient temperature and the contents of the vessel were mixed without sealing for 10 minutes. Benzylazide (10.2 ml, 81.6 mmol) was added and the vessel was sealed again and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography using a gradient of 5-40% ethyl acetate in hexane to elute to give 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

The compound of Example 149A (7.17 g, 14.1 mmol), the compound of 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) in a large hermetically sealed tube in an inert nitrogen atmosphere. 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 using a gradient of 10-50% ethyl acetate in hexane to elute to give 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

The compound of 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 and washed with a 1N hydrochloric acid solution, washed with brine, and the combined organic layers were dried over sodium sulfate. After filtration, the solvents were removed under reduced pressure to obtain the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.16 (s, 1H), 8.11-8.18 (m, 2H), 7.66-7.76 (m, 1H), 7.54-7.62 (m, 1H), 7, 31-7.43 (m, 3H), 7.22-7.29 (m, 2H), 5.93 (s, 2H). MS (ESI +) m / z 320.0 (M + H) ⁺ .

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 at ambient temperature for nights. 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 obtain the title compound. The crude product was used in the next step without further analysis.

Example 150B

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

4-Fluorophenylacetylene (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 stirred in a hermetically sealed vessel at 50 ° C. within 30 minutes. The mixture was cooled to ambient temperature and the contents of the vessel were mixed without sealing for 10 minutes. The compound of Example 150A (1.28 g, 6.30 mmol) was added and the vessel was again hermetically sealed and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography using a gradient of 5-35% ethyl acetate in hexane to elute to give 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

The compound of 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) were combined in toluene (2.0 ml) in a 4 ml vessel under an inert nitrogen atmosphere. The vessel was sealed and heated at 150 ° C for 30 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 10-50% ethyl acetate in hexane to elute to give 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

The compound of 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 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 using a gradient of 0-6% methanol in dichloromethane for elution to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.42 (s, 1H), 8.04 (s, 1H), 7.67 (d, J = 8.14 Hz, 2H), 7.26-7.41 (m, 4H), 7.22 (d, J = 8.48 Hz, 2H), 7.03-7.15 (m, 2H), 5.62 (s, 2H), 5.36 (s, 2H). MS (ESI +) m / z 453.1 (M + H) ⁺ .

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-Fluorophenylacetylene (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 stirred in a hermetically sealed vessel at 50 ° C. within 2 hours. The mixture was cooled to ambient temperature and the contents of the vessel were mixed without sealing for 10 minutes. Benzylazide (850 μl, 6.80 mmol) was added and the vessel was again hermetically sealed and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography using a gradient of 5-35% ethyl acetate in hexane to elute to give 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

The compound of 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) were combined in toluene (2.0 ml) in a 4 ml vessel under an inert nitrogen atmosphere. The vessel was sealed and heated to 150 ° C. for 30 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 10-50% ethyl acetate in hexane to elute to give 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

The compound of Example 151B (135 mg, 0.363 mmol) was treated with hydrazine hydrate (1.0 ml) in ethanol (1.0 ml) and stirred and heated to 65 ° C. for 3 hours. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography using a gradient of 0-6% methanol in dichloromethane for elution to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.40 (s, 1H), 8.02 (s, 1H), 7.24-7.38 (m, 7H), 7.03-7.14 (m, 2H), 6.98 (d, J = 7.29, 2.20 Hz, 2H), 5.50 (s, 2H), 5.35 (s, 2H). MS (ESI +) m / z 385.1 (M + H) ⁺ .

Example 152

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

The title compound was prepared according to the procedure described in Example 119B using the compound of Example 80A instead of benzyl azide and using tetrahydro-2H-pyran-4-carbonyl chloride instead of benzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.30 (s, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.69 (d, J = 8.48 Hz, 1H), 7.53 (d, J = 8.65, 1.53 Hz, 1H), 4.48 (d, J = 7.12 Hz, 2H), 3.79-3.90 (m, 2H), 3.62-3.74 ( m, 2H), 3.18-3.30 (m, 2H), 2.76-2.88 (m, 1H), 2.64-2.76 (m, 2H), 2.00-2, 17 (m, 1H), 1.20-1.58 (m, 8H). MS (ESI +) m / z 396.0 (M + H) ⁺ .

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-Ethynyltoluene (456 μl, 3.62 mmol) was added to 1,1,1-tributyl-N, N-dimethylstannanamine (1.21 g, 3.62 mmol) and the mixture was stirred in a hermetically sealed vessel at 70 ° C. within 3 hours. The mixture was cooled to ambient temperature and the contents of the vessel were mixed without sealing for 10 minutes. Benzylazide (678 μl, 5.42 mmol) was added and the vessel was again sealed and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography using a gradient of 5-45% ethyl acetate in hexane to elute to give 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

The compound of Example 153A (119 mg, 0.221 mmol), the compound of 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) ) were combined in toluene (2.0 ml) in a 4 ml vessel under an inert nitrogen atmosphere. The vessel was sealed and heated at 150 ° C for 20 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 5-45% ethyl acetate in hexane to elute to give 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

The compound of 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 using a gradient of 1-6% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.07 (s, 1H), 7.97 (s, 1H), 7.73 (s, 1H), 7.44-7.53 (m, 3H), 7.39 (t, J = 6, 95 Hz, 1H), 7.28-7.35 (m, 2H), 7.21-7.29 (m, 3H), 6.86-6.95 (m, 2H), 5.28-5 45 (m, 2H); 1.59 (s, 3H). MS (ESI +) m / z 366.1 (M + H) ⁺ .

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 described in Example 81B, using the compound of Example 149C instead of the compound of Example 81A and using 1-methylpiperazine instead of piperidine and tetrahydrofuran instead of dimethylformamide. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.20 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.57-7.69 (m, 2H), 7.31-7.44 (m, 3H), 7.23-7.30 (m, 2H), 5.36-5.83 (m, 2H), 3.40-3.65 (m, J = 4.75 Hz, 2H), 2 38-2.49 (m, 2H), 2.10-2.22 (m, 2H), 1.89 (s, 3H), 1.40 (t, J = 4.92 Hz, 2H). MS (ESI +) m / z 402.2 (M + H) ⁺ .

Example 155

5 - {[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 described in Example 81B using the compound of Example 149C instead of the compound of Example 81A and using 4-hydroxypiperidine instead of piperidine and tetrahydrofuran instead of dimethylformamide. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.15-13.24 (m, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.55-7.68 (m, 2H), 7.32-7, 43 (m, 3H), 7.23-7.30 (m, 2H), 5.41-5.83 (m, J = 65.10 Hz, 2H), 4.58 (d, J = 3, 39 Hz, 1H), 3.74-3.91 (m, 1H), 3.37-3.48 (m, 2H), 2.66-2.79 (m, 1H), 2.25-2 47 (m, 1H), 1.54-1.68 (m, 1H), 1.20-1.36 (m, 1H), 0.74-0.90 (m, 1H), 0.40 -0.60 (m, 1H). MS (ESI +) m / z 403.1 (M + H) ⁺ .

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-Fluorophenylacetylene (440 μl, 3.88 mmol) was added to 1,1,1-tributyl-N, N-dimethylstannanamine (1.30 g, 3.89 mmol) and the mixture was stirred in a sealed vessel at 50 ° C in for 40 minutes. The mixture was cooled to ambient temperature and the contents of the vessel were mixed without sealing for 10 minutes. The compound of Example 80A (710 μl, 5.68 mmol) was added and the vessel was sealed again and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography using a gradient of 5-50% ethyl acetate in hexane to elute to give 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

The compound of Example 156A (433 mg, 0.787 mmol), the compound of 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) were combined in toluene (2.0 ml) in a 4 ml vessel under an inert nitrogen atmosphere. The vessel was sealed and heated to 150 ° C for 20 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 5-45% ethyl acetate in hexane for elution and triturated with methanol to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.40-8.48 (m, J = 0.68 Hz, 1H), 8.25 (d, J = 8.82 Hz, 1H), 7.82-7.91 (m, 1H), 7 73 (d, J = 8.48, 1.70 Hz, 1H), 7.50-7.60 (m, 2H), 7.38-7.49 (m, 2H), 4.13 (d , J = 7.12 Hz, 2H), 3.76 (d, J = 1 1.36, 2.54 Hz, 2H), 3.10-3.25 (m, 2H), 2.70 (s , 3H), 1.86-2.08 (m, 1H), 1.37 (d, J = 12.55, 1.70 Hz, 2H), 1.03-1.23 (m, 2H). MS (ESI +) m / z 420.2 (M + H) ⁺ .

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 described in Example 81B, using the compound of Example 149C instead of the compound of Example 81A and using dimethylamine instead of piperidine and tetrahydrofuran instead of dimethylformamide. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.19 (s, 1H), 8.15 (s, 1H), 7.96 (t, J = 1.19 Hz, 1H), 7.62 (d, J = 1.36 Hz, 2H), 7.33-7.44 (m, 3H), 7.24-7.33 (m, 2H), 5.59 (s, 2H), 2.92 (s, 3H), 2.21 (s, 3H). MS (ESI +) m / z 347.1 (M + H) ⁺ .

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 described in Example 81B, using the compound of Example 149C instead of the compound of Example 81A and using benzylamine instead of piperidine and tetrahydrofuran instead of dimethylformamide. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.15 (s, 1H), 9.35 (t, J = 6.10 Hz, 1H), 8.01 (d, J = 12.55 Hz, 2H), 7.68 (d, J = 8 82, 1.36 Hz, 1H), 7.53 (d, J = 8.82 Hz, 1H), 7.17-7.41 (m, 10H), 5.66 (s, 2H), 4 41 (d, J = 6.10 Hz, 2H). MS (ESI +) m / z 409.1 (M + H) ⁺ .

Example 159

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

The title compound was prepared according to the procedure described in Example 81B using DL-alpha- (methylaminomethyl) benzyl alcohol instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.01 (s, 1H), 8.29 (s, 1H), 8.17 (s, 1H), 7.73-7.85 (m, 1H), 7.62-7.72 (m, 1H), 7.16-7.43 (m, 5H), 6.86 (s, 1H), 5.17 (d, J = 4.39 Hz, 1H), 4.89 (s, 1H), 3.71 (d, J = 5.49 Hz, 2H); 3.10 (s, 3H). MS (ESI +) m / z 363.1 (M + H) ⁺ .

Example 160

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

The title compound was prepared according to the procedure described in Example 81B using (S) -2-amino-2-phenylethanol in place of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.37 (s, 1H), 9.05 (d, J = 8.14 Hz, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 7.89 (d, J = 8.65, 1.53 Hz, 1H), 7.70 (d, J = 8.82 Hz, 1H), 7.20-7.46 (m, 6H), 5.02-5.13 ( m, 1H), 4.98 (t, J = 5.59 Hz, 1H), 3.61-3.82 (m, 2H). MS (ESI +) m / z 349.0 (M + H) ⁺ .

Example 161

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

The title compound was prepared according to the procedure described in Example 81B using 2- (benzylamino) ethanol instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.37 (s, 1H), 9.05 (d, J = 8.48 Hz, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 7.89 (d, J = 8.65, 1.53 Hz, 1H), 7.70 (d, J = 8.82 Hz, 1H), 7.22-7.45 (m, 6H), 5.02-5.14 ( m, 1H), 4.98 (t, J = 5.76 Hz, 1H), 3.61-3.81 (m, 2H). MS (ESI +) m / z 349.0 (M + H) ⁺ .

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 μl, 5.29 mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate, washed with 1 N sodium hydroxide solution, then with 1 N hydrochloric acid solution, then with brine. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to obtain 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

The compound of Example 153A (436 mg, 0.808 mmol), Example 162A (205 mg, 0.810 mmol), dichlorbis (triphenylphosphine) palladium (II) (56 mg, 0.080 mmol) and copper thiophene-2-carboxylate (239 mg, 1.25 mmol) were combined in toluene (2.0 ml) in a 4 ml vessel under an inert nitrogen atmosphere. The vessel was sealed and heated to 150 ° C. for 30 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 10-50% ethyl acetate in hexane to elute to give 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

The compound of 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 hour and then diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography using a gradient of 30-80% ethyl acetate in hexane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.63 (s, 1H), 7.70 (s, 1H), 7.44-7.52 (m, 1H), 7.38-7.43 (m, 1H), 7.29-7, 38 (m, 4H), 7.22-7.29 (m, 3H), 6.89-6.96 (m, J = 6.44, 3.05 Hz, 2H), 5.30-5, 48 (m, 2H), 2.32 (s, 3H), 1.58 (s, 3H). MS (ESI +) m / z 380.1 (M + H) ⁺ .

Example 163

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

Example 163 A

5- (1-Benzyl-5-o-tolyl-1H-1,2,3-triazol-4-yl) -2-fluorobenzonitrile

The compound of 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) were combined in toluene (2.0 ml) in a 4 ml vessel under an inert nitrogen atmosphere. The vessel was sealed and heated at 150 ° C for 30 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 10-50% ethyl acetate in hexane to elute to give 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

The compound of Example 163A (202 mg, 0.548 mmol) was treated with hydrazine hydrate (1.0 ml) in ethanol (1.0 ml) and stirred and heated to 60 ° C. overnight. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography using a gradient of 35-85% ethyl acetate in hexane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.38 (s, 1H), 8.11 (s, 1H), 7.41-7.49 (m, 1H), 7.33-7.40 (m, J = 6.95, 6.95 Hz, 1H), 7.28-7.32 (m, 2H), 7.21-7.28 (m, 3H), 7.00-7.06 (m, 1H), 6.86-6, 95 (m, 3H), 5.27-5.44 (m, 4H), 1.58 (s, 3H). MS (ESI +) m / z 381.1 (M + H) ⁺ .

Example 164

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

The title compound was prepared according to the procedure described in Example 88 using 2- (but-3-ynyl) isoindolin-1,3-dione instead of 3-phenyl-1-propine. The crude product was treated with 25% TFA / dichloromethane and purified by reverse phase HPLC using an acetonitrile / water gradient gradient of 0.1% TFA to obtain the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.33 (s, 1H), 8.65 (s, 1H), 8.22 (s, 1H), 8.18 (d, J = 1.53 Hz, 1H), 7.78-7.90 (m, 5H), 7.71-7.75 (m, 1H), 3.92 (t, J = 7.21 Hz, 2H), 3.08 (t, J = 7.21 Hz, 2H) . MS (ESI +) m / z 359.0 (M + H) ⁺ .

Example 165

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

The title compound was prepared according to the procedure described in Example 88 using 2,4-dichloro-1- (prop-2-ynyloxy) benzene instead of 3-phenyl-1-propine. The crude product was treated with 25% TFA / dichloromethane and purified by reverse phase HPLC using an acetonitrile / water gradient gradient of 0.1% TFA to obtain the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.38 (s, 1H), 8.93 (s, 1H), 8.28 (d, J = 1.53 Hz, 1H), 8.23 (s, 1H), 7.88 (d, J = 8.90, 1.84 Hz, 1H), 7.76 (d, J = 8.90 Hz, 1H), 7.59 (d, J = 2.46 Hz, 1H), 7.39-7 49 (m, 2H); 5.37 (s, 2H). MS (ESI +) m / z 359.9 (M + H) ⁺ .

Example 166

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

The title compound was prepared according to the procedure described in Example 88 using 1,3-dichloro-2- (prop-2-ynyloxy) benzene instead of 3-phenyl-1-propine. The crude product was treated with 25% TFA / dichloromethane and purified by reverse phase HPLC using an acetonitrile / water gradient gradient of 0.1% TFA to obtain the title compound. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.39 (s, 1H), 8.97 (s, 1H), 8.29 (d, J = 1.53 Hz, 1H), 8.24 (s, 1H), 7.89 (d, J = 9.00, 1.98 Hz, 1H), 7.76 (d, J = 8.85 Hz, 1H), 7.51-7.55 (m, 2H), 7.19-7.26 ( m, J = 8.24, 8.24 Hz, 1H), 5.23 (s, 2H). MS (ESI +) m / z 359.9 (M + H) ⁺ .

Example 167

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

The compound of 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 and diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography using a gradient of 0-7% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.08 (s, 1H), 8.02 (s, 1H), 7.77 (s, 1H), 7.50-7.58 (m, 2H), 7.37-7.49 (m, 4H), 4.11 (d, J = 7.12 Hz, 2H), 3.76 (d, J = 1 1.53, 2.71 Hz, 2H), 3.11-3.24 (m, 2H), 1.88-2.03 (m, 1H), 1.30-1.43 (m, J = 12.72, 1.86 Hz, 2H), 1.04-1.22 (m, 2H). MS (ESI +) m / z 378.1 (M + H) ⁺ .

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 slowly added 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 with excess water, absorbed on silica gel and purified by silica gel chromatography using a gradient of 5-30% ethyl acetate in hexane to elute to give 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 according to the procedure described in Example 88 using the compound of Example 168A instead of 3-phenyl-1-propine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.36 (s, 1H), 8.78 (s, 1H), 8.22 (d, J = 2.03, 0.68 Hz, 1H), 8.20 (s, 1H), 8.10 (d, J = 1.02 Hz, 1H), 7.80-7.87 (m, 2H), 7.75-7.80 (m, 1H), 7.68-7.74 (m, 1H ), 7.39-7.46 (m, 1H), 7.13-7.19 (m, 1H), 5.81 (s, 2H). MS (ESI +) m / z 316.0 (M + H) ⁺ .

Example 169

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

The title compound was prepared according to the procedure described in Example 81B using the compound of Example 149C instead of the compound of Example 81A and using tetrahydrofuran instead of dimethylformamide.^oneH NMR (300 MHz, DMSO-d₆) δ ppm 13.20 (s, 1H), 8.16 (s, 1H), 7.95-8.00 (m, J = 1.02 Hz, 1H), 7.62-7.68 (m, 1H) 7.57-7.63 (m, 1H), 7.31-7.44 (m, 3H), 7.24-7.30 (m, 2H), 5.36-5.84 (m, J = 69.17 Hz, 2H), 3.43-3.59 (m, 2H), 2.43-2.59 (m, 2H), 1.17-1.46 (m, J = 39, 67 Hz, 4H), 0.49-0.65 (m, 2H). MS (ESI +) m / z 387.1 (M + H)⁺.

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-Ethynyltoluene (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 stirred in a hermetically sealed vessel at 70 ° C. within 2 hours. The mixture was cooled to ambient temperature and the contents of the vessel were mixed without sealing for 10 minutes. The compound of Example 80A (648 mg, 4.59 mmol) was added and the vessel was again sealed and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography using a gradient of 5-50% ethyl acetate in hexane to elute to give 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- silt) ethanone

The compound of Example 170A (432 mg, 0.791 mmol), the compound of 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) were combined in toluene (2.0 ml) in a 4 ml vessel under an inert nitrogen atmosphere. The vessel was sealed and heated at 150 ° C for 20 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 20-70% ethyl acetate in hexane to elute to give 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

The compound of 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 and diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography using a gradient of 35-100% ethyl acetate in hexane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.08 (s, 1H), 7.98 (s, 1H), 7.68-7.74 (m, J = 1.02, 1.02 Hz, 1H), 7.49-7.56 ( m, 1H), 7.45-7.49 (m, 3H), 7.41-7.45 (m, J = 7.46 Hz, 2H), 4.10 (d, J = 13.73, 6.95 Hz, 1H), 3.89 (d, J = 13.90, 7.80 Hz, 1H), 3.77 (d, J = 10.51, 2.71 Hz, 2H), 3, 10-3.24 (m, 2H), 1.92 (s, 3H), 1.88-1.98 (m, 1H), 1.26-1.43 (m, 2H), 1.04- 1.21 (m, 2H). MS (ESI +) m / z 374.1 (M + H) ⁺ .

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

The compound of 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) were combined in toluene (2.0 ml) in a 4 ml vessel under an inert nitrogen atmosphere. The vessel was sealed and heated to 150 ° C. for 30 minutes. The mixture was absorbed on silica gel and purified by silica gel chromatography using a gradient of 10-50% ethyl acetate in hexane to elute to give 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

The compound of Example 171A (175 mg, 0.465 mmol) was treated with hydrazine hydrate (2.0 ml) in ethanol (2.0 ml) and the mixture was stirred and heated to 65 ° C for 2 hours. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography using a gradient of 1-8% methanol in dichloromethane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.39 (s, 1H), 8.08 (s, 1H), 7.45-7.55 (m, 1H), 7.37-7.45 (m, 3H), 7.01-7, 08 (m, J = 8.48 Hz, 1H), 6.89-6.97 (m, 1H), 5.34 (s, 2H), 4.09 (d, J = 13.73, 6, 95 Hz, 1H), 3.89 (d, J = 13.73, 7.63 Hz, 1H), 3.70-3.81 (m, 2H), 3.08-3.24 (m, 2H ), 1.91 (s, 3H), 1.84-1.99 (m, 1H), 1.22-1.41 (m, 2H), 1.04-1.20 (m, 2H). MS (ESI +) m / z 389.1 (M + H) ⁺ .

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 described in Example 81B using the compound of Example 149C instead of the compound of Example 81A, morpholine instead of piperidine and tetrahydrofuran instead of dimethylformamide. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.22 (s, 1H), 8.18 (s, 1H), 7.95-8.03 (m, 1H), 7.64-7.70 (m, 1H), 7.57-7, 64 (m, 1H), 7.33-7.45 (m, 3H), 7.24-7.31 (m, 2H), 5.76 (s, 1H), 5.52 (s, 1H) 3.33-3.59 (m, 4H); 2.61-2.74 (m, 2H); 2.45-2.59 (m, 2H). MS (ESI +) m / z 389.1 (M + H) ⁺ .

Example 173

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

In an argon atmosphere, a vessel containing the compound of 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 potassium carbonate (33 mg, 0.24 mmol) in DME (2 ml) and water (0.2 ml) were covered with a lid and heated at 80 ° C. in a heating device with shaking for 48 hours. The solvent was evaporated under reduced pressure and the product was purified by reverse phase HPLC using an acetonitrile / water gradient 0.1% TFA gradient elution method to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.85 (s, 1H), 8.18 (s, 1H), 7.26-7.34 (m, 3H), 7.19-7.25 (m, 2H), 7.16-7, 19 (m, 2H), 7.02 (t, J = 8.13 Hz, 4H), 5.47 (s, 2H), 3.80 (s, 3H). MS (ESI +) m / z 397.1 (M + H) ⁺ .

Example 174

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

The title compound was prepared according to the procedure described in Example 81B using (S) - (-) - 2-amino-3-phenyl-1-propanol instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.36 (s, 1H), 8.47 (d, J = 8.82 Hz, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 7.87 (d, J = 8.82, 1.70 Hz, 1H), 7.69 (d, J = 8.82 Hz, 1H), 7.23-7.31 (m, 3H), 7.22 (s, 1H) 7.12-7.21 (m, 1H), 4.90 (t, J = 5.59 Hz, 1H), 4.07-4.28 (m, 1H), 3.40-3.58 (m, 2H), 2.89-3.00 (m, 1H), 2.75-2.86 (m, 1H). MS (ESI +) m / z 363.0 (M + H) ⁺ .

Example 175

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

The title compound was prepared according to the procedure described in Example 81B using (1S, 2R) - (-) - cis-1-amino-2-indanol instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.38 (s, 1H), 8.42 (s, 1H), 8.24 (s, 1H), 8.16 (d, J = 8.48 Hz, 1H), 7.91 (d, J = 8.82, 1.70 Hz, 1H), 7.71 (d, J = 8.48 Hz, 1H), 7.45 (s, 1H), 7.16-7.32 (m, 4H) , 5.36-5.47 (m, 2H), 4.50-4.61 (m, 1H), 3.14 (d, J = 15.43, 5.26 Hz, 1H), 2.90 (d, J = 16.28, 1.70 Hz, 1H). MS (ESI +) m / z 361.0 (M + H) ⁺ .

Example 176

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

The title compound was prepared according to the procedure described in Example 81B using 3-phenylmorpholine hydrochloride instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.38 (s, 1H), 8.32-8.46 (m, 1H), 8.24 (s, 1H), 7.81-7.96 (m, 1H), 7.70 (d, J = 8.82 Hz, 1H), 7.37-7.55 (m, 4H), 7.26-7.37 (m, 2H), 5.34-5.71 (m, 1H), 4 51 (d, J = 13.22 Hz, 1H), 3.78-4.39 (m, 3H), 3.59 (t, J = 1 1.36 Hz, 1H), 3.33-3 41 (m, 1H). MS (ESI +) m / z 375.0 (M + H) ⁺ .

Example 177

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

The title compound was prepared according to the procedure described in Example 81B using benzylamine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.36 (s, 1H), 9.35 (t, J = 6.27 Hz, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 7.89 (d, J = 8.82, 1.70 Hz, 1H), 7.69 (d, J = 8.82 Hz, 1H), 7.33-7.40 (m, 4H), 7.32 (s, 1H) 7.22-7.30 (m, 1H); 4.48 (d, J = 6.10 Hz, 2H). MS (ESI +) m / z 319.0 (M + H) ⁺ .

Example 178

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

The title compound was prepared according to the procedure described in Example 81B using (S) - (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl) methanol instead of piperidine. 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 according to the procedure described in Example 81B using (R) -3-amino-3-phenylpropanol instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.37 (s, 1H), 9.24 (d, J = 8.48 Hz, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 7.88 (d, J = 8.82, 1.70 Hz, 1H), 7.69 (d, J = 8.82 Hz, 1H), 7.38-7.46 (m, 2H), 7.34 (t, J = 7.46 Hz, 2H), 7.19-7.30 (m, 2H), 5.09-5.27 (m, 1H), 4.62 (t, J = 4.92 Hz, 1H), 3.37-3.52 (m, 2H), 2.00-2.16 (m, 1H), 1.84-2.00 (m, 1H). MS (ESI +) m / z 363.1 (M + H) ⁺ .

Example 180

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

The title compound was prepared according to the procedure described in Example 81B using (S) -3-amino-3-phenylpropanol instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.36 (s, 1H), 9.24 (d, J = 8.14 Hz, 1H), 8.39 (s, 1H), 8.22 (s, 1H), 7.88 (d, J = 8.65, 1.53 Hz, 1H), 7.69 (d, J = 8.81 Hz, 1H), 7.37-7.45 (m, 2H), 7.29-7.37 ( m, 2H), 7.19-7.29 (m, 2H), 5.08-5.30 (m, 1H), 4.55-4.68 (m, 1H), 3.37-3, 51 (m, 2H), 2.00-2.14 (m, 1H), 1.83-1.99 (m, 1H). MS (ESI +) m / z 363.0 (M + H) ⁺ .

Example 181

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

The title compound was prepared according to the procedure described in Example 81B using 1-aminoindan instead of piperidine. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 13.37 (s, 1H), 9.13 (d, J = 8.14 Hz, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 7.89 (d, J = 8.82, 1.36 Hz, 1H), 7.70 (d, J = 8.82 Hz, 1H), 7.35 (s, 1H), 7.15-7.32 (m, 4H) 5.55 (q, J = 7.91 Hz, 1H), 2.95-3.08 (m, 1H), 2.76-2.94 (m, 1H), 2.37-2, 49 (m, 1H); 2.01-2.15 (m, 1H). MS (ESI +) m / z 345.0 (M + H) ⁺ .

Example 182

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

The title compound was prepared according to the procedure described in Example 81B using 2-aminoindane instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.37 (s, 1H), 9.08 (d, J = 7.46 Hz, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 7.89 (d, J = 8.82, 1.70 Hz, 1H), 7.69 (d, J = 8.82 Hz, 1H), 7.31 (s, 1H), 7.10-7.28 (m, 4H) 4.63-4.79 (m, 1H); 3.24 (d, J = 15.77; 7.63 Hz, 2H); 2.96-3.08 (m, 2H). MS (ESI +) m / z 345.0 (M + H) ⁺ .

Example 183

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

The title compound was prepared according to the procedure described in Example 81B using alpha-ethylbenzylamine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.36 (s, 1H), 9.18 (d, J = 8.82 Hz, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 7.88 (d, J = 8.82, 1.36 Hz, 1H), 7.69 (d, J = 8.48 Hz, 1H), 7.39-7.48 (m, 2H), 7.34 (t, J = 7.29 Hz, 2H), 7.19-7.29 (m, 2H), 4.84-5.00 (m, 1H), 1.69-2.04 (m, 2H), 0.91 (t, J = 7.29 Hz, 3H). MS (ESI +) m / z 347.1 (M + H) ⁺ .

Example 184

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

The title compound was obtained in the form of a TFA salt in accordance with the procedure described in Example 173 using 3- (dimethylamino) phenylboronic acid instead of 4-methoxyphenylboronic acid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 11.52 (s, 1H), 8.17 (s, 1H), 7.22-7.35 (m, 4H), 7.08-7.15 (m, 2H), 7.03 (d, J = 6.71 Hz, 2H), 6.82 (d, J = 8.39, 2.29 Hz, 1H), 6.48-6.54 (m, 2H), 5.47 (s, 2H ), 2.78 (s, 6H). MS (ESI +) m / z 410.2 (M + H) ⁺ .

Example 185

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

The title compound was obtained in the form of a TFA salt in accordance with the procedure described in Example 173 using 4- (dimethylamino) phenylboronic acid instead of 4-methoxyphenylboronic acid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 11.65 (s, 1H), 8.17 (s, 1H), 7.23-7.38 (m, 3H), 7.12-7.16 (m, 2H), 7.01-7, 09 (m, 4H), 6.74-6.78 (m, 2H), 5.45 (s, 2H), 2.95 (s, 6H). MS (ESI +) m / z 410.2 (M + H) ⁺ .

Example 186

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

The title compound was prepared according to the procedure described in Example 173 using 3-acetamidophenylboronic acid instead of 4-methoxyphenylboronic acid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 10.05 (s, 1H), 8.14 (s, 1H), 7.69 (d, J = 8.54 Hz, 1H), 7.54 (s, 1H), 7.41 (t, J = 7.93 Hz, 1H), 7.24-7.32 (m, 3H), 7.08-7.16 (m, 2H), 6.93-7.04 (m, 3H), 5, 48 (s, 2H); 2.01 (s, 3H). MS (ESI +) m / z 424.2 (M + H) ⁺ .

Example 187

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

The title compound was prepared according to the procedure described in Example 173 using 4-acetamidophenylboronic acid instead of 4-methoxyphenylboronic acid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 10.14 (s, 1H), 8.07 (s, 1H), 7.66 (d, J = 8.85 Hz, 2H), 7.24-7.32 (m, 3H), 7.18 -7.22 (m, 2H), 7.04-7.11 (m, 2H), 6.98-7.02 (m, 2H), 5.48 (s, 2H), 5.35 (s , 2H); 2.04-2.10 (m, 3H). MS (ESI +) m / z 424.1 (M + H) ⁺ .

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 according to the procedure described in Example 173 using 3- (1H-pyrazol-1-yl) phenylboronic acid instead of 4-methoxyphenylboronic acid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 11.40 (s, 1H), 8.45 (d, J = 2.75 Hz, 1H), 8.09 (s, 1H), 7.99 (d, J = 8.24, 1.53 Hz , 1H), 7.80-7.85 (m, 1H), 7.74 (d, J = 1.83 Hz, 1H), 7.56 (t, J = 7.93 Hz, 1H), 7 , 20-7.30 (m, 3H), 7.06-7.16 (m, 3H), 6.98-7.04 (m, 2H), 6.53-6.54 (m, 1H) 5.55 (s, 2H); 5.35 (s, 2H). MS (ESI +) m / z 433.2 (M + H) ⁺ .

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 according to the procedure described in Example 173 using 1-methyl-1H-pyrazol-4-ylboronic acid instead of 4-methoxyphenylboronic acid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 11.78 (s, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.43 (s, 1H), 7.27-7.41 (m, 4H), 7 24 (d, J = 8.54 Hz, 1H), 7.05-7.11 (m, J = 7.02 Hz, 2H), 5.54 (s, 2H), 3.86 (s, 3H). MS (ESI +) m / z 370.9 (M + H) ⁺ .

Example 190

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

The title compound was prepared according to the procedure described in Example 173 using 3- (phenylcarbamoyl) phenylboronic acid instead of 4-methoxyphenylboronic acid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 11.41 (s, 1H), 10.22 (s, 1H), 8.07-8.12 (m, 2H), 7.95 (s, 1H), 7.73 (d, J = 7, 63 Hz, 2H), 7.60 (t, J = 7.78 Hz, 1H), 7.43 (d, J = 7.63 Hz, 1H), 7.32-7.39 (m, 2H) , 7.21-7.30 (m, 3H), 7.05-7.15 (m, 3H), 7.00 (d, J = 6.71 Hz, 2H), 5.54 (s, 2H ), 5.36 (s, 2H). MS (ESI +) m / z 486.2 (M + H) ⁺ .

Example 191

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

The title compound was prepared according to the procedure described in Example 173 using 3- (benzylcarbamoyl) phenylboronic acid instead of 4-methoxyphenylboronic acid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 11.41 (s, 1H), 9.04 (t, J = 5.95 Hz, 1H), 8.07 (s, 1H), 8.01 (d, J = 7.93 Hz, 1H), 7.85 (s, 1H), 7.56 (t, J = 7.78 Hz, 1H), 7.41 (d, J = 7.63 Hz, 1H), 7.21-7.35 (m , 8H), 7.01-7.11 (m, 2H), 6.96 (d, J = 7.32, 2.14 Hz, 2H), 5.52 (s, 2H), 5.35 ( s, 2H); 4.45 (d, J = 5.80 Hz, 2H). MS (ESI +) m / z 500.2 (M + H) ⁺ .

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 obtained in the form of a TFA salt in accordance with the procedure described in Example 173 using 1-methyl-1H-indol-5-ylboronic acid instead of 4-methoxyphenylboronic acid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 11.35 (s, 1H), 8.14 (s, 1H), 7.54 (d, J = 8.54 Hz, 1H), 7.50 (d, J = 1.53 Hz, 1H), 7.42 (d, J = 3.05 Hz, 1H), 7.24-7.33 (m, 3H), 6.97-7.05 (m, 5H), 6.44 (d, J = 2.75 Hz, 1H), 5.46 (s, 2H), 5.33 (s, 2H), 3.83 (s, 3H). MS (ESI +) m / z 420.1 (M + H) ⁺ .

Example 193

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

The title compound was prepared according to the procedure described in Example 173 using 3-methoxyphenylboronic acid instead of 4-methoxyphenylboronic acid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 11.40 (s, 1H), 8.08 (s, 1H), 7.34-7.40 (m, 1H), 7.24-7.32 (m, 3H), 7.03-7, 11 (m, 3H), 6.98-7.02 (m, 2H), 6.80-6.85 (m, 2H), 5.49 (s, 2H), 5.35 (s, 2H) 3.66 (s, 3H). MS (ESI +) m / z 397.1 (M + H) ⁺ .

Example 194

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

In an argon atmosphere, a vessel containing the compound of Example 125B (35 mg, 0.09 mmol), 3-morpholinophenylboronic acid (21 mg, 0.09 mmol), PdCl ₂ (dppf). Dichloromethane (7 mg, 0.009 mmol) and potassium carbonate (24 mg, 0.18 mmol) in DME (1 ml) and water (0.1 ml) were covered with a lid and heated at 80 ° C. in a heating device with shaking for 3 days. The solvent was evaporated under reduced pressure, and the product was purified by reverse phase HPLC using an acetonitrile / water gradient gradient of 0.1% TFA to obtain the title compound in the form of a TFA salt. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 11.52 (s, 1H), 8.14 (s, 1H), 7.26-7.34 (m, 4H), 6.98-7.12 (m, 5H), 6.67-6, 75 (m, 2H), 5.47 (s, 2H), 3.57-3.73 (m, 4H), 2.91-3.03 (m, 4H). MS (ESI +) m / z 452.2 (M + H) ⁺ .

Example 195

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

The title compound was prepared according to the procedure described in Example 81B using isoindoline instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.38 (s, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 7.93 (d, J = 8.82, 1.36 Hz, 1H), 7.71 (d, J = 8.48 Hz, 1H), 7.30-7.47 (m, 5H), 5.18 (s, 2H), 4.92 (s, 2H). MS (ESI +) m / z 331.0 (M + H) ⁺ .

Example 196

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

The title compound was prepared according to the procedure described in Example 81B using 1-methyl-3-phenylpiperazine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.12 (s, 1H), 8.28-8.36 (m, 1H), 8.18 (s, 1H), 7.83 (d, J = 8.79, 1.46 Hz, 1H) 7.67 (d, J = 8.79 Hz, 1H), 7.48 (d, J = 7.69 Hz, 2H), 7.30-7.40 (m, 2H), 7.21- 7.29 (m, 1H), 7.14 (s, 1H), 5.56-5.73 (m, J = 5.86 Hz, 1H), 3.99-4.19 (m, J = 8.42 Hz, 1H), 3.38-3.47 (m, 1H), 3.05-3.21 (m, J = 7.69 Hz, 1H), 2.80 (d, J = 1 1.72 Hz, 1H), 2.41 (d, J = 12.08, 4.39 Hz, 1H), 2.24 (s, 3H), 2.02-2.16 (m, 1H). MS (ESI +) m / z 388.1 (M + H) ⁺ .

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-triazole-5-carbonyl) piperidin-4-ylcarbamate

The title compound was prepared according to the procedure described in Example 81B, using the compound of Example 149C instead of the compound of Example 81B and using 4-Boc-aminopiperidine instead of piperidine. 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

The compound of Example 197A (101 mg, 0.21 mmol) was dissolved in 4 M hydrochloric acid in dioxane (4 ml) and methanol (1 ml) and stirred at ambient temperature for 2 hours. The solvents were removed under reduced pressure to obtain the title compound in the form of an HCl salt. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.18 (s, 1H), 7.92-8.08 (m, J = 1.36 Hz, 3H), 7.53-7.70 (m, 2H), 7.24-7.47 ( m, 5H), 5.40-5.73 (m, J = 3.39 Hz, 2H), 4.34-4.63 (m, 1H), 3.44-3.53 (m, J = 3.39 Hz, 1H), 2.95-3.17 (m, 2H), 2.76-2.94 (m, J = 1 1.02, 11.02 Hz, 1H), 1.87- 2.03 (m, J = 1 1.87 Hz, 1H), 1.30-1.52 (m, J = 10.85 Hz, 2H), 0.66-0.91 (m, J = 10 , 17 Hz, 1H). MS (ESI +) m / z 402.2 (M + H) ⁺ .

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-indazole-1-carboxylate

The compound of Example 102B (200 mg, 0.55 mmol) and N, N-dimethylpyridin-4-amine (5 mg, 0.04 mmol) was dissolved in methylene chloride. The mixture was stirred at room temperature while adding a solution of di-tert-butyl dicarbonate (120 mg, 0.55 mmol) in 5 ml of methylene chloride dropwise. The reaction mixture was allowed to stir at room temperature for 8 hours, concentrated in vacuo, dissolved in methylene chloride (10 ml) and washed with dilute aqueous HCl (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 give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.29 (s, 2H), 7.43-7.59 (m, 3H), 7.23-7.38 (m, 6H), 6.98 (d, J = 7.17, 2.39 Hz, 2H), 6.38 (s, 2H), 5.52 (s, 2H), 1.55 (s, 9H). MS (ESI +) m / z 467 (M + H) ⁺ .

Example 198B

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

The compound of 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 allowed to stir at room temperature. Benzoyl chloride (14 mg, 0.1 mmol) was added to the mixture. The reaction mixture was allowed to stir at room temperature overnight, concentrated in vacuo, and purified by reverse phase HPLC (CH ₃ CN / H ₂ O / NH ₄ OAc) to give a Boc-protected precursor. The precursor was treated with a 1: 1 mixture of TFA / dichloromethane (2 ml) for 1 hour and concentrated in vacuo to give the title compound in the form of a TFA salt. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.84 (s, 1H), 10.70 (s, 1H), 8.01 (d, J = 6.99 Hz, 2H), 7.87 (s, 1H), 7.50-7.69 (m, 3H), 7.36-7.48 (m, 5H), 7.18-7.35 (m, 5H), 6.92-7.03 (m, 2H), 5.48 (s , 2H). MS (ESI +) m / z 471 (M + H) ⁺ .

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 according to the procedure described in Example 198B using benzenesulfonyl chloride instead of benzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.69 (s, 1H), 10.61 (s, 1H), 7.99 (s, 1H), 7.70-7.76 (m, 2H), 7.45-7.62 (m, 6H), 7.24-7.36 (m, 7H), 6.99 (d, J = 6.99, 2.21 Hz, 2H), 5.50 (s, 2H). MS (ESI +) m / z 507 (M + H) ⁺ .

Example 200

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

The compound of 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 hours, concentrated and purified by reverse phase-HPLC (CH ₃ CN / H ₂ O / NH ₄ OAc) to give a Boc-protected precursor. The precursor was treated with a 1: 1 mixture of TFA / dichloromethane (2 ml) for 1 hour and concentrated in vacuo to give the title compound in the form of a TFA salt. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.54 (s, 1H), 9.51 (s, 1H), 9.42 (s, 1H), 8.28 (s, 1H), 7.45-7.51 (m, 3H), 7 , 36-7.42 (m, 2H), 7.24-7.35 (m, 7H), 6.98 (d, J = 7.17, 2.39 Hz, 2H), 6.87-6 94 (m, 2H); 5.50 (s, 2H); 3.74 (s, 3H). MS (ESI +) m / z 516 (M + H) ⁺ .

Example 201

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

The title compound was obtained in the form of a TFA salt in accordance with the procedure described in Example 198B using butyryl chloride instead of benzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.77-10.84 (m, 1H), 8.07 (s, 1H), 7.97 (d, J = 8.82 Hz, 1H), 7.64 (d, J = 8.82, 1.47 Hz, 1H), 7.43-7.57 (m, 3H), 7.22-7.38 (m, 5H), 6.91-7.06 (m, 2H), 5.50 (s, 2H), 2.33 (t, J = 7.17 Hz, 2H), 1.54-1.60 (m, 2H), 0.91 (t, J = 7.35 Hz, 3H) . MS (ESI +) m / z 437 (M + H) ⁺ .

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 according to the procedure described in Example 198B using isobutyryl chloride instead of benzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.66 (s, 1H), 10.12 (s, 1H), 7.80 (s, 1H), 7.42-7.55 (m, 4H), 7.33-7.39 (m, 1H), 7.22-7.32 (m, 5H), 6.97 (d, J = 6.99, 2.57 Hz, 2H), 5.48 (s, 1H), 2.59-2 69 (m, 1H); 1.07 (d, J = 6.99 Hz, 6H). MS (ESI +) m / z 437 (M + H) ⁺ .

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 according to the procedure described in Example 198B using cyclopropanecarbonyl chloride instead of benzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.45-10.64 (s, 1H), 7.91 (s, 1H), 7.43-7.55 (m, 3H), 7.31-7.43 (m, 2H), 7, 23-7.30 (m, 5H), 6.97 (d, J = 7.17, 2.39 Hz, 2H), 5.48 (s, 2H), 1.77-1.91 (m, 1H), 0.69-0.87 (m, 4H). MS (ESI +) m / z 435 (M + H) ⁺ .

Example 204

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

The compound of 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 at 120 ° C for 15 minutes in a CEM-Discover microwave device. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by reverse phase-HPLC (CH ₃ CN / H ₂ O / NH ₄ OAc) to obtain the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.35 (s, 1H), 8.55 (d, J = 8.82 Hz, 1H), 8.36 (s, 1H), 8.17 (d, J = 8.64, 1.65 Hz , 1H), 8.06 (d, J = 7.54, 2.39 Hz, 4H), 7.51-7.72 (m, 6H), 7.26-7.45 (m, 5H), 5.71 (s, 2H), 1.76-1.87 (m, 1H), 1.11 (d, J = 6.62 Hz, 2H), 0.44 (d, J = 4.41 Hz , 2H). MS (ESI +) m / z 539 (M + H) ⁺ .

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-S-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazole-1-carboxylate

The title compound was prepared according to the procedure described in Example 198A using the compound of Example 89B instead of the compound of Example 102A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.26 (s, 1H), 7.96-8.07 (m, 1H), 7.86-7.95 (m, 1H), 7.35-7.46 (m, 3H), 7, 28-7.35 (m, 2H), 6.35-6.47 (m, 2H), 5.70 (s, 2H), 1.72-1.84 (m, 1H), 1.60 ( s, 9H), 0.99-1.10 (d, J = 1.84 Hz, 2H), 0.38 (d, J = 3.68 Hz, 2H). MS (ESI +) m / z 431 (M + H) ⁺ .

Example 205B

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

The compound of 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 allowed to stir at room temperature and 3-fluorobenzoyl chloride (11.1 mg, 0.58 mmol) was added to the mixture. The reaction mixture was allowed to stir at room temperature overnight, concentrated and purified by reverse phase-HPLC (CH ₃ CN / H ₂ O / NH ₄ OAc) to give a Boc-protected precursor. The precursor was treated with a 1: 1 mixture of TFA / dichloromethane (2 ml) for 1 hour and concentrated in vacuo to give the title compound in the form of a TFA salt. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.58 (s, 1H), 7.75 (s, 1H), 7.51-7.60 (m, 1H), 7.46 (d, J = 8.82, 1.47 Hz, 1H) 7.15-7.28 (m, 2H), 7.10 (d, J = 2.21 Hz, 1H), 6.88-7.05 (m, 6H), 5.31 (s, 2H ), 1.35-1.47 (m, J = 5.15 Hz, 1H), 0.68 (d, J = 8.27, 1.65 Hz, 2H), 0.03 (d, J = 5.52 Hz, 2H). MS (ESI +) m / z 453 (M + H) ⁺ .

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 according to the procedure described in Example 205B using benzoyl chloride instead of 3-fluorobenzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.89 (s, 1H), 10.83 (s, 1H), 8.02-8.15 (m, 3H), 7.83 (d, J = 8.82, 1.47 Hz, 1H) 7.50-7.66 (m, 4H), 7.24-7.43 (m, 5H), 5.67 (s, 2H), 1.77 (m, 1H), 0.99-1 10 (m, 2H); 0.39 (m, 2H). MS (ESI +) m / z 435 (M + H) ⁺ .

Example 207

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

To a solution of the compound of Example 89B (18.3 mg, 0.05 mmol) in dimethylformamide (2 ml) was added acetic acid (15 mg, 0.25 mmol) and benzaldehyde (6.4 mg, 0.06 mmol). The reaction mixture was stirred at room temperature overnight. Sodium triacetoxyborohydride (NaBH (OAc) ₃ , 32 mg, 0.15 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 3 hours, concentrated and purified by reverse phase-HPLC (CH ₃ CN / H ₂ O / NH ₄ OAc) to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.09 (s, 1H), 9.24 (s, 1H), 8.02-8.10 (m, 3H), 7.84-7.90 (m, 1H), 7.49-7, 67 (m, 4H), 7.25-7.45 (m, 5H), 5.70 (s, 2H), 3.30 (s, 2H), 1.88-1.95 (m, 1H) 1.01-1.09 (m, 2H); 0.43 (d, J = 4.04 Hz, 2H). MS (ESI +) m / z 421 (M + H) ⁺ .

Example 208

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

The title compound was prepared according to the procedure described in Example 81B using (R) - (+) - 2-amino-3-phenyl-1-propanol (37 mg, 0.245 mmol) instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.36 (s, 1H), 8.46 (d, J = 8.82 Hz, 1H), 8.37 (s, 1H), 8.22 (s, 1H), 7.87 (dd, J = 8.82, 1.36 Hz, 1H), 7.69 (d, J = 8.82 Hz, 1H), 7.12-7.35 (m, 6H), 4.89 (t, J = 5.59 Hz, 1H), 4.13-4.25 (m, 1H), 3.40-3.58 (m, 2H), 2.90-2.99 (m, 1H), 2.74 -2.87 (m, 1H). MS (ESI +) m / z 363.0 (M + H) ⁺ .

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 isoamyl nitrite (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 give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.45 (s, 1H), 8.26 (d, J = 8.82 Hz, 1H), 8.17 (d, J = 1.70 Hz, 1H), 7.77 (dd, J = 8 82, 2.03 Hz, 1H); 2.72 (s, 3H).

Example 209B

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

The compound of 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) were combined in a sealed vessel with dioxane (10 ml) and water (1 ml) in an inert atmosphere of nitrogen and the mixture was heated to 110 ° C overnight. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography using a gradient of 45-90% ethyl acetate in hexane to elute to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.00 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.92 (s, 2H), 7.55-7.61 (m, 1H), 7 48-7.54 (m, 1H); 7.25-7.40 (m, 5H); 5.35 (s, 2H). MS (ESI +) m / z 274.9 (M + H) ⁺ .

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 a catalytic amount of dimethylaminopyridine (~ 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 a 1N sodium hydroxide solution (two times), a 0.1N hydrochloric acid solution, and saturated saline. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound. MS (ESI +) m / z 210.8 (M-Boc) ⁺ .

Example 210B

tert-Butyl 3-methyl-5 - ((trimethylsilyl) ethynyl) -1H-indazole-1-carboxylate

The compound of Example 210A (7.55 g, 24.3 mmol), dichlorobis (triphenylphosphine) palladium (II) (870 mg, 1.24 mmol) and copper (I) iodide (250 mg, 1.31 mmol) were combined in triethylamine (60 ml) in an inert atmosphere of nitrogen. Trimethylsilylacetylene (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 using a gradient of 10-40% ethyl acetate in hexane to elute to give the title compound. MS (ESI +) m / z 228.9 (M-Boc) ⁺ .

Example 210C

5-Ethinyl-3-methyl-1H-indazole

The compound of Example 210B (7.26 g, 22.1 mmol) was dissolved in methanol (170 ml). A 1N potassium hydroxide solution (45 ml) 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 obtain the title compound. MS (ESI +) m / z 157.1 (M + H) ⁺ .

Example 210D

ethyl 5- (3-methyl-1H-indazol-5-yl) isoxazole-3-carboxylate

The compound of Example 210C (411 mg, 2.63 mmol) was dissolved in toluene (15 ml) and triethylamine (478 μl) and heated to 90 ° C. Ethyl chloroximidoacetate (480 mg, 3.17 mmol) dissolved in toluene (15 ml) was added slowly dropwise over 30 minutes. After addition, the mixture was diluted with ethyl acetate and washed with 1 N hydrochloric acid. The organic layer was concentrated under reduced pressure, and the resulting residue was triturated with methanol to give the title compound. MS (ESI +) m / z 271.9 (M + H) ⁺ .

Example 210E

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

The compound of 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 1 N hydrochloric acid. The product precipitated in a separatory funnel and was filtered to give 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 according to the procedure described in Example 81B using the compound of Example 210E instead of the compound of Example 81A and using (R) -3-amino-3-phenylpropan-1-ol instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.93 (s, 1H), 8.45 (d, J = 8.82 Hz, 1H), 8.33 (s, 1H), 7.84 (d, J = 8.82, 1.70 Hz , 1H), 7.59 (d, J = 9.16 Hz, 1H), 7.21-7.29 (m, 5H), 7.13-7.21 (m, 1H), 4.89 ( t, J = 5.59 Hz, 1H), 4.10-4.26 (m, 1H), 3.42-3.56 (m, 2H), 2.88-3.00 (m, 1H) 2.75-2.87 (m, 1H); 2.55 (s, 3H). MS (ESI +) m / z 377.1 (M + H) ⁺ .

Example 211

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

In an argon atmosphere, a vessel containing the compound of Example 125B (35 mg, 0.09 mmol), 3-hydroxyphenylboronic acid (12 mg, 0.09 mmol), PdCl ₂ (dppf). Dichloromethane (7 mg, 0.009 mmol) and potassium carbonate (24 mg, 0.18 mmol) in DME (1 ml) and water (0.1 ml) were covered with a lid and heated at 80 ° C. in a heating device with shaking for 3 days. The solvent was evaporated and the product was purified by reverse phase HPLC using an acetonitrile / water 0.1% TFA gradient elution method to give the title compound. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 11.40 (s, 1H), 9.68 (s, 1H), 8.09 (s, 1H), 7.24-7.35 (m, 5H), 6.98-7.13 (m, 3H), 6.88 (d, J = 8.09, 1.98 Hz, 1H), 6.73 (s, 1H), 6.60-6.66 (m, 1H), 5.47 (s , 2H); 5.35 (s, 2H). MS (ESI +) m / z 383.1 (M + H) ⁺ .

Example 212

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

The title compound was prepared according to the procedure described in Example 173 using 3-carbamoylphenylboronic acid instead of 4-methoxyphenylboronic acid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 11.41 (s, 1H), 8.07 (s, 1H), 7.97-8.03 (m, 2H), 7.83-7.87 (m, 1H), 7.53 (t, J = 7.78 Hz, 1H), 7.45 (s, 1H), 7.38 (d, J = 7.63 Hz, 1H), 7.23-7.30 (m, 3H), 7, 00-7.10 (m, 2H), 6.96 (d, J = 7.48, 1.98 Hz, 2H), 5.51 (s, 2H), 5.35 (s, 2H). MS (ESI +) m / z 410.1 (M + H) ⁺ .

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 according to the procedure described in Example 173 using 4- (methylsulfonyl) phenylboronic acid instead of 4-methoxyphenylboronic acid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 11.44 (s, 1H), 7.94-8.01 (m, 3H), 7.58 (d, J = 8.54 Hz, 2H), 7.22-7.30 (m, 3H) 7.04-7.13 (m, 2H), 6.98 (d, J = 7.48, 1.98 Hz, 2H), 5.56 (s, 2H), 5.37 (s, 2H ), 3.28 (s, 3H). MS (ESI +) m / z 445.2 (M + H) ⁺ .

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 according to the procedure described in Example 205B using 2-chlorobenzoyl chloride instead of 3-fluorobenzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.94 (s, 1H), 8.24 (s, 1H), 7.85 (d, J = 8.82, 1.47 Hz, 1H), 7.65 (d, J = 6.99, 1.84 Hz, 1H), 7.43-7.61 (m, 4H), 7.26-7.42 (m, 5H), 5.68 (s, 2H), 1.71-1.83 (m, 1H), 1.04-1.12 (m, 2H), 0.37-0.45 (m, 2H). MS (ESI +) m / z 469 (M + H) ⁺ .

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 according to the procedure described in Example 205B using 4-chlorobenzoyl chloride instead of 3-fluorobenzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.53 (s, 1H), 7.65-7.71 (m, 3H), 7.42 (d, J = 8.82, 1.47 Hz, 1H), 7.18-7.24 ( m, 2H), 7.12-7.18 (m, 1H), 6.93-7.02 (m, 3H), 6.83-6.92 (m, 3H), 5.27 (s, 2H), 1.30-1.44 (m, 1H), 0.59-0.67 (m, 2H), -0.07-0.04 (m, 2H). MS (ESI +) m / z 469 (M + H) ⁺ .

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 according to the procedure described in Example 205B using ethanesulfonyl chloride instead of 3-fluorobenzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.19 (s, 1H), 8.15 (s, 1H), 7.82 (d, J = 8.64, 1.65 Hz, 1H), 7.53 (d, J = 8.82 Hz , 1H), 7.35-7.45 (m, 3H), 7.27-7.35 (m, 2H), 5.69 (s, 2H), 3.30 (q, J = 7, 35 Hz, 2H), 1.74, 1.87 (m, 1H), 1.27-1.36 (m, 3H), 1.02-1.12 (m, 2H), 0.34-0 44 (m, 2H). MS (ESI +) m / z 423 (M + H) ⁺ .

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 according to the procedure described in Example 205B using benzenesulfonyl chloride instead of 3-fluorobenzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.75 (s, 1H), 10.69 (s, 1H), 8.02 (s, 1H), 7.71-7.83 (m, 3H), 7.43-7.60 (m, 4H), 7.34-7.43 (m, 3H), 7.27-7.34 (m, 2H), 5.69 (s, 2H), 1.69-1.83 (m, 1H) 0.99-1.11 (m, 2H); 0.31-0.45 (m, 2H). MS (ESI +) m / z 471 (M + H) ⁺ .

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 according to the procedure described in Example 205B using 2-chlorobenzene-1-sulfonyl chloride instead of 3-fluorobenzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.36 (s, 1H), 10.60 (s, 1H), 7.67 (s, 1H), 7.62 (d, J = 7.91, 1.65 Hz, 1H), 7.40 (d, J = 8.82, 1.47 Hz, 1H), 7.14-7.27 (m, 2H), 7.00-7.12 (m, 4H), 6.96-7.00 (m, 1H), 6.90-6.95 (m, 2H), 5.31 (s, 2H), 1.29-1.44 (m, 1H), 0.61-0.74 (m , 2H), -0.05-0.05 (m, 2H). MS (ESI +) m / z 505 (M + H) ⁺ .

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 in the form of an HCl salt according to the procedure described in Example 205B using 3-chlorobenzene-1-sulfonyl chloride instead of 3-fluorobenzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.84 (s, 1H), 10.86 (s, 1H), 8.00 (s, 1H), 7.82 (s, 1H), 7.72 (d, J = 7.72 Hz, 1H ), 7.64 (d, J = 1.84 Hz, 1H), 7.57 (d, J = 7.72 Hz, 1H), 7.50 (d, J = 8.82 Hz, 1H), 7.34-7.45 (m, 3H), 7.28-7.34 (m, 2H), 5.69 (s, 2H), 1.71-1.83 (m, 1H), 1, 06 (m, 2H); 0.37 (m, 2H). MS (ESI +) m / z 505 (M + H) ⁺ .

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 obtained in the form of an HCl salt according to the procedure described in Example 205B using 4-chlorobenzene-1-sulfonyl chloride instead of 3-fluorobenzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.80 (s, 1H), 10.79 (s, 1H), 8.00 (s, 1H), 7.73-7.83 (m, 3H), 7.56-7.64 (m, 2H), 7.49 (d, J = 8.82 Hz, 1H), 7.34-7.45 (m, 3H), 7.28-7.34 (m, 2H), 5.69 (s , 2H), 1.71-1.86 (m, 1H), 0.99-1.12 (m, 2H), 0.31-0.43 (m, 2H). MS (ESI +) m / z 505 (M + H) ⁺ .

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 obtained in the form of an HCl salt according to the procedure described in Example 205B using 2,5-dimethylfuran-3-sulfonyl chloride instead of 3-fluorobenzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.82 (s, 1H), 10.48 (s, 1H), 8.00 (s, 1H), 7.78 (d, J = 8.64, 1.65 Hz, 1H), 7.50 (d, J = 9.19 Hz, 1H), 7.34-7.45 (m, 3H), 7.28-7.33 (m, 2H), 6.20 (s, 1H), 5, 69 (s, 2H), 2.11 (s, 6H), 1.71-1.84 (m, 1H), 1.01-1.11 (m, 2H), 0.32-0.41 ( m, 2H). MS (ESI +) m / z 489 (M + H) ⁺ .

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 according to the procedure described in Example 207 using 2-chlorobenzaldehyde instead of benzaldehyde. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.55 (s, 1H), 8.20 (s, 1H), 7.69 (d, J = 8.46, 1.47 Hz, 1H), 7.49 (d, J = 8.82 Hz , 1H), 7.34-7.46 (m, 4H), 7.23-7.33 (m, 5H), 5.69 (s, 2H), 4.56 (s, 2H), 1, 72-1.83 (m, 1H), 0.99-1.09 (m, 2H), 0.35-0.42 (m, 2H). MS (ESI +) m / z 455 (M + H) ⁺ .

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 according to the procedure described in Example 207 using 3-chlorobenzaldehyde instead of benzaldehyde. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.53 (s, 1H), 8.15 (s, 1H), 7.59-7.77 (m, 1H), 7.25-7.48 (m, 10H), 5.68 (s, 2H), 4.49 (s, 2H), 1.71-1.80 (m, 1H), 1.04 (s, 2H), 0.38 (s, 2H).

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 according to the procedure described in Example 205B using 3-chlorobenzoyl chloride instead of 3-fluorobenzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.99 (s, 1H), 8.12 (s, 2H), 8.03 (d, J = 7.72 Hz, 1H), 7.83 (d, J = 8.46 Hz, 1H), 7.68 (s, 1H), 7.58 (t, J = 8.09 Hz, 2H), 7.33-7.44 (m, 3H), 7.25-7.33 (m, 2H) 5.68 (s, 2H); 1.72-1.86 (m, 1H); 0.99-1.12 (m, 2H); 0.34-0.45 (m, 2H). MS (ESI +) m / z 470 (M + H) ⁺ .

Example 225

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

The title compound was prepared according to the procedure described in Example 205B using furan-2-carbonyl chloride instead of 3-fluorobenzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.36 (s, 1H), 7.71 (s, 1H), 7.42 (d, J = 8.82, 1.47 Hz, 1H), 7.15 (d, J = 8.82 Hz , 1H), 7.06 (d, J = 3.31 Hz, 1H), 6.93-7.03 (m, 3H), 6.86-6.93 (m, 2H), 6.31 ( d, J = 3.49, 1.65 Hz, 1H), 5.28 (s, 1H), 1.31-1.45 (m, 1H), 0.59-0.71 (m, 2H) , -0.05-0.05 (m, 2H). MS (ESI +) m / z 425 (M + H) ⁺ .

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 according to the procedure described in Example 207 using acetaldehyde instead of benzaldehyde. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.56 (s, 1H), 8.30-8.42 (m, 1H), 7.90-8.17 (m, 2H), 7.20-7.45 (m, 5H), 5, 70 (s, 2H), 1.78-1.93 (m, 2H), 1.67 (s, 1H), 1.06 (m, 3H), 0.95 (m, 2H), 0.29 -0.48 (m, 2H). MS (ESI +) m / z 359 (M + H) ⁺ .

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 according to the procedure described in Example 207 using 4-chlorobenzaldehyde instead of benzaldehyde. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.01 (s, 1H), 9.25 (s, 1H), 8.25-8.33 (m, 1H), 8.09 (d, J = 8.46 Hz, 1H), 7.84 -7.97 (m, 2H), 7.57-7.73 (m, 2H), 7.26-7.51 (m, 6H), 5.70 (s, 2H), 1.71-1 84 (m, 1H); 0.97-1.15 (m, 2H); 0.36-0.47 (m, 2H). MS (ESI +) m / z 455 (M + H) ⁺ .

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 according to the procedure described in Example 207 using furan-3-carbaldehyde instead of benzaldehyde. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.21 (s, 1H), 7.90 (s, 1H), 7.71-7.82 (m, 1H), 7.55-7.68 (m, 2H), 7.24-7, 51 (m, 6H), 5.68 (s, 2H), 4.33 (s, 2H), 1.67-1.85 (m, 1H), 0.95-1.13 (m, 2H) 0.30-0.42 (m, 2H). MS (ESI +) m / z 411 (M + H) ⁺ .

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

The compound of 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. The reaction mixture was stirred at 80 ° C for 12 hours, concentrated and purified by reverse phase-HPLC (CH ₃ CN / H ₂ O / NH ₄ OAc) to give a Boc-protected precursor. The precursor was dissolved in methanol and treated with excess HCl in dioxane (4 M, 0.5 mmol). The reaction mixture was allowed to stir for 5 hours and concentrated in vacuo to give the title compound in the form of an HCl salt. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.73 (s, 1H), 10.19 (s, 1H), 8.40 (s, 1H), 7.83 (d, J = 8.82, 1.47 Hz, 1H), 7.64 -7.75 (m, 1H), 7.49 (d, J = 8.82 Hz, 1H), 7.35-7.45 (m, 3H), 7.27-7.35 (m, 2H ), 5.69 (s, 2H), 2.33 (s, 3H), 1.73-1.84 (m, 1H), 1.02-1.11 (m, 2H), 0.35- 0.43 (m, 2H). MS (ESI +) m / z 522 (M + H) ⁺ .

Example 230

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

The title compound was obtained in the form of an HCl salt according to the procedure described in Example 205B using furan-3-carbonyl chloride instead of 3-fluorobenzoyl chloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 10.64 (s, 1H), 8.46 (s, 1H), 8.13 (s, 1H), 7.74-7.84 (m, 2H), 7.52-7.58 (m, 1H), 7.33-7.46 (m, 3H), 7.24-7.33 (m, 3H), 7.06 (s, 1H), 5.68 (s, 2H), 1.70 -1.86 (m, 1H), 0.99-1.09 (m, 2H), 0.33-0.44 (m, 2H). MS (ESI +) m / z 425 (M + H) ⁺ .

Example 231

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

The title compound was prepared according to the procedure described in Example 81B using (S) - (-) - 1-phenylpropylamine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.37 (s, 1H), 9.20 (d, J = 8.48 Hz, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 7.88 (d, J = 8.81, 1.70 Hz, 1H), 7.69 (d, J = 8.81 Hz, 1H), 7.38-7.49 (m, 2H), 7.18-7.38 ( m, 4H), 4.83-5.02 (m, 1H), 1.73-1.97 (m, 2H), 0.86-0.97 (m, 3H). MS (ESI +) m / z 347.0 (M + H) ⁺ .

Example 232

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

The title compound was prepared according to the procedure described in Example 81B using (R) - (-) - 1-phenylpropylamine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.37 (s, 1H), 9.20 (d, J = 8.48 Hz, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 7.88 (d, J = 8.65, 1.53 Hz, 1H), 7.69 (d, J = 8.81 Hz, 1H), 7.39-7.48 (m, 2H), 7.18-7.38 ( m, 4H), 4.85-4.99 (m, 1H), 1.74-1.97 (m, 2H), 0.91 (t, J = 7.29 Hz, 3H). MS (ESI +) m / z 347.0 (M + H) ⁺ .

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 combined in a sealed vessel with dioxane (10 ml) and water (1 ml) under an inert nitrogen atmosphere 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 using a gradient of 10-50% ethyl acetate in hexane to elute to give the title compound. MS (ESI +) m / z 290.0 (M + H) ⁺ .

Example 233B

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

The compound of Example 233A (591 mg, 2.13 mmol) was treated with hydrazine hydrate (4.0 ml) in ethanol (3.0 ml) and 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 give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.32 (s, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 7.44 (d, J = 8.48, 1, 70 Hz, 1H), 7.25-7.41 (m, 5H), 7.21 (d, J = 8.82 Hz, 1H), 5.35 (s, 2H), 5.24-5, 30 (m, 2H). MS (ESI +) m / z 290.0 (M + H) ⁺ .

Example 234

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

A solution of the compound of Example 149C (51 mg, 0.16 mmol) dissolved in dimethylformamide (0.5 ml) was added to a 20 ml vessel, followed by the addition of (S) - (+) - tetrahydrofurfurylamine (18.2 mg, 0, 18 mmol) dissolved in dimethylformamide (0.9 ml). 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 mixture was filtered through a Si-carbonate cartridge (6 ml - 1 g), supplied by Silicycle Chemical Division, and the filtrate was transferred into 20 ml vessels. The reaction mixture was monitored by LC / MS and concentrated to dryness. The residue was dissolved in a 1: 1 DMSO / methanol mixture and purified by reverse phase HPLC (Agilent, gradient 5% -100% TFA / water, over 8 minutes). ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.35-1.54 (m, 1H), 1.64-1.96 (m, 3H), 3.17-3.26 (m, 1H), 3.32-3.38 (m, 1H ), 3.50-3.77 (m, 2H), 3.81-4.00 (m, 1H), 5.58-5.74 (m, 2H), 7.21-7.41 (m 5H), 7.54-7.66 (m, 1H), 7.68-7.84 (m, 1H), 8.01-8.19 (m, 2H). MS (ESI-) m / z 401 (MH) ^- .

Example 235

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

The title compound was prepared according to the procedure described in Example 234 using 2-aminoethylisopropyl ether instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 0.98 (d, 6H), 3.31-3.45 (m, 4H), 3.45-3.57 (m, 1H), 5.61-5.74 (m, 2H), 7, 25-7.46 (m, 5H), 7.57-7.65 (m, 1H), 7.68-7.80 (m, 1H), 8.04-8.13 (m, 2H). MS (ESI +) m / z 405 (M + H) ⁺ .

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 according to the procedure described in Example 234 using (R) - (-) - tetrahydrofurfurylamine instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.34-1.60 (m, 1H), 1.65-1.94 (m, 3H), 3.16-3.26 (m, 1H), 3.33-3.39 (m, 1H ), 3.51-3.77 (m, 2H), 3.78-4.00 (m, 1H), 5.60-5.73 (m, 2H), 7.26-7.45 (m 5H), 7.56-7.68 (m, 1H), 7.71-7.79 (m, 1H), 8.01-8.15 (m, 2H). MS (ESI-) m / z 401 (MH) ^- .

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 according to the procedure described in Example 234 using 3-aminomethyltetrahydrofuran instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.36-1.59 (m, 1H), 1.67-2.00 (m, 1H), 2.19-2.45 (m, 1H), 3.11-3.23 (m, 2H ), 3.45-3.77 (m, 2H), 5.45-6.14 (m, 2H), 7.16-7.44 (m, 5H), 7.50-7.84 (m , 2H); 7.96-8.25 (m, 2H). MS (ESI +) m / z 403 (M + H) ⁺ .

Example 238

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

The title compound was prepared according to the procedure described in Example 234 using cyclopentylamine instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.19-1.63 (m, 6H), 1.71-1.99 (m, 2H), 3.99-4.37 (m, 1H), 5.52-5.77 (m, 2H) ), 7.22-7.45 (m, 5H), 7.55-7.83 (m, 2H), 7.95-8.20 (m, 2H). MS (ESI-) m / z 385 (MH) ^- .

Example 239

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

The title compound was prepared according to the procedure described in Example 234 using aminomethylcyclopentane instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.02-1.28 (m, 2H), 1.34-1.73 (m, 6H), 1.83-2.17 (m, 1H), 3.03-3.17 (m, 2H) ), 5.51-5.80 (m, 2H), 7.20-7.42 (m, 5H), 7.52-7.81 (m, 2H), 7.93-8.19 (m , 2H). MS (ESI +) m / z 401 (M + H) ⁺ .

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 according to the procedure described in Example 234 using N-methylethylamine hydrochloride instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 0.33-0.56 (m, 1H), 0.90-1.14 (m, 2H), 2.15-2.25 (m, 2H), 2.58-2.69 (m, 1H ), 2.82-3.01 (m, 1H), 3.35-3.52 (m, 1H), 5.40-5.67 (m, 2H), 7.14-7.48 (m 5H), 7.56-7.79 (m, 2H), 7.90-8.24 (m, 2H). MS (ESI +) m / z 361 (M + H) ⁺ .

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 according to the procedure described in Example 234 using methylisopropylamine instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 0.22-0.51 (m, 2H), 0.84-1.09 (m, 4H), 1.96-2.13 (m, 2H), 2.74-2.87 (m, 1H ), 4.44-4.92 (m, 1H), 5.43-5.67 (m, 2H), 7.20-7.44 (m, 5H), 7.51-7.73 (m , 2H); 7.84-8.14 (m, 2H). MS (ESI +) m / z 375 (M + H) ⁺ .

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 according to the procedure described in Example 234 using N- (2-methoxyethyl) methylamine instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 2.25-2.42 (m, 2H), 2.74-3.06 (m, 4H), 3.40-3.75 (m, 3H), 5.38-5.73 (m, 2H) ), 7.18-7.45 (m, 5H), 7.53-7.74 (m, 2H), 7.85-8.19 (m, 2H). MS (ESI +) m / z 391 (M + H) ⁺ .

Example 243

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

The title compound was prepared according to the procedure described in Example 234 using aniline instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 5.65-5.79 (m, 2H), 7.04-7.55 (m, 10H), 7.54-7.84 (m, 2H), 7.95-8.21 (m, 2H ) MS (ESI +) m / z 395 (M + H) ⁺ .

Example 244

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

The title compound was prepared according to the procedure described in Example 234 using 4-chloroaniline instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 5.70-5.74 (m, 2H), 7.25-7.42 (m, 7H), 7.43-7.52 (m, 2H), 7.54-7.66 (m, 1H ), 7.68-7.77 (m, 1H), 8.03-8.15 (m, 2H). MS (ESI-) m / z 427 (MH) ^- .

Example 245

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

The title compound was prepared according to the procedure described in Example 234 using N- (3-aminopropyl) morpholine instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 2.94-3.13 (m, 6H), 3.46-3.61 (m, 2H), 3.63-3.79 (m, 4H), 5.61-5.88 (m, 2H) ), 7.19-7.46 (m, 5H), 7.56-7.88 (m, 2H), 7.88-8.30 (m, 2H). MS (ESI-) m / z 430 (MH) ^- .

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 obtained in the form of a TFA salt in accordance with the procedure described in Example 234 using N, N, N-trimethylethylenediamine instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 2.28-2.42 (m, 3H), 2.73-3.00 (m, 6H), 3.07-3.19 (m, 2H), 3.56-3.80 (m, 2H) ), 5.55-5.68 (m, 2H), 7.24-7.47 (m, 5H), 7.56-7.78 (m, 2H), 7.91-8.02 (m , 1H), 8.10-8.17 (m, 1H). MS (ESI +) m / z 404 (M + H) ⁺ .

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 according to the procedure described in Example 234 using 2- (propylamino) ethanol instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 0.22-0.39 (m, 1H), 0.80-1.06 (m, 3H), 1.50-1.75 (m, 1H), 2.65-2.78 (m, 1H) ), 2.80-2.94 (m, 1H), 2.97-3.09 (m, 1H), 3.37-3.50 (m, 1H), 3.51-3.63 (m , 1H), 3.61-3.73 (m, 1H), 5.39-5.74 (m, 2H), 7.20-7.44 (m, 5H), 7.50-7.85 (m, 2H); 7.86-8.25 (m, 2H). MS (ESI +) m / z 405 (M + H) ⁺ .

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 obtained in the form of a TFA salt in accordance with the procedure described in Example 234 using N, N, N-trimethyl-1,3-propanediamine instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.06-8.23 (m, 1H), 7.85-8.05 (m, 1H), 7.57-7.73 (m, 2H), 7.19-7.48 (m, 5H ), 5.41-5.74 (m, 2H), 3.36-3.45 (m, 2H), 2.88-3.10 (m, 3H), 2.60-2.86 (m 5H); 2.24-2.42 (m, 4H); 1.73-1.91 (m, 1H). MS (ESI +) m / z 418 (M + H) ⁺ .

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 in the form of a TFA salt in accordance with the procedure described in Example 234 using N, N-diethyl-N-methylethylenediamine instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 7.82-8.24 (m, 2H), 7.56-7.76 (m, 2H), 7.15-7.49 (m, 5H), 5.54-5.71 (m, 2H) ), 3.60-3.77 (m, 2H), 3.20-3.24 (m, 2H), 3.13-3.18 (m, 2H), 3.03-3.11 (m , 2H); 2.32-2.44 (m, 3H); 0.63-1.41 (m, 6H). MS (ESI +) m / z 432 (M + H) ⁺ .

Example 250

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

The title compound was prepared according to the procedure described in Example 234 using N-ethylbenzylamine instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 7.81-8.20 (m, 2H), 7.49-7.71 (m, 2H), 7.24-7.51 (m, 9H), 6.39-7.18 (m, 2H) ), 5.41-5.74 (m, 2H), 4.53-4.84 (m, 1H), 3.82-4.00 (m, 1H), 3.37-3.54 (m , 1H), 2.61-2.78 (m, 1H), 0.91-1.08 (m, 1H), 0.27-0.45 (m, 2H). MS (ESI +) m / z 437 (M + H) ⁺ .

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 according to the procedure described in Example 234 using N-benzylethanolamine instead of (S) - (+) - tetrahydrofurfurylamine. 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 according to the procedure described in Example 234 using (R) - (+) - 3-hydroxypiperidine hydrochloride instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 7.83-8.22 (m, 2H), 7.51-7.78 (m, 2H), 7.23-7.45 (m, 5H), 5.46-5.75 (m, 2H) ), 3.80-4.31 (m, 1H), 3.40-3.68 (m, 1H), 2.58-3.15 (m, 2H), 2.19-2.49 (m , 1H); 0.31-2.14 (m, 4H). MS (ESI +) m / z 403 (M + H) ⁺ .

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 described in Example 234 using isonipecotamide instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 7.86-8.24 (m, 2H), 7.53-7.70 (m, 2H), 7.22-7.46 (m, 5H), 5.42-5.77 (m, 2H) ), 4.19-4.48 (m, 1H), 2.65-3.10 (m, 2H), 2.27-2.47 (m, 1H), 2.05-2.24 (m , 1H), 1.65-1.89 (m, 1H), 1.29-1.55 (m, 1H), 0.98-1.27 (m, 1H), 0.52-0.87 (m, 1H). MS (ESI +) m / z 430 (M + H) ⁺ .

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 according to the procedure described in Example 234 using 2,6-dimethylmorpholine instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 7.87-8.27 (m, 2H), 7.50-7.76 (m, 2H), 7.12-7.45 (m, 5H), 5.46-5.68 (m, 2H) ), 4.16-4.43 (m, 1H), 2.61-2.98 (m, 1H), 2.16-2.41 (m, 2H), 1.77-2.13 (m , 1H), 0.86-1.39 (m, 3H), 0.38-0.83 (m, 3H). MS (ESI +) m / z 417 (M + H) ⁺ .

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 according to the procedure described in Example 234 using 1-acetylpiperazine instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 7.89-8.41 (m, 2H), 7.55-7.86 (m, 2H), 7.07-7.51 (m, 5H), 5.44-5.82 (m, 2H ), 3.46-3.70 (m, 3H), 3.35-3.49 (m, 2H), 2.57-2.93 (m, 3H), 1.61-2.03 (m , 3H). MS (ESI +) m / z 430 (M + H) ⁺ .

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 according to the procedure described in Example 234 using 1-phenylpiperazine instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (SOO MHz, DMSO-d ₆ / D ₂ O) δ ppm 7.79-8.38 (m, 2H), 7.53-7.73 (m, 2H), 7.22-7.46 (m, 5H), 7.05-7.19 (m, 2H) ), 6.64-6.79 (m, 3H), 5.54-5.68 (m, 2H), 3.50-3.90 (m, 2H), 2.93-3.15 (m , 2H); 2.62-2.89 (m, 2H); 2.19-2.43 (m, 2H). MS (ESI-) m / z 462 (MH) ^- .

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 according to the procedure described in Example 234 using (R) - (+) - 2-amino-3-methyl-1-butanol instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 7.95-8.31 (m, 2H), 7.52-7.96 (m, 2H), 7.18-7.46 (m, 5H), 5.42-5.86 (m, 2H) ), 3.68-3.94 (m, 1H), 3.38-3.59 (m, 2H), 1.49-2.08 (m, 1H), 0.50-1.20 (m , 6H). MS (ESI +) m / z 405 (M + H) ⁺ .

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 according to the procedure described in Example 234 using (S) - (-) - 2-amino-3-methyl-1-butanol instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 7.94-8.36 (m, 2H), 7.52-7.84 (m, 2H), 7.18-7.51 (m, 5H), 5.57-5.76 (m, 2H) ), 3.75-3.94 (m, 1H), 3.35-3.54 (m, 2H), 1.70-1.94 (m, 1H), 0.54-1.09 (m , 6H). MS (ESI +) m / z 405 (M + H) ⁺ .

Example 259

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

The title compound was prepared according to the procedure described in Example 234 using 1- (3-aminopropyl) indazole instead of (S) - (+) - tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 8.57-8.85 (m, 1H), 7.92-8.16 (m, 2H), 7.60-7.80 (m, 2H), 7.47-7.55 (m, 2H ), 7.19-7.40 (m, 5H), 5.54-5.75 (m, 2H), 3.83-4.21 (m, 2H), 3.19-3.26 (m , 2H); 1.79-2.06 (m, 2H). MS (ESI +) m / z 427 (M + H) ⁺ .

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 obtained in the form of a hydrochloric acid salt according to the procedure described in Example 229 using isocyanatoethane instead of 3-isocyanato-5-methyl-2- (trifluoromethyl) furan. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.38 (s, 1H), 9.47 (s, 1H), 8.38 (s, 1H), 7.85-7.97 (m, 1H), 7.78 (d, J = 8, 82, 1.47 Hz, 1H), 7.34-7.50 (m, 4H), 7.24-7.33 (m, 2H), 5.69 (s, 2H), 3.17-3 29 (m, 2H), 1.70-1.83 (m, 1H), 1.12 (t, J = 7.17 Hz, 3H), 1.00-1.08 (m, 2H), 0.37 (d, J = 3.68 Hz, 2H). MS (ESI +) m / z 402 (M + H) ⁺ .

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 obtained in the form of a hydrochloric acid salt according to the procedure described in Example 229 using isocyanatobenzene instead of 3-isocyanato-5-methyl-2- (trifluoromethyl) furan. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.47-12.78 (m, 1H), 9.64 (s, 1H), 8.39 (s, 1H), 7.70-7.95 (m, 1H), 7.45-7, 60 (m, 3H), 7.27-7.45 (m, 7H), 7.02 (m, 1H), 5.69 (s, 2H), 1.79 (m, 1H), 1.07 (m, 2H); 0.40 (m, 2H). MS (ESI +) m / z 450 (M + H) ⁺ .

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 obtained in the form of a hydrochloric acid salt in accordance with the procedure described in Example 229, using (isocyanatomethyl) benzene instead of 3-isocyanato-5-methyl-2- (trifluoromethyl) furan. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.42 (s, 1H), 9.61 (s, 1H), 8.37 (s, 1H), 8.23-8.33 (m, 1H), 7.79 (d, J = 8, 82, 1.47 Hz, 1H), 7.36-7.50 (m, 4H), 7.28-7.36 (m, 6H), 7.21-7.27 (m, 1H), 5 69 (s, 2H), 4.45 (d, J = 5.88 Hz, 2H), 1.65-1.79 (t, J = 8.27, 8.27 Hz, 1H), 0, 99-1.08 (m, 2H); 0.30-0.43 (m, 2H). MS (ESI +) m / z 464 (M + H) ⁺ .

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 obtained in the form of a hydrochloric acid salt according to the procedure described in Example 229 using 1-chloro-2-isocyanatobenzene instead of 3-isocyanato-5-methyl-2- (trifluoromethyl) furan. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.74 (s, 1H), 10.23 (s, 1H), 8.44 (s, 1H), 8.34 (d, J = 8.09 Hz, 1H), 7.83 (d, J = 8.82, 1.47 Hz, 1H), 7.46-7.55 (m, 2H), 7.35-7.45 (m, 3H), 7.28-7.35 (m, 3H ), 7.03-7.12 (m, 1H), 5.70 (s, 2H), 1.70-1.86 (m, 1H), 1.00-1.12 (m, 2H), 0.33-0.45 (m, 2H). MS (ESI +) m / z 484 (M + H) ⁺ .

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 obtained in the form of a hydrochloric acid salt according to the procedure described in Example 229 using 1-chloro-3-isocyanatobenzene instead of 3-isocyanato-5-methyl-2- (trifluoromethyl) furan. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.66 (s, 1H), 10.02 (s, 1H), 9.71 (s, 1H), 8.22-8.48 (m, 1H), 7.71-7.91 (m, 2H), 7.51 (d, J = 8.46 Hz, 1H), 7.37-7.46 (m, 2H), 7.26-7.37 (m, 5H), 7.02-7 11 (m, 1H), 5.69 (s, 2H), 1.73-1.89 (m, 1H), 0.99-1.11 (m, 2H), 0.33-0.48 (m, 2H). MS (ESI +) m / z 484 (M + H) ⁺ .

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 obtained in the form of a hydrochloric acid salt according to the procedure described in Example 229 using 1-chloro-4-isocyanatobenzene instead of 3-isocyanato-5-methyl-2- (trifluoromethyl) furan. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.65 (s, 1H), 9.96 (s, 1H), 9.68 (s, 1H), 8.37 (s, 1H), 7.81 (d, J = 8.82, 1, 47 Hz, 1H), 7.53-7.60 (m, 2H), 7.50 (d, J = 8.82 Hz, 1H), 7.39-7.44 (m, 1H), 7, 33-7.40 (m, 4H), 7.27-7.32 (m, 2H), 5.69 (s, 2H), 1.71-1.87 (m, 1H), 1.00- 1.12 (m, 2H); 0.34-0.44 (m, 2H). MS (ESI +) m / z 484 (M + H) ⁺ .

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 according to the procedure described in Example 198A using the compound of Example 125B instead of the compound of Example 102B. The product was used directly in subsequent reactions without determining its characteristics.

Example 266B

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

The title compound was obtained in the form of a TFA salt in accordance with the procedure described in Example 205B using the compound of Example 266A instead of the compound of Example 205A. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.97 (s, 1H), 10.89 (s, 1H), 8.28 (s, 1H), 8.05-8.14 (m, 2H), 7.88 (d, J = 8, 82, 1.47 Hz, 1H), 7.58-7.67 (m, 2H), 7.54 (t, J = 7.35 Hz, 2H), 7.29-7.45 (m, 3H ), 7.23 (d, J = 6.99 Hz, 2H), 5.73 (s, 2H). MS (ESI +) m / z 521 (M + H) ⁺ .

Example 267

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

Example 267A

3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propannitrile

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) was added acrylonitrile (3.4 ml, 52 mmol) followed by 1.8-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 minimal amount of dichloromethane and purified by silica gel chromatography using a gradient of 10-50% ethyl acetate in heptane to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.03 (s, 1H), 7.64 (s, 1H), 4.40 (t, J = 6.4 Hz, 2H), 3.06 (t, J = 6.4 Hz, 2H), 1.26 (s, 12H). MS (ESI +) m / z 247.3 (M + H) ⁺ .

Example 267B

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

5-Bromo-1H-indazole-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) were added to the microwave vessel , 39 mmol) followed by the addition of a solution of the compound of Example 267A (0.212 g, 0.858 mmol) in 1,2-dimethoxyethane (2.50 ml) and then water (1.25 ml). The mixture was heated in a CEM microwave device at about 150 ° C for about 20 minutes (maximum pressure 275 psi (19 kg / cm ² ), time to rise to a predetermined level of about 2 minutes, maximum power 200 watts) and 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 under reduced pressure on silica gel and purified by chromatography on silica gel using a step gradient of dichloromethane / methanol / ammonium hydroxide (990: 9: 1 → 985: 13.5: 1.5 → 980: 18: 2), to obtain a solid. This solid was dissolved in a minimum amount of hot acetonitrile (~ 2 ml), filtered to remove minor amounts of insoluble matter, washing with methanol (<0.5 ml), and allowed to precipitate at ambient temperature. The resulting solid that formed overnight was collected by filtration, washing with additional acetonitrile, and dried in a vacuum oven at about 60 ° C for about 2 hours to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.35 (s, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.84 (s, 1H), 7.44 (dd, J = 8.54, 1, 26 Hz, 1H), 7.23 (d, J = 8.62 Hz, 1H), 5.32 (s, 2H), 4.42 (t, J = 6.36 Hz, 2H), 3.10 (t, J = 6.43 Hz, 2H). MS (ESI +) m / z 253.2 (M + H) ⁺ .

Example 268

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

Example 268A

2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) acetamide

Suspension of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (2.00 g, 10.3 mmol), 2-bromoacetamide (2.14 g , 15.5 mmol) and potassium carbonate (2.14 g, 15.5 mmol) in acetone (60 ml) were heated at about 50 ° C for about 3.5 days. The reaction mixture was then cooled to ambient temperature, filtered through diatomaceous earth, washing with additional acetone, and then concentrated under reduced pressure. The crude material was then dissolved in a minimal amount of dichloromethane and purified by chromatography on silica gel using a gradient of 80-100% ethyl acetate in heptane to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.88 (s, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 7.24 (s, 1H), 4.77 (s, 2H), 1.26 (s , 12H). MS (ESI +) m / z 252.2 (M + H) ⁺ .

Example 268B

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

The title compound was prepared according to the procedure described in Example 267B using the compound of Example 268A instead of the compound of Example 267A and using heating at about 120 ° C. for about 10 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.32 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.77 (s, 1H), 7.48 (s, 1H), 7.45 (d , J = 8.6 Hz, 1H), 7.26 (s, 1H), 7.22 (d, J = 8.7 Hz, 1H), 5.28 (s, 2H), 4.78 (s , 2H). MS (ESI +) m / z 257.2 (M + H) ⁺ .

Example 269

methyl 3- [4- (3-amino-1H-indazol-5-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 according to the procedure described in Example 267A using methyl acrylate instead of acrylonitrile. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.91 (s, 1H), 7.57 (s, 1H), 4.35 (t, J = 6.73 Hz, 2H), 2.87 (t, J = 6.75 Hz, 2H), 3.59 (s, 3H); 1.24 (s, 12H). MS (ESI +) m / z 281.2 (M + H) ⁺ .

Example 269B

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

The title compound was prepared according to the procedure described in Example 267B using the compound of Example 269A instead of the compound of Example 267A and using heating at about 120 ° C. for about 20 minutes. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.32 (s, 1H), 8.00 (s, 1H), 7.85 (s, 1H), 7.76 (s, 1H), 7.42 (d, J = 8.50 Hz, 1H ), 7.21 (d, J = 8.61 Hz, 1H), 5.28 (s, 2H), 4.37 (t, J = 6.71 Hz, 2H), 3.61 (s, 3H ), 2.92 (t, J = 6.69 Hz, 2H). MS (ESI +) m / z 286.2 (M + H) ⁺ .

Example 270

3- [4- (3-amino-1H-indazol-5-yl) -1H-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 according to the procedure described in Example 267A using acrylamide instead of acrylonitrile (0.72 g, 53%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.84 (s, 1H), 7.56 (s, 1H), 7.37 (s, 1H), 6.88 (s, 1H), 4.30 (t, J = 6.80 Hz, 2H ), 2.60 (t, J = 6.79 Hz, 2H), 1.24 (s, 12H). MS (ESI +) m / z 266.2 (M + H) ⁺ .

Example 270B

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

The title compound was prepared according to the procedure described in Example 267B using the compound of Example 270A instead of the compound of Example 267A and using heating at about 120 ° C. for about 15 minutes (0.056 g, 22%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.32 (s, 1H), 7.94 (d, J = 0.53 Hz, 1H), 7.84 (s, 1H), 7.75 (d, J = 0.54 Hz, 1H), 7.42 (m, 2H), 7.20 (d, J = 8.26 Hz, 1H), 6.89 (s, 1H), 5.27 (s, 2H), 4.32 (t, J = 6.89 Hz, 2H); 2.65 (t, J = 6.89 Hz, 2H). MS (ESI +) m / z 271.0 (M + H) ⁺ .

Example 271

[4- (3-amino-1H-indazol-5-yl) -1H-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 according to the procedure described in Example 268A using 2-bromoacetonitrile instead of 2-bromoacetamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.99 (s, 1H); 7.66 (s, 1H); 5.45 (s, 2H); 1.25 (s, 12H).

Example 271B

tert-butyl 3- (bis (tert-butoxycarbonyl) amino) -5-bromo-1H-indazole-1-carboxylate

To 5-bromo-1H-indazole-3-amine (2.00 g, 9.43 mmol) in tetrahydrofuran (20 ml) was added 4- (dimethylamino) pyridine (0.230 g, 1.886 mmol) and di-tert-butyl dicarbonate ( 6.18 g, 28.3 mmol). The reaction mixture 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 then washed sequentially with 1 N hydrochloric acid solution (2 × 25 ml), 1 N sodium hydroxide solution (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 give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.05 (d, J = 8.95 Hz, 1H), 7.99 (d, J = 1.90 Hz, 1H), 7.81 (dd, J = 8.94, 1.89 Hz, 1H), 1.65 (s, 9H), 1.40 (s, 18H). MS (ESI +) m / z 512.2 (M + H) ⁺ .

Example 271C

tert-butyl 3- (bis (tert-butoxycarbonyl) amino) -5- (1- (cyanomethyl) -1H-pyrazol-4-yl) -1H-indazole-1-carboxylate

The compound of Example 271A (0.682 g, 2.93 mmol), the compound of Example 271B (1.25 g, 2.44 mmol), cesium carbonate (1.99 g, 6.10 mmol), 1,4-dioxane were loaded into the vessel (12.5 ml) and water (2.50 ml). After a vacuum / nitrogen purge cycle through the membrane, Tris (dibenzylideneacetone) dipalladium (0) (0.112 g, 0.122 mmol) and tri-tert-butylphosphonium tetrafluoroborate (0.085 g, 0.29 mmol) were added and the lid was closed after purging with nitrogen. After about 6 hours at ambient temperature, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate and dichloromethane (each 50 ml). The layers were separated and the aqueous layer was extracted with additional dichloromethane (2 × 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 using a gradient of 20-60% ethyl acetate in heptane to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.43 (s, 1H), 8.19 (s, 1H), 8.08 (d, J = 9.22 Hz, 1H), 7.93 (m, 2H), 5.53 (s, 2H ), 1.67 (s, 9H), 1.39 (s, 18H). MS (ESI +) m / z 539.3 (M + H) ⁺ .

Example 271D

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

To a solution of tert-butyl 3- (bis (tert-butoxycarbonyl) amino) -5- (1- (cyanomethyl) -1H-pyrazol-4-yl) -1H-indazole-1-carboxylate (0.30 g, 0.557 mmol ) trichloroacetic acid (2.0 ml) was added in dichloromethane (4.0 ml). After about 45 minutes, the reaction mixture was slowly quenched with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (3 × 25 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a crude solid. A white precipitate, which was suspended both in the starting aqueous layer and in the saturated 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 suction filtration and dried in a vacuum oven at about 70 ° C. to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.37 (s, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.89 (s, 1H), 7.49-7.41 (m, 1H), 7 24 (d, J = 8.71 Hz, 1H), 5.52 (s, 2H), 5.31 (s, 2H). MS (ESI +) m / z 239.1 (M + H) ⁺ .

Example 272

4- (3-amino-1H-indazol-5-yl) -N, N-dimethyl-1H-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 in a microwave device (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 hours. 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 an acetonitrile / water gradient gradient elution method (0.05 M ammonium acetate) to obtain the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.42 (s, 1H), 8.25 (s, 1H), 8.21 (d, J = 1.36 Hz, 1H), 7.92 (d, J = 1.37 Hz, 1H), 7.74 (dd, J = 8.66, 1.58 Hz, 1H), 7.23 (d, J = 8.68 Hz, 1H), 5.35 (s, 2H), 2.87 (s , 6H). MS (ESI +) m / z 307.2 (M + H) ⁺ .

Example 273

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

The title compound was prepared according to the procedure described in Example 272 using 2-iodopyrazine instead of 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.61 (s, 1H), 9.18 (d, 1H, J = 1.6), 8.66 (dd, 1H, J = 1.7, 2.4), 8.59 (d, 1H , J = 1.0), 8.51 (d, 1H, J = 2.5), 8.04 (dd, 1H, J = 1.8, 8.8), 7.35 (d, 1H, J = 9.2), 5.54 (s, 2H). MS (ESI +) m / z 212.2 (M + H) ⁺ .

Example 274

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

The title compound was prepared according to the procedure described in Example 272 using 2-iodothiophene instead of 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.47 (s, 1H), 7.99 (d, 1H, J = 1.4), 7.55 (dd, 1H, J = 1.8, 8.8), 7.43 (dd, 1H , J = 1.0, 5.1), 7.35 (dd, 1H, J = 1.1, 3.6), 7.26 (d, 1H, J = 8.6), 7.10 ( dd, 1H, J = 3.5, 5.1), 5.42 (d, 2H, J = 8.8). MS (ESI +) m / z 216.1 (M + H) ⁺ .

Example 275

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

The title compound was prepared according to the procedure described in Example 272 using 5-iodopyrimidin-2-amine instead of 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.40 (s, 1H), 8.53 (s, 2H), 7.91 (dd, 1H, J = 0.7, 1.5), 7.47 (dd, 1H, J = 1.8 , 8.6), 7.28 (dd, 1H, J = 0.7, 8.7), 6.64 (s, 2H), 5.36 (s, 2H), ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.41 (s, 1H), 8.53 (s, 2H), 7.92 (m, 1H), 7.47 (dd, J = 8.66, 1.74 Hz, 1H), 7.28 (dd, J = 8.63, 0.65 Hz, 1H), 6.64 (s, 2H), 5.36 (s, 2H). MS (ESI +) m / z 227.2 (M + H) ⁺ .

Example 276

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

The title compound was prepared according to the procedure described in Example 272 using 3-iodo-2-methoxypyridine instead of 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.43 (s, 1H), 8.14 (dd, 1H, J = 1.9, 5.0), 7.86 (s, 1H), 7.71 (dd, 1H, J = 2.0 , 7.2), 7.42 (dd, 1H, J = 1.7, 8.7), 7.26 (d, 1H, J = 8.6), 7.09 (dd, 1H, J = 5.0, 7.3), 5.38 (s, 2H), 3.89 (s, 3H). MS (ESI +) m / z 241.2 (M + H) ⁺ .

Example 277

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

The title compound was prepared according to the procedure described in Example 272 using 3-bromimidazo [1,2-a] pyridine instead of 4-iodo-N, N-dimethyl-1H-imidazole 1-sulfonamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.52 (dt, 1H, J = 1.2, 7.0), 7.99 (dd, 1H, J = 0.7, 1.7), 7.68 (s, 1H), 7.65 (dt, 2H, J = 1.2, 9.0), 7.46 (dd, 1H, J = 1.8, 8.6), 7.39 (dd, 1H, J = 0.8, 8 6), 7.28 (ddd, 1H, J = 1.2, 6.6, 9.2), 6.96 (td, 1H, J = 1.3, 6.7), 5.47 ( s, 2H). MS (ESI +) m / z 250.2 (M + H) ⁺ .

Example 278

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

The compound of Example 65 (257 mg, 0.685 mmol) was dissolved in ethanol (15 ml). The reaction mixture was hydrogenated in an H-Cube apparatus using palladium hydroxide (20%) on carbon at a temperature of about 80 ° C and a pressure of about 60 psi (4.29 kg / cm ² ) for about 8 hours. The solvent was removed under reduced pressure, and the residue was purified by reverse phase HPLC using a gradient elution method with acetonitrile / water (0.05 M ammonium acetate) to obtain the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.16-8.37 (m, 1H), 7.10-7.46 (br s, 2H), 7.00-7.34 (br s, 2H), 6.87-7.24 (broad s, 2H), 3.33-3.34 (m, 2H). MS (ESI +) m / z 286.2 (M + H) ⁺ .

Example 279

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

The title compound was prepared according to the procedure described in Example 272 using 5-iodo-1H-pyrazole instead of 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.87-7.94 (m, 3H), 7.60-7.63 (m, 1H), 7.48 (dd, J = 8.55, 1.62 Hz, 1H), 7.19- 7.32 (m, 2H); 5.25-5.28 (m, 2H). MS (ESI +) m / z 200.1 (M + H) ⁺ .

Example 280

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

The title compound was prepared according to the procedure described in Example 272 using 5-iodo-4-methyl-1H-imidazole instead of 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.85 (s, 1H), 7.52 (d, 2H, J = 6.6), 7.22 (m, 1H), 5.3 2 (br s, 2H), 2.37 (s , 3H). MS (ESI +) m / z 214.1 (M + H) ⁺ .

Example 281

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

The title compound was prepared according to the procedure described in Example 272 using 4-iodo-1H-imidazole instead of 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.07 (s, 1H), 7.66 (s, 1H), 7.63 (d, 1H, J = 8.6), 7.37 (s, 1H), 7.20 (d, 1H, J = 8.8), 5.28 (s, 2H). MS (ESI +) m / z 200.1 (M + H) ⁺ .

Example 282

N ² , N ² -dimethyl-N ¹ - {5- [1- (3-methylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-yl} glycinamide

Example 282A

5-bromo-1H-indazole-3-amine

The title compound was prepared according to the procedure described in Example 62D using 5-bromo-2-fluorobenzonitrile instead of the compound of Example 62C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.55 (s, 1H), 7.92 (d, J = 1.87 Hz, 1H), 7.30 (dd, J = 8.79, 1.89 Hz, 1H), 7.19 (d , J = 8.78 Hz, 1H), 5.41 (s, 2H).

Example 282B

tert-butyl 3-amino-5-bromo-1H-indazole-1-carboxylate

The title compound was prepared according to the procedure described in Example 64A using the compound of Example 282A instead of the compound of Example 62D. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.12 (d, J = 1.93 Hz, 1H), 7.95-7.81 (m, 1H), 7.65 (dd, J = 8.85, 1.96 Hz, 1H), 6 39 (d, J = 4.44 Hz, 1H); 1.58 (m, 9H).

Example 282C

tert-butyl 5-bromo-3- (2- (dimethylamino) acetamido) -1H-indazole-1-carboxylate

Tetrahydrofuran (200 ml) was added to a mixture of the compound 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 room temperature for about 2 hours. 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 × 100 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol in dichloromethane (5%), to obtain the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.72 (s, 1H), 8.19 (d, 1H, J = 1.6), 8.03 (d, 1H, J = 9.0), 7.76 (dd, 1H, J = 2 , 0, 9.0), 3.22 (s, 2H), 2.32 (s, 6H), 1.63 (s, 9H).

Example 282D

tert-butyl 3- (2- (dimethylamino) acetamido) -5 - ((trimethylsilyl) ethynyl) -1H-indazole-1-carboxylate

To a mixture of the compound of Example 282C (2.56 g, 6.44 mmol), bis (triphenylphosphine) palladium (II) chloride (0.225 g, 0.321 mmol) and copper (I) iodide (0.073 g, 0.383 mmol) was added triethylamine (20 ml, 144 mmol) followed by ethinyltrimethylsilane (0.760 g, 7.73 mmol). The reaction mixture was heated at about 60 ° C for about 3 hours. The reaction mixture was diluted with dichloromethane (100 ml), washed with water (20 ml) and brine (20 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate in dichloromethane (10%) to elute to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.69 (s, 1H), 8.08 (s, 1H), 8.04 (d, 1H, J = 9.0), 7.62 (d, 1H, J = 8.8), 3, 21 (s, 2H), 2.30 (s, 6H), 1.61 (s, 9H), 0.23 (s, 9H).

Example 282E

2- (dimethylamino) -N- (5-ethynyl-1H-indazol-3-yl) acetamide

To the compound of Example 282D (0.303 g, 0.731 mmol) in methanol (5 ml) was added an aqueous solution of potassium hydroxide (1.46 ml, 1.46 mmol, 1.0 N solution). The reaction mixture was stirred at room temperature for about 1 hour. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (80 ml). The organic layer was separated and washed with water (10 ml) and brine (10 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.89 (s, 1H), 10.14 (s, 1H), 8.00 (d, 1H, J = 12.1), 7.44 (s, 2H), 7.38 (d, 1H, J = 8.6), 4.02 (s, 1H), 3.17 (s, 2H), 2.33 (s, 6H).

Example 282F

N ² , N ² -dimethyl-N ¹ - {5- [1- (3-methylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-yl} glycinamide

To a suspension of the compound 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), then water (1.2 ml) . A solution of (R) -2 - ((S) -1,2-dihydroxyethyl) -4-hydroxy-5-oxo-2,5-dihydrofuran-3-sodium olate (0.057 ml, 0.066 mmol, 1.6 M in water) and an aqueous solution of copper (II) sulfate pentahydrate (0.019 ml, 6.6 μmol, 0.34 M). 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 a gradient elution method with acetonitrile / water (0.05 M ammonium acetate) to obtain the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.77 (s, 1H), 10.05 (s, 1H), 8.56 (s, 1H), 8.24 (s, 1H), 7.82 (d, 1H, J = 8.6) 7.50 (d, 1H, J = 8.8), 7.28 (t, 1H, J = 7.6), 7.16 (m, 4H), 5.59 (s, 2H), 3 18 (s, 2H); 2.34 (s, 6H); 2.30 (s, 3H). MS (ESI +) m / z 390.3 (M + H) ⁺ .

Example 283

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

The title compound was prepared according to the procedure described in Example 272 using 1-benzyl-4-iodo-1H-imidazole instead of 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.29 (s, 1H), 8.07 (s, 1H), 7.79 (s, 1H), 7.61 (d, 1H, J = 8.6), 7.46 (s, 1H) 7.36 (m, 5H), 7.17 (d, 1H, J = 8.8), 5.28 (s, 2H), 5.22 (s, 2H). MS (ESI +) m / z 290.2 (M + H) ⁺ .

Example 284

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

The title compound was prepared according to the procedure described in Example 282F using 1- (azidomethyl) -4-tert-butylbenzene instead of 1- (azidomethyl) -3-methylbenzene. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.88 (s, 1H), 10.05 (s, 1H), 8.57 (s, 1H), 8.23 (s, 1H), 7.81 (d, 1H, J = 8.8) 7.50 (d, 1H, J = 8.8), 7.41 (d, 2H, J = 8.2), 7.30 (d, 2H, J = 8.2), 3.18 ( s, 2H), 2.34 (s, 6H), 1.26 (s, 9H). MS (ESI +) m / z 432.2 (M + H) ⁺ .

Example 285

N ² , N ² -dimethyl-N ¹ - {5- [1- (2-piperidin-1-yl-ethyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-yl} glycinamide

The title compound was prepared according to the procedure described in Example 282F using 1- (2-azidoethyl) piperidine instead of 1- (azidomethyl) -3-methylbenzene. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.91 (s, 1H), 10.07 (s, 1H), 8.47 (s, 1H), 8.22 (s, 1H), 7.80 (dd, 1H, J = 1.2, 8.7), 7.52 (d, 1H, J = 8.8), 4.49 (t, 2H, J = 6.4), 3.19 (s, 2H), 2.76 (t, 2H, J = 6.4), 2.41 (s, 4H), 2.35 (s, 6H), 1.69 (s, 3H), 1.47 (m, 4H), 1.37 (dd , 2H, J = 5.2, 10.2). MS (ESI-) m / z 395.3 (MH) ^- .

Example 286

N ² , N ² -dimethyl-N ¹ - {5- [1- (2-morpholin-4-yl-ethyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-yl} glycinamide

The title compound was prepared according to the procedure described in Example 282F using 4- (2-azidoethyl) morpholine instead of 1- (azidomethyl) -3-methylbenzene. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.83 (s, 1H), 10.07 (s, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 7.81 (dd, 1H, J = 1.3, 8.7), 7.52 (d, 1H, J = 8.8), 4.53 (t, 2H, J = 6.3), 3.55 (m, 4H), 3.19 (s, 2H), 2.80 (t, 2H, J = 6.3), 2.45 (m, 4H), 2.35 (s, 6H). MS (ESI-) m / z 397.3 (MH) ^- .

Example 287

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

The title compound was prepared according to the procedure described in Example 282F using 4- (2-azidoethyl) -3,5-dimethylisoxazole instead of 1- (azidomethyl) -3-methylbenzene. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.90 (s, 1H), 10.07 (s, 1H), 8.44 (s, 1H), 8.21 (s, 1H), 7.78 (dd, 1H, J = 1.3, 8.7), 7.52 (d, 1H, J = 8.8), 4.51 (t, 2H, J = 6.7), 3.19 (s, 2H), 2.93 (t, 2H, J = 6.7), 2.35 (s, 6H), 2.08 (d, 6H, J = 4.3). MS (ESI-) m / z 407.2 (MH) ^- .

Example 288

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

The title compound was prepared according to the procedure described in Example 282F using 4- (2-azidoethyl) -3,5-dimethyl-1H-pyrazole instead of 1- (azidomethyl) -3-methylbenzene. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.85 (s, 1H), 10.06 (s, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 7.78 (d, 1H, J = 8.8) 7.51 (d, 1H, J = 8.8), 4.42 (t, 2H, J = 6.9), 3.19 (s, 2H), 2.89 (t, 2H, J = 7.0), 2.35 (s, 6H), 1.97 (s, 6H). MS (ESI-) m / z 406.2 (MH) ^- .

Example 289

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

The title compound was prepared according to the procedure described in Example 282F using 2-azido-2-methylpropanoic acid instead of 1- (azidomethyl) -3-methylbenzene. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.77 (s, 1H), 10.03 (s, 1H), 8.47 (s, 1H), 8.22 (s, 1H), 7.85 (dd, 1H, J = 0.9, 8.7), 7.49 (d, 1H, J = 8.6), 3.21 (s, 2H), 2.36 (s, 6H), 1.77 (s, 6H). MS (ESI-) m / z 370.2 (MH) ^- .

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 according to the procedure described in Example 282F using ethyl 2-azidoacetate instead of 1- (azidomethyl) -3-methylbenzene. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.87 (s, 1H), 10.08 (s, 1H), 8.51 (s, 1H), 8.26 (s, 1H), 7.82 (dd, 1H, J = 1.4, 8.7), 7.53 (d, 1H, J = 8.8), 5.44 (s, 2H), 4.21 (q, 2H, J = 7.0), 3.19 (s , 2H); 2.35 (s, 6H); 1.24 (t, 3H, J = 7.1). MS (ESI +) m / z 372.2 (M + H) ⁺ .

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 according to the procedure described in Example 282F using (azidomethyl) trimethylsilane instead of 1- (azidomethyl) -3-methylbenzene. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.04 (s, 1H), 10.20 (s, 1H), 8.46 (s, 1H), 8.36 (s, 1H), 7.94 (dd, 1H, J = 1.3, 8.7), 7.65 (d, 1H, J = 8.8), 4.18 (s, 2H), 3.33 (s, 2H), 2.49 (s, 6H), 0.25 (m, 9H). MS (ESI +) m / z 372.2 (M + H) ⁺ .

Example 292

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

The title compound was prepared according to the procedure described in Example 233A, using the compound of Example 282C instead of 5-bromo-2-fluorobenzonitrile and using furan-3-ylboronic acid instead of 1-benzyl-4- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 12.70 (s, 1H), 9.98 (s, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.72 (t, 1H, J = 1.6) 7.59 (dd, 1H, J = 1.4, 8.7), 7.45 (d, 1H, J = 8.8), 6.87 (s, 1H), 3.17 (s, 2H), 2.33 (s, 6H). MS (ESI +) m / z 285.2 (M + H) ⁺ .

Example 293

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

The title compound was prepared according to the procedure described in Example 233A, using the compound of Example 282C instead of 5-bromo-2-fluorobenzonitrile and using 1H-pyrazol-5-ylboronic acid instead of 1-benzyl-4- (4.4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.68 (s, 1H), 10.01 (s, 1H), 8.12 (s, 1H), 7.80 (d, 1H, J = 9.0), 7.69 (s, 1H) 7.46 (d, 1H, J = 8.6), 6.60 (d, 1H, J = 2.0), 3.17 (d, 2H, J = 6.4), 2.34 ( s, 6H). MS (ESI +) m / z 285.2 (M + H) ⁺ .

Example 294

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

The title compound was prepared according to the procedure described in Example 233A, using the compound of Example 282C instead of 5-bromo-2-fluorobenzonitrile and using pyrimidin-5-ylboronic acid instead of 1-benzyl-4- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 12.87 (s, 1H), 10.11 (s, 1H), 9.16 (s, 1H), 9.09 (s, 2H), 8.16 (s, 1H), 7.75 (dd , 1H, J = 1.5, 8.8), 7.60 (d, 1H, J = 8.8), 3.18 (s, 2H), 2.33 (s, 6H). MS (ESI +) m / z 297.2 (M + H) ⁺ .

Example 295

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

The title compound was prepared according to the procedure described in Example 233A, using the compound of Example 282C instead of 5-bromo-2-fluorobenzonitrile and using benzo [c] [1,2,5] oxadiazol-5-ylboronic acid instead of 1 -benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 12.87 (s, 1H), 10.15 (s, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 8.16 (d, 1H, J = 9.4) 7.99 (dd, 1H, J = 1.1, 9.4), 7.85 (m, 1H), 7.59 (d, 1H, J = 8.8), 3.19 (s, 2H), 2.34 (s, 6H). MS (ESI +) m / z 337.2 (M + H) ⁺ .

Example 296

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

The title compound was prepared according to the procedure described in Example 233A, using the compound of Example 282C instead of 5-bromo-2-fluorobenzonitrile and using 4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) -1H-pyrazole instead of 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 12.62 (s, 1H), 9.94 (s, 1H), 7.95 (s, 2H), 7.87 (s, 1H), 7.58 (d, 1H, J = 8.8) 7.42 (d, 1H, J = 8.8); 3.16 (s, 2H); 2.34 (s, 6H). MS (ESI +) m / z 285.2 (M + H) ⁺ .

Example 297

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

The title compound was prepared according to the procedure described in Example 233A, using the compound of Example 282C instead of 5-bromo-2-fluorobenzonitrile and using 1-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1H-pyrazole instead of 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 12.64 (s, 1H), 9.98 (s, 1H), 8.04 (s, 1H), 7.86 (s, 1H), 7.76 (s, 1H), 7.55 (dd , 1H, J = 1.6, 8.6), 7.43 (d, 1H, J = 8.8), 3.87 (s, 3H), 3.17 (s, 2H), 2.35 (s, 6H). MS (ESI +) m / z 299.2 (M + H) ⁺ .

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 prepared according to the procedure described in Example 233A, using the compound of Example 282C instead of 5-bromo-2-fluorobenzonitrile and using 3,5-dimethyl-4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -1H-pyrazole instead of 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole . ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 12.63 (s, 1H), 10.02 (s, 1H), 7.63 (s, 1H), 7.46 (m, 1H), 7.27 (dd, 1H, J = 1.6, 8.6), 3.16 (s, 2H), 2.32 (s, 6H), 2.18 (s, 6H). MS (ESI +) m / z 323.2 (M + H) ⁺ .

Example 299

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

The title compound was prepared according to the procedure described in Example 233A using the compound of Example 282C instead of 5-bromo-2-fluorobenzonitrile and using N, N-dimethyl-5- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) pyrimidin-2-amine instead of 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H- pyrazole. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 12.72 (s, 1H), 10.03 (s, 1H), 8.62 (s, 2H), 7.91 (s, 1H), 7.58 (dd, 1H, J = 1.6, 8.6), 7.51 (d, 1H, J = 8.5), 3.16 (s, 8H), 2.33 (s, 6H). MS (ESI +) m / z 340.2 (M + H) ⁺ .

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 prepared according to the procedure described in Example 233A using the compound of Example 282C instead of 5-bromo-2-fluorobenzonitrile and using 4- (5- (4,4,5,5-tetramethyl-1,3) , 2-dioxaborolan-2-yl) pyrimidin-2-yl) morpholine instead of 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole . ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 12.74 (s, 1H), 10.03 (s, 1H), 8.67 (s, 2H), 7.94 (s, 1H), 7.60 (dd, 1H, J = 1.8, 8.8), 7.52 (d, 1H, J = 8.5), 3.74 (m, 4H), 3.67 (m, 4H), 3.17 (s, 2H), 2.33 (s, 6H). MS (ESI +) m / z 382.2 (M + H) ⁺ .

Example 301

N ² , N ² -dimethyl-N ¹ - {5- [1- (2-morpholin-4-yl-ethyl) -1H-pyrazol-4-yl] -1H-indazol-3-yl} glycinamide

The title compound was prepared according to the procedure described in Example 233A using the compound of Example 282C instead of 5-bromo-2-fluorobenzonitrile and using 4- (2- (4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethyl) morpholine instead of 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl) -1H-pyrazole. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 12.63 (s, 1H), 9.96 (s, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.77 (s, 1H), 7.54 (dd , 1H, J = 1.5, 8.8), 7.43 (d, 1H, J = 8.5), 4.24 (t, 2H, J = 6.6), 3.54 (m, 4H), 3.16 (s, 2H), 2.73 (t, 2H, J = 6.6), 2.41 (s, 4H), 2.34 (s, 6H). MS (ESI +) m / z 398.3 (M + H) ⁺ .

Example 302

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

Example 302A

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

The title compound was prepared according to the procedure described in Example 142A using toluene instead of hexane and using (azidomethyl) benzene instead of the compound of Example 80A. The crude product was used in the 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 according to the procedure described in Example 142B using the compound of Example 302A instead of the compound of Example 142A and using 2-fluoro-5-iodobenzonitrile instead of the compound of Example 87A. MS (ESI +) 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 according to the procedure described in Example 62D using the compound of Example 302B instead of the compound of 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 according to the procedure described in Example 64A using the compound of Example 302C instead of the compound of Example 62D.

Example 302E

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

The title compound was prepared according to the procedure described in Example 64B using the compound of Example 302D instead of the compound of Example 64A and using dimethylaminoacetyl chloride hydrochloride instead of methoxyacetyl chloride. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.76 (s, 1H), 10.06 (s, 1H), 8.18 (s, 1H), 7.79 (d, 1H, J = 8.8), 7.50 (d, 1H, J = 8.8), 7.34 (m, 5H), 5.68 (s, 2H), 3.16 (s, 2H), 2.32 (s, 6H), 1.76 (m, 1H ), 1.05 (q, 2H, J = 6.1), 0.39 (q, 2H, J = 5.4). MS (ESI +) m / z 416.3 (M + H) ⁺ . MS (ESI +) m / z 416.3 (M + H) ⁺ .

Example 303

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

Example 303A

3-amino-5- (1-benzyl-1H-pyrazol-4-yl) indazole-1-carboxylic acid tert-butyl ester

The title compound was prepared according to the procedure described in Example 64A using the compound of Example 233B instead of the compound of Example 62D (0.925 g, 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.19 (s, 1H), 8.04 (s, 1H), 7.90-7.95 (m, 1H), 7.87 (s, 1H), 7.74 (d, J = 1, 6 Hz, 1H), 7.28-7.36 (m, 5H), 6.27 (s, 2H), 5.37 (s, 2H), 1.58 (s, 9H). MS (ESI +) m / z 390 (M + H) ⁺ .

Example 303B

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

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 concentrated under reduced pressure. The residue was suspended in tetrahydrofuran (3 ml) and added to a suspension of the compound 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 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure, diluted with dichloromethane (20 ml) and washed with 15% aqueous sodium hydroxide solution (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 a gradient elution method with acetonitrile / water (0.05 M ammonium acetate) to obtain the title salt acetate compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.97 (s, 1H), 8.21 (s, 1H), 7.83 (s, 1H), 7.82 (s, 1H), 7.56 (d, J = 8.7 Hz, 1H ), 7.43 (d, J = 8.6 Hz, 1H), 7.32-7.40 (m, 2H), 7.25-7.32 (m, 3H), 5.35 (s, 2H), 3.16 (s, 2H), 2.33 (s, 6H), 1.91 (s, 3H). MS (ESI +) m / z 375 (M + H) ⁺ .

Example 304

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

The title compound was prepared according to the procedure described in Example 303B using 2- (tert-butoxycarbonyl (methyl) amino) acetic acid instead of 2- (dimethylamino) acetic acid and using the compound of Example 64A instead of the compound of Example 303A. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.56 (s, 1H), 8.28 (s, 1H), 7.78-7.88 (m, 1H), 7.45-7.56 (m, 1H), 7.28-7, 45 (5H, m), 5.64 (2H, s), 2.37 (s, 2H), 1.89 (s, 3H). MS (ESI +) m / z 362 (M + H) ⁺ .

Example 305

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

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 the compound 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 an additional amount of 2-bromoacetyl chloride (0.11 ml, 1.2 mmol) was added. The reaction mixture was stirred for another 15 minutes, then concentrated under reduced pressure to obtain the title compound as a brown solid. This substance 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-yl-acetamide

To a solution of the compound of Example 305A (44 mg, 0.086 mmol) and diisopropylethylamine (0.015 ml, 0.086 mmol) in acetonitrile (1 ml) was added pyrrolidine (0.021 ml, 0.25 mmol) and the reaction mixture was heated at about 60 ° C for about 15 minutes. The reaction mixture was cooled to ambient temperature and trifluoroacetic acid (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 a gradient elution method with acetonitrile / water (0.05 M ammonium acetate) to obtain the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.58 (s, 1H), 8.24 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.27-7.45 (m, 5H), 5.64 (s, 2H), 3.35 (s, 2H), 2.65 (s, 4H), 1.76 (s, 4H). MS (ESI +) m / z 402 (M + H) ⁺ .

Example 306

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

The title compound was prepared according to the procedure described in Example 305B using cyclopentanamine instead of pyrrolidine (0.004 g, 12%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.56 (s, 1H), 8.31 (s, 1H), 7.73-7.86 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.7 Hz , 1H), 7.29-7.45 (m, 5H), 5.64 (s, 2H), 3.37 (s, 2H), 2.99-3.14 (m, 1H), 1, 60-1.80 (m, 4H); 1.30-1.50 (m, 4H). MS (ESI +) m / z 416 (M + H) ⁺ .

Example 307

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

To a solution of the compound of Example 305 A (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 heated at about 60 ° C for about 1 hour. The reaction mixture was cooled to ambient temperature and hydrochloric acid was added (4 N solution in dioxane, 1 ml). 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 gradient method (0.05 M ammonium acetate) to obtain the title salt acetate compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.18 (s, 1H), 8.28 (s, 1H), 8.56 (s, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.30-7.45 (m, 5H), 5.64 (s, 2H), 3.45 (s, 2H), 2.18-2.26 (m, 1H), 1.89 (s, 3H), 0.37-0.45 (m, 2H), 0.29-0.37 (m, 2H). MS (ESI +) m / z 388 (M + H) ⁺ .

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 obtained in the form of an acetate salt in accordance with the procedure described in Example 307 using tetrahydro-2H-pyran-4-amine instead of cyclopropanamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.56 (s, 1H), 8.31 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.31-7.45 (m, 5H), 5.64 (s, 2H), 3.84 (d, J = 11.2 Hz, 2H), 3.43 (s, 2H), 3.30 (t, J = 10.8 Hz, 2H), 2.62-2.74 (m, 1H), 1.88 (s, 3H), 1.75-1.85 (m, 2H), 1, 24-1.39 (m, 2H). MS (ESI +) m / z 432 (M + H) ⁺ .

Example 309

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

The title compound was obtained in the form of a diacetate salt in accordance with the procedure described in Example 307 using pyrrolidin-3-ol instead of cyclopropanamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.09 (s, 1H), 8.22 (s, 1H), 8.58 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.28-7.45 (m, 5H), 5.64 (s, 2H), 4.16-4.26 (m, 1H), 3.34 (s, 2H), 2.77-2.93 (m, 2H), 2.52-2.65 (m, 2H), 1.98-2.13 (m, 1H), 1.87 (s, 6H) 1.56-1.69 (m, 1H). MS (ESI +) m / z 418 (M + H) ⁺ .

Example 310

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

The title compound was obtained in the form of an acetate salt in accordance with the procedure described in Example 307 using piperidin-3-ol instead of cyclopropanamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.05 (s, 1H), 8.56 (s, 1H), 8.23 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.29-7.44 (m, 5H), 5.64 (s, 2H), 3.55-3.67 (m, 1H), 3.20 (s, 2H), 2.77-2.88 (m, 1H), 2.60-2.70 (m, 1H), 2.22-2.35 (m, 1H), 2.12-2.23 ( m, 1H), 1.88 (s, 3H), 1.66-1.78 (m, 2H), 1.43-1.59 (m, 1H), 1.13-1.27 (m, 1H). MS (ESI +) m / z 432 (M + H) ⁺ .

Example 311

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

The title compound was obtained in the form of an acetate salt in accordance with the procedure described in Example 307, using dimethylamine instead of cyclopropanamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.48 (s, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.30-7.44 (m, 5H), 5.64 (s, 2H), 2.60 (d, J = 6.1 Hz, 2H), 2.54 (d, J = 6.3 Hz, 2H), 2.21 (s, 6H), 1.90 (s, 3H). MS (ESI +) m / z 390 (M + H) ⁺ .

Example 312

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

The title compound was prepared according to the procedure described in Example 307 using morpholine instead of cyclopropanamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.10 (s, 1H), 8.57 (s, 1H), 8.23 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.29-7.46 (m, 5H), 5.64 (s, 2H), 3.59-3.71 (m, 4H), 3.22-3, 28 (m, 2H); 2.54-2.64 (m, 4H). MS (ESI +) m / z 418 (M + H) ⁺ .

Example 313

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

The title compound was obtained in the form of a diacetate salt according to the procedure described in Example 307, using 1-methylpiperazine instead of cyclopropanamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.57 (s, 1H), 8.25 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.32-7.43 (m, 5H), 5.64 (s, 2H), 3.22 (s, 2H), 2.53-2.65 (m, 4H), 2.31-2, 45 (m, 4H), 2.17 (s, 3H), 1.85 (s, 6H). MS (ESI +) m / z 431 (M + H) ⁺ .

Example 314

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

The title compound was prepared according to the procedure described in Example 307 using piperazin-2-one instead of cyclopropanamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.21 (s, 1H), 8.57 (s, 1H), 8.22 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.31-7.46 (m, 5H), 5.64 (s, 2H), 3.36 (s, 2H), 3.24 (s, 2H), 3 17 (s, 2H); 2.78 (s, 2H). MS (ESI +) m / z 431 (M + H) ⁺ .

Example 315

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

The title compound was obtained in the form of an acetate salt in accordance with the procedure described in Example 307, using propan-2-amine instead of cyclopropanamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.56 (s, 1H), 8.31 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.31-7.44 (m, 5H), 5.64 (s, 2H), 3.39 (s, 2H), 2.73-2.86 (m, 1H), 1.90 (s, 3H), 1.04 (d, J = 6.1 Hz, 6H). MS (ESI +) m / z 390 (M + H) ⁺ .

Example 316

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

The title compound was obtained in the form of an acetate salt in accordance with the procedure described in Example 307, using cyclohexanamine instead of cyclopropanamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.55 (s, 1H), 8.31 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.30-7.44 (m, 5H), 5.64 (s, 2H), 3.40 (s, 2H), 1.90 (s, 3H), 1.80-1.88 (m, 2H), 1.63-1.73 (m, 2H), 1.50-1.60 (m, 1H), 1.02-1.29 (m, 5H). MS (ESI +) m / z 430 (M + H) ⁺ .

Example 317

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

To a mixture of the compound 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 stirred at ambient temperature for about 1.5 hours. Hydrochloric acid (4 N solution 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 gradient gradient elution method (0.05 M ammonium acetate) to obtain the title compound as an acetate salt. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.35 (s, 1H), 8.57 (s, 1H), 8.22 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.33-7.42 (m, 5H), 5.64 (s, 2H), 2.13 (s, 3H). MS (ESI-) m / z 331 (MH) ^- .

Example 318

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

The title compound was prepared according to the procedure described in Example 307 using cyclobutanamine instead of cyclopropanamine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.56 (s, 1H), 8.29 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.31-7.45 (m, 5H), 5.64 (s, 2H), 3.31 (s, 2H), 2.01-2.20 (m, 2H), 1.48-1, 83 (m, 5H). MS (ESI +) m / z 402 (M + H) ⁺ .

Example 319

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

To a solution of the compound 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 (4 N solution in dioxane, 3 ml) and stirred at room temperature for about 4.5 hours. Diethyl ether (5 ml) was added and the precipitate was collected by filtration. The crude material was purified by reverse phase HPLC using a gradient elution method with acetonitrile / water (0.05 M ammonium acetate) to obtain the title compound as an acetate salt. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.34 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.31-7.48 (m, 5H), 5.65 (s, 2H), 3.18 (dd, J = 6.6, 12.7 Hz, 2H) 1.51 (dd, J = 7.1, 14.3 Hz, 2H); 0.91 (t, J = 7.3 Hz, 3H). MS (ESI +) m / z 376 (M + H) ⁺ .

Example 320

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

To a solution of the compound 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 a 1N aqueous solution of hydrochloric acid (10 ml). The organic part was separated, dried under reduced pressure and treated with hydrochloric acid (4 N solution 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 gradient method (0.05 M ammonium acetate) to obtain the title compound as an acetate salt. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.12 (s, 1H), 8.61 (s, 1H), 8.24 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.29-7.48 (m, 5H), 5.64 (s, 2H), 3.29 (d, J = 9.2 Hz, 2H), 1.31 (t, J = 7.3 Hz, 3H). MS (ESI +) m / z 383 (M + H) ⁺ .

Example 321

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

A mixture of the compound of 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, 0.76 mmol) in 1.2 -dichloroethane (5 ml) was stirred at ambient temperature for about 2.5 hours. Hydrochloric acid (4 N solution in dioxane, 4 ml) was added and the reaction mixture was stirred for about 16 hours. The precipitate was collected by filtration, washing with ether (10 ml). The solid was dissolved in dichloromethane (10 ml) and treated with trifluoroacetic acid (0.1 ml) and the reaction mixture was stirred at room temperature for about 2 hours. The reaction mixture was neutralized by the addition of a 15% aqueous sodium hydroxide solution (about 15 ml) and the organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC using a gradient elution method with acetonitrile / water (0.05 M ammonium acetate) to obtain the title compound as an acetate salt. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.43 (s, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.32-7.45 (m, 5H), 7.26 (d, J = 8.6 Hz, 1H), 6.08 (t, J = 5.7 Hz, 1H), 5.64 (s, 2H), 3.12 (t, J = 6.2 Hz, 2H), 1.04-1.22 (m, 1H), 0.35-0.53 (m, 2H), 0.17-0.32 (m, 2H ) MS (ESI +) m / z 345 (M + H) ⁺ .

Example 322

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

The title compound was prepared according to the procedure described in Example 319 using isocyanatoethane instead of 1-isocyanatopropane. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.32 (s, 1H), 8.49 (s, 1H), 8.42 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.31-7.49 (m, 5H), 5.65 (s, 2H), 3.23 (d, J = 6.9 Hz, 2H), 1.12 (t, J = 7.1 Hz, 3H). MS (ESI +) m / z 362 (M + H) ⁺ .

Example 323

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

A suspension of the compound of Example 64A (200 mg, 0.51 mmol) and diisopropylethylamine (0.089 ml, 0.51 mmol) in tetrahydrofuran (5 ml) was stirred for about 15 minutes at ambient temperature, then 4-bromobutanoyl chloride (0.059 ml, 0.51 mmol). The reaction mixture was stirred for about 16 hours. The precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was taken up in acetonitrile (5 ml) and 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 room temperature and concentrated under reduced pressure. The residue was treated with hydrochloric acid (4 N solution 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 gradient method (0.05 M ammonium acetate) to obtain the title compound as an acetate salt. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.84 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.29-7.46 (m, 5H), 5.64 (s, 2H), 3.96 (t, J = 6.9 Hz, 2H), 2.56 (t, J = 7.9 Hz, 2H); 2.25-2.12 (m, 2H). MS (ESI +) m / z 359 (M + H) ⁺ .

Example 324

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

The title compound was obtained in the form of a diacetate salt according to the procedure described in Example 303B using 4- (dimethylamino) butanoic acid instead of 2- (dimethylamino) acetic acid and using the compound of Example 64A instead of the compound of Example 303A. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.34 (s, 1H), 8.53 (s, 1H), 8.22 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.30-7.41 (m, 5H), 5.62 (s, 2H), 2.41 (t, J = 7.2 Hz, 2H), 2.28 (t, J = 6.8 Hz, 2H), 2.14 (s, 6H), 1.84 (s, 6H), 1.74-1.77 (m, 2H). MS (ESI-) m / z 462 (MH) ^- .

Example 325

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

The title compound was prepared according to the procedure described in Example 81B using 3,4-dihydro-1H-isochromen-4-amine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (br s, 1H), 9.02 (d, 1H), 8.4 (m, 1H), 8.22 (m, 1H), 7.75 (m, 2H), 7.2 -7.4 (m, 5H), 5.24 (m, 1H), 4.75 (m, 2H), 4.02 (m, 1H), 3.8 (m, 1H). MS m / z (ESI +) 361 (M + H) ⁺ .

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) followed by the addition of HATU (60 mg, 0.15 mmol) dissolved in N, N-dimethylformamide (0.8 ml). Then a solution of 1-cyclohexylmethanamine (17 mg, 0.17 mmol) dissolved in N, N-dimethylformamide (0.8 ml) was added, followed by diisopropylethylamine (56 μl, 0.31 mmol) dissolved in N, N- dimethylformamide (0.8 ml). The resulting mixture was shaken for 3 hours at 40 ° C. The reaction mixture was filtered, monitored by LC / MS and concentrated to dryness. Residues were dissolved in 1: 1 dimethyl sulfoxide / methanol and purified by reverse phase HPLC (Phenomenex® Luna® C8 (2) column 5 μm 100Å AXIA ™ (30 mm × 75 mm), 50 ml / min, 10-100% acetonitrile / 0.1% trifluoroacetic acid in water) to give the title product. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 0.91-0.97 (m, 2H), 1.12-1.27 (m, 4H), 1.61-1.75 (m, 5H), 3.08-3.16 (m, 2H) ), 7.22-7.24 (m, 1H), 7.71-7.75 (m, 1H), 7.87-7.92 (m, 1H), 8.23-8.27 (m , 1H), 8.38-8.41 (m, 1H). MS (ESI +) m / z 325 (M + H) ⁺ ; (ESI-) m / z 323 (MH) ^- .

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 that 1- (3-chlorophenyl) methanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 4.47-4.52 (m, 2H), 7.27-7.29 (m, 1H), 7.30-7.42 (m, 4H), 7.72-7.75 (m, 1H ), 7.89-7.93 (m, 1H), 8.25-8.28 (m, 1H), 8.41-8.42 (m, 1H). MS (ESI +) m / z 353 (M + H) ⁺ ; (ESI-) m / z 351 (MH) ^- .

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 that 1- (2-methoxyphenyl) methanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 3.82-3.86 (m, 3H), 4.45-4.50 (m, 2H), 6.92-6.97 (m, 1H), 7.01-7.04 (m, 1H) ), 7.19-7.24 (m, 1H), 7.26-7.31 (m, 2H), 7.69-7.77 (m, 1H), 7.88-7.93 (m , 1H), 8.24-8.28 (m, 1H), 8.38-8.44 (m, 1H). MS (ESI +) m / z 349 (M + H) ⁺ ; (ESI-) m / z 347 (MH) ^- .

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 that 1- [2- (trifluoromethyl) phenyl] methanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 4.66-4.73 (m, 2H), 7.29-7.33 (m, 1H), 7.49-7.60 (m, 2H), 7.67-7.79 (m, 3H) ), 7.91-7.94 (m, 1H), 8.26-8.28 (m, 1H), 8.41-8.45 (m, 1H). MS (ESI +) m / z 387 (M + H) ⁺ ; (ESI-) m / z 385 (MH) ^- .

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 that 1- [3- (trifluoromethyl) phenyl] methanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 4.57-4.61 (m, 2H), 7.28-7.31 (m, 1H), 7.59-7.77 (m, 5H), 7.90-7.94 (m, 1H ), 8.27-8.28 (m, 1H), 8.40-8.43 (m, 1H). MS (ESI-) m / z 385 (MH) ^- .

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 that 1- [4- (trifluoromethyl) phenyl] methanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 4.55-4.60 (s, 2H), 7.27-7.30 (m, 1H), 7.54-7.59 (m, 2H), 7.70-7.76 (m, 3H ), 7.88-7.94 (m, 1H), 8.24-8.28 (m, 1H), 8.40-8.44 (m, 1H). MS (ESI +) m / z 387 (M + H) ⁺ ; (ESI-) m / z 385 (MH) ^- .

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 that 1-pyridin-2-ylmethanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 4.74-4.84 (s, 2H), 7.30-7.34 (m, 1H), 7.68-7.81 (m, 3H), 7.89-7.97 (m, 1H ), 8.22-8.33 (m, 2H), 8.40-8.45 (m, 1H), 8.67-8.76 (m, 1H). MS (ESI +) m / z 320 (M + H) ⁺ ; (ESI-) m / z 318 (MH) ^- .

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 that 1-pyridin-3-ylmethanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 4.61-4.68 (s, 2H), 7.27-7.31 (m, 1H), 7.70-7.75 (m, 1H), 7.83-7.94 (m, 2H) ), 8.24-8.28 (m, 1H), 8.31-8.37 (m, 1H), 8.40-8.44 (m, 1H), 8.69-8.74 (m , 1H); 8.77-8.82 (m, 1H). MS (ESI +) m / z 320 (M + H) ⁺ ; (ESI-) m / z 318 (MH) ^- .

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 that 1-pyridin-4-ylmethanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 4.73-4.80 (s, 2H), 7.30-7.33 (m, 1H), 7.73-7.78 (m, 1H), 7.89-7.97 (m, 3H ), 8.25-8.30 (m, 1H), 8.40-8.46 (m, 1H), 8.76-8.83 (m, 2H). MS (ESI-) m / z 318 (MH) ^- .

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 that 1- (2-chlorophenyl) methanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 4.54-4.58 (s, 2H), 7.27-7.32 (m, 1H), 7.33-7.42 (m, 3H), 7.47-7.49 (m, 1H ), 7.71-7.77 (m, 1H), 7.88-7.98 (m, 1H), 8.24-8.27 (m, 1H), 8.41-8.44 (m , 1H). MS (ESI +) m / z 353 (M + H) ⁺ ; (ESI-) m / z 351 (MH) ^- .

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 that 1- (4-chlorophenyl) methanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 4.42-4.49 (m, 2H), 7.22-7.31 (m, 1H), 7.34-7.49 (m, 4H), 7.70-7.76 (m, 1H ), 7.84-7.92 (m, 1H), 8.17-8.30 (m, 1H), 8.35-8.47 (m, 1H). MS (ESI-) m / z 351 (MH) ^- .

Example 337

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

The title compound was prepared according to the procedure described in Example 81B using 1-phenyl-2-piperidin-1-ylethanamine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (br s, 1H), 9.12 (d, 1H), 8.4 (s, 1H), 8.22 (s, 1H), 7.9 (d, 1H), 7.7 (d, 1H), 7.2-7.4 (m, 6H), 5.2 (m, 1H), 3.2 (m, 2H), 2.3 (m, 4H), 1.2- 1.4 (m, 6H). MS (ESI +) m / z 416 (M + H) ⁺ .

Example 338

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

The title compound was prepared according to the procedure described in Example 81B using 2- (1H-indazol-1-yl) -1-phenylethanamine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (br s, 1H), 9.5 (d, 1H), 8.4 (s, 1H), 8.22 (s, 1H), 7.78 (m, 1H), 7.52 (d, 2H), 7.72 (d, 2H), 7.2-7.4 (m, 5H), 6.85 (s, 1H), 5.44 (m, 1H), 4.44 ( m, 2H). MS (ESI +) m / z 399 (M + H) ⁺ .

Example 339

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

The title compound was prepared according to the procedure described in Example 81B using 2-morpholin-4-yl-1-phenylethanamine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (br s, 1H), 9.2 (d, 1H), 8.4 (s, 1H), 8.22 (s, 1H), 7.9 (d, 1H), 7.7 (d, 1H), 7.2-7.4 (m, 6H), 5.2 (m, 1H), 3.6 (m, 4H), 3.4 (m, 2H), 2.4 ( m, 4H). MS (ESI +) m / z 418 (M + H) ⁺ .

Example 340

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

The title compound was prepared according to the procedure described in Example 81B using 2- (4-methylpiperazin-1-yl) -1-phenylethanamine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.6 (br s, 1H), 9.14 (d, 1H), 8.4 (s, 1H), 8.22 (s, 1H), 7.9 (d, 1H), 7.7 (d, 1H), 7.2-7.4 (m, 6H), 5.2 (m, 1H), 3.2 (m, 2H), 2.4 (m, 4H), 2.2 ( m, 4H); 2.1 (m, 3H). MS (ESI +) m / z 432 (M + H) ⁺ .

Example 341

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

The title compound was prepared according to the procedure described in Example 81B using 1-phenyl-2-pyrrolidin-1-ylethanamine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (br s, 1H), 9.14 (d, 1H), 8.4 (s, 1H), 8.22 (s, 1H), 7.9 (d, 1H), 7.7 (d, 1H), 7.2-7.4 (m, 6H), 5.18 (m, 1H), 3.2 (m, 2H), 2.4 (m, 4H), 1.8 ( m, 3H). MS (ESI +) m / z 402.5 (M + H) ⁺ .

Example 342

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

The title compound was prepared according to the procedure described in Example 81B using tert-butyl 2-amino-2-phenylethylcarbamate instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (br s, 1H), 9.14 (d, 1H), 8.4 (s, 1H), 8.22 (s, 1H), 7.9 (d, 1H), 7.7 (d, 1H), 7.2-7.4 (m, 6H), 7.00 (t, 1H), 5.18 (m, 1H), 3.2 (m, 2H), 1.4 ( s, 9H). MS (ESI +) m / z 449 (M + H) ⁺ .

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 that 1- (1-naphthyl) methanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 4.93-4.99 (m, 2H), 7.28-7.32 (m, 1H), 7.48-7.66 (m, 4H), 7.70-7.76 (m, 1H) ), 7.86-7.92 (m, 2H), 7.96-8.00 (m, 1H), 8.18-8.23 (m, 1H), 8.24-8.27 (m , 1H), 8.38-8.44 (m, 1H). MS (ESI-) m / z 367 (MH) ^- .

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 that 2-phenylethanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 2.84-2.92 (t, 2H), 3.47-3.57 (t, 2H), 7.18-7.35 (m, 6H), 7.69-7.77 (m, 1H ), 7.86-7.91 (m, 1H), 8.22-8.29 (m, 1H), 8.37-8.44 (m, 1H). MS (ESI +) m / z 333 (M + H) ⁺ ; (ESI-) m / z 331 (MH) ^- .

Example 345

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

The title compound was prepared using the procedure described in Example 326, except that 2-pyridin-2-yl-ethanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 3.22-3.29 (t, 2H), 3.71-3.75 (t, 2H), 7.14-7.26 (m, 1H), 7.70-7.75 (m, 1H ), 7.81-7.94 (m, 3H), 8.23-8.29 (m, 1H), 8.35-8.44 (m, 2H), 8.71-8.83 (m , 1H). MS (ESI +) m / z 334 (M + H) ⁺ ; (ESI-) m / z 332 (MH) ^- .

Example 346

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

The title compound was prepared using the procedure described in Example 326, except that 2-pyridin-3-yl-ethanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 3.01-3.13 (t, 2H), 3.55-3.70 (t, 2H), 7.14-7.26 (m, 1H), 7.70-7.77 (m, 1H ), 7.84-7.95 (m, 2H), 8.25-8.29 (m, 1H), 8.36-8.45 (m, 2H), 8.69-8.75 (m , 1H); 8.77-8.84 (m, 1H). MS (ESI +) m / z 334 (M + H) ⁺ ; (ESI-) m / z 332 (MH) ^- .

Example 347

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

The title compound was prepared using the procedure described in Example 326, except that 2-pyridin-4-ylethanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 3.12-3.23 (t, 2H), 3.67-3.71 (t, 2H), 7.20-7.21 (m, 1H), 7.69-7.76 (m, 1H ), 7.86-7.91 (m, 3H), 8.25-8.27 (m, 1H), 8.38-8.41 (m, 1H), 8.70-8.77 (m , 2H). MS (ESI +) m / z 334 (M + H) ⁺ ; (ESI-) m / z 332 (MH) ^- .

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 that 2- (2-chlorophenyl) ethanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 2.99-3.05 (t, 2H), 3.54-3.61 (t, 2H), 7.21-7.23 (m, 1H), 7.26-7.33 (m, 2H) ), 7.35-7.40 (m, 1H), 7.41-7.47 (m, 1H), 7.70-7.75 (m, 1H), 7.87-7.93 (m , 1H), 8.23-8.31 (m, 1H), 8.37-8.44 (m, 1H). MS (ESI +) m / z 367 (M + H) ⁺ ; (ESI-) m / z 365 (MH) ^- .

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 that 2- (3-chlorophenyl) ethanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 2.89 (t, 2H), 3.54 (t, 2H), 7.19-7.42 (m, 5H), 7.69-7.77 (m, 1H), 7.86-7, 94 (m, 1H), 8.22-8.29 (m, 1H), 8.38-8.42 (m, 1H). MS (ESI-) m / z 365 (MH) ^- .

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 that 2- (4-chlorophenyl) ethanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 2.86 (t, 2H), 3.50 (t, 2H), 7.17-7.24 (m, 1H), 7.27-7.41 (m, 4H), 7.71-7, 76 (m, 1H), 7.85-7.91 (m, 1H), 8.21-8.29 (m, 1H), 8.34-8.44 (m, 1H). MS (ESI-) m / z 365 (MH) ^- .

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 that N-benzyl-N-ethylamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.06-1.19 (m, 3H), 3.37-3.49 (m, 2H), 4.69-4.76 (m, 2H), 7.21-7.28 (m, 1H ), 7.28-7.49 (m, 5H), 7.69-7.78 (m, 1H), 7.83-7.97 (m, 1H), 8.24-8.32 (m , 1H); 8.36-8.46 (m, 1H). MS (ESI +) m / z 347 (M + H) ⁺ ; (ESI-) m / z 345 (MH) ^- .

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 that N-methyl-N- (1-naphthylmethyl) amine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 3.04-3.11 (m, 3H), 5.20-5.35 (m, 2H), 7.20-7.31 (m, 1H), 7.33-7.66 (m, 4H ), 7.66-7.77 (m, 1H), 7.81-8.18 (m, 4H), 8.20-8.28 (m, 1H), 8.31-8.45 (m , 1H). MS (ESI +) m / z 383 (M + H) ⁺ ; (ESI-) m / z 381 (MH) ^- .

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 that N-methyl-N- (2-phenylethyl) amine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 2.86-2.97 (m, 2H), 3.06-3.13 (m, 3H), 3.70-3.74 (m, 2H), 6.64-7.39 (m, 6H ), 7.69-7.92 (m, 2H), 8.24-8.44 (m, 2H). MS (ESI +) m / z 347 (M + H) ⁺ ; (ESI-) m / z 345 (MH) ^- .

Example 354

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

The title compound was prepared using the procedure described in Example 326, except that N-methyl-N- (2-pyridin-2-yl-ethyl) amine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 3.07-3.22 (m, 3H), 3.26-3.39 (m, 2H), 3.92-4.04 (m, 2H), 6.85-7.14 (m, 1H ), 7.65-8.05 (m, 4H), 8.23-8.56 (m, 3H), 8.65-8.86 (m, 1H). MS (ESI +) m / z 348 (M + H) ⁺ ; (ESI-) m / z 346 (MH) ^- .

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 that (1R) -1-phenylethanamine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.49-1.54 (m, 3H), 5.12-5.20 (m, 1H), 7.23-7.29 (m, 2H), 7.33-7.46 (m, 4H ), 7.71-7.75 (m, 1H), 7.87-7.91 (m, 1H), 8.22-8.28 (m, 1H), 8.37-8.42 (m , 1H). MS (ESI +) m / z 333 (M + H) ⁺ ; (ESI-) m / z 331 (MH) ^- .

Example 356

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

The title compound was prepared using the procedure described in Example 326, except that 1,2,3,4-tetrahydronaphthalen-1-amine was used instead of 1-cyclohexylmethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.72-2.09 (m, 4H), 2.68-2.85 (m, 2H), 5.19-5.26 (m, 1H), 7.12-7.24 (m, 4H) ), 7.29-7.35 (m, 1H), 7.69-7.77 (m, 1H), 7.86-7.93 (m, 1H), 8.25-8.30 (m , 1H), 8.38-8.43 (m, 1H). MS (ESI-) m / z 357 (MH) ^- .

Example 357

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

The title compound was prepared according to the procedure described in Example 81B using (1S) -1- (1-naphthyl) ethanamine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (br s, 1H), 9.4 (d, 1H), 8.4 (s, 1H), 8.25 (s, 1H), 8.22 (br s, 1H), 7 95 (d, 1H), 7.85 (m, 2H), 7.65 (m, 2H), 7.5 (m, 3H), 7.3 (s, 1H), 5.9 (m, 1H), 1.65 (d, 3H). MS (ESI +) m / z 382.9 (M + H) ⁺ .

Example 358

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

The title compound was prepared according to the procedure described in Example 81B using (1R) -1- (1-naphthyl) ethanamine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (br s, 1H), 9.4 (d, 1H), 8.4 (s, 1H), 8.25 (s, 1H), 8.22 (br s, 1H), 7 95 (d, 1H), 7.85 (m, 2H), 7.65 (m, 2H), 7.5 (m, 3H), 7.3 (s, 1H), 5.9 (m, 1H), 1.65 (d, 3H). MS (ESI +) m / z 382.9 (M + H) ⁺ .

Example 359

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

The title compound was prepared according to the procedure described in Example 81B using N ³ , N ³ -dimethyl-1-phenylpropane-1,3-diamine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (br s, 1H), 9.4 (d, 1H), 8.4 (s, 1H), 8.25 (s, 1H), 7.92 (m, 1H), 7.7 (m, 1H), 7.3-7.5 (m, 6H), 5.15 (m, 1H), 3.2 (m, 2H), 7.75 (s, 6H), 2.35 ( m, 1H); 2.15 (m, 1H). MS (ESI +) m / z 390 (M + H) ⁺ .

Example 360

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

The title compound was prepared according to the procedure described in Example 81B using 1- (2,3-dihydro-1,4-benzodioxin-5-yl) methanamine instead of piperidine. ¹ H NMR (SOO MHz, DMSO-d ₆ ) δ ppm 13.4 (br s, 1H), 9.24 (t, 1H), 8.4 (s, 1H), 8.25 (s, 1H), 7.92 (d, 1H), 7.7 (d, 1H), 7.24 (s, 1H), 6.9 (m, 3H), 4.4 (d, 2H), 4.3 (d, 2H), 4.25 (d, 2H) . MS (ESI +) m / z 377 (M + H) ⁺ .

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 according to the procedure described in Example 81B using 1- (3,4-dihydro-2H-1,5-benzodioxepin-6-yl) methanamine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (br s, 1H), 9.2 (t, 1H), 8.4 (s, 1H), 8.25 (s, 1H), 7.92 (d, 1H), 7.7 (d, 1H), 7.24 (s, 1H), 6.9 (m, 3H), 4.42 (d, 2H), 4.15 (m, 4H), 2.2 (m, 2H) . MS (ESI +) m / z 391 (M + H) ⁺ .

Example 362

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

The title compound was prepared according to the procedure described in Example 81B using (1-methyl-1H-indol-4-yl) methylamine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (br s, 1H), 9.24 (t, 1H), 8.4 (s, 1H), 8.25 (s, 1H), 7.92 (d, 1H), 7.7 (d, 1H), 7.38 (m, 3H), 7.18 (m, 1H), 7.0 (d, 1H), 6.6 (s, 1H), 4.7 (d, 2H) 3.8 (s, 3H). MS (ESI +) m / z 372 (M + H) ⁺ .

Example 363

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

The title compound was prepared according to the procedure described in Example 81B using 3-phenylpyrrolidine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (br s, 1H), 8.4 (m, 1H), 8.25 (s, 1H), 7.92 (d, 1H), 7.8 (d, 1H), 7.24 (m, 6H), 4.4 (m, 1H), 3.4 (m, 2H), 2.4 (m, 2H), 2.0 (m, 2H). MS (ESI +) m / z 359 (M + H) ⁺ .

Example 364

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

The title compound was prepared according to the procedure described in Example 81B using 2-phenylpyrrolidine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (br s, 1H), 8.4 (m, 1H), 8.25 (s, 1H), 7.92 (d, 1H), 7.8 (d, 1H), 7.24 (m, 6H), 5.6 (m, 0.3H), 5.2 (m, 0.7H), 4.0 (m, 2H), 1.8-2.0 (m, 4H). MS (ESI +) m / z 390 (M + H) ⁺ .

Example 365

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

The title compound was prepared according to the procedure described in Example 81B using 2-phenylpiperidine instead of piperidine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (br s, 1H), 8.4 (m, 1H), 8.25 (s, 1H), 7.92 (d, 1H), 7.8 (d, 1H), 7.24 (m, 6H), 5.6 (m, 0.3H), 5.2 (m, 0.7H), 4.0 (m, 2H), 1.8-2.0 (m, 6H). MS (ESI +) m / z 373 (M + H) ⁺ .

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) followed by the addition of HATU (60 mg, 0.16 mmol) dissolved in N, N-dimethylformamide (0.5 ml). Then, a solution of (S) -1-phenylethanamine (22 mg, 0.18 mmol) dissolved in N, N-dimethylformamide (0.6 ml) was added, followed by diisopropylethylamine (56 μl, 0.32 mmol) dissolved in N N-dimethylformamide (0.2 ml). The resulting mixture was shaken for 3 hours at 40 ° C. The reaction mixture was filtered, monitored by LC / MS and concentrated to dryness. Residues were dissolved in 1: 1 dimethyl sulfoxide / methanol and purified by reverse phase HPLC (Phenomenex® Luna® C8 (2) column 5 μm 100Å AXIA ™ (30 mm × 75 mm), 50 ml / min, 10-100% acetonitrile / 0.1% trifluoroacetic acid in water) to give the title product. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.50 (d, 3H), 5.06-5.22 (m, 1H), 7.23-7.29 (m, 2H), 7.34-7.38 (m, 2H), 7, 40-7.45 (m, 2H), 7.70-7.75 (m, 1H), 7.87-7.92 (m, 1H), 8.25-8.27 (m, 1H), 8.39-8.41 (m, 1H); 9.28 (d, 1H). MS (ESI +) m / z 333 (M + H) ⁺ ; (ESI-) m / z 331 (MH) ^- .

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 that (1R) -1- (4-methylphenyl) ethanamine was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.49 (d, 3H), 2.25-2.31 (m, 3H), 5.09-5.18 (m, 1H), 7.14-7.18 (m, 2H), 7, 23-7.24 (m, 1H), 7.28-7.32 (m, 2H), 7.70-7.75 (m, 1H), 7.86-7.92 (m, 1H), 8.22-8.29 (m, 1H); 8.37-8.42 (m, 1H); 9.19 (d, 1H). MS (ESI +) m / z 347 (M + H) ⁺ ; (ESI-) 345 (MH) ^- .

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 that (1S) -1- (4-methylphenyl) ethanamine was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.48 (d, 3H), 2.26-2.30 (m, 3H), 5.05-5.23 (m, 1H), 7.15-7.17 (m, 2H), 7, 22-7.25 (m, 1H), 7.28-7.32 (m, 2H), 7.67-7.79 (m, 1H), 7.86-7.93 (m, 1H), 8.22-8.30 (m, 1H), 8.38-8.41 (m, 1H), 9.21 (d, 1H). MS (ESI-) m / z 345 (MH) ^- .

Example 369

N - [(1R, 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 that (1R, 2S) -1-aminoindan-2-ol was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 2.89-2.96 (m, 1H), 3.13-3.21 (m, 1H), 4.55-4.61 (m, 1H), 5.40-5.47 (m, 1H) ), 7.21-7.34 (m, 4H), 7.39-7.42 (m, 1H), 7.72-7.77 (m, 1H), 7.91-7.95 (m , 1H), 8.25-8.29 (m, 1H), 8.42-8.45 (m, 1H). MS (ESI-) m / z 359 (MH) ^- .

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 that (1R, 2R) -1-aminoindan-2-ol was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 2.72-2.83 (m, 1H), 3.13-3.30 (m, 1H), 4.44-4.53 (m, 1H), 5.24-5.32 (m, 1H) ), 7.10-7.18 (m, 1H), 7.20-7.27 (m, 3H), 7.30-7.33 (m, 1H), 7.72-7.78 (m , 1H), 7.91-7.93 (m, 1H), 8.24-8.29 (m, 1H), 8.41-8.45 (m, 1H), 9.17 (d, 1H ) MS (ESI-) m / z 359 (MH) ^- .

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 that (1R) -1- (4-bromophenyl) ethanamine was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.50 (d, 3H), 5.08-5.18 (m, 1H), 7.21-7.27 (m, 1H), 7.36-7.41 (m, 2H), 7, 50-7.59 (m, 2H), 7.70-7.76 (m, 1H), 7.86-7.93 (m, 1H), 8.23-8.29 (m, 1H), 8.38-8.41 (m, 1H); 9.32 (d, 1H). MS (ESI +) m / z 411 (M + H) ⁺ .

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 that (lS) -1- (4-bromophenyl) ethanamine was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.49 (d, 3H), 5.09-5.19 (m, 1H), 7.23-7.25 (m, 1H), 7.37-7.40 (m, 2H), 7, 53-7.57 (m, 2H), 7.71-7.75 (m, 1H), 7.87-7.92 (m, 1H), 8.25-8.27 (m, 1H), 8.38-8.41 (m, 1H); 9.32 (d, 1H). MS (ESI) negative ion 409 (MH) ^- .

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 that (1R) -1- (4-chlorophenyl) ethanamine was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.50 (d, 3H), 5.10-5.21 (m, 1H), 7.22-7.26 (m, 1H), 7.38-7.47 (m, 4H), 7, 70-7.75 (m, 1H), 7.87-7.92 (m, 1H), 8.20-8.28 (m, 1H), 8.38-8.41 (m, 1H), 9.33 (d, 1H). MS (ESI-) m / z 365 (MH) ^- .

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 that (1S) -1- (4-chlorophenyl) ethanamine was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.49 (d, 3H), 5.12-5.19 (m, 1H), 7.23-7.25 (m, 1H), 7.39-7.47 (m, 4H), 7, 71-7.74 (m, 1H), 7.87-7.91 (m, 1H), 8.25-8.27 (m, 1H), 8.37-8.43 (m, 1H), 9.32 (d, 1H). MS (ESI-) m / z 365 (MH) ^- .

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 that (1S) -1- (2-naphthyl) ethanamine was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.61 (d, 3H), 5.30-5.38 (m, 1H), 7.25-7.26 (m, 1H), 7.48-7.55 (m, 2H), 7, 60-7.63 (m, 1H), 7.72-7.75 (m, 1H), 7.88-7.95 (m, 5H), 8.25-8.28 (m, 1H), 8.39-8.43 (m, 1H); 9.39 (d, 1H). MS (ESI-) m / z 381 (MH) ^- .

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 that 2-amino-2- (4-ethoxyphenyl) ethanol was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.32 (t, 3H), 3.62-3.67 (m, 1H), 3.70-3.73 (m, 1H), 3.96-4.06 (m, 2H), 4, 98-5.06 (m, 1H), 6.87-6.91 (m, 2H), 7.23-7.36 (m, 3H), 7.70-7.75 (m, 1H), 7.88-7.91 (m, 1H), 8.25-8.27 (m, 1H), 8.39-8.42 (m, 1H). MS (ESI-) m / z 391 (MH) ^- .

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 that 2-amino-2- (4-isopropylphenyl) ethanol was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.18 (d, 6H), 2.81-2.91 (m, 1H), 3.65-3.70 (m, 1H), 3.72-3.74 (m, 1H), 5, 01-5.09 (m, 1H), 7.20-7.28 (m, 3H), 7.29-7.35 (m, 2H), 7.72-7.80 (m, 1H), 7.87-7.95 (m, 1H), 8.24-8.29 (m, 1H), 8.38-8.44 (m, 1H). MS (ESI-) m / z 389 (MH) ^- .

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 that 2-amino-2- (3,4-dimethylphenyl) ethanol was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 2.30 (d, 6H), 3.56-3.63 (m, 1H), 3.65-3.73 (m, 1H), 5.32-5.42 (m, 1H), 7, 06-7.08 (m, 2H), 7.23-7.28 (m, 2H), 7.69-7.76 (m, 1H), 7.87-7.95 (m, 1H), 8.25-8.28 (m, 1H); 8.39-8.43 (m, 1H). MS (ESI-) m / z 375 (MH) ^- .

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 that 2-amino-2- (2-methoxyphenyl) ethanol was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 3.60-3.66 (m, 2H), 3.84-3.88 (m, 3H), 5.37-5.48 (m, 1H), 6.95 (t, 1H), 7, 00-7.06 (m, 1H), 7.24-7.31 (m, 2H), 7.32-7.36 (m, 1H), 7.71-7.77 (m, 1H), 7.85-7.97 (m, 1H), 8.24-8.28 (m, 1H), 8.40-8.45 (m, 1H). MS (ESI +) m / z 379 (M + H) ⁺ ; negative ion 377 (MH) ^- .

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 that 2-amino-2- (4-methylphenyl) ethanol was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 2.26-2.32 (m, 3H), 3.65-3.70 (m, 1H), 3.72-3.75 (m, 1H), 5.01-5.08 (m, 1H) ), 7.10-7.21 (m, 2H), 7.25-7.35 (m, 3H), 7.70-7.77 (m, 1H), 7.86-7.95 (m , 1H), 8.26-8.28 (m, 1H), 8.39-8.46 (m, 1H). MS (ESI +) m / z 363 (M + H) ⁺ ; (ESI-) m / z 361 (MH) ^- .

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 that (1R) -1- (2-methoxyphenyl) ethanamine was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.43 (d, 3H), 3.82-3.86 (m, 3H), 5.41-5.50 (m, 1H), 6.95 (t, 1H), 7.00-7, 05 (m, 1H), 7.23-7.29 (m, 2H), 7.35-7.39 (m, 1H), 7.71-7.76 (m, 1H), 7.88- 7.92 (m, 1H), 8.25-8.27 (m, 1H), 8.37-8.43 (m, 1H). MS (ESI +) m / z 363 (M + H) ⁺ ; (ESI-) m / z 361 (MH) ^- .

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 that (1S) -1- (3,4-difluorophenyl) ethanamine was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.50 (d, 3H), 5.09-5.24 (m, 1H), 7.21-7.30 (m, 2H), 7.35-7.44 (m, 1H), 7, 44-7.53 (m, 1H), 7.68-7.82 (m, 1H), 7.86-7.94 (m, 1H), 8.26-8.27 (m, 1H), 8.39-8.42 (m, 1H). MS (ESI-) m / z 367 (MH) ^- .

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 that (1R) -1- (3-methoxyphenyl) ethanamine was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.50 (d, 3H), 3.75-3.77 (m, 3H), 5.01-5.19 (m, 1H), 6.80-6.87 (m, 1H), 6, 97-7.02 (m, 2H), 7.21-7.32 (m, 2H), 7.70-7.75 (m, 1H), 7.87-7.95 (m, 1H), 8.22-8.31 (m, 1H); 8.37-8.43 (m, 1H). MS (ESI-) m / z 361 (MH) ^- .

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 that (1R) -1- [3- (trifluoromethyl) phenyl] ethanamine was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.54 (d, 3H), 5.22-5.29 (m, 1H), 7.23-7.27 (m, 1H), 7.58-7.69 (m, 2H), 7, 71-7.75 (m, 2H), 7.77-7.83 (m, 1H), 7.87-7.92 (m, 1H), 8.24-8.29 (m, 1H), 8.38-8.42 (m, 1H). MS (ESI-) m / z 399 (MH) ^- .

Example 385

N- [1- (2,3-dihydro-1,4-benzodioxin-6-yl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide

The title compound was prepared using the procedure described in Example 366, except that 1- (2,3-dihydro-1,4-benzodioxin-6-yl) ethanamine was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 1.46 (d, 3H), 4.18-4.25 (m, 4H), 5.01-5.10 (m, 1H), 6.80-6.95 (m, 3H), 7, 22-7.24 (m, 1H), 7.70-7.74 (m, 1H), 7.87-7.91 (m, 1H), 8.26-8.27 (m, 1H), 8.39-8.41 (m, 1H). MS (ESI-) m / z 389 (MH) ^- .

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 that 2-amino-2- (3,5-dichlorophenyl) ethanol was used instead of (S) -1-phenylethanamine. ¹ H NMR (500 MHz, DMSO-d ₆ / D ₂ O) δ ppm 3.68-3.72 (m, 1H), 3.76-3.78 (m, 1H), 5.02-5.10 (m, 1H), 7.26-7.29 (m, 1H) ), 7.47-7.52 (m, 3H), 7.72-7.75 (m, 1H), 7.89-7.93 (m, 1H), 8.25-8.28 (m , 1H), 8.39-8.44 (m, 1H). MS (ESI-) m / z 415 (MH) ^- .

Example 387

tert-butyl 5- (1-benzyl-1H-1,2,3-triazol-4-yl) -3 - [({[[6- (trifluoromethyl) pyridin-2-yl] amino} carbonyl) amino] -1H indazole-1-carboxylate

A solution of triphosgene in dichloromethane was cooled to 0 ° C in a nitrogen atmosphere. A mixture of triethylamine (0.426 ml, 3.07 mmol) and the compound of Example 64A (150 mg, 0.384 mmol) in dichloromethane (2 ml) was then slowly added dropwise. The resulting mixture was stirred at room temperature for 1 hour. Then 6- (trifluoromethyl) pyridin-2-amine (62.3 mg, 0.384 mmol) was added, followed by stirring overnight at room temperature. The precipitate was filtered off and washed with dichloromethane and water. The product was dried in vacuo to give the title compound. MS m / z 579.3 (M + Η) ⁺ .

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 with a mixture of dimethylformamide and dichloromethane in a nitrogen atmosphere and stirred for 15 minutes. Then carbonyldiimidazole was added portionwise. The resulting solution was stirred at room temperature for 1 hour. Then, the compound of Example 62 was added, followed by stirring at 60 ° C for 2 hours and then at room temperature overnight. The reaction mixture was poured into ice water and brine was added. The cooled solution was decanted and the residue was taken up in dichloromethane and washed with water (2 ×). The organic layer was dried with magnesium sulfate and the volatiles were removed under reduced pressure. The decanted solution was extracted with ethyl acetate (3 ×). The combined organic layers were washed with brine (2 ×), dried with 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 obtain the title compound. MS m / z 579.3 (M + Η) ⁺ .

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 in a nitrogen atmosphere at room temperature for 15 minutes. Carbonyldiimidazole was added portionwise. The resulting mixture was stirred at room temperature for 1 hour. Then, the compound of Example 62 was added and the mixture was stirred overnight at room temperature. Volatile material was removed under reduced pressure and the residue was added to ice water. Sodium chloride was added and thick oil precipitated from the cooled solution. The solution was decanted. The residue was washed with water (3 ×) and then dried. From the decanted solution, a precipitate was separated from the water / dimethylformamide mixture overnight. It turned out that this is the starting material, which was filtered and drained. The residue containing the product was crystallized in dichloromethane, collected by filtration, washed with a small amount of dichloromethane and ether. The product was dried to give the title compound. MS m / z 376.3 (M + Η) ⁺ .

Example 390

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

Example 62 was suspended in dichloromethane together with a catalytic amount of dimethylaminopyridine. A solution of di-tert-butyl dicarbonate in dichloromethane (160 ml) was added over 1 hour. The reaction mixture was stirred for approximately 40 hours. Silica gel was added and the mixture was concentrated. This silica-containing mixture was added to a silica gel column and the material was eluted first with dichloromethane and then with 1% methanol / dichloromethane and finally with 2% methanol / dichloromethane. Fractions containing the desired product were combined and concentrated to give the title compound. MS m / z 391.3 (M + Η) ⁺ .

Example 391

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

2- (piperidin-1-yl) acetic acid was combined with dimethylformamide and pyridine. The mixture was stirred for 15 minutes at room temperature and then carbonyldiimidazole was added portionwise. Stirring was continued at room temperature for 1 hour, and then the compound of Example 64A was added, while stirring was continued for 24 hours. The reaction mixture was heated to 60 ° C for 14 hours. A small amount of the title compound was obtained. MS m / z 416.3 (M + Η) ⁺ .

Example 392

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

2-Morpholinoacetic acid was combined with dimethylformamide and pyridine. The mixture was stirred for 15 minutes at room temperature, then carbonyldiimidazole was added portionwise. Stirring was continued at room temperature for 1 hour, and then the compound of Example 64A was added, while stirring was continued for 28 hours. The reaction mixture was heated to 60 ° C for 4 hours and then stirring was continued overnight at room temperature. The reaction mixture was again heated to 60 ° C for 7 hours. A small amount of the title compound was obtained. MS m / z 418.3 (M + Η) ⁺ .

Example 393

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

1-Methylpiperidin-3-carboxylic acid hydrochloride was combined with dimethylformamide and pyridine. The mixture was stirred for 15 minutes at room temperature and then carbonyldiimidazole was added portionwise. Stirring was continued at room temperature for 1 hour, and then the compound of Example 64A was added, while stirring was continued for 28 hours. The reaction mixture was heated to 60 ° C for 4.25 hours and then stirring was continued overnight at room temperature. The reaction mixture was again heated 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 Inhibition Assay

The compounds of formula (I) were tested for their ability to inhibit His6-N-terminally recombinant human ROCK-2, residues 11-552, expressed by baculovirus in Sf21 cells (Upstate). In 384-well V-bottomed polypropylene plates (Axygen) 1 nM (final concentration) in 10 μl of recombinant His6-N-terminal recombinant human ROCK-2, residues 11-552 expressed by baculovirus in Sf21 cells (Upstate ), mixed with 2 μM (final concentration) in 10 μl of biotinylated peptide substrate (Biotin-Aha-KEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK (SEQ ID NO: I)) (Genemed) and various inhibitor concentrations (2% DMSO final concentration) in reaction buffer (25 HEPES, pH 7.5, 0.5 mM DTT, 10 mM MgCl _2, 100 mM Na ₃ VO _4, 0.075 mg / ml Triton X-100), and the reaction initsiirova and by the addition of 5 uM unlabelled ATP containing 0.01 uCi ^[33 P] -ATP (Perkin Elmer). The reaction was quenched after 1 hour by adding 50 μl of a stop buffer (50 mm EDTA, 2M NaCl final concentration). After stopping the reaction, 80 μl of the reaction mixtures were transferred to 384-well streptavidin-coated FlashPlates (Perkin Elmer) plates, incubated for 10 minutes at room temperature, washed 3 times with 0.05% Tween-20 / PBS using an automatic device washing the ELX-405 plates (BioTek) and counting using a TopCount plate scintillation reader (Packard).

ROCK-1 Inhibition Assay

The compounds of formula (I) were tested for their ability to inhibit His6-N-terminally recombinant human ROCK-1, amino acids 17-535, expressed by baculovirus in Sf21 cells (Upstate). In 384-well V-bottomed polypropylene plates (Axygen) 2 nM (final concentration) in 10 μl of recombinant His6-N-terminal recombinant human ROCK-1, amino acids 17-535 expressed by baculovirus in Sf21 cells (Upstate ) were mixed with 2 μM (final concentration) of biotinylated peptide substrate (Biotin-Aha-VRRLRRLTAREAA (SEQ ID NO: 2)) (Genemed) and various inhibitor concentrations (2% DMSO final concentration) in 10 μl of reaction buffer (25 mM HEPES , pH 7.5, 0.5 mm DTT, 10 mm MgCl ₂ , 100 μm Na ₃ VO ₄ , 0.075 mg / ml Triton X-100) and the reaction was initiated by put add 5 µM unlabeled ATP containing 0.01 µCi [ ³³ P] -ATP (Perkin Elmer). The reaction was quenched after 1 hour by adding 50 μl of a stop buffer (50 mm EDTA, 2M NaCl final concentration). After stopping the reaction, 80 μl of the reaction mixtures were transferred to 384-well streptavidin-coated FlashPlates (Perkin Elmer) plates, incubated for 10 minutes at room temperature, washed 3 times with 0.05% Tween-20 / PBS using an automatic device washing the ELX-405 plates (BioTek) and counting using a TopCount plate scintillation reader (Packard).

GSK Inhibition Assay

The compounds of formula (I) were tested for their ability to inhibit His6 N-terminal GSK-3 expressed by baculovirus in Sf21 cells (Upstate). In 384-well v-shaped polypropylene plates (Axygen), 10 μl of N-terminal recombinant His-labeled GSK3 expressed by baculovirus in Sf21 cells (Upstate) was mixed with 10 μl of biotinylated peptide substrate (biotin-ahx-YRRAAVPHPSPSSR p) EDEEE (SEQ ID NO: 3)), 2 μM final concentration (Genemed), and various inhibitor concentrations (2% DMSO final concentration) in the reaction buffer (20 mM HEPES, pH 7.5, 1 mM DTT, 10 mM MgCl ₂ 100 μM Na ₃ VO ₄ , 0.075 mg / ml Triton X-100) and the reaction was initiated by adding 20 μM [ ³³ P] -ATP, 5 μM final concentration, 2 mCi / μmol (Perkin Elm er). The reaction was quenched after 1 hour by adding 50 μl of a stop buffer (50 mm EDTA, 2M NaCl final concentration). After stopping the reaction, 80 μl of the reaction mixtures were transferred to 384-well streptavidin-coated FlashPlates (Perkin Elmer) plates, incubated for 10 minutes at room temperature, washed 3 times with 0.05% Tween-20 / PBS using an automatic device washing the ELX-405 plates (BioTek) and counting using a TopCount plate scintillation reader (Packard).

Human GSK-3β Inhibition Assay

The compounds were tested for their ability to inhibit human glycogen synthase kinase-3 beta (hGSK-3β) as regards its ability to phosphorylate biotin-YRRAAVPPSPSLSRHSSPHQ (pS) EDEEE. Compounds were incubated with 0.5 μCi ³³ P-ATP, 10 μM ATP, 0.0125U hGSK-3β (solutions for determining cell signal activity from Upstate) and 1 μM substrate (Biotin-YRRAAVPPSPSLSRHSSPHQ (pS) EDEEE (SEQ ID NO: 3 )) in 50 mM HEPES, 10 mM MgCl ₂ , 100 μM Na ₃ VO ₄ , 1 mM DTT, 0.0075% Triton, 2% DMSO (total volume 50 μl) for 30 minutes at room temperature. The incubation was stopped by adding an equal volume of 100 mm EDTA, 4 M NaCl ₂ . 80 μl of this mixture was added to streptavidin-coated FlashPlates plates (PerkinElmer). After the washing step, the ³³ P inclusion was determined using a MicroBeta liquid microplate scintillation counter (PerkinElmer). IR ₅₀ values were determined by fitting the sigmoidal dose-response curve to the count at various concentrations in GraphPad Prism.

Human GSK-3α Inhibition Assay

The compounds were tested for their ability to inhibit human glycogen synthase kinase-3 alpha (hGSK-3α), 0.5 nM final concentration, with respect to phosphorylation of biotin-YRRAAVPPSPSLSRHSSPHQ (pS) EDEEE (SEQ ID NO: 3). Compounds were incubated with 0.5 Ci ³³ P-ATP, 10 M ATP, 0.0125U hGSK-3 (solutions for determining cellular signal activity from Upstate) and 2 μM substrate (biotin-YRRAAVPPSPSLSRHSSPHQ (pS) EDEEE) in 50 mM HEPES, 10 mM MgCl ₂ , 100 μM Na ₃ VO ₄ , 1 mM DTT, 0.0075% Triton, 2% DMSO (total volume 50 μl) for 30 minutes at room temperature. Incubation was stopped by adding an equal volume of 100 mM EDTA, 4M NaCl ₂ . 80 μl of this mixture was added to streptavidin-coated FlashPlates plates (PerkinElmer). After the washing step, ³³ P incorporation was determined using a liquid microplate scintillation counter (PerkinElmer). IR ₅₀ values were determined by fitting the sigmoidal dose-response curve to the number of pulses at various concentrations in GraphPad Prism.

JAK2 Inhibition Assay

Jak2 kinase activity was determined using a homogeneous, time-resolved, in vitro fluorescence (HTRF) kinase assay (Mathis, G., HTRF (R) Technology. J Biomol Screen, 1999.4 (6): p. 309- 314). Specifically, 10 μl of His6-labeled C-terminus recombinant human JAK2, the 808-amino acid expressed by baculovirus in Sf21 cells (Upstate), was mixed with 10 μl of inhibitor (various concentrations, final concentration of DMSO 2%) and 10 μl of ATP ( 5 μM final concentration) in the reaction buffer (50 mM HEPES, pH 7.5, 10 mM MgCl ₂ , 2 mM MnCl ₂ , 0.1% BSA and 1 mM DTT, final volume 40 μl). The reaction mixture was initiated by adding 10 μl of Bio-PDK peptides (Biotin-Ahx-KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC (SEQ ID NO: 4), final concentration 0.5 μM) in a 384 black well plate (Packard). After 60 minutes of incubation at room temperature, the reaction was quenched by adding 60 μl of stop / developing buffer to obtain 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 BCF, 0.005% Tween-20, 0.05% BSA). The quenched reaction mixture was allowed to stand at room temperature for 1 hour and then read in a time resolution fluorescence detector (Envision, Perkin Elmer) at 615 nm and 665 nm simultaneously. The ratio between the 615 nm and 665 nm signals was used to calculate the IR ₅₀ value.

Methods - Analysis of β-catenin reporter gene

Compounds were tested for their ability to modulate β-catenin-modulated gene transcription in a LEF / TCF (T cell factor) reporter gene assay. Human neuroblastoma cells SY-SY5Y were unstably transfected with 80 ng / well of TOPFLASH plasmid (Upstate cell signaling solutions) containing two sets of three copies of the TCF binding site upstream of the thymidine kinase minimal promoter and an open moth luciferase reading frame or using 80 ng / well of the FOPFLASH plasmid (Upstate cell signaling solutions) containing three copies of the mutated TCF binding site upstream of thymidine kinases of the minimal promoter and an open reading frame moth luciferase. In addition, all cells were unstably transfected with a 20 ng / well pRL-TK plasmid (Promega) containing the herpes simplex virus thymidine kinase promoter to ensure low to medium Renilla luciferase expression levels. The transfection medium was replaced with a serum-free medium containing the test substance and incubated for 24 hours at 37 ^° C. The incubation was stopped and quantification was performed using a Dual Glo Luciferase Assay (Promega) assay as indicated, and a Pherastar reader was used for counting ( BMG).

Moth luciferase activity was normalized to Renilla luciferase activity per well. Then, the normalized TOPFLASH response was compared with the normalized FOPFLASH response, thereby obtaining a specific LEF / TCF signal. The maximum response is the maximum ratio between the normalized TOPFLASH and FOPFLASH signals. Sigmoidal dose-response curves were constructed using Graphpad Prism.

A mouse model of acute asthma

Female Balb / c mice were purchased from Taconic and placed in the Abbott Bioresearch Center. Animals were used at the age of 8-12 weeks. All protocols have been approved by the Institutional Animal Care and Use Committee (IACUC). Dexamethasone (Dex) and ovalbumin (OVA) were purchased from Sigma. Endotoxin was removed from ovalbumin using DetoxiGel (Pierce), according to the manufacturer's protocol, and the final substance contained less than 0.1 EU / mg protein. Alum Imject was purchased from Pierce.

Animals were sensitized to OVA on days 0 and 7 by intraperitoneal injection of 8 μg OVA in 2 mg alum. On days 14 and 16, animals received intranasal stimulation of 0.3 μg OVA in 50 μl of sterile PBS. The animals were administered intraperitoneally a representative compound of formula (I) (dissolved with 0.5% HMPC, 0.02% Tween 80 in water) twice a day at doses of 3, 10 and 30 mg / kg / dose, starting on day 13 daily time. The final dose of the compound was administered 30 minutes before the measurement of airway hyperresponsiveness (AHR). Dexamethasone was administered orally once a day on days 13-17 at a dose of 3 mg / kg. All end results were analyzed on day 17 24 hours after the second OVA stimulation. AHR was analyzed using whole body plethysmography of unconscious immobilized animals. Briefly, a surgical level of anesthesia was provided by intraperitoneal injection of ketamine and xylazine. A tracheal cannula was inserted surgically between the third and fourth tracheal rings. Spontaneous breathing was prevented by intravenous (iv) injection of pancuronium bromide into the jugular vein. The animals were placed in a plethysmograph to study the whole organism (Buxco) and artificial lung ventilation was performed with 0.2 ml of room air at 150 breaths per minute using a controlled volume automatic breathing apparatus (Harvard Apparatus). The pressure in the lung and the flow in the plethysmograph were measured using sensors and the resistance of the lungs was calculated as the pressure / flow ratio using the Biosystem Xa program. The resistance was measured on the baseline, as well as the resistance after stimulation with methacholine (3, 10 or 30 mg / ml), the delivery of which was carried out using the in-line ultrasonic inhaler. After completing a lung function test, the lungs were washed 4 times with 0.5 ml sterile PBS. Wash fluid was analyzed for IL-13, AMCase, Muc5ac, and cell infiltrates. The effectiveness of the test compound was tested at doses of 3, 10 and 30 mg / kg bid (6, 20, 60 mg / kg / day). OVA stimulation caused an increase in lung resistance to 6.90 cm H ₂ O / ml / s versus 4.65 cm H ₂ O / ml / s in animals stimulated with PBS. Treatment of mice with the test compound significantly inhibited (p <0.001) methacholine-induced airway resistance up to 4.55 cm H ₂ O / ml / s and 4.77 cm H ₂ O / ml / s at doses ranging from 1 to 100 mg / kg Preferred compounds require a dose of less than 50 mg / kg for the manifestation of this response. For the most preferred compounds, a dose of less than 30 mg / kg is required for the manifestation of this response. This inhibition was equivalent to the measurements obtained in the group with PBS stimulation (4.65 cm H ₂ O / ml / s) and in the treatment group 3 mg / kg dexamethasone (4.76 cm H ₂ O / ml / s).

Measurement of IL-13: IL-13 concentrations in the bronchoalveolar wash fluid (BAL) were measured using an ELISA assay (R & D Systems), in accordance with the manufacturer's instructions. Concentrations of IL-13 in BAL fluid were significantly induced up to 102.5 pg / ml in OVA-stimulated mice compared to a level lower than that determined in the PBS-stimulated group. Significant inhibition of this induction (p <0.05) by 60% was observed after administration of the test compounds at a dose of 30 mg / kg. There was no noticeable inhibition in the dose groups of 3 mg / kg or 10 mg / kg.

AMCase measurement: mammalian acid chitinase activity (AMCase) was determined at 1:10 dilution of BAL fluid with 0.01% BSA, 30 mM sodium citrate, 60 mM sodium phosphate, pH 5.2, in the presence of 80 μM 4-methylumbelliferyl β-DN , N'-diacetylchitobioside. The reaction mixtures were incubated for 15 minutes at room temperature and the reactions were quenched by adding 100 μl of 1 M glycine / NaOH pH 10.6. Product formation was determined by fluorescence emission at 460 nm with excitation at 385 nm using a Fluorskan Ascent fluorometer. Induction of AMCase activity up to 28.5U was observed in OVA-stimulated animals, compared to 2.17U in PBS-stimulated animals. Significant inhibition of this induction (p <0.01) by 35% was observed after administration of the test compounds in the dose administration group of 30 mg / kg.

MUC5AC Measurement: MUC5AC mucin gene concentrations were determined in an ELISA assay format. Briefly, BAL samples were diluted 1: 2 in buffer (2% BSA in PBS) and plated in 96-well high protein binding plates (Costar) and dried. After a series of washes for 1 hour, a 1: 100 dilution of biotinylated MUC5AC antibody (Clone 45M, Lab Vision) was added. The plates were washed and 1: 3000 dilution of streptavidin-HRP (Southern Biotech) was added to the plate for 15 minutes. The tablets were then developed using TMB substrate (Sigma) for 30 minutes. The reaction was stopped using 1M H ₂ SO ₄ and then the tablets were read in a spectrophotometer at OD 450 nm. MUC5AC levels decreased by more than 50% after administration of test compounds.

Determination of the Antinociceptive Effect: Neuropathic Pain Models

Model of neuropathic pain caused by ligation of the spinal nerve (L5 / L6). As previously described in detail by Kim and Chung (Kim SH; Chung JM An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992, 50, 355-363), a 1.5 cm incision was made dorsally to the lumbosacral plexus . In anesthetized rats, the paraspinal muscles (on the left side) were separated from the spinous processes, L5 and L6 spinal nerves were isolated and tightly ligated with 3-0 silk threads. After hemostasis, the wound was sutured and smeared with an antibiotic-based ointment. Rats were allowed to recover and were then placed in a cage with soft litter for 14 days before the mechanical allodynia behavior test.

A model of neuropathic pain caused by ligation of the sciatic nerve. As described previously in detail by 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), the anesthetized rats were cut 1.5 cm 0.5 cm below the pelvic area and released the femoral biceps and gluteus external muscles (right side). The sciatic nerve was exposed, isolated and four loose ligatures (5-0 chromium catgut) were placed around it with a separation of 1 mm. The rats were allowed to recover and were then placed in a soft-litter cage for 14 days before the mechanical allodynia behavior test, as described above. In addition, animals were also tested for cold allodynia by dipping their hind paw in a bath of cold water (4.5 ° C) and determining the latency of the paw withdrawal.

Selected analogs of the compounds of formula (I), which were administered either intraperitoneally or orally, showed more than 30% inhibition of tactile allodynia in the Chung and Bennett neuropathic pain models described herein at doses ranging from 1-150 mg / kg.

Summarizing the above, a representative compound of formula (I) in a mouse model of acute asthma was effective in inhibiting airway resistance at a dose in the range of 1 to 100 mg / kg. High dose treatment (30 mg / kg) also inhibited IL-13 induction, as well as AMCase activity and MUC5AC levels in BAL fluid.

Representative compounds of formula (I) in rat models of neuropathic pain were effective, as demonstrated by more than 30% inhibition of tactile allodynia at doses ranging from 1-150 mg / kg.

The compounds of formula (I) were found to inhibit human ROCK-2, His-labeled at the N-terminus of GSK-3β, human GSK-3β, His6-labeled recombinant human JAK2 and moth luciferase, showing an IC ₅₀ value of from about 1, 0 μM to about 10 μM, preferably from about 100 nM to about 1.0 μM. More preferably, the compounds of formula (I) were found to inhibit human ROCK-2, His-N-labeled GSK-3β, human GSK-3β, His6-labeled, recombinant human JAK2 and moth luciferase, showing an IC ₅₀ value from about 10 nM to about 100 nM and, most preferably, less than 10 nM. In addition, some compounds of formula (I) demonstrated inhibition of human ROCK-2 with a selectivity of more than 10 times greater than a panel of 50 kinase targets. Some compounds of formula (I) demonstrated inhibition of human GSK-3β with a selectivity of more than 10 times greater than a panel of 50 kinase targets. Some compounds of formula (I) demonstrated inhibition of His6-labeled recombinant human JAK2 with a selectivity of more than 10 times that of a panel of 50 kinase targets.

Administration Methods

The present invention also provides pharmaceutical compositions that include the compounds of the present invention. Pharmaceutical compositions include the compounds of the present invention formulated with one or more non-toxic pharmaceutically acceptable carriers.

The pharmaceutical compositions of the present invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, topically (for example, in the form of powders, ointments or drops), buccally or as an oral or nasal spray. The term “parenteral” as used herein refers to methods of administration that include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

The term "pharmaceutically acceptable carrier", as used herein, means a non-toxic inert solid, semi-solid or liquid excipient, diluent, encapsulating substance or excipient for any type of formulation. Some examples of substances that can serve as pharmaceutically acceptable carriers include sugars, such as, but not limited to, lactose, glucose, and sucrose; starches, 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; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethyl alcohol and phosphate buffered saline, as well as other non-toxic compatible lubricants, such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, perfumes and fragrances, preservatives and antioxidants may also be present at the discretion of the person making the composition.

The pharmaceutical compositions of the present invention for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use. Examples of suitable aqueous and non-aqueous vehicles, diluents, solvents or excipients include water, ethanol, polyols (such as glycerin, propylene glycol, polyethylene glycols and the like), vegetable oils (such as olive oil), organic esters for injection (such as ethyl oleate) and suitable mixtures of such substances. Suitable fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size, in the case of dispersions, and by using surfactants.

These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersing agents. Prevention of the action of microorganisms can be achieved by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenolsorbic acid and the like. It may also be desirable to include isotonic substances such as sugars, sodium chloride and the like. Prolonged absorption of the pharmaceutical preparation for injection can be achieved by the inclusion of substances that slow down absorption, such as aluminum monostearate and gelatin.

In some cases, to prolong the action of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be done by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. The absorption rate of the drug will then depend on its dissolution rate, which, in turn, may depend on the size of the crystals and crystalline form. Alternatively, delayed absorption of a parenterally administered dosage form is provided by dissolving or suspending the drug in an oil vehicle.

Depot preparations for injection are prepared by forming microencapsulating drug matrices 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 release of the drug can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot drugs for injection are also obtained by capturing the drug in liposomes or microemulsions that are compatible with body tissues.

Compositions for injection can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or another sterile medium for injection immediately before use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable carrier or excipient, such as sodium citrate or dicalcium phosphate and / or a) excipients or bulking agents such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; c) humectants, such as glycerin; d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) 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 include buffering agents.

Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using carriers such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

Solid dosage forms, such as tablets, dragees, capsules, pills and granules, can be prepared with coatings and coatings, such as enteric coatings and other coatings well known in the art of formulating pharmaceutical compositions. They may optionally contain substances that make the drug opaque, and may also have a composition that allows them to release the active ingredient (s) only, or predominantly, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of fillable compositions that can be used include polymeric substances and waxes.

The active compounds may also be in microencapsulated form, if appropriate, with one or more of the above carriers.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents traditionally used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular cottonseed oil, peanut oil, corn oil, oilseed oil, olive oil, castor oil and kun utnoe oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures of such materials.

In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, perfumes and flavorings.

Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and esters of sorbitan, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures of such substances.

Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating carriers or excipients, such as cocoa butter, polyethylene glycol or suppository wax, which are solid at room temperature but liquid at body temperature, and therefore melt in the rectum or vagina and release the active compound.

The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are typically derived from phospholipids or other lipid substances. Liposomes are formed from single or multilayer hydrated liquid crystals that are 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 the form of liposomes 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 phosphatidylcholines (lecithins), which are used individually or together.

Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of the compounds of the present invention include powders, sprays, ointments, and inhalation preparations. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers or propellants that may be required. Formulations for administration to the eye, ophthalmic ointments, powders and solutions are also contemplated as being within the scope of the present invention.

Actual dose levels of the active ingredients in the pharmaceutical compositions of the present invention may vary so as to obtain an amount of the active compound (s) that is effective to achieve the desired therapeutic response for a particular patient, compositions and route of administration. The choice of dose level will depend on the activity of the particular compound, the route of administration, the severity of the condition to be treated, and the condition and previous medical history of the patient to be treated.

When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention can be used in pure form when such forms exist, 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, with a reasonable benefit / risk ratio applicable to any medical treatment. However, it should be understood that the total daily dose of the compounds and compositions of the present invention depends on the opinion of the attending physician, within the framework of sound medical practice. The specific level of therapeutically effective dose for any given patient will depend on many factors, including the disorder to be treated and the severity of the disorder; the activity of the particular compound used; specific composition used; age, body weight, general health, gender and diet of the patient; time of administration, route of administration and rate of excretion of the particular compound used from the body; duration of treatment; drugs used in combination with or at the same time as the specific compound to be used; and similar factors well known in medicine.

The term "pharmaceutically acceptable salt", as used in this application, means salts derived from inorganic or organic acids. Salts can be obtained in situ during the final isolation and purification of compounds of formula (I), or they can be prepared separately by reacting the free base form of the compound of formula (I) with an inorganic or organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanohydrochloride, hexanohydrochloride, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, fumarate, methanesulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, sulfate (D) tartrate, (DL) tartre t, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate.

The term “pharmaceutically acceptable prodrug” or “prodrug” as used herein represents prodrugs of the compounds of the present invention which, according to a sound medical assessment, are suitable for use in contact with human and lower animal tissues, without excessive toxicity, irritation, allergic reactions, etc. The prodrugs of the present invention can be rapidly converted in vivo to compounds of formula (I), for example, by hydrolysis in the blood.

The present invention provides compounds of formula (I) formed synthetically or formed by in vivo bioconversion.

The compounds of the present invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemihydrates. Typically, solvated forms with pharmaceutically acceptable solvents such as water and ethanol, among others, are equivalent to unsolvated forms for the purposes of the present invention.

The total daily dose of the compounds of the present invention for administration to humans or lower animals may range from about 0.003 to about 30 mg / kg / day. For oral administration, more preferred doses may range from about 0.01 to about 10 mg / kg / day. If desired, the effective daily dose may be divided into several doses for administration purposes; therefore, compositions containing a single dose may contain such amounts or fractional parts of this dose that make up the daily dose.

Protein kinases can be divided into broad groups based on the identity of the amino acid (s) they are targeting (serine / threonine, tyrosine, lysine and histidine). For example, tyrosine kinases include receptor tyrosine kinases (RTK), such as growth factors, and non-receptor tyrosine kinases, such as the src kinase family. There are also dual specificity protein kinases that target both tyrosine and serine / threonine, such as cyclin-dependent kinases (CDKs) and mitogen-activated protein kinases (MAPKs).

Tyrosine protein kinases (PTKs) form a large family of kinases that regulate cell-to-cell signaling that are involved in growth, differentiation, adhesion, motility, and death (Pearson, M. et al., In Protein Tyrosine Kinases; Fabbro, D., McCormick, F., Eds .; Humana Press Inc., 2006; pp 1-29.). Members of the tyrosine kinase family include, but are not limited to, Yes, BMX, Syk, EphA1, FGFR3, RYK, MUSK, JAK1, and EGFR. Tyrosine kinases are divided into two classes, namely, receptor-type and non-receptor-type tyrosine kinases. Interestingly, the entire family of tyrosine kinases consists of at least 90 characterized kinases, of which at least 58 receptor type kinases and at least 32 non-receptor kinases, and includes at least a total of 30 subfamilies. Tyrosine kinases are associated with various 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 involved in most forms of human malignant diseases and are associated with a wide range of different congenital syndromes (Robertson et al., Trends Genet. 16: 265-271, 2000). Non-receptor tyrosine kinases represent a group of intracellular enzymes that do not have extracellular and transmembrane sequences. Currently, more than 32 families of non-receptor tyrosine kinases have been identified (Robinson et al., Oncogene 19, 5548-5557, 2000). Representative examples include Src, Btk, Csk, ZAP70 and Kak families. In particular, the Src family is the largest non-receptor tyrosine kinase family consisting of Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk tyrosine protein kinases. The Src kinase family is associated with oncogenesis, cell proliferation, and tumor progression. It has been found that many of the tyrosine protein kinases are involved in cellular signaling pathways that are associated with various pathological conditions, including, but not limited to, cancer and hyperproliferative disorders and immune disorders.

CDK cyclin-dependent kinases represent a group of intracellular enzymes that control passage through the cell cycle and play a significant role in cell proliferation (Cohen, P. Nature Reviews Drug Discovery 1, 309-315, 2002). Representative examples of CDK include, but are not limited to, cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 7 (CDK7), cyclin-dependent kinase 6 (CDK6), and cell division control protein 2 (CDC2). CDKs are involved in the regulation of transitions between different phases of the cell cycle, for example, the transition from the resting stage in G1 (the interval between mitosis and the beginning of DNA replication for a new cell division cycle) to phase S (the period of active DNA synthesis) or the transition from G2 to phase M, in which active mitosis and cell division occurs (Rowell et al. Critical Reviews in Immunology 26 (3), 189-212, 2006). CDK complexes are formed through the association of a regulatory cyclin subunit (e.g., cyclin A, B1, B2, D1, D2, D3, and E) and a catalytic kinase subunit (e.g., cdc2 (CDK1), CDK2, CDK4, CDK5, and CDK6). CDKs demonstrate absolute dependence on the cyclin subunit to phosphorylate their substrates that they are targeting, and various kinase / cyclin pairs have the function of regulating movement through specific parts of the cell cycle. In addition, CDKs are involved in various disease states, including, but not limited to, those showing a cancer phenotype, various tumor disorders, and neurological disorders (Pallas et al. Current Medicinal Chemistry: Central Nervous System Agents 5 (2), 101- 109, 2005).

Mitogen-activated protein kinases (MAPs) are involved in signal transduction to the cell nucleus in response to extracellular stimuli. Representative examples of MAP kinases include, but are not limited to, mitogen-activated protein kinase 3 (MAPK3), mitogen-activated protein kinase 1 (MAPK7), mitogen-activated protein kinase 8 (JNK1), mitogen-activated protein kinase kinase 10 (p kinase kinase 14) (p. (MAPK 10), JNK3 alpha protein kinase, stress-activated protein kinase JNK2 and mitogen-activated protein kinase 14 (MAPK14). MAP kinases are a family of proline directed serine / threonine kinases that mediate signal transduction from extracellular receptors or heat shock or UV radiation (Barr et al., Trends in Pharmacological Sciences 27 (10), 525-530, 2006). MAP kinases are activated through phosphorylation of threonine and tyrosine with dual-specific protein kinases, including tyrosine kinases, such as growth factors. Cell proliferation and differentiation have been shown to be under the regulatory control of various MAP kinase cascades (Sridhar et al., Pharmaceutical Research, 17:11 1345-1353, 2000). Thus, the MAP kinase pathway plays a critical role in various disease states, for example, defects in the activity of MAP kinases have been shown to lead to aberrant cell proliferation and carcinogenesis (Qi et al., Journal of Cell Science 118 (16), 3569-3572 , 2005). Moreover, the activity of MAP kinases is also associated with insulin resistance associated with type 2 diabetes (Fujishiro et al. Recent Research Developments in Physiology 1 (Pt. 2), 801-812, 2003).

p90 Ribosomal S6 kinases (Rsk) are serine / threonine kinases that play a role in mitogen-activated cell growth and proliferation, differentiation, and cell survival. Examples of members of the Rsk kinase family include, but are not limited to, ribosomal protein kinase S6, 90 kDa, polypeptide 2 (Rsk3), ribosomal protein kinase S6, 90 kDa, polypeptide 6 (Rsk4), ribosomal protein kinase S6, 90 kDa, polypeptide 3 (Rsk2) and ribosomal protein kinase S6, 90 kDa, polypeptide 1 (Rsk1 / p90Rsk). Members of the Rsk family are activated by kinases associated with extracellular signal and phosphoinositide-dependent protein kinase 1 (Frodin and Gammeltoft, Mol. Cell. Endocrinol. 151, 65-77, 1999). Under normal conditions, RSK kinases are localized in the cytoplasm of the cell, and when stimulated by mitogens, activated (phosphorylated kinases bound to the extracellular signal) RSK transiently move to the plasma membrane, where they become fully activated. Fully activated RSK phosphorylates substrates that are involved in cell growth, proliferation, differentiation, and cell survival (Clark et al. Cancer Research 65, 3108-3116, 2005). RSK signaling pathways are also associated with cell cycle modulation (Gross et al., J. Biol. Chem. 276, 46099-46103, 2001). Currently available evidence suggests that small molecules that inhibit Rsk may be useful therapeutic agents for the prevention and treatment of cancer and inflammatory diseases.

Members of the control point protein kinase (CHK) family are serine / threonine kinases, which play an important role in the development of the cell cycle. Examples of members of the family of protein kinase control points include, but are not limited to, CHK1 and CHK2. Control point kinases are control systems that coordinate the development of the cell cycle, affecting the formation, activation and subsequent inactivation of cyclin-dependent kinases. Control point kinases prevent the development of the cell cycle at the wrong time, maintain the metabolic balance of cells when the cell “stops” at a certain point in the cell cycle, and, in some cases, can induce apoptosis (programmed cell death) when the requirements of the control point were not satisfied ( Nurse, Cell, 91, 865-867, 1997; Hartwell et al., Science, 266, 1821-1828, 1994). Control point kinase family members are associated with proliferative disorders, cancer phenotypes, and other diseases associated with 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 multigenic mitotic serine-threonine kinases that functions as a class of new oncogenes. These kinases include aurora-A and aurora-B. Aurora kinases are overactive and / or overexpressed in some solid tumors, including, but not limited to, breast, ovarian, prostate, pancreatic, and colorectal cancer. In particular, aurora-A is a centrosomal kinase that plays an important role in cell cycle development and cell proliferation. Aurora-A is located on the 20q13 region of the chromosome, which is often amplified in some different types of malignant tumors, such as colorectal cancer, breast and bladder cancer. There is also a close relationship between aurora-A and a high histo-prognostic level of aneuploidy, which makes this kinase a potential prognostic vector. Inhibition of aurora kinase activity can reduce cell proliferation, tumor growth, and potentially carcinogenesis. A detailed description of the function of aurora kinase is presented in Journal of Cell Science, 119, 3664-3675, 2006.

Rho-associated twisted helix serine / threonine protein kinases ROCK-1 and ROCK-2 are thought to play a major role in cytoskeletal dynamics, acting as downstream effectors of the Rho / Rac family of cytokine-activated and small GTPase growth factors. ROCK phosphorylates various substrates, including, but not limited to, myosin light chain phosphatase, myosin light chain, ezrin-radixin-moesin proteins, and LIM (for Lin11, Is1l, and Mec3) kinases. ROCK also mediates the formation of actin stress fibers and focal adhesion in various types of cells. ROCKs play an important role in cell migration by enhancing cell contractility, and they are necessary for the retraction of the tails of monocytes and cancer cells. ROCK inhibitors have also been shown to reduce tumor cell dispersion in vivo. Recent experiments have identified new ROCK functions in cells, including centrosomal location and regulation of cell size, which may contribute to various physiological and pathological conditions (Mueller et al, Nature Reviews Drug Discovery 4, 387-398, 2005). Members of the ROCK family are attractive targets for intervention in various pathologies, including cancer and cardiovascular diseases. ROCK inhibitors can be useful therapeutic agents for the treatment of hypertension, angina pectoris and asthma. In addition, Rho is thought to play a role in peripheral circulatory disorders, arteriosclerosis, inflammation, and autoimmune diseases and, thus, is a useful target for therapy (Shimokawa et al, Arteriosclerosis, Thrombosis and Vascular Biology, 25, 1767-1775 , 2005).

The limited success of pharmacotherapeutic approaches in spinal cord injury is largely associated with the inability of damaged nerve fibers in the white matter of the human spinal cord to resume growth and again establish synaptic contacts with their disconnected neuron partners. Aggressive microenvironment, characterized by the presence of a wide variety of molecular inhibitors of neuritis growth in the lesion site, in scar tissue and on the central nervous system myelin, is the cause of this irreversible arrest of neuritis growth. In tissue culture, these neuritis growth inhibitors often induce highly dramatic responses, including the collapse of the formation and loss of neuritis. Scar tissue in the human brain and spinal cord is a strong and persistent barrier to any regeneration of neuritis growth, and ROCK inhibitors could help damaged fibers grow or spread beyond this regeneration-inhibiting tissue. Various facts indicate that as a result of damage to the brain and spinal cord, a strong activation of the RhoA-ROCK pathway occurs. Due to the continued presence of neuritis growth inhibitors in the area of the lesion or around it and in the central nervous system of myelin, such activation could potentially persist for a long time, making ROCK inhibition an attractive target not only for emergency treatment of acute and subacute cases, but also for chronic treatment of spinal cord injury. ROCK inhibition by two different small ROCK inhibitor molecules (Y-27632 and fasudil) stimulated or accelerated functional recovery in various models of spinal cord injury in mice and rats when they are topically or systemically administered immediately after injury in a single dose or for several weeks (Dergham , P. et al. Rho signaling pathway targeted to promote spinal cord repair. J. Neurosci. 22, 6570-6577, 2002; Hara, M. et al. Protein kinase inhibition by fasudil hydrochloride promotes neurological recovery after spinal cord injury in rats J. Neurosurg. Spine 93, 94-101, 2000 .; Fournier, AE et al. ROCK inhibition enhances axonal regeneration in the injured CNS. J. Neurosci. 23, 1416-1423, 2003; Sung, JK et al. A possible role of RhoA / Rho-kinase in experimental spinal cord injury in rat. Brain Res. 959, 29-38, 2003; Tanaka, H. et al. Cytoplasmic p21 (Cipl / WAFl) enhances axonal regeneration and functional recovery after spinal cord injury in rats. Neuroscience 127, 155-164, 2004). In these studies, ROCK inhibition not only enhanced nerve fiber growth outside the lesion site, but also had a neuroprotective effect and reduced tissue damage and void formation. Based on these rodent studies, ROCK inhibitors, which have a neuroprotective and stimulating neuroregeneration effect, could be of significant benefit to patients with spinal cord injury. In addition, they could normalize blood flow in the spinal cord, due to their vasodilating effect, thus further contributing to tissue conservation.

Pathologically, Alzheimer's disease is characterized at the microscopic level by intracellular neurofibrillary plexuses and extracellular amyloid aggregates. The neurofibrillary plexuses contain an aberrantly phosphorylated tau protein, microtubule-associated protein and substrate for ROCK, while amyloid aggregates are formed primarily by toxic amyloid-β (Aβ) peptides having 42 amino acids in length. It has recently been shown (Zhou, Y. et al. Nonsteroidal anti-inflammatory drugs can lower amiloidogenic Aβ42 by inhibiting Rho. Science 302, 1215-1217, 2003) that in Aβ42 secreting cells and in transgenic PDAPP MOUSES producing large quantities Aβ42, some non-steroidal anti-inflammatory drugs (NSAIDs) lowered Aβ42 levels by inhibiting the RhoA-ROCK pathway. The ROCK inhibitor, Y-27632, was effective in reducing Aβ42 levels in both cell culture and PDAPP transgenic mice when administered by intracerebroventricular injection. Activation of Rho by geranyl geranyl pyrophosphate, a lipid necessary for membrane attachment of Rho, increased Aβ42 levels; this increase was completely prevented by Y-27632. The ROCK inhibitor, Y-27632, which was used in animal models of Alzheimer's disease, was effective, causing a decrease in the level of toxic Aβ42, but had no effect on total Aβ levels, and this effect of Rho or ROCK inhibitors is at least one mechanism by which NSAIDs lower Aβ42 levels. In addition to many other therapeutic interventions, these inhibitors have such a well-documented advantage that they stimulate the renewable growth of neuritis, and therefore it is possible that inhibition of this pathway can lead to the restoration of the amyloid-damaged neural chain.

The most important in the pathogenesis of the disease is the migration of leukocytes beyond the endothelium of the brain to the central nervous system and the inflammatory cascade stimulated by these cells, which ultimately leads to demyelination of the CNS fibers and damage and loss of neuritis. White blood cells need active RhoA and ROCK to move beyond the endothelium of the brain, since their trans-endothelial migration was prevented by the ROCK inhibitor Y-2763294.

The neuroprotective effects of the FOCK inhibitors of fasudil and hydroxyfasudil are not limited to models of spinal cord injury, but there have also been reports of this effect in cerebral multi-infarct models of gerbils and rats (Toshima Y, Satoh S, Ikegaki I, Asano T. A new model of cerebral microthrombosis in rats and the neuroprotective effect of a Rho-kinase inhibitor. Stroke 31, 2245-2250, 2000; Satoh, S. et al. Pharmacological profile of hydroxy fasudil as a selective ROCK inhibitor on ischemic brain damage. Life Si. 69, 1441-1453, 2001; Kitaoka, Y. et al. Involvement of RhoA and possible neuroprotective effect of fasudil, a ROCK inhibitor, in NMDA-induced neurotoxicity in the rat retina. Brain Res.l018, 111-118, 2004). In rodent shock models, some regeneration inhibitors, such as the ROCK-activating NgR1 complex and one of its ligands, NOGO-A, were neutralized 24 hours or even 1 week after cerebral stroke induction, and improved functional recovery was observed (Lee, JK, Kim, JE, Sivula, M. & Strittmatter, SM Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity. J. Neurosci. 24, 6209-6217, 2004; Wiessner, C. et al. Anti-Nogo-A antibody infusion 24 hours after experimental stroke improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats. J. Cereb. Blood Flow Metab. 23, 154-165, 2003). Blocking ROCK is therefore an achievable neuroregenerative strategy; in addition, such a strategy has the advantage that the therapeutic window for using these inhibitors may be larger than for thrombolytic or neuroprotective treatment options for stroke.

Damage to nerve cells in the peripheral nervous system or in the human central nervous system can lead to a state of chronic pain known as neuropathic pain. It has recently been shown that inflammatory mediators, such as lysophosphatidic acid (LPA), which is produced in response to damage, are involved in the initiation of neuropathic pain in a murine model of peripheral nerve damage (Inoue, M. et al. Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling. Nature Med. 10, 712-718, 2004). LPA is present at lesions in the peripheral nervous system and central nervous system and exerts its function by binding to G-protein-coupled LPA receptors, which leads to activation of the RhoA-ROCK pathway. The ROCK inhibitor, Y-27632, prevents the initiation of neuropathic pain after nerve damage or LPA injection, then another ROCK inhibitor, H-1152, alleviates neuropathic pain in the L5 spinal nerve dissection model (Tatsumi, S. et al. Involvement of Rho-kinase in iflammatory and neuropathic pain through phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS). Neuroscience 131, 491-498, 2005). The results of these tests show that ROCK is a potential drug target that is responsible for the induction as well as the maintenance of chronic pain conditions.

Moreover, Schueller et al. (Abstract 1216, 8th World Congress on Inflammation, Copenhagen, DenMark, June 16-20, 2007) demonstrated that SLx-2119, an orally bioavailable, potent, and highly selective ROCK 2 inhibitor, reduces atherogenesis in the presence of very elevated lipid levels in groups consisting of out of 8 ApoE-knockout mice, which suggests that selective inhibition of ROCK 2 has the potential to limit atherosclerosis.

70 kDa ribosomal S6 kinase (p70S6K) is activated by various mitogens, growth factors and hormones. P70S6K activation occurs through phosphorylation at various sites, and the main target of activated kinase is the 40S ribosomal protein S6, the main component of the mechanism involved in the synthesis of proteins in mammalian cells. In addition, p70S6K activation is associated with cell cycle control, differentiation of nerve cells, regulation of cell motility and cellular response, which is important for tumor metastases, immunity and tissue repair. Modulation of the activity of p70S6 kinase can also be of therapeutic use in 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 also in Immunol. Cell Biol. 78, 447-51, 2000.

Glycogen synthase kinase 3 (GSK-3) is a widely expressed, constitutively active serine / threonine kinase that phosphorylates cell substrates and thereby regulates a wide range of different cellular functions, including development, metabolism, gene transcription, protein translation, cytoskeletal organization, regulation cell cycle and apoptosis. GSK-3 was originally described as a key enzyme involved in glycogen metabolism, but it is now known to regulate a wide range of cellular functions. Two forms of this enzyme have been identified previously, GSK-3 + ƒ and GSK-3 + ƒ. GSK-3 + ƒ activity is negatively regulated by protein kinase B / Akt and the Wnt signaling pathway. Therefore, small molecules that are GSK-3 inhibitors may have some therapeutic applications, including the treatment and prevention of neurodegenerative diseases and the stimulation of neurogenesis in various neurological disorders (Gartner et al. J. Cell Science, 2006, 119, 3927-3934. Zhou et al Neuron, 2004, 42, 897-912), type II diabetes, bipolar disorder, stroke, cancer, osteoarthritis, osteoporosis, rheumatoid arthritis (Cuzzocrea et al. Clinical Immunology, 2006, 120, 57-67) and chronic inflammatory disease. General overview: Kockeritz et al., Current Drug Targets, 7, 1377-1388, 2006. Overview of neurological uses: 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). It is suggested that the participation of protein kinases in the development of human malignant tumors can occur through the following: (1) genomic rearrangements (for example, BCR-ABL in chronic myelogenous leukemia), (2) mutations leading to constitutively active kinase activity, for example, acute myelogenous leukemia and gastrointestinal tumors, (3) impaired regulation of kinase activity by activation of oncogenes or loss of tumor suppressor functions, as, for example, in cancer with oncogenic RAS, (4) impaired regulation of kinase asset spine resulting in over-expression, as in the case of EGFR, and (5) ectopic expression of growth factors that can contribute to the development and preservation of the tumor phenotype (Fabbro et al, Pharmacology & Therapeutics 93:. 79-98, 2002).

Some cancers are associated with angiogenesis. Angiogenesis is the growth of new capillary blood vessels from a pre-existing vasculature (Risau, W., Nature 386: 671-674, 1997). It has been shown that protein kinases can contribute to the development and maintenance of a tumor phenotype (Fabbro et al., Pharmacology & Therapeutics 93: 79-98, 2002). For example, VEGF A-D and their four receptors are associated with phenotypes that include neovascularization and increased vascular permeability, such as tumor angiogenesis and lymphangiogenesis (Matter, A., Drug Discov. Today 6: 1005-1023, 2001).

It was recognized that a single agent approach that specifically targets one kinase or single kinase pathway may not be sufficient to treat diseases and disorders, in particular cancer, for some reason. Models suggest that 5 to 7 mutations are needed to convert a normal cell to a malignant one. In addition, it is generally accepted that cancer results from changes in several pathways, in particular, protein kinase pathways that are associated with processes such as cell growth, proliferation, apoptosis, motility, or invasion. In most cancers, a common characteristic is the simultaneous overexpression and / or hyperactivation of various protein kinases, such as receptor and non-receptor kinases, serine / threonine kinases, P13 kinases and cell cycle-related kinases. In fact, some of these kinases, either alone or in combination with other kinases, are involved in various processes important for cell survival, proliferation, growth and malignant transformation, motility and invasion, leading to metastases and angiogenesis or inflammation and diseases, disorders and conditions associated with them.

Therefore, blocking a single kinase target may be clinically insufficient, since there are several kinase targets that affect the progression of a condition, disease, or disorder. In addition, blocking a single kinase target may be clinically insufficient, since excessive kinase-mediated pathways and alternative oncogenic or inflammatory mechanisms can compensate for a blocked kinase target. Moreover, the use of a single agent can also increase the likelihood of developing resistance to this agent.

Cardiovascular disease accounts for nearly a quarter of total annual deaths worldwide. Vascular disorders, such as atherosclerosis and restenosis, are the result of impaired growth of the walls of blood vessels and limitation of blood flow to vital organs. Various kinase pathways, such as JNK, are activated by atherogenic stimuli and are regulated through local production of cytokines and growth factors in vascular cells (Yang et al, Immunity 9: 575, 1998). Ischemia and ischemia, together with reperfusion in the heart, kidney, or brain, lead to cell death and scarring, which can result in congestive heart failure, renal failure, or cerebral dysfunction. During organ transplantation, reperfusion of previously ischemic donor organs leads to acute leukocyte-mediated tissue damage and a decrease in transplant function. Ways of ischemia and reperfusion 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 tissues is also associated with kinase activity (Pombo et al., J. Biol. Chem. 269: 26546-26551, 1994).

Claims (18)

1. The compound of formula (I)

or its pharmaceutically acceptable salt, where
A represents

R ₁ represents hydrogen or R _a R _b N;
R ₂ represents hydrogen;
R ₃ represents alkyl, alkoxy, aryl, cyano, cycloalkyl, halogen, haloalkyl, heteroaryl, nitro or R _g R _h N-;
R _a and R _b each represents hydrogen;
R _g and R _h each independently represent hydrogen, C _1-10 alkyl or C _1-10 alkylcarbonyl;
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 _x1v , R _xv , R _xvi , R _xvii and R _xviii each independently represents C _1-10 alkoxy, C _1-10 alkoxy-C _1-10 alkyl, C _1-10 alkoxycarbonyl, C _1-10 alkoxycarbonyl-C _1-10 alkyl, aryl, aryl-C _{1- 10} alkyl, aryl-C _1-10 - (hydroxy) alkyl, aryloxyalkyl, arylcarbonyl, arylthioalkyl, carboxy, carboxy-C _1-10 alkyl, C _1-10 cyanoalkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-C _1-10 alkyl, C _3-8 cycloalkylcarbonyl, halogen, heteroaryl, heteroaryl-C _1-10 alkyl, heterocycle, heterocycle-C _1-10 , C _1-10 alkyl, heterocyclecarbonyl, C _1-10 hydroxyalkyl, C _1-10 trialkylsi lil-C _1-10 alkyl, H ₂ NC (O) -C _1-10 alkyl, Z _a Z _b N-, Z _a Z _b N-C _1-10 alkyl, Z _c Z _d NC (O) - or Z _c Z _d NS (O) ₂ ; Z _a and Z _b each independently represent hydrogen, C _1-10 alkyl, alkoxycarbonyl-C _1-10 alkyl, aryl, aryl-C _1-10 alkyl, C _3-8 cycloalkyl, H ₂ NC (O) -, H ₂ TN-C _1-10 alkylC (O) -, H ₂ NC (O) -C _1-10 alkyl, C _1-10 dialkylNC (O) - or C _1-10 dialkylNC (O) -alkyl-;
Z _c and Z _d each independently represent hydrogen, C _1-10 alkyl, C _1-10 alkoxy-C _1-10 alkyl, aryl, aryl-C _1-10 alkyl, aryl-C _1-10 (hydroxy) alkyl, _C3-8 cycloalkyl, _{C3-8 cycloalkyl-C1-10} alkyl, heteroaryl-C _1-10 alkyl, heterocycle geterotsiklS _1-10 alkyl, C _1-10 hydroxyalkyl, H ₂ NC (O) -C _{1- 10} alkyl-, C _1-10 dialkylNC (O) -C _1-10 alkyl-, C _1-10 dialkylN-C _1-10 alkyl- or CHZ _e Z _f ;
Z _e represents aryl or heteroaryl;
Z _f represents heteroaryl-C _1-10 alkyl or heterocycle-C _1-10 alkyl;
m is 0;
It has a value of 0 or 1;
b is 0, 1 or 2;
c is 0, 1, 2 or 3; d is 0, 1, 2, 3 or 4,
where aryl means phenyl, dihydroindenyl, indenyl, naphthyl,
dihydronaphthalenyl or tetrahydronaphthalenyl;
where heteroaryl means furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, benzyl azolazole, benzyl azolazole, triazolaziazolazole, triazolaziazolazole, triazolaziazolazole, triazolaziazolazole, triazolazoles , benzodioxolyl, benzothiophenyl, chromenyl, cinnolinyl, furopyridine, indolyl, indazolyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine, quinolinyl, thienopyridine or thienopyridinyl; and
where the heterocycle means azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolidinyl, isoxazolidinyl , 3-dione, morpholinyl, oxadiazoline, oxadiazolidine, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazoline, thiadiazolidine, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioksidotiomorfolinil, ti supported, tritianil, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl, 3, 4-dihydro-1H-isochromen-4-yl, 2,3-dihydro-1H-indolyl, succinimidyl, 1,2,3,4-tetrahydroquinolinyl, 2,3,4,4a, 9,9a-hexahydro-1H- carbazolyl, 5a, 6,7,8,9,9a-hexahydro-dibenzo [b, d] furanyl or 5a, 6,7,8,9,9a-hexahydrobenzo [b, d] thienyl. 2. The compound according to claim 1, where A represents (ii), (iii), (iv), (vii), (x), (xiv), (xv), (xvi), (xvii) or (xviii ) 3. The compound according to claim 2, where a represents (ii),

R ₁₁ represents C _1-10 alkoxy-C _1-10 alkyl, C _1-10 alkoxycarbonyl, aryl, aryl-C _1-10 alkyl, aryl-C _1-10 (hydroxy) alkyl, aryloxy-C _1-10 alkyl , arylcarbonyl, alkoxycarbonyl-C _1-10 alkyl, aryl-C _1-10 thioalkyl, carboxy, carboxy-C _1-10 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-C _1-10 alkyl, C _{3- 8} cycloalkylcarbonyl, halogen, heteroaryl, heteroaryl-C _1-10 alkyl, heterocycle, heterocycle-C _1-10 alkyl, heterocycle carbonyl, C _1-10 hydroxyalkyl, C _1-10 trialkylsilyl-C _1-10 alkyl, Z _a Z _b N -, Z _a Z _b N — C _1-10 alkyl or Z _c Z _d NC (O) -;
Z _a and Z _b each independently represent hydrogen, C _1-10 alkyl or H ₂ N — C _1-10 alkylC (O) -;
Z _c and Z _d each independently represent hydrogen, C _1-10 alkyl, C _1-10 alkoxy-C _1-10 alkyl, aryl, aryl-C _1-10 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl -C _1-10 alkyl, heteroaryl-C _1-10 alkyl, heterocycle-C _1-10 alkyl, C _1-10 hydroxyalkyl or C _1-10 dialkyl N-C _1-10 alkyl-; and
b is 0, 1, or 2. 4. The compound according to claim 3, where
R ₁₁ represents aryl, aryl-C _1-10 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-C _1-10 alkyl or halogen;
b is 1 or 2. 5. The compound according to claim 1, where a represents (iii),

R _iii represents aryl-C _1-10 alkyl; and
c is 1. 6. The compound according to claim 2, where a represents (iii)

R _iii represents C _1-10 alkoxycarbonyl-C _1-10 alkyl, aryl-C _1-10 alkyl, C _1-10 cyanoalkyl, heterocycle-C _1-10 alkyl or H ₂ NC (O) -C _1-10 alkyl -;
c is 0, 1 or 2. 7. The compound according to claim 2, where a represents (iv)

R _iv represents aryl, aryl-C _1-10 alkyl, heterocycle, heterocycle-C _1-10 alkyl or Z _a Z _b N-C _1-10 alkyl or Z _c Z _d NS (O) ₂ -;
Z _a and Z _b each independently represent hydrogen or C _1-10 alkyl;
Z _c and Z _d each represent C _1-10 alkyl; and
c is 0 or 1. 8. The compound according to claim 2, where a represents (vii)

R _vii represents C _1-10 alkoxycarbonyl, aryl, aryl-C _1-10 alkyl, C _3-8 cycloalkyl, heterocycle-C _1-10 alkyl, heterocyclecarbonyl, C _1-10 hydroxyalkyl or Z _c Z _d NC (O) -;
Z _c and Z _d each independently represent hydrogen, C _1-10 alkyl, C _1-10 alkoxy-C _1-10 alkyl, aryl, aryl-C _1-10 alkyl, aryl-C _1-10 (hydroxy) alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-C _1-10 alkyl, heteroaryl-C _1-10 alkyl, heterocycle, heterocycle-C _1-10 alkyl, C _1-10 hydroxyalkyl or CHZ _e Z _f ;
Z _e represents aryl or heteroaryl;
Z _f represents heteroaryl-C _1-10 alkyl or heterocycle-C _1-10 alkyl; and b is 1. 9. The compound according to claim 2, where a represents (vii)

R _vii represents C _1-10 alkoxycarbonyl, aryl-C _1-10 alkyl, C _3-8 cycloalkyl, heterocycle-C _1-10 alkyl, heterocyclecarbonyl, C _1-10 hydroxyalkyl or Z _c Z _d NC (O) -;
Z _c and Z _d each independently represent hydrogen, C _1-10 alkyl, C _1-10 alkoxy-C _1-10 alkyl, aryl, aryl-C _1-10 alkyl, aryl-C _1-10 (hydroxy) alkyl, C _3-8 cycloalkyl, heteroaryl-C _1-10 alkyl, heterocycle-C _1-10 alkyl or C _1-10 hydroxyalkyl; and
b is 1. 10. The method according to claim 2, where a represents (vii)

R _vii represents aryl-C _1-10 alkyl; and
b is 1. 11. The compound according to claim 2, where a represents (x)

R ₁ represents hydrogen;
R _x represents aryl or Z _a Z _b N-;
Z _a and Z _b each independently represent hydrogen, C _1-10 alkyl, aryl or aryl-C _1-10 alkyl; and
b is 1 or 2. 12. The compound according to claim 2, where a represents (xiv)

R ₁ represents hydrogen;
R _xiv represents Z _a Z _b N-;
Z _a and Z _b each independently represent hydrogen or C _3-8 cycloalkyl; and
c is 1. 13. The compound according to claim 2, where a represents (xv)

R _xv represents Z _a Z _b N-;
Z _a and Z _b each independently represent hydrogen, C _1-10 alkoxycarbonyl-C _1-10 alkyl, aryl, aryl-C _1-10 alkyl or C _3-8 cycloalkyl; and
d is 0 or 1. 14. The compound according to claim 2, where a represents (xvi)

R ₁ represents hydrogen;
Rx _vii is Z _a Z _b N-;
Z _a and Z _b each independently represent hydrogen or C _3-8 cycloalkyl; and
d is 1. 15. The compound according to claim 2, where a represents (xvii)

R ₁ represents hydrogen;
R _xvii represents Z _a Z _b N - or aryl;
Z _a and Z _b each independently represent hydrogen, C _1-10 alkyl, C _1-10 alkoxycarbonyl-C _1-10 alkyl, aryl, aryl-C _1-10 alkyl, C _1-10 cycloalkyl or H ₂ NC (O ) -C _1-10 alkyl; and
d is 0 or 1. 16. The compound according to claim 2, where a represents (xviii)

R ₁ represents R _a R _b N-;
c is 0. 17. A compound selected from the group including:
5- (1-benzyl-1H-1,2,3-triazol-5-yl) -1H-indazole compound with 5- (1-benzyl-1H-1,2,3-triazol-4-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] -1H-1,2,3-triazol-4-yl} -1H-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;
5- [4- (4-fluorophenyl) -1- (1-phenylethyl) -1H-imidazol-5-yl] -1H-indazole;
4- (1H-indazol-5-yl) -N-phenyl-1,3-thiazol-2-amine;
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;
5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine;
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-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-imidazole;
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-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-yl-ethyl) -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-oxoethanol;
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;
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-dioxidothiomorpholin-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] beta-alaninate;
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- [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-1H-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} piperidin-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} glycine;
(4-fluorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl] methanone;
(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-indazole-3-amine;
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- sludge) 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-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 - [(18) -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] -1H-indazol-3-amine;
2- {2- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] ethyl} -1H-isoindol-1,3 (2H) -dione;
5- {4 - [(2,4-Dichlorophenoxy) methyl] -1H-1,2,3-triazol-1-yl} -1H-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-amine;
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-tetrahydroisoquinolin-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] -1H-1,2,3-triazol-4-yl} -1H-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-1H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] phenyl} acetamide;
N- {4- [4- (3-amino-1H-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-1H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] -N-phenylbenzamide;
3- [4- (3-amino-1H-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 - [(1R) -1-benzyl-2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1-benzyl-1H-pyrazol-4-yl) -1H-indazole;
3- [4- (3-amino-1H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] phenol;
3- [4- (3-amino-1H-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;
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) -1, -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- (1 H-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-yl-ethyl) -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-triazole-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-carboxamide;
3- [4- (3-amino-1H-indazol-5-yl) -1H-pyrazol-1-yl] propannitrile;
2- [4- (3-amino-1H-indazol-5-yl) -1H-pyrazol-1-yl] acetamide;
methyl 3- [4- (3-amino-1H-indazol-5-yl) -1H-pyrazol-1-yl] propanoate;
3- [4- (3-amino-1H-indazol-5-yl) -1H-pyrazol-1-yl] propanamide;
[4- (3-amino-1H-indazol-5-yl) -1H-pyrazol-1-yl] acetonitrile;
4- (3-amino-1H-indazol-5-yl) -N, N-dimethyl-1H-imidazole-1-sulfonamide;
5-imidazo [1,2-a] pyridin-3-yl-1H-indazol-3-amine;
5- (1H-pyrazol-5-yl) -1H-indazol-3-amine;
5- (1H-imidazol-4-yl) -1H-indazol-3-amine;
5- (1-benzyl-1H-imidazol-4-yl) -1H-indazol-3-amine;
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-yl-ethyl) 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-yl-ethyl) 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-yl-ethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (2-pyridin-3-yl-ethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (2-pyridin-4-yl-ethyl) 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-yl-ethyl) 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-yl-isoxazole-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- (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; or
N- [1- (3,5-Dichlorophenyl) -2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide. 18. A pharmaceutical composition having kinase inhibitory activity comprising a therapeutically effective amount of a compound according to any one of claims 1-17 in combination with a pharmaceutically acceptable carrier.