JP2014074057A - 5-heteroaryl substituted indazoles as kinase inhibitors - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide compounds which inhibit specific combinations of kinases or target kinase pathways.SOLUTION: The present invention relates to 5-substituted indazole compounds represented by the specified general formula (I) or pharmaceutically acceptable salts of the compounds. The present invention relates also to methods of making the compounds, and to compositions containing the compounds useful for inhibiting kinases such as Glycogen Synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus Kinases (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim1 and nek2.

Description

  The present invention relates to a 5-substituted indazole-containing compound, a method for producing the compound, glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinases (JAK), AKT, PAK4, PLK, CK2, KDR, The present invention relates to a composition comprising said compound useful for inhibiting kinases such as MK2, JNK1, Aurora, pim1 and nek2.

  Protein kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine, serine, threonine or histidine residue on a protein substrate. Protein kinases clearly play a role in normal cell growth. Many of the growth factor receptor proteins have an intracellular domain that functions as a protein kinase, and it is through this function that they signal. The interaction of growth factors with their receptors is a necessary event in the normal regulation of cell growth, and the phosphorylation status of substrate proteins is implicated in the regulation of cell proliferation.

  It is widely known that abnormal protein phosphorylation can be directly related to certain disease states or can be a factor contributing to the development of such diseases. As a result, protein kinases have become targets for new pharmaceutical research (Cohen, P. Nature Reviews Drug Discovery, 1: 309-315, 2002). Various protein kinase inhibitors have been used clinically in the treatment of a wide variety of 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 major role in cell signaling. Protein kinases can exert positive or negative regulatory effects depending on their target protein. Protein kinases are involved in specific signaling pathways that regulate cellular functions such as but not limited to metabolism, cell cycle progression, cell adhesion, vascular function, apoptosis and angiogenesis. As a result, dysfunction of intracellular signaling is associated with many diseases, the most characteristic being cancer and diabetes. There is ample evidence for the regulation of signaling by cytokines and the association of signal molecules with proto-oncogenes and tumor suppressor genes. Similarly, the relationship between diabetes, viral infections and related conditions is also related to the regulation of protein kinases.

  Because protein kinases regulate almost all cellular processes such as metabolism, cell proliferation, cell differentiation and cell survival, it is attractive as a target for therapeutic intervention for various disease states. For example, cell cycle control and angiogenesis in which protein kinases play a very important role include cancer, inflammatory diseases, abnormal angiogenesis and related diseases, atherosclerosis, macular degeneration, diabetes, obesity and pain ( It is a cellular process associated with many disease states (but not limited to).

  Protein kinase modulators having useful activity against multiple kinases or multiple kinase pathways by elucidating the complexity of protein kinase pathways and the relationships and interactions between various protein kinases and kinase pathways, The importance of developing medicines that can act as regulators or inhibitors becomes clear.

  Thus, the intracellular signaling cascade of the protein kinase pathway is complex, suggesting the possibility of requiring agents that simultaneously affect multiple pathways to obtain meaningful clinical activity. A single drug that provides a combined effect has been suggested to be an attractive idea, but identifies a single drug that targets the correct combination of multiple pathways that are clinically effective in certain disease situations And need to use.

  Glycogen synthase kinase-3 (GSK-3) is a serine / threonine kinase encoded by two isoforms GSK-3α and GSK-3β having molecular weights of 51 and 47 kDa, respectively. They share 97% sequence similarity in their kinase catalytic domains. The GSK-3α isoform has an extended glycine-rich N-terminal tail. A few splice variants of GSK-3β have been identified with an insertion of 13 amino acids within the kinase domain (expressed in about 15% of the total). This mutant had low activity against tau. GSK-3 is highly conserved throughout evolution, is found in all mammals, and so far has high homology in the kinase domain. Both isoforms are ubiquitously expressed in mammalian tissues such as the brain. A pharmacological GSK-3 inhibitor cannot selectively inhibit one of the isoforms.

  GSK-3β plays an important role in the control of metabolism, differentiation and survival. It was initially identified as an enzyme that can inhibit glycogen synthase by phosphorylating it. Later confirmed that GSK-3β is identical to tau protein kinase 1 (TPK1), an enzyme that phosphorylates tau protein at an epitope that is also found to be hyperphosphorylated in Alzheimer's disease and some taupathies It was done.

  Interestingly, it has been proposed that protein kinase B (AKT) phosphorylation of GSK-3β results in loss of kinase activity, and this inhibition may mediate part of the neurotrophic effect. Furthermore, phosphorylation of β-catenin (a protein involved in cell survival) by GSK-3β results in its degradation by the ubiquitination-dependent proteasome pathway.

  Thus, it appears that inhibition of GSK-3β activity can produce neurotrophic activity. Lithium, a non-competitive inhibitor of GSK-3β, enhances neurite formation in some models, and further induces survival factors such as Bcl-2 and inhibition of expression of pro-apoptotic factors such as P53 and Bax There is evidence that it can increase the survival of

  Further studies have shown that β-amyloid increases GSK-3β activity and increases tau protein phosphorylation. Furthermore, this hyperphosphorylation and the neurotoxic effects of β-amyloid are blocked by lithium chloride and GSK-3β antisense mRNA. Taken together, these findings suggest that GSK-3β may link between two major pathological processes in Alzheimer's disease, abnormal APP (amyloid precursor protein) processing and tau protein hyperphosphorylation. The

  These experimental findings indicate that GSK-3β can be used in the prevention and treatment of neuropathological consequences and cognitive and attention deficits associated with Alzheimer's disease, and other acute and chronic neurodegenerative diseases. Other dementias such as Parkinson's disease, taupathy (eg, frontotemporal parietal dementia, basal ganglia degeneration, Pick's disease, progressive supranuclear palsy) and vascular dementia; acute brain Infarctions and other trauma; cerebrovascular disorders (eg, macular degeneration with age); brain and spinal cord trauma; peripheral neuropathy; retinopathy and glaucoma, but are not limited to these.

  GSK-3β is non-insulin dependent diabetes and obesity; manic depression; schizophrenia; alopecia; inflammation; breast cancer, non-small cell lung cancer, thyroid cancer, T-cell or B-cell leukemia and some virus-induced tumors It may also be useful in the treatment of other diseases such as cancer.

  Rho kinases (ROCKs), the first Rho effector to be described, are serine / threonine kinases that are important in the basic processes of cell migration, cell proliferation and cell survival. Abnormal activation of the Rho / ROCK pathway has been observed in various disorders. Examples of disease states in which compounds of the present invention may have beneficial therapeutic effects due to anti-vasospastic activity include hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, brain after subarachnoid hemorrhage There are cardiovascular diseases such as vasospasm, pulmonary hypertension and atherosclerosis. Muscle relaxation properties are also useful in the treatment of asthma, male erectile dysfunction, female sexual dysfunction and overactive bladder syndrome. Damage to the adult vertebrate brain and spinal cord inhibits neurite growth and sprouting by activating ROCK. Inhibition of ROCK induces new axonal growth, axonal re-extension across lesions within the CNS, accelerated degeneration and accelerated functional recovery after acute nerve injury (spinal cord injury, brain trauma) in mammals . Inhibition of the Rho / ROCK pathway has also been shown to be effective in stroke, inflammatory and demyelinating diseases, other animal models of neurodegeneration such as Alzheimer's disease and pain treatment. Therefore, Rho / ROCK pathway inhibitors are effective in preventing neurodegeneration and stimulating nerve regeneration and treating pain in various neurological disorders such as spinal cord injury, Alzheimer's disease, stroke, multiple sclerosis, and amyotrophic lateral sclerosis. Can be. ROCK inhibitors have been shown to have anti-inflammatory properties. Accordingly, 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 rheumatoid arthritis, osteoarthritis, asthma, hypersensitivity. It can be used as a treatment for other inflammatory diseases such as ulcerative colon syndrome, Crohn's disease, psoriasis, ulcerative colitis, lupus and inflammatory bowel disease. ROCK inhibitors are thought to be useful in the treatment of cancer and tumor metastasis because they reduce cell proliferation and cell migration. Furthermore, since there is evidence to suggest that ROCK inhibitors suppress cytoskeletal reorganization during viral invasion, the drugs may be therapeutically effective for antiviral and antibacterial applications. ROCK inhibitors are also useful in the treatment of insulin resistance and diabetes. Furthermore, ROCK inhibitors have been shown to improve the progression of cystic fibrosis (Abstract S02.3, 8th World Congress on Inflammation, Copenhagen, Denmark, June 16-20, 2007).

  Furthermore, Rho-related coiled-coil forming protein kinases (ROCK) -1 and -2 have been shown to promote myosin light chain (MLC) phosphorylation through inhibition of MLC phosphatase and phosphorylation of MLC. Thereby, actin-myosin contraction is regulated. Recent reports have shown that ROCK inhibition results in disruption of inflammatory cell chemotaxis and smooth muscle inhibition in an asthma-related lung inflammation model. Thus, inhibitors of the Rho / ROCK pathway should be useful in the treatment of asthma.

  Janus kinases (JAKs) are an important family of intracellular protein tyrosine kinases (PTKs), with four mammalian members, JAK1, JAK2, JAK3 and TYK2, and homologues in chickens, fish and Drosophila. JAK plays a very important role in several important intracellular signaling pathways, such as the JAK / STAT pathway, named after the core name of cytokine signaling mediation. It is this central role in cytokine signaling that supports the idea that specific JAK inhibitors can be used in therapy in situations where cytokine activity causes disease. Important examples of this 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 (JAK) family of protein tyrosine kinases (PTKs), is an important intracellular mediator of cytokine signaling. Mutations in the JAK2 gene are associated with blood cancer, and abnormal JAK activity is also associated with many immune diseases such as rheumatoid arthritis.

  Aurora kinases are a family of multigene mitotic serine-threonine kinases that function as a new oncogene class. These kinases include Aurora-A, Aurora-B and Aurora-B members. They are overactivated and / or overexpressed in several solid tumors such as but not limited to breast cancer, ovarian cancer, prostate cancer, pancreatic cancer and colorectal cancer. In particular, Aurora-A is a centrosome kinase, the position of which is determined by the cell cycle and plays an important role in cell cycle progression and cell proliferation. Aurora-A is on chromosome 20q13, which is very often amplified in several different types of malignant tumors such as colorectal cancer, breast cancer and bladder cancer. Inhibition of Aurora kinase activity may help to reduce cell growth, tumor growth and possibly tumorigenesis.

Cohen, P.A. Nature Reviews Drug Discovery, 1: 309-315, 2002. Abstract S02.3, 8th World Congress on Information, Copenhagen, Denmark, June 16-20, 2007.

  Accordingly, there remains a need for the development of methods that involve the use of a single agent that can target a particular combination of kinases or kinase pathways. In particular, such methods achieve clinical efficacy by affecting the correct combination of multiple targets.

  In a main embodiment, the present invention provides a compound of formula (I) below or a pharmaceutically acceptable salt thereof.

式中、
Ａは、

Where
A is

であり；
Ｒ_１は、水素、アルキル、アリール、複素環、ヘテロアリール、Ｒ_ａＲ_ｂＮ−、Ｒ_ｃＲ_ｄＮ−Ｃ（Ｏ）−またはＲ_ｃＲ_ｄＮ−Ｓ（Ｏ）_２−であり；
Ｒ_２は、水素、アルコキシカルボニル、アルキル、アルキルカルボニル、アリールカルボニル、複素環カルボニルまたはＲ_ｅＲ_ｆＮ−アルキル−Ｃ（Ｏ）−であり；
Ｒ_３は、アルキル、アルコキシ、アリール、シアノ、シクロアルキル、ハロゲン、ハロアルキル、ヘテロアリール、ニトロまたはＲ_ｇＲ_ｈＮ−であり；
Ｒ_４は、アルキル、アルコキシアルキル、アリール、シクロアルキル、ヘテロアリール、複素環、複素環アルキル、Ｒ_ｊＲ_ｋＮ−またはＲ_ｊＲ_ｋＮ−アルキル−であり；
Ｒ_５は、アルキル、アリールまたはヘテロアリールであり；
Ｒ_６は、アルキル、アルコキシアルキル、Ｒ_ｊＲ_ｋＮ−アルキル−、アリール、シクロアルキルまたはヘテロアリールであり；
Ｒ_７は、アルキル、アリールまたはヘテロアリールであり；
Ｒ_ａおよびＲ_ｂはそれぞれ独立に、水素、アルキル、アリールアルキル、シクロアルキル、シクロアルキルアルキル、ヘテロアリールアルキル、Ｒ_４−Ｃ（Ｏ）−またはＲ_５−Ｓ（Ｏ）_２−であり；
Ｒ_ｃおよびＲ_ｄはそれぞれ独立に、水素、アルキルまたはヘテロアリールであり；
Ｒ_ｅおよびＲ_ｆはそれぞれ独立に、水素、アルキル、アリールアルキル、ヘテロアリールアルキル、Ｒ_６−Ｃ（Ｏ）−またはＲ_７−Ｓ（Ｏ）_２−であり；
Ｒ_ｇおよびＲ_ｈはそれぞれ独立に、水素、アルキルまたはアルキルカルボニルであり；
Ｒ_ｊおよびＲ_ｋはそれぞれ独立に、水素、アルキル、アリール、アリールアルキル、シクロアルキル、ヘテロアリールまたは複素環であり；
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およびＲ_{ｘｘｉｉｉ}はそれぞれ独立に、アルキル、アルコキシ、アルコキシアルキル、アルコキシカルボニル、アルコキシカルボニルアルキル、アリール、アリールアルキル、アリール（ヒドロキシ）アルキル、アリールオキシアルキル、アリールカルボニル、アリールチオアルキル、カルボキシ、カルボキシアルキル、シアノアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルキルカルボニル、ハロゲン、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、複素環カルボニル、ヒドロキシアルキル、トリアルキルシリルアルキル、Ｈ_２ＮＣ（Ｏ）−アルキル、Ｚ_ａＺ_ｂＮ−、Ｚ_ａＺ_ｂＮアルキル、Ｚ_ｃＺ_ｄＮＣ（Ｏ）−またはＺ_ｃＺ_ｄＮＳ（Ｏ）_２−であり、Ｒ_ｘｉｖ、Ｒ_ｘｖ、Ｒ_ｘｖｉおよびＲ_ｘｖｉｉは化合物（ｘｉｖ）、（ｘｖ）、（ｘｖｉ）または（ｘｖｉｉ）上の任意の開放原子価に存在することができ；
Ｚ_ａおよびＺ_ｂはそれぞれ独立に、水素、アルキル、アルコキシカルボニルアルキル、アリール、アリールアルキル、シクロアルキル、Ｈ_２ＮＣ（Ｏ）−、Ｈ_２ＮアルキルＣ（Ｏ）−、Ｈ_２ＮＣ（Ｏ）−アルキル、ジアルキルＮＣ（Ｏ）−またはジアルキルＮＣ（Ｏ）−アルキル−であり；
Ｚ_ｃおよびＺ_ｄはそれぞれ独立に、水素、アルキル、アルコキシアルキル、アリール、アリールアルキル、アリール（ヒドロキシ）アルキル、シクロアルキル、シクロアルキルアルキル、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキル、Ｈ_２ＮＣ（Ｏ）−アルキル−、ジアルキルＮＣ（Ｏ）−アルキル−、ジアルキルＮ−アルキル−またはＣＨＺ_ｅＺ_ｆであり；
Ｚ_ｅは、アリールまたはヘテロアリールであり；
Ｚ_ｆは、ヘテロアリールアルキル、複素環アルキルまたはＺ_１Ｚ_２Ｎ−アルキル−であり；
ｍは、０、１または２であり；
ａは、０または１であり；
ｂは、０、１または２であり；
ｃは、０、１、２または３であり；
ｄは、０、１、２、３または４である。

Is;
R ₁ is hydrogen, alkyl, aryl, heterocycle, heteroaryl, R _a R _b N—, R _c R _d N—C (O) — or R _c R _d N—S (O) ₂ —;
R ₂ is hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, heterocyclic carbonyl or R _e R _f N-alkyl-C (O) —;
R ₃ is alkyl, alkoxy, aryl, cyano, cycloalkyl, halogen, haloalkyl, heteroaryl, nitro or R _g R _h N-;
R ₄ is alkyl, alkoxyalkyl, aryl, cycloalkyl, heteroaryl, heterocycle, heterocyclealkyl, R _j R _k N- or R _j R _k N-alkyl-;
R ₅ is alkyl, aryl or heteroaryl;
R ₆ is alkyl, alkoxyalkyl, R _j R _k N-alkyl-, aryl, cycloalkyl or heteroaryl;
R ₇ is alkyl, aryl or heteroaryl;
R _a and R _b are each independently hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, R ₄ —C (O) — or R ₅ —S (O) ₂ —;
R _c and R _d are each independently hydrogen, alkyl or heteroaryl;
R _e and R _f are each independently hydrogen, alkyl, arylalkyl, heteroarylalkyl, R ₆ —C (O) — or R ₇ —S (O) ₂ —;
R _g and R _h are each independently hydrogen, alkyl or alkylcarbonyl;
R _j and R _k are each independently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heterocycle;
_{R i, R ii, R iii} , R iv, R v, R vi, R vii, R viii, R ix, R x, R xi, R xii, R xiii, R xiv, R xv, R xvi, R xvii , R _xviii , R _xix , R _xx , R _xxi , R _xxii and R _xxiii are each independently alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl, aryl (hydroxy) alkyl, aryloxy Alkyl, arylcarbonyl, arylthioalkyl, carboxy, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocycle Alkyl, heterocycle carbonyl, hydroxyalkyl, _{trialkylsilylalkyl,} H 2 NC (O) - _{alkyl, Z a Z b N-, Z} a Z b N _{-alkyl, Z c Z d NC (O} ) - or _Z c Z _d NS (O) ₂ — and R _xiv , R _xv , R _xvi and R _xvii can be present at any open valence on compound (xiv), (xv), (xvi) or (xvii) Can;
Z _a and Z _b are each independently 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 dialkyl NC (O) -alkyl-;
Z _c and Z _d are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl (hydroxy) alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl, H ₂ NC (O) -alkyl-, dialkyl NC (O) -alkyl-, dialkyl N-alkyl- or CHZ _e Z _f ;
Z _e is aryl or heteroaryl;
Z _f is heteroarylalkyl, heterocyclic alkyl 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;
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 suitable carrier.

  An object of the present invention is to provide a compound useful for the prevention or treatment of diseases caused by abnormal protein kinase activity. Furthermore, the present invention also provides a pharmaceutically effective composition of the compound of the present invention useful in the prevention or treatment of the above diseases.

  The present invention also includes at least one formula that may be present as a pharmaceutically acceptable salt or prodrug in the presence or absence of a pharmaceutically acceptable carrier, dragee, adjuvant or other adjuvant material. It also relates to a pharmaceutical composition comprising the 5-substituted indazole compound of (I).

  The compounds of the present invention have inhibitory activity against GSK-3, ROCK-1, ROCK-2, JAK2 and other kinases and are useful in the inhibition of such kinases. Certain compounds of the present invention are selective for one or more kinases and may be useful in the selective inhibition of such kinases. Accordingly, the compounds of the present invention are effective in producing compositions that allow prophylactic and / or therapeutic treatment of diseases caused by abnormal GSK-3 activity, particularly neurodegenerative diseases such as Alzheimer's disease. Useful as an ingredient. In addition, the compounds of the present invention may be used in other Parkinson's disease, taupathy (eg, frontotemporal parietal dementia, corticobasal degeneration, Pick's disease, progressive supranuclear paralysis) and other vascular dementias such as Neurodegenerative diseases such as dementia; acute cerebral infarction and other trauma; cerebrovascular disorders (eg macular degeneration with age); brain and spinal cord trauma; peripheral neuropathy; retinopathy and glaucoma; and non-insulin dependent Other diseases such as diabetes (such as type II diabetes) and obesity; such as manic depression; schizophrenia; alopecia; breast cancer, non-small cell lung cancer, thyroid cancer, T-cell or B-cell leukemia and some virus-induced tumors It is also useful as an active ingredient in the manufacture of a composition for prophylactic and / or therapeutic treatment of cancer.

  The compounds of the present invention have the above formula (I). Specifically, in the compound of formula (I), A is (ii), (iii), (iv), (vii), (x), (xiv), (xv), (xvi), (xvii), There may be, but is not limited to, compounds that are (xviii), (xix), (xx), (xxi), (xxii), or (xxiii).

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

であり；
Ｒ_１が、水素、アリール、ヘテロアリール、複素環、Ｒ_ａＲ_ｂＮ−またはＲ_ｃＲ_ｄＮ−Ｃ（Ｏ）−であり；Ｒ_２が、水素、アルコキシカルボニル、複素環カルボニル、アルキルカルボニルまたはＲ_ｅＲ_ｆＮ−アルキル−Ｃ（Ｏ）−であり；Ｒ_４が、アルキル、アルコキシアルキル、アリール、シクロアルキル、複素環、複素環アルキル、Ｒ_ｊＲ_ｋＮ−またはＲ_ｊＲ_ｋＮ−アルキル−であり；Ｒ_５が、アルキル、アリールまたはヘテロアリールであり；Ｒ_ａおよびＲ_ｂがそれぞれ独立に、水素、アリールアルキル、シクロアルキルアルキル、Ｒ_４−Ｃ（Ｏ）−またはＲ_５−Ｓ（Ｏ）_２−であり；Ｒ_ｃおよびＲ_ｄがそれぞれ独立に、水素またはヘテロアリールであり、Ｒ_ｅおよびＲ_ｆがそれぞれ独立に、水素またはアルキルであり、Ｒ_ｊおよびＲ_ｋがそれぞれ独立に、水素、アルキル、アリール、シクロアルキルまたは複素環であり；Ｒ_ｉｉが、アルキル、アルコキシアルキル、アルコキシカルボニル、アリール、アリールアルキル、アリール（ヒドロキシ）アルキル、アリールオキシアルキル、アリールカルボニル、アルコキシカルボニルアルキル、アリールチオアルキル、カルボキシ、カルボキシアルキル、シクロアルキル、シクロアルキルアルキル、シクロアルキルカルボニル、ハロゲン、ヘテロアリール、ヘテロアリールアルキル、複素環、複素環アルキル、複素環カルボニル、ヒドロキシアルキル、トリアルキルシリルアルキル、Ｚ_ａＺ_ｂＮ−、Ｚ_ａＺ_ｂＮアルキル−またはＺ_ｃＺ_ｄＮＣ（Ｏ）−であり；Ｚ_ａおよびＺ_ｂがそれぞれ独立に、水素、アルキルまたはＨ_２ＮアルキルＣ（Ｏ）−であり；Ｚ_ｃおよびＺ_ｄがそれぞれ独立に、水素、アルキル、アルコキシアルキル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、ヘテロアリールアルキル、複素環アルキル、ヒドロキシアルキルまたはジアルキルＮ−アルキル−であり；ｍが０であり；ｂが０、１または２である式（Ｉ）の化合物が開示される。

Is;
R ₁ is hydrogen, aryl, heteroaryl, heterocyclic, R _a R _b N— or R _c R _d N—C (O) —; R ₂ is hydrogen, alkoxycarbonyl, heterocyclic carbonyl, alkylcarbonyl Or R _e R _f N-alkyl-C (O) —; R ₄ is alkyl, alkoxyalkyl, aryl, cycloalkyl, heterocycle, heterocyclealkyl, R _j R _k N- or R _j R _k N -Alkyl-; R ₅ is alkyl, aryl or heteroaryl; R _a and R _b are each independently hydrogen, arylalkyl, cycloalkylalkyl, R ₄ —C (O) — or R ₅ —. S _{(O) 2} - a and; _{R c} and _{R d} are each independently hydrogen or heteroaryl, _{R e} and _{R f} are each independently hydrogen or aralkyl Is Le, independently R _j and R _k are each hydrogen, alkyl, aryl, cycloalkyl, or heterocycle; R _ii is an alkyl, alkoxyalkyl, alkoxycarbonyl, aryl, arylalkyl, aryl (hydroxy) alkyl , Aryloxyalkyl, arylcarbonyl, alkoxycarbonylalkyl, arylthioalkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocycle Carbonyl, 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 are each independently And hydrogen, alkyl or H ₂ N alkyl C (O) —; Z _c and Z _d are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl A compound of formula (I) is disclosed wherein m is 0; b is 0, 1 or 2; heterocyclic alkyl, hydroxyalkyl or dialkyl N-alkyl-;

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

であり；
Ｒ_１が、水素またはＲ_ａＲ_ｂＮ−であり；Ｒ_２が、水素であり；Ｒ_４が、Ｒ_ｊＲ_ｋＮ−アルキル−であり；Ｒ_ａおよびＲ_ｂがそれぞれ独立に、水素またはＲ_４−Ｃ（Ｏ）−であり；Ｒ_ｊおよびＲ_ｋが、それぞれアルキルであり；Ｒ_ｉｉｉが、アルコキシカルボニルアルキル、アルキル、アリールアルキル、シアノアルキル、複素環アルキルまたはＨ_２ＮＣ（Ｏ）−アルキル−であり；ｃが、０、１または２であり；ｍが０である式（Ｉ）の化合物が開示される。

Is;
R ₁ is hydrogen or R _a R _b N—; R ₂ is hydrogen; R ₄ is R _j R _k N-alkyl-; R _a and R _b are each independently hydrogen or R ₄ -C (O) - and is; _{R j} and _{R k} are each an _{alkyl; R iii} is, alkoxycarbonylalkyl, alkyl, arylalkyl, cyanoalkyl, heterocyclealkyl, or _H 2 NC (O) - Disclosed are compounds of formula (I), wherein alkyl is; c is 0, 1 or 2; m is 0.

  In another embodiment of this invention A is (iv):

であり；
Ｒ_１が、水素またはＲ_ａＲ_ｂＮ−であり；Ｒ_２が、水素であり；Ｒ_ａおよびＲ_ｂが、それぞれ水素であり；Ｒ_ｉｖが、アリール、アリールアルキル、複素環、複素環アルキル、Ｚ_ａＺ_ｂＮアルキルまたはＺ_ｃＺ_ｄＮＳ（Ｏ）_２−であり；Ｚ_ａおよびＺ_ｂがそれぞれ独立に、水素またはアルキルであり；Ｚ_ｃおよびＺ_ｄが、それぞれアルキルであり；ｃが、０、１または２であり；ｍが０である式（Ｉ）の化合物が開示される。

Is;
R ₁ is hydrogen or R _a R _b N—; R ₂ is hydrogen; R _a and R _b are each hydrogen; R _iv is aryl, arylalkyl, heterocycle, heterocyclealkyl Z _a Z _b N alkyl or Z _c Z _d NS (O) ₂ —; Z _a and Z _b are each independently hydrogen or alkyl; Z _c and Z _d are each alkyl; Are 0, 1 or 2; compounds of formula (I) wherein m is 0 are disclosed.

  In another embodiment of this invention A is (vii):

であり；
Ｒ_１が、水素、アルキルまたはＲ_ａＲ_ｂＮであり；Ｒ_２が水素であり；Ｒ_ａおよびＲ_ｂがそれぞれ水素であり；Ｒ_ｖｉｉが、アルキル、アルコキシカルボニル、アリール、アリールアルキル、シクロアルキル、複素環アルキル、複素環カルボニル、ヒドロキシアルキルまたはＺ_ｃＺ_ｄＮＣ（Ｏ）−であり；Ｚ_ｃおよびＺ_ｄがそれぞれ独立に、水素、アルキル、アルコキシアルキル、アリール、アリールアルキル、アリール（ヒドロキシ）アルキル、シクロアルキル、シクロアルキルアルキル、ヘテロアリールアルキル、複素環、複素環アルキル、ヒドロキシアルキルまたはＣＨＺ_ｅＺ_ｆであり；Ｚ_ｅが、アリールまたはヘテロアリールであり、Ｚ_ｆが、ヘテロアリールアルキル、複素環アルキルまたはＺ_１Ｚ_２Ｎ−アルキル−であり；ｂが１であり；ｍが０である式（Ｉ）の化合物が開示される。

Is;
R ₁ is hydrogen, alkyl or R _a R _b N; R ₂ is hydrogen; R _a and R _b are each hydrogen; R _vii is alkyl, alkoxycarbonyl, aryl, arylalkyl, cycloalkyl , Heterocyclic alkyl, heterocyclic carbonyl, hydroxyalkyl or Z _c Z _d NC (O) —; Z _c and Z _d are each independently hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl (hydroxy) Alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl or CHZ _e Z _f ; Z _e is aryl or heteroaryl, Z _f is heteroarylalkyl, hetero ring alkyl or _Z 1 _Z 2 N-alkyl By and; b is located at 1; m is a compound of formula (I) wherein 0 is disclosed.

  In another embodiment of this invention A is (x):

であり；
Ｒ_１が水素であり；Ｒ_２が水素であり；Ｒ_ｘが、アルキル、アリールまたはＺ_ａＺ_ｂＮ−であり；Ｚ_ａおよびＺ_ｂがそれぞれ独立に、水素、アルキル、アリールまたはアリールアルキルであり；ｂが１または２であり；ｍが０である式（Ｉ）の化合物が開示される。

Is;
R ₁ is hydrogen; R ₂ is hydrogen; R _x is alkyl, aryl or Z _a Z _b N—; Z _a and Z _b are each independently hydrogen, alkyl, aryl or arylalkyl There is disclosed a compound of formula (I) wherein b is 1 or 2 and m is 0.

  In another embodiment of this invention A is (xiv):

であり；
Ｒ_１が水素であり；Ｒ_２が水素であり；Ｒ_ｘｉｖがＺ_ａＺ_ｂＮ−であり；Ｚ_ａおよびＺ_ｂがそれぞれ独立に、水素またはシクロアルキルであり；ｃが１であり；ｍが０である式（Ｉ）の化合物が開示される。

Is;
R ₁ is hydrogen; R ₂ is hydrogen; R _xiv is Z _a Z _b N—; Z _a and Z _b are each independently hydrogen or cycloalkyl; c is 1; Disclosed are compounds of formula (I), wherein is 0.

  In another embodiment of this invention A is (xv):

であり；
Ｒ_１が水素またはＲ_ａＲ_ｂＮ−であり；Ｒ_２が水素であり；Ｒ_ａおよびＲ_ｂがそれぞれ水素であり；Ｒ_ｘｖがＺ_ａＺ_ｂＮ−であり；Ｚ_ａおよびＺ_ｂがそれぞれ独立に、水素、アルコキシカルボニルアルキル、アリール、アリールアルキルまたはシクロアルキルであり；ｄが０または１であり；ｍが０である式（Ｉ）の化合物が開示される。

Is;
R ₁ is hydrogen or R _a R _b N—; R ₂ is hydrogen; R _a and R _b are each hydrogen; R _xv is Z _a Z _b N—; Z _a and Z _b are Disclosed are compounds of formula (I), each independently hydrogen, alkoxycarbonylalkyl, aryl, arylalkyl or cycloalkyl; d is 0 or 1; and m is 0.

  In another embodiment of this invention A is (xvi):

であり；
Ｒ_１が水素であり；Ｒ_２が水素であり；Ｒ_ｘｖｉがＺ_ａＺ_ｂＮ−であり；Ｚ_ａおよびＺ_ｂがそれぞれ独立に、水素またはシクロアルキルであり；ｄが１であり；ｍが０である式（Ｉ）の化合物が開示される。

Is;
R ₁ is hydrogen; R ₂ is hydrogen; R _xvi is Z _a Z _b N—; Z _a and Z _b are each independently hydrogen or cycloalkyl; d is 1; Disclosed are compounds of formula (I), wherein is 0.

  In another embodiment of this invention A is (xvii):

であり；
Ｒ_１が水素であり；Ｒ_２が水素であり；Ｒ_ｘｖｉｉがアリールまたはＺ_ａＺ_ｂＮ−であり；Ｚ_ａおよびＺ_ｂがそれぞれ独立に、水素、アルキル、アルコキシカルボニルアルキル、アリール、アリールアルキル、シクロアルキルまたはＨ_２ＮＣ（Ｏ）−アルキル−であり；ｄが０または１であり；ｍが０である式（Ｉ）の化合物が開示される。

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

  In another embodiment of this invention A is (xviii):

であり；
Ｒ_１がＲ_ａＲ_ｂＮ−であり；Ｒ_２が水素であり；Ｒ_ａおよびＲ_ｂがそれぞれ水素であり；ｃが０であり；ｍが０である式（Ｉ）の化合物が開示される。

Is;
Disclosed are compounds of formula (I), wherein R ₁ is R _a R _b N—; R ₂ is hydrogen; R _a and R _b are each hydrogen; c is 0; and m is 0 The

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

であり；
Ｒ_１がＲ_ａＲ_ｂＮ−であり；Ｒ_２が水素であり；Ｒ_ａおよびＲ_ｂがそれぞれ水素であり；ｃが０であり；ｍが０である式（Ｉ）の化合物が開示される。

Is;
Disclosed are compounds of formula (I), wherein R ₁ is R _a R _b N—; R ₂ is hydrogen; R _a and R _b are each hydrogen; c is 0; and m is 0 The

  In another embodiment of this invention A is (xx):

であり；
Ｒ_１がＲ_ａＲ_ｂＮ−であり；Ｒ_２が水素であり；Ｒ_４がＲ_ｊＲ_ｋＮ−アルキル−であり；Ｒ_ａおよびＲ_ｂがそれぞれ、水素またはＲ_４−Ｃ（Ｏ）−であり；Ｒ_ｊおよびＲ_ｋが独立にアルキルであり；Ｒ_ｘｘがＺ_ａＺ_ｂＮ−または複素環であり；Ｚ_ａおよびＺ_ｂが独立に水素またはアルキルであり；ｃが０または１であり；ｍが０である式（Ｉ）の化合物が開示される。

Is;
R ₁ is R _a R _b N—; R ₂ is hydrogen; R ₄ is R _j R _k N-alkyl-; R _a and R _b are each hydrogen or R ₄ —C (O) R _j and R _k are independently alkyl; R _xx is Z _a Z _b N— or a heterocycle; Z _a and Z _b are independently hydrogen or alkyl; c is 0 or 1 A compound of formula (I) wherein m is 0 is disclosed.

  In another embodiment of this invention A is (xxi):

であり；
Ｒ_１がＲ_ａＲ_ｂＮ−であり；Ｒ_２が水素であり；Ｒ_ａおよびＲ_ｂがそれぞれ水素であり；Ｒ_ｘｘｉがアルコキシであり；ｄが１であり；ｍが０である式（Ｉ）の化合物が開示される。

Is;
A formula in which R ₁ is R _a R _b N-; R ₂ is hydrogen; R _a and R _b are each hydrogen; R _xxi is alkoxy; d is 1; and m is 0 A compound of I) is disclosed.

  In another embodiment of this invention A is (xxii):

であり；
Ｒ_１がＲ_ａＲ_ｂＮ−であり；Ｒ_２が水素であり；Ｒ_４がＲ_ｊＲ_ｋＮ−アルキル−であり；Ｒ_ａおよびＲ_ｂがそれぞれ独立に水素またはＲ_４−Ｃ（Ｏ）−であり；Ｒ_ｊおよびＲ_ｋがそれぞれアルキルであり；ｃが０であり；ｍが０である式（Ｉ）の化合物が開示される。

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

  In another embodiment of this invention A is (xxiii):

であり；
Ｒ_１がＲ_ａＲ_ｂＮ−であり；Ｒ_２が水素であり；Ｒ_ａおよびＲ_ｂがそれぞれ水素であり；ｃが０であり；ｍが０である式（Ｉ）の化合物が開示される。

Is;
Disclosed are compounds of formula (I), wherein R ₁ is R _a R _b N—; R ₂ is hydrogen; R _a and R _b are each hydrogen; c is 0; and m is 0 The

Particular embodiments envisioned as part of this invention include compounds of formula (I) such as:
5- (1-Benzyl-1H-1,2,3-triazol-5-yl) -1H with 5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole -An indazole complex;
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;
3-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} methyl benzoate;
4-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} methyl benzoate;
5- [1- (2,4-dimethylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (3,5-dimethylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (2,3-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (2,4-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (2,5-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [1- (3,5-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- {1- [2,4-bis (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;
N-cyclohexyl-6- (1H-indazol-5-yl) imidazo [2,1-b] [1,3] thiazol-5-amine;
N-cyclohexyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyridin-3-amine;
N-cyclohexyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrazin-3-amine;
5- [1-benzyl-4- (4-fluorophenyl) -1H-imidazol-5-yl] -1H-indazole;
N- {3- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] propyl} -N, N-dimethylamine;
N-cyclohexyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine;
5- [4- (4-fluorophenyl) -1- (1-phenylethyl) -1H-imidazol-5-yl] -1H-indazole;
2- (1H-indazol-5-yl) -N-isopropylimidazo [1,2-a] pyrimidin-3-amine;
4- (1H-indazol-5-yl) -N-phenyl-1,3-thiazol-2-amine;
5- (2-methyl-1,3-thiazol-4-yl) -1H-indazole;
N-ethyl-4- (1H-indazol-5-yl) -1,3-thiazol-2-amine;
N-benzyl-4- (1H-indazol-5-yl) -1,3-thiazol-2-amine;
4- (1H-indazol-5-yl) -1,3-thiazol-2-amine;
4- (1H-indazol-5-yl) -N- (2-phenylethyl) -1,3-thiazol-2-amine;
N-benzyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine;
N-butyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine;
N- (4-chlorophenyl) -2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine;
2- (1H-indazol-5-yl) -N- (4-methoxyphenyl) imidazo [1,2-a] pyrimidin-3-amine;
2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidine;
Methyl N- [2- (1H-indazol-5-yl) imidazo [1,2-a] pyridin-3-yl] glycinate;
N-benzyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyridin-3-amine;
N- (4-chlorophenyl) -2- (1H-indazol-5-yl) imidazo [1,2-a] pyridin-3-amine;
2- (1H-indazol-5-yl) -N- (4-methoxyphenyl) imidazo [1,2-a] pyridin-3-amine;
Tert-butyl 4- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] piperidine-1-carboxylate;
3,5-bis (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole;
5- (1-benzyl-1H-1,2,3-triazol-4-yl) -3-phenyl-1H-indazole;
5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine;
5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1-[(1-methylpiperidin-4-yl) carbonyl] -1H-indazol-3-amine;
N- [5- (1-Benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-methoxyacetamide;
N ¹ - [5- (-4- 1- ^{benzyl-1H-1,2,3-triazol-yl)-1H-indazol-3-yl]} -N ^{2, N} 2 - dimethyl glycinamide;
Ν- [5- (1-Benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] butanamide;
5- [4- (4-fluorophenyl) -1-piperidin-4-yl-1H-imidazol-5-yl] -1H-indazole;
5- {4- (4-fluorophenyl) -1- [2- (1-methylpyrrolidin-2-yl) ethyl] -1H-imidazol-5-yl} -1H-indazole;
5- {4- (4-fluorophenyl) -1- [3- (4-methylpiperazin-1-yl) propyl] -1H-imidazol-5-yl} -1H-indazole;
Ethyl 5- (1H-indazol-5-yl) isoxazole-3-carboxylate;
5- (1H-indazol-5-yl) -N-methylisoxazole-3-carboxamide;
5- (3-benzylisoxazol-5-yl) -1H-indazole;
N- [5- (1-Benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide;
5- (3-propylisoxazol-5-yl) -1H-indazole;
N-benzyl-4- (1H-indazol-5-yl) -5-phenyl-1,3-thiazol-2-amine;
4- (1H-indazol-5-yl) -N, 5-diphenyl-1,3-thiazol-2-amine;
5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazole;
5- (1-benzyl-4-cyclopropyl-1H-1,2,3-triazol-5-yl) -1H-indazole;
2- (1H-indazol-5-yl) -3-phenylimidazo [1,2-a] pyrimidine;
5- [1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- [3- (piperidin-1-ylcarbonyl) isoxazol-5-yl] -1H-indazole;
5- (1H-indazol-5-yl) -N-phenylisoxazole-3-carboxamide;
N-cyclohexyl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- [3- (piperidin-1-ylmethyl) isoxazol-5-yl] -1H-indazole;
[5- (1H-indazol-5-yl) isoxazol-3-yl] methanol;
5- (1H-indazol-5-yl) -N- (2-methoxyethyl) isoxazole-3-carboxamide;
5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazole;
5- (4-benzyl-1H-1,2,3-triazol-1-yl) -1H-indazole;
5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine;
5- (1-benzyl-4-cyclopropyl-1H-1,2,3-triazol-5-yl) -1H-indazol-3-amine;
5- (3-isobutylisoxazol-5-yl) -1H-indazol-3-amine;
5- (3-benzylisoxazol-5-yl) -1H-indazol-3-amine;
N- {2- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] ethyl} -N, N-dimethylamine;
5- [4- (4-fluorophenyl) -1- (3-morpholin-4-ylpropyl) -1H-imidazol-5-yl] -1H-indazole;
5- [4- (4-fluorophenyl) -1- (3-pyrrolidin-1-ylpropyl) -1H-imidazol-5-yl] -1H-indazole;
5- {4- (4-fluorophenyl) -1- [2- (4-methylpiperidin-1-yl) ethyl] -1H-imidazol-5-yl} -1H-indazole;
5- [1- (1-benzylpiperidin-4-yl) -4- (4-fluorophenyl) -1H-imidazol-5-yl] -1H-indazole;
5- [4- (4-fluorophenyl) -1- (2-morpholin-4-ylethyl) -1H-imidazol-5-yl] -1H-indazole;
5- [1- (1-benzylpyrrolidin-3-yl) -4- (4-fluorophenyl) -1H-imidazol-5-yl] -1H-indazole;
2- {4- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] piperidin-1-yl} -2-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-dioxidethiomorpholin-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;
N- [2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-yl] -ethyl 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-a] pyrimidin-3-yl]-.beta.-alanine amide;
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-methyl Phenyl) urea;
5- (1H-indazol-5-yl) -N- (2-isopropoxyethyl) isoxazole-3-carboxamide;
5- [3- (morpholin-4-ylcarbonyl) isoxazol-5-yl] -1H-indazole;
5- (1H-indazol-5-yl) -N- (3-morpholin-4-ylpropyl) isoxazole-3-carboxamide;
N- [2- (1H-imidazol-4-yl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
(3R) -1-{[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} piperidin-3-ol;
1-{[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} piperidine-3-carboxamide;
2- [2- (4-{[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} piperazin-1-yl) ethoxy] ethanol;
5- {3-[(4-methyl-1,4-diazepan-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole;
N- (3-hydroxypropyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-[(1R) -2-hydroxy-1-phenylethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- [3- (1H-imidazol-1-yl) propyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- [3- (2-oxopyrrolidin-1-yl) propyl] isoxazole-3-carboxamide;
N- {2- [4- (aminosulfonyl) phenyl] ethyl} -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] (3-chlorophenyl) methanone;
[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] (cyclopropyl) methanone;
5- [5-cyclopropyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
N ¹ -{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] methyl} glycinamide;
(4-fluorophenyl) [4- (1Η-indazol-5-yl) -1- (tetrahydro-2Η-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-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- Il) Methanone;
5- [1-benzyl-5- (2-methylphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
5- {1-benzyl-5-[(4-methylpiperazin-1-yl) carbonyl] -1H-1,2,3-triazol-4-yl} -1H-indazole;
1-{[1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] carbonyl} piperidin-4-ol;
1-acetyl-5- [5- (4-fluorophenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole;
1-benzyl-4- (1H-indazol-5-yl) -N, N-dimethyl-1H-1,2,3-triazole-5-carboxamide;
N, 1-dibenzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide;
N- (2-hydroxy-2-phenylethyl) -5- (1H-indazol-5-yl) -N-methylisoxazole-3-carboxamide;
N-[(1S) -2-hydroxy-1-phenylethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-benzyl-N- (2-hydroxyethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- [1-benzyl-5- (2-methylphenyl) -1H-1,2,3-triazol-4-yl] -3-methyl-1H-indazole;
5- [1-benzyl-5- (2-methylphenyl) -1H-1,2,3-triazol-4-yl] -1H-indazol-3-amine;
2- {2- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] ethyl} -1H-isoindole-1,3 (2H) -dione;
5- {4-[(2,4-dichlorophenoxy) methyl] -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- [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-ylethyl) -1H-1,2,3-triazole-5-carboxamide;
1-benzyl-N- [2- (dimethylamino) ethyl] -4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide;
1-benzyl-N- (2-hydroxyethyl) -4- (1H-indazol-5-yl) -N-propyl-1H-1,2,3-triazole-5-carboxamide;
1-benzyl-N- [3- (dimethylamino) propyl] -4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide;
1-benzyl-N- [2- (diethylamino) ethyl] -4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide;
N, 1-dibenzyl-N-ethyl-4- (1H-indazol-5-yl) -1H-1,2,3-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- (lH-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;
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] propanenitrile;
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-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-imidazol-5-yl) -1H-indazol-3-amine;
5- (1H-imidazol-4-yl) -1H-indazol-3-amine;
^{N 2,} N ² - dimethyl ^{-N 1 - {5- [1- (} 3- methylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-yl] glycinamide;
5- (1-benzyl-1H-imidazol-4-yl) -1H-indazol-3-amine;
^{N 1 - {5- [1- (} 4-tert- ^{butylbenzyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-yl}} -N ^{2, N} 2 - dimethylglycine An amide;
^{N 2,} N ² - dimethyl ^{-N 1 - {5- [1- (} 2- piperidin-1-ylethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-yl] Glycinamide;
^{N 2,} N ² - dimethyl ^{-N 1 - {5- [1- (} 2- morpholin-4-ylethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-yl} Glycinamide;
^{N 1 - (5- {1- [} 2- (3,5- dimethyl-isoxazol-4-yl) ethyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-yl ) ^{-N 2, N} 2 - dimethyl glycinamide;
^{N 1 - (5- {1- [} 2- (3,5- dimethyl-1H-pyrazol-4-yl) ethyl]-1H-1,2,3-triazol-4-yl}-1H-indazole -3 - ^yl) -N ^{2, N} 2 - dimethyl glycinamide;
2- (4- {3-[(N, N-dimethylglycyl) amino] -1H-indazol-5-yl} -1H-1,2,3-triazol-1-yl) -2-methylpropanoic acid ;
(4- {3-[(N, N-dimethylglycyl) amino] -1H-indazol-5-yl} -1H-1,2,3-triazol-1-yl) ethyl 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 - dimethyl glycinamide;
^{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- ^{benzo-oxadiazol-5-yl)-1H-indazol-3-yl]} -N ^{2, N} 2 - dimethyl glycinamide;
^{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 - dimethyl glycinamide;
N ¹ - {5- [2- (dimethylamino) ^{pyrimidin-5-yl]-1H-indazol-3-yl}} -N ^{2, N} 2 - dimethyl glycinamide;
^{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-ylethyl)-1H-pyrazol-4-yl]-1H-indazol-3-yl] glycinamide;
^{N 1 - [5- (-1H-} 1,2,3- ^{triazol-4-1-benzyl-5-cyclopropyl-yl)-1H-indazol-3-yl]} -N ^{2, N} 2 - dimethyl glycinamide;
N ¹ - [5- (1- ^{Benzyl-1H-pyrazol-4-yl)-1H-indazol-3-yl]} -N ^{2, N} 2 - dimethyl glycinamide;
N ¹ - [5- (-4- 1- benzyl-1H-1,2,3-triazol-yl)-1H-indazol-3-yl] -N ² - methyl glycine amide;
N- [5- (1-Benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-pyrrolidin-1-ylacetamide;
N ¹ - [5- (-4- 1- benzyl-1H-1,2,3-triazol-yl)-1H-indazol-3-yl] -N ² - cyclopentyl glycinamide;
N ¹ - [5- (-4- 1- benzyl-1H-1,2,3-triazol-yl)-1H-indazol-3-yl] -N ² - cyclopropyl glycinamide;
N ¹ - [5- (-4- 1- benzyl-1H-1,2,3-triazol-yl)-1H-indazol-3-yl] -N ² - tetrahydro -2H- pyran-4-yl glycinamide;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2- (3-hydroxypyrrolidin-1-yl) acetamide;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2- (3-hydroxypiperidin-1-yl) acetamide;
N ¹ - [5- (-4- 1- ^{benzyl-1H-1,2,3-triazol-yl)-1H-indazol-3-yl]} -N ^{3, N} 3 - dimethyl -β- alanine amide;
N- [5- (1-Benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-morpholin-4-ylacetamide;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2- (4-methylpiperazin-1-yl) 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- (-4- 1- benzyl-1H-1,2,3-triazol-yl)-1H-indazol-3-yl] -N ² - isopropyl glycinamide;
N ¹ - [5- (-4- 1- benzyl-1H-1,2,3-triazol-yl)-1H-indazol-3-yl] -N ² - cyclohexyl glycinamide;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] acetamide;
N ¹ - [5- (-4- 1- benzyl-1H-1,2,3-triazol-yl)-1H-indazol-3-yl] -N ² - cyclobutyl glycinamide;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N′-propylurea;
N- [5- (1-Benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] ethanesulfonamide;
5- (1-benzyl-1H-1,2,3-triazol-4-yl) -N- (cyclopropylmethyl) -1H-indazol-3-amine;
N- [5- (1-Benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -N′-ethylurea;
1- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] pyrrolidin-2-one;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -4- (dimethylamino) butanamide;
N-3,4-dihydro-1H-isochromen-4-yl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- (cyclohexylmethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- (3-chlorobenzyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (2-methoxybenzyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- [2- (trifluoromethyl) benzyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- [3- (trifluoromethyl) benzyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- [4- (trifluoromethyl) benzyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (pyridin-2-ylmethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (pyridin-3-ylmethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (pyridin-4-ylmethyl) isoxazole-3-carboxamide;
N- (2-chlorobenzyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- (4-chlorobenzyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (1-phenyl-2-piperidin-1-ylethyl) isoxazole-3-carboxamide;
N- [2- (1H-imidazol-1-yl) -1-phenylethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (2-morpholin-4-yl-1-phenylethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- [2- (4-methylpiperazin-1-yl) -1-phenylethyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (1-phenyl-2-pyrrolidin-1-ylethyl) isoxazole-3-carboxamide;
tert-butyl 2-({[5- (1H-indazol-5-yl) isoxazol-3-yl] carbonyl} amino) -2-phenylethylcarbamate;
5- (1H-indazol-5-yl) -N- (1-naphthylmethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (2-phenylethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (2-pyridin-2-ylethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (2-pyridin-3-ylethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N- (2-pyridin-4-ylethyl) isoxazole-3-carboxamide;
N- [2- (2-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- [2- (3-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- [2- (4-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-benzyl-N-ethyl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-methyl-N- (1-naphthylmethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-methyl-N- (2-phenylethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-methyl-N- (2-pyridin-2-ylethyl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1R) -1-phenylethyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-1,2,3,4-tetrahydronaphthalen-1-ylisoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1S) -1- (1-naphthyl) ethyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1R) -1- (1-naphthyl) ethyl] isoxazole-3-carboxamide;
N- [3- (dimethylamino) -1-phenylpropyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- (2,3-dihydro-1,4-benzodioxin-5-ylmethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- (3,4-dihydro-2H-1,5-benzodioxepin-6-ylmethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1-methyl-1H-indol-4-yl) methyl] isoxazole-3-carboxamide;
5- {3-[(3-phenylpyrrolidin-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole;
5- {3-[(2-phenylpyrrolidin-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole;
5- {3-[(2-phenylpiperidin-1-yl) carbonyl] isoxazol-5-yl} -1H-indazole;
5- (1H-indazol-5-yl) -N-[(1S) -1-phenylethyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1R) -1- (4-methylphenyl) ethyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1S) -1- (4-methylphenyl) ethyl] isoxazole-3-carboxamide;
N-[(1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-[(1R, 2R) -2-hydroxy-2,3-dihydro-1H-inden-1-yl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-[(1R) -1- (4-bromophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-[(1S) -1- (4-bromophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-[(1R) -1- (4-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N-[(1S) -1- (4-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1S) -1- (2-naphthyl) ethyl] isoxazole-3-carboxamide;
N- [1- (4-Ethoxyphenyl) -2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- [2-hydroxy-1- (4-isopropylphenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- [1- (3,4-dimethylphenyl) -2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- [2-hydroxy-1- (2-methoxyphenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- [2-hydroxy-1- (4-methylphenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1R) -1- (2-methoxyphenyl) ethyl] isoxazole-3-carboxamide;
N-[(1S) -1- (3,4-difluorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-[(1R) -1- (3-methoxyphenyl) ethyl] isoxazole-3-carboxamide;
5- (1H-indazol-5-yl) -N-{(1R) -1- [3- (trifluoromethyl) phenyl] ethyl} isoxazole-3-carboxamide;
N- [1- (2,3-dihydro-1,4-benzodioxin-6-yl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
N- [1- (3,5-dichlorophenyl) -2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide;
5- (1-Benzyl-1H-1,2,3-triazol-4-yl) -3-[({[6- (trifluoromethyl) pyridin-2-yl] amino} carbonyl) amino] -1H- Indazole-1-tert-butyl 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-ylacetamide;
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-morpholin-4-ylacetamide; and N- [5- ( 1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -1-methylpiperidine-2-carboxamide and the like, but are not limited thereto.

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

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

  As used herein, the term “alkenyl” is a straight or branched chain containing 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the elimination of two hydrogens. Means hydrocarbon. Representative examples of alkenyl include ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl and 3-decenyl. However, it is not limited to these.

  The term “alkoxy” as used herein, means an alkyl group, as de? Ned 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 de? Ned herein, appended to the parent molecular moiety through another alkoxy group, as de? Ned 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 de? Ned herein, appended to the parent molecular moiety through an alkyl group, as de? Ned 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 de? Ned herein, appended to the parent molecular moiety through an alkylene group, as de? Ned 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 de? Ned herein, appended to the parent molecular moiety through a carbonyl group, as de? Ned 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 de? Ned herein, appended to the parent molecular moiety through an alkyl group, as de? Ned 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 hydrocarbon having 1 to 10 carbon atoms. Representative examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2, Examples include, but are not limited to, 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 de? Ned herein, appended to the parent molecular moiety through a carbonyl group, as de? Ned herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl.

  The term “alkylcarbonylalkyl” as used herein, means an alkylcarbonyl group, as de? Ned herein, appended to the parent molecular moiety through an alkyl group, as de? Ned herein. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.

  The term “alkylcarbonyloxy” as used herein, means an alkylcarbonyl group, as de? Ned 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 hydrocarbon of 1 to 10 carbon atoms. Representative examples of alkylene include —CH ₂ —, —CH (CH ₃ ) —, —C (CH ₃ ) ₂ —, —CH ₂ CH ₂ —, —CH ₂ CH ₂ CH ₂ —, —CH ₂ CH _2. Examples include, but are not limited to, 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, attached to the parent molecular moiety through a —NR _g — group, as defined herein. To do.

  The term “alkylsulfinyl” as used herein, means an alkyl group, as de? Ned herein, appended to the parent molecular moiety through a sulfinyl group, as de? Ned 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 alkyl 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 de? Ned herein, appended to the parent molecular moiety through a sulfonyl group, as de? Ned 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 de? Ned herein, appended to the parent molecular moiety through an alkyl group, as de? Ned 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 de? Ned 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 de? Ned herein, appended to the parent molecular moiety through an alkylene group, as de? Ned herein. Representative examples of alkylthioalkyl include, but are not limited to, methylthiomethyl and 2- (ethylthio) ethyl.

  The term “alkynyl” as used herein is a straight or branched hydrocarbon group having from 2 to 10 carbon atoms, preferably straight chain and having at least one carbon-carbon triple bond. Point to. 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 phenyl fused to naphthyl or cycloalkyl, or phenyl fused to cycloalkenyl, or phenyl fused to a monocyclic heteroaryl ring as defined herein, or a single atom as defined herein. Phenyl fused to a cyclic heterocycle. The bicyclic aryl of the present invention must be attached to the parent molecular moiety through any available carbon atom contained within the phenyl ring. Representative examples of bicyclic aryl include 2,3-dihydro-1,4-benzodioxin-5-yl, 2,3-dihydro-1,4-benzodioxin-6-yl, 3,4-dihydro- Such as, but not limited to, 2H-1,5-benzodioxepin-6-yl, dihydroindenyl, indenyl, indol-4-yl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl is not. Tricyclic aryl is bicyclic aryl fused to anthracene or phenanthrene, or cycloalkyl, or bicyclic aryl fused to cycloalkenyl, or bicyclic aryl fused to phenyl. The tricyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the tricyclic aryl. Representative examples of tricyclic aryl rings include, but are not limited to, azulenyl, dihydroanthracenyl, fluorenyl, and tetrahydrophenanthrenyl.

The aryl group of the present invention is independently alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfinylalkyl, Alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, aryl ^* NC (O)-, aryl ^* NHC (O) NH-, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, mercapto, morpholino, _nitro, Z ₁ Z 2 N- Others may be substituted with 1, 2, 3, 4 or 5 substituents selected from _{(Z 3} Z 4 N) carbonyl. Aryl ^* may be substituted with 1, 2 or 3 substituents independently selected from alkyl, halo, cyano or nitro. Z ₁ and Z ₂ are each independently selected from hydrogen, alkyl or alkylcarbonyl.

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

  The term “aryl (hydroxy) alkyl” as used herein, as defined herein, is attached to the parent molecular moiety through an alkylene group having one hydroxy group, as defined herein. An aryl group is meant. 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 de? Ned herein, appended to the parent molecular moiety through a carbonyl group, as de? Ned 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 de? Ned 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 de? Ned herein, appended to the parent molecular moiety through an alkylene group, as de? Ned 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 a —N ₃ group.

  The term “azidoalkyl” as used herein, means an azido group, as de? Ned herein, appended to the parent molecular moiety through an alkylene group, as de? Ned 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 de? Ned herein, appended to the parent molecular moiety through an alkylene group, as de? Ned 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 de? Ned herein, appended to the parent molecular moiety through an alkylene group, as de? Ned herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl and 3-cyanopropyl.

  As used herein, the term “cycloalkenyl” is monocyclic or contains 3 to 10 carbons and contains at least one carbon-carbon double bond formed by elimination of 2 hydrogens. Means a bicyclic ring system. Representative examples of monocyclic ring systems include 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yl and 3-cyclopenten-1-yl, It is not limited to these. Examples of bicyclic ring systems include another monocyclic cycloalkyl ring as defined herein, a monocyclic aryl ring as defined herein, a monocyclic heterocycle as defined herein or a There are monocyclic cycloalkenyl ring systems fused to a monocyclic heteroaryl as defined herein. The bicyclic ring system of the present invention must be attached to the parent molecular moiety through an available carbon atom in the cycloalkenyl ring. Representative examples of bicyclic ring systems include 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 and the like, but are not limited thereto.

  The term “cycloalkyl” as used herein means a monocyclic, bicyclic or spirocyclic ring system. Examples of monocyclic ring systems are saturated cyclic hydrocarbon groups containing 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Examples of bicyclic cycloalkyl groups of the present invention include a monocyclic cycloalkyl ring fused to another monocyclic cycloalkyl ring, a monocyclic cycloalkyl ring fused to a cycloalkenyl, or a phenyl ring. A monocyclic cycloalkyl ring, or a monocyclic cycloalkyl ring fused to a monocyclic heteroaryl ring as defined herein, or a monocyclic cyclofused to a monocyclic heterocycle as defined herein. There is an alkyl ring. The bicyclic cycloalkyl ring system of the invention must be attached to the parent molecular moiety through an available carbon atom within the monocyclic cycloalkyl ring.

The cycloalkyl group of the present invention includes alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, carboxy, cyano, formyl, halo. Substituted with 1, 2, 3 or 4 substituents selected from alkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, oxo, Z ₁ Z ₂ N— or (Z ₃ Z ₄ N) carbonyl Also good.

  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 de? Ned herein, appended to the parent molecular moiety through a carbonyl group, as de? Ned 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 de? Ned herein, appended to the parent molecular moiety through an alkylene group, as de? Ned 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, as de? Ned herein, appended to the parent molecular moiety through an alkoxy group, as de? Ned 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, as de? Ned herein, appended to the parent molecular moiety through an alkylene group, as de? Ned 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. 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 2 double bonds and can contain 1, 2, 3 or 4 heteroatoms. The 6-membered ring contains 3 double bonds and can contain 1, 2, 3 or 4 heteroatoms. The 5 or 6 membered heteroaryl is attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryl include furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl. However, it is not limited to these. Bicyclic heteroaryl is a monocyclic aryl ring as defined herein, a monocyclic cycloalkyl ring as defined herein, a monocyclic cycloalkenyl ring as defined herein, another monocyclic Consists of heteroaryl or monocyclic heteroaryl fused to a monocyclic heterocycle as defined herein. The bicyclic heteroaryl ring system of the present invention must be attached to the parent molecular moiety through an available carbon atom in the heteroaryl ring. Bicyclic heteroaryl is attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the bicyclic heteroaryl. Representative examples of bicyclic heteroaryl include benzofuranyl, benzooxadiazolyl, 1,3-benzothiazolyl, benzimidazolyl, benzodioxolyl, benzothiophenyl, chromenyl, cinnolinyl, furopyridine, indolyl, indazolyl, isoindolyl, isoquinolinyl, Examples include, but are not limited to, naphthyridinyl, oxazolopyridine, quinolinyl, thienopyridine, and thienopyridinyl.

The heteroaryl group of the present invention is independently alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, 1 selected from 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 It may be substituted with 2, 3 or 4 substituents. Substituted heteroaryl groups of the present invention can exist as tautomers. The present invention encompasses 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.

  As used herein, the term “heterocycle” or “heterocyclic” refers to a monocyclic, bicyclic, tricyclic or spiro ring system containing 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. The 3 or 4 membered ring contains one heteroatom selected from the group consisting of O, N and S. The 5-membered ring contains 0 or 1 double bond and 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S. The 6- or 7-membered ring contains 1, 2 or 3 heteroatoms selected from the group consisting of 0, 1 or 2 double bonds and O, N and S. A monocyclic heterocycle is linked to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of monocyclic heterocycles include azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazol Azolidinyl, isoxazolinyl, isoxazolinyl, isoindoline-1,3-dione, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl , Pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomolylinyl) Holin sulfone), there are such thiopyranyl and trithianyl, but are not limited thereto. The bicyclic heterocycle of the present invention includes a phenyl group, a cycloalkyl group as defined herein, a cycloalkenyl group as defined herein, another monocyclic heterocycle group or monocycle as defined herein. Defined as a monocyclic heterocycle fused to a spirocyclic ring in which one carbon atom of the formula heterocycle is bridged by 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 within the heterocycle. Representative examples of bicyclic heterocycles include 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 and 1,2,3,4-tetrahydroquinolinyl However, it is not limited to these. A tricyclic heterocycle is fused to a bicyclic heterocycle fused to phenyl, a bicyclic heterocycle fused to cycloalkyl, a bicyclic heterocycle fused to cycloalkenyl, or a monocyclic heterocycle Bicyclic heterocycle. The tricyclic heterocycle is linked to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the tricyclic heterocycle. Representative examples of tricyclic heterocycles include 2,3,4,4a, 9,9a-hexahydro-1H-carbazoyl, 5a, 6,7,8,9,9a-hexahydrodibenzo [b, d] furanyl And 5a, 6,7,8,9,9a-hexahydrodibenzo [b, d] thienyl, but not limited thereto.

The heterocycles of the present invention are independently alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, aryl , Benzyl, 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) optionally substituted by 1, 2 or 3 substituents selected from carbonyl.

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

  The term “heterocyclic carbonyl” as used herein, means a heterocycle, as de? Ned herein, appended to the parent molecular moiety through a carbonyl group, as de? Ned herein.

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

  The term “hydroxyalkyl” as used herein, means at least one hydroxy group, as de? Ned herein, appended to the parent molecular moiety through an alkylene group, as de? Ned 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 de? Ned herein, appended to the parent molecular moiety through a carbonyl group, as de? Ned 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 de? Ned herein, appended to the parent molecular moiety through an alkylene group, as de? Ned herein. Representative examples of hydroxyalkoxyalkyl include, but are not limited to, (2-hydroxy-ethoxy) -ethyl and (3-hydroxyl-propoxyl) -ethyl.

  The term “hydroxy protecting group” or “O-protecting group” means a substituent that protects a hydroxyl group against undesirable reactions during synthetic procedures. Examples of hydroxy protecting groups include substituted methyl ethers such as methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl) -ethoxymethyl, benzyl and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl Ethers such as 2,2,2-trichloroethyl and t-butyl; silyl ethers such as trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclic acetals and ketals such as methylene acetal, acetonide and Examples include, but are not limited to, benzylidene acetals; cyclic orthoesters such as methoxymethylene; cyclic carbonates; and cyclic boronic esters. Commonly used hydroxy protecting groups are the work of Green et al. (TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999)).

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

  As used herein, the term “nitrogen protecting group” means a group for protecting an amino group against undesired reactions during synthesis. 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 a —NO ₂ group.

  The term “trialkylsilyl” as used herein, means three independently selected alkyl groups, as defined herein, attached to the parent molecular moiety through a silicon atom. Examples Representatives of trialkylsilyl include, but are not limited to, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, and triisopropylsilyl.

  The term “trialkylsilylalkyl” as used herein, means a trialkylsilyl group, as de? Ned herein, appended to the parent molecule through an alkylene group, as de? Ned herein. Representative examples of trialkylsilylalkyl include, but are not limited to, trimethylsilylmethyl, 2-trimethylsilylethyl, and 2-t-butyldimethylsilylethyl.

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

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

As used herein, the term “(Z ₃ Z ₄ N) carbonyl” refers to NZ ₃ Z _{4 as} defined herein attached to the parent molecular moiety through a carbonyl group as defined herein. Means group. 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 herein, means a ═O moiety.

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

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

The term “sulfonamido” as used herein, means a —SO ₂ NH ₂ group.

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

  The compounds of the present invention can exist as stereoisomers with asymmetric or chiral centers. These stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” as used herein are the arrangements defined in IUPAC (IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30). . The present invention contemplates various stereoisomers and mixtures thereof, and these are specifically included within the scope of the present invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds of the present invention can be prepared synthetically from commercially available raw materials containing asymmetric or chiral centers, or a racemic mixture is prepared followed by resolution known to those skilled in the art. Can be manufactured. Examples of these resolution methods include (1) addition of enantiomeric mixtures to chiral auxiliaries, separation of the resulting diastereomeric mixtures by recrystallization or chromatography, and from optically pure product auxiliaries. Or (2) direct separation of a mixture of optical enantiomers on a chiral chromatography column.

  The compounds and methods of the present invention can be better understood with reference to the following examples, which are intended to illustrate the invention and not to limit the scope of the invention. Absent. Moreover, any references in this specification are hereby incorporated by reference.

  Compound names are assigned using NamePro naming software provided by ACD / Labs. Alternatively, compound names are provided by MDL Information Systems GmbH (formerly Beilstein Information system) in Frankfurt, Germany, CHEMDRAW® ULTRA version 6.0.2 software package and ISIS Draw version Assigned using AUTONOM naming software that is part of 2.5, and compound names use the Struct = Name naming algorithm that is part of the CHEMDRAW® ULTRA version 9.0.7 software package. It is assigned by.

Abbreviations The abbreviations used in the following schemes and examples are as follows: DMF: NN-dimethylformamide, DMSO: dimethylsulfoxide, EtOAc: ethyl acetate, CHCl ₃ : chloroform, CH ₂ Cl ₂ : dichloromethane, CH ₃ CN: acetonitrile, THF: tetrahydrofuran, HATU: O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, EDC or EDCI: 1- (3-dimethylaminopropyl ) -3-ethylcarbodiimide hydrochloride, LC / MS: liquid chromatography / mass _{spectrometry,} NH 4 OAc: ammonium acetate, NaBH _{(OAc) 3:} sodium triacetoxyborohydride, PBS: bovine serum albumin, PBS: phosphate acid Impact saline, TMS: trimethylsilyl, MW: microwave, DMAP: 4- (dimethylamino) pyridine, dppf: 1,1′-bis (diphenylphosphino) ferrocene, TFA: trifluoroacetic acid, BINAP: 2, 2 '-Bis (diphenylphosphino) -1,1'-binaphthyl, TBAF: tetrabutylammonium fluoride, Tween: polyoxoethylene sorbitan monolaurate, HPLC: high performance liquid chromatography, DME: 1,2-dimethoxyethane , Boc: tert-butoxycarbonyl, BSA: bovine serum albumin, DTT: dithiothreitol, ATP: adenosine triphosphate, EDTA: ethylenediaminetetraacetic acid, HPMC: hydroxypropylmethylcellulose, TMB: 3, 3 ', 5, 5' -Te La methyl benzidine, and HEPES: 4-a (2-hydroxyethyl) -1-piperazine-ethanesulfonic acid.

Preparation of the Compounds of the Invention The compounds and methods of the invention are better understood in the context of the following synthetic schemes and examples that illustrate the means by which the compounds of the invention can be prepared.

As shown in Scheme 1, compounds of formula 2 that are representative of compounds of formula (I) can be prepared accordingly. R ₁ and R ₂ are as defined in formula (I) and X ₁ is iodo, bromo or chloro and can be obtained from commercial sources or synthesized according to methods known in the literature A compound of formula 1 is prepared in the presence of a palladium catalyst as reagent A-M ₁ (A is defined by formula (I), M ₁ is —Sn (R _z ) ₃ or —B (OR _y ) ₂ , R _z is alkyl or aryl and R _y is hydrogen, alkyl, aryl, or two R _y groups together with the boron atom to which they are attached form 1,3-dioxoborolane) Upon treatment, the compound of formula 2 is obtained. Such a reaction between a compound of formula 1 commonly known as Stille coupling and a compound of formula A-Sn (R _z ) ₃ is carried out at a temperature of about 25 ° C. to about 150 ° C. in a solvent such as toluene or DMF. , Tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), tris in the presence or absence of a ligand such as tri (2-furyl) phosphine or triphenylarsine (Dibenzylideneacetone) utilizes a palladium catalyst such as, but not limited to, dipalladium or palladium diacetate. In addition, Li (I), Cu (I) or Mn (II) salts can be added to increase reactivity and specificity. The reaction between the compound of formula 1 , commonly known as Suzuki coupling, and the compound of formula AB (OR _y ) ₂ consists of tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II) , A palladium catalyst such as, but not limited to, tris (dibenzylideneacetone) dipalladium or palladium diacetate. Aqueous K ₃ PO _{4 in} palladium ligands such as 2- (dicyclohexylphosphino) biphenyl, tri-t-butylphosphine or tris (2-furyl) phosphine, solvents such as toluene, dimethoxyethane, dioxane, water or DMF A base such as, but not limited to, cesium carbonate, potassium carbonate or Na ₂ CO ₃ can be added at a temperature of about 25 ° C. to about 150 ° C. The reaction can also be performed by heating in a microwave reactor oven.

Many organic stannanes are commercially available or have been described in the literature, but by treatment with a hexaalkyldistannan of formula ((R ₂ ) ₃ Sn) ₂ in the presence of Pd (Ph ₃ P) ₄ , A Another stannane can also be produced from halide or A-triflate. Similarly, from the corresponding halide or triflate (A-halo or A-triflate) by the metal exchange with organolithium followed by the addition of alkyl borate in the absence of a commercially available organoboron reagent, A- B (OR _y ) ₂ can be produced.

Compounds of formula 2 wherein R ₁ and R ₂ are as defined in formula (I) and A is a heteroaryl ring linked to the parent moiety via a nitrogen atom are prepared according to the method shown in Scheme 2. be able to. In the presence of a base such as (but not limited to) sodium t-butoxide or cesium carbonate and a metal catalyst such as, but not limited to, copper metal, CuI or palladium diacetate, and as appropriate A compound of formula I together with a ligand such as, but not limited to, BINAP or tri-tert-butylphosphine, is converted to a reagent of formula AH (where H is the nitrogen atom contained in heteroaryl ring A). The compound of formula 2 is obtained.

As described above in Scheme 1, the compound of formula (I) can be synthesized using the Stille coupling described in Scheme 3. In the presence of dichlorobis (triphenylphosphine) palladium (II) and (thiophene-2-carbonyloxy) copper in toluene under heating conditions, a compound of formula 3 wherein R _ii is defined by formula (I) Treatment with a compound of formula 4 wherein R ₁ is defined by formula (I) and P ₁ is a nitrogen protecting group such as, but not limited to, tert-butyloxycarbonyl or acetyl The compound of formula 5 is obtained. When the protecting group is tert-butyloxycarbonyl, hydrochloric acid or trifluoroacetic acid in a solvent such as acetic acid or dioxane, or when the protecting group is acetyl, sodium hydroxide, lithium hydroxide in an aqueous mixture of THF, isopropanol or dioxane Alternatively, treatment of a compound of formula 5 under conditions known to remove a protecting group such as potassium hydroxide yields a compound of formula 6 representative of a compound of formula (I) wherein A is (ii). .

The compound of formula 3 used in scheme 3 to obtain the compound of formula (I) can be prepared according to the method shown in scheme 4. A compound of formula 7 , which can be obtained from commercial sources or prepared according to methods known to those skilled in the art, can be obtained as 1,1,1-tributyl-N, N-dimethylstanamine or methylethyl When treated with carbamate, the compound of formula 8 is obtained. Heating an alkyne of formula 8 in the presence of a compound of formula 9 (R _ii is defined in formula (I) and N ₃ is an azide) provides a compound of formula 3 .

As shown in Scheme 5, a compound of formula 12 representing a compound of formula (I) where A is (ii) can be prepared according to the scheme. The presence of copper iodide, dichlorobis (triphenylphosphine) palladium (II) and triethylamine in a compound of formula 10 wherein R ₁ is defined by formula (I) and X ₁ is iodo, bromo, chloro or triflate Treatment with TMS acetylene below, followed by treatment with tetrabutylammonium fluoride or potassium hydroxide gives compounds of formula 11 . The reaction can be carried out in a solvent such as (but not limited to) DMF at room temperature or under heated conditions. When the compound of formula 11 is treated with R ₁₁ -Cl, sodium azide, copper sulfate and metal copper under heating conditions in a solvent such as dioxane, representative of the compound of formula (I) where A is (ii) To obtain a compound of formula 12 .

Alternatively, the compound of formula 13 is treated with TMS-acetylene in the presence of copper iodide, dichlorobis (triphenylphosphine) palladium (II) and triethylamine and then with tetrabutylammonium fluoride or potassium hydroxide, A compound of formula 14 is obtained. The reaction can be carried out in a solvent such as (but not limited to) DMF at room temperature or under heated conditions. Treatment of a compound of formula 14 with a compound of formula 9 _^ in which R ₁₁ is defined by formula (I) or sodium azide, copper sulfate and metallic copper under heating conditions gives the compound of formula 15 . When the compound of formula 15 is heated in the presence of hydrazine in ethanol, the compound of formula 16 is obtained. Treatment of the compound of formula 16 with di-tert-butyl dicarbonate and a catalytic amount of DMAP in a solvent such as THF or acetonitrile provides the compound of formula 17 . The compound of formula 17 is treated with a compound of formula 18 in the presence of a base such as pyridine in a solvent such as dichloromethane (but not limited to), treatment with trifluoroacetic acid, the compound of formula 19 Is obtained. Treatment of the compound of formula 16 with a carboxylic acid using carboxylic acid-amine coupling conditions known to those skilled in the art provides the compound of formula 19A . Standard carboxylate amine coupling conditions include 1-hydroxy-7-azabenzotriazole (HOAT) or 1-hydroxybenzotriazole hydrate (HOAT) in a solvent such as but not limited to dichloromethane. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1,3 in the presence or absence of an auxiliary reagent such as (but not limited to) HOBT) Dicyclohexylcarbodiimide (DCC), bis (2-oxo-3-oxazolinyl) phosphinic chloride (BOPCl), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyl Uronium hexafluorophosphate (HATU) or O-benzotriazol-1-yl- , N, N ', and the like is added a coupling reagent N'- tetramethyluronium tetrafluoroborate (TBTU), etc. (but not limited to).

Compounds of formula 24 that are representative of compounds of formula (I) can be prepared according to the scheme. The compound of formula 20 X ₁ is halo or triflate, the compound of formula 21 under heating, treatment with base, such as acetic anhydride and potassium acetate (but not limited to), a compound of formula 22 Is obtained. A compound of formula 22 may be prepared from a base such as sodium azide, copper sulfate, sodium carbonate and the compound of formula 23 (R _ii is defined by formula (I) and is available from commercial sources The compound of formula 24 is obtained.

As depicted in Scheme 8, compounds of formulas 29 and 30 , which are representative of compounds of formula (I), can be prepared according to the scheme. A compound of formula 25 in which R ₁ is defined by formula (I) and X ₁ is halo or triflate is converted to a compound of formula 23 _^ , copper iodide, dichlorobis (triphenyl) in DMF at room temperature or under heating conditions. Treatment with (phosphine) palladium (II) and triethylamine gives the compound of formula 27 . Treatment of a compound of formula 27 with a compound of formula 9 under heating conditions in a solvent such as but not limited to dioxane, provides compounds of formula 29 and 30 .

Compounds of formula 32 , wherein A is (vii) and R ₁ and R _vii are representative of compounds of formula (I) as defined in formula (I), can be prepared according to the scheme. Treatment of an aldehyde of formula 31 obtainable from a commercial source, where R _vii is defined by formula (I), with hydroxylamine hydrochloride and aqueous sodium hydroxide gives an oxime intermediate, which is Oxidation with chloramine T · trihydrate, followed by treatment with copper sulfate and copper wire and the compound of formula 11 , yields the compound of formula 32 .

Compounds of formula 38 , which are representative of compounds of formula (I) wherein A is (x) can be prepared according to the scheme. May be obtained from commercial sources, the compounds of formula 33 where R _1, which can be prepared by one skilled in the art are defined in formula (I) _^ a, using known acid coupling conditions to those skilled in the art Treatment with N, O-dimethylhydroxylamine gives the compound of formula 34. Standard carboxylic acid-amine coupling conditions include 1-hydroxy-7-azabenzotriazole (HOAT) or 1-hydroxybenzotriazole hydrate in a solvent such as but not limited to dichloromethane. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1, in the presence or absence of an auxiliary reagent such as (but not limited to) (HOBT) 3-dicyclohexylcarbodiimide (DCC), bis (2-oxo-3-oxazolinyl) phosphinic chloride (BOPCl), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'- Tetramethyluronium hexafluorophosphate (HATU) or O-benzotriazol-1-y -N, N, N ', and the like is added a coupling reagent N'- tetramethyluronium tetrafluoroborate (TBTU), etc. (but not limited to). Treatment of the compound of formula 34 with a Grignard reagent such as benzylmagnesium bromide in a solvent such as tetrahydrofuran at room temperature or below gives the compound of formula 35 . Treatment of a compound of formula 35 with a protecting group reagent such as (but not limited to) di-tert-butyl dicarbonate and a catalytic amount of DMAP in a solvent such as THF or acetonitrile yields a compound of formula 36 Is obtained. The compound of formula 36, without heating or under heating, in a solvent such as THF (but not limited to), when treated with pyridinium tribromide, the compound of formula 36A can be obtained. Treatment of a compound of formula 36A with a compound of formula 37 with or without heating and then treating the product under conditions that remove the nitrogen protecting group yields a compound of formula 38 . Commonly used nitrogen protecting groups and methods for their removal are described by Green et al. (TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York). (1999)).

A person of ordinary skill in the art treating a compound of formula 36 wherein R ₁ is defined by formula (I) and P ₁ is a nitrogen protecting group with a compound of formula 39 under heating conditions and then removing the nitrogen protecting group Treatment of the product according to methods described in the literature under conditions known in ii. Yields compounds of formula 40 which are representative of compounds of formula (I) wherein A is (xvii).

As depicted in Scheme 12, a compound of formula 47 representing a compound of formula (I) where A is (x) can be prepared according to the scheme. Treatment of a compound of formula 41 in which R ₁ is defined by formula (I) with di-tert-butyl dicarbonate and a catalytic amount of DMAP in a solvent such as THF or acetonitrile yields a compound of formula 42. . Treatment of the compound of formula 42 with tributyl (1-ethoxyvinyl) stannane and dichlorobis (triphenylphosphine) palladium (II) provides the compound of formula 44 . Treatment of a compound of formula 44 with pyridinium tribromide in THF provides a compound of formula 45 . The compound of formula 45 in a solvent such as ethanol (but not limited to), the R _x is treated with a compound of formula 46 as defined in formula (I), a compound of formula 47 is obtained.

As shown in Scheme 13, compounds of Formula 51 , which represent compounds of Formula (I) where A is (iv), can be prepared according to the scheme. Any of the compounds of formula 48 wherein R ₁ is defined by formula (I) and are available from commercial sources, or can be prepared according to literature procedures or according to the methods described herein. Heating in the presence of both a compound of formula 49 and a compound of formula 50 that is commercially available or can be prepared by one skilled in the art using procedures described in the literature provides the compound of formula 51 .

As shown in Scheme 14, a compound of Formula 55 , which represents a compound of Formula (I), where A is (xiv), (xv), (xvi) or (xvii) can be prepared according to the scheme. Treatment of a compound of formula (52) where R ₁ is defined by formula (I) with butyllithium, followed by treatment with DMF, followed by an acidic workup provides a compound of formula 48 . A compound of formula 48 is converted to a compound of formula 51 (X is —CH—, —N— or —S—, Y is —CH—, —N— or a bond) and scandium tri (triflate). Treatment and then treatment with a compound of formula 54 (Z _a is defined in formula (I)) gives a compound of formula 55 .

As depicted in Scheme 15, compounds of formula 56 , which are representative of compounds of formula (I), wherein A is (vii) can be prepared according to the scheme. A compound of the formula (11) in which R ₁ is defined by the formula (I) is mixed with a base such as (but not limited to) triethylamine and the like such as ethyl 2-chloro-2- (hydroxyimino) acetate (this The compound of formula 56 is obtained. The reaction can be performed in a solvent such as but not limited to toluene and may require the use of heating.

As depicted in Scheme 16, compounds of formula 29 that are representative of compounds of formula (I) where A is (ii) can be prepared according to the scheme. A compound of formula (27), wherein R ₁ is defined by formula (I), is converted to a compound of formula 9 , R _ii C (O) Cl or ICl in a solvent such as but not limited to tetrahydrofuran. Treatment with CuI and triethylamine gives the compound of formula 29 . The reaction can be carried out at room temperature or with heating.

As depicted in Scheme 17, compounds of Formula 57 that are representative of compounds of Formula (I) where A is (vi) can be prepared according to the scheme. Treatment of a compound of formula 45 where R ₁ is defined by formula (I) with ammonium formate and formic acid provides a compound of formula 57 .

As depicted in Scheme 18, compounds of formula 58 , which are representative of compounds of formula (I), wherein A is (vii) can be prepared according to the scheme. Treatment of a compound of formula 48 where R ₁ is defined by formula (I) with nitromethane provides a compound of formula 58 (Organic Preparations and Procedures International, 2001, 33, 381-386).

As depicted in Scheme 19, a compound of formula 60 , which is representative of a compound of formula (I) where A is (vi), can be prepared according to the scheme. Compounds of formula 48 , wherein R ₁ is defined by formula (I), are converted to 1- (isocyanomethylsulfonyl) -4-methylbenzene, 59 and potassium carbonate in a solvent such as methanol or tetrahydrofuran (limited to this). Treatment with a suitable base), followed by treatment with a suitable acid, such as hydrochloric acid, provides the compound of formula 60 .

As depicted in Scheme 20, compounds of formula 63 that are representative of compounds of formula (I) where A is (vi) can be prepared according to the scheme. Treatment of a compound of formula 33 where R ₁ is defined by formula (I) with a suitable chlorinating agent such as thionyl chloride provides the compound of formula 61 . Treatment of the compound of formula 61 with 2- (trimethylsilyl) -2H-1,2,3-triazole 62 in a solvent such as sulfolane provides the compound of formula 63 .

As depicted in Scheme 21, compounds of formula 66 that are representative of compounds of formula (I) where A is (ix) can be prepared according to the scheme. Treatment of a compound of formula 61 in which R ₁ is defined by formula (I) with hydrazine in a suitable solvent such as tetrahydrofuran provides a compound of formula 64 . A compound of formula 64 when treated with trimethyl orthoformate 65 in the presence of a catalytic amount of p- toluenesulfonic acid in a solvent such as tetrahydrofuran, a compound of formula 66 is obtained.

As depicted in Scheme 22, the compound of formula 69 , wherein A is representative of the compound of formula (I), as defined in formula (I), can be prepared according to the scheme. _Ry is hydrogen, alkyl, aryl in the presence of palladium catalyst using the Suzuki reaction conditions described in Scheme 1 in the presence of heteroaryl iodide (AI), or two R _y groups are The compound of formula 67 , which forms 1,3-dioxoborolane with their bonded boron atoms, gives the compound of formula 68 . The compound of formula 68 is converted to the compound of formula 69 upon treatment with hydrazine according to the method described in Scheme 6.

As depicted in Scheme 23, compounds of formula 74 wherein R _ii and R ₄ are representative of compounds of formula (I) as defined for formula (I) are those wherein X ₁ is iodo, bromo or chloro The compound of formula 70 is produced as a raw material. As shown in Scheme 6, treatment of the compound of formula 70 first with hydrazine and then with di-tert-butyl dicarbonate provides the compound of formula 71 . When the compound of formula 71 is reacted with the acid chloride of formula 18 in the presence of a base such as potassium carbonate in tetrahydrofuran at room temperature for 2 to 8 hours, the compound of formula 72 is obtained. Alternatively, the compound of formula 72 can be prepared from the compound of formula 71 using the conditions described in Scheme 6. Reaction of the compound of formula 72 with (trimethylsilyl) acetylene under the conditions described in Schemes 5 and 6 yields the compound of formula 73 . Copper (II) sulfate and sodium (R) -2-((S) -1,2-dihydroxyethyl) -4-hydroxy-5-oxo-2,5-dihydro at 0 to 80 ° C. over 1 to 6 hours Treatment with R _ii -N ₃ in aqueous t-butanol in the presence of furan-3-olate provides the compound of formula 74 from the compound of formula 73 .

As depicted in Scheme 24, compounds of formula 76 , wherein A and R ₄ are representative of compounds of formula (I), as defined for formula (I), are obtained from compounds of formula 75 . Using the Suzuki reaction conditions described in Scheme 1, in the presence of a palladium catalyst, AB (OR _y ) ₂ (A is as defined for formula (I) and R _y is hydrogen, alkyl, aryl. or, by the two R _y groups treating a compound of formula 75 in which they are formed 1,3 Jiokisobororan with boron atom bonded), to give compounds of formula 76.

As depicted in Scheme 25, compounds of formula 80 , wherein R _ii and R ₄ are representative of compounds of formula (I), as defined for formula (I), are prepared according to the scheme. Reaction of compounds of formulas 77 and 78 under Still coupling conditions described in Scheme 3 yields compounds of formula 79 . When the compound of formula 79 is reacted according to the method described in Scheme 6, the compound of formula 80 is obtained.

As depicted in Scheme 26, Formulas 82 , 83 , 84 , wherein A, R ₄ , R ₅ , R _a and R _j are representative of compounds of Formula (I) as defined for Formula (I) Compounds of and 85 are prepared from compounds of formula 81 . The compound of formula 82 can be obtained by treating the compound of formula 81 with the acid chloride 18 in a solvent such as tetrahydrofuran in the presence of a base such as potassium carbonate or triethylamine. An alternative solvent is dichloromethane and an alternative base is pyridine. The acid chloride can be prepared from the corresponding carboxylic acid by treatment with oxalyl chloride with a catalytic amount of N, N-dimethylformamide. To produce the compound of formula 83, the compound of formula 81 can be treated with R _j NCO in heated pyridine. The compound of formula 84 is prepared from the compound of formula 81 by treatment with R ₅ SO ₂ Cl in pyridine at or near room temperature. The compound of formula 85 is reduced 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. Removal of the t-butoxycarbonyl protecting group by an amination reaction followed by treatment with trifluoroacetic acid in dichloromethane is also prepared from the compound of formula 81 .

As depicted in Scheme 27, compounds of formula 87 where A, R _j and R _k are as defined for formula (I) can be prepared from compounds of formula 86 . The compound of formula 86 is prepared according to the method described for the compound of formula 82 in Scheme 26. The compound of formula 86 can then be heated in the presence of a base such as amine, HNR _j R _k and triethylamine in a solvent such as acetonitrile to give a compound of formula 87 . Alternatively, in place of the amine, a heterocyclic ring such as pyrrolidine, piperidine, piperazine and morpholine can be used.

As depicted in Scheme 28, a compound of formula 89 in which A, R ₁ , R ₂ , R ₃ , m, Z _c and Z _d are as defined for formula (I) is prepared from a compound of formula 88 be able to. Compounds of formula 88 can be prepared according to the methods described in Schemes 1 to 4, 7 to 9, 22, 24 and 26. In preparing the compound of formula 88 , the carboxylic acid moiety pendant group on A can be protected as an ester and then hydrolyzed to expose the carboxylic acid by methods known to those skilled in the art of organic synthesis. Treatment of the compound of formula 88 with an amine (HNZ _c Z _d ) using carboxylic acid-amine coupling conditions known to those skilled in the art provides the compound of formula 89 . Standard carboxylic acid amine coupling conditions include 1-hydroxy-7-azabenzotriazole (HOAT) or optionally in a solvent such as but not limited to dichloromethane or N, N-dimethylformamide. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide in the presence or absence of adjuvant reagents such as but not limited to 1-hydroxybenzotriazole hydrate (HOBT) Hydrochloride (EDCI), 1,3 dicyclohexylcarbodiimide (DCC), bis (2-oxo-3-oxazolinyl) phosphinic chloride (BOPCl), O- (7-azabenzotriazol-1-yl) -N, N , N ′, N′-Tetramethyluronium hexafluorophosphate (HAT Or a coupling reagent such as (but not limited to) O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium tetrafluoroborate (TBTU) is there.

EXAMPLES The compounds and methods of the present invention can be better understood with reference to the following examples, which are intended to illustrate the invention and limit the scope of the invention. It is not a thing.

Example 1
5- (1-Benzyl-1H-1,2,3-triazol-5-yl) -1H with 5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole -Indazole complex (Example 1A)
A solution of tert-butyl 4 -iodo-1H-indazole-1-carboxylate 5-iodo-1 -methylaniline (20 g, 83.24 mmol) in chloroform (250 mL) was cooled in an ice bath and acetic anhydride (21. 2 g, 208.11 mmol) in chloroform (50 mL) was added dropwise. When the addition was complete, 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 layer was dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure. The crude solid was washed with methanol, dissolved in tetrahydrofuran (200 mL) and treated with a heated aqueous solution of KOH (60 g) (water 200 mL). The mixture was stirred for 15 minutes and treated with 6N HCl to pH1. The layers were separated and the organic layer was dried over sodium sulfate, filtered and 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 (ca. 5 mg) were added. The mixture was stirred at room temperature for 2 hours, diluted with water, extracted with dichloromethane, dried over sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to give the title compound. MS (ESI +) m / z 344.9 (M + H) ^<+> .

(Example 1B)
Tert-Butyl 5-((trimethylsilyl) ethynyl) -1H-indazole-1-carboxylate 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) under 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 1N hydrochloric acid. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 5% to 40% ethyl acetate / hexanes to give the title compound. MS (ESI +) m / z 215.0 (M-99) ^<+> .

(Example 1C)
5- Ethynyl -1H-indazole Example 1B (7.93 g, 25.2 mmol) was dissolved in methanol (150 mL). 1N potassium hydroxide solution (50 mL) was added and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the resulting slurry was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give 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 with 5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole -To the indazole complex microwave vial was added 100.0 mg (0.70 mmol) of Example 1C and 94 mg (0.70 mmol) of benzyl azide. The mixture was heated at 160 ° C. for 20 minutes using microwave irradiation (CEM-Discoverer, 100 Watts, 1 minute ramp time). The mixture was dissolved in ethyl acetate and purified by silica gel chromatography eluting with 75% ethyl acetate / hexanes to give the title compound. ¹ 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)
In a 5- (1H-1,2,3-triazol-5-yl) -1H-indazole microwave vial, 100.0 mg (0.70 mmol) of Example 1C, 81 mg (0.7 mmol) of trimethylsilyl azide, CuI (4 mg) ) And dimethylformamide / methanol (1 mL, 9: 1). The mixture was heated at 160 ° C. for 20 minutes using microwave irradiation (CEM-Discover, 100 Watts, 1 minute ramp time). The mixture was dissolved in ethyl acetate and the organic layer was washed with water. The organic layer was dried over anhydrous MgSO ₄ , filtered, concentrated under reduced pressure and purified by silica gel chromatography eluting with 80% ethyl acetate / hexanes 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)
A solution of tert-butyl 5-iodo-1H-indazole-1-carboxylate 4-iodo-2-methylaniline (20 g, 83.24 mmol) in chloroform (250 mL) was cooled in an ice bath and used with a dropping funnel. A solution of acetic anhydride (21.2 g, 208.11 mmol) in chloroform (50 mL) was added dropwise. When the addition was complete, 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, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude solid was washed with methanol, dissolved in tetrahydrofuran (200 mL) and treated with a heated aqueous solution of KOH (60 g) (water 200 mL). The mixture was stirred for 15 minutes and treated with 6N HCl to pH1. The layers were separated and the organic layer was dried over sodium sulfate, filtered and 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 (about 5 mg) were added. . The mixture was stirred at room temperature for 2 hours, quenched with water, extracted with dichloromethane, dried over sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to give the title compound. MS (ESI +) m / z 344.9 (M + H) ^<+> .

(Example 3B)
Tert-Butyl 5-((trimethylsilyl) ethynyl) -1H-indazole-1-carboxylate 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) were combined in triethylamine (70 mL) under 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 1N hydrochloric acid. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 5% to 40% ethyl acetate / hexanes to give the title compound. MS (ESI +) m / z 215.0 (M-99) ^<+> .

(Example 3C)
5- Ethynyl -1H-indazole Example 3B (7.93 g, 25.2 mmol) was dissolved in methanol (150 mL). 1N potassium hydroxide solution (50 mL) was added and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the resulting slurry was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give 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 3D)
5- (1-Benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole Example 3C (40 mg, 0.28 mmol), benzyl azide (37 mg, 0.28 mmol), CuSO ₄ (14 mg , 0.056 mmol) and Cu wire (14 mg) were combined in tert-butanol (0.5 mL) and water (0.5 mL) and heated in a CEM-discover microwave at 125 ° C. and 100 Watts for 10 minutes. To the mixture was added 1M HCl and water and the product was extracted with dichloromethane and purified by silica gel chromatography (50% ethyl acetate / hexanes) to give 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 Teflon® coated micro-flea stir bar Into a 5 mL CEM microwave reaction tube was added 300 μL of an aqueous solution containing 17.6 mg (0.124 mmol) of Example 3C and 7.80 mg (0.118 mmol) of sodium azide, and then 15.79 μL of 2-methyl-benzyl bromide ( 0.118 mmol; 21.80 mg, 0.95 equivalent) (added undiluted) was added. To the suspension was added tert-butanol 300 μL; copper wire 25 mg; and finally 50 μL of 1N copper sulfate pentahydrate in water. The microwave reaction vessel was capped and heated in a CEM-discover microwave at 100 watts power at 125 ° C. for 10 minutes with stirring. After cooling to room temperature, the mixture was diluted with 0.25N aqueous HCl and the aqueous suspension was extracted with dichloromethane. The organic layer was washed with distilled water and saturated aqueous NaCl solution, then dried over anhydrous sodium sulfate and filtered. The dehydrated solution was diluted with acetonitrile and the soluble organic material was filtered through a glass wool layer with additional anhydrous sodium sulfate. A small sample of the filtrate was removed and used for subsequent LC / MS analysis. The solution containing the desired triazole product was evaporated under reduced pressure and then redissolved in 1.50 mL of 1: 1 DMSO / methanol. The crude triazole product solution was purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution 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)
Example 5 Using 3-methyl-benzyl bromide instead of 5- [1- (3-methylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole 2-methylbenzyl bromide The title compound was prepared according to the procedure described in. 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 4-methyl-benzyl bromide was used instead of 2-methylbenzyl bromide Example 4 The title compound was prepared according to the procedure described in. 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 3-methoxylbenzyl bromide was used instead of 2-methyl-benzyl bromide Example 4 The title compound was prepared according to the procedure described in. 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)
Example 5 Using 2-fluorobenzyl bromide instead of 5- [1- (2-fluorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole 2-methyl-benzyl bromide The title compound was prepared according to the procedure described in. 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
Example 5 using 3-fluorobenzyl bromide instead of 5- [1- (3-fluorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole 2-methyl-benzyl bromide The title compound was prepared according to the procedure described in. ¹ 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 4-fluorobenzyl bromide was used instead of 2-methyl-benzyl bromide Example 4 The title compound was prepared according to the procedure described in. 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)
Example 5 Using 2-chlorobenzyl bromide instead of 5- [1- (2-chlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole 2-methyl-benzyl bromide The title compound was prepared according to the procedure described in. 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)
Example 5 Substituting 3-chlorobenzyl bromide for 5- [1- (3-chlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole 2-methyl-benzyl bromide The title compound was prepared according to the procedure described in. 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 4-chlorobenzyl bromide was used instead of 2-methyl-benzyl bromide Example 4 The title compound was prepared according to the procedure described in. 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 / z307.7 ( M-H) -.

(Example 14)
Example 5 Using 2-bromobenzyl bromide instead of 5- [1- (2-bromobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole 2-methyl-benzyl bromide The title compound was prepared according to the procedure described in. 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)
Example 5 Using 2-nitrobenzyl bromide instead of 5- [1- (2-nitrobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole 2-methyl-benzyl bromide The title compound was prepared according to the procedure described in. 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)
Example 5 Substituting 3-nitrobenzyl bromide for 5- [1- (3-nitrobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole 2-methyl-benzyl bromide The title compound was prepared according to the procedure described in. 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 Example 4 using 4-nitrobenzyl bromide instead of 2-methyl-benzyl bromide The title compound was prepared according to the procedure described in. 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 2-cyanobenzyl bromide was used instead of 2-methyl-benzyl bromide The title compound was prepared according to the procedure described in Example 4. 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 3-cyanobenzyl bromide is used instead of 2-methyl-benzyl bromide The title compound was prepared according to the procedure described in Example 4. 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 4-cyanobenzyl bromide was used instead of 2-methyl-benzyl bromide The title compound was prepared according to the procedure described in Example 4. 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 instead of 2-methyl-benzyl bromide 2-trifluoromethylbenzyl bromide The title compound was prepared according to the procedure described in Example 4 using 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 instead of 2-methyl-benzyl bromide 3-trifluoromethylbenzyl bromide The title compound was prepared according to the procedure described in Example 4 using 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)
4- {1- [4- (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole instead of 2-methyl-benzyl bromide 4-trifluoromethylbenzyl bromide The title compound was prepared according to the procedure described in Example 4 using 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 2-methyl-benzyl bromide instead of 3-trifluoromethoxybenzyl bromide The title compound was prepared according to the procedure described in Example 4 using 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)
4- {1- [4- (trifluoromethoxy) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole instead of 2-methyl-benzyl bromide 4-trifluoromethoxybenzyl bromide The title compound was prepared according to the procedure described in Example 4 using 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)
Instead of 5- [1- (4-tert-butylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole 2-methyl-benzyl bromide, 4-tert-butylbenzyl bromide was used. The title compound was prepared according to the procedure described in Example 4. 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)
3-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} benzoic acid methyl 2- methyl -benzyl bromide instead of 3-carbomethoxybenzyl bromide The title compound was prepared according to the procedure described in Example 4 using 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)
4-{[4- (1H-indazol-5-yl) -1H-1,2,3-triazol-1-yl] methyl} methyl benzoate instead of methyl 2-methyl-benzyl bromide 4-carbomethoxybenzyl bromide The title compound was prepared according to the procedure described in Example 4 using 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)
Instead of 5- [1- (2,4-dimethylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole 2-methyl-benzyl bromide, 2,4-dimethylbenzyl chloride is used. The title compound was prepared according to the procedure described in Example 4. 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)
Instead of 5- [1- (3,5-dimethylbenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole 2-methyl-benzyl bromide, 3,5-dimethylbenzyl bromide was used. The title compound was prepared according to the procedure described in Example 4. 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)
Instead of 5- [1- (2,3-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole 2-methyl-benzyl bromide, 2,3-dichlorobenzyl chloride is used. The title compound was prepared according to the procedure described in Example 4. 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)
Instead of 5- [1- (2,4-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole 2-methyl-benzyl bromide, 2,4-dichlorobenzyl chloride is used. The title compound was prepared according to the procedure described in Example 4. 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 / z341.8 ( M-H) -.

(Example 33)
Instead of 5- [1- (2,5-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole 2-methyl-benzyl bromide, 2,5-dichlorobenzyl chloride is used. The title compound was prepared according to the procedure described in Example 4. 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)
Instead of 5- [1- (3,5-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] -1H-indazole 2-methyl-benzyl bromide, 3,5-dichlorobenzyl chloride is used. The title compound was prepared according to the procedure described in Example 4. 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)
Instead of 5- {1- [2,4-bis (trifluoromethyl) benzyl] -1H-1,2,3-triazol-4-yl} -1H-indazole 2-methyl-benzyl bromide 2,4- The title compound was prepared according to the procedure described in Example 4 using 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, a solution of 1.6 Mn-butyllithium in hexane (40 mL, 63.44 mmol) was added dropwise. Dimethylformamide (3.9 mL, 50.75 mmol) was added and the mixture was warmed to room temperature and stirred for 15 minutes. The mixture was quenched with water, extracted with ethyl acetate, preabsorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10% to 30% ethyl acetate / hexanes 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 Example 36A (50 mg, 0.34 mmol) and 2-aminothiazole (28 mg 0.34 mmol) was combined with scandium trifate (8 mg, 0.017 mmol) in dehydrated methanol (1 mL) in a 4 mL vial. The vial was sealed and shaken at room temperature for 30 minutes. Cyclohexyl isocyanide (42 mL, 0.34 mmol) was added and the mixture was shaken at room temperature for 2 days. The mixture was purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution to afford the title compound as 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- 2-aminopyridine in place of 2-aminothiazole and following the procedure described in Example 36B. The title compound was prepared. 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)
Instead of N-cyclohexyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrazin-3-amine- 2-aminopyrazine-2-aminothiazole, following the procedure described in Example 36B. The title compound was prepared. 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 = 0.58 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)
To a 20 mL scintillation vial of 5- [1-benzyl-4- (4-fluorophenyl) -1H-imidazol-5-yl] -1H-indazole was added 50.0 mg (0.34 mmol) of Example 36A. To the solid was added 2.0 mL of a dimethylformamide solution containing 0.46 mmol (49 mg) of benzylamine and 50 mg of powder activated 4Å molecular sieves. The vial was capped and heated on an orbital shaker at 60 ° C. for 4 hours. The vial was allowed to cool to room temperature and the cap was removed. To the suspension was added anhydrous potassium carbonate 32 mg (0.23 mmol) and then α- (p-toluenesulfonyl) -4-fluorobenzylisonitrile 66 mg (0.23 mmol). The vial was capped and heated on a shaker at 60 ° C. overnight. The vial was removed from the shaker, allowed to cool to room temperature, and the resulting suspension was filtered. The filtrate was evaporated under reduced pressure with moderate heating on a Savant Speed Vac. The crude residue was redissolved in 1: 1 DMSO / methanol and purified by reverse phase HPLC using acetonitrile / water TFA gradient elution to give the title compound as 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 (DCI) m / z 369 (M + H) ^<+> .

(Example 40)
N- {3- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] propyl} -N, N-dimethylamine instead of benzylamine N ^The title compound was prepared as the TFA salt according to the procedure described in Example 39 using 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 (DCI) m / z 364 (M + H) ^<+> .

(Example 41)
N-cyclohexyl-2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-amine described in Example 36B using pyrimidine-2-amine instead of thiazol-2 -amine The title compound was prepared as a TFA salt according to the procedure. 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 = 11.009 Hz, 2H) 1.00-1.14 (m, 3H). MS (ESI +) m / z 333.1 (M + H) ^<+> .

(Example 42)
In Example 39, 1-phenylethanamine was used instead of 5- [4- (4-fluorophenyl) -1- (1-phenylethyl) -1H-imidazol-5-yl] -1H-indazolebenzylamine. The title compound was prepared according to the described procedure. 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 (DCI) m / z 383 (M + H) ^<+> .

(Example 43)
2- (1H-indazol-5-yl) -N-isopropylimidazo [1,2-a] pyrimidin-3-amine In a 4 mL vial, Example 36A (42 mg, 0.287 mmol) and 2-aminopyrimidine (27 mg, 0.284 mmol) was combined with scandium trifate (7 mg, 0.014 mmol) in dehydrated methanol (2 mL). The vial was sealed and shaken at room temperature for 30 minutes. Isopropyl isocyanide (27 mL, 0.286 mmol) was added and the mixture was shaken overnight at room temperature and then at 40 ° C. for 2 hours. The mixture was absorbed onto silica gel and purified using silica gel chromatography eluting with a gradient of 0% to 5% methanol / dichloromethane 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 0.03 (d, J = 6.78, 4.07 Hz, 1H) 6.54 (d, J = 4.75 Hz, 1H) 4.86 (d, J = 0.09 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 (ca. 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 room temperature overnight. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 40% ethyl acetate / hexanes to give the title compound. MS (ESI +) m / z 297.2 (M + H) ^<+> .

(Example 44B)
Tert-Butyl 5-acetyl-1H-indazole-1-carboxylate Example 44A (5.12 g, 17.2 mmol), tributyl (1-ethoxyvinyl) tin (7.0 mL, 20.7 mmol) and dichlorobis (triphenyl) Phosphine) palladium (II) (672 mg, 0.957 mmol) was combined in toluene (85 mL). Nitrogen was bubbled through the mixture for 5 minutes and the mixture was heated in a sealed tube at 100 ° C. overnight. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 40% ethyl acetate / hexanes to give the title compound. MS (ESI +) m / z 283.0 (M + Na) ^<+> .

(Example 44C)
Tert-Butyl 5- (2-bromoacetyl) -1H-indazole-1-carboxylate Example 44B (1.60 g, 6.15 mmol) and pyridinium tribromide (1.98 g, 6.19 mmol) in tetrahydrofuran Combined and heated to 40 ° C. for 2 hours. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 40% ethyl acetate / hexanes 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 In a 4 mL vial, Example 44C (71 mg, 0.208 mmol) and 1-phenyl-2-thiourea ( 33 mg, 0.217 mmol) were combined in ethanol (300 mL). The vial was shaken overnight at 80 ° C. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of methanol / dichloromethane (0% to 5%) 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, substituting thioacetamide for 1-phenyl-2-thiourea. . 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 Substituting ethylthiourea for 1-phenyl-2-thiourea according to the procedure described in Example 44D The compound was prepared. 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)
Example 44D substituting 1-benzyl-2-thiourea for N-benzyl-4- (1H-indazol-5-yl) -1,3-thiazol-2-amine 1-phenyl-2-thiourea The title compound was prepared according to the procedure described in 1. 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 using thiourea instead of 1-phenyl-2-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 Implemented using 1-phenethylthiourea instead of 1-phenyl-2-thiourea The title compound was prepared according to the procedure described in Example 44D. 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- amineisopropyl isocyanide was used in place of benzyl isocyanide to prepare the title compound according to the procedure described in Example 43. did. 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 -amineisopropyl isocyanide was used in place of butyl isocyanide to prepare the title compound according to the procedure described in Example 43. did. 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)
As described in Example 43, 4-chlorophenyl isocyanide was used in place of N- (4-chlorophenyl) -2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3 -amineisopropyl isocyanide. The title compound was prepared according to the procedure. 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)
Example 43 uses 4-methoxyphenyl isocyanide instead of 2- (1H-indazol-5-yl) -N- (4-methoxyphenyl) imidazo [1,2-a] pyrimidin-3 -amineisopropyl isocyanide. The title compound was prepared according to the described procedure. 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 is prepared according to the procedure described in Example 44D using 2-aminopyrimidine instead of 1-phenyl-2-thiourea. did. 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 0.03 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)
N- [2- (1H-Indazol-5-yl) imidazo [1,2-a] pyridin-3-yl] glycinate 2-aminothiazole instead of 2-aminopyridine and cyclohexyl isocyanide The title compound was prepared as the TFA salt using methyl 2-isocyanoacetate according to the procedure described in Example 36B. 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 2-aminothiazole is used instead of 2-aminopyridine, and benzyl isocyanide is used instead of cyclohexyl isocyanide. The title compound was prepared according to the procedure described in Example 36B. The final product precipitated from solution and was isolated after filtration. ¹ H NMR (400 MHz, DMSO-d ₆ ) dppm 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 .14Hz, 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 Uses 2-aminopyridine instead of 2-aminothiazole and replaces with cyclohexylisocyanide The title compound was prepared according to the procedure described in Example 36B using 1-chloro-4-isocyanobenzene. 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 Instead of 2-aminothiazole, 2-aminopyridine was used to give cyclohexyl isocyanide. The title compound was prepared according to the procedure described in Example 36B using 1-isocyano-4-methoxybenzene instead. 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)
4- [4- (4-Fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] piperidine-1-carboxylate instead of tert-butylbenzylamine 4-aminopiperidine The title compound was prepared according to the procedure described in Example 39 using tert-butyl-1-carboxylate. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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)
To a solution of tert-butyl 5-bromoindazole 5-bromo-3-iodo-1H-indazole-1-carboxylate (10 g, 50.75 mmol) in dimethylformamide (100 mL) was added KOH (10 g, 177.63 mmol). It was. Over a period of 2 hours, iodine (20 g, 78.80 mmol) was added. The mixture was treated with an aqueous solution of Na ₂ S ₂ O ₃ (20 g) (water 200 mL), extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The solid was dissolved in dichloromethane (350 mL) and treated with di-tert-butyl dicarbonate (14.4 g, 65.98 mmol) and dimethylaminopyridine (10 mg, 0.08 mmol). The mixture was stirred at room temperature for 20 minutes and passed directly through a silica gel bed to give the title compound. _{MS (DCI / NH 3) m} / z422.9 (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 Example 60A (2.1 g, 5 mmol) To a solution in toluene (10 mL) was added an aqueous solution of Pd (PPh ₃ ) ₄ (173 mg, 0.15 mmol), Na ₂ CO ₃ (1.1 g, 10 mmol) (water 5 mL) and phenylboric acid (671 mg, 5.5 mmol). A solution in methanol (3 mL) was added. The mixture was stirred at room temperature for 5 days, quenched with water, extracted with ethyl acetate and purified by silica gel chromatography eluting with 5% ethyl acetate / hexanes to give the title compounds as a mixture. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.28 (d, J = 1.53 Hz, 1 H) 8.12 (d, J = 8.85 Hz, 1 H) 7.97-8.04 (m, 3 H ) 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 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) was 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 compound. 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 = I.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 Example 60C (350 mg, 0.85 mmol) in tetrahydrofuran ( To a solution in 5 mL) was added a solution of 1M TBAF in tetrahydrofuran (2 mL, 2 mmol). After 10 minutes, the solvent was removed under reduced pressure and the crude mixture was purified by silica gel chromatography eluting with 5% ethyl acetate / hexanes to give the title compound. 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 Substituting Example 60D for Example 3C and following the procedure described in Example 3D. The compound was prepared. 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 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) 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)
Example 61A was used instead of Example 60C instead of 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. 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 Substituting Example 61B for Example 3C and following the procedure described in Example 3D, The title compound was prepared. 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 under a nitrogen atmosphere, 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). Trimethylsilylacetylene (4.2 mL, 29.7 mmol) was added and the mixture was heated to 100 ° C. The mixture solidified and was monitored by LC / MS. After completion, the mixture was diluted with methylene chloride and washed with 1N HCl. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of ethyl acetate / hexane (5% to 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-Ethynyl-2-fluorobenzonitrile tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 70 mL) was added to a solution of (Example 62A (5.05 g, 23.2 mmol) in tetrahydrofuran (50 mL) to yield 20 The mixture was diluted with methylene chloride and washed with water The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 5% to 40% ethyl acetate / 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 Example 62B (1.68 g, 11.6 mmol) was dissolved in tert-butanol (14 mL). Benzyl azide (2.14 g, 15.8 mmol) was added and the mixture was transferred to 14 microwave vials (1.0 mL each). Water (0.5 mL), strips of copper wire and 1 M copper sulfate solution (II) (0.5 mL) are added to each microwave vial, and the vials are each for 10 minutes at 125 ° C. with 100 Watts at CEM − Heated with Discover microwave. The vials were recombined, diluted with ethyl acetate and washed with water and brine. The organic material was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 5% to 50% ethyl acetate / hexanes 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- aminehydrazine hydrate (18 mL) in Example 62C (1.93 g) in ethanol (10 mL). 6.94 mmol). The mixture was heated to 95 ° C. overnight. The mixture was diluted with ethyl acetate and washed with water. Part of the product precipitated with a separatory funnel and was filtered to give the title compound. The ethyl acetate layer was concentrated under reduced pressure and the resulting solid was triturated with methanol to give additional 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 Example 62D (44 mg 0.152 mmol), 1-methylpiperidine-4-carboxylic acid hydrochloride (27 mg, 0.150 mmol) and HATU (61 mg, 0.160 mmol) were combined in tetrahydrofuran (2 mL). Diisopropylethylamine (110 mL, 0.631 mmol) was added and the mixture was heated to 90 ° C. for 30 minutes. The mixture was diluted with methylene chloride and washed with 1N sodium hydroxide. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 5% to 15% methanol / dichloromethane 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 = 11.19 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 Example 62D (1.80 g, 6.20 mmol) And suspended in methylene chloride (100 mL) containing 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 onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 5% methanol / dichloromethane 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 Example 64A (45 mg, 0.115 mmol) was salified. Dissolved in methylene (1.5 mL) and pyridine (0.5 mL). Methoxyacetyl chloride (18 μL, 0.197 mmol) was added and the mixture was stirred at room temperature for 2 hours. The solvent is removed using a stream of warm nitrogen, the mixture is poured onto a silica gel column, and the product is purified by silica gel chromatography eluting with a gradient of 0% to 5% methanol / dichloromethane to give 5- (1-benzyl). -1H-1,2,3-triazol-4-yl) -3- (2-methoxyacetamido) -1H-indazole-1-carboxylate tert-butyl (58 mg) was obtained. The intermediate was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (1 mL) and stirred at room temperature overnight. The solvent was 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 - dimethyl glycinamide 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 3 portions over 2 hours and the mixture was stirred at room temperature overnight. Trifluoroacetic acid (2 mL) was added and the mixture was stirred for 3 hours. The mixture was diluted with methylene chloride and washed with 1N sodium hydroxide. The organic layer was absorbed onto silica gel and purified using silica gel chromatography eluting with a gradient of 5% to 15% methanol / dichloromethane 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 Example 64A (76 mg, 0.195 mmol) was added to methylene chloride (2 mL). And dissolved in pyridine (0.2 mL). Butyryl chloride (26 μL, 0.250 mmol) was added and the mixture was stirred at room 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 eluting with a gradient of 1% to 8% methanol / dichloromethane 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)
As described in Example 39, piperidin-4-amine was used instead of 5- [4- (4-fluorophenyl) -1-piperidin-4-yl-1H-imidazol-5-yl] -1H-indazolebenzylamine. The title compound was prepared according to the procedure of 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
Instead of 5- {4- (4-fluorophenyl) -1- [2- (1-methylpyrrolidin-2-yl) ethyl] -1H-imidazol-5-yl} -1H-indazolebenzylamine 2- ( The title compound was prepared according to the procedure described in Example 39 using 1-methylpyrrolidin-2-yl) ethanamine. 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)
Instead of 5- {4- (4-fluorophenyl) -1- [3- (4-methylpiperazin-1-yl) propyl] -1H-imidazol-5-yl} -1H-indazolebenzylamine 3- ( The title compound was prepared according to the procedure described in Example 39 using 4-methylpiperazin-1-yl) propan-1-amine. 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 Example 3C (1.83 g, 12.9 mmol) was dissolved in toluene (60 mL) and triethylamine (2.2 mL) and allowed to warm. The temperature was 90 ° C. 2-Chloro-2- (hydroxyimino) ethyl acetate (1.89 g, 12.5 mmol) was dissolved in toluene (15 mL) and added dropwise over 30 minutes. After the addition, the mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid. The organic layer was concentrated under reduced pressure and the resulting residue was triturated with methanol to 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 71A)
5- (1H-indazol-5-yl) isoxazole-3-carboxylic acid Example 70 (1.50 g, 5.83 mmol) was dissolved in tetrahydrofuran (100 mL), methanol (10 mL) and water (10 mL). Potassium hydroxide (680 mg, 12.1 mmol) was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the resulting residue was triturated with a mixture of 1N hydrochloric acid and methanol to give a solid that was filtered to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 Example 71A (46 mg, 0.201 mmol), HATU (88 mg, 0.231 mmol) and diisopropylethylamine (133 μL, 0.764 mmol) Were combined in tetrahydrofuran (2 mL). Monomethylamine (40% aqueous solution) (50 μL) was added and the reaction was stirred at 50 ° C. for 2 hours. The mixture was diluted with methylene chloride and washed with 1N sodium hydroxide, 1N hydrochloric acid and brine. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10% to 50% ethyl acetate / hexanes 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-indazolephenylacetaldehyde (90 +%) (266 mg, 2.38 mmol) was dissolved in tert-butanol (1 mL) and water (1 mL). Hydroxylamine hydrochloride (79 mg, 1.14 mmol) was added followed by 6N sodium hydroxide solution (19 μL, 31.7 mmol). The mixture was stirred for 30 minutes. Chloramine-T.trihydrate (308 mg, 1.09 mmol) was added slowly over 5 minutes, followed by copper (II) sulfate and copper wire strips. Example 3C (154 mg, 1.08 mmol) was added and the mixture was stirred at 50 ° C. for 2 hours and then at room temperature overnight. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10% to 50% ethyl acetate / hexanes 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 Example 64A (72 mg, 0.184 mmol) was added to methylene chloride (2 mL). And dissolved in pyridine (0.2 mL). Benzoyl chloride (36 μL, 0.310 mmol) was added and the mixture was stirred at room 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 eluting with a gradient of 1% to 8% methanol / dichloromethane 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)
The title compound was prepared according to the procedure described in Example 72 substituting butyraldehyde for 5- (3-propylisoxazol-5-yl) -1H-indazolephenylacetaldehyde . ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 workup, 6N HCl was added to pH 6 to produce a solid that 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 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 solvent was distilled off 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 with ethyl acetate to give the title compound. MS (ESI +) m / z 206.0 (M + H) ^<+> .

(Example 75C)
A solution of 1- (1H-indazol-5-yl) -2-phenylethanone (Example 75B (900 mg, 4.39 mmol) in tetrahydrofuran (10 mL) was cooled under argon using an ice bath and 2M benzyl Treated with a solution of magnesium chloride in tetrahydrofuran (6.6 mL, 13.16 mmol) The reaction was stirred at room temperature overnight and then another equivalent of benzylmagnesium chloride was added The mixture was heated at 70 ° C. for 9 hours. One more equivalent of benzylmagnesium chloride was added, and the reaction was heated for an additional 90 minutes at 70 ° C., allowed to cool to room temperature, saturated aqueous ammonium chloride was added, and the product was extracted with ethyl acetate and 30% acetic acid. Purify by silica gel column chromatography with ethyl / hexane to give the title compound. .MS (ESI +) m / z237.1 (M + H) +.

(Example 75D)
To a suspension of tert-butyl 5- (2-phenylacetyl) -1H-indazole-1-carboxylate (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 (ca. 2 mg) were added The mixture was stirred for 15 minutes, passed through a silica gel bed and eluted with dichloromethane, and evaporated under reduced pressure to give the title compound. MS (ESI +) m / z 337.0 (M + H) ^<+> .

(Example 75E)
Using a dropping funnel to a solution of Example 75D (336 mg, 1 mmol) in tetrahydrofuran (20 mL) heated to 40 ° C. in a 2-bromo-1- (1H-indazol-5-yl) -2-phenylethanone oil bath. Then, a solution of pyridinium tribromide (352 mg, 1.1 mmol) in tetrahydrofuran (20 mL) was added dropwise over 10 minutes. The reaction mixture was heated for an additional 2 hours, cooled, filtered and the filtrate evaporated to give the title compound. MS (ESI-) m / z 212.9 (MH) ^- .

(Example 75F)
Example 75E (50 mg, 0.16 mmol) and 1-benzylthiourea in N-benzyl-4- (1H-indazol-5-yl) -5-phenyl-1,3-thiazol-2- amineethanol (1 mL) A vial containing (26 mg, 0.16 mmol) was capped and heated on a heater shaker at 80 ° C. for 2 hours. The crude product solution was purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution to give the title compound as 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 Substituting 1-phenylthiourea for 1-benzylthiourea and following the procedure described in Example 75F. The compound was prepared as a TFA salt. 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)
Example 44A (2.31 g, 7.77 mmol), cyclopropylacetylene (620 mg, 9.37 mmol) under an inert atmosphere of tert-butyl nitrogen 5- (cyclopropylethynyl) -1H-indazole-1-carboxylate , Dichlorobis (triphenylphosphine) palladium (II) (170 mg, 0.242 mmol) and copper (I) iodide (92 mg, 0.483 mmol) were combined in triethylamine (10 mL). The mixture was heated to 100 ° C. in a sealed tube for 4 hours. The mixture was diluted with methylene chloride and washed with 1N hydrochloric acid. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 5% to 50% ethyl acetate / hexanes 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 Example 77A (145 mg, 0.51 mmol) and benzyl azide (82 mg, 0.62 mmol) Was heated undiluted in a CEM-Discover microwave 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 / hexane as 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 by 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)
Example 75E (80 mg, 0.25 mmol) and pyrimidin-2-amine (23 mg, 0 ) in 2- (1H-indazol-5-yl) -3-phenylimidazo [1,2-a] pyrimidineethanol (1 mL). .25 mmol) was capped and heated on a heater shaker at 80 ° C. for 21 hours. The crude product solution was purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution to afford 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 room temperature overnight. The resulting slurry was diluted with diethyl ether and washed with water. The organic layer was concentrated under reduced pressure to give the title compound. The product was used directly in the next reaction without characterization.

(Example 80B)
5- [1- (Tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-4-yl] -1H-indazole Example 80A (122 mg, 0.864 mmol) and Example 3C ( 150 mg, 0.619 mmol) was combined with tert-butanol (1 mL) and water (1 mL) in a microwave vial. A small piece of copper wire and then copper (II) sulfate (5 mg, 0.02 mmol) were added and the vial was stirred with a microwave (CEM-discover) apparatus at 125 ° C. and 100 W for 10 minutes. The mixture was diluted with methylene chloride and washed with 1N hydrochloric acid. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 5% methanol / dichloromethane to give the title compound. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 = 11.70) 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 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 room temperature for 2 hours. The solvent was removed under reduced pressure and the resulting residue was triturated with a mixture of 1N hydrochloric acid and methanol to give a solid that was filtered to give 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 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 was stirred at 45 ° C. for 2 hours. The mixture was diluted with ethyl acetate and washed with 1N sodium hydroxide, 1N hydrochloric acid, water (3 times) and brine. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 5% methanol / dichloromethane 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)
The title compound was prepared according to the procedure described in Example 81B substituting aniline for 5- (1H-indazol-5-yl) -N-phenylisoxazole-3-carboxamide 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 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 was stirred at 45 ° C. for 2 hours. The mixture was diluted with ethyl acetate and washed with 1N sodium hydroxide, 1N hydrochloric acid, water (3 times) and brine. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 5% methanol / dichloromethane 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 Example 81B (22 mg, 0.0742 mmol) was dissolved in tetrahydrofuran (2.5 mL) under an inert atmosphere of nitrogen. It was. 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 onto silica gel and purified by silica gel chromatography eluting with a gradient of methanol / dichloromethane (0% to 7%) 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 Example 70 (84 mg, 0.366 mmol) was dissolved in tetrahydrofuran (8 mL). Lithium aluminum hydride (1.0 M in tetrahydrofuran) (3.0 mL) was added in 1.0 mL portions over 2 hours. After the last addition, the mixture was stirred for an additional 30 minutes. The mixture was diluted with methylene chloride, washed with water and the organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 20% methanol / dichloromethane 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 Substituting 2-methoxyethylamine for piperidine, the title compound is prepared according to the procedure described in Example 81B. did. 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 room 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 solvent was 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-triazolephenylethynyltri -n-butyltin (8.25 g, 21.1 mmol) and benzyl azide (2.3 mL, 18 4 mmol) and heated to 150 ° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5% to 40% ethyl acetate / hexanes 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 in an inert atmosphere of nitrogen in a microwave vial , Example 87A (139 mg, 0.486 mmol), Example 87B (284 mg, 0.542 mmol), dichlorobis (triphenylphosphine) palladium (II) (40 mg, 0.057 mmol) and copper thiophene-2-carboxylate (167 mg) , 0.876 mmol) in toluene (1.5 mL). The vial was heated in a microwave (CEM-Discover) device at 125 watts to 150 ° C. for 20 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 5% to 40% ethyl acetate / hexanes 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 Example 87C (95 mg, 0.242 mmol) in tetrahydrofuran (2.0 mL), methanol (1 0.0 mL) and water (1.0 mL) and potassium hydroxide (64 mg, 1.14 mmol) was added. The mixture was stirred for 2 hours, diluted with ethyl acetate and washed with water. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 5% methanol / dichloromethane 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 Example 87A (969 mg, 3.39 mmol), 3-phenyl-1-propyne (392 mg, 3.37 mmol) , Sodium azide (278 mg, 4.28 mmol), sodium ascorbate (68 mg, 3.43 mmol), sodium carbonate (75 mg, 0.708 mmol) and L-proline (78 mg, 8.98 mmol) in dimethyl sulfoxide and water Combined in a 1: 1 mixture (10 mL). Copper (II) sulfate pentahydrate (46 mg, 0.184 mmol) was added and the mixture was stirred at 65 ° C. for 3 hours. 6N sodium hydroxide (1 mL) was added and the mixture was stirred for 30 minutes to deprotect indazole. The mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid. The organic layer was concentrated under reduced pressure and the resulting residue was triturated with methanol. The remaining solid was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 5% methanol / dichloromethane 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- (cyclopropylethynyl) -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) was combined in triethylamine (15 mL) under an inert atmosphere of nitrogen. Cyclopropylacetylene (1.8 mL) was added and the mixture was heated at 60 ° C. until it became a black solid. The mixture was diluted with methylene chloride and washed with 1N hydrochloric acid. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 5% to 40% ethyl acetate / hexanes 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 Example 89A (211 mg, 1.14 mmol) and benzyl azide (143 μL, 1.14 mmol) were combined in a microwave (CEM-Discover) vial and heated at 160 ° C. with 100 Watts for 26 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 20% to 60% ethyl acetate / hexanes to give an inseparable mixture of triazole regioisomers. The mixture of regioisomers 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 onto silica gel and purified by silica gel chromatography eluting with a gradient of 1% to 6% methanol / dichloromethane 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 as a by-product, following the procedure described in Example 89B Isolated. 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)
Procedure described in Example 72 using isovaleraldehyde instead of 2-fluoro-5- (3-isobutylisoxazol-5-yl) benzonitrile phenylacetaldehyde and using Example 62B instead of Example 3C The title compound was prepared according to 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 = 8.9 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 Example 91A (75 mg, 0.307 mmol) was added to hydrazine hydrate (1.5 mL) in ethanol (1.0 mL). Was added. The mixture was heated to 70 ° C. overnight in a sealed vial. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 5% methanol / dichloromethane 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, substituting Example 62B for Example 3C. The crude product was used in the next step without further purification or characterization.

(Example 92B)
5- (3- Benzylisoxazol -5-yl) -1H-indazol-3-amine Example 92A (65 mg, 0.234 mmol) was added to hydrazine hydrate (1.5 mL) in ethanol (1.0 mL). Was added. The mixture was heated to 70 ° C. overnight in a sealed vial. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 20% methanol / dichloromethane 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)
2 instead of N- {2- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] ethyl} -N, N-dimethylaminebenzylamine The title compound was prepared according to the procedure described in Example 39 using dimethylaminoethylamine. ¹ H NMR (500 MHz, c) 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)
Instead of 5- [4- (4-fluorophenyl) -1- (3-morpholin-4-ylpropyl) -1H-imidazol-5-yl] -1H-indazolebenzylamine, 3-morpholinopropylamine was used, The title compound was prepared according to the procedure described in Example 39. 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)
Instead of 5- [4- (4-fluorophenyl) -1- (3-pyrrolidin-1-ylpropyl) -1H-imidazol-5-yl] -1H-indazolebenzylamine, 3-pyrrolidinopropylamine was used. The title compound was prepared according to the procedure described in Example 39. 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)
Instead of 5- {4- (4-fluorophenyl) -1- [2- (4-methylpiperidin-1-yl) ethyl] -1H-imidazol-5-yl} -1H-indazolebenzylamine 2- ( The title compound was prepared according to the procedure described in Example 39 using 4-methylpiperidin-1-yl) ethanamine. 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 = 11.60 Hz, 2H) 2.37 (t, J = 6.56 Hz, 2H) 1.71-1 .85 (m, 2H) 1.45 (d, J = 11.29 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-indazolebenzylamine instead of 4-amino-N-benzylpiperidine The title compound was prepared according to the procedure described in Example 39. 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 = 11.90 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-ylethyl) -1H-imidazol-5-yl] -1H-indazolebenzylamine was used instead of 2-morpholinoethylamine. The title compound was prepared according to the procedure described in 39. 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
Instead of 5- [1- (1-benzylpyrrolidin-3-yl) -4- (4-fluorophenyl) -1H-imidazol-5-yl] -1H-indazolebenzylamine, 3-pyrrolidinobenzylamine was used. The title compound was prepared according to the procedure described in Example 39. 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 has been deleted and is not included in this document.

(Example 101)
Instead of 2- {4- [4- (4-fluorophenyl) -5- (1H-indazol-5-yl) -1H-imidazol-1-yl] piperidin-1-yl} -2- oxoethanolbenzylamine The title compound was prepared according to the procedure described in Example 39 using 1- (4-aminopiperidin-1-yl) -2-hydroxyethanone. 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, IH ) 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 Example 87B (415 mg, 0.792 mmol), 5-bromo-2-fluorobenzo Nitrile (158 mg, 0.790 mmol), dichlorobis (triphenylphosphine) palladium (II) (52 mg, 0.074 mmol) and copper thiophene-2-carboxylate (226 mg, 1.19 mmol) under an inert atmosphere of nitrogen. Combined in toluene (2 mL) in a microwave vial. The vial was heated in a microwave apparatus (CEM-Discover) at 150 ° C. and 125 watts for 20 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of ethyl acetate / hexane (5% to 40%) to give the title compound. MS (ESI +) m / z 355.1 (M + H) ^<+> .

(Example 102B)
5- (1-Benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amine Example 102A (120 mg, 0.339 mmol) in ethanol (1.0 mL) In hydrazine hydrate (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 onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 5% methanol / dichloromethane 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)
The 2- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] propan-2-ol crude reaction mixture was quenched with 2 mL of 1N aqueous NaOH and 1 at room temperature. The title compound was prepared according to the procedure described in Example 88 using 2-methyl-3-butyn-2-ol in place of 3-phenyl-1-propyne, except stirring for 5 hours. The suspension was dried by heated forced nitrogen gas evaporation before 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)
As described in Example 88, methylpropargyl ether was used instead of 5- [4- (methoxymethyl) -1H-1,2,3-triazol-1-yl] -1H-indazole 3-phenyl-1-propyne. The title compound was prepared according to the procedure. 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 Instead of 3-phenyl-1-propyne, 2-phenyl-3-propyne The title compound was prepared according to the procedure described in Example 88 using butyn-2-ol. 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 Substituting 1-pentyne for 3-phenyl-1-propyne and following the procedure described in Example 88. The title compound was prepared. 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)
Instead of 1- [1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] propan-2-ol 3-phenyl-1-propyne, penta-4-yne- The title compound was prepared according to the procedure described in Example 88 using 2-ol. 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 instead of 3-phenyl-1-propyne 4-pentyne-1- The title compound was prepared according to the procedure described in Example 88 using oals. 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 = I.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 3-phenyl-1-propyne The title compound was prepared according to the procedure described in Example 88 using 1-propargyl-1H-benzotriazole instead. 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 / z315.0 ( M-H) -.

(Example 110)
In Example 88, phenylpropargyl sulfide was used instead of 5- {4-[(phenylthio) methyl] -1H-1,2,3-triazol-1-yl} -1H-indazole- 3-phenyl-1-propyne. The title compound was prepared according to the described procedure. 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 3-phenyl-1-propyne was used instead of cyclopropylacetylene according to the procedure described in Example 88. The title compound was prepared. 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 = I.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)
Instead of 5- [4- (2-phenylethyl) -1H-1,2,3-triazol-1-yl] -1H-indazole 3-phenyl-1-propyne, 1-phenyl-1-butyne was used, The title compound was prepared according to the procedure described in Example 88. 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)
Example of using 3-cyclohexyl-1-propyne instead of 5- [4- (cyclohexylmethyl) -1H-1,2,3-triazol-1-yl] -1H-indazole 3-phenyl-1-propyne The title compound was prepared according to the procedure described in 88. 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 3-phenyl-1-propyne is used in place of cyclopentylacetylene according to the procedure described in Example 88. The compound was prepared. 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 Instead of 3-phenyl-1-propyne, 1-ethynyl-1-cyclohexanol is used. The title compound was prepared according to the procedure described in Example 88. 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 3-phenyl-1-propyne is used instead of phenylpropargyl ether as described in Example 88. The title compound was prepared according to the procedure. 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)
Instead of 5- {4-[(1,1-dioxidethiomorpholin-4-yl) methyl] -1H-1,2,3-triazol-1-yl} -1H-indazole 3-phenyl-1-propyne The title compound was prepared according to the procedure described in Example 88 using N-propargylthiomorpholine-sulfone. 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)
In place of 5- [4- (3-phenylpropyl) -1H-1,2,3-triazol-1-yl] -1H-indazole 3-phenyl-1-propyne, 1-phenyl-1-pentyne was used. The title compound was prepared according to the procedure described in Example 88. 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 Example 3C (230 mg, 1.62 mmol) in dichloromethane (10 mL) was added di-tert-butyl dicarbonate (459 mg, 2.1 mmol) and one bite. Of dimethylaminopyridine (ca. 3 mg) was added and the mixture was stirred at room temperature for 30 min. Water was added and the product was extracted with dichloromethane, dried over sodium sulfate, filtered and evaporated under reduced pressure to give the title compound. MS (ESI +) m / z 265.0 (M + Na) ^<+> .

(Example 119B)
[1-Benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] (phenyl) methanone Example 119A (90 mg, 0.37 mmol), benzyl azide (0 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) under argon. The vial was capped and shaken for 16 hours. The solvent was distilled off and the product was purified by silica gel column chromatography with 5-30% ethyl acetate / hexane. The crude material was treated with TFA (0.5 mL) / dichloromethane (1 mL) and purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution 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)
1 instead of N, N-diethyl-N-{[1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] methyl} amine 3-phenyl-1-propyne The title compound was prepared according to the procedure described in Example 88 using 1,1-diethylpropargylamine. 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)
EXAMPLE 43 N- [2- (1H-indazol-5-yl) imidazo [1,2-a] pyrimidin-3-yl] -β-alaninate ethyl isocyanopropionate was used instead of ethyl isocyanopropionate. The title compound was prepared according to the procedure described in. 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-triazoletributyl (1-propynyl) tin (3.87 g, 11.8 mmol) and benzyl azide (2.2 mL, 17 6 mmol) and heated to 150 ° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5% to 40% ethyl acetate / hexanes to give the title compound. MS (ESI +) m / z 464.2 (M + H) ^<+> .

(Example 122B)
1- (5- (I-Benzyl-5-methyl-1H-1,2,3-triazol-4-yl) -1H-indazol-1-yl) ethanone Example 87A (235 mg, 0.821 mmol), carried out 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) under an inert atmosphere of nitrogen Were combined in toluene (2.0 mL) in a microwave vial. The vial was heated at 125 watts in a microwave apparatus (CEM-Discover) at 150 ° C. for 20 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 5% to 40% ethyl acetate / hexanes 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 Example 122B (109 mg, 0.329 mmol) 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 onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 5% methanol / dichloromethane 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 Example 122A (415 mg, 0.792 mmol), 5-bromo-2-fluorobenzo Nitrile (158 mg, 0.790 mmol), dichlorobis (triphenylphosphine) palladium (II) (52 mg, 0.074 mmol) and copper thiophene-2-carboxylate (226 mg, 1.19 mmol) under an inert atmosphere of nitrogen. Combined in toluene (2 mL) in a microwave vial. The vial was heated in a microwave apparatus (CEM-Discover) at 150 ° C. and 125 watts for 20 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 5% to 40% ethyl acetate / hexanes 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 Example 123A (120 mg, 0.339 mmol) in ethanol (1.0 mL) Treated with hydrazine hydrate (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 onto silica gel and purified by silica gel chromatography eluting with a gradient of methanol / dichloromethane (0% to 5%) 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-a] pyrimidin-3-yl] -β- alaninamide Example 121 (42 mg, 0.120 mmol) and 7N ammonia in methanol ( In 1.0 mL) and heated to 60 ° C. overnight. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of methanol / dichloromethane (1% to 7%) 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 Example 62B (200 mg, 1.38 mmol), benzyl azide (0.176 mL, 1 .38 mmol), tetrahydrofuran (12 mL), triethylamine (0.230, 1.56 mmol), CuI (263 mg, 1.38 mmol) and ICl (0.069 mL, 1.38 mmol) under argon at room temperature for 24 hours. Stir. 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% to 20%) to give the title compound. MS (ESI +) m / z 404.9 (M + H) ^<+> .

(Example 125B)
Example 125A (50 mg, 0.12 mmol) in 5- (1-benzyl-5-iodo-1H-1,2,3-triazol-4-yl) -1H-indazol-3-amineethanol (1 mL) and Hydrazine monohydrate (IML) was heated at 95 ° C. for 2 hours. Water was added and the solid was collected by filtration and further purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution to give the title compound as 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-methyl Phenyl) urea (Example 126A)
1- (3- (1-Benzyl-4- (3-cyano-4-fluorophenyl) -1H-1,2,3-triazol-5-yl) phenyl) -3-m-tolylurea Example 125A ( 94 mg, 0.23 mmol), 1- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -3-m-tolylurea (in WO 2004/113304) Prepared according to the described procedure) (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) The vial under argon was capped and heated on a heater shaker at 80 ° C. for 90 minutes. The solvent was distilled off and the product was extracted with methanol / dichloromethane. Silica gel column chromatography using 10% ethyl acetate / hexane gave 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-methyl Example 126A (25 mg, 0.05 mmol) and hydrazine monohydrate (0.5 mL) in phenyl) urea ethanol (2 mL) were heated at 80 ° C. for 1 hour. The crude mixture was loaded onto a silica gel column and eluted with a gradient of 0% to 5% methanol / 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 81A (37 mg, 0.18 mmol) dissolved in dimethylformamide (0.8 mL) in a 20 mL vial. The solution was added followed by HATU (61 mg, 0.18 mmol) dissolved in dimethylformamide (0.8 mL). Next, a solution of 2-isopropoxyethanamine (20 mg, 0.20 mmol) dissolved in dimethylformamide (0.9 mL) was added, followed by diisopropylethylamine (42 mg, 0.2 mL) dissolved in dimethylformamide (0.8 mL). 36 mmol) was added. The mixture was shaken at 40 ° C. for 3 hours. The crude reaction mixture was filtered with methanol through a Si-carbonate cartridge (6 mL, 2 g) supplied from Silicycle Chemical Division, checked by LC / MS and concentrated to dryness. . The residue was dissolved in 1: 1 DMSO / methanol and purified by reverse phase HPLC (Agilent, 5% to 100% TFA / water gradient, 8 min operation). 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 2-isopropoxyethanamine was used in place of morpholine to prepare the title compound according to the procedure described in Example 127. did. 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 instead of 2-isopropoxyethanamine, 3-morpholinopropan-1-amine was used, Following the procedure described in Example 127, the title compound was obtained as a TFA salt. 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 2-isopropoxyethanamine instead of 2- (1H-imidazole- The title compound was prepared according to the procedure described in Example 127 using 4-yl) ethanamine. 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 2-isopropoxyethanamine instead of (R) -piperidine-3- The title compound was prepared according to the procedure described in Example 127 using all hydrochloride. 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} piperidine-3-carboxamide 2-perpropoxyethanamine was used instead of piperidine-3-carboxamide in Example 127 The title compound was prepared according to the described procedure. 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 instead of 2-isopropoxyethanamine 2- The title compound was obtained as a TFA salt following the procedure described in Example 127 using (2- (piperazin-1-yl) ethoxy) ethanol. 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 2-isopropoxyethanamine instead of 1-methyl-1,4 -The title compound was obtained as the TFA salt using diazepan and following the procedure described in Example 127. 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 2-isopropoxyethanamine was used in place of 3-aminopropan-1-ol. The title compound was prepared according to the described procedure. 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)
(R) -2-amino instead of N-[(1R) -2-hydroxy-1-phenylethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide 2-isopropoxyethanamine The title compound was prepared according to the procedure described in Example 127 using 2-phenylethanol. 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-imidazol-1-yl) propyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide 2-isopropoxyethanamine instead of 3- (1H-imidazole- The title compound was prepared according to the procedure described in Example 127 using 1-yl) propan-1-amine. 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 2-isopropoxyethanamine instead of 1- (3-amino The title compound was prepared according to the procedure described in Example 127 using propyl) pyrrolidin-2-one. 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)
4- (2-aminoethyl) instead of N- {2- [4- (aminosulfonyl) phenyl] ethyl} -5- (1H-indazol-5-yl) isoxazole-3-carboxamide 2-isopropoxyethanamine The title compound was prepared according to the procedure described in Example 127 using benzenesulfonamide. 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)
Instead of [1-benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] (3-chlorophenyl) methanone benzoyl chloride, 3-chlorobenzoyl chloride was used, The title compound was prepared according to the procedure described in Example 119B. 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 Substituting cyclopropanecarbonyl chloride for benzoyl chloride The title compound was prepared according to the procedure described in 119B. 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-triazolecyclopropylacetylene (142 mg, 2.15 mmol). Added 1,1,1-tributyl-N, N-dimethylstannananamine (716 mg, 2.14 mmol) in hexane (3.0 mL) and stirred in a sealed vial at 70 ° C. for 2 hours. The mixture was cooled to room temperature and stirred for 10 minutes without sealing the vial. Example 80A (455 mg, 3.22 mmol) was added and the vial was resealed and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of ethyl acetate / hexane (5% to 50%) 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 Example 142A (220 mg, 0.444 mmol), Example 87A (128 mg, 0.447 mmol), dichlorobis (triphenylphosphine) palladium (II) (33 mg, 0.047 mmol) and copper thiophene-2-carboxylate ( 127 mg, 0.666 mmol) was combined in toluene (2.0 mL) in a 4 mL vial under an inert atmosphere of nitrogen. The vial was sealed and heated at 150 ° C. for 20 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 5% to 70% ethyl acetate / hexanes 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 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 onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 8% methanol / dichloromethane 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 = I 1.36, 3.56 Hz, 2H) 3.42 (t, J = 11.53 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) -1H-1,2,3-triazol-5-yl) methyl) isoindoline-1,3-dione N-propargylphthalimide (2.35 mg, 12 0.7 mmol) in 1,1,1-tributyl-N, N-dimethylstannananamine (4.23 mg, 12.7 mmol) in hexane (3.0 mL) and 2 hours at 70 ° C. in a sealed vial. Stir. The mixture was cooled to room temperature and stirred for 10 minutes without sealing the vial. Benzyl azide (2.0 mL, 16.0 mmol) was added and the vial was resealed and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 10% to 50% ethyl acetate / hexane 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) isoindoline-1,3-dione 143A (567 mg, 0.934 mmol), Example 87A (268 mg, 0.934 mmol), dichlorobis (triphenylphosphine) palladium (II) (67 mg, 0.095 mmol) and copper thiophene-2-carboxylate (268 mg, 1. 41 mmol) was combined in toluene (2.5 mL) under an inert atmosphere of nitrogen in a microwave vial. The vial was heated at 125 watts in a microwave apparatus (CEM-Discover) to 150 ° C. for 20 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10% to 50% ethyl acetate / hexanes 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 Example 143B (140 mg, 0.294 mmol) in ethanol (0.7 mL) Of hydrazine hydrate (0.7 mL) and stirred at room temperature overnight. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 1% to 6% methanol / dichloromethane 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 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 room temperature overnight. The mixture is absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 6% methanol / dichloromethane to give tert-butyl 2-((1-benzyl-4- (1Η-indazol-5-yl). ) -1H-1,2,3-triazol-5-yl) methylamino) -2-oxoethylcarbamate. The carbamate was dissolved in tetrahydrofuran (2 mL), 0.5 mL of 1N hydrochloric acid in diethyl ether was added, and the mixture was stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure and diethyl ether was added to the mixture and stirred at room temperature overnight. The solvent was removed by decantation and the resulting residue was dried under a stream of nitrogen to give the title compound as the hydrochloride salt. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.21 (s, 1H) 9.02 (t, J = 0.09 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 = 0.09 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 benzoyl chloride The title compound was prepared according to the procedure described in Example 119B using 4-fluorobenzoyl chloride in place of and using Example 80A in place 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 = I1.36) 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)
To (4-chlorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl] methanone benzoyl chloride The title compound was prepared according to the procedure described in Example 119B using 4-chlorobenzoyl chloride instead and Example 80A instead of benzyl azide. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.10 (s, 1H) 8.00 (s, 1H) 7.77 (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 = 11.19, 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)
To (3-chlorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl] methanone benzoyl chloride The title compound was prepared according to the procedure described in Example 119B using 3-chlorobenzoyl chloride instead and 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 = 11.53, 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)
To (2-chlorophenyl) [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl] methanone benzoyl chloride The title compound was prepared according to the procedure described in Example 119B using 2-chlorobenzoyl chloride instead and Example 80A instead of benzyl azide. 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 = 11.19, 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)
Cyclopentane instead of cyclopentyl [4- (1H-indazol-5-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-1,2,3-triazol-5-yl] methanone benzoyl chloride The title compound was prepared according to the procedure described in Example 119B using carbonyl chloride and substituting Example 80A for 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 = 11.53, 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 In a large sealed tube, methyl propiolate (5.75 g, 68.4 mmol) was converted to methyl ethyl ( To tributylstannyl) carbamate (26.9 g, 68.6 mmol). The mixture was heated to 70 ° C. overnight. The mixture was cooled to room temperature and stirred for 10 minutes without sealing the vial. Benzyl azide (10.2 mL, 81.6 mmol) was added and the vial was resealed and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5% to 40% ethyl acetate / hexanes 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 Example 149A (7.17 g, 14.1 mmol), Example 87A (4.02 g, 14.1 mmol), dichlorobis (triphenylphosphine) palladium (II) (1.01 mg, 1.44 mmol) and copper thiophene-2-carboxylate (4.07 mg, 21.3 mmol) Were combined in toluene (55 mL) under an inert atmosphere of nitrogen. The tube was sealed and heated at 150 ° C. for 30 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10% to 50% ethyl acetate / hexanes 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 Example 149B (3.40 mg, 9.06 mmol) in tetrahydrofuran (100 mL), methanol ( 10 mL) and water (10 mL) and potassium hydroxide (1.63 g, 29.1 mmol) was added. The mixture was stirred for 3 hours, diluted with ethyl acetate, washed with 1N hydrochloric acid, washed with brine, and the combined organic layers were dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure to give 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 (Examples) 150A)
To a solution of 4- (trifluoromethyl) benzyl bromide (4.26 g, 17.8 mmol) in 1- (azidomethyl) -4- (trifluoromethyl) benzenedimethylsulfoxide (15 mL) was added sodium azide (2.30 g). 35.4 mmol) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure to give the title compound. The crude product was used in the next step without further characterization.

(Example 150B)
5- (4-Fluorophenyl) -4- (tributylstannyl) -1- (4- (trifluoromethyl) benzyl) -1H-1,2,3-triazole 4-fluorophenylacetylene (524 mg, 4.36 mmol) ) Was added to 1,1,1-tributyl-N, N-dimethylstannananamine (1.46 g, 4.37 mmol) and the mixture was stirred in a sealed vial at 50 ° C. for 30 minutes. The mixture was cooled to room temperature and stirred for 10 minutes without sealing the vial. Example 150A (1.28 g, 6.30 mmol) was added and the vial was resealed and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5% to 35% ethyl acetate / hexanes 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 Example 150B (485 mg , 0.795 mmol), 5-bromo-2-fluorobenzonitrile (143 mg, 0.715 mmol), dichlorobis (triphenylphosphine) palladium (II) (49 mg, 0.070 mmol) and copper thiophene-2-carboxylate (205 mg) 1.08 mmol) was combined in toluene (2.0 mL) in a 4 mL vial under an inert atmosphere of nitrogen. The vial was sealed and heated at 150 ° C. for 30 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10% to 50% ethyl acetate / hexanes 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 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 onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 6% methanol / dichloromethane 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 converted to 1,1,1-tributyl. In addition to -N, N-dimethylstannananamine (1.46 g, 4.37 mmol), the mixture was stirred in a sealed vial at 50 ° C. for 2 hours. The mixture was cooled to room temperature and stirred for 10 minutes without sealing the vial. Benzyl azide (850 μL, 6.80 mmol) was added and the vial was resealed and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5% to 35% ethyl acetate / hexanes 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 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) Combined in toluene (2.0 mL) in a 4 mL vial under inert atmosphere. The vial was sealed and heated at 150 ° C. for 30 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10% to 50% ethyl acetate / hexanes 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 Example 151B (135 mg, 0.363 mmol) Treated with hydrazine hydrate (1.0 mL) in ethanol (1.0 mL), 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 onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 6% methanol / dichloromethane 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- Yl) The title compound was prepared according to the procedure described in Example 119B using Example 80A in place of methanone benzyl azide and tetrahydro-2H-pyran-4-carbonyl chloride in place 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 -In addition to dimethylstannananamine (1.21 g, 3.62 mmol), the mixture was stirred in a sealed vial at 70 ° C for 3 hours. The mixture was cooled to room temperature and stirred for 10 minutes without sealing the vial. Benzyl azide (678 μL, 5.42 mmol) was added and the vial was resealed and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5% to 45% ethyl acetate / hexane 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 Example 153A (119 mg, 0.221 mmol) Example 87A (63 mg, 0.221 mmol), dichlorobis (triphenylphosphine) palladium (II) (16 mg, 0.023 mmol) and copper thiophene-2-carboxylate (65 mg, 0.341 mmol) were inerted with nitrogen. Combined in toluene (2.0 mL) in a 4 mL vial under atmosphere. The vial was sealed and heated at 150 ° C. for 20 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 5% to 45% ethyl acetate / hexanes 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 Example 153B (42 mg, 0.103 mmol) was added to 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 onto silica gel and purified by silica gel chromatography eluting with a gradient of 1% to 6% methanol / dichloromethane 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 Example 149C instead of Example 81A The title compound was prepared according to the procedure described in Example 81B 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)
1-{[1-Benzyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazol-5-yl] carbonyl} piperidin-4-ol Example 149C instead of Example 81A The title compound was prepared according to the procedure described in Example 81B 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-dimethylstannananamine (1.30 g, 3.89 mmol) and the mixture was stirred in a sealed vial at 50 ° C. for 40 minutes. The mixture was cooled to room temperature and stirred for 10 minutes without sealing the vial. Example 80A (710 μL, 5.68 mmol) was added and the vial was resealed and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5% to 50% ethyl acetate / hexanes 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 Examples 156A (433 mg, 0.787 mmol), Example 87A (205 mg, 0.717 mmol), dichlorobis (triphenylphosphine) palladium (II) (55 mg, 0.078 mmol) and copper thiophene-2-carboxylate (224 mg, 1. 17 mmol) was combined in toluene (2.0 mL) in a 4 mL vial under an inert atmosphere of nitrogen. The vial was sealed and heated to 150 ° C. for 20 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 5% to 45% ethyl acetate / hexanes 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 = 11.36, 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 Example 149C was used instead of Example 81A and replaced with piperidine The title compound was prepared according to the procedure described in Example 81B using dimethylamine and substituting tetrahydrofuran for 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 Example 149C was used instead of Example 81A, and benzylamine was used instead of piperidine. The title compound was prepared according to the procedure described in Example 81B using 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)
DL-α- (methylaminomethyl) benzyl alcohol was used instead of N- (2-hydroxy-2-phenylethyl) -5- (1H-indazol-5-yl) -N-methylisoxazole-3-carboxamide piperidine. The title compound was prepared according to the procedure described in Example 81B. 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)
(S) -2-amino-2-phenylethanol instead of N-[(1S) -2-hydroxy-1-phenylethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide piperidine The title compound was prepared according to the procedure described in Example 81B using 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 piperidine was used instead of 2- (benzylamino) ethanol as described in Example 81B. The title compound was prepared according to the procedure. 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 added to methylene chloride (15 mL) and diisopropylethylamine (0. 7 mL). Acetic anhydride (500 μL, 5.29 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with 1N sodium hydroxide, then 1N hydrochloric acid and then brine. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to give the title compound. MS (ESI +) m / z 252.7 (M + H) ^<+> .

(Example 162B)
1- (5- (1-Benzyl-5-o-tolyl-1H-1,2,3-triazol-4-yl) -3-methyl-1H-indazol-1-yl) ethanone Example 153A (436 mg, 0.808 mmol), Example 162A (205 mg, 0.810 mmol), dichlorobis (triphenylphosphine) palladium (II) (56 mg, 0.080 mmol) and copper thiophene-2-carboxylate (239 mg, 1.25 mmol) Combined in toluene (2.0 mL) in a 4 mL vial under an inert atmosphere of nitrogen. The vial was sealed and heated at 150 ° C. for 30 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10% to 50% ethyl acetate / hexanes 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 Example 162B (202 mg, 0.548 mmol) was treated with tetrahydrofuran. (5.0 mL), methanol (0.5 mL) and water (0.5 mL) were dissolved, and potassium hydroxide (133 mg, 2.37 mmol) was added. The mixture was stirred for 1 hour, then diluted with methylene chloride and washed with water. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 30% to 80% ethyl acetate / hexanes 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 163A)
5- (1-Benzyl-5-o-tolyl-1H-1,2,3-triazol-4-yl) -2-fluorobenzonitrile Example 153A (450 mg, 0.834 mmol), 5-bromo-2- Fluorobenzonitrile (167 mg, 0.835 mmol), dichlorobis (triphenylphosphine) palladium (II) (56 mg, 0.080 mmol) and copper thiophene-2-carboxylate (242 mg, 1.27 mmol) in an inert atmosphere of nitrogen Combined in toluene (2.0 mL) in a 4 mL vial below. The vial was sealed and heated at 150 ° C. for 30 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10% to 50% ethyl acetate / hexanes 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 Example 163A (202 mg, 0.548 mmol) was treated with ethanol. Treated with hydrazine hydrate (1.0 mL) in (1.0 mL), stirred and heated to 60 ° C. overnight. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 35% to 85% ethyl acetate / hexanes 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-isoindole-1,3 (2H) -dione 3- The title compound was prepared according to the procedure described in Example 88 using 2- (but-3-ynyl) isoindoline-1,3-dione instead of phenyl-1-propyne. The crude product was treated with 25% TFA / dichloromethane and purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution to give 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)
Instead of 5- {4-[(2,4-dichlorophenoxy) methyl] -1H-1,2,3-triazol-1-yl} -1H-indazole 3-phenyl-1-propyne, 2,4-dichloro The title compound was prepared according to the procedure described in Example 88 using -1- (prop-2-ynyloxy) benzene. The crude product was treated with 25% TFA / dichloromethane and purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution to give 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)
1,3-dichloro instead of 5- {4-[(2,6-dichlorophenoxy) methyl] -1H-1,2,3-triazol-1-yl} -1H-indazole 3-phenyl-1-propyne The title compound was prepared according to the procedure described in Example 88 using 2- (prop-2-ynyloxy) benzene. The crude product was treated with 25% TFA / dichloromethane and purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution to give 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 Example 156B (168 mg, 0.401 mmol) was dissolved in tetrahydrofuran (5.0 mL), methanol (0.5 mL) and water (0.5 mL), and potassium hydroxide (138 mg, 2.46 mmol) was added. The mixture was stirred for 1 hour, diluted with methylene chloride and washed with water. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 7% methanol / dichloromethane 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 = 11.53, 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-indazoleindazole (530 mg, 4.49 mmol) was dissolved in dimethylformamide (4 mL). Sodium hydride (60% suspension in mineral oil, 231 mg, 5.78 mmol) was added slowly and the mixture was stirred for 10 minutes. Propargyl bromide (80 wt% in toluene, 5.0 mL) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed excessively with water, absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 5% to 30% ethyl acetate / hexanes to give the title compound. MS (ESI +) m / z 157.1 (M + H) ^<+> .

(Example 168B)
Example 168A was replaced with 1-{[1- (1H-indazol-5-yl) -1H-1,2,3-triazol-4-yl] methyl} -1H-indazole 3-phenyl-1-propyne The title compound was prepared according to the procedure described in Example 88. 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 Using Example 149C instead of Example 81A, dimethylformamide The title compound was prepared according to the procedure described in Example 81B using tetrahydrofuran instead. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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-dimethylstannananamine (1.53 g, 4.58 mmol) and the mixture was stirred in a sealed vial at 70 ° C. for 2 hours. The mixture was cooled to room temperature and stirred for 10 minutes without sealing the vial. Example 80A (648 mg, 4.59 mmol) was added and the vial was resealed and heated to 130 ° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5% to 50% ethyl acetate / hexanes 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- Yl) ethanone Example 170A (432 mg, 0.791 mmol), Example 87A (222 mg, 0.776 mmol), dichlorobis (triphenylphosphine) palladium (II) (58 mg, 0.083 mmol) and copper thiophene-2-carboxylate (231 mg, 1.21 mmol) were combined in toluene (2.0 mL) in a 4 mL vial under an inert atmosphere of nitrogen. Was sealed and heated at 150 ° C. for 20 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 20% to 70% ethyl acetate / hexanes 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 Example 170B (184 mg, 0.443 mmol) was dissolved in tetrahydrofuran (3.0 mL), methanol (0.3 mL) and water (0.3 mL), and potassium hydroxide (140 mg, 2.50 mmol) was added. The mixture was stirred for 3 hours, diluted with methylene chloride and washed with water. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 35% to 100% ethyl acetate / hexanes 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 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 vial under an inert atmosphere of nitrogen. The vial was sealed and heated at 150 ° C. for 30 minutes. The mixture was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10% to 50% ethyl acetate / hexanes 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 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 onto silica gel and purified by silica gel chromatography eluting with a gradient of 1% to 8% methanol / dichloromethane 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 Example 149C was used instead of Example 81A to give piperidine The title compound was prepared according to the procedure described in Example 81B using morpholine instead 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 DME (2 mL) and water (0.2 mL) Of Example 125B (50 mg, 0.12 mmol), 4-methoxyphenylboric acid (20 mg, 0.13 mmol), PdCl ₂ (dppf) dichloromethane (10 mg, 0.01 mmol) and potassium carbonate (33 mg, 0.24 mmol) The vial was capped under argon and heated on a heater shaker at 80 ° C. for 48 hours. The solvent was removed under reduced pressure and the product was purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution 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 piperidine instead of (S)-(−)-2-amino- The title compound was prepared according to the procedure described in Example 81B using 3-phenyl-1-propanol. 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)
Instead of N-[(1S, 2R) -2-hydroxy-2,3-dihydro-1H-inden-1-yl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide piperidine ( The title compound was prepared according to the procedure described in Example 81B using 1S, 2R)-(−)-cis-1-amino-2-indanol. 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-indazolepiperidine was used in place of 3-phenylmorpholine hydrochloride and following the procedure described in Example 81B. The title compound was prepared. 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 = I 1.36 Hz, 1H) 3.33-3.41 (m) 1H). MS (ESI +) m / z 375.0 (M + H) ^<+> .

(Example 177)
The title compound was prepared according to the procedure described in Example 81B substituting benzylamine for N-benzyl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide 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 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 methanol 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 piperidine instead of (R) -3-amino-3-phenylpropanol The title compound was prepared according to the procedure described in Example 81B using 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 piperidine instead of (S) -3-amino-3-phenylpropanol The title compound was prepared according to the procedure described in Example 81B using 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 piperidine was used instead of 1-aminoindane as described in Example 81B The title compound was prepared according to the procedure. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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 piperidine was used instead of 2-aminoindane as described in Example 81B The title compound was prepared according to the procedure. 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 In place of α-ethylbenzylamine in place of piperidine, the title compound was prepared according to the procedure described in Example 81B. Manufactured. 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)
Instead of 5- {1-benzyl-5- [3- (dimethylamino) phenyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3-amine 4-methoxyphenylboric acid The title compound was prepared as the TFA salt according to the procedure described in Example 173 using 3- (dimethylamino) phenylboric 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)
Instead of 5- {1-benzyl-5- [4- (dimethylamino) phenyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3-amine 4-methoxyphenylboric acid The title compound was prepared as the TFA salt according to the procedure described in Example 173 using 4- (dimethylamino) phenylboric 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 4-methoxyphenylboric acid The title compound was prepared according to the procedure described in Example 173 using 3-acetamidophenylboric acid instead. 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 4-methoxyphenylboric acid The title compound was prepared according to the procedure described in Example 173 using 4-acetamidophenylboric acid instead. 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 4-methoxyphenyl The title compound was prepared according to the procedure described in Example 173 using 3- (1H-pyrazol-1-yl) phenylboric acid in place of boric 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 4-methoxyphenylborohydride The title compound was prepared according to the procedure described in Example 173 using 1-methyl-1H-pyrazol-4-ylboronic acid in place of 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)
Instead of 3- [4- (3-amino-1H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] -N-phenylbenzamide 4-methoxyphenylboric acid The title compound was prepared according to the procedure described in Example 173 using 3- (phenylcarbamoyl) phenylboric 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)
Instead of 3- [4- (3-amino-1H-indazol-5-yl) -1-benzyl-1H-1,2,3-triazol-5-yl] -N-benzylbenzamide 4-methoxyphenylboric acid The title compound was prepared according to the procedure described in Example 173 using 3- (benzylcarbamoyl) phenylboric 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 4-methoxyphenylboro The title compound was prepared as the TFA salt according to the procedure described in Example 173 using 1-methyl-1H-indol-5-ylboric acid instead of 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 = I .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 instead of 4-methoxyphenylboric acid The title compound was prepared according to the procedure described in Example 173 using phenylboric 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 under argon DME (1 mL) Example 125B (35 mg, 0.09 mmol), 3-morpholinophenylboric acid (21 mg, 0.09 mmol), PdCl ₂ (dppf) dichloromethane (7 mg, 0.009 mmol) and potassium carbonate in water (0.1 mL) A vial containing (24 mg, 0.18 mmol) was capped and heated on a heater shaker at 80 ° C. for 3 days. The solvent was removed under reduced pressure and the product was purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution to give the title compound as 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 piperidine is used instead of isoindoline and according to the procedure described in Example 81B. The title compound was prepared. 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)
Example of using 1-methyl-3-phenylpiperazine instead of 5- {3-[(4-methyl-2-phenylpiperazin-1-yl) carbonyl] isoxazol-5-yl} -1H-indazolepiperidine The title compound was prepared according to the procedure described in 81B. 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 = 11.72 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-triazol-5-carbonyl) piperidin-4-ylcarbamate Example 81B instead of Example The title compound was prepared according to the procedure described in Example 81B using 149C, substituting 4-Boc-aminopiperidine for 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 Example 197A (101 mg, 0.201 mmol) ) Was dissolved in 4M hydrochloric acid / dioxane (4 mL) and methanol (1 mL) and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give the title compound as the 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 = 11.02, 11.02 Hz, 1H) 1.87-2.03 (M, J = 11.87 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 Example 102B (200 mg, 0.55 mmol) ) And N, N-dimethylpyridin-4-amine (5 mg, 0.04 mmol) were dissolved in methylene chloride. While stirring the mixture at room temperature, a solution of di-tert-butyl dicarbonate (120 mg, 0.55 mmol) in methylene chloride (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 8 hours, concentrated under reduced pressure, dissolved in methylene chloride (10 mL) and washed with dilute aqueous HCl (1 N, 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 Example 198A (37.5 mg, 0.08 mmol) And pyridine (12.7 mg, 0.16 mmol) were dissolved in methylene chloride (2 mL). The mixture was stirred at room temperature. Benzoyl chloride (14 mg, 0.1 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and purified by reverse phase HPLC (CH ₃ CN / H ₂ O / NH ₄ OAc) to give the Boc protected precursor. The precursor was treated with 1: 1 TFA / dichloromethane (2 mL) for 1 h and concentrated under reduced pressure to give the title compound as 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)
Instead of N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzenesulfonamidobenzoyl chloride, benzenesulfonyl chloride is used. The title compound was prepared according to the procedure described in Example 198B. 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 Examples 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 the Boc protected precursor. The precursor was treated with 1: 1 TFA / dichloromethane (2 mL) for 1 h and concentrated under reduced pressure to give the title compound as 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] butanamidobenzoyl chloride was used instead of butyryl chloride The title compound was prepared as the TFA salt according to the procedure described in Example 198B. 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-methylpropanamidobenzoyl chloride instead of isobuty The title compound was prepared according to the procedure described in Example 198B using ril 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)
Instead of N- [5- (1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] cyclopropanecarboxamidobenzoyl chloride, cyclopropanecarbonyl chloride is used. The title compound was prepared according to the procedure described in Example 198B. 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 in a CEM microwave tube Example 89B (33 mg, 0.1 mmol) was dissolved in tetrahydrofuran (0.6 mL). Benzoyl chloride (28 mg, 0.2 mmol) was added and the mixture was heated in a CEM-discover microwave apparatus at 120 ° C. for 15 minutes. 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 give 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 Example instead of Example 102A The title compound was prepared according to the procedure described in Example 198A using 89B. 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 Example 205A (25 mg, 0 0.058 mmol) and pyridine (9.2 mg, 0.116 mmol) were dissolved in methylene chloride (1 mL). The mixture was stirred at room temperature and 3-fluorobenzoyl chloride (11.1 mg, 0.58 mmol) was added to the mixture. The reaction mixture was stirred at room temperature overnight, concentrated and purified by reverse phase HPLC (CH ₃ CN / H ₂ O / NH ₄ OAc) to give the Boc protected precursor. The precursor was treated with 1: 1 TFA / dichloromethane (2 mL) for 1 h and concentrated under reduced pressure to give the title compound as 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 to 1.47 (m, J = 5.15 Hz, 1H), 0.68 (d, J = 8.27, 1.65 Hz, 2H), 0 0.03 (d, J = 5.52 Hz, 2H). MS (ESI +) m / z 453 (M + H) ^<+> .

(Example 206)
Instead of N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamido 3-fluorobenzoyl chloride, benzoyl chloride is used. The title compound was prepared according to the procedure described in Example 205B. 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 Example 89B (18.3 mg, 0.05 mmol) To a solution of dimethylformamide (2 mL), acetic acid (15 mg, 0.25 mmol) and benzaldehyde (6.4 mg, 0.06 mmol) were added. 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 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 piperidine instead of (R)-(+)-2-amino- The title compound was prepared according to the procedure described in Example 81B using 3-phenyl-1-propanol (37 mg, 0.245 mmol). 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 room 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 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). Combined with dioxane (10 mL) and water (1 mL) in a sealed vial under a nitrogen inert atmosphere and heated the mixture to 110 ° C. overnight. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 45% to 90% ethyl acetate / hexanes 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)
5-Bromo-3-methyl-1H-indazole-1-carboxylate tert-butyl 5-bromo-3-methyl-1H-indazole (5.11 g, 24.2 mmol) and catalytic amount of dimethylaminopyridine (about 30 mg) Was dissolved in methylene chloride (100 mL). Di-tert-butyl dicarbonate (5.9 g, 27.0 mmol) was added and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the resulting residue was diluted with ethyl acetate and washed with 1N sodium hydroxide (twice), 0.1N hydrochloric acid and brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound. MS (ESI +) m / z 210.8 (M-Boc) ^<+> .

(Example 210B)
Tert-Butyl 3-methyl-5-((trimethylsilyl) ethynyl) -1H-indazole-1-carboxylate Example 210A (7.55 g, 24.3 mmol), dichlorobis (triphenylphosphine) palladium (II) (870 mg, 1.24 mmol) and copper (I) iodide (250 mg, 1.31 mmol) were combined in triethylamine (60 mL) under 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 0.1M hydrochloric acid. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 10% to 40% ethyl acetate / hexanes to give the title compound. MS (ESI +) m / z 228.9 (M-Boc) ^<+> .

(Example 210C)
5- Ethynyl -3-methyl-1H-indazole Example 210B (7.26 g, 22.1 mmol) was dissolved in methanol (170 mL). 1N potassium hydroxide solution (45 mL) was added and the mixture was stirred at room 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 give the title compound. MS (ESI +) m / z 157.1 (M + H) ^<+> .

(Example 210D)
Ethyl 5- (3-methyl-1H-indazol-5-yl) isoxazole-3-carboxylate Example 210C (411 mg, 2.63 mmol) was dissolved in toluene (15 mL) and triethylamine (478 μL) and allowed to warm. The temperature was 90 ° C. Ethyl chlorooxymidoacetate (480 mg, 3.17 mmol) dissolved in toluene (15 mL) was slowly added dropwise over 30 minutes. After the addition, the mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid. The organic layer was concentrated under reduced pressure and the resulting residue was triturated with methanol to 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 Example 210D (325 mg, 1.20 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (1 mL) and water (1 mL). Potassium hydroxide (150 mg, 2.67 mmol) was added. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and washed with 1N 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 Example 210E was used instead of Example 81A, The title compound was prepared according to the procedure described in Example 81B 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 under argon, DME (1 mL) and water ( Example 125B (35 mg, 0.09 mmol), 3-hydroxyphenylboric acid (12 mg, 0.09 mmol), PdCl ₂ (dppf) dichloromethane (7 mg, 0.009 mmol) and potassium carbonate (24 mg, 0.1 mL). A vial containing 0.18 mmol) was capped and heated at 80 ° C. for 3 days with a heater shaker. The solvent was distilled off and the product was purified by reverse phase HPLC using acetonitrile / water 0.1% TFA gradient elution 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 4-methoxyphenylboric acid instead of 3-carbamoyl The title compound was prepared according to the procedure described in Example 173 using phenylboric 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)
Instead of 5- {1-benzyl-5- [4- (methylsulfonyl) phenyl] -1H-1,2,3-triazol-4-yl} -1H-indazol-3-amine 4-methoxyphenylboric acid The title compound was prepared according to the procedure described in Example 173 using 4- (methylsulfonyl) phenylboric 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)
Instead of N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-chlorobenzamido 3-fluorobenzoyl chloride The title compound was prepared according to the procedure described in Example 205B using 2-chlorobenzoyl 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-chlorobenzamido instead of 3-fluorobenzoyl chloride The title compound was prepared according to the procedure described in Example 205B using 4-chlorobenzoyl 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 Ethane instead of 3-fluorobenzoyl chloride The title compound was prepared according to the procedure described in Example 205B using sulfonyl 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 instead of 3-fluorobenzoyl chloride The title compound was prepared according to the procedure described in Example 205B using sulfonyl 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 3-fluorobenzoyl chloride The title compound was prepared according to the procedure described in Example 205B using 2-chlorobenzene-1-sulfonyl chloride instead. 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, 1 H), 7.40 (d, J = 8.82, 1.47 Hz, 1 H), 7.14-7.27 (m, 2 H), 7.00-7.12 (m, 4 H ), 6.96-7.00 (m, 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 3-fluorobenzoyl chloride The title compound was prepared as the HCl salt according to the procedure described in Example 205B using 3-chlorobenzene-1-sulfonyl chloride instead. 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 = I.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 3-fluorobenzoyl chloride The title compound was prepared as the HCl salt according to the procedure described in Example 205B using 4-chlorobenzene-1-sulfonyl chloride instead. 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 prepared as the HCl salt according to the procedure described in Example 205B using 2,5-dimethylfuran-3-sulfonyl chloride in place 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)
Instead of 5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N- (2-chlorobenzyl) -1H-indazol-3-aminebenzaldehyde 2-chloro The title compound was prepared according to the procedure described in Example 207 using 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)
3-chloro instead of 5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N- (3-chlorobenzyl) -1H-indazol-3-aminebenzaldehyde The title compound was prepared according to the procedure described in Example 207 using 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)
Instead of N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -3-chlorobenzamido 3-fluorobenzoyl chloride The title compound was prepared according to the procedure described in Example 205B using 3-chlorobenzoyl 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)
Instead of N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-furamido 3-fluorobenzoyl chloride The title compound was prepared according to the procedure described in Example 205B using furan-2-carbonyl 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)
Example 207 uses acetaldehyde instead of 5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N-ethyl-1H-indazole-3-aminebenzaldehyde. The title compound was prepared according to the described procedure. 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)
4- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N- (4-chlorobenzyl) -1H-indazol-3-aminebenzaldehyde instead of 4-chloro The title compound was prepared according to the procedure described in Example 207 using 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)
Furan-3 instead of 5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -N- (3-furylmethyl) -1H-indazol-3-aminebenzaldehyde The title compound was prepared according to the procedure described in Example 207 using carbaldehyde. 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 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 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 the Boc protected precursor. The precursor was dissolved in methanol and treated with excess HCl / dioxane (4M, 0.5 mmol). The reaction was stirred for 5 hours and concentrated under reduced pressure to give the title compound as the 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)
Instead of N- [5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -3-furamide 3-fluorobenzoyl chloride The title compound was prepared as the HCl salt following the procedure described in Example 205B using furan-3-carbonyl 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 replaced with (S)-(−)-1-phenylpropylamine instead of piperidine The title compound was prepared according to the procedure described in Example 81B. 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 replaced with (R)-(−)-1-phenylpropylamine instead of piperidine The title compound was prepared according to the procedure described in Example 81B. 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) was combined in a sealed vial with dioxane (10 mL) and water (1 mL) under an inert atmosphere of nitrogen and the mixture was heated to 110 ° C. overnight. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed onto silica gel and purified by silica gel chromatography eluting with a gradient of 10% to 50% ethyl acetate / hexanes 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 Example 233A (591 mg, 2.13 mmol) was hydrazine hydrate (4.0 mL) in ethanol (3.0 mL). ), Stirred and heated to 70 ° C. overnight. The mixture was diluted with methylene chloride and washed with water. The organic layer was concentrated under reduced pressure and the resulting residue was triturated with methanol to 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 In a 20 mL vial, dimethylformamide ( A solution of Example 149C (51 mg, 0.16 mmol) dissolved in 0.5 mL) was added followed by (S)-(+)-tetrahydrofurfurylamine (18.2 mg, dissolved in dimethylformamide (0.9 mL). 0.18 mmol) was added. A solution of HATU (68 mg, 0.18 mmol) dissolved in dimethylformamide (0.5 mL) was added, followed by a solution of diisopropylethylamine (0.087 mL, 0.5 mmol) dissolved in dimethylformamide (0.5 mL). It was. The mixture was shaken at 50 ° C. overnight. The reaction solution was filtered through a Si-carbonate cartridge (6 mL-1 g) supplied from Siricycle Chemical Division, and the filtrate was transferred to a 20 mL vial. The reaction was checked by LC / MS and concentrated to dryness. The residue was dissolved in 1: 1 DMSO / methanol and purified by reverse phase HPLC (Agilent, 5% to 100% TFA / water gradient, 8 min run). 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 / z401 ( M-H) -.

(Example 235)
1-Benzyl-4- (1H-indazol-5-yl) -N- (2-isopropoxyethyl) -1H-1,2,3-triazole-5-carboxamide (S)-(+)-tetrahydrofurfurylamine The title compound was prepared according to the procedure described in Example 234 using 2-aminoethyl isopropyl ether instead. 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 (S)-(+) The title compound was prepared according to the procedure described in Example 234 using (R)-(−)-tetrahydrofurfurylamine instead of 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 / z401 ( M-H) -.

(Example 237)
1-Benzyl-4- (1H-indazol-5-yl) -N- (tetrahydrofuran-3-ylmethyl) -1H-1,2,3-triazole-5-carboxamide (S)-(+)-tetrahydrofurfurylamine The title compound was prepared according to the procedure described in Example 234 using 3-aminomethyltetrahydrofuran instead. 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)
Instead of 1-benzyl-N-cyclopentyl-4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide (S)-(+)-tetrahydrofurfurylamine, cyclopentylamine is used. The title compound was prepared according to the procedure described in Example 234. 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 / z385 ( M-H) -.

(Example 239)
Instead of 1-benzyl-N- (cyclopentylmethyl) -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide (S)-(+)-tetrahydrofurfurylamine The title compound was prepared according to the procedure described in Example 234 using aminomethylcyclopentane. 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)
Instead of 1-benzyl-N-ethyl-4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide (S)-(+)-tetrahydrofurfurylamine The title compound was prepared according to the procedure described in Example 234 using N-methylethylamine hydrochloride. 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)
Instead of 1-benzyl-4- (1H-indazol-5-yl) -N-isopropyl-N-methyl-1H-1,2,3-triazole-5-carboxamide (S)-(+)-tetrahydrofurfurylamine The title compound was prepared according to the procedure described in Example 234 using methyl isopropylamine. 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 (S)-(+)- The title compound was prepared according to the procedure described in Example 234 using N- (2-methoxyethyl) methylamine in place of 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 (S)-(+)-tetrahydrofurfurylamine is used instead of aniline The title compound was prepared according to the procedure described in Example 234. 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)
Instead of 1-benzyl-N- (4-chlorophenyl) -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide (S)-(+)-tetrahydrofurfurylamine The title compound was prepared according to the procedure described in Example 234 using 4-chloroaniline. 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-ylethyl) -1H-1,2,3-triazole-5-carboxamide (S)-(+)-tetrahydro The title compound was prepared according to the procedure described in Example 234 using N- (3-aminopropyl) morpholine instead of furfurylamine. 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 / z430 ( M-H) -.

(Example 246)
1-benzyl-N- [2- (dimethylamino) ethyl] -4- (1H-indazol-5-yl) -N-methyl-1H-1,2,3-triazole-5-carboxamide (S)-( The title compound was prepared as the TFA salt according to the procedure described in Example 234 using N, N, N-trimethylethylenediamine instead of +)-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 (S)-(+)- The title compound was prepared according to the procedure described in Example 234 using 2- (propylamino) ethanol in place of tetrahydrofurfurylamine. ¹ H NMR (300 MHz, DMSO-d ₆ / D ₂ O) δ ppm 0.22 to 0.39 (m, 1H) 0.80 to 1.06 (m, 3H) 1.50 to 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 (S)-( The title compound was prepared as the TFA salt according to the procedure described in Example 234 using N, N, N-trimethyl-1,3-propanediamine instead of +)-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 (S)-(+ The title compound was prepared as the TFA salt according to the procedure described in Example 234 using N, N-diethyl-N-methylethylenediamine instead of) -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 0.03-3.11 (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 (S)-(+)-tetrahydrofurfurylamine instead of N The title compound was prepared according to the procedure described in Example 234 using ethylbenzylamine. 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 (S)-(+)-tetrahydrofurfuryl The title compound was prepared according to the procedure described in Example 234 using N-benzylethanolamine instead of ruamine. 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 (S)-( The title compound was prepared according to the procedure described in Example 234 using (R)-(+)-3-hydroxypiperidine hydrochloride instead of +)-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 (S)-(+)-tetrahydro The title compound was prepared according to the procedure described in Example 234 using isonipecotamide instead of furfurylamine. 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 (S)-(+) The title compound was prepared according to the procedure described in Example 234 using 2,6-dimethylmorpholine instead of 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 (S)-(+)-tetrahydro The title compound was prepared according to the procedure described in Example 234 using 1-acetylpiperazine instead of furfurylamine. 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 (S)-(+)-tetrahydro The title compound was prepared according to the procedure described in Example 234 using 1-phenylpiperazine instead of furfurylamine. ¹ H NMR (500 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 (M-H) ^<+> .

(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 in place 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 in place 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-imidazol-1-yl) propyl] -4- (1H-indazol-5-yl) -1H-1,2,3-triazole-5-carboxamide (S)- The title compound was prepared according to the procedure described in Example 234 using 1- (3-aminopropyl) imidazole instead of (+)-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 3 -isocyanato-5 The title compound was prepared as the hydrochloride salt following the procedure described in Example 229 using isocyanatoethane in place of 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 3-isocyanato-5 The title compound was prepared as the hydrochloride salt following the procedure described in Example 229 using isocyanatobenzene in place of 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 3-isocyanato-5 The title compound was prepared as the hydrochloride salt following the procedure described in Example 229 using (isocyanatomethyl) benzene in place of 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 3- The title compound was prepared as the hydrochloride salt following the procedure described in Example 229 using 1-chloro-2-isocyanatobenzene in place of 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 3- The title compound was prepared as the hydrochloride salt following the procedure described in Example 229 using 1-chloro-3-isocyanatobenzene in place of 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 3- The title compound was prepared as the hydrochloride salt following the procedure described in Example 229 using 1-chloro-4-isocyanatobenzene in place of 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 Example 125B instead of Example 102B The title compound was prepared according to the procedure described in Example 198A. The product was used directly in the next reaction without characterization.

(Example 266B)
N- [5- (1-Benzyl-5-iodo-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] benzamide Example 266A was used instead of Example 205A, The title compound was prepared as a TFA salt according to the procedure described in Example 205B. 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), 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] propanenitrile (Example 267A)
3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propanenitrile 4- (4,4,5,5 To a solution of -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) and then Was added 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 dissolved in a minimum amount of dichloromethane and purified by silica gel chromatography eluting with a gradient of 10% to 50% ethyl acetate / 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] propanenitrile microwave vial was charged with 5-bromo-1H-indazol-3-amine (0.14 g, 0.66 mmol), tetrakis (triphenylphosphine) palladium (0) (0.076 g, 0.066 mmol) and sodium carbonate (0.147 g, 1.39 mmol) were added, followed by Example 267A (0.212 g, 0 .858 mmol) in 1,2-dimethoxyethane (2.50 mL) followed by water (1.25 mL). The mixture was heated in a CEM microwave apparatus at about 150 ° C. for about 20 minutes (maximum pressure about 1.90 MPa (275 psi), about 2 minutes ramp, up to 200 watts), then the mixture was concentrated under reduced pressure. Methanol (20 mL) was added and the resulting mixture was stirred for about 1 hour. Insoluble material was removed by filtration. The filtrate is concentrated on silica gel under reduced pressure and silica gel eluting with a stepwise gradient of dichloromethane / methanol / ammonium hydroxide (990: 9: 1 to 985: 13.5: 1.5 to 980: 18: 2) Purification by chromatography gave a solid. This solid was dissolved in a minimum amount of hot acetonitrile (about 2 mL), filtered to remove a small amount of insoluble material, washed with methanol (about 0.5 mL), and allowed to stand at room temperature. The resulting solid produced overnight was collected by filtration, washed 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 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, A suspension of 15.5 mmol) in acetone (60 mL) was heated at about 50 ° C. for about 3.5 days. The reaction mixture was cooled to room temperature, washed with additional acetone, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude material was dissolved in a minimum amount of dichloromethane and purified by silica gel chromatography eluting with a gradient of 80% to 100% ethyl acetate / 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 Example 268A was used instead of Example 267A and heated at about 120 ° C. for about 10 minutes. The title compound was prepared according to the procedure described in Example 267B. 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)
3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) propanoic acid methyl acrylonitrile instead of methyl acrylate The title compound was prepared according to the procedure described in Example 267A. 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)
3- [4- (3-Amino-1H-indazol-5-yl) -1H-pyrazol-1-yl] methyl propanoate Use Example 269A instead of Example 267A and heat at about 120 ° C. for about 20 minutes The title compound was then prepared according to the procedure described in Example 267B. 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 (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 Using Example 270A instead of Example 267A, heating at about 120 ° C. for about 15 minutes The title compound was prepared according to the procedure described in Example 267B. 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 2-bromoacetamide instead of 2-bromoacetamide The title compound was prepared according to the procedure described in Example 268A using ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 799 (s, 1H), 7.66 (s, 1H), 5.45 (s, 2H), 1.25 (s, 12H).

(Example 271B)
5-Bromo-1H-indazole-3-amine (2.00 g, in tert-butyltetrahydrofuran (20 mL) 3- (bis (tert-butoxycarbonyl) amino) -5-bromo-1H-indazole-1-carboxylic acid To 9.43 mmol) was added 4- (dimethylamino) pyridine (0.230 g, 1.886 mmol) and di-tert-butyl dicarbonate (6.18 g, 28.3 mmol). The reaction was heated at 50 ° C. for about 2 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was dissolved in diethyl ether (100 mL) and then washed sequentially with 1N hydrochloric acid (2 × 25 mL), 1N sodium hydroxide (2 × 25 mL) and brine (25 mL). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried in a vacuum dryer at about 60 ° C. to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.05 (d, J = 8.95 Hz, 1 H), 7.99 (d, J = 1.90 Hz, 1 H), 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)
3- (Bis (tert-butoxycarbonyl) amino) -5- (1- (cyanomethyl) -1H-pyrazol-4-yl) -1H-indazole-1-carboxylate was added to a tert-butyl vial in Example 271A (0 682 g, 2.93 mmol), Example 271B (1.25 g, 2.44 mmol), cesium carbonate (1.99 g, 6.10 mmol), 1,4-dioxane (12.5 mL) and water (2.50 mL). Put. After vacuum / nitrogen purge through septum, tris (dibenzylideneacetone) dipalladium (0) (0.112 g, 0.122 mmol) and tri-t-butylphosphonium tetrafluoroborate (0.085 g, 0.29 mmol) And a cap was applied to the vial after flushing with nitrogen. After about 6 hours at room temperature, the reaction was partitioned between saturated aqueous sodium bicarbonate and dichloromethane (50 mL each). The layers were separated and the aqueous layer was extracted with additional dichloromethane (2 x 50 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude oil was dissolved in a minimum amount of dichloromethane and purified by silica gel chromatography eluting with a gradient of 20% to 60% ethyl acetate / 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 3- (bis (tert-butoxycarbonyl) amino) -5- (1- (cyanomethyl) -1H- To a solution of tert-butyl pyrazol-4-yl) -1H-indazole-1-carboxylate (0.30 g, 0.557 mmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (2.0 mL). After about 45 minutes, the reaction was slowly quenched with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (3 x 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. The white precipitate suspended in both the initial aqueous layer and the brine layer was filtered and added to the crude solid. The resulting solid was triturated with dichloromethane / methanol (19: 1). The remaining solid was collected by vacuum filtration and dried in a vacuum dryer 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-sulfonamido 3-cyano-4-fluorophenylboric 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) was combined in dimethoxyethane (4 mL) and water (1.5 mL). The reaction mixture was heated in a microwave apparatus (CEM-Discover) at about 150 ° C. for about 25 minutes. The organic layer was separated and the solvent was removed under reduced pressure. To the residue was added ethanol (0.7 mL) and hydrazine monohydrate (1 mL). The reaction mixture was heated at about 80 ° C. for about 20 hours. The reaction mixture was partitioned between water (5 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 (0.05 M ammonium acetate) gradient elution method to give 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)
Procedure described in Example 272 using 2-iodopyrazine instead of 5-pyrazin-2-yl-1H-indazole-3-amine 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide The title compound was prepared according to 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)
Procedure described in Example 272 using 2-iodothiophene instead of 5-thien-2-yl-1H-indazol-3-amine 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide The title compound was prepared according to 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)
Instead of 5- (2-aminopyrimidin-4-yl) -1H-indazol-3-amine 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide, 5-iodopyrimidin-2-amine was used. The title compound was prepared according to the procedure described in Example 272. 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)
Instead of 5- (2-methoxypyridin-3-yl) -1H-indazole-3-amine 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide, 3-iodo-2-methoxypyridine was used. The title compound was prepared according to the procedure described in Example 272. 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)
3-bromoimidazo [1 instead of 5-imidazo [1,2-a] pyridin-3-yl-1H-indazol-3-amine 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide , 2-a] pyridine and the title compound was prepared according to the procedure described in Example 272. 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 Example 65 (257 mg, 0.685 mmol) Was dissolved in ethanol (15 mL). The reaction mixture was hydrogenated with palladium hydroxide (20%) / carbon in an H-Cube apparatus at about 80 ° C. and about 0.41 MPa (about 60 psi) for about 8 hours. The solvent was removed under reduced pressure and the residue was purified by reverse phase HPLC using an acetonitrile / water (0.05 M ammonium acetate) gradient elution method to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.16-8.37 (m, 1H), 7.10-7.46 (bs, 2H), 7.00-7.34 (bs, 2H), 6.87-7.24 (bs, 2H), 3.33-3.34 (m, 2H). MS (ESI +) m / z 286.2 (M + H) ^<+> .

(Example 279)
5- (1H-pyrazol-5-yl) -1H-indazole-3-amine 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide was used instead of 5-iodo-1H-pyrazole, The title compound was prepared according to the procedure described in Example 272. 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 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide instead of 5-iodo-4- The title compound was prepared according to the procedure described in Example 272 using methyl-1H-imidazole. 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), 5.32 (bs, 2H). 2.37 (s, 3H). MS (ESI +) m / z 214.1 (M + H) ^<+> .

(Example 281)
Instead of 5- (1H-imidazol-4-yl) -1H-indazole-3-amine 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide, 4-iodo-1H-imidazole was used, The title compound was prepared according to the procedure described in Example 272. 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-indazol-3-amine The title compound was prepared according to the procedure described in Example 62D using 5-bromo-2-fluorobenzonitrile in place 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 substituting Example 282A for 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, 1 H), 6.39 (d, J = 4.44 Hz, 1 H), 1.58 (m, 9 H).

(Example 282C)
Tert-Butyl 5-bromo-3- (2- (dimethylamino) acetamido) -1H-indazole-1-carboxylate Example 282B (24.43 g, 78 mmol), potassium carbonate (81 g, 587 mmol) and 2- (dimethyl To a mixture of amino) acetyl chloride hydrochloride (43.3 g, 274 mmol) was added tetrahydrofuran (200 mL). 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 x 100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol / dichloromethane (5%) to give 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) acetamide) -5-((trimethylsilyl) ethynyl) -1H-indazole-1-carboxylate Example 282C (2.56 g, 6.44 mmol), bis (triphenylphosphine ) A mixture of palladium (II) chloride (0.225 g, 0.321 mmol) and copper (I) iodide (0.073 g, 0.383 mmol) was added to triethylamine (20 mL, 144 mmol) followed by ethynyltrimethylsilane (0. 760 g, 7.73 mmol) was added. The reaction mixture was heated at about 60 ° C. for about 3 hours. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate / dichloromethane (10%) 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)
Example 282D (0.303 g, 0.731 mmol) in 2- (dimethylamino) -N- (5-ethynyl-1H-indazol-3-yl) acetamidemethanol (5 mL) was added aqueous potassium hydroxide (1. 46 mL, 1.46 mmol, 1.0 N solution) was added. 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, washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 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 embodiment To a suspension of Example 282E (0.16 g, 0.660 mmol) in tert-butanol (1.2 mL), 1- (azidomethyl) -3-methylbenzene (0.098 g, 0.667 mmol), then water ( 1.2 mL) was added. Sodium (R) -2-((S) -1,2-dihydroxyethyl) -4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate solution (0.057 mL, 0.066 mmol, 1 .6M aqueous solution) and copper (II) sulfate pentahydrate aqueous solution (0.019 mL, 6.6 μmol, 0.34 M) were added. The reaction mixture was heated at about 60 ° C. for about 2 hours. The solvent was removed under reduced pressure and the residue was purified by reverse phase HPLC using an acetonitrile / water (0.05 M ammonium acetate) gradient elution method to give 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)
Instead of 5- (1-benzyl-1H-imidazol-4-yl) -1H-indazol-3-amine 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide, 1-benzyl-4- The title compound was prepared according to the procedure described in Example 272 using iodo-1H-imidazole. 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 - dimethylglycine The title compound was prepared according to the procedure described in Example 282F using 1- (azidomethyl) -4-tert-butylbenzene instead of amide 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-ylethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-yl] The title compound was prepared according to the procedure described in Example 282F using 1- (2-azidoethyl) piperidine instead of glycinamide 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 (M-H) ^- .

(Example 286)
^{N 2,} N ² - dimethyl ^{-N 1 - {5- [1- (} 2- morpholin-4-ylethyl)-1H-1,2,3-triazol-4-yl]-1H-indazol-3-yl] The title compound was prepared according to the procedure described in Example 282F using 4- (2-azidoethyl) morpholine instead of glycinamide 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 (M-H) ^- .

(Example 287)
^{N 1 - (5- {1- [} 2- (3,5- dimethyl-isoxazol-4-yl) ethyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-3-yl ) ^-N 2, ^{N 2} - using dimethyl glycinamide 1- (azidomethyl) -3 instead of methylbenzene 4- (2-azidoethyl) -3,5-dimethyl isoxazole, according to the procedure described in example 282F The title compound was prepared. 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 (M-H) ^- .

(Example 288)
^{N 1 - (5- {1- [} 2- (3,5- dimethyl-1H-pyrazol-4-yl) ethyl]-1H-1,2,3-triazol-4-yl}-1H-indazole -3 -Yl ) -N ² , N ² -dimethylglycinamide 4- (2-azidoethyl) -3,5-dimethyl-1H-pyrazole was used instead of 1- (azidomethyl) -3-methylbenzene in Example 282F. The title compound was prepared according to the described procedure. 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 / z406.2 ( M-H) -.

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 in place 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 / z370.2 ( M-H) -.

(Example 290)
(4- {3-[(N, N-dimethylglycyl) amino] -1H-indazol-5-yl} -1H-1,2,3-triazol-1-yl) ethyl acetate 1- (azidomethyl)- The title compound was prepared according to the procedure described in Example 282F using ethyl 2-azidoacetate instead of 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 1 The title compound was prepared according to the procedure described in Example 282F using (azidomethyl) trimethylsilane in place of-(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)
Example 1 282C was used instead of N ^1- [5- (3-furyl) -1H-indazol-3-yl] -N ² , N ² -dimethylglycinamide 5-bromo-2-fluorobenzonitrile, Benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H described in Example 233A using furan-3-ylboric acid instead of 1-pyrazole The title compound was prepared according to the procedure of 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 - a [5- (1H-pyrazol-5-yl)-1H-indazol-3-yl] Example 282C in place of the glycinamide 5-bromo-2-fluorobenzonitrile 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole is used instead of 1H-pyrazol-5-ylboric acid The title compound was prepared according to the procedure described in Example 233A. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.68 (s, 1H), 10.1 (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)
Example 282C was used instead of N ² , N ² -dimethyl-N ^1- (5-pyrimidin-5-yl-1H-indazol-3-yl) glycinamide 5-bromo-2-fluorobenzonitrile, Benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H described in Example 233A using pyrimidin-5-ylboric acid in place of 1-pyrazole The title compound was prepared according to the procedure of 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- ^{benzo-oxadiazol-5-yl)-1H-indazol-3-yl]} -N ^{2, N} 2 - dimethyl glycine amide 5-bromo-2-fluorobenzonitrile Example 282C was used instead of 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole instead of benzo [c] The title compound was prepared according to the procedure described in Example 233A using [1,2,5] oxadiazol-5-ylboric acid. 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 - a [5- (1H-pyrazol-4-yl)-1H-indazol-3-yl] Example 282C in place of the glycinamide 5-bromo-2-fluorobenzonitrile Instead of 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole, 4- (4,4,5,5- The title compound was prepared according to the procedure described in Example 233A using 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] instead of glycinamide 5-bromo-2-fluorobenzonitrile Example 282C was used instead of 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole and 1-methyl-4- ( The title compound was prepared according to the procedure described in Example 233A using 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 5-bromo-2-fluorobenzonitrile Example 282C was used instead and 3,5-dimethyl instead of 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole The title compound was prepared according to the procedure described in Example 233A using -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)
Instead of N ^1- {5- [2- (dimethylamino) pyrimidin-5-yl] -1H-indazol-3-yl} -N ² , N ² -dimethylglycinamide 5-bromo-2-fluorobenzonitrile Using Example 282C, N, N-dimethyl-5 instead of 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole The title compound was prepared according to the procedure described in Example 233A using-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2-amine. 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 - instead of [5- (2-morpholin-4-yl-pyrimidin-5-yl)-1H-indazol-3-yl] glycinamide 5-bromo-2-fluorobenzonitrile Example 282C was used instead of 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole and 4- (5- ( The title compound was prepared according to the procedure described in Example 233A using 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2-yl) morpholine. 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-ylethyl)-1H-pyrazol-4-yl]-1H-indazol-3-yl] glycinamide 5-Bromo - Example 282C was used instead of 2-fluorobenzonitrile and was replaced with 1-benzyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole 4- (2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) ethyl) morpholine The title compound was prepared according to the procedure described in Example 233A. 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 - dimethyl glycine amide ( Example 302A)
Example 1 using 1-benzyl-5-cyclopropyl-4- (tributylstannyl) -1H-1,2,3-triazolehexane instead of toluene and using (azidomethyl) benzene instead of Example 8A The title compound was prepared according to the procedure described in 142A. 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 Example 302A was used instead of Example 142A, and 2- The title compound was prepared according to the procedure described in Example 142B using fluoro-5-iodobenzonitrile. 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 Example 302B was used instead of Example 62C, and Example 62D was The title compound was prepared according to the described procedure. MS (ESI-) m / z 299.2 (M-H) ^- .

(Example 302D)
Tert-Butyl 3-amino-5- (1-benzyl-5-cyclopropyl-1H-1,2,3-triazol-4-yl) -1H-indazole-1-carboxylate Example instead of Example 62D The title compound was prepared according to the procedure described in Example 64A using 302C.

(Example 302E)
^{N 1 - [5- (-1H-} 1,2,3- ^{triazol-4-1-benzyl-5-cyclopropyl-yl)-1H-indazol-3-yl]} -N ^{2, N} 2 - dimethyl glycinamide embodiment The title compound was prepared according to the procedure described in Example 64B using Example 302D instead of Example 64A and 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 - dimethyl glycine amide (Example 303A)
3-Amino-5- (1-benzyl-1H-pyrazol-4-yl) -indazole-1-carboxylic acid tert-butyl ester Substituting Example 233B for Example 62D and following the procedure described in Example 64A The title compound was prepared (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 - dimethyl glycine amide 2- (dimethylamino) acetate (32 mg, 0. 308 mmol) and oxalyl chloride (0.31 mL, 0.61 mmol) in dichloromethane (5 mL) and dimethylformamide (2 drops) were stirred at room temperature for about 1 h and concentrated under reduced pressure. The residue was suspended in tetrahydrofuran (3 mL) and added to a suspension of Example 303A (40 mg, 0.103 mmol) and potassium carbonate (43 mg, 0.308 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for about 30 minutes, 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 room temperature, concentrated under reduced pressure, diluted with dichloromethane (20 mL), and washed with 15% aqueous sodium hydroxide (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 an acetonitrile / water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 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- (-4- 1- benzyl-1H-1,2,3-triazol-yl)-1H-indazol-3-yl] -N ² - instead of methyl glycine amide 2- (dimethylamino) acetate The title compound was prepared according to the procedure described in Example 303B using 2- (tert-butoxycarbonyl (methyl) amino) acetic acid and substituting Example 64A for 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-ylacetamide (Example 305A)
Tert-Butyl 5- (1-benzyl-1H-1,2,3-triazol-4-yl) -3- (2-bromoacetamido) -1H-indazole-1-carboxylate Example 64A (500 mg, 1. To a suspension of 28 mmol) in tetrahydrofuran (12 mL) was added diisopropylethylamine (0.22 mL, 1.28 mmol). The reaction mixture was stirred at room temperature for about 15 minutes, then 2-bromoacetyl chloride (0.11 mL, 1.2 mmol) was added. The reaction mixture was stirred at room temperature for about 16 hours and additional 2-bromoacetyl chloride (0.11 mL, 1.2 mmol) was added. The reaction mixture was stirred for an additional 15 minutes and concentrated under reduced pressure to give the title compound as a brown solid. This material was used without further purification.

(Example 305B)
N- [5- (1-Benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-pyrrolidin-1- ylacetamide Example 305A (44 mg, 0. To a solution of 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 room 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 (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 an acetonitrile / water (0.05 M ammonium acetate) gradient elution method to afford 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- (-4- 1- benzyl-1H-1,2,3-triazol-yl)-1H-indazol-3-yl] -N ² - instead of cyclopentyl glycine amide pyrrolidine using cyclopentanamine The title compound was prepared according to the procedure described in Example 305B (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 - cyclopropyl glycinamide Example 305A (100mg, 0. To a solution of 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 room temperature and hydrochloric acid (4N solution in dioxane, 1 mL) was added. The reaction mixture was stirred at room temperature for about 16 hours. The reaction mixture was concentrated under reduced pressure and purified by crude material using acetonitrile / water (0.05 M ammonium acetate) gradient elution reverse phase HPLC to afford the title compound as the acetate salt. 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 cyclo The title compound was prepared as the acetate salt following the procedure described in Example 307 using tetrahydro-2H-pyran-4-amine instead of propanamine. 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-hydroxypyrrolidin-1-yl) acetamidocyclopropanamine The title compound was prepared as the diacetate salt according to the procedure described in Example 307 using pyrrolidin-3-ol instead. 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-hydroxypiperidin-1-yl) acetamidocyclopropanamine The title compound was prepared as the acetate salt following the procedure described in Example 307 using piperidin-3-ol instead. 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- (-4- 1- ^{benzyl-1H-1,2,3-triazol-yl)-1H-indazol-3-yl]} -N ^{3, N} 3 - dimethyl -β- alanine amide cyclopropanamine The title compound was prepared as the acetate salt following the procedure described in Example 307 using dimethylamine instead. 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)
In place of N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-morpholin-4-ylacetamidocyclopropanamine The title compound was prepared according to the procedure described in Example 307. 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) acetamidocyclopropanamine The title compound was prepared as the diacetate following the procedure described in Example 307 using 1-methylpiperazine instead. 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) acetamidocyclopropanamine The title compound was prepared according to the procedure described in Example 307 using piperazin-2-one instead of. 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 - propane instead of isopropyl glycinamide cyclopropanamine -2 The title compound was prepared as the acetate salt using the amine and following the procedure described in Example 307. 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)
Cyclohexane amine instead of cyclohexyl glycinamide cyclopropanamine - N ¹ - [5- (1- Benzyl-1H-1,2,3-triazol-4-yl)-1H-indazol-3-yl] -N ² The title compound was prepared as the acetate salt using the procedure described in Example 307. 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 Example 64A (20 mg, 0.051 mmol) and diisopropylethylamine (0. To a mixture of 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 room temperature for about 1.5 hours. Hydrochloric acid (4N solution in dioxane, 1.5 mL) was added and the mixture was stirred at room temperature for about 16 hours. The solvent was removed under reduced pressure and the crude material was purified by reverse phase HPLC using an acetonitrile / water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the 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- (-4- 1- benzyl-1H-1,2,3-triazol-yl)-1H-indazol-3-yl] -N ² - cyclobutanamine instead cyclobutyl glycinamide cyclopropanamine The title compound was prepared according to the procedure described in Example 307 using 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 Example 64A (75 mg, 0.19 mmol) To a solution in pyridine (2 mL) was added 1-isocyanatopropane (16 mg, 0.19 mmol) and the reaction mixture was stirred at room 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 room temperature and water (5 mL) was added. The resulting precipitate was collected by filtration, treated with hydrochloric acid (4N solution in dioxane, 3 mL) and stirred at room temperature for about 4.5 hours. Diethyl ether (5 mL) was added and the precipitate was collected by filtration. The crude material was purified by reverse phase HPLC using an acetonitrile / water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the 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 Example 64A (75 mg, 0.19 mmol) in pyridine (2 mL To the solution in) was added ethanesulfonyl chloride (25 mg, 0.19 mmol) and the reaction mixture was stirred at room temperature for about 3 hours. Additional sulfonyl chloride (25 mg, 0.19 mmol) was added and the reaction mixture was stirred for about 48 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (10 mL) and washed with 1N aqueous hydrochloric acid (10 mL). The organic portion was separated, dried in vacuo, treated with hydrochloric acid (4N 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 acetonitrile / water (0.05 M ammonium acetate) gradient elution to afford the title compound as the 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 Example 64A (100 mg, 0.256 mmol), cyclopropane A mixture of carbaldehyde (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) at room temperature. Stir for about 2.5 hours. Hydrochloric acid (4N solution in dioxane, 4 mL) was added and the reaction mixture was stirred for about 16 hours. The precipitate was collected by filtration and washed with ether (10 mL). The solid was dissolved in dichloromethane (10 mL) 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 15% aqueous sodium hydroxide (ca. 15 mL), the organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC using an acetonitrile / water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the 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 instead of 1-isocyanatopropane isocyanatoethane The title compound was prepared according to the procedure described in Example 319 using 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 Example 64A (200 mg, 0.51 mmol) and diisopropyl A suspension of ethylamine (0.089 mL, 0.51 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature for about 15 minutes, and then 4-bromobutanoyl chloride (0.059 mL, 0.51 mmol) was added. The reaction mixture was stirred for about 16 hours. The precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was taken up in acetonitrile (5 mL), treated with diisopropylethylamine (0.089 mL, 0.51 mmol) and heated at about 60 ° C. for about 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with hydrochloric acid (4N 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 (0.05 M ammonium acetate) gradient elution method to afford the title compound as the 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)
Instead of N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -4- (dimethylamino) butanamide 2- (dimethylamino) acetic acid The title compound was prepared as the diacetate according to the procedure described in Example 303B using 4- (dimethylamino) butanoic acid, substituting Example 64A for 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. 2Hz, 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 / z462 ( M-H) -.

(Example 325)
N-3,4-dihydro-1H-isochromen-4-yl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide piperidine instead of 3,4-dihydro-1H-isochromen-4-amine The title compound was prepared according to the procedure described in Example 81B using ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (brs, 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, carried out) Example 71A) was dissolved in N, N-dimethylformamide (0.8 mL) and then HATU (60 mg, 0.15 mmol) dissolved in N, N-dimethylformamide (0.8 mL) was added. A solution of 1-cyclohexylmethanamine (17 mg, 0.17 mmol) dissolved in N, N-dimethylformamide (0.8 mL) was added, followed by diisopropylethylamine (0.8 mL) dissolved in N, N-dimethylformamide (0.8 mL). 56 μL, 0.31 mmol) was added. The resulting mixture was shaken at 40 ° C. for 3 hours. The reaction was filtered, checked by LC / MS and concentrated to dryness. The residue was dissolved in 1: 1 dimethyl sulfoxide / methanol and reverse phase HPLC (Phenomenex® Luna® C8 (2) 5 μm 100Å AXIA ™ column (30 mm × 75 mm), 50 mL / And 10% to 100% acetonitrile / 0.1% aqueous trifluoroacetic acid) to give the title product. ¹ HΝMR (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 (M−H) ⁻ .

(Example 327)
N- (3-Chlorobenzyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide Example 1 except that 1- (3-chlorophenyl) methanamine was used instead of 1-cyclohexylmethanamine The title compound was prepared using the procedure described in 326. 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 / z353} (M + H) +; (ESI-) m / z351 (M-H) -.

(Example 328)
5- (1H-indazol-5-yl) -N- (2-methoxybenzyl) isoxazole-3-carboxamide Implemented except 1- (2-methoxyphenyl) methanamine was used instead of 1-cyclohexylmethanamine The title compound was prepared using the procedure described in Example 326. 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 / z349} (M + H) +; (ESI-) m / z347 (M-H) -.

(Example 329)
5- (1H-indazol-5-yl) -N- [2- (trifluoromethyl) benzyl] isoxazole-3-carboxamide 1- [2- (trifluoromethyl) phenyl] instead of 1-cyclohexylmethanamine The title compound was prepared using the procedure described in Example 326 except using methanamine. 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 (M−H) ⁻ .

(Example 330)
5- (1H-indazol-5-yl) -N- [3- (trifluoromethyl) benzyl] isoxazole-3-carboxamide 1- [3- (trifluoromethyl) phenyl] instead of 1-cyclohexylmethanamine The title compound was prepared using the procedure described in Example 326 except using methanamine. 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 / z385 ( M-H) -.

(Example 331)
5- (1H-indazol-5-yl) -N- [4- (trifluoromethyl) benzyl] isoxazole-3-carboxamide 1- [4- (trifluoromethyl) phenyl] instead of 1-cyclohexylmethanamine The title compound was prepared using the procedure described in Example 326 except using methanamine. 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 (M−H) ⁻ .

(Example 332)
5- (1H-indazol-5-yl) -N- (pyridin-2-ylmethyl) isoxazole-3-carboxamide except that 1-pyridin-2-ylmethanamine was used instead of 1-cyclohexylmethanamine, The title compound was prepared using the procedure described in Example 326. 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 (M−H) ⁻ .

(Example 333)
5- (1H-indazol-5-yl) -N- (pyridin-3-ylmethyl) isoxazole-3-carboxamide except that 1-pyridin-3-ylmethanamine was used instead of 1-cyclohexylmethanamine, The title compound was prepared using the procedure described in Example 326. 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 (M−H) ⁻ .

(Example 334)
5- (1H-indazol-5-yl) -N- (pyridin-4-ylmethyl) isoxazole-3-carboxamide 1-Pyridin-4-ylmethanamine was used instead of 1-cyclohexylmethanamine, The title compound was prepared using the procedure described in Example 326. 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 Example 1 except that 1- (2-chlorophenyl) methanamine was used instead of 1-cyclohexylmethanamine The title compound was prepared using the procedure described in 326. 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 / z353} (M + H) +; (ESI-) m / z351 (M-H) -.

(Example 336)
N- (4-Chlorobenzyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide Example 1 except that 1- (4-chlorophenyl) methanamine was used instead of 1-cyclohexylmethanamine The title compound was prepared using the procedure described in 326. 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)
1-phenyl-2-piperidin-1-ylethanamine instead of 5- (1H-indazol-5-yl) -N- (1-phenyl-2-piperidin-1-ylethyl) isoxazole-3-carboxamide piperidine The title compound was prepared according to the procedure described in Example 81B using ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (brs, 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-imidazol-1-yl) -1-phenylethyl] -5- (IH-indazol-5-yl) isoxazole-3-carboxamide piperidine instead of 2- (1H-imidazole-1 The title compound was prepared according to the procedure described in Example 81B using -yl) -1-phenylethanamine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (brs, 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)
Instead of 5- (1H-indazol-5-yl) -N- (2-morpholin-4-yl-1-phenylethyl) isoxazole-3-carboxamide piperidine, 2-morpholin-4-yl-1-phenylethane The title compound was prepared according to the procedure described in Example 81B using amine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (brs, 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)
2- (4-Methylpiperazine instead of 5- (1H-indazol-5-yl) -N- [2- (4-methylpiperazin-1-yl) -1-phenylethyl] isoxazole-3-carboxamidepiperidine The title compound was prepared according to the procedure described in Example 81B using -1-yl) -1-phenylethanamine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.6 (brs, 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)
1-phenyl-2-pyrrolidin-1-ylethanamine instead of 5- (1H-indazol-5-yl) -N- (1-phenyl-2-pyrrolidin-1-ylethyl) isoxazole-3-carboxamide piperidine The title compound was prepared according to the procedure described in Example 81B using ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (brs, 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 instead of piperidine tert-butyl 2-amino-2-phenyl The title compound was prepared according to the procedure described in Example 81B using ethyl carbamate. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (brs, 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 Example 1 except that 1- (1-naphthyl) methanamine was used instead of 1-cyclohexylmethanamine The title compound was prepared using the procedure described in 326. 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 As described in Example 326 except that 2-phenylethanamine was used instead of 1-cyclohexylmethanamine. The title compound was prepared using the procedure 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 (M−H) ⁻ .

(Example 345)
5- (1H-indazol-5-yl) -N- (2-pyridin-2-ylethyl) isoxazole-3-carboxamide except that 2-pyridin-2-ylethanamine was used instead of 1-cyclohexylmethanamine Prepared the title compound using the procedure described in Example 326. ¹ H NMR (500 MHz, DMSO-J 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 / z334} (M + H) +; (ESI-) m / z332 (M-H) -.

(Example 346)
5- (1H-indazol-5-yl) -N- (2-pyridin-3-ylethyl) isoxazole-3-carboxamide 1-cyclohexylmethanamine was used instead of 2-pyridin-3-ylethanamine Prepared the title compound using the procedure described in Example 326. 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 / z334} (M + H) +; (ESI-) m / z332 (M-H) -.

(Example 347)
5- (1H-indazol-5-yl) -N- (2-pyridin-4-ylethyl) isoxazole-3-carboxamide 1-cyclohexylmethanamine was used instead of 2-pyridin-4-ylethanamine Prepared the title compound using the procedure described in Example 326. 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 / z334} (M + H) +; (ESI-) m / z332 (M-H) -.

(Example 348)
N- [2- (2-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide 1-cyclohexylmethanamine was used instead of 2- (2-chlorophenyl) ethanamine Prepared the title compound using the procedure described in Example 326. 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 (M−H) ⁻ .

(Example 349)
N- [2- (3-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide 1-cyclohexylmethanamine was used instead of 2- (3-chlorophenyl) ethanamine Prepared the title compound using the procedure described in Example 326. 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 / z365 ( M-H) -.

(Example 350)
N- [2- (4-Chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide 1-cyclohexylmethanamine was used instead of 2- (4-chlorophenyl) ethanamine Prepared the title compound using the procedure described in Example 326. 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 / z365 ( M-H) -.

(Example 351)
Example 326 except that N-benzyl-N-ethylamine was used instead of N-benzyl-N-ethyl-5- (1H-indazol-5-yl) isoxazole-3-carboxamide 1-cyclohexylmethanamine. The title compound was prepared using the described procedure. 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 / z347} (M + H) +; (ESI-) m / z345 (M-H) -.

(Example 352)
5- (1H-indazol-5-yl) -N-methyl-N- (1-naphthylmethyl) isoxazole-3-carboxamide instead of 1-cyclohexylmethanamine N-methyl-N- (1-naphthylmethyl) The title compound was prepared using the procedure described in Example 326 except that the amine was used. 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 / z383} (M + H) +; (ESI-) m / z381 (M-H) -.

(Example 353)
5- (1H-indazol-5-yl) -N-methyl-N- (2-phenylethyl) isoxazole-3-carboxamide instead of 1-cyclohexylmethanamine N-methyl-N- (2-phenylethyl) The title compound was prepared using the procedure described in Example 326 except that the amine was used. 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 / z347} (M + H) +; (ESI-) m / z345 (M-H) -.

(Example 354)
5- (1H-indazol-5-yl) -N-methyl-N- (2-pyridin-2-ylethyl) isoxazole-3-carboxamide 1-cyclohexylmethanamine instead of N-methyl-N- (2- The title compound was prepared using the procedure described in Example 326 except using (pyridin-2-ylethyl) amine. 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 / z348} (M + H) +; (ESI-) m / z346 (M-H) -.

(Example 355)
5- (1H-indazol-5-yl) -N-[(1R) -1-phenylethyl] isoxazole-3-carboxamide 1-cyclohexylmethanamine was used instead of (1R) -1-phenylethanamine. The title compound was prepared using the procedure described in Example 326 except 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 (M−H) ⁻ .

(Example 356)
5- (1H-indazol-5-yl) -N-1,2,3,4-tetrahydronaphthalen- 1 -ylisoxazole - 3-carboxamide 1-cyclohexylmethanamine instead of 1,2,3,4- The title compound was prepared using the procedure described in Example 326 except that tetrahydronaphthalen-1-amine was used. 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 piperidine instead of (1S) -1- (1-naphthyl) ethanamine The title compound was prepared according to the procedure described in Example 81B using ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (brs, 1H), 9.4 (d, 1H), 8.4 (s, 1H), 8.25 (s, 1H), 8.22 (Brs, 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 piperidine instead of (1R) -1- (1-naphthyl) ethanamine The title compound was prepared according to the procedure described in Example 81B using ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (brs, 1H), 9.4 (d, 1H), 8.4 (s, 1H), 8.25 (s, 1H), 8.22 (Brs, 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 piperidine instead of N ³ , N ³ -dimethyl-1-phenylpropane- The title compound was prepared according to the procedure described in Example 81B using 1,3-diamine. ¹ H Ν MR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (brs, 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)
Instead of Ν- (2,3-dihydro-1,4-benzodioxin-5-ylmethyl) -5- (1H-indazol-5-yl) isoxazole-3-carboxamide piperidine, 1- (2,3-dihydro The title compound was prepared according to the procedure described in Example 81B using -1,4-benzodioxin-5-yl) methanamine. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 13.4 (brs, 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 piperidine instead of 1- (3 , 4-Dihydro-2H-1,5-benzodioxepin-6-yl) methanamine, and the title compound was prepared according to the procedure described in Example 81B. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (brs, 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)
Instead of 5- (1H-indazol-5-yl) -N-[(1-methyl-1H-indol-4-yl) methyl] isoxazole-3-carboxamide piperidine (1-methyl-1H-indole-4 -The title compound was prepared according to the procedure described in Example 81B using methylamine. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (brs, 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-indazolepiperidine was used according to the procedure described in Example 81B, substituting 3-phenylpyrrolidine. The compound was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (brs, 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-indazolepiperidine was used according to the procedure described in Example 81B, substituting 2-phenylpyrrolidine. The compound was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (brs, 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-indazolepiperidine was used according to the procedure described in Example 81B, substituting 2-phenylpiperidine. The compound was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 13.4 (brs, 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), then HATU (60 mg, 0.16 mmol) dissolved in N, N-dimethylformamide (0.5 mL) was added. It was. Then a solution of (S) -I-phenylethanamine (22 mg, 0.18 mmol) dissolved in N, N-dimethylformamide (0.6 mL) was added followed by N, N-dimethylformamide (0.2 mL). Diisopropylethylamine (56 μL, 0.32 mmol) dissolved in was added. The resulting mixture was shaken at 40 ° C. for 3 hours. The reaction was filtered, checked by LC / MS and concentrated to dryness. The residue was dissolved in 1: 1 dimethylsulfoxide / methanol and reverse phase HPLC (Phenomenex® Luna® C8 (2) 5 μm 100Å AXIA ™ column (30 mm × 75 mm), 50 mL / min. Purification by 10% to 100% acetonitrile / 0.1% aqueous trifluoroacetic acid) gave the title product. ¹ HΝMR (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 (M−H) ⁻ .

(Example 367)
(1R) instead of 5- (1H-indazol-5-yl) -Ν-[(1R) -1- (4-methylphenyl) ethyl] isoxazole-3-carboxamide (S) -1-phenylethanamine The title compound was prepared using the procedure described in Example 366 except that -1- (4-methylphenyl) ethanamine was used. 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 (M-H) < ^{- >} .

(Example 368)
(1S) instead of 5- (1H-indazol-5-yl) -N-[(1S) -1- (4-methylphenyl) ethyl] isoxazole-3-carboxamide (S) -1-phenylethanamine The title compound was prepared using the procedure described in Example 366 except that -1- (4-methylphenyl) ethanamine was used. 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 / z345 ( M-H) -.

(Example 369)
N-[(1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide (S) -1 The title compound was prepared using the procedure described in Example 366 except that (1R, 2S) -1-aminoindan-2-ol was used in place of 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 (S) -1 The title compound was prepared using the procedure described in Example 366 except that (1R, 2R) -1-aminoindan-2-ol was used instead of 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)
(1R) instead of N-[(1R) -1- (4-bromophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide (S) -1-phenylethanamine The title compound was prepared using the procedure described in Example 366 except that -1- (4-bromophenyl) ethanamine was used. 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)
(1S) instead of N-[(1S) -1- (4-bromophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide (S) -1-phenylethanamine The title compound was prepared using the procedure described in Example 366 except that -1- (4-bromophenyl) ethanamine was used. 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) anion 409 (MH) ^- .

(Example 373)
N-[(1R) -1- (4-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide (S) -1-phenylethanamine instead of (1R)- The title compound was prepared using the procedure described in Example 366 except that 1- (4-chlorophenyl) ethanamine was used. 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 / z365 ( M-H) -.

(Example 374)
N-[(1S) -1- (4-chlorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide (S) -1-phenylethanamine instead of (1S)- The title compound was prepared using the procedure described in Example 366 except that 1- (4-chlorophenyl) ethanamine was used. 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 / z365 ( M-H) -.

(Example 375)
5- (1H-indazol-5-yl) -N-[(1S) -1- (2-naphthyl) ethyl] isoxazole-3-carboxamide (S) -1-phenylethanamine instead of (1S)- The title compound was prepared using the procedure described in Example 366 except that 1- (2-naphthyl) ethanamine was used. 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 / z381 ( M-H) -.

(Example 376)
N- [1- (4-Ethoxyphenyl) -2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide (S) -1-phenylethanamine instead of 2-amino The title compound was prepared using the procedure described in Example 366 except using 2- (4-ethoxyphenyl) ethanol. 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 (S) -1-phenylethanamine instead of 2-amino The title compound was prepared using the procedure described in Example 366 except that 2- (4-isopropylphenyl) ethanol was used. 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 (S) -1-phenylethanamine instead of 2 The title compound was prepared using the procedure described in Example 366 except using -amino-2- (3,4-dimethylphenyl) ethanol. 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 (S) -1-phenylethanamine instead of 2-amino The title compound was prepared using the procedure described in Example 366 except using 2- (2-methoxyphenyl) ethanol. 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) ⁺ ; anion 377 (M−H) ⁻ .

(Example 380)
N- [2-hydroxy-1- (4-methylphenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide (S) -1-phenylethanamine instead of 2-amino The title compound was prepared using the procedure described in Example 366 except using -2- (4-methylphenyl) ethanol. 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 / z363} (M + H) +; (ESI-) m / z361 (M-H) -.

(Example 381)
(1R) instead of 5- (1H-indazol-5-yl) -N-[(1R) -1- (2-methoxyphenyl) ethyl] isoxazole-3-carboxamide (S) -1-phenylethanamine The title compound was prepared using the procedure described in Example 366 except that -1- (2-methoxyphenyl) ethanamine was used. 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 / z363} (M + H) +; (ESI-) m / z361 (M-H) -.

(Example 382)
Instead of N-[(1S) -1- (3,4-difluorophenyl) ethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide (S) -1-phenylethanamine ( The title compound was prepared using the procedure described in Example 366 except 1S) -1- (3,4-difluorophenyl) ethanamine was used. 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)
(1R) instead of 5- (1H-indazol-5-yl) -N-[(1R) -1- (3-methoxyphenyl) ethyl] isoxazole-3-carboxamide (S) -1-phenylethanamine The title compound was prepared using the procedure described in Example 366 except that -1- (3-methoxyphenyl) ethanamine was used. 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 / z361 ( M-H) -.

(Example 384)
Instead of 5- (1H-indazol-5-yl) -N-{(1R) -1- [3- (trifluoromethyl) phenyl] ethyl} isoxazole-3-carboxamide (S) -1-phenylethanamine The title compound was prepared using the procedure described in Example 366 except that (1R) -1- [3- (trifluoromethyl) phenyl] ethanamine was used. 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 (S) -1-phenyl 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 in place of ethanamine. 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)
Instead of N- [1- (3,5-dichlorophenyl) -2-hydroxyethyl] -5- (1H-indazol-5-yl) isoxazole-3-carboxamide (S) -1-phenylethanamine, 2- The title compound was prepared using the procedure described in Example 366 except using amino-2- (3,5-dichlorophenyl) ethanol. 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 / z415 ( M-H) -.

(Example 387)
5- (1-Benzyl-1H-1,2,3-triazol-4-yl) -3-[({[6- (trifluoromethyl) pyridin-2-yl] amino} carbonyl) amino] -1H- A solution of tert-butyltriphosgene indazole-1-carboxylate in dichloromethane was cooled to 0 ° C. under nitrogen. A mixture of triethylamine (0.426 mL, 3.07 mmol) and 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 and then stirred at room temperature overnight. The precipitate was filtered 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- The 3-carboxylic acid hydrochloride was combined with a mixture of dimethylformamide and dichloromethane under nitrogen and stirred for 15 minutes. Next, carbonyldiimidazole was added in small portions. The resulting solution was stirred at room temperature for 1 hour. Then Example 62 was added and then stirred at 60 ° C. for 2 hours and then at room temperature overnight. The reaction mixture was poured into ice water and brine was added. The cold solution was separated by decantation and the residue was taken up in dichloromethane and washed with water (twice). The organic layer was dehydrated with magnesium sulfate and volatiles were removed under reduced pressure. The solution removed by the gradient method was extracted with ethyl acetate (3 times). The combined organic layers were washed with brine (2 times), dried over magnesium sulfate and concentrated. The residue was taken up in a small amount of acetone and then placed in distilled water. The precipitate was collected by filtration, washed with water and dried to give 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 under nitrogen Was dissolved in dimethylformamide and pyridine at room temperature for 15 minutes. Carbonyldiimidazole was added in small portions. The resulting mixture was stirred at room temperature for 1 hour. Example 62 was then added and the mixture was stirred at room temperature overnight. Volatile material was removed under reduced pressure and the remainder was added to ice water. Sodium chloride was added resulting in a viscous oil from the cold solution. The solution was separated by a gradient method. The residue was washed with water (3 times) and then dried. From the solution separated by decantation, precipitation occurred overnight from a water / dimethylformamide mixture. This proved to be a raw material, which was filtered off and discarded. The product residue was crystallized in dichloromethane, collected by filtration and washed with a small amount of dichloromethane and ether. The product was dried to give the title compound. MS m / z 376.3 (M + Η) ⁺ .

(Example 390)
Tert-Butyl 3-amino-5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazole-1-carboxylate Example 62 together with a catalytic amount of dimethylaminopyridine in dichloromethane Suspended in A solution of di-tert-butyl dicarbonate in dichloromethane (160 mL) was added over 1 hour. The reaction mixture was stirred for about 40 hours. Silica gel was added and the mixture was concentrated. This silica mixture was added to a silica gel column and the resulting one eluted first with dichloromethane, 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-ylacetamido 2- (piperidin-1-yl) ) Acetic acid was combined with dimethylformamide and pyridine. The mixture was stirred at room temperature for 15 minutes and then carbonyldiimidazole was added in small portions. Stirring was continued for 1 hour at room temperature, then Example 64A was added, and then stirring was continued for 24 hours. The reaction mixture was warmed to 60 ° C. for 14 hours. A small amount of the title compound was obtained. MS m / z 416.3 (M + Η) ⁺ .

(Example 392)
N- [5- (1-benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -2-morpholin-4-ylacetamide 2-morpholinoacetic acid was converted to dimethylformamide And combined with pyridine. The mixture was stirred at room temperature for 15 minutes and then carbonyldiimidazole was added in small portions. Stirring was continued for 1 hour at room temperature, then Example 64A was added and then stirring was continued for 28 hours. The reaction mixture was warmed to 60 ° C. for 4 hours and then stirred at room temperature overnight. The reaction mixture was warmed again to 60 ° C. for 7 hours. A small amount of the title compound was obtained. MS m / z 418.3 (M + Η) ⁺ .

(Example 393)
N- [5- (1-Benzyl-1H-1,2,3-triazol-4-yl) -1H-indazol-3-yl] -1-methylpiperidine-2-carboxamide 1-methylpiperidine-3-carvone The hydrochloride salt was combined with dimethylformamide and pyridine. The mixture was stirred at room temperature for 15 minutes and then carbonyldiimidazole was added in small portions. Stirring was continued for 1 hour at room temperature, then Example 64A was added and then stirring was continued for 28 hours. The reaction mixture was warmed to 60 ° C. for 4.25 hours and then stirring was continued at room temperature overnight. The reaction mixture was warmed again 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 examined for their ability to inhibit N-terminal His6-labeled recombinant human ROCK-2 residues 11 to 552 expressed by baculovirus in Sf21 cells (Upstate). Recombinant N-terminal His6-labeled recombinant human ROCK-2 residues 11 to 552 expressed by baculovirus in 1 nM (final concentration) / 10 μL Sf21 cells (Upstate) in 384-well V-bottom polypropylene plates (Axygen) , 2 μM (final concentration) / 10 μL biotin-treated peptide in 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) substrate was mixed with (biotin -Aha-KEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK (SEQ ID NO: 1)) (Genemed), and various concentrations of inhibitor (final ^{2% DMSO), 0.01μCi [33} P] -ATP (Perkin Elm The reaction was initiated by the addition of 5μM unlabeled ATP containing r). After 1 hour, the reaction was stopped by adding 50 μL of stop buffer (50 mM EDTA, 2M NaCl final concentration). 80 μL of the stopped reaction solution was transferred to a 384 well streptavidin-coated flash plate (FlashPlate; Perkin Elmer), incubated at room temperature for 10 minutes, and 0.05 times using an ELX-405 automatic plate washer (BioTek). The plate was washed three times with% Tween-20 / PBS, and counted with a TopCount Scintillation Plate Reader (Packard).

ROCK-1 Inhibition Assay Compounds of formula (I) were examined for their ability to inhibit N-terminal His6-labeled recombinant human ROCK-1 residues 17-535 expressed by baculovirus in Sf21 cells (Upstate). Recombinant N-terminal His6-labeled recombinant human ROCK-1 amino acids expressed by baculovirus in 384 well V-bottom polypropylene plates (Axygen) in 2 nM (final concentration) / 10 μL Sf21 cells (Upstate) in reaction buffer 17-535 of 2 μM (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). Biotin-treated peptide substrate (Biotin-Aha-VRRLRRLTAREAA (SEQ ID NO: 2)) (Genemed) and various concentrations of inhibitor (final 2% DMSO) mixed with 0.01 μCi [ ³³ P] -ATP (Perkin Elmer) 5 μM not yet The reaction was initiated by the addition of identification ATP. After 1 hour, the reaction was stopped by adding 50 μL of stop buffer (50 mM EDTA, 2M NaCl final concentration). 80 μL of the stopped reaction solution was transferred to a 384 well streptavidin-coated flash plate (FlashPlate; Perkin Elmer), incubated at room temperature for 10 minutes, and 0.05 times using an ELX-405 automatic plate washer (BioTek). The plate was washed three times with% Tween-20 / PBS, and counted with a TopCount Scintillation Plate Reader (Packard).

GSK inhibition assay The compounds of formula (I) were examined for their ability to inhibit N-terminal His6-labeled GSK-3 expressed by baculovirus in Sf21 cells (Upstate). Recombinant N-terminal His6-labeled GSK3 expressed by baculovirus in 10 μL of Sf21 cells (Upstate) in a 384-well V-bottom polypropylene plate (Axygen) in reaction buffer (25 mM HEPES, pH 7.5, 1 mM DTT, 10 mM) 10 μL of biotinylated peptide substrate (Biotin-ahx-YRRAAVPPSPSLSRHSSPHS (p) EDEEEE (SEQ ID NO: 3)) in MgCl ₂ , 100 μM Na ₃ VO ₄ , 0.075 mg / mL Triton X-100), final concentration 2 μM (Genemed) ) And various concentrations of inhibitors (final 2% DMSO), and the reaction was started by adding 20 μL [ ³³ P] -ATP, final concentration 5 μM, 2 mCi / μmol (Perkin Elmer). After 1 hour, the reaction was stopped by adding 50 μL of stop buffer (50 mM EDTA, 2M NaCl final concentration). 80 μL of the stopped reaction solution was transferred to a 384 well streptavidin-coated flash plate (FlashPlate; Perkin Elmer), incubated at room temperature for 10 minutes, and 0.05 times using an ELX-405 automatic plate washer (BioTek). The plate was washed three times with% Tween-20 / PBS, and counted with a TopCount Scintillation Plate Reader (Packard).

Human GSK-3β inhibition assay compounds were tested for their ability to inhibit human glycogen synthase kinase-3β (hGSK-3β) phosphorylating biotin-YRRAAVPPSPSLSRHSSSPHQ (pS) EDEEEE. 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), compounds were combined with 0.5 μCi ³³ P-ATP, 10 μM ATP, 0. Incubated with 0125U hGSK-3β (Upstate cell signaling solution) and 1 μM substrate (Biotin-YRRAAVPPSPSLSRHSSPHQ (pS) EDEEEE (SEQ ID NO: 3)) for 30 minutes at room temperature. 100 mM EDTA equal volume, the addition of 4M NaCl _2, was stopped incubated. 80 μL of this mixture was added to a flash plate (PerkinElmer) coated with streptavidin. After the washing step, ³³ P incorporation was quantified with a MicroBeta microplate liquid scintillation counter (PerkinElmer). IC ₅₀ was determined by fitting a sigmoidal dose-response curve to the counts obtained at various concentrations with GraphPad Prism.

The human GSK-3α inhibition assay compound was tested for its ability to inhibit the final concentration of 0.5 nM human glycogen synthase kinase-3α (hGSK-3α) to phosphorylate biotin-YRRAAVPPSPSLSRHSSPHQ (pS) EDEEE (SEQ ID NO: 3) It was. 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), compounds were combined with 0.5 μCi ³³ P-ATP, 10 μM ATP, 0. Incubated with 0125U hGSK-3 (Upstate cell signaling solution) and 2 μM substrate (Biotin-YRRAAVPPSPSLSRHSSSPHQ (pS) EDEEE) for 30 minutes at room temperature. 100 mM EDTA equal volume, the addition of 4M NaCl _2, was stopped incubated. 80 μL of this mixture was added to a flash plate (PerkinElmer) coated with streptavidin. After the washing step, ³³ P incorporation was quantified with a MicroBeta microplate liquid scintillation counter (PerkinElmer). IC ₅₀ was determined by fitting a sigmoidal dose-response curve to the counts obtained at various concentrations with GraphPad Prism.

JAK2 Inhibition Assay Homogenous time-resolved fluorescence (HTRF) in vitro kinase assay (Mathis, G., HTRF® Technology. J Biomol Screen, 1999. 4 (6): p. 309-314). The assay was performed. Specifically, baculo in 10 μL Sf21 cells (Upstate) in reaction buffer (50 mM HEPES, pH 7.5, 10 mM MgCl ₂ , 2 mM MnCl ₂ , 0.1% BSA and 1 mM DTT, 40 μL final volume). Virus-expressed C-terminal His6-labeled recombinant human JAK2, amino acid 808 to the ends were mixed with 10 μL inhibitor (various concentrations, 2% final DMSO) and 10 μL ATP (5 μM final concentration). The reaction was initiated by adding 10 μL of Bio-PDK peptide (Biotin-Ahx-KTFCGTPEYLAPEVRREPRILEEEEQEMFRDFDYIADWC (SEQ ID NO: 4), 0.5 μM final concentration) in a black 384 well plate (Packard). After incubation at room temperature for 60 minutes, the reaction was stopped by adding 60 μL of stop / development buffer, 30 mM EDTA, 1 μg / mL streptavidin-APC (Prozyme), 50 ng / mL anti-phosphotyrosine mAbPT66-K europium cryptate , 30 mM HEPES, pH 7.5, 120 mM BCF, 0.005 Tween-20, 0.05% BSA). The reaction solution whose reaction was stopped was allowed to stand at room temperature for 1 hour, and then read with a time-division fluorescence detector (Envision, Perkin Elmer) simultaneously at 615 nm and 665 nm. The ratio between the 615 nm and 665 nm signals was used to calculate the IC50.

Methods-β-catenin reporter gene assay compounds were examined for their ability to regulate β-catenin regulated gene transcription in a LEF / TCF (T cell factor) reporter gene assay. SY-SY5Y human neuroblastoma cells were transformed into 80 ng / well TOPFLASH plasmid (upstate cell signaling solution) containing 3 sets of 3 copies of the TCF binding site upstream of the thymidine kinase minimal promoter and firefly luciferase reading frame. Alternatively, it was transiently transfected with 80 ng / well of FOPFLASH plasmid (upstate cell signaling solution) containing thymidine kinase minimal promoter and 3 copies of the mutant TCF binding site upstream of the firefly luciferase reading frame. In addition, all cells were transiently transferred with 20 ng / well pRL-TK plasmid (Promega) containing the herpes simplex virus thymidine kinase promoter to obtain low to moderate levels of Renilla luciferase expression. The transfection medium was replaced with serum-free medium containing the test substance and incubated at 37 ° C. for 24 hours. Incubation was stopped and quantified using a Dual Glo luciferase assay (Promega) according to instructions and quantified with a Ferastar reader (BMG).

  Firefly luciferase activity was normalized with respect to Renilla luciferase activity per well. The normalized TOPFLASH response was then compared with the normalized FOPFLASH response to obtain a LEF / TCF specific signal. The maximum response is the maximum ratio between the normalized TOPFLASH signal and the FOPFLASH signal. A sigmoid dose-response curve was fitted using a graph pad prism.

Acute Asthmatic Mouse Asthma Model Female Balb / c mice were purchased from Taconic and bred at Abbott Bioresearch Center. Animals were used at 8-12 weeks of age. All protocols were approved by the Institutional Animal Care and Use Committee (IACUC). Dexamethasone (Dex) and ovalbumin (OVA) were purchased from Sigma. Endotoxin was removed from ovalbumin using detoxigel (DetoxiGel; Pierce) according to the manufacturer's protocol and the final product contained less than 0.1 EU / mg protein. Alum Injection was purchased from Pierce.

On days 0 and 7, animals were sensitized to OVA by intraperitoneal injection of 8 μg OVA in 2 mg alum. On days 14 and 16, animals were administered nasally with 0.3 μg of OVA in 50 μL of sterile PBS. Starting from the afternoon of day 13, the compound of formula (I) (0.5% HMPC, 0.02% Tween 80 typical of animals) twice daily at doses of 3, 10 and 30 mg / kg / dose In aqueous solution) was administered intraperitoneally. Airway hyperresponsiveness (AHR) was measured 30 minutes after administration of the final dose of compound. Dexamethasone was orally administered once daily from day 13 to day 17 at a dose of 3 mg / kg. On day 17, all endpoints were analyzed 24 hours after the second OVA challenge. AHR was assessed using restraint whole body plethysmography under anesthesia. That is, surgical anesthesia was induced by intravenous injection of ketamine and xylazine. A tracheal cannula was surgically inserted between the third and fourth tracheal cartilage rings. Spontaneous breathing was prevented by intravenous (iv) injection of pancuronium bromide into the tail vein. The animals were placed in a whole body respirometer (Buxco) and mechanically ventilated with 0.2 mL room air at 150 breaths / min using a volume controlled ventilator (Harvar Apparatus). The pressure in the lungs and the flow rate in the spirometer were measured using a transducer, and the lung resistance was calculated as pressure / flow rate using Biosystem Xa (Biosystem Xa) software. Baseline resistance as well as resistance after methacholine loading (3, 10 or 30 mg / mL) delivered with an in-line ultrasonic nebulizer were measured. Upon completion of the lung function test, the lungs were lavaged 4 times with 0.5 mL sterile PBS. The lavage fluid was analyzed for IL-13, AMCase, Muc5ac and cell infiltrate. The efficacy of the test compound was examined at doses of 3, 10 and 30 mg / kg (twice daily) (6, 20, 60 mg / kg / day). The OVA loading, increase in the pulmonary resistance to 6.90cmH ₂ O / mL / s occurs, it is an animal loaded with PBS against was 4.65cmH ₂ O / mL / s. Treatment of mice with test compounds significantly reduced methacholine-induced airway resistance to doses ranging from 1 to 100 mg / kg up to 4.55 cmH ₂ O / mL / sec and 4.77 cmH ₂ O / mL / sec (P <0.001). Preferred compounds require doses of less than 50 mg / kg to show said response. Most preferred compounds require doses of less than 30 mg / kg to show said response. This inhibition is equivalent to the measurement obtained in the PBS loading group (4.65 cmH ₂ O / mL / sec) and equivalent to the treatment with 3 mg / kg dexamethasone (4.76 cmH ₂ O / mL / sec). It was.

IL-13 measurement The IL-13 concentration in the bronchoalveolar lavage fluid (BAL) was measured by ELISA (R & D Systems) according to the manufacturer's instructions. IL-13 concentration in BAL fluid was significantly induced to 102.5 pg / mL in OVA loaded mice compared to the level under detection in the PBS loaded group. This induction was significantly inhibited by 60% after administering the test compound at a dose of 30 mg / kg (p <0.05). There was no significant inhibition in the 3 mg / kg dose group and the 10 mg / kg dose group.

AMCase measurement 1 % of BAL solution containing 80 μM 4-methylumbelliferyl β-DN, N′-diacetylchitobioside in the presence of 0.01% BSA, 30 mM sodium citrate, 60 mM sodium phosphate, pH 5.2 : Acidic mammalian chitinase (AMCase) activity was measured with 10 dilutions. The reaction was incubated at room temperature for 15 minutes and quenched by adding 100 μL of 1M glycine / NaOH (pH 10.6). Product formation was confirmed by fluorescence emission at 460 nm with excitation at 385 nm on a Fluoroskan Ascent Fluorometer. AMCase activity was induced to 28.5 U in OVA-loaded animals compared to 2.17 U in PBS-loaded animals. This induction was significantly inhibited in the 30 mg / kg group by 35% after test compound administration (p <0.01).

MUC5AC measurement The concentration of the mucin gene MUC5AC was quantified by ELISA. That is, BAL samples were diluted 1: 2 with buffer (2% BSA / PBS), plated in high protein binding 96 well plates (Costar) and dried. After a series of washings, a 1: 100 dilution of biotin-treated MUC5AC antibody (clone 45M, Lab Vision) was added for 1 hour. The plate was washed and a 1: 3000 dilution of streptavidin-HRP (Southern Biotech) was added to the plate for 15 minutes. The plate was then developed with TMB substrate (Sigma) for 30 minutes. The reaction was stopped with 1 MH ₂ SO ₄ and then read on a spectrophotometer at OD 450 nm. Following test compound administration, the level of MUC5AC dropped by more than 50%.

Measurement of antinociception: a model of neuropathic pain
Report of the spinal nerve (L5 / L6) ligation model Kim and Chun of neuropathic pain (Kim SH, Anx. 50,355-363), a 1.5 cm incision was made on the dorsal side of the lumbosacral plexus according to the method reported in detail. In anesthetized rats, the paraspinal muscle group (left side) was separated from the spinous processes, the L5 and L6 spinal nerves were isolated and strongly ligated with 3-0 silk. After hemostasis, the wound was sutured and covered with antibiotic ointment. Rats were allowed to recover and then placed in soft bedding cages and subjected to behavioral testing for mechanical allodynia after 14 days.

Report of Bennett G. J., Bennett GJ; Peripheral mononeuropathies in rat products in the disorders of the sciatic nerve ligation model, 87 107), a 1.5 cm incision was made 0.5 cm below the pelvis to separate the biceps and superficial muscles (right side) in anesthetized rats according to the method reported in detail in 107) did. The sciatic nerve was exposed and isolated, and 4 loose ligatures (5-0 chrome intestine) were placed around them at 1 mm intervals. Rats were allowed to recover and then placed in a cage with soft bedding, and the behavioral test for mechanical allodynia was performed 14 days later. Furthermore, the animals were also tested for cold allodynia by immersing their hind paws in a cold water bath (4.5 ° C.) and determining the waiting time for paw withdrawal.

  Certain analogs of compounds of formula (I) administered intraperitoneally or orally are dosed in the range of 1 to 150 mg / kg and are described in the neuropathic pain Chun and Bennett described herein. The model showed more than 30% inhibition of contact allodynia.

  In summary, representative compounds of formula (I) in a mouse model of acute asthma were effective in inhibiting airway resistance at a dose range of 1 to 100 mg / kg. High dose (30 mg / kg) treatment also inhibited IL-13 induction and AMCase activity and MUC5AC levels in BAL fluid.

  Representative compounds of formula (I) in a rat model of neuropathic pain were effective as shown by more than 30% inhibition of contact allodynia at doses ranging from 1 to 150 mg / kg.

The compound of formula (I) exhibits an IC ₅₀ of about 1.0 μM to about 10 μM, preferably about 100 nM to about 1.0 μM, indicating that human ROCK-2, N-terminal His-labeled GSK-3β, human GSK-3β, It was found to inhibit His6-tagged recombinant human JAK2 and firefly luciferase. More preferably, the compound of formula (I) exhibits an IC ₅₀ of from about 10 nM to about 100 nM, most preferably less than 10 nM, and represents human ROCK-2, N-terminal His-labeled GSK-3β, human GSK-3β, His6-labeled set It was found to inhibit recombinant human JAK2 and firefly luciferase.

  In addition, certain compounds of formula (I) showed inhibition of human ROCK-2 with greater than 10-fold selectivity for the 50 kinase target group. Certain compounds of formula (I) showed inhibition of human GSK-3β with greater than 10-fold selectivity for the 50 kinase target group. Certain compounds of formula (I) showed inhibition of His6-labeled recombinant human JAK2 with greater than 10-fold selectivity for the 50 kinase target group.

Method of Administration The present invention further provides a pharmaceutical composition comprising a compound of the present invention. The pharmaceutical composition comprises a compound of the invention formulated with one or more non-toxic pharmaceutically acceptable carriers.

  The pharmaceutical composition of the present invention is administered to humans and other mammals by oral administration, rectal administration, parenteral administration, intracisternal administration, vaginal administration, topical administration (eg, by powder, ointment or drops), buccal administration. Can be administered orally or as a nasal spray. The term “parenteral” as used herein refers to modes of administration including intravenous, intramuscular, intraperitoneal, subcutaneous and intraarticular injection and infusion.

  As used herein, the term “pharmaceutically acceptable carrier” means any type of non-toxic, inert solid, semi-solid or liquid filler, diluent, capsule forming material or formulation aid. To do. Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch Celluloses such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate and derivatives thereof (but not limited to them); tragacanth gum powder; malt; gelatin; talc; cocoa butter and suppository wax Agents (but not limited to); 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 ; Ethyl oleate And esters such as, but not limited to, 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 buffer solution and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate according to the judgment of the formulator (limited to these) As well as colorants, mold release agents, coating agents, sweeteners, flavors and fragrances, preservatives and antioxidants.

  Pharmaceutical compositions of the present invention for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile injectable solutions or dispersions immediately before use. There are sterile powders that denature. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyhydric alcohols (such as glycerin, propylene glycol, polyethylene glycol), vegetable oils (such as olive oil), injectable organic esters (olein) And the like, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

  These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the activity of microorganisms can be ensured by incorporating various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol sorbic acid and the like. It may be desirable to include isotonic agents such as sugars, sodium chloride and the like. Inclusion of agents that delay absorption such as aluminum monostearate and gelatin can provide long-term absorption of injectable pharmaceutical preparations.

  In some cases, it may be desirable to delay the absorption of the drug from subcutaneous or intramuscular injection in order to sustain the action of the drug. This can be done by using a suspension of crystalline or amorphous material with low water solubility. At this time, the absorption rate of the drug depends on its dissolution rate, which can depend on the crystal size and crystal form. Alternatively, delayed absorption of a parenteral formulation is accomplished by dissolving or suspending the drug in an oil vehicle.

  Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

  Injectable preparations can be sterilized by filtration through a bacteria retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use. it can.

  Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid preparations, the active compound is contained in at least one inert pharmaceutically acceptable carrier or excipient such as sodium citrate or disodium phosphate and / or a) starch, lactose, sucrose, glucose, Fillers or extenders such as mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerin; d) agar, calcium carbonate, potatoes Or disintegrants such as tapioca starch, alginic acid, certain silicates and sodium carbonate; e) dissolution retardants such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) cetyl alcohol and glyceryl monostearate Wetting agents such as h) Absorbents such as phosphorus and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, lubricants such as sodium lauryl sulfate, and can be mixed with these mixtures. In the case of capsules, tablets and pills, the formulation may also include buffering agents.

  Similar types of solid compositions can also be utilized as fillers in soft and hard-filled gelatin capsules using carriers such as lactose or lactose and high molecular weight polyethylene glycols.

  Solid formulations of tablets, dragees, capsules, pills and granules can be prepared using coatings and shells such as enteric coatings and other coatings known in the pharmaceutical formulation art. These may optionally contain an opacifying agent, and may be of a composition that releases the active ingredient preferentially only in a certain part of the intestinal tract or in that part in some cases. . Examples of embedding compositions that can be used include polymeric substances and waxes.

  The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned carriers.

  Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, liquid formulations may be prepared from inert diluents commonly used in the art such as water and other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol. , Benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene It may contain glycols and sorbitan fatty acid esters, and mixtures thereof.

  In addition to inert diluents, the oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

  Suspensions are suspended in addition to the active compound, for example ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum meta-hydroxide, bentonite, agar, tragacanth and mixtures thereof. A turbidity agent can be contained.

  Preferably, the composition for rectal or vaginal administration is a cocoa butter, polyethylene glycol or suppository that melts in the rectum or vaginal cavity to release the active compound because it is solid at room temperature but liquid at body temperature Suppositories that can be prepared by mixing a compound of the present invention with a suitable nonirritating carrier such as a wax.

  The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are derived from phospholipids and other liquid substances. Liposomes are formed by mono- or multi-lamellar 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 composition of the present invention in the form of liposomes can contain a stabilizer, preservative, excipient and the like in addition to the compound of the present invention. Preferred liquids are natural and synthetic phospholipids and phosphatidylcholines (lecithins) used separately or together.

  Methods for forming liposomes are known in the art (see, eg, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), p. 33 et seq. reference).

  Formulations for topical administration of the compounds of this invention include powders, sprays, ointments and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants that may be required. It is contemplated that ophthalmic formulations, eye ointments, powders and solutions are also encompassed within the scope of the present invention.

  The actual dosage level of the active ingredients in the pharmaceutical composition of the invention can be varied to obtain an amount of active compound that is effective in obtaining the desired therapeutic response in a particular patient, composition and dosage form. . The selected dose level will depend on the activity of the particular compound, the route of administration, the severity of the condition being treated, the condition and medical history of the patient being treated.

  For use in the above and other therapies, a therapeutically effective amount of any of the compounds of the present invention may be administered in pure form or in the form of a pharmaceutically acceptable salt, ester or prodrug if such form exists. Can be used. The expression “therapeutically effective amount” of a compound of the invention means an amount of the compound sufficient to treat a disorder with a reasonable benefit / risk ratio applicable to any medical treatment. It will be apparent, however, that the total daily dose of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level in a particular patient is the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, systemicity of the patient Health status, gender and diet; time of administration, route of administration and excretion rate of the specific compound used; duration of treatment; drugs used in combination with or simultaneously with the specific compound used; and known in the medical field It depends on various elements such as similar elements.

  As used herein, the term “pharmaceutically acceptable salts” refers to salts derived from inorganic or organic acids. The salt can be prepared in situ during the final isolation and purification of the compound of formula (I) or separately by reacting the free base of the compound of formula (I) with an inorganic or organic acid. . Typical acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate Salt, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothion) Acid salt), lactate, maleate, fumarate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectate, persulfate, 3-phenylpropiate Onnate, picrate, pivalate, propionate, succinate, sulfate, (L) tartrate, (D) tartrate, (DL) tartrate, thiocyanate, phosphate, glutami Salt, bicarbonate, p- there are such toluenesulfonate and undecanoate, but is not limited thereto.

  The term “pharmaceutically acceptable prodrug” or “prodrug” as used herein is within the scope of sound medical judgment and is in contact with human and lower animal tissues. Represents prodrugs of the compounds of the invention that are suitable for use and do not cause inappropriate toxicity, irritation, allergic response, and the like. The prodrugs of the invention can be rapidly converted in vivo to a compound of formula (I), for example by hydrolysis in blood.

  The present invention contemplates compounds of the present invention formed by synthetic means or formed by in vivo biotransformation.

  The compounds of the present invention can exist in unsolvated forms as well as solvated forms, such as hydrated forms such as hemihydrate. In general, the solvated forms, particularly with water and pharmaceutically acceptable solvents such as ethanol, are equivalent to the unsolvated forms with respect to the present invention.

  The total daily dose of the compounds of this invention administered to a human or lower animal can range from about 0.003 to about 30 mg / kg / day. For oral administration, more preferred doses can range from about 0.01 to about 10 mg / kg / day. If desired, the effective daily dose can be divided into multiple doses for administration. Consequently, a single dose composition can contain an amount that constitutes a daily dose or a portion thereof.

  Protein kinases can be divided into a broad group based on the identity of the amino acids they target (serine / threonine, tyrosine, lysine and histidine). For example, tyrosine kinases include receptor tyrosine kinases (RTKs) such as growth factors and non-receptor tyrosine kinases such as the src kinase family. There are also bispecific protein kinases that target both tyrosine and serine / threonine, such as cyclin dependent kinases (CDKs) and mitogen activated protein kinases (MAPKs).

  Protein tyrosine kinases (PTKs) comprise a large family of kinases that control intercellular signals involved in growth, differentiation, adhesion, movement and death (Pearson, M. et al., In Protein Tyrosine Kinases; Fabbro, D. et al.). , McCorick, F., Eds .; Humana Press Inc., 2006; pp 1-29). Tyrosine kinase members include, but are not limited to, Yes, BMX, Syk, EphA1, FGFR3, RYK, MUSK, JAK1 and EGFR. Tyrosine kinases are distinguished into two types, tyrosine kinases, receptor type and non-receptor type. Interestingly, the entire family of tyrosine kinases consists of at least 90 characterized kinases, with at least 58 receptor types and at least 32 non-receptor type enzymes comprising at least 30 total subfamilies. Tyrosine kinases have been suggested in many human diseases such as diabetes and cancer (Pearson, M. et al., In Protein Tyrosine Kinases; Fabbro, D., McCorick, F., Eds .; Humana Press). Inc., 2006; pp 1-29). Tyrosine kinases have been implicated in most forms of human malignancies and have been associated with a great variety of 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 family. In particular, the Src family of non-receptor tyrosine kinase families is the largest consisting of Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk protein tyrosine kinases. The Src family of kinases has been linked to carcinogenesis, cell proliferation and tumor progression. Many of the protein tyrosine kinases have been found to be involved in cell signaling pathways involved in various pathologies including, but not limited to, cancer and hyperproliferative disorders and immune disorders.

  Cyclin-dependent kinases, or CDKs, represent a group of intracellular enzymes that control progression through the cell cycle and have a very important role in cell proliferation (Cohen, P. Nature Reviews Drug Discovery 1 309-315, 2002). Representative examples of CDKs include cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 7 (CDK7), cyclin-dependent kinase 6 (CDK6), and cell division control 2 protein (CDC2). It is not limited. CDKs progress from G1 quiescence (gap between initiation of DNA replication in a new phase of mitosis and cell division) to S (timing of active DNA synthesis) or active mitosis from G2. And in the regulation of transitions between different phases of the cell cycle, such as progression to M phase where cell division occurs (Rowell et al. Critical Reviews in Immunology 26 (3), 189-212, 2006). The CDK complex is an association of regulatory cyclin subunits (eg, cyclin A, B1, B2, D1, D2, D3 and E) and catalytic kinase subunits (eg, cdc2 (CDK1), CDK2, CDK4, CDK5 and CDK6). Formed by. CDKs show an absolute dependence on cyclin subunits in phosphorylating target substrates, and different kinase / cyclin pairs function to regulate progression through specific sites in the cell cycle. In addition, CDKs have been suggested in various disease states such as, but not limited to, those exhibiting a cancer phenotype, various oncological diseases and neuropathies (Pallas et al. Current Medical Chemistry: Central). Nervous System Agents 5 (2), 101-109, 2005).

  Mitogen-activated protein (MAP) kinase is involved in the transmission of signals to the nucleus of the cell in response to extracellular stimuli. Representative examples of MAP kinases include mitogen activated protein kinase 3 (MAPK3), mitogen activated protein kinase 1 (ERK2), mitogen activated protein kinase 7 (MAPK7), mitogen activated protein kinase 8 (JNK1), mitogen Examples include, but are not limited to, activated protein kinase 14 (p38α), mitogen activated protein kinase 10 (MAPK10), JNK3α protein kinase, stress activated protein kinase JNK2, and mitogen activated protein kinase 14 (MAPK14). is not. 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 Pharmaceutical Sciences 27 (10), 525). -530, 2006). MAP kinases are activated through phosphorylation of threonine and tyrosine by bispecific protein kinases including tyrosine kinases such as growth factors. Cell proliferation and differentiation has been shown to be under the control of multiple MAP kinase cascades (Sridhar et al., Pharmaceutical Research, 17:11 1345-1353, 2000). Thus, the MAP kinase pathway plays a very important role in many disease states, for example, defects in the activity of MAP kinases have been shown to lead to abnormal cell proliferation and carcinogenesis (Qi et al. , Journal of Cell Science 118 (16), 3569-3572, 2005). Furthermore, MAP kinase activity has also been suggested in type II diabetes-related insulin resistance (Fujishiro et al. Reent Research Developments in Physiology 1 (Pt. 2), 801-812, 2003).

  p90 ribosomal S6 kinases (Rsk) are serine / threonine kinases that function in mitogen-activated cell growth and proliferation, differentiation and cell survival. Examples of members of the Rsk family of kinases include ribosomal protein S6 kinase, 90 kDa, polypeptide 2 (Rsk3), ribosomal protein S6 kinase, 90 kDa, polypeptide 6 (Rsk4), ribosomal protein S6 kinase, 90 kDa, polypeptide 3 ( Rsk2) and ribosomal protein S6 kinase, 90 kDa, polypeptide 1 (Rsk1 / p90Rsk) and the like, but are not limited thereto. Rsk family members are activated by extracellular signal-related kinases and phosphoinositide-dependent protein kinase 1 (Frodin and Gameltoft, Mol. Cell. Endocrinol. 151, 65-77, 1999). Under baseline conditions, RSK kinases are localized in the cytoplasm of the cell, and when stimulated by mitogens, activated (phosphorylated by extracellular associated kinases) RSK temporarily translocates to the plasma membrane Then, it becomes a fully activated state. Fully activated RSK phosphorylates substrates involved in cell growth, proliferation, differentiation and cell survival (Clark et al. Cancer Research 65, 3108-3116, 2005). The RSK signaling pathway has also been associated with cell cycle regulation (Gross et al., J. Biol. Chem. 276, 46099-46103, 2001). Current data suggests that small molecules that inhibit Rsk can be useful therapeutic agents in the prevention and treatment of cancer and inflammatory diseases.

  Members of the checkpoint protein kinase family (CHK) are serine / threonine kinases that play an important role in cell cycle progression. Examples of checkpoint family members include, but are not limited to, CHK1 and CHK2. Checkpoint kinases are control systems that regulate cell cycle progression by affecting the formation, activation and subsequent inactivation of cyclin-dependent kinases. Checkpoint kinases prevent cell cycle progression at inappropriate time points, maintain cell metabolic balance while stopping cells, and in some cases apoptosis (programmed cell death) if checkpoint requirements are not met ) (Nurse, Cell, 91, 865-867, 1997; Hartwell et al., Science, 266, 1821-1828, 1994). Members of the checkpoint family of kinases have been suggested in cell proliferation disorders, cancer phenotypes and other diseases related to DNA damage and repair (Kumagai and Dunphy Cell Cycle, 5, 1265-1268 (2006); Xiao et al., Molecular Cancer Therapeutics 5, 1935-1943, 2006).

  Aurora kinases are a family of multigene mitotic serine-threonine kinases that function as a class of new oncogenes. These kinases include Aurora-A and Aurora-B members. Aurora kinase is over-activated and / or over-expressed in several solid tumors such as but not limited to breast cancer, ovarian cancer, prostate cancer, pancreatic cancer and colorectal cancer. In particular, Aurora-A is a centrosome kinase that plays an important role in cell cycle progression and cell proliferation. Aurora-A is in the 20q13 chromosomal region that is very often amplified in several different types of malignant tumors such as colorectal cancer, breast cancer and bladder cancer. There is also a high correlation between Aurora-A and high tissue prognostic grade aneuploidy, whereby kinases can be a prognostic vehicle. Inhibition of Aurora kinase activity can reduce cell proliferation, tumor growth and possibly tumorigenesis. Detailed descriptions of Aurora kinase function are reviewed in the literature (Journal of Cell Science, 119, 3664-3675, 2006).

  Rho-related coiled-coil-containing proteins serine / threonine kinases ROCK-1 and ROCK-2 are thought to play a major role in cytoskeletal mechanics by acting as downstream effectors of the Rho / Rac family of cytokines and growth factor-activated small GTPases . ROCK phosphorylates various substrates such as, but not limited to, myosin light chain phosphatase, myosin light chain, ezrin-radixin-moesin protein and LIM (in the case of Lin1, Isl1 and Mec3) kinases. ROCK is also involved in the formation of actin tension fibers and focal adhesion in various cell types. ROCKs have an important role in cell migration by enhancing cell contractility and are required for tail regression of monocytes and cancer cells. ROCK inhibitors have also been shown to reduce tumor cell seeding in vivo. Recent experiments have established new functions of ROCK in cells such as centrosome localization and cell size regulation that are thought to contribute to various physiological states and pathological conditions (Müller et al, Nature Reviews Drug Discovery 4, 387-398, 2005). ROCK family members are promising intervention targets in a variety of pathologies such as cancer and cardiovascular disease. ROCK inhibitors can be useful therapeutics for hypertension, angina and asthma. In addition, Rho is a useful target for treatment because it is expected to play a role in peripheral circulatory disturbances, atherosclerosis, inflammation and autoimmune diseases (Shimokawa et al, Arteriosclerosis, Thrombosis, and Vascular Biology). , 25, 1767-1775, 2005).

  A significant proportion of pharmacotherapeutic approaches in spinal cord injury have been limited in succession to degenerate and reconstruct synaptic junctions with the ruptured neurons in the white matter of the human spinal cord This is because it cannot be done. The adverse microenvironment characterized by the presence of a very diverse molecular neurite growth inhibitor at the lesion site, scar tissue and CNS myelin is responsible for this irreversible arrest of neurite growth. In tissue culture, these neurite growth inhibitors often elicit very prominent responses such as neurite formation and disruption of retraction. Scar tissue in the human brain and spinal cord is a strong and persistent barrier to degenerative neurite growth, and ROCK inhibitors are thought to help damaged fibers to grow and sprouting beyond this degeneration-inhibited tissue It is done. Various evidence indicates that damage to the brain and spinal cord results in a strongly activated RhoA-ROCK pathway. Because of the persistent presence of neurite growth inhibitors at or around the lesion site and CNS myelin, it is believed that such activation may last for a long time, ROCK inhibition is It is a promising target for chronic as well as acute and subacute treatment of spinal cord injury. Inhibition of ROCK by two different small molecule ROCK inhibitors (Y-27632 and Fasudil) has been observed in various mouse and rat spinal cord injury models when administered locally or systemically immediately after injury in a single dose or over several weeks. Stimulated or promoted functional recovery (Dergham, P. et al. Rho signaling pathway targeted to promote spinal cord repair. J. Neurosci. 22, 6570-6657, 2002; Hara, M. inb. hydrochloride promotes neurological recovery after spinal cord Injury in rats. J. Neurosurg. Spine 93, 94-101, 2000.; Founder, A. E. et al. ROCK inhibition enhancement in the injured in the CNS. , JK et al. A possible roll of RhoA / Rho-kinase in experimental spinal cord injury in rat.Brain Res. 959, 29-38, 2003; Tanka, H. et al. enhances axonal regener tion and functional recovery after spinal cord injury in rats.Neuroscience 127,155-164,2004). In these studies, ROCK inhibition not only promoted nerve fiber growth beyond the lesion site, but was also neuroprotective and reduced tissue damage and cavitation. Based on these rodent studies, it is believed that ROCK inhibitors with neuroprotective and neurodegenerative stimulating activity can have significant effects in patients with spinal cord injury. Furthermore, they are thought to be able to further promote tissue preservation by normalizing spinal blood flow due to the vasodilatory effect.

  Pathologically, Alzheimer's disease is characterized by intracellular neurofibrillary tangles and extracellular amyloid aggregates at a microscopic level. Neurofibrillary tangles include aberrantly phosphorylated tau protein, microtubule-associated protein and ROCK substrate, and amyloid aggregates are formed primarily by the toxic 42 amino acid long amyloid-β (Aβ) peptide. Recently, in cells that secrete Aβ42 and in transgenic PDAPP mice that produce large amounts of Aβ42, it has been shown that several NSAIDs reduce Aβ42 by inhibiting the RhoA-ROCK pathway (Zhou, Y. et. al. Nonsterial anti-inflammatory drugs can lower amyloidogenic Aβ42 by inhibiting Rho. Science 302, 1215-1217, 2003). The ROCK inhibitor Y-27632 was effective in reducing Aβ42 levels in both cell cultures and PDAPP transgenic mice after intracerebroventricular injection. Activation of Rho by geranylgeranyl pyrophosphate, a lipid required for Rho membrane attachment, increased Aβ42 levels. This increase was completely prevented by Y-27632. The ROCK inhibitor Y-27632 used in the animal Alzheimer's disease model was effective in reducing the amount of toxic Aβ42 levels, but had no effect on total Aβ levels, and Rho or ROCK inhibitors This effect is at least one mechanism by which NSAIDs reduce Aβ42 levels. In addition to many other therapeutic interventions, these inhibitors have the well-established advantage of stimulating the degenerative growth of neuritis, so inhibition of this pathway results in the repair of amyloid-damaged neural circuits There is a possibility to make it.

  The most important in the pathogenesis of the disease is the migration of leukocytes across the brain endothelium into the CNS and the inflammatory cascade stimulated by the cells, thereby ultimately demyelinating the CNS fiber bundles and the neurites Damage and loss occur. Since leukocyte transendothelial migration was prevented by the ROCK inhibitor Y-276294, leukocytes require RhoA and ROCK that are active in their journey across the brain endothelium.

  The neuroprotective activity of the ROCK inhibitors fasudil and hydroxyfasudil is not limited to the spinal cord injury model, but has also been reported in cerebral multiple infarct models in 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 Sd.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 stroke models, several degeneration inhibitors such as ROCK-activated NgR1 complex and one of its ligands, NOGO-A, are neutralized and function even 24 hours or 1 week after stroke induction. Improvement in recovery has been observed (Lee, JK, Kim, JE, Sivula, M. & Strittermatter, SM Nogo receptor antagonistic promoters by the recovery of the United States of America. 6209-6217, 2004; Wiesner, C. et al. Anti-Nogo-A antibody information 24 hours after experimental stroke. improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats.J.Cereb.Blood FlowMetab .23,154-165,2003). Thus, blocking ROCK is a viable neurodegenerative strategy. Furthermore, such strategies have the advantage that the therapeutic window of treatment in the use of these inhibitors may be greater than thrombolytic or neuroprotective stroke treatment options.

  Nerve damage in the human peripheral nervous system or CNS can result in a chronic pain condition known as neuropathic pain. Recently, inflammatory mediators such as lysophosphatidic acid (LPA) that occur in response to injury have been shown to be involved in the initiation of neuropathic pain in a mouse model of peripheral nerve injury (Inoue, M. et al. .Initiation of neuropathic pain requirements lysophathic acid acid receptor signaling. Nature Med. 10, 712-718, 2004). LPA is present in PNS and CNS at the lesion site and exerts its function by binding to G protein-coupled LPA receptors, thereby resulting in activation of the RhoA-ROCK pathway. ROCK inhibitor Y-27632 prevents the onset of neuropathic pain after nerve injury or LPA injection, another ROCK inhibitor H-1152 alleviates neuropathic pain in the L5 spinal nerve transection model (Tatsumi, S. et al. Involvement of Rho-kinase in inflammatory and neuropathic pain thrombophorous of urinary of myristoylated aline. The results of these studies indicate that ROCK can be a drug target responsible for inducing and maintaining persistent pain states.

  In addition, Schueler et al. (Schueller et al., Abstract 1216, 8th World Congress on Inflammation, Copenhagen, Denmark, June 16-20, 2007) is a potent and highly selective inhibitor of ROCK2 that is orally bioavailable. SLx-2119 reduces atherogenesis under a markedly elevated lipid level in a group of 8 ApoE knockout mice, where selective inhibition of ROCK2 may suppress atherosclerosis It is made clear to show that.

  The 70 kDa ribosomal S6 kinase (p70S6K) is activated by many mitogens, growth factors and hormones. Activation of p70S6K occurs via phosphorylation at many sites and the primary target of the activated kinase is 40S ribosomal protein S6, a major component of the mechanism involved in protein synthesis in mammalian cells . Furthermore, p70S6K activation has been suggested in cell responses that are important in cell cycle control, neuronal differentiation, cell motility regulation and tumor metastasis, immunity and tissue repair. Modulation of p70S6 kinase activity may also have therapeutic implications in disorders such as cancer, inflammation and various neurological disorders. A detailed discussion of p70S6K kinase is in the literature (Prog. Cell Cycle Res., 1, 21-32, 1995, and Immunol. Cell Biol. 78, 447-51, 2000).

  Glycogen synthase kinase 3 (GSK-3) phosphorylates cellular substrates to control a wide variety of cellular functions such as development, metabolism, gene transcription, protein translation, cytoskeletal organization, cell cycle regulation and apoptosis. It is a constitutively active serine / threonine kinase that is resident. GSK-3 was initially reported as a major enzyme involved in glycogen metabolism, but is now known to control a variety of cellular functions. Two forms of enzyme, GSK-3 + f and GSK-3 + f, have been identified so far. The activity of GSK-3 + f is negatively regulated by the protein kinase B / Akt and Wnt signaling pathways. Thus, small molecule inhibitors of GSK-3 are useful for the treatment and prevention of neurodegenerative diseases and 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 diseases. It can have several therapeutic uses such as stimulation. In the overview, there is a report of Kockeritz et al. (Kokeritz et al., Current Drug Targets, 7, 1377-1388, 2006). A comprehensive list of neurological uses can be found in the literature (Current Drug Targets, 7 (11), 1389-1397 and 1399-1409, 2006).

  Protein kinases have become a promising target for cancer therapy (Fabbro et al., Pharmacology & Therapeutics 93: 79-98, 2002). The involvement of protein kinases in the development of human malignancies is: (1) genomic rearrangements (eg BCR-ABL in chronic myeloid leukemia), (2) constitutively active kinases such as acute myeloid leukemia and gastrointestinal tumors Mutations that cause activity, (3) deregulation of kinase activity by activation of oncogenes or loss of tumor suppressor function in cancers with oncogenic RAS, (4) kinase activity by overexpression as in EGFR It has been proposed that it can occur by deregulation of (5) ectopic expression of growth factors that can contribute to the development and maintenance of malignant phenotypes (Fabbro et al., Pharmacology & Therapeutics 93: 79-98, 2002) ).

  Certain cancers are associated with angiogenesis. Angiogenesis is the growth of new capillaries from already existing vasculature (Risau, W., Nature 386: 671-674, 1997). It has been shown that protein kinases can contribute to the development and maintenance of malignant phenotypes (Fabbro et al., Pharmacology & Therapeutics 93: 79-98, 2002). For example, VEGF A to D and their four receptors have been suggested with phenotypes involved in neovascularization and increased vascular permeability such as tumor angiogenesis and lymphangiogenesis (Matter, A., Drug Discov). Today 6: 1005-1023, 2001).

  Recognizing that a single drug approach that specifically targets one kinase or one kinase pathway may be inadequate for treating diseases and disorders, especially cancer, for several reasons Has been. The model suggests that 5 to 7 mutations are required for progression of normal cells to malignant cells. Furthermore, it is widely recognized that cancer is the result of changes in multiple pathways, particularly protein kinase pathways, associated with processes such as cell growth, proliferation, apoptosis, motility or invasion. In most cancers, a common feature is the simultaneous overexpression and / or activation of diverse protein kinases such as receptor and non-receptor kinases, serine / threonine kinases, PB kinases and cell cycle related kinases. Excessive. In fact, some of these kinases, alone or in combination with other kinases, cause cell survival, proliferation, growth and growth, resulting in metastasis and angiogenesis or inflammation, and their associated diseases, disorders and conditions. It has been suggested in many processes important in malignant transformation, exercise and invasion.

  Thus, blocking one target kinase may be clinically inadequate because there are multiple target kinases that affect the progression of a condition, disease or disorder. Furthermore, blocking of one target kinase may be clinically inadequate because overlapping kinase-mediated pathways and other oncogenic or inflammatory mechanisms may compensate for the blocked target kinase . Furthermore, the use of a single drug may increase the probability that resistance to that drug will occur.

  Cardiovascular disease accounts for nearly one quarter of the world's annual deaths. Vascular disorders, such as atherosclerosis and restenosis, occur due to abnormal growth of blood vessel walls and restriction of blood flow to vital organs. Various kinase pathways such as JNK are activated by atherogenic stimuli and are regulated through local cytokine and growth factor production in vascular cells (Yang et al, Immunity 9: 575, 1998). Ischemia and ischemia combined with reperfusion in the heart, kidney, or brain results in cell death and scar formation, which can ultimately result in congestive heart failure, renal failure, or brain dysfunction. In organ transplantation, reperfusion of donor organs with a history of ischemia results in acute leukocyte-mediated tissue damage and delayed graft function. Various kinases are mediated in the ischemia and reperfusion pathways. For example, the JNK pathway has been associated with leukocyte mediated tissue damage (Li et al., Mol. Cell. Biol. 16: 5947-5954, 1996). Finally, promotion of apoptosis in heart tissue has also been linked to kinase activity (Pombo et al., J. Biol. Chem. 269: 26546-26551, 1994).

Claims (5)

Following formula:

[Where:
A is (xiv):

Is;
R ₁ is hydrogen;
R _xiv is Z _a Z _b N- and can be present at any open valence on formula (xiv);
Z _a and Z _b are each independently hydrogen or cycloalkyl;
c is 1. ]
Or a pharmaceutically acceptable salt of the compound. Following formula:

[Where:
A is (xv):

Is;
R ₁ is hydrogen or H ₂ N—;
R _xv is Z _a Z _b N— and can be present at any open valence on formula (xv);
Z _a and Z _b are each independently hydrogen, alkoxycarbonylalkyl, aryl, arylalkyl, or cycloalkyl;
d is 0 or 1. ]
Or a pharmaceutically acceptable salt of the compound. Following formula:

[Where:
A is (xvi):

Is;
R ₁ is hydrogen;
R _xvi is Z _a Z _b N— and can be present at any open valence on formula (xvi);
Z _a and Z _b are each independently hydrogen or cycloalkyl;
d is 1. ]
Or a pharmaceutically acceptable salt of the compound. Following formula:

[Where:
A is (xvii):

Is;
R ₁ is hydrogen;
R _xvii is Z _a Z _b N- or aryl and can be present at any open valence on formula (xvii);
Z _a and Z _b are each independently hydrogen, alkyl, alkoxycarbonylalkyl, aryl, arylalkyl, cycloalkyl or H ₂ NC (O) -alkyl;
d is 0 or 1. ]
Or a pharmaceutically acceptable salt of the compound. Following formula:

[Where:
A is (xviii ′):

Is;
R ₁ is H ₂ N—. ]
Or a pharmaceutically acceptable salt of the compound.