EA042028B1 - Heterocyclylamine-Substituted Triazoles as Rho-Associated Protein Kinase Modulators - Google Patents

Description

The present invention relates to new compounds and pharmaceutical compositions containing these new compounds. More specifically, the invention relates to compounds useful as Rho-associated protein kinase (ROCK) modulators, eg inhibitors of ROCK1 and/or ROCK2. This invention also relates to methods for preparing compounds, the use of these compounds and methods of treatment using compounds. Therefore, the compounds of the invention can be used to treat diseases mediated by ROCK.

State of the art

Rho kinase (ROCK) is a member of the supercoiled serine-threonine protein kinase family and exists in two isoforms, ROCK1 and ROCK2 (Ishizaki, T. et al., EMBO J. 15: 1885-1893 (1996)). ROCK has been identified as an effector molecule of RhoA, a small GTP binding protein (G protein). Both molecules are ubiquitously expressed in tissues and play key roles in many cellular signaling pathways. Upon receptor activation, RhoA activates ROCK, which in turn controls several cellular functions including cell migration, cell adhesion, actin reorganization, cytokinesis, and smooth muscle contraction (Riento, K. et al., Nat. Rev. Mol. Cell Biol 4:446-456 (2003)); (Somlyo, A.P., Nature, 389:908-911 (1997)). The purpose of some embodiments of the present invention is to provide a ROCK modulator, including both ROCK1 and ROCK2, for example, an inhibitor of ROCK (ROCK1 and/or ROCK2).

Although ROCK1 and ROCK2 share similar kinase domains with 92% homology, they may have different downstream targets and hence different modes of action in cell physiology. For example, ROCK2 specifically phosphorylates STAT3 in lymphocytes, resulting in Th17 cell differentiation and Treg suppression (Zanin-Zhorov A. et al., PNAS 111(47): 16814-16819 (2014)), while myosin light chain (MLC) specifically phosphorylated by ROCK1 in smooth muscle cells (Sebbagh M. et al., Nat Cell Biol 3: 346-352 (2001); demonstrating a major role for ROCK1 in vasoconstriction leading to increased blood pressure. SiRNA experiments have demonstrated distinct roles for ROCK1 and ROCK2 in many cell types, such as rat embryonic fibroblast cells, where ROCK1 was found to be important in stress fiber formation and stabilization of focal adhesion sites, while ROCK2 activity was involved in phagocytosis of coated matrix beads (Yoneda, A., et al. al., J. Cell Biol (2005) Therefore, it is an object of some embodiments of the invention to provide a selective inhibitor of ROCK, for example selective for inhibition of ROCK1 or an inhibitor ROCK2. Preferably, the purpose of some embodiments of the present invention is to provide a selective inhibitor of ROCK2.

ROCK-deficient mice and small molecule inhibitors have helped to understand the roles that ROCK isoforms play in disease and have provided evidence that ROCK inhibitors will be useful in the treatment of a number of indications where unmet need is high, including diabetes, inflammation, Alzheimer's disease, hypertension, and fibrosis. After feeding WT and ROCK2(±) mice on a high fat diet for 17 weeks, it was shown that insulin resistance did not develop in ROCK2(±) mice with observed normal expression of insulin and GLUT4. The myocardial performance index was also increased (Soliman et al., Am J Physiol Heart Circ Physiol. 309(1):H70-81 (2015)).

ROCK2 also plays a significant role in cardiac hypertrophy. Cardiomyocyte-specific deletion of ROCK2 demonstrates normal cardiac anatomy, functional and hemodynamic parameters under basal conditions, but after development of angiotensin II infusion-induced cardiac hypertrophy, mice exhibited significantly less cardiac hypertrophy, intraventricular fibrosis, cardiac apoptosis, and oxidative stress compared to control mice. (Okamoto et al., FASEB J 4:1439-49 (2013)). The role of ROCK1 was further explored in an ischemic/reperfusion cardiomyopathy (I/RC) model by occlusion of the left anterior descending artery. ROCK1 KO mice were protected from developing I/RC-mediated myocardial dysfunction and had reduced cardiac fibrosis. Fibroblast formation from human peripheral blood mononuclear cells was impaired in cells with lower ROCK1 expression (Haudek et al., Cardiovasc Res. 83(3):511-8 (2009)). It has also been shown that ROCK activity is increased in patients with myocardial function (Dong et al., Int J Cardiol 167(6):2813-9 (2013)). The combination of increased Rhokinase activity and a pro-natriuretic B-type N-terminal peptide predicts worse cardiovascular outcome in patients with acute coronary syndrome.

ROCK2 also plays an important role in fibrosis: two reports have shown that bleomycin-induced pulmonary fibrosis improves in both ROCK1(±) and ROCK2(±) animals, and mice with a targeted deletion of ROCK2 show a decrease in cardiac fibroblasts. cardiac hypertrophy and fibrosis with angiotensin II infusion (Shimizu T JACC April 5, 2016 Volume 67, Issue 13; ATS 2014 A60. LUNG FIBROSIS: ANIMAL MODELS I). In addition, ROCK2 expression and function have been shown to be increased in bronchial epithelial tissue and fibrotic lesions in patients with idiopathic pulmonary fibrosis (Shimizu Y Int J Immunopathol Pharmacol. 27(1):37-44 (2014)).

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A number of ATP-competitive inhibitors of ROCK kinase activity have been developed, with the non-isoform selective Y-27632 and Fasudil being the most widely known and used. These inhibitors exhibit a relatively high degree of specificity for ROCK, however, when used at higher concentrations, they can also inhibit other kinases such as members of the protein kinase A and C family and citronkinase (Ishizaki et al., 2000; Ikenoya et al., 2002). Fasudil was approved in Japan and China in 1995 for the prevention and treatment of cerebral vasospasm following subarachnoid hemorrhage. In clinical studies, fasudil has shown positive effects in patients with pulmonary arterial hypertension, systemic hypertension, vasospastic angina, stroke, and congestive heart failure (Masumoto et al., 2001, 2002; Fukumoto et al., 2005; Kishi et al., 2005; Shibuya et al., 2005). Additional research indicates that a ROCK inhibitor would be useful in the treatment of cardiovascular disease. In a rat model of stroke, fasudil has been shown to reduce both infarct volume and neurological deficit, and the ROCK inhibitor Y-27632 has been shown to improve ventricular hypertrophy, fibrosis, and function in a congestive heart failure model in Dahl rats sensitive to developing hypertension with saline ingestion. diets (Toshima, Y., Stroke, 31:2245-2250 (2000); Kobayashi, N. et al., Cardiovasc. Res., 55:757-767 (2002). Other studies show an association between ROCK and atherosclerosis. In a porcine model of IL-1 beta-induced coronary stenosis, long-term treatment with fasudil has been shown to progressively reduce coronary stenosis and also promote regression of coronary constrictive remodeling (Shimokawa, Ch. et al., Cardiovasc. Res., 51: 169-177 ( 2001)).In a similar model, the ROCK inhibitor Y-27632 also inhibited neointima formation in rats (Sawada, N. et al., Circulation, 101:2030-2033 (2000)).

In addition, both Y27632 and Fasudil have shown efficacy in bleomycin-induced pulmonary fibrosis (Shimizu Y et al., Am J Respir Crit Care Med. 163(1):210-7 (2001)); Jiang C et al., Int J Mol Sci. 13(7):8293-307 (2012)), and fasudil has been shown to be effective in renal fibrosis in a rat model of unilateral ureteral obstruction (Shin-ichi S., Eur. J. Pharm. 29:169-174 (2002 )) and liver fibrosis in type 2 diabetic rats induced by a high fat diet combined with streptozotocin (Zhou H et al., Chin Med J, 127(2):225-31 (2014)). In addition, fasudil-treated mice were significantly protected from lung and skin fibrosis after repeated subcutaneous injections of hypochlorous acid (HOCl) (Bei Y et al., Exp Lung Res, 42(1):44-45 (2016)). These results provide additional evidence that the ROCK signaling pathway promotes fibrotic processes in a number of tissues and fibrotic diseases and highlights the importance of targeting ROCK as an antifibrotic agent in cardiovascular and metabolic diseases. A selective inhibitor of ROCK2 (KD025) has been described and has also demonstrated effective results in inflammatory disease models and cells isolated from sick patients by suppressing Th17 cells and follicular T-helper (TFH). KD025 effectively improves chronic graft-versus-host disease (cGVHD) in two models: a complete major histocompatibility complex (MHC) mismatch model of the cGVHD multi-organ system with bronchiolitis obliterans syndrome and a minor MHC mismatch model of sclerodermatous GVHD. Treatment with KD025 resulted in the normalization of pathogenic lung function by suppressing antibody and collagen deposition in the lung (Flynn R et al., Blood 127(17):2144-54 (2016)). KD025 suppression of the ROCK2 signaling pathway in normal human T cells or peripheral blood mononuclear cells from patients with active systemic lupus erythematosus (SLE) has also been shown to reduce the number and function of TFH cells induced by ex vivo activation (Weiss JM et al., Sci Signal, 9(437):ra73 (2016)). Further ex vivo stimulation of T cells from healthy individuals demonstrated that oral administration of KD025 was able to reduce the ability of T cells to secrete IL-21 and IL-17 by 90% and 60%, respectively (Zanin-Zhorov A et al., Proc Natl Acad. Sci, 111(47): 16814-9 (2014)). Given the demonstrated effect of ROCK on smooth muscle, ROCK inhibitors may also be useful in other diseases including smooth muscle hyperreactivity, asthma, and glaucoma (Shimokawa, h. et al., Arterioscler. Thromb. Vase. Biol., 25:1767-1775 ( 2005)). Thus, the selective suppression of ROCK2 provides a new opportunity for the treatment of a number of autoimmune and inflammatory-fibrotic conditions. ROCK also plays a significant role in pathologies of the central nervous system (CNS). For example, ROCK signaling has been shown to be elevated in the serum, spleen, brain, and spinal cord of patients with multiple sclerosis (MS) compared to healthy individuals. In vitro neuronal injury by scratching and TNF-α stimulation also causes an increase in ROCK activity. When sera from MS patients were co-cultured in vitro with mouse cortical neurons, MS sera caused neurite contraction and reduced cell viability. Co-cultivation with fasudil partially restored the synaptic morphology of neurons, which clearly indicates the neuroprotective effect of ROCK inhibition (Chen C et al., Neuromolecular Med. 17(4):465-65 (2015)). Intravitreal administration of fasudil improved retinal function in the R6/2 mouse model of Huntington's disease, suggesting that inhibition of ROCK may lead to a slowing or reversal of neuronal dysregulation (Li M et al., PloS One. 8(2):e56026 (2013)) . Oral administration of Y-27632 also

- 2 042028 made it possible to improve coordination and balance in the rotating rod test in model R6/2; this treatment also reduced the level of soluble huntingtin protein (Htt) (Li M et al., Neurobiol Dis. 36(3):413-20 (2009)). ROCK2 (RI) interference with small hairpin RNA (ShRNA) also significantly improved movement disorder and attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic (DA) neuron loss in a mouse model of Parkinson's disease. . In addition, ROCK2 shRNA inhibits microglial M1 activation in the substantia nigra (SN), demonstrating reduced activity of the TLR2/NF-KB signaling pathway and reduced expression levels of iNOS and inflammatory factors, including interleukin IL-1e and IL-6 (Zhang Q et al. , Mol Med Rep. 14(6):4947-4956 (2016)). In another study, fasudil was shown to have a protective effect on DN in the MPTP model (Zhao Y et al., J Neurol Sci 353(l-2):28-37 (2015)). Further experiments with RNAi-mediated knockdown demonstrated that reduced expression of both ROCK1 and ROCK2 suppressed endogenous production of Ae40 in neurons, and Άβ40 levels were reduced in the brains of heterozygous ROCK1 knockout mice compared to control wild-type littermates, suggesting that ROCK may also be a valid target for the treatment of Alzheimer's disease (HendersonB et al., J Neurochem, 138(4):525-31 (2016)).

Some studies also demonstrate that ROCK inhibition would be useful in cancer therapy. Y-27632 and Fasudil have been shown to down-regulate existing expression in the PANC-1 pancreatic cancer cell line and render cells susceptible to gemcitabine-induced cell death (Takeda H., Anticancer Res 36(12):6311-6318 (2016)). Oral administration of fasudil has also been shown to reduce tumor size in a transgenic mouse model of human gastric cancer (Hinsenkamp I et al., Neoplasia 18(8):500-l 1 (2016)). Fasudil has also been shown to inhibit proliferation and migration and induce apoptosis in urothelial cancer cells (Abe H et al., BMC Cancer 7; 14:412 (2014)).

In addition, it is an object of some embodiments of this invention to provide novel therapies, e.g., treatments for diabetes, inflammation, Alzheimer's disease, hypertension, fibrosis, cancer, central nervous system pathologies, and other conditions associated with ROCK1 and/or ROCK2. In particular, it is an object of some embodiments of this invention to provide compounds that have comparable potency to existing ROCK therapies.

The purpose of some embodiments of this invention is to provide compounds that exhibit reduced cytotoxicity or increased solubility relative to prior art compounds and existing treatments.

Another object of some embodiments of this invention is to provide compounds having a suitable pharmacokinetic profile and a suitable duration of action after dosing. An additional object of some embodiments of this invention is to provide compounds in which the metabolized fragment or fragments of the drug after absorption are GRAS (considered as safe). Certain embodiments of the present invention serve some or all of the above purposes.

Brief summary of the invention

In one aspect, the present invention provides a compound of formula (I) and a pharmaceutically acceptable salt thereof

(I) where A ¹ , A ² each independently represents CR ⁷ ;

A ³ is independently selected from CR ⁷ or N;

B is a 5-10 membered carbocyclic ring system or a 5-10 membered heterocyclic ring system containing 1, 2, 3 or 4 heteroatoms selected from N, O and S;

R ¹ is LR ² where L is a bond or -L1-L ² - where L ¹ is selected from a bond, -(CRARB)^-, -O(CRARB)1-3-, -(CRARB^O- and -NR ^c (CRARB)1.3-, and

L ² is selected from the bond, -(CRARB)^-, -O-, -NRD-, -C(O)NR ^D -, -NRDC(O)-, -C(O)O-, -OC(O) -, -C(O)-, -S(O)2NR ^d -, -NR ^d S(O)2-, -S(O) ₂ -, -S(O)(NR ^d )-, -NR ^d C(O)NR ^e -, -OC(O)NR ^d - and -C(O)NR ^d S(O) ₂ -, and

R ² is selected from H, CN, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl, C ₁ . ₆ alkyl substituted with -ORF, C ₁ . ₆ alkyl substituted with -NRFRG, C ₁ . ₄ haloalkyl substituted with -ORF, C ₃ . ₈ cycloalkyl substituted with OH, C ₁ . ₄ alkyl substituted with 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S, C ₁ . ₄ alkyl substituted by 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, -(CR ^H RI)1.3OR ^F , -(CRHRI^^NRFRG -(CR ⁿ R ^o )1.3C (O)OR ^f , -(CR ⁿ R ^o )1.3C(O)NR ^f R ^g , Cz.1o carbocyclic ring system and 3-10-membered heterocyclic ring system containing 1,

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2, 3 or 4 heteroatoms selected from N, O and S, where the carbocyclic ring or heterocyclic ring system is unsubstituted or substituted by: =O, -NR ^F R ^G , -C(O)R ^F , halogen, -CN, C ₁ . ₄ alkyl, C ₁ . ₄ haloalkyl or C ₁ . ₄ alkyl substituted with OR ^F ;

R ⁴ is independently selected at each occurrence from halo, C1.4 alkyl, C1.6 haloalkyl, -CN, -ORJ, =O, C1.4 alkyl substituted with -ORJ, -NRJR ^K , C1. ₄ alkyl substituted with -NRJR ^K , C ₃ . ₈ cycloalkyl, C ₁ . ₄ alkyl substituted with C ₃ . ₈ cycloalkyl, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S, and C ₁ . ₄ alkyl substituted with 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S;

R ⁵ is selected from H, C1.4 alkyl, C1.4 alkyl substituted with -OR ^L , C1. ₄ alkyl substituted with -NR ^L R ^L , C ₃ . ₈ cycloalkyl, substituted or unsubstituted phenyl, 3-8-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S, C ₁ . ₄ alkyl substituted with C ₃ . ₈ cycloalkyl, C ₁ . ₄ alkyl substituted by 3-8-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S, and substituted or unsubstituted by 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N , O and S, where the phenyl or heteroaryl group may be substituted with 1 or 2 R ⁹ ;

R ⁶ is selected from H and C ₁ . ₄ alkyl;

R ⁷ is selected from H, halo, -OR ^M , C _1-4 alkylα, C ₁ . ₆ haloalkyl, C ₁ . ₄ alkenyls, -CN and C ₃ . ₈ cycloalkyl;

R ⁸ is selected from H, halo, C ₁ . ₄ alkyl, C ₁ . ₆ haloalkyl, -CN and C ₃ . ₈ cycloalkyl;

R ⁹ is selected from halogen or C ₁ . ₄ alkyl;

n is 0, 1, or 2;

R ^a and R ^B are selected from H, C ₁ . ₄ alkyl or C ₁ . ₄ haloalkyls or R ^A and R ^B together with the atom to which they are attached form a 3-6 membered cycloalkyl ring or a 3-6 membered heterocycloalkyl ring containing 1, 2 or 3 heteroatoms selected from N, O and S ;

R ^C , RD, R ^e , R ^f and R ^g are each independently selected from H, C ₁ . ₄ alkyl and C ₁ . ₄ haloalkyl;

RH and RI are each H except that one pair of RH and RI on one carbon atom together with that carbon atom form a 3-6 membered cycloalkyl ring or a 3-6 membered heterocycloalkyl ring containing 1, 2 or 3 a heteroatom selected from N, O and S; And

RJ, R ^K , R ^l , R ^m , R ⁿ and R ^O are each independently selected from H or C ₁ at each occurrence. ₄ alkyl.

In some embodiments, A ¹ , A ² and A ³ are each independently selected from C-H, CF, C-Cl, CMe, C-Et, Ci-Pr, C-cyclopropyl, C-ethenyl, C-propenyl, C- CN or C-CF3

In some embodiments, A ³ is N.

In some embodiments, R ⁸ is H, O, F, CN, or Me.

In some embodiments, R ⁶ is selected from H or methyl.

Ά

In some embodiments, N is:

R ⁵ R ^S or ^RS % ^O .... ......... ^In some embodiments A... υ υ-α » J υ > ν- _ν ν- _ν ν- _ν ^ν X ^Ν is chosen from: > _\ Τ * Τ Λ \ Ν- _ν ^Ζ ηο ^Ζ Α^ ^Ν \ 4 ^Χχ -Ν \ ίΧ X___Ν ₅ X___Ν _s

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In some embodiments, the compound of formula (I) is a compound of formula (Ia)

where m is 1 or 2.

In some embodiments, R ⁵ is selected from H, C _1-4 alkyl, C _1-4 alkyl substituted with -ORL, C _1-4 alkyl substituted with -NRLRL, C _3-8 cycloalkyl substituted or unsubstituted with phenyl, C _{1- 4} alkyl substituted by 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S and substituted or unsubstituted 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N , O and S, where the phenyl or heteroaryl group may be substituted with 1 or 2 R ⁹ .

implementation

In some variants

selected from

In some embodiments, B is selected from a 5- or 6-membered carbocyclic ring that is aromatic or unsaturated, a 5- or 6-membered heterocyclic ring containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, which is an aromatic or unsaturated, 9- or 10-membered carbocyclic bicyclic ring system, or a 9- or 10-membered heterocyclic bicyclic ring system containing 1, 2, or 3 heteroatoms selected from N, O, and S, where the bicyclic ring system is either aromatic, or one of the rings in the bicyclic ring system is aromatic or unsaturated and the other ring is saturated. In some embodiments, B is selected from a 6-membered carbocyclic ring and a 10-membered heterocyclic fused bicyclic ring system containing 1, 2, or 3 heteroatoms selected from N, O, and S.

In some embodiments, B is selected from phenyl, pyrazole, pyridyl, piperidyl, azaindole, isoindoline, tetrahydroisoquinoline, tetrahydroisoquinolone, furan, indazole, benzpyrazole, pyrimidine, pyridone, tetrahydropyridine, dihydropyran, piclopentene, cyclohexenyl, chroman, chromanone, benzodioxane, tetrahydronaphthalene, dihydrobenzoxazine , benzomorpholine, tetrahydroquinoline, naphthyridine, quinoline, isoquinoline and dihydroisobenzofuran, or B is

- 5 042028 (R ⁴ ) _n |

In some embodiments ^{, R} is selected from

( ^R4 ).

In some embodiments, L ¹ may be selected from the relationship, -(CR ^A R ^B )1.3- and -O(CR ^A R ^B )1_3-.

In some embodiments, L ² may be selected from the bond, -NRD-, -C(O)NR ^D -, -NR ^d C(O)-, -C(O)O-, -C(O)-, - NR ^d C(O)NR ^e - and -OC(O)NR ^d -.

In some embodiments, R ^A and R ^B may be independently selected from H, C ₁ . ₄ alkyl and C ₁ . ₄ haloalkyl and/or RC and ^RD are independently selected from H and methyl.

In some embodiments, R ² is selected from H, CN, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, t-pentyl, difluoroethyl, difluoropropyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, 2-hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, hydroxypropyl, 2-methyl-2-hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, hydroxycyclopropyl, hydroxycyclobutyl, hydroxycyclopentyl, hydroxycyclohexyl, hydroxycycloheptyl, aziridinyl, N-acetylaziridinyl, N-alkylaziridinyl, azetidinyl, N-acetylazetidinyl, N-alkylazetidinyl, 2-methylpropane-2-amine, phenyl, chlorophenyl, pyrrolidinyl, difluoropyrrolidinyl, trifluoroethylpyrrolidinyl, N-methylpyrrolidinyl, tetrahydrofuranyl, sulfolanyl, dihydropyran, tetrahydropyranyl, tetrahydropyranoimidazolyl, pyrrolidinyl imidetrazolidinyl, imidahydropyranyl methylimidazolyl, piperazinyl, N-methylpiperazinyl, trifluoromethylpiperazinyl, oxadiazolyl, dimethyldig hydrooxazolyl, pyrazolyl, N-methylpyrazolyl, ethylpyrazolyl, 4-hydroxypyridyl, 2-hydroxypyridyl, pyridyl, tetrahydrofuran substituted methyl, pyridine substituted ethyl, -NMe ₂ substituted ethyl, OMe substituted ethyl, OH substituted ethyl; or selected from:

In some embodiments, R ⁴ is F, Cl, methyl, CF3, Et, iPr, CN, OH,

OMe, Oi-Pr, \u003d O, CH2OH, CH ₂ OMe, NH ₂ , NMe ₂ , CH ₂ NH ₂ , CH ₂ NMe ₂ , or morpholinyl.

In yet another aspect, the present invention relates to a compound selected from:

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In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient. In some embodiments, the implementation of the pharmaceutical composition contains an additional pharmaceutically active agent.

In yet another aspect, the use of a compound of the present invention is provided for the treatment of a condition that is treatable by inhibition of ROCK1 and/or ROCK2.

In some embodiments, the condition is a condition selected from fibrotic diseases, autoimmune, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer.

In some embodiments, the condition treatable by ROCK1 and/or ROCK2 inhibition is selected from sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, atopic dermatitis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barré disease, Graves' disease, Addison's disease, Raynaud's phenomenon or autoimmune hepatitis, arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, degenerative arthritis, polymyalgia rheumatica, ankylosing spondylitis, reactive arthritis, gout, pseudogout, inflammatory joint disease, systemic lupus erythematosus, polymyositis and fibromyalgia, types of arthritis including Achilles tendinitis, achondroplasia, acromegalic arthropathy, adhesive capsulitis, adult-onset Still's disease, anserine bursitis, avascular necrosis, Behcet's syndrome, bicipital tendonitis, Blount's disease, brucellar spondylitis, bursitis, calcaneal bursitis, excruciating disease crystallization of calcium pyrophosphate dihydro

- 36 042028 ta (CPPD), crystal deposition disease, Kaplan syndrome, carpal tunnel syndrome, chondrocalcinosis, chondromalacia patella, chronic synovitis, chronic recurrent multifocal osteomyelitis, Churg-Strauss syndrome, Cogan syndrome, glucocorticoid-induced osteoporosis, osteosternal syndrome, CREST syndrome , cryoglobulinemia, degenerative joint disease, dermatomyositis, diabetic digital sclerosis, diffuse idiopathic skeletal hyperostosis (DISH), discitis, discoid lupus erythematosus, drug-induced lupus syndrome, Duchenne muscular dystrophy, Dupuytren's contracture, Ehlers-Danlos syndrome, enteropathic arthritis, epicondylitis, erosive inflammatory osteoarthritis, exercise-induced compartment syndrome, Fabry disease, familial Mediterranean fever, Farber's lipogranulomatosis, Felty's syndrome, fifth disease, flat feet, foreign body synovitis, Freiberg's disease, fungal arthritis, Gaucher's disease, giant cell arteritis, gonococcal arthritis, Goodpasture's syndrome, granulomatous arteritis, hemarthrosis, hemochromatosis, Henoch-Schönlein purpura, hepatitis B surface antigen, hip dysplasia, Hurler's syndrome, hypermobility syndrome, leukocytoclastic vasculitis, hypertrophic osteoarthropathy, immune complex disease, impingement syndrome, Jaccous arthropathy , juvenile ankylosing spondylitis, juvenile dermatomyositis, juvenile rheumatoid arthritis, Kawasaki disease, Kienbock disease, Legg-Calve-Perthes disease, Lesch-Nyhan syndrome, linear scleroderma, lipoid dermatoarthritis, Löfgren's syndrome, Lyme disease, malignant synovioma, Marfan syndrome, mediopatellar syndrome folds, metastatic carcinomatous arthritis, mixed connective tissue disease (MCTD), mixed cryoglobulinemia, mucopolysaccharidosis, multiple reticulohistiocytosis, multiple epiphyseal dysplasia, mycoplasmal arthritis, myofascial pain syndrome, neonatal lupus neuropathic arthropathy, nodular panniculitis, ochronosis, ulnar bursitis, Osgood-Schlatter disease, osteoarthritis, osteochondromatosis, osteogenesis imperfecta, osteomalacia, osteomyelitis, osteonecrosis, osteoporosis, overlapping syndrome, pachydermoperiostosis, Paget's disease of the bone, palindromic rheumatism, patellofemoral pain syndrome joint, Pellegrini-Stied syndrome, pigmented villonodular synovitis, piriformis syndrome, plantar fasciitis, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, popliteal cysts, posterior tibial tendinitis, Pott's disease, prepatellar bursitis, prosthetic joint infection, pseudoxanthoma elasticum, psoriatic arthritis, Raynaud's syndrome, reactive arthritis (Reiter's syndrome), reflex sympathetic dystrophy syndrome, relapsing polychondritis, posterior calcaneal bursitis, rheumatic fever, rheumatoid vasculitis, rotator cuff tendinitis, sacroiliitis, salmonella osteomyelitis, sarcoidosis, lead gout, Scheuermann's osteochondrosis, scleroderma, septic arthritis, seronegative arthritis, shigella arthritis, shoulder-hand syndrome, sickle cell arthropathy, Sjögren's syndrome, epiphysiolysis of the femoral head, spinal stenosis, spondylolysis, staphylococcal arthritis, Stickler syndrome, subacute cutaneous lupus, Sweet's syndrome, Sydenham's chorea, syphilitic arthritis, systemic lupus erythematosus (SLE), Takayasu's arteritis, tarsal tunnel syndrome, tennis elbow, Tietze's syndrome, transient osteoporosis, traumatic arthritis, acetabular bursitis, tuberculous arthritis, ulcerative colitis arthritis, undifferentiated syndrome connective tissue dysplasia (UCTS), urticarial vasculitis, viral arthritis, Wegener's granulomatosis, Whipple's disease, Wilson's disease, yersinia arthritis, and conditions involving vascularization and/or inflammation, including atherosclerosis, rheumatoid arthritis (RA), hemangiomas, angiofibromas, and psoriasis, angiogenic diseases including retinopathy of prematurity (re trolental fibroplasia), corneal transplant rejection, corneal neovascularization associated with complications of refractive surgery, corneal neovascularization associated with complications caused by contact lenses, corneal neovascularization associated with pterygium and recurrent pterygium, corneal ulcer and non-specific ocular surface disease, insulin-dependent diabetes mellitus , multiple sclerosis, myasthenia gravis, Crohn's disease, autoimmune nephritis, primary biliary cirrhosis, acute pancreatitis, graft rejection, allergic inflammation, contact dermatitis and delayed-type hypersensitivity reactions, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, cognitive impairment caused by inflammation of neurons, Osler-Weber syndrome, restenosis and fungal, parasitic and viral infections, including cytomegalovirus infections.

In yet another aspect of the present invention, the use of a compound is provided for the treatment of a condition selected from fibrotic diseases, autoimmune, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer.

In another aspect of the present invention, there is provided a method of treating a condition that is treatable by inhibition of ROCK1 and/or ROCK2, wherein the method comprises administering a therapeutic amount of a compound of the invention to a patient in need thereof.

In yet another aspect, the invention provides a method for treating a condition selected from fibrotic diseases, autoimmune, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer, wherein the method comprises administering a therapeutic

- 37,042,028 of a compound of any formula disclosed herein to a patient in need thereof.

In another aspect, the present invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment of a condition selected from fibrotic diseases, autoimmune, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer.

Detailed description

In embodiments, the present invention relates to a compound of formula (I) and pharmaceutically acceptable salts thereof

(I) where A ¹ , A ² or A ³ each independently selected from CH, CR ⁷ or N;

B is a 5-10 membered carbocyclic ring system or a 5-10 membered heterocyclic ring system;

R ¹ is LR ² where L is a bond or -L ¹ -L ² - where L ¹ is selected from a bond, -(CR ^A R ^B )·;-. -OlCRARB)·;-, -(CRARByA)- and -NR(CR ^A R ^B r _; -, and

L ² is selected from the bond, -(CR ^A R ^B )1.3-, -O-, -NRD-, -C(O)NR ^D -, -NR ^D C(O)-, -C(O)O-, -OC(O)-, -C(O)-, -S(O)2NR ^d -, -NR ^d S(O)2-, -S(O)2-, -S(O)(NR ^d ) -, -NR ^d C(O)NR ^e -, -OC(O)NR ^d - and -C(O)NR ^d S(O)2-, and

R ² is selected from H, CN, C1.6 alkyl, C1.6 haloalkyl, C1.6 alkylα, substituted -ORF, C1-6 alkyl, substituted -NR ^f R ^g , C1. ₄ haloalkyl substituted with -OR ^F , C3.8 cycloalkyl substituted with OH, C1.4 alkyl substituted with 3-8-membered heterocycloalkyl, C1.4 alkyl substituted with 6-membered heteroaryl, -(CRHR^^ORF -(CRHR^^NR^ G -(CR ⁿ R ^o )1.3C(O)OR ^f , -(CR ⁿ R ^o )1.3C(O)NR ^f R ^g _the ring or heterocyclic ring system is unsubstituted or substituted by: =O, -NR ^F R ^G , _-C (O)R ^F , halo, -CN, _C1.4 alkyl, _C1.4 haloalkyl, or _C1.4 alkyl substituted ^-ORF ;

R ⁴ is independently selected at each occurrence from halo, C1.4alkylα, C1.6haloalkyl, -CN, -ORJ, =O, C1.4alkyl substituted with -ORJ, -NRJR ^K , C1. ₄ alkyl substituted with -NRJR ^K , C ₃ . ₈ cycloalkyl, C ₁ . ₄ alkyl substituted with C ₃ . ₈ cycloalkyl, 3-8 membered heterocycloalkyl and C ₁ . ₄ alkyl substituted with 3-8 membered heterocycloalkyl;

R ⁵ is selected from H, C ₁ . ₄ alkyl, C ₁ . ₄ alkyl substituted with -ORL, C ₁ . ₄ alkyl substituted with -NRLRL, C ₃ . ₈ cycloalkyl, substituted or unsubstituted with phenyl, 3-8 membered heterocycloalkyl, C ₁ . ₄ alkyl substituted with C ₃ . ₈ cycloalkyl, C ₁ . ₄ alkyl substituted with 3-8 membered heterocycloalkyl and substituted or unsubstituted with 5- or 6-membered heteroaryl, where the phenyl or heteroaryl group may be substituted with 1 or 2 R ⁹ ;

R ⁶ is selected from H and C ₁ . ₄ alkyl;

R ⁷ is selected from H, halo, -OR ^M , C ₁ . ₄ alkyl, C ₁ . ₆ haloalkyl, C ₁ . ₄ alkenylα, -CN and C _3-8 cycloalkyl;

R ⁸ is selected from H, halo, C ₁ . ₄ alkyl, C ₁ . ₆ haloalkyl, -CN and C _3-8 cycloalkyl;

R ⁹ is selected from halogen or C ₁ . ₄ alkyl;

n is 0, 1, or 2;

R ^a and R ^B are selected from H, C ₁ . ₄ alkyl or C ₁ . ₄ haloalkyl or R ^A and R ^B together with the atom to which they are attached form a 3-6 membered cycloalkyl ring or a 3-6 membered heterocycloalkyl ring;

R ^C , R ^d , R ^e , R ^f and R ^g are each independently selected from H, C ₁ . ₄ αkyl and C ₁ . ₄ haloalkyl;

RH and RI are each H except that one pair of RH and RI on one carbon atom together with that carbon atom form a 3-6 membered cycloalkyl ring or a 3-6 membered heterocycloalkyl ring; And

RJ, R ^K , R ^l , R ^m , R ⁿ and R ^O are each independently selected from H or C ₁ at each occurrence. ₄ alkylα.

In embodiments, the present invention relates to a compound of formula (I) and pharmaceutically acceptable salts thereof:

(I) where A ¹ , A ² or A ³ each independently selected from CH, CR ⁷ or N;

B is a 5-10 membered carbocyclic ring system or a 5-10 membered heterocyclic ring system;

R ¹ is LR ² where L is -L ¹ -L ² - where L ¹ is selected from the bond, -(CR ^A R ^B ) ₁ . _3- ,

-O(CR ^A R ^B )1.3-, -(CR ^A R ^B )o-3O- and -NR ^c (CR ^a R ^b )1.3-, and

- 38 042028

L ² is selected from the bond, -(CR ^a R ^b )i- ₃ -, -O-, -NR ^D -, -C(O)NR ^D -, -NR ^D C(O)-, -C(O) O-, -OC(O)-, -C(O)-, -S(O)2NR ^d -, -NR ^d S(O)2-, -S(O)2-, -S(O)( NR ^d )-, -NR ^d C(O)NR ^e -, -OC(O)NR ^d - and -C(O)NR ^d S(O)2-, and

R ² is selected from H, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl substituted with -OR ^f , C1-6 alkyl substituted with -NR ^f R ^g , C3_8 cycloalkyl substituted with OH, C1-4 alkyl substituted with 3-8- -(CR ^H RI)1-3OR ^F , -(CR ^H RI)1-3NR ^F R ^G , C3-1o carbocyclic ring system and 3-10 membered heterocyclic ring system systems where the carbocyclic ring or heterocyclic ring system is unsubstituted or substituted with: =O, -NR ^f R ^g , halogen, C _1-4 alkyl or C _1-4 alkyl substituted with -OR ^F ;

R ⁴ is selected from halo, C1-4 alkyl, C1-6 haloalkyl, -CN, -OR ^j , =O, C1-4 alkyl substituted with -OR ^j , -NR ^j R ^k , C1-4 alkyl substituted with -NR ^j R ^k , C3-8 cycloalkyl, C _1-4 alkyl substituted with C _3-8 cycloalkyl, 38-membered heterocycloalkyl and C _1-4 alkyl substituted with 3-8 membered heterocycloalkyl;

R ⁵ is selected from H, C1-4αalkyl, C1-4αalkyl substituted with -OR ^l , C3-8 cycloalkyl substituted or unsubstituted with phenyl, 3-8 membered heterocycloalkyl, C _1-4 alkyl substituted with C _3-8 cycloalkyl, C _{1 -4} αalkyl substituted with 3-8 membered heterocycloalkyl and substituted or unsubstituted with 5- or 6-membered heteroaryl, where the phenyl or heteroaryl group may be substituted with 1 or 2 R ⁹ ;

R ⁶ is selected from H and C _1-4 alkyl;

R ⁷ is selected from H, halo, -OR ^m , C _1-4 alkyl, C _1-6 haloalkyl, -CN and C _3-8 cycloalkyl;

R ⁸ is selected from H, halogen, C _1-4 αkyl, C _1-6 haloalkyl, -CN and C _3-8 cycloalkyl;

R ⁹ is selected from halo or C _1-4 alkyl;

n is 0, 1, or 2;

R ^a and R ^b are selected from H, C _1-4 alkyl or C _1-4 haloalkyl, or R ^a and R ^b together with the atom to which they are attached form a 3-6 membered cycloalkyl ring or a 3-6 membered heterocycloalkyl ring;

R ^c , R ^d , R ^e , R ^f and R ^g are each independently selected from H and C _1-4 αkyl;

R ^h and RI are each H, except that one pair of RH and RI on one carbon atom together with this carbon atom form a 3-6 membered cycloalkyl ring or a 3-6 membered heterocycloalkyl ring; And

R ^j , R ^k , R ^l and R ^m are each independently selected at each occurrence from H or C _1-4 alkyl.

In embodiments, A ¹ , A ² and A ³ are each independently selected from C-H, CF, C-Cl, C-Me, C-Et, Ci-Pr, C-cyclopropyl, C-CN, C-CF ₃ or N. Optionally, at least two of A ¹ , A ² and A ³ are CH.

In embodiments A ¹ , A ² and A ³ are each independently selected from C-H, CF, C-Cl, C-Me, C-Et, Ci-Pr, C-cyclopropyl, C-ethenyl, C-propenyl, C -CN, C-CF ₃ or N. Optionally, at least two of A ¹ , A ² and A ³ are CH.

In embodiments, A ¹ is C-H, C-Cl, CF, C-ethenyl, C-propenyl, or CMe. In embodiments, A ² is CH or CF. In embodiments, A ³ is CH. In embodiments

A ¹ is C-H, C-Cl, CF, C-ethenyl, C-propenyl, or C-Me;

A ² is CH or CF; And

And ³ represents C-H.

In embodiments, A ¹ , A ² and A ³ are each CH. In embodiments, A ¹ is C-Cl, A ² is C-H, and A ³ is C-H. In embodiments, A ¹ is CF, A ² is C-H, and A ³ is C-H. In embodiments, A ¹ is C-Me, A ² is C-H, and A ³ is C-H. In embodiments, A ¹ is C-H, A ² is CF, and A ³ is C-H. In embodiments, A ¹ is C-ethenyl, A ² is C-H, and A ³ is C-H. In embodiments, A ¹ is C-propenyl, A ² is C-H, and A ³ is C-H.

Accordingly, R ⁷ may be H, Cl, F, CN, methyl, ethyl, isopropyl, ethenyl, propenyl, trifluoromethyl or cyclopropyl. In embodiments, R ⁷ is H, Cl, F, CN, methyl, ethyl, or cyclopropyl.

R ⁸ may be H, Cl, F, CN or Me. In embodiments, R ⁸ is H or methyl.

In embodiments, R ⁶ is selected from H or methyl. Preferably R ⁶ is H.

As known to those skilled in the art, and for the avoidance of doubt, the structure ^N is an aromatic 5-membered ring, where one of the nitrogen atoms in the ring is substituted with R ⁵ . As is well known

- 39 042028 cialist, and for the avoidance of doubt, the structure

is a bicyclic group with a 5-membered and 6-membered ring, where the 6-membered ring is an aromatic ring.

In options

implementation is:

In embodiments, R ⁵ is selected from H, C1.4 alkyl, C1.4 alkyl, substituted with -ORL, C1.4 alkyl, substituted with -NR ^L R ^L , C3. ₈ cycloalkyl, substituted or unsubstituted with phenyl, C ₁ . ₄ alkyl substituted with 3-8 membered heterocycloalkyl and substituted or unsubstituted with 5- or 6-membered heteroaryl, where the phenyl or heteroaryl group may be substituted with 1 or 2 R ⁹ .

In embodiments, R ⁵ is selected from H, C1.4 alkyl, C1.4 alkyl substituted with -OR ^L , C1. ₄ alkyl substituted with -NR ^L R ^L , C3.8 cycloalkyl substituted or unsubstituted with phenyl, C1.4 alkyl substituted with 3-8 membered heterocycloalkyl and substituted or unsubstituted with 5- or 6-membered heteroaryl, where the phenyl or heteroaryl group may be substituted 1 or 2 R ⁹ . Optionally, R ⁵ is selected from H or C1. ₄ alkylα. Optionally, R ^L is independently selected at each occurrence from H or methyl.

In embodiments, R ⁵ is selected from H, methyl, ethyl, isobutyl, isopropyl, isopropanol, cyclopropyl, -CH ₂ CH ₂ OH, -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ NHCH ₃ , phenyl, fluorophenyl, pyridyl, piperidyl, ethyl substituted with morpholine, and ethyl substituted with piperidine. Optionally, R ⁵ may be selected from H or methyl.

In embodiments, is:

R ⁵ is selected from H,

_C1 . ₄ alkyl, C ₁ . ₄ alkyl substituted with -ORL,

In embodiments

- 40 042028

C _3-8 cycloalkyl substituted or unsubstituted with phenyl and substituted or unsubstituted with 5- or 6-membered heteroaryl, wherein the phenyl or heteroaryl group may be substituted with 1 or 2 R ⁹ .

In embodiments, R ⁵ is selected from H, C1-4 alkyl, C1-4 alkyl, substituted -ORL, C3-8 cycloalkyl, substituted or unsubstituted with phenyl, and substituted or unsubstituted with 5- or 6-membered heteroaryl, where the phenyl or heteroaryl group may be substituted with 1 or 2 ^R9 . Optionally, R ⁵ is selected from H or C1_ ₄ alkyl.

In embodiments, R ⁵ is selected from H, methyl, isopropyl, cyclopropyl, -CH2CH2OH, phenyl, fluorophenyl, and pyridyl. Optionally, R ⁵ may be selected from H or methyl.

N s

/Nn is R ⁵ where R ⁵

In embodiments, is:

In preferred embodiments, optionally is methyl.

In embodiments, the compound of formula (I) is a compound according to formula (Ia)

where m is 1 or 2. Preferably, m is 1.

^R8

N

H

In embodiments

^R8

N

OR can be:

- 41 042028

Preferably,

may represent:

Any discussion of formula (I) in this invention may equally apply to a compound of formula (Ia).

B can be selected from a 5- or 6-membered carbocyclic ring that is aromatic or unsaturated, a 5- or 6-membered heterocyclic ring that is aromatic or unsaturated, a 9- or 10-membered carbocyclic bicyclic ring system, or

A 9- or 10-membered heterocyclic bicyclic ring system, wherein the bicyclic ring system is either aromatic or one of the rings in the bicyclic ring system is aromatic or unsaturated and the other ring is saturated.

B can be selected from a 5- or 6-membered carbocyclic ring that is aromatic or unsaturated. B may be selected from a 5- or 6-membered heterocyclic ring which is aromatic or unsaturated. B can be selected from a 9- or 10-membered carbocyclic bicyclic ring system wherein the bicyclic ring system is either aromatic or one of the rings in the bicyclic ring system is aromatic or unsaturated and the other ring is saturated. B can be selected from a 9- or 10-membered heterocyclic bicyclic ring system where the bicyclic ring system is either aromatic or one of the rings in the bicyclic ring system is aromatic or unsaturated and the other ring is saturated.

In a preferred embodiment, B is selected from a 6-membered carbocyclic ring (optionally where the ring is aromatic or unsaturated) or a 10-membered heterocyclic fused bicyclic ring system (optionally where one of the rings is aromatic).

In embodiments, B is selected from phenyl, pyrazole, pyridyl, piperidyl, azaindole, isoindoline, tetrahydroisoquinoline, tetrahydroisoquinolone, furan, indazole, benzpyrazole, pyrimidine, pyridone, tetrahydropyridine, dihydropyran, cyclopentene, cyclohexenyl, chroman, chromanone, benzodioxane, tetrahydronaphthalene, dihydrobenzoxazine , benzomorpholine, tetrahydroquinoline, nafquinoline, isoquinoline and dihydroisobenzofuran, or B is thyridine,

In embodiments, B is selected from phenyl, pyrazole, pyridyl, azaindole, isoindoline, tetrahydroisoquinoline, tetrahydroquinolone, furan, indazole, benzpyrazole, pyrimidine, pyridone, tetrahydropyridine, dihydropyran, cyclopentene, cyclohexenyl, chroman, chromanone, benzodioxane, tetrahydronaphthalene, dihydrobenzoxazine, benzomorpholine, and tetrahydroquinoline, or B represents

yourself

In embodiments, B is selected from phenyl, pyridyl, tetrahydroisoquinoline, tetrahydroquinolone, and tetrahydroquinoline.

In embodiments

may represent:

- 42 042028

- 43 042028

In embodiments, the compound of formula (I) is a compound according to formulas (IIa), (IIb), or (IIc):

In embodiments, the compound of formula (I) is a compound according to formulas (III), (IIIb) or (IIIc):

L ¹ can be selected from the relationship, -(CR ^A R ^B )1.3- and -O(CR ^a R ^b )1_ ₃ -. Preferably, L ¹ is a bond or -O(CR ^a R ^b ) ₁ _ ₃ -.

L ² can be selected from the bond, -NR ^D -, -C(O)NR ^D -, -NR ^D C(O)-, -C(O)O-, -C(O)-, -NR ^D C (O)NR ^E - and -OC(O)NR ^d -.

For the avoidance of doubt, when L ¹ is a bond and L ² is

- 44 042028 connection, then L in all aspects is a connection. This can be seen as the absence of L.

In embodiments, L is selected from the bond, -(CR ^a R ^b )0-3O-, -(CR ^a R ^b )o-3NR ^C -, -(CR ^a R ^b ) ₀ . ₃ C(O)NR ^c -, -(CR ^a R ^b )o-3NR ^C C(0)-, -(CR ^a R ^b )o.3C(0)0-, -(CRARBbOQO)-, -C (O)-, -(CR ^a R ^b )o-3S(0)2NR ^C -,

-(CR ^a R ^b )o.3NR ^C S(0)2-, -S(O)2-, -NR ^C C(O)NR ^d -, -(CR ^a R ^b )o-30C(0) NR ^C -, -O(CR ^a R ^b )i-3O-, -O(CR ^a R ^b )i-3NR ^c -, -0(CR ^a R ^b )o-3C(0)NR ^C -, - O(CR ^a R ^b )i-3S(O)2NR ^C -, -O(CR ^a R ^b )i-3C(O)NR ^C S(O)2- and -NR ^d (CR ^a R ^b )i -3C(O)NR ^C -.

R ^a and R ^B may be independently selected from H, C _1-4 alkyl and C _1-4 haloalkyl. Optionally, R ^A and R ^B may be independently selected from H, methyl, trifluoromethyl, and difluoromethyl. Optionally, R ^A and R ^B may be H or methyl. Preferably R ^A and R ^B are H.

RC and R ^d may be independently selected from H and methyl. Preferably RC and ^RD are both H.

In embodiments, L is selected from a bond, -CH2-, -CH2CH2-, -O-, -OC(O)-, -C(O)O-, -OCH2-, -O(CH ₂ ) ₂ -, -OCH2CH2NH -, -OCH2C(O)NH-, -OC(Me)HC(O)NH-, -OC(MehC(O)NH-, -OCH2C(O)O-, -OCH2S(O)2NH-, -OCH ₂ CH ₂ NHC(O)-, -O(CH2)3NHC(O)-, -OCH2CH2NHS(O)2-, -OCH2CH2NHC(O)NH-, -CH2NHQO)-, -CH2NHS(O)2-, - CHNHC(O)NH-, -CH ₂ C(O)-, -(CH ₂ ) ₂ C(O)-, -CH2C(O)NH-, -(CH ₂ ) ₂ C(O)NH-, - CH ₂ C(O)O-, -CH2OC(O)NH-, -C(O)-, -C(O)CH2NH-, -C(O)NH-, -C(O)NHCH2-, -NHCH2C (O)-, -NHCH ₂ C(O)NH-, -N(Me)CH ₂ C(O)NH-, -NHC(O)-, -NHC(O)NH-, -S(O) ₂ -, -CH(CHF ₂ )NH- or -CH(CF ₃ )NH-.

Optionally, L is selected from the bond, -O-, -OCH2-, -OCH ₂ CH ₂ NH-, -OCH ₂ C(O)NH-, -OC(Me)HC(O)NH-, -OC(Me) 2C(O)NH-, -OCH2CH2NHC(O)-, -O(CH ₂ )3NHC(O)-, -OCH2CH2NHC(O)NH-, -CH2NHC(O)-, -CHNHC(O)NH-, - CH2C(O)NH-, -(CH ₂ ) ₂ C(O)NH-, -CH2OC(O)NH-, -C(O)-, -C(O)CHNH-, -C(O)NH- , -C(O)NHCH ₂ -, -NHCH ₂ c(o)NH-, -N(Me)CH ₂ C(O)NH-, -NHC(O)-, -NHC(O)NH-, - CH(CHF ₂ )NH- or -CH(CF3)NH-.

Preferably, L is selected from the bond, -O-, -OCH ₂ C(O)NH-, -CH ₂ C(O)NH-, -C(O)-, -C(O)CH ₂ NH-, -C (O)NH-, or -C(O)NHCH2-.

In embodiments of formulas (IIa) or (IIIa), L ¹ is preferably a bond or -O(CR ^a R ^b )1-3-. In embodiments of formulas (IIa) or (IIIa), L ² is preferably -C(O)NR ^d -. In embodiments of formulas (IIa) or (IIIa), L is preferably a bond, -OCH2C(O)NH-, or -C(O)NH-.

In embodiments of formulas (IIb) or (IIIb), L ¹ is preferably a bond. In embodiments of formulas (IIb) or (IIIb), L ² is preferably -C(O)-. In embodiments of formulas (IIb) or (IIIb), L is preferably a bond or -C(O)NH-.

In embodiments of formulas (IIc) or (IIIc), L ¹ is preferably a bond. In embodiments of formulas (IIc) or (IIIc), L ² is preferably a bond or —C(O)—. In embodiments of formulas (IIc) or (IIIc), L is preferably a bond.

In embodiments, R ² is selected from H, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkyl substituted with -ORF, C _3-8 cycloalkyl (optionally C _3-5 cycloalkyl), C _4-6 cycloalkyl, substituted with -OH, phenyl, 36-membered heterocyclic ring system, where given phenyl and heterocyclic ring system are unsubstituted or substituted by: halogen, C _1-4 alkyl or -C(O)RF.

In embodiments, R ² is selected from H, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkyl substituted with -ORF, C _3-8 cycloalkyl (optionally C _3-5 cycloalkyl), C _4-6 cycloalkyl substituted with -OH, a 3-6 membered heterocyclic ring system, wherein the heterocyclic ring system is unsubstituted or substituted with: C _1-4 alkyl or -C(O)RF.

In embodiments, R ² is selected from H, CN, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, t-pentyl, allyl, propargyl, difluoroethyl, difluoropropyl, trifluoroethyl , trifluoropropyl, trifluoroisopropyl, isopropanol, n-butanol, sec-butanol, propanol, tert-butanol, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piclogeptyl, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, cycloheptanol, aziridinyl, N-acetylaziridinyl, N-alkylaziridinyl, azetidinyl , N-acetylazetidinyl, N-alkylazetidinyl, 2methylpropan-2-amine, phenyl, chlorophenyl, pyrrolidinyl, difluoropyrrolidinyl, trifluoroethylpyrrolidinyl, N-methylpyrrolidinyl, tetrahydrofuranyl, sulfolanyl, dihydropyran, tetrahydropyranyl, tetrahydropyranoimidazolyl, morpholinyl, imidazolyl, ethyltetrahydroimidazopyridine, N -methylpiperazinyl, trifluoromethylpiperazinyl, oxadiazolyl, dimethyldihydrooxazolyl, pyrazolyl, N-methylpyrazolyl, ethylpi razolyl, 4-pyridone, 2-pyridone, pyridyl, methyl substituted with tetrahydrofuran, ethyl substituted with pyridine, ethyl substituted with -NMe ₂ , ethyl substituted with OMe, ethyl substituted with OH; or selected from:

- 45 042028

In embodiments, R ² is selected from H, CN, methyl, ethyl, isopropyl, tert-butyl, sec-butyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, isopropanol, sec-butanol, propanol, tert-butanol, cyclopropyl, cyclopentyl, cyclobutanol, cyclohexanol, azetidinyl , Nacetylazetidinyl, tetrahydrofuranyl, phenyl, chlorophenyl, pyrrolidinyl, difluoropyrrolidinyl, trifluoroethylpyrrolidinyl, N-methylpyrrolidinyl, sulfolanyl, tetrahydropyranyl, morpholinyl, pyridyl, imidazolyl, methyl substituted with tetrahydrofuran, ethyl substituted with pyridine, ethyl substituted with -NMe ₂ , ethyl, OMe , ethyl substituted with OH; or selected from:

In embodiments, R ² is selected from H, CN, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, sec-butyl, allyl, propargyl, trifluoroethyl, trifluoroisopropyl, isopropanol, sec-butanol, propanol, tert -butanol, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, cycloheptanol, aziridinyl, N-acetylaziridinyl, N-alkylaziridinyl, azetidinyl, N-acetylazetidinyl, Nalkylazetidinyl, pyrrolidinyl, N-methylpyrrolilidinyl, , dihydropyran, tetrahydropyranyl, morpholinyl, piperazinyl, N-methylpiperazinyl, oxadiazolyl, 4-pyridone, 2-pyridone, pyridyl, methyl substituted with tetrahydrofuran, ethyl substituted with pyridine, ethyl substituted with -NMe ₂ , ethyl substituted with OMe, ethyl substituted with OH; or selected from:

συνν σννν

In embodiments, R ² is selected from H, CN, methyl, ethyl, isopropyl, t-butyl, sec-butyl, trifluoroethyl, trifluoroisopropyl, isopropanol, sec-butanol, propanol, t-butanol, cyclopropyl, cyclopentyl, cyclobutanol, cyclohexanol, azetidinyl, N -acetylazetidinyl, tetrahydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, sulfolanyl, tetrahydropyranyl, morpholinyl, pyridyl, methyl substituted with tetrahydrofuran, ethyl substituted with pyridine, ethyl substituted with -NMe ₂ , ethyl substituted with OMe, ethyl substituted with OH; or selected from:

- 46 042028

In embodiments, R ² is selected from H, methyl, ethyl, isopropyl, t-butyl, sec-butyl, trifluoroethyl, trifluoroisopropyl, isopropanol, sec-butanol, propanol, t-butanol, cyclopropyl, cyclopentyl, cyclobutanol, cyclohexanol, azetidinyl, N -acetylazetidinyl, tetrahydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, tetrahydropyranyl, morpholinyl and pyridyl.

In embodiments, R ² is not selected from H when B is a 6-membered monocyclic ring, eg phenyl, pyridyl, pyrimidinyl. In embodiments, R ² is not selected from H when B is a phenyl ring. Accordingly, one skilled in the art will appreciate that this leads to a situation where B cannot be unsubstituted with a 6-membered ring or a phenyl ring, depending on the particular circumstances.

In embodiments, R ⁴ is selected from halogen, C _1-4 αkylα, C ₁ .4 haloalkyl, -CN, C ₁ . ₄ alkyl substituted with -ORJ, C ₁ . ₄ alkyl substituted with -NRJR ^K , and 3-8 membered heterocycloalkyl.

RJ and ^RK are each independently selected from H or methyl at each occurrence.

In embodiments, R ⁴ is F, Cl, methyl, CF ₃ , Et, iPr, CN, OH, OMe, Oi-Pr, =O, CH2OH, CH ₂ OMe, NH ₂ , NMe ₂ , CH ₂ NH ₂ , CH ₂ NMe ₂ or morpholinyl.

In embodiments, n is 0. In an alternative embodiment, n is 1.

In embodiments, n is 1 or 2. In an alternative embodiment, n is 2.

In embodiments, the compound of formula (I) is a compound according to formula (IV)

.......... ..... ^<IV) .. . " 4 ... .

In embodiments, n is preferably 1. In embodiments, R is preferably -OMe. In embodiments of formula (IV), n is preferably 1 and R ⁴ is preferably —OMe.

In embodiments, the compound of formula (I) is a compound according to formula (IVa)

(IVa)

In embodiments, the compound of formula (I) is a compound according to formula (V)

(V)

In embodiments of formula (V), n is preferably 0.

In embodiments, the compound of formula (I) is a compound according to formulas (VIa), (VIb) or (VIc)

(via)

- 47 042028

In embodiments of formulas (VIa) or (VIb), n is preferably 0. In embodiments of formulas (Via) or (VIb), n may be 1 or 2.

In embodiments, the compound of formula (I) is a compound according to

In embodiments of formulas (VIIa), (VIIb) or (VIIc), R ⁷ may be H, Cl, ethyl or cyclopropyl.

In embodiments of formulas (VIIa), (VIIb) or (VIIc), R ⁵ may be H or Me. In embodiments of formulas (VIIa), (VIIb) or (VIIc), R ⁴ may be OMe and n is 0 or 1. Any of the embodiments of this paragraph may be combined in any way to provide an embodiment of the invention.

In embodiments of formulas (VIIa), (VIIb), or (VIIc), R ⁸ is H; R ⁷ is H, Cl, ethyl or cyclopropyl; R ⁵ is H or Me; R ⁴ is OMe; and n is 0 or 1.

In embodiments, the present invention provides a compound of formula (Ib) and pharmaceutically acceptable salts thereof:

where B is a 5-10 membered carbocyclic ring system or a 5-10 membered heterocyclic ring system, where the ring systems are either monocyclic or fused bicyclic systems;

R ¹ is LR ^2A , R ^2B or absent;

L is -L^L ² -, where L ¹ is selected from the bond, -(CR ^A R ^B )1_3-, -O(CR ^A R ^B )1- ₃ -, -(CR ^A R ^B ) _0-3 O- and -NR ^C (CR ^A R ^B )1-3-, and

L ² is selected from -O-, -NR ^D -, -C(O)NR ^D -, -NR ^D C(O)-, -C(O)O-, -OC(O)-, -C(O )-, -S(O)2NR ^D -, -NR ^D S(O)2-, -S(O)2-, -NR ^d C(O)NR ^e -, -OC(O)NR ^d - and -C(O)NR ^d S(O)2-;

R ^2A is selected from H, CN, C1.6 alkyl, C1.6 haloalkyl, C1.6 alkyl substituted with -OR ^D , C1. ₆ alkyl substituted with -NR ^f R ^g , C3-8 cycloalkyl, C3-8 cycloalkyl substituted with OH, substituted or unsubstituted 3-8 membered heterocycloalkyl, 6-membered heteroaryl, C1_4 alkyl substituted with 3-8 membered heterocycloalkyl, C1_4 alkyl substituted with 6 -membered heteroaryl, -(CR ^H R ^I _{) 1-3} OR ^F , -(CR ^H R ^I ) _1-3 NR ^F R ^G ;

R ^2b is phenyl, C ₁ _ ₄ alkyl substituted with phenyl, 5-10 membered heterocyclic

- 48 042028 ring system, C _1-4 alkyl substituted with 5-10 membered heterocyclic ring system, -O-C _1-4 alkyl substituted with 5-10 membered heterocyclic ring system, wherein said heterocyclic ring system is unsubstituted or substituted : halogen, C ₁ _ ₄ alkyl or =O;

R ⁴ is selected from halo, C1.4 alkyl, C1.6 haloalkyl, -CN, -ORJ, =O, C1.4 alkyl substituted with -ORJ, -NRJR ^K , C1_4 alkyl substituted with -NRJR ^K , C ₃ _ ₈ cycloalkyl, and 3 -8-membered heterocycloalkyl;

R ⁵ is selected from H, C ₁ _ ₄ alkyl, C _3-8 cycloalkyl, substituted or unsubstituted with phenyl, and substituted or unsubstituted with 5- or 6-membered heteroaryl, where the phenyl or heteroaryl group may be substituted with 1 or 2 R ⁹ ;

R ⁶ is selected from H and C1_ ₄ alkyl;

R ⁷ is selected from H, halo, C1. ₄ alkyl, C1. ₆ haloalkyl, -CN and C _3-8 cycloalkyl;

R ⁸ is selected from H _, halo, _{C1_4} alkyl, _{C1_6} haloalkyl, -CN and _{C3_8} cycloalkyl;

R ⁹ is selected from halogen or C1_ ₄ alkyl;

n is 0, 1, or 2;

m is 0, 1, or 2;

R ^a and R ^B are selected from H, _{C1_4} alkyl or _{C1_4} haloalkyl, or R ^A and R ^B together with the atom to which they are attached form a 3-6 membered cycloalkyl ring or a 3-6 membered heterocycloalkyl ring;

R ^C , RD, R ^e , R ^f and R ^g are each independently selected from H and C1_ ₄ alkyl;

RH and R ¹ are each H except that one pair of RH and R ¹ on one carbon atom together with that carbon atom form a 3-6 membered cycloalkyl ring or a 3-6 membered heterocycloalkyl ring; And

RJ and ^RK are selected from H or _{C1_4} alkyl.

In embodiments, the compound of formula (I) is a compound according to formula (VIII)

(VIII)

In embodiments of formula (VIII), R ⁸ may be H. In embodiments of formula (VIII), R ⁷ may be C3-8 cycloalkyl. In embodiments of formula (VIII), R ⁶ may be H. In embodiments of formula (VIII), R ⁵ may be _{C1_4} alkyl. In embodiments of formula (VIII), R ² may be a substituted or unsubstituted 3-10 membered heterocyclic ring. Any of the embodiments of this paragraph may be combined in any way to provide an embodiment of the invention.

In embodiments of formula (VIII), R ⁸ is H; R ⁷ is cyclopropyl; R ⁶ is H; R ⁵ is methyl; and R ² is a substituted or unsubstituted 3-10 membered heterocyclic ring containing two or three nitrogen atoms.

In embodiments of formula (VIII), R ² is a substituted or unsubstituted 5-membered ring containing two nitrogen atoms. In embodiments of formula (VIII), R ² is a substituted or unsubstituted 9-membered ring containing two nitrogen atoms. In embodiments of formula (VIII), R ² is a substituted or unsubstituted 9-membered ring containing three nitrogen atoms.

In embodiments of formula (VIII), R ² is a substituted or unsubstituted 9-membered heterocyclic ring containing a 5-membered heterocyclic ring containing 1 or 2 nitrogen atoms fused to a 6-membered heterocyclic ring containing 1 or 2 nitrogen atoms. In embodiments of formula (VIII), R ² is unsubstituted or substituted with hydrogen, methyl, ethyl, n-propyl, i-propyl, halogen, trifluoromethyl, or trifluoroethyl.

In embodiments of formula (VIII), R ² is selected from methylpyrazole, ethylpyrazole, methylimidazole, and tetrahydropyranoimidazole.

In embodiments of formula (VIII), R ² may be:

In embodiments, the compound of formula (I) is a compound according to formulas (IXa) or (IXb):

- 49 042028

(IXa) (IXb)

In embodiments of formulas (IXa) or (IXb), R ⁸ may be H. In some embodiments, R ⁷ may be H, halo, C1-4 alkyl, or C3-8 cycloalkyl. In some embodiments, R ⁶ may be H. In some embodiments, R ⁵ may be C1-4 alkyl. In some embodiments, R ⁴ may be H or -ORJ, where RJ is selected from H or C1_4 alkyl. _In some embodiments, ^RD may be H. In embodiments _, R ² may be _{C1_6} alkyl, _{C1_6} haloalkyl, or _{C3_8} cycloalkyl. In embodiments of formulas (IXa) or (IXb), R ⁸ is H; R ⁷ is C1_4alkyl or C3_8cycloalkyl; R ⁶ is H; R ⁵ is methyl, R ⁴ is H or -OMe, ^RD is H, and R ² is C1. ₆ dlkyl, C ₁ _ ₆ haloalkyl or C ₃ _ ₈ cycloalkyl. In embodiments of formulas (IXa) or (IXb), R ⁷ is selected from methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In embodiments of formulas (IXa) or (IXb), R ² is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, sec-butyl t-pentyl, difluoroethyl, difluoropropyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

In embodiments, a compound of formula (I) is a compound according to formula (Xa) or (Xb):

In embodiments of formulas (Xa) or (Xb), R ⁸ may be H. In some embodiments, R ⁷ may be C1_4 alkyl or C3_8 cycloalkyl. In some embodiments, R ⁶ may be H. In some embodiments, R ⁵ may be _{C1_4} alkyl. In some embodiments, R ⁴ may be H or -ORJ, where RJ is selected from H or C1_4 alkyl. In some embodiments, ^RD may be H. In embodiments _, R ² may be _{C1_6} alkyl, _{C1_6} haloalkyl, or C3-8 cycloalkyl. In embodiments of formulas (Xa) or (Xb), R ⁸ is H; R ⁷ is C1_4alkyl or C3_8cycloalkyl; R ⁶ is H; R ⁵ is methyl, R ⁴ is H or -OMe, ^RD is H, and R ² is _{C1_6} alkyl, C ₁ . ₆ haloalkyl or C ₃ _ ₈ cycloalkyl. In embodiments of formulas (Xa) or (Xb), R ⁷ is selected from methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In embodiments of formulas (Xa) or (Xb), R ² is selected from methyl, ethyl, n-propyl, i-propyl, p-butyl, i-butyl, t-butyl, sec-butyl, t-pentyl, difluoroethyl, difluoropropyl, trifluoroethyl , trifluoropropyl, trifluoroisopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In embodiments, a compound of formula (I) is a compound according to formula (XI):

where R ¹⁰ is absent or represents H, C ₁ _ ₄ alkyl or C ₁ _ ₄ haloalkyl;

R ¹¹ is absent or represents H, C ₁ _ ₄ alkyl or C ₁ _ ₄ haloalkyl;

- 50 042028

R ¹² is H, C _1-4 alkyl or C ₁ . ₄ haloalkyl;

R ¹³ is independently at each occurrence selected from H, ═O, -NR ^F R ^G , halo, -CN, C _1-4 alkyl, C _1-4 haloalkyl, or Aralkyl substituted with -OR ^F ; and o is 1, 2, or 3.

In embodiments, the compound of formula (I) is a compound according to formulas (XIa), (XIb), (XIc), or (XId):

(Xia)(XIb)

(XIc) (XId)

In embodiments of formulas (XI), (XIa), (XIb), (XIc), or (XId), R ⁸ may be H. In some embodiments, R ⁷ may be H, halo, C1-4 alkyl, or C3-8 cycloalkyl . In some embodiments, R ⁶ may be H. In some embodiments, R ⁵ may be C1-4 alkyl. In some embodiments, R ⁴ may be H or -ORJ, where RJ is selected from H or C1_4 alkyl. In some embodiments, R ¹⁰ may be absent or be H, C1. ₄ alkyl, C ₁ . ₄ alkyl substituted with -OR ^l , C1_4 alkyl substituted with -NR ^L R ^L , C3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C ₁ _ ₄ alkyl substituted with C _3-8 cycloalkyl, or C ₁ _ ₄ alkyl substituted with 3 -8-membered heterocycloalkyl. In some embodiments, R ¹¹ may be absent or be H, C1.4 alkyl, C1.4 alkyl, substituted with -OR ^l , C1.4 alkyl substituted with -NR ^L R ^L , C3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C1_4 alkyl, substituted with C3-8 cycloalkyl, or C1_4 alkyl substituted with 3-8 membered heterocycloalkyl. In some embodiments _, R ¹² may be H, _{C1_4} alkyl, _{C1_4} haloalkyl, _C1 . ₄ alkyl substituted with -OR ^L , C1_4 alkyl substituted with -NR ^L R ^L , _C3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C ₁ _ ₄ alkyl substituted with C _3-8 cycloalkyl, or C ₁ _ ₄ alkyl substituted 3-8 membered heterocycloalkyl. In some embodiments, R ¹³ is independently at each occurrence selected from H, ═O, -NR ^f R ^g , halo, -CN, C ₁ _ ₄ alkylα, C ₁ _ ₄ haloalkyl, or C ₁ _ ₄ alkyl substituted with -OR ^F .

In embodiments of formulas (XI), (XIa), (XIb), (XIc) or (XId), R ¹⁰ is absent or is H, C ₁ _ ₄ alkyl, C ₁ _ ₄ alkyl, substituted with -OR ^L , C1_4 alkyl, substituted -NR ^L R ^L , _{C3_8} cycloalkyl, 38-membered heterocycloalkyl, C ₁ . ₄ alkyl substituted with C _3-8 cycloalkyl, or C ₁ _ ₄ alkyl substituted with 3-8 membered heterocycloalkyl. Optionally, R ¹⁰ is absent or represents H or C ₁ _ ₄ alkyl. In embodiments of formulas (XI), (XIa), (XIb), (XIc) or (XId), R ¹¹ is absent or is H, C1.4alkyl, C1.4alkyl substituted with -OR ^L , C1. ₄ alkyl substituted with -NR ^L R ^L , C3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C1.4 alkyl substituted with C3-8 cycloalkyl, or C1_4 nalkyl substituted with 3-8 membered heterocycloalkyl. Optionally, R ¹¹ is absent or is H or C1_ ₄ alkyl.

In embodiments of formulas (XI), (XIa), (XIb), (XIc) or (XId), R ¹² is H, C1.4 alkyl, C1_4 haloalkyl, C1_4 alkyl substituted with -OR ^L , C1_ ₄ alkyl substituted with -NR ^L R ^L , C3-8 cycloalkyl, 38 membered heterocycloalkyl, C1_4 alkyl substituted with C3-8 cycloalkyl, or C1_4 alkyl substituted with 3-8 membered heterocycloalkyl. Optionally R ¹² is _H , _{C1_4} alkyl or _{C1_4} haloalkyl.

In embodiments of formulas (XI), (XIa), (XIb), (XIc) or (XId), R ¹⁰ and R ¹¹ are independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i -butyl, tert-butyl, cyclopropyl, -CH ₂ CH ₂ OH, -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ NHCH ₃ , piperidyl, ethyl substituted with morpholine, and ethyl substituted with piperidine. Optionally, R ¹⁰ and R ¹¹ are independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, or t-butyl.

In embodiments of formulas (XI), (XIa), (XIb), (XIc) or (XId), R ¹² is selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert -butyl, trifluoromethyl, trifluoroethyl, cyclopropyl, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2NHCH3, piperidyl, ethyl substituted with morpholine, and ethyl substituted with piperidine. Optionally, R ¹² is selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, t-butyl, trifluoromethyl, or trifluoroethyl.

- 51 042028

The present invention relates to compounds of formula (I) selected from:

- 52 042028

- 53 042028

- 54 042028

- 55 042028

- 56 042028

- 57 042028

- 58 042028

- 59 042028

- 60 042028

- 61 042028

- 62 042028

- 63 042028

- 64 042028

- 65 042028

- 66 042028

- 67 042028

- 68 042028

- 69 042028

- 70 042028

- 71 042028

- 72 042028

- 73 042028

- 74 042028

- 75 042028

- 76 042028

- 77 042028

- 78 042028

- 79 042028

- 80 042028

- 81 042028

The present invention also relates to compounds of formula (I) selected from:

- 82 042028

- 83 042028

- 84 042028

In an embodiment, compounds of the present invention are provided having a ROCK2 binding capacity within the +++ or ++++ category, as defined elsewhere herein. In an embodiment, compounds of the present invention are provided having a ROCK2 binding IC50 value of < 3 μM. In an embodiment, compounds of the present invention are provided having a ROCK2 binding IC ₅₀ value of < 0.3 μM. Optionally, binding capacity is determined using the ROCK2 inhibition assay defined in the examples.

In an aspect of the invention, the compounds of the present invention are provided for use as a drug.

According to another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient.

In an embodiment, the pharmaceutical composition may be a combination product containing an additional pharmaceutically active agent. The additional pharmaceutically active agent may be, for example, anti-inflammatory agents, anti-fibrotic agents, chemotherapeutic agents, anti-cancer agents, immunosuppressive agents, anti-tumor vaccines, cytokine therapeutic agents, or tyrosine kinase inhibitors.

According to another aspect, there is provided a compound of the present invention for use in the treatment of a condition that is modulated by ROCK1 and/or ROCK2. In general, conditions that are modulated by ROCK (please note that ROCK refers to either one or both of ROCK1 and ROCK2) are conditions that can be treated by inhibiting ROCK using a compound of the present invention. A compound of any formula disclosed herein may be used in the treatment of a condition treatable by ROCK inhibition. As noted above, the ROCK signaling pathway plays an important role in a number of conditions. Therefore, the condition treatable by inhibition of ROCK1 and/or ROCK2 is selected from fibrotic diseases, autoimmune, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer.

Condition treatable by inhibition of ROCK1 and/or ROCK2 selected from sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, atopic dermatitis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barré disease, Graves' disease, Addison's disease, Phenomenon Raynaud or autoimmune hepatitis, arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, degenerative arthritis, polymyalgia rheumatica, ankylosing spondylitis, reactive arthritis, gout, pseudogout, inflammatory joint disease, systemic lupus erythematosus, polymyositis, and fibromyalgia.

Additional types of arthritis include Achilles tendinitis, achondroplasia, acromegalic arthropathy, adhesive capsulitis, adult-onset Still's disease, anserine bursitis, avascular necrosis, Behcet's syndrome, bicipital tendonitis, Blount's disease, brucellar spondylitis, bursitis, calcaneal bursitis, calcium crystal deposition disease pyrophosphate dihydrate (CPPD), crystal deposition disease, Kaplan syndrome, carpal tunnel syndrome, chondrocalcinosis, chondromalacia patella, chronic synovitis, chronic recurrent multifocal osteomyelitis, Churg-Strauss syndrome, Cogan syndrome, glucocorticoid-induced osteoporosis, osteosternal syndrome, CREST syndrome, cryoglobulinemia , degenerative joint disease, dermatomyositis, diabetic digital sclerosis, diffuse idiopathic skeletal hyperostosis (DISH), discitis, discoid lupus erythematosus, drug lupus syndrome, muscular

- 85 042028 Duchenne dystrophy, Dupuytren's contracture, Ehlers-Danlos syndrome, enteropathic arthritis, epicondylitis, erosive-inflammatory osteoarthritis, exercise-induced compartment syndrome, Fabry disease, familial Mediterranean fever, Farber's lipogranulomatosis, Felty's syndrome, fifth disease, flat feet, synovitis induced by a foreign body, Freiberg's disease, fungal arthritis, Gaucher's disease, giant cell arteritis, gonococcal arthritis, Goodpasture's syndrome, granulomatous arteritis, hemarthrosis, hemochromatosis, Henoch-Schonlein purpura, hepatitis B surface antigen, hip dysplasia, Hurler's syndrome, hypermobility syndrome , leukocytoclastic vasculitis, hypertrophic osteoarthropathy, immune complex disease, impingement syndrome, Jaccous arthropathy, juvenile ankylosing spondylitis, juvenile dermatomyositis, juvenile rheumatoid arthritis, Kawasaki disease, Kienböck disease, Legg-Calve-Perthes disease, Lesch-Nyhan syndrome, Linein scleroderma, lipoid dermatoarthritis, Löfgren's syndrome, Lyme disease, malignant synovioma, Marfan's syndrome, mediopatellar fold syndrome, metastatic carcinomatous arthritis, mixed connective tissue disease (MCTD), mixed cryoglobulinemia, mucopolysaccharidosis, multiple reticulohistiocytosis, multiple epiphyseal dysplasia, mycoplasmal arthritis, myofascial arthritis pain syndrome, neonatal lupus, neuropathic arthropathy, nodular panniculitis, ochronosis, ulnar bursitis, Osgood-Schlatter disease, osteoarthritis, osteochondromatosis, osteogenesis imperfecta, osteomalacia, osteomyelitis, osteonecrosis, osteoporosis, cross syndrome, pachydermoperiostosis, Paget's disease of the bone, palindromic rheumatism, syndrome patellofemoral pain, Pellegrini-Stied syndrome, pigmented villonodular synovitis, piriformis syndrome, plantar fasciitis, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, popliteal fossa cysts, posterior tibial tendinitis ovary bone, Pott's disease, prepatellar bursitis, prosthetic joint infection, pseudoxanthoma elasticum, psoriatic arthritis, Raynaud's syndrome, reactive arthritis (Reiter's syndrome), reflex sympathetic dystrophy syndrome, relapsing polychondritis, posterior calcaneal bursitis, rheumatic fever, rheumatoid vasculitis, rotator cuff tendonitis shoulder, sacroiliitis, salmonella osteomyelitis, sarcoidosis, lead gout, Scheuermann's osteochondrosis, scleroderma, septic arthritis, seronegative arthritis, shigella arthritis, shoulder-hand syndrome, sickle cell arthropathy, Sjögren's syndrome, epiphysiolysis of the femoral head, spinal stenosis , spondylolysis, staphylococcal arthritis, Stickler's syndrome, subacute cutaneous lupus, Sweet's syndrome, Sydenham's chorea, syphilitic arthritis, systemic lupus erythematosus (SLE), Takayasu's arteritis, tarsal tunnel syndrome, tennis elbow, Tietze's syndrome, transient osteoporosis, traumatic arthritis, acetabular bursi t, tuberculous arthritis, ulcerative colitis arthritis, undifferentiated connective tissue dysplasia syndrome (UCTS), urticarial vasculitis, viral arthritis, Wegener's granulomatosis, Whipple's disease, Wilson's disease, yersinia arthritis, and conditions involving vascularization and/or inflammation, including atherosclerosis, rheumatoid arthritis arthritis (RA), hemangiomas, angiofibromas and psoriasis.

Other non-limiting examples of angiogenic disease are retinopathy of prematurity (retrolental fibroplasia), corneal transplant rejection, corneal neovascularization associated with complications of refractive surgery, corneal neovascularization associated with complications caused by contact lenses, corneal neovascularization associated with pterygium and recurrent pterygium, corneal ulcer disease. and non-specific ocular surface disease, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Crohn's disease, autoimmune nephritis, primary biliary cirrhosis, acute pancreatitis, transplant rejection, allergic inflammation, contact dermatitis and delayed-type hypersensitivity reactions, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, cognitive impairment due to neuronal inflammation, Osler-Weber syndrome, restenosis, and fungal, parasitic, and viral infections, including cytomas egalovirus infections.

Any of the conditions described above as being treatable by inhibition of ROCK1 and/or ROCK2 may be treated with a compound of the invention, or may be treated with a method comprising administering a compound of the invention, or may be treated with a medicament made using a compound of the present invention. In an aspect of the present invention, the compound of the invention may be used in the treatment of: fibrotic diseases, autoimmune, inflammatory-fibrotic conditions, inflammatory conditions, disorders of the central nervous system, or cancer.

In embodiments, a compound of the invention may be used in the treatment of a condition selected from idiopathic pulmonary fibrosis (IPF); systemic sclerosis (SSC); interstitial lung disease (ILD); type 1 and type 2 diabetes; diabetic nephropathy; non-alcoholic steatohepatitis (NASH); non-alcoholic fatty liver disease (NAFLD); arterial hypertension, atherosclerosis, restenosis, stroke, heart failure, coronary spasm, cerebral vasospasm, peripheral circulatory disorders, peripheral arterial occlusive disease, ischemic/reperfusion injury, pulmonary hypertension and angina pectoris, erectile dysfunction, pulmonary fibrosis, liver fibrosis and fibrosis kidneys, glaucoma, intraocular hypertension

- 86 042028 diseases, retinopathy, rheumatoid arthritis, psoriasis, psoriatic arthritis, Sjögren's syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), SLE, cGVHD, inflammatory bowel disease, intestinal stenosis, disorders involving degeneration or physical damage to nerve tissue, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, liver cancer, bladder cancer, hepatoma, lung squamous cell carcinoma, non-small cell lung cancer, lung adenocarcinoma, small cell lung cancer, various types head and neck cancer, breast cancer, colon cancer, colorectal cancer, abdominal cancer, hepatocellular cancer, gastrointestinal cancer, esophageal cancer, endometrial or uterine cancer, salivary gland carcinoma, squamous cell carcinoma, pituitary cancer, astrocytoma, sarcoma soft tissue, pancreatic cancer, glio lastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vaginal cancer, thyroid cancer, hepatocarcinoma, brain cancer, endometrial cancer, testicular cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer and melanoma.

In an aspect of this invention, there is provided a method for treating a condition that is modulated by ROCK1 and/or ROCK2, wherein the method comprises administering a therapeutic amount of a compound of the invention to a patient in need thereof.

The method of treatment may be a method of treating a condition treatable by inhibition of ROCK1 and/or ROCK2.

The invention also provides a method for treating a condition selected from fibrotic diseases, autoimmune, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer, wherein the method comprises administering a therapeutic amount of a compound of any formula disclosed herein to a patient in need thereof. . In embodiments, the method may be used to treat a condition selected from idiopathic pulmonary fibrosis (IPF); systemic sclerosis (SSC); interstitial lung disease (ILD); type 1 and type 2 diabetes; diabetic nephropathy; non-alcoholic steatohepatitis (NASH); non-alcoholic fatty liver disease (NAFLD); arterial hypertension, atherosclerosis, restenosis, stroke, heart failure, coronary spasm, cerebral vasospasm, peripheral circulatory disorders, peripheral arterial occlusive disease, ischemic/reperfusion injury, pulmonary hypertension and angina pectoris, erectile dysfunction, pulmonary fibrosis, liver fibrosis and fibrosis kidney disease, glaucoma, intraocular hypertension, retinopathy, rheumatoid arthritis, psoriasis, psoriatic arthritis, Sjögren's syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), SLE, cGVHD, inflammatory bowel disease, intestinal stenosis, disorders including degeneration or physical damage to nerve tissue, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, liver cancer, bladder cancer, hepatoma, lung squamous cell carcinoma, non-small cell lung cancer, and lung denocarcinoma, small cell lung cancer, various types of head and neck cancer, breast cancer, colon cancer, colorectal cancer, abdominal cancer, hepatocellular cancer, gastrointestinal tract cancer, esophageal cancer, endometrial or uterine cancer, salivary gland carcinoma, squamous cell carcinoma, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vaginal cancer, thyroid cancer, hepatocarcinoma, brain cancer, endometrial cancer, testicular cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer, and melanoma, wherein the method comprises administering a therapeutic amount of a compound of any formula disclosed herein to a patient in need thereof.

In some embodiments, the compounds of the invention are for use in the treatment of, or are used in a method of treating: idiopathic pulmonary fibrosis (IPF); systemic sclerosis (SSC); interstitial lung disease (ILD); type 1 and type 2 diabetes; diabetic nephropathy; non-alcoholic steatohepatitis (NASH); non-alcoholic fatty liver disease (NAFLD); arterial hypertension, atherosclerosis, restenosis, stroke, heart failure, coronary spasm, cerebral vasospasm, peripheral circulatory disorders, peripheral arterial occlusive disease, ischemic/reperfusion injury, pulmonary hypertension and angina pectoris, erectile dysfunction, pulmonary fibrosis, liver fibrosis and fibrosis kidneys. In some embodiments, the compounds of the invention are for use in, or are used in a method of treating: glaucoma, intraocular hypertension, retinopathy, rheumatoid arthritis, psoriasis, psoriatic arthritis, Sjögren's syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), SLE and cGVHD, inflammatory bowel disease and intestinal stenosis.

In some embodiments, the compounds of the invention are for use in the treatment of, or are used in a method of treating disorders of the central nervous system. Such disorders may include degeneration or physical damage to neural tissue, including, but not limited to, Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral

- 87 042028 sclerosis (ALS) or multiple sclerosis.

In some embodiments, the compounds of the invention are for use in the treatment of, or are used in a method of treating, cancer. Examples include, but are not limited to: liver cancer, bladder cancer, hepatoma, squamous cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, small cell lung cancer, various head and neck cancers, breast cancer, colon cancer, colorectal cancer, abdominal cancer, hepatocellular cancer, gastrointestinal cancer, esophageal cancer, endometrial or uterine cancer, salivary gland cancer, squamous cell carcinoma, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vaginal cancer, thyroid cancer, hepatocarcinoma, brain cancer, endometrial cancer, testicular cancer, cholangiocarcinoma, gallbladder carcinoma, stomach cancer and melanoma.

In another aspect of the invention, a pharmaceutical composition is provided, wherein the composition comprises a compound of the invention and pharmaceutically acceptable excipients. In an embodiment, the pharmaceutical composition may be a combination product containing an additional pharmaceutically active agent. The additional pharmaceutically active agent may be one disclosed elsewhere herein. In an aspect of the present invention, the use of a compound of the invention in the manufacture of a medicament for use in the treatment of any of the conditions disclosed herein is provided. In an embodiment, the compounds of the present invention are at least five times more potent inhibitors of ROCK2 compared to ROCK1. Accordingly, the compounds of the invention can be at least five times more selective for ROCK2 than for ROCK1.

The following are definitions of terms used in this application. Any term not defined here has the generally accepted meaning as a person skilled in the art understands this term.

The term halogen refers to one of the group 17 halogens of the periodic table. In particular, this term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to bromine or iodine. The term alkyl refers to a straight or branched hydrocarbon chain. For example, the term C ₁ . ₆ αalkyl refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Alkylene groups may also be linear or branched and may have two attachment sites to the rest of the molecule. In addition, the alkylene group may, for example, be one of those alkyl groups listed in this paragraph. The alkyl and alkylene groups may be unsubstituted or substituted with one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, for example, fluorine, chlorine, bromine and iodine, OH, C ₁ . ₆ alkoxy.

The term alkyl ether refers to a straight or branched hydrocarbon chain with one oxygen atom in it. For example, the term C ₂ _ ₆ alkyl ether refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, where the chain of carbon atoms is interrupted by one oxygen atom, for example, -CH2OCH3, -(CH ₂ ) ₂ OCH ₃ , -(CH ₂ ) ₃ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , -CH ₂ O(CH ₂ ) ₂ CH ₃ or -(CH ₂ ) ₂ OCH ₂ CH ₃ .

The term alkoxy refers to an alkyl group that is attached to a molecule through an oxygen atom. For example, the term C ₁ . ₆ alkoxy refers to a group in which the alkyl portion may be linear or branched and may contain 1, 2, 3, 4, 5 or 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, tert-butyl, n-pentyl and n-hexyl. Therefore, the alkoxy group may be methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentoxy and n-hexoxy. The alkyl portion of the alkoxy group may be unsubstituted or substituted with one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, for example, fluorine, chlorine, bromine and iodine, OH, C ₁ . ₆ alkoxy. The term haloalkyl refers to a hydrocarbon chain substituted with at least one halogen atom, independently selected at each occurrence, for example, fluorine, chlorine, bromine and iodine. For example, the term C ₁ . ₆ haloalkyl refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms substituted with at least one halogen. The halogen atom may be present at any position in the hydrocarbon chain. For example, _C1 . ₆ haloalkyl may be chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, such as 1-chloromethyl and 2-chloroethyl, trichloroethyl, such as 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl, such as 1fluoromethyl and 2- fluoroethyl, trifluoroethyl, for example 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.

The term alkenyl refers to a branched or linear hydrocarbon chain containing at least one double bond. For example, the term C ₂ _ ₆ alkenyl refers to a branched or linear hydrocarbon chain containing at least one double bond and containing 2, 3, 4, 5 or 6 carbon atoms. The double bond(s) may be represented as the E or Z isomer. The double bond can be in any possible position of the hydrocarbon chain. For example, C ₂ _ ₆ alkenyl

- 88 042028 may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl. The term alkynyl refers to a branched or linear hydrocarbon chain containing at least one triple bond. For example, the term C ₂ - ₆ alkynyl refers to a branched or linear hydrocarbon chain containing at least one triple bond and containing 2, 3, 4, 5 or 6 carbon atoms. The triple bond can be in any possible position of the hydrocarbon chain. For example, C ₂ _ ₆ alkynyl can be ethynyl, propynyl, butynyl, pentynyl and hexynyl. The term heteroalkyl refers to a branched or linear hydrocarbon chain containing at least one heteroatom selected from N, O and S located between any carbon atom in the chain or at the end of the chain. For example, the term Cl. ₆ heteroalkyl refers to a branched or linear hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms and at least one heteroatom selected from N, O and S located between any carbon atom in the chain or on end of the chain. For example, the hydrocarbon chain may contain one or two heteroatoms. _C1 . ₆ heteroalkyl can be bonded to the rest of the molecule via a carbon atom or heteroatom. For example, _C1 . ₆ heteroalkyl may be C _1-6 N-alkyl, C _1-6 N,N-alkyl or C _1-6 O-alkyl.

The term carbocyclic refers to a saturated, unsaturated, or aromatic carbon-containing ring system. The carbocyclic system may be a monocyclic or fused polycyclic ring system, eg bicyclic or tricyclic. The carbocyclic fragment may contain from 3 to 14 carbon atoms, for example, from 3 to 8 carbon atoms in a monocyclic system and from 7 to 14 carbon atoms in a polycyclic system. The term carbocyclic includes cycloalkyl moieties, cycloalkenyl moieties, aryl ring systems, and fused ring systems, including an aromatic moiety. The term heterocyclic refers to a saturated, unsaturated, or aromatic ring system containing at least one heteroatom selected from N, O, or S. A heterocyclic system may contain 1, 2, 3, or 4 heteroatoms, such as 1 or 2. Heterocyclic system may be a monocyclic or fused polycyclic ring system, eg bicyclic or tricyclic. The heterocyclic fragment may contain from 3 to 14 carbon atoms, for example, from 3 to 8 carbon atoms in a monocyclic system and from 7 to 14 carbon atoms in a polycyclic system. The term heterocyclic encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties, and heteroaromatic moieties. For example, the heterocyclic group may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran. The term C ₃ - ₈ cycloalkyl refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. For example, C ₃ - ₈ cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term C ₃ _ ₈ cycloalkenyl refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms that is not aromatic. The ring may contain more than one double bond, provided that the ring system is not aromatic. For example, C ₃ _ ₈ cycloalkyl may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl, and cycloatadienyl. The term heterocycloalkyl refers to a saturated hydrocarbon ring system containing carbon atoms and at least one ring heteroatom selected from N, O, and S. For example, 1, 2, or 3 heteroatoms may be present, optionally 1 or 2. Heterocycloalkyl may be bonded to the rest of the molecule through any carbon atom or heteroatom. The heterocycloalkyl may have one or more, for example one or two, bonds to the rest of the molecule: these bonds may pass through any of the atoms in the ring. For example, heterocycloalkyl may be C ₃ _ ₈ heterocycloalkyl. The term C ₃ _ ₈ heterocycloalkyl refers to a saturated hydrocarbon ring system containing at least 3, 4, 5, 6, 7, or 8 atoms, where one of the atoms is a ring heteroatom selected from N, O, and S. Heterocycloalkyl may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine and tetrahydropyran.

The term heterocycloalkenyl refers to an unsaturated hydrocarbon ring system that is not aromatic, containing carbon atoms and at least one ring heteroatom selected from N, O, and S. For example, 1, 2, or 3 heteroatoms may be present, optionally 1 or 2. Heterocycloalkenyl may be linked to the rest of the molecule through any carbon atom or heteroatom. The heterocycloalkenyl may contain one or more, for example one or two, bonds to the rest of the molecule: these bonds may pass through any of the atoms in the ring. For example, heterocycloalkenyl may be C ₃ _ ₈ heterocycloalkenyl. The term C ₃ _ ₈ heterocycloalkenyl refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 atoms, at least one of which is a ring heteroatom selected from N, O, and S. Heterocycloalkenyl can be tetrahydropyridine, dihydropyran, dihydrofuran,

- 89 042028 pyrroline.

The term aromatic, when applied to a substituent as a whole, means a single ring or polycyclic ring system with 4n+2 electrons in a conjugated π system within a ring or ring system where all the atoms involved in the conjugated π system are in the same plane. The term aryl refers to an aromatic hydrocarbon ring system. The ring system contains 4n+2 electrons in a conjugated π system within the ring, where all the atoms involved in the conjugated π system are in the same plane. For example, aryl may be phenyl and naphthyl. The aryl system itself may be substituted with other groups.

The term heteroaryl refers to an aromatic hydrocarbon ring system with at least one heteroatom in one ring or in a fused ring system selected from O, N and S. The ring or ring system has 4n+2 electrons in a conjugated π system where all the atoms participating in the conjugated π-system are in the same plane. For example, heteroaryl can be imidazole, thiene, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, and indole. The term alkaryl refers to an aryl group, as defined above, linked to C ₁ _ ₄ alkyl, where the C ₁ _ ₄ alkyl group provides attachment to the rest of the molecule. Benzyl refers to -CH ₂ phenyl, and benzoyl refers to -C(O)phenyl.

The term alkheteroaryl refers to a heteroaryl group, as defined above, linked to C ₁ _ ₄ alkyl, where the alkyl group provides attachment to the rest of the molecule.

The term halogen as used herein includes F, Cl, Br, and I. Halogen may be Br. The halogen may be I.

A bond ending in ‘ ’ indicates that the bond is linked to another atom that is not shown in the structure. A bond terminating within the ring structure and not terminating at an atom of the ring structure means that the bond may be bonded to any of the atoms in the ring structure, as long as the valence allows it.

The bond indicated by the solid line and the dotted line is a bond that can be either single or double where chemically possible. For example, the bond below could be a single bond or a double bond.

When a fragment is substituted, it may be substituted at any point on the fragment where it is chemically possible and meets the requirements of atomic valency. The fragment may be substituted with one or more substituents, for example 1,2, 3 or 4 substituents; optionally, there are 1 or 2 substituents in the group. Where there are two or more substituents, the substituents may be the same or different. The substituent(s) may be selected from OH, NHR, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(O)H, acyl, acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, nitro, halogen, C ₁ _ ₆ alkyl, C ₁ _ ₆ alkoxy, C ₁ _ ₆ haloalkyl, C ₃ - ₈ cycloalkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, aryl, heteroaryl or alkaryl. If the substituting group is an alkyl group, the substituent may be ═O. R may be selected from H, C ₁ _ ₆ alkyl, C ₃ - ₈ cycloalkyl, phenyl, benzyl or phenethyl, for example R is H or C ₁ _ ₃ alkyl. If a fragment is substituted with two or more substituents and two of the substituents are adjacent, adjacent substituents may form a C ₄ - ₈ ring together with atoms of the fragment on which the substituents are substituted, where the C ₄ - ₈ ring is a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7 or 8 carbon atoms and 1, 2 or 3 heteroatoms.

Substituents are present only at positions where it is chemically possible, and one skilled in the art can easily decide (experimentally or theoretically) which substitutions are chemically possible and which are not.

Ortho, meta and parasubstitution are well understood terms in the art. Without a doubt, ortho substitution is a substitution scheme in which adjacent carbon atoms have a substituent, whether it be a simple group, such as the fluorine group in the example below, or other parts of the molecule, as shown by the bond ending in “ ”

Meta substitution is a substitution scheme in which two substituents are on carbon atoms, with one carbon atom removed from the other, i.e. with one carbon atom between the substituted carbons. In other words, there is a substituent on the second atom from the atom with another substituent. For example, the following groups are meta-substituted.

- 90 042028

n

A substitution pair is a substitution scheme in which two substituents are on carbon atoms, with the two carbon atoms spaced apart, i.e. with two carbons between the substituted carbons. In other words, there is a substituent on the third atom from the atom with another substituent. For example, the following groups are para-substituted.

By the term acyl is meant an organic radical obtained, for example, from an organic acid by removing a hydroxyl group, for example a radical having the formula RC(O)-, where R can be selected from H, C ₁ . ₆ alkyl, C _3-8 cycloalkyl, phenyl, benzyl or phenylethyl, for example R is H or C _1-3 alkyl. In one embodiment, the acyl is an alkylcarbonyl. Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl, and butyryl. A specific acyl group is acetyl.

Throughout the specification, the disclosure of a compound also encompasses pharmaceutically acceptable salts, solvates and stereoisomers thereof. When a compound has a stereocenter, the present invention contemplates both (R) and (S) stereoisomers, equally the present application contemplates mixtures of stereoisomers or a racemic mixture. When a compound of the invention has two or more stereocenters, any combination of (R) and (S) stereoisomers is contemplated. The combination of (R) and (S) stereoisomers may result in a diastereomeric mixture or a single diastereoisomer. The compounds of the present invention may be present as a single stereoisomer or may be mixtures of stereoisomers, eg racemic mixtures and other enantiomeric mixtures, as well as diastereomeric mixtures. When the mixture is a mixture of enantiomers, the enantiomeric excess may be any of those disclosed above. When a compound is a single stereoisomer, the compounds may still contain other diastereoisomers or enantiomers as impurities. Therefore, one stereoisomer does not necessarily have an enantiomeric excess (e.e.) or a diastereomeric excess (d.e.) of 100%, but may have an e.e. or d.e. about at least 85%, at least 60% or less. For example, e.e. or d.e. may be 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, or 10% or more.

The present invention provides pharmaceutically acceptable salts of the compounds of the invention. These may include acid addition salts and base salts of the compounds. They may be acid addition salts and base salts of the compounds. In addition, the invention provides solvates of the compounds. They may be hydrates or other solvated forms of the compound. Suitable acid addition salts are prepared from acids which form non-toxic salts. Examples of salts include acetates, aspartates, benzoates, besylates, bicarbonates/carbonates, bisulfates/sulfates, borates, camsylates, citrates, edisylates, esylates, formates, fumarates, gluceptates, gluconates, glucuronates, hexafluorophosphates, hibenzenes, hydrochlorides/chlorides, hydrobromides/bromides , hydroiodides/iodides, isethionates, lactates, malates, maleates, malonates, mesylates, methyl sulfates, naphthylates, 1,5-naphthalenedisulfonates, 2-napsilates, nicotinates, nitrates, orotates, oxalates, palmitates, pamoates, phosphates/hydrophosphates/dihydrophosphates, sugars , stearates, succinates, tartrates, tosylates and trifluoroacetates.

Suitable base salts are derived from bases which form non-toxic salts. Examples include salts of aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc. Hemi-salts of acids and bases, such as hemisulfate and hemicalcium salts, can also be formed. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of the compounds of formula (I) may be prepared by one or more of three methods:

(i) by reacting a compound of the invention with a specific acid or base;

(ii) by removing an acid or alkaline labile protecting group from a suitable precursor of a compound of the invention, or by ring-opening a suitable cyclic precursor, eg lactone or lactam, using a specified acid or base; or (iii) by converting one salt of a compound of the invention to another by reaction with a suitable acid or base, or by using a suitable ion exchange column.

All three reactions are generally carried out in solution. The resulting salt may precipitate and be collected by filtration, or may be isolated by evaporating the solvent. The degree of ionization of the resulting salt can vary from fully ionized to almost non-ionized.

- 91 042028 no.

The compounds of the invention may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term hydrate is used when said solvent is water.

Included within the scope of the invention are complexes such as clathrates, drug-excipient inclusion complexes of the guest-host type, where, unlike the aforementioned solvates, the drug and excipient are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes containing two or more organic and/or inorganic components, which may be present in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

Hereinafter, all references to compounds of any formula include references to their salts, solvates and complexes, as well as solvates and complexes of their salts.

Compounds of the invention include compounds of a number of formulas as defined herein, including all of their polymorphs and crystalline forms, their prodrugs and isomers (including optical, geometric and tautomeric isomers) as defined below, and isotopically labeled compounds of the invention.

The present invention also includes all pharmaceutically acceptable isotopically labeled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as ² H and ³ H, carbon such as 11 C, ¹³ C and ¹⁴ C, chlorine such as ³⁶ Cl, fluorine such as ¹⁸ F, iodine , such as ¹²³ I and ¹²⁵ I, nitrogen, such as ¹³ N and ¹⁵ N, oxygen, such as ¹⁵ O, ¹⁷ O, and ¹⁸ O, phosphorus, such as ³² P, and sulfur, such as ³⁵ S.

Certain isotopically labeled compounds, such as those containing a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.

Radioactive isotopes of tritium, i.e. ³ H and carbon-14, i.e. ¹⁴ C are particularly useful for this purpose due to their ease of incorporation and easy detection methods.

Replacement with heavier isotopes such as deuterium, i.e. ² H may confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be considered preferable in some circumstances.

Prior to purification, the compounds of the present invention may exist as a mixture of enantiomers, depending on the synthesis method used. Enantiomers may be separated by conventional methods known in the art. Thus, the invention covers individual enantiomers as well as mixtures thereof.

At some steps in the process for preparing the compounds of the invention, it may be necessary to protect potential reactive functional groups that are not desirable to be reacted, and therefore to cleave said protecting groups. In such a case, any compatible protecting radical may be used. In particular methods of protection and deprotection, the radicals described in T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994). All of the above reactions and procedures for preparing new starting materials used in the previous methods are generally accepted, and suitable reagents and reaction conditions for their implementation or preparation, as well as methods for separating the target products will be well known to specialists in this field of technology with reference to analogues in publications. and examples and getting them. In addition, the compounds of the present invention, as well as intermediates for their preparation, can be purified according to various well-known methods such as, for example, crystallization or chromatography.

One or more compounds of the invention may be combined with one or more pharmaceutical agents, e.g., anti-inflammatory agents, anti-fibrotic agents, chemotherapeutic agents, anti-cancer agents, immunosuppressants, anti-tumor vaccines, cytokine therapy, or tyrosine kinase inhibitors, to treat conditions modulated by ROCK inhibition, e.g. , fibrotic diseases, autoimmune, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer.

A method of treatment or compound for use in the treatment of fibrotic diseases, autoimmune, inflammatory fibrotic conditions, inflammatory conditions, disorders of the central nervous system or cancer, as defined above, can be used as the sole therapy or

- 92 042028 is a combination therapy with an additional active agent.

A method of treatment or a compound for use in the treatment of fibrotic diseases, autoimmune, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders may include additional active agents in addition to the compound of the invention. Additional active agents may be one or more active agents used to treat the condition to be treated with the compound of the invention and the additional active agent. Additional active agents may include one or more of the following active agents:

(i) steroids, such as corticosteroids, including glucocorticoids and mineralocorticoids, e.g., alklomethasone, alklomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetazothirate, propionate, cloprednol, cortisone, cortisone acetate, cortizol, deoxycortone, desonide, deoxymethasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolon, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortone butyl, fluorocortolone butyl, fluorocortolone butyl, , fluocortolone pivalate, fluorometholone, flupredniden, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone, enbutate prednisone, methylprednisolone, mometasone, paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, thixocortol, thixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, such as a combination of two or more of the steroids mentioned in this paragraph;

(ii) TNF inhibitors, eg etanercept; monoclonal antibodies (eg, infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)); fusion proteins (eg, etanercept (Enbrel)); and 5-HT2A agonists (eg, 2,5-dimethoxy-4-iodomamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide);

(iii) anti-inflammatory drugs, such as non-steroidal anti-inflammatory drugs;

(iv) dihydrofolate reductase inhibitors/antifolates, eg methotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim, pemetrexed, ralitrexed and pralatrexate; and (v) immunosuppressants, e.g., cyclosporins, tacrolimus, sirolimus, pimecrolimus, angiotensin II receptor inhibitors (e.g., valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan, candesartan, eprosartan) and ACE inhibitors, e.g., sulfhydryl-containing agents (e.g., captopril, zofenopril), dicarboxylate-containing agents (eg, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, zofenopril, trandolapril), phosphate-containing agents (eg, fosinopril), casokinins, lactokinins, and lactotripeptides; (vi) antifibrotic agents, eg pirfenidone, nintedanib, anti-IL-13 monoclonal antibodies (eg tralokinumab, QAX576, lebrikizumab), simtuzumab, FG-3019, lysophosphatidic acid receptor antagonists (eg BMS-986020, AM966), LOXL2 inhibitors, BET bromodomain inhibitors (eg, JQ1), HDAC inhibitors (eg, vorinostat), thrombin inhibitors (eg, dabigatran), factor Xa inhibitors (eg, apixaban, rivaroxaban), 15-PGDH inhibitors, anti-αvβ6 monoclonal antibodies (eg, BG00011 ), anti-CTGG monoclonal antibodies (eg, FG-3019), PARP1 inhibitors, NOX4 inhibitors, and PAI-1 inhibitors.

(vii) for CNS therapy, eg levodopa, dopamine agonists, apomorphine, glutamate antagonist, anticholinergics, COMT inhibitors, MAO-B inhibitors, riluzole (Rilutek), tetrabenazine (Xenazine), haloperidol (Haldol), chlorpromazine, risperidone (Risperdal) , quetiapine (Seroquel), amantadine, levetiracetam (Keppra), clonazepam (Klonopin), donepezil (Aricept), galantamine (Razadyne), rivastigmine (Exelon), memantine (Ebixa, Axura), aducanumab, ocrelizumab, interferon beta-1a (Avonex , Rebif), peginterferon beta-1a (Plegridy), teriflunomide (Aubagio), fingolimod (Gilenya), mitoxantrone (Novantrone), dimethyl fumarate (Tecfidera), natalizumab (Tysabri);

A method of treatment or a compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, hematological tumors, lymphoma, carcinoma, leukemia and disorders of the central nervous system may include, in addition to the compound of the invention, standard surgical practices, or methods of radiation therapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anticancer agents:

(i) antiproliferative/antineoplastic drugs and combinations thereof, such as alkylating agents (e.g. cisplatin, oxaliplatin, carboplatin, cyclophosphamide, mustargen, uramustine, bendamustine, melphalan, chlorambucil, chlormethine, busulfan, temozolomide, nitrosoureas, ifosamide, pipobroman, triethylene -melamine, triethylenethiophoporamine, carmustine, lomustine, streptozocin and dacarbazine); antimetabolites (eg gemcitabine) and antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexide, methotrexate, pemetrexed, cytosine arabinoside,

- 93 042028 floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, gemcitabine and hydroxyurea); antibiotics (eg anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (eg vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxoids such as taxol, taxotere and polokinase inhibitors); proteasome inhibitors such as carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (eg epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, mitoxantrone and camptothecin); bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol™), nab-paclitaxel, docetaxel, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (especially IFN-α), etoposide and teniposide;

(ii) cytostatic agents such as antiestrogen (eg, tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifene), antiandrogens (eg, bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists, or LHRH agonists (eg, goserelin, leuprorelin and buserelin), progestogens (eg megestrol acetate), aromatase inhibitors (eg anastrozole, letrozole, vorazole and exemestane) and 5a-reductase inhibitors such as finasteride; and navelbine, CPT-11, anastrozole, letrozole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine;

(iii) anti-invasive agents, eg dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, or anti-heparanase antibodies;

(iv) inhibitors of growth factor function, for example, such inhibitors, including antibodies to growth factor and antibodies to growth factor receptor, for example, anti-erbB2 antibody trastuzumab [Herceptin™], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, for example , epidermal growth factor family inhibitors (e.g. EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib, 6-acrylamido-N(3-chloro-4fluorophenyl)-7-(3-morpholinopropoxy)-quinazoline-4-amine (CI 1033) , erbB2 tyrosine kinase inhibitors such as lapatinib) and antibodies to costimulatory molecules such as CTLA-4,4-1BB and PD-1 or antibodies to cytokines (IL-10, TGF-beta); hepatocyte growth factor family inhibitors; inhibitors of the family of insulin-like growth factors; modulators of protein regulators of cell apoptosis (eg Bcl-2 inhibitors); platelet growth factor family inhibitors such as imatinib and/or nilotinib (AMN107); serine-threonine kinase inhibitors (eg, Ras/Raf signaling inhibitors, such as farnesyl transferase inhibitors, eg, sorafenib, tipifarnib, and lonafarnib), MEK and/or AKT kinase inhibitors, c-kit inhibitors, ab1- kinases, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor kinase inhibitors; aurorakinase inhibitors and cyclin-dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors; and a CCR2, CCR4, or CCR6 modulator;

(v) anti-angiogenic agents that inhibit the actions of vascular endothelial growth factor, for example, an antibody against vascular endothelial cell growth factor - bevacizumab (Avastin™); thalidomide; lenalidomide; and, for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib, and pazopanib;

(vi) gene therapy approaches, including, for example, approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2;

(vii) immunotherapeutic approaches, including, for example, antibody therapy such as alemtuzumab, rituximab, ibritumomab, tiuxetan (Zevalin®) and ofatumumab; interferons such as interferon a; interleukins such as IL-2 (aldesleukin); interleukin inhibitors, for example IRAK4 inhibitors; cancer vaccines, including prophylactic and therapeutic vaccines such as HPV vaccines such as Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); gp100; dendritic cell vaccines (such as Ad.p53 DC); and toll-like receptor modulators, for example TLR-7 or TLR-9 agonists; and (viii) cytotoxic agents, eg fludaribine (fludara), cladribine, pentostatin (Nipent™);

(ix) steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, eg alklomethasone, alklomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasolate, clobetasone, propionate, cloprednol, cortisone, cortisone acetate, cortizol, deoxycortone, desonide, deoxymethasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolon, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortone butyl, fluorocortolone butyl, fluorocortolone butyl, , fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate eprednisone, methylprednisolone, mometasone, paramethasone,

- 94 042028 mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, thixocortol, thixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, such as a combination of two or more of the steroids mentioned in this paragraph;

(x) targeted therapies, for example, including PI3Kd inhibitors, for example, idelalisib and perifosine; PD-1, PD-L1, PD-L2 and CTL4-A modulators, antibodies and vaccines; other IDO inhibitors (such as indoxymod); monoclonal antibodies against PD-1 (such as MK-3475 and nivolumab); monoclonal antibodies against PD-L1 (such as MEDI-4736 and RG-7446); monoclonal antibodies against PD-L2; and anti-CTLA-4 antibodies (such as ipilimumab);

(xi) chimeric antigen receptors, cancer vaccines and arginase inhibitors.

Such combined treatment can be achieved by the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products use the compounds of the present invention in the therapeutically effective dosage range described above and the other pharmaceutically active agent within its approved dosage range. The compounds of the invention may exist in single crystal form or as a mixture of crystalline forms, or they may be amorphous. Thus, compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They can be obtained, for example, in the form of solid compacted masses, powders or films by methods such as precipitation, crystallization, freeze drying, spray drying or evaporation drying. Microwave or RF drying can be used for this purpose.

For the aforementioned compounds of the invention, the dose administered will, of course, vary depending on the compound used, the route of administration, the preferred mode of treatment, and the disorder in question. For example, if the compound of the invention is administered orally, the daily dose of the compound of the invention may be from 0.01 micrograms per kilogram of body weight (μg/kg) to 100 milligrams per kilogram of body weight (mg/kg).

A compound of the invention, or a pharmaceutically acceptable salt thereof, may be used alone, but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or a pharmaceutically acceptable salt thereof, are in combination with a pharmaceutically acceptable adjuvant, diluent, or carrier. Conventional techniques for selecting and preparing suitable pharmaceutical formulations are described, for example, in Pharmaceuticals - The Science of Dosage Form Designs, M. E. Aulton, Churchill Livingstone, 1988.

Depending on the route of administration of the compounds of the invention, the pharmaceutical composition which is used to administer the compounds of the invention will preferably contain from 0.05 to 99 wt.% (percentage by mass) of the compounds of the invention, more preferably from 0.05 to 80 wt.% compounds of the invention, even more preferably from 0.10 to 70 wt.% of the compounds of the invention, and even more preferably from 0.10 to 50 wt.% of the compounds of the invention, with all weight percent based on the total weight of the composition.

Pharmaceutical compositions may be administered topically (eg, to the skin) in the form of, for example, creams, gels, lotions, solutions, suspensions, or systemically, for example, by oral administration in the form of tablets, capsules, syrups, powders, or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.

For oral administration, the compounds of the invention may be mixed with an adjuvant or carrier, eg lactose, sucrose, sorbitol, mannitol; starch, for example potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatin or polyvinylpyrrolidone; and/or a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin and the like, and then compressed into tablets. If coated tablets are required, the tablet cores prepared as described above may be coated with a concentrated sugar solution which may contain, for example, acacia gum, gelatin, talc and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a highly volatile organic solvent.

To prepare soft gelatin capsules, the compounds of the invention may be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound using the above-mentioned tablet excipients. Also, liquid or semi-solid formulations of a compound of the invention may be presented in hard gelatin capsules. Liquid oral preparations may be in the form of syrups or suspensions, for example solutions containing a compound of the invention in combination with sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain colors, flavors, sweeteners (such as saccharin), preservatives and/or carboxymethyl cellulose as a thickening agent, or other adjuvants known to those skilled in the art.

- 95 042028 of this area. For intravenous (parenteral) administration, the compounds of the invention may be administered as a sterile aqueous or oily solution.

The dosage size of the compounds of the invention for therapeutic purposes will, of course, vary with the nature and severity of the conditions, the age and sex of the animal or patient, and the route of administration, in accordance with known principles of medicine.

It is expected that dosage levels, frequency of administration and duration of treatment with the compounds of the invention will vary depending on the composition and clinical indications, age and comorbidities of the patient.

Examples and synthesis

The terms used herein have the following meanings: Boc is tert-butoxycarbonyl; dba is dibenzylideneacetone; DCE stands for 1,2-dichloroethane; DCM is dichloromethane; DIPEA stands for N,N-diisopropylethylamine; DMAP is 4-(dimethylamino)pyridine; DMF is N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; dppf is 1,1'-bis(diphenylphosphino)ferrocene; EDC stands for N-(3-dimethylaminopropyl)-N'ethylcarbodiimide; EtOAc is ethyl acetate; HATU is 1-[bis(dimethylamino)methylene]1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HOBt is 1hydroxybenzotriazole, hydrate; HPLC stands for High Performance Liquid Chromatography; IPA stands for 2-propanol; LC-MS stands for liquid chromatography/mass spectrometry; LiHMDS is lithium bis(trimethylsilyl)amide; MHM stands for monoisotopic mass; min denotes a minute; Pet. Ether stands for petroleum ether; PG is a protecting group; PTSA stands for p-toluenesulfonic acid, monohydrate; TLC stands for thin layer chromatography; Rf is the chromatographic mobility index; RT stands for retention time; r.t. denotes room temperature; SCX stands for strong cation exchanger; SEM is 2-(trimethylsilyl)ethoxymethyl; TBME is tert-butyl methyl ether; TEA stands for triethylamine; TFA stands for trifluoroacetic acid; THF stands for tetrahydrofuran and THP stands for tetrahydropyran.

Solvents, reagents, and starting materials were purchased from commercial suppliers and used as received unless otherwise noted. All reactions were carried out at room temperature unless otherwise noted.

The characterization and purity of the compound was verified by UV LC-MS using a Waters Acquity SQ Detector 2 (ACQ-SQD2#LCA081). The diode array detector wavelength was 254 nm and the MS was in positive and negative electrospray mode (m/z: 150-800). A 2 µl aliquot was injected into the pre-column (0.2 µm x 2 mm filters) and UHPLC column (C18, 50 x 2.1 mm, < 2 µm) in sequence maintained at 40°C. Samples were eluted at a flow rate of 0.6 ml/min with a mobile phase system consisting of A (0.1% (v/v) formic acid in water) and B (0.1% (v/v) formic acid in acetonitrile) according to the gradients shown in Table 1. . 1 below. RT retention times are in minutes.

Table 1

Method A: short acid Time (min) %A %IN 0 95 5 0.3 95 5 2 5 95 2.6 95 5 3 95 5 Method B: long acid Time (min) %A %IN 0 95 5 1.1 95 5 6.1 5 95 7 5 95 7.5 95 5 8 95 5

Compound characterization was also performed by UV LC-MS using Waters Alliance 2695 micromass ZQ (K98SM4 512M-LAA434). The diode array detector wavelength was 254 nm and the MS was in positive and negative electrospray mode (m/z: 150-650). An aliquot of 10 µl was injected into an HPLC column (C18, 75x4.6 mm, 2.5 µm) at room temperature, which was controlled at 19°C. Samples were eluted at a flow rate of 0.9 ml/min with a mobile phase system consisting of A (0.1% (v/v) formic acid in 95:5 (v/v)

- 96 042028 water: acetonitrile) and B (0.1% (v/v) formic acid in 95:5 (v/v) acetonitrile: water) according to the gradients shown in Table. 2 below. RT retention times are in minutes.

table 2

Method C (5 minute acid) Time (min) %A %IN %WITH %D 0 90 5 5 0 4.0 0 95 5 0 4.49 0 95 5 0 4.5 95 5 0 0 Method D (7 Minute Acid) Time (min) %A %IN %WITH %D 0 90 5 5 0 0.5 90 5 5 0 5.0 0 95 5 0 5.49 0 95 5 0 6.0 90 10 0 0 7.0 90 10 0 0 Method E (15 minute acid) Time (min) %A %IN %With %D 0 95 0 5 0 2.0 95 0 5 0 12.0 0 95 5 0 14.0 0 95 5 0 14.1 95 0 5 0

Compound characterization was also performed by UV LC-MS using the following.

1. LC: Agilent Technologies 1290 series, binary pump, diode array detector, Agilent Poroshell 120 EC-C18 column, 2.7 µm, 4.6x50 mm. Mobile phase: A: 0.05% formic acid in water (v/v), B: 0.05% formic acid in MeCN (v/v). Flow rate: 1 ml/min at 25°C. Detector: 214 nm, 254 nm. Stop time - 5 min.

2. MS: G6120A, Quadrupole LC-MS, Ion source: API-ES, TIC: 70 ~ 1000 m/z, Fragmenter: 70, Drying gas flow: 12 L/min, Atomizer pressure: 36 psi ), drying gas temperature: 350°C, Vcap: 3000 V.

3. Sample preparation: Samples were dissolved in methanol at 1~10µg/mL, then filtered through a 0.22µm filter membrane. Injection volume: 1~10µl.______

Method F Time(min) %A %IN 0.00 90 10 0.50 90 10 4.00 10 90 4.50 0 100 4.51 90 10 5.00 90 10

NMR was also used to characterize the final compounds. 1H NMR spectra were obtained at room temperature, unless otherwise noted, on Bruker AVI 500 instruments with either 5 mm Dual or 5 mm QNP Z-gradient probe, Bruker DRX500 with 5 mm QNP Z-gradient probe or Bruker AVIII400 Nanobay with 5mm BBFO transducer. Chemical shifts are given in ppm (millionths

- 97 042028 parts) and refer to either TMS (0.00 ppm), DMSO-d6 (2.50 ppm), CDC13 (7.26 ppm), or MeOD-d4 (3.31 ppm). The NH or OH signals that are exchanged with the deuterated solvent are not reported. Optionally, the Rf values of the compound were measured on TLC plates with a layer of silica gel. The compound was purified by flash silica column chromatography or preparative LC-MS. Purification by LC-MS was performed using a Waters 3100 mass detector in positive and negative electrospray mode (m/z. 150-800) with a Waters 2489 UV/Vis detector. Samples were eluted at a flow rate of 20 ml/min on a preparative XBridge™ C18 5 µM OBD 19x100 mm column with a mobile phase system consisting of A (0.1% (v/v) formic acid in water) and B (0.1% (v/v) ./about.) formic acid in acetonitrile) in accordance with the gradient indicated in table. 3 below.

Table 3

Time (min) %A %IN 0 90 10 1.5 90 10 11.7 5 95 13.7 5 95 14 90 90 15 90 90

Intermediate 1: 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole

3.4 -dihydro-2H-pyran (0.25 ml, 2.75 mmol), and the reaction mixture was stirred at room temperature for 18 h. Solvents were removed under reduced pressure, and the remaining solid was taken up in EtOAc (25 ml) and washed with saturated aqueous NaHCO ₃ (2x20 ml). The aqueous layer was extracted with EtOAc (2x20 ml). The combined organic extracts were dried (phase separator) and concentrated. The crude material was purified by flash column chromatography (SiO ₂ ) eluting with 20-55% EtOAc in petroleum ether to give 3,5-dibromo-1-tetrahydropyran-2-yl-1,2,4-triazole (753 mg , 2.42 mmol, 97% yield) as a white solid. LC-MS (ES+, Method C): 2.73 min, m/z 311.8 [M+H] ⁺ .

1H NMR (500 MHz, DMSO-d6): δ 5.47 (dd, J=9.0, 3.0 Hz, 1H), 4.02-4.09 (m, 1H), 3.66-3.71 (m, 1H), 2.28-2.39 (m, 1H), 2.10-2.19 (m, 1H), 1.92-1.96 (m, 1H), 1.62-1.77 (m, 3H).

Intermediate 2: 2-[(3,5-dibromo-1,2,4-triazol-1-yl)methoxy]ethyltrimethylsilane

A solution of 3,5-dibromo-4H-1,2,4-triazole ( 454 mg, 2.00 mmol) in THF (4.5 ml) and the mixture was stirred at 0°C for 30 min. 2(trimethylsilyl)ethoxymethyl chloride (0.42 ml, 2.40 mmol) was added dropwise, the cooling bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction was stopped by adding water (10 ml) and was extracted with EtOAc (3x15 ml). The combined organics were dried (phase separator) and concentrated to give 2-[(3,5-dibromo-1,2,4-triazol-1yl)methoxy]ethyl-trimethyl-silane (663 mg, 1.86 mmol, 93% yield) as a colorless oil. LC-MS (ES ⁺ , Method C): 3.66 min, m/z 357.9 [M+H] ⁺ .

1H NMR (500 MHz, CDCl3): δ 5.45 (s, 2H), 3.70-3.65 (m, 2H), 0.96-0.91 (m, 2H), 0.00 (s, 9H).

General method for the synthesis of intermediates 3 and 4:

Br^Y^x^Br R4, base \ /G -------------------* \ //

HN-N DMF, r.t. N-N

R

Intermediate 3: 3,5-dibromo-1-methyl-1,2,4-triazole

- 98 042028

Iodomethane (3.02 ml, 48.5 mmol) of one portion. This caused a strong exothermic effect from 17°C to 38°C after one minute. The reaction mixture was stirred overnight, diluted with 150 ml EtOAc and then filtered to remove most of the inorganic substances. The solvent was removed under reduced pressure, the resulting yellow oily solid was partitioned between EtOAc (250 ml) and water (100 ml) and the aqueous layers were washed with EtOAc (150 ml). The combined organics were washed with brine (50 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo to give 3,5-dibromo-1-methyl-1,2,4-triazole (6.2 g, 25.8 mmol, 58% yield) as a yellow solid. UPLC-MS (ES+, Method A): 1.79 min, m/z 241.7 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.83 (3H).

Intermediate 4: 3,5-dibromo-1-isopropyl-1,2,4-triazole

Sodium hydride (172 mg, 4.30 mmol) was added to a solution of 3,5-dibromo-1H-1,2,4-triazole (750 mg, 3.31 mmol) in DMF (12 mL). The reaction mixture was stirred at 40°C for 30 min. After the formation of the sodium salt, 2-iodopropane (0.40 ml, 3.97 mmol) was added. The reaction mixture was diluted with water (120 ml) and extracted with diethyl ether.

The aqueous layers were extracted twice with additional diethyl ether and the combined organic layers were dried over MgSO ₄ . The solvents were then removed under vacuum to give 3,5dibromo-1-isopropyl-1,2,4-triazole (631 mg, 2.23 mmol, 67% yield).

1H NMR (400 MHz, DMSO-d6) δ 4.68 (hept, J=6.6 Hz, 1H), 1.39 (d, J=6.6 Hz, 6H).

Intermediate 5: 3,5-dibromo-1-phenyl-1,2,4-triazole

3,5-Dibromo-1Н-1,2,4-triazole (419 mg, 1.85 mmol) was added to a solution of phenylboronic acid (300 mg, 2.46 mmol), pyridine (0.2 ml, 2.46 mmol), copper(II) acetate ( 335 mg, 1.85 mmol) and 3A molecular sieves in dry DCM (8 ml) and stirred at 25° C. overnight. After completion of the reaction, controlled by LC-MS, a saturated solution of NH ₄ Cl (20 ml) was added to the reaction mixture, then washed with water, and the organic layers were combined and concentrated. The crude material was purified by flash column chromatography eluting with 15-50% EtOAc in petroleum ether to give 3,5-dibromo-1-phenyl-1,2,4-triazole (454 mg, 1.50 mmol, 60% yield) . LC-MS (ES ⁺ , Method A): 1.74 min, m/z 304.0 [M+H] ⁺ .

Intermediate 6: 3,5-dibromo-1-(2-fluorophenyl)-1,2,4-triazole

Suspension of 3,5-dibromo-4H-1,2,4-triazole (453.7 mg, 2 mmol), 2-fluorophenylboronic acid (420 mg, 3 mmol), copper (II) acetate (363 mg, 2 mmol), carbonate sodium (318 mg, 3 mmol) and pyridine (0.24 ml, 3 mmol) in toluene (2 ml) were heated at 70°C overnight. The reaction mixture was cooled to room temperature and filtered through a pad of celite (eluting with EtOAc). The filtrate was washed with saturated aqueous NH ₄ Cl (15 ml) and water (10 ml), dried and concentrated. The crude material was purified by flash column chromatography (SiO ₂ ) eluting with 20-50% EtOAc in petroleum ether to give 3,5-dibromo-4-(2-fluorophenyl)-1,2,4-triazole (98 mg , 0.31 mmol, 15% yield) as a colorless oil which crystallized on standing. The regioisomer was confirmed by the DEPT/QUAT experiment (undistorted enhancement by polarization transfer). LC-MS (ES ⁺ , Method D): 5.61 min, m/z 321.7 [M+H] ⁺ .

1H NMR (400 MHz, CDC13): δ 7.57 (m, 1H), 7.46 (m, 1H), 7.36-7.32 (m, 1H), 7.32-7.28 (m, 1H).

Intermediate 7: 2-(3,5-dibromo-1,2,4-triazol-4-yl)pyridine

ABOUT

II 7 ^-Br

N-n

3 5-dibromo-4H-1,2,4-triazole (0.08 ml, 2.20

- 99 042028 mmol) in one portion, and the reaction mixture was stirred at 25°C during the night. The reaction mixture was cooled to room temperature and the solvents were removed under reduced pressure. The residue was dissolved in EtOAc (15 ml) and washed with H ₂ O (15 ml). The aqueous layer was extracted with EtOAc (2x15 ml) and the combined organics were washed with brine, dried (phase separator) and concentrated. The crude material was purified by column chromatography (SiO ₂ ) eluting with 30-60% EtOAc in petroleum ether to give 2-(3,5-dibromo-1,2,4-triazol-4-yl)pyridine (285 mg, 0.94 mmol, 43% yield). UPLC-MS (ES ⁺ , Method A): 1.53 min, m/z 304.9 [M+H] ⁺ .

Intermediate 8: 2-(3,5-dibromo-1,2,4-triazol-1-yl)pyridine and intermediate 9:4-(3,5-dibromo-1,2,4-triazol-1 - yl) pyridine

3, 5-dibromo-1H-1,2,4-triazole (0.08 ml, 11.02 mmol) in one portion, and the reaction mixture was stirred at 25° C. overnight. The solvents were removed under vacuum and the residue was partitioned between 50 ml DCM and 35 ml water, passed through a phase separator cartridge, and concentrated under vacuum. The crude material was purified by column chromatography (SiO2) eluting with 10-60% EtOAc in petroleum ether to give 2-(3,5-dibromo-1,2,4-triazol-1-yl)pyridine (1.95 g, 6.4 mmol, 58% yield) as a white crystalline solid.

Intermediate 8: UPLC-MS (ES ⁺ , Method A): 1.53 min, m/z 304.9 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.66 (ddd, J=4.7, 1.9, 0.8 Hz, 1H), 8.15 (td, J=7.8, 1.9 Hz, 1H), 7.82 (dt, J=8.1, 1.0 Hz, 1H), 7.66 (ddd, J=7.5, 4.9, 1.0 Hz, 1H).

Structure confirmed by DEPT NMR. The second compound was isolated to give 4-(3,5-dibromo-1,2,4-triazol-1-yl)pyridine (120 mg, 0.40 mmol, 3.6% yield).

Intermediate 9: UPLC-MS (ES ⁺ , Method A): 1.33 min, m/z 304.9 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ 8.93-8.80 (m, 2H), 7.82-7.74 (m, 2H).

Structure confirmed by DEPT NMR.

Intermediate 10: 5-bromo-1-tetrahydropyran-2-yl-indazole

To a stirred solution of 5-bromomindazole (394 mg, 2.0 mmol) in anhydrous DCM (4.0 mL) was added 3,4-dihydro-2H-pyran (0.36 mL, 4.0 mmol) and PTSA (190 mg, 1.0 mmol), and the reaction mixture stirred at room temperature for 3 hours, the Reaction was stopped with saturated aqueous NaHCO ₃ (10 ml) and diluted with DCM (20 ml). The layers were separated and the aqueous portion was extracted with DCM (15 ml).

The combined organics were dried (phase separator) and concentrated and the crude material was purified by flash column chromatography (SiO ₂ eluting with 5-15% EtOAc in petroleum ether) to give 5-bromo-1-tetrahydropyran-2-yl-indazole (427 mg, 1.43 mmol, 71% yield) as an orange oil. LC-MS (ES+, Method C): 3.37 min, m/z 282.0 [M+H] ⁺ .

Intermediate 11: 5-isothiocyanato-1-tetrahydropyran-2-yl-indazole

N,N'-Thiocarboniddiimidazole (164 mg, 0.92 mmol) was added to a stirred solution of 1(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (200 mg, 0.92 mmol) in DCM (5 ml) , and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (10 ml), the layers were separated, and the aqueous part was extracted with DCM (2x10 ml). The combined organics were washed with brine (10 ml), dried (phase separator) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO ₂ ) eluting with 45-75% EtOAc in petroleum ether to give 5-isothiocyanato-1-tetrahydropyran-2-ylindazole (143 mg, 0.55 mmol, 60% yield) as orange oil. LC-MS (ES ⁺ , Method C): 3.62 min, m/z 260.0 [M+H] ⁺ .

1H NMR (500 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.86-7.82 (m, 1H), 7.50 (dd, J=9.0, 2.0 Hz , 1H), 5.90 (dd, J=9.5, 2.5 Hz, 1H), 3.89 (m, 1H), 3.82-3.69 (m, 1H), 2.43-2.34 (m, 1H), 2.01 (m, 2H), 1.83-1.71 (m, 1H), 1.60 (m, 2H).

- 100 042028

Method for the synthesis of intermediate 12:

Stage 1: 4-methyl-5-nitro-1-tetrahydropyran-2-yl-indazole /Α/ΝΟ ₂ ό

A suspension of 4-methyl-5-nitro-1H-indazole (1.00 g, 5.64 mmol) in DCM (10 mL) was treated with 3,4dihydro-2H-pyran (1.55 mL, 16.93 mmol) and PTSA (107 mg, 0.56 mmol). After 16 hours, LC-MS showed complete conversion. The reaction mixture was diluted with saturated aqueous NaHCO ₃ and extracted three times with DCM. The combined organic layers were passed through a phase separator and concentrated in vacuo. Purification by flash column chromatography (80 g SiO ₂ , EtOAc/heptane - 10% to 30%) gave 4-methyl-5-nitro-1-tetrahydropyran-2-yl-indazole (1.42 g, 5.45 mmol, 97 % yield) as an orange amorphous solid. UPLC-MS (ES+, Method A): 1.80 min, m/z 262.1 [M+H] ⁺ .

Intermediate 12: 4-methyl-1-tetrahydropyran-2-yl-indazol-5-amine __1lH ₂ ν χζ b

A solution of 4-methyl-5-nitro-1-tetrahydropyran-2-yl-indazole (1.42 g, 5.45 mmol), EtOH (20 ml), THF (20 ml) and water (5 ml) was treated with iron (3.65 g, 65.44 mmol) and ammonium chloride (3.50 g, 65.44 mmol). The reaction mixture was heated to 60°C. After 1 h, LC-MS showed a slow conversion, and the reaction mixture was heated to 90°C. After 4 hours, LC-MS showed no starting material. The reaction mixture was diluted with saturated aqueous NaHCO ₃ and extracted five times with DCM. The combined organic layers were passed through a phase separator and concentrated in vacuo to give 4-methyl-1-tetrahydropyran-2-yl-indazol-5-amine (1.25 g, 5.45 mmol, 100% yield) as an amorphous solid. UPLC-MS (ES ⁺ , Method A): 1.06 min, m/z 232.2 [M+H] ⁺ .

Intermediate 13: 1-tetrahydropyran-2-yl-indazol-5-amine:

b

A solution of 5-nitro-1-tetrahydropyran-2-yl-indazole (72 g, 291.2 mmol) in EtOAc (750 ml) was evacuated and purged with nitrogen several times, palladium was added, 10 wt% on a powdered carbon carrier, 50% humidity ( 3.83 g, 18 mmol), and pumping/flushing was repeated, after which the mixture was placed in a hydrogen atmosphere with maximum vigorous stirring with a stirrer. The exothermic reaction continued for a long period (~2 h). After 3 hours the mixture was filtered to remove Pd/C and washed thoroughly with ethyl acetate. The solution was evaporated in vacuo to give a white solid which was triturated with 1:1 petroleum ether/diethyl ether and filtered, finally rinsing with petroleum ether and drying to give 1-tetrahydropyran-2-ylindazole-5-amine (58.9 g, 271.1 mmol, 93% yield) as a white solid. LC-MS (ES ⁺ , Method C): 1.14 min, m/z 218.1 [M+H] ⁺ .

Stage 1: 5-nitro-1-tetrahydropyran-2-yl-indazole

To a suspension of 5-nitroindazole (100 g, 613.0 mmol) in DCM (1200 ml) was added p-toluenesulfonic acid, monohydrate (11.7 g, 61.3 mmol) and the solution was stirred at 25°C. 3,4 Dihydro-2H-pyran (168 mL, 1839 mmol) was then slowly added to the reactor at 20° C. and the reaction mixture slowly turned into a dark brown solution. After the addition, the reaction mixture was stirred at 25° C. for 1 h. The mixture was transferred to a separator, washed with water (1.5 l), dried over MgSO ₄ , filtered and then evaporated under vacuum to obtain a dark brown oil. The residue was taken up in DCM (100 ml), purified through a 1.2 kg pad of silica agglomerate (eluent: 100% DCM to DCM/EtOAc; 95:5) and then triturated with diethyl ether to give 5-nitro-1

- 101 042028 tetrahydropyran-2-yl-indazole (144 g, 582.4 mmol, 95% yield) as a crystalline off-white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.81 (d, J=2.1 Hz, 1H), 8.41 (d, J=0.8 Hz, 1H), 8.24 (dd, J=9.3, 2.2 Hz, 1H) , 7.93-7.91 (m, 1H), 5.96-5.93 (m, 1H), 3.91-3.86 (m, 1H), 3.80-3.74 (m, 1H), 2.45-2.30 (m, 1H), 1.99-2.02 ( m, 2H), 1.82-1.67 (m, 1H), 1.61-1.56 (m, 2H).

Intermediate 14: 4-chloro-1-tetrahydropyran-2-yl-indazol-5-amine

N-Chlorosuccinimide (29.5 g, 220.9 mmol) was added in portions to a stirred solution of 1(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (30.00 g, 138.08 mmol) in MeCN (1250 ml) in a round-bottomed flask completely covered with foil to remove any light from the reaction at 0°C. The reaction mixture was stirred in the dark and the progress of the reaction was checked regularly by LC-MS. After 2 hours, 3.50 g NCS was added and the reaction mixture was stirred for an additional 30 minutes, after which time the reaction was complete. The reaction was allowed to warm to room temperature (final temperature was 15°C). 10% sodium metabisulphite (500 ml) was added to the reaction and stirring continued for 20 minutes. The reaction was extracted with diethyl ether, the organic layer was washed with water and brine, dried over MgSO ₄ , filtered and concentrated under vacuum. The crude mixture was purified by flash chromatography eluting with EtOAc/petroleum ether (0-40%) to give 4-chloro-1-tetrahydropyran-2-yl-indazol-5-amine (22.20 g, 88.20 mmol, 64% yield ) as a yellow powder after trituration in diethyl ether. UPLC-MS (ES+, Method A): 1.53 min, m/z 252.1 [M+H] ⁺ .

General method for the synthesis of 4-alkyl-5-aminoindazoles 15 and 16

Stage 1: 4-bromo-1-tetrahydropyran-2-yl-indazol-5-amine

N-Bromosuccinimide (4.71 g, 26.46 mmol) was added in portions to a stirred solution of 1(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (5.00 g, 23.01 mmol) in MeCN (150 mL) in a round-bottomed flask completely covered with foil to remove any light from the reaction. The reaction mixture was stirred in the dark and monitored by UPLC-MS until completion. The reaction was stopped with 150 ml of water and 100 ml of EtOAc, and the layers were separated. The aqueous layer was further extracted with 100 ml EtOAc and the combined organics were washed with sodium thiosulfate solution and brine, then dried over sodium sulfate, filtered and concentrated in vacuo to give a dark orange sticky solid. The material was triturated with diethyl ether and petroleum ether to give a dark pink solid. This material was purified by column chromatography eluting with 5-30% EtOAc in petroleum ether to give a solid which was triturated with petroleum ether and filtered to give 4-bromo-1-tetrahydropyran-2-ylindazole-5-amine (3.50 g , 11.82 mmol, 51% yield) as a yellow solid. UPLC-MS (ES ⁺ , Method A): 1.59 min, m/z 298.0 [M+H] ⁺ .

Intermediate 15: 4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5-amine

4-Bromo-1-tetrahydropyran-2-yl-indazol-5-amine (1.00 g, 3.21 mmol), tribasic potassium phosphate (2.04 g, 9.62 mmol) and cyclopropylboronic acid (826 mg, 9.62 mmol) were suspended in toluene (15 ml) and water (3 ml) and completely degassed by purging with nitrogen. Palladium(II) acetate (72 mg, 0.32 mmol) and tricyclohexylphosphine (90 mg, 0.32 mmol) were added, followed by additional degassing.

- 102 042028 zation, and the reaction was closed and heated to 100°C for 18 hours, the Reaction was cooled and separated. Organics were loaded anhydrous on silica gel and purified on a 40 g silica gel column eluting with 0-50% EtOAc in petroleum ether to give 4-cyclopropyl-1-tetrahydropyran-2-ylindazole-5-amine (580 mg, 2.23 mmol , 70% yield) as a pale brown oil which crystallized on standing. UPLC-MS (ES+, Method A): 1.19 min, m/z 258.4 [M+H] ⁺ .

Intermediate 16: 4-ethyl-1-tetrahydropyran-2-yl-indazol-5-amine

Following the procedure used for intermediate 15, using 4-bromo-1-tetrahydropyran-2-yl-indazol-5-amine (1.00 g, 3.21 mmol) and ethylboronic acid (711 mg, 9.62 mmol), 4-ethyl-1- tetrahydropyran-2-yl-indazol-5-amine (500 mg, 2.02 mmol, 63% yield) as a brown oil. UPLC-MS (ES ⁺ , Method A): 1.13 min, m/z 246.5 [M+H] ⁺ .

Method for the synthesis of intermediate 17:

Stage 1: N-benzyl-6-fluoro-1-tetrahydropyran-2-yl-indazol-5-amine

Sodium tert-butoxide (321 mg, 3.34 mmol) was added to a stirred mixture of 5-bromo-6-fluoro-1tetrahydropyran-2-yl-indazole (500 mg, 1.67 mmol), benzylamine (0.55 ml, 5.01 mmol), palladium acetate (II) (37 mg, 0.17 mmol), (±)-BINAP (208 mg, 0.33 mmol) and toluene (5 mL) at room temperature The reaction was evacuated, purged with nitrogen, and stirred at 100°С for 18 h. The reaction mixture then cooled to room temperature and the solvent was removed under vacuum. The residue was loaded onto silica gel and purified by column chromatography eluting with 0-100% EtOAc in petroleum ether to give N-benzyl-6-fluoro-1-tetrahydropyran-2-yl-indazol-5-amine (294 mg, 0.90 mmol , 54% yield) as a yellow oil. UHPLC-MS (ES ⁺ , Method A), 1.92 min, m/z 326.3 [M+H] ⁺ .

Intermediate 17: 6-fluoro-1-tetrahydropyran-2-yl-indazol-5-amine

A solution of N-benzyl-6-fluoro-1-tetrahydropyran-2-yl-indazol-5-amine (367 mg, 1.12 mmol) and ethyl acetate (20 ml) was stirred at room temperature. Palladium, 10 wt% on a powdered carbon carrier (50 mg) was added to the reaction mixture and the flask was attached to a hydrogen balloon. The reaction mixture was degassed twice and purged with hydrogen, and then stirred under a hydrogen atmosphere for 18 hours, after which the reaction was completed according to LC-MS. The reaction mixture was then degassed and purged with nitrogen, filtered through a pad of Celite® and the filter cake was washed with EtOAc (20 mL). The filtrate was purified by column chromatography eluting with 0-10% MeOH in DCM to give 6-fluoro-1-tetrahydropyran-2-yl-indazol-5-amine (240 mg, 1.02 mmol, 80% yield) as a brown oil . UPLC-MS (ES ⁺ , Method A), 1.29 min, m/z 236.2 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ/ppm: 7.89 (1H, d, J=0.8 Hz), 7.32 (1H, d, J=10.4 Hz), 7.30 (1H, d, J=8.0 Hz), 5.62 (1H, dd, J=9.2 Hz, 2.4 Hz), 4.07-3.99 (1H, m), 3.80-3.72 (1H, m), 2.58-2.46 (1H, m), 2.20-2.05 (2H,

m), 1.84-1.61 (3Н, m), exchangeable _NH2 was not observed. Method for the synthesis of intermediate 18:

- 103 042028

Step 1: N-(6-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)-1,1-diphenylmethanimine

4,5-Bis(diphenylphosphino)-9,9-dimethylxantheme (183 mg, 0.32 mmol) and tris(dibenzylideneacetone)dipalladium (0) (145 mg, 0.16 mmol) were added to a stirred mixture of 5-bromo-6-chloro-1tetrahydropyran -2-yl-indazole (1.00 g, 3.17 mmol), benzophenone imine (0.64 ml, 3.8 mmol), cesium carbonate (2.06 g, 6.34 mmol) and 1,4-dioxane (20 ml) at room temperature under nitrogen atmosphere. The reaction was degassed, purged with nitrogen, and heated to 100° C. for 2 hours, after which the reaction was completed according to LC-MS. The reaction was cooled to room temperature and the solvent was removed under vacuum. The residue was suspended in EtOAc (10 ml) and filtered through a pad of Celite® and the filter cake was washed with EtOAc (10 ml). The filtrate was concentrated in vacuo and then the residue was purified by column chromatography eluting with 0-50% EtOAc in petroleum ether to give Ν-(6-χλορ1-tetrahydropyran-2-yl-indazol-5-yl)-1,1- diphenylmethanimine (944 mg, 2.27 mmol, 71% yield) as a yellow solid. UPLC-MS (ES ⁺ , Method A) 2.20 min, m/z 416.3, 418.3 [M+H] ⁺ .

1H NMR (400 MHz, CDCl3) δ/ppm: 7.85-7.79 (3H, m), 7.62 (1H, m), 7.55-7.50 (1H, m), 7.48-7.43 (2H, m), 7.27-7.24 ( 3Н, m), 7.21-7.17 (2Н, m), 6.83 (1H, s), 5.59 (1H, dd, J=9.6 Hz, 2.4 Hz), 4.09-4.03 (1H, m), 3.793.74 (1H , m), 2.55–2.45 (1H, m), 2.17–2.03 (2H, m), 1.83–1.65 (3H, m).

Intermediate 18: 6-chloro-1-tetrahydropyran-2-yl-indazol-5-amine

Sodium acetate (2.38 mg, 29.05 mmol) was added to a stirred solution of Ν-(6-χλορ-1tetrahydropyran-2-yl-indazol-5-yl)-1,1-diphenylmethanimine (944 mg, 2.27 mmol), hydroxylamine hydrochloride (221 mg, 3.18 mmol) and methanol (10 ml) at room temperature. The reaction mixture was stirred for 2 h, then heated to 50°C for 1 h, after which LC-MS showed complete consumption of starting material.

The reaction was cooled to room temperature and the solvent was removed under vacuum. The residue was partitioned between saturated aqueous NH ₄ Cl (100 ml) and EtOAc (100 ml). The organic layer was separated and the aqueous layers were extracted with EtOAc (100 ml). The combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by column chromatography eluting with 0-10% MeOH in DCM to give 6-chloro-1-tetrahydropyran-2-yl-indazol-5-amine (400 mg, 1.59 mmol, 70% yield) as a brown solid. UPLC-MS (ES+, Method A), 1.49 min, m/z 252.1 [M+H] ⁺ .

1H NMR (400 MHz, CDCl3) δ/ppm: 7.94 (1H, s), 7.72 (1H, s), 6.54-6.28 (1H, m), 5.66 (1H, dd, J=9.2 Hz, 2.4 Hz), 4.05-3.99 (1H, m), 3.81-3.73 (1H, m), 2.56-2.46 (1H, m), 2.12-2.05 (2H, m), 1.83-1.66 (3H, m), 1.951.35 (2H , br s).

General Synthesis of Intermediates 19-23:

The method for preparing intermediate 19 is shown below. Additional intermediates, which were obtained in a similar way from commercially available methylhydroxybenzoates, are presented in table. 4.

Intermediate 19: 4-[2-(isopropylamino)-2-oxoethoxy]-3-methoxybenzoic acid

_Hydroxide potassium (109 mg, 1.9 mmol) and the reaction mixture was stirred at room temperature for 18 hours. Methanol was removed under reduced pressure and EtOAc (20 ml) and 1 M aqueous HCl (15

- 104 042028 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2x20 ml). The combined organics were dried (phase separator) and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO ₂ ) eluting with 1-15% MeOH in DCM to give 4-[2-(isopropylamino)-2-oxoethoxy]-3-methoxybenzoic acid (229 mg, 0.86 mmol, 88% yield) as a white solid. LC-MS (ES+, Method C): 1.70 min, m/z 268.1 [M+H] ⁺ .

1H NMR (500 MHz, CD3OD): δ 7.81 (br s, 1H), 7.67-7.62 (m, 2H), 7.04 (d, J=8.0 Hz, 1H), 4.57 (s, 2H),

4.13-4.04 (m, 1H), 3.93 (s, 3H), 1.20 (s, 3H), 1.18 (s, 3H).

Stage 1: methyl 4-[2-(isopropylamino)-2-oxoethoxy]-3-methoxybenzoate

To a stirred solution of methyl vanillate (228 mg, 1.50 mmol) and potassium carbonate (829 mg, 6.00 mmol) in DMF (10 mL) at room temperature under N2 was added 2-χλορ-Νisopropylacetamide (274 mg, 2.00 mmol) in one portion, and the reaction was heated at 80°C for 18 hours the Solvents were removed under reduced pressure, and the residue was divided between EtOAc (20 ml) and N ₂ About (20 ml). The layers were separated and the aqueous layer was further extracted with EtOAc (2x15 ml). The combined organics were washed with H2O (20 ml) and brine (20 ml), dried (phase separator) and concentrated. The crude material was purified by flash column chromatography (SiO2 eluting with 30-80% EtOAc in petroleum ether) to give methyl 4-[2-(isopropylamino)-2-oxoethoxy]-3-methoxybenzoate (278 mg, 0.99 mmol, 66% yield ) as an off-white solid. LC-MS (ES ⁺ , Method C): 2.22 min, m/z 282.1 [M+H] ⁺ .

1H NMR (500 MHz, CDCl3): δ 7.66 (dd, J=8.5, 2.0 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.68 ( s, 1H), 4.54 (s, 2H), 4.15 (dp, J=8.0, 6.5 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 1.19 (s, 3H), 1.18 (s , 3H).

Compounds obtained in a manner analogous to that described above are shown in Table 1 below. 4.

Table 4

General method for the synthesis of intermediates 24-45: R ¹ -CI or R ¹ -Br y

K ₂ CO ₃ , DMF, B ₂ Pin ₂ , H / Ό ° C or Pd (dppf) CI ₂ _R

[I .J * [I .J * θ Ύπ

X OH ^r1_| ' ^a 92CO3 X O' ^r1 KOAc, dioxane ,^-J 1 acetone, reflux 100 °CXO ^R

The method for preparing intermediate 24 is shown below. Additional intermediates, which were obtained in a similar way from commercially available bromophenols, are presented in table. 5.

Intermediate yl)phenoxy]-N-isopropylacetamide

24: 2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-

The vial was loaded with 2-(4-bromo-2-fluorophenoxy)-N-isopropylacetamide (306 mg, 1.05 mmol), bis(pinacolato)diborone (348 mg, 1.37 mmol) and potassium acetate (311 mg, 3.16 mmol) . 1.4-105042028 dioxane (8.5 ml) was added and the solution was degassed with N2 for 10 min. Pd(dppf)Cl2-DCM complex (86 mg, 0.11 mmol) was added and the sealed reaction mixture was heated at 100°C for 18 h. The mixture was filtered through a pad of celite (eluting with EtOAc) and washed with H2O (20 ml). The aqueous layer was back-extracted with EtOAc (2x20 ml) and the combined organics were dried (phase separator) and concentrated. The crude material was purified by flash column chromatography (SiO ₂ , eluting with 30-80% EtOAc in petroleum ether) to give 2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolane -2-yl)phenoxy]-N-isopropylacetαmide (288 mg, 0.85 mmol, 81% yield) as a yellow oil which solidified on standing. LC-MS (ES+, Method C): 3.20 min, m/z 338.2 [M+H] ⁺ .

¹ H NMR (500 MHz, CDCl3): δ 7.57-7.49 (m, 2H), 6.93 (t, J=8.0 Hz, 1H), 6.48 (s, 1H), 4.52 (s, 2H), 4.18 (dp, J= 8.0, 6.5 Hz, 1H), 1.33 (s, 12H), 1.21 (d, J=6.5 Hz, 6H).

Step 1: 2-(4-bromo-2-fluorophenoxy)-N-isopropylacetamide

2-χλορ-Νisopropylacetamide ( 176 mg, 1.30 mmol) and the reaction was heated at 80°C for 18 h. The solvents were removed under reduced pressure and the residue was partitioned between EtOAc (20 ml) and H ₂ O (20 ml). The layers were separated and the aqueous portion was extracted with EtOAc (2x15 ml). The combined organics were dried (phase separator) and concentrated. The crude material was purified by flash column chromatography (SiO2, eluting with 30-60% EtOAc in petroleum ether) to give 2-(4-bromo-2fluoro-phenoxy)-N-isopropylacetamide (307 mg, 0.95 mmol, 95% yield) as brown oil. LCMS (ES ⁺ , Method C): 2.80 min, m/z 292.0 [M+H] ⁺ .

Compounds obtained in a manner analogous to that described above are shown in Table 1 below. 5.

Table 5

Intermediate connection no. Structure LC-MS 25 Y Y n AoA \ LC-MS (ES+, Method C): 3.17 min, m/z 367.3 [M+Na] ⁺ 26 A - o, in ° ^with LC-MS (ES+, Method C): 3.51 min, m/z 449.4 [M+H] ⁺ 27 LC-MS (ES+, Method C): 3.17 min, m/z 334.2 [M+H] ⁺ 28 Aq-A LC-MS (ES-, Method C): 3.48 min, m/z 346.2 [M-H]' 29 A, ABOUT LC-MS (ES+, Method C): 2.95 min, m/z 318.2 [M+H] ⁺ thirty 9 about LC-MS (ES+, Method C): 2.96 min, m/z 334.2 [M+H] ⁺ 31 g 0 9° LC-MS (ES+, Method C): 3.84 min, m/z 378.1 [M+H] ⁺ 32 <9 0 LC-MS (ES+, Method C): 3.02 min, m/z 334.1 [M+H] ⁺

- 106 042028

33 Υγη LC-MS (ES+, Method C): 1.76 min, m/z 320.0 [M+H] ⁺ 34 LC-MS (ES+, Method D): 3.68 min, m/z 364.1 [M+H] ⁺ 35 X X n . LC-MS (ES+, Method C): 3.08 min, m/z 337.2 [M+H] ⁺ 36 ABOUT LC-MS (ES+, Method C): 3.38 min, m/z 334.2 [M+H] ⁺ 37 cN °C n O LC-MS (ES+, Method C): 2.78 min, m/z 349.1 [M+H] ⁺ 38 n X ,bXn R / ⁰ \\ /k \ kXo v \ O LC-MS (ES+, Method A): 1.73 min, m/z 321.0 [M+H] ⁺ 39 kk^o V o UPLC-MS (ES ⁺ , Method A): 1.81 min, m/z 323.3 [M+H] ⁺ 40 9 ,F _n ° \\ /k \ kho % ' \ o F LC-MS (ES+, Method D): 3.94 min, m/z 273.9 [M-pinacol+H] ⁺ 41 X. _o ° Vokr NN LC-MS (ES+, Method C): 2.83 min, m/z 347.1 [M+H] ⁺ 42 ⁰ Xh Ϊ UPLC-MS (ES+, Method A): 2.02 min, m/z 348.0 [M+H] ⁺ 43 CW n / CX χ< ^Ν Ύ LC-MS (ES+, Method C): 3.03 min, m/z 350.1 [M+H] ⁺ 44 ₀ ⁰ \XX o oD/ LC-MS (ES+, Method C): 3.18 min, m/z 463.1 [M+H] ⁺

Intermediate 45: N-isopropyl-2-[2-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)-1-pyridyl]acetamide

Following the method used to prepare intermediate 24 using bis(pinacolato)diborone (66 mg, 0.26 mmol) and 2-(4-bromo-2-oxo-1-pyridyl)-P-isopropylacetamide (55 mg, 0.2 mmol) , gave N-iso1fopyl-2-[2-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1pyridyl]acetamide (64 mg, 100%).

1H NMR (500 MHz, CDCl3) δ 7.37 (dd, 1H), 7.05 (s, 1H), 6.80 (m, 1H), 6.50 (dd, 1H), 4.48 (s, 2H), 3.95 (m, 1H) , 1.30 (s, 12H), 1.10 (d, 6H).

Stage 1: 2-(4-bromo-2-oxo-1-pyridyl)-N-isopropylacetamide

To a stirred solution of 4-bromopyridin-2-ol (210 mg, 1.21 mmol) and potassium carbonate (667 mg,

- 107 042028

4.83 mmol) in dry DMF (7 ml) at room temperature under nitrogen atmosphere was added 2-chloro-Chisopropylacetamide (213 mg, 1.57 mmol) and the reaction was heated at 80° C. overnight. The mixture was cooled to room temperature and the solvents were removed under reduced pressure. The residue was dissolved in EtOAc (20 ml) and washed with H ₂ O (15 ml). The aqueous layer was extracted with EtOAc (2x15 ml) and the combined organics were washed with brine, dried (phase separator) and concentrated. The crude material was purified by column chromatography (SiO ₂ , eluting with 1-10% MeOH in DCM) to give an inseparable 96:4 mixture of 2-(4-bromo-2-oxo-1-pyridyl)-chisopropylacetamide (143 mg, 0.52 mmol , 43% yield) and 2-[(4-bromo-2-pyridyl)oxy]-misopropylacetamide (6 mg, 0.02 mmol, 2% yield). UPLC-MS (ES ⁺ , Method A): 1.14 min, m/z 274.8 [M+H] ⁺ .

Ή NMR (500 MHz, CDC1 ₃ ) δ 7.24 (d, J=4.9 Hz, 1H), 6.82 (d, J=2.1 Hz, 1H), 6.48 (s, 1H), 6.38 (dd, J=7.3, 2.2 Hz, 1H), 4.42 (s, 2H), 4.03-3.87 (m, 1H), 1.10 (d, J=6.6 Hz, 6H).

Compounds obtained in a manner analogous to that described above are shown in Table 1 below. 6a and 6b.

Synthesis of carbamate and urea boronates 49 and 50

2-aminopropane

CDI, THF, r.t.

X \u003d OH, NH ₂

Intermediate 49: [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl Nisopropylcarbamate.

Stage 1: (4-bromophenyl)methyl N-isopropylcarbamate

Vg

1, G-Carbonyldiimidazole (0.45 ml, 3.21 mmol) was added to a stirred solution of 4-bromobenzyl alcohol (300 mg, 1.6 mmol) in THF (8 ml) and the reaction mixture was stirred at 25°C for 2 h. 2-Aminopropane ( 0.41 ml, 4.81 mmol) and the reaction mixture was stirred at 25°C for an additional 4 h. The solvent was then removed under vacuum and the residue was taken up in EtOAc (10 ml) and water (10 ml). The layers were separated and the aqueous portion was back-extracted with EtOAc (2x10 ml). The combined organics were washed with brine (10 ml), dried (phase separator) and concentrated in vacuo. The crude material was purified by column chromatography

- 108042028 (SiO ₂ , eluting with 20-70% EtOAc in petroleum ether) to give (4-bromophenyl)methyl-Nisopropylcarbamate (334 mg, 1.23 mmol, 76% yield) as a white solid. UPLC-MS (ES ⁺ , Method A): 3.12 min, m/z 272.20 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.59-7.53 (m, 2H), 7.33-7.27 (m, 2H), 7.19 (d, J=7.7 Hz, 1H), 4.97 (s, 2H), 3.65-3.53 (m, 1H), 1.05 (d, J=6.6 Hz, 6H).

Intermediate 49: [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl Nisopropylcarbamate

Following the preparation of intermediate 24, using bis(pinacolato)diborone (145 mg, 0.57 mmol) and (4-bromophenyl)methyl N-isopropylcarbamate (120 mg, 0.44 mmol) gave [4-(4,4,5,5tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl]methyl N-isopropylcarbamate (130 mg, 0.44 mmol, 100% yield) as a brown gum. UPLC-MS (ES ⁺ , Method A): 3.50 min, m/z 320.1 [M+H] ⁺ .

Intermediate 51: 1-isopropyl-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]methyl]urea.

Stage 1: 1-[(4-bromophenyl)methyl]-3-isopropylurea

1,1'-Carbonyldiimidazole (0.25 ml, 1.8 mmol) was added to a stirred solution of 4-bromobenzylamine hydrochloride (200 mg, 0.90 mmol) in THF (8 ml) and the reaction mixture was stirred at 25°C for 2 h. 2-Aminopropane was added (0.23 ml, 2.7 mmol) and the reaction mixture was stirred at 25° C. overnight. LC-MS showed completion of the reaction, then the solvents were removed under vacuum. The residue was taken up in EtOAc (10 ml) and 1 M HCl (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2x10 ml). The combined organics were washed with brine (10 ml), dried (phase separator) and concentrated in vacuo. The crude material was purified by column chromatography (SiO ₂ , eluting with 0-60% EtOAc in petroleum ether) to give 1[(4-bromophenyl)methyl]-3-isopropylurea (245 mg, 0.90 mmol, 100% yield) as white solid. UPLC-MS (ES ⁺ , Method A): 2.48 min, m/z 274.0 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.41 (m, 2H), 7.19-7.14 (m, 2H), 4.58 (s, 1H), 4.31 (d, J=5.9 Hz, 2H), 4.17 (d , J=7.9 Hz, 1H), 3.91-3.83 (m, 1H), 1.15-1.13 (m, 6H).

Intermediate 50: 1-isopropyl-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]methyl]urea

Following the procedure for preparing intermediate 24, using 1-[(4-bromophenyl)methyl]-3isopropylurea (80 mg, 0.30 mmol) and bis(pinacolato)diborone (97 mg, 0.38 mmol), 1-isopropyl-3-[[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]urea (95 mg, 0.30 mmol, 100% yield) as a brown gum. UPLC-MS (ES ⁺ , Method A): 2.80 min, m/z 319.08 [M+H] ⁺ .

Intermediate 51: N-isopropyl-2-[2-morpholino-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenoxy]acetamide.

Stage 1: 4-(5-bromo-2-methoxyphenyl)morpholine

The vial was loaded with 4-bromo-2-iodoanisole (500 mg, 1.6 mmol), 4,5-bis(diphenylphosphino)-9,9dimethylxantheme (92 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium (0) (73 mg, 0.08 mmol) and sodium tert-butoxide (0.2 ml, 1.92 mmol) in toluene (7 ml). Morpholine (0.14 ml, 1.6 mmol) was added and the mixture was sealed and stirred at 80°C for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (15 ml) and water (10 ml) and filtered twice through a pad of celite . The layers were separated, the aqueous layer was extracted with EtOAc (2x10 ml) and the combined organics were dried (phase separator) and concentrated. Purification by flash column chromatography (SiO ₂ , eluting with 25-35% EtOAc in petroleum ether) gave 4-(5-bromo-2-methoxyphenyl)morpholine (113 mg, 0.41 mmol, 26% yield) as a yellow oil which crystallized while standing. UPLC-MS (ES+, Method A): 1.73 min, m/z 273.9 [M+H] ⁺ .

- 109 042028

Y NMR (400 MHz, CDC1 ₃ ) δ 7.10 (dd, >8.6, 2.4 Hz, 1H), 6.99 (d, >2.4 Hz, 1H), 6.73 (d, >8.6 Hz, 1H), 3.90-3.85 (m , 4H), 3.84 (s, 3H), 3.08–3.02 (m, 4H).

Stage 2: 4-bromo-2-morpholinophenol

A solution of boron tribromide (1M in heptane) (0.7 ml, 4.1 mmol) was added to a solution of 4-(5-bromo-2-methoxyphenyl)morpholine (223 mg, 0.82 mmol) in dry DCM (3 ml) at -78°C under nitrogen atmosphere . The mixture was allowed to warm to room temperature and stirred overnight. An additional 3 equivalents of a solution of boron tribromide (1M in heptane) was added and the reaction mixture was stirred for 48 h. The mixture was then cooled to -78°C and the reaction was stopped with saturated aqueous NaHCO 3 (15 ml) and then extracted with EtOAc (2x15 ml) , the combined organics were washed with water and brine (15 ml), dried (phase separator) and concentrated in vacuo. The residue was purified by flash chromatography eluting with 20-33% EtOAc in petroleum ether to give 4-bromo-2-morpholinophenol (100 mg, 0.39 mmol, 47% yield) as a brown oil. UPLC-MS (ES ⁺ , Method A): 1.55 min, m/z 260.0 [M+H] ⁺ .

'n NMR (500 MHz, CDClj) δ 7.25 (d, J=2.4 Hz, 1H), 7.20 (dd, J=8.6, 2.4 Hz, 1H), 6.88-6.71 (m, 2H), 3.86 (t, J =4.4 Hz, 4H), 2.86 (t, J=4.5 Hz, 4H).

Step 3: 2-(4-bromo-2-morpholinophenoxy)-X-isopropylacetamide

2chloro-M-isopropylacetamide ( 81 mg, 0.60 mmol) in one portion and the reaction was heated at 80° C. overnight. An additional 0.2 equivalents of 2-chloro-X-isopropylacetamide (81 mg, 0.60 mmol) was added and the reaction was allowed to stir overnight. Solvents were removed under reduced pressure, the residue was partitioned between EtOAc (20 ml) and H ₂ O (20 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (2x15 ml) and the combined organics were washed with brine, dried (phase separator) and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 60-100% EtOAc in petroleum ether) to give 2-(4-bromo-2-morpholinophenoxy)-N-isopropylacetamide (89 mg, 0.25 mmol, 67% yield) as a yellow oil which crystallized at standing. UPLC-MS (ES ⁺ , Method A): 1.63 min, m/z 359.1 [M+H] ⁺ .

Y NMR (400 MHz, CDC1 ₃ ) δ 7.14 (dd, >8.6, 2.4 Hz, 1H), 7.07 (d, >2.3 Hz, 1H), 6.91 (d, >8.2 Hz, 1H), 6.76 (d, > 8.6 Hz, 1H), 4.51 (s, 2H), 4.18 (dp, >8.2, 6.6 Hz, 1H), 3.93-3.82 (m, 4H), 3.10-3.00 (t, 4H), 1.19 (d, >6.6 Hz, 6H).

Intermediate 51: X-isopropyl-2-[2-morpholino-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenoxy]acetamide

Following the procedure for the preparation of intermediate 24, using bis(pinacolato)diborone (95 mg, 0.38 mmol) and 2-(4-bromo-2-morpholinophenoxy)-X-isopropylacetamide (112 mg, 0.31 mmol) gave X-isopropyl-2 -[2-morpholino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetamide (125 mg, 0.31 mmol, 100% yield). UPLC-MS (ES ⁺ , Method A): 1.71 min, m/z 405.3 [M+H] ⁺ .

General method for preparing intermediates 52-55

NaOH, MeOH ³ 'y% A ° \ 50 ° C AAx _o zxyOH

About h ₂ n. _r ,pg

HATU, DIPEA, DMF, r.t.

ABOUT

B O bis(pinacolato)diboron

YA ₀ /~XzNH. _r zPG Pd(dppf)CI ₂ , KOAc, ΥΛθζ^γΝΗ.^ΡΟ

P 1,4-dioxane, 100°C D

- 110042028

Intermediate 52: tert-Butyl 3-[[2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenoxy]acetyl]amino]pyrrolidine-1 -carboxylate\/o

P\ ° mG τ^ν-4 o o

The vial was loaded with tert-butyl 3-[[2-(4-bromo-2-methoxyphenoxy)acetyl]amino]pyrrolidine-1-carboxylate (109 mg, 0.25 mmol), potassium acetate (75 mg, 0.76 mmol), and bis(pinacolato) diborone (77 mg, 0.30 mmol). 1,4-dioxane (2.5 ml) was added and the solution was degassed with nitrogen for 10 min. The complex [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (21 mg, 0.03 mmol) was added. The sealed vial was heated at 100° C. for 4 hours. The mixture was cooled to room temperature, filtered through a phase separator and concentrated under reduced pressure to give tert-butyl 3-[[2-[2-methoxy-4-(4.4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetyl]amino]pyrrolidine-1-carboxylate (119 mg, 0.25 mmol, 100% yield). LC-MS (ES+, Method C): 3.24 min, m/z 477.1 [M+H] ⁺ .

Compounds obtained in a manner analogous to that described above are shown in Table 1 below. 7.

Step 1: methyl 2-(4-bromo-2-methoxyphenoxy)acetate o

A solution of 4-bromo-2-methoxyphenol (10 g, 49.25 mmol), methyl bromoacetate (5.59 ml, 59.11 mmol) and potassium carbonate (27.23 g, 197.02 mmol) in 1,4-dioxane (100 ml) was heated to 80°С over 18 hours. The mixture was concentrated under reduced pressure to a white solid which was partitioned between water and dichloromethane. The organic layer was separated, the aqueous layers were washed three times with dichloromethane, and the organics were combined, washed with water and brine, dried (MgSO ₄ ) and concentrated under reduced pressure to give methyl 2-(4-bromo-2-methoxyphenoxy)acetate (13 g, 47.26 mmol, 96% yield) as a colorless oil which crystallized overnight. LC-MS (ES ⁺ , Method C): 2.89 min, m/z 276.85 [M+H] ⁺ .

1H NMR (400 MHz, CDCl3) δ 7.05-7.02 (m, 1H), 7.01 (d, J=2.3 Hz, 1H), 6.73 (d, J=8.3 Hz, 1H), 4.69 (s, 2H), 3.90 (s, 3Н), 3.82 (s, 3Н).

Stage 2: 2-(4-bromo-2-methoxyphenoxy)acetic acid

A solution of methyl 2-(4-bromo-2-methoxyphenoxy)acetate (13.00 g, 47.3 mmol) and sodium hydroxide (9.45 g, 236 mmol) in methanol (150 ml) was heated to 50°C for 18 h, after which the mixture concentrated under reduced pressure to a white powder, dissolved in water, and the product was isolated from the solution by adding dropwise 2N. HCl. The white solid was filtered off and dried under vacuum to give 2-(4-bromo-2-methoxyphenoxy)acetic acid (12 g, 46.0 mmol, 97% yield) as a white powder. LC-MS (ES ⁺ , Method C): 2.24 min, m/z 262.81 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ 7.14 (d, J=2.3 Hz, 1H), 7.04 (dd, J=8.6, 2.3 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 4.67 (s, 2H), 3.80 (s, 3Н), 3.36 (s, 1H).

Stage 3: tert-butyl 3-[[2-(4-bromo-2-methoxyphenoxy)acetyl]amino]pyrrolidine-1-carboxylate

A solution of 2-(4-bromo-2-methoxyphenoxy)acetic acid (3.2 g, 12.26 mmol) and N,Ndiisopropylethylamine (10.68 ml, 61.29 mmol) in DMF (5 ml) was stirred for 5 min, 2-(7- aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (5.59 g, 14.71 mmol) and the solution was stirred for 1 h after which 1-Boc-3-aminopyrrolidine was added (2.68 ml, 14.71 mmol) and the reaction mixture was stirred at room temperature for 24 h. The solvent was removed under reduced pressure to give an orange oily solid which was dissolved in EtOAc and washed with water and then with brine and dried (MgSO ₄ ). The organics were concentrated under reduced pressure to give an orange solid. Further purification by flash chromatography eluting with 30-50% EtOAc in petroleum ether gave tert-butyl 3-[[2-(4-bromo-2-methoxyphenoxy)acetyl]amino]pyrrolidine-1-carboxylate (3.74 g, 8.71 mmol, 71% yield) as a yellow oil which foamed under vacuum. LCMS (ES ⁺ , Method C): 3.02 min, m/z 430.9 [M+H] ⁺ .

- 111 042028 ¹ H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.16 (d, J=2.3 Hz, 1H), 7.05 (dd, J=8.6, 2.3 Hz, 1H), 6.85 ( d, J=8.6Hz, 1H), 4.48(s, 2H), 4.25(t, J=6.2Hz, 1H), 3.81(s, 3H), 3.45(td, J=13.1, 12.0,6.2Hz, 1H ), 3.31-3.22 (m, 2H), 3.07 (dd, J=11.0.5.0 Hz, 1H), 2.02 (dt, J=13.4, 6.7 Hz, 1H), 1.79 (s, 1H), 1.41 (s, 9H).

Table 7

(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-N cf ₃ ch ₂ nh ₂ o

T3P, THF Jbjj H^F

65°C

Intermediate 56: 2-methoxy-4(2,2,2-trifluoroethyl)benzamide

Pd(dppf)CI ₂ , KOAc, bis(pinacolato)diborone, 85°C

Y O

Stage 1: 4-bromo-2-methoxybenzoic acid.

Methyl 4-bromo-2-methoxybenzoate (3.00 g, 12.24 mmol) was stirred in a mixture of sodium hydroxide (20 ml, 20 mmol) and THF (20 ml) at 40°C for 18 h. The mixture was then cooled to room temperature, and the organic solvent was removed under vacuum. The resulting solution was stirred and concentrated HCl was added dropwise to pH ~5. This caused a white solid to be isolated which was filtered off and dried under vacuum to give 4-bromo-2-methoxybenzoic acid (2.69 g, 11.64 mmol, 95% yield) as a white solid. UHPLCMS (ES+, Method A), 1.43 min, m/z 231.0, 233.0 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ/ppm: 12.85 (1H, s), 7.58 (1H, d, J=8.0 Hz), 7.34 (1H, d, J=1.6 Hz), 7.20 (1H, dd, J=8.0 Hz, 1.6 Hz), 3.84 (3Н, s).

Stage 2: 4-bromo-2-methoxy-N-(2,2,2-trifluoroethyl)benzamide.

Propylphosphonic anhydride (10.4 ml, 17.46 mmol) was added to a stirred solution of trifluoroethylamine (0.93 ml, 11.64 mmol), 4-bromo-2-methoxybenzoic acid (2.69 g, 11.64 mmol) and THF (100 ml) at room temperature under nitrogen atmosphere. The reaction was heated to 65°C for 72 h, then cooled to room temperature, and the solvent was removed under vacuum. The residue was purified by column chromatography eluting with 0-100% EtOAc in petroleum ether to give 4-bromo-2methoxy-N-(2,2,2-trifluoroethyl)benzamide (2.30 g, 7.37 mmol, 63% yield) as white solid. UPLC-MS (ES ⁺ , Method A), 1.73 min, m/z 312.0, 314.0 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ/ppm: 8.14-8.07 (1H, br s), 8.11 (1H, d, J=8.8 Hz), 7.28 (1H, dd, J=9.4 Hz, 2.0 Hz), 7.18 (1H, d, J=2.0 Hz), 4.16 (2H, qd, J=9.2 Hz, 6.4 Hz), 4.03 (3H, s).

Intermediate 56: 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-K(2,2,2-trifluoroethyl)benzamide.

A complex of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane chloride (471 mg, 0.58 mmol) was added to a stirred mixture of 4-bromo-2-methoxy-N-(2,2,2-trifluoroethyl)benzamide (1.80 g, 5.77 mmol), bis(pinacolato)diborone (1.76 g, 6.92 mmol), potassium acetate (1.70 g, 17.3 mmol) and 1,4-dioxane (20 ml) at room temperature. The reaction was degassed, purged with nitrogen and stirred at 85°C

- 112 042028 for 1 h. The reaction was cooled to room temperature and the solvent was removed under vacuum. EtOAc (50 ml) was added, the resulting suspension was filtered through a Celite pad and the filter cake was washed with EtOAc (50 ml). The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography eluting with 0-100% EtOAc in petroleum ether to give 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-N-(2,2,2-trifluoroethyl)benzamide (1.90 g, 5.29 mmol, 92% yield) as a brown oil which solidified on standing. UPLC-MS (ES+, Method A), 1.89 min, m/z 360.3 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ/ppm: 8.37-8.31 (1H, m), 8.22 (1H, d, J=8.0 Hz), 7.54 (1H, d, J=8.0 Hz), 7.43 (1H, s), 4.23-4.14 (2Н, m), 4.06 (3Н, s), 1.38 (12Н, s).

Intermediate 57: N-isopropyl-2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)anilino]acetamide

Ν Η

2-(4-Bromo-2-methoxyanilino)-Niisopropylacetamide (110 mg, 0.37 mmol), potassium acetate (79 mg, 0.81 mmol) and bis(pinacolato)diborone (104 mg, 0.40 mmol) were suspended in 1,4- dioxane (1.46 ml). The suspension was then degassed with nitrogen for 5 min, then [1,1'bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane chloride complex (15 mg, 0.02 mmol) was added. The mixture was further degassed for another 5 minutes, then heated to 80° C. with stirring overnight. The reaction mixture was left to cool to room temperature, filtered through a pad of celite, which was washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography eluting with 0-40% ethyl acetate in petroleum ether to give N-isopropyl-2-[2-methoxy-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan2-yl)anilino]acetamide (58 mg, 0.16 mmol, 45% yield) as a yellow oil which solidified on standing. UPLC-MS (ES ⁺ , Method A): 1.75 min, m/z 349.2 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 7.37 (dd, J=7.8, 1.2 Hz, 1H), 7.20 (d, J=1.0 Hz, 1H), 6.49 (d, J=7.8 Hz, 1H), 4.18- 4.08 (m, 1H), 3.92 (s, 3H), 3.79 (s, 2H), 1.33 (s, 12H), 1.09 (d, J=6.6Hz, 6H), 2H replaceable.

Stage 1: 2-(4-bromo-2-methoxyanilino)-N-isopropylacetamide

To a solution of 2-chloro-N-isopropylacetamide (201 mg, 1.48 mmol) in ethanol (1.73 mL) was added 4-bromo-o-anisidine (300 mg, 1.48 mmol) and potassium carbonate (615 mg, 4.45 mmol). The reaction mixture was then allowed to stir at 80° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in EtOAc and washed with NaOH (4.0 M). The aqueous layer was extracted with EtOAc (x3), the organic layers were combined, washed with saturated brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 30-50% acetonitrile (with 0.1% formic acid added) in water (with 0.1% formic acid added) to give 2-(4-bromo-2-methoxyanilino)-N-isopropylacetamide (110 mg, 0.36 mmol, 25% yield) as a white solid. UPLC-MS (ES ⁺ , Method A): 1.65 min, m/z 301.2 [M+H] ⁺ .

1H NMR (400 MHz, CDCl3) δ 6.98 (dd, J=8.3, 2.7 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.47-6.41 (m, 1H), 6.34 (d, J= 8.3 Hz, 1H), 4.18-4.08 (m, 1H), 3.87 (s, 3H), 3.73 (s, 2H), 1.11 (d, J=6.6 Hz, 6H).

Intermediate 58: 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4dihydroisoquinolin-1-one

Oh oh

6-Bromo-2-methyl-3,4-dihydroisoquinolin-1-one (250 mg, 1.04 mmol), bis (pinacolato) diborone (397 mg, 1.56 mmol), potassium acetate (306 mg, 3.12 mmol) and 1, 4-dioxane (10 mL) was degassed by nitrogen bubbling, then [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane chloride complex (85 mg, 0.10 mmol) and additional 1,4-dioxane (10 mL) were added .

The resulting mixture was further degassed and then heated to 95° C. for

- 113 042028

h. The reaction mixture was left to cool to room temperature and filtered through a layer of celite. Solvents were evaporated to give crude 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1-one as a brown gum. UPLC-MS (ES+, Method A): 1.71 min, m/z 288.2 [M+H] ⁺ .

Intermediate 59: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-one

Following the procedure for the preparation of intermediate 58, using 7-bromochroman-4-one (500 mg, 2.2 mmol) and bis(pinacolato)diborone (1678 mg, 6.61 mmol), 7-(4,4,5,5-tetramethyl- 1,3,2dioxaborolan-2-yl)chroman-4-one (422 mg, 1.54 mmol, 70% yield) as a clear resin. UHPLCMS (ES ⁺ , Method A): 1.88 min, m/z 275.2 [M+H] ⁺ .

Intermediate 60: N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolαn-2yl)phenyl]propanamide

Following the procedure for preparing intermediate 58 using N-(4-6pom-2methoxyphenyl)propanamide (255 mg, 0.99 mmol) and bis(pinacolato)diborone (281 mg, 1.09 mmol), crude N-[2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanamide (302 mg, calc. yield) as a yellow oil. UPLC-MS (ES ⁺ , Method A): 1.81 min, m/z 306.3 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 8.42 (d, J=7.9 Hz, 1H), 7.88 (s, 1H), 7.44 (dd, J=8.0, 1.0 Hz, 1H), 7.27 (d, J=1.1 Hz), 3.92 (s, 3H), 2.49–2.38 (m, 2H), 1.34 (s, 12H), 1.31–1.24 (m, 3H).

Step 1: N-(4-bromo-2-methoxyphenyl)propanamide

Propionyl chloride (0.13 ml, 1.48 mmol) was added dropwise at room temperature to a solution of 4-bromo-o-anisidine (300 mg, 1.48 mmol) and triethylamine (0.21 ml, 1.48 mmol) in DCM (1.86 ml). The reaction mixture was allowed to stir for 1 hour. The reaction mixture was diluted with DCM, washed with water and saturated brine. The organic layer was dried over Na ₂ SO ₄ , filtered, and then the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography eluting with 0-40% EtOAc in petroleum ether to give N-(4bromo-2-methoxyphenyl)propanamide (309 mg, 1.19 mmol, 81% yield) as a yellow oil. UPLC-MS (ES ⁺ , Method A): 1.64 min, m/z 258.1 [M+H] ⁺ .

1H NMR (400 MHz, CDCl3) δ 8.30 (d, J=8.7 Hz, 1H), 7.72-7.62 (m, 1H), 7.08 (dd, J=8.6, 2.4 Hz, 1H), 6.99 (d, J= 2.1 Hz, 1H), 3.88 (s, 3H), 2.42 (q, J=7.6 Hz, 2H), 1.25 (t, J=7.5 Hz, 3H).

Intermediate 61: 1-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]-3-methylurea °\

NH n

Following the procedure for preparing intermediate 58, using 1-(4-bromo-2-methoxyphenyl)3-methylurea (127 mg, 0.49 mmol) and bis(pinacolato)diborone (137 mg, 0.54 mmol), 1-[2methoxy-4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methylurea (151 mg, 0.59 mmol, 100% yield) as a yellow-orange oil. UPLC-MS (ES ⁺ , Method A): 1.62 min, m/z 307.3 [M+H] ⁺ .

1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=8.5 Hz, 1H), 7.43 (dd, J=8.0, 1.2 Hz, 1H), 7.25-7.24 (m, 1H), 6.91 (br s, 1H ), 4.71-4.53 (br s, 1H), 3.89 (s, 3H), 2.87 (s, 3H), 1.34 (s, 12H).

- 114 042028

Step 1: Phenyl N-(4-bromo-2-methoxyphenyl) carbamate

To a solution of 4-bromo-o-anisidine (300 mg, 1.48 mmol) and pyridine (0.01 ml, 0.11 mmol) in ethyl acetate (2.55 ml) was added phenyl chloroformate (0.2 ml, 1.56 mmol) with stirring at 0°C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was washed with water (x3) and dried over Na ₂ SO ₄ before filtering. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography eluting with 0-45% EtOAc in petroleum ether to give phenyl N-(4-bromo-2-methoxyphenyl)carbamate (400 mg, 1.24 mmol, 84% yield ) as an off-white solid. UPLC-MS (ES+, Method A): 1.99 min, m/z 322.2 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, J=8.2 Hz, 1H), 7.53 (br s, 1H), 7.45-7.39 (m, 2H), 7.28-7.24 (m, 1H), 7.24- 7.19 (m, 2H), 7.13 (dd, J=8.7, 2.1 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 3.94 (s, 3H).

Stage 2: 1-(4-bromo-2-methoxyphenyl)-3-methylurea

To a solution of phenyl N-(4-bromo-2-methoxyphenyl)carbamαtα (400 mg, 1.24 mmol) in DCM (4.97 mL) was added a solution of methylamine (2.0 M in THF) (0.62 mL, 1.24 mmol). The reaction mixture was stirred at 35°C for 10 days. The reaction mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography eluting with 20-100% EtOAc in petroleum ether followed by 0-10% MeOH in DCM to give 1-(4-bromo-2-methoxyphenyl) -3-methylurea (127 mg, 0.49 mmol, 39% yield). UPLC-MS (ES ⁺ , Method A): 1.46 min, m/z 259.1 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 7.97 (d, J=8.6 Hz, 1H), 7.07 (dd, J=8.6, 2.0 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H), 6.68- 6.63 (m, 1H), 4.57-4.47 (m, 1H), 3.85 (s, 3H), 2.86 (d, J=4.8 Hz, 3H).

General method for the preparation of intermediates 62 and 63 ethyl bromoacetate

i) KOtBu, EtOH, H ₂ O, 60°C

Nai, K ₂ CO ₃ ,

DMF, 110°C

X \u003d CH ₂ , O bis (pinacolato) diboron Pd (dppf) CI ₂ , COAc, 1,4-dioxane, I0 ° C

Stage 1: ethyl 2-(6-bromo-3,4-dihydro-2H-quinolin-1-yl)acetate

Br\

6-Bromo-1,2,3,4-tetrahydroquinoline (250 mg, 1.18 mmol), ethyl bromoacetate (0.18 ml, 1.65 mmol), sodium iodide (265 mg, 1.77 mmol) and potassium carbonate (326 mg, 2.36 mmol) in DMF (2 ml) was heated to 110°C, and the resulting yellow suspension was allowed to stir at this temperature for 1 h. The reaction was stopped with water (50 ml) and was extracted with EtOAc (3x25 ml). The organic layers were collected, dried over sodium sulfate, filtered and evaporated in vacuo to give ethyl 2-(6-bromo-3,4-dihydro-2H-quinolin-1-yl)acetate (383 mg, 0.87 mmol, 74% yield) as an orange oil. UPLC-MS (ES ⁺ , Method A), 2.04 min, m/z 298.0 [M+H] ⁺ .

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Step 2: 2-(6-bromo-3,4-dihydro-2H-quinolin-1-yl)-N-isopropylacetamide

2-(6-Bromo-3,4-dihydro-2H-quinolin-1-yl)acetate (360 mg, 1.21 mmol) was dissolved in ethanol (3.5 ml) and water (0.50 ml). Potassium 2-methylpropan-2-olate (203 mg, 1.81 mmol) was added and the mixture was allowed to stir at 60°C for 30 min. The reaction was allowed to cool to room temperature and further cooled by adding ice. To this completely soluble mixture was added 1 M HCl solution until a precipitate appeared (~pH 2-3). The light yellow-orange precipitate was filtered off, washing with ice water. The solid turned into an orange gum after filtration. The resin was washed off the filter with DCM. The organic layer was dried over Na ₂ SO ₄ and filtered. 2-Aminopropane (0.1 mL, 1.21 mmol) was immediately added to the filtrate, followed by propylphosphonic anhydride (0.36 mL, 1.21 mmol), and the mixture was stirred for 20 min. The reaction mixture was then diluted with water and extracted with DCM. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a crude yellow oil. Further purification by flash column chromatography eluting with 5-95% ethyl acetate in petroleum ether gave 2-(6-bromo-3,4-dihydro-2H-quinolin-1-yl)-N-isopropylacetamide (214 mg, 0.69 mmol, 57% yield) as a colorless powder. UPLC-MS (ES+, Method A), 1.83 min, m/z 311.1 [M+H] ⁺ .

Intermediate 62: N-isopropyl-2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)3,4-dihydro-2H-quinolin-1-yl] acetamide

Following the procedure for preparing intermediate 58 using 2-(6-bromo-3,4-dihydro-2Iquinolin-1-yl)-N-isopropylacetamide (100 mg, 0.32 mmol) and bis(pinacolato)diborone (106 mg, 0.42 mmol ), gave N-isopropyl-2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2Hquinolin-1-yl]acetamide ( 139 mg, 0.31 mmol, 97% yield) as a clear resin. UPLC-MS (ES ⁺ , Method A), 1.91 min, m/z 359.4 [M+H] ⁺ . Compounds obtained in a manner analogous to that described above are shown in Table 1 below. 8.

Table 8

Intermediate connection no. Structure LC-MS 63 0^)4 CD-O α t g \ 9 -θ Method A, 1.76 min, m/z 361.4 [M+H] ⁺

Intermediate 64: 2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]-N-methylacetamide

(COCI) ₂ , DMF MeNH ₂ , DCM, rt

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Stage 1: 4-bromo-2-methoxy-1-[(E)-2-nitrovinyl]benzene

NO, iy Br

Nitromethane (4.19 ml) was added to a flask containing 4-bromo-2-methoxybenzaldehyde (300 mg, 1.4 mmol) and ammonium acetate (140 mg, 1.81 mmol). The reaction was then allowed to stir at 90° C. for 90 minutes. The reaction mixture was allowed to cool to room temperature and partitioned between saturated sodium bicarbonate solution and DCM. The aqueous layer was extracted with DCM (x3). The combined organic extracts were combined, filtered through a hydrophobic frit and the solvent removed under reduced pressure to give crude 4-bromo-2-methoxy-1-[(E)-2-nitrovinyl]benzene (332 mg, 1.29 mmol, 92% yield) as orange oil, which was immediately used in the next step. UPLC-MS (ES+, Method A): 1.91 min, m/z 258 [M+H] ⁺ .

Stage 2: 4-bromo-2-methoxy-1-(2-nitroethyl)benzene

NO, V Br

Sodium borohydride (53 mg, 1.42 mmol) was added to a solution of 4-bromo-2-methoxy-1-[(E)-2-nitrovinyl]benzene (332 mg, 1.29 mmol) in methanol (4.29 ml) and the reaction was allowed to stir at room temperature. temperature for 1 h. The reaction was then carefully stopped with saturated ammonium chloride solution, and the aqueous layer was extracted three times with DCM. The organic extracts were combined, filtered through a hydrophobic frit, and all solvent was removed under reduced pressure. Purification by flash silica gel column chromatography eluting with 0-15% ethyl acetate in petroleum ether gave 4-bromo-2-methoxy-1-(2-nitroethyl)benzene (91 mg, 0.35 mmol, 27% yield) as transparent resin. UPLC-MS (ES ⁺ , Method A): 1.86 min, no mass ion detected.

Stage 3: 2-(4-bromo-2-methoxyphenyl)acetic acid

Sodium nitrite (90 mg, 1.27 mmol) was added to a solution of 4-bromo-2-methoxy-1-(2-nitroethyl)benzene (132 mg, 0.51 mmol) in DMSO (1.27 ml) and glacial acetic acid (0.29 ml, 5.07 mmol) and the reaction mixture was stirred at 60° C. overnight. Then the reaction mixture was left to cool to room temperature and acidified to pH 1 with an aqueous solution of 2 M HCl. This mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water, brine, dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-25% ethyl acetate in petroleum ether gave 2-(4-bromo-2-methoxyphenyl)acetic acid (51 mg, 0.21 mmol, 41% yield) as a yellow oil. UPLC-MS (ES ⁺ , Method A): 1.53 min, m/z 245.0 [M+H] ⁺ .

Step 4: 2-(4-bromo-2-methoxyphenyl)-M-methylacetamide

Vg

A drop of DMF was added to a solution of oxalyl chloride (0.02 ml, 0.25 mmol) and 2-(4-bromo-2-methoxyphenyl)acetic acid (51 mg, 0.21 mmol) in DCM (1.04 ml) at room temperature and left to stir at room temperature for 10 min. Then the reaction mixture was cooled to 0°C and a 2 M solution of methylamine (0.26 ml, 0.52 mmol) in THF was carefully added. The reaction mixture was allowed to stir at room temperature for 10 min, partitioned between water and DCM. The aqueous layer was extracted with DCM (x3). The combined extracts were filtered through a hydrophobic frit and all volatiles were removed under reduced pressure. Purification by column chromatography eluting with 40-100% ethyl acetate in petroleum ether gave 2-(4-bromo-2-methoxyphenyl)-M-methylacetamide (9 mg, 0.04 mmol, 18% yield) as a clear gum. UPLC-MS (ES ⁺ , Method A) 1.42 min, m/z 260.1 [M+H] ⁺ .

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Intermediate 65: 2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]-N-methylacetamide

Suspension of 2-(4-bromo-2-methoxyphenyl)-N-methylacetamide (21 mg, 0.08 mmol), bis(pinacolato)diborone (26 mg, 0.10 mmol) and potassium acetate (20 mg, 0.21 mmol) in 1.4 -dioxane (1.59 mL) was degassed under nitrogen for 5 min, then [1,1'bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane chloride complex (6 mg, 0.01 mmol) was added. The mixture was degassed for another 5 minutes and then heated to 90° C. overnight. The reaction mixture was allowed to cool to room temperature, filtered through a pad of celite, and the pad of celite was washed with DCM. The filtrate was collected and water was added. The aqueous layer was extracted with DCM (x3). The organic extracts were filtered through a hydrophobic frit and the solvent was removed under reduced pressure. Purification by flash silica gel column chromatography eluting with 0-100% ethyl acetate in petroleum ether gave 2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)phenyl]-Ni methylacetamide (16 mg, 0.05 mmol, 65% yield) as a clear resin. UPLC-MS (ES+, Method B): 1.59 min, m/z 306.3 [M+H] ⁺ .

General method A:

The method for preparing the compound of the present invention is shown below. Additional compounds that can be obtained in a similar way from commercially available acid chlorides or intermediate compounds 11, 13, 19, 20-23 using the General method A, are presented in table. 9.

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

A solution of N-[5-(4-methoxyphenyl)-4H-1,2,4-triazol-3-yl]-1-tetrahydropyran-2-yl-indazol-5-amine (110 mg, 0.28 mmol) in hydrogen chloride ( 1.25 M in MeOH, 0.38 ml, 0.48 mmol) was stirred at room temperature under N2 for 48 h. The solvents were removed under reduced pressure to give N-[5-(4-methoxyphenyl)-4H-1,2,4-triazole -3-yl]-1H-indazol-5-amine dihydrochloride (10 mg, 0.28 mmol, 99% yield) as a white solid. LC-MS (ES ⁺ , Method E): 5.84 min, m/z 307.1 [M+H] ⁺ .

1H NMR (500 MHz, DMSO-d6): δ 9.69 (s, 1H), 8.04 (s, 1H), 8.01 (s, 1H), 7.96 (d, J=9.0 Hz, 2H), 7.51 (d, J =9.0 Hz, 1H), 7.42 (dd, J=9.0, 2.0 Hz, 1H), 7.11 (d, J=9.0 Hz, 2H), 3.83 (s, 3H).

Stage 1: N-4-methoxy-N-[(1-tetrahydropyran-2-ylindazol-5-yl)carbamothioyl]benzamide

To a stirred solution of potassium thiocyanate (64 mg, 0.66 mmol) in anhydrous MeCN (3.0 mL) at room temperature under N2 was added 4-methoxybenzoyl chloride (90 μL, 0.66 mmol), and

- 118 042028 the mixture was heated at 85°C for 3.5 hours the Mixture was left to cool to room temperature and then filtered under reduced pressure. 1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-5amine (130 mg, 0.60 mmol) was added in one portion and the reaction mixture was stirred at room temperature for an additional 2 hours. The solvents were removed under reduced pressure and the crude material was purified by flash column chromatography (SiO ₂ ) eluting with 0-8% MeOH in DCM to give 4-methoxy-N-[(1-tetrahydropyran-2-ylindazol-5-yl)carbamothioyl]benzamide (251 mg, 0.60 mmol, 100% yield) as a foamy orange solid. LC-MS (ES+, Method C): 3.39 min, m/z 411.1 [M+H] ⁺ .

1H NMR (500 MHz, CDCl3): δ 12.64 (s, 1H), 9.05 (s, 1H), 8.12 (d, J=2.0 Hz, 1H), 8.05 (s, 1H), 7.88 (d, J=9.0 Hz, 2H), 7.64 (d, J=9.0 Hz, 1H), 7.56 (dd, J=9.0, 2.0 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H), 5.73 (dd, J=9.0 , 3.0 Hz, 1H), 4.07-4.00 (m, 1H), 3.91 (s, 3H), 3.79-3.72 (m, 1H), 2.61-2.51 (m, 1H), 2.21-2.12 (m, 1H), 2.09 (dd, J=13.3, 3.6 Hz, 1H), 1.84-1.62 (m, 3H).

Step 2: N-[5-(4-methoxyphenyl)-4H-1,3,4-triazol-3-yl]-1-tetrahydropyran-2-yl-indazol-5-amine

Hydrazine hydrate ( ₁₄₆ μl , 3.00 mmol) and the reaction was heated at 65° C. for 3.5 h. ,4-triazol-3-yl]-1-tetrahydropyran-2-yl-indazol-5-amine (11 mg, 0.28 mmol, 47% yield) as an off-white solid. LC-MS (ES ⁺ , Method C): 2.63 min, m/z 391.1 [M+H] ⁺ .

Compounds obtained in a manner analogous to that described above are shown in Table 1 below. 9.

Table 9

Example Structure LC-MS ‘NMR 2 I Z SR IZ Xz IZ 1 Q / Method E, 5.95 min, m/z 307.1 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 13.64 (s, 1H), 12.81 (s, 1H), 9.23 (s, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.57 ( d, J = 7.7 Hz, 1H), 7.53 (dd, J = 2.6, 1.5 Hz, 1H), 7.50 - 7.35 (m, 3H), 7.04 (s, 1H), 3.83 (s, 3H). 3 n ^Ν ΐ 1 ^H H Method E, 6.15 min, m/z 337.1 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 9.63 (br s, 2H), 8.04 (d, J = 1.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.42 (dd, J = 9.0, 2.0 Hz, 1H), 7.20 (d, J = 2.0 Hz, 2H), 6.63 (dd, J = 2.0 Hz, 1H), 3.82 (s, 6H ). 4 P? 1 ZI A ZIz T Method E, 6.10 min, m/z 307.1 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 9.41 (s, 1H), 8.10 (s, 1H), 8.04 (d, J=7.5 Hz, 1H), 7.99 (s, br), 7.55-7.49 ( m, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.42 (dd, J = 9.0, 2.0 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.13 (dd, J = 7.5 Hz, 1H), 3.98 (s, 3H). 5 IZ xz IZ 1 0 °\ Method E, 5.86 min, m/z 321.0 [M+H] ⁺ 'HNMR (500 MHz, DMSO-d ₆ ) δ 12.38 (s, 1H), 9.15 (s, 1H), 8.15-7.97 (m, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.39 (dd , J = 9.0, 2.0 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.09 (d, J = 8.5 Hz, 2H), 3.83 (s, 3H), 2.45 (s, 3H). 6 Iz CP IZ IZ 1 IZ^ Method E, 5.83 min, m/z 392.1 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 13.61 (s, 1H), 12.82 (s, 1H), 9.21 (s, 1H), 8.09 (s, 1H), 8.017.90 (m, 2H), 7.63-7.55 (m, 2H), 7.51-7.35 (m, 3H), 7.04 (s, 1H), 4.51 (s, 2H), 4.02-3.92 (m, 1H), 1.10 (d, J = 6.5 Hz, 6H).

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7 Μ- ΗΝ 1 ηϊ O Method E, 5.72 min, m/z 392.1 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 13.38 (br s, IH), 12.81 (s, IH), 9.18 (s, IH), 8.10 (s, IH), 8.01-7.93 (m, 2H) , 7.91 (d, J= 8.5 Hz, 2H), 7.42 (s, 2H), 7.09 (d, J= 8.5 Hz, 2H), 4.51 (s, 2H), 3.96 (m, IH), 1.10 (d, J = 6.5 Hz, 6H). 8 N- hn' 1 BH ,41 Η . η ^Η η bAo Λ \ ο •2HCI Method E, 5.68 min, m/z 422.1 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 9.50 (s, IH), 8.03 (s, IH), 8.01 (s, IH), 7.82 (d, J = 7.8 Hz, IH), 7.62 (d, J= 2.1 Hz, IH), 7.54 (dd, J = 8.3, 2.1 Hz, IH), 7.48 (d, J = 8.8 Hz, IH), 7.41 (dd, J = 8.8, 2.2 Hz, IH), 7.05 ( d, J = 8.5 Hz, IH), 4.52 (s, 2H), 3.97–3.85 (m, 4H), 1.10 (d, J = 6.5 Hz, 6H). 9 ^ην Α Ν η νπΙ ^Η Η V ο •2HCI Method E, 5.09 min, m/z 394.3 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 9.39 (s, IH), 8.05 (s, IH), 7.98 (s, IH), 7.91 (q, J = 4.5 Hz, IH), 7.60 (d, J = 2.0 Hz, IH), 7.53 (dd, J = 8.5, 2.0 Hz, IH), 7.46 (d, J = 9.0 Hz, IH), 7.41 (dd, J = 9.0, 2.0 Hz, IH), 7.04 ( d, J = 8.5 Hz, IH), 4.53 (s, 2H), 3.88 (s, 3H), 2.67 (d, J = 4.5 Hz, 3H). 10 Ό. TEd d^ η 0 Method E, 6.07 min, m/z 406.3 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 13.26 (s, IH), 12.79 (s, IH), 9.14 (s, IH), 8.09 (s, IH), 7.94 (s, IH), 7.84- 7.73 (m, 3H), 7.41 (s, 2H), 6.95 (d, J = 8.5 Hz, IH), 4.53 (s, 2H), 3.94 (ddt, J = 14.5, 13.0.6.5 Hz, lH), 2.30 (s, 3H), 1.10 (d, J = 6.5 Hz, 6H). eleven 1 z ΖΙ Ζ^5 τ Method E, 6.08 min, m/z 351.0 [M+H] ⁺ SH NMR (400 MHz, DMSO-d ₆ ) δ 12.78 (s, IH), 9.14 (s, IH), 8.08 (t, J = 1.4 Hz, IH), 7.94 (s, IH), 7.40 (q, J = 1.9, 1.4 Hz, 2H), 7.32 (d, J = 7.6 Hz, 2H), 7.12 (dt, J = 8.8, 1.1Hz, IH), 3.90 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H)

General method B:

NEt ₃ , K ₂ CO ₃ , MeCN, 80 °C

(R ³ O) ₂ B PG G\

Pd(dppf)CI ₂ DCM

K ₂ CO ₃ , 1,4-dioxane

H ₂ O, 80 °C

HCI, IPA or

TFA, DCM

The process for preparing the compound of the invention is shown below. Additional compounds which can be prepared in a similar manner from intermediates 1, 2, 13 and 14 using commercially available boronic acids, boronate esters or intermediates 25, 27-38, 40-42 and 45-50 using general method B, are presented in table. 10.

Example 12 2-[2-fluoro-4-[5-(1H-indazol-5-ylamino)-4H-1,2,4-triazol-3-yl]phenoxy]-N-isopropylacetamide

2-[2-Fluoro-4-[5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl solution ]phenoxy]-K-isopropylacetamide (100 mg, 0.16 mmol) in a solution of hydrogen chloride - isopropanol, 5 N. (3.00 ml, 9.00 mmol) was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and passed through an ion exchange cartridge (SCX, eluting with 1 M NH ₃ in MeOH). The crude material was purified by preparative HPLC (30-80% MeCN in H ₂ O) to give 2-[2-fluoro-4-[5-(1H-indazol-5-ylamino)-4H-1,2,4- triazol-3-yl]phenoxy]-N-isopropylacetamide (15 mg, 0.03 mmol, 21% yield) as an off-white solid. LC-MS (ES+, Method E): 5.90 min, m/z 410 [M+H] ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ): δ 12.51 (s, 1H), 8.66 (s, 1H), 7.97 (s, 1H), 7.92 (s, 1H), 7.49-7.41 (m, 3H), 7.22 (t, J=8.5 Hz, 1H), 4.58 (s, 2H), 3.99-3.94 (m, 1H), 1.15 (d, J=6.5 Hz, 6H).

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Stage 1: N[5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-1-tetrahydropyran-2-ylindazol-5-amine

LiHMDS (1M in THF, 0.46 ml , 0.46 mmol) drop by drop. The solution was stirred at 0°C for 30 min, then a solution of 2-[(3,5-dibromo-1,2,4-triazol-1yl)methoxy]ethyltrimethylsilane (125 mg, 0.35 mmol) in THF (1 mL) was added . The cooling bath was removed and the mixture was stirred at room temperature for 1.5 h. The reaction was stopped by careful addition of saturated aqueous NH ₄ Cl (10 ml) and extracted with DCM (3x15 ml). The combined organics were dried (phase separator) and concentrated. The crude material was purified by flash column chromatography (SiO ₂ , eluting with 30-80% EtOAc in petroleum ether) to give N-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole-3- yl]-1tetrahydropyran-2-yl-indazol-5-amine (123 mg, 0.25 mmol, 71% yield) as an orange oil. LCMS (ES+, Method C): 3.83 min, m/z 495.0 [M+H] ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ): δ 7.99 (d, J=1.0 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.35 ( dd, J=9.0, 2.0 Hz, 1H), 6.86 (s, 1H), 5.70 (dd, J=9.5, 3.0 Hz, 1H), 5.40 (s, 2H), 4.05-3.96 (m, 1H), 3.78 -3.71 (m, 1H), 3.71-3.65 (m, 2H), 2.60-2.50 (m, 1H), 2.20-2.05 (m, 2H), 1.79-1.65 (m, 3H), 1.02-0.94 (m, 2H), 0.02 (s, 9H).

Stage 2: 2-[2-fluoro-4-[5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3 - yl]phenoxy]-N-isopropylacetamide

The vial was loaded with N-[5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]-1tetrahydropyran-2-yl-indazol-5-amine (74 mg, 0.15 mmol), 2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenoxy]-N-isopropylacetamide (intermediate 24) (56 mg, 0.17 mmol) and carbonate potassium (62 mg, 0.45 mmol). 1,4-dioxane (1.25 ml) and water (0.25 ml) were added and the mixture was degassed with nitrogen for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (6 mg, 0.01 mmol) complex was added in one portion, the vial was sealed, and the reaction was heated at 80°C overnight. The reaction mixture was diluted with EtOAc (15 ml) and water (10 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (2x10 ml) and the combined organics were dried (phase separator) and concentrated. The crude material was purified by flash column chromatography (SiO2 eluting with 0-5% MeOH in DCM) to give 2-[2-fluoro-4-[5-[(1tetrahydropyran-2-ylindazol-5-yl)amino]- 2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3yl]phenoxy]-N-isopropylacetamide (101 mg, 0.14 mmol, 93% yield) as a brown oily solid. LC-MS (ES ⁺ , Method C): 3.80 min, m/z 624.3 [M+H] ⁺ . Compounds obtained in a manner analogous to that described above are shown in Table 1 below. 10.

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Table 10

Example Structure LC-MS Ή NMR 13 ^4.0 1 ZI ² d' ZI -Z. T Method E, 7.28 min, m/z 383.1 [M+H] ⁺ Ή NMR (500 MHz. DMSO-d ₆ ): δ 13.36 (s, 1H), 12.80 (s, 1H), 9.18 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.91 ( d, J = 8.5 Hz, 2H), 7.48 (d, J = 7.0 Hz, 2H), 7.44-7.39 (m, 4H), 7.37-7.33 (m, 1H), 7.16 (d, J= 8.5 Hz, 2H ), 5.18 (s, 2H). 14 N- ΗΝ ] Q NN _H o Method E, 6.00 min, m/z 417.1 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ , @343K): δ 13.46 (s, 1H), 12.66 (s, 1H), 9.11-8.72 (m, 1H), 8.21 (dd, J = 9.0, 2.0 Hz, 2H), 7.96 (s, 2H), 7.68 (s, 1H), 7.46 (s, 2H), 7.26 (s, 1H), 4.72 (s, 2H), 3.95 (dq, J= 13.0, 6.5 Hz, 1H ), 1.13 (d, J= 6.5 Hz, 6H). 15 ^ΗΝ Λ ChadHDL ^N N DDo V 'o Method E, 4.43 min, m/z 421.4 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 12.81 (s, 1H), 9.31 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.11 (t, J= 1.5 Hz, 1H) , 7.95 (s, 1H), 7.94 (d, J = 2.5 Hz, 1H), 7.82 (dd, J = 8.5, 2.5 Hz, 1H), 7.43 (d, J = 1.5 Hz, 2H), 7.06 (d, J = 8.5 Hz, 1H), 4.61 (s, 2H), 3.93 (dp, J = 8.0, 6.5 Hz, 1H), 3.81 (s, 2H), 1.07 (d, J = 6.5 Hz, 6H). 16 Until I 1 ΖΤ ΖΙ ζ Method E, 4.65 min, m/z 393.2 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 13.33-12.62 (m, 2H), 9.16 (s, 1H), 8.21 (d, J = 2.5 Hz, 1H), 8.15 (d, J = 7.5 Hz, 1H), 8.07 (s, 1H), 7.97 (dd, J = 9.5, 2.5 Hz, 1H), 7.94 (s, 1H), 7.45-7.39 (m, 2H), 6.51 (d, J = 9.5 Hz, 1H ), 4.62 (s, 2H), 3.85 (dq, J = 13.5, 6.5 Hz, 1H), 1.09 (d, J = 6.5 Hz, 6H). 17 I Ζ dr ΙΖ Ρζ ΙΖ 1 /G L / Method E, 5.77, m/z 365.1 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 13.45 (s, 1H), 12.80 (s, 1H), 9.14 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.91 ( d, J = 9.0 Hz, 2H), 7.41 (s, 2H), 7.08 (s, 2H), 4.88 (s, 2H), 3.72 (s, 3H). 18 N- ΗΝ P G W N-N ChaddLL Method E, 5.78 min, m/z 406.2 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 8.05 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.92-7.88 (m, 2H), 7.47 (d, J = 9.0 Hz, 1H), 7.41 (dd, J = 9.0, 2.0 Hz, 1H), 7.06-7.01 (m, 2H), 4.74 (q, J = 6.5 Hz, 1H), 3.87 (dp, J = 8.0 , 6.5 Hz, 1H), 1.44 (d, J = 6.5 Hz, ZV), 1.08 (d, J = 6.5 Hz, ZV), 1.02 (d, J = 6.5 Hz, ZV). 19 ^nm D LW Ν-Ν Chdhrdt Method E, 6.17 min, m/z 418.0 [M-Η]' Ή NMR (500 MHz, DMSO-d ₆ ): δ 8.09 (d, J = 2.0 Hz, 1H), 7.99 (s, 1H), 7.92-7.87 (m, 3H), 7.47 (d, J = 9.0 Hz, 1H), 7.42 (dd, J = 9.0, 2.0 Hz, 1H), 7.02-6.97 (m, 2H), 3.97 (dp, J = 8.0, 6.5 Hz, 1H), 1.49 (s, 6H), 1.06 (d , J = 6.5 Hz, 6H). 20 ^ην Λ ίΊΧχίί o Method E, 5.54 min, m/z 390.2 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 13.55 (s, 1H), 12.78 (s, 1H), 9.15 (s, 1H), 8.12 (s, 1H), 8.05-7.84 (m, 3H), 7.70 (d, J = 7.5 Hz, 1H), 7.51-7.24 (m, 4H), 3.82 (dq, J = 13.5, 6.5 Hz, 1H), 2.85 (dt, J = 14.0, 7.5 Hz, 2H), 2.36 (dq, J = 4.5, 2.5, 2.0 Hz, 2H), 1.01 (dd, 7 = 6.5, 1.5 Hz, 6H). 21 Λ I 1 ZI ζι ζ I Method E, 2.68 min, m/z 406.2 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 9.55 (s, 1Η), 8.03 (d, J = 16.5 Hz, 2H), 7.96–7.86 (m, 3H), 7.48 (d, J = 9.0 Hz, 1H), 7.41 (dd, J = 9.0, 2.0 Hz, 1H), 7.11-7.04 (m, 2H), 4.24 (t, J = 6.0 Hz, 2H), 3.86 (dt, J = 7.5, 6.5 Hz, 1H ), 2.52 (t, 2H), 1.06 (d, J = 6.5 Hz, 6H). 22 z IZX. IZ 1P / z z Method E, 4.42 min, m/z 350.0 [M+H]+ Ή NMR (400 MHz, DMSO-d ₆ ): δ 9.51 (s, 1Η), 8.04 (d, J = 2.0 Hz, 3H), 8.01 (d, J = 1.0 Hz, 1H), 7.99–7.92 (m, 2H), 7.48 (d, J = 9.0 Hz, 1H), 7.42 (dd, J = 9.0, 2.0 Hz, 1H), 7.13-7.07 (m, 2H), 4.15 (t, J = 6.0 Hz, 2H), 2.97 (q, J = 6.5 Hz, 2H), 2.06 (p, J = 6.5 Hz, 2H). 23 I z CP IZ K IZ 1 0 / ZI ^Ο1=:: ^ Method E, 5.59 min, m/z 406.1 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 9.40 (s, 1Η), 8.05 (d, J = 2.0 Hz, 1H), 8.02 (s, 2H), 7.94-7.89 (m, 2H), 7.47 ( d, J = 9.0 Hz, 1H), 7.41 (dd, J = 9.0, 2.0 Hz, 1H), 7.13-7.06 (m, 2H), 4.06 (t, J = 6.0 Hz, 2H), 3.43 (q, J = 5.5 Hz, 2H), 2.40 (q, J = 6.5 Hz, 1H), 1.00 (d, J = 6.5 Hz, 6H).

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24 25 26 27 28 29 thirty 31 32 33 ην' 1 4h J ^{ν-ν Η} Η ΆΟ Ν^ ην' 1 » u/XA 0 Ν^ ην' 1 Q Πλ and 0 N^ ΗΝ 1 A ΛκΑ u / 0 nA 4 W Ν-Ν _η . Αχχν _η α Ο yj Η ϊΛ Αγ Αγ ^Η η ΊΑσ ν ' 0 X, _!Υ o • HCI ^hn X Г Ν-Ν AC ^Η Η ΥΑό Α % ° Ο. χ Ν Ννν/ 0 Ν=\ Ν···/jA / ^ΗΝ Αν Anh hA V^/^N - ^z H Method E, 4.23 min, m/z 336.1 [M+H] ⁺ Method E, 5.73 min, m/z 410.0 [M+H] ⁺ Method E, 2.83 min, m/z 406.1 [M+H] ⁺ Method E , 2.84 min, m/z 422.2 [M+H] ⁺ Method B, 2.31 min, m/z 393.1 [M+H] ⁺ Method B, 2.67 min, m/z 393.1 [M+H] ⁺ Method E, 6.18 min, m/z 426.0 [M+H] ⁺ Method E, 4.92 min, m/z 351.0 [M+H] ⁺ Method C, 1.98 min, m/z 420.1 [M+H] ⁺ Method B, 2.41 min, m/z 407.2 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ) δ 12.79 (s, 1H), 9.18 (s, 1H), 8.10 (s, 1H), 7.93 (d, J = 6.5 Hz, 1H), 7.92-7.87 (m , 2H), 7.44–7.38 (m, 2H), 7.10–7.03 (m, 2H), 3.98 (t, J = 6.0 Hz, 2H), 2.89 (t, J = 6.0 Hz, 2H). Ή NMR (400 MHz, DMSO-d ₆ ): δ 9.22 (s, 1Η), 8.13 (d, J= 1.5 Hz, 1H), 7.99-7.85 (m, 3H), 7.43-7.34 (m, 2H), 6.96-6.87 (m, 2H), 4.51 (s, 2H), 4.00-3.89 (m, 1H), 1.09 (d, J = 6.5 Hz, 6H). Ή NMR (400 MHz, DMSO-d ₆ ): δ 12.52 (s, 2H), 8.59 (s, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.70 (d, J= 8.5 Hz, 1H), 7.53-7.38 (m, 3H), 6.96-6.85 (m, 2H), 4.49 (s, 2H), 4.06-3.92 (m, 1H), 2.58 (s, 3H), 1.15 (d, J = 6.5Hz, 6H). Ή NMR (400 MHz, DMSO-d ₆ ): δ 12.79 (m, 2H), 9.05 (s, 1H), 8.15 (s, 1H), 8.01-7.88 (m, 3H), 7.45-7.35 (m, 2H ), 6.78 (d, J = 2.5 Hz, 1H), 6.69 (dd, J = 8.5, 2.5 Hz, 1H), 4.53 (s, 2H), 3.96 (m, 4H), 1.11 (d, J = 6.5 Hz , 6H). Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.96 (s, 1H), 12.89 (s, 1H), 9.45 (s, 1H), 8.06 (m, 3H), 7.67 (s, 1H), 7.54- 7.36 (m, 2H), 7.01-6.88 (m, 1H), 6.76 (d, J = 7.0 Hz, 1H), 4.53 (s, 2H), 3.90-3.79 (m, 1H), 1.09 (d, J= 6.5Hz, 6H). Ή NMR (400 MHz, DMSO-d ₆ ): δ 12.82 (s, 1H), 9.40 (s, 1H), 8.70 (d, J = 2.5, 1.0 Hz, 1H), 8.24 (dd, J = 8.5, 2.5 Hz, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.45-7.38 (m, 2H), 7.04 (d, J = 8.5, 1.0 Hz , 1H), 4.72 (s, 2H), 3.95–3.85 (m, 1H), 1.07 (d, J = 6.5 Hz, 6H). Ή NMR (400 MHz, CD ₃ OD): δ 8.25 (d, J = 1.0 Hz, 1H), 7.89 (d, J = 9.0 Hz, 2H), 7.69 (dd, J = 9.0, 1.0 Hz, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.18 (d, J = 9.0 Hz, 2H), 4.60 (s, 2H), 4.11 (p, ./ 6.5 Hz. 1H), 1.20 (d,./ 6.5 Hz. 6H). Ή NMR (500 MHz, DMSO-d ₆ ): δ 12.82 (s, 1H), 9.43 (s, 1H), 8.13 (s, 1H), 7.94 (s, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.41 (s, 2H), 6.96 (d, J = 8.5 Hz, 2H), 4.37 (s, 2H). Ή NMR (500 MHz, DMSO-d ₆ ): δ 13.27 (s, 1H), 12.80 (s, 1H), 9.21 (s, 1H), 8.10 (d, J = 1.5 Hz, 1H), 7.94 (s, 1H), 7.93-7.88 (m, 2H), 7.82 (t, J = 5.5 Hz, 1H), 7.41 (d, J = 1.5 Hz, 2H), 7.06 (d, J = 8.5 Hz, 2H), 4.05 ( t, J = 6.5 Hz, 2H), 3.20 (q, J = 6.5 Hz, 2H), 2.36–2.31 (m, 1H), 1.87 (p, J = 6.5 Hz, 2H), 1.00 (d, J = 6.5 Hz, 6H). 1H NMR (400 MHz, DMSO-d6): δ 12.88 (s, 1H), 9.41 (s, 1H), 8.11 - 7.94 (m, 2H), 7.83 (d, J=7.6 Hz, 1H), 7.67 (d , J =7.1Hz, 1H), 7.52 - 7.36 (m, 2H), 6.94 (d, J= 1.8 Hz, 1H), 6.73 (dd, J = 7.0, 1.9 Hz, 1H), 4.09 (t, J = 6.7 Hz, 2H), 3.88 - 3.73 (m, J = 6.8 Hz, 1H), 2.60-2.40 (m, 2H, under DMSO peak), 0.99 (d, J = 6.6 Hz, 6H), 1 NH exchangeable not visible.

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34 vz IZ xz IZ1 0=4 ^1 Method E, 6.23 min, m/z 355.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 9.51 (s, IH), 8.05 (d, J= 1.9 Hz, IH), 8.03-7.96 (m, 3H), 7.52-7.47 (m, 3H), 7.42 ( dd, J = 8.9, 2.0 Hz, IH), 7.21 (d, J = 7.8 Hz, IH), 5.06 (s, 2H), 3.67-3.57 (m, IH), 1.06 (d, J = 6.6 Hz, 6H ). 2 exchangeable NH are not visible. 35 if p 1 ZI ZI zA3z I Method E, 4.87 min, m/z 407.0 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.53 (s, 2Н), 8.65 (s, IH), 8.19 (s, IH), 7.97–7.88 (m, 3H), 7.44 (d, J = 1.5 Hz, 3H), 6.48 (d, J = 9.4 Hz, IH), 4.18 (t, J = 6.6 Hz, 2H), 3.90–3.80 (m, IH), 2.55 (t, J = 6.7 Hz, 2H), 1.02 ( d, J = 6.6 Hz, 6H). 36 IZ^ ./ 1 ZI ZIz I Method E, 6.31 min, m/z 428.0 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.14 (s, IH), 12.85 (s, IH), 9.30 (s, IH), 8.06 (d, J = 2.0 Hz, IH), 7.98 (s, IH) , 7.92 (d, J= 8.0 Hz, IH), 7.69-7.60 (m, 2H), 7.46 (d, J= 9.0 Hz, IH), 7.41 (dd, J= 9.0, 2.0 Hz, IH), 4.59 ( s, 2H), 3.99-3.87 (m, IH), 1.09 (d, J= 6.5 Hz, 6H). 37 \ P po IZ ! - 1 ZI ^g x ZI 'z I Method E, 5.17 min, m/z 427.9 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.15 (s, IH), 9.70 (s, IH), 8.04 (d, J = 0.9 Hz, IH), 8.02 (d, J = 1.9 Hz, IH), 7.97 -7.92 (m, 2H), 7.51 (d, J = 8.9 Hz, IH), 7.42 (dd, J = 8.9, 2.0 Hz, IH), 7.12-7.06 (m, 2H), 4.82 (s, 2H), 3.29(s, 3H). 2 exchangeable NH are not visible: 38 IZ xz IZ 1 7 o=\ ^ZI Method E, 6.35 min, m/z 426.0 [M+H] ⁺ Ή NMR (400 MHz DMSO-de): δ 13.22 (s, IH), 12.83 (s, IH), 9.20 (s, IH), 8.07 (s, IH), 8.01 (d, J = 2.0 Hz, IH) , 7.96 (s, IH), 7.88 (dd, J = 8.5, 2.0 Hz, IH), 7.85 (d, J = 8.0 Hz, IH), 7.46 - 7.38 (m, 2H), 7.15 (d, J = 8.5 Hz, IH), 4.64 (s, 2H), 3.93 (m, IH), 1.11 (d, J = 6.5 Hz, 6H). 39 IZ X=z IZ I £ o I Method E, 4.99 min, m/z 293.0 [M+H] ⁺ Ή NMR (400 MHz, CD ₃ OD): δ 8.37 - 8.32 (m, IH), 8.03 (d, J = 1.9 Hz, IH), 7.82 7.77 (m, 2H), 7.74 (d, J = 8.9 Hz, IH), 7.58 (dd, J = 9.0, 2.0 Hz, IH), 7.00 - 6.94 (m, 2H), 4 exchangeable protons (3 x NH and 1 x OH) are not observed due to being hydrochloric salt 40 0> IZ Xz IZ 1 ² zA 1 o % Method E, 5.46 min, m/z 419.0 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de): δ 9.37 (s, IH), 8.07 - 8.04 (m, IH), 7.99 (s, IH), 7.61 (d, J = 2.0 Hz, IH), 7.55 (dd , J = 8.4, 2.0 Hz, IH), 7.46 (d, J = 8.9 Hz, IH), 7.41 (dd, J = 8.9, 2.0 Hz, IH), 7.26 (d, J = 8.4 Hz, IH), 5.40 (s, 2H), 3.86 (s, 3H), 2.54 (s, 3H). 3 NH are not visible. TFA salt 41 IZ^ IZ .· 1 ZI A ZI AC z I Method E, 5.44 min, m/z 391.1 [M+H] ^{+ F} H NMR (400 MHz, DMSO-de): δ 13.49 (s, IH), 12.81 (s, IH), 9.28 (s, IH), 8.10 (t, J = 1.4 Hz, IH), 7.98 - 7.89 ( m, 3H), 7.42 (d, J = 1.9 Hz, 2H), 7.37 (d, J = 7.9 Hz, 2H), 6.25 (t, J = 5.9 Hz, IH), 5.82 (d, J = 7.8 Hz, IH), 4.25 (d, J = 5.4 Hz, 2H), 3.70 (m, IH), 1.05 (d, J = 6.5 Hz, 6H) 42 I z CP IZ xz IZ I c A ^1 Method B, 3.18 min, m/z 420.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.40 (s, IH), 12.77 (s, IH), 9.11 (s, IH), 8.10 (s, IH), 7.93 (s, IH), 7.83-7.69 ( m, 3H), 7.41 (s, 2H), 6.97 (s, IH), 4.54 (s, 2H), 4.00–3.88 (m, IH), 2.75–2.69 (m, 2H), 1.23 (d, J = 7.2 Hz, ZN), 1.10 (d, J = 6.5 Hz, 6H). 460 Cl 1 H _H 0 \ JTJ //APnAf nA^Z ⁿ ~n ' \ HI H OMe F Method B, 3.32 min, m/z 466.1 [M+H]+ IH NMR (400 MHz, DMSO-d6) δ 13.35 (s, IH), 12.73 (s, IH), 8.72 (s, IH), 8.70 (t, IH), 8.08 (s, IH), 7.91 (d, J = 8.9 Hz, IH), 7.84 (d, J = 8.0 Hz, IH), 7.68 (d, J = 1.4 Hz, IH), 7.64 (dd, J =8.1, 1.4 Hz, IH), 7.56 (d, J = 8.9 Hz, 1H), 4.13 (m, 2H), 3.98 (s, 3H) 461 Cl°/2 | H__/r-A/ X£v H Method B, 3.05 min, m/z 456.2 [M+H]+ IH NMR (400 MHz, DMSO-d6) δ 13.29 (s, IH), 12.30 (bs, IH), 8.78 (bs, IH), 8.05 (s, IH), 7.98 (s, IH), 7.79 (d, J = 7.9 Hz, IH), 7.57 - 7.51 (m, 2H), 7.49 (dd, J = 8.3, 1.9 Hz, IH), 7.02 (d, J = 8.3 Hz, IH), 4.50 (s, 2H), 3.98 - 3.89 (m, IH), 3.87 (s, 3H), 1.10 (d, J = 6.6 Hz, 6H) 462 1t! ^H /—v P ^N V ^N /^Y j F Ό JJ) HlPnALf nAA ⁿ 'N —\ η / HF Method B, 3.08 min, m/z 446.4 [M+H]+ IH NMR (400 MHz, DMSO-d6) δ 13.01 (s, IH), 12.36 (s, IH), 8.70 (s, 2H), 8.13 (s, IH), 7.82 (d, J = 8.0 Hz, IH) , 7.64 (s, IH), 7.60 (dd, J = 8.0, 1.4 Hz, IH), 7.37 (s, 2H), 4.13 (m, 2H), 3.96 (s, 3H), 2.46 (s, 3H). 463 1 ° f ^HN \ Ό JJ //V/ ^HN 'NH Method B, 2.75 min, m/z 436.3 [M+H]+ IH NMR (400 MHz, DMSO-d6) δ 12.97 (s, IH), 12.12 (s, IH), 8.58 (s, IH), 8.10 (s, IH), 7.77 (d, J = 7.8 Hz, IH) , 7.52 (s, IH), 7.44 (dd, J = 8.4, 1.9 Hz, IH), 7.35 (s, 2H), 6.99 (s, IH), 4.48 (s, 2H), 3.92 (m, IH), 3.85 (s, 3H), 2.45 (s, 3H), 1.10 (d, J = 6.6 Hz, 6H).

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General method C:

LiHMDS, THF, 0 °C - r.t. or

(R ³ O) ₂ B PG

G\

Pd(dppf)CI ₂ .DCM

K ₂ CO ₃ , 1,4-dioxane

H ₂ O.80 °C

NEt ₃ , K ₂ CO ₃ , HCl, IPA or

MeCN, 80°C ^TF A DCM

The process for preparing the compound of the invention is shown below. Additional compounds which can be prepared in a similar manner from intermediates 3-9, 12-14, 17 and 18 using commercially available boronic acids, boronate esters or intermediates 43, 44, 51-65 using general method C are presented in tab. eleven.

Example 43 4-[5-[(4-Chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-N-ethyl-2fluorobenzamide

4-[5-[(4-Chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-Niethyl-2fluorobenzamide ( 100 mg, 0.20 mmol) was dissolved/suspended in methanol (3 ml) and HCl (4.0 M in dioxane) (6.01 ml, 24.02 mmol) was added. The reaction mixture was stirred at 25°C for 18 h with the formation of a white precipitate. The reaction mixture was concentrated in vacuo and dissolved in water, and the solution was immediately purified by ion exchange chromatography (SCX, eluting with 1M NH3 in MeOH). The solvent was removed in vacuo, the tarry residue was dissolved in DCM and a white solid precipitated immediately. The solid was triturated with diethyl ether and filtered. The solid was then dried under vacuum for 3 days to give 4-[5-[(4-chloro-1H-indazol-5yl)αmino]-1-methyl-1,2,4-triazol-3-yl]-N -ethyl-2-fluorobenzamide (50 mg, 0.12 mmol, 60% yield) as a white solid. UPLC-MS (ES+, Method B): 3.19 min, m/z 414.3 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ 13.42 (s, 1H), 8.63 (s, 1H), 8.32 (dt, J=6.1, 3.0 Hz, 1H), 8.11 (s, 1H), 7.74-7.53 ( m, 5H), 3.82 (s, 3H), 3.27 (qd, J=7.2, 5.5 Hz, 2H), 1.11 (t, J=7.2 Hz, 3H).

Step 1: N-(5-bromo-2-methyl-1,2,4-triazol-3-yl)-4-chloro-1-tetrahydropyran-2-yl-indazol-5-amine

To a stirred solution of 4-chloro-1-tetrahydropyran-2-yl-indazol-5-amine (14.47 g, 57.50 mmol) and 3,5-dibromo-1-methyl-1H-1,2,4-triazole (13.85 g , 57.50 mmol) in dry THF (150 ml) at -20°C under N2 atmosphere, a solution of sodium bis(trimethylsilyl)amide (1.0 M in THF) (57.50 ml, 57.50 mmol) was added, and the mixture was stirred at 0°C for 20 minutes. An additional solution of sodium bis(trimethylsilyl)amide (1.0 M in THF, 28.75 mL) was added and the reaction mixture was stirred for 20 min. The mixture was quenched with saturated aqueous NH ₄ Cl (150 ml) and extracted with EtOAc (250 ml). The layers were separated and the aqueous layer was further extracted with EtOAc (2x100 ml). The combined organics were dried over MgSO ₄ and concentrated in vacuo. The solid residue was triturated with diethyl ether and filtered, washed with additional diethyl ether to give N-(5-bromo-2-methyl-1,2,4-triazol-3-yl)-4-chloro-1-tetrahydropyran-2-yl -indazol-5-amine (19.75 g, 47.97 mmol, 83% yield) as a white solid. UPLC-MS (ES ⁺ , Method A): 2.79 min, m/z 413.0 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.15 (d, J=0.8 Hz, 1H), 7.74 (dd, J=8.9, 0.9 Hz, 1H), 7.51 (d, J= 8.9 Hz, 1H), 5.88 (dd, J=9.5, 2.4 Hz, 1H), 3.94-3.86 (m, 1H), 3.79-3.73 (m, 1H), 3.71 (s, 3H), 2.46-2.33 (m , 1H), 2.11-1.95 (m, 2Н), 1.83-1.54 (m, 3H).

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Step 2: 4-[5-[(4-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]N-ethyl -2-fluorobenzamide

N-Ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (83 mg, 0.28 mmol), N-(5bromo-2-methyl -1,2,4-triazol-3-yl)-4-chloro-1-tetrahydropyran-2-yl-indazol-5-amine (117 mg, 0.28 mmol) and potassium carbonate (82 mg, 0.60 mmol) were dissolved / suspended in 1,4-dioxane (2 ml) and water (0.5 ml). The reaction mixture was completely degassed by bubbling with nitrogen. Then the complex [1,1'bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (23 mg, 0.03 mmol) was added, followed by additional degassing, and then the reaction was heated to 90°С for 4 h. The reaction was evaporated under vacuum for silica gel and purified on a 4 g silica gel column eluting with 25-100% EtOAc in petroleum ether to give 4-[5-[(4-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]- 1-methyl-1,2,4triazol-3-yl]-N-ethyl-2-fluorobenzamide (100 mg, 0.19 mmol, 67% yield) as a pale yellow oil. UPLC-MS (ES+, Method A): 1.73 min, m/z 498.5 [M+H] ⁺ .

Ή NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.9 Hz, 1H), 8.12 (t, J=8.1 Hz, 1H), 8.03 (d, J=0.8 Hz, 1H), 7.93 (dd, J =8.2, 1.5Hz, 1H), 7.79 (dd, J=13.2, 1.5Hz, 1H), 7.59 (dd, J=9.1, 0.9Hz, 1H), 6.77 (dt, J=12.1, 5.4Hz, 1H) , 6.59 (s, 1H), 5.70 (dd, J=9.2, 2.7 Hz, 1H), 4.02 (dq, J=10.4, 2.5, 2.1 Hz, 1H), 3.82 (s, 3H), 3.75 (ddd, J =13.1, 8.5, 3.1 Hz, 1H), 3.52 (tt, J=7.4, 5.8 Hz, 2H), 2.60-2.46 (m, 1H), 2.23-2.05 (m, 3H), 1.84-1.64 (m, 2H ), 1.32-1.17 (m, 3H).

Compounds obtained in a manner analogous to that described above are shown in Table 1 below. eleven.

Table 11

Example Structure LC-MS Ή NMR 44 νΛ ^Η \\ \ ο Method B, 5.96 min, m/z 406.0 [m+n] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 12.90 (s, 1H), 8.84 (s, 1H), 8.18 (dd, J = 2.0, 1.0 Hz, 1H), 8.02 (d, J = 1.0 Hz, 1H), 7.90 (d, J = 9.0 Hz, 3H), 7.56 (dd, J = 9.0, 2.0 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.02 (d, J = 9.0 Hz, 2H), 4.48 (s, 2H), 3.96 (dp, J = 8.0, 6.5 Hz, 1H), 3.78 (s, 3H), 1.10 (d, J = 6.5 Hz, 6H) 45 I z ΙΖ ζ 1 ζ % ΖΞΕ d ΞΕ Method E, 4.82 min, m/z 449.1 [m+n] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.91 (s, 1H), 8.85 (s, 1H), 8.46 (d, J = 7.5 Hz, 1H), 8.17 (d, J = 1.5 Hz, 1H), 8.01 (d, J = 1.0 Hz, 14), 7.57-7.48 (m, 44), 6.98 (d, J=8.9 Hz, 14), 4.59-4.5 (m, 14), 4.46 (s, 24), 3.87 (s, 34), 3.79 (s, 34), 3.53 (t, J = 7.5 Hz, 24), 3.43 (t, J = 7.5 Hz, 24). 46 X ζ Ζ ^/ ζ' 1 ο=\ ^ζι Method B, 3.26 min, m/z 450.4 [m+n] ⁺ *4 NMR (400 MHz, DMSO-d ₆ ) δ 13.06 (s, 14), 8.00 (s, 14), 7.77 (d, J = 7.8 Hz, 14), 7.54-7.49 (m, 34), 7.32 ( d, J = 1.8 Hz, 14), 7.06 (dd, J = 8.9, 2.2 Hz, 14), 6.99 (d, J = 8.3 Hz, 14), 4.48 (s, 24), 3.97-3.88 (m, 14 ), 3.86 (s, 34), 3.39 (s, 34), 3.28 (s, 34), 1.09 (d, J = 6.6 Hz, 64). 47 ^ην Α 'BH O Method B, 2.83 min, m/z 374.4 [m+ng Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.92 (s, 14), 8.92 (s, 14), 8.18 (s, 14), 8.02 (s, 14), 7.92 (s, 24), 7.87 (s , 14), 7.57 (dd, J = 8.8, 1.8 Hz, 14), 7.50 (d, J = 8.8, 14), 3.81 (s, 34), 3.58 (t, J = 6.8 Hz, 24), 3.06 ( t, J = 6.8 Hz, 24), 3.04 (s, 34).

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48 Cl hn—/ A—NH > ^N \ H VNH o Method E, 5.07 min, m/z 483.0 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (br s, 1H), 8.47 (m, 2H), 8.08 (s, 1H), 7.577.50 (m, 2H), 7.41 (d, J = 2.0 Hz, 1H), 7.35 (dd, J = 8.5, 2.0 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 4.54 (m, 1H), 4.47 (s, 2H), 3.81 (s, 3H ), 3.76 (s, 3H), 3.56 (t, J = 7.5 Hz, 2H), 3.47 (t, J = 7.5 Hz, 2H). One NH was not observed 49 Cl HN—/ 7— NH >N _HH - ^N 'Z>6X ^/^0 \\ \__/ 0 Method E, 4.88 min, m/z 497.0 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.39 (s, br), 8.45 (s, 1H), 8.08 (d, J = 1.0 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.57-7.50 (m, 2H), 7.41 (d, J = 2.0 Hz, 1H), 7.35 (dd, J = 8.5, 2.0 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 4.45 (s , 2H), 4.13 (ddq, J = 12.0, 7.5, 4.5 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 2.87 (dd, J= 11.0, 6.5 Hz, 1H), 2.81 ( m, 1H), 2.69 (m, 1H), 1.90 (did, J = 13.0, 8.1, 6.2 Hz, 1H), 1.48 (m, 1H). One CH is hidden under the DMSO peak and one NH was not observed 50 ci ^N )—4 OH X/Wo 0 Method E, 6.07 min, m/z 526.0 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 8.46 (s, 1H), 8.10 (s, 1H), 7.65-7.48 (m, 2H), 7.40 (m, 3H), 6.96 (d, J = 7.0 Hz, 1H), 4.87 (s, 1H), 4.45 (s, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 3.53–3.42 (m, 2H), 1.84 ( s, 2H), 1.71–1.50 (m, 6H). 51 Cl ^N< Y-Z HN-/ V-NH HH ^'nXX. Υ/'Ό \\ \_I 0 Method E, 5.86 min, m/z 498.0 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.36 (s, br), 8.44 (s, 1H), 8.16 (d, J = 7.0 Hz, 1H), 8.10-8.05 (m, 1H), 7.57 (d , J =9.0 Hz, 1H), 7.52 (d,J= 11.5 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.35 (dd, J = 8.5, 2.0 Hz, 1H), 6.90 (d , J = 8.5 Hz, 1H), 4.48 (s, 2H), 4.29 (did, J= 11.0, 7.5, 4.0 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.73 (m, 2H), 3.67 (td, J = 8.0, 5.5 Hz, 1H), 3.47 (dd, J = 9.0, 4.0 Hz, 1H), 2.09 (dq, J = 12.5, 7.5 Hz, 1H), 1.811.69 (m , 1H). 52 Cl N^Y—/ HN—/ Y-NH ( 9 = ⁷ Ht ,__ _H YYo ft \ 0 Method E, 3.12 min, m/z 525.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.37 (s, 1H), 8.43 (s, 1H), 8.22 (s, 1H), 8.09 (d, J = 9.3 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 3.6 Hz, 1H), 7.45-7.39 (m, 2H), 6.93 (d, J = 8.2 Hz, 1H), 4.50 (s, 2H), 3.92 (dq , J = 13.5, 6.7 Hz, 1H), 3.75 (m, 7H), 3.02 (t, J = 4.5 Hz, 4H), 1.08 (d, J = 6.6 Hz, 6H). 53 Cl _u P / #4/ N /r\^ Ό ^N 'n4^ /N'N^^^ ⁷ H Method E, 2.87 min, m/z 426.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.37 (s, br), 8.48 (s, 1H), 8.17 (t, J = 5.8 Hz, 1H), 8.09 (s, 1H), 7.61-7.51 (m , 2H), 7.43-7.37 (m, 2H), 7.16 (d, J= 8.2 Hz, 1H), 4.21 (d, J = 5.8 Hz, 2H), 3.83 (s, 3H), 3.79 (s, 3H) , 1.88 (s, 3H) 54 ? H HM ⁰ / / \s—/ HN-\ n I 1 E—\ 7 ^X /N'N '-- H Method B, 3.28 min, m/z 465.4 [M+H] ⁺ Ή NMR (400 MHz, CDCE+TMS): δ 10.32 (br.s 1Η), 8.22 (d, J = 9.0 Hz, 1H), 8.10 (s, 1H), 7.92-7.86 (m, 2H), 7.47 ( d, J = 9.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.49 (s, 1H), 4.56 (s, 2H), 4.24 (d, J = 7.4 Hz, 1H), 4.09- 4.00 (m, 1H), 3.84 (s, 3H), 3.62 (t, J = 6.0 Hz, 2H), 2.93 (t, J = 5.7 Hz, 2H), 1.19 (d, J = 6.6 Hz, 6H). 55 Ci Η P / /ChT n J 1 1 />—\ / V N^V ,Ν-Υ ⁷ \=/ O H ^x Method B, 3.15 min, m/z 465.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.39 (s, br), 8.56 (s, 1H), 8.18 (t, J = 5.7 Hz, 1H), 8.11-8.09 (m, 1H), 7.76 (d , J = 8.0 Hz, 1H), 7.61-7.53 (m, 2H), 7.52-7.45 (m, 2H), 3.91 (s, 3H), 3.81 (s, 3H), 3.34-3.23 (m, 2H), 1.11 (t, J = 7.2 Hz, ZN) 56 9 ¹ H __ 0—n ^z J) TT Y\=/ Ό N^X z ^N ~N H Method B, 3.52 min, m/z 383.3 [M+H] ^{+ X} H NMR (400 MHz, DMSO-d ₆ ) δ 13.40 (s, 1H), 8.61 (s, 1H), 8.11 (s, 1H), 8.02-7.92 (m, 4H), 7.60 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H) 57 9 ¹ H ° °A / \ rC / ^{NH N} JI 1 r 2>-k / - N-^Y^ ,N- _n ⁷ \=/ H ^{z N} Method B, 2.85 min, m/z 426.4 [M+H] ^{+ X} NMR (400 MHz, DMSO-d ₆ ) 13.37 (s, 1H), 8.48 (s, 1H), 8.11-8.06 (m, 1H), 7.757.64 (m, 1H), 7.61-7.51 (m, 2H ), 7.40-7.35 (m, 2H), 7.16 (d, J= 8.2 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.38 (s, 2H), 2.57 (d, J = 4.6 Hz, ZN)

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9 ¹ n ο- Method Β, Ή NMR (400 MHz, DMSO-de): δ 13.35 (s, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 7.82 (d, J = 58 π Όο Ν^Χ / Η ^Ν Ν-ν eV -Ν ΗΝ— Ό 3.13 min, m/z 481.4 [M+H] ⁺ 7.7 Hz, 1H), 7.61-7.51 (m, 2H), 7.20 (dd, J = 8.4, 2.1 Hz, 1H), 7.13 (d, J = 2.1 Hz, 1H), 6.47 (d, J = 8.2 Hz, 1H), 4.22-4.18 (m, 2H), 3.90-3.81 (m, 3H), 3.73 (s, 3H), 3.473.42 (m, 2H), 1.04 (d, J = 7.0 Hz, 6H). CI ι ι-ι Method B Ή NMR (400 MHz, DMSO-de): δ 13.35 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 7.72 (d, J 59 ζ ^χ ζ 4 Gu Ν ΗΝ-( Η ^Λ 3.32 min, m/z 479.4 [M+H] ⁺ 7.2 Hz, 1H), 7.59-7.49 (m, 2H), 7.43-7.36 (m, 2H), 6.35 (d, J8.6 Hz, 1H), 3.91-3.81 (m, 1H), 3.78 (s, 2H ), 3.72 (s, 3H), 3.37–3.34 (m, 2H), 2.72–2.67 (m, 2H), 1.91–1.85 (m, 2H), 1.04 (d, 7.0 Hz, 6H). 60 V Χ^/ ^ν 0ο Ν^Χ^ Η Η ^Ν Χ^>Ν /Ν'Ν ΧΝ V 0 Method B, 3.22 min, m/z 405.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de): δ 13.36 (s, 1H), 8.40 (s, 1H), 8.10 (s, 1H), 8.09-8.05 (m, 1H), 7.71-7.69 (m, 1H) , 7.53-7.50 (m, 2H), 7.38-7.21 (m, 5H), 5.31 (s, 2H), 3.72 (s, 3H) 61 X z Η ^Ν χ^Ν /Ν'Ν V.J. t' 0 N—' b Method B, 2.92 min, m/z 438.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de): δ 13.38 (s, 1H), 8.56 (s, 1H), 8.10 (s, 1H), 7.92-7.86 (m, 2H), 7.61 (d, J = 8.9 Hz , 1H), 7.58-7.52 (m, 1H), 7.46-7.40 (m, 2H), 3.81 (s, 3H), 3.76-3.21 (m, 8H) 62 CI ζώ Ν-^Χ Η Η -Ν^Ν / ^Ν 'Ν ΗΝ— Ο) Method B, 2.79 min, m/z 382.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de): δ 13.39 (s, br), 8.56 (s, 1H), 8.46 (q, J = 4.3 Hz, 1H), 8.10 (s, 1H), 7.92-7.87 (m , 2H), 7.87-7.82 (m, 2H), 7.60 (d, J= 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 3.81 (s, 3H), 2.78 (d, J = 4.5 Hz, ZN) 63 CI ^Ν Γχ\ ην-Ύχ Η ' ^N yN / ^Ν Ν G ο— Method B, 3.31 min, m/z 369.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de): δ 13.38 (s, 1H), 8.49 (s, 1H), 8.09 (s, 1H), 7.85-7.78 (m, 2H), 7.60 (d, J = 8.8 Hz , 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.35–7.29 (m, 2H), 4.42 (s, 2H), 3.79 (s, 3H), 3.29 (s, 3H) / Method B 64 CI | Η %νχ ^Ν \ ___Γ- \ ABOUT ΗΝ 4 -X 2.47 min, m/z 499.5, Ή NMR (400 MHz DMSO-de): δ 13.38 (s 1H), 8.46 (s 1H), 8.09(s, 1H), 7.92-7.85 (m, 1H), 7.59-7.51 (m, 2H), 6.94 ( d, ./8.4 Hz. 1H), 4.49 (s, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 4 II 1 1 ΝΧ/ Г Η / ^ν ⁷ ^ 501.5 [M+H] ⁺ 3.39-3.22 (m, 3H), 2.55-2.42 (m, 2H), 2.28 (br s, 6H) ϊ ¹ Η Method B 65 Ό GC Η Ν ζ ^Ν 'Ν 2.78 min, m/z 327.1, 329.1, 331.1 [M+H] ⁺ Ή NMR (400 MHz DMSO-de): δ 13.41 (s 1H), 8.81 (s 1H), 8.10 (s, 1H), 7.54 (d, J8.8 Hz 1H) 7.43(d, ./8.8.1H), 3.71(s, 3H) 66 CI Η _χ Ν Ν /Ν-Ν ο- 1 ο Method B, 1.47 min, m/z 395.3, 397.3 Ή NMR (400 MHz, DMSO-de): δ 13.39 (s, 1H), 8.61 (s, 1H), 8.10 (s, 1H), 7.78 (d, J 8.2 Hz, 1H), 7.62-7.48 (m, 3H), 7.38 (d, J 1.2 Hz, 1H), 4.54 (t, J6.3 Hz, 2H), 3.81 (s, 3H), 2.79 (t, 76.3 Hz, 2H). Η [M+N] ⁺ 67 CI / Η Ν^ΊΓ^γ ^Ν ' ΗΝ-Ά^ χ^Ν N-G \ 0 θ' -Ν \ / ΧΝ X ⁴ Ο Method B, 3.29 min, m/z 493.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.36 (s, 1H), 8.42 (s, 1H), 8.08 (s, 1H), 7.63-7.50 (m, 3H), 7.39-7.32 (m, 2H), 6.90 (d, J = 8.8 Hz, 1H), 3.97-3.87 (m, 1H), 3.80-3.74 (m, 6H), 3.53 (s, 2H), 2.75 (s, 3H), 1.08 (d, J = 6.6Hz, 6H) 68 ϊ ¹ Η χΑ/ ^Ν Ν JJ Ν-ΧΧ Η ' χ^Ν z ^N 'N \ 0 θ' -ο ⁷ ΗΝ—ζ Ο Method B, 3.22 min, m/z 470.4 [M+H] ⁺ 1H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 8.46 (s, 1H), 8.08 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.59-7.50 (m, 2H), 7.41 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 8.4, 1.9 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.43 (s, 2H), 3.89 ( dq, J = 13.5, 6.5 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 1.07 (d, J = 6.6 Hz, 6H).

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69 C Ϊ' n J ^Ν Λ J Τ νΆΖ /Ν'-n Η Method B, 3.20 min, m/z 410.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.37 (s, 1H), 8.47 (s, 1H), 8.08 (s, 1H), 7.60-7.51 (m, 2H), 7.38 (dd, 7=2.6, 1.4 Hz, 1H), 7.30 (dt,7 = 7.6, 1.2 Hz, 1H), 7.24 (d,7 = 7.9 Hz, 1H), 6.95 (ddd,7 = 8.2, 2.6, 1.1 Hz, 1H), 3.77 ( s, 3H), 3.75-3.70 (m, 4H), 3.123.07 (m, 4H). 70 Cl ^N J—L HN—Z / ^N H /N ₄ X/^ ^{N N} \\ X <X^nh ₂ Method B, 2.24 min, m/z 341.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 8.46 (s, 1H), 8.34 (d, J = 22 Hz, 1H), 8.08 (s, 1H), 7.82 (dd, J = 8.7, 2.3 Hz, 1H), 7.55 (q, J = 8.9 Hz, 2H), 6.52 (d, J = 8.7 Hz, 1H), 6.45 (s, 2H), 3.74 (s, 3H). 71 Cl _n I %-NH XV ^N W Λ H Method B, 2.88 min, m/z 427.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.37 (s, br), 8.42 (s, 1H), 8.14-8.07 (m, 2H), 7.98 (s, 1H), 7.62-7.50 (m, 2H) , 7.40-7.30 (m, 2H), 6.77 (dd, J = 9.3, 4.6 Hz, 1H), 3.86 (s, 3H), 3.76 (s, 3H), 2.63 (d, J = 4.6 Hz, ZN) 72 1 A Method B, 3.29 min, m/z 383.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.37 (s, br), 8.44 (s, 1H), 8.08 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.56-7.51 ( m, 1H), 7.31 (dd, J = 8.4, 2.0 Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.25 (s, 4H), 3.81(s, 3H) 73 I H __ HN-4 /-x^A^NN ₄ /X-/ O O J Τ V-/ nAL / ^N ~NH Method B, 2.77 min, m/z 396.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.38 (s, br), 8.48 (s, 1H), 8.35 (t, J = 5.9 Hz, 1H), 8.09 (dd, J = 1.6, 1.0 Hz, 1H), 7.81-7.76 (m, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.54 (dd, J = 8.8, 0.8 Hz, 1H), 7.26 (d, J = 5.7 Hz, 2H), 4.25 (d, J = 8.8 Hz, 2H), 3.78 (s, 3H), 1.87 (s, 3H) 74 / 9 ¹ H °x ζ^ΑχχΝ NF ^N \ O JN nA> _z ⁿ 'N H Method B, 3.13 min, m/z 356.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.40 (s, br), 8.64 (s, 1H), 8.18 (dd, J - 5.3, 0.7 Hz, 1H), 8.12-8.08 (m, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.58-7.53 (m, 1H), 7.36 (dd, J = 5.3, 1.3 Hz, 1H), 7.11-7.09 (m, 1H), 3.86 (s, 3H) , 3.82(s, 3H) 75 pO=s—? h ^-<A< ⁿ ^n /=\ nJ ] Г /)—(\ ? nX _z nJ r1 Method B, 3.01 min, m/z 432.3 [M+H] ⁺ !HNMR (400 MHz, DMSO-d ₆ ): δ 13.38 (s, 1H), 8.51 (s, 1H), 8.11-8.08 (m, 1H), 7.867.82 (m, 1H), 7.78-7.72 (m , 1H), 7.62-7.52 (m, 3H), 7.40-7.34 (m, 1H), 7.34-7.29 (m, 1H), 4.17 (d, J = 6.4 Hz, 2H), 3.80 (s, 3H), 2.85(s, 3H) 76 Cl _μ 1 H ,—N /x^X/NN / \ ⁿ 3j and H Method B, 2.65 min, m/z 327.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.41 (s, 1H), 9.18 (s, 1H), 9.13 (s, 2H), 8.72 (s, 1H), 8.10 (dd, J = 1.6, 1.0 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.9, 0.8 Hz, 1H), 3.84 (s, 3H) 77 Ϊ ¹ H _/° ^{- N} JJ T nA^ /N~ _n A—/ H Method B, 3.12 min, m/z 385.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 8.45 (s, 1H), 8.08 (s, 1H), 7.60-7.49 (m, 2H), 7.38 (d, J = 7.8 Hz , 2H), 6.95 (d, J = 8.2 Hz, 1H), 3.76 (s, 9H). 78 0 O=A° H Method B, 3.39 min, m/z 474.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.40 (s, br), 8.66 (s, 1H), 8.10 (dd, J = 1.5, 0.7 Hz, 1H), 8.10–8.05 (m, 2H), 7.78-7.72 (m, 2H), 7.58 (d, J = 8.8 Hz, 1H), 7.57-7.53 (m, 1H), 3.84 (s, 3H), 3.66-3.58 (m, 4H), 2.90-2.82 ( m, 4H) 79 A to ZI X 0 Method B, 2.57 min, m/z 411.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.37 (s, br), 8.57 (d, J = 2.4 Hz, 1H), 8.46 (s, 1H), 8.08 (s, 1H), 7.91 (dd, J = 8.9, 2.4 Hz, 1H), 7.63-7.48 (m, 2H), 6.84 (d, J = 8.9 Hz, 1H), 3.75 (s, 3H), 3.68 (t, J = 4.9 Hz, 4H), 3.47 (t, J = 4.8 Hz, 4H).

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80 9 ¹ n ____ he ^Ν Ρυ Η Method B, 2.86 min, m/z 355.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.39 (s, br), 8.49 (s, 1H), 8.11-8.08 (m, 1H), 7.847.80 (m, 1H), 7.74-7.68 (m , 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.57–7.53 (m, 1H), 7.367.30 (m, 1H), 7.30–7.24 (m, 1H), 5.22 (t, J = 5.8 Hz, 1H), 4.50 (d, J = 5.8 Hz, 2H), 3.79 (s, 3H) 81 CI 1 H ΗΝ-^ Method B, 2.04 min, m/z 330.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.37 (s, 1H), 8.35 (s, 1H), 8.07 (s, 1H), 7.51 (s, 2H), 6.41 (s, 1H), 3.68 (s , 3H), 3.50 (s, 2H), 2.81 (d, J= 6.0 Hz, 2H), 2.09 (s, 2H), 1.23 (s, 1H). 82 ϊ th r-ch ν ν LLd VM Η Method B, 2.95 min, m/z 369.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.40 (s, 1H), 8.56 (s, 1H), 8.10 (s, 1H), 7.91-7.84 (m, 2H), 7.61 (d, J = 8.8 Hz, 1H), 7.58-7.53 (m, 1H), 7.45-7.38 (m, 2H), 3.81 (s, 3H), 2.98 (br s, 3H), 2.92 (br s, 3H) 83 1' Η J° V ⁷ <ώΥΉ> ^ΝΗ /Ν-ν ⁴ - Η ^ζ Method B, 3.18 min, m/z 426.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 9.06 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 8.02 (d, J = 8.3 Hz, 1H ), 7.61-7.52 (m, 2H), 7.45-7.36 (m, 2H), 3.86 (s, 3H), 3.78 (s, 2H), 2.45-2.35 (m, 3H), 1.06 (t, J = 7.5 Hz, ZN) 84 ί ¹ Η Ν JJ ' /YV--/ ζ ^Ν 'Ν Η Method B, 2.15 min, m/z 344.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.64-13.10 (br s, 1H), 8.32 (s, 1H), 8.09-8.04 (m, 1H), 7.55-7.48 (m, 2H), 6.34-6.27 (m, 1H), 3.69 (s, 3H), 3.18 (s, 1H), 3.02-2.92 (m, 1H), 2.04-1.82 (m, 3H), 1.72-1.59 (m, 1H), 1.49-1.37 (m, 1H), 2 exchangeable NH are not visible. 85 / Λ° ci Ρ ι Η ΛΑ ^ν ΓΤ j Χ ζ ^Ν 'Ν Η Method B, 3.35 min, m/z 399.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 8.50 (s, 1H), 8.10 (s, 1H), 7.65-7.52 (m, 2H), 7.47-7.40 (m, 1H) , 7.40-7.34 (m, 1H), 7.29 (t, J= 7.9 Hz, 1H), 6.98-6.89 (m, 1H), 4.16-4.03 (m, 2H), 3.79 (s, 3H), 3.70-3.63 (m, 2H), 3.30 (s, 3H) 86 9' η / ^С| z/Y^v-Yy-o' u J Υ >Ad ζ ^Ν Ν — Η Method B, 3.69 min, m/z 389.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.39 (s, 1H), 8.51 (s, 1H), 8.10 (s, 1H), 7.82-7.73 (m, 2H), 7.64-7.53 (m, 2H) , 7.17 (d, J = 8.5 Hz, 1H), 3.88 (s, 3H), 3.78 (s, 3H). 87 θ' η I jA ^Ν ΓΧ J Υ />A_/ /Ν'Ν '-- Η Method B, 3.09 min, m/z 469.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.36 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.61-7.50 (m , 2H), 7.33-7.25 (m, 2H), 6.34 (d, J = 8.2 Hz, 1H), 5.41-5.31 (m, 1H), 3.94-3.85 (m, 1H), 3.83 (s, 3H), 3.74 (s, 3H), 3.64 (d, J = 4.8 Hz, 2H), 1.05 (d, J = 6.6 Hz, 6H) 88 9 ¹ η ____ he η j Ύ Α \JT ζ ^Ν 'Ν Η Method B, 2.80 min, m/z 355.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.39 (s, 1H), 8.49 (s, 1H), 8.09 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.64-7.52 (m , 2H), 7.32 (d, J = 8.4 Hz, 2H), 5.21 (t, J = 5.7 Hz, 1H), 4.50 (d, J = 5.6 Hz, 2H), 3.79 (s, 3H) 89 ι ^{1 Η ΗΟ} ν_ nJ Τ G/UA /) n-AJ _χ νΑ ΑνΖ Η ^ζ Method B, 2.80 min, m/z 341.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.46 (s, br), 10.91 (s, 1H), 8.97 (s, 1H), 8.14 (dd, J = 1.4, 1.0 Hz, 1H), 7.78 ( dd, J = 7.8, 1.7 Hz, 1H), 7.58 (dd, J = 8.8, 0.8 Hz, 1H), 7.51 (d, J= 8.8 Hz, 1H), 7.26-7.18 (m, 1H), 6.90-6.80 (m, 2H), 3.84 (s, 3H) 90 θ', Η _s Ζ ^Ν '> L .N^JY__/ /) /—\ Π / ⁷ ΑΧ V ^N Ζ° ΐ ° Method B, 3.34 min, m/z 398.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.42 (s, 1H), 9.20 (d, J = 2.1 Hz, 1H), 9.05 (d, J = 2.1 Hz, 1H), 8.7l(s, 1H ), 8.56 (t, J = 2.1 Hz, 1H), 8.11 (dd, J = 1.5,0.6 Hz, 1H), 7.627.54 (m, 2H), 4.37 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.33 (t, J = 7.1 Hz, ZN) 91 CI / Η ν Α/Υ ^Ν >= ^Ν /=\ ην-ΑΥ _n HjT° ^h Method B, 2.79 min, m/z 341.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.36 (s, 1H), 9.59 (s, 1H), 8.39 (s, 1H), 8.07 (d, J = 1.5 Hz, 1H), 7.68-7.61 (m , 2H), 7.59 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.9 Hz, 1H), 6.75 (d, J = 8.7 Hz, 2H), 3.74 (s, 3H).

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92 ^ν Π Ν--Χ Η CI Η Νυν η /N l=\u Method B, 3.16 min, m/z 379.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.37 (s, br), 12.91 (s, 1H), 8.51 (s, 1H), 8.10 (d, J = 1.5 Hz, 1H), 7.96 (s, 1H ), 7.90 (s, 1H), 7.64-7.51 (m, 3H), 3.82 (s, 3H), 2.61 (s, 3H). 93 Ν ^Ζ Η CI ό Η Ν^Ν _χ /Ν-ν -=N >-A_J Method B, 2.36 min, m/z 326.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.39 (s, br), 9.00 (d, J = 2.1 Hz, 1H), 8.62 (s, 1H), 8.54 (dd, J= 4.8, 1.7 Hz, 1H ), 8.15-8.08 (m, 2H), 7.63-7.52 (m, 2H), 7.41 (dd, J= 8.0, 4.8 Hz, 1H), 3.81 (s, 3H). 94 CI Η Λ ν _ζ Ε>Α7Λ /N\ Method B, 2.41 min, m/z 439.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.41 (s, br), 8.58 (s, 1H), 8.53-8.45 (m, 1H), 8.10 (s, 1H), 7.87 (q, J = 8.6 Hz , 4H), 7.60–7.52 (m, 2H), 3.81 (s, 3H), 3.41 (q, J = 6.3 Hz, 2H), 2.36–2.29 (m, 6H), 2 exchangeable NH are not visible. 95 ^v Π Η CI Η ' ^N ^ ^N y /Ν-ν o— Ό Method B, 3.41 min, m/z 355.3 [M+H] ⁺ *Н NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 8.50 (s, 1H), 8.09 (s, 1H), 7.64-7.52 (m, 2H), 7.46-7.41 (m, 1H ), 7.39-7.35 (m, 1H), 7.30 (t, J = 7.9 Hz, 1H), 6.92 (ddd, J = 8.2, 2.7, 0.9 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H) CI Method B 96 v; v- Η Η ^ ^Ν γΝ / ^Ν ~Ν ο-, >~AJ1 3.41 min, m/z 315.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.39 (s, 1H), 8.56 (s, 1H), 8.10 (s, 1H), 7.69 (s, 1H), 7.58-7.49 (m, 2H), 6.71 (d, J = 3.4 Hz, 1H), 6.56-6.51 (m, 1H), 3.77 (s, 3H) 97 C Η Η Ν υ ^ν >^ _ζ ^ν 'Ν ,___( N' 04 Method B, 3.05 min, m/z 408.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.40 (s, 1H), 8.57 (s, 1H), 8.10 (s, 1H), 7.86 (d, J 7.9 Hz, 1H), 7.78 (d, 77.8 Hz, 1H), 7.72 (s, 1H), 7.61-7.53 (m, 2H), 3.81 (s, 3H), 3.52 (t, 76.8 Hz, 2H), 3.01 (s, 3H), 2.99 (t, 76.8 Hz, 2H). CI η Method B Ή NMR (400 MHz, CDC1 ₃ ) δ 10.82 (s, 1H), 8.06 (d, 7 = 1.0 Hz, 1H), 8.02 (d, J = 9.0 98 Yr ό /Ν^Ν /Ν-ν -cc 2.71 min, m/z 331.3 Hz, 1H), 7.36 (dd, J = 9.0, 1.0 Hz, 1H), 6.70 (It, J = 3.0, 1.6 Hz, 1H), 6.48 (s, 1H), 4.34 (q, J = 2.8 Hz, 2H ), 3.91 (t, 7 = 5.4 Hz, 2H), 3.77 (s, 3H), 2.60 (ddd, J = 4.4, 2.5, 1.2 Η [M+N] ⁺ Hz, 2H). 99 ^Ν Οί Ν-^ Η CI Η ν^ν /Ν-ν o° Method B, 3.32 min, m/z 355.3 [M+H] ⁺ Ή NMR (400 MHz, CDC1 ₃ ) δ 8.07 (s, 2H), 8.01 (d, J = 24.8 Hz, 2H), 7.72 (s, 1H), 7.54 (d, J = 4.7 Hz, 1H), 7.42 ( d, J = 9.0 Hz, 1H), 6.99–6.91 (m, 2H), 3.85 (s, 3H), 3.80 (s, 3H). 100 /Ί Η CI ό Η ζ ^Ν γΝ /Ν-Ν it Method B, 3.32 min, m/z 341.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.38 (s, 1H), 9.41 (s, 1H), 8.47 (s, 1H), 8.11-8.08 (m, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.57-7.52 (m, 1H), 7.30-7.25 (m, 2H), 7.17 (t, J = 8.0 Hz, 1H), 7.59 (ddd, J = 8.0, 2.5, 1.1 Hz, 1H) , 3.78(s, 3H) 101 Η ϊ ¹ Η ^Ν χγΝ ΛΓ o— sg ^he Method B, 2.86 min, m/z 371.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.36 (s, 1H), 9.19 (s, 1H), 8.40 (s, 1H), 8.08 (dd, J = 1.7, 0.9 Hz, 1H), 7.58 ( d, J = 8.9 Hz, 1H), 7.55-7.51 (m, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.27 (dd, J = 8.2, 1.9 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 3.78 (s, 3H), 3.75 (s, 3H) 102 CI Ν%Π Η Η Ν _χ / ν Ν-ν M ^G S ^h o Method A, 1.41 min, m/z 410.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.37 (s, 1H), 8.40 (s, 1H), 8.08 (s, 1H), 7.73-7.66 (m, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.57-7.51 (m, 1H), 6.98-6.89 (m, 2H), 3.75 (s, 3H), 3.75-3.70 (m, 4H), 3.17-3.10 (m, 4H) CI Ι_1 Method B Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.38 (s, br), 8.57 (dd, J = 2.3, 0.6 Hz, 1H), 8.53 (s, 103 n^j J M — τ ^Ν >— /Ν-ν /=N A ss° 3.68 min, m/z 384.4 1H), 8.09 (dd, J = 1.5, 1.0 Hz, 1H), 8.02 (dd, J = 8.5, 2.4 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.54 (dd, J= 8.8 , 0.8 Hz, 1H), 6.78-6.73 (m, 1H), 5.31-5.21 (m, 1H), 3.78 (s, 3H), Η [M+N] ⁺ 1.29 (d, J=6.2 Hz, 6H)

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104 I ¹ n \ / ζ-X^ ^Ν χ^Ν /X/ Υ y K-P N-XX / ^N ~N - Η Method B, 3.33 min, m/z 373.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.37 (s, br), 8.49 (s, 1H), 8.09 (dd, J = 1.5, 1.0 Hz, 1H), 7.72 (t, J = 8.8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 8.8, 0.8 Hz, 1H), 6.87 (dd, J = 12.8, 2.4 Hz, 1H), 6.80 (dd, J = 8.7 , 2.5 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H) 105 Ι,Ζ ζ ⁴ / ^ΖΙ g D, O Method B, 2.41 min, m/z 424.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.38 (s, 1H), 8.49 (s, 1H), 8.09 (s, 1H), 7.82-7.76 (m, 2H), 7.59 (d, J = 8.8 Hz, 1H), 7.57-7.52 (m, 1H), 7.32 (d, J = 8.3 Hz, 2H), 3.79 (s, 3H), 3.60-3.53 (m, 4H), 3.46 (s, 2H), 2.38 -2.30(m, 4H) 106 CI Ο 1 ^Η / ^γΧΝ _ν HhX <ΤΥ ηνΧΧ /.fAXo Method B, 3.06 min, m/z 452.4 [M+H] ⁺ Ή NMR (400 MHz, CDC1 ₃ ) δ 8.07 (d,J = 8.3Hz, 2H), 8.06–7.88 (m, 2Н), 7.80 (d,J = 8.3Hz, 2Н), 7.32 (d,J = 9.0 Hz, 1H), 6.95-6.87 (m, 1H), 6.74 (s, 1H), 4.09 (qd,J = 7.2, 3.0Hz, 1H), 3.88 (dt,J = 8.3, 6.7Hz, 1H), 3.78 (d,J = 4.6Hz, 5Н), 3.34 (ddd,J = 13.9, 7.6, 4.9Hz, 1Н), 2.08-1.95 (m, 1Н), 1.98-1.83 (m, 2Н), 1.67-1.53 (m , 1H), 1 exchangeable NH is not visible. 107 ? Η / <Χ Jx ^N Η ' Method B, 2.94 min, m/z 343.3 [M+H] ⁺ Ή NMR (400 MHz, CD ₃ OD) δ 8.10 (s, 1H), 7.60 (dd,J=8.8, 1.1 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 6.45 (s, 1H) , 4.06 (s, 3H), 3.85 (s, 3H), 2.21 (s, 3H), 2 exchangeable NH are not visible. 108 ? τζ ⁴ A Method B, 2.94 min, m/z 315.3 [M+H] ⁺ Ή NMR (400 MHz, CD ₃ OD) δ 8.09 (dd,J = 7.3, 0.8Hz, 1Н), 7.51–7.48 (m, 2H), 6.416.37 (m, 1H), 3.77 (s, 3H), 2.74-2.66 (m, 2H), 2.49 (tp,J = 7.6, 2.8Hz, 2H), 1.99 (tt,J = 8.1, 6.9Hz, 2H), 2 exchangeable NH are not visible. 109 ? Η y-AzX /=\ ν D Τ Γ 2 ΝΧ / ^Ν -Ν ^λ -' Method B, 2.32 min, m/z 340.3 [M+H] ⁺ Ή NMR (400 MHz, CD3OD) δ 8.94 (dd, J = 2.2, 0.8Hz, 1H), 8.20 (dd, J = 8.1, 2.2Hz, 1H), 8.11 (d, J= 1.0Hz, 1H), 7.63 (d, J = 8.9Hz, 1H), 7.54 (dd, J =8.8, 1.0Hz, 1H), 7.34 (d, J = 8.1Hz, 1H), 3.86 (s, 3H), 2.56 (s, 3H) , 2 exchangeable NH are not visible. BY Ν CI 1 Η ___/ h D Τ U >-\j Ν-X^ /NN Η ⁷ Method B, 3.44 min, m/z 350.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.42 (s, br), 8.65 (s, 1H), 8.14-8.09 (m, 3H), 7.82 (dt,J = 7.7, 1.5 Hz, 1H), 7.64 -7.53 (m, 3H), 3.82 (s, 3H). 111 ? Η ζχΧ / ΧΝ Χ ^{Ν Ν} χί U U Χνη Ν-Χ^ / ^Ν 'Ν Η Method B, 2.39 min, m/z 315.2 [M+H] ⁺ Ή NMR (400 MHz, CD ₃ OD) δ 8.11 (s, 1H), 7.99 (s, 1H), 7.80 (s, 1H), 7.52 (d, J = 1.1Hz, 2H), 3.82 (s, 3H) , 2 exchangeable NH are not visible. 112 ? Η Υ .A Ν.___Ν _ζ ^Ν 'Ν <Ο Τ+Χ νΧ ζ ^ν ~ν Η Method B, 3.23 min, m/z 357.4 [M+H] ⁺ Ή NMR (400 MHz, CD ₃ OD): δ 8.10 (d, J= 1.0 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.54 - 7.48 (m, 2H), 6.64 (d, J = 2.0 Hz, 1H), 5.57 (hept, J = 6.7 Hz, 1H), 3.86 (s, 3H), 1.46 (d, J = 6.6 Hz, 6H). (2 x exchangeable Η) 113 Cl Mr. ι η X <^yy_N Method B, 3.36 min, m/z 369.3 [M+H] ⁺ Ή NMR (400 MHz, CD ₃ OD): δ 8.11 (s, 1H), 7.92 (q, J = 1.3, 0.9 Hz, 1H), 7.86 (dt, J = 7.3, 1.8 Hz, 1H), 7.62 (d , J = 8.9 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.42 - 7.35 (m, 2H), 4.49 (s, 2H), 3.85 (s, 3H), 3.39 (s, 3H) . (2 x exchangeable Η) 114 ϊ ^{1 n} 2'<α xry Η F Method B, 3.36 min, m/z 373.3 [M+H] ⁺ Ή NMR (400 MHz, CD ₃ OD): δ 8.10 (s, 1Η), 7.61 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.37 (dd, J= 5.9 , 3.2 Hz, 1H), 7.11 (dd, J= 10.2, 9.0 Hz, 1H), 6.95 (dt, J= 9.0, 3.5 Hz, 1H), 3.86 (s, 3H), 3.78 (s, 3H). (2 x exchangeable Η) 115 / Ο ζ-ζ X τζ ⁴ A ζ Method B, 2.63 min, m/z 373.3 [M+H] ⁺ Ή NMR (400 MHz, CD ₃ OD): δ 8.11 (d, J = 0.6 Hz, 1H), 8.02 (d, J = 0.7 Hz, 1H), 7.87 (d, J = 0.7 Hz, 1H), 7.52 ( s, J = 0.8 Hz, 2H), 4.30 (t, J = 5.2 Hz, 2H), 3.81 (s, 3H), 3.76 - 3.71 (m, 2H), 3.31 (s, 3H). (2 x exchangeable Η)

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116 A \ 7 ¹ 1 Method B, 2.35 min, m/z 437.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.40 (s, br), 8.49 (s, 1H), 8.09 (s, 1H), 7.80 - 7.76 (m, 2H), 7.61 - 7.51 (m, 2H ), 7.30 (ddd, J = 6.2, 4.4, 1.5 Hz, 2H), 3.78 (s, 3H), 3.55 3.40 (m, 5H), 2.38(s, 8H). 117 ? _BH /N Method B, 2.20 min, m/z 428.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.39 - 13.33 (m, 1H), 8.40 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H), 8.01 (s, 1H), 7.66 ( d, J = 0.7 Hz, 1H), 7.52 (s, 2H), 4.21 (t, J = 6.4 Hz, 2H), 3.72 (s, 3H), 3.51 (d, J = 4.8 Hz, 4H), 2.71 ( s, 2H), 2.40 (s, 4H). 118 1' ⁿ /''o- N D Τ τ // 4-2/ Ό / ^N N -- H Method B, 3.36 min, m/z 413.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.40 (s, br), 8.60 (s, 1H), 8.10 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 3.0 Hz, 2H), 7.52 (d, J = 1.4 Hz, 1H), 7.47 (dd, J = 8.0, 1.4 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.77 ( s, 3H). 119 Cl _μ / νΊΠ T aV / ⁿ -n H Method B, 2.83 min, m/z 329.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.39 (s, br), 8.64 (s, 1H), 8.10 (s, 1H), 7.60 - 7.51 (m, 2H), 7.40 (d, J= 1.9 Hz, 1H), 6.52 (d, J = 1.9 Hz, 1H), 4.05 (s, 3H), 3.81 (s, 3H) 120 <xVvmA N-/ ⁷ O H/ ^N Method B, 2.45 min, m/z 340.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.38 (s, br), 8.42 (s, 1H), 8.09 (s, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.56 - 7.51 ( m, 1H), 7.12 - 7.08 (m, 1H), 7.03 - 6.96 (m, 2H), 6.54 - 6.48 (m, 1H), 5.10 (s, 2H), 3.76 (s, 3H) 121 N-, 9' n O NJJ n %\/NH z ⁿ -n H Method B, 2.28 min, m/z 365.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.38 (s, 1H), 11.67 (s, 1H), 9.32 (s, 1H), 8.42 (s, 1H), 8.20 (d, J = 5.7 Hz, 1H), 8.10 (s, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.58 - 7.52 (m, 1H), 7.38 (dd, J = 5.7 , 1.0 Hz, 1H), 3.81 (s, 3H) 122 ? n _N /=\ NJ Jr Αθ / ^N 'N Method B, 2.68 min, m/z 462.4 [M+H] ⁺ Ή NMR (400 MHz, CD ₃ OD): δ 8.10 (s, 1H), 7.93 - 7.89 (m, 2H), 7.87 - 7.81 (m, 2H), 7.62 - 7.49 (m, 2H), 6.97 - 6.92 ( m, 2H), 6.49 - 6.44 (m, 2H), 4.38 (dd, J = 5.4, 4.0 Hz, 2H), 4.33 (dd, J = 5.5, 4.1 Hz, 2H), 3.82 (s, 3H). (2 x exchangeable Η) 123 Cl _H H ₂ N /=4 N \ TJN NM ^ / ^N N - H Method B, 3.07 min, m/z 340.3 [M+H] ⁺ Ή NMR (400 MHz, CD ₃ OD) δ 8.10 (s, 1H), 7.81 (dd, J = 7.9, 1.6 Hz, 1H), 7.65 (d, J = 8.9Hz, 1H), 7.52 (dd,7= 8.9, 1.0 Hz, 1H), 7.1O (ddd, J= 8.6, 7.2, 1.6 Hz, 1H), 6.79 (dd, J = 8.2, 1.2 Hz, 1H), 6.66 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 3.85 (s, 3H). (4 x exchangeable Η) 124 І _N /=N NHn ⁷ || Τ r >—c //4 Method B, 2.89 min, m/z 383.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.41 (s, 1H), 9.01 (dd, J = 2.1, 0.9 Hz, 1H), 8.80 (d, J = 5.1 Hz, 1H), 8.69 (s, 1H), 8.29 (dd, J = 8.2, 2.1 Hz, 1H), 8.11 (s, 1H), 8.04 (dd, J = 8.2, 0.8 Hz, 1H), 7.57 (d, J = 3.8 Hz, 2H), 3.83 (s, 3H), 2.81 (d, J = 4.8 Hz, 3H) 125 Ϊ ¹ H 0 _Μ ^Ύ ^Ν Υ ^Ν νΠ-5-- ^ΝΗ ^ 4 JI J 11 "n-4^ /Nn - ⁰ H Method B, 2.84 min, m/z 404.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.40 (s, br), 8.62 (s, 1H), 8.10 (s, 1H), 8.01 - 7.94 (m, 2H), 7.86 - 7.79 (m, 2H ), 7.61 - 7.53 (m, 2H), 7.38 (s, 2H), 3.82 (s, 3H). 126 9 ¹ H ΓΜΥ ^Ν Υ ^Ν \-Χ ^{Λ NH} n ]1 J, //V_y nAJ z ⁿ ~n H Method B, 2.07 min, m/z 330.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.37 (br s, 1H), 8.33 (s, 1H), 8.07 (s, 1H), 7.56 7.49 (m, 2H), 6.39 - 6.34 (m, 1H ), 3.69 (s, 3H), 3.31 - 3.27 (m, 2H), 2.83 (dd, J = 5.6, 5.6 Hz, 2H), 2.32 - 2.45 (m, 2H). 1 x exchangeable proton Η. 127 Cl 1 ^{H n} Co UI/I Method B, 2.36 min, m/z 369.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.37 (s, br), 8.53 (d, J = 3.0 Hz, 1H), 8.43 (s, 1H), 8.08 (t, J = 1.3 Hz, 1H) , 7.86 (dd, J = 8.9, 2.4 Hz, 1H), 7.62 - 7.49 (m, 2H), 6.63 (d, J = 8.9 Hz, 1H), 3.74 (s, 3H), 3.03 (s, 6H).

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128 9' f Υ/Ανay Ν Jl J T νΎυ An — Η Method B, 2.38 min, m/z 372.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 8.58 (s, 1H), 8.30 (s, 1H), 8.10 (s, 1H), 7.65 (dd, J = 8.0, 1.6 Hz, 1H), 7.61 - 7.47 (m, 4H), 3.85 (s, 2H), 3.79 (s, 3H). NH ₂ exchangeable protons 129 Ϊ ¹ Η Ν Υν ^Ν /=\ ⁴ JJ ΤAL/ νΥχ / ^ν -ν '—\ Η he Method B, 2.35 min, m/z 342.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.39 (s, br), 9.99 (s, 1H), 8.59 (s, 1H), 8.48 (d, J = 1.8 Hz, 1H), 8.12 - 8.05 ( m, 2H), 7.18 - 7.05 (m, 3H), 3.79 (s, 3H). 130 ϊ ¹ Η _Ν h Λ J Τ νΎΥ /Ν-ν '—\ Η ' νη ₂ Method B, 2.24 min, m/z 341.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.39 (s, 1H), 8.54 (s, 1H), 8.20 (d, J = 1.85 Hz, 1H), 8.12 - 8.09 (m, 1H), 7.87 ( d, J = 2.85 1H), 7.58 - 7.52 (m, 2H), 7.36 - 7.31 (m, 1H), 5.39 (br.s, 2H), 3.79 (s, 3H) 131 9 ¹ η ,___ _h ο /aV ⁿ y ⁿ \J}A CU J ΝΗ ₂ Η Method B, 2.70 min, m/z 368.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.40 (s, 1H), 8.57 (s, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.88 (m, 4H), 7.64 - 7.52 (m, 2H), 7.37 (s, 1H), 3.81 (s, 3H) 132 Cl _u νη ₂ 4 J Τ Υ / ^ν ~~ν Η Method B, 2.35 min, m/z 342.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.38 (s, br), 8.43 (s, 1H), 8.09 (s, 1H), 7.59 - 7.01 (m, 1H), 7.11 - 7.08 (m, 1H ), 7.03 - 6.97 (m, 2H), 6.53 - 6.48 (m, 2H), 5.14 (bs, 2H), 3.76 (s, 3H) 133 C! _Η ΝΗ ₂ /=9 ^ν ΤΎ Τ Hj ν-Ύ / ^ν ' _Ν 9- ⁷ Η ' Method A, 1.09 min, m/z 342.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.40 (s, br), 8.62 (s, 1H), 8.12 - 8.09 (m, 1H), 7.88 (d, J = 5.41 Hz, 1H), 7.54 ( m, 2H), 6.96 - 6.91 (m, 2H), 6.26 (br.s, 2H), 3.81 (s, 3H). 134 I ¹ η ν II 1 1 /А\А νΥ/ / ⁿ -n ν Η / Method A, 1.29 min, m/z 329.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.40 (s, br), 8.65 (s, 1H), 8.11 - 8.07 (m, 1H), 7.58 - 7.51 (m, 2H), 7.40 (d, J = 2.0 Hz, 1H), 6.51 (d, J = 2.0 Hz, 1H), 4.05 (s, 3H), 3.80 (s, 3H) 135 Ο. / f _Η V-NH NJ Τ Ύ />—<\ } Method A, 1.28 min, m/z 382.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.41 (s, br), 8.56 (s, 1H), 8.55 - 8.49 (m, 1H), 8.31 - 8.27 (m, 1H), 8.11 - 8.07 (m , 1H), 7.99 - 7.92 (m, 1H), 7.82 - 7.52 (m, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.57 - 7.54 (m, 1H) 7.47 (t, J = 7.66 Hz , 1H) 3.81 (s, 3H) 3.17 (d, J = 5.1Hz, ZN) 136 Yf Ϊ ¹ HP aA/Yn /=< cd t g νΎΥ /N- _n 9—7 H ^Z Method B, 4.15 min, m/z 409.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d6) δ 13.41 (s, br), 8.62 (s, 1H), 8.12-8.09 (m, 1H), 7.85 (dt, J= 7.8, 1.3 Hz, 1H), 7.71- 7.68 (m, 1H), 7.66-7.50 (m, 3H), 7.39-7.34 (m, 1H), 3.81 (s, 3H). 137 A ^H P h ii T Y V-/ ν-Ay /Nn H Method B, 4.21 min, m/z 417.3 [M+H] ⁺ 1H NMR (400 MHz, DMSO-d6) δ 13.40-13.35 (m, 1H), 8.50 (s, 1H), 8.09 (t, J = 1.2 Hz, 1H), 7.89-7.80 (m, 2H), 7.63- 7.50 (m, 2H), 7.49-7.36 (m, 2H), 7.24-7.10 (m, 1H), 7.09-6.94 (m, 4H), 3.78 (s, 3H) 138 I ¹ H Vf AaajA n;JJX nYa / ⁿ 'N h Method B, 4.13 min, m/z 409.2 [M+H] ⁺ 1H NMR (400 MHz, DMSO-d6) δ 13.40 (s, 1H), 8.59 (s, 1H), 8.10 (s, 1H), 7.98-7.89 (m, 2H), 7.57 (q, J = 8.9 Hz, 2H), 7.42-7.31 (m, 2H), 3.80 (s, 3H).

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139 About x ^ZI 7- Method B, 2.96 min, m/z 450.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de): δ 13.02 (brs, 1H), 8.40 (brs, 2H), 8.24 (s, 1H), 8.11 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H ), 7.38 - 7.29 (m, 3H), 6.89 (d, J = 8.4 Hz, 1H), 4.42 (s, 2H), 3.97 - 3.85 (m, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 2.44 (s, 3H), 1.07 (d, J = 6.6 Hz, 6H). 140 0 HN—^ ^NH 1 Η __/ y—4 NN /==4-0 ⁷ b O J T >A_/ νΆΧ / ^ν ~ ν — Η Method B, 2.30 min, m/z 463.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de): δ 12.99 (br s, 1H), 8.72 (d, J = 7.3 Hz, 1H), 8.26 (br s, 1H), 8.23 (s, 1H), 8.12 (s , 1H), 7.39 - 7.29 (m, 4H), 6.90 (d, J = 8.4 Hz, 1H), 4.65 (sextet, J = 7.4 Hz, 1H), 4.49 (s, 2H), 3.98 (t, J = 8.9 Hz, 2H), 3.88 (t, J = 8.7 Hz, 2H), 3.80 (s, 3H), 3.72 (s, 3H), 2.44 (s, ZH). 1 H exchangeable 141 \ Λ~ΝΗ , ο ^h _z ⁿ AJ Η ___/ y--/ Aw ⁿ yN/=W 0 n1 τ τ АА / ^N ~N '-- H Method B, 2.34 min, m/z 477.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de): δ 13.01 (s, br), 8.23 (s, 1H), 8.12 (s, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.40 - 7.28 (m , 4H), 6.88 (d, J = 8.4 Hz, 1H), 4.44 (s, 2H), 4.18 - 4.09 (m, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 2.85 (ddd, J = 24.7, 9.6, 6.3 Hz, 2H), 2.74 - 2.69 (m, 1H), 2.45 (s, 3H), 1.93 - 1.85 (m, 1H), 1.52 - 1.43 (m, 1H). 1 pyrrolidine proton under the DMSO peak. 1 N exchangeable. 142 O ^N /XX NN O F ^F N^S/ 1 Method B, 3.43 min, m/z 464.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ/ppm: 13.08 (1H, s), 8.69 (1H, t, J = 6.4Hz), 8.62 (1H, s), 8.12-8.07 (2H, br), 7.80 (1H, d, J = 8.0Hz), 7.60-7.56 (2H, w), 7.46 (1H, d, J = 11.2Hz), 4.11 (2H, qd, J = 6.4Hz, 10.0Hz), 3.95 (ZN , s), 3.83 (ZN, s). 143 H ,___ _k o ⁿ / JLJL n-v v/hn-a- H ^G O Method B, 3.64 min, m/z 438.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ/ppm: 13.07 (1H, s), 8.61 (1H, s), 8.12-8.08 (2H, b), 7.86 (1H, s), 7.79 (1H, d, J = 8.8Hz), 7.58-7.49 (2Н, w), 7.46 (1Н, d, J = 10.8Hz), 3.95 (ЗН, s), 3.82 (ЗН, s), 1.38 (9Н, s) 144 LL _w ZI i Z, 1 7 Method B, 3.57 min, m/z 480.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ/ppm: 13.15 (1H, s), 8.68 (1H, t, J = 6.4Hz), 8.47 (1H, s), 8.11 (1H, s), 8.02 (1H , s), 7.80-7.76 (2H, w), 7.56-7.52 (2H, w), 4.16-4.06 (2H, w), 3.93 (ZH, s), 3.81 (ZH, s). 145 1' ^H Ji ⁰ ArYUM i? n 1 T J. in \JT / N^Y' ^N HN—< H \ \ Method B, 3.66 min, m/z 498.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.37 (s, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.51 (q, J = 8.9 Hz, 2H), 7.43-7.33 (m, 2H), 6.93 (d, J = 8.4 Hz, 1H), 4.72 (p, J = 6.5 Hz, 1H), 4.44 (s, 2H), 3.91 (dq, J = 13.7, 6.8 Hz, 1H), 3.82 (s, 3H), 1.45 (d, J = 6.5 Hz, 6H), 1.08 (d, J = 6.6 Hz, 6H). 146 / d H Y Z ΞΕ Method E, 7.19 min, m/z 485.9 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de): δ 12.91 (s, br), 8.96 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.02 (s, 1H), 7.96 (d, J = 9.0 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.71 (td, J = 8.0, 1.5 Hz, 1H), 7.66-7.58 (m, 1H), 7.58-7.38 (m, 4H) , 7.06 (d, J = 9.0 Hz, 2H), 4.50 (s, 2H), 3.96 (dp, J = 8.0, 6.5 Hz, 1H), 1.10 (d, J = 6.5 Hz, 6H). 147 O \ / Η X ^{N 0} Method B, 4.08 min, m/z 499.4 [M+H]+ Ή NMR (400 MHz, DMSO-de) δ 13.02 (s, br), 11.09 (s, 1H), 8.64 (m, Hz, 1H), 8.44 (d,J = 1.3 Hz, 1H), 8.14–8.07 ( m, 2H), 8.01 (dt,J = 8.4, 1.0 Hz, 1H), 7.82 (d,J = 7.8 Hz, 1H), 7.75-7.65 (m, 3H), 7.58 (d, J = 8.8 Hz, 1H ), 7.42 (m, Hz, 1H), 7.06 (d, J = 8.9 Hz, 1H), 4.52 (s, 2H), 3.98–3.89 (m, 1H), 3.93 (3, 3H), 1.11 (d, J = 6.6 Hz, 6H). 148 O / H r ^N hnA ηνΎ Ν,ρΥ ^{0 0} Method B, 4.13 min, m/z 469.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.02 (s, 1Η), 11.10 (s, 1H), 8.64 (dd, J = 5.0, 1.0 Hz, 1H), 8.45 (d, J= 1.9 Hz, 1H) , 8.15-8.06 (m, 4H), 8.01-7.92 (m, 2H), 7.69 (dd, J = 8.9, 2.0 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.41 (m, 1H ), 7.15-7.08 (m, 2H), 4.53 (s, 2H), 3.97 (m, 1H), 1.11 (d, J = 6.6 Hz, 6H) 149 ? n p hn—<a hnAAnAA about And Method B, 3.06 min, m/z 559.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de): δ 13.38 (s, 1Η), 8.62 (s, 1H), 8.27 (d, J = 21.3 Hz, 2H), 8.07 (d, J = 0.9 Hz, 1H), 7.74 - 7.70 (m, 2H), 7.60 - 7.54 (m, 3H), 7.52 - 7.46 (m, 2H), 7.45 - 7.39 (m, 2H), 6.94 (d, J = 8.4 Hz, 1H), 4.50 ( d, J = 2.0 Hz, 2H), 4.31 (s,

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1H), 3.82 (s, 3H), 3.03 (s, 2H), 2.87 (d, J= 11.5 Hz, 1H), 2.07 (dt, J= 13.7, 6.9 Hz, 2H), 1.73 (d, 7 = 7.2 Hz, 1H). 150 ^C| \ 1 s il 1 Method B, 3.41 min, m/z 543.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.40 (s, 1H), 9.14 (s, 1H), 8.73 (d, J = 6.8 Hz, 3H), 8.11 (s, 1H), 7.90 (s, 2H) , 7.81 (d, J= 8.0 Hz, 1H), 7.68-7.51 (m, 4H), 4.12(qd, J = 9.7, 6.4 Hz, 2H), 3.95 (s, 3H). 151 I Η ηνΎ O / ° Method B, 4.61 min, m/z 533.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.41 (s, 1H), 11.74 (s, 1H), 8.85 (d, J=9.0 Hz, 1H), 8.67 (dd,J=4.9, 1.6 Hz, 1H ), 8.16-8.11 (m, 2H), 8.05 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.70 (dd, J = 7.8, 2.8 Hz, ZN), 7.45 (dd, J = 7.3, 5.0 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 4.53 (s, 2H), 4.01–3.88 (m, 1H), 3.94 (s, 3H), 1.12 ( d, J = 6.5 Hz, 6H). 152 ? ^H HN—/ ^h ' ^nJ UUAn ^/ ^m ^h il J o nA / Method B, 3.08 min, m/z 533.3 [M+H] ⁺ Ή NMR (400 MHz, CDC1 ₃ ) δ 10.49 (s, 1H), 8.87-8.81 (m, 2H), 8.47 (d, J = 9.0 Hz, 1H), 8.16-8.03 (m, 1H), 7.81-7.68 (m, 3H), 7.51 (dd, J = 9.0, 1.0 Hz, 1H), 7.21 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H) , 4.57 (s, 2H), 4.25-4.07 (m, 1H), 4.00 (s, 3H), 1.20 (d, J = 6.6 Hz, 6H). 153 ci V / H Af An /° H ^XI Method B, 4.86 min, m/z 543.2 [M+H] ^{+ X} H NMR (400 MHz, DMSO-d ₆ ) d 13.44 (s, 1H), 11.76 (s, 1H), 8.86-8.73 (m, 2H), 8.70 (dd, J =5.0, 1.8 Hz, 1H), 8.23-8.12 (m, 2H), 8.09 (d, J = 8.3 Hz, 1H), 7.94-7.81 (m, 3H), 7.71 (d, ./9.0 Hz, 1H), 7.49 (ddd, J = 7.3, 5.0, 1.1Hz, 1H), 4.15 (qd, J = 9.7, 6.4 Hz, 2H), 4.05 (s, 3H).

General way D:

The process for preparing the compound of the invention is shown below. Additional compounds that can be obtained in a similar way using Intermediate compounds 1, 2 and 39 and General method D, are presented in table. 12.

Example 154 2-[4-[5-(1H-indazol-5-ylamino)-4H-1,2,4-triazol-3-yl]phenoxy]-1-morpholinoethanone

1-Morpholino-2-[4-[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2-ylindazol-5yl)amino]-1,2,4-triazol-3-yl]phenoxy] solution ethanol (44 mg, 0.07 mmol) in hydrogen chloride (1.25 M in MeOH, 3.0 ml, 3.75 mmol) was stirred at room temperature under N ₂ overnight. Solvents were removed under reduced pressure and the remaining solid was purified by preparative HPLC to give 2-[4-[5-(1H-indazol-5-ylamino)-4H-1,2,4-triazol-3-yl] phenoxy]-1 morpholinoethanone (15 mg, 0.03 mmol, 45% yield) as a white solid. LC-MS (ES+, Method E): 5.22 min, m/z 420.1 [M+H] ⁺ .

1H NMR (500 MHz, DMSO-d6): δ 13.36 (s, 1H), 12.80 (s, 1H), 9.17 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.89 (d , J=9.0 Hz, 2H), 7.41 (d, J=1.5 Hz, 2H), 7.06 (d, J=8.5 Hz, 2H), 4.92 (s, 2H), 3.63 (t, J=5.0 Hz, 2H ), 3.58 (t, J=5.0 Hz, 2H), 3.50-3.44 (m, 4H).

Stage 1: methyl 2-[4-[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]1,2,4-triazol-3-yl]phenoxy] acetate

The vial was loaded with N-(5-bromo-1-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-1-tetrahydropyran-2-yl

- 136 042028 indazol-5-amine (134 mg, 0.30 mmol), [4-(2-methoxy-2-oxoethoxy)phenyl]boronic acid (95 mg, 0.45 mmol) and potassium carbonate (124 mg, 0.90 mmol). 1,4-dioxane (2.0 ml) and water (0.40 ml) were added and the solution was degassed with N2 for 10 min. Pd(dppf)Cl ₂ -DCM complex (25 mg, 0.03 mmol) was added, the vial was sealed, and the reaction was heated at 80°C for 18 h. The mixture was diluted with EtOAc (15 ml) and water (15 ml), and layers shared. The aqueous layer was extracted with EtOAc (2x15 ml) and the combined organics were dried (phase separator) and concentrated. The crude material was purified by flash column chromatography (SiO ₂ , eluting with 30-60% EtOAc in petroleum ether) to give methyl 2-[4-[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2- ylindazol-5-yl)amino]-1,2,4triazol-3-yl]phenoxy]acetate (80 mg, 0.15 mmol, 50% yield) as a yellow foamy solid. LC-MS (ES+, Method C): 3.37 min, m/z 533.2 [M+H] ⁺ .

Stage 2: 2-[4-[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]-1,2,4triazol-3-yl]phenoxy]acetic acid

A solution of methyl 2-[4-[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]-1,2,4triazol-3-yl]phenoxy]acetate (80 mg, 0.15 mmol) and potassium hydroxide (25 mg, 0.45 mmol) in methanol (2.4 mL) and water (0.6 mL) were stirred at room temperature under N2 atmosphere overnight. The methanol was removed under reduced pressure and the remaining aqueous mixture was acidified to pH 4 with the addition of 5% aqueous KHSO4 solution. The mixture was extracted with EtOAc (3x15 ml) and the combined organics were washed with brine (15 ml), dried (phase separator) and concentrated. The crude material was purified by flash column chromatography (SiO ₂ , eluting with 5-20% MeOH in DCM) to give 2-[4-[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2-ylindazole- 5-yl)amino]-1,2,4triazol-3-yl]phenoxy]acetic acid (71 mg, 0.14 mmol, 91% yield) as a white solid. LC-MS (ES ⁺ , Method C): 2.85 min, m/z 519.3 [M+H] ⁺ .

Step 3: 1-morpholino-2-[4-[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2-ylindazol-5yl)amino]-1,2,4-triazol-3-yl] phenoxy]ethanone

To a stirred solution of 2-[4-[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2-ylindazol-5yl)amino]-1,2,4-triazol-3-yl]phenoxy]acetic acid (71 mg, 0.14 mmol) and HATU (68 mg, 0.18 mmol) in anhydrous DMF (2 mL) at room temperature under N2 were added DIPEA (48 μL, 0.27 mmol) and morpholine (18 μL, 0.21 mmol), and the reaction the mixture was stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was taken up in EtOAc (20 ml) and washed with 5% aqueous KHSO4 (2x10 ml) and brine (10 ml). The organics were dried (phase separator) and concentrated. The crude material was purified by flash column chromatography (SiO2 eluting with 0-10% MeOH in DCM) to give 1-morpholino-2-[4[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2- ylindazol-5-yl)amino]-1,2,4-triazol-3yl]phenoxy]ethanone (44 mg, 0.07 mmol, 55% yield) as a yellow oily solid. LC-MS (ES ⁺ , Method C): 2.88 min, m/z 588.3 [M+H] ⁺ .

Compounds obtained in a manner analogous to that described above are shown in Table 1 below. 12. Ex in table. 12 stands for Example.

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Table 12

Example Structure LC-MS sh nmr 155 XZI Z=\J. Method E, 5.20 min, m/z 408.1 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 13.45 (s, 1H), 12.80 (s, 1H), 9.15 (s, 1H), 8.17 (t, J = 5.5 Hz, 1H), 8.10 (s, 1H), 8.00-7.86 (m, 3H), 7.42 (s, 2H), 7.09 (d, J = 8.5 Hz, 2H), 4.56 (s, 2H), 3.41-3.36 (m, 2H), 3.35-3.27 (m, 2H), 3.25 (s, 3H). 156 U' ΙΖ Ζ n ΙΖ s ζ' ^Η ΞΕ Method E, 4.38 min, m/z 419.2 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): 12.82 (s, 1H), 9.24 (s, 1H), 8.15-8.06 (m, 2H), 7.95 (s, 1H), 7.92 (d, J = 8.5 Hz , 2H), 7.43 (s, 2H), 7.09 (d, J = 8.5 Hz, 2H), 4.54 (s, 2H), 4.23-4.13 (m, 1H), 2.94-2.80 (m, 2H), 2.76- 2.67 (m, 1H), 1.92 (td, J = 14.0, 8.0 Hz, 1H), 1.61–1.49 (m, 1H). Three protons were not observed due to overlap with the residual DMSO signal. 157 I Z ΙΖkz IZ 1 with λ & I Method E, 4.45 min, m/z 419.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 12.81 (s, 1H), 9.18 (s, 1H), 8.15-8.01 (m, 2H), 7.97-7.85 (m, 3H), 7.42 (d, J = 1.5 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 4.53 (s, 2H), 4.17 (qd, J = 7.5, 3.5 Hz, 1H), 2.94–2.79 (m, 2H), 2.75 -2.66 (m, 1H), 1.92 (did, J = 12.5, 8.0, 6.0 Hz, 1H), 1.54 (ddt, J = 12.5, 8.0, 5.5 Hz, 1H). Three protons were not observed due to overlap with the residual DMSO signal. 158 e Ύ C 1 ZI ^Η Χ 'Ζ Method E, 4.41 min, m/z 417.1 [M-H]- Ή NMR (400 MHz, DMSO-d ₆ ): δ 12.82 (s, 1H), 9.19 (s, 1H), 8.15-8.03 (m, 2H), 7.98-7.88 (m, 3H), 7.43 (d, J = 1.4 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 4.54 (s, 2H), 4.23-4.12 (m, 1H), 2.93-2.81 (m, 2H), 2.71 (ddd, J= 10.6, 8.1, 5.9 Hz, 1H), 1.93 (did, J = 12.7, 8.2, 6.1 Hz, 1H), 1.55 (ddt, J = 12.8, 8.2, 5.4 Hz, 1H). Three protons were not observed due to overlap with the residual DMSO signal. 159 I sn ΙΖ Az IZ 1 c X (U Method E, 5.15 min, m/z 420.1 [M+H] ⁺ Ή NMR (500 MHz, DMSO-de): δ 13.45 (s, 1H), 12.79 (s, 1H), 9.13 (s, 1H), 8.33 (d, J= 7.0 Hz, 1H), 8.11 (s, 1H ), 8.01-7.83 (m, 3H), 7.41 (s, 2H), 7.09 (s, 2H), 4.56 (s, 2H), 4.38-4.28 (m, 1H), 3.84-3.74 (m, 2H), 3.68 (td, J = 8.0, 5.5 Hz, 1H), 3.51 (dd, J= 9.0, 4.0 Hz, 1H), 2.10 (dtd, J= 12.5, 8.0, 6.5 Hz, 1H), 1.86-1.76 (m, 1H). 160 Iz CH IZ Az IZ I c 1 ό Method E, 6.14 min, m/z 418.1 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 13.38 (s, 1H), 12.81 (s, 1H), 9.17 (s, 1H), 8.10 (s, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.95 (s, 1H), 7.93-7.88 (m, 2H), 7.42 (s, 2H), 7.08 (d, J= 8.5 Hz, 2H), 4.52 (s, 2H), 4.14-4.03 (m , 1H), 1.86-1.76 (m, 2H), 1.68-1.59 (m, 2H), 1.55-1.39 (m, 4H). 161 cA IZ Az IZ 1 c X Method E, 5.88 min, m/z 404.1 [M+H] ⁺ Ή NMR (500 MHz, DMSO-d ₆ ): δ 13.37 (s, 1H), 12.80 (s, 1H), 9.17 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 7.98-7.87 (m, 3H), 7.42 (s, 2H), 7.09 (d, J = 8.5 Hz, 2H), 4.51 (s, 2H), 4.34-4.22 (m, 1H), 2.20-2.11 (m, 2H), 2.06-1.95 (m, 2H), 1.691.58 (m, 2H). 162 Si th HX/ ^H η V ^v 0 Method E, 5.38 min, m/z 389.9 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.37 (s, 1H), 12.80 (s, 1H), 9.16 (s, 1H), 8.17 (d, J =4.5 Hz, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.91 (d, J = 9.0 Hz, 2H), 7.42 (d, J = 1.5 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H), 4.51 (s, 2H), 2.74–2.68 (m, 1H), 0.64 (td, J = 7.0, 4.5 Hz, 2H), 0.53–0.46 (m, 2H). 163 .0 . 1 ZI z^ zHA 'z T Method E, 4.37 min, m/z 433.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.33 (s, 1H), 12.80 (s, 1H), 9.15 (s, 1H), 8.21 (d, J = 7.5 Hz, 1H), 8.10 (s, 1H), 7.98-7.87 (m, 3H), 7.42 (s, 2H), 7.08 (d, J = 8.5 Hz, 2H), 4.54 (s, 2H), 4.25 (dtt, J = 9.5, 7.5, 4.5 Hz , 1H), 2.65-2.58 (m, 2H), 2.41-2.30 (m, 2H), 2.25 (s, 3H), 2.16-2.08 (m, 1H), 1.64 (dddd, J = 13.0, 8.0, 6.5, 4.5 Hz, 1H). 164 ^hn 0l Q Й Γ ^ν πΠ ^H h CXo % 0 Method E, 5.34 min, m/z 405.8 [M+H] ⁺ 'HNMR (500 MHz, DMSO-d ₆ ): δ 13.46 (s, 1H), 12.80 (s, 1H), 9.13 (s, 1H), 8.188.03 (m, 2H), 8.00-7.88 (m, 3H ), 7.43 (s, 2H), 7.11 (d, J = 8.4 Hz, 2H), 4.62 (s, 2H), 4.12-4.02 (m, 1H), 3.77 (dd,J= 11.0.5.1Hz, 1H) , 3.70 (dd, J = 11.0.6.8 Hz, 1H), 3.54 (dd,J= 10.9, 5.1Hz, 1H), 3.46 (dd, J= 11.0, 6.4 Hz, 1H). 165 0X X IZ 1 c 7 _ZI ό Method E, 5.94 min, m/z 433.9 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): δ 13.31 (s, 1H), 12.80 (s, 1H), 9.17 (s, 1H), 8.21 (d, J =8.0 Hz, 1H), 8.O9 ( s, 1H), 7.94 (s, 1H), 7.58 (d, J= 2.0 Hz, 1H), 7.51 (dd,J = 8.5,2.0 Hz, 1H), 7.41 (d, J = 1.5 Hz, 2H), 7.02 (d, J =8.5 Hz, 1H), 4.49 (s, 2H), 4.34-4.18 (m, 1H), 3.88 (s, 3H), 2.22-2.10 (m, 2H), 2.03-1.89 (m, 2H), 1.69-1.59 (m, 2H). 464 r ⁿ xC /ХхХчД /kri NH W 7.kr$ HA/ ^N V F Method B, 3.12 min, m/z 579.1 [M+H]+ Ή (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.61-7.49 (m, 4H), 7.01 (d, J = 8.0 Hz, 1H), 4.54 (s, 2H), 4.49-4.41 (m, 1H ), 3.91 (s, 3H), 3.83 (s, 3H), 3.21 (d, J = 10 Hz, 1H), 3.16 (d, J = 9.6 Hz, 1H), 3.05–2.97 (m, 1H), 2.92 (dd, J = 6.8, 9.2, 1H), 2.74 (dd, J = 4.0, 10.0, 1H), 2.68-2.61 (m, 1H), 2.33-2.23 (m, 1H), 1.79-1.69 (m, 1H ). 3 NH not observed

- 138042028

General method E:

The process for preparing the compound of the invention is shown below. Additional compounds that can be obtained in a similar way from intermediate compounds 4, 12, 13, 15 and 16 using commercially available boronic acids, boronate esters, using General method E, are presented in table. 13.

Example 166 4-[5-[(4-Chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-Nisopropylbenzamide

Hydrogen chloride (4.0 M in 1,4-dioxane) (2.49 mL, 9.94 mmol) was slowly added to a stirred solution of 4-[5-[(4-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino] -1-methyl-1,2,4-triazol-3-yl]-Nisopropylbenzamide (80 mg, 0.16 mmol) in MeOH (2 ml) at 25°C. The reaction mixture was stirred at ambient temperature for 18 hours. The pale yellow solution was concentrated under reduced pressure and the crude residue was immediately purified by ion exchange chromatography (SCX, eluting with 1 M NH ₃ in MeOH). The solution was evaporated in vacuo on silica gel and the product was purified by column chromatography on a 4 g silica gel column eluting with 30-100% EtOAc/petroleum ether. Purified fractions were evaporated in vacuo, triturated with diethyl ether/petroleum ether, filtered and dried to give 4-[5-[(4-chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4triazole -3-yl]-N-isopropylbenzamide (47 mg, 0.11 mmol, 70% yield) as an off-white solid. UPLC-MS (ES+, Method B): 3.18 min, m/z 410.3 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 13.42 (s, 1H), 8.59 (s, 1H), 8.27 (d, J=7.8 Hz, 1H), 8.11 (s, 1H), 7.927.82 (m , 4H), 7.63-7.53 (m, 2H), 4.16-4.03 (m, 1H), 3.81 (s, 3H), 1.16 (d, J=6.6 Hz, 6H).

Stage 1: ethyl 4-[5-[(4-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3yl]benzoate

Potassium carbonate (705 mg, 5.10 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (805 mg, 2.91 mmol) and N-(5- bromo-2-methyl-1,2,4-triazol-3-yl)-4-chloro-1-tetrahydropyran-2-yl-indazol-5amine (described in Example 43, Step 1) (1.00 g, 2.43 mmol) dissolved/suspended in 1,4-dioxane (15 ml) and water (4 ml). The reaction mixture was completely degassed by bubbling with nitrogen. Then complex [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane chloride (198 mg, 0.24 mmol) was added followed by further degassing, and then the reaction was heated to 100°C for 3 h. The layers were separated and the organics were evaporated in vacuo on silica gel and purified on an 80 g silica gel column eluting with 20-60% EtOAc in petroleum ether to give ethyl 4-[5-[(4-chloro-1tetrahydropyran-2-yl-indazol-5- yl)amino]-1-methyl-1,2,4-triazol-3-yl]benzoate (1.06 g, 2.19 mmol, 90%) as a white solid. UPLC-MS (ES+, Method A): 1.98 min, m/z 481.4 [M+H] ⁺ .

Ή NMR (400 MHz, CDCl3) δ 8.23 (d, J=9.1 Hz, 1H), 8.19-8.02 (m, 5H), 7.60 (dd, J=9.0, 1.0 Hz, 1H), 6.51 (s, 1H) , 5.72 (dd, J=9.2, 2.7 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 4.08-3.99 (m, 1H), 3.85 (s, 3H), 3.82-3.70 (m, 1H ), 2.61-2.48 (m, 1H), 2.21-2.06 (m, 2H), 1.88-1.63 (m, 3H), 1.42 (t, J=7.1 Hz, 3H).

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Stage 2: 4-[5-[(4-Chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3yl]benzoic acid

Sodium hydroxide (6.57 mL, 13.14 mmol) was added to a stirred suspension of ethyl 4-[5-[(4-chloro1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4- triazol-3-yl]benzoate (790 mg, 1.64 mmol) in THF (10 ml) and MeOH (10 ml) at 25°C. The reaction turned yellow and the solids dissolved. The reaction mixture was stirred at 25° C. for 18 hours. The reaction was evaporated in vacuo and then diluted with water. The pH was then adjusted to pH 2 with 2.0 M HCl and the solid precipitated out of solution. The solid was extracted twice with EtOAc. The combined organic layers were then washed with saturated brine, dried over MgSO ₄ and the solvent was removed in vacuo to give 4-[5-[(4-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1- methyl-1,2,4-triazol-3yl]benzoic acid (470 mg, 1.02 mmol, 62% yield) as a yellow solid. UPLC-MS (ES+, Method A): 1.65 min, m/z 453.4 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.99 (s, 1H), 8.68 (s, 1H), 8.16 (d, J=0.8 Hz, 1H), 8.00-7.90 (m, 4H), 7.76 (dd , J=8.9, 0.9 Hz, 1H), 7.67 (d, J=8.9 Hz, 1H), 5.89 (dd, J=9.6, 2.3 Hz, 1H), 3.90 (s, 1H), 3.83 (s, 3H) , 3.77 (ddd, J=11.4, 8.1, 6.0 Hz, 1H), 2.49-2.34 (m, 1H), 2.02 (d, J=15.8 Hz, 2H), 1.76 (s, 1H), 1.60 (dq, J =8.1, 4.3, 3.7 Hz, 2H).

Step 3: 4-[5-[(4-Chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]N-isopropylbenzamide

To a stirred solution of 4-[5-[(4-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl1,2,4-triazol-3-yl]benzoic acid (80 mg , 0.18 mmol), N,N-diisopropylethylamine (0.09 ml, 0.53 mmol) and 2-aminopropane (0.03 ml, 0.35 mmol) in THF (5 ml) was added propylphosphonic anhydride, 50 wt.% in ethyl acetate (0.16 ml, 0.27 mmol ) and the solution was stirred for 16 hours. The yellow solution was evaporated in vacuo and purified by silica gel column chromatography eluting with 30100% EtOAc in petroleum ether to give 4-[5-[(4-chloro-1-tetrahydropyran- 2-yl-indazol-5yl)amino]-1-methyl-1,2,4-triazol-3-yl]-X-isopropylbenzamide (80 mg, 0.15 mmol, 87% yield) as an off-white solid. UPLC-MS (ES ⁺ , Method A): 1.71 min, m/z 494.5 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 8.21 (d, J=9.0 Hz, 1H), 8.17-8.09 (m, 2H), 8.05 (d, J=0.9 Hz, 1H), 7.85-7.77 (m, 2H ), 7.60 (dd, J=9.2, 0.9 Hz, 1H), 6.51 (s, 1H), 5.97 (d, J=7.8 Hz, 1H), 5.72 (dd, J=9.2, 2.7 Hz, 1H), 4.384 .23 (m, 1H), 4.08-3.99 (m, 1H), 3.85 (s, 3H), 3.83-3.70 (m, 1H), 2.54 (tdd, J=13.2, 9.9, 3.9 Hz, 1H), 2.23 -2.02 (m, 2H), 1.89-1.66 (m, 3H), 1.29 (d, J=6.5 Hz, 6H).

Compounds obtained in a manner analogous to that described above are shown in Table 1 below. 13.

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Table 13

Example Structure LC-MS Ή NMR 167 N ^ \ - HN-H Y NH I ^-N _x I / ^N \ O Method E, 6.07 min, m/z 436.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.90 (s, IH), 8.85 (s, IH), 8.16 (d, J = 2.0 Hz, IH), 8.01 (s, IH), 7.77 (d, J = 8.0 Hz, IH), 7.58-7.48 (m, 4H), 6.99 (d, J = 9.0 Hz, IH), 4.47 (s, 2H), 3.93 (m, IH), 3.87 (s, 3H), 3.78 ( s, 3H), 1.10 (d, J = 6.5 Hz, 6H). 168 Ν^^— HN—U y-NH । ^= ⁷ N / O N. ν γ XY ⁷ O Method B, 2.99 min, m/z 392.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.95 (s, IH), 8.96 (s, IH), 8.27-8.16 (m, 2H), 8.04 (t, J = 1.2 Hz, IH), 7.83 (d, J = 7.9 Hz, IH), 7.69-7.61 (m, 2H), 7.62-7.48 (m, 2H), 3.97 (s, 3H), 3.83 (s, 3H), 3.31 (qd, J = 7.2, 5.7 Hz , 2H), 1.13 (t, J = 7.2 Hz, ZN). 169 ΗΝ—/ V ^NFI 1 \=/ )=N A ^N ₄ H . ν ν O Method B, 3.24 min, m/z 406.4 [M+H] ^{+ X} H NMR (400 MHz, DMSO-de) δ 12.95 (s, IH), 8.95 (s, IH), 8.19 (dd, J = 2.0, 0.8 Hz, IH), 8.04 (s, IH), 7.97 (d , J = 7.7 Hz, IH), 7.78 (d, J = 7.9 Hz, IH), 7.69–7.48 (m, 4H), 4.16–3.97 (m, IH), 3.97 (s, 3H), 3.83 (s, 3H), 1.18 (d, J = 6.5 Hz, 6H). 170 ΗΝ~/ y—ΝΗ | \^/ )=Ν A ^-Ν ₄ H . N 1 O Method B, 3.57 min, m/z 420.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.95 (s, IH), 8.95 (s, IH), 8.19 (d, J = 1.9 Hz, IH), 8.04 (t, J = 1.2 Hz, IH), 7.92 -7.81 (m, 2H), 7.70-7.61 (m, 2H), 7.58 (dd, J = 9.0, 2.0 Hz, IH), 7.52 (d, J = 8.8 Hz, IH), 3.99 (s, 3H), 3.83 (s, 3H), 1.39 (s, 9H). 171 Cl hUgCh HN-/ y-NH ⁷⁼⁷ > ^N \ ^F \ F --N ₄ LAE H Ν γ ^Ν-^'Τ O Method B, 3.35 min, m/z 450.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.42 (s, IH), 9.14 (t, J = 6.3 Hz, IH), 8.61 (s, IH), 8.12 (s, IH), 7.98-7.88 (m, 4H), 7.64-7.53 (m, 2H), 4.09 (qd, J = 9.8, 6.5 Hz, 2H), 3.82 (s, 3H). 172 ci HN-Xy-NH I )= ^N . Ό T^Q ^n ₄ \ \ N y KU'' ⁷ 0 Method B, 2.98 min, m/z 468.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.40 (s, IH), 8.56 (s, IH), 8.10 (s, IH), 7.627.44 (m, 4H), 7.21 (d, J = 7.7 Hz, IH), 3.83 (s, 3H), 3.81 (s, 3H), 3.62 (m, 4H), 3.51 (m, 2H), 3.18-3.10 (m, 2H). 173 Cl nC/Un , , ^{0H 3=7} And Y γ-Loh ^N. A—GT— ^0H N y ft ^N ~J 0 Method B, 2.62 min, m/z 498.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.40 (s, IH), 8.56 (s, IH), 8.10 (s, IH), 7.627.51 (m, 2H), 7.45 (d, J = 6.7 Hz, 2H), 7.31-7.23 (m, IH), 4.83 (t, J = 5.4 Hz, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.68 (m, 2H), 3.56 (m, 2H ), 3.47 (m, J = 5.5 Hz, 4H). 174 Cl ^N< y_7 HN-/ I ^= ⁷ )=NA n _s A^yy h N y Κ,Ν- 0 Method B, 2.97 min, m/z 412.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.41 (s, IH), 8.59 (s, IH), 8.21-8.08 (m, 2H), 7.78 (d, J = 7.9 Hz, IH), 7.61-7.53 ( m, 2H), 7.52–7.45 (m, 2H), 3.90 (s, 3H), 3.81 (s, 3H), 2.79 (d, J = 4.6 Hz, ZH). 175 Cl H^ChgCh HN—/ y-NH । \=/ )=NA ^N ₄ Y/Y H . ^N V LUCH 0 Method B, 3.73 min, m/z 454.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.41 (s, IH), 8.58 (s, IH), 8.11 (s, IH), 7.85 (s, IH), 7.77 (d, J = 8.0 Hz, IH) , 7.67-7.45 (m, 4H), 3.92 (s, 3H), 3.81 (s, J = 0.9 Hz, ZH), 1.37 (s, 9H). 176 Cl HN-/ V-NH ^= ⁷ >N -N ₄ A-YU\ H /4 ν γ K/ ^N O Method B, 3.30 min, m/z 422.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.42 (s, IH), 8.66 (d, J = 7.7 Hz, IH), 8.60 (s, IH), 8.11 (s, IH), 7.93-7.82 (m, 4H), 7.63-7.53 (m, 2H), 4.42 (h, J = 8.2 Hz, IH), 3.81 (s, 3H), 2.19(ddt, J = 10.9, 6.9,3.1 Hz, 2H), 2.14-1.97 (m, 2H), 1.66 (tt, J = 10.9, 6.9 Hz, 2H). 177 Cl chU-Ch HN-/ V-NH ^= ⁷ >N --N. U~-UU\ H ν γ 0 Method B, 3.02 min, m/z 408.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.42 (s, IH), 8.59 (s, IH), 8.48 (d, J = 4.2 Hz, IH), 8.11 (s, IH), 7.92–7.79 (m, 4H), 7.63-7.52 (m, 2H), 3.81 (s, 3H), 2.84 (m, IH), 0.74-0.62 (m, 2H), 0.65-0.52 (m, 2H). 178 N^\—/ HN—/ /-ΝΗ I \^/ >n A v —N _x Y-Yy H XF Ν γ V/NX O Method B, 3.36 min, m/z 460.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.03 (s, IH), 8.68 (t, J = 6.5 Hz, IH), 8.36 (s, IH), 8.14 (s, IH), 7.76 (d, J = 8.1 Hz, IH), 7.53-7.44 (m, 2H), 7.41-7.29 (m, 2H), 4.10 (qd, J = 9.7, 6.5 Hz, 2H), 3.91 (s, 3H), 3.77 (s, 3H ), 2.46 (s, 3H).

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179 ην—/ /A I 4=/>n A N„ ΛΥΎ H / n V \ 0 Method B, 3.20 min, m/z 420.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 8.34 (s, 1H), 8.14 (s, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.72-7.65 (m , 1H), 7.50-7.41 (m, 2H), 7.35 (m, J = 8.8 Hz, 2H), 4.12-3.98 (m, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 2.46 ( s, 3H), 1.16 (d, J = 6.5 Hz, 6H). 180 n^\—/ HN—/ I \=/ )=NA ^N _x VW H / NVX/ ⁷ O Method B, 2.97 min, m/z 406.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.06-13.01 (m, 1H), 8.35 (s, 1H), 8.23-8.11 (m, 2H), 7.74 (d, J = 7.9 Hz, 1H), 7.50 -7.41 (m, 2H), 7.35 (q, J = 8.8 Hz, 2H), 3.89 (s, 3H), 3.77 (s, 3H), 3.28 (qd,/=7.2, 5.6 Hz, 2H), 2.46 ( s, 3H), 1.10 (t, J = 7.2 Hz, ZN). 181 N%—/ HN—/ Υ ^Ν β 1 \=/ >NA ^N ₄ H . ^N ν Υ/ ^Ν Ύ o Method B, 3.54 min, m/z 434.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.04-12.98 (m, 1H), 8.32 (s, 1H), 8.13 (t, J = 1.2 Hz, 1H), 7.83 (s, 1H), 7.75 (d , J = 8.0 Hz, 1H), 7.51-7.42 (m, 2H), 7.35 (m, J = 8.8 Hz, 2H), 3.91 (s, 3H), 3.77 (s, 3H), 2.46 (s, 3H) , 1.37(s, 9H). 182 nA—/ HN—/ y-NH | WV >NA ^n _s VW h N y o Method B, 3.03 min, m/z 418.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 8.32 (s, 1H), 8.20–8.05 (m, 2H), 7.65 (d, J = 7.9 Hz, 1H), 7.49–7.40 (m, 2H), 7.35 (m, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 2.88-2.77 (m, 1H), 2.46 (s, 3H), 0.74-0.62 (m, 2H ), 0.54 (dt, J = 72, 4.5 Hz, 2H). 183 F nW HN—/ V-NH । W >NA -n _x AYY h / N y £n \ O Method B, 3.25 min, m/z 424.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 8.67 (s, 1H), 8.19 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.59 (dd, J = 8.8, 7.4 Hz, 1H), 7.53-7.44 (m, 2H), 7.40 (d, J = 8.8 Hz, 1H), 4.06 (dq, J = 13.4, 6.7 Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 1.16 (d, J = 6.5 Hz, 6H). 184 F nW HN—/ I A=/ γΝ AF\ F ^Nn zV^Wf H >F ^N V 0 Method B, 3.40 min, m/z 464.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 8.73–8.65 (m, 2H), 8.19 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.59 (dd , J = 8.8, 7.4 Hz, 1H), 7.56-7.47 (m, 2H), 7.40 (dd, J= 8.8, 1.1 Hz, 1H), 4.11 (qd, J = 9.7, 6.5 Hz, 2H), 3.92 ( s, 3H), 3.82 (s, 3H). 185 nW HN—/ T-NH I \=/ >NA H / Ν γ V^z ^N ~~ ^/ o Method B, 3.14 min, m/z 420.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (d, J = 1.5 Hz, 1H), 8.27 (s, 1H), 8.21–8.12 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H ), 7.48 (d, J= 1.4 Hz, 1H), 7.44 (dd, /=8.0, 1.4 Hz, 1H), 7.38 (dd, J = 8.7, 1.0 Hz, 1H), 7.27 (d, J = 8.7 Hz , 1H), 3.89 (s, 3H), 3.75 (s, 3H), 3.33–3.25 (m, 2H), 2.94 (q,/= 7.5 Hz, 2H), 1.23 (t,/ = 7.5 Hz, ZN) , 1.11 (t,/ = 7.2 Hz, ZN). 186 HN-/ y-NH 1 4=/ >NA -N ₄ VW H / Ν Λ \\n -/ O Method B, 3.37 min, m/z 434.6 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 8.27 (s, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 1.4 Hz, 1H), 7.44 (dd, J = 8.0, 1.4 Hz, 1H), 7.38 (dd, J = 8.7, 1.0 Hz, 1H ), 7.27 (d, J = 8.8 Hz, 1H), 4.12–3.98 (m, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 2.94 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, ZH), 1.16 (d, / = 6.6 Hz, 6H). 187 4W HN—/ Γ ^Ν β 1 \=/ >NA --Ν'-V-X'rt H ν γ >^ ^Ν Ύ 0 Method B, 3.19 min, m/z 432.9 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 8.08 (d, J = 4.3 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.45 (d, / = 1.4 Hz, 1H), 7.43 (dd, J = 7.9, 1.4 Hz, 1H), 7.37 (dd, J = 8.7, 1.0 Hz, 1H), 7.27 (d , J = 8.7 Hz, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 2.93 (q, J = 7.5 Hz, 2H), 2.88–2.76 (m, 1H), 1.23 (t, J = 7.5 Hz, ZN), 0.74–0.64 (m, 2H), 0.58–0.49 (m, 2H).

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188 HN—/ V-NH I \=/ )=Ν λ Α/Ύ n / ν ν ' O Method B, 3.23 min, m/z 432.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.32 (s, 1H), 8.17 (t, J = 5.7 Hz, 1H), 8.06 (t, J = 1.2 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.52-7.46 (m, 2H), 7.437.36 (m, 2H), 3.90 (s, 3H), 3.79 (s, 3H), 3.32-3.25 (m, 2H), 2.20-2.08 (m, 1H), 1.11 (t, J = 7.2 Hz, 3H), 1.02-0.92 (m, 2H), 0.90-0.79 (m, 2H). 189 Ν^\—/ ΗΝ—/ y— ^Ν Η 1 \=/ )=Ν o Method B, 3.46 min, m/z 446.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.32 (s, 1H), 8.06 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.53-7.44 (m, 2H), 7.45-7.34 (m, 2H), 4.14-3.97 (m, 1H), 3.90 (s, 3H), 3.79 (s, 3H), 2.20- 2.08 (m, 1H), 1.16 (d, J= 6.6 Hz, 6H), 1.02-0.91 (m, 2H), 0.90-0.79 (m, 2H). 190 f n x o z^A^ ^N F=\jJ H D Method B, 3.64 min, m/z 454.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.41 (br s, 1H), 8.52 (br s, 1H), 8.20 (t, J = 5.7 Hz, 1H), 8.10 (s, 1H), 7.78 (d , J = 7.9 Hz, 1H), 7.59-7.46 (m, 4H), 4.76 (hept, J = 6.5 Hz, 1H), 3.90 (s, 3H), 3.29 (qd, J = 7.1, 5.6 Hz, 2H) , 1.47 (d, J = 6.5 Hz, 6H), 1.22–1.07 (t, 3H). 191 Clθ n d Method B, 3.87 min, m/z 468.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.41 (s, 1H), 8.52 (s, 1H), 8.10 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.59-7.46 (m, 4H), 4.76 (hept, J = 6.4 Hz, 1H), 4.06 (ddt, J= 13.1, 7.7, 6.6 Hz, 1H), 3.90 (s, 3H) , 1.47 (d, J = 6.5 Hz, 6H), 1.16 (d, J = 6.5 Hz, 6H). 192 Cl O I Η / ο ζ^Α^ν^ν /LE Ch D JI ^{F Η} \ G Method B, 4.02 min, m/z 508.4 [M+H] ⁺ Tl NMR (400 MHz, DMSO-d ₆ ) δ 13.41 (s, 1H), 8.68 (t, J = 6.5 Hz, 1H), 8.54 (s, 1H), 8.10 (s, 1H), 7.83-7.74 (m , 1H), 7.59-7.48 (m, 4H), 4.77 (hept, J = 6.5 Hz, 1H), 4.11 (qd, J = 9.7, 6.5 Hz, 2H), 3.92 (s, 3H), 1.48 (d, J= 6.5 Hz, 6H).

General way F:

R ₄ NH ₂ , ТЗР, THF or HATU, DMF, rt

The process for preparing the compound of the invention is shown below. Additional compounds that can be obtained in a similar way from intermediate compounds 3 and 14 using commercially available boronic acids, boronate esters, using General method B, are presented in table. 14.

Example 193 4-[5-[(4-Chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-N-isopropyl-2methoxybenzamide

To a stirred solution of N,N-diisopropylethylamine (0.08 ml, 0.45 mmol), 2-aminopropane (0.01 ml, 0.17 mmol) and 4-[5-[(4-chloro-1H-indazol-5-yl)amino]-1 -methyl-1,2,4-triazol-3-yl]-2methoxybenzoic acid (60 mg, 0.15 mmol) in DMF (1 ml) was added 2-(7-aza-1H-benzotriazol-1-yl)1,1 ,3,3-tetramethyluronium hexafluorophosphate (HATU) (63 mg, 0.17 mmol) and the solution was stirred for 16 h at 25°C. The resulting brown solution was loaded onto an SCX ion exchange cartridge and washed with methanol. The product was then eluted with 1.0 M MeOH/NH ₃ . The solution was evaporated in vacuo and the resulting resin was then purified by flash column chromatography eluting with 1-10% MeOH in DCM. Target fractions were concentrated to dryness under vacuum

- 143 042028 to obtain 4-[5-[(4-chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-N-isopropyl-2methoxybenzamide ( 36 mg, 0.08 mmol, 53% yield) as a white solid. UPLC-MS (ES ⁺ , Method B): 3.40 min, m/z 440.4 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ 13.40 (s, 1H), 8.57 (s, 1H), 8.10 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.71 (d, J= 7.9 Hz, 1H), 7.61-7.53 (m, 2H), 7.52-7.46 (m, 2H), 4.10-4.01 (m, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 1.16 (d , J=6.5 Hz, 6H).

Stage 1: 4-[5-[(4-Chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-2-methoxybenzoic acid

4-[5-[(4-Chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-2methoxybenzoic acid (1.16 g , 2.4 mmol) was suspended in 1,4-dioxane (10 ml) and HCl (4.0 M in dioxane) (6.01 ml, 24.02 mmol) was added.

The reaction mixture was stirred at 25°C for 21 h with the formation of a pink precipitate. The reaction was partially evaporated under vacuum, diluted with diethyl ether and filtered, and the solid was washed with additional diethyl ether. The solid was then dried to give 4-[5-[(4-chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-2-methoxybenzoic acid (940 mg, 2.29 mmol, 95% yield) as a pale pink solid. UPLC-MS (ES ⁺ , Method A): 1.33 min, m/z 399.3 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ + 3 drops of CD ₃ CO ₂ D) δ 8.15 (d, J=0.8 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.65-7.49 (m, 3Н), 7.47 (dd, J=8.1, 1.5 Hz, 1H), 3.87 (s, 3Н), 3.84 (s, 3Н).

Stage 2: 4-[5-[(4-Chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]2-methoxybenzoic acid

Sodium hydroxide (4.83 mL, 9.66 mmol) was added to a stirred suspension of methyl 4-[5-[(4-chloro1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4- triazol-3-yl]-2-methoxybenzoate (1.2 g, 2.41 mmol) in THF (6 ml) and methanol (6 ml) at 25°C. The reaction mixture was stirred for 3 h, evaporated under vacuum and dissolved in 10 ml of water. The pH was then adjusted to pH 4 with 2.0 M HCl and the solid precipitated out of solution. The solid was extracted with EtOAc (x2). The organics were then washed with saturated brine and dried over MgSO ₄ . Solvent was removed in vacuo to give 4-[5-[(4-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl1,2,4-triazol-3-yl]-2 -methoxybenzoic acid (1.16 g, 2.38 mmol, 98% yield) as a pale pink solid. UPLC-MS (ES+, Method A): 1.63 min, m/z 483.4 [M+H] ⁺ .

Stage 3: methyl 4-[5-[(4-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol3-yl]-2-methoxybenzoate

Methyl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (780.6 mg, 2.67 mmol), N(5-bromo-2-methyl-1 ,2,4-triazol-3-yl)-4-chloro-1-tetrahydropyran-2-yl-indazol-5-amine (1.0 g, 2.43 mmol) and potassium carbonate (705.02 mg, 5.1 mmol) were suspended in 1, 4-dioxane (15 ml) and water (4 ml). The reaction mixture was completely degassed by nitrogen bubbling. Then the complex [1,1'bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (198 mg, 0.24 mmol) was added, followed by additional degassing, and then the reaction was heated to 90°C for 18 h. The reaction was evaporated under vacuum. Further purification by flash chromatography on silica gel eluting with 30100% EtOAc in petroleum ether gave methyl 4-[5-[(4-chloro-1-tetrahydropyran-2-yl-indazol-5yl)amino]-1-methyl- 1,2,4-triazol-3-yl]-2-methoxybenzoate (800 mg, 1.59 mmol, 66% yield) as an off-white solid. UPLC-MS (ES ⁺ , Method A): 1.80 min, m/z 497.4 [M+H] ⁺ .

Compounds obtained in a manner analogous to that described above are shown in Table 1 below. 14.

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Table 14

Example Structure LC-MS Ή NMR 194 CI hChH HN—# y-NH I > ^Ν _χ F _F XX n X ν \ X ^F Χζχ un 0 Method B, 3.76 min, m/z 494.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.40 (s, 1H), 8.58 (s, 1H), 8.47 (d, J = 9.0 Hz, 1H), 8.10 (s, 1H), 7.67-7.47 (m , 5H), 4.85–4.81 (m, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 1.34 (d, J = 7.0 Hz, ZH). 195 G ΙΖ J 7 ^ζ 'ι Method B, 3.22 min, m/z 438.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.40 (s, br), 8.57 (s, 1H), 8.10 (m, J = 4.5 Hz, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.61-7.53 (m, 2H), 7.51-7.44 (m, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 2.87-2.79 (m, 1H), 0.69 (m, J = 7.0, 4.7 Hz, 2H), 0.57–0.51 (m, 2H). 196 Cl νΧ—Ζ HN—# y——NH I 4=/ )=Ν A XX Η _ ν \ XX/ λ k 0 Method B, 3.13 min, m/z 482.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.40 (s, br), 8.57 (s, 1H), 8.10 (s, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.61-7.54 (m, 2H), 7.537.46 (m, 2H), 4.05-3.94 (m, 1H), 3.90 (s, 3H), 3.89-3.82 (m, 2H), 3.81 (s, 3H), 3.45-3.37 (m, 2H), 1.85-1.74 (m, 2H), 1.62-1.48 (m, 2H). 197 Cl Ν^\—ζ ΗΝ-/V-NM 1 X ο Method B, 3.19 min, m/z 452.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.39 (s, 1H), 8.55 (s, 1H), 8.10 (d, J = 1.4 Hz, 1H), 7.61-7.53 (m, 2H), 7.47 (s , 1H), 7.45 (d, J= 1.4 Hz, 1H), 7.21-7.17 (m, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.42 (t, J = 6.8 Hz, 2H) , 3.11 (t, J = 6.5 Hz, 2H), 1.91–1.72 (m, 4H). 198 CI νΧ—Ζ ΗΝ—U LH I 4=/ )=Ν A -'-“Xt 0 ^h he Method B, 2.96 min, m/z 468.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.41 (s, 1H), 8.57 (s, 1H), 8.30 (s, 1H), 8.11 (s, 1H), 7.77 (d, J - 7.9 Hz, 1H ), 7.61-7.53 (m, 2H), 7.52-7.46 (m, 2H), 4.76 (t, J = 5.7 Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.52 (d, J = 5.7 Hz, 2H), 0.82–0.66 (m, 4H). 199 Cl nX_-z ΗΝ-/ Λ ^N d 1 \=/ )=NA -X XX n Ν \ \\ Ch/X 0 Method B, 3.28 min, m/z 423.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.41 (s, 1H), 11.22 (s, 1H), 8.64 (s, 1H), 8.11 (s, 1H), 7.80 (d, 7=8.1 Hz, 1H ), 7.61-7.51 (m, 4H), 3.94 (s, 3H), 3.83 (s, 3H). 200 CI νΧΧ HN—/ y— NH 1 \=/ >Ν 1 ^-Ν ₄ XX Η ρ ^Ν \ Χ/ ^Ν --ΧΧ XX \ / ο 0 Method B, 3.04 min, m/z 516.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.40 (s, 1H), 8.61-8.54 (m, 2H), 8.10 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.60-7.54 (m, 2H), 7.53-7.49 (m, 2H), 4.73 (m, J= 7.4 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.48-3.45 (m, 1H), 3.31-3.29 (m, 1H), 3.26-3.12 (m, 2H), 2.48-2.39 (m, 1H), 2.24-2.21 (m,, 1H). 201 CI νΧ—Ζ HN—/ /X 1 X ⁷ AND ζ^/θ F --Ν ₄ XX Η k ^Ν VK/ ^N ^ ^F 0 Method B, 3.56 min, m/z 480.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.41 (s, 1H), 8.69 (t, J = 6.4 Hz, 1H), 8.61 (s, 1H), 8.11 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.62–7.47 (m, 4H), 4.134.10 (m, 2H), 3.92 (s, 3H), 3.82 (s, 3H). 202 Cl νΧ—Ζ HN—-/ nX 1 ^=/ >N A ^N ₄ XX n ^Ν Χ/χ ^Ν Ύ^^ 0 Method B, 2.49 min, m/z 481.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.41 (s, 1H), 8.58 (s, 1H), 8.19 (d, J = 7.2 Hz, 1H), 8.11 (s, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.60-7.54 (m, 2H), 7.52-7.47 (m, 2H), 4.37 (m, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 2.69-2.59 ( m, 2H), 2.42 (dd, J = 9.4, 4.5 Hz, 1H), 2.35 (m, 1H), 2.26 (s, 3H), 2.19 (m, 1H), 1.72–1.60 (m, 1H). 203 Cl νΧ—Ζ HN—/ y—NH ι \=/ )=Ν ABOUT Method B, 2.84 min, m/z 398.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.40 (s, br), 8.58 (s, 1H), 8.10 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 2.5 Hz, 1H), 7.61-7.47 (m, 5H), 3.92 (s, 3H), 3.81 (s, 3H). 465 ¹ __ HN ^- V ^Ν Ν Χ\_7 X Method B, 2.99 min, m/z 439.4 [M+H]+ Ή NMR (400 MHz, DMSO-d6) δ 13.02 (s, br), 9.34 (s, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 7.88 (m, 4H), 7.40 (m, 2H), 3.80 (s, 3H), 2.14 (m, 1H), 1.55 (m, 2H), 1.28 (m, 2H), 0.97 (m, 2H), 0.83 (m, 2H).

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General way G:

The process for preparing the compound of the invention is shown below. Additional compounds that can be prepared in a similar manner from commercially available boronic acids, boronate esters, or intermediate 15 using General Method B are shown in Table 1. 15.

Example 204: N-t-butyl-2-[4-[5-[(4-chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl] -2methoxyphenoxy]acetamide

To a stirred solution of 2-[4-[5-[(4-chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-2methoxyphenoxy]acetic acid dihydrochloride (100 mg, 0.21 mmol), butylamine (0.02 ml, 0.24 mmol) and N,N-diisopropylethylamine (0.11 ml, 0.64 mmol) in DMF (1 ml) were added 1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (90 mg, 0.24 mmol) and the solution was stirred for 16 hours. The resulting brown solution was loaded onto an SCX ion exchange cartridge and washed with methanol. The product was then eluted with 1.0 M MeOH/NH ₃ . The solution was evaporated in vacuo and the residue triturated with DCM/diethyl ether to give a pale pink solid which was filtered, washed with additional diethyl ether and dried to give N-tert-butyl-2-[4-[5-[(4- chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-2methoxyphenoxy]acetamide (52 mg, 0.11 mmol, 49% yield) as a pale pink solid substances. UPLC-MS (ES+, Method B): 3.53 min, m/z 484.4 [M+H] ⁺ .

Ή NMR (400 MHz, DMSO-d6) δ 13.37 (s, 1H), 8.46 (s, 1H), 8.16-8.06 (m, 1H), 7.66-7.50 (m, 2H), 7.457.33 (m, 3H ), 6.94 (d, J=8.4 Hz, 1H), 4.41 (s, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 1.29 (s, 9H).

Stage 1: 2-[4-[5-[(4-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3yl]-2 -methoxyphenoxy]acetic acid

Methyl 2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate (6.57 g, 20.40 mmol), N-(5-bromo -2-methyl-1,2,4-triazol-3-yl)-4-chloro-1-tetrahydropyran-2-yl-indazol-5-amine (described in example 43, step 1) (6.00 g, 14.57 mmol ) and potassium carbonate (4.23 g, 30.61 mmol) were suspended in 1,4dioxane (80 ml) and water (20 ml). The reaction mixture was completely degassed by bubbling with nitrogen. Then complex [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (1.19 g, 1.46 mmol) was added, followed by further degassing, and then the reaction was heated to 80°C for 18 h. The reaction mixture was concentrated under vacuum. The residue was purified with an NH2 ion exchange column eluting with MeOH followed by 2.0 M formic acid in MeOH to give a residue which was then triturated with diethyl ether to give 2-[4-[5-[(4-chloro-1-tetrahydropyran-2 -yl-indazol-5yl)amino]-1-methyl-1,2,4-triazol-3-yl]-2-methoxyphenoxy]acetic acid; formic acid (3.72 g, 6.65 mmol, 46% yield) as a pale brown solid. UPLC-MS (ES ⁺ , Method A):

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1.58 min, m/z 513.4 [M+H]+.

1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 2H), 8.50 (s, 1H), 8.17-8.11 (m, 2H), 7.74 (dd, J=9.0, 0.9 Hz, 1H), 7.65 ( d, J=9.0 Hz, 1H), 7.44-7.32 (m, 2H), 6.86 (d, J=8.5 Hz, 1H), 5.87 (dd, J=9.6, 2.4 Hz, 1H), 4.67 (s, 2H ), 3.90 (d, J=11.5 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.76-3.72 (m, 1H), 2.48-2.33 (m, 1H), 2.09-1.96 ( m, 2H), 1.83-1.55 (m, 3H).

Stage 2: 2-[4-[5-[(4-Chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-2methoxyphenoxy]acetic acid dihydrochloride

Hydrogen chloride (4.0 M in dioxane) (32.36 mL, 129.45 mmol) was added slowly to the stirred suspension of 2-[4-[5-[(4-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]- 1-methyl-1,2,4-triazol-3-yl]-2methoxyphenoxy]acetic acid (3.32 g, 6.47 mmol) in 1,4-dioxane (30 ml) at 25°C. The reaction mixture was stirred at room temperature for 6 hours. The reaction was diluted with diethyl ether and filtered. The resulting solid was washed with diethyl ether and dried under high vacuum to give 2-[4-[5-[(4-chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4- triazol3-yl]-2-methoxyphenoxy]acetic acid dihydrochloride (3.20 g, 6.38 mmol, 98% yield) as a pale brown solid. UPLC-MS (ES+, Method A): 1.28 min, m/z 429.3 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.17 (d, J=0.9 Hz, 1H), 7.65-7.55 (m, 2H), 7.43 (d, J=2.0 Hz, 1H) , 7.38 (dd, J=8.4, 2.0 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 4.72 (s, 2H), 3.87 (s, 3H), 3.80 (s, 3H). 2H are replaced.

Compounds obtained in a manner analogous to that described above are shown in Table 1 below. 15.

Table 15

Example Structure LC-MS SNR 205 CI ΗΝ—# γ-ΝΗ I )=Ν o OH AA ^HN ~A N \ \\ /—U A AAo a Method B, 3.05 min, m/z 500.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.37 (s, 1H), 8.46 (s, 1H), 8.12-8.07 (m, 1H), 7.61-7.51 (m, 2H), 7.42 (d, J = 1.9 Hz, 1H), 7.37 (dd, J = 8.3, 1.9 Hz, 1H), 7.30 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.94 (t, J = 5.6 Hz, 1H), 4.42 (s, 2H), 3.79 (d, J = 17.0 Hz, 6H), 3.38 (dd, J = 6.3, 3.9 Hz, 2H), 1.23 (s, 6H). 206 CI HN-/ /Ά 1 \ X=/ )=Ν o he hn- ⁷ N \ \\ /A Method B, 2.82 min, m/z 486.4 [M+H] ^{+ l} H NMR (400 MHz, DMSO-de) δ 13.37 (s, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.81 (t, J = 5.8 Hz, 1H), 7.56 (q, J = 8.9 Hz, 2H), 7.42 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.3, 1.9 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.75 (d, J = 4.7 Hz, 1H), 4.51 (s, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 3.68 (ddd, J= 11.4, 6.6, 5.0 Hz, 1H), 3.19-2.99 (m, 2H), 1.01 (d, J= 6.2 Hz, ZN). 207 CI ^ν Α7 ΗΝ—/ /Ά 1 _x / )=Ν A /-OH -Ν' ΗΝ—/ ΑΑο k Method B, 2.91 min, m/z 500.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.37 (s, 1H), 8.46 (s, 1H), 8.09 (t, J = 1.2 Hz, 1H), 7.66 (t, J = 6.0 Hz, 1H), 7.61 -7.52 (m, 2H), 7.42 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.3, 1.9 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 4.55 (d, J = 1.5 Hz, ZN), 3.82 (s, ZN), 3.77 (s, ZN), 3.10 (d, J = 6.0 Hz, 2H), 1.04 (s, 6H). 208 ΐ ¹ Η Τ M=r°vA° Ν%7 /Ν'Ν -\ \ / Η Ο ΗΝ—( / OH Method B, 2.85 min, m/z 486.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.67 (d, J = 8.1 Hz , 1H), 7.61-7.51 (m, 2H), 7.42 (d, J = 2.0 Hz, 1H), 7.36 (dt, J = 8.6, 2.1 Hz, 1H), 6.95 (dd, J = 8.5, 2.0 Hz, 1H), 4.81-4.73 (m, 1H), 4.55-4.41 (m, 2H), 3.92-3.72 (m, 7H), 3.34 (d, J = 2.0 Hz, 2H), 1.05 (dd, J = 6.7, 2.0 Hz, ZN).

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209 Cl o ^HN ~/ ^he 1 Η __/ ___/ ^Ν. Ν Γ,--λ / V ^N Gli Υ / ^{0 0} νΆζ Ν- _ν ^ζ \=/ Η ^/ Method B, 2.91 min, m/z 498.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 8.46 (s, 1H), 8.09 (d, J = 0.9 Hz, 1H), 7.89 (t, J = 5.7 Hz, 1H), 7.62-7.51 (m, 2H), 7.43 (d, J = 1.9 Hz, 1H), 7.37 (dd, J = 8.4, 1.9 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.41 (s , 1H), 4.52 (s, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 3.28 (d, J = 5.7 Hz, 2H), 0.59–0.43 (m, 4H). 210 ci η θ Υ \ yGzN JD ν 1ι Ύ Υ ya Y ⁰ nAA / ⁿ -n '— Method B, 3.50 min, m/z 524.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.37 (s, 1H), 8.58 (d, J = 9.0 Hz, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.56 (q, J = 8.9 Hz, 2H), 7.45-7.31 (m, 2H), 6.89 (d, J = 8.4 Hz, 1H), 4.67 (dt, J = 15.6, 7.6 Hz, 1H), 4.58 (s, 2H), 3.79 (d, J = 15.7 Hz, 5H), 1.28 (d, J = 7.0 Hz, ZN). 211 γ3H Cl _n U DC <0Υ ^Ν ΗΑ ⁰ nA/ An — Η Method B, 2.85 min, m/z 498.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.37 (s, 1H), 8.45 (s, 1H), 8.11 (d, J = 17.0 Hz, 2H), 7.56 (q, J = 8.9 Hz, 2H), 7.44-7.31 (m, 2H), 6.90 (d, J = 8.4 Hz, 1H), 4.71 (t, J = 5.8 Hz, 1H), 4.42 (s, 2H), 3.79 (d, J = 15.2 Hz, 6H ), 3.42 (d, J = 5.8 Hz, 2H), 0.77–0.66 (m, 2H), 0.67–0.56 (m, 2H). 212 ci _n about nm--DD ^0N b 'nA/ /An Method B, 2.92 min, m/z 526.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 8.45 (s, 1H), 8.09 (s, 1H), 7.72 (d, J = 7.9Hz, 1H), 7.62-7.50 (m , 2H), 7.46-7.31 (m, 2H), 6.91 (d, J = 8.4Hz, 1H), 4.54 (d, J = 4.4Hz, 1H), 4.45 (s, 2H), 3.79 (d, J = 16.3Hz, 6H), 3.39 (q, J = 7.0Hz, 1H), 3.35 (s, 1H), 1.87-1.67 (m, 4H), 1.22 (q, J= 11.9, 11.4Hz, 4H). 213 O ^0H o U ? and L r-4 av ⁿ v ⁿ \Ja-o ⁰ N 11 J li U\=JN^Z z ^N 'NH Method B, 3.13 min, m/z 526.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.37 (s, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.56 (q, J = 8.9 Hz, 2H), 7.42 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.4, 1.9 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.62 (s, 1H ), 4.48 (d, J = 2.7 Hz, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 3.50–3.40 (m, 1H), 3.27 (t, J = 9.4 Hz, 1H), 1.88 -1.76 (m, 2H), 1.59 (d, J = 21.6 Hz, 2H), 1.29-1.12 (m, 4H). 214 ' HN-A ^0H I ¹ HJ AND Gv ⁿ Y ⁿ \/Vo 0 NJ| 1 'gud yy n- _n h Method B, 2.81 min, m/z 498.4 [M+H] ⁺ Ή NMR (400 MHz, CD ₃ OD) δ 8.10 (d, J = 0.9 Hz, 1H), 7.64–7.54 (m, 2H), 7.56–7.48 (m, 2H), 7.02 (dd, J = 8.5, 0.9 Hz, 1H), 4.53 (d, J = 4.0 Hz, 2H), 4.50-4.35 (m, 1H), 4.06-3.80 (m, 7H), 2.77-2.65 (m, 1H), 2.39-2.26 (m, 2H), 1.91 (dddd, J = 10.8, 9.0, 6.8, 2.9 Hz, 1H), 4 no exchangeable NH were observed. 215 o Y=N Cl _H 0 HN \ _n a^ ⁿ _y n ₀ /L 'yU Άν H ^z Method B, 2.86 min, m/z 533.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.37 (s, 1H), 8.57-8.51 (m, 1H), 8.45 (d, J = 10.8 Hz, 2H), 8.09 (s, 1H), 7.76 (td , J = 7.6, 1.8 Hz, 1H), 7.56 (q, J = 8.8 Hz, 2H), 7.45-7.33 (m, 3H), 7.27 (ddd, J= 7.5, 4.8, 1.1 Hz, 1H), 6.97 ( d, J = 8.4 Hz, 1H), 5.04 (p, J = 7.0 Hz, 1H), 4.57 (s, 2H), 3.80 (d, J = 19.0 Hz, 6H), 1.40 (d, J = 6.9 Hz, ZN). 216 o \ ΗΝ—\ I ¹ H 7 A Av ⁿ V ⁿ \ / vo 0 n J| 1 ' /T^J nA/ An 'H Method B, 2.62 min, m/z 533.4 [M+H] ^{+ X} H NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 8.58-8.48 (m, 2H), 8.498.41 (m, 2H), 8.09 (s, 1H), 7.72 (dt, J = 7.9, 2.0 Hz, 1H), 7.56 (q, J = 8.9 Hz, 2H), 7.42 (d, J = 1.9 Hz, 1H), 7.38-7.30 (m, 2H), 6.91 (d, J = 8.4 Hz , 1H), 5.02 (p, J = 7.1 Hz, 1H), 4.54 (s, 2H), 3.78 (d, J = 8.6 Hz, 6H), 1.43 (d, J = 7.1 Hz, ZN). 217 ^Cl and Y dU * Ν 1 /) - \ / N-U / Ν'Ν ^λ - Η ^z Method B, 3.48 min, m/z 496.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.37 (s, 1H), 8.45 (s, 1H), 8.09 (s, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.56 (q, J = 8.8 Hz, 2H), 7.44-7.32 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 4.46 (s, 2H), 4.05 (dq, J = 14.0, 7.0 Hz, 1H), 3.79 ( d, J = 17.0 Hz, 5H), 1.80 (dt, J = 12.2, 6.1 Hz, 2H), 1.63 (s, 2H), 1.58-1.46 (m, 2H), 1.49-1.33 (m, 2H), 1 exchangeable NH is not visible. 218 Cl _u 0 ^Η / ^Ν C 1 Η / —Ζ Α~' HUTASU ^FF νΑζ /Ν-ν ^= ⁷ Η Method B, 3.51 min, m/z 524.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 8.59 (d, J = 9.0 Hz, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.61-7.50 (m , 2H), 7.42 (d, J = 1.9 Hz, 1H), 7.35 (dd, J = 8.4, 1.9 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 4.66 (dq, J = 15.7, 7.8 Hz, 1H), 4.58 (s, 2H), 3.79 (d, J = 15.4 Hz, 6H), 1.27 (d, J = 7.1 Hz, ZN). 219 ϊ /° aV YyVv/M ^{0 F} ν Ji J J. rV/ ν^Λ ζ ^Ν 'Ν Η Method B, 3.05 min, m/z 524.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) 13.38 (s, 1H), 8.59 (d, J = 9.0 Hz, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.61 - 7.50 (m, 2H), 7.42 (d, J = 1.9 Hz, 1H), 7.35 (dd, J = 8.4, 1.9 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 4.66 (dq, J = 15.7, 7.8 Hz, 1H), 4.58 (s, 2H), 3.79 (d, J = 15.4 Hz, 6H), 1.27 (d, J = 7.1 Hz, ZN).

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General way H:

The process for preparing the compound of the invention is shown below. Additional compounds that can be obtained in a similar way using commercially available sulfonyl chlorides or acid chlorides using the General method H, are presented in table. 16.

Example 220: N-[2-[4-[5-(1H-indazol-5-ylamino)-4H-1,2,4-triazol-3-yl]phenoxy]ethyl]methanesulfonamide

A solution of tert-butyl X-[5-[4-[2-(methanesulfonamido)ethoxy]phenyl]-1-tetrahydropyran-2-yl-1,2,4 triazol-3-yl]-N-(1-tetrahydropyran- 2-ylindazol-5-yl)carbamate (65 mg, 0.10 mmol) in hydrogen chloride (4M in dioxane, 4.0 ml, 16.0 mmol) and IPA (2 ml) were stirred at room temperature overnight. Solvents were removed under reduced pressure and the residue was purified by preparative HPLC to give N-[2-[4-[5-(1H-indazol-5-ylamino)-4H-1,2,4-triazol-3yl]phenoxy] ethyl]methanesulfonamide (14 mg, 0.03 mmol, 36% yield) as a white solid. LC-MS (ES+, Method E): 5.43 min, m/z 414.0 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6): δ 13.39 (br s, 1H), 12.80 (s, 1H), 9.15 (s, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.92 ( d, 2H), 7.42 (s, 2H), 7.32 (s, 1H), 7.10 (d, J=8.5 Hz, 2H), 4.11 (t, J=5.5 Hz, 2H), 3.37 (t, J=5.5 Hz, 2H), 2.97 (s, 3H).

Stage 1: tert-Butyl N-(5-bromo-1-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-N-(1-tetrahydropyran2-ylindazol-5-yl)carbamate

To a stirred solution of X-(5-bromo-1-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-1tetrahydropyran-2-yl-indazol-5-amine (500 mg, 1.12 mmol) in DCM (12.5 ml) was added di-tert-butyl dicarbonate (732 mg, 3.35 mmol) and DMAP (14 mg, 0.11 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (10 ml), the layers were separated, and the aqueous part was extracted with DCM (2x10 ml). The combined organics were dried (phase separator) and concentrated in vacuo. The crude material was purified by flash column chromatography (SiO ₂ , eluting with 10-60% EtOAc in petroleum ether) to give tert-butyl N-(5-bromo-1-tetrahydropyran-2-yl-1,2,4-triazol-3 -yl)-N-(1-tetrahydropyran-2-ylindazol-5yl)carbamate (607 mg, 1.11 mmol, 99% yield) as a yellow foam. LC-MS (ES ⁺ , Method C): 3.78 min, m/z 549.0 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ): δ 7.99 (d, J=1.0 Hz, 1H), 7.72 (t, J=1.5 Hz, 1H), 7.58 (dq, J=9.0, 1.0 Hz, 1H), 7.42 (dt, J=9.0, 2.0 Hz, 1H), 5.70 (dd, J=9.0, 3.0 Hz, 1H), 5.42 (ddd, J=9.0, 3.0, 1.5 Hz, 1H), 4.08-3.95 (m, 2H ),

- 149 042028

3.77-3.60 (m, 2H), 2.52 (m, 1H), 2.31 (m, 1H), 2.13 (m, 2H), 2.07 (m, 1H), 1.94 (m, 1H), 1.77-1.61 (m, 6H), 1.45 (s, 9H).

Step 2: tert-butyl N[5-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-1,2,4-triazol-3-yl]-Ni(1tetrahydropyran-2-ylindazol-5-yl)carbamate

The vial was charged with tert-butyl N(5-bromo-1-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-N(1tetrahydropyran-2-ylindazol-5-yl)carbamate (565 mg, 1.03 mmol), potassium carbonate (285 mg, 2.06 mmol) and 4-hydroxybenzeneboronic acid (231 mg, 1.24 mmol). 1,4-dioxane (8 ml) and water (1.6 ml) were added and the mixture was degassed with N2 for 10 min. The Pd(dppf)Cl ₂ -DCM complex (84 mg, 0.10 mmol) was added in one portion, the vial was sealed, and the reaction was heated at 80° C. overnight. The mixture was allowed to cool to room temperature, diluted with EtOAc (15 ml) and water (10 ml) and filtered through a pad of celite. The layers were separated, the aqueous portion was extracted with EtOAc (2x10 ml) and the combined organics were washed with brine (10 ml), dried (phase separator) and concentrated in vacuo. The crude material was purified by flash column chromatography (SiO ₂ , eluting with 0-60% EtOAc in petroleum ether) to give tert-butyl N-[5-(4-hydroxyphenyl)-1tetrahydropyran-2-yl-1,2,4 -triazol-3-yl]-N-(1-tetrahydropyran-2-ylindazol-5-yl)carbamate (426 mg, 0.76 mmol, 74% yield) as a white foam. LC-MS (ES+, Method C): 3.41 min, m/z 561.1 [M+H] ⁺ .

Stage 3: tert-butyl N-[5-[4-[2-(beuyloxycarbonylamino)ethoxy]phenyl]-1-tetrahydropyran-2-yl1,2,4-triazol-3-yl]-N-(1-tetraαhydropyran -2-ylindazol-5-yl)carbamate

To a stirred solution of tert-butyl N-[3-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-1,2,4triazol-3-yl]-N-(1-tetrahydropyran-2-ylindazol-5-yl )carbamate (426 mg, 0.76 mmol) and potassium carbonate (210 mg, 1.52 mmol) in DMF (5 mL) was added benzyl(2-bromoethyl)carbamate (392 mg, 1.52 mmol) and the reaction mixture was stirred at room temperature for night. An additional equivalent of benzyl (2-bromoethyl)carbamate (190 mg, 0.75 mmol) was added and the reaction was heated at 50° C. for an additional 4 h. The mixture was allowed to cool to room temperature and the solvents were removed under reduced pressure. The residue was partitioned between EtOAc (20 ml) and water (20 ml), the layers were separated and the aqueous part was back-extracted with EtOAc (3x10 ml). The combined organics were dried (phase separator) and concentrated in vacuo. The crude material was purified by flash column chromatography (SiO2 eluting with 10-60% EtOAc in petroleum ether) to give tert-butyl N-[5-[4-[2-(benzyloxycarbonylamino)ethoxy]phenyl]-1-tetrahydropyran- 2-yl-1,2,4triazol-3-yl]-N-(1-tetrahydropyran-2-ylindazol-5-yl)carbamate (423 mg, 0.57 mmol, 75% yield) as a white foam. LC-MS (ES ⁺ , Method C): 4.05 min, m/z 738.3 [M+H] ⁺ .

Step 4: tert-butyl N-[5-[4-(2-aminoethoxy)phenyl]-1-tetra-alpha-hydropyran-2-yl-1,2,4-tri-alpha-zol-3-yl]-N-(1-tetrahydropyran-2 -ylindazol-5-yl)carbamate

A slurry of carbon-supported palladium (10 wt.%, 40 mg, 0.21 mmol) in DCM (0.2 ml) and methanol (2 ml) was added to a stirred solution of tert-butyl N-[5-[4-[2(benzyloxycarbonylamino)ethoxy ]phenyl]-1-tetrahydropyran-2-yl-1,2,4-triazol-3-yl]-N-(1tetrahydropyran-2-ylindazol-5-yl)carbamate (399 mg, 0.54 mmol) in methanol (10 ml). The reaction mixture was stirred under H2 atmosphere at room temperature overnight. The mixture was filtered through a pad of celite (eluting with EtOAc) and the filtrate concentrated under reduced pressure to give t-butyl N-[5-[4-(2-aminoethoxy)phenyl]-1-tetrahydropyran-2-yl-1,2,4 -triazol-3-yl]-N-(1tetrahydropyran-2-ylindazol-5-yl)carbamate (273 mg, 0.41 mmol, 75% yield) as yellow glass

- 150 042028 fine solid. LC-MS (ES ⁺ , Method C): 2.42 min, m/z 604.1 [M+H] ⁺ .

Stage 5: tert-butyl X-[5-[4-[2-(methanesulfonamido)ethoxy]phenyl]-1-tetrahydropyran-2-yl-1,2,4triazol-3-yl]-X-(1-tetrahydropyran -2-ylindazol-5-yl)carbamate

To a stirred solution of tert-butyl X-[5-[4-(2-aminoethoxy)phenyl]-1-tetrahydropyran-2-yl1,2,4-triazol-3-yl]-X-(1-tetrahydropyran-2- ylindazol-5-yl)carbamate (80 mg, 0.13 mmol) and triethylamine (55 μl, 0.40 mmol) in DCM (2 ml) was added methanesulfonyl chloride (20 μl, 0.20 mmol) and the reaction mixture was stirred at room temperature for 1 h The reaction was stopped with water (10 ml), the layers were separated and the aqueous part was extracted with DCM (2x10 ml). The combined organics were dried (phase separator) and concentrated. The crude material was purified by flash column chromatography (SiO ₂ , eluting with 40-90% EtOAc in petroleum ether) to give t-butpl X-[5-[4-[2-(methanesulfonamido)ethoxy]phenyl]-1-tetrahydropyran -2-yl-1,2,4-triazol-3-yl]X-(1-tetrahydropyran-2-ylindazol-5-yl)carbamate (65 mg, 0.09 mmol, 72% yield) as a white glassy solid . LC-MS (ES+, Method C): 3.44 min, m/z 682.0 [M+H] ⁺ .

Compounds obtained in a manner analogous to that described above are shown in Table 1 below. 16.

Intermediate connections.

Table 16

Example Structure LC-MS Ή NMR 221 N T J T >-O n ^Ν Method E, 5.08 min, m/z 378.0 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.41 (s, IH), 12.79 (s, IH), 9.13 (s, IH), 8.12 (d,J = 11.4.5.9 Hz, 2H), 7.94 (s, IH), 7.92-7.88 (m, 2H), 7.42 (s, 2H), 7.09 (d, J = 8.3 Hz, 2H), 4.05 (t, J = 5.7 Hz, 2H), 3.43 (q, J =5.6 Hz, 2H), 1.84 (s, 3H). 222 Ν=\ ΗΝ-^/ m Η ____ .---/ --- OS J Y Ν- _ν χ-- ² Η Method E, 4.84 min, m/z 413.04 [M+H] ⁺ Ή NMR (400 MHz, CD ₃ OD) δ 8.16 (d, J = 1.0 Hz, IH), 7.997.91 (m, 2H), 7.91–7.86 (m, 3H), 7.70 (dt, J =9.0, 0.9 Hz, IH), 7.46 (dd, J = 8.9, 2.0 Hz, IH), 7.20-7.10 (m, 3H), 6.95 (ddd, J = 7.6, 6.5, 1.1Hz, IH), 4.36 (t, J = 5.0 Hz, 2H), 3.87 (t, J =5.0 Hz, 2H). 4 NH were not observed. 223 ην-Α ____/ 0 Η Η / Ο ν ιι ι ν AA/ νΑα ν—ν Η Method E, 6.03 min, m/z 420.1 [M+H] ⁺ Ή NMR (400 MHz, CD ₃ OD) δ 8.32 (s, IH), 8.00 (s, IH), 7.88 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.4 Hz, IH), 7.55 (d, J = 8.5 Hz, IH), 7.14 (d, J = 8.0 Hz, 2H), 4.15 (d, J = 5.1 Hz, 2H), 3.61 (t, J = 5.0 Hz, 2H), 2.13-2.02 (m, 3H), 0.94 (d, J = 6.0 Hz, 6H). 4 NH were not observed.

- 151 042028

General method I:

The process for preparing the compound of the invention is shown below. Additional compounds that can be obtained in a similar way, using General method I, are presented in table. 17.

Example 224: 1-[2-[4-[5-(1H-Indazol-5-ylamino)-4H-1,2,4-triazol-3-yl]phenoxy]ethyl]-3isopropylurea dihydrochloride

•2HCI

tert-Butyl solution -ylindazol-5-yl)carbamate (55 mg, 0.08 mmol) in 4 M hydrochloric acid in dioxane (4 ml, 16 mmol) and IPA (2 ml) was stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was triturated with diethyl ether to give 1-[2-[4-[5-(1H-indazol-5-ylamino)-4H-1,2,4-triazol-3-yl]phenoxy ]ethyl]-3isopropylurea dihydrochloride (38 mg, 0.08 mmol, 96% yield) as a white solid. LC-MS (ES+, Method E): 5.64 min, m/z 421.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.70 (s, 1H), 8.04 (d, J=1.0 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.97-7.92 (m , 2Н), 7.51 (d, J=9.0 Hz, 1H), 7.42 (dd, J=9.0, 2.0 Hz, 1H), 7.14-7.09 (m, 2Н), 4.02 (t, J=5.5 Hz, 2Н) , 3.67 (p, J=6.5 Hz, 1H), 3.38 (t, J=5.5 Hz, 2H), 1.02 (d, J=6.5 Hz, 6H).

Stage 1: tert-butyl X-[5-[4-[2-(isopropylcarbamoylamino)ethoxy]phenyl]-1-tetrahydropyran-2yl-1,2,4-triazol-3-yl]-N-(1-tetrahydropyran -2-ylindazol-5-yl)carbamate

To a stirred solution of tert-butyl X-[5-[4-(2-aminoethoxy)phenyl]-1-tetrahydropyran-2-yl1,2,4-triazol-3-yl]-X-(1-tetrahydropyran-2- ylindazol-5-yl)carbamate (80 mg, 0.13 mmol) in THF (2 ml) was added 1,1'-carbonyldiimidazole (43 mg, 0.27 mmol) and the reaction mixture was stirred at room temperature for 2 h. aminopropane (46 μl, 0.54 mmol) and the reaction mixture was stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was partitioned between EtOAc (10 ml) and water (10 ml). The layers were separated and the aqueous portion was extracted with EtOAc (2x10 ml). The combined organics were washed with brine (10 ml), dried (phase separator) and concentrated. The crude material was purified by flash column chromatography (SiO ₂ , eluting with 50-90% EtOAc in petroleum ether) to give tert-butyl N-[5-[4-[2-(isopropylcarbamoylamino)ethoxy]phenyl]-1-tetrahydropyran -2-yl-1,2,4-triazol-3-yl]-N-(1tetrahydropyran-2-ylindazol-5-yl)carbamate (50 mg, 0.07 mmol, 55% yield) as a resinous solid. UPLC-MS (ES ⁺ , Method A): 1.97 min, m/z 689.6 [M+H] ⁺ .

Compounds obtained in a manner analogous to that described above are shown in Table 1 below. 17.

- 152 042028

Table 17

Example Structure LC-MS ‘NMR 225 IqjT.Z. Az IZ 1 A ZI % Method B, 5.61 min, m/z 433.1 [M+H]+ ^1H NMR (400 MHz, DMSOd ₆ , @ 353K) δ 13.17 (s, 1H), 12.55 (s, 1H), 8.66 (s, 1H), 8.01 (s, 1H), 7.96-7.86 (m, 3H) , 7.53-7.36 (m, 2H), 7.07 (d, 7=8.3Hz, 2H), 5.95 (s, 1H), 4.10 (t, J=6.2Hz, 2H), 3.44 (q, J=6.1Hz, 2H), 3.273.22 (m, 4H), 1.85-1.76 (m, 4H).

Example 226 1-[4-[5-(1H-Indazol-5-ylamino)-4H-1,2,4-triazol-3-yl]phenoxy]-Nisopropylmethanesulfonamide

tert-Butyl N[5-[4-(isopropylsulfamoylmethoxy)phenyl]-1-tetrahydropyran-2-yl-1,2,4-triazol-3yl]-N-(1-tetrahydropyran-2-ylindazol-5-yl) carbamate (85 mg, 0.12 mmol) was dissolved in a solution of hydrogen chloride-1,4-dioxane, 4 M (3 ml, 12 mmol) and IPA (2 ml) and the reaction mixture was stirred at room temperature overnight. Solvents were removed under vacuum. The crude residue was purified by preparative HPLC (30-80% MeCN in H ₂ O) to give 1-[4-[5-(1H-indazol-5-ylamino)4H-1,2,4-triazol-3-yl ]phenoxy]-N-isopropylmethanesulfonamide (12 mg, 0.03 mmol, 23% yield) as a white solid. LC-MS (ES+, Method E): 6.11 min, m/z 428.00 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 13.50 (brs, 1H), 12.81 (s, 1H), 9.17 (s, 1H), 8.09 (d, J=1.5 Hz, 1H), 7.967.91 (m , 3H), 7.52 (s, 1H), 7.42 (d, J=1.7 Hz, 2H), 7.28-7.21 (m, 2H), 5.22 (s, 2H), 3.53 (m, J=6.6 Hz, 1H) , 1.11 (d, J=6.6 Hz, 6H).

Stage 1: 1-chloro-N-isopropylmethanesulfonamide

0 I

H

A solution of chlormesyl chloride (0.12 ml, 1.3 mmol) in ether (4 ml) was added to a stirred solution of 2-aminopropane (0.12 ml, 1.37 mmol) and 4-methylmorpholine (0.16 ml, 1.44 mmol) in ether (2 ml) at 0°C, and the reaction mixture was stirred at 0°C for 5 hours, the Solution was diluted with EtOAc (10 ml) and 1 M HCl (5 ml). The layers were separated and the aqueous phase was extracted with EtOAc (2x5 ml). The combined organics were washed with brine (10 ml), dried (phase separator) and concentrated to give 1-chloro-N-isopropylmethanesulfonamide (136 mg, 0.79 mmol, 58% yield) as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ 4.48 (s, 2H), 4.45 (s, 1H), 3.75-3.63 (m, 1H), 1.28 (d, J=6.5 Hz, 6H).

Stage 2: tert-butyl N-[5-[4-(isopropylsulfamoylmethoxy)phenyl]-1-tetrahydropyran-2-yl-1,2,4triazol-3-yl]-N-(1-tetrahydropyran-2-ylindazol- 5-yl)carbamate

A mixture of tert-butyl N-[5-(4-hydroxyphenyl)-1-tetrahydropyran-2-yl-1,2,4-triazol-3-yl]-N-(1tetrahydropyran-2-ylindazol-5-yl)carbamate (119 mg, 0.21 mmol), 1-χλορ-Νisopropylmethanesulfonamide (0.02 ml, 0.21 mmol) and potassium carbonate (29 mg, 0.21 mmol) in DMF (2 ml) were heated at 60°C over the weekend. Potassium iodide (71 mg, 0.42 mmol), additional potassium carbonate (29 mg, 0.21 mmol) and 1-chloro-N-isopropylmethanesulfonamide (0.02 ml, 0.21 mmol) were added and the reaction mixture was stirred at 60°C for 7 days. The solvents were removed under vacuum and the residue was partitioned between EtOAc (10 ml) and water (10 ml). The layers were separated and the aqueous portion was extracted with EtOAc (2x10 ml). The combined organics were washed with brine (10 ml), dried (phase separator) and concentrated in vacuo. The crude material was purified by column chromatography (SiO ₂ , eluting with 45-55% EtOAc in petroleum ether) to give

- 153 042028 tert-butyl N-[5-[4-(isopropylsulfamoylmethoxy)-phenyl]-1-tetrahydropyran-2-yl-1,2,4-triazol-3-yl] 5-yl)carbamate (85 mg, 0.07 mmol, 32% yield) as a clear glassy solid. LC-MS (ES+, Method C): 3.76 min, m/z 696.32 [M+H] ⁺ .

Example 227: N-(1-acetylazetidin-3-yl)-2-[4-[5-(1H-indazol-5-ylamino)-4H-1,2,4-triazol-3-yl]-2methoxyphenoxy] acetamide

To a stirred solution of N-(1-acetylazetidin-3-yl)-2-[2-methoxy-4-[2-tetrahydropyran-2-yl-5[(1-tetrahydropyran-2-ylindazol-5-yl)amino] -1,2,4-triazol-3-yl]phenoxy]acetamide (28 mg, 0.04 mmol) in DCM (3 mL) trifluoroacetic acid (66 μL, 0.87 mmol) was added at room temperature under nitrogen atmosphere and the reaction mixture was stirred at 25°C overnight. Solvents were removed under reduced pressure and the residue was purified by preparative HPLC (30-80% MeCN in H ₂ O) to give N-(1-apetylazetidin-3-yl)-2-[2-methoxy-4-[2- tetrahydropyran-2-yl-5-[(1tetrahydropyran-2-ylindazol-5-yl)amino]-1,2,4-triazol-3-yl]phenoxy]acetamide (28 mg, 0.04 mmol) as off-white solid. LC-MS (ES ⁺ , Method E): 5.02 min, m/z 477.0 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6, 353K): δ 13.25 (s, 1H), 12.55 (s, 1H), 8.70 (s, 1H), 8.37 (d, J=6.6 Hz, 1H), 8.06- 7.95 (m, 1H), 7.91 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.54 (dd, J=8.3, 2.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H ), 7.09 (d, J=8.4 Hz, 1H), 4.59-4.49 (m, 3H), 4.41-3.94 (m, 3H), 3.91 (s, 3H), 3.84 (s, 1H), 1.76 (s, 3H).

Stage 1: benzyl 3-[[2-[2-methoxy-4-[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2-ylindazol-5yl)amino]-1,2,4-triazole -3 -yl]phenoxy]acetyl]amino]azetidine-1-carboxylate

To a stirred solution of 2-[2-methoxy-4-[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2ylindazol-5-yl)amino]-1,2,4-triazol-3-yl] phenoxy]acetic acid (302 mg, 0.55 mmol), 2-(7-aza-1Hbenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (272 mg, 0.72 mmol) in dry DMF ( 3 ml) at room temperature under nitrogen atmosphere, a solution of benzyl 3-amino-1-azetidinecarboxylate (206 μl, 0.83 mmol) in DMF (2 ml) and N,N-diisopropylethylamine (287 μl, 1.65 mmol) was added, and the reaction mixture was stirred at 25 °C throughout the night. The solvents were removed under reduced pressure and the residue was taken up in EtOAc (15 ml) and washed with 5% KHSO4 (2x10 ml) and brine (10 ml). The organics were dried (phase separator) and concentrated. The crude material was purified by column chromatography (SiO ₂ , eluting with 50-100% EtOAc in petroleum ether) to give benzyl 3-[[2-[2-methoxy-4-[2-tetrahydropyran-2-yl-5-[( 1-tetrahydropyran-2ylindazol-5-yl)amino]-1,2,4-triazol-3-yl]phenoxy]acetyl]amino]azetidine-1-carboxylate (214 mg, 0.29 mmol, 53% yield) as oily solid. LC-MS (ES ⁺ , Method C): 3.38 min, m/z 737.3 [M+H] ⁺ .

Step 2: N-(azetidin-3-yl)-2-[2-methoxy-4-[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2ylindazol-5-yl)amino]-1, 2,4-triazol-3 -yl]phenoxy]acetamide

Suspension of benzyl 3-[[2-[2-methoxy-4-[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2-ylindazol5-yl)amino]-1,2,4-triazol-3 -yl]phenoxy]acetyl]amino]azetidine-1-carboxylate (214 mg, 0.29 mmol) and palladium, 10 wt.% on a powdered carbon carrier, dry (21 mg, 0.20 mmol) in methanol (3 ml) were stirred under atmosphere hydrogen overnight. Additional palladium, 10 wt% on powdered carbon support (21 mg, 0.20 mmol) was added and the reaction mixture was stirred under hydrogen atmosphere for an additional 48 h. Additional palladium, 10 wt% on powdered carbon support (21 mg, 0.20 mmol) and the reaction mixture was stirred under a hydrogen atmosphere for an additional 24 h. [2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]-1,2,4-triazol-3

- 154 042028 yl]phenoxy]acetamide (52 mg, 0.09 mmol, 30% yield). LC-MS (ES+, Method D): 3.68 min, m/z 603.0 [M+H] ⁺ .

Step 3: N-(1-acetylazetidin-3-yl)-2-[2-methoxy-4-[2-tetrahydropyran-2-ul-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]- 1,2,4-triazol-3-yl]phenoxy]acetamide

To a stirred solution of N-(azetidin-3-yl)-2-[2-methoxy-4-[2-tetrahydropyran-2-yl-5-[(1tetrahydropyran-2-ylindazol-5-yl)amino]-1, 2,4-triazol-3-yl]phenoxy]acetamide (52 mg, 0.09 mmol) and triethylamine (36.09 μl, 0.26 mmol) in anhydrous DCM (2 ml) at 0°C was added acetyl chloride (9.2 μl, 0.13 mmol) drops. The cooling bath was removed and the reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with DCM (15 ml) and washed with water (10 ml). The organics were dried (phase separator) and concentrated, and the crude material was purified by column chromatography (SiO ₂ , eluting with 50-100% EtOAc in petroleum ether) to give N(1-acetylasetidin-3-yl)-2-[2- methoxy-4-[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2ylindazol-5-yl)amino]-1,2,4-triazol-3-yl]phenoxy]acetamide (28 mg, 0.04 mmol, 50% yield) as an off-white oily solid. LC-MS (ES ⁺ , Method C): 2.47 min, m/z 645.7 [M+H] ⁺ .

Example 228: N-[5-[4-[(3-Aminooxetan-3-yl)methoxy]phenyl]-4H-1,2,4-triazol-3-yl]-1 H-indazol-5 amine.

Example 229: N-[5-[4-[[3-(ethylα-mino)oxetan-3-yl]methoxy]phenyl]-4H-1,2,4-triazol-3-yl]-1Hindazol-5-amine

To a stirred solution of N-[5-[4-[(3-aminooxetan-3-yl)methoxy]phenyl]-1-tetrahydropyran-2yl-1,2,4-triazol-3-yl]-1-tetrahydropyran-2 -yl-indazol-5-amine (60 mg, 0.11 mmol) and N-[5-[4-[[3(ethylamino)oxetan-3-yl]methoxy]phenyl]-1-tetrahydropyran-2-yl-1 ,2,4-triazol-3-yl]-1tetrahydropyran-2-yl-indazol-5-amine (59 mg, 0.10 mmol) in dry DCM (3 ml) at room temperature under nitrogen atmosphere was added trifluoroacetic acid (157.5 µl, 2.06 mmol) and the reaction mixture was stirred at 25° C. overnight. The mixture was purified by ion exchange chromatography (SCX eluting with 1 M NH3 in MeOH) and preparative HPLC (20-50% MeCN in H ₂ O) to give N-[5-[4-[[3-(ethylamino)oxetane-3 -yl]methoxy]phenyl]-4H-1,2,4-triazol-3-yl]-1H-indazol-5-amine (10.9 mg, 0.02 mmol, 20% yield) as a white solid and N-[ 5-[4-[(3-aminooxetan-3yl)methoxy]phenyl]-4H-1,2,4-triazol-3-yl]-1H-indazol-5-amine (19 mg, 0.04 mmol, 44% yield ) as an off-white solid. Example 228: LC-MS (ES ⁺ , Method E): 4.25 min, m/z 378.1 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6): δ 13.22 (s, 1H), 12.81 (s, 1H), 9.16 (s, 1H), 8.10 (s, 1H), 7.94 (d, J=2.5 Hz, 2H ), 7.92 (s, 1H), 7.42 (d, J=1.5 Hz, 2H), 7.13 (d, J=9.0 Hz, 2H), 4.48 (d, J=6.0 Hz, 2H), 4.39 (d, J =6.0 Hz, 2H), 4.13 (s, 2H), 2.27 (s, 2H).

Example 229: LC-MS (ES ⁺ , Method E): 4.44 min, m/z 405.9 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6): δ 12.80 (s, 2H), 9.17 (s, 1H), 8.11 (t, J=1.5 Hz, 1H), 7.94 (s, 2H), 7.91 (d, J =2.5 Hz, 2H), 7.43-7.41 (m, 2H), 7.13 (d, J=9.0 Hz, 2H), 4.52 (d, J=6.0 Hz, 2H), 4.43 (d, J=6.0 Hz, 2H ), 4.21 (s, 2H), 2.66-2.59 (m, 2H), 1.04 (t, J=7.0 Hz, 3H).

Stage 1: benzyl N-[3-(hydroxymethyl)oxetan-3-yl]carbamate

To a stirred solution of (3-amino-3-oxetanyl)methanol (103 mg, 1 mmol) in DCM (4.5 ml) was added a solution of sodium bicarbonate (252 mg, 3 mmol) in water (4.5 ml). Benzyl chloroformate (0.17 mL, 1.2 mmol) was added and the biphasic mixture was vigorously stirred at 25° C. overnight. The mixture was diluted with water (5 ml) and extracted with DCM (3x15 ml). The combined organics were dried (phase separator) and concentrated, and the crude material was purified using a column

- 155 042028 chromatography (SiO ₂ , eluting with 50-100% EtOAc in petroleum ether) to give benzyl N-[3(hydroxymethyl)oxetan-3-yl]carbamate (182 mg, 0.77 mmol, 77% yield) as a colorless oil solid. LC-MS (ES ⁺ , Method C): 1.74 min, m/z 260.0 [M+Na] ⁺ .

¹ H NMR (400 MHz, CDCl3): δ 7.41-7.30 (m, 5H), 5.34 (s, 1H), 5.10 (s, 2H), 4.71 (d, J=6.5 Hz, 2H), 4.53 (d, J=6.5 Hz, 2H), 4.04 (s, 2H), 2.48 (s, 1H).

Step 2: [3-(benzyloxycarbonylamino)oxetan-3-yl]methylmethanesulfonate

Methansulfonyl chloride was added to a stirred solution of benzyl N-[3-(hydroxymethyl)oxetan-3-yl]carbamate (171 mg, 0.72 mmol) and triethylamine (301 µl, 2.16 mmol) in DCM (2 ml) at 0°C under nitrogen atmosphere. (84 µl, 1.08 mmol). The cooling bath was removed and the reaction mixture was stirred at 25°C for 1.5 h. The reaction was stopped with H2O (10 ml) and extracted with DCM (3x15 ml). The combined organics were washed with brine (15 ml), dried (phase separator) and concentrated to give [3-(benzyloxycarbonylamino)oxetan-3-yl]methyl methanesulfonate (227 mg, 0.72 mmol, 100% yield). LC-MS (ES+, Method C): 2.32 min, m/z 316.1 [M+H] ⁺ .

Stage 3: benzyl ^[3-[(4-bromophenoxy)methyl]oxetan-3-yl]carbamate

A suspension of 4-bromophenol (96 mg, 0.55 mmol), [3-(benzyloxycarbonylamino)oxetan-3yl]methylmethanesulfonate (227 mg, 0.72 mmol) and potassium carbonate (230 mg, 1.66 mmol) in MeCN (5.5 ml) was heated at 80°C C in a nitrogen atmosphere overnight. The solvents were removed under reduced pressure and the residue was partitioned between water (15 ml) and EtOAc (20 ml). The layers were separated and the aqueous portion was extracted with EtOAc (2x20 ml). The combined organics were washed with water (20 ml) and brine (20 ml), dried (phase separator) and concentrated. The crude material was purified by column chromatography (SiO ₂ , eluting with 30-50% EtOAc in petroleum ether) to give benzyl N-[3-[(4-bromophenoxy)methyl]oxetan-3-yl]carbamate (193 mg, 0.49 mmol , 89% yield) as a white solid. LC-MS (ES ⁺ , Method D): 6.02 min, m/z 392.9 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ): δ 7.41-7.29 (m, 7H), 6.79 (d, J=8.5 Hz, 2H), 5.33 (s, 1H), 5.09 (s, 2H), 4.83 (d, J=6.5 Hz, 2H), 4.61 (d, J=6.5 Hz, 2H), 4.34 (s, 2H).

Step 4: Benzyl N-[3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]oxetan-3yl]carbamate

Benzyl N-[3-[(4-bromophenoxy)methyl]oxetan-3-yl]carbamate (193 mg, 0.49 mmol), potassium acetate (251.53 mg, 2.56 mmol), and bis(pinacolato)diborone (282 mg , 1.11 mmol). 1,4-dioxane (5 ml) was added and the solution was degassed with nitrogen for 10 minutes. The complex [1,1'bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (70 mg, 0.09 mmol) was added and the sealed vial was heated at 100°C overnight. The reaction mixture was cooled to room temperature, filtered through a phase separator, and the filtrate was concentrated under reduced pressure to give benzyl N-[3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl )phenoxy]methyl]oxetan-3-yl]carbamate (215 mg, 99% yield). LC-MS (ES ⁺ , Method C): 3.58 min, m/z 439.9 [M+H] ⁺ .

- 156 042028

Step 5: benzyl N[3-[[4-[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2-ylindazol-5yl)amino]-1,2,4-triazol-3-yl] phenoxy]methyl]oxetan-3 -yl]carbamate

N-Bromo-1-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)-1-tetrahydropyran-2-ylindazol-5-amine (169 mg, 0.38 mmol) and potassium carbonate (157 mg, 1.13 mmol). A solution of benzyl N[3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]oxetan-3-yl]carbamate (216 mg, 0.49 mmol) in 1,4-dioxane (3 mL) and water (0.60 mL), and the solution was degassed with nitrogen for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium (II) chloride dichloromethane complex (31 mg, 0.04 mmol) was added and the sealed vial was heated at 80° C. overnight. The mixture was allowed to cool to room temperature, degassed with nitrogen for 10 min, and an additional complex of [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (31 mg, 0.04 mmol) was added. The vial was hermetically sealed and the mixture was heated at 80° C. overnight. The reaction mixture was filtered through a pad of Celite (eluting with EtOAc) and the filtrate was washed with water (15 ml). The aqueous portion was further extracted with EtOAc (2x15 ml) and the combined organics were dried (phase separator) and concentrated. The crude material was purified by flash column chromatography (SiO ₂ , eluting with 40-80% EtOAc in petroleum ether) to give benzyl N-[3-[[4-[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2- ylindazol-5-yl)amino]-1,2,4-triazol-3yl]phenoxy]methyl]oxetan-3-yl]carbamate (154 mg, 0.23 mmol, 60% yield) as a light brown oily solid. LC-MS (ES+, Method C): 3.60 min, m/z 680.3 [M+H] ⁺ .

Stage 6:

N-[5-[4-[(3-Aminooxetan-3-yl)methoxy]phenyl]-1-tetrahydropyran-2-yl-1,2,4-triazol-3-yl]-1tetrahydropyran-2-yl- indazole-5-amine.

N-[5-[4-[[3-(ethylamino)oxetan-3-yl]methoxy]phenyl]-1-tetrahydropyran-2-yl-1,2,4-triazol-3-yl]-1tetrahydropyran-2 -yl-indazol-5-amine

Suspension of benzyl N-[3-[[4-[2-tetrahydropyran-2-yl-5-[(1-tetrahydropyran-2-ylindazol-5yl)amino]-1,2,4-triazol-3-yl]phenoxy ]methyl]oxetan-3-yl]carbamate (154 mg, 0.23 mmol) and palladium, 10 wt.% on a powdered carbon carrier, dry (15 mg, 0.14 mmol) in ethanol (3 ml) was stirred under hydrogen atmosphere overnight . Additional palladium, 10 wt% on powdered carbon carrier, dry (15 mg, 0.14 mmol) was added and the reaction mixture was stirred under a hydrogen atmosphere for an additional 4 h. obtaining an inseparable mixture of N-[5-[4-[(3aminooxetan-3-yl)methoxy]phenyl]-1-tetrahydropyran-2-yl-1,2,4-triazol-3-yl]-1-tetrahydropyran-2yl -indazol-5-amine (60 mg, 0.11 mmol, 48% yield) and N-[5-[4-[[3-(ethylamino)oxetan-3yl]methoxy]phenyl]-1-tetrahydropyran-2-yl- 1,2,4-triazol-3-yl]-1-tetrahydropyran-2-yl-indazol-5amine (59 mg, 0.10 mmol, 45% yield). LC-MS (ES ⁺ , Method C): 2.34 min, m/z 546.0 [M+H] ⁺ (49%); 2.47 min, m/z 574.3 [M+H] ⁺ (51%).

Example 230: N-[5-[4-[2-(isopropylamino)ethoxy]phenyl]-4H-1,2,4-triazol-3-yl]-1 H-indazol-5-amine

tert-Butyl N-[5-[4-[2-(isopropylamino)ethoxy]phenyl]-1-tetrahydropyran-2-yl-1,2,4-triazol-3-yl]N-(1-tetrahydropyran-2 -ylindazol-5-yl)carbamate (94 mg, 0.15 mmol) was dissolved in IPA (3 ml) and hydrogen chloride (4M in 1,4-dioxane) (3.00 ml, 12 mmol) was added and the reaction mixture was stirred overnight at room temperature. The solvents were removed under vacuum, the residue was triturated with diethyl ether (2x3 ml) and purified using SCX-2 column chromatography, eluting with 1M NH3 in MeOH. The crude material was purified by preparative HPLC (30-80% MeCN in H ₂ O) with half

- 157 042028 X-[5-[4-[2-(isopropylamino)ethoxy]phenyl]-4H-1,2,4-triazol-3-yl]-1H-indazol-5-amine (5 mg, 0.01 mmol, 8% yield) as a white solid. LC-MS (ES ⁺ , Method E): 4.72 min, m/z 378.1 [M+H] ⁺ .

Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.21 (s, 1H), 12.80 (s, 1H), 9.14 (s, 1H), 8.10 (d, >1.4 Hz, 1H), 7.94 (s, 1H) , 7.93-7.86 (m, 2H), 7.42 (d, >1.4 Hz, 2H), 7.12-7.02 (m, 2H), 4.07 (t, >5.8 Hz, 2H), 2.89 (t, >5.7 Hz, 2H ), 2.77 (hept, >6.2 Hz, 1H), 1.00 (d, >6.2 Hz, 6H), 1 H exchangeable.

Stage 1: tert-butyl X-[5-[4-[2-(isopropylamino)ethoxy]phenyl]-1-tetrahydropyran-2-yl-1,2,4triazol-3-yl]-M-( 1 -tetrahydropyran -2-ylindazol-5-yl)carbamate

Acetone (0.05 ml, 0.62 mmol) was added to a stirred solution of tert-butyl N-[5-[4-(2aminoethoxy)phenyl]-1-tetrahydropyran-2-yl-1,2,4-triazol-3-yl]- M-(1-tetrahydropyran-2-ylindazol-5yl)carbamate (75 mg, 0.12 mmol) and Ν,N-diisopropylethylamine (0.04 ml, 0.25 mmol) in methanol (8 ml). Sodium cyanoborohydride (31 mg, 0.50 mmol) and acetic acid (glacial) (0.01 ml, 0.25 mmol) were added and the reaction mixture was stirred at 25°C overnight. Solvents were removed in vacuo and the residue taken up in EtOAc (10 ml) and saturated NaHCO ₃ solution (10 ml). The layers were separated and the aqueous portion was back-extracted with EtOAc (2x10 ml). The combined organic layers were washed with brine (10 ml), dried (phase separator) and concentrated in vacuo to give t-butyl X-[5-[4-[2-(isopropylamino)ethoxy]phenyl]-1-tetrahydropyran-2-yl -1,2,4-triazol-3-yl]X-(1-tetrahydropyran-2-ylindazol-5-yl)carbamate (80 mg, 0.12 mmol, 100% yield) as a gray solid. LC-MS (ES ⁺ , Method C): 3.21 min, m/z 646.13 [M+H] ⁺ .

Ή NMR (400 MHz, CDC1 ₃ ) δ 8.05–7.96 (m, 3H), 7.82–7.78 (m, 1H), 7.60–7.55 (m, 1H), 7.51 (ddd, >8.9, 2.0, 1.1 Hz, 1H ), 6.95-6.88 (m, 2H), 5.69 (dd, >9.1, 2.8 Hz, 1H), 5.42 (dd, >9.4, 2.7 Hz, 1H), 4.11 (dd, >6.0, 4.6 Hz, 2H), 3.99 (d, >11.4 Hz, 1H), 3.69 (dt, >28.9, 10.4 Hz, ZN), 3.01 (t, >5.2 Hz, 2H), 2.89 (p, >6.2 Hz, 1H), 2.59–2.42 ( m, 2H), 2.17 (d, >3.5 Hz, 2H), 2.06 (s, 1H), 1.95 (d, >13.3 Hz, 1H), 1.75-1.64 (m, 6H), 1.46 (s, 9H), 1.11 (d, >6.2 Hz, 6H).

Example 231: [4-[5-(1H-Indazol-5-ylamino)-1-methyl-1,2,4-triazol-3-yl]-2-methoxyphenyl]methyl N-pyrrolidin-3-ylcarbamate

A solution of tert-butyl 3-[[2-methoxy-4-[1-methyl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]-1,2,4triazol-3-yl]phenyl] methoxycarbonylamino pyrrolidine-1-carboxylate (119 mg, 0.18 mmol) in DCM (1.2 ml) was treated with TFA (0.21 ml, 2.76 mmol) at 25°C. The reaction mixture was stirred for 48 h, then diluted with saturated aqueous NaHCO ₃ and extracted with EtOAc (x5). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by silica gel flash chromatography (12 g SiO ₂ , eluting with 10-100% MeOH in DCM) to give [4-(5-(1 H-indazol-5-ylamino)-1-methyl-1, 2,4-triazol-3-yl]-2-methoxyphenyl]methyl N-pyrrolidin-3-ylcarbamate (36 mg, 0.08 mmol, 42% yield) as purple amorphous solid UHPLC (ES ⁺ , Method B): 2.54 min, m/z 463.4 [M+H] ⁺ .

Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.95 (br s, 1H), 8.99 (m, 1H), 8.19-8.15 (m, 1H), 8.03-8.01 (m, 1H), 7.60-7.49 (m , 3 H), 7.42-7.32 (m, 1H), 5.26-4.92 (m, 2H), 3.94-3.85 (m, 4H), 3.81 (s, 3H), 3.44-3.22 (m, 1H), 3.22- 3.09 (m, 1H), 2.99-2.91 (m, 1H), 1.96-1.88 (m, 1H), 1.66-1.59 (m, 1H). 3xNH were not observed.

Step 1: [2-methoxy-4-[1-methyl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]-1,2,4-triazol-3yl]phenyl]methanol

A mixture of (4-bromo-2-methoxyphenyl)methanol (57 mg, 0.26 mmol), tetrahydroxydiborane (71 mg, 0.79 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (12 mg, 0.03 mmol) was purged nitrogen. Degassed ethanol (1.5 ml) was added and the solution was purged with nitrogen. XPhos Pd G2 (10 mg, 0.01 mmol) was added and the reaction mixture was again purged with nitrogen. The reaction was heated to 80° C. and stirred for 2 hours. The reaction was cooled to room temperature. A degassed solution of 1.8 M

-158042028 potassium carbonate in water (0.44 ml, 0.79 mmol), followed by the addition of a solution of N-(5-bromo-2-methyl1,2,4-triazol-3-yl)-1-tetrahydropyran-2-yl-indazol- 5-amine (100 mg, 0.26 mmol) in degassed ethanol (1 ml) and the mixture was purged with nitrogen. The reaction mixture was heated to 80° C. and allowed to stir for 16 hours. The reaction mixture was diluted with methanol, filtered through a plug of celite (washed with MeOH) and concentrated to give the crude material. The crude material was purified by silica gel flash chromatography (12 g SiO ₂ , eluting with 1.5-15% MeOH in DCM/DCM) to give [2-methoxy-4-[1-methyl-5-[(1-tetrahydropyran-2 -ylindazol-5-yl)amino]-1,2,4-triazol-3yl]phenyl]methanol (18 mg, 0.04 mmol, 16% yield) as a brown amorphous solid. UPLC-MS (ES+, Method A): 1.50 min, m/z 435.3 [M+H] ⁺ .

Stage 2: tert-butyl 3-[[2-methoxy-4-[1-methyl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]1,2,4-triazol-3-yl ]phenyl]methoxycarbonylamino]pyrrolidine-1-carboxylate

Solution of (3R)-1-{[(2-methyl-2-propanyl)oxy]carbonyl}-3-pyrrolidinecarboxylic acid (51 mg, 0.24 mmol), diphenylphosphoryl azide (0.06 ml, 0.27 mmol), triethylamine (0.04 ml, 0.29 mmol) in anhydrous toluene (0.50 mL) was stirred at 110°C. After 1 h, the reaction mixture was cooled to room temperature and added to a solution of [2-methoxy-4-[1-methyl-5-[(1-tetrahydropyran-2-ylindazol-5yl)amino]-1,2,4-triazol- 3-yl]phenyl]methanol (80 mg, 0.18 mmol) in anhydrous toluene (1 ml). The reaction mixture was heated to 110° C. and stirred for 72 hours. The solution was diluted with saturated aqueous NaHCO ₃ and extracted with EtOAc (3x). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (25 g SiO ₂ , eluting with 10-100% EtOAc in heptane) to give tert-butyl 3[[2-methoxy-4-[1-methyl-5-[(1-tetrahydropyran- 2-ylindazol-5-yl)amino]-1,2,4-triazol-3yl]phenyl]methoxycarbonylamino]pyrrolidine-1-carboxylate (116 mg, 0.18 mmol, 100% yield) as a purple oil. UPLC-MS (ES ⁺ , Method A): 1.85 min, m/z 647.5 [M+H] ⁺ .

Example 232 2-[4-[5-(1H-Indazol-5-ylamino)-2-methyl-1,2,4-triazol-3-yl]-2-methoxyphenoxy]-Nisopropylacetamide

N-isopropyl-2-[2-methoxy-4-[2-methyl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]1,2,4-triazol-3-yl]phenoxy solution ]acetamide (185 mg, 0.36 mmol) and trifluoroacetic acid (0.41 ml, 5.34 mmol) in DCM (5 ml) were stirred for 16 h. -50% MeOH in water to give formic acid; 2-[4-[5-(1H-indazol-5-ylamino)-2-methyl-1,2,4-triazol-3-yl]-2methoxyphenoxy]-N-isopropylacetamide (60 mg, 0.12 mmol, 35% yield) as a white amorphous solid. UPLC-MS (ES ⁺ , Method B): 3.04 min, m/z 436.4 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.78 (s, 1H), 9.14 (s, 1H), 8.08 (s, 1H), 7.94 (s, 1H), 7.83 (d, J=7.8 Hz, 1H ), 7.40-7.35 (m, 3H), 7.31 (dd, J=8.3, 1.9 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 4.54 (s, 2H), 3.97-3.89 (m, 1H), 3.90 (s, 3Н), 3.87 (s, 3Н), 1.10 (d, J=6.6 Hz, 6Н).

Step 1: 2-[4-(5-Amino-2-methyl-1,2,4-triazol-3-yl)-2-methoxyphenoxy]-N-isopropylacetamide

A mixture of N-isopropyl-2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy]acetamide (646 mg, 1.85 mmol), potassium carbonate (383 mg, 2.77 mmol) and 5-bromo-1-methyl1,2,4-triazol-3-amine (204 mg, 1.16 mmol) in 1,4-dioxane (3 ml) and water (0.75 ml) were purged with nitrogen. The complex [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (94 mg, 0.12 mmol) was added and the reaction mixture was additionally purged with nitrogen and heated to 80°C. The reaction mixture was allowed to stir for 22 hours. The reaction mixture was diluted with EtOAc, passed through a plug of Celite (washed with EtOAc), filtered and concentrated to give the crude material. The material was purified by silica gel flash chromatography (25 g SiO2, eluting with 5-25% EtOAc in heptane) to give 2-[4-(5-amino-2-methyl-1,2,4-triazol-3-yl )-2-methoxyphenoxy]-N

- 159 042028 isopropylacetamide (316 mg, 0.99 mmol, 86% yield) as a dark gray crystalline solid. UPLC-MS (ES+, Method A): 1.13 min, m/z 320.3 [M+H] ⁺ .

Step 2: N-isopropyl-2-[2-methoxy-4-[2-methyl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]1,2,4-triazol-3-yl ]phenoxy]acetamide

A mixture of 5-bromo-1-tetrahydropyran-2-yl-indazole (100 mg, 0.36 mmol), 2-[4-(5-amino-2-methyl-1,2,4triazol-3-yl)-2-methoxyphenoxy ]-N-isopropylacetamide (125 mg, 0.39 mmol), palladium (II) chloride (2aminoethyl) benzenide - bis (2-methyl-2-propanyl) (2',4',6'-triisopropyl-2-biphenylyl)phosphine (1:1:1:1) (24 mg, 0.04 mmol) and di-tert-butyl-XPhos (15 mg, 0.04 mmol) were purged with nitrogen. Anhydrous THF (1.5 ml) was added and the reaction mixture was purged with nitrogen followed by the addition of 2 M sodium tert-butoxide in THF (0.27 ml, 0.53 mmol) and further purged with nitrogen. The reaction mixture was stirred at 25°C. The reaction mixture was diluted with EtOAc, passed through a plug of celite (washed with EtOAc), filtered and concentrated to give N-isopropyl-2-[2-methoxy-4-[2-methyl-5-[(1tetrahydropyran-2-ylindazol-5-yl )amino]-1,2,4-triazol-3-yl]phenoxy]acetamide (185 mg, 0.39 mmol, 100%). UPLC-MS (ES ⁺ , Method A): 1.63 min, m/z 520.5 [M+H] ⁺ .

Example 233: N-isopropyl-2-[2-methoxy-4-[1-methyl-5-[(3-methyl-1H-indazol-5-yl)amino]-1,2,4triazol-3-yl] phenoxy]acetamide

n. a solution of hydrogen chloride in dioxane (1.00 ml, 4.00 mmol) was added to a solution of N-isopropyl-2[2-methoxy-4-[1-methyl-5-[(3-methyl-1-tetrahydropyran-2-yl-indazol-5 -yl)amino]-1,2,4-triazol-3yl]phenoxy]acetamide (143 mg, 0.27 mmol) in methanol (1 ml). The reaction was allowed to stir at room temperature for 16 hours. The solvents were removed under reduced pressure and the residue was purified by SCX (washed with methanol (x2) followed by addition of 1 M NH ₃ in MeOH (x2)). The compound was dried under vacuum to give N-isopropyl-2-[2-methoxy-4-[1-methyl-5-[(3methyl-1H-indazol-5-yl)amino]-1,2,4-triazol-3 -yl]phenoxy]acetamide (21 mg, 0.05 mmol, 18% yield). LC-MS (ES ⁺ , Method B): 3.10 min, m/z 450.4 [M+H] ⁺ .

1H NMR (400 MHz DMSO-d6): 12.48 (s, 1H), 8.88 (s, 1H), 8.15 (d, J=1.6 Hz 1H), 7.91 (d, 7.3 Hz 1H), 7.53-7.58 ( m, 2H), 7.50 (dd, J=8.3 1.8 Hz, 1H), 7.41 (d, J=8.8 Hz 1H), 7.00 (d, J=8.3 Hz, 1H) 4.48 (s, 2H), 3.973.89 (m, 1H), 3.88 (s, 3H), 3.79 (s, 3H), 2.48 (s, 3H), 1.10 (d, J=6.6 Hz, 6H).

Stage 1: 3-methyl-5-nitro-1H-indazole

Hydrazine monohydrate (0.10 ml, 3.26 mmol) was added to a solution of 1-(2-fluoro-5-nitrophenyl)ethanone (300 mg, 1.63 mmol) in DMF (6.50 mL). The reaction was heated to 110°C and left to stir for 16 hours, the Reaction mixture was cooled to room temperature and stopped 1 M HCl (10 ml) and was extracted with DCM (3x5 ml).

The organics were combined and washed with ice-cold brine (3 x 25 ml). The organics were dried using a phase separator and concentrated in vacuo to give 3methyl-5-nitro-1H-indazole (228 mg, 1.29 mmol, 79%). UPLC-MS (ES ⁺ , Method A): 1.38 min, m/z 178 [M+H] ⁺ .

Stage 2: 3-methyl-5-nitro-1-tetrahydropyran-2-yl-indazole

To a solution of 3-methyl-5-nitro-1H-indazole (228 mg, 1.29 mmol) p-tosic acid (66 mg, 0.39 mmol) in DCM (6 ml) , 1.54 mmol), and the reaction mixture was left to stir at 25°C for 16 h. The reaction was stopped with NaHCO ₃ (1M, 15 ml), extra

- 160 042028 was diluted with DCM, washed through activated charcoal and concentrated in vacuo to give 3-methyl-5-nitro-1-tetrahydropyran-2-yl-indazole (292 mg, 1.18 mmol, 87%). UHPLC-MS (ES+, Method A): 1.80 min, m/z, no mass ions observed [M+H] ⁺ .

Stage 3: 3-methyl-1-tetrahydropyran-2-yl-indazol-5-amine

Powdered zinc (224 mg, 3.42 mmol) and ammonium chloride (183 mg, 3.42 mmol) were added to a stirred solution of 3-methyl-5-nitro-1-tetrahydropyran-2-yl-indazole (298 mg, 1.14 mmol) in ethyl acetate ( 6 ml) at room temperature. The reaction mixture was stirred at 25° C. for 18 hours. The reaction mixture was diluted and filtered to remove zinc, and the filter cake was washed with EtOAc (50 ml). The filtrate was evaporated in vacuo to give 3-methyl-1-tetrahydropyran-2-ylindazole-5-amine (249 mg, 1.08 mmol, 94% yield) as a yellow-orange solid. UHPLCMS (ES ⁺ , Method A): 1.04 min, m/z 232 [M+H] ⁺ .

Stage 4: N-[5-bromo-2-methyl-1,2,4-triazol-3-yl)-1-tetrahydropyran-2-yl-indazol-5-amine

A solution of lithium diisopropylamide (1.43 ml, 2.86 mmol) in THF (10.60 ml) under nitrogen was cooled to -10°C. 3-methyl-1-tetrahydropyran-2-yl-indazol-5-amine (265 mg, 1.15 mmol) in THF (5.34 ml) was added, the reaction mixture was stirred for 15 min and 3,5-dibromo-1-methyl was added -1H-1,2,4triazole (331 mg, 1.37 mmol) in THF (5.34 ml). The reaction was warmed to room temperature and stirred for 16 h. The reaction was quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc (3x20 ml). The combined organics were dried with a phase separator and concentrated in vacuo. The crude material was purified by flash chromatography eluting with 20-75% EtOAc in heptane to give N-(5-bromo-2-methyl-1,2,4-triazol-3-yl)-1-tetrahydropyran-2- ylindazole-5-amine (98 mg, 0.26 mmol, 23% yield). UHPLC-MS (ES ⁺ , Method A): 1.63 min, m/z mass ions were not observed [M+H] ⁺ .

Step 4: N-isopropyl-2-[2-methoxy-4-[1-methyl-5-[(3-methyl-1-tetrahydropyran-2-yl-indazol-5yl)amino]-1,2,4- triazol-3-yl]phenoxy]acetamide ^X o

The complex [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (22 mg, 0.03 mmol) was added to a completely degassed solution of N-isopropyl-2-[2-methoxy-4-(4.4.5 ,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetamide (100 mg, 0.29 mmol), potassium carbonate (92 mg, 0.67 mmol), and N-(5-bromo-2-methyl-1,2 ,4-triazol-3-yl)-3-methyl-1-tetrahydropyrαn-2-yl-indazol-5-amine (104 mg, 0.27 mmol) in a mixture of water (6.4 ml) and THF (6.4 ml). The reaction was heated to 100°C and left to stir for 16 hours, the Reaction mixture was cooled to room temperature and stopped NaHCO ₃ . The reaction mixture was extracted with EtOAc (3x20 ml), the organics were combined, dried with a phase separator and concentrated under vacuum to give Nisopropyl-2-[2-methoxy-4-[1-methyl-5-[(3-methyl-1- tetrahydropyran-2-yl-indazol-5-yl)amino]-1,2,4triazol-3-yl]phenoxy]acetamide (142 mg, 0.29 mmol, 100%). UPLC-MS (ES ⁺ , Method A): 1.64 min, m/z 534.5 [M+H] ⁺ .

Example 234 7-[5-[(4-Chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]chroman-4-ol

7-[5-[(4-Chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]chroman-4-one (55 mg, 0.14 mmol) was dissolved in MeOH (5 ml) and NaBH ₄ (13 mg, 0.35 mmol) was added. The mixture was allowed to stir for 1 h. Additional NaBH ₄ (6 mg, 0.17 mmol) was added and the reaction mixture was stirred for 30 min. The reaction was stopped by adding saturated NH4Cl and diluted with EtOAc. The layers were separated and the aqueous layers were extracted twice with ethyl acetate. The organic layers were combined and

- 161 042028 centered under reduced pressure. The residue was purified on a 25 g C-18 column eluting with 5-60% MeCN in water (0.1% formic acid) and then on an SCX-2 ion exchange column eluting with 1N HCl. NH3 solution in MeOH to give 7-[5-[(4-chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3yl]chroman-4-ol (32 mg, 0.08 mmol, 58% yield) as a white powdery solid. UPLC-MS (ES+, Method B): 2.92 min, m/z 397.1 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6): 13.38 (s, 1H), 8.47 (s, 1H), 8.08 (s, 1H), 7.62-7.53 (m, 2H), 7.37-7.28 (m, 2H), 7.17 (d, J=1.7 Hz, 1H), 5.38 (d, J=5.5 Hz, 1H), 4.60 (q, J=5.0 Hz, 1H), 4.20-4.16 (m, 2H), 3.77 (s, 3H ), 2.04-1.94 (m, 1H), 1.89-1.81 (m, 1H).

Example 235: 2-[4-[5-(1 H-indazol-5-ylamino)-1-methyl-1,2,4-triazol-3-yl]-2-methoxyphenoxy]-N (2,2, 2-trifluoro-1-methylethyl)acetamide

Palladium hydroxide (20% on carbon carrier) (6 mg) was added to a stirred solution of 2-[4-[5-[(4-chloro-1H-indazol-5-yl)amino]-1-methyl-1,2, 4-triazol-3-yl]-2-methoxyphenoxy]-N-(2,2,2trifluoro-1-methylethyl)acetamide (113 mg, 0.21 mmol) in methanol (7 ml) under nitrogen atmosphere. The flask was evacuated and filled with hydrogen (x3). The reaction was then vigorously stirred for 6 hours at 40° C., then filtered through a PTFE filter under vacuum to remove the palladium. The filtrate was concentrated in vacuo and the residue was purified by silica gel flash chromatography eluting with 0-10% MeOH in DCM. Additionally, the desired crude material was purified by reverse phase chromatography followed by an SCX-2 ion exchange column, washed with methanol and eluted with 1 M NH ₃ /MeOH to give 2-[4-[5-(1H-indazol-5-ylamino)-1 -methyl-1,2,4-triazol-3-yl]-2-methoxyphenoxy]-N-(2,2,2trifluoro-1-methyl-ethyl)acetamide (10 mg, 0.02 mmol, 8% yield). UPLC-MS (ES ⁺ , Method B): 3.33 min, m/z 490.4 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 8.87 (s, 1H), 8.63 (d, J=9.0 Hz, 1H), 8.17 (d, J=1.9 Hz, 1H), 8.02 (t, J=1.3 Hz, 1H), 7.58-7.49 (m, 4H), 6.95 (d, J=8.2 Hz, 1H), 4.69 (dt, J=15.7, 7.6 Hz, 1H), 4.62 (s , 2Н), 3.87 (s, 3Н), 3.79 (s, 3Н), 1.29 (d, J=7.0 Hz, 3Н).

Step 1: 2-[4-[5-[(4-Chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-2-methoxyphenoxy] N-(2,2,2-trifluoro-1-methylethyl)acetamide

F

To a stirred solution of 2-[4-[5-[(4-chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3yl]-2-methoxyphenoxy]acetic acid dihydrochloride (100 mg, 0.21 mmol) in a vial in DMF (1 ml) was added 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (90 mg, 0.24 mmol), N,N-diisopropylethylamine (0.11 ml, 0.64 mmol) and 1,1,1-trifluoropropan-2-amine (27 mg, 0.24 mmol). The reaction mixture was stirred at 25° C. overnight. Additional 1,1,1-trifluoropropan-2-amine (27 mg, 0.24 mmol) was added and the reaction mixture was stirred for an additional 2 h. The crude reaction mixture was loaded onto an SCX-2 column and eluted with 1 M NH ₃ in MeOH. Solvents were removed in vacuo to give 2-[4-[5-[(4-chloro-1H-indazol-5-yl)amino]-1-methyl1,2,4-triazol-3-yl]-2-methoxyphenoxy] -N-(2,2,2-trifluoro-1-methylethyl)acetamide (112 mg, 0.21 mmol, 100%). UPLC-MS (ES ⁺ , Method A): 1.54 min, m/z 524.4 [M+H] ⁺ .

Example 236: 1-[6-[5-[(4-Chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-3,4-dihydro -1Nisoquinolin-2-yl]-2-methylpropan- 1-one

4-Chloro-N-[2-methyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,2,4-triazol-3-yl]-1 H-indazol-5-amine (0.82 ml, 0.13 mmol) was dissolved in DMF (2 ml). N,N-diisopropylethylamine (0.05 ml, 0.26 mmol) was added followed by isobutyryl chloride (0.01 ml, 0.11 mmol). The reaction was allowed to stir for 15 min and diluted with saturated NH ₄ Cl to form a precipitate. DCM was added and the phases were separated. The aqueous layer was further extracted with DCM. The organic layers were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Further purification by flash chromatography on silica gel eluting with 5-100% (1/10 methanol/ethyl acetate in petroleum ether) gave 1-[6-[5-[(4-chloro-1H-indazol-5-yl)amino ]-1-methyl-1,2,4-triazol-3-yl]-3,4dihydro-1H-isoquinolin-2-yl]-2-methylpropan-1-one (45 mg, 0.1 mmol, 76% yield) . UHPLC-MS (ES ⁺ ,

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Method B): 3.42 min, m/z 450.3 [M+H]+.

1H NMR (400 MHz, DMSO-d6, rotamers mixture): 13.40 (s, 1H), 8.50 (s, 1H), 8.10 (s, 1H), 7.69-7.52 (m, 4H), 7.20 (d, J= 8.0 Hz, 1H), 4.71 (s, 0.8H), 4.60 (s, 1.2H), 3.78 (s, 3H), 3.75-3.62 (m, 2H), 3.01-2.91 (m, 1H), 2.87 (t , J=5.3 Hz, 1.2H), 2.76 (t, J=5.3 Hz, 0.8H), 1.04-0.97 (m, 6H).

Example 237 4-chloro-N-[2-methyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,2,4-triazol-3-yl]-1Hindazol-5-amine tert-Butyl 6-[5-[(4-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]3.4 -dihydro-1H-isoquinoline-2-carboxylate (430.0 mg, 0.7600 mmol) was dissolved in hydrogen chloride (4.0 M in dioxane) (3.81 ml, 15.25 mmol).

The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was passed through an SCX-2 column eluting with 1N HCl. NH ₃ in MeOH to give 4-chloro-N-[2-methyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,2,4-triazol-3-yl]-1H -indazol5-amine hydrochloride (315 mg, 0.76 mmol, 99% yield). UPLC-MS (ES+, Method B): 2.37 min, m/z 380.3 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6): 13.45 (s 1H), 9.37 (s, 2H), 8.59 (s, 1H), 8.10 (s, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.66 (s, 1H), 7.59-7.53 (m, 2H), 7.22 (d, J=8.0 Hz, 1H), 4.26 (s, 2H), 3.80 (s, 3H), 3.36 (s, 2H), 3.02 (t, J=6.1 Hz, 2H).

Step 1: tert-butyl 6-[5-[(4-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4triazol-3-yl]-3 ,4-dihydro-1 H-isoquinoline-2-carboxylate

Potassium carbonate (692 mg, 5.01 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) complex dichloromethane chloride (205 mg, 0.25 mmol), N-(5-bromo-2-methyl-1, 2,4-triazol-3-yl)-4-chloro-1tetrahydropyran-2-yl-indazol-5-amine (1031 mg, 2.51 mmol) and tert-butyl 6-(4,4,5,5-tetramethyl- 1,3,2dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (900 mg, 2.51 mmol) was degassed with nitrogen. A degassed solution of 1,4-dioxane (16 ml) and water (4 ml) was added to the solid mixture, and the resulting suspension was degassed with nitrogen for 5 min. The mixture was heated to 90°C for 40 h, cooled to room temperature, and then filtered through a pad of celite. All volatiles were removed under reduced pressure and the residue was purified by flash column chromatography eluting with 40-100% EtOAc in petroleum ether to give tert-butyl 6-[5-[(4-chloro-1tetrahydropyran-2-yl- indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-3,4-dihydro-1H-isoquinoline-2carboxylate (450 mg, 0.80 mmol, 32% yield) as yellow solid. UPLC-MS (ES ⁺ , Method A): 2.08 min, m/z 564.5 [M+H] ⁺ .

Connections in the table. 18 below were prepared in a manner analogous to the preparation of the compounds above.

Table 18

238 Ϊ y ln /\2 o J Ν XJ νΧ ζ ^Ν 'Ν Η Method B, 3.33 min, m/z 448.4 [M+H]+ Ή NMR (400 MHz, DMSO-de): 13.39 (s br), 8.50 (s, 1H), 8.10 (s, 1H), 7.69-7.52 (br, 4H), 7.20 (d, J 8.0 Hz, br) , 4.90 (s, 0.85H), 4.61 (s, 1.15H), 3.89 (t, J 5.4 Hz, 1.15Н), 3.78 (s, ZN), 3.66 (tJ 5.4Hz, 0.8H), 2.91 (t, J 5.3Hz, 1.2Н), 2.76 (t, J 5.3 Hz, 0.8Н), 2.10–2.01 (t, 1Н), 0.78–0.68 (t, 4Н). 239 F /—(yF ,___. /—NH ^F ?' Η ν JJ ΙΓ Υνί νΧ Χν Η Method B, 3.13 min, m/z 519.5 [M+H]+ Ή NMR (400 MHz, DMSO-de): 13.38 (s, 1H), 8.48 (s, 1H), 8.10 (s, 1H), 7.71-7.53 (t, 4H), 7.24-7.17 (t, W), 4.65-4.56 (t, 2H), 3.79 (s, 3H), 3.71-3.65 (t, 1H), 3.613.54 (t, 3H), 3.33-3.22 (t, 2H), 2.88 (t, J 5.6 Hz , W), 2.79 (t, J 5.6 Hz, 1H). 1 NH exchangeable was not observed.

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Example 240 4-[5-(1H-indazol-5-ylamino)-1-methyl-1,2,4-triazol-3-yl]-2-methoxy-N-(2,2,2trifluoroethyl)benzamide

2-Methoxy-4-[1-methyl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]-1,2,4-triazol-3-yl]-Ni(2,2,2trifluoroethyl )benzamide (24 mg, 0.05 mmol) was suspended in MeOH (3 mL) and hydrogen chloride (4.0 M in dioxane, 0.32 mL, 1.28 mmol) was added. The reaction mixture was stirred at 25° C. for 18 hours. The reaction was then evaporated in vacuo, taken up in MeOH and passed through an SCX ion exchange column eluting with MeOH followed by 1.0 M MeOH/NH ₃ . The solvent was removed in vacuo and the residue was triturated with DCM/diethyl ether to give a white solid which was dried overnight at 50° C. to give 4-[5-(1H-indazol-5-ylamino)-1-methyl-1 ,2,4-triazol-3-yl]-2-methoxy-N(2,2,2-trifluoroethyl)benzamide (8 mg, 0.02 mmol, 39% yield) as a white solid. UHPLCMS (ES+, Method B): 3.37 min, m/z 446.3 [M+H] ⁺ .

Ή NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 8.97 (s, 1H), 8.72 (t, J=6.4 Hz, 1H), 8.20 (d, J=1.9 Hz, 1H), 8.04 (s, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.72-7.64 (m, 2H), 7.58 (dd, J=8.9, 2.0 Hz, 1H), 7.52 (d, J=8.9 Hz, 1H), 4.13 (qd, J=9.7, 6.5 Hz, 2Н), 3.99 (s, 3Н), 3.84 (s, 3Н).

Stage 1: 4-[5-[(4-Chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]2-methoxy -N-(2,2,2-trifluoroethyl)benzamide

To a stirred solution of N,N-diisopropylethylamine (0.65 ml, 3.73 mmol), 4-[5-[(4-chloro-1tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2, 4-triazol-3-yl]-2-methoxybenzoic acid (600 mg, 1.24 mmol) and trifluoroethylamine (0.11 ml, 1.37 mmol) in DMF (5 ml) was added 2-(7-aza-1Ibenzotriazol-1-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (520 mg, 1.37 mmol) and the solution was stirred for 16 h at 25°C. The resulting brown solution was evaporated in vacuo, the crude material was dissolved in EtOAc and washed with water (x2), brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 25-100% EtOAc in petroleum ether to give 4-[5-[(4-chloro-1tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1 ,2,4-triazol-3-yl]-2-methoxy-N-(2,2,2trifluoroethyl)benzamide (574 mg, 1.02 mmol, 82% yield). UPLC-MS (ES ⁺ , Method A): 1.84 min, m/z 564.5 [M+H] ⁺ .

Stage 2: 2-methoxy-4-[1-methyl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino1-1,2,4-triazol-3yl]-N-(2,2, 2-trifluoroethyl)benzamide

A stirred solution of 4-[5-[(4-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl1,2,4-triazol-3-yl]-2-methoxy-N -(2,2,2-trifluoroethyl)benzamide (77 mg, 0.14 mmol) in MeOH (7 ml) was purged with nitrogen, then palladium hydroxide (20% on carbon support) (10 mg) was added.

The reaction was then evacuated and refilled with hydrogen (from a balloon). The reaction was then left to stir overnight at 40°C, filtered and evaporated under vacuum. The residue was purified by flash column chromatography eluting with 30-100% EtOAc in petroleum ether to give 2-methoxy-4-[1-methyl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino] -1,2,4-triazol-3-yl]-N(2,2,2-trifluoroethyl)benzamide (24 mg, 0.04 mmol, 33% yield). UPLC-MS (ES ⁺ , Method A): 1.74 min, m/z 530.5 [M+H] ⁺ .

- 164 042028

Example 241 2-[4-[5-[(4-Chloro-1H-indazol-5-yl)amino]-1-(2-hydroxyethyl)-1,2,4-triazol-3-yl]-2methoxyphenoxy ]-Niisopropylacetamide

HCl in dioxane (1.03 ml, 4.12 mmol) was slowly added to a stirred solution of 2-[4-[5-[(4chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-(2-tetrahydropyran -2-yloxyethyl)-1,2,4-triazol-3yl]-2-methoxyphenoxy]-Niisopropylacetamide (138 mg, 0.21 mmol) in 1,4-dioxane (3 ml) at 25°С. The reaction mixture was stirred at room temperature for 18 h. The reaction was evaporated in vacuo, taken up in MeOH and passed through an SCX ion exchange column eluting with MeOH, then eluted with 1.0 M NH3 MeOH. Further purification by flash column chromatography eluting with 50-100% EtOAc/petroleum ether gave 2-[4-[5-[(4-chloro-1H-indazol-5-yl)amino]-1-(2hydroxyethyl) -1,2,4-triazol-3-yl]-2-methoxyphenoxy]-N-isopropylacetamide (14 mg, 0.03 mmol, 13% yield). UPLC-MS (ES+, Method B): 3.14 min, m/z 500.4 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ 13.36 (s, 1H), 8.70 (s, 1H), 8.07 (s, 1H), 7.94 (d, J=9.0 Hz, 1H), 7.80 (d, J =7.9 Hz, 1H), 7.56 (dd, J=8.9, 1.0 Hz, 1H), 7.49-7.40 (m, 2H), 6.96 (d, J=8.4 Hz, 1H), 5.73 (s, 1H), 4.47 (s, 2Н), 4.26 (t, J=5.0 Hz, 2Н), 3.91 (dq, J=7.7, 6.5 Hz, 1H), 3.84 (s, 5H), 3.17 (d, J=5.3 Hz, OH) , 1.09 (d, J=6.6 Hz, 6H).

Step 1: 2-(3,5-dibromo-1,2,4-triazol-1-yl)ethanol

Br\_N ,Ν'Ν ns/

A solution of 3,5-dibromo-4H-1,2,4-triazole (500 mg, 2.2 mmol), 2-bromoethanol (0.31 ml, 4.41 mmol) and triethylamine (0.92 ml, 6.61 mmol) in DMA (8 ml) was stirred at 55°C for 24 hours and then filtered. The solvent was removed under reduced pressure to give a waxy yellow solid which was then purified by flash column chromatography (0-30% EtOAc in petroleum ether) to give 2-(3,5-dibromo-1,2,4-triazole- 1-yl)ethanol (356 mg, 1.31 mmol, 60% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 5.02 (s, 1H), 4.19 (t, J=5.3 Hz, 2H), 3.74 (t, J=5.3 Hz, 2H).

Step 2: 3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole

To a stirred solution of 2-(3,5-dibromo-1,2,4-triazol-1-yl)ethanol (350 mg, 1.29 mmol) and 3,4dihydro-2H-pyran (0.35 ml, 3.88 mmol) in DMA ( 5 mL) TsOH (22 mg, 0.13 mmol) was added and the resulting mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the resulting crude solid was purified by flash column chromatography, eluting with 30 -60% EtOAc in petroleum ether to give 3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole (295 mg, 0.83 mmol, 64% yield) as a white solid .

1H NMR (400 MHz, DMSO-d6) δ 4.53 (t, J=3.3 Hz, 1H), 4.42-4.25 (m, 2H), 3.91 (ddd, J=11.0, 7.1, 4.0 Hz, 1H), 3.72 ( ddd, J=11.0, 5.6, 4.0 Hz, 1H), 3.49-3.27 (m, 2H), 1.77-1.19 (m, 6H).

Stage 3: N-[5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]-4-chloro-1tetrahydropyran-2-yl-indazol-5-amine

To a stirred solution of 3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole (157 mg, 0.40 mmol) and 4-chloro-1-tetrahydropyran-2-yl-indazol- 5-amine (100 mg, 0.40 mmol) in dry THF (2 mL) at –20°C under nitrogen atmosphere, a solution of sodium bis(trimethylsilyl)amide (2.0 M in THF) (0.40 mL,

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0.79 mmol), and the mixture was stirred and allowed to warm to 0°C for 20 min. The mixture was quenched with saturated aqueous NH4Cl (5 ml) and extracted with EtOAc (10 ml). The layers were separated and the aqueous layer was further extracted with EtOAc (1x10 ml). The combined organics were dried (MgSO ₄ ) and concentrated. The orange sticky residue was purified by flash column chromatography eluting with 20-50% EtOAc in petroleum ether to give N-[5-6pom-2-(2tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3- yl]-4-chloro-1-tetrahydropyran-2-yl-indazol-5-amine (130 mg, 0.23 mmol, 59% yield) as a yellow-orange resin. UPLC-MS (ES+, Method A): 1.98 min, m/z 527.3 [M+H] ⁺ .

Stage 4: 2-[4-[5-[(4-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-(2-tetrahydropyran-2yloxyethyl)-1,2,4- triazol-3-yl]-2-methoxyphenoxy]-N-isopropylacetamide

N-Isopropyl-2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolαn-2-yl)phenoxy]αcetamide (104 mg, 0.30 mmol), N-[ 5-bromo-2-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]-4-chloro-1tetrahydropyran-2-yl-indazol-5-amine (130 mg, 0.25 mmol ) and potassium carbonate (72 mg, 0.52 mmol) were suspended in 1,4-dioxane (2 ml) and water (0.5 ml). The reaction mixture was degassed by bubbling with nitrogen. Then [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) (16 mg, 0.02 mmol) was added, followed by additional degassing, and then the reaction mixture was heated to 80°С for 18 h. The reaction was evaporated under vacuum on silica gel and purified by silica gel chromatography eluting with 30-100% EtOAc/petroleum ether to give 2-[4-[5-[(4-chloro-1-tetrahydropyran-2yl-indazol-5-yl) amino]-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazol-3-yl]-2-methoxyphenoxy]-Nisopropylacetamide (52 mg, 0.07 mmol, 30% yield) as pale brown resins. UPLC-MS (ES ⁺ , Method A): 1.98 min, m/z 668.6 [M+H] ⁺ .

Example 242: 2-[4-[5-[(4-Chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-2methoxyphenoxy]-N- (2-methoxyethyl)acetamide

2-Methoxyethylamine (0.16 ml, 1.81 mmol) was added to the solution/suspension of methyl 2-[4-[5-[(4-chloro1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazole -3-yl]-2-methoxyphenoxy]acetate (80 mg, 0.18 mmol) in THF (1 ml) and stirred at 25°C for 16 h.

The reaction was diluted with water (20 ml) and the resulting solid was filtered off. The solid was further washed with water and dried under high vacuum for 16 h to give 2-[4-[5-[(4-chloro-1H-indazol-5-yl)αmino]-1-methyl-1,2, 4-triazol-3-yl]-2-methoxyphenoxy]N-(2-methoxyethyl)acetamide (59 mg, 0.12 mmol, 66% yield) as a beige solid. UPLC-MS (ES ⁺ , Method B): 2.98 min, m/z 486.4 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.93 (t, J=5.7 Hz, 1H), 7.61-7.52 (m, 2H), 7.42 (d, J=2.0 Hz, 1H), 7.37 (dd, J=8.3, 1.9 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 4.49 (s, 2H), 3.82 ( s, 3H), 3.77 (s, 3H), 3.37 (dd, J=6.7, 5.2 Hz, 2H), 3.33-3.28 (m, 2H), 3.25 (s, 3H).

Stage 1: methyl 2-[4-[5-[(4-chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-2methoxyphenoxy]acetate

Hydrogen chloride (1.25 M in MeOH, 2.05 ml, 46.79 mmol) was added to a solution of 2-[4-[5-[(4-chloro-1tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1 ,2,4-triazol-3-yl]-2-methoxyphenoxy]acetic acid (400 mg, 0.78 mmol) in MeOH (1 ml) at 25°C and stirred at room temperature overnight. Additional 4.0 M HCl in dioxane (1.0 ml) was added to the reaction and stirred at room temperature for 2 h. The reaction was diluted with diethyl ether and filtered, washed with diethyl ether and dried to give methyl 2-[4-[5-[(4- chloro-1H-indazol-5yl)amino]-1-methyl-1,2,4-triazol-3-yl]-2-methoxyphenoxy]acetate (240 mg, 0.54 mmol, 69% yield) as a pale brown solid substances. UPLC-MS (ES ⁺ , Method B): 1.42 min, m/z 443.3 [M+H] ⁺ .

- 166 042028

1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.14 (d, J=0.7 Hz, 1H), 7.61-7.55 (m, 2H), 7.42 (d, J=2.0 Hz, 1H) , 7.36 (dd, J=8.4, 2.0 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 4.82 (s, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 3.69 ( s, 3H). 1H exchangeable.

Connections in the table. 19 below were obtained in a manner similar to that described above.

Table 19

Example Structure LC-MS NMR 243 ΞΕ ABOUT Ah X Method B, 2.74 min, m/z 472.4 [M+H] ⁺ SH NMR (400 MHz, DMSO-de) δ 13.37 (s, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.88 (t, J = 5.7 Hz, 1H), 7.56 (q, J = 8.9 Hz, 2H), 7.42 (d, J = 1.9 Hz, 1H), 7.37 (dd, J = 8.3, 1.8 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.49 (s, 2H) , 3.82 (s, 3H), 3.77 (s, 3H), 3.43 (t, J = 6.0 Hz, 2H), 3.21 (q, J = 5.9 Hz, 2H). He was not observed

244:

2-[4-[5-[(4-Chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-2 Example of methoxyphenoxy]-^(2- methoxyethyl)acetamide

N-Isopropyl-2-[4-[5-[(1-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridin-5-yl)amino]-4H-1,2,4triazol-3-yl]phenoxy ]acetamide (9 mg, 0.02 mmol) was stirred in a solution of hydrogen chloride - methanol, 1.25 M (2 ml, 2.5 mmol) overnight. The solvents were removed under reduced pressure to give

N-isopropyl-2-[4-[5-( 1 H-pyrazolo[3,4-c] pyridin-5-ylamino)-4H-1,2,4-triazol-3 yl]phenoxy]acetamide hydrochloride (8 mg, 0.02 mmol, 99% yield) as a brown solid. UPLC-MS (ES ⁺ , Method B): 2.72 min, m/z 393.3 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.05 (s, 1H), 8.32 (s, 1H), 8.13-7.92 (m, 3H), 7.86 (s, 1H),

7.15-7.01 (m, 2H), 4.53 (s, 2H), 3.94 (s, 1H), 1.09 (d, J=5.3 Hz, 6H).

Stage 1: methyl 4-[2-(isopropylamino)-2-oxoethoxy]beuoate

Potassium carbonate (1817 mg, 13.15 mmol) of one portion. The mixture was heated at 80° C. overnight, cooled and partitioned between EtOAc and H ₂ O. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organics were washed with H2O and brine, dried (phase separator) and concentrated to give crude methyl 4-[2-(isopropylamino)-2-oxoethoxy]benzoate (870 mg, 3.18 mmol, 97% yield). LC-MS (ES ⁺ , Method C): 2.32 min, m/z 252.0 [M+H] ⁺ .

Step 2: 2-[4-(5-amino-4H-1,2,4-triazol-3-yl)phenoxy]-N-isopropylacetamide

Sodium methoxide (5.2 ml, 10.38 mmol) was added to a stirred solution of aminoguanidine hydrochloride (1148 mg, 10.38 mmol) in anhydrous methanol (12 mL) cooled to 0°C. The cooling bath was then removed and the mixture was stirred at room temperature for 10 minutes. A solution of methyl 4-[2-(isopropylamino)-2-oxo-ethoxy]benzoate (870 mg, 3.46 mmol) in anhydrous MeOH (8 ml) was added and the reaction was heated at 65° C. overnight. The mixture was cooled and concentrated under reduced pressure. The residue was partitioned between EtOAc and saturated NaHCO ₃ . The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic extracts were dried (phase separator) and concentrated under reduced pressure to give 2-[4-(5-amino-4H-1,2,4-triazol3-yl)phenoxy]-N-isopropylacetamide (398.5 mg, 1.45 mmol, 42% yield) as a yellow solid. UPLC-MS (ES+, Method A): 1.33 min, m/z 276.0 [M+H] ⁺ .

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Stage 3: n-isopropyl-2-[4-[5-[(1-tetrahydropyran-2-ylpyrazolo[3,4-c]pyridin-5-yl)amino]-4H1,2,4-triazol-3-yl ]phenoxy]acetamide

2-[4-(5-Amino-4H-1,2,4-triazol-3-yl)phenoxy]-N-isopropylacetamide (100 mg, 0.36 mmol), sodium tert-butoxide (73 mg, 0.76 mmol), 5-bromo-1-tetrahydropyran-2-yl-pyrazolo[3,4c]pyridine (133 mg, 0.47 mmol) and tert-butanol (4 ml) and degassed under nitrogen atmosphere. Then palladium (II) chloride (2-aminoethyl)benzenide - bis(2-methyl-2-propanyl)(2',4',6'-triisopropyl-2biphenylyl)phosphine (1:1:1:1) (5 mg, 0.01 mmol) and bis(1,1-dimethylethyl)[2',4',6'-tris(1-methylethyl)[1,1'biphenyl]-2-yl]-phosphine (4 mg, 0.01 mmol ). The vial was sealed and the reaction was heated at 90°C overnight, cooled, filtered through a phase separator and concentrated under reduced pressure. The crude material was purified by flash column chromatography (SiO ₂ ) eluting with 0-6% MeOH in DCM to give N-isopropyl-2-[4-[5-[(1-tetrahydropyran-2-ylpyrazolo[3.4c] pyridin-5-yl)amino]-4H-1,2,4-triazol-3-yl]phenoxy]acetamide (9 mg, 0.02 mmol, 5% yield). UPLC-MS (ES+, Method A): 1.54 min, m/z 477.4 [M+H] ⁺ .

Example 245: 1-[6-[5-[(4-Chloro-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-3,4-dihydro -1Nisoquinolin-2-yl]-2-methyl-propan-1-one

4-Chloro-N[2-methyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,2,4-triazol-3-yl]-1 H-indazol-5-amine ( 0.82 ml, 0.13 mmol) was dissolved in DMF (2 ml). Ν,N-diisopropylethylamine (0.05 ml, 0.26 mmol) was added followed by isobutyryl chloride (0.01 ml, 0.11 mmol). The reaction was left to stir for 15 min and diluted with saturated NH ₄ Cl. DCM was added and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with 5-100% (1/10 methanol/ethyl acetate in petroleum ether) to give 1-[6-[5[(4-chloro-1H-indazol-5-yl)amino]- 1-methyl-1,2,4-triazol-3-yl]-3,4-dihydro-1 H-isoquinolin-2-yl]-2methyl-propan-1-one (45 mg, 0.1 mmol, 76% yield ). UPLC-MS (ES ⁺ , Method E): 3.42 min, m/z 450.3 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6): 13.40 (s 1H), 8.50 (s, 1H), 8.10 (s, 1H), 7.69-7.52 (m, 4H), 7.20 (d, J=8.0 Hz, 1H ), 4.71 (s, 0.8H), 4.60 (s, 1.2H), 3.78 (s, 3H), 3.75-3.62 (m, 2H), 3.01-2.91 (m, 1H), 2.87 (t, J=5.3 Hz, 1.2H), 2.76 (t, J=5.3 Hz, 0.8H), 1.04-0.97 (m, 6H). NMR confirmed the presence of rotamers 0.8/1.2.

Connections in the table. 20 below was obtained in a manner similar to that described above.

Table 20

Example Structure LC-MS Ή NMR 246 ϊ Ν h D T D ο/ _z N~ _n H Method B, 3.33 min, m/z 448.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de): 13.39 (s 1H), 8.50 (s, 1H), 8.10 (s, 1H), 7.69-7.52 (br, 4H), 7.20 (d, J 8.0 Hz, 1H) ,4.90 (s, 0.85H), 4.61 (s, 1.15H), 3.89 (t, J 5.4 Hz, 1.15H), 3.78 (s, 3H), 3.66 (tJ 5.4Hz, 0.8H), 2.91 (t, J 5.3 Hz, 1.2H), 2.76 (t, J 5.3 Hz, 0.8H), 2.10–2.01 (m, 1H), 0.78–0.68 (br, 4H). 247 F /—X __ /—NH ^F ϊ ¹ and Vh d J Г H Method B, 3.13 min, m/z 519.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ): 13.38 (s, 1H), 8.48 (s, 1H), 8.10 (s, 1H), 7.71-7.53 (m, 4H), 7.24-7.17 (t, 1H) , 4.65-4.56 (t, 2H), 3.79 (s, 3H), 3.71-3.65 (t, 1H), 3.613.54 (t, 3H), 3.33-3.22 (t, 2H), 2.88 (t, J 5.6 Hz, 1H), 2.79 (t, J 5.6 Hz, 1H). 1 NH exchangeable was not observed.

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Intermediate 66: 1-tetrahydropyran-2-ylindazol-5-ol

Methanesulfonic acid (0.02 ml, 0.37 mmol) was added to a stirred solution of 1H-indazol-5-ol (0.5 g, 3.7 mmol), 3,4-dihydro-2H-pyran (0.34 ml, 3.73 mmol), DCM (20 ml) and THF (20 ml) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 72 hours. The solvent was removed in vacuo and the residue partitioned between water (100 ml) and DCM (100 ml). The organic layer was separated, dried over sodium sulfate, and the solvent was removed under vacuum. The residue was purified by silica gel flash column chromatography eluting with 0-100% EtOAc in petroleum ether to give 1-tetrahydropyran-2-ylindazol-5-ol (442 mg, 2.03 mmol, 54% yield) as a white solid . UPLC-MS (ES+, Method A), 1.34 min, m/z 219.1 [M+H] ⁺ .

Intermediate 67: 1-tetrahydropyran-2-ylpyrazolo[3,4-b]pyridine-5-amine

Suspension of 5-nitro-1-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridine (1.2 g, 4.83 mmol) in EtOAc (12 ml) and 10% palladium on a carbon carrier (dry, 0.03 g, 0.3 mmol ) was vigorously stirred for 6 h at room temperature under a pressure of 1 atmosphere H ₂ . The mixture was filtered through Celite™ and the filtrate was evaporated to give 1-tetrahydropyran-2-ylpyrazolo[3,4-b]pyridine-5-amine (1.05 g, 4.8 mmol, 99% yield) as a colorless foam. UPLC-MS (ES ⁺ , Method A): 1.04 min, m/z 219.3 [M+H] ⁺ .

Stage 1: 5-nitro-1-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridine

To a suspension of 5-nitro-1H-pyrazolo[3,4-b]pyridine (1 g, 6.1 mmol) in DCM (12 mL) was added rtoluenesulfonic acid, monohydrate (0.12 g, 0.61 mmol), and the solution was stirred at room temperature. Then 3,4-dihydro-2H-pyran (1.7 mL, 18.3 mmol) was added slowly and the reaction mixture was stirred at room temperature for 1 h. The mixture was partially evaporated and purified by silica gel column chromatography eluting with 10-50% EtOAc in petroleum ether to give 5-nitro-1-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridine (1.2 g, 4.8 mmol, 79% yield) as an off-white solid. UPLC-MS (ES ⁺ , Method A): 1.60 min, m/z 249.1 [M+H] ⁺ .

Intermediate 68: 6-methyl-1-tetrahydropyran-2-yl-indazol-5-amine nh ₂

A suspension of 6-methyl-5-nitro-1-tetrahydropyran-2-yl-indazole (1250 mg, 4.78 mmol) in EtOAc (12 mL) and 10% palladium on a carbon carrier (dry, 0.03 g, 0.3 mmol) was vigorously stirred in for 18 hours at room temperature under a pressure of 1 atmosphere of H2. The mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with 10-70% EtOAc in petroleum ether to give a brown oil which was triturated with diethyl ether to give 6-methyl-1-tetrahydropyran-2-yl-indazol- 5-amine (833 mg, 3.6 mmol, 75% yield) as a beige solid. UPLC-MS (ES ⁺ , Method A): 1.07 min, m/z 232.2 [M+H] ⁺ .

Stage 1: 6-methyl-5-nitro-1-tetrahydropyran-2-yl-indazole

To a cream suspension of 5-nitro-1H-pyrazolo[3,4-b]pyridine (1.00 g, 6.1 mmol) in DCM (12 ml) to

- 169 042028 p-toluenesulfonic acid, monohydrate (0.12 g, 0.61 mmol) was added and the solution was stirred at room temperature. Then 3,4-dihydro-2H-pyran (1.7 ml, 18.3 mmol) was slowly added and the reaction mixture was stirred at room temperature for one hour. The mixture was partially evaporated and purified by silica gel column chromatography eluting with 10-50% EtOAc in petroleum ether to give 5-nitro-1-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridine (1.2 g, 4.8 mmol, 79% yield) as an off-white solid. UPLC-MS (ES ⁺ , Method A): 1.79 min, m/z 262.1 [M+H] ⁺ .

Intermediate 69: 3-methyl-1-tetrahydropyran-2-yl-indazol-5-amine

A suspension of 3-methyl-5-nitro-1-tetrahydropyran-2-yl-indazole (620 mg, 2.4 mmol) in EtOAc (40 mL) and 10% palladium on carbon (65% moisture, 400 mg) was vigorously stirred for 18 h at room temperature under a pressure of 1 atmosphere H ₂ . The mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure to give 3-methyl-1-tetrahydropyran-2-ylindazole-5-amine (540 mg, 2.3 mmol, 98% yield) as a pink solid. LC-MS (ES+, Method F), 1.50 min, m/z 232.1 [M+H] ⁺ .

Stage 1: 3-methyl-5-nitro-1-tetrahydropyran-2-yl-indazole

A solution of 3-methyl-5-nitro-1H-indazole (500 mg, 2.82 mmol) was treated with p-toluenesulfonamide (48 mg, 0.28 mmol) and 3,4-dihydro-2H-pyran (0.39 ml, 4.23 mmol) at room temperature and left to stir overnight. The reaction mixture was neutralized with saturated aqueous NaHCO ₃ (100 ml) and then extracted with DCM (50 mlx3), the combined organic layers were dried over Na ₂ SO ₄ and evaporated under vacuum. The crude material was purified by silica gel column chromatography eluting with 10% EtOAc in petroleum ether to give 3-methyl-5-nitro-1-tetrahydropyran-2-yl-indazole (640 mg, 2.45 mmol, 87% yield) as a white solid substances. LCMS (ES ⁺ , Method F), 3.74 min, m/z 262.1 [M+H] ⁺ .

Intermediate 16: 4-ethyl-1-tetrahydropyran-2-yl-indazol-5-amine

A suspension of 1-tetrahydropyran-2-yl-4-vinylindazol-5-amine (17 g, 70 mmol) dissolved in MeOH (150 ml) and 10% palladium on a carbon carrier (dry, 0.7 g, 7 mmol) was vigorously stirred for 2 hours at room temperature under a pressure of 1 atmosphere H ₂ . The mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with 10-60% EtOAc in petroleum ether to give 4-ethyl-1-tetrahydropyran-2-yl-indazol-5-amine (7.9 g, 32.2 mmol, 46% output) as oil. UPLC-MS (ES ⁺ , Method A): 1.06 min, m/z 246.5 [M+H] ⁺ .

Stage 1: 1-tetrahydropyran-2-yl-4-vinylindazol-5-amine

4-Bromo-1-tetrahydropyran-2-yl-indazol-5-amine (30 g, 101 mmol), potassium trifluoro(vinyl)borate (1-) (20.35 g, 151.96 mmol) and cesium carbonate (99 g, 304 mmol) was suspended in 1,4-dioxane (750 ml) and water (250 ml) and completely degassed by bubbling nitrogen. Complex [1,1'bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane chloride (2.1 g, 2.5 mmol) was added followed by additional degassing and the reaction was heated to 100°C for 5 h. The reaction was cooled, then diluted with 500 ml EtOAc and 250 ml brine. The reaction mixture was filtered, separated, and the organics were dried over sodium sulfate, filtered and evaporated in vacuo with

- 170 042028 to give a brown oil which was subjected to silica gel column chromatography eluting with 0-60% EtOAc in petroleum ether to give 1-tetrahydropyran-2-yl-4-vinylindazol-5-amine (19.3 g, 75.4 mmol, 74% output) as oil. UPLC-MS (ES+, Method A): 1.21 min, m/z 244.4 [M+H] ⁺ .

Intermediate 70: 3-chloro-1-tetrahydropyran-2-yl-indazol-5-amine

A suspension of 3-chloro-5-nitro-1-tetrahydropyran-2-yl-indazole (2.5 g, 8.9 mmol) in EtOAc (50 mL) and 10% palladium on carbon (65% moisture, 1 g) was vigorously stirred for 18 h at room temperature under a pressure of 1 atmosphere H ₂ . The mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with 15-25% EtOAc in petroleum ether to give 3-chloro-1-tetrahydropyran-2-ylindazole-5-amine (1.4 g, 63% yield) in form of a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.47 (d, J=8.9 Hz, 1H), 6.91 (dd, J=9.0, 2.1 Hz, 1H), 6.61 (d, J=2.0 Hz, 1H), 5.67 (dd, J=9.7, 2.5 Hz, 1H), 5.12 (s, 2H), 3.90 - 3.81 (m, 1H), 3.76 - 3.58 (m, 1H), 2.35 - 2.20 (m, 1H), 2.05 - 1.86 (m, 2H), 1.77 - 1.63 (m, 1H), 1.54 (m, 2H).

Stage 1: 3-chloro-5-nitro-1-tetrahydropyran-2-yl-indazole

A solution of 3-chloro-5-nitro-1H-indazole (5 g, 25.3 mmol) was treated with p-toluenesulfonic acid (435 mg, 2.5 mmol) and 3,4-dihydro-2H-pyran (3.5 ml, 38 mmol) at room temperature. temperature and left to stir for 18 hours, the Reaction mixture was neutralized with saturated aqueous NaHCO ₃ (100 ml) and then was extracted with DCM (3x100 ml). The combined organic layers were dried over sodium sulfate and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with 10-20% EtOAc in petroleum ether to give 3-chloro-5nitro-1-tetrahydropyran-2-yl-indazole (5 g, 17.8 mmol, 70% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (d, J=2.1 Hz, 1H), 8.36 (dd, J=9.3, 2.2 Hz, 1H), 8.05 (d, J=9.3 Hz, 1H), 6.00 (dd, J=9.5, 2.2 Hz, 1H), 3.94 - 3.84 (m, 1H), 3.85 - 3.68 (m, 1H), 2.38 - 2.24 (m, 1H), 2.08 - 1.97 (m, 2H), 1.82 - 1.66 (m, 1H), 1.65 - 1.51 (m, 2H).

Intermediate 71: 3-fluoro-1-tetrahydropyran-2-yl-indazol-5-amine

Iron (842 mg, 15.1 mmol) and ammonium chloride were added to a suspension of 3-fluoro-5-nitro-1-tetrahydropyran-2-yl-indazole (800 mg, 3.02 mmol) in EtOH (30 mL) and water (5 mL). (484 mg, 9.0 mmol) and the mixture was heated at 70° C. for 3 h. The reaction was cooled to room temperature, EtOAc (50 ml) was added and the mixture was stirred for 10 min, then filtered through a pad of Celite™. The combined filtrate was washed with brine, dried over sodium sulfate and concentrated to give 3fluoro-1-tetrahydropyran-2-yl-indazol-5-amine (560 mg, 2.4 mmol, 79% yield) as a yellow solid. LC-MS (ES ⁺ , Method F), 2.21 min, m/z 236.1 [M+H] ⁺ .

Stage 1: 3-fluoro-5-nitro-1H-indazole

Selectfluor (13.03 g, 36.8 mmol) and acetic acid (8 mL) were added to a solution of 5-nitroindazole (6 g, 5.63 mmol) in acetonitrile (8 mL). The reaction mixture was heated under microwave conditions at 150° C. for 1 hour. The reaction was stopped with water and extracted with EtOAc. The combined organic layers were dried over sodium sulfate, evaporated in vacuo and purified by silica gel column chromatography eluting with 10-20% EtOAc in petroleum ether to give 3-fluoro-5-nitro1H-indazole (1020 mg, 5.6 mmol, 15% yield) as a brown solid.

1H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.74 (d, J=1.6 Hz, 1H), 8.24 (dd, J=9.2, 2.0 Hz, 1H), 7.69 (dd, J= 9.2, 2.0 Hz, 1H).

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Stage 2: 3-fluoro-5-nitro-1-tetrahydropyran-2-yl-indazole

A solution of 3-fluoro-5-nitro-1Н-indazole (500 mg, 2.8 mmol) was treated with p-toluenesulfonamide (47 mg, 0.28 mmol) and 3,4-dihydro-2H-pyran (0.4 ml, 4.2 mmol) at 15°C C and left to stir overnight. The reaction mixture was neutralized with saturated aqueous NaHCO ₃ (100 ml) and then extracted with DCM (3x100 ml), the combined organic layers were dried over Na ₂ SO ₄ and evaporated under vacuum. The crude material was purified by silica gel column chromatography eluting with 10-20% EtOAc in petroleum ether to give 3-fluoro-5-nitro-1-tetrahydropyran-2-ylindazole (370 mg, 0.91 mmol, 33% yield) as yellow oil.

¹ H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J=2.1 Hz, 1H), 8.34 (dd, J=9.4, 2.2 Hz, 1H), 7.99 (dd, J=9.4, 2.0 Hz, 1H ), 5.93 (m, 1H), 3.94 - 3.84 (m, 1H), 3.85 - 3.67 (m, 1H), 2.31 - 2.16 (m, 1H), 2.08 - 1.92 (m, 2H), 1.74 (m, 1H ), 1.57 (m, 2H).

Intermediate 72: 4-isopropyl-1-tetrahydropyran-2-yl-indazol-5-amine

A^NH ₂ (Ar

4-Isopropenyl-1-tetrahydropyran-2-yl-indazol-5-amine (190 mg, 0.74 mmol) was dissolved in MeOH (10 mL) and purged with nitrogen. Then 10% carbon-supported palladium (dry, 8 mg, 0.07 mmol) was added and the reaction was placed under a hydrogen atmosphere and stirred vigorously for 30 minutes. The reaction mixture was filtered and evaporated in vacuo to give 4-isopropyl-1-tetrahydropyran-2-yl-indazol-5-amine (180 mg, 0.7 mmol, 94% yield) as an oil. UPLC-MS (ES+, Method A): 1.14 min, m/z 260.4 [M+H] ⁺ .

Stage 1: 4-isopropenyl-1-tetrahydropyran-2-yl-indazol-5-amine _ ^nh, ⁿ Alj

Ca°

4-Bromo-1-tetrahydropyran-2-yl-indazol-5-amine (250 mg, 0.84 mmol), potassium isopropenyltrifluoroborate (137 mg, 0.93 mmol) and cesium carbonate (1100 mg, 3.4 mmol) were suspended in 1,4- dioxane (5 ml) and water (2 ml) and completely degassed by sparging with nitrogen. Complex [1,1'bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane chloride (69 mg, 0.08 mmol) was added, followed by additional degassing, and the reaction was heated to 100°C for 3 h. The reaction was cooled, then diluted with 100 ml EtOAc and 25 ml brine were separated and the organics were dried over sodium sulfate, filtered and evaporated in vacuo to give a brown oil. Further purification by silica gel column chromatography eluting with 0-75% EtOAc in petroleum ether gave 4-isopropenyl-1-tetrahydropyran-2-yl-indazol-5-amine (200 mg, 0.78 mmol, 92% yield) as oils. UPLC-MS (ES ⁺ , Method A): 1.22 min, m/z 258.4 [M+H] ⁺ .

Intermediate 73: 7-chloro-1-tetrahydropyran-2-yl-indazol-5-amine

Iron powder (446 mg, 8.0 mmol) and chloride ammonium (256 mg, 4.8 mmol) and the mixture was heated at 70° C. for 5 h. After cooling to room temperature, EtOAc (30 ml) was added and the mixture was stirred for 10 min, then filtered through a pad of Celite™.

The combined filtrate was washed with brine, dried over Na ₂ SO ₄ and concentrated to give 7-chloro-1-tetrahydropyran-2-yl-indazol-5-amine (400 mg, 1.59 mmol, 99% yield) as a yellow solid. LC-MS (ES ⁺ , Method F): 2.67 min, m/z 252.1 [M+H] ⁺ .

- 172 042028

Stage 1: 7-chloro-5-nitro-1-tetrahydropyran-2-yl-indazole

A solution of 7-chloro-5-nitro-1H-indazole (1200 mg, 6.07 mmol) was treated with p-toluenesulfonic acid (117 mg, 0.61 mmol) and 3,4-dihydro-2H-pyran (0.8 ml, 9.1 mmol) at 15 °C and left to stir for 18 hours, the Reaction mixture was neutralized with saturated aqueous NaHCO ₃ (50 ml) and then was extracted with DCM (3x50 ml). The combined organic layers were dried over Na ₂ SO ₄ and evaporated in vacuo to give crude material which was purified by silica gel column chromatography eluting with 5-20% EtOAc in petroleum ether to give 7-chloro-5-nitro-1tetrahydropyran-2 -yl-indazole (450 mg, 1.6 mmol, 26% yield) as a yellow solid. LCMS (ES+, Method F): 3.98 min, m/z mass ion was not observed [M+H] ⁺ .

Intermediate 74: 1-[2-(3,5-dibromo-1,2,4-triazol-1-yl)ethyl]piperidine

1-(2-Chloroethyl)piperidine hydrochloride (243 mg, 1.32 mmol), 3,5-dibromo-1H-1,2,4-triazole (250 mg, 1.1 mmol) and potassium carbonate (640 mg, 4.6 mmol) were added to DMF (5 ml) in a 25 ml round bottom flask. The reaction was then stirred for 18 hours at 50° C. under nitrogen. The solvent was removed under vacuum, water was added and the product was extracted with DCM (3 times). The organic phase was dried using a phase separator and the solvent was removed under vacuum. The product was purified by silica gel column chromatography eluting with 0-10% MeOH in DCM to give [1-[2-(3,5-dibromo-1,2,4-triazol-1-yl)ethyl]piperidine (224 mg, 0.66 mmol, 60% yield) as a yellow oil. UPLC-MS (ES ⁺ , Method A), 0.87 min, m/z 339.0 [M+H] ⁺ .

Intermediate 75: 4-[2-(3,5-dibromo-1,2,4-triazol-1-yl)ethyl1-morpholine

N-Chloroethylmorpholine hydrochloride (197 mg, 1.32 mmol), 3,5-dibromo-1H-1,2,4-triazole (250 mg, 1.1 mmol) and potassium carbonate (456 mg, 3.3 mmol) were added to DMF (5 ml ) in a 25 ml round bottom flask. The reaction was then stirred at 50° C. under a nitrogen atmosphere. The solvent was removed under vacuum, water was added and the product was extracted with DCM (3x). The organic phase was dried using a phase separator and the solvent was removed under vacuum. The product was purified by silica gel column chromatography eluting with 0-10% MeOH in DCM to give [4-[2-(3,5-dibromo-1,2,4-triazol-1yl)ethyl]morpholine (374 mg, 1.1 mmol, 99% yield). UPLC-MS (ES ⁺ , Method A), 0.65 min, m/z 341.0 [M+H] ⁺ .

Intermediate 76: 3,5-dibromo-1-(2-methoxyethyl)-1,2,4-triazole

Br ^ ^N ^ Br __ _/ nn -o ⁷

Solution of 3,5-dibromo-1I-1,2,4-triazole (250 mg, 1.1 mmol), 2-bromoethyl methyl ether (0.17 ml, 2.2 mmol) and triethylamine (0.46 ml, 3.3 mmol) in DMA (5 ml) stirred at 55° C. for 18 hours. The reaction mixture was filtered and the solvent was removed under vacuum. The product was purified by silica gel column chromatography eluting with 0-100% EtOAc in petroleum ether to give 3,5-dibromo-1-(2-methoxyethyl)-1,2,4-triazole (260 mg, 0.91 mmol, 83 % yield) as a colorless oil. UPLC-MS (ES ⁺ , Method A), 1.34 min, m/z 285.9 [M+H] ⁺ .

Intermediate 77: 3,5-dibromo-1-isobutyl-1,2,4-triazole

Sodium tert-butoxide (372 mg, 3.9 mmol) was added to a solution of 3,5-dibromo-1N-1,2,4-triazole (800 mg, 3.53 mmol) in DMF (5 ml) and stirred at room temperature for 15 min. 1-Bromo-2-methylpropane (531 mg, 3.9 mmol) was added dropwise and the reaction was heated to 50°C for 2 h and then to room temperature for 18 h. The reaction was stopped with water (50 ml) and extracted with diethyl ether (3x10 ml). The combined organics were washed with brine and dried

- 173 042028 over sodium sulfate. The solvent was removed in vacuo to give 3,5-dibromo-1-isobutyl-1,2,4-triazole (276 mg, 0.97 mmol, 27% yield) as a colorless oil.

1H NMR (400 MHz, CDCl ₃ ) δ 3.94 (dd, J=7.3, 1.0 Hz, 2H), 2.34 - 2.22 (m, 1H), 0.96 (dd, J=6.8, 0.9 Hz, 6H).

Intermediate 78: 3,5-dibromo-1-cyclopropyl-1,2,4-triazole

A mixture of 3,5-dibromo-III-1,2,4-triazole (700 mg, 3.1 mmol), 2,2'-bipyridyl (60 mg, 0.39 mmol), copper (II) acetate (140 mg, 0.77 mmol) , potassium carbonate (852 mg, 6.2 mmol) and cyclopropylboronic acid (795 mg, 9.3 mmol) were dissolved in toluene (5 ml) and water (1.5 ml) and stirred at 70°C for 18 h. The reaction mixture was cooled to room temperature , stopped NH ₄ Cl (saturated aqueous), and the products were extracted with DCM. The combined organic fractions were dried using a phase separator and evaporated under vacuum. The crude mixture was dissolved in DCM and dry loaded onto silica gel. Purification by silica gel column chromatography eluting with 1060% EtOAc in petroleum ether gave 5-dibromo-1-cyclopropyl-1,2,4-triazole and 1-allyl-3,5dibromo-1,2,4-triazole (123 mg, 0.46 mmol, 15% yield) as an inseparable mixture. UPLC-MS (ES+, Method A): 1.52 min, m/z 267.9 [M+H] ⁺ .

Intermediate 79: 3,5-dibromo-1-ethyl-1,2,4-triazole

Sodium tert-butoxide (372 mg, 3.9 mmol) was added to a solution of 3,5-dibromo-1H-1,2,4-triazole (800 mg, 3.53 mmol) in DMF (5 ml) and stirred at room temperature for 15 min. Bromoethane (422 mg, 3.9 mmol) was added dropwise and the reaction was heated to 50° C. for 2 h. The reaction was stopped with water (50 ml) and extracted with diethyl ether (3x10 ml). The organics were washed with brine, dried over sodium sulfate and evaporated in vacuo to give 3,5-dibromo-1-ethyl-1,2,4-triazole (663 mg, 2.6 mmol, 74% yield) as a colorless oil.

1H NMR (400 MHz, CDCl ₃ ) δ 4.19 (q, J=7.3 Hz, 2H), 1.47 (t, J=7.2 Hz, 3H).

Intermediate 80: t-butyl 4-(3,5-dibromo-1,2,4-triazol-1-yl)piperidine-1carboxylate

Vg

O /--K to ν j / ⁰

Sodium hydride (34 mg, 0.86 mmol) was slowly added to a solution of 3,5-dibromo-1H-1,2,4-triazole (150 mg, 0.66 mmol) and DMF (3.9 ml) at room temperature, and the solution was stirred at 45 °C for 30 min. Then tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (0.15 ml, 0.79 mmol) was added in portions. The reaction mixture was stirred at 85°C for 2 days. The reaction was stopped with NH4Cl (aq. saturated) and extracted with DCM. The combined organic fractions were dried using a phase separator and evaporated under vacuum. The crude residue was dissolved in DCM, evaporated in vacuo on silica gel and purified by silica gel flash chromatography eluting with 10-90% EtOAc in petroleum ether to give tert-butyl 4-(3,5-dibromo-1,2,4triazole -1-yl)piperidine-1-carboxylate (140 mg, 0.34 mmol, 52% yield) as a pale yellow oil. UPLC-MS (ES ⁺ , Method A): 1.82 min, m/z 411.0 [M+H] ⁺ .

Stage 1: tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate

Oh / o ^z \

Methanesulfonyl chloride (0.23 ml, 3.0 mmol) was slowly added to a solution of N-Boc-4hydroxypiperidine (0.49 ml, 2.5 mmol), triethylamine (0.69 ml, 4.9 mmol) and DCM (4 ml) under nitrogen in a dried flask. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was stopped with NH ₄ Cl (aqueous saturated) and was extracted with DCM. The combined organic fractions were washed with Na ₂ CO ₃ (aqueous saturated), dried with a phase separator and evaporated in vacuo to give t-butyl 4methylsulfonyloxypiperidine-1-carboxylate (625 mg, 2.2 mmol, 90% yield) as an off-white solid .

1H NMR (400 MHz, CDCl ₃ ) δ 4.88 (m, 1H), 3.71 (m, 2H), 3.31 (m, 2H), 3.01 (s, 3Н), 1.97 (m, 2H), 1.82 (m, 2H ), 1.46 (s, 9H).

- 174 042028

Intermediate 81: tert-Butyl N-[2-(3,5-dibromo-1,2,4-triazol-1-yl)ethyl]-N-methylcarbamate

A 100 ml round bottom flask was charged with 2-(3,5-dibromo-1,2,4-triazol-1-yl)-N-methylethanamine (644 mg, 2.27 mmol) and DCM (35 ml). Di-tert-butyl dicarbonate (505 mg, 2.3 mmol) and triethylamine (0.47 ml, 3.4 mmol) were added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was stopped with brine and extracted with DCM. The combined organic fractions were dried with a phase separator and evaporated in vacuo to give tert-butyl X-[2-(3,5-dibromo-1,2,4-triazol-1-yl)ethyl]-N-methylcarbamate (81 mg , 0.21 mmol, 9% yield) as a colorless oil. UPLC-MS (ES ⁺ , Method A): 1.64 min, m/z 385.1 [M+H] ⁺ .

Step 1: 2-[tert-butoxycarbonyl(methyl)amino]ethyl]ethylmethanesulfonate

Methanesulfonyl chloride (0.6 ml, 7.7 mmol) was slowly added to a solution of tert-butyl (2hydroxyethyl)methylcarbamate (1120 mg, 6.4 mmol), triethylamine (1.8 ml, 12.8 mmol) and DCM (11 ml) under nitrogen atmosphere.

The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with NH4Cl (aq. saturated) and extracted with DCM. The combined organic fractions were washed with Na ₂ CO ₃ (aqueous saturated), dried with a phase separator and evaporated under vacuum to give 2-[tert-butoxycarbonyl(methyl)amino]ethyl methanesulfonate (1.33 g, 5.24 mmol, 82% yield) as yellow oils.

¹ H NMR (400 MHz, CDCl3) δ 4.32 (m, 2H), 3.55 (m, 2H), 3.01 (s, 3H), 2.92 (s, 3H), 1.45 (s, 9H).

Step 2: 2-(3,5-dibromo-1,2,4-triazol-1-yl)-N-methylethanamine

Triethylamine (2.0 ml, 14.5 mmol) was slowly added to a solution of 3,5-dibromo-1H-1,2,4-triazole (1.1 g, 4.83 mmol), 2-[tert-butoxycarbonyl(methyl)amino]ethyl methanesulfonate (1467 mg , 5.8 mmol) in DMF (22 ml). The reaction mixture was then stirred at 65° C. for 18 hours. The reaction mixture was quenched with NH ₄ Cl (aq. saturated) and extracted with DCM. The combined organic fractions were dried using a phase separator and evaporated under vacuum. The residue was dissolved in DCM. Purification by silica gel column chromatography eluting with 0-5% MeOH in DCM gave 2-(3,5-dibromo-1,2,4-triazol-1-yl)-N-methylethanamine (644 mg, 2.27 mmol, 47% yield) as an orange liquid. UPLC-MS (ES ⁺ , Method A): 1.70 min, m/z 283.9 [M+H] ⁺ .

Intermediate 82: 3,5-dibromo-1-[2-(methoxymethoxy)propyl]-1,2,4-triazole

Chloromethyl methyl ether (0.12 ml, 1.35 mmol) was added to a solution of 1-(3,5-dibromo-1,2,4triazol-1-yl)propan-2-ol (257 mg, 0.9 mmol), N,N-diisopropylethylamine ( 0.3 ml, 1.8 mmol) and DCM (4.5 ml). The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was quenched with brine and extracted with DCM. The combined organic fractions were dried using a phase separator and evaporated under vacuum. The residue was dissolved in DCM and purified by silica gel column chromatography eluting with 10-90% EtOAc in petroleum ether to give 3,5-dibromo-1-[2-(methoxymethoxy)propyl]-1,2,4-triazole ( 173 mg, 0.53 mmol, 59% yield) as a colorless oil which solidified on standing to a white solid. UPLC-MS (ES+, Method A): 1.50 min, m/z 330.0 [M+H] ⁺ .

Step 1: 1-(3,5-dibromo-1,2,4-triazol-1-yl)propan-2-one

Chloracetone (0.7 ml, 8.8 mmol) was slowly added to a solution of 3,5-dibromo-1H-1,2,4-triazole (1000 mg, 4.4 mmol), triethylamine (1.84 ml, 13 mmol) and DMF (20 ml) at room temperature, and the reaction

- 175 042028 this mixture was stirred at 65°C for 3 hours and at room temperature for 2 days. The reaction mixture was stopped with NH ₄ Cl (aqueous saturated) and was extracted with DCM. The combined organic fractions were dried using a phase separator and evaporated under vacuum. The residue was dissolved in DCM and purified by silica gel column chromatography eluting with 10-90% EtOAc in petroleum ether to give 1-(3,5-dibromo-1,2,4-triazol-1-yl)propan-2- she (1102 mg, 3.9 mmol, 88% yield) as a white solid. UPLC-MS (ES+, Method A): 1.19 min, m/z 283.9 [M+H] ⁺ .

Step 2: 1-(3,5-dibromo-1,2,4-triazol-1-yl)propan-2-ol

Sodium borohydride (67 mg, 1.8 mmol) was slowly added to a solution of 1-(3,5-dibromo-1,2,4-triazol1-yl)propan-2-one (250 mg, 0.88 mmol) and MeOH (5 ml) . The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with NH4Cl (aq. saturated) and extracted with DCM. The combined organic fractions were dried with a phase separator and evaporated in vacuo to give 1-(3,5-dibromo-1,2,4-triazol-1-yl)propan-2-ol (257 mg, 0.9 mmol, 100% yield ) as a colorless oil. UPLC-MS (ES ⁺ , Method A): 1.16 min, m/z 286.0 [M+H] ⁺ .

Intermediate 83: 2-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy]-N-isopropylacetamide

To a solution of 2-(4-bromo-3-chloro-phenoxy)-N-isopropylacetamide (1 g, 3.26 mmol), potassium acetate (960 mg, 9.8 mmol) and bis(pinacolato)diborone (1240 mg, 4.9 mmol) in 1,4-dioxane (50 mL) was added 1,1'bis(diphenylphosphino)ferrocene]dichloropalladium (II) (238 mg, 0.33 mmol) and the reaction was heated at 85°С under N ₂ for 18 h. cooled to room temperature, filtered through a phase separator, and the filtrate was concentrated under reduced pressure. The residue was taken up in DCM, washed with water, brine, dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give 2-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)phenoxy]-Nisopropylacetamide (1.5 g, 3.18 mmol, 98% yield). LC-MS (ES+, Method F): 3.79 min, m/z 354.1 [M+H] ⁺ .

Step 1: 2-(4-bromo-3-chlorophenoxy)-N-isopropylacetamide

A mixture of 4-bromo-3-chlorophenol (5 g, 24.1 mmol), 2-chloro-N-isopropylacetamide (4.25 g, 31.3 mmol), potassium carbonate (33.3 g, 241 mmol) in acetone (100 ml) was stirred at the boil with reflux refrigeration overnight.

The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 15-50% EtOAc in petroleum ether to give 2-(4-bromo-3-chlorophenoxy)-N-isopropylacetamide (6.9 g, 21.4 mmol, 89% yield) as white solid. LC-MS (ES ⁺ , Method F): 2.31 min, m/z 306.0 [M+H] ⁺ .

The following boronate intermediates in Table. 21 was prepared using a method similar to that presented for intermediate 83.

- 176 042028

Table 21

Intermediate 89: 2,2-dimethyl-1-[6-(4,4,5,5-tetramethyl-1,3,2-daoxaborolan-2-yl)3,4-dihydro-1H-isoquinoline-2 -yl] propane-1 -one

To a solution of 1-(6-bromo-3,4-dihydro-1H-isoquinolin-2-yl)-2,2-dimethylpropan-1-one (500 mg, 1.69 mmol), potassium acetate (497 mg, 5 mmol) and bis(pinacolato)diborone (514 mg, 2.0 mmol) in 1,4-dioxane (10 mL), Pd(dppf)Cl ₂ (247 mg, 0.34 mmol) was added, and the reaction was heated at 85°C under N ₂ in for 18 hours the Reaction mixture was cooled to room temperature, filtered through a phase separator, and the filtrate was concentrated under reduced pressure. The crude was dissolved in DCM and washed with water, brine and dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give crude 2,2-dimethyl-1-[6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)3,4-dihydro-1H-isoquinolin-2-yl]propan-1-one (estimated quantitative yield). UPLC-MS (ES+, Method F), 3.22 min, m/z 344.2 [M+H] ⁺ .

Step 1: 1-(6-bromo-3,4-dihydro-1H-isoquinolin-2-yl)-2,2-dimethylpropan-1-one OCV O

Trimethylacetyl chloride (0.64 ml, 5.2 mmol) was added at 0° C and the solution was stirred at 25°C for 2 hours. Water (60 ml) was added and extracted with DCM (30 mlx3), the combined organics were washed with brine and dried over Na ₂ SO ₄ . The solution was filtered and evaporated in vacuo to give 1-(6-bromo-3,4-dihydro-III-isoquinolin-2-yl)-2,2-dimethylpropan-1-one (1390 mg, 4.7 mmol, 99% yield) as light yellow solid. UPLC-MS (ES ⁺ , Method F), 4.02 min, m/z 298.0 [M+H] ⁺ .

The following compound was obtained in a similar manner.

- 177 042028

Intermediate 90: 1-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-Schizoquinolin-2-yl]propan-1-one

UPLC-MS (ES ⁺ , Method A), 1.79 min, m/z 316.3 [M+H] ⁺ .

Intermediate 91: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2trifluoroethyl)-3,4-dihydro-1H-isoquinoline

To a solution of 6-bromo-2-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-isoquinoline (200 mg, 0.68 mmol), potassium acetate (200 mg, 2.0 mmol) and bis(pinacolato)diborone (259 mg, 1.0 mmol) in 1,4-dioxane (10 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (50 mg, 0.07 mmol) and the reaction was heated at 85°C for atmosphere of N ₂ for 18 hours, the Reaction mixture was cooled to room temperature, filtered through a phase separator, and the filtrate was evaporated under vacuum. The crude materials were dissolved in DCM and washed with water, brine and dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-2-(2,2,2trifluoroethyl)-3,4-dihydro-1H-isoquinoline (estimated quantitative yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.25 (d, J=52.6 Hz, 2H), 6.54 (s, 1H), 3.67 - 3.45 (m, 1H), 3.43 - 3.23 (m, 2H), 3.21 - 2.93 (m, 2H), 2.75 - 2.48 (m, 2H), 2.35 - 2.18 (m, 1H), 0.92 (s, 12H).

Stage 1: 6-bromo-2-(2,2,2-trifluoroethyl)-3,4-dihydro-III-isoquinoline

A mixture of 6-bromo-1,2,3,4-tetrahydroisoquinoline (800 mg, 3.8 mmol), 2,2,2 trifluoroethyl trifluoromethanesulfonate (1051 mg, 4.5 mmol) and potassium carbonate (1043 mg, 7.5 mmol) in NMP (10 ml) stirred at 40°C for 18 hours.

The reaction mixture was filtered and the filtrate was evaporated under vacuum. The residue was purified by silica gel column chromatography eluting with 2% EtOAc in petroleum ether to give 6-bromo-2-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-isoquinoline (800 mg, 2.72 mmol , 72% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 7.36 - 7.26 (m, 2H), 7.03 (d, J=8.1 Hz, 1H), 3.79 - 3.74 (m, 2H), 3.38 3.28 (m, 2H), 2.90 (m, 2H), 2.82 (m, 2H).

Example 248: 1-[6-[5-[(4-cyclopropyl-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-1-methyl3,4 -dihydro-1H-isoquinolin-2-yl]ethanone

Hydrogen chloride (0.38 ml, 1.52 mmol) was added to a solution of 1-[6-[5-[(4-cyclopropyl-1tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4- triazol-3-yl]-1-methyl-3,4-dihydro-Schizoquinolin-2-yl]ethanone (32 mg, 0.06 mmol) in MeOH (5 ml). The mixture was stirred at 45° C. for 2 hours and concentrated under reduced pressure. The residue was taken up in MeOH (1 ml) and purified by anion exchange chromatography (SCX-2 cartridge) eluting with 3M NH3 in MeOH to give 1[6-[5-[(4-cyclopropyl-1H-indazol-5-yl )amino]-1-methyl-1,2,4-triazol-3-yl]-1-methyl-3,4-dihydro-1Hisoquinolin-2-yl]ethanone (19 mg, 0.04 mmol, 72% yield) in form of a yellow solid. UHPLCMS (ES ⁺ , Method B): 3.04 min, m/z 442.6 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ): 13.00 (s, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 7.66 (m, 1H), 7.60 (m, 1H), 7.41 (d , J=8.8 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.21 (m, 1H), 5.45 (q, J=6.8 Hz, 0.6H), 5.05 (q, J=6.8 Hz, 0.4Н), 4.43 (m, 0.3Н), 3.82 (m, 0.7Н), 3.76 (s, 3Н), 3.43 (m, 0.5Н), 2.94 (m, 0.5Н), 2.87 (m, 0.5Н) , 2.80 (m, 0.5H), 2.71 (m, 1.0H), 2.21 (m, 2H), 2.10 (s, 1.2H), 2.07 (s, 1.8H), 1.45 (d, J=6.8 Hz, 1.1 H), 1.33 (d, J=6.8 Hz, 1.9H), 0.99–0.93 (m, 2H), 0.84–0.77 (m, 2H).

Stage 1: N-[2-(3-bromophenyl)ethyl]acetamide

I „ H v r

A mixture of 2-(3-bromophenyl)ethanamine (0.7 ml, 4.9 mmol), acetic anhydride (1 ml, 10.6 mmol), three

- 178 042028 ethylamine (1.4 ml, 10.0 mmol) and DCM (25 ml) were stirred at room temperature for 18 h, diluted with DCM (50 ml) and washed with NaHCO3 (aqueous saturated) (50 ml). The organic phase was separated and dried over Na ₂ SO ₄ , filtered, evaporated under vacuum. The residue was purified by silica gel column chromatography eluting with 20-100% EtOAc in petroleum ether to give N-[2-(3-bromophenyl)ethyl]acetamide (1.19 g, 4.92 mmol, 99% yield). UPLC-MS (ES+, Method A): 1.41 min, m/z 243.9 [M+H] ⁺ .

Stage 2: 6-bromo-1-methyl-3,4-dihydroisoquinoline

N-[2-(3-Bromophenyl)ethyl]acetamide (1 g, 4.1 mmol) was mixed with 83% polyphosphoric acid (3.4 g, 41 mmol) and heated to 200°C for 4 h. The mixture was poured into stirred ice water (80 ml) and the pH was adjusted to 10 with 28% aqueous NH4OH. The aqueous layer was extracted with DCM (3x80 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give 6-bromo-1-methyl-3,4-dihydroisoquinoline (840 mg, 3.75 mmol, 91% yield) as a brown oil. UPLC-MS (ES ⁺ , Method A): 0.97 min, m/z 223.7 [M+H] ⁺ .

Step 3: 6-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline ^Br <^ _NH

6-Bromo-1-methyl-3,4-dihydroisoquinoline (520 mg, 2.3 mmol) was dissolved in MeOH (15 ml) and cooled to 0°C. Sodium borohydride (175 mg, 4.6 mmol) was added and the reaction was allowed to warm to room temperature. After 1 h additional sodium borohydride (175.0 mg, 4.63 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. HCl in 1,4-dioxane (3 ml) until the pH of the mixture is 3-4. The reaction was evaporated in vacuo and the resulting solid was dissolved in water (30 ml). The mixture was basified to pH 11-12 with 5 M NaOH. The aqueous phase was extracted with EtOAc (3x40 ml) and the combined organic fractions were dried over Na2SO4 and evaporated in vacuo to give 6-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline (522 mg, 2.3 mmol, 99% yield) in the form of amber oil. UPLC-MS (ES ⁺ , Method A): 1.04 min, m/z 228.0 [M+H] ⁺ .

Stage 4: 1 - (6-bromo-1 -methyl-3,4-dihydro-1 H-isoquinolin-2-yl) ethanone

A mixture of 6-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline (519 mg, 2.3 mmol) in DCM (15 ml), triethylamine (0.65 ml, 4.66 mmol) and acetic anhydride (0.33 ml, 3.5 mmol) stirred at 20° C. for 18 h, diluted with DCM (30 ml) and washed with saturated aqueous NaHCO3 (20 ml). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 20-100% EtOAc in petroleum ether to give 1-(6-bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (380 mg , 1.42 mmol, 62% yield) as a yellow oil. UPLC-MS (ES ⁺ , Method A): 1.60 min, m/z 269.9 [M+H] ⁺ .

Step 5: 1-[1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinolin2-yl]ethanone

bis (pinacolato) diborone (306 mg, 1.2 mmol), 1- (6-bromo-1-methyl-3,4-dihydro-1H-isoquinolin-2yl) ethanone (162 mg, 0.6 mmol), potassium acetate (178 mg , 1.8 mmol) and 1,4-dioxane (6 ml) were stirred and degassed for 5 min by bubbling N2. The complex [1,1'bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (49 mg, 0.06 mmol) was added and the mixture was degassed for 5 min by bubbling N2. The reaction mixture was stirred overnight at 90°C. The reaction was evaporated in vacuo and the crude material was purified by silica gel column chromatography eluting with 60-100% EtOAc in petroleum ether to give 1-[1-methyl-6(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (126 mg, 0.4 mmol, 66% yield) as a colorless oil. UPLC-MS (ES ⁺ , Method A): 1.74 min, m/z 316.1 [M+H] ⁺ .

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Step 6: 1-[6-[5-[(4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4triazol-3-yl]-1 -methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethenone

N-(5-bromo-2-methyl-1,2,4-triazol-3-yl)-4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5-amine (182 mg, 0.44 mmol), 1 -[1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1Hisoquinolin-2-yl]ethanone (125 mg, 0.40 mmol), potassium carbonate (137 mg, 0.99 mmol) in 1,4-dioxane (4 ml), and water (0.4000 ml) were stirred and degassed for 5 min by N2 bubbling. The complex [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (32 mg, 0.04 mmol) was added and the mixture was degassed for 5 min by N2 bubbling. The reaction was irradiated for 3 hours at 100°C under microwave reactor conditions. The volatiles were evaporated, the crude residue was dissolved in DCM and adsorbed onto silica. Purification by silica gel chromatography eluting with 20-100% EtOAc in petroleum ether gave 1-[6-[5-[(4-cyclopropyl-1-tetrahydropyran-2-ylindazol-5-yl)amino]-1-methyl -1,2,4-triazol-3-yl]-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]ethenone (32 mg, 0.06 mmol, 15% yield). UPLC-MS (ES ⁺ , Method A): 1.64 min, m/z 526.7 [M+H] ⁺ .

Example 249 4-cyclopropyl-N-[5-(2-ethyl-1-methyl-3,4-dihydro-1H-isoquinolin-6-yl)-2-methyl-1,2,4triazol-3-yl ]-1 H-indazole-5-amine

4-Cyclopropyl-N-[5-(2-ethyl-1-methyl-3,4-dihydro-1H-isoquinolin-6-yl)-2-methyl-1,2,4-triazol-3yl]-1H -indazol-5-amine (21 mg, 0.05 mmol, 88% yield) was synthesized following the method in Example XX from 4-cyclopropyl-N-[5-(2-ethyl-1-methyl-3,4-dihydro- 1H-isoquinolin-6-yl)-2-methyl-1,2,4-triazol-3-yl]-1tetrahydropyran-2-yl-indazol-5-amine (29 mg, 0.06 mmol). UPLC-MS (ES ⁺ , Method B): 2.43 min, m/z 428.4 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6): 13.00 (s, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 7.58 (br. d, J=8.0 Hz, 1 H), 7.51 (s , 1H), 7.42 - 7.34 (m, 2H), 7.10 (d, J=8.0 Hz, 1H), 3.89-3.78 (m, 1H), 3.75 (s, 3H), 2.89 (m, 1H), 2.79 (m, 1H), 2.71-2.61 (m, 2H), 2.60-2.53 (m, 2H), 2.11 (m, 1H), 1.21 (d, J=6.6 Hz, 3H), 1.05 (t, J= 7.0 Hz, 3H), 0.98 0.92 (m, 2H), 0.83 - 0.77 (m, 2H).

Stage 1: 6-bromo-2-ethyl-1-methyl-3,4-dihydro-1H-isoquinoline

Borane dimethylsulfide (2.07 ml, 4.13 mmol) was slowly added to a solution of 1-(6-bromo-1-methyl3,4-dihydro-1H-isoquinolin-2-yl)ethanone (213 mg, 0.79 mmol) in anhydrous THF (8 ml ) and cooled to 0°C. The mixture was then heated to 70°C. After completion, the reaction was slowly stopped with MeOH (2 ml) at room temperature and heated to 70°C for 1 h, cooled, diluted with EtOAc (30 ml) and washed with NaHCO ₃ (aqueous saturated) (20 ml). The layers were separated and the organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was dissolved in MeOH (2 ml) and purified by anion exchange chromatography (SCX-2 cartridge) eluting with 3.5 M NH3 in MeOH to give 6-bromo-2-ethyl-1-methyl-3,4-dihydro-1H -isoquinoline (173 mg, 0.68 mmol, 85% yield) as a yellow oil. UPLC-MS (ES ⁺ , Method A): 1.07 min, m/z 255.9 [M+H] ⁺ .

Stage 2: 2-ethyl-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1Nisoquinoline

Intermediate from Example 248, Step 5, 6-bromo-2-ethyl-1-methyl-3,4-dihydro-1Hisoquinoline (75 mg, 0.3 mmol), bis(pinacolato)diborone (150 mg, 0.59 mmol), acetate potassium (87 mg, 0.89 mmol) and 1,4-dioxane (3 mL) were obtained after purification by silica gel column chromatography eluting with 20-100% EtOAc in petroleum ether to give 2-ethyl-1-methyl-6- (4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline (36 mg, 0.12 mmol, 40% yield) as a yellow oil. UPLC-MS (ES+, Method A): 1.26 min, m/z 302.1 [M+H] ⁺ .

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Intermediate 92: Nethyl-2,2,2-trifluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)phenyl]ethanamine

2,2,2-trifluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]ethanamine (150 mg, 0.5 mmol), MeOH (5 ml) and acetaldehyde (0.03 ml, 0.5 mmol). The reaction mixture was stirred at room temperature for 1 h and sodium borohydride (28 mg, 0.75 mmol) was added slowly. The reaction mixture was stirred at room temperature for an additional 1 h, the Reaction was stopped with Na ₂ CO ₃ (aqueous saturated) and was extracted with DCM and EtOAc. The organic fractions were evaporated in vacuo and the residue was taken up in DCM. Insolubles were filtered off and the filtrate was evaporated in vacuo to give N-ethyl-2,2,2-trifluoro-1[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]ethanamine (108 mg, 0.33 mmol, 66% yield) as a clear oil. UPLC-MS (ES+, Method A): 1.68 min, m/z 330.1 [M+H] ⁺ .

Step 1: 1-(4-bromophenyl)-2,2,2-trifluoroethanamine

4-bromo-2,2,2-trifluoroacetophenone (1.5 g, 5.9 mmol) and toluene (30 ml) were loaded into a 250 ml round bottom flask. The solution was cooled to 0°C and lithium bis(trimethylsilyl)amide (6.5 ml, 6.5 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 min and borane dimethylsulfide (5.9 ml, 11.8 mmol) was added slowly at 0°C. The mixture was stirred at room temperature for an additional 1 hour, cooled to 0° C. and 2N hydrochloric acid was added. NaOH (9 ml). The mixture was stirred at room temperature for 1.5 h, then partitioned between EtOAc and water. The organic layer was washed with water and brine, dried with a phase separator and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with 0% to 70% EtOAc in petroleum ether to give 1-(4-bromophenyl)-2,2,2-trifluoroethanamine (1339 mg, 5.27 mmol, 88.9% yield) as a colorless liquid. UPLC-MS (ES ⁺ , Method A): 1.27 min, m/z 256.0 [M+H] ⁺ .

Intermediate 93: 1-2,2,2-trifluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]ethanamine

1-(4-Bromophenyl)-2,2,2-trifluoroethanamine (1.34 g, 5.27 mmol), bis(pinacolato)diborone (1605 mg, 6.32 mmol), complex [1,1'- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (430 mg, 0.53 mmol) and potassium acetate (1550 mg, 15.8 mmol) and purged with nitrogen. 1,4-Dioxane (24 ml) was degassed by bubbling N ₂ and then added to the mixture and the suspension was stirred at 90° C. for 1.5 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The organic layer was washed with water, saturated brine and evaporated in vacuo. The residue was dissolved in DCM, adsorbed onto silica gel and purified by silica gel column chromatography eluting with 0% to 60% EtOAc in petroleum ether to give 2,2,2-trifluoro-1-[4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanamine (917 mg, 3.05 mmol, 58% yield) as a clear oil. UPLC-MS (ES ⁺ , Method A): 1.48 min, m/z 302.1 [M+H] ⁺ .

Intermediate 94: N-ethyl-2,2-difluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]ethanamine

1-(4-Bromophenyl)-N-ethyl-2,2-difluoroethanamine (185 mg, 0.7 mmol), bis(pinacolato)diborone (214 mg, 0.84 mmol), complex [1,1' -bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (57 mg, 0.07 mmol) and potassium acetate (207 mg, 2.1 mmol) and purged with N2. Degassed 1,4-dioxane (3 ml) was added to the mixture and the suspension was stirred at 90°C for 1.5 h. The reaction mixture was cooled to room temperature and partitioned between DCM and water. The organic layer was washed with water, brine and evaporated in vacuo. The residue was dissolved in DCM and evaporated under vacuum on silica gel. The product was purified using column chromatography.

- 181 042028 fii on silica gel, eluting with 10% to 100% EtOAc in petroleum ether, then 0% to 5% MeOH in

DCM, receipt

N-ethyl-2,2-difluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)phenyl]ethanamine (115 mg, 0.37 mmol, 53% yield ) as a clear oil. UPLC-MS (ES+, Method A): 1.30 min, m/z 312.3 [M+H] ⁺ .

Step 1: 1-(4-bromophenyl)-2,2-difluoroethanone

A dry 100 ml flask was charged with 4-iodobromobenzene (2 g, 7.0 mmol) and THF (20 ml). The solution was cooled to -78°C and a solution of n-butyllithium (3.1 ml, 7.8 mmol) was added slowly. The reaction mixture was stirred at -78°C for 30 min. Ethyl difluoroacetate (0.8 ml, 7.8 mmol) was then added dropwise and the reaction mixture was stirred at -78°C for 1 h. The reaction mixture was stirred at 78°C for an additional 1 h, then at 0°C for 1 h. The reaction was then stopped with 1N. HCl (3 ml) and extracted with DCM. The combined organic fractions were washed with brine, dried with a phase separator and evaporated in vacuo. The crude residue was dissolved in DCM, evaporated in vacuo on silica gel and purified by silica gel column chromatography eluting with 0% to 50% EtOAc in petroleum ether to give 1-(4-bromophenyl)-2,2-difluoroethanone (1123 mg , 4.78 mmol, 68% yield) as a yellow liquid. UPLC-MS (ES-, Method A): 2.05 min, m/z 233.1 [M-H] ^- .

Step 2: 1-(4-bromophenyl)-N-ethyl-2,2-difluoroethanamine

1-(4-Bromophenyl)-2,2-difluoro-ethanone (287 mg, 1.2 mmol), MeOH (5 mL), ethylamine (1.8 mL, 3.66 mmol), and titanium (IV) isopropoxide were loaded into a dry 100-mL flask. (0.7 ml, 2.44 mmol). The reaction mixture was stirred at 55° C. for 18 hours. The resulting suspension was cooled to 0° C. and sodium borohydride (92 mg, 2.44 mmol) was added in portions. The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was quenched with ammonium hydroxide (33% in water) and the solvents were removed in vacuo. The residue was suspended in EtOAc and insolubles (TiO ₂ ) were filtered through a pad of Celite™. The filtrate was evaporated in vacuo and the crude material was purified by silica gel column chromatography eluting with 10% to 100% EtOAc in petroleum ether to give 1-(4-bromophenyl)-X-ethyl-2,2-difluoroethanamine (185 mg , 0.70 mmol, 58% yield) as a colorless oil. UPLC-MS (ES ⁺ , Method A): 1.11 min, m/z 264.0 [M+H] ⁺ .

The following boronate intermediates in Table. 22 were obtained using a method similar to that presented in step 1 and step 2 for example 343.

Table 22

Method C Structure Analysis Intermediate 95 O- A /=( O Method A, 1.99 min, m/z 334.3 [M+H] ⁺ Intermediate 96 ~U ⁰ ' / \ /° YAYA Ή NMR (400 MHz, DMSO-c/e) δ 8.45 (1, J = 5.7 Hz, 1H), 7.72 - 7.41 (br, 3H), 3.57 (s, 3H), 3.34 - 3.18 (m, 2H), 1.18 1.15 (t, 12N), 1.14 - 1.09 (t, ZN). Intermediate 97 Ho /=/ oh Method F, 3.28 min, m/z 290.2 [M+H] ⁺ Intermediate 98 / ¹ co o' ^h o A Method F, 3.02 min, m/z 306.2 [M+H] ⁺ Intermediate 99 F. -Ao _x /=\ R apa Method F, 2.07 min, m/z 294.2 [M+H] ⁺ Intermediate 100 ^F \ ^{F F} \ -Ho / A / ° A Method F, 3.79 min, m/z 344.1 [M+H] ⁺

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Intermediate 101 F BUT _H / A o , ^B A / A / BUT HN ^ F Method F, 1.80 min, m/z 230.1 [M+H] ⁺ Intermediate 102 Intermediate 103 Intermediate 104 Intermediate 105 Intermediate 106 Intermediate 107 Ύ°' aY r A ⁱⁿ mAv F o - /A r /A / ⁱⁿ A /A /O HN-AJ F o - O 1 Ύ° /=\ p \ ^F Α ^Β ΆΥΛ ^ρ / Ύ ⁰ ' / \ ρ AAF A-O _h / \u003d N about _T\u003e A JA / 7% HN ^ Method F, 3.53 min, m/z 312.2 [M+H] ⁺ Method A, 1.81 min, m/z 429.1 [M+H] ⁺ Method A, 2.10 min, m/z 483.2 [M+H] ⁺ Method A , 1.86 min, m/z 344.1 [M+H] ⁺ Method F, 1.50 min, m/z 219.1 [Mpinacol+H] ⁺ Method F, 1.70 min, m/z 195.1 [Mpinacol+H] ⁺ Intermediate 108 Ho ΛΑ ρ <] Method A, 1.67 min, m/z 288.1 [M+H] ⁺ Intermediate 109 Λο /=Ν Ο FF Τ >A /l A ^F 7^0 HlA Method A, 1.22 min, m/z 249.0 [Mpinacol+H] ⁺ Software Intermediate Ύθ ΛΑ ρ /ο ~Μην^ W Method F, 4.10 min, m/z 327.10 [M+H] ⁺ Intermediate 111 ΗΟ _χ /=Ν Ο ζ ^Β Υ but Μ; ηνΑο— Method A, 0.90 min, m/z 236.9 [M+H] ⁺ Intermediate 112 Ύ°' / ⁼ \ /P 7^ο' ^Β ^/ηνΑ F Method A, 1.78 min, m/z 306.2 [M+H] ⁺ Intermediate 113 ΛΑΡ ο— Method A, 1.72 min, m/z 318.2 [M+H] ⁺ Intermediate 114 Ύ ⁰ / ⁼ \ ρ Method A, 1.62 min, m/z 276.2 [M+H] ⁺ Intermediate 115 Ε ^F / ^F /=\ ρ , ^b Y / Z^o nA Ή NMR (400 MHz, DMSO-Ab) δ 8.49 (t, J = 5.6 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.92 (d, J = 7.0 Hz, 1H), 7.52 (d , J = 7.5 Hz, 1H), 3.28 - 3.20 (m, 2H), 1.32 (s, 12H), 1.10 (t, J = 7.4 Hz, ZN). Intermediate 116 R -Ao 2=\ p A ^B fA F Ή NMR (400 MHz, DMSO-Ab) δ 8.69 (t, J = 7.3 Hz, 1H), 7.77 - 7.45 (m, 2H), 3.29 (t, J = 6.8 Hz, 2H), 1.22 - 1.07 (m, 15H). Intermediate 117 Method F, 4.07 min, m/z 366.10 [M+H] ⁺

- 183 042028

General Method J: The method for preparing the compound of the invention is shown below. Additional compounds that can be obtained in a similar way, using General method J, are presented in table. 23.

Example 250 2-[2-chloro-4-[5-(1H-indazol-5-ulamino)-1-methyl-1,2,4-triazol-3-yl]phenoxu]-Nisopropylacetamide

To a stirred solution of HCl-MeOH (1.6 M, 3 ml, 4.8 mmol) was added 2-[2-chloro-4-[1-methyl-5[(1-tetrahydropiran-2-ylindazol-5-yl)amino]-1 ,2,4-triazol-3-yl]phenoxy]-N-isopropylacetamide (100 mg, 0.19 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified using a reverse phase column (40 g, C 18, 50% MeCN in water) to give the desired product 2-[2-chloro4-[5-(1H-indazol-5-ylamino)-1-methyl-1 ,2,4-triazol-3-yl]phenoxy]-N-isopropylacetamide (50 mg, 0.11 mmol, 60% yield) as a white solid. LC-MS (ES+, Method F): 2.82 min, m/z 440.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.89 (s, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 7.94 (s, 1H), 7.88 (m , 2H), 7.5 (dd, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 1H), 4.61 (s, 2H), 3.97-3.88 (m, 1H), 3.79 (s, 3H) , 1.11 (d, J=2.4 Hz, 6H).

Stage 1: 2-chloro-4-[1-methyl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]-1,2,4-triazol-3yl]phenol ό

A mixture of N-(5-bromo-2-methyl-1,2,4-triazol-3-yl)-1-tetrahydropyran-2-yl-indazol-5-amine (250 mg, 0.66 mmol), 2-chloro- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (337 mg, 1.33 mmol), potassium carbonate (275 mg, 2.0 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (49 mg, 0.07 mmol) was stirred at 110°C in water (4 ml) and 1,4-dioxane (20 ml). The reaction mixture was filtered and concentrated and then purified by silica gel column chromatography eluting with 50% EtOAc in petroleum ether to give 2-chloro-4-[1-methyl-5-[(1-tetrahydropyran-2-ylindazol-5yl) amino]-1,2,4-triazol-3-yl]phenol (200 mg, 0.47 mmol, 71% yield).

LC-MS (ES ⁺ , Method F): 3.10 min, m/z 425.1 [M+H] ⁺ .

Stage 2: 2-[2-chloro-4-[1-methyl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]-1,2,4-triazol-3yl]phenoxy]-N -isopropylacetamide

A mixture of 2-chloro-4-[1-methyl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]-1,2,4-triazol-3yl]phenol (200 mg, 0.47 mmol), 2-chloro-N-isopropylacetamide (96 mg, 0.71 mmol) and potassium carbonate (520 mg, 3.8 mmol) in acetone (15 ml) were stirred at 65°C for 36 h. Then filtered and purified using silica gel column chromatography , eluting with 0-100% EtOAc in petroleum ether to give 2-[2-chloro-4-[1-methyl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]-1,2, 4-triazol-3yl]phenoxy]-N-isopropylacetαmide (108 mg, 0.20 mmol, 44% yield). LC-MS (ES ⁺ , Method F): 3.76 min, m/z 524.1 [M+H] ⁺ .

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Table 23

Example Structure LC-MS Ή NMR 470 0 k D J J. />Ά_Χ ⁿ / ^N N N Method F, 2.35 min, m/z 406.2 [M+H]+ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.90 (s, br), 8.84 (s, 1H), 8.22 (s, 1H), 8.02 (s, 1H), 7.89 (d, J=8.8 Hz, 3H ), 7.56 (d, J=8Hz, 1H), 7.48 (d, J=8.8Hz, 1H), 7.01 (d, 1=8.8Hz, 2H), 4.48 (s, 2H), 4.00-3.91 (m , 1H), 3.78 (s, 3H), 1.09 (d, J=7.2 Hz, 6H) 471 Ϊ n _ L 0 / ^N ~N Η Method F, 2.65 min, m/z 440.1 [M+H]+ 1H NMR (400 MHz, DMSOd ₆ ) δ 13.36 (s 1H), 8.43 (s, 1H), 8.08 (s,lH), 7.87 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.7 Hz , 2H), 7.61-7.52 (dd, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.44 (s, 2H), 3.98-3.89 (m, 1H), 3.76 (s, 3H), 1.09 (d,J = 6.8 Hz, 6H). 472 ηι 0 ? Η __/ /-X / οΙϊΗχ ⁿ yKhL / ^Ν Ν Η Method F, 3.0 min, m/z 474.1 [M+H]+ 1H NMR (400 MHz, DMSOd ₆ ) δ 13.38 (s, 1H), 8.52 (s, 1H), 8.09 (s, 1H), 7.80 (d, J = 7.8 Hz, 2H), 7.72 (dd, J = 8.6 , 1.8 Hz, 1H), 7.63-7.51 (m, 2H), 7.03 (d, J = 8.7 Hz, 1H), 4.58 (s, 2H), 3.97-3.85 (m, 1H), 3.77 (s, 3H) , 1.08 (d, J = 6.6 Hz, 6H). 473 f/? / Η __/ ,—\ / Λν-ο ^{7 Ν} \ ΑΎΎ Υ>Λ_χ ^Η / ^Ν 'Ν -- Η Method F, 2.62 min, m/z 424.2 [M+H]+ 1H NMR (400 MHz, DMSOd ₆ ) δ 12.89 (s, 1H), 8.87 (s, 1H), 8.17 (s, 1H), 8.03 (s, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.72 (s, 1H), 7.70 (d, J = 6.8 Hz, 1H), 7.57 - 7.49 (dd, J = 8.8 Hz, 2H), 7.12(1, J = 8.8 Hz, 1H), 4.58 (s, 2H ), 3.99–3.89 (m, 1H), 3.79 (s, 3H) 1.10 (d, J = 6.8 Hz, 6H). 474 ΖΞΕ 0 Ο. ΙΖ^° Method F, 2.82 min, m/z 458.1 [M+H]+ 1H NMR (400 MHz, DMSOd ₆ ) δ 13.38 (s, 1H), 8.51 (s, 1H), 8.08 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8.9 Hz, 4H), 7.05 (t, J = 8.7 Hz, 1H), 4.54 (s, 2H), 3.91 (m, J = 6.8 Hz, 1H), 3.76 (s, 3H), 1.06 (d, J = 6.5 Hz, 6H). 475 <ΧΤ ^η Η Method F, 2.91 min, m/z 508.1 [M+H]+ 1H NMR (400 MHz, DMSOd ₆ ) δ 13.33 (s, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.26-7.23 (m, 1H), 4.56 (s, 2H), 3.99-3.90 (m, 1H), 3.78 (s, 3H), 1.09-1.08 (d, J = 6.8 Hz, 6H)

- 185 042028

Example 251 4-[5-[(4-cyclopropyl-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-Nethylbenzamide

Hydrogen chloride (1.65 ml, 6.6 mmol) was added to a solution of 4-[5-[(4-cyclopropyl-1-tetrahydropyran2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3 -yl]-N-ethylbenzamide (64 mg, 0.13 mmol) in MeOH (2 ml). The reaction was then stirred at room temperature for 18 hours. The solvent was removed under vacuum and the crude material was purified on an SCX SPE cartridge. The resulting product was purified by silica gel column chromatography eluting with 60-100% EtOAc in petroleum ether to give 4-[5-[(4-cyclopropyl-1H-indazol-5-yl)amino]-1-methyl- 1,2,4-triazol-3-yl]-N-ethylbenzamide (14 mg, 0.035 mmol, 26% yield). UPLC-MS (ES ⁺ , Method B): 2.91 min, m/z 402.4 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.48 (t, J=5.5 Hz, 1H), 8.32 (s, 1H), 8.07 (s, 1H), 7.86 (q, J =8.5 Hz, 4H), 7.49 - 7.27 (m, 2H), 3.79 (s, 3H), 3.26 (q, 2H), 2.13 (m, 1H), 1.12 (t, J=7.2 Hz, 3H), 1.02 - 0.92 (m, 2H), 0.83 (m, 2H).

Stage 1: N-(5-bromo-2-methyl-1,2,4-triazol-3-yl)-4-cyclopropyl-1-tetrahydropyran-2-yl-indazol5-amium

To a stirred solution of 3,5-dibromo-1-methyl-1H-1,2,4-triazole (7.96 g, 33 mmol) and 4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5-amine (8.5 g, 33 mmol) in dry THF (300 ml) at -20°C in a nitrogen atmosphere was added a solution of sodium bis(trimethylsilyl)amide (1.0 M in THF) (72.7 ml, 72.7 mmol). The reaction was then stirred and allowed to warm to 0°C for 30 minutes. The mixture was quenched with saturated aqueous NH ₄ Cl (150 ml) and extracted with EtOAc (250 ml). The layers were separated and the aqueous layer was further extracted with EtOAc (250 ml). The combined organics were dried over sodium sulfate, filtered and evaporated in vacuo. The resulting solid was triturated with diethyl ether and filtered to give N-(5-bromo-2-methyl1,2,4-triazol-3-yl)-4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5 -amine (11.05 g, 26.5 mmol, 80% yield) as a creamy solid.

UPLC-MS (ES+, Method A): 1.65 min, m/z 417.3/419.3 [M+H] ⁺ .

Stage 2: methyl 4-[5-[(4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4triazol-3-yl]benzoate

To a stirred solution of N-(5-bromo-2-methyl-1,2,4-triazol-3-yl)-4-cyclopropyl-1tetrahydropyran-2-yl-indazol-5-amine (9 g, 21.6 mmol) and 4-(methoxycarbonyl)benzeneboronic acid (4.7 g, 25.9 mmol) in 1,4-dioxane (200 ml) and water (40 ml) was added potassium carbonate (9 g, 65 mmol). The mixture was carefully degassed with nitrogen, then the complex [1,1'bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (0.88 g, 1.08 mmol) was added. The suspension was degassed for 5 minutes and then stirred at 100° C. for 5 hours. The reaction mixture was cooled to room temperature and diluted with 100 ml of water and 250 ml of EtOAc. The organics were first washed with 100 ml saturated brine, then the organics were dried over sodium sulfate, filtered and evaporated in vacuo to give a brown semi-solid which was triturated with diethyl ether to give methyl 4-[5-[(4-cyclopropyl-1-tetrahydropyran -2-ylindazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]benzoate (9.65 g, 20.4 mmol, 95% yield) as an off-white solid. UPLC-MS (ES ⁺ , Method A): 1.85 min, m/z 473.6 [M+H] ⁺ .

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Stage 3: 4-[5-[(4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4triazol-3-yl]benzoic acid

An aqueous solution of 2 M sodium hydroxide (51 ml, 102 mmol) was added to the stirred suspension of methyl

4-[5-[(4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3yl]benzoate (9.65 g, 20.4 mmol ) in THF (150 ml) and MeOH (150 ml) at 25°C. The reaction mixture was stirred at room temperature for 3 h.

The organic solvent was removed in vacuo and the aqueous layers were diluted with 350 ml water, adjusted to pH 4 with 4 M HCl and extracted with 500 ml DCM. The organics were dried over sodium sulfate, filtered and evaporated in vacuo to give an off-white solid. The solid was suspended in diethyl ether and filtered to give 4-[5-[(4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3- yl]benzoic acid (8.7 g, 19 mmol, 93% yield) as a pale cream solid. UPLC-MS (ES ⁺ , Method A): 1.60 min, m/z 459.5 [M+H] ⁺ .

Step 4: 4-[5-[(4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4triazol-3-yl]-N-ethylbenzamide

Propylphosphonic anhydride (0.1 ml, 0.33 mmol) was added to a stirred solution of Ndiisopropylethylamine (0.11 ml, 0.65 mmol), ethylamine in THF (2 M) (0.07 ml, 1.09 mmol), and 4-[5-[(4-cyclopropyl-1-tetrahydropyran- 2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]benzoic acid (100 mg, 0.22 mmol) in DCM (5 ml) and the reaction mixture was stirred in for 16 hours at room temperature. The reaction was washed with aqueous saturated sodium bicarbonate and brine, and dried using a phase separator. The resulting solution was adsorbed onto silica gel and purified by silica gel column chromatography eluting with 50-100% EtOAc in petroleum ether to give 4-[5-[(4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5 -yl)amino]-1methyl-1,2,4-triazol-3-yl]-X-ethylbenzamide (64 mg, 0.13 mmol, 60% yield) as a pale yellow solid. UPLC-MS (ES ⁺ , Method A): 1.59 min, m/z 486.6 [M+H] ⁺ .

Example 252: N-cyclopropyl-4-[5-[(4-ethyl-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-2methoxybenzamide

Hydrogen chloride (4.0 M in dioxane) (2.24 ml, 9.0 mmol) was added slowly to a stirred solution of N-cyclopropyl-4-[5-[(4-ethyl-1-tetrahydropyran-2-yl-indazol-5-yl)αmino] -1-methyl-1,2,4-triazol3-yl]-2-methoxybenzamide (85 mg, 0.16 mmol) in MeOH (2 ml) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The pale yellow solution was evaporated in vacuo and purified using an SCX SPE cartridge. The resulting product was purified by silica gel column chromatography eluting with 30-100% EtOAc in petroleum ether and evaporated in vacuo to give N-cyclopropyl-4-[5-[(4-ethyl-1H-indazol-5-yl )αmino]-1-methyl1,2,4-triazol-3-yl]-2-methoxybenzamide (10 mg, 0.023 mmol, 14% yield) as a white solid. UPLC-MS (ES+, Method B): 3.19 min, m/z 432.3 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 8.08 (d, J=4.3 Hz, 1H), 7.64 (d, J= 8.0 Hz, 1H), 7.45 (d, J=1.4 Hz, 1H), 7.43 (dd, J=7.9, 1.4 Hz, 1H), 7.37 (dd, J=8.7, 1.0 Hz, 1H), 7.27 (d, J=8.7 Hz, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 2.93 (q, J=7.5 Hz, 2H), 2.88 - 2.76 (m, 1H), 1.23 (t, J=7.5 Hz, 3H), 0.74 0.64 (m, 2H), 0.58 - 0.49 (m, 2H).

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Stage 1: methyl 4-[5-[(4-ethyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol3-yl]-2-methoxybenzoate

X o— n o— ν D J T

Ν-ΧΧ / ^Ν Ν

Сх°

[3-Methoxy-4-(methoxycarbonyl)phenyl]boronic acid (435 mg, 2.07 mmol), N-(5-6ρομ-2methyl-1,2,4-triazol-3-yl)-4-ethyl-1- Tetrahydropyran-2-yl-indazol-5-amine (800 mg, 1.97 mmol) and potassium carbonate (573 mg, 4.15 mmol) were dissolved/suspended in 1,4-dioxane (15 ml) and water (4 ml). The reaction mixture was completely degassed by bubbling nitrogen. Then the complex [1,1'bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (161 mg, 0.2 mmol) was added, followed by additional degassing, and then the reaction was heated to 90°С for 18 h. The reaction was evaporated under vacuum for silica gel and purified by silica gel column chromatography eluting with 25-100% EtOAc in petroleum ether to give methyl 4-[5-[(4-ethyl-1-tetrahydropyran-2-ylindazol-5-yl)amino]-1 -methyl-1,2,4-triazol-3-yl]-2-methoxybenzoate (755 mg, 1.54 mmol, 78% yield) as a pale yellow gum. UPLC-MS (ES+, Method A): 1.73 min, m/z 491.5 [M+H] ⁺ .

Stage 2: 4-[5-[(4-Ethyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-2methoxybenzoic acid , hydrochloride

XX ^He Hee XXXX ό

Sodium hydroxide 2.0 M (6.0 ml, 12 mmol) was added to a stirred suspension of ethyl 4-[5-[(4ethyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2, 4-triazol-3-yl]-2-methoxybenzoate (755 mg, 1.5 mmol) in THF (10 ml) and MeOH (10 ml) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction was evaporated in vacuo and then dissolved in water. The pH was then adjusted to 2 with 2.0 M HCl and the resulting solid was extracted with EtOAc (x2). The organics were washed with saturated brine and dried over MgSO ₄ The solvent was removed in vacuo and the resulting solid was triturated in diethyl ether, filtered and washed with additional diethyl ether to give 4-[5[(4-ethyl-1-tetrahydropyran-2- yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-2-methoxybenzoic acid hydrochloride (505 mg, 0.98 mmol, 66% yield) as a beige solid . UHPLCMS (ES ⁺ , Method A): 1.56 min, m/z 477.5 [M+H] ⁺ .

Stage 3: N-cyclopropyl-4-[5-[(4-ethyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4triazol-3-yl]- 2-methoxybenzamide

To a stirred solution of 4-[5-[(4-ethyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl1,2,4-triazol-3-yl]-2-methoxybenzoic acid (80 mg, 0.17 mmol), N,N-diisopropylethylamine (0.09 ml, 0.5 mmol) and cyclopropylamine (0.02 ml, 0.34 mmol) in THF (5 ml) were added propylphosphonic anhydride (0.08 ml, 0.25 mmol) and the solution was stirred in for 16 h. The pale yellow solution was evaporated in vacuo on silica gel and the crude material was purified by silica gel column chromatography eluting with 30-100% EtOAc in petroleum ether to give N-cyclopropyl-4-[5-[(4- ethyl1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-2-methoxybenzamide (85 mg, 0.16 mmol, 97% yield) as colorless resin. UPLC-MS (ES ⁺ , Method A): 1.65 min, m/z 516.5 [M+H] ⁺ .

The following examples (250), described in table. 24 were prepared in a manner similar to that presented in examples 251, 252. Various coupling reagents other than those described in step 1 of example 251 can be used, such as BOP, PyBOP, EDC/HoBT, HATU, or acyl chloride.

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Table 24

Example Structure LC-MS ¹ II NMR 253 1 m g-X ^HN \ N AL / \ HELL JI νΑΑ / ^Ν 'Ν ' - N Method F, 2.39 min, m/z 396.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 8.55 (s, 1H), 8.48 (t, J=5.2 Hz, 1H), 8.1 (s, 1H), 7.87 (m, 4H ), 7.57 (m, 2H), 3.81 (s, 3H), 3.29-3.24 (m, 2H), 1.12 (1, J=6.8 Hz, ZN) 254 Cl CI / 1 n J ΗΝ- ⁷ /xAAvN / \—Ζ AD J GAAa/L /Ν- _ν '—' ^u Η Method F, 2.57 min, m/z 430.0 [M+H] ⁺ ΉNMR (400 MHz, DMSO-d ₆ ) δ 13.4 (s, 1H), 8.61 (s, 1H), 8.43 (t, J=5.2 Hz, 1H), 8.1 (s, 1H), 7.81-7.79 (m, 2H), 7.58 (m, 2H), 7.43 (d, J=7.6 Hz, 1H), 3.81 (s, 3H), 3.27-3.2 (m, 2H), 1.1 (t, J=7.2 Hz, ZN) 255 AA-AL / ^Ν Ν Η Method F, 2.81 min, m/z 456.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.4 (s, 1H), 8.62 (d, J=7.2 Hz, 2H), 8.1 (s, 1H), 7.79-7.77 (m, 2H), 7.58 (m , 2H), 7.37 (d, J=7.6 Hz, 1H), 3.81 (s, 3H), 1.37 (s, 3H), 0.73-0.7 (m, 2H), 0.6-0.57 (m, 2H) 256 Cl οι / 1 Η J HN--V ΛΑ/ ' a D τ AD ο νΑΑ / ^Ν Ν ^υ Η Method F, 3.07 min, m/z 458.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.4 (s, 1H), 8.59 (s, 1H), 8.1 (s, 1H), 8.04 (s, 1H), 7.79-7.77 (m, 2H), 7.58 (m, 2H), 7.37 (d, J=7.6 Hz, 1H), 3.8 (s, 3H), 1.35 (s, 9H) 257 ϊ μ /—\ HN-M' /x/O\A AA/ \ AD J Τ ο / ^Ν Ν Η Method F, 2.90 min, m/z 424.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.4 (s, 1H), 8.54 (s, 1H), 8.1 (s, 1H), 7.877.85 (m, 2H), 7.81-7.76 (m, 3H) , 7.57 (m, 2H), 3.8 (s, 3H), 1.37 (s, 9H) 258 j ¹ Η __ HN—D /-^Αχ/Ν Ν /=\/ A VU Method F, 2.60 min, m/z 422.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.4 (s, 1H), 8.66 (s, 1H), 8.56 (s, 1H), 8.1 (s, 1H), 7.84 (m, 4H), 7.57 (m , 2H), 3.8 (s, 3H), 1.36 (s, 3H), 0.74–0.71 (m, 2H), 0.61–0.58 (m, 2H) 259 ? η D' hn-DD Λ \ 7 ⁴⁷ \ D Τ Τ ο / ^Ν Ν - Η Method F, 1.95 min, m/z 471.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.41 (s, 1H), 8.89 (d, J=6.8 Hz , 1H), 8.61 (s, 1H), 8.1 (s, 1H), 7.82-7.8 (m , 2H), 7.61-7.55 (m, 2H), 7.44 (d, J=7.6 Hz , 1H), 4.4-4.35 (m , 1H), 3.81 (s, 3H), 3.58 (t, J=6 Hz , 2H), 2.95 (t, J=6 Hz , 2H), 2.24 (s, 3H) 260 \ / ^ΖΙ Method F, 2.12 min, m/z 445.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.4 (s, 1H), 10.58 (s, 1H), 9.0 (s, 1H), 8.6(s, 1H), 8.36 (d, J=4.8 Hz, 1H ), 8.27 (d, J=8.4 Hz, 1H), 8.11 (s, 1H), 8.0 (q, Jl=8 Hz, J2=14 Hz , 4H), 7.58 (q, L=8.4 Hz, 12=16.4 Hz , 2H), 7.51-7.48 (m, 1H), 3.83 (s, 3H) 261 w Χλ^α Η Method F, 3.06 min, m/z 444.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.39 (s, 1H), 10.26 (s, 1H), 8.57 (s, 1H), 8.190(s, 1H), 7.98(1, 8.8Hz, 4H), 7.77(d, J=8Hz, 2H), 7.62-7.55(m, 2H), 7.35(1, 1=8.4Hz, 2H), 7.1(t, 1=7.2Hz, 1H), 3.82(s, 3H ) 262 ? Η \__ ην-Α /-^ΑχχΝχΜΜ ?=Α_/ A D D Τ Χ\_/ό νΑ^ /Ν-ν Η Method F, 2.56 min, m/z 410.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.36 (s, 1H), 8.51 (s, 1H), 8.43 (1, J=5.6 Hz, 1H), 8.09(s, 1H), 7.81(d, J =8 Hz, 1H), 7.71 (s, 1H), 7.65-7.6 (m, 2H), 7.54 (d, J=8.8 Hz, 1H), 3.82 (s, 3H), 3.29-3.24 (m, 2H) , 2.59 (s, 3H), 1.11 (1, J=7.2 Hz, ZN) 263 ? Η _ HN-DD ,^ALxD AA/ AD J Τ />Α/Λ NV /Ν-Ν ^ν Η Method F, 1.85 min, m/z 437.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.42 (s, 1H), 9.07–9.05 (d, J = 6.4 Hz, 1H), 8.56 (s, 1H), 8.10 (s, 1H), 7.93–7.88 (m, 4H), 7.59-7.54 (m, 2H), 4.69-4.64 (m, 1H), 4.09 (1, J = 8.4 Hz, 2H) 3.81 (m, 5H), 2.68 (s, 3H)

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264 Ά \ / ¹ 1 Method F, 2.87 min, m/z 452.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.39 (s, IH), 8.56 (s, IH), 8.24 (s, IH), 8.10 (s, IH), 7.68 - 7.70 (m, IH), 7.53 - 7.59 (m, 2H), 7.46 - 7.48 (m, 2H), 3.88 (s, 3H), 3.80 (s, 3H), 1.37 (s, 3H), 0.71 - 0.72 (m, 2H), 0.59 - 0.60 ( m, 2H). 265 ϊ ¹ AND ^C % ΗΝ-X /^ζΑν^ν ΡΡ—A vV Η Method F, 2.59 min, m/z 430.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.36 (s, IH), 8.62 (t, 1=5.2Hz, IH), 8.57 (s, IH), 8.09 (s, IH), 7.59 (s, IH) , 7.84-7.78 (m, 2H), 7.60 (d, J=8.8 Hz, IH), 7.53 (d, J=8.8 Hz, IH), 3.8 (s, 3H), 3.32-3.27(m, 2H), 1.12 (t, J=7.2 Hz, ZN) 266 CI , ^Ν =\ z-JLUn ^Ν ΡΧ Jj Ν УУ Ο /Ν- _ν ^u Η Method F, 2.53 min, m/z 445.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.39 (s, IH), 10.78 (s, IH), 8.58 (s, IH), 8.39 (d, J=4.8 Hz, IH), 8.18 (d, J= 8.4 Hz, IH), 8.1 (s, IH), 8.05 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.4 Hz , 2H), 7.86-7.82 (m, IH), 7.59 (q, L=8.8 Hz, 12=21.2 Hz, 2H), 7.18-7.15 (m, IH), 3.82 (s, 3H) 267 7 7 % Method F, 1.93 min, m/z 467.2 [M+H] ⁺ ΉNMR (400 MHz, DMSO-de) δ 13.44 (s, IH), 8.59 (s, IH), 8.41 (d, J = 6.9 Hz, IH), 8.09 (s, IH), 7.67 (d, J = 8 Hz, IH), 7.59-7.54 (m, 2H), 7.51 (s, IH), 7.48 (d, J - 8.0 Hz, IH), 4.45 - 4.36 (m, IH), 3.90 (s, 3H), 3.81 (s, 3H), 3.55 (t, J = 6.8 Hz, 2H), 2.93 (t, J = 6.7 Hz, 2H), 2.24 (s, 3H). 268 Α Η ΑΑ° X -Π Method B, 3.35 min, m/z 450.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.39 (s, IH), 9.20 (t, J = 6.3 Hz, IH), 8.59 8.54 (m, IH), 8.35 (s, IH), 8.10 (s, IH ), 8.02 (m, IH), 7.86 (m, IH), 7.63 - 7.47 (m, 3H), 4.08 (m, 2H), 3.82 (s, 3H). 269 ο ₄ CI >-ΝΗ 1 Η __/ V /=\ Ρ AjT J Ν PJ Ν-Ά^ /Ν'Ν '—' Η Method B, 3.03 min, m/z 408.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.39 (s, IH), 8.53 (d, J = 4.1 Hz, 2H), 8.27 (s, IH), 8.10 (s, IH), 7.95 (m, IH) , 7.77 (m, IH), 7.58 (q, J =8.8 Hz, 2H), 7.45 (m, IH), 3.81 (s, 3H), 2.85 (m, IH), 0.68 (m, 2H), 0.61 - 0.54 (m, 2H). 270 C) Cl ν ^ΝΗ ι ^Η ^-Γ γζ^ζΑχχ ^Ν χ^Ν /=4 / ^Ν ΡΙ J Y Ν^Α / ^Ν 'Ν Η Method B, 3.18 min, m/z 410.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.39 (s, IH), 8.54 (s, IH), 8.33 (d, J = 7.8 Hz, IH), 8.29 (t, J= 1.7 Hz, IH), 8.10 (s, IH), 7.95 (m, IH), 7.80 (m, IH), 7.64 - 7.52 (m, 2H), 7.46 (t, J = 7.8 Hz, IH), 4.16 - 4.01 (m, IH), 3.82 (s, 3H), 1.16 (d, J = 6.6 Hz, 6H). 271 Η? ΗΝ-Ζ Ν D Τ Ν Ό /Ν-ν ^u η Τ CI Method F, 2.95 min, m/z 440.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.43 (s, IH), 9.07 (s, IH), 8.18-8.16 (m, 2H), 7.94 (d, J=8 Hz, IH), 7.79-7.77 ( m, 2H), 7.66-7.64 (m, 2H), 4.12-4.03 (m, IH), 3.97 (s, 3H), 3.83 (s, 3H), 1.18 (d, J=6.4 Hz, 6H) 272 V ° / d ζ—Ζ ΗΝ ⁷ ζ^^Α^ν ν /A/ ν D Τ Τ /lrAD Ν^χΑ _ζ ^ν 'Ν ^w Η Method B, 3.23 min, m/z 432.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.02 (s, IH), 8.32 (s, IH), 8.17 (t, J = 5.7 Hz, IH), 8.06 (t, J = 1.2 Hz, IH), 7.75 (d, J = 8.0 Hz, IH), 7.52 - 7.46 (m, 2H), 7.43 - 7.36 (m, 2H), 3.90 (s, 3H), 3.79 (s, 3H), 3.32 - 3.25 (m, 2H ), 2.20–2.08 (m, IH), 1.11 (t, J = 7.2 Hz, ZH), 1.02–0.92 (m, 2H), 0.90–0.79 (m, 2H). 273 yy _V N Apy ^s UU ST U UU ο ζ ^Ν Ν — Η Method B, 3.46 min, m/z 446.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.02 (s, IH), 8.32 (s, IH), 8.06 (s, IH), 7.91 (d, J = 7.7 Hz, IH), 7.71 (d, J = 7.9 Hz, IH), 7.53 - 7.44 (m, 2H), 7.45 - 7.34 (m, 2H), 4.14 - 3.97 (m, IH), 3.90 (s, 3H), 3.79 (s, 3H), 2.20 - 2.08 (m, IH), 1.16 (d, J = 6.6 Hz, 6H), 1.02 - 0.91 (m, 2H), 0.90 - 0.79 (m, 2H). 274 V ο— Λχ-Ο ΗΝ-< <Υ Ύ Τ >-\jr μ νΑζ /Ν-ν A η Method B, 3.17 min, m/z 476.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.00 (s, IH), 8.22 (s, IH), 8.06 (d, J = 1.2 Hz, IH), 7.74 (d, J = 7.9 Hz, IH), 7.45 - 7.31 (m, 4H), 6.92 (d, J = 8.4 Hz, IH), 4.44 (s, 2H), 3.91 (m, IH), 3.81 (s, 3H), 3.33 (s, 3H), 2.13 ( m, IH), 1.08 (d, J = 6.6 Hz, 6H), 1.02 - 0.90 (m, 2H), 0.89 - 0.77 (m, 2H) 275 ζ ζζ' ₄ ζζ % ζ 1 Method B, 2.51 min, m/z 473.3 [M+H] ⁺ Ή NMR (400 MHz, MeOH-d ₄ ) δ 8.17 (s, IH), 7.87 (d, J = 8.2 Hz, IH), 7.70 (d, J = 1.4 Hz, IH), 7.63 (dd, J = 8.2 , 1.4 Hz, IH), 7.44 (m, 2H), 4.61 (p, J = 6.9 Hz, IH), 4.01 (s, 3H), 3.86 (s, 3H), 3.84 - 3.79 (m, 2H), 3.28 (m, 2H), 2.45 (s,

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3H), 2.14 (m, 1H), 1.11-0.98 (m, 2H), 0.96 - 0.81 (m, 2H) 3 NH were not observed 276 ϊ Η / HN—\. ^{F ,} ^Α^Ν Ν ΛΑ/ ¥-F Method B, 3.38 min, m/z 470.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.02 (s, IH), 8.95 (t, J = 6.4 Hz, IH), 8.30 (s, IH), 8.07 (s, IH), 7.75 - 7.67 (m, 2H), 7.44 - 7.37 (m, 2H), 7.37 - 7.33 (m, IH), 4.05 (m, 2H), 3.79 (s, 3H), 2.34 (s, 3H), 2.21 - 2.08 (m, IH) , 1.03 - 0.90 (m, 2H), 0.89-0.76 (m, 2H) 277 ] Η __/ ΗΝ—\ /^Α^Ν^Ν / ' B D J Γ Η/Λ n-U / ^Ν Ν — Η Method B, 3.00 min, m/z 416.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.02 (s, IH), 8.28 (s, IH), 8.23 (t, J = 5.6 Hz, IH), 8.10 - 8.04 (m, IH), 7.71 - 7.63 ( m, 2H), 7.50 - 7.35 (m, 2H), 7.30 (d, J = 7.7 Hz, IH), 3.78 (s, 3H), 3.24 (m, 2H), 2.34 (s, 3H), 2.20 - 2.08 (m, IH), 1.11 (t, J = 7.2 Hz, ZH), 1.02 - 0.90 (m, 2H), 0.89 - 0.78 (m, 2H). 278 ν / Udu VU lL-P ^F Η Method B, 3.04 min, m/z 486.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.01 - 12.96 (m, IH), 9.13 (t, J = 6.3 Hz, IH), 8.23 (s, IH), 8.06 (d, J = 1.3 Hz, IH) , 7.73 (d, J = 7.9 Hz, IH), 7.55 (d, J = 1.6 Hz, IH), 7.48 (dd, J = 8.0, 1.6 Hz, IH), 7.41 (d, J = 8.8 Hz, IH) , 7.36 (d, J = 8.8 Hz, IH), 4.18 - 4.04 (m, 2H), 3.86 (s, 3H), 3.78 (s, 3H), 2.21 - 2.09 (m, IH), 1.03 - 0.93 (m , 2H), 0.87 - 0.78 (m, 2H). 279 V ^/ _JL ^ N NDL n ^z j TT />A/L / ^N 'N ^U H Method B, 2.72 min, m/z 432.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.01 - 12.96 (m, IH), 8.51 (t, J = 5.6 Hz, IH), 8.21 (s, IH), 8.06 (t, J = 1.2 Hz, IH) , 7.67 (d, J = 8.0 Hz, IH), 7.49 (d, J = 1.6 Hz, IH), 7.42 (dd, J = 8.2, 1.7 Hz, 2H), 7.36 (d, J = 8.8 Hz, IH) , 3.84 (s, 3H), 3.77 (s, 3H), 3.34 - 3.24 (m, 2H), 2.15 (m, IH), 1.13 (t, J= 7.2 Hz, ZH), 1.03 - 0.93 (m, 2H ), 0.86 - 0.77 (m, 2H). 280 V ° . ⁼ H 7 HN—\ F ζ-υΑΑΑχΛ ^Λγ —Ζ Method B, 3.54 min, m/z 486.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.02 (s, IH), 8.66 (t, J = 6.4 Hz, IH), 8.35 (s, IH), 8.07 (s, IH), 7.77 (d, J = 8.0 Hz, IH), 7.56 - 7.49 (m, 2H), 7.45 - 7.35 (m, 2H), 4.11 (m, 2H), 3.80 (s, 3H), 3.33 (s, 3H), 2.20 - 2.08 (m , IH), 1.02 0.91 (m, 2H), 0.90 - 0.79 (m, 2H). 281 ] Η ,__ _k HN-yF ^N ^Ν _h Y\__7 Y-F ^N d JN P-D/O F nA^ z ^N 'N -' Η Method B, 3.38 min, m/z 482.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.01 (s, IH), 9.17 (s, IH), 8.32 (s, IH), 8.06 (d, J = 1.2 Hz, IH), 7.91 - 7.83 (m, 4H), 7.45 - 7.35 (m, 2H), 3.79 (s, 3H), 2.18 - 2.09 (m, IH), 1.34 - 1.28 (m, 2H), 1.14 (s, 2H), 1.00 - 0.93 (m, 2H), 0.86 0.79 (m, 2H). 282 ^γ0γΛ/°\-4° \ VU D/AUCH n Method B, 3.28 min, m/z 430.5 [M+H] ⁺ SNMR (400 MHz, DMSO-de) δ 13.01 (s, IH), 8.31 (s, IH), 8.15 (d, J= 8.2 Hz, IH), 8.06 (s, IH), 7.91 - 7.81 (m, 4H ), 7.43 - 7.34 (m, 2H), 3.91 (p, J = 7.0 Hz, IH), 3.78 (s, 3H), 2.13 (m, IH), 1.60 - 1.41 (m, 2H), 1.12 (d, J= 6.6 Hz, ZN), 0.96 (m, 2H), 0.90 - 0.79 (m, 5H). 283 | n ___ o G> / ^ \-4 [ H ⁷ D JI OJhn- ⁷ N ^ \ zz ^N N Η Method B, 3.18 min, m/z 428.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.01 (s, IH), 8.57 (t, J= 5.7 Hz, IH), 8.31 (s, IH), 8.06 (t, J = 1.2 Hz, IH), 7.93 - 7.80 (m, 4H), 7.46 - 7.32 (m, 2H), 3.79 (s, 3H), 3.13 (t, J = 6.2 Hz, 2H), 2.14 (m, IH), 1.08 - 0.99 (m, IH ), 0.99 - 0.92 (m, 2H), 0.82 (m, 2H), 0.46 - 0.39 (m, 2H), 0.25 - 0.19 (m, 2H). 284 1 Η __ ΗΝ-\ . ΖΑ-Ζ Ο J ν ^V_/o fF nAA z ^{N n} — H Method B, 2.88 min, m/z 468.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.02 (s, IH), 8.78 (t, J = 6.3 Hz, IH), 8.33 (s, IH), 8.07 (t, J = 1.1 Hz, IH), 7.95 - 7.85 (m, 4H), 7.46 - 7.35 (m, 2H), 5.49 (t, J = 6.4 Hz, IH), 3.80 (s, 3H), 3.85-3.71 (m, 2H), 3.71 - 3.58 (m , 2H), 2.20 - 2.08 (m, IH), 1.02 - 0.91 (m, 2H), 0.90 - 0.78 (m, 2H). 285 ZLAN /Y^-/r VU HUGL, ^F H Method B, 3.31 min, m/z 470.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.05 - 13.00 (m, IH), 8.70 (t, J = 5.6 Hz, IH), 8.33 (s, IH), 8.07 (t, J = 1.2 Hz, IH) , 7.95 - 7.81 (m, 4H), 7.46 - 7.35 (m, 2H), 3.80 (s, 3H), 3.50 (m, 2H), 2.64 - 2.51 (m, 2H), 2.20 - 2.06 (m, IH) , 1.02 - 0.92 (m, 2H), 0.83 (m, 2H)

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286 ΡνΑΑΑΐΥ cu he Η Method B, 2.80 min, m/z 446.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.05 - 12.99 (m, 1H), 8.32 (s, 1H), 8.26 (t, J = 6.1 Hz, 1H), 8.07 (d, J = 1.2 Hz, 1H ), 7.94 - 7.81 (m, 4H), 7.46 - 7.35 (m, 2H), 4.56 (s, 1H), 3.80 (s, 3H), 3.25 (d, J = 6.1 Hz, 2H), 2.20 - 2.06 ( m, 1H), 1.10 (s, 6H), 1.02–0.92 (m, 2H), 0.87–0.78 (m, 2H). 287 ΞΕΖ ΖΞ H 0 Method B, 2.88 min, m/z 428.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.33 (s, 1H), 8.07 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.41 (t, J = 6.5 Hz, 2H), 3.80 (s, 3H), 3.69 (s, 2H), 2.14 (m, 1H), 1.42 (s, 6H), 1.02 - 0.92 (m, 2H), 0.83 (m, 2H). 288 ΐζ Υ \ Η ο i ο Method B, 2.70 min, m/z 444.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.59 (dd, J = 9.1, 7.1 Hz, 1H), 8.32 (s, 1H), 8.07 (s, 1H), 7.92 - 7.82 (m, 4H), 7.46 - 7.35 (m, 2H), 5.06 (dd, J = 30.2, 5.4 Hz, 1H), 4.37 (dq,J= 43.1, 5.8 Hz, 1H), 3.97 - 3.80 (m, 1H ), 3.80 (s, 3H), 2.58 - 2.53 (m, 1H), 2.28 (m, 1H), 2.21 - 2.06 (m, 2H), 1.92 (m, 1H), 1.02 - 0.91 (m, 2H), 0.83(m, 2H) 289 ϊ Η _ ΗΝ-χΥ ⁿ Ca J Υ ν./ ο ζ ^Ν Ν Η Method B, 3.52 min, m/z 444.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 8.42 - 8.26 (m, 2H), 8.06 (s, 1H), 7.86 (q, J = 8.5 Hz, 4H), 7.45 - 7.34 (m, 2H), 3.79 (s, 3H), 3.09 (d, J = 6.3 Hz, 2H), 2.13 (m, 1H), 0.96 (m, 2H), 0.89 (s, 9H), 0.82 (m, 2H). 290 Υ Η ΗΝ—\ _c Ν Υ\7 Y ^f 4 JJ Y # 4-4/ O F nY^ z ^N 'N ^and n Method B, 3.07 min, m/z 438.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.48 (t, J = 5.5 Hz, 1H), 8.32 (s, 1H), 8.07 (s, 1H), 7.86 (q, J = 8.5 Hz, 4H), 7.49 - 7.27 (m, 2H), 3.79 (s, 3H), 2.13 (m, 1H), 1.12(1, J =7.2Hz, ZN), 1.02-0.92 (m, 2H) , 0.83 (m, 2H). 251 1 n HN—\ C M™ Η Method B, 2.91 min, m/z 402.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.48 (t, J = 5.5 Hz, 1H), 8.32 (s, 1H), 8.07 (s, 1H), 7.86 (q, J = 8.5 Hz, 4H), 7.49 - 7.27 (m, 2H), 3.79 (s, 3H), 3.30 (q, 2H under water peak), 2.13 (m, 1H), 1.12 (t, J = 72 Hz, WN ), 1.02 0.92 (m, 2H), 0.83 (m, 2H). 291 ϊ n __ ΗΝ A _Ζ ΝΗ ₂ /αΑ/ ^ν υ ^ν χ Υ\-Ζ to ν J Τ Τ />γ/Λ ' νΎυ ζ ^Ν 'Ν - Η Method B, 2.41 min, m/z 445.3 [M+H] ⁺ Ή NMR (400 MHz, CDC1 ₃ ) δ 13.03 (br s, 1H), 8.33 (m, 2H), 8.07 (s, 1H), 7.88 (m, 4H), 7.40 (m, 2H), 3.79 (s, 3H), 3.21 (d, J= 6.12 Hz, 2H), 2.87 (br s, 2H), 2.14 (m, 1H), 1.04 (s, 6H), 0.97 (m, 2H), 0.83 (m, 2H) . 292 1 Η __ ΗΝ—\ ^ν Π Υ Τ Η/Λ / νΥα ζ ^ν 'Ν — Η Method B, 3.32 min, m/z 430.4 [M+H] ⁺ Ή NMR (400 MHz, CDC1 ₃ ) δ 13.02 (s, 1H), 8.47 (t, J= 5.80 Hz, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 7.87 (q, J= 8.45 Hz, 4H), 7.40 (m, 2H), 3.80 (s, 3H), 3.08 (t, J= 6.42 Hz, 2H), 2.16 (m, 1H), 1.84 (m, 1H), 0.97 (m, 2H ), 0.89 (d, J= 6.85 Hz, 6H), 0.83 (m, 2H). 293 | Η ,—χ ΗΝ-\ zJv ^N Y Υ\—4 ^°n nJ J Y ζ ^ν 'Ν Η Method B, 2.75 min, m/z 444.3 [M+H] ⁺ Ή NMR (400 MHz, CDC1 ₃ ) δ 13.02 (s, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 8.06 (s, 1H), 7.85 (s, 4H), 7.40 (m, 2H ), 4.75 (t, J= 5.78 Hz, 1H), 3.79 (s, 3H), 3.52 (d, J= 5.87 Hz, 2H), 2.14 (m, 1H), 0.97 (m, 2H), 0.83 (m , 2H), 0.76 (m, 2H), 0.70 (m, 2H). 294 ϊ η __ HN-VJ /Jv ^N v ^N Υ\_7 AJJ Γ '^L/L N0C /N'-N ^υ Η Method B, 3.10 min, m/z 428.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 8.64 (s, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 7.90-7.76 (m, 4H), 7.47 - 7.30 (m, 2H), 3.78 (s, 3H), 2.13 (m, 1H), 1.35 (s, 3H), 1.03 - 0.90 (m, 2H), 0.83 - 0.79 (m, 2H), 0.77 - 0.69 (m, 2H), 0.64–0.55 (m, 2H). 295 ζ^ IZ ΖΙ Η ό 1 I ° P\ Method B, 3.10 min, m/z 416.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 8.31 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.06 (s, 1H), 7.92 - 7.79 (m , 4H), 7.47 - 7.28 (m, 2H), 4.17 - 4.02 (m, 1H), 3.79 (s, 3H), 2.13 (m, 1H), 1.15 (d, J = 6.6 Hz, 6H), 1.00 - 0.92 (m, 2H), 0.86-0.78 (m, 2H).

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296 ϊ Η ,___ ο ο. AU Η Method B, 2.88 min, m/z 446.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.97 (t, J = 5.8 Hz, 1H), 8.33 (s, 1H), 8.07 (s, 1H), 7.90 (q, J = 8.6 Hz, 4H), 7.42 (t, J = 7.6 Hz, 2H), 4.01 (d, J = 5.8 Hz, 2H), 3.80 (s, 3H), 3.66 (s, 3H), 2.20 - 2.10 (m , 1H), 0.97 (m, 2H), 0.83 (m, 2H). 297 It! r—χ hn-Af Ν /=\_/ U-F N, I J T F /n-n -- H Method B, 3.43 min, m/z 470.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.87 (d, J= 8.72 Hz, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 7.91 (m, 4H ), 7.40 (m, 2H), 4.86 (m, 1H), 3.80 (s, 3H), 2.14 (m, 1H), 1.37 (d, J= 7.01 Hz, ZH), 0.97 (m, 2H), 0.83 (m, 2H). 298 F 1 H __ HN—\J ^F z-^Ax/N^N XA—Y h 1 JI ^ν/Λ νΆΑ _z ⁿ --n ^u H Method B, 3.37 min, m/z 478.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.59 (d, J= 7.20 Hz, 1H), 8.33 (s, 1H), 8.07 (s, 1H), 7.88 (q, J = 8.42 Hz, 4H), 7.40 (m, 2H), 4.43 (m, 1H), 3.80 (s, 3H), 2.17 (m, 6H), 1.84 (m, 1H), 0.97 (m, 2H), 0.83 (m, 2H). 299 V ^{4 T} %° o i IZ >-^3 C _Z zi z Method B, 2.93 min, m/z 432.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.57 (d, J= 3.84 Hz, 1H), 8.32 (s, 1H), 8.07 (s, 1H), 7.88 (q, J = 7.70 Hz, 4H), 7.40 (q, J= 7.51 Hz, 2H), 4.75 (m, 1H), 3.79 (s, 3H), 2.83 (m, 1H), 2.14 (m, 1H), 1.14 (m , 2H), 0.96 (m, 2H), 0.82 (m, 2H). 300 V Λ=Ν ALk^n /lT^ ¹ ' VU X AAL Η Method B, 2.91 min, m/z 454.3 [M+H] ⁺ SH NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 10.43 (s, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.95 (m , 4H), 7.57 (s, 1H), 7.41 (q, J= 7.63 Hz, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 2.15 (m, 1H), 0.96 (m, 2H) , 0.84 (m, 2H). 301 V nL - I Η __ ΗΝ-Χ ζ-Α^Νχ^Ν /==4/ Υ-0 ^Ν Π J Ν Ht/Λ 0 ⁴ ν-4Α / ^ν 'Ν ^υ Η Method B, 3.43 min, m/z 488.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.63 (d, J = 7.7 Hz, 1H), 8.33 (s, 1H), 8.07 (br. s, 1H), 7.90 (s , 4H), 7.43 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 4.29 (m, 1H), 3.80 (s, 3H), 3.66 (s, 3H), 2.25 -2.10 (m, 2H), 0.99-0.95 (m, 2H), 0.98 (d, J = 6.8 Hz, ZH), 0.94 (d, J = 6.8 Hz, ZH), 0.86-0.81 (m, 2H). 302 303 304 305 V ^Η χ—\ ] Η ΗΝ-Χ z-^Ax-n ν LA / \-ο ₄ bh j D Ό o ν^Α /Ν- _ν ^- ^{7 u} Η V α° Η __ HN—\ 1 bh j γ αΑ_/ ^ό _νΆΑ ^ν- _ν ^- ^{7 υ} Η \ Η -Ζ ⁴ - B D τ τ ν_Χ Ν^ΑΑ /Ν-ν Η Method B, 3.64 min, m/z 502.5 [M+H] ⁺ Method B, 2.84 min, m/z 444.4 [M+H] ⁺ Method B, 3.64 min, m/z 502.5 [M+H] ⁺ Method B , 3.02 min, m/z 472.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.75 (d, J = 7.6 Hz, 1H), 8.33 (s, 1H), 8.07 (br. s, 1H), 7.93–7.87 (m, 4H), 7.45-7.37 (m, 2H), 4.50 (m, 1H), 3.80 (s, 3H), 3.65 (s, 3H), 2.15 (m, 1H), 1.80 (m, 1H), 1.70 (m, 1H), 1.58 (m, 1H), 1.00-0.95 (m, 2H), 0.93 (d, J = 6.5 Hz, ZN), 0.88 (d, J = 6.5 Hz, ZN), 0.860.81 (m, 2H). Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.55 (d, J = 6.5 Hz, 1H), 8.32 (s, 1H), 8.07 (br. s, 1H), 7.91–7.85 (m, 4H), 7.42 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 4.45 (m, 1H), 3.89-3.82 (m, 2H), 3.80 (s, 3H), 3.71 (m, 1H), 3.58 (m, 1H), 2.20-2.09 (m, 2H), 1.93 (m, 1H), 1.00-0.94 (m, 2H), 0.86-0.80 (m, 2H) . Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.64 (d, J = 7.6 Hz, 1H), 8.33 (s, 1H), 8.07 (br. s., 1H), 7.93- 7.87 (m, 4H), 7.43 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 4.35 (m, 1H), 3.80 (s, 3H), 3.65 (s, 3H ), 2.15 (m, 1H), 1.97 (m, 1H), 1.52 (m, 1H), 1.27 (m, 1H), 1.00–0.94 (m, 2H), 0.90 (d, J = 6.80 Hz, ZN) , 0.87 (t, J= 7.4 Hz, ZN), 0.85–0.81 (m, 2H). Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.31 (s, 1H), 8.11 (d, J= 8.0 Hz, 1H), 8.07 (br.s, 1H), 7.90-7.85 (m, 4H), 7.43 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 4.60 (d, J = 5.2 Hz, 1H), 3.80 (s, 3H), 3.64 (m, 1H), 3.42 (m, 1H), 2.14 (m, 1H), 1.91 (m, 1H), 1.83 (m, 1H), 1.70-1.57 (m, 2H), 1.32-1.14 (m, 4H ), 1.00–0.94 (m, 2H), 0.87–0.80 (m, 2H). 306 1 _ ΗΝ^ /--Α^Ν Ν /=\/ Υ-ΝΗ ₂ ν j Τ Τ ΑνΑο Ο ^Ζ nAC Α'Ν Η Method B, 2.56 min, m/z 431.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.68 (t, J = 5.9 Hz, 1H), 8.32 (s, 1H), 8.07 (s, 1H), 7.90 (s, 4H ), 7.50 - 7.33 (m, 3H), 7.03 (s, 1H), 3.81 (d, J = 5.0 Hz, 5H), 2.14 (d, J = 5.5 Hz, 1H), 0.98 (t, J = 7.1 Hz , 2H), 0.83 (d, J = 4.5 Hz, 2H).

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307 r—NH F Is vU γΑ H Method B, 2.87 min, m/z 511.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 8.32 (s, 1H), 8.07 (d, J = 1.5 Hz, 1H), 7.94 - 7.82 (m, 2H), 7.40 (q , J = 10.1, 9.4 Hz, 4H), 7.32 (d, J = 5.1 Hz, 1H), 5.17 (t, J = 5.7 Hz, 2H), 4.50 (d, J = 5.7 Hz, 2H), 4.10 (q , J = 5.2 Hz, 2H), 3.79 (s, 3H), 3.08 (d,J = 4.7 Hz, 1H), 2.13 (m, 1H), 0.96 (m, 2H), 0.860.78 (m, 2H) . 308 Y h __ o he ^N LLE ( ^N ₄ JTT 4—# HnA J nW^ n- _n ⁿ¹ ' ¹ H Method B, 3.14 min, m/z 472.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ + D ₂ O) δ 8.06 (s, 1H), 7.86-7.81 (m, 2H), 7.797.74 (m, 2H), 7.73 (s, 1H), 7. 42-7.35 (m, 2H), 3.75 (s, 3H), 3.55 (s, 2H), 2.07 (m, 1H), 2.00-1.89 (m, 2H), 1.77-1.58 (m, 4H), 1.58-1.46 (m, 2H), 0.99-0.90 (m, 2H), 0.78-0.72 (m, 2H). 3 NH were not observed. 309 | h ,___, it _h /^A^nn /Le ) AJU H \ Method B, 3.23 min, m/z 474.4 [M+H] ⁺ *H NMR (400 MHz, DMSO-d ₆ + D ₂ O) δ 8.07-8.02 (m, 2H), 7.88-7.84 (m, 2H), 7.84-7.80 (m, 2H), 7.42-7.35 (m, 2H), 4.04 (m, W), 3.76 (s, ZH), 3.39 (dd, J = 10.7, 6.0 Hz, 1H), 3.32 (dd, J= 10.7, 6.0 Hz, 1H), 2.09 (m, 1H ), 1.58 (m, 1H), 1.49–1.29 (m, 2H), 0.99–0.91 (m, 2H), 0.86 (d, J = 6.6 Hz, ZV), 0.84 (d, J = 6.6 Hz, ZV) , 0.80-0.74 (m, 2H). 3 NH were not observed. 310 V l ^he Yv "rvn vU JAH / H Method B, 2.86 min, m/z 446.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ + D ₂ O) δ 8.08 (s, 1Η), 8.05 (d, J = 8.6 Hz, 1H), 7.90-7.83 (m, 4H), 7.44-7.37 (m, 2H), 3.86 (m, 1H), 3.78 (s, 3H), 3.45 (dd, J = 10.8, 6.0 Hz, 1H), 3.38 (dd, J= 10.8, 6.0 Hz, 1H), 2.11 (m, 1H ), 1.64 (m, 1H), 1.44 (m, 1H), 0.99–0.91 (m, 2H), 0.86 (t, J = 7.4 Hz, ZH), 0.82–0.77 (m, 2H) 311 312 313 314 252 315 F. ^F I and x ^F N /L/ ) N 1 JI, V_/o HO nXz / ^N -N - H JzG rd Ύ lp^A H ^x X p- / 1 tl l-Z hn-- ⁷ hJ JI //L/L nW /Ν—n ^- ^{7 u} H Ί H f HN—/ z~WW^N r\1 ' ^N CX J ν Η/Λ nW / ⁿ ~-n — H Ί N /-( ^{0 ΗΝ} Ά /-Y/ ^N v ^N / \W aj J G o/L nWV / ^N N H nA AWW H 0— Method B, 3.07 min, m/z 486.4 [M+H] ⁺ Method B, 3.17 min, m/z 428.4 [M+H] ⁺ Method B, 3.14 min, m/z 420.4 [M+H] ⁺ Method B , 3.37 min, m/z 434.6 [M+H] ⁺ Method B, 3.19 min, m/z 432.3 [M+H] ⁺ Method B, 2.46 min, m/z 461.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.79 (d, J= 8.92 Hz, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 7.93 (s, 4H ), 7.41 (m, 2H), 5.17 (t, J= 6.02 Hz, 1H), 4.80 (m, 1H), 3.80 (m, 4H), 3.73 (m, 1H), 2.14 (m, 1H), 0.97 (m, 2H), 0.84 (m, 2H). Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.42 (d, J= 4.28 Hz, 1H), 8.31 (s, 1H), 8.06 (s, 1H), 7.84 (m, 4H ), 7.40 (m, 2H), 3.79 (s, 3H), 2.54 (m, 1H), 2.14 (m, 1H), 1.06 (d, J= 6.04 Hz, ZH), 0.95 (m, ZH), 0.82 (m, 2H), 0.74 (m, 1H), 0.48 (m, 1H) Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (d, J = 1.5 Hz, 1H), 8.27 (s, 1H), 8.21 8.12 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.48 (d,J= 1.4 Hz, 1H), 7.44 (dd,J = 8.0, 1.4 Hz, 1H), 7.38 (dd, J = 8.7, 1.0 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 3.33 - 3.25 (m, 2H), 2.94 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, ZV), 1.11 (t, J = 7.2 Hz, ZV). ^X H NMR (400 MHz, DMSO-de) δ 13.03 (s, 1H), 8.27 (s, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 1.4 Hz, 1H), 7.44 (dd, J = 8.0, 1.4 Hz, 1H), 7.38 (dd, J = 8.7, 1.0 Hz, 1H ), 7.27 (d, J = 8.8 Hz, 1H), 4.12 - 3.98 (m, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 2.94 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, ZH), 1.16 (d, J = 6.6 Hz, 6H). Ή NMR (400 MHz, DMSO-de) δ 13.03 (s, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 8.08 (d, J = 4.3 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 1.4 Hz, 1H), 7.43 (dd, J = 7.9, 1.4 Hz, 1H), 7.37 (dd, J = 8.7, 1.0 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 2.93 (q, J = 7.5 Hz, 2H), 2.88 - 2.76 (m, 1H), 1.23 (t, J = 7.5 Hz, ZN), 0.74 - 0.64 (m, 2H), 0.58 - 0.49 (m, 2H). 'HNMR (400 MHz, CD ₃ OD) δ 8.16 (d, J= 1.0 Hz, 1H), 7.86 (d, J= 8.2 Hz, 1H), 7.68 (d, J= 1.4 Hz, 1H), 7.60 (dd , J = 8.2, 1.5 Hz, 1H), 7.43 (dd, J = 8.8, 1.0 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 4.61 (m, 1H), 3.98 (s, 3H) , 3.88 - 3.78 (m, 5H), 3.32 - 3.29 (m, 2H), 3.05 (q, J = 7.5 Hz, 2H), 2.46 (s, 3H), 1.34 (t, J = 7.6 Hz, 3H). 3 NH not observed

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316 1 d A hn-\F yF NJJ J. V \__7O F νΆ^ / ^N -NH Method B, 3.45 min, m/z 474.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 8.66 (t, J = 6.5 Hz, 1H), 8.29 (s, 1H), 8.15 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.51 (d, J= 1.4 Hz, 1H), 7.47 (dd, 7=8.1, 1.4 Hz, 1H), 7.38 (dd, J = 8.7, 1.0 Hz, 1H), 7.27 (d ,7=8.7 Hz, 1H), 4.10 (m, 2H), 3.90 (s, 3H), 3.76 (s, 3H), 2.94 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz , 3H). 317 ά ϊγ Q I IZ u Method B, 2.96 min, m/z 426.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 8.85 (t, J = 5.9 Hz, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.86 (s, 4H ), 7.37 (d, J = 8.8 Hz, 1H), 7.28 (t, J = 9.3 Hz, 1H), 6.12 tt, 1H), 3.76 (s, 3H), 3.65 (m, 2H), 2.93 (q, J= 7.5 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H). 318 | η __ HN—\ N 4m ' h ⁷ JJ Г АА_/ъ N^^A / ^N 'N - H Method B, 3.00 min, m/z 404.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (s, 1Η), 8.20 (d, J = 40.7 Hz, 2H), 7.84 (s, 4H), 7.38 (d, J = 8.7 Hz, 1H), 7.32 (s, 1H), 7.28 (d, J = 8.8 Hz, 1H), 4.17 4.00 (m, 1H), 3.75(s, 3H), 2.94 (q, J = 7.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H), 1.16 (d, J = 6.6 Hz, 6H). 319 | H __ HN—ζ J_ _F n /=\j nJ JJ oJb nA ² z ^N 'N '—H Method B, 3.29 min, m/z 466.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 8.56 (d, J = 7.2 Hz, 1H), 8.34 8.07 (m, 2H), 7.95 - 7.76 (m, 4H), 7.47 - 7.18 (m, 2H), 4.48 - 4.35 (m, 1H), 3.75 (s, 3H), 2.98 - 2.89 (m, 2H), 2.32 - 2.20 (m, 1H), 2.20 - 2.03 (m, 2H), 1.88 - 1.77 (m, 1H), 1.21 (t, J = 7.5 Hz, ZN). 2H not observed 320 ] H __ HN—\ /%Aa ^N M 4\-/ )— n ⁷ d τ τ j 4__y o ⁷ N^<A z ^N 'N ^U H Method B, 3.23 min, m/z 418.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1Η), 8.45 (t, J = 6.0 Hz, 1H), 8.25 (s, 1H), 8.14 (d, J = 1.3 Hz, 1H), 7.83 (d, J = 2.0 Hz, 4H), 7.37 (d, J = 8.7 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 3.75 (s, 3H), 3.06 (t, J = 6.4 Hz, 2H), 2.93 (q, J = 7.4 Hz, 2H), 1.83 (m, 1H), 1.21 (t, J = 7.5 Hz, 3H), 0.87 (d, J = 6.7 Hz, 6H). 321 ] H __ HN-\/ zAkzN^MA\—/ U NJTT Ch-A o /N'N ^u H Method B, 3.43 min, m/z 432.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.08 - 12.97 (m, 1Η), 8.34 (t, J = 6.4 Hz, 1H), 8.25 (s, 1H), 8.14 (t, J = 1.3 Hz, 1H ), 7.90 - 7.79 (m, 4H), 7.37 (dd, J = 8.7, 1.1 Hz, 1H), 7.27 (d, J= 8.7 Hz, 1H), 3.75 (s, 3H), 3.09 (d, J = 6.4 Hz, 2H), 2.93 (q, J = 7.5 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H), 0.89 (s, 9H). 322 323 324 325 326 Id ^-x hnAJ _c zMv ^N v ^N \ ΛΑ-Ch / ^F n 1 JJ АЦо F z ^N ~N ° H H HN-/ n JI T J. //A^j/4 nAA / ^N 'N — H H , HN-/ /^v ^N v ^N ΛΑ—Χ. n JJT AV-Zc νΆΜ ^{/ n} ~ ^nh pl / W Method B, 3.35 min, m/z 458.4 [M+H] ⁺ Method B, 2.81 min, m/z 390.4 [M+H] ⁺ Method F, 2.22 min, m/z 362.2 [M+H] ⁺ Method F , 2.39 min, m/z 396.1 [M+H] ⁺ Method F, 2.41 min, m/z 380.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.04 (s, 1H), 8.86 (d, J = 8.8 Hz, 1H), 8.28 (s, 1H), 8.16 (d, J= 1.3 Hz, 1H), 7.89 (s, 4H), 7.41-7.36 (m, 1H), 7.28 (d, J = 8.7 Hz, 1H), 4.93 - 4.78 (m, 1H), 3.77 (s, 3H), 2.94 (q, J = 7.5 Hz, 2H), 1.36 (d, J = 7.1Hz, 3H), 1.22 (1.7 = 7.5 Hz, ZN). SH NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.45 (t, J = 5.5 Hz, 1H), 8.24 (s, 1H), 8.13 (br. s, 1H), 7.85–7.78 (m, 4H), 7.36 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 3.74 (s, 3H), 3.29-3.21 (m, 2H), 2.92 (q, J = 7.5 Hz, 2H), 1.20 (t, J = 7.5 Hz, SA), 1.09 (t, J = 7.2 Hz, SA). Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.92 (s, 1H), 8.93 (s, 1H), 8.52 (t, J=5.2 Hz, 1H), 8.19 (s, 1H), 8.04-8.02 (m , 3H), 7.91 (d, J=8 Hz, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 3.82 (s, 3H), 3.33-3.27 (m, 2H), 1.14 (t, J=7.2 Hz, ZH) Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.94 (s, 1H), 9.01 (s, 1H), 8.48 (t, J=5.2 Hz, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.96-7.93 (m, 2H), 7.61-7.59 (m, 1H), 7.53-7.48 (m, 2H), 3.83 (s, 3H), 3.33-3.23 (m, 2H), 1.14 (t, J=7.2 Hz, ZH) Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.92 (s, 1H), 8.96 (s, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 7.86-7.84 (d, J=8 Hz, 1H), 7.74-7.67 (m, 2H), 7.60-7.51 (m, 2H ), 3.83 (s, 3H), 3.30-3.25 (m, 2H), 1.12 (1.7=7.2 Hz, ZN) 327 A/ vu la/l H Method F, 2.44 min, m/z 396.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.90 (s, 1H), 8.96 (s, 1H), 8.65 (1.1=5.6Hz, 1H), 8.15 (s, 1H), 7.99 (m, 3H ), 7.87 (d, J=8.4Hz, 1H), 7.56 (d, 1=9.2Hz, 1H), 7.49(d, J=8.4, 1H), 3.84 (s, 3H), 3.29-3.27 (m, 2H), 1.14(1.1=7.2Hz, ZN)

- 195 042028

328 7 Γν °' Λι~ J ηνΧ/ ^ν m Method B, 2.32 min, m/z 447.3 Ή NMR (400 MHz, DMSO-de) δ 13.01 (s, 1H), 8.41 (d, J = 7.1 Hz, 1H), 8.33 (s, 1H), 8.13 (s, 1H), 7.65 (d, J = 7.9 Hz, 14), 7.48 (d,J= 1.4 Hz, 14), 7.45 (dd, J = 8.0, 1.4 Hz, 14), 7.41 - 7.29 (m, 24), 4.48 - 4.34 (m, 14), 3.89(s, 34), n [M+H] ⁺ 3.77 (s, 34), 3.62 - 3.53 (m, 24), 3.01 - 2.92 (m, 24), 2.46 (s, 34), 2.26 (s, 34). 329 / Method B Ή NMR (400 MHz, DMSO-de) δ 13.04 - 12.99 (m, 14), 8.36 - 8.27 (m, 24), 1 N N ρ- Γ \ π' ΗΝ—' 2.34 min, 8.13 (t, J= 1.2 Hz, 14), 7.82 (d, J=8.0 Hz, 14), 7.50 (d, J= 1.4 Hz, 14), 7.47 Η Μ / ^ν ~ν DDS m/z 449.3 [M+H] ⁺ (dd, J = 8.0, 1.4 Hz, 14), 7.41 - 7.29 (m, 24), 3.91 (s, 34), 3.77 (s, 34), 3.38 (m, 24), 2.48 - 2.43 (m, 54 ), 2.24(s, 64) 330 Ν^ Η ιζ ο—CR/' Method B, 3.19 min, m/z 447.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.51 (s, 14), 9.24 (s, 14), 8.74 (d, J = 2.5 Hz, 14), 8.71 (t, J = 6.4 Hz, 14), 8.66 (d, J = 2.5 Hz, 14), 8.13 (s, 14), 7.85 (d, J =8.0 Hz, 14), 7.69 (dd, J=8.0, 1.4 Hz, 14), 7.67 (d, J = 1.3 Hz, 14), 4.13 (m, 6.4 Hz, 24), 3.99 (s, 34), 3.87 (s, 34). 331 Ν ^Ζ Ν Η Η Τ Ύ Υ /> L ρ- J y. ΗΝ— Method B, 3.05 min, m/z 407.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.51 (s, 14), 9.22 (s, 14), 8.74 (d, J = 2.5 Hz, 14), 8.66 (d, J = 2.4 Hz, 14), 8.13 (s, 14), 7.95 (d, J = 7.7 Hz, 14), 7.78 (d, J = 7.9 Hz, 14), 7.66 (dd, 7 = 7.9, 1.4 Hz, 14), 7.63 (d, J= 1.3 Hz, 14), 4.15-4.01 (m, 14), 3.97 (s, 34), 3.86 (s, 34), 1.18 (d, J = 6.6 Hz, 64). 332 Ν ^Ζ Ν' Η M ^Υην^Ι Method B, 2.87 min, m/z 405.3 [M+H]+ Ή NMR (400 MHz, DMSO-de) δ 13.51 (s, 14), 9.22 (s, 14), 8.73 (d, J = 2.5 Hz, 14), 8.65 (d, J = 2.4 Hz, 14), 8.12 (d, J = 4.1 Hz, 24), 7.73 (d, J = 7.9 Hz, 14), 7.64 (dd, J = 7.9, 1.4 Hz, 14), 7.61 (d, J = 1.5 Hz, 14), 3.94 (s, 34), 3.86 (s, 34), 2.91 - 2.79 (m, 14), 0.76 - 0.64 (m, 24), 0.61 - 0.52 (m, 24). 333 N* N' Method B, 3.01 min, m/z 418.2 Ή NMR (400 MHz, DMSO-de) δ 12.89 (s, 14), 8.20 (s, 14), 8.09 (d, J = 4.3 Hz, 14), 7.98 (t, J = 1.3 Hz, 14), 7.70 (s, 14), 7.67 (d, J = 7.9 Hz, 14), 7.51 7.46 (m, 24), 7.42 (m, 14), 3.87 (s, 34), 3.75 (s, 34), 2.83 (m , 14), 2.37(s, Η [M+N] ⁺ 34), 0.74 - 0.64 (m, 24), 0.59 - 0.50 (m, 24) 334 Η ^Χ^Ν Ν 11 T \ λ p-J J HN—< Method B, 3.18 min, Ή NMR (400 MHz, DMSO-de) δ 12.89 (s, 14), 8.20 (s, 14), 7.98 (d, J = 1.2 Hz, 14), 7.92 (d, J = 7.7 Hz, 14), 7.71 (d, J = 8.0 Hz, 24), 7.54 - 7.45 (m, 24), Ν ^Ζ Ν' _/Ν γ m/z 420.3 7.42 (s, 14), 4.13 - 3.99 (m, 14), 3.90 (s, 34), 3.76 (s, 34), 2.38 (s, 34), 1.16 Η [M+N] ⁺ (d, J=6.5Hz, 64) 335 Ν ^Ζ J Yr =8 ο _? HN—\F /==4/ ¥-F VPb f Method B, 3.33 min, m/z 460.2 Ή NMR (400 MHz, DMSO-de) δ 12.90 (s, 14), 8.67 (t, J = 6.4 Hz, 14), 8.22 (s, 14), 7.98 (s, 14), 7.78 (d, J = 8.0 Hz, 14), 7.71 (s, 14), 7.57 - 7.49 (m, 24), 7.42 (s, 14), 4.12 (m, 24), 3.93 (s, 34), 3.76 (s, 34), 2.38(s, 34) Η [M+N] ⁺ 336 Ν ^Ζ Ν' ΖΙ o— / J HN-γ Method B, 3.53 min, m/z 438.4 Ή NMR (400 MHz, DMSO-de) δ 13.36 (s, 14), 8.65 (s, 14), 8.19 (s, 14), 7.84 (s, 14), 7.77 (d, J = 8.0 Hz, 14) , 7.66 - 7.55 (m, 14), 7.55 - 7.45 (m, 24), 7.40 (dd, J = 8.8, 1.1 Hz, 14), 3.92 (s, 34), 3.81 (s, 34), 1.37 (s , 94). Η [M+N] ⁺ 337 /_ Method B Ή NMR (400 MHz, DMSO-de) δ 13.03 - 12.98 (m, 14), 8.97 (t, J = 6.3 Hz, G Η 3.66 min, m/z 514.5 [M+H] ⁺ 14), 8.19 (s, 14), 8.08 (t, J = 1.3 Hz, 14), 7.78-7.70 (m, 24), 7.60 (d, J=8.8 Hz, 14), 7.47 - 7.34 (m, 24), 4.35 (t, J = 5.2 Hz, 24), 4.06 (m, 24), 3.78 (t, J = 5.2 Hz, 24), 3.33 (s, 34 ), 2.36 (s, 34), 2.11 (m, 14), 1.12-0.97 (m, 24), 0.90 - 0.79 (m, 24). 338 Method B Ή NMR (400 MHz, DMSO-de) δ 13.02 (s, 14), 8.84 (t, J= 6.32 Hz, 14), 8.33 ϊ ^Η HN— 3.19 min, (s, 14), 8.07 (s, 14), 7.91 (m, 44), 7.41 (q, J= 7.58 Hz, 24), 3.80 (s, 34), 3.72 N^ N' ΌΛ F F m/z 452.4 (m, 24), 2.14 (m, 14), 1.62 (m, 34), 0.97 (m, 24), 0.83 (m, 24). Η [M+N] ⁺ 339 ^nnz Method B Ή NMR (400 MHz, DMSO-de) δ 13.02 (s, 14), 10.81 (s, 14), 8.33 (s, 14), 8.07 P Η ΧγγΝ D _ζ ^ν 'Ν ,___ HN—< J CH 2.98 min, m/z 454.4 [M+H] ⁺ (s, 14), 8.00 (d, J= 8.60 Hz, 24), 7.91 (d, J= 8.60 Hz, 24), 7.60 (d, J= 2.20 Hz, 14), 7.42 (q, J= 9.39 Hz , 24), 6.59 (d, J= 2.20 Hz, 14), 3.80 (s, 34), 3.78 (s, 34), 2.14 (m, 14), 0.97 (m, 24), 0.82 (m, 24) .

Example 338 4-[5-[(4-cyclopropyl-III-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-N-(2,2difluoropropyl)benzamide

4-[5-[(4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5yl)amino]-1-methyl-1,2,4-triazol-3-yl]- N-(2,2-difluoropropyl)benzamide (37 mg, 0.07 mmol) and MeOH (2 ml). Hydrogen chloride 4N was added to the solution. in dioxane (0.87 ml, 3.5 mmol) dropwise, and the reaction mixture was stirred at room temperature for 18 h. The solvent was removed under vacuum, and then purified using an SCX SPE cartridge. The resulting product was evaporated under vacuum, in DCM and MeOH, washed with brine and evaporated under vacuum. The residue was dissolved in water and acetonitrile (9:1) and freeze-dried overnight to give 4-[5-[(4-cyclopropyl1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazole -3-yl]-N-(2,2-difluoropropyl)benzamide (23.9 mg, 0.05

- 196 042028 mmol, 76% yield) as a white powder. UPLC-MS (ES ⁺ , Method B): 3.19 min, m/z 452.4 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.84 (t, J=6.32 Hz, 1H), 8.33 (s, 1H), 8.07 (s, 1H), 7.91 (m, 4Н), 7.41 (q, J=7.58 Hz, 2Н), 3.80 (s, 3Н), 3.72 (m, 2H), 2.14 (m, 1H), 1.62 (t, J=19.01 Hz, 3Н), 0.97 ( m, 2H), 0.83 (m, 2H).

Step 1: 4-[5-[(4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4triazol-3-yl]-N-(2 ,2-difluoropropyl)benzamide

4-[5-[(4-Cyclopropyl-1-tetrahydropyran-2-yl-indazol-5yl)amino]-1-methyl-1,2,4-triazol-3-yl]benzoic acid (300 mg, 0.65 mmol), DCM (6 ml) and DMF (0.03 ml). Oxalyl chloride (0.08 ml, 0.98 mmol) was added slowly and the reaction mixture was stirred at room temperature for 40 min. The solvents were removed under vacuum and the residue was dissolved in DCM. The solution was then added to a test tube in a carousel with 2,2-difluoro-1-propanamine hydrochloride (30 mg, 0.23 mmol), DCM (2 ml) and triethylamine (0.15 ml, 1.09 mmol) and the reaction mixture was stirred at room temperature for 1 h. The solvents were removed in vacuo and the residue was dissolved in DCM and evaporated on silica gel. The compound was then purified by silica gel column chromatography eluting with 10-100% EtOAc in petroleum ether to give 4-[5-[(4cyclopropyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1- methyl-1,2,4-triazol-3-yl]-N-(2,2difluoropropyl)benzamide (37 mg, 0.07 mmol, 31% yield) as an off-white solid. UPLC-MS (ES ⁺ , Method A): 1.69 min, m/z 536.5 [M+H] ⁺ .

Example 340: 4-[5-[(4-cyclopropyl-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-N-ethylpiperidine-1-carboxamide

Palladium, 10 wt.% on a powdered carbon carrier, dry (2.4 mg, 0.02 mmol) was added to 4-[5-[(4-cyclopropyl-1H-indazol-5-yl)amino]-1-methyl-1,2 ,4-triazol-3-yl]-N-ethyl-3,6-dihydro-2Hpyridine-1-carboxamide (90 mg, 0.22 mmol) in EtOH (5 mL) and stirred for 18 h at room temperature under a hydrogen atmosphere . Additional palladium, 10 wt% on powdered carbon carrier, dry (2.4 mg, 0.02 mmol), was added with 6 drops of 1 M HCl in MeOH, and the reaction mixture was stirred for 48 h at room temperature under a hydrogen atmosphere. Additional palladium, 10 wt.% on powdered carbon carrier, dry (2.4 mg, 0.02 mmol) was added with 6 drops of 4N. HCl in 1,4-dioxane and the reaction mixture was stirred for 18 hours at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite™ and washed with MeOH. Solvents were evaporated in vacuo and purified by silica gel column chromatography eluting with a gradient of 10% MeOH in EtOAc to give 4-[5-[(4-cyclopropyl-III-indazol5-yl)amino]-1-methyl-1,2 ,4-triazol-3-yl]-N-ethylpiperidine-1-carboxamide (53 mg, 0.12 mmol, 53% yield) as an off-white solid. UPLC-MS (ES+, Method B): 2.32 min, m/z 409.3 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 8.01 (s, 1H), 7.35 (m, 2H), 6.39 (m , 1H), 3.88 (m, 2H), 3.63 (s, 3Н), 2.13 (s, 1H), 3.02 (m, 2H), 2.73 (m, 2H), 2.05 (m, 1H), 1.76 (m, 2H), 1.44 (m, 2H), 0.99 (m, 5H), 0.77 (m, 2H).

Example 341 2H-pyridine-1-carboxamide

A m solution of hydrogen chloride in 1,4-dioxane (1.25 ml, 4.99 mmol) was added to a solution of 4-[5-[(4cyclopropyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1 ,2,4-triazol-3-yl]-N-ethyl-3,6dihydro-2H-pyridine-1-carboxamide (245.0 mg, 0.5000 mmol) in MeOH (5 ml).

The reaction mixture was stirred for 18 hours at room temperature, concentrated under reduced pressure. Further purification by silica gel flash column chromatography eluting with 10% MeOH in EtOAc gave 4-[5-[(4-cyclopropyl-1H-indazol-5-yl)amino]-1methyl-1,2,4-triazol- 3-yl]-N-ethyl-3,6-dihydro-2H-pyridine-1-carboxamide (129 mg, 0.31 mmol, 61% yield) as an off-white solid. UPLC-MS (ES ⁺ , Method B): 2.59 min, m/z 407.3 [M+H] ⁺ .

- 197 042028 ¹ H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.14 (s, 1), 8.05 (s, 1H), 7.35 (s, 1H), 7.73 (t, J=5.3 Hz, 1H), 6.31 (m, 1H), 3.87 (d, J=3.1 Hz, 2H), 3.69 (s, 3H), 3.43 (t, J=5.6 Hz, 2H), 3.05 (m, 2H), 2.38 (m, 2H), 2.09 (m, 1H), 1.01 (t, J=7.1 Hz, 3Н), 0.95 (m, 2H), 0.78 (m, 2H).

Stage 1: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine

Trifluoroacetic acid (1.2 ml, 16.2 mmol) was added to N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.5 g, 1.6 mmol) in DCM (30 ml) at room temperature, and the reaction the mixture was stirred for 1 h.

The solvent was removed under vacuum. Additional DCM was added and the reaction was again evaporated in vacuo to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6tetrahydropyridine 2,2,2 -trifluoroacetic acid, salt (637 mg, 1.46 mmol, 90% yield). UPLC-MS (ES+, Method A): 1.03 min, m/z 210.2 [M+H] ⁺ .

Stage 2: N-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1carboxamide

About yyOV

A solution of ethyl isocyanate (0.11 ml, 1.43 mmol) in DCM (10 ml) was added dropwise over 15 min to a vigorously stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1,2,3,6tetrahydropyridine-di-trifluoroacetic acid, salt (627 mg, 1.43 mmol) and N,Ndiisopropylethylamine (1.25 ml, 7.2 mmol) in water (15 ml) at 0°C. The reaction mixture was stirred at room temperature for 20 h. Sodium chloride (7.0 g) was added to the reaction mixture, and the organic phase was separated. The aqueous phase was further extracted with DCM (3x75 ml). The crude material was then purified by silica gel column chromatography eluting with 0-6% MeOH in EtOAc to give N-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-3,6-dihydro-2H-pyridine-1-carboxamide (251 mg, 0.78 mmol, 54% yield). UPLC-MS (ES ⁺ , Method A): 1.48 min, m/z 281 [M+H] ⁺ .

Step_3: 4-[5-[(4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4triazol-3-yl]-N-ethyl-3 ,6-dihydro-2H-pyridine-1-carboxamide

A mixture of N-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1carboxamide (219 mg, 0.7800 mmol), X-(5-bromo-2-methyl-1,2,4-triazol-3-yl)-4-cyclopropyl-1tetrahydropyran-2-yl-indazol-5-amine (Step 1 in Example 251) (217 mg, 0.52 mol) and potassium carbonate (144 mg, 1.04 mmol) in 1,4-dioxane and water (3:1, 8 mL) were degassed by nitrogen bubbling for 15 min. 1,1'-Bis(diphenylphosphino)ferrocene-palladium complex (11) dichloromethane dichloride (42 mg, 0.05 mmol) was added and the mixture was again degassed by nitrogen bubbling for 15 min. The mixture was then heated under microwave conditions at 130° C. for 90 minutes. The mixture was filtered through a pad of Celite®. The filter cake was washed with EtOAc. Water was added to the filtrate and the layers were separated. The aqueous layer was extracted with EtOAc (x2). The combined organic extracts were washed with water, brine, dried over MgSO ₄ , filtered and then concentrated under reduced pressure. Further purification by flash column chromatography gave 4-[5-[(4-cyclopropyl-1tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl ]-N-ethyl-3,6-dihydro-2Hpyridine-1-carboxamide (256 mg, 0.50 mmol, 96% yield). UPLC-MS (ES ⁺ , Method A): 1.45 min, m/z 491 [M+H] ⁺ (96%).

Example 342: 1-[4-[5-[(4-Cyclopropyl-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-1piperidyl]propan- 1-on

nsoon

Following the experimental method described for example 340, example 342 was synthesized in a similar manner. UPLC-MS (ES ⁺ , Method B): 2.42 min, m/z 394.3 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 8.20 (s, lH), 8.03 (s, 2H), 7.34 (m, 2H), 4.29 (d, J=13.4 Hz,

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1H), 3.80 (d, J=13.4 Hz, 1H), 3.63 (s, 3H), 3.06 (m, 1H), 2.29 (q, J=7.4 Hz, 2H), 2.05 (m, 2H), 1.82 ( m, 2Н), 1.51 (m, 2H), 1.39 (m, 2H), 0.97 (t, J=7.4 Hz, 3Н), 0.93 (m, 2H), 0.77 (m, 2H).

Intermediate 88: 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2Hpyridin-1-yl]propan-1-one

Propylphosphonic anhydride (0.21 ml, 0.72 mmol) was added to 4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine; 2,2,2-trifluoroacetic acid (209 mg, 0.48 mmol), N,N-diisopropylethylamine (0.42 ml, 2.4 mmol) and propionic acid (propanoic acid) (0.04 ml, 0.48 mmol) in THF (1.6 ml), and the reaction mixture was stirred at room temperature for 3 hours. The reaction was evaporated under vacuum, the residue was taken up in EtOAc (20 ml) and the organics were washed with 20 ml of water and 10 ml of saturated brine. The organics were then separated, dried (MgSO ₄ ) and evaporated in vacuo. The crude material was then purified by silica gel column chromatography eluting with 20-100% EtOAc in petroleum ether to give 1-[4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydro-2H-pyridin-1-yl]propan-1-one (152 mg, 0.41 mmol, 86% yield). UPLC-MS (ES+, Method A): 1.57 min, m/z 266 [M+H] ⁺ .

Example 343: 4-[5-[(4-cyclopropyl-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-N-(2,2,2trifluoroethyl )benzamide

Hydrogen chloride (4.0 M in dioxane) (2.6 ml, 10.4 mmol) was slowly added to a stirred solution of 4-[5-[(4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl -1,2,4-triazol-3-yl]-N(2,2,2-trifluoroethyl)benzamide (104 mg, 0.19 mmol) in MeOH (2 ml) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The pale yellow solution was concentrated under reduced pressure and the crude residue was purified using an SCX SPE cartridge. The resulting product was purified by silica gel column chromatography eluting with 30-100% EtOAc in petroleum ether. The product was then dried by lyophilization overnight from acetonitrile/water to give 4-[5-[(4-cyclopropyl-1H-indazol-5-yl)amino]-1-methyl-1,2,4triazol-3-yl]- N-(2,2,2-trifluoroethyl)benzamide (57 mg, 0.124 mmol, 66% yield) as a white solid. UPLC-MS (ES ⁺ , Method B): 3.31 min, m/z 456.4 [M+H] ⁺ .

1H NMR (DMSO-d ₆ ) δ 13.02 (s, 1H), 9.10 (t, J=6.3 Hz, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 8.00 - 7.86 (m, 4H) , 7.46 - 7.35 (m, 2H), 4.09 (m, 2H), 3.80 (s, 3H), 2.14 (m, 1H), 1.04 - 0.91 (m, 2H), 0.91 - 0.76 (m, 2H).

Step 1: 4-[5-[(4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4triazol-3-yl]-N-(2 ,2,2-trifluoroethyl)benzamide

Potassium carbonate (56 mg, 0.4 mmol), X-bromo-2-methyl-1,2,4-triazol-3-yl)-4-cyclopropyl-1tetrahydropyran-2-yl-indazol-5-amine (80 mg, 0.19 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-P-(2,2,2-trifluoroethyl)benzamide (69 mg, 0.21 mmol) were dissolved/suspended in 1,4-dioxane (3 ml) and water (2 ml). The reaction mixture was completely degassed by bubbling nitrogen. Then complex [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (16 mg, 0.02 mmol) was added, followed by additional degassing, and then the reaction was heated to 90°C for 18 h. The reaction was evaporated on silica gel and purified by silica gel column chromatography eluting with 20-100% EtOAc in petroleum ether to give 4-[5-[(4-cyclopropyl-1-tetrahydropyran-2-ylindazol-5-yl)amino]-1-methyl -1,2,4-triazol-3-yl]-X-(2,2,2-trifluoroethyl)benzamide (104 mg, 0.19 mmol, 99% yield) as a pale yellow gum. UPLC-MS (ES ⁺ , Method A): 1.76 min, m/z 540.5 [M+H] ⁺ .

Step 2: 4-bromo-X-(2,2,2-trifluoroethyl)benzamide

Propylphosphonic anhydride (8.35 ml, 14 mmol), and the solution was stirred for 3 h at room temperature. The pale yellow solution was evaporated in vacuo and dissolved in EtOAc. organic matter

- 199 042028 washed with water (x2), saturated brine, dried over MgSO ₄ , filtered and evaporated under vacuum to obtain 4-bromo-N-(2,2,2-trifluoroethyl)benzamide (2.62 g, 9.3 mmol, 99% yield ) as a creamy solid. UPLC-MS (ES+, Method A): 1.65 min, m/z 283.9 [M+H] ⁺ .

Step 3: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2-trifluoroethyl)benzamide

4-Bromo-N-(2,2,2-trifluoroethyl)benzamide (2610 mg, 9.25 mmol) was added to a stirred mixture of bis(pinacolato)diborone (2.82 g, 11.1 mmol), potassium acetate (2.72 g, 27.8 mmol) in 1,4-dioxane (40 ml) at room temperature. The reaction was degassed, purged with nitrogen, and the complex [1,1'bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (755 mg, 0.93 mmol) was added, followed by additional degassing. The reaction was closed and stirred at 85° C. for 3 hours. The reaction was cooled to room temperature and the solvent was removed under vacuum. EtOAc (50 ml) was added, the resulting suspension was loaded onto silica gel and the residue was purified by column chromatography eluting with 10-50% EtOAc in petroleum ether to give 4-(4,4,5,5-tetramethyl-1, 3,2dioxaborolan-2-yl)-N-(2,2,2-trifluoroethyl)benzamide (2.68 g, 8.14 mmol, 88% yield) as a pale yellow/cream solid. UPLC-MS (ES ⁺ , Method A), 1.82 min, m/z 330 [M+H] ⁺ .

Example 344 N-cyclopropyl-4-[5-[(4-cyclopropyl-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol3-yl]benzamide

Hydrogen chloride (4.0 M in dioxane) (2.1 mL, 8.5 mmol) was added slowly to a stirred solution of N-cyclopropyl-4-[5-[(4-cyclopropyl-1-tetrahydropyran-2-yl-undazol-5-yl)amino] -1-methyl-1,2,4triazol-3-yl]benzamide (78 mg, 0.16 mmol) in MeOH (2 ml) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The pale yellow solution was concentrated under reduced pressure and the crude residue was purified using an SCX SPE cartridge. The resulting solution was evaporated in vacuo on silica gel and the product was purified by silica gel column chromatography eluting with 30-100% EtOAc in petroleum ether. The product was dried by lyophilization from acetonitrile/water overnight to give N-cyclopropyl-4-[5-[(4cyclopropyl-1H-indazol-5-yl)amino]-1-methyl-1,2,4-truazol-3- yl]benzamide (40 mg, 0.096 mmol, 61% yield) as a white solid. UPLC-MS (ES ⁺ , Method A): 2.95 min, m/z 414.3 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.45 (d, J=4.2 Hz, 1H), 8.32 (s, 1H), 8.07 (s, 1H), 7.91 7.79 (m, 4H), 7.46 - 7.35 (m, 2H), 3.79 (s, 3H), 2.85 (m, 1H), 2.13 (m, 1H), 0.96 (m, 2H), 0.83 (m, 2H), 0.68 (m , 2H), 0.57 (m, 2H).

Step 1: N-cyclopropyl-4-[5-[(4-cyclopropyl-1-tetrahydropyran-2-yl-indazol-5-ul)amino]-1methyl-1,2,4-triazol-3-yl]benzamide

Potassium carbonate (83 mg, 0.6 mmol), N-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) benzamide (56 mg, 0.19 mmol) and N-bromo- 2-methyl-1,2,4-triazol-3-yl)-4-piclopropyl-1tetrahydropyran-2-yl-indazol-5-amine (82 mg, 0.19 mmol) was dissolved/suspended in 1,4-dioxane (3 ml) and water (1 ml). The reaction mixture was completely degassed by bubbling nitrogen. Then the complex [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (23 mg, 0.03 mmol) was added, followed by additional degassing, and then the reaction was heated to 90°C for 18 h. The reaction was evaporated on silica gel and purified by flash column chromatography eluting with 30-100% EtOAc in petroleum ether to give N-cyclopropyl-4-[5-[(4-cyclopropyl-1-tetrahydropyran-2yl-indazol-5-yl)amino] -1-methyl-1,2,4-triazol-3-yl]benzamide (78 mg, 0.16 mmol, 80% yield) as a pale yellow dry film. LC-MS (ES ⁺ , Method A): 1.60 min, m/z 498.6 [M+H] ⁺ .

Compounds obtained in a manner analogous to that described above are shown in Table 1 below. 25.

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Table 25

Example Structure LC-MS Ή NMR 345 rf Ϊ y g-Ch lau'I'Kh ¹ LA/ n ^z III Ch-y o / ^N 'N ^and n Method F, 2.76 min, m/z 464.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.4 (s, 1H), 8.65 (s, 1H), 8.5 (t, J=5.6 Hz, 1H), 8.1-8.08 (m, 3H), 7.6-7.5 ( m, 3H), 3.82 (s, 3H), 3.27-3.2 (m, 2H), 1.09 (t, >7.2 Hz, ZN) 346 ? N/hnA VU n Method F, 2.44 min, m/z 410.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.38 (s, 1H), 8.51 (s, 1H), 8.24 (t, J = 6.4 Hz, 1H), 8.09 (s, 1H), 7.68-7.66 (m, 2H), 7.60-7.54 (q, J = 8.8 Hz, 2H), 7.31-7.29 (d, J = 7.6 Hz, 1H ), 3.79 (s, 3H), 3.26-3.20 (m, 2H), 2.33 (s , 3H), 1.10(1, J = 7.2 Hz, ZN) 347 1 st А hY λ^Α^Ν N /=4/ nJ J n АА_/ъ nA> / ⁿ -n ^u H Method F, 2.21 min, m/z 426.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.36 (s, 1H), 8.51 (t, J = 5.6, 1H), 8.43 (s, 1H), 8.08 (s, 1H), 7.68-7.66 (d, J = 8 Hz, 1H), 7.60-7.50 (m, 3H), 7.437.41 (d,./ 8 Hz. 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.31-3.26 (m, 2H), 1.13 (t, J =7.2 Hz, ZN) 348 a DD 1 η J r~\ / z^A^ ^N v^\ Av-o ⁷ hnA O JY τΛΖ n^A z ^N 'NH Method F, 3.24 min, m/z 508.1 [M+H] ⁺ C NMR (400 MHz, DMSO-de) δ 13.38 (s, 1H), 8.55 (s, 1H), 8.09 (s, 1H), 8.03-8.00 (m, 2H), 7.64-7.62 (d, 1=8.0 Hz, 1H), 7.58 - 7.52(m, 2H), 7.187.15 (d, >8.8 Hz, 1H), 4.64(s, 2H), 3.91-3.86(m, 1H), 3.78(s, 3H), 1.091.07 (d, >6.8Hz, 6H) 349 N Cl Ch ¹ /? | H __/ r-\ / ,>Αζ ^Ν \Λ l\-Q HnA u Y Y HA NV /N'N H Method F, 2.80 min, m/z 465.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.38 (s, 1H), 8.55 (s, 1H), 8.09–8.01 (m, 3H), 7.93 (d, >7.6 Hz, 1H), 7.6 (d, > 8.8 Hz, 1H), 7.54 (d, >8.8 Hz, 1H), 7.1 (d, >8.8 Hz, 1H), 4.68 (s, 2H), 3.93-3.85 (m, 1H), 3.78 (s, 3H) , 1.07 (d, >6.4 Hz, 6H) 350 0 i ¹ η Λ Λ 1 /yVyMh ^{0 hn} \ n JJ 1 nA / ^N N H Method F, 2.83 min, m/z 454.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.36 (s, 1H), 8.42 (s, 1H), 8.08 (s, 1H), 7.74 (d, >7.6 Hz, 1H), 7.63-7.57 (m, 3H ), 7.55-7.51 (m, 1H), 6.81 (d, >8.4 Hz, 1H), 4.46 (s, 2H), 3.97-3.88 (m, 1H), 3.76 (s, 3H), 2.22 (s, 3H ), 1.08 (d, >6.4 Hz, 6H) 351 1 ^H Д / <Ayh>° ^hn ^ νΆΑ n- _n V- ^{7 H} ill N Method F, 2.74 min, m/z 465.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.35 (s, 1H), 8.58 (s, 1H), 8.09 (s, 1H), 7.95 (d, >7.6 Hz, 1H), 7.87 (d, >8.8 Hz , 1H), 7.74 (d, >8.8 Hz, 1H), 7.5 (d, >8.8 Hz, 1H), 7.42 (d, >2.4 Hz, 1H), 7.31 (d, >2.4 Hz, 1H), 4.56 ( s, 2H), 3.98-3.9 (m, 1H), 3.82 (s, 3H), 1.08 (d, >6.4 Hz, 6H) 352 1 ^H ,=4 AND J ^HN ^ nA> / ⁿ ~n A H Cl Method F, 2.77 min, m/z 474.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.35(s, 1H), 8.52(s, 1H), 8.08(s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 8.7, 2.4 Hz, 1H), 4.49(s, 2H), 4.01 - 3.86 (m, 1H), 3.79(s, 3H), 1.08 (d, J = 6.6 Hz, 6H). 353 1 ^H I / aVy ⁿ \4a ^HN \ h H 1 J, Ch/ ⁴ nXX / ⁿ ~n ) H —o Method F, 2.39 min, m/z 470.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.34 (s, 1H), 8.40 (s, 1H), 8.07 (s, 1H), 7.90-7.88 (d, J= 7.6 Hz, 1H), 7.60-7.50 ( m, 3H), 6.67 (s, 1H), 6.54-6.52 (d, J= 8.4 Hz, 1H), 4.46 (s, 2H), 3.99-3.90 (m, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 1.10-1.083 (d, J =6.8 Hz, 6H) 354 1 ^H r<J ^HN ^ νΆ z ⁿ 'NAH / Method F, 2.80 min, m/z 454.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.34(s, 1H), 8.41 (s, 1H), 8.07 (s, 1H), 7.86-7.84 (d, >8.0, 1H), 7.67-7.65(d, >8.4, 1H), 7.62-7.59(d, >8.8 Hz, 1H), 7.53-7.50(d, >8.8 Hz, 1H), 6.82(s„ 1H), 6.79-6.76(d, >8.4Hz, 1H ), 4.42(s, 2H), 3.94(s, 1H), 3.77(s, 3H), 2.50(s, 3H), 1.07(s, 6H) 355 1 ^H Д / #Α>/ ^Ν \Λ A\- o hnA Όυ T Н/ nHA / ⁿ ~n A HF Method F, 2.64 min, m/z 458.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.35 (s, 1H), 8.47 (s, 1H), 8.08 (s, 1H), 7.91 (d, >7.6Hz, 1H), 7.72(1, >8.8Hz , 1H), 7.59 (d, >8.8 Hz, 1H), 7.53 (d, >8.8 Hz, 1H), 6.87 (d, >14.0Hz, 1H), 6.82(d, >8.8Hz, 1H), 4.48( s, 2H), 3.94(s, 1H), 3.78(s, 3H), 1.08(d, >6.8Hz, 6H)

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356 Ϊ' th > Ν ^Ζ JI J Τ o / ^Ν Ν ^U Η Method F, 2.45 min, m/z 414.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 8.59-8.56 (m, 2H), 8.09 (s, 1H), 7.88 (t, J=8.0 Hz, 1H), 7.70-7.68 (m, 2H), 7.60-7.53 (m, 2H), 3.82 (s, 3H), 3.30-3.25 (m, 2H), 1.12 (t, J =12 Hz, ZN) 357 ? η ^F -V ΗΝ- ⁷ hj J Y />^ν/υ N^V / ^Ν ~Ν Η Method F, 2.77 min, m/z 464.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.36 (bs, 1H), 8.78 (t, 1H), 8.58 (s, 1H), 8.25 (s, 1H), 8.13 (d, 1H), 8.09 (s , 1H), 7.86 (d, 1H) 7.61 (d, 1H), 7.51 (d, 1H), 3.82 (s, 3H), 3.35-3.28 (m, 2H), 1.14 (t, 3H) 358 λ ^Ν X Ν Λ Ο J Ν V_#o ζ ^ν 'Ν ^υ Η Method F, 2.48 min, m/z 421.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.99 (s, 1H), 10.32 (s, 1H), 8.61 (d, J=5.2 Hz, 2H), 8.15 (d, J= 8.0 Hz, 1H), 8.10 (s, 1H), 7.78 (d, J=8 Hz, 1H), 7.58 (m, 2H), 3.85 (s, 3H), 3.75-3.70 (m, 2H), 1.16 (t, J=7.2 Hz , ZN). 359 ?' Η \ ΗΝ—\ l\_/ ^{4 N} fj[ J Ν O ζ ^Ν 'Ν ^υ Η F Method F, 2.65 min, m/z 432.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.92 (s, 1H), 8.93 (s, 1H), 8.52 (t, J=5.2 Hz, 1H), 8.19 (s, 1H), 8.04-8.02 (m , 2H), 7.91 (d, J=8 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 3.82 (s, 3H), 3.33-3.27 (m, 2H), 1.14 (t, J= 7.2 Hz, VN) 360 ϊ ¹ Η L nL d ji Τ X //Al / ^Ν ~Ν )—' Η F Method F, 2.85 min, m/z 432.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 8.84 (s, 1H), 8.39 (t, J=5.2 Hz, 1H), 8.09 (s, 1H), 7.61-7.53 (m , 3H), 7.53 (dd, J=10.4 Hz, 1H), 3.82 (s, 3H), 3.31-3.24 (m, 2H), 1.14 (t, J=7.2 Hz, ZN) 361 νυ lLchl Η F Method F, 2.81 min, m/z 432.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.39 (s, 1H), 8.70 (t, J = 5.6 Hz, 1H), 8.65 (s, 1H), 8.10 (s, 1H), 7.58 (q, J = 20.0 Hz, 2H), 7.46-7.44 (m, 2H), 3.81 (s, 3H), 3.29-3.22 (m, 2H), 1.10 (t, J = 7.2 Hz, ZN) 362 οι η \/ ^F L / <ΑυΑ>° υ νΎϊ^ /Ν-ν Η Method F, 2.97 min, m/z 476.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.36 (s, 1H), 8.54 (s, 1H), 8.08 (s, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.58-7.49 (m , 3H), 6.89 (t, J=7.6 Hz, 1H), 4.59 (s, 2H), 3.94-3.86 (m, 1H), 3.79 (s, 3H), 1.06 (d, J=6.4 Hz, 6H) 363 X 9 1 Method B, 3.21 min, m/z 549.3 [M+H] ⁺ 1Н-NMR (400 MHz, DMSO-de) δ 13.43 (s, 1H), 8.60 (s, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.14 (s, 1H), 7.75 (d, J = 8 Hz, 1H), 7.62-7.51 (m, 4H), 4.474.35 (m, 1H), 3.93 (s, 3H), 3.85 (s, 3H), 3.36-3.29 (m, 2H), 3.02- 2.88 (m, 2H), 2.75-2.64 (m, 2H), 2.25-2.12 (m, 1H), 1.83-1.70 (m, 1H). 364 ϊ ¹ id τ-Όη Ν J[ Τ J V-J7 Ό Ν-^Υ / ^Ν 'Ν Η Method B, 2.82 min, m/z 394.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 8.55 (s, 1H), 8.09 (s, 1H), 7.91 (br s, 1H), 7.84 (d, J= 8.16 Hz, 1H), 7.79 (d, J= 8.48 Hz, 1H), 7.73 (s, 1H), 7.57 (q, J= 8.07 Hz, 2H), 3.81 (s, 3H), 3.35 (m, 2H), 2.91 ( m, 2H). 365 ϊ ^{1 Η} A ο ν \DL An^A-ZXiN-Qh Η Method B, 2.66 min, m/z 503.2 [M+H] ⁺ 1H NMR (400 MHz, DMSO-d ₆ ) δ 13.43 (s, 1H), 8.61 (s, 1H), 8.31 (d, J = 8.5 Hz, 1H), 8.14 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.66 - 7.51 (m, 4H), 4.68 - 4.50 (m, 1H), 3.95 (s, 3H), 3.85 (s, 3H), 3.37 - 3.23 (m, 2H), 3.06 ( q, J = 14.3 Hz, 1H), 2.85 - 2.73 (m, 1H), 1 NH was not observed 366 YLm YtVf ΎΛ f Η Method B, 3.34 min, m/z 464.3 [M+H] ⁺ Ή NMR (400MHz, DMSO-d ₆ ) δ 13.39 (s, 1H), 8.97 (t, J = 6.4Hz, 1H), 8.54 (s, 1H), 8.10 (s, 1H), 7.75-7.70 (m, 2H), 7.62-7.54 (m, 2H), 7.36 (d, J = 8.4Hz, 1H), 4.05 (m, 2H), 3.81 (s, 3H), 2.24 (s, 3H). 367 1 And>- ^ν υΙ J Τ yV-# / ^N 'N H Method F, 1.88 min, m/z 394.0 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.53 (s, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.59-7.53 (m, 4H), 7.04 (d, J = 7.6 Hz , 1H), 3.77 (s, 3H), 3.46 (s, 2H), 2.81 (t, J = 5.6 Hz, 2H), 2.58 (t, J = 5.6 Hz, 2H), 2.32 (s, 3H)

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368 Ϊ ^{1 n} y I j ^HN ^ _N y /Nn Y HF Method F, 3.09 min, m/z 476.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.39 (s, 1H), 8.59 (s, 1H), 8.09 (s, 1H), 7.88-7.86 (d, J = 7.6 Hz, 1H), 7.57 (q, J = 19.6 Hz, 2H), 7.47-7.41 (m, 2H), 4.54 (s, 2H), 3.97-3.87 (m, 1H), 3.79 (s, 3H), 1.07 (d, J = 6.4 Hz, 6H ) 369 Cl ^F /P | ¹ H / U / DgUuDi ^hn \ NJJ Ji nA^ z ^N 'NA HF Method F, 2.85 min, m/z 476 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.38 (s, 1H), 8.55 (s, 1H), 8.08 (s, 1H), 7.95(d, J = 7.6, 1H), 7.60-7.51 (m, 3H ), 7.06-7.01 (m, 1H), 4.59 (s, 2H), 3.94-3.86 (m, 1H), 3.78 (s, 3H), 1.07 (d, J=6.4 Hz, 6H) 370 ^f NA nJ ^JI Method F, 2.70 min, m/z 397.0 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.4 (s, 1H), 9.03(d, J=1.2 Hz, 1H ), 8.82 (t, J=6.0 Hz, 1H), 8.68 (s, 1H), 8.3 (dd, J=8.0 Hz, 1H), 8.1 (s, 1H), 8.O6 (d, J=8.0 Hz, 1H), 7.58 (q, L=7.2 Hz, 12=14.0 Hz , 2H), 3.83 (s, ZN), 3.31-3.28 (m, 2H), 1.1 (1.1=7.2 Hz, ZN) 371 ΛύΛΑ νΆΑ /N- _n '—' H Method F, 3.25 min, m/z 464.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.38 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.65-7.53 (m, 4H), 7.21 (d, 1=8 Hz, 1H), 4.67 (s, 2H), 3.78-3.75 (m, 5H), 1.22 (s, 9H), 2.82 (m, 2H) 372 Ϊ H rC ^N x ^F N D YY ) VjZ^ F uY /N—n H Method F, 3.50 min, m/z 462.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.37 (s, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.60-7.53 (m, 4H), 7.06 (d, 1=8 Hz, 1H), 3.80(s, 2H), 3.77 (s, 3H), 3.38–3.35 (m, 2H), 2.90 (t, J = 6.0 Hz, 2H), 2.82 (t, J = 5.6 Hz, 2H). Cl VX / 1 Id \A hn-- ⁷ n /Lsh N D Τ Τ ) Ό νΑ^ Αν '—' Η Method F, 2.94 min, m/z 447.0 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.40 (s, 1H), 10.78 (t, J = 5.6Hz, 1H), 9.74 (m, 1H), 9.05 (m, 1H), 8.73 (s, 1H) , 8.53 (d, J= 7.6 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.12 (s, 1H), 7.71 (m, 1H), 7.60 (m, 2H), 3.91 (s, 3H), 3.46 (m, 2H), 1.22 (ζ7 =7.2 Hz, ZN) 374 ? Η nD-O, -oUtoh ^{0 Cl} nA/ ν- _ν '—' Η Method A, 1.66 min, m/z 528.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.38 (s, 1H), 8.50 (s, 1H), 8.39-8.29 (bs, 1H), 8.09 (s, 1H), 7.79-7.72 (m, 3H), 7.72 - 7.62 (m, 1H), 7.63-7.52 (m, 3H), 7.26-7.22 (m, 2H), 7.18-7.01 (bs, 1H), 4.04 (s, 2H), 3.78 (s, 3H) 375 V ο— Η ,__/ 0— /νν ^Ν ν ^Ν \ Yb- ^A _ν Method B, 3.35 min, m/z 419.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.02 (s, 1H), 8.35 (s, 1H), 8.07 (t, J = 1.1 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 1.4 Hz, 1H), 7.47 (dd, J = 8.1, 1.4 Hz, 1H), 7.42 - 7.36 (m, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.78 ( s, 3H), 2.20 - 2.08 (m, 1H), 1.02 - 0.91 (m, 2H), 0.90 - 0.79 (m, 2H). 376 V θ ΛΊ X Η / ΗΝΧ |LP ^F Shch/U /UA ^vn a _f VU Η Method B, 3.26 min, m/z 555.3 [M+H] ⁺ δ-NMR (400 MHz, DMSO-de) δ 13.05 (s, 1H), 8.36 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.10 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.56-7.50 (m, 2H), 7.437.22 (m, 2H), 4.47-4.35 (m, 1H), 3.93 (s, 3H), 3.82 (s, 3H), 3.36- 3.27 (m, 2H), 3.02-2.88 (m, 2H), 2.75-2.65 (m, 2H), 2.25-2.12 (m, 2H), 1.82-1.71 (m, 1H), 1.06-0.96 (m, 2H ), 0.90–0.83 (m, 2H). 377 I Id g-L ⁴ NH Shower nA/ /N- _n ^- ^{7 u} H Method B, 2.87 min, m/z 400.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.00 (s, 1H), 8.31 (s, 1H), 8.06 (s, 1H), 7.90 (br s, 1H), 7.83 (d, J= 8.08 Hz, 1H ), 7.78 (dd, J= 8.08 Hz, 1.46 Hz, 1H), 7.72 (s, 1H), 7.39 (q, J= 7.21 Hz, 2H), 3.79 (s, 3H), 3.35 (m, 2H), 2.91 (t, J= 6.72 Hz, 2H), 2.12 (m, 1H), 0.95 (m, 2H), 0.81 (m, 2H). 343 YXoA H Method B, 3.31 min, m/z 456.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.02 (s, 1H), 9.10 (t, J = 6.3 Hz, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 8.00 - 7.86 (m, 4H), 7.46 - 7.35 (m, 2H), 4.09 (m, 2H), 3.80 (s, 3H), 2.14 (m, 1H), 1.04-0.91 (m, 2H), 0.91-0.76 (m, 2H) 378 ϊ Η ,-N HN—\F H Method B, 3.50 min, m/z 457.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.03 (s, 1H), 9.34 (t, J = 6.7 Hz, 1H), 9.07 (dd, J = 0.9, 2.1 Hz, 1H), 8.46 (s, 1H) , 8.33 (dd, J = 2.1, 8.0 Hz, 1H), 8.12-8.04 (m, 2H), 7.42-7.37 (m, 2H), 4.15-4.02 (m, 2H), 3.82 (s, 3H), 2.21 -2.10 (m, 1H), 1.03-0.93 (m, 2H), 0.89-0.80 (m, 2H).

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379 ALiCn /adX PT JY P/L N^XX / ^N 'N Η 0— Method B, 2.86 min, m/z 445.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.52 (d, J = 1.4 Hz, 1H), 8.40 (s, 1H), 8.34 (d, J = 4.7 Hz, 1H), 8.05 (s, 1H), 7.74 (d, J = 1.4 Hz, 1H), 7.38 (s, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 2.81 (m, 1H), 2.13 (m , 1H), 0.96 (m, 2H), 0.84 (m, 2H), 0.66 (m, 2H), 0.55 - 0.49 (m, 2H). 380 XX_ _N αχ Xu n Method B, 3.15 min, m/z 432.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 8.39 - 8.32 (m, 2H), 8.06 (s, 1H), 7.68 (dd, J = 8.1, 1.5 Hz, 1H), 7.59 - 7.50 (m, 2H), 7.44 - 7.35 (m, 2H), 3.79 (s, 3H), 2.82 (m, 1H), 2.13 (m, 1H), 1.00 - 0.92 (m, 2H), 0.85 0.79 ( m, 2H), 0.68 (td, J = 7.1, 4.7 Hz, 2H), 0.56 - 0.50 (m, 2H). 381 ί n ΞΖ C ΖΙ Ζ Method B, 3.09 min, m/z 387.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.40 (s, 1H), 8.05 (d, J = 14.7 Hz, 3H), 7.83 (d, J = 8.0 Hz, 1H), 7.46 - 7.33 (m, 2H), 5.39 (s, 2H), 3.82 (s, 3H), 2.13 (m, 1H), 0.99-0.91 (m, 2H), 0.81 (m, 2H). 344 Ϊ n HN^J X\/ ΤΥ YY xAJo νΆΧ ζ ^Ν 'Ν ^υ Η Method B, 2.95 min, m/z 414.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.45 (d, J = 4.2 Hz, 1H), 8.32 (s, 1H), 8.07 (s, 1H), 7.91 - 7.79 (m , 4H), 7.46 - 7.35 (m, 2H), 3.79 (s, 3H), 2.85 (m, 1H), 2.13 (m, 1H), 0.96 (m, 2H), 0.83 (m, 2H), 0.68 ( m, 2H), 0.57 (m, 2H). 382 ϊ Η __, ⁿ Olj Υ ^χ< ^Ν Ν^ΧΧ ζ ^Ν 'Ν Η Method B, 2.08 min, m/z 350.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.97 (s, 1H), 8.17 - 8.00 (m, 2H), 7.42 7.27 (m, 2H), 6.29 (s, 1H), 3.68 (s, 3H), 3.28 (t, 2H) 2.94 (s, 2H), 2.41 (s, 2H), 2.25 (s, 3H), 2.09 (m, 1H), 1.01 - 0.92 (m, 2H), 0.83 - 0.73 (m, 2H ). 383 V ο— Η __/ ΗΝ—<4 <T Υ Υ />Λ/Λ Ν^ΧΧ / ^Ν Ν ^U Η Method B, 3.15 min, m/z 444.4 [M+H] ⁺ Ή NMR (DMSO-d ₆ ) δ 13.02 (s, 1H), 8.32 (s, 1H), 8.11-8.04 (m, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.46 - 7.33 (m, 2H), 3.87 (s, 3H), 3.79 (s, 3H), 2.82 (m, 1H), 2.14 (m, 1H), 1.02 - 0.92 (m, 2H), 0.83 (m, 2H), 0.69 (m, 2H), 0.59 - 0.50 (m, 2H) 384 VF ₄ F Η ,__ _{_} YF ΑΧ—< XU Η Method B, 2.67 min, m/z 428.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 7.83 (d, J= 8.40 Hz, 2H), 7.49 (d, J = 8.20 Hz, 2H), 7.40 (q, J= 8.91 Hz, 2H), 4.48 (m, 1H), 3.77 (s, 3H), 2.13 (m, 1H), 0.96 (m, 2H), 0.82 (m , 2H). 2 H not observed 385 V II ϊ Η __ HN-S— Ν Ν U\D A THU Ύ Υ Ν^ΧΧ / ^Ν 'Ν Η Method B, 2.85 min, m/z 438.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (br. d„ J = 0.6 Hz, 1H), 7.84-7.79 (m, 2H), 7.60 (t, J= 6.1 Hz, 1H), 7.44-7.36 (m, 4H), 4.17 (d, J= 6.1 Hz, 2H), 3.82 (s, 3H), 2.85 (s, 3H), 2.15 (m, 1H), 1.00-0.94 (m, 2H), 0.90- 0.84 (m, 2H). 2 NH were not observed. 386 V E F ______. Y-F /^Λ^Ν Ν WOO XU Η Method B, 2.85 min, m/z 456.4 [M+H] ⁺ *H NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 8.28 (s, 1H), 8.06 (s, 1H), 7.84 (d, J= 8.32 Hz, 2H), 7.49 (d, J= 8.20 Hz, 2H), 7.39 (m, 2H), 4.38 (m, 1H), 3.78 (s, 3H), 2.72 (m, 1H), 2.46 (m, 1H), 2.12 (m, 1H), 0.99 (t, J= 7.24 Hz, ZN), 0.95 (m, 2H), 0.81 (m, 2H). 1 NH not observed 387 VF Η ,__1 ΗΝ—\ Ζ^Χϊ^Ν^Ν /=^/ ' ν/ JJ Ν ο_/Λ Ν<<Χ ζ ^Ν ' ^Ν Η Method B, 3.12 min, m/z 420.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.37 (s, 1H), 8.29 (m, 1H), 8.07 (s, 1H), 7.70 (dd, J= 8.06, 1.42 Hz , 1H), 7.62 (t, J= 7.72 Hz, 1H), 7.56 (dd, J= 11.58, 1.30 Hz, 1H), 7.40 (m, 2H), 3.80 (s, 3H), 3.27 (m, 2H) , 2.13 (m, 1H), 1.11 (t, J= 7.18 Hz, ZN), 0.97 (m, 2H), 0.83 (m, 2H). 388 VF. Η Y-F Ν /==4/ XU ΧΧ^<Ν-\ Η Method B, 2.50 min, m/z 438.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 7.82 (d, J= 7.42 Hz, 2H), 7.40 (m, 4H ), 6.06 (t, J= 55.75 Hz, 1H), 4.00 3.90 (m, 1H), 3.78 (s, 3H), 2.48 - 2.40 (m, 2H), 2.12 (m, 1H), 0.98 (m, 5H ), 0.81 (m, 2H) 1 NH was not observed 389 Υ η ,____ z^A/N^N /==\. ΤΥ J Υ U\-UU / ^Ν ' ^Ν <4 Method B, 2.32 min, m/z 386.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 7.58 (dd, J = 8.0 Hz, 1H), 7.48 (br. s , 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 3.88 (s, 2H), 3.75 (s , 3H), 2.97 (t,

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J = 5.9 Hz, 2Н), 2.70 (t, J = 5.9 Hz, 2Н), 2.11 (m, 1Н), 0.99–0.93 (t, 2Н), 0.84–0.77 (t, 2Н). 1 NH not observed 390 m /=4 / S Xi Η Method B, 2.90 min, m/z 408.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, br), 8.67 (t, 1H), 8.30 (s, 1H), 8.15 - 8.06 (t, 3H), 8.01 - 7.92 (t, 3H) , 7.88 (td, J = 7.7, 1.9 Hz, 1H), 7.48–7.32 (t, 3H), 3.80 (s, 3H), 2.15 (t, 1H), 1.06–0.91 (t, 2H), 0.83 (t , 2H). 391 1 η ,____ Si SHmuh- Method B, 3.10 min, m/z 442.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, br), 8.23 (s, 1H), 8.05 (s, 1H), 7.65 (m, 1H), 7.61 (s, 1H), 7.41 (d , J = 8.6 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.18 ( d, J= 8.0 Hz, 1H), 4.63 (s, 0.87H), 4.59 (s, 1.13H). 3.76 (s, 3H), 3.67-3.61 (m, 2H), 2.86 (t, J= 5.7 Hz, 1.16H), 2.75 (t, J = 5.7 Hz, 0.84H), 2.40 (q, J = 7.2 Hz , 2H), 2.12 (m, 1H), 1.03–0.97 (m, 3H), 0.97–0.92 (m, 2H), 0.83–0.78 (m, 2H). rotamers 392 1 η ____ Clj ΤchU ζ ^Ν ' ^Ν Η Method B, 2.24 min, m/z 332.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.04 (s, 1Η), 8.57 (dd, J = 6.04, 1.50 Hz, 2H), 8.44 (s, 1H), 8.07 (m, 1H), 7.73 (dd , J = 6.04, 1.50 Hz, 2H), 7.40 (dd, J = 11.0, 8.86 Hz, 2H), 3.82 (m, 3H), 2.13 (t, 1H), 0.95 (m, 2H), 0.82 (m, 2H). 341 1 Η _____ ο FSD Lgo- ^{7 ην} - \ Η Method B, 2.59 min, m/z 407.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.99 (s, br), 8.14 (s, 1H), 8.05 (s, 1H), 7.73 (t, J= 5.3 Hz, 1H), 7.35 (s, 2H ), 6.31 (t, 1H), 3.87 (d, J= 3.1 Hz, 2H), 3.69 (s, 3H), 3.43 (t, J = 5.6 Hz, 2H), 3.05 (m, 2H), 2.38 (m , 2H), 2.09 (m, 1H), 1.01 (t, J = 7.1 Hz, ZH), 0.95 (m, 2H), 0.78 (t, 2H). 393 1 η ,__ _{_} ο ζ^Α^ν^ν ΙΓ\Λ H D JL '- ζ ^Ν 'Ν Η Method B, 2.69 min, m/z 392.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.98 (s, br), 8.15 (s, 1H), 8.05 (s, 1H), 7.35 (s, 2H), 6.33 (m, 1H), 4.03 (m , 2H), 3.69 (s, 3H), 3.56 (dt, J = 19.6, 5.5 Hz, 2H), 2.33 (t, 5H), 0.97 (m, 5H), 0.77 (t, 2H). 394 Η J ΗΝ-Χ z-_/y/N Ν /=4/ H 1 A T H_/ o ζ ^Ν 'Ν -- Η Method F, 2.24 min, m/z 376.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.93 (s, 1H), 8.96 (s, 1H), 8.28 (t, J = 5.6 Hz, 1H), 8.18 (s, 1H), 8.03 (s, 1H ), 7.83-7.80 (m, 2H), 7.60 (d, J = 92 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 3.82 (s , 3H), 3.293.22 (m, 2H), 2.40 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H) 395 !d ^ch-x ^H V 7-/ν ^Ν Ύί ^Ν χ /V/ h D J T Ch-D o ζ ^Ν 'Ν ^and n Method F, 2.03 min, m/z 392.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 8.86 (s, 1H), 8.54 (t, J = 52 Hz, 1H), 8.14 (s, 1H), 7.99 (s, 1H ), 7.85 (d, J= 8.0 Hz, 1H), 7.56-7.48 (m, 4H), 3.86 (s, 3H), 3.80 (s, 3H) 3.32-3.28 (t, 2H), 1.15 (t, J = 7.2 Hz, ZN) 396 0 N .__/ r—\ / ^vV ^N Ur° ^HN \ h D JL rV# z ^N 'N Η Method F, 2.63 min, m/z 420.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.90 (s, 1H), 8.82 (s, 1H), 8.17 (s, 1H), 8.02 (s, 1H), 7.77-7.74 (m, 3H), 7.57 -7.49 (t, 2H), 6.88 (d, J = 8.4 Hz, 1H), 4.50 (s, 2H), 3.99-3.90 (m, 1H), 3.77 (s, 3H), 2.28 (s, 3H), 1.10 (d, J = 6.4 Hz, 6H) 397 °d c. Ό y ιζ u Method F, 3.04 min, m/z 474.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.92 (s, 1H), 8.91 (s, 1H), 8.18-8.16 (d, J=8.4 Hz, 1H), 8.13 (s, 2H), 7.67-7.65 (d, 1=7.2Hz, 2H), 7.57-7.50 (m, 2H), 7.24-7.22 (d, J=8.8.1H), 4.67 (s, 2H), 3.95-3.87 (m, 1H), 3.80 (s, 3H), 1.111.09 (d, 1=6.8Hz, 6H) 398 RF n r—( hnA ^Ν / D Τ Τ 4—-/ Ο ζ ^Ν 'Ν -- Η Method F, 2.56 min, m/z 430.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.94 (s, 1H), 8.98 (s, 1H), 8.54 (t, J=5.6 Hz, 1H), 8.26-8.23 (t, 2H), 8.14 (s , 1H), 8.03 (s, 1H), 7.59 (d, J=8 Hz, 2H), 7.52 (d, J=8.8 Hz, 1H), 3.84 (s, 3H), 3.32-3.22 (m, 2H) , 1.11 (t, J=7.2 Hz, ZN) 399 U\X CU Η Method F, 2.33 min, m/z 376.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.91 (s, 1H), 8.91 (s, 1H), 8.47 (t, J=5.2 Hz, 1H), 8.16 (s, 1H), 8.0-7.99 (m , 2H), 7.76-7.71 (m, 2H), 7.58 (d, J=9.2 Hz, 1H), 7.5 (d, J=8.8 Hz, 1H), 3.83 (s, 3H), 3.3-3.26 (m, 2H), 2.68 (s, 3H), 1.14 (t, J=7.2 Hz, ZN)

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400 401 402 403 404 // 0 N-XX z ^N 'N '- Η 0 ^H \—X / rVJ hnA uj Y p\j ' N^V / ^N 'NHH % /? H \< / ^vVv-GUo ^HN \ 4 JJ J. rvT 'nA /Nn h H Method F, 2.70 min, m/z 431.2 [M+H] ⁺ Method F, 2.60 min, m/z 420.2 [M+H] ⁺ Method F, 2.70 min, m/z 474.2 [M+H] ⁺ Method F , 2.55 min, m/z 431.2 [M+H] ⁺ Method F, 2.18 min, m/z 436.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.91 (s, 1H), 8.92 (s, 1H), 8.19-8.17 (m, 3H), 8.03 (s, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.58 (d, J=9.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.17 (d, J=9.2 Hz, 1H), 4.72 (s, 2H), 3.98-3.88 ( m, 1H), 3.8 (s, 3H), 1.09 (d, .1=6.4 Hz, 6H) Ή NMR (400 MHz, DMSO-de) δ 12.90 (s, 1H), 8.86 (s, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 7.91-7.89 (d, J=8.0, 1H ), 7.85-7.83 (d, J=8.4 Hz, 1H), 7.587.56 (d, J=8.8 Hz, 1H), 7.50-7.48 (d, J=9.2 Hz, 1H), 6.87-6.84 (d, J=12.0, 2H), 4.6(s, 2H), 3.99-3.94(m, 1H), 3.80(s, 3H), 2.59(s, 3H), l.ll-1.09(d, J=6.8, 6H ) Ή NMR (400 MHz, DMSO-de) δ 12.87 (s, 1H), 8.89 (s, 1H), 8.15(s, 1H), 8.02–8.00 (d, J = 7.2 Hz, 1H), 7.94 (s, 1H), 7.80-7.78 (d, J = 8.4 Hz, 1H), 7.56-7.46 (m, 2H), 7.38 (s, 1H), 7.31-7.29 (d, J= 8.4 Hz, 1H), 4.60 (s , 2H), 4.00–3.92 (m, 1H), 3.80 (s, 3H), 1.11–1.10 (d, J = 6.4 Hz, 6H) Ή NMR (400 MHz, DMSO-de) δ 12.88 (s, 1H), 9.0 (s, 1H), 8.39 (s, 1H), 8.05(d, J=8.8 Hz, 1H), 7.98 (d, J= 7.6 Hz, 1H), 7.9 (s, 1H), 7.61-7.59 (m, 1H), 7.48-7.47 (m, 2H), 7.37 (dd, J=2.8 Hz, 1H), 4.59 (s, 2H), 4.0-3.91 (m, 1H), 3.83 (s, 3H), 1.1 (d, J=6.4Hz, 6H) Ή NMR (400 MHz, DMSO-de) δ 12.87 (s, 1H), 8.81 (s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.92–7.90 (d, J = 7.6 Hz, 1H), 7.68-7.66 (d, J = 8.8 Hz, 1H), 7.54-7.47 (m, 2H), 6.71 (s, 1H), 6.61-6.59 (m, 1H), 4.49 (s, 2H), 4.01 -3.93 (m, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 1.12-1.10 (d, J = 6.4 Hz, 6H) 405 n A A ΑΥΥΥΥ Y ' _N A / ^N NH Method F, 2.52 min, m/z 424.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.90 (s, 1H), 8.89 (s, 1H), 8.15(s, 1H), 7.99 (s, 1H), 7.95-7.92 (d, 1=10.4Hz, 1H), 7.90-7.88(d, J=5.2Hz, 1H), 7.577.54(d, J=8.8Hz, 1H), 7.49-7.47(d, J=8.8Hz, 1H), 6.91-6.90(d , 1=4.4Hz, 1H), 6.88(s, 1H), 4.52(s, 2H), 3.96(s, 1H), 3.79(s, 3H), l.ll-1.09(d, J= 6.4Hz, 6H) 406 H ^F \_ HN-U z^zvA / \—X ^Ν Π J Г ojS / ^N ~N H Method F, 2.27 min, m/z 380.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.92 (s, 1H), 8.96 (s, 1H), 8.61 (t, J = 5.6, 1H), 8.16 (s, 1H), 8.09 (t, J = 8.0 , 1H), 8.02 (s, 1H), 7.78-7.72 (m, 2H), 7.58-7.50 (m, 2H), 3.83 (s, 3H), 3.31-3.27 (m, 2H), 1.12 (1.7 \u003d 7.2 Hz, ZN) 407 HAH j nA ⁿ yh>° y _N A / ^N N H Method F, 2.63 min, m/z 440.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.89(s, 1H), 8.89(s, 1H), 8.15(s, 1H), 8.03 - 7.90(m, 2H), 7.80 (d, J = 8.7 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H), 7.02 (dd, J = 8.6, 1.9 Hz, 1H), 4.53(s, 2H), 4.00 - 3.91 (m, 1H), 3.80(s, 3H), 1.10 (d, J = 6.6 Hz, 6H). 408 F fY ^f j H HN- ⁷ z--AW ^N ^ ^N \ / \__2 ^N Y /J n //v/q nAX ζ ^Ν 'Ν 'H Method F, 2.61 min, m/z 430.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.92 (s, 1H), 8.97 (s, 1H), 8.80 (t, J=5.2 Hz, 1H), 8.30 (s, 1H), 8.20 - 8.17 (m, 2H), 8.00 (m, 1H), 7.95 (s, 1H), 7.55 (m, 1H), 7.48 (m, 1H) 3.84 (s, 3H), 3.33-3.27 (m, 2H), 1.14 (t, J=7.2 Hz, ZN) 409 F / Η / HN— ⁷ z^/vA X\—X / j T TuL/b nA / ^Ν Ν A Η F Method F, 2.66 min, m/z 398.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.92 (s, 1H), 8.99 (s, 1H), 8.43 (t, J=5.2 Hz, 1H), 8.15 (s, 1H), 8.03 (s, 1H) , 7.83-7.79 (m, 1H), 7.59 (dd, J=8 Hz, 1H), 7.53 (dd, J=8.8 Hz, 2H), 3.83 (s, 3H), 3.33-3.25 (m, 2H), 1.14 (t, J=7.2 Hz, ZN)

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410 Αυλ ΑΧ W MM? H F Method F, 2.63 min, m/z 398.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.91 (s, 1H), 8.99 (s, 1H), 8.74 (t, J = 5.6 Hz, 1H), 8.19 (s, 1H), 8.05 (s, 1H) , 7.62-7.50 (m, 4H), 3.83 (s, 3H), 3.293.24 (m, 2H), 1.12(1, J = 7.2 Hz, ZN) 411 F / J , H \__/ m Y Ar ^x nA / ⁿ ~n H Method F, 2.8 min, m/z 442.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.89 (s, 1H), 8.92 (s, 1H), 8.16 (s, 1H), 8.0-7.96 (m, 2H), 7.72 (t, J=7.2 Hz, 1H), 7.57-7.48 (m, 2H), 6.98 (t, J=8 Hz, 1H), 4.64 (s, 2H), 3.97-3.81 (m, 1H), 3.41 (s, 3H), 1.09 (d , J=6.4Hz, 6H) 412 N // / Η X HN—/ z-^^^N^NA\_/ a d Τ X /C/L 'nAL / ⁿ -n H Method F, 2.33 min, m/z 387.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.93 (s, 1H), 10.36 (s, 1H), 8.99 (s, 1H), 8.77 (s, 1H) 8.28 (d, J=8 Hz, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 7.84 (d, 1=8Hz, 1H), 7.58 (d, J=8Hz, 1H), 7.51 (s, 1H), 3.86 (s, 3H) , 3.79-3.73 (m, 2H), 1.19 (t, J=6.8 Hz, ZN) 413 H ^F \_ HN-Y ΛνΧΧΝ AX/ A D J G Η_/Λ nA / ^N NAHF Method F, 2.60 min, m/z 398.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.92 (s, 1H), 8.99 (s, 1H), 8.45-8.42 (m, 1H), 8.16 (d, J= 1.2 Hz, 1H), 8.03 (s, 1H), 7.83-7.79 (m, 1H), 7.61-7.57 (m, 1H), 7.54-7.50 (m, 2H), 3.84 (s, 3H), 3.30-3.27 (m, 2H), 1.13 (t, J=7.2 Hz, ZN) 414 H r-/ ⁴ⁿ ΛνΑχΑ Lu-/ AD JN XJ nA _z N- _N H Method F, 1.70 min, m/z 360.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.92 (s, 1H), 8.87 (s, 1H), 8.17(s, 1H), 8.02(s, 1H), 7.73-7.71 (m, 2H), 7.58- 7.49 (m, 2H), 7.10 (d, J = 8.4 Hz, 1H), 3.79 (s, 3H), 3.50 (s, 2H), 2.88 (t, J = 5.6 Hz, 2H), 2.61 (t, J = 5.6Hz, 2H), 2.35(s, 3H) 415 H ^F r-4 Ol T Ar ^x / ^N 'NA HF Method F, 2.90 min, m/z 442.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.91 (s, 1H), 8.94 (s, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H) , 7.63-7.49 (m, 4H), 4.57 (s, 2H), 3.973.89 (m, 1H), 3.80 (s, 3H), 1.09 (d, J = 6.4 Hz, 6H) 416 ^hn ^ νΆ^ n- _n AHF Method F, 2.74 min, m/z 442.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 12.89 (s, 1H), 8.95 (s, 1H), 8.15 (s, 1H), 8.02-7.98(m, 2H), 7.75 (dd, J= 11.9, 6.9 Hz, 1H), 7.57-7.49 (m, 2H), 7.08 (dd, J= 11.9, 7.1 Hz, 1H), 4.63 (s, 2H), 3.96-3.88 (m, 1H), 3.80 (s, 3H) , 1.09 (d, J=6.6 Hz, 6H) 417 H Method B, 3.12 min, m/z 444.5 [M+H] ⁺ Ή NMR (400MHz, DMSO-de) δ 13.01 (s, 1H), 8.95 (t, J = 6.4Hz, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.70-7.67 (m, 2H ), 7.39-7.31 (m, 3H), 4.05 (m, 2H), 3.75 (s, 3H), 2.45 (s, 3H), 2.33 (s, 3H). 418 ΑΑΥΥΑ VU //Ln F H Method F, 2.89 min, m/z 431.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.03 (s, 1H), 9.34 (t, J=6.4 Hz, 1H), 9.04 (s, 1H), 8.46 (s, 1H), 8.3-8.28 (m, 1H), 8.13 (s, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.35 (q, J=8.8 Hz, 2H), 4.11-4.03 (m, 2H), 3.8 (s, 3H), 2.45(s, 3H) 419 1 Η Ά-Ζ hn-\F ^χ/Αχ^Ν /Αν YF ν D Τ T Y % // % F nA / ⁿ ~n ^ ^{-7 u} Method F, 3.02 min, m/z 466.1 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.01 (s, 1H), 9.15(1, J=6.0 Hz, 1H ), 8.43 (s, 1H), 8.12 (s, 1H), 7.66 (t, J= 7.2 Hz, 1H), 7.40-7.30 (m, 3H), 4.13-4.05(m, 2H), 3.79 (s, 3H), 2.45 (s, 3H). 420 VAn rjV N/ji JNY—/ o 'nA n- _n a^ ^υ H 0— Method B, 2.64 min, m/z 419.3 [M+H] ⁺ Ή NMR (400 MHz, Chloroform-d) δ 8.50 (d, J = 1.4 Hz, 1H), 8.39 (s, 1H), 8.34 (d, J =4.7 Hz, 1H), 8.13 (s, 1H), 7.71 (d, J= 1.5 Hz, 1H), 7.34 (m, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 2.80 (m, 1H), 2.45 (s, 3H), 0.66 (m, 2H), 0.52 (m, 2H). 1 NH not observed 421 1 dr—\ hn-\F z^Ay ^N \^NA\/ YF h d J Τ Η./Λ f nAJ /N- _n '—' H Method B, 3.03 min, m/z 430.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-de) δ 13.02 (s, 1H), 9.10 (t, J - 6.3 Hz, 1H), 8.34 (s, 1H), 8.17-8.11 (m, 1H), 7.90 (m, 4H), 7.36 (q, J= 8.8 Hz, 2H), 4.08 (m, 2H), 3.78 (s, 3H), 2.46 (s, 3H)

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422 Η __ νη ₂ Ν УХ-/ F ^ν Γύ ύ υ Η/η Ν^Χ ζ ^Ν 'Ν / Η ^F Method B, 2.46 min, m/z 402.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, Br), 8.27 (s, 1H), 8.13 (s, 1H), 7.80 (d, J= 8.40 Hz, 2H), 7.48 (d, J = 8.24 Hz, 2H), 7.34 (m, 2H), 4.49 (m, 1H), 3.75 (s, 3H), 2.45 (s, 3H). 2 NH not observed 423 D,L yGr VU λ,ΧΖΛ f Η Method B, 3.18 min, m/z 444.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.04 (s, 1H), 9.10 (t, J = 6.3 Hz, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 7.89 (s, 4H ), 7.38 (dd, J= 8.7, 1.0 Hz, 1H), 7.28 (d, J= 8.8 Hz, 1H), 4.15 - 4.01 (m, 2H), 3.77 (s, 3H), 2.94 (q, J = 7.5 Hz, 2H), 1.22 (1.7 = 7.5 Hz, ZN). 424 Λ,Ιί.Ν A-GA vV χη, g Η Method B, 3.22 min, m/z 458.4 [M+H] ⁺ Ή NMR (400 MHz, Chloroform-d) δ 10.32 (s, 1H), 8.10 (s, 1H), 7.95 7.84 (m, 2H), 7.45 - 7.28 (m, 3H), 6.13-6.02 (m, 2H) , 4.11 (m, 2H), 3.57 (s, 3H), 3.04 (q, J = 7.6 Hz, 2H), 2.48 (s, 3H), 1.34 (t, J = 7.6 Hz, ZN). 425 Dr Η ,__ _{_} Ο F. F ,ΧΧχ Y-f \JU Ι,Χ^ Η Method B, 3.33 min, m/z 458.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.07 (s, 1H), 9.08 (t, J= 6.29 Hz, 1H), 8.31 (d, J= 17.84 Hz, 2H), 7.87 (s, 4H), 7.37 (d, J= 8.56 Hz, 1H), 7.20 (d, J= 8.68 Hz, 1H), 4.07 (m, 2H), 3.77 (s, 3H), 3.51 (quintuplet, J= 7.03 Hz, 1H), 1.39 (d, J= 7.09 Hz, 6H). 426 ] η _ ΗΝ—X ζΧκζ ^Ν Χ Χ\—Ζ 4 D Τ Ν H-/ Ό νΧ / ⁿ 'N —' ^υ Η Method B, 2.78 min, m/z 388.3 [M+H] ⁺ 1H NMR (400 MHz, DMSO-i/e) δ: 13.22 (s, 1H), 8.55 (s, 1H), 8.49 (t, J = 5.6 Hz, 1H), 8.35 (d, J= 1.0 Hz, 1H ), 7.92 - 7.78 (m, 4H), 7.52 (m, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.16 (m, lH), 6.06 (m, 1H), 5.56 (m, 1H), 3.78 (s, 3H), 3.28 (m, 2H), 1.12 (t, J = 7.2 Hz, ZN) 427 \ Η ___ ο F. F Η ^ζ Method B, 3.11 min, m/z 430.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.50 (s, 1H), 9.14 (t, J = 6.3 Hz, 1H), 8.94 (s, 1H), 8.11-8.04 (m, 3H), 7.98 (d , J= 8.5 Hz, 2H), 7.61 (dd, J= 8.9, 2.1 Hz, 1H), 7.44 (dd, J = 8.8, 0.7 Hz, 1H), 4.11 (m, 6.5 Hz, 2H), 3.83 (s , 3H), 2.49 (s, 3H). 428 ^F \ Η __ hn-\F kk/kN /XΖ Y-F ν JJ Γ χ/Λ F Ν^X /X ^υ Η Method B, 3.32 min, m/z 434.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.42 (s, 1H), 9.19 - 9.08 (m, 2H), 8.15 (d, J = 1.9 Hz, 1H), 8.07 (d, J = 8.4 Hz, 2H ), 7.99 (d, J = 8.5 Hz, 2H), 7.69 (dd, J = 9.2, 2.1 Hz, 1H), 7.49 (dd, J = 9.0, 2.3 Hz, 1H), 4.12 (m, 6.2 Hz, 2H ), 3.85 (s, 3H). 429 Χ _γΛ /ΧΧ vQ Αχ ^f Η Method B, 3.61 min, m/z 480.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.16 (s, 1H), 9.17 (s, 1H), 8.71 (t, J = 6.4 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.74 - 7.63 (m, 3H), 7.56 (d, J = 9.0 Hz, 1H), 4.14 (m, 2H), 4.00 (s, 3H), 3.86 (s , 3H). 430 ^C \ η __ HN-\ ^F χν ^Ν Χ Λ\~ζ χ h D J T UA_/o f Ν^Χ / ^Ν Ν Η Method B, 3.39 min, m/z 450.2 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.17 (s, 1H), 9.15 (d, J = 6.9 Hz, 2H), 8.16 (dd, J = 2.1, 0.8 Hz, 1H), 8.13 - 8.04 (m , 2H), 8.04 - 7.96 (m, 2H), 7.74 (dd, J = 9.1, 2.1 Hz, 1H), 7.57 (dd, J = 9.0, 0.7 Hz, 1H), 4.11 (m, 2H), 3.85 ( s, 3H). 431 Q— Η __/ / Xr ^N Y ^N vTr7 ^Η / ^Ν \ ν ι j /Uhu X νΧ ζ ^ν -ν % Method B, 2.98 min, m/z 450.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.87 (s, 1H), 8.09 (s, 1H), 7.97 (t, J = 1.2 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.68 (s, 1H), 7.41 (dd, J = 8.3, 1.5 Hz, 2H), 7.36 (dd, J = 8.3, 1.9 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.44 (s , 2H), 3.98 - 3.84 (m, 1H), 3.82 (s, 3H), 3.72 (s, 3H), 2.37 (s, 3H), 1.08 (d, J = 6.6 Hz, 6H) 432 ο— / Η / ΗΝ—k h 1 J ϊ χ/Λ νΧΧζ ^ν Ν Η F ^x Method B, 3.64 min, m/z 438.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.07 (s, 1H), 8.61 (s, 1H), 8.12-8.08 (m, 2H), 7.86 (s, 1H), 7.79 (d, J = 8.8Hz, 1H), 7.58-7.49 (m, 2H), 7.46 (d, J = 10.8Hz, 1H), 3.95 (s, 3H), 3.82 (s, 3H), 1.38 (s, 9H). 433 0'/? Η __/ f—\ / хххх ^ΗΝ \ 4 JJ J. GM Ν^Χ ζ ^Ν - ^{ν H N} Method B, 2.89 min, m/z 437.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.49 (s, 1H), 9.16 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.66 (d, J = 2.5 Hz, 1H), 8.12 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.53 (dt, J = 3.9, 1.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 1H), 4.48 (s, 2H ), 3.98 3.90 (m, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 1.10 (d, J = 6.6 Hz, 6H).

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434 Cl _n J'J / ν D J J. 2\JF ^x nXJXn h^n οΎ Method B, 2.60 min, m/z 569.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.41 (s, 1H), 8.67 (s, 1H), 8.12 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 9.2 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.40 (dd, J = 8.4, 2.0 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.47 (s, 2H), 4.32 (t, J = 6.0 Hz, 2H), 4.00-3.89 (m, 1H), 3.85 (s, 3H), 3.56 (t, J = 4.4 Hz , 4H), 2.80 (t, J = 6.0 Hz, 2H), 2.53-2.48 (m, 4H), 1.11 (d, 7=6.4 Hz, 6H). 435 n\ Method B, 3.98 min, m/z 506.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.40 (s, 1H), 8.94 (t, J = 6.4 Hz, 1H), 8.49 (s, 1H), 8.10 (s, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.59 - 7.47 (m, 2H), 7.34 (d, J = 7.8 Hz, 1H), 4.06 (m, 2H), 3.99 (d, J = 7.3 Hz, 2H), 2.33 (s , 3H), 2.28 - 2.21 (m, 1H), 0.96 (d, J = 6.6 Hz, 6H). 436 ? _n j 20Ύ22 ^{0 HN} ^ / ^Ν 'Ν — AND ί Method B, 3.78 min, m/z 512.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 1.4 Hz, 2H), 7.39 (d, J = 1.9 Hz, 1H), 7.34 (dd, J = 8.3, 1.9 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.43 (s, 2H ), 3.96 (d, J = 7.3 Hz, 2H), 3.94 - 3.85 (m, 1H), 3.80 (s, 3H), 2.22 (m, 1H), 1.07 (d, J = 6.6 Hz, 6H), 0.94 (d, J = 6.7 Hz, 6H). 437 ϊ Ν αΧ ^N d J Ν Wo F νΧ ✓Ν'Ν ^υ Η \ Method B, 4.10 min, m/z 522.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.40 (s, 1H), 8.65 (t, J = 6.5 Hz, 1H), 8.53 (s, 1H), 8.10 (s, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.60 - 7.47 (m, 4H), 4.16 - 4.05 (m, 2H), 4.01 (d, J = 7.3 Hz, 2H), 3.91 (s, 3H), 2.30 - 2.20 (m, 1H), 0.96 (d, J =6.7 Hz, 6H). 438 1 Η hn-x ^f /Xd YF Ν D JI Χ\_/ο F νΧΧ'Ν ^υ Η X Method B, 3.61 min, m/z 500.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 9.12 (t, J = 6.3 Hz, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 7.95 (q, J = 8.4 Hz, 4H), 7.59 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 4.37 (t, J = 5.3 Hz, 2H), 4.10 (m, 2H), 3.79 (t, J = 5.3 Hz, 2H), 3.34 (s, 3H), 2.18 - 2.06 (m, 1H), 1.08 - 0.98 (m, 2H), 0.88 0.79 (m, 2H) 439 Υ r _with Μ X ην-Χ ζΧχ/ ^Ν Χ ΛΧΧ Λ F ν D J Σ Υ/ό ^f νΧΧ'Ν ^Μ Η 2 Method B, 3.79 min, m/z 530.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 8.67 (t, J = 6.5 Hz, 1H), 8.21 (s, 1H), 8.08 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.63 - 7.52 (m, 3H), 7.39 (d, J = 8.8 Hz, 1H), 4.37 (t, J = 5.3 Hz, 2H), 4.18 - 4.04 (m, 2H), 3.93 (s, 3H), 3.78 (t, J= 5.2 Hz, 2H), 3.34 (s, 3H), 2.11 (m, 1H), 1.08-0.98 (m, 2H), 0.84 (m, 2H) 440 1 _ ηνΧΙ /ΧχζΝ,ΐΐ Χ-Α ^ί ΧαΧ^ Η Χ Method B, 3.30 min, m/z 458.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.03 - 12.98 (m, 1H), 8.47 (d, J = 4.3 Hz, 1H), 8.20 (s, 1H), 8.09 (t, J = 1.3 Hz, 1H ), 7.95 - 7.88 (m, 2H), 7.89 7.81 (m, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 4.36 (t, J = 5.2 Hz, 2H), 3.78 (t, J = 5.3 Hz, 2H), 3.33 (s, 3H), 2.91 - 2.79 (m, 1H), 2.12 (m, 1H), 1.08 - 0.98 (m, 2H), 0.88 - 0.79 (m, 2H), 0.74 - 0.63 (m, 2H), 0.66 - 0.54 (m, 2H). 441 V ρ— c d X ΗΝ-\ ^F /r-X^/N Ν /=^/ X ^F ν D Τ χχ#Ό ^f νΧ^ζ ^Ν 'Ν - Η Method B, 3.70 min, m/z 500.6 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.66 (t, J = 6.5 Hz, 1H), 8.34 (s, 1H), 8.07 (d, J = 1.4 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.38 (s, 2H), 4.28 - 4.02 (m, 4H), 3.92 (s, 3H), 2.15 (m, 1H) , 1.41 (t, J = 7.1 Hz, ZH), 1.01 - 0.89 (m, 2H), 0.82 (td, J = 6.1, 4.2 Hz, 2H). 442 [Η ην-Χ ζΧκ/Χν ΥΧ / ^F ν D Τ τ # vj/o ^f νΧΧν Η \ \ ην-Ύ Method B, 2.61 min, m/z 525.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.05 (s, 1H), 9.10 (t, J= 6.24 Hz, 1H), 8.35 (s, 1H), 8.08 (s, 1H), 7.91 (s, 4H ), 7.38 (s, 1H), 7.37 (s, 1H), 4.49 (m, 1H), 4.08 (m, 2H), 3.17 (m, 2H), 2.68 (m, 2H), 2.13 (m, 1H) , 1.98 (m, 4H), 0.93 (m, 2H), 0.80 (m, 2H). 1 NH not observed 443 Υ Η ην-X ,^-Χ^Χ^ν XX/ Xf n D J ν x\_/of nXX ⁿ 'N ^u HX H Method B, 2.58 min, m/z 499.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.99 (s, 1H), 9.10 (br s, 1H), 9.10 (t, J= 6.24 Hz, 1H), 8.07 (s, 1H), 7.94 (q, J= 8.60 Hz, 4H), 7.53 (d, J= 9.05 Hz, 1H), 7.39 (d, J= 8.80 Hz, 1H), 4.27 (m, 2H), 4.09 (m, 2H), 3.04 (m, 2H), 2.41 (s, 3H), 2.12 (m, 1H), 1.03 (m, 2H), 0.83 (m, 2H). 1 NH not observed

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444 ϊ Η ην— ν ΛΑ / YF Ν D Τ Τ # F /'N ^Η γ /^ΟΗ Method B, 3.34 min, m/z 500.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.97 (s, 1H), 9.12 (t, J= 6.41 Hz, 1H), 8.44 (s, 1H), 8.09 (s, 1H), 7.97 (m, 4H ), 7.77 (d, J= 8.92 Hz, 1H), 7.41 (d, J= 8.80 Hz, 1H), 5.62 (d, J= 3.91 Hz, 1H), 4.15 (m, 5H), 2.03 (m, 1H ), 1.21 (d, J= 6.04 Hz, 3H), 1.09 (m, 2H), 0.81 (m, 2H). 445 ° - /9 N D J J. Y\JT ^χ νΧΧ ^ν 'Ν Ό Method B, 2.63 min, m/z 533.4 [M+H] ^{+ 1H} NMR (400 MHz, DMSO-d ₆ ) δ 12.91 (s, Br), 9.27 (s, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.55-7.48 (m, 4H), 6.99 (d, J = 8.0 Hz, 1H), 4.47 (s, 2H), 4.27 (t, J = 6.0 Hz, 2H), 3.97-3.89 (m, 1H ), 3.87 (s, 3H), 2.74-2.65 (m, 2H), 2.49-2.42 (m, 4H), 1.55-1.46 (m, 4H), 1.43-1.34 (m, 2H), 1.10 (d, J =6.4 Hz, 6H). 446 0' Method B, 2.54 min, m/z 535.4 [M+H] ^{+ 1H} NMR (400 MHz, DMSO-d ₆ ) δ 12.91 (s, Br), 8.98 (s, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.59-7.46 (m, 4H), 7.00 (d, J = 6.4 Hz, 1H), 4.47 (s, 2H), 4.29 (t, J = 6.8 Hz, 2H), 3.98-3.89 (m, 1H ), 3.87 (s, 3H), 3.57–3.48 (m, 4H), 2.73 (t, J = 7.2 Hz, 2H), 2.49–2.45 (m, 4H), 1.09 (d, 7.6 Hz, 6H). 447 θ /? ^{/ _} Method B, 3.19 min, m/z 480.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.94 (s, br), 8.81 (s, 1H), 8.25-8.21 (m, 1H), 8.06 (s, 1H), 7.81 (d, J = 7.6 Hz , 1H), 7.62-7.51 (m, 4H), 7.04 (d, J = 8.8 Hz, 1H), 4.52 (s, 2H), 4.39 (t, J = 5.6 Hz, 2H), 4.02-3.93 (m, 1H), 3.92 (s, 3H), 3.78 (t, J = 5.2 Hz, 2H), 3.32 (s, 3H), 1.13 (d, J = 6.4 Hz, 6H). 448 1 9 1 id rY hn-\ ^f X r ^v BH J Τ F νΛΛ^ ^ν 'ν '— ^u Method B, 3.52 min, m/z 504.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 8.66 (t, J = 6.4 Hz, 1H), 8.23 (s, 1H), 8.13 (s, 1H), 7.77 (d, J =7.9 Hz, 1H), 7.51 (s, 2H), 7.44 - 7.33 (m, 2H), 4.35 (t, J= 5.4 Hz, 2H), 4.11 (m, 2H), 3.92 (s, 3H), 3.77 (t, J = 5.3 Hz, 2H), 3.33 (s, 3H), 2.46 (s, 3H). 449 ι 0— DЪTSCHGA n d Method B, 3.69 min, m/z 488.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 8.65 (t, J = 6.4 Hz, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.51 (d, 7=7.2 Hz, 2H), 7.40 - 7.27 (m, 2H), 4.71 (m, 1H), 4.11 (m, 2H), 3.91 (s, 3H), 2.45 (s, 3H), 1.47 (d, J = 6.5 Hz, 6H) 450 ι O II H, / /—K / Χλ-Ο ΗΝ—< ν I I I. //%_# nX%/ ^N ~N I D Method B, 3.29 min, m/z 478.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 - 12.97 (m, 1Η), 8.13 (d, J = 12.9 Hz, 2H), 7.74 (d, J = 7.9 Hz, 1H), 7.41 - 7.25 (m , 4H), 6.91 (d, J = 8.4 Hz, 1H), 4.67 (m, 1H), 4.43 (s, 2H), 3.98 - 3.84 (m, 1H), 3.80 (s, 3H), 2.43 (s, 3H), 1.44 (d, J = 6.5 Hz, 6H), 1.08 (d, J = 6.6 Hz, 6H) 451 Η ί Method B, 3.73 min, m/z 486.5 [M+H] ^{+ X} H NMR (400 MHz, DMSO-d ₆ ) δ 13.03 - 13.00 (m, 1H), 8.92 (t, J = 6.4 Hz, 1H), 8.29 - 8.08 (m, 2H), 7.66 (d, J = 7.9 Hz, 2H), 7.40 - 7.25 (m, 3H), 4.12 - 3.98 (m, 2H), 3.95 (d, J = 7.3 Hz, 2H), 2.44 (s, 3H), 2.32 (s, 3H), 2.24 (m, 6.9 Hz, 1H), 0.96 (d, J = 6.7 Hz, 6H). 452 ι ° /? ^H __/ r-\ / Ay- ^{o 7} Method B, 3.49 min, m/z 492.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.99 (s, br), 8.20 - 8.10 (m, 2H), 7.73 (d, J = 7.9 Hz, 1H), 7.41 - 7.24 (m, 4H), 6.89 (d, J = 8.4 Hz, 1H), 4.42 (s, 2H), 3.86 - 3.96 (m, 3H), 3.79 (s, 3H), 2.44 (s, 3H), 2.23 (m, 1H), 1.07 ( d, J = 6.6 Hz, 6H), 0.95 (d, J = 6.7 Hz, 6H). 453 ^FH --(/ Method B, 3.34 min, m/z 474.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (d, J = 1.6 Hz, 1H), 9.11 (t, J = 6.3 Hz, 1H), 8.24 (s, 1H), 8.13 (dd, J = 1.6 , 0.8 Hz, 1H), 7.98 - 7.86 (m, 4H), 7.44 - 7.34 (m, 2H), 4.35 (t, J = 5.4 Hz, 2H), 4.16 - 4.02 (m, 2H), 3.78 (t, J = 5.4 Hz, 2H), 3.33 (s, 3H), 2.46 (s, 3H). 454 I Η / hn-\F Ν ^Ν / ^F 4 ^Z DDT 4_/ό f nXX/NN H Method B, 3.38 min, m/z 488.4 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.04 - 12.98 (m, 1H), 8.96 (t, J = 6.3 Hz, 1H), 8.20 (s, 1H), 8.13 (dd,7 = 1.6,0.9 Hz , 1H), 7.74-7.66 (m, 2H), 7.45 7.32 (m, 3H), 4.34 (t, J = 5.4 Hz, 2H), 4.06 (m, 2H), 3.78 (t, J = 5.4 Hz, 2H ), 3.35 (s, 3H), 2.46 (s, 3H), 2.35 (s, 3H). 455 I Η ,____. ο F. F \ΑΧ Χν^^Π^ η _ζ ο Method B, 3.87 min, m/z 502.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.03 - 13.00 (m, 1H), 8.64 (t, J = 6.5 Hz, 1H), 8.29 (s, 1H), 8.13 (t, J = 1.2 Hz, 1H ), 7.76 (d, J = 8.0 Hz, 1H), 7.50 7.44 (m, 2H), 7.37 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 4.16 - 4.03 ( m, 2H), 3.97 (d, J = 7.3 Hz, 2H), 3.90 (s, 3H), 2.45 (s, 3H), 2.25 (m, 1H), 0.96 (d, J = 6.7 Hz, 6H). 456 1 Ρ with ,J _V N _V N /=LX \AJ Xy^AkL F n V Method B, 3.54 min, m/z 486.3 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 8.65 (br t, J= 6.48 Hz, 1H), 8.33 (s, 1H), 8.13 (s, 1H), 7.75 (d, J= 7.92 Hz, 1H), 7.46 (m, 2H), 7.38 (m, 2H), 4.10 (m, 2H), 3.90 (s, 3H), 3.43 (m, 1H), 2.49 (s, 3H), 1.13 (m, 2H), 1.08 (m, 2H). 457 1 O— n / hn-\F XXk U-F Ν/ D Τ X ν_7Ό F νΧΧ ^Ν 'Ν - ^υ Η Method B, 3.47 min, m/z 474.5 [M+H] ⁺ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 8.65 (t, J = 6.5 Hz, 1H), 8.32 (s, 1H), 8.13 (d, J= 1.2 Hz, 1H), 7.75 (d, J =8.0 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.39 - 7.27 (m, 2H), 4.21 - 4.06 (m, 4H), 3.90 (s, 3H), 2.45 (s, 3H), 1.39 (1.7 = 7.1 Hz, 3H).

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Intermediate 118: tert-Butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate F o tert-Butyl 3,3-difluoro-4-(trifluoromethylsulfonyloxy)pyrrolidine-1-carboxylate (1500 mg, 4.22 mmol), obtained , following example 160, WO2017103611, was dissolved in DMF (20 ml) and cooled in an ice bath under N2 atmosphere. Tetrabutylammonium azide (1200 mg, 4.22 mmol) in DMF (20 mL) was added slowly over 15 min via an addition funnel. The reaction mixture was stirred in an ice bath, allowed to gradually warm to room temperature and stirred for 3 hours. The reaction was diluted with ethyl acetate (50 ml), washed with saturated aqueous NaHCO ₃ (x2) and brine (x2). The organic phase was dried with a phase separator and pumped to vacuum/purged with N2 (3 times) followed by the addition of palladium, 10 wt.% on a powdered carbon carrier, dry (150 mg, 1.4 mmol). Then 3 cycles of pumping to vacuum/purge of H2 were carried out, and the reaction was left to stir at room temperature overnight in an atmosphere of hydrogen. The crude material was filtered through a pad of Celite™ and the solvent was removed in vacuo. The product was purified by silica gel column chromatography eluting with 0-5% MeOH in DCM to give tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate (934 mg, 4.2 mmol, 99% yield) as a colorless oils. UPLC-MS (ES+, Method A), 1.04 min, m/z 167.0 [M(tBu)+H] ⁺ .

Example 458: 4-[5-[(4-isopropenyl-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]-N-(2,2,2trifluoroethyl )benzamide

Si XA / l f n

Hydrogen chloride (4.0 M in dioxane) (2.2 ml, 8.8 mmol) was added slowly to a stirred solution of 4-[5-[(4-isopropenyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl -1,2,4-triazol-3-yl]-N(2,2,2-trifluoroethyl)benzamide (64 mg, 0.12 mmol) in MeOH (2 ml) at room temperature. The reaction mixture was stirred at ambient temperature for 18 hours. The reaction was evaporated in vacuo and purified using an SCX SPE cartridge. The resulting product was purified by silica gel column chromatography eluting with 20-70% EtOAc in petroleum ether to give the product as a pale yellow gum. This substance was dissolved in 1.5 ml of CH3CN and diluted with ~5 ml of water. The sample was then freeze-dried to give 4-[5-[(4-isopropenyl-1H-indazol-5yl)amino]-1-methyl-1,2,4-triazol-3-yl]-N-(2,2, 2-trifluoroethyl)benzamide (27 mg, 0.06 mmol, 47% yield) as a pale yellow powdery solid. UPLC-MS (ES ⁺ , Method B): 3.32 min, m/z 456.3 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-06) δ 13.10 (s, 1H), 9.10 (t, J=6.3 Hz, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.93 7.87 (m, 4H ), 7.48 (m, 1H), 7.40 (d, J=8.8 Hz, 1H), 5.33 (q, J=1.7 Hz, 1H), 5.11 (dd, J=2.2, 1.1 Hz, 1H), 4.08 (m , 2Н), 3.73 (s, 3H), 2.10 (d, J=1.2 Hz, 3Н).

Stage 1: ethyl 4-[5-[(4-isopropenyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4triazol-3-yl]benzoate

Ethyl 4-[5-[(4-chloro-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3yl]benzoate (166 mg, 0.35 mmol ), potassium isopropenyl trifluoroborate (56 mg, 0.38 mmol) and cesium carbonate (450 mg, 1.38 mmol) were dissolved/suspended in 1,4-dioxane (5 ml) and water (2 ml) and completely degassed by bubbling nitrogen.

[1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) (23 mg, 0.03 mmol) was added, followed by additional degassing, and the reaction was heated to 100°C for 18 h. The reaction was cooled and water was removed using a pipette. The organics were adsorbed onto silica gel and the compound was purified by silica gel column chromatography eluting with 25-80% EtOAc in petroleum ether to give ethyl 4-[5-[(4-isopropenyl-1-tetrahydropyran-2-yl-indazol- 5-yl)amino]-1methyl-1,2,4-triazol-3-yl]benzoate (149 mg, 0.30 mmol, 89% yield) as a yellow gum. UPLC-MS (ES ⁺ , Method A): 1.96 min, m/z 487.6 [M+H] ⁺ .

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Stage 2: 4-[5-[(4-isopropenyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4 triazol-3-yl]benzoic acid

Sodium hydroxide (1.22 ml, 2.45 mmol) was added to a stirred suspension of ethyl 4-[5-[(4isopropenyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4- triazol-3-yl]benzoate (149 mg, 0.31 mmol) in THF (10 ml) and MeOH (10 ml) at room temperature. The reaction turned yellow and the solids dissolved. The reaction mixture was stirred at room temperature for 18 hours. The reaction was evaporated in vacuo and then suspended in water. The pH was adjusted to 2 with 2.0 M HCl and the solid precipitated out of solution. The solid was extracted with EtOAc (x2). The organics were then washed with saturated brine and dried over MgSO ₄ . The solvent was removed under vacuum to give 4-[5-[(4-isopropenyl-1-tetrahydropyran-2-ylindazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]benzoic acid (128 mg, 0.28 mmol, 91% yield) as a yellow solid. UPLC-MS (ES+, Method A): 1.63 min, m/z 459.4 [M+H] ⁺ .

Step 3: 4-[5-[(4-isopropenyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1-methyl-1,2,4triazol-3-yl]-N-(2 ,2,2-trifluoroethyl)benzamide ac Cu XA-Aa f

sl°

To a stirred solution of 4-[5-[(4-isopropenyl-1-tetrahydropyran-2-yl-indazol-5-yl)amino]-1methyl-1,2,4-triazol-3-yl]benzoic acid (64 mg , 0.14 mmol), N,N-diisopropylethylamine (0.07 ml, 0.42 mmol) and trifluoroethylamine (21 mg, 0.21 mmol) in THF (5 ml) was added propylphosphonic anhydride (0.12 ml, 0.21 mmol), and the solution was stirred for 16 h The pale yellow solution was evaporated in vacuo on silica gel and the crude material was purified by silica gel column chromatography eluting with 20-100% EtOAc in petroleum ether to give 4-[5-[(4-isopropenyl-1tetrahydropyran-2-yl -indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3-yl]A-(2,2,2-trifluoroethyl)benzamide (64 mg, 0.12 mmol, 85% yield) in pale yellow resin. UPLC-MS (ES ⁺ , Method A): 1.75 min, m/z 540.6 [M+H] ⁺ .

Example 459: N-ethyl-4-[5-[(4-isopropenyl-1H-indazol-5-yl)amino]-1-methyl-1,2,4-triazol-3yl]benzamide

N g—\ ^HN A \ ji YY _n Az z ⁿ 'NH

UPLC-MS (ES ⁺ , Method B): 2.96 min, m/z 402.5 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ 13.15 (bs, 1H), 8.49 (t, J=5.6 Hz, 2H), 7.97 (d, J=1.0 Hz, 1H), 7.93 - 7.81 (m, 4H) , 7.50 (dd, J=8.8, 1.0 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 5.34 (t, J=1.9 Hz, 1H), 5.12 (dd, J=2.2, 1.1 Hz, 1H), 3.74 (s, 3Н), 3.28 (m, 2Н), 2.10 (s, 3Н), 1.12 (t, J=7.2 Hz, 3Н).

1-Methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole

Yxaccn

Potassium acetate (199 mg, 2.0 mmol), bis(pinacolato)diborone (257 mg, 1.0 mmol), and 4-(4-bromophenyl)-1methylpyrazole (160 mg, 0.67 mmol) were stirred in DMF (1 mL) and MeCN (4 ml), and the mixture was degassed with N2.

The complex [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane chloride (55 mg, 0.07 mmol) was added and the mixture was heated for 18 h at 80°C. The reaction mixture was concentrated and purified by silica gel column chromatography eluting with 5-20% EtOAc in petroleum ether to give 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]pyrazole (163 mg, 0.57 mmol, 85% yield) as a white solid. LC-MS (ES ⁺ , Method A): 1.79 min, m/z 285.0 [M+H] ⁺ .

Stage 1: 4-(4-bromophenyl)-1-methylpyrazole

1-Methylpyrazole-4-boronic acid pinacol ester (300 mg, 1.44 mmol), 1,4-dibromobenzene (0.2 ml, 1.6 mmol) and potassium carbonate (399 mg, 2.9 mmol) were stirred in water (1 ml) and 1, 4-dioxane (4

- 212 042028 ml), and the mixture was degassed with N2. Tetrakis(triphenylphosphine)palladium (0) (167 mg, 0.14 mmol) was added and the tube was sealed and heated at 80°C for 18 h. The reaction mixture was immediately evaporated under vacuum on silica gel and purified by silica gel column chromatography, eluting 5-40% EtOAc in petroleum ether to give 4-(4-bromophenyl)-1-methylpyrazole (160 mg, 0.67 mmol, 47% yield) as a white solid. LC-MS (ES+, Method A): 1.66 min, m/z 237.1 [M+H] ⁺ .

The following intermediates were prepared in a similar manner.

Name Structure Analysis 1-methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2dao xaborolan-2-yl)phenyl]pyrazole Method A, 1.85 min, m/z 285.3 [M+H]+ 1-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2daoxaborolan-2-yl)phenyl]pyrazole \ \ /=\Λν Method A, 1.85 min, m/z 285.3 [M+H]+ 2-(4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl]-1H-imidazole 7 co Method A, 1.21 min, m/z 271.0 [M+H]+ trimethyl-[2-[[5-methyl-2-[4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]imidazol-1yl]methoxy]ethyl]silane ___ N-/ xy LU 3 \ V AU ? , Method A, 1.69 min, m/z 415.1 [M+H]+. tert-butyl 5-ethyl-3-[4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]pyrazole-1-carboxylate Ah /=\ Method A, 2.29 min, m/z 399.3 [M+H]+ 2-(4-(4,4,5,5-tetramethyl-1,3,2daoxaborolan-2-yl)phenyl]-3,4,6,7tetrahydropyrano[3,4-4]imidazole /=\ Ao ^,B A^AiA/ ⁰ η Method A, 1.24 min, m/z 327.1 [M+H]+ 5-ethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2daoxaborolan-2-yl)phenyl]-1,4,6,7tetrahydroimidazo[4,5-c]pyridine Η Method A, 1.15 min, m/z 354.2 [M+H]+

2-(4-Bromophenyl)-4-methyl-1 H-imidazole

4-Bromobenzamidine, HCl salt (2005 mg, 10.07 mmol) and chloroacetone (1.2 ml, 15.1 mmol) were taken up in DMF (50 ml), then treated with potassium carbonate (5.57 g, 40.3 mmol) and heated to 100°C for 18 h. The reaction was evaporated under vacuum and then transferred into DCM (70 ml). The organics were washed with water (70 ml) and then passed through a phase separator. The product was adsorbed onto silica gel and then purified by silica gel column chromatography eluting with 0-40% EtOAc in DCM to give 2-(4-bromophenyl)-4-methyl-1H-imidazole (1206 mg, 5.09 mmol, 50% yield ) as an off-white/yellow powdery solid. UPLC-MS (ES ⁺ , Method A): 1.02 min, m/z 236/238 [M+H] ⁺ .

2-[[2-(4-Bromophenyl)-4-methyl-imidazol-1-yl]methoxy]ethyltrimethylsilane

2-(4-Bromophenyl)-4-methyl-1H-imidazole (474 mg, 2 mmol) was taken up in dry DMF (10 mL) then treated with potassium carbonate (553 mg, 4 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride ( 0.42 ml, 2.4 mmol) and then heated to 60°C for 14 h. The reaction was evaporated under vacuum and the residue was treated with saturated aqueous NH ₄ Cl. The aqueous layers were extracted with DCM (25 ml) and then washed with water. The organics were passed through a phase separator and evaporated to dryness. The residue was purified by silica gel column chromatography eluting with 25-75% EtOAc in DCM to give 2-[[2-(4-bromophenyl)-4-methylimidazol-1-yl]methoxy]ethyltrimethylsilane (108 mg, 0.29 mmol, 15% yield) as a colorless oil. UPLC-MS (ES ⁺ , Method A): 1.57 min, m/z 367.2, 369.2 [M+H] ⁺ .

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-(4-Bromophenyl)pentan-1,3-dione

Lithium bis(trimethylsilyl)amide (10.05 mL, 10.05 mmol) was slowly added to 4'-bromoacetophenone (1 g, 5.0 mmol) in THF (30 mL) under N ₂ and stirred for 30 min at 0°C. Propionyl chloride (0.66 ml, 7.5 mmol) was added and the mixture was warmed to room temperature and stirred for 1 h. The solvent was removed in vacuo and EtOAc (30 ml) was added. The organics were washed with saturated brine, dried with a phase separator and adsorbed onto silica gel. The product was purified by silica gel column chromatography eluting isocratically with 10% DCM in petroleum ether to give 1-(4-bromophenyl)pentan-1,3-dione (461 mg, 1.8 mmol, 36% yield) as a pale yellow solid. LC-MS (ES ⁺ , Method A): 2.05 min, m/z 256.9 [M+H] ⁺ .

-(4-Bromophenyl)-5-ethyl-1 H-pyrazole

Hydrazine hydrate (0.26 ml, 5.3 mmol) was slowly added to a solution of 1-(4-bromophenyl)pentane-1,3dione (670 mg, 2.63 mmol) in MeOH (20 ml), and the mixture was heated for 1.5 h at 80°С . The reaction mixture was evaporated under vacuum, dissolved in EtOAc, and the organic solution was washed with saturated brine. The organics were dried with a phase separator and adsorbed to give the crude, 3-(4-bromophenyl)-5-ethyl-1H-pyrazole (593 mg, 2.4 mmol, 90% yield) as a pale yellow solid. LC-MS (ES ⁺ , Method A): 1.73 min, m/z 251.1 [M+H] ⁺ .

tert-Butyl 3-(4-bromophenyl)-5-ethylpyrazole-1-carboxylate

Sodium hydride (60% dispersion in mineral oil) (113 mg, 4.7 mmol) was added to a solution of 3(4-bromophenyl)-5-ethyl-1H-pyrazole (593 mg, 2.4 mmol) in DMF (20 mL) and stirred in for 15 min at room temperature. Di-tert-butide dicarbonate (618 mg, 2.8 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with DCM, dried with a phase separator and adsorbed onto silica gel. The product was purified by silica gel column chromatography eluting with 5-10% EtOAc in petroleum ether to give tert-butyl 3-(4-bromophenyl)-5-ethylpyrazole-1-carboxylate (330 mg, 0.94 mmol, 40% yield) as a pale yellow oil. LC-MS (ES ⁺ , Method A): 2.20 min, m/z 351.2 [M+H] ⁺ .

2-(4-Bromophenyl)-1,4,6,7-tetrahydropyrano[3,4-c1]imidazole n

3-Bromotetrahydro-4H-pyran-4-one (0.26 ml, 2.1 mmol) and potassium carbonate (880 mg, 6.4 mmol) were added to a solution of 4-bromobenzenecarboximidamide hydrochloride (1:1) (0.26 ml, 2.1 mmol) in MeCN ( 3 ml), and the mixture was heated to 80°C for 18 hours, the Reaction was then heated under microwave conditions for 8 hours at 140°C. The reaction was cooled and diluted with EtOAc, washed with brine (x2) and dried with a phase separator. The solvents were evaporated in vacuo and the residue was purified by silica gel column chromatography eluting with 70-100% EtOAc in petroleum ether to give 2-(4-bromophenyl)-1,4,6,7-tetrahydropyrano[3,4-c1 ]imidazole (75 mg, 0.27 mmol, 13% yield) as a pale yellow solid. LC-MS (ES ⁺ , Method A): 1.09 min, m/z 279.0 [M+H] ⁺ .

tert-Butyl 2-(4-bromophenyl)-3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate

1-tert-Butoxycarbonyl-3-bromo-4-oxopiperidine (0.26 ml, 3.6 mmol) and potassium carbonate (1490 mg, 11 mmol) were added to a solution of 4-bromobenzenecarboximidamide hydrochloride (1:1) (0.26 ml, 3.6 mmol) in acetonitrile (10 ml), and the mixture was heated to 120°C for 4 h under microwave conditions. The mixture was diluted with EtOAc, the organic layer was washed with brine (x2) and dried using a phase separator. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluting with 30-100% EtOAc in petroleum ether to give t-butyl 2-(4-bromophenyl)3,4,6,7-tetrahydroimidazo[4,5 -c]pyridine-5-carboxylate (929 mg, 2.45 mmol, 68% yield) as a yellow solid. UPLC-MS (ES ⁺ , Method A): 1.31 min, m/z 378.0 [M+H] ⁺ .

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2-(4-Bromophenyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine ^βγ αΥ _ν Υνη

Η

Hydrogen chloride (4.0 M in dioxane) (4.16 ml, 16.63 mmol) was added to a solution of tert-butyl 2-(4bromophenyl)-3,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (629 mg , 1.7 mmol), and the mixture was stirred for 3 h at 25°C. The reaction mixture was evaporated under vacuum and passed through an ion exchange cartridge (SCX, eluting with 1 M NH ₃ in MeOH). The resulting solution was evaporated in vacuo to give 2-(4-bromophenyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine (460 mg, 1.65 mmol, 99% yield) in as a pale yellow solid. UPLC-MS (ES+, Method A): 0.91 min, m/z 278.0 [M+H] ⁺ .

1-[2-(4-Bromophenyl)-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl]ethanone o

Acetic acid (glacial) (0.14 ml, 2.48 mmol), propylphosphonic anhydride (0.74 ml, 2.48 mmol) and N-diisopropylethylamine (1.15 ml, 6.62 mmol) were added to a solution of 2-(4-bromophenyl)-4,5,6,7tetrahydro -1H-imidazo[4,5-c]pyridine (460 mg, 1.65 mmol) in THF (5 ml) and the mixture was stirred for 2 h at 25°C. The reaction mixture was evaporated in vacuo and the residue was dissolved in EtOAc, washed with saturated sodium bicarbonate (aq) and brine, and dried over MgSO ₄ The organics were evaporated in vacuo to give 1-[2-(4-bromophenyl)-1,4,6 ,7-tetrahydroimidazo[4,5c]pyridin-5-yl]ethanone (500 mg, 1.56 mmol, 94% yield) as a yellow solid. UPLC-MS (ES ⁺ , Method A): 1.04 min, m/z 320.0 [M+H] ⁺ .

2-(4-Bromophenyl)-5-ethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine n

Diisobutylaluminum hydride (1.0 M in THF) (4.26 ml, 4.26 mmol) was added to a solution of 1-[2-(4bromophenyl)-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl]ethanone (682 mg, 2.13 mmol) in THF (5 ml) and stirred for 3 h at 40°C. Water was added and the aqueous layers were extracted with EtOAc. The combined organics were washed with saturated brine and dried, dried with a phase separator, evaporated in vacuo on celite and purified with a reverse phase column (25 g, C-18, 5-95% MeCN in water) to give 2-(4- bromophenyl)-5-ethyl-1,4,6,7tetrahydroimidazo[4,5-c]pyridine (204 mg, 0.67 mmol, 31% yield) as a pale yellow oil. LCMS (ES ⁺ , Method A): 0.98 min, m/z 306.0 [M+H] ⁺ .

Example Structure LC-MS W NMR 460 SHd /AG Of j TN/A νΥ^ / ^ν 'Ν n Method B, 3.08 min, m/z 411.4 [M+H]+ SH NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 8.06 (d, J = 1.3 Hz, 1H), 7.86 (d, J = 0.8 Hz, 1H), 7.82 - 7.77 (m, 2H), 7.58 - 7.52 (m, 2H), 7.48 - 7.34 (m, 2H), 3.85 (s, 3H), 3.76 (s, 3H), 2.20 - 2.07 (m, 1H), 1.03 - 0.91 (m, 2H), 0.87 - 0.76 (m, 2H). 461 Z IZ' ΖΞΕ ri ό Ci \ Method B, 3.34 min, m/z 411.3 [M+H]+ SH NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.50 - 7.41 (m, 2H), 7.39 (s, 1H), 6.42 (d, J = 1.9 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 2.14 (s, 1H), 0.99 -0.93 (m, 2H), 0.81 (m, 2H). 462 ζ ΞΕΖ' Ο ^- ΖΙ ri ό Υ \ / \=ζ Method B, 3.24 min, m/z 411.3 [M+H]+ Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (s, 1H), 8.31 (s, 1H), 8.07 (d, J = 1.3 Hz, 1H), 7.98 - 7.91 (m, 2H), 7.59 - 7.52 (m, 2H), 7.51 - 7.43 (m, 2H), 7.40 (s, 1H), 6.43 (d, J = 1.9 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 2.20 - 2.09 (m, 1H), 0.97 (m, 2H), 0.82 (m, 2H). 463 ] Η _ N—/ ζΥΥΥ ΑΥ// || νΥχ / ^ν 'Ν η Η Method B, 2.48 min, m/z 411.3 [M+H]+ SH NMR (400 MHz, DMSO-d ₆ ) δ 13.01 (s, 1H), 12.23 (d, J = 23.3 Hz, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 7.93 - 7.80 (m , 4H), 7.41 (t, J = 9.0 Hz, 2H), 6.80 (d, J = 92.7 Hz, 1H), 3.78 (s, 3H), 1.56 (s, 1H), 1.24 (s, 3H), 0.97 - 0.91 (m, 2H), 0.88 - 0.78 (m, 2H). 464 ϊ η __ζ~-Υ^· ΥJ JrY' ^NH Η Method B, 3.31 min, m/z 425.3 [M+H]+ Ή NMR (400 MHz, DMSO-de + D ₄ Acetic acid) δ 8.06 (d, J = 1.0 Hz, 1H), 7.89 - 7.81 (m, 2H), 7.79 - 7.71 (m, 2H), 7.50 - 7.35 ( m, 2H), 6.47 (s, 1H), 3.78 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 2.14 (m, 1H), 1.21 (t, J = 7.6 Hz, ZN), 1.03 - 0.93 (m, 2H), 0.86 - 0.78 (m, 2H). 3 x NH not observed

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465 It! rx II A ^Ν ΟΓ J Χ XX ' / ^N ' NH H Method B, 2.48 min, m/z 453.2 [M+H]+ Ή NMR (400 MHz, DMSO-de) δ 13.02 (s, 1H), 12.39 (s, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 7.86 (s, 4H), 7.50 - 7.36 ( m, 2H), 4.54 (s, 2H), 3.92 - 3.84 (m, 2H), 3.79 (d, J = 1.8 Hz, ZH), 2.14 (s, 1H), 1.24 (s, 2H), 0.97 (d , J = 8.3 Hz, 2H), 0.82 (d, J = 5.5 Hz, 2H). 466 1 H , . HN—. XX ΝΎ^ / ^N -N H Method B, 2.38 min, m/z 397.2 [M+H]+ Ή NMR (400 MHz, DMSO-de) δ 13.00 (s, 1H), 12.65 (br. s, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.87 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.15 (br. s, 2H), 3.79 ( s, 3H), 2.14 (m, 1H), 1.00–0.93 (m, 2H), 0.85–0.79 (m, 2H). REDX11069 467 7 Mx IZz Method B, 2.41 min, m/z 415.3 [M+H]+ Ή NMR (400 MHz, DMSO-de): 13.01 (s, 1H), 12.19 (s, 1H), 8.34 (s, 1H) 8.06 (s, 1H), 8.02 (t, J = 8.0 Hz, 1H), 7.73 (dd, J = 8.0, 1.5 Hz, 1H), 7.62 (dd, J = 12.4, 1.5 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H ), 7.24 (br.s, 1H), 7.08 (br. s, 1H), 3.79 (s, 3H), 2.14 (m, 1H), 0.99-0.93 (m, 2H), 0.85-0.79 (m, 2H ). 468 N^%^ / ^N 'NH H Method B, 2.80 min, m/z 534.3 [M+H]+ Ή NMR (400 MHz, Methanol-LD: 8.15 (d, J = 0.9 Hz, 1H), 8.01 - 7.93 (m, 2H), 7.86 - 7.79 (m, 2H), 7.44 (q, J = 8.9 Hz, 2H ), 3.83 (s, 3H), 3.80 (s, 2H), 3.31 (q, 2H), 3.06 (t, J = 5.7 Hz, 2H), 2.75 (t, J = 5.7 Hz, 2H), 2.13 (It , J = 8.5, 5.5 Hz, 1H), 1.07 - 0.99 (m, 2H), 0.83 (Id, J = 6.0, 4.1 Hz, 2H) 3 exchangeable NH were not observed 469 1 H _ N—/% /YA II A / ⁿ Ol j X nAM /N-- _n '' _H H Method B, 2.43 min, m/z 428.4 [M+H]+ Ή NMR (400 MHz, DMSO-de) δ: 13.03 (s, 1H), 12.24 (s, 1H), 8.28 (s, 1H), 8.07 (d, J = 1.0 Hz, 1H), 7.84 (s, 4H ), 7.41 (q, J = 8.8 Hz, 2H), 3.78 (s, 3H), 2.70 (t, J = 5.5 Hz, 2H), 2.56 (q, J = 7.1 Hz, 2H), 2.14 (tt, J = 8.6, 5.5 Hz, 1H), 1.08 (t, J = 7.1 Hz, ZH), 1.01–0.93 (m, 2H), 0.81 (Id, J = 6.1, 4.2 Hz, 2H).

ROCK2 binding activity.

The ROCK2 inhibition assay was performed using the ROCK2 N-terminal 6-His labeled catalytic domain 11-552 protein construct (Dundee University, UK). The protein was purified from the baculovirus expression system. Long chain protein S6 (KEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK) was used as a substrate. Kinase reactions were performed in a volume of 15 µl in a 96-well plate (black, half well volume) using 1.25 nM constitutively active ROCK2 kinase, 100 µM long chain S6 protein, 20 µM ATP and test compound in DMSO (or for controls, DMSO alone). ). The final concentration of DMSO was <1%. The assay buffer was 50 mM HEPES, pH 7.5, supplemented with 0.2 mM EDTA, 10 mM magnesium acetate, 0.01% Tween-20, 1 mM DTT, and 0.01% BSA. Test compounds were pre-incubated with ROCK2 kinase for 1 hour before addition of ATP and long chain S6 protein. After an additional 1 hour incubation, available ADP was measured using the ADP-Glo Kinase Assay (Promega) according to the manufacturer's instructions. Luminescence was measured on PHERAstar FS (BMG Labtech). The test compound concentration required to inhibit ADP production by 50% (IC ₅₀ ) was calculated using a four parameter logistic function with Dotmatics software.

In table. 26 shows the ROCK2 binding activity determined in the assay as described above for some compounds of the formula, classified based on the ROCK2 IC ₅₀ value of the compound as +, ++, +++ and ++++. Category + denotes compounds with an IC ₅₀ value for ROCK2 > 10 µM. Category ++ denotes compounds with an IC ₅₀ value for ROCK2 between 10 and 3 μM. Category +++ denotes compounds with an IC ₅₀ value for ROCK2 from 3 to 0.3 µM. Category ++++ denotes compounds with an IC ₅₀ value for ROCK2 < 0.3 µM.

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Example ID ROCK2 category in the ADP-Glo kinase activity assay 188 ++++ 144 ++ 150 ND 182 ++++ 181 ++++ 184 +++ 177 ++++ 176 ++++ 166 ++++ 190 ND 175 ++++ 170 ++++ 169 ++++ 168 ++++ 174 ++++ 180 ++++

Example ID ROCK2 category in the ADP-Glo kinase activity assay 105 ++++ 104 ++++ 103 ++++ 102 ++++ 101 ++++ 100 ++++ 99 ++++ 98 + 219 ++++ 47 ++++ 97 ++++ 96 +++ 95 ++++ 94 ++++ 93 ++ 92 +++

Table 26

Example ID ROCK2 category in the ADP-Glo kinase activity assay 52 +++ 148 ++++ 147 ++++ eleven ++ 51 ++++ 223 ++ 50 ++++ 231 ++++ 49 ++++ 48 ++++ 45 ++++ 243 +++ 167 ++++ 42 ++++ 41 ++ 40 +++

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119 ++ 118 ++++ 117 +++ 116 +++ 115 ++++ 114 ++++ 113 + 112 +++ 111 +++ BUT +++ 109 ++ 108 +++ 107 +++ 106 ++++ 466 ND 469 ++++ 248 ++++ 249 ++ 459 ++++ 458 ++++ 426 ++++ 340 + 88 +++ 465 ++++ 341 +++ 392 +++ 464 ++++ 463 ++++ 391 ++++ 390 ++++ 389 ++ 312 ++++ 388 +++ 387 ++++ 465 ++++ 323 ++++ 462 ++++ 461 ++++ 460 ++++ 386 +++ 311 ++++ 422 + 420 +++ 374 ++++ 373 +++ 419 ++++ 372 ++++ 271 ++++ 418 +++

207 ++++ 16 +++ 206 ++++ 15 +++ 205 ++++ 10 ++++ 242 ++++ 9 +++ 243 ++++ 12 ++++ 57 +++ 13 +++ 56 ++++ 8 ++++ 55 ++++ 7 ++++ 232 +++ 4 + 46 + 3 +++ 45 ++++ 1 +++ 44 +++ 6 ++++ 54 ++++ 2 +++ 53 +++ 293 ++++ 385 ++++ 292 ++++ 310 ++++ 291 ++ 309 ++++ 251 ++++ 308 ++++ 290 ++++ 307 +++ 289 ++++ 306 +++ 288 ++++ 384 +++ 383 ++++ 339 ++++ 287 ++++ 425 +++ 286 ++++ 305 ++++ 285 ++++ 304 ++++ 444 ++++ 338 ++++ 424 ++++ 303 ++++ 428 ++++ 302 ++++ 443 ++++ 301 ++++ 430 ++++ 300 ++++ 344 ++++ 299 ++++ 429 ++++ 298 ++++ 284 ++++ 297 ++++ 423 ++++ 322 ++++ 427 ++++ 321 ++++ 381 ++++ 320 ++++ 283 ++++ 319 ++++ 282 ++++ 318 ++++ 281 ++++ 317 ++++ 442 ++++ 296 +++ 421 ++++ 295 ++++ 380 ++++ 294 ++++ 379 +++ 364 ++++ 353 ++++ 280 ++++ 352 ++++ 316 ++++ 403 ++++ 268 ++++ 351 ++++ 464 ++++ 260 ++++ 335 + 259 ++ 376 ++++ 275 +++

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371 ++++ 363 ++++ 315 +++ 378 ++++ 411 ++++ 336 ++++ 441 ++++ 362 ++++ 375 ++++ 457 ++++ 361 +++ 274 ++++ 456 ++++ 410 +++ 402 ++++ 337 ++++ 360 ++++ 326 ++++ 440 ++++ 409 ++++ 350 ++++ 437 ++++ 408 +++ 349 ++++ 455 ++++ 359 +++ 258 ++++ 454 ++++ 267 ++++ 257 ++++ 453 ++++ 358 ++++ 256 ++++ 439 ++++ 266 ++++ 255 +++ 438 ++++ 332 ++ 254 +++ 436 ++++ 331 +++ 253 ++++ 435 ++++ 330 ++++ 401 ++++ 452 ++++ 279 ++++ 348 ++++ 451 ++++ 278 ++++ 347 ++++ 343 ++++ 277 ++++ 346 ++++ 463 ++++ 276 ++++ 400 ++++ 462 ++++ 433 +++ 399 ++++ 370 ++++ 447 ++++ 325 +++ 369 ++++ 434 ++++ 324 ++++ 416 ++++ 327 ++++ 345 ++ 368 ++++ 265 ++++ 398 ++ 415 ++++ 357 ++++ 397 ++++ 367 ++ 407 ++++ 250 ++++ 414 ++ 264 ++++ 396 ++++ 413 ++++ 263 +++ 395 ++++ 412 ++++ 406 ++++ 394 +++ 450 ++++ 356 ++++ 153 ++++ 449 ++++ 262 ++++ 152 ++++ 417 ++++ 446 ++++ 151 + 366 ++++ 445 ++++ 432 ++ 270 ++++ 329 ++ 252 ++++ 269 ++++ 328 ++ 314 ++++ 461 ++++ 405 ++++ 313 ++++ 460 ++++ 355 ++++ 273 ++++ 365 ++++ 354 ++++ 272 ++++ 448 ++++ 261 ++++ 201 ++++ 377 ++++ 404 ++++ 470 ++++ 471 ++++ 472 ++++ 473 ++++ 474 ++++ 475 ++++

Throughout the description and claims of this specification, the words include and contain and their variations mean including, but not limited to, and they are not intended to exclude (and do not exclude) other fragments, additives, components, integers or steps. Throughout the specification and claims of this specification, the singular encompasses the plural unless the context requires otherwise.

Characteristics, integers, characteristics, compounds, chemical moieties, or groups described in conjunction with a particular aspect, embodiment, or example of the invention should be understood as applicable to any other aspect, embodiment, or example described herein, if they do not contradict him. All features disclosed in this specification (including any appended claims, abstract and drawings), and/or all steps of any methodology or method so disclosed, may be combined in any combination except combinations where at least some of these features and/or steps are mutually exclusive. The invention is not limited to the details of any of the above embodiments. The invention extends to any new feature or any new combination of features disclosed in this specification (including any appended claims, abstract and drawings), or to any new step or any new combination of steps of any technique or process so disclosed.

The attention of the reader is directed to all materials and documents that are filed simultaneously with or precede this description in connection with this application, and which are open to public review with this description, and the contents of all such materials and documents are incorporated herein by reference.

Claims (29)

CLAIM 1. The compound of formula (I) and its pharmaceutically acceptable salt where A ¹ and A ² each independently represents CR ⁷ ; A ³ is independently selected from CR ⁷ or N; B is a 5-10 membered carbocyclic ring system or a 5-10 membered heterocyclic ring system containing 1, 2, 3 or 4 heteroatoms selected from N, O and S; R ¹ is LR ² where L is a bond or -L1-L ² - where L ¹ is selected from the link, -(CRARB)·;-. -O(CR ^x RB)-;-. -(CR ^a R ^b )o;O- and -NRC (CR ^A R ^B ) ;-; And L ² is selected from the link, -(CR ^A R ^B )1. ₃ -, -O-, -NR ^D -, -C(O)NR ^D -, -NR ^D C(O)-, -C(O)O-, -OC(O)-, -C(O) -, -S(O)2NR ^d -, -NR ^d S(O)2-, -S(O)2-, -S(O)(NR ^d )-, -NR ^d C(O)NR ^e - , -OC(O)NR ^d - and -C(O)NR ^d S(O)2-; And R ² is selected from H, CN, C1.6 alkyl, C1.6 haloalkyl, C1.6 alkylα, substituted with -ORF, C1-6 alkyl substituted with -NR ^f R ^g , C1.4 haloalkyl substituted with -OR ^F , C3.8 cycloalkyl substituted with OH , C1.4alkyl substituted by 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S, C1.4alkyl substituted by 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N , O and S, -(CR ^h R ⁱ )1.3OR ^f , -(CR ^h R ⁱ )1.3NR ^f R ^g , -(CR ⁿ R ^o )1.3C(O)OR ^f , -(CR ⁿ R ^o )1.3C(O)NR ^f R ^g , C3. ₁₀ carbocyclic ring system and 3-10 membered heterocyclic ring system containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, where the carbocyclic ring or heterocyclic ring system is unsubstituted or substituted: =O, -NR ^F R ^G , -C(O)R ^F , halogen, -CN, C ₁ .4 alkyl, C ₁ .4 haloalkyl or C ₁ .4 alkyl substituted with -OR ^F ; R ⁴ is independently selected at each occurrence from halo, C1.4alkylα, C1.6haloalkyl, -CN, -ORJ, =O, C1.4alkyl substituted with -ORJ, -NRJR ^K , C1. ₄ alkyl substituted with -NRJR ^K , C ₃ . ₈ cycloalkyl, C ₁ . ₄ alkyl substituted with C ₃ . ₈ cycloalkyl, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S, and C ₁ . ₄ alkylα substituted with 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S; R ⁵ is selected from H, C ₁ . ₄ alkyl, C ₁ . ₄ alkyl substituted with -ORL, C ₁ . ₄ alkyl substituted with -NRLRL, C ₃ . ₈ cycloalkyl, substituted or unsubstituted phenyl, 3-8-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S, C ₁ . ₄ alkyl substituted with C ₃ . ₈ cycloalkyl, C ₁ . ₄ αalkyl substituted by 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S, and substituted or unsubstituted 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N , O and S, where the phenyl or heteroaryl group may be substituted with 1 or 2 R ⁹ ; R ⁶ is selected from H and C ₁ . ₄ alkyl; R ⁷ is selected from H, halo, -OR ^M , C ₁ . ₄ alkyl, C ₁ . ₆ haloalkyl, C ₁ . ₄ alkenyl, -CN and C _3-8 cycloalkyl; R ⁸ is selected from H, halo, C ₁ . ₄ alkyl, C ₁ . ₆ haloalkyl, -CN and C _3-8 cycloalkyl; R ⁹ is selected from halogen or C ₁ . ₄ alkyl; n is 0, 1, or 2; R ^a and R ^B are selected from H, C ₁ . ₄ alkyl or C ₁ . ₄ haloalkyls or R ^A and R ^B together with the atom to which they are attached form a 3-6 membered cycloalkyl ring or a 3-6 membered heterocycloalkyl ring containing 1, 2 or 3 heteroatoms selected from N, O and S ; R ^C , R ^d , R ^e , R ^f and R ^g are each independently selected from H, C ₁ . ₄ alkyl and C ₁ . ₄ haloalkyl; R ^H and RI are each H except that one pair of R ^H and RI on one carbon atom together with that carbon atom form a 3-6 membered cycloalkyl ring or a 3-6 membered heterocycloalkyl ring containing 1, 2 or 3 heteroatoms selected from N, O and S; And RJ, R ^K , R ^l , R ^m , R ⁿ and R ^O are each independently selected from H or C ₁ at each occurrence. ₄ alkylα. 2. The compound according to claim 1, where A ¹ , A ² and A ³ are each independently selected from C-H, CF, C-Cl, C-Me, C-Et, C-iPr, C-cyclopropyl, C-ethenyl , C-propenyl, C-CN or C-CF ₃ . 3. The compound according to claim 1, where A ³ represents N. 4. A compound according to claim 1 or 2, wherein R ⁸ is H, Cl, F, CN, or Me. 5. A compound according to any one of the preceding claims, wherein R ⁶ is selected from H or methyl. 6. A compound according to any preceding claim, wherein ^N is: - 221 042028 7. A compound according to any one of the preceding claims, wherein ^N is selected from: 8. The compound according to any one of claims 1, 2 or 4, where the compound is a compound of formula (Ia) where m is 1 or 2. 9. A compound according to any one of claims 1-6 or 8, wherein R ⁵ is selected from H, C1. ₄ alkyl, C ₁ . ₄ alkyl substituted with -ORL, C ₁ . ₄ alkyl substituted with -NRLRL, C ₃ . ₈ cycloalkyl, substituted or unsubstituted phenyl, C1. ₄ alkyl substituted by 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S and substituted or unsubstituted 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N , O and S, where the phenyl or heteroaryl group may be substituted with 1 or 2 R ⁹ . from: 10. Connection according to any preceding paragraph, where selected - 222 042028 11. The compound according to any preceding claim, wherein B is selected from a 5- or 6-membered carbocyclic ring which is aromatic or unsaturated, a 5- or 6-membered heterocyclic ring containing 1, 2, 3, or 4 heteroatoms selected from N, O and S, which is aromatic or unsaturated, of a 9- or 10-membered carbocyclic bicyclic ring system, or a 9- or 10-membered heterocyclic bicyclic ring system containing 1, 2, or 3 heteroatoms selected from N, O, and S, where the bicyclic ring system is either aromatic, or one of the rings in the bicyclic ring system is aromatic or unsaturated and the other ring is saturated. 12. A compound according to any one of the preceding claims, wherein B is selected from a 6-membered carbocyclic ring and a 10-membered heterocyclic fused bicyclic ring system containing 1, 2, or 3 heteroatoms selected from N, O, and S. 13. The compound according to any one of claims 1 to 11, wherein B is selected from phenyl, pyrazole, pyridyl, piperidyl, azaindole, isoindoline, tetrahydroisoquinoline, tetrahydroisoquinolone, furan, indazole, benzpyrazole, pyrimidine, pyridone, tetrahydropyridine, dihydropyran, cyclopentene, cyclohexenyl , chroman, chromanone, benzodioxane, tetrahydronaphthalene, dihydrobenzoxazine, benzomorpholine, tetrahydroquinoline, naphthyridine, quinoline, isoquinoline and dihydroisobenzofuran, or B is yourself: selected from: 14. Connection according to any one of claims 1-12, where 15. A compound according to any preceding claim, wherein L ¹ is selected from the bond, -(CR ^A R ^B )1.3- and -O(CR ^x R ^fi )-;-. 16. A compound according to any preceding claim, wherein L ² may be selected from a bond, -NRD-, -C(O)NR ^d -, -NR ^d C(O)-, -C(O)O-, -C( O)-, -NR ^d C(O)NR ^e - and -OC(O)NR ^d -. 17. A compound according to any one of the preceding claims, wherein R ^A and R ^B are independently selected from H, C ₁ . ₄ alkyl and C ₁ . ₄ haloalkyl and/or RC and ^RD are independently selected from H and methyl. 18. The compound according to any preceding claim, wherein R ² is selected from H, CN, methyl, ethyl, n propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, t-pentyl, difluoroethyl, difluoropropyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, 2-hydroxypropyl, 1-hydroxybutyl, 2hydroxybutyl, hydroxypropyl, 2-methyl-2-hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, hydroxycyclopropyl, hydroxycyclobutyl, hydroxycyclopentyl, hydroxycyclohexyl, hydroxycycloheptyl, aziridinyl , N-acetylaziridinyl, N-alkylaziridinyl, azetidinyl, N-acetylazetidinyl, N-alkylazetidinyl, 2-methylpropan-2-amine, phenyl, chlorophenyl, pyrrolidinyl, difluoropyrrolidinyl, trifluoroethylpyrrolidinyl, N-methylpyrrolidinyl, tetrahydrofuranyl, sulfolanyl, dihydropyran, tetrahydropyranyl, tetrahydropyranonimidazolyl, , ethyltetrahydroimidazopyridine, methylimidazolyl, piperazinyl, N-methylpiperazinyl, trifluoromethylpiperazinyl, oxadiazine olyl, dimethyldihydrooxazolyl, pyrazolyl, N-methylpyrazolyl, ethylpyrazolyl, 4-hydroxypyridyl, 2hydroxypyridyl, pyridyl, methyl substituted with tetrahydrofuran, ethyl substituted with pyridine, ethyl substituted with -NMe ₂ , ethyl substituted with OMe, ethyl substituted with OH; or selected from: - 223 042028 19. The compound according to claim 1, in which R ⁴ is F, Cl, methyl, CF3, Et, iPr, CN, OH, OMe, Oi- Pr, =O, CH2OH, CH2OMe, NH2, NMe2, CH2NH2, CH2NMe2 or morpholinyl. 20. Compound selected from: - 224 042028 - 225 042028 - 226 042028 - 227 042028 - 228 042028 - 229 042028 - 230 042028 - 231 042028 - 232 042028 - 233 042028 - 234 042028 - 235 042028 - 236 042028 - 237 042028 - 238 042028 - 239 042028 - 240 042028 - 241 042028 - 242 042028 - 243 042028 - 244 042028 - 245 042028 - 246 042028 - 247 042028 - 248 042028 - 249 042028 - 250 042028 - 251 042028 - 252 042028 - 253 042028 - 254 042028 - 255 042028 - 256 042028 - 257 042028 21. Pharmaceutical composition containing a compound according to any one of paragraphs. 1-20 and a pharmaceutically acceptable excipient. 22. Pharmaceutical composition according to claim 21, containing an additional pharmaceutically active agent. 23. The use of a compound according to any one of claims 1 to 20 for the treatment of a condition that is treatable by inhibition of ROCK1 and/or ROCK2. 24. Use according to claim 23, wherein the condition is a condition selected from fibrotic diseases, autoimmune, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer. 25. Use according to claims 23, 24, wherein the condition treatable by ROCK1 and/or ROCK2 inhibition is selected from sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, atopic dermatitis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barré, Graves' disease, Addison's disease, Raynaud's phenomenon or autoimmune hepatitis, arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, degenerative arthritis, polymyalgia rheumatica, ankylosing spondylitis, reactive arthritis, gout, pseudogout, inflammatory joint disease, systemic lupus erythematosus, polymyositis and fibromyalgia, types of arthritis including Achilles tendinitis, achondroplasia, acromegalic arthropathy, adhesive capsulitis, adult-onset Still's disease, anserine bursitis, avascular necrosis, Behçet's syndrome, bicipital tendinitis, Blount's disease, brucellar spondylitis, bursitis, calcaneal bursitis, postponed illness calcium pyrophosphate dihydrate (CPPD), crystal deposition disease, Kaplan syndrome, carpal tunnel syndrome, chondrocalcinosis, chondromalacia patella, chronic synovitis, chronic recurrent multifocal osteomyelitis, Churg-Strauss syndrome, Cogan syndrome, glucocorticoid-induced osteoporosis, bone sternal syndrome, syndrome CREST, cryoglobulinemia, degenerative joint disease, dermatomyositis, diabetic digital sclerosis, diffuse idiopathic skeletal hyperostosis (DISH), discitis, discoid lupus erythematosus, drug-induced lupus syndrome, Duchenne muscular dystrophy, Dupuytren's contracture, Ehlers-Danlos syndrome, enteropathic arthritis, epicondylitis, erosive - inflammatory osteoarthritis, exercise-induced compartment syndrome, Fabry disease, familial Mediterranean fever, Farber's lipogranulomatosis, Felty's syndrome, fifth disease, flat feet, foreign body synovitis, Freiberg's disease, fungal arthritis, more Gaucher disease, giant cell arteritis, gonococcal arthritis, Goodpasture's syndrome, granulomatous arteritis, hemarthrosis, hemochromatosis, Henoch-Schönlein purpura, hepatitis B surface antigen, hip dysplasia, Hurler's syndrome, hypermobility syndrome, leukocytoclastic vasculitis, hypertrophic osteoarthropathy, immune complex disease, syndrome impingement, Jaccous arthropathy, juvenile ankylosing spondylitis, juvenile dermatomyositis, juvenile rheumatoid arthritis, Kawasaki disease, Kienböck disease, Legg-Calve-Perthes disease, Lesch-Nyhan syndrome, linear scleroderma, lipoid dermatoarthritis, Löfgren's syndrome, Lyme disease, malignant synovioma, Marfan syndrome, mediopatellar fold syndrome, metastatic carcinomatous arthritis, mixed connective tissue disease - 258 042028 (MCTD), mixed cryoglobulinemia, mucopolysaccharidosis, multiple reticulohistiocytosis, multiple epiphyseal dysplasia, mycoplasmal arthritis, myofascial pain syndrome, neonatal lupus, neuropathic arthropathy, nodular panniculitis, ochronosis, ulnar bursitis, Osgood-Schlatter disease, osteoarthritis, osteochondromatosis imperfecta, osteogenesis, osteomalacia, osteomyelitis, osteonecrosis, osteoporosis, cross syndrome, pachydermoperiostosis, Paget's disease of the bone, palindromic rheumatism, patellofemoral joint pain syndrome, Pellegrini-Stied syndrome, pigmented villonodular synovitis, piriformis syndrome, plantar fasciitis, polyarteritis nodosa, polymyalgia rheumatica , polymyositis, popliteal cysts, posterior tibial tendinitis, Knott's disease, prepatellar bursitis, prosthetic joint infection, pseudoxanthoma elasticum, psoriatic arthritis, Raynaud's syndrome, reactive arthritis/Reiter's syndrome, reflex sympathetic syndrome dystrophy, recurrent polychondritis, posterior calcaneal bursitis, rheumatic fever, rheumatoid vasculitis, rotator cuff tendinitis, sacroiliitis, salmonella osteomyelitis, sarcoidosis, lead gout, Scheuermann's osteochondrosis, scleroderma, septic arthritis, seronegative arthritis, shigella arthritis, syndrome humero-hand, sickle cell arthropathy, Sjögren's syndrome, epiphyseolysis of the femoral head, spinal stenosis, spondylolysis, staphylococcal arthritis, Stickler's syndrome, subacute cutaneous lupus, Sweet's syndrome, Sydenham's chorea, syphilitic arthritis, systemic lupus erythematosus (SLE), Takayasu's arteritis , tarsal tunnel syndrome, tennis elbow, Tietze syndrome, transient osteoporosis, traumatic arthritis, acetabular bursitis, tuberculous arthritis, ulcerative colitis arthritis, undifferentiated connective tissue dysplasia syndrome (UCTS), urticarial vasculitis, viral arthritis, Wegener's granulomatosis, Whipple's disease, Wilson, Jer cyanotic arthritis and conditions involving vascularization and/or inflammation including atherosclerosis, rheumatoid arthritis (RA), hemangiomas, angiofibromas and psoriasis, angiogenic diseases including retinopathy of prematurity (retrolental fibroplasia), corneal transplant rejection, corneal neovascularization associated with complications of refractive surgery , corneal neovascularization associated with contact lens complications, corneal neovascularization associated with pterygium and recurrent pterygium, corneal ulcer and non-specific ocular surface disease, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Crohn's disease, autoimmune nephritis, primary biliary cirrhosis , acute pancreatitis, transplant rejection, allergic inflammation, contact dermatitis and delayed-type hypersensitivity reactions, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, cognitive impairment, baths with inflammation of neurons, Osler-Weber syndrome, restenosis and fungal, parasitic and viral infections, including cytomegalovirus infections. 26. The use of a compound according to any one of claims 1 to 20 for the treatment of a condition selected from fibrotic diseases, autoimmune, inflammatory-fibrotic conditions, inflammatory conditions, disorders of the central nervous system, or cancer. 27. A method of treating a condition that is treatable by inhibition of ROCK1 and/or ROCK2, wherein the method comprises administering a therapeutic amount of a compound according to any one of claims 1-20 to a patient in need thereof. 28. A method of treating a condition, wherein the condition is selected from fibrotic diseases, autoimmune, inflammatory fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer, wherein the method comprises administering a therapeutic amount of a compound according to any one of claims 1 to 20 to a patient in need thereof. . 29. The use of a compound according to any one of claims 1 to 20 for the manufacture of a medicament for the treatment of a condition selected from fibrotic diseases, autoimmune, inflammatory fibrotic conditions, inflammatory conditions, disorders of the central nervous system, or cancer.