EA044043B1 - INHIBITORS OF RHO-ASSOCIATED SUPERCOIL PROTEIN KINASE - Google Patents

Description

Technical field of the invention

This invention relates to inhibitors of ROCK1 and/or ROCK2. Methods of inhibiting ROCK1 and/or ROCK2 useful for treating a disease are also provided.

BACKGROUND OF THE INVENTION

Rho-associated coiled-coil containing protein kinases (ROCK) are members of the serine/threonine kinase family. Two isoforms have been identified, ROCK1 and ROCK2. Both isoforms are activated by GTP-bound forms of Rho GTPase and, upon activation, phosphorylate a number of downstream substrates. ROCKs play important roles in numerous cellular processes, including smooth muscle cell contraction, proliferation, cell adhesion, and cell migration. Therefore, ROCK inhibitors have potential therapeutic utility in a wide range of pathological conditions, including, for example, asthma, cancer, erectile dysfunction, glaucoma, insulin resistance, renal failure, pulmonary hypertension, neuronal degeneration and osteoporosis.

Fibrosis is characterized by excessive accumulation of fibrotic components of the extracellular matrix (ECM), such as collagen and fibronectin, in damaged tissue and ultimately leads to permanent scarring, organ failure such as that seen in idiopathic pulmonary fibrosis (IPF), end-stage liver failure, renal failure and heart failure (Julian and Olson, 2014). Regardless of tissue type and etiology, it is now known that organ fibrosis is the final pathological result of an aberrant wound healing response to tissue injury. Initial or repeated damage to the uppermost epithelial cells occurs, which triggers wound healing reactions. A common feature of all fibrotic diseases is the activation of ECM-producing myofibroblasts, which are the main cell type dominant in fibrotic tissue remodeling and normal wound healing. In contrast to regulated wound healing, during which myofibroblasts undergo apoptosis after the healing process, in fibrosis myofibroblasts become resistant to apoptosis and produce extracellular matrix in increased quantities. Together, excess ECM deposition and increased collagen matrix cross-linking make the ECM stiffer in fibrotic tissue. Increased matrix stiffness has been identified as playing an active role in disease progression by establishing a feedback loop called mechanotransduction (Moraes, 2015). Profibrotic cells respond to extracellular mechanical forces by exhibiting more rigid cytoskeletal properties and consequently alter their intracellular signaling cascades toward disease susceptibility.

ROCK kinases, as the main effector proteins of the small GTPase Rho, are key regulators of the contractility of the cellular cytoskeleton and actomyosin. Once activated, ROCK phosphorylates multiple downstream substrates, including myosin light chain (MLC, at threonine 18 and serine 19) and myosin light chain phosphatase (MYPT1, at threonine 853), to drive the polymerization of globular G-actin into filamentous F-actin and assembly of the apparatus actomyosin contraction. ROCKs are key regulators of mechanotransduction signaling, and cells involved in tissue fibrotic responses, namely epithelial cells, endothelial cells and myofibroblasts, are primarily regulated by ROCK activity. Thus, ROCK inhibitors (ROCKi) may have therapeutic applications in fibrotic diseases.

The essence of the invention

The present invention relates to a compound having formula (IIj)

where L ¹ represents CH;

L ² represents N;

R ² is selected from the group consisting of H, halogen, cyano, lower alkyl,

C3-C6 cyclic alkyl, lower alkoxy and C ₁ -C ₃ perfluoroalkyl;

R ³ is selected from the group consisting of H, halogen, hydroxy, -NRR', cyano, lower alkyl, lower alkoxy and C ₁ -C ₃ -perfluoroalkyl;

alternatively, R ² and R ³ together form a fused phenyl or a fused 5-6 membered ring having 0 to 3 ring heteroatoms, unsubstituted or substituted with -C(=O)-lower alkyl or lower alkyl;

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R ⁵ is selected from H, halogen, lower alkyl and lower alkoxy;

R ⁶¹ represents H;

each R is independently selected from H and lower alkyl;

each R' is independently selected from H and lower alkyl;

a selected from 1-10; and x is selected from 1-2;

wherein the lower alkyl is C ₁ -C ₄ -alkyl;

lower alkoxy is -O-C ₁ -C ₄ -alkyl; and the heteroatom is nitrogen, oxygen or sulfur; or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to a compound having formula (IIk)

where R ² is selected from the group consisting of H, halogen, cyano, lower alkyl, C ₃ -C ₆ cyclic alkyl, lower alkoxy and C ₁ -C ₃ -perfluoroalkyl;

R ³ is selected from the group consisting of H, halogen, hydroxy, -NRR', cyano, lower alkyl, lower alkoxy and C ₁ -C ₃ -perfluoroalkyl;

alternatively, R ² and R ³ together form a fused phenyl or a fused 5-6 membered ring having 0 to 3 ring heteroatoms and unsubstituted or substituted with -C(=O)-lower alkyl or lower alkyl;

R ⁵ is selected from H, halogen, lower alkyl and lower alkoxy;

R ⁶¹ represents H;

each R is independently selected from H and lower alkyl;

each R' is independently selected from H and lower alkyl;

a selected from 1-10; and x is selected from 1-2;

wherein the lower alkyl is C ₁ -C ₄ -alkyl;

lower alkoxy is -O-C ₁ -C ₄ -alkyl; and the heteroatom is nitrogen, oxygen or sulfur; or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the compounds proposed above are a compound of the formula

a pharmaceutically acceptable salt thereof.

More preferably, the present invention relates to a compound which is

Preferably, the pharmaceutically acceptable salt of the compounds of the present invention is a hydrochloride salt.

In another aspect, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound

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or a pharmaceutically acceptable salt thereof with the addition of one or more pharmaceutically acceptable excipients or carriers.

In yet another aspect, the present invention relates to a pharmaceutical composition containing a therapeutically effective amount of a hydrochloride salt of the compound

with the addition of one or more pharmaceutically acceptable excipients or carriers.

In a preferred embodiment, the pharmaceutical compositions proposed above are formulated in solid dosage form for oral administration.

In yet another aspect, the present invention provides a method of treating pulmonary fibrosis in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of any of the above compounds or the above pharmaceutical composition.

In a preferred embodiment, the pulmonary fibrosis is idiopathic pulmonary fibrosis.

Brief description of the figures

Fig. 1a. Representative results of the Z'-Lyte assay. The ROCK inhibitors of this invention demonstrate unambiguous nanomolar potency against both ROCK isoforms.

Fig. 1b. ELISA analysis in A7R5 cells. A7R5 cells were treated with a 9-point 2-fold serial dilution of compounds and ppMlc levels (T18/S19) were determined to calculate cellular IC50 values of compounds. The compounds of the invention gave IC50 in cells of up to 100 nM.

Fig. 1s. Western blot of A7R5 cell lysates to visualize ppMlc (T18/S19) levels after treatment with compound from Example 192 (Example 192) for 90 min. A7R5 cells were treated with the compound and ppMlc (T18/S19) levels were visualized by Western blotting. ROCK (Kadmon) effectively blocked phosphorylation of ROCK targets MLC and MYPT1 at 110 nM.

Fig. 2a. Silencing ROCK1 and ROCK2 protein expression in human HFF fibroblasts reduced stress fiber formation. Simultaneous silencing of ROCK1 and ROCK2 expression was carried out by transfection of targeting siRNAs, and F-actin content was visualized by phalloidin staining.

Fig. 2b. Example 228 inhibited the formation of F-actin stress fibers in CCD18lu human lung fibroblasts.

Fig. 3. Immunofluorescence staining of MKL1 in human lung fibroblasts. Human lung fibroblasts CCD18Lu were treated with the indicated compound for 3 h, fixed and stained with MKL1, F-actin and DAPI. Of note, ROCKi effectively abolished stress fiber formation while blocking the nuclear accumulation of MKL1.

Fig. 4a. The ROCK inhibitor blocked mechanotransduction. HFF cells were cultured in Prime Coat plates coated with silicone gel of increasing stiffness (2 kPa or 30 kPa). Cells were treated with compounds for 24 h, and mRNA expression was quantified using Taqman qPCR.

Fig. 4b. The ROCK inhibitor reduced basal as well as TGFe1-induced aSMA expression in human lung fibroblasts. LL24 cells were treated for 24 h, and mRNA expression was quantified by Taqman qPCR.

Fig. 4s. A ROCK inhibitor reduced aSMA protein levels in human lung fibroblasts. Human CCD18Lu lung fibroblasts were cultured on plastic substrate for 5 days with or without inhibitors. aSMA and control proteins were visualized by Western blotting.

Fig. 4d. ROCK inhibitors can be efficiently screened using a cell-based assay of the ACTA2 promoter-driven luciferase reporter gene. NIH3T3 cells stably expressing ACTA2 promoter-driven luciferase were seeded in 96-well plates until confluent and treated with a 9-point serial dilution of the compounds in combination in TGFei for 24 hours. Luciferase activity was measured and the IC50 of the compounds was calculated. According to this analysis, many of the compounds of the invention gave IC50s of up to 200 nM.

Fig. 5. ROCK inhibitor (Example 228) blocked integrin αΎβ6-mediated latent activation of TGFe. Integrin αΎβ6-positive Detroit 562 cells were seeded and treated with compounds in combination with the par1 ligand thrombin for 2 h, lysed, and TGFe signaling detected by phosphorylation of the transcription factors Smad2/3.

Fig. 6. ELISA of CCN1 in the cell culture medium of CCD18Lu fibroblasts. Cells were treated with ROCK inhibitor in combination with TGFe for 40 hours. CCN1 content was measured using a human CCN1 ELISA kit from R&D Systems.

Fig. 7a. ROCK inhibitors protected the integrity of epithelial junctions. MDCK cells were cultured at confluence for 3 days, and intracellular calcium was chelated by adding 5 mM EGTA with or without the addition of ROCK inhibitor. The integrity of cell junctions was visualized by immunofluorescent staining of the p120 adhesion molecule. Counter-staining of F-actin and nucleus was performed.

Fig. 7b. ROCK inhibitors blocked thrombin-induced MLC phosphorylation. Mouse endothelial cell line SVEC4-10 cells were cultured and treated with increasing doses of thrombin in combination with ROCKi for 10 min. The ppMLC signal was detected by Western blotting.

Fig. 8. A ROCK inhibitor is active in blocking the secretion of the fibrotic agent LPA or thrombin-induced monocyte chemoattractant protein-1 (MCP-1 or C-C chemokine motif ligand 2, CCL2) from endothelial cells. Murine SVEC410 endothelial cells were treated with 50 μM LPA or 5 U/ml thrombin with or without ROCK inhibition for 24 h, and the level of secreted MCP-1 was measured by ELISA.

Fig. 9a. The ROCK inhibitor is active in a mouse model of pulmonary fibrosis. Representative images of lung sections stained with Masson's trichrome to visualize fibrosis in mouse lungs after 21 days of ROCK inhibitor treatment in a model of bleomycin-induced lung injury.

Fig. 9b. Quantification of positive ROCK inhibitor activity in an in vivo model of pulmonary fibrosis. Ashcroft fibrosis scores, percentage α-smooth muscle actin (aSMA) positive area, and total leukocyte counts in bronchoalveolar lavage fluid obtained from the lungs of mice in a model of bleomycin-induced lung fibrosis treated with the compound of Example 192.

Fig. 10a. A ROCK inhibitor is therapeutically active in a mouse model of pulmonary fibrosis. Representative images of lung sections stained with Masson's trichrome to visualize fibrosis in mouse lungs following therapeutic treatment with ROCK inhibitor in a model of bleomycin-induced lung injury.

Fig. 10b. Quantification of fibrosis score reduction in histopathological analysis of images obtained from ROCK inhibitor- and vehicle-treated mice in a model of bleomycin-induced lung injury.

Fig. 10s. Analysis of ROCK target recruitment in lung tissue from a model of bleomycin-induced pulmonary fibrosis. Western blotting and image quantification demonstrate decreased ROCK target phosphorylation and decreased CCN1 protein levels (a direct result of ROCK inhibition) in mice treated with the ROCK inhibitor of Example 192.

Fig. 11a. The ROCK inhibitor is active in a mouse model of renal fibrosis. Representative images of kidney sections stained with Masson's trichrome to visualize collagen and fibrosis in ROCK inhibitor-treated mice in a ureteral obstruction (UO)-induced renal fibrosis model.

Fig. 11b. Quantification of the reduction in interstitial fibrosis score in histopathological analysis of images obtained from ROCK inhibitor- and basal solution-treated mice in a model of OM-induced renal fibrosis.

Fig. 12a. Inhibition of ROCK stabilizes endothelial barrier function in a mouse model of histamine-induced vascular permeability. Representative images of histamine-induced Evans blue dye sweating in the skin of ROCK inhibitor and basal solution-treated mice compared to the control compound (salbutamol). The ROCK inhibitor induces stabilization of the vascular barrier after administration of a single dose of the compound 1 hour before histamine injection.

Fig. 12b. Quantification of reduction in spot size and Evans blue dye amount in the skin of ROCK inhibitor-treated mice following capillary leak induction by histamine injection.

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Detailed Description of the Invention

ROCK inhibitors.

Compounds of this invention include those having formula (IIj)

where L ¹ represents CH;

L ² represents N;

R ² is selected from the group consisting of H, halogen, cyano, lower alkyl, C ₃ -C ₆ cyclic alkyl, lower alkoxy and C ₁ -C ₃ -perfluoroalkyl;

R ³ is selected from the group consisting of H, halogen, hydroxy, -NRR', cyano, lower alkyl, lower alkoxy and C ₁ -C ₃ -perfluoroalkyl;

alternatively, R ² and R ³ together form a fused phenyl or a fused 5-6 membered ring having 0 to 3 ring heteroatoms, unsubstituted or substituted with -C(=O)-lower alkyl or lower alkyl;

R ⁵ is selected from H, halogen, lower alkyl and lower alkoxy;

R ⁶¹ represents H;

each R is independently selected from H and lower alkyl;

each R' is independently selected from H and lower alkyl;

a selected from 1-10; and x is selected from 1-2;

wherein the lower alkyl is C1- _C4 alkyl;

lower alkoxy is -O-C ₁ -C ₄ -alkyl; and the heteroatom is nitrogen, oxygen or sulfur;

or a pharmaceutically acceptable salt thereof;

or formula (IIk)

where R ² is selected from the group consisting of H, halogen, cyano, lower alkyl, C ₃ -C ₆ cyclic alkyl, lower alkoxy and C ₁ -C ₃ -perfluoroalkyl;

R ³ is selected from the group consisting of H, halogen, hydroxy, -NRR', cyano, lower alkyl, lower alkoxy and C ₁ -C ₃ -perfluoroalkyl;

alternatively, R ² and R ³ together form a fused phenyl or a fused 5-6 membered ring having 0 to 3 ring heteroatoms and unsubstituted or substituted with -C(=O)-lower alkyl or lower alkyl;

R ⁵ is selected from H, halogen, lower alkyl and lower alkoxy;

R ⁶¹ represents H;

each R is independently selected from H and lower alkyl;

each R' is independently selected from H and lower alkyl;

a selected from 1-10; and x is selected from 1-2;

wherein the lower alkyl is C1- _C4 alkyl;

lower alkoxy is -O-C ₁ -C ₄ -alkyl; and the heteroatom is nitrogen, oxygen or sulfur; or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the compounds of this invention are

- 5 044043 is a compound that has the formula

a pharmaceutically acceptable salt thereof.

Most preferably, a compound that is

A preferred pharmaceutically acceptable salt of said compound is the hydrochloride salt.

The term alkyl refers to a radical of saturated aliphatic groups, including straight alkyl groups, branched alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups and cycloalkyl-substituted alkyl groups. In preferred embodiments, the straight-chain or branched alkyl has 8 or fewer carbon atoms on its backbone (eg, C1-C8 in the case of a straight chain, C ₃ -C ₈ in the case of a branched chain), and more preferably 6 or less. Likewise, preferred cycloalkyls have 3-8 carbon atoms in their ring structure and, more preferably, have 3-6 carbon atoms in their ring structure.

Unless the number of carbon atoms is specifically stated, as used herein, lower alkyl means an alkyl group as defined above, but having from one to four carbon atoms, and more preferably from one to three carbon atoms. In preferred embodiments, the substituent designated herein as alkyl is lower alkyl. Lower alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

The term cycloalkyl refers to saturated carbocyclic groups having 3-8 carbon atoms in the ring. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term substituted alkyl refers to an alkyl group as defined above having one to three substituents. The substituents are selected from the group consisting of halogen, hydroxy, lower alkoxy, amino, lower alkylamino, nitro, cyano, lower perfluoroalkyl, lower perfluoroalkoxy and carboxyl.

Substituted lower alkyl refers to a lower alkyl group as defined above having one to three substituents. The substituents are selected from the group consisting of halogen, hydroxy, lower alkoxy, amino, nitro, cyano, lower perfluoroalkyl, lower perfluoroalkoxy and carboxyl.

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

As used herein, the terms alkoxy or alkoxy refer to an alkyl group as defined above that is attached via an oxygen atom. Representative alkoxy groups include methoxy, ethoxy, propyloxy, t-butoxy and the like. The term lower alkoxy refers to an alkoxy substituent in which the lower alkyl is linked via an oxygen atom, wherein the lower alkyl moiety is as defined above.

The terms amine and amino refer to both unsubstituted and substituted amines, for example, a moiety that can be represented by the general formula

where R and R' are each independently selected from H and lower alkyl.

As used herein, the term aryl includes 5- and 6-membered single-ring aromatic groups that may contain zero to four heteroatoms, for example, benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyri

- 6 044043 midin, etc. Those aryl groups that contain heteroatoms in the ring structure may also be called aryl heterocycles or heteroaryl groups. The aromatic ring may be substituted at one or more positions on the ring with substituents such as those described above. The term aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbon atoms are common to the two connected rings (the rings are fused rings), wherein at least one of the rings is aromatic. The term substituted aryl refers to an aryl group as defined above having one to three substituents. The substituents are selected from the group consisting of halogen, hydroxy, lower alkoxy, amino, lower alkylamino, nitro, cyano, lower perfluoroalkyl, lower perfluoroalkoxy and carboxyl.

As used herein, the term aralkyl refers to an alkyl group substituted with an aryl group. Preferably the alkyl group is lower alkyl as described above.

The term substituted aralkyl refers to an aralkyl group as defined above having one to three substituents on the aryl moiety. The substituents are selected from the group consisting of halogen, hydroxy, lower alkoxy, amino, lower alkylamino, nitro, cyano, lower perfluoroalkyl, lower perfluoroalkoxy and carboxyl.

The term heterocycle or heterocyclyl refers to non-aromatic heterocycles having 13 ring heteroatoms.

The term substituted heterocycle refers to a heterocyclic group as defined above having from one to three substituents. The substituents are selected from the group consisting of halogen, hydroxy, lower alkoxy, amino, lower alkylamino, nitro, cyano, lower perfluoroalkyl, lower perfluoroalkoxy and carboxyl. As used herein, the term heteroatom means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen and sulfur. The most preferred are nitrogen and oxygen.

In the context of this document, it is assumed that the definition of each expression, for example, alkyl, m, n, R ¹ , R ² , etc., if it appears more than once in any structure, is independent of its definition elsewhere in the same structure.

It should be understood that substitution or substituted includes the indirect clause that such substitution is made in accordance with the permissible valency of the replaced atom and substituent and that the substitution results in a stable compound, for example, which is not subject to spontaneous transformations, for example, due to rearrangement, cyclization, elimination etc.

As used herein, the term substituted is intended to include all valid substituents for organic compounds. In broad terms, acceptable substituents include acyclic and cyclic, branched and straight-chain, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.

Exemplary substituents include, for example, those described above herein. Acceptable substituents may be one or more and may be the same or different for the respective organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, may contain hydrogen substituents and/or any permissible organic substituents described herein that satisfy the valency of the heteroatoms. This invention is not intended to be limited in any way by the permissible organic substituents.

As used herein, the expression protecting group refers to temporary substituents that protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include carboxylic acid esters, alcohol silyl esters, and aldehyde and ketone acetals and ketals, respectively. There is a review of the field of protecting group chemistry (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991).

Certain compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention considers all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, to be within the scope of the invention . Additional symmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included in this invention.

In one aspect, this invention provides compounds of formulas IIj and which are ROCK inhibitors. ROCK exists in two forms, ROCK1 (ROCKe; p160-ROCK) and ROCK2 (ROCKa). In some embodiments, a compound of Formulas I-IV selectively inhibits ROCK1. In some embodiments, a compound of Formulas I-IV selectively inhibits ROCK2. In some embodiments, the compound of formulas I-IV is non-selective for inhibition of ROCK1 and ROCK2. In the context of this invention, selectivity means that the inhibitor exhibits

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An IC50 that is at least 2-fold, at least 5-fold, at least 10-fold, or at least 25-fold lower for one kinase compared to the IC50 for another kinase.

Methods for determining kinase inhibition are known in the art. For example, the kinase activity of an enzyme and the inhibitory ability of a test compound can be determined by measuring enzyme-specific phosphorylation of a substrate. Commercial assays and kits are available and can be used for this purpose. For example, kinase inhibition can be determined using the IMAP® assay (Molecular Devices). This analytical method involves the use of a fluorescently labeled peptide substrate. Phosphorylation of the labeled peptide by the kinase of interest stimulates the binding of the peptide to the trivalent metal nanoparticle through a specific high-affinity interaction between the phospho group and the trivalent metal. Proximity to the nanoparticle results in increased fluorescent polarization. Inhibition of the kinase by a kinase inhibitor prevents phosphorylation of the substrate and thus limits the binding of the fluorescently labeled substrate to the nanoparticle. Such an assay can be compatible with a microwell assay format, allowing simultaneous determination of the IC50 of multiple compounds.

Methods for treating diseases.

In one aspect of the present invention, there is provided a method of treating a patient suffering from a disease, comprising administering to the patient in need of such treatment a therapeutically effective amount of a compound of the present invention. As used herein, the expression "therapeutically effective amount" means an amount of a compound, material, or composition containing a compound of this invention that is effective to produce some desired therapeutic effect in at least a subpopulation of cells in the animal's body at an acceptable benefit/risk ratio, applicable to any medical treatment, for example, if side effects are acceptable, applies to any medical treatment.

Fibrous disorders.

ROCKs are key regulators of mechanotransduction signaling, and cells involved in tissue fibrotic responses, namely epithelial cells, endothelial cells and myofibroblasts, are regulated by ROCK activity. Thus, the ROCK inhibitors of the invention may have therapeutic use in fibrotic diseases. The present invention provides a method of treating a fibrotic disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formulas I-IV. Non-limiting examples of fibrotic disorders include pulmonary fibrosis, including cystic and idiopathic pulmonary fibrosis, radiation-induced lung injury, liver fibrosis, including cirrhosis, myocardial fibrosis, including arterial fibrosis, endomyocardial fibrosis, myocardial infarction, arterial stiffness, atherosclerosis, restenosis, arthrofibrosis, disease Crohn's, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma/systemic sclerosis, mediastinal fibrosis, keloid and hypertrophic scars, glial scarring or renal fibrosis.

Pharmaceutical compositions.

In one aspect, the present invention provides pharmaceutically acceptable compositions that contain a therapeutically effective amount of one or more compounds of formulas IIj and IIk formulated together with one or more pharmaceutical excipients. As described below, the pharmaceutical compositions of this invention can be prepared, in particular, in solid or liquid form, including those adapted for the following: (1) oral administration, for example, liquid dosage forms (aqueous or non-aqueous solutions or suspensions), tablets, for example , intended for buccal, sublingual and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection in the form of, for example, a sterile solution or suspension, or a sustained release form; (3) topical application, such as a cream, ointment, or controlled-release patch or spray applied to the skin; (4) intravaginal or intrarectal application, for example, in the form of a pessary, cream or foam; (5) sublingual use; (6) ophthalmic use; (7) transdermal application; or (8) nasal administration.

The expression pharmaceutically acceptable is used herein to refer to those compounds, materials, compositions and/or dosage forms that are medically suitable for use in contact with human and animal tissue and are characterized by toxicity, irritation, allergic reactions or other problems or complications. corresponding to an acceptable benefit/risk ratio.

As used herein, the expression pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition, or base solution, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, magnesium silicate talc, calcium or zinc stearate, or stearic acid). acid) or in- 8 044043 encapsulating solvent material involved in the transfer or transport of a given compound from one organ or part of the body to another organ or other part of the body. Each carrier must be acceptable in terms of compatibility with the other ingredients of the dosage form and not cause harm to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as coconut oil and suppository waxes; (9) oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) pH-buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical forms.

As noted above, some embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. In this regard, the term pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds of this invention. These salts can be prepared in situ during the manufacture of the stock administration solution or dosage form or by separately reacting the purified compound of the invention in its free base form with a suitable organic or inorganic acid and isolating the salt thus obtained during subsequent purification. Representative salts include hydrobromic, hydrochloric, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate , lactobionate and lauryl sulfonate salts, etc. (See, for example, Berge et al. (1977) Pharmaceutical Salts, J. Pharm. Sci. 66:1-19).

Pharmaceutically acceptable salts of the subject compounds include conventional non-toxic salts or quaternary ammonium salts of compounds, for example, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts derived from organic acids, such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfamic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isothionic, etc.

In other cases, the compounds of this invention may contain one or more acidic functional groups and, therefore, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of the compounds of this invention. These salts can similarly be prepared in situ during the manufacture of the stock administration solution or dosage form, or by separately reacting the purified compound of the invention in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, ammonium or a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. (see, for example, Berge et al., above).

Also present in the compositions may be wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents, preservatives and antioxidants.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelators such as acetic acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

Dosage forms of this invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral

- 9 044043 introductions. The dosage forms may be conveniently presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient that can be combined with the carrier material to form a unit dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with the carrier material to form a unit dosage form will generally be that amount of the compound that produces a therapeutic effect. In general, of one hundred percent, this amount will range from about 0.1% to about 99% of the active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.

In certain embodiments, the dosage form of this invention contains an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle-forming agents, such as bile acids, and polymeric carriers, such as polyesters and polyanhydrides; and a compound of this invention. In certain embodiments, the above dosage form makes the compound of this invention orally bioavailable.

Methods for preparing dosage forms or compositions include the steps of combining a compound of this invention with a carrier and, optionally, one or more auxiliary ingredients. In general, dosage forms are prepared by uniformly and carefully combining the compound of this invention with liquid carriers or particulate solid carriers, or both, and then, if necessary, molding the product.

The dosage forms of the invention suitable for oral administration may be in the form of capsules, starch capsules, pills, tablets, lozenges, powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion. or water in oil, or in the form of an elixir or syrup, or in the form of lozenges (using an inert base such as gelatin or glycerin, or sucrose and gum arabic) and/or in the form of mouth rinses, etc., which are all contain a predetermined amount of a compound of this invention as an active ingredient. The compound of this invention can also be administered as a bolus, electuary or paste.

In the solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, lozenges, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable excipients, including a pharmaceutically acceptable carrier such as citrate sodium or dicalcium phosphate, and/or any of the following: (1) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; (3) humectants such as glycerin; (4) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarders such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds and surfactants such as poloxamer and sodium lauryl sulfate; (7) wetting agents such as, for example, cetyl alcohol, glycerol monostearate and nonionic surfactants; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid and mixtures thereof; (10) dyes; and (11) controlled release agents such as crospovidone or ethylcellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard shell gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using a binder (eg, gelatin or hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (eg, sodium starch glycolate or crosslinked sodium carboxymethylcellulose), surfactant or dispersing agent. Molded tablets can be prepared by molding in a suitable device a mixture of a powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions of this invention, such as dragees, capsules, pills and granules, can optionally be scored or formulated with coatings or coatings, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. dosage forms. They can also be formulated to provide a sustained or controlled release of the active ingredient, using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microcaps

- 10 044043 sula. They can be prepared for rapid release, for example by lyophilizing. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injection medium immediately before use. These compositions may also optionally contain opacifiers and may be formulated such that they release only the active ingredient(s) or, preferably, in a specific part of the gastrointestinal tract, optionally in a delayed manner. Examples of encapsulating compositions that can be used include polymeric substances and waxes. The active ingredient may also be present in microencapsulated form, optionally with one or more of the excipients described above.

Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water and other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate , propylene glycol, 1,3-butylene glycol, oils (especially cottonseed, peanut, corn, wheat germ, olive, castor and sesame oils), glycerin, tetrahydrofuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof.

In addition to diluents, oral compositions may also contain additional excipients such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, colors, flavoring agents and preservatives.

Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Dosage forms of the pharmaceutical compositions of the invention for rectal or vaginal administration can be presented in the form of a suppository, which can be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers containing, for example, coconut oil, polyethylene glycol, wax for suppositories or salicylate, and which is solid at room temperature but liquid at body temperature and therefore melts in the rectal or vaginal cavity and releases the active compound.

Dosage forms of this invention that are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or sprays containing such carriers as are suitable as known in the art.

Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalers. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be necessary.

Ointments, pastes, creams and gels may contain, in addition to the active compound of the invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and oxide zinc, or mixtures thereof.

Powders and sprays may contain, in addition to the compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

Transdermal patches have the additional advantage of providing controlled delivery of the compound of this invention into the body. Such dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Suction enhancers can also be used to increase the flow of the compound through the skin. The rate of such flow can be controlled by installing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

Ophthalmic dosage forms, eye ointments, powders, solutions, etc. are also intended to be within the scope of this invention.

The pharmaceutical compositions of this invention, suitable for parenteral administration, contain one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted as sterile solutions or dispersions for injection immediately before use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostatic agents, solutes,

- 11 044043 which make the dosage form isotonic with the blood of the intended recipient, or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerin, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper flow can be maintained, for example, by using coating materials such as lecithin, maintaining the required particle size in the case of dispersions, and using surfactants.

These compositions may also contain additional excipients such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the effects of microorganisms on the compounds in question can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, etc. It may be necessary to include isotonic agents such as sugars, sodium chloride and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

In some cases, to prolong the effect of the drug, it is necessary to slow down the absorption of the drug after subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material having poor solubility in water. Therefore, the rate of absorption of a drug depends on the rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug is achieved by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are prepared by molding microcapsule matrices of the compounds in question in biodegradable polymers such as polylactide-polyglycolide. Depending on the drug to polymer ratio and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot forms are also prepared by enclosing the drug in liposomes or microemulsions that are compatible with body tissues.

When the compounds of this invention are administered as pharmaceuticals to humans and animals, they can be used alone or in the form of a pharmaceutical composition containing, for example, from 0.1 to 99% (more preferably from 10 to 30%) of the active ingredient in the combination with a pharmaceutically acceptable carrier.

Routes of administration and doses.

The preparations of this invention can be administered orally, parenterally, topically or rectally. Of course, they are used in forms suitable for each route of administration. For example, they are administered in the form of tablets or capsules, by injection, inhalation, in the form of ophthalmic lotion, ointment, suppository, etc., administration by injection, infusion or inhalation; local administration via lotion or ointment; and rectal administration via suppositories. Oral administration is preferred.

As used herein, the expressions parenteral and parenterally administered mean modes of administration other than enteral and local administration, typically by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal , subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrathoracic injection and infusion.

As used herein, the expressions systemically administered, systemically administered, peripherally administered, and peripherally administered mean the administration of a compound, drug, or other material other than directly into the central nervous system so that it enters the patient's system and thereby becomes metabolized. and similar processes, for example, as in the case of subcutaneous administration.

These compounds can be administered to humans and other animals for therapy by any suitable route of administration, including oral, nasal, e.g., spray, rectal, intravaginal, parenteral, intracisternal, and topical, e.g., powders, ointments, or drops, including buccal and sublingual.

Regardless of the chosen route of administration, the compounds of this invention, which can be used in a suitable hydrated form, and/or the pharmaceutical compositions of this invention are prepared in pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

Actual dosage levels of active ingredients in pharmaceutical compositions according to this

- 12 044043 the invention can be varied so as to obtain an amount of active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without toxicity to the patient.

The dosage level chosen will depend on a number of factors, including the potency of the particular compound of this invention or its ester, salt or amide used, route of administration, time of administration, rate of elimination or metabolism of the particular compound used, rate and extent of absorption, duration of treatment, other drugs drugs, compounds and/or materials used in combination with the particular compound used, age, sex, weight, pathological condition, general health and medical history of the patient being treated, and similar factors well known in the medical field.

A physician or veterinarian appropriately skilled in the art can readily determine and prescribe the required effective amount of the pharmaceutical composition. For example, a physician or veterinarian may begin with dosages of the compounds of the invention used in a pharmaceutical composition at levels below those required to obtain the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will be that amount of compound that is the lowest dose effective to produce a therapeutic effect. Such effective dose will generally depend on the factors described above. In general, oral, intravenous, intracerebroventricular and subcutaneous dosages of the compounds of this invention to a patient, when used for the indicated analgesic effect, will range from about 0.0001 to about 100 mg per kilogram of body weight per day.

In certain embodiments, a dose of the compound or composition is administered to the subject every day, every other day, every two days, every three days, once a week, twice a week, thrice a week, or once every two weeks. If necessary, an effective daily dose of the active compound can be administered in two, three, four, five, six or more dosage units administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. In some embodiments, the dose(s) of the compound or composition is administered for 2 days, 3 days, 5 days, 7 days, 14 days, or 21 days. In certain embodiments, the dose of the compound or composition is administered for 1 month, 1.5 months, 2 months, 2.5 months, 3 months, 4 months, 5 months, 6 months, or more.

The above dosing regimens are for illustrative purposes only and should not be considered limiting. One skilled in the art will understand that all dosages are within the scope of this invention.

The patient receiving such treatment is any animal in need thereof, including primates, particularly humans, and other mammals such as horses, cattle, pigs and sheep; as well as poultry and domestic animals in general.

Compounds for use in the methods of this invention can be administered alone or in the form of mixtures with pharmaceutically acceptable carriers, and can also be administered in combination with antimicrobial agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides. Thus, combination therapy includes sequential, simultaneous and separate administration of the active compound in such a way that the therapeutic effect of the first administered component does not completely disappear during the administration of the subsequent one.

The addition of the active compound of the invention to animal feed is preferably accomplished by preparing an appropriate pre-feed containing the active compound in an effective amount and incorporating the pre-feed into the complete diet.

Alternatively, an intermediate concentrate or feed additive containing the active ingredient may be mixed into the feed. The manner in which such premixes and complete rations can be prepared and administered is described in books (such as Applied Animal Nutrition, W.H. Freedman and CO., San Francisco, U.S.A., 1969 or Livestock Feeds and Feeding O and B books, Corvallis, Ore. ., U.S.A., 1977).

Microemulsification technology can be used to improve the bioavailability of lipophilic (water-insoluble) pharmaceutical agents. Examples include Trimetrine (Dordunoo, S.K., et al., Drug Development and Industrial Pharmacy, 17(12), 1685-1713, 1991) and REV 5901 (Sheen, P.C., et al., J Pharm Sci 80(7), 712 -714, 1991). Among other things, microemulsification provides increased bioavailability due to preferential absorption in the lymphatic system instead of the circulatory system, thereby bypassing the liver and preventing degradation of compounds in the hepatobiliary circulation.

Controlled release.

The release characteristics of the dosage form of this invention depend on the encapsulating material, the concentration of the encapsulated drug, and the presence of release modifying agents. Release can be made pH dependent, for example by using a pH sensitive coating that allows release only at low temperatures.

- 13 044043 pH, such as in the stomach, or a higher pH, such as in the intestines. An enteric coating may be used to prevent release before passing through the stomach. Several types of coating or mixture of cyanamide encapsulated in different materials can be used to provide initial release in the stomach followed by release in the intestines. Release can also be controlled by the inclusion of salts or pore-forming agents, which can enhance water uptake or drug release by diffusion from the capsule. Can also be used in excipients that modify the solubility of the drug to control the rate of release. Agents that enhance matrix degradation or release from the matrix may also be included. They can be added to the drug product, added as a separate phase (ie, particulate), or co-dissolved in the polymer phase, depending on the compound. Some types of degradation enhancers include inorganic salts such as ammonium sulfate and ammonium chloride, organic acids such as citric acid, benzoic acid and ascorbic acid, inorganic bases such as sodium carbonate, potassium carbonate, zinc carbonate and zinc hydroxide, and organic bases , such as protamine sulfate, spermine, choline, ethanolamine, diethanolamine and triethanolamine, as well as surfactants such as Tween® and Pluronic®. Pore-forming agents that impart microstructure to the matrices (i.e., water-soluble compounds such as inorganic salts and sugars) are added in particulate form. Their range should be from one to thirty percent (wt./wt. polymer).

Absorption can also be adjusted by changing the residence time of the particles in the intestine. This can be achieved, for example, by coating the particles with a mucoadhesive polymer or selecting it as an encapsulating material. Examples include most polymers with free carboxyl groups, such as chitosan, celluloses and, in particular, polyacrylates (as used herein, polyacrylates refer to polymers containing acrylate groups and modified acrylate groups, such as cyanoacrylates and methacrylates).

It is understood and expected that variations in the principles of the invention described herein may be made by one skilled in the art, and such modifications are intended to be included within the scope of the invention. The following examples further illustrate the present invention, but should not be construed as limiting in any way the scope of the present invention. All references cited herein are incorporated by reference in their entirety.

It is understood and expected that variations in the principles of the invention described herein may be made by one skilled in the art, and such modifications are intended to be included within the scope of the invention. The following examples further illustrate the present invention, but should not be construed as limiting in any way the scope of the present invention. All references cited herein are incorporated by reference in their entirety.

Examples

Example 1.

All solvents and reagents were obtained commercially and used as received. ¹ H NMR spectra were recorded on a Bruker instrument (300 MHz or 400 MHz) in the indicated deuterated solvents. Chemical shift values are given in ppm and interaction constants are given in hertz. All final compounds were purified by flash chromatography using silica gel with a sieve number of 220-400, or reverse phase HPLC with CH ₃ CN/water as solvents. Thin layer chromatography was carried out on silica gel plates 60 F-254 (0.25 mm thick). Visualization was performed using UV light and/or 10% phosphomolybdic acid in ethanol. Nominal (low resolution) mass spectra were recorded on a Waters LCT or Applied Biosystems API 3000 mass spectrometer. High resolution mass spectra (HRMS) were recorded on a Waters LCT or Agilent TOF mass spectrometer. All other LC-MS experiments were performed on an Agilent 1100 HPLC system coupled to an Agilent single quadrupole mass spectrometer. The purity of the compound was determined by LC-MS with wavelengths of 230 nm and 254 nm. All final compounds reported herein are >95% pure.

Scheme 1

2 3

Method A.

A reaction was carried out with a solution of compounds of general structure 1 (1 eq.), Boc-protected amine (1-3

- 14 044043 eq.) and DIPEA (3 eq.) in DMSO at 100-110°C. The reaction mixture was cooled to room temperature and quenched by adding water, and the crude residue was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude compound of general structure 2, which was used in the next step without further purification. HCl/dioxane (4H) or TFA was added to a solution of compounds of general structure 2 in CH ₂ Cl ₂ . The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC to obtain the final compounds of general structure 3.

Method B.

A reaction was carried out with a solution of compounds of general structure 1 (1 eq.), Bn-protected amine (1-3 eq.) and DIPEA (3 eq.) in DMSO at 100-110°C. The reaction mixture was cooled to room temperature and quenched by adding water, and the crude residue was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude residue with general structure 2. The crude product was used in the next step without further purification or purified by preparative TLC. HCl (12H, 2 eq) and Pd/C (wet, 0.1 eq) were added to a mixture of compound 2 in MeOH. The reaction mixture was stirred at room temperature for 16 hours under an H ₂ atmosphere. The mixture was filtered through a celite filter and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC to obtain the final compounds with general structure 3.

Method C.

A solution of compounds of general structure 1 (1 eq.), unprotected secondary mine (1-3 eq.) and DIPEA (2 eq.) in DMSO or DMF was stirred at 100-110°C for several hours. The residue was purified by reverse-phase preparative HPLC to obtain the final compounds with general structure 3.

Method D

HCl/dioxane (4H, 2 equiv.) was added to a solution of compounds of general structure 1 (1 eq.) in CH ₂ Cl ₂ (300.00 μl). After stirring the mixture at 15°C for 30 minutes, the mixture was concentrated under reduced pressure to obtain a crude residue. The residue was dispersed in t-BuOH (300.00 µl), amine (1 eq.) was added. The reaction mixture was then stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature and dispersed in CH ₂ Cl ₂ . TFA facilitated the removal of Boc protecting groups. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by reverse-phase preparative HPLC to obtain the final compounds with general structure 3.

Method E.

A solution of compounds of general structure 1 (1 eq.), Boc-protected amine or amino alcohol (1-1.2 eq.) in i-PrOH was stirred at 170°C under microwave irradiation for 1 hour. The solution was purified by the reverse-phase preparative method HPLC to obtain compound of general structure 2. Compound of general structure 2 was dissolved in CH ₂ Cl ₂ and TFA was added. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC to obtain the final compounds with general structure 3.

Method F

A reaction was carried out with a solution of compounds of general structure 1 (1 eq.), Boc-protected amine (1-3 eq.) and DIPEA (3 eq.) in DMSO at 100-110°C. The reaction mixture was cooled to room temperature and quenched by adding water, and the crude residue was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude compound of general structure 2, which was used in the next step without further purification. HCl/dioxane (4H) or TFA was added to a solution of compounds of general structure 2 in CH ₂ Cl ₂ . The reaction mixture was stirred at room temperature for 2 hours and the mixture was concentrated under reduced pressure to obtain compound of general structure 3. The corresponding aldehyde was added to a solution of compound 3 in MeOH and TFA (2 eq.) at room temperature. The reaction mixture was stirred at room temperature for 16 hours and NaBH ₃ CN (2 eq.) was added. The reaction mixture was stirred for 1 hour. The solvent was removed under reduced pressure. The crude material was dissolved in EtOAc and washed with water. The combined organic phases were dried and the solvent was removed under reduced pressure. The residue was purified by reverse phase preparative HPLC to give the final compound.

- 15 044043

Scheme 2

Method G.

The reaction was carried out with a solution of compounds of general structure 4 (1 eq.), Boc-protected amine (1-3 eq.) and DIPEA (3 eq.) in DMSO at 100-110°C. The reaction mixture was cooled to room temperature and quenched by adding water, and the crude residue was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a crude compound of general structure 5, which was purified using silica gel chromatography. 4-pyridinylboronic acid (1 eq.), K ₂ CO ₃ (2 eq.), Pd(dppf)Cl ₂ (0.05 eq.) was added to a solution of compounds of general structure 5 in dioxane and water. The reaction mixture was stirred for 16 hours at 100°C. The reaction mixture was diluted with water and extracted with EtOAc, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude compound of general structure 6. To a solution of compounds of general structure 6 in CH ₂ Cl ₂ was added HCl/dioxane (4H) or TFA. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC to obtain the final compounds of general structure 7.

Example 2.

2-(3-benzyl-1,4-diazepan-1-yl)-N-(1H-indazol-5-yl)-5,7-dihydrofuro[3,4-b]pyrimidin-4-amine

The reaction was carried out following general protocol C. The residue was purified by reverse phase preparative HPLC to give 2-(3-benzyl-1,4-diazepan-1-yl)-N-(1H-indazol-5-yl)-5, 7dihydrofuro[3,4-th]pyrimidin-4-amine as a yellow solid (22%).

^1H NMR (400 MHz, DMSO- _d6 ) δ 12.96 (s, 1H), 8.73 (s, 1H), 8.13 (s, 1H), 7.96-7.87 (m, 1H), 7.49-7.44 (m, 2H), 7.29-7.25 (m, 2H), 7.20-7.16 (m, 3H), 4.87 (s, 2H) , 4.67 (s, 2H), 3.91-3.85 (m, 1H), 3.81-3.77 (m, 1H), 3.60-3.53 (m, 2H), 3 .09-3.05 (m, 1H), 2.76-2.60 (m, 4H), 1.89-1.82 (m, 1H), 1.47-1.37 (m, 1H) . MS (ER+) m/e 442.4 (m+H) ⁺ .

Example 3.

N-(2-(1,4-diazepan-1-yl)-5-methylpyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 32 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(1,4-diazepan-1-yl)-5methylpyrimidin-4-yl)-1H-indazol-5-amine as a white solid (35% ).

^1H NMR (400 MHz, DMSO-Y6) δ 12.93 (s, 1H), 8.05-8.19 (m, 2H), 7.94-7.99 (m, 1H), 7.71 -7.76 (m, 1H), 7.60 (t, J=7.2 Hz, 1H), 7.41-7.47 (m, 1H), 3.58-3.74 (m, 4H ), 3.46 (s, 1H), 3.27 (s, 1H), 2.79 (s, 1H), 2.64 (t, J=5.2 Hz, 1H), 2.05 (s , 3H), 1.72 (dd, J=11.2, J=5.6 Hz, 2H). MS (ER+) m/e 324.1 (M+H) ⁺ .

- 16 044043

Example 4.

N-(5-chloro-2-(1,4-diazepan-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 32 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-chloro-2-(1,4-diazepan-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (35 %).

1H NMR (400 MHz, CD3OD) δ 8.02 (s, 2H), 7.93 (s, 1H), 7.59 (dd, J=8.8, 1.6 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 3.76 (t, J=6.0 Hz, 4H), 2.97 (t, J=4.8 Hz, 2H), 2.87 (t , J=6.0 Hz, 2H), 1.89 (t, J=4.8 Hz, 2H). MS (ER+) m/e 344.0 (M+H) ⁺ .

Example 5.

N-(2-(1,4-diazepan-1-yl)-6-methylpyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(1,4-diazenan-1-yl)-6methylpyrimidin-4-yl)-1H-indazol-5-amine as a white solid (50% ).

1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), 7.97 (s, 1H), 7.49 (s, 2H), 5.92 (s, 1H), 3.94-3 .88 (m, 4H), 3.12 (t, J=5.2 Hz, 2H), 2.97 (t, J=5.6 Hz, 2H), 2.22 (s, 3H), 2 .02 (t, J=5.6 Hz, 2H). MS (ER+) m/e 324.1 (M+H) ⁺ .

Example 6.

2-(1,4-diazepan-1 -yl)-N-(1 H-indazol-5 -yl)quinazolin-4-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give 2-(1,4-diazepan-1-yl)-N-(1H-indazol5-yl)quinazolin-4-amine as a light red solid (51%) .

1H NMR (400 MHz, DMSO- _d6 ) δ 13.02 (br s, 1H), 9.55-9.494 (m, 1H), 8.30-8.20 (m, 2H), 8.02 (d, J=11.2 Hz, 1H), 7.74-7.71 (m, 2H), 7.59-7.52 (m, 2H), 7.33 (t, J=8.4 Hz, 1H), 7.17-7.11 (m, 1H), 3.80-3.31 (m, 6H), 2.86 (m, 1H), 2.68 (d, J=5, 6 Hz, 1H), 1.78 (m, 2H). MS (ER+) m/e 360.1 (M+H) ⁺ .

Example 7.

N-(2-(1,4-diazepan-1-yl)-5-methoxypyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(1,4-diazepan-1-yl)-5methoxypyrimidin-4-yl)-1H-indazol-5-amine as a white solid (40% ).

1H NMR (400 MHz, CD3OD) δ 8.22 (s, 1H), 7.99 (s, 1H), 7.64 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7, 60 (s, 1H),

- 17 044043

7.50 (d, J=9.2 Hz, 1H), 3.89 (s, 3H), 3.79 (t, J=5.6 Hz, 4H), 3.02 (t, J=5 .2 Hz, 2H), 2.86 (t, J=5.6 Hz, 2H), 1.981.92 (m, 2H). MS (ER+) m/e 340.1 (M+H) ⁺ .

Example 8.

N-(2-(1,4-diazepan-1-yl)-5,6-dimethylpyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(1,4-diazepan-1-yl)-5,6dimethylpyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid ( 20%).

Ή NMR (400 MHz, DMSO-I6) δ 8.32 (s, 2H), 8.16 (s, 1H), 7.98 (s, 1H), 7.95 (s, 1H) 7.55 ( d, J=7.6 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 3.67-3.76 (m, 4H), 3.12 (s, 2H), 3.02 (s, 2H), 2.22 (s, 3H), 2.07 (s, 3H), 1.95 (s, 2H). MS (ER+) m/e 338.2 (M+H)+.

Example 9.

2-(1,4-diazepan-1-yl)-N-(1H-indazol-5-yl)-5,6,7,8-tetrahydroquinazolin-4-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give 2-(1,4-diazepan-1-yl)-N-(1H-indazol5-yl)-5,6,7,8-tetrahydroquinazolin-4-amine as white solid (43%).

^1H NMR (400 MHz, DMSO-Y6) δ 12.19 (s, 1H), 9.73 (s, 1H), 9.50 (br s, 2H), 8.11 (s, 1H), 7.87 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 3.92 (m, 2H), 3.75 (m, 2H), 3.16 (m, 4H), 2.81 (m, 2H), 2.53 (m, 2H), 2.05 (m, 2H), 1.79 (m , 4H). MS (ER+) m/e 364.2 (M+H) ⁺ .

Example 10.

2-(1,4-diazepan-1-u4)-N-(1H-indazol-5-yl)thieno[3,2-d]pyrimidin-4-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give 2-(1,4-diazepan-1-yl)-N-(1H-indazol5-yl)thieno[3,2-y]pyrimidin-4-amine as white solids (58%).

1H NMR (400 MHz, DMSO-Y6) δ 13.79 (br s, 1H), 11.14 (s, 1H), 9.54 (br s, 2H), 8.33 (s, 1H) , 8.14 (s, 1H), 8.00 (s, 1H), 7.72-7.35 (m, 3H), 3.92 (m, 4H), 3.24 (m, 4H), 2.15 (m, 2H). MS (ER+) m/e 366.1 (M+H) ⁺ .

Example 11.

2-(1,4-diazepan-1-nn)-N-(1H-indazol-5-yl)-5,7-dihydrofuro[3,4-th]pyrimidin-4-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give 2-(1,4-diazepan-1-yl)-N-(1H-indazol5-yl)-5,7-dihydrofuro[3,4--pyrimidin-4 -amine as a white solid (40%).

- 18 044043

1H NMR (400 MHz, CD ₃ OD) δ 8.07 (s, 1H), 8.00 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.50 (d , J=8.8 Hz, 1H),

4.95-4.92 (m, 2H), 4.79-4.78 (m, 2H), 4.88-4.83 (m, 4H), 3.07-3.04 (m, 2H ), 2.94-2.91 (m, 2H), 2.00-1.94 (m,

2H). MS (ER+) m/e 352.1 (M+H)+.

Example 12.

2-(1,4-diazepan-1-yl)-N-(1H-indazol-5-yl)-5,7-dihydrothieno[3,4-d]pyrimidin-4-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give 2-(1,4-diazepan-1-yl)-N-(1H-indazol5-yl)-5,7-dihydrothieno[3,4-d]pyrimidin-4 -amine as a yellow solid (40%).

^1H NMR (400 MHz, DMSO-I6) δ 12.99 (s, 1H), 8.49 (s, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7. 60 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 4.04 (s, 2H), 3.98 (s, 2H), 3, 73-3.65 (m, 4H), 2.86-2.80 (m, 2H), 2.68-2.67 (m, 2H), 1.76-1.73 (m, 2H). MS (ER+) m/e 352.1 (M+H)+.

Example 13.

N-(5,6-dimethyl-2-(3-methylpiperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 32 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5,6-dimethyl-2-(3-methylpiperazin1-yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (32 %).

1H NMR (400 MHz, CD ₃ OD) δ 8.33 (s, 2H), 7.99 (s, 1H), 7.86 (s, 1H), 7.54-7.48 (m, 2H) , 4.59 (d, J=14.2 Hz, 2H), 3.35 (m, 1H), 3.28-3.23 (m, 1H), 3.19-3.00 (m, 2H ), 2.93-2.89 (m, 1H), 2.33 (s, 3H), 2.14 (s, 3H), 1.28 (d, J=6.4 Hz, 3H). MS (ER+) m/e 338.1 (m+H) ⁺ .

Example 14.

N-(2-(3-ethylpiperazin-1-yl)-5,6-dimethylpyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 32 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-ethylpiperazin-1-yl)-5,6dimethylpyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (37% ).

1H NMR (400 MHz, CD3OD) δ 8.07 (s, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.46 (dd, J=8.8, 2.0 Hz, 1H), 4.49 (d, J=13.6 Hz, 1H), 4.38 (d, J=14.8 Hz, 1H ), 3.47-3.37 (m, 2H), 3.23-3.10 (m, 2H), 3.093.01 (m, 1H), 2.48 (s, 3H), 2.22 ( s, 3H), 1.64-1.51 (m, 2H), 0.79 (t, J=7.6 Hz, 3H). MS (ER+) m/e 352.1 (M+H)+.

Example 15.

N-(2-(3-isopropylpiperazin-1-yl)-5,6-dimethylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following general protocol A. The reaction time in the first stage was 32 h,

- 19 044043 and the crude material was further used without additional purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-isopropylpiperazin-1-yl)5,6-dimethylpyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (25 %).

1H NMR (400 MHz, CD ₃ OD) δ 8.46 (s, 2H), 7.97 (s, 1H), 7.85 (s, 1H), 7.53-7.47 (m, 2H) , 4.78 (d, J=9.6 Hz, 1H), 4.66 (d, J=12.0 Hz, 1H), 3.34 (m, 1H), 3.14-3.03 ( m, 2H), 2.84-2.81 (m, 2H), 2.32 (s, 3H), 2.16 (s, 3H), 1.85-1.78 (m, 1H), 0 .99 (d, J=6.8 Hz, 3H), 0.91 (d, J=6.8 Hz, 3H). MS (ER+) m/e 366.2 (M+H) ⁺ .

Example 16.

N-(2-(3-isopropyl-1,4-diazepan-1-yl)-5,6-dimethylpyrimidin-4-yl)-1 H-ind azol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(2-(3-isopropyl-1,4-diazepan-1-yl)-5,6-dimethylpyrimidin-4yl)-1H- indazol-5-amine as a yellow solid (12%).

Ή NMR (400 MHz, CD3OD) δ 8.45 (br s, 2H), 8.00 (s, 1H), 7.85 (s, 1H), 7.53-7.47 (m, 2H) , 4.30-4.18 (m, 2H), 3.49-3.38 (m, 3H), 3.10 (m, 1H), 3.00 (m, 1H), 2.33 (s , 3H), 2.16-2.15 (m, 4H), 2.08-2.06 (m, 1H), 1.74 (m, 1H), 0.83-0.79 (m, 6H ). MS (ER+) m/e 380.1 (M+H) ⁺ .

Example 17.

4-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)piperazin-2-one

N x^r-'N XX? HN

Ν Ν y k^NH

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give 4-(4-((1H-indazol-5-yl)amino)pyrimidin-2-yl)piperazin-2-one as a beige solid substances (62%). MS (ER+) m/e 310.1 (M+H) ⁺ .

Example 18.

2-(3-phenyl-1,4-diazepan-1-yl)-N-(4-(pyridin-4-yl)phenyl)pyrimidin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(3-phenyl-1,4-diazepan-1-yl)-N-(4-(pyridin-4yl)phenyl)pyrimidine-4 -amine as a yellow solid (18%).

^1H NMR (400 MHz, Methanol- _d4 ) δ 8.56-8.54 (m, 2H), 8.43 (s, 1H), 7.99 (d, J=6.0 Hz, 1H) , 7.68 (m, 2H), 7.59 (m, 2H), 7.50-7.39 (m, 7H), 6.18 (d, J=6.0 Hz, 1H), 4, 80-4.74 (m, 1H), 4.56 (dd, J=10.8, 2.4 Hz, 1H), 4.46 (m, 1H), 3.92 (dd, J=15, 6, 10.4 Hz, 1H), 3.59-3.53 (m, 2H), 3.21-3.09 (m, 1H), 2.47-2.31 (m, 2H). MS (ER+) m/e 423.0 (M+H).

- 20 044043

Example 19.

N-(2-(5-isopropyl-1,4-diazepan-1-yl)-5,6-dimethylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(2-(5-isopropyl-1,4-diazepan-1-yl)-5,6-dimethylpyrimidin-4yl)-1H- indazol-5-amine as a white solid (44%).

1H NMR (400 MHz, CD3OD) δ 8.51 (br s, 2H), 8.00 (s, 1H), 7.91 (d, J=0.8 Hz, 1H), 7.57-7 .49 (m, 2H), 4.12-4.02 (m, 1H), 3.99-3.93 (m, 1H), 3.86-3.79 (m, 1H), 3.71 -3.64 (m, 1H), 3.44-3.35 (m, 1H), 3.20-3.13 (m, 2H), 2.34 (s, 3H), 2.15 (s , 3H), 2.11-1.99 (m, 2H), 1.85-1.75 (m, 1H), 0.99 (t, J=6.4 Hz, 6H). MS (ER+) m/e 380.1 (M+H) ⁺ .

Example 20.

N-(5,6-dimethyl-2-(3-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(5,6-dimethyl-2-(3-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl) -1Hindazol-5-amine as a light yellow oil (32%).

1H NMR (400 MHz, CD3OD) δ 8.42 (s, 2H), 7.83 (s, 1H), 7.80 (s, 1H), 7.46 (dd, J=8.8, 1, 6 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.16 (t, J=6.4 Hz , 2H), 7.02 (m, 2H), 4.52-4.40 (m, 2H), 4.30 (m, 1H), 3.64-3.57 (m, 1H), 3, 48-3.43 (m, 2H), 3.03-2.96 (m, 1H), 2.41-2.28 (m, 4H), 2.24-2.14 (m, 4H). MS (ER+) m/e 414.1 (M+H) ⁺ .

Example 21.

N-(5,6-dimethyl-2-(5-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(5,6-dimethyl-2-(5-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl) -1Hindazol-5-amine as a yellow solid (9%).

^1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.83 (d, J=0.8 Hz, 1H), 7.56 (d, J=9.2 Hz, 1H) , 7.51-7.43 (m, 6H), 4.51 (d, J=10.8 Hz, 1H), 4.07-3.97 (m, 3H), 3.67 (t, J =11.2 Hz, 1H), 3.44 (m, 1H), 2.58 (m, 1H), 2.49 (s, 3H), 2.22 (s, 3H), 2.18-2 .15 (m, 1H). MS (ER+) m/e 414.1 (M+H) ⁺ .

Example 22.

N-(5,6-dimethyl-2-(3 -methyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following general protocol A. The reaction time in the first stage was 48 h,

- 21 044043 and the crude material was further used without additional purification. The final residue was purified by reverse phase preparative HPLC to give N-(5,6-dimethyl-2-(3-methyl-1,4diazepan-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine in as a yellow solid (22%).

1H NMR (400 MHz, CD3OD) δ 8.39 (s, 2H), 8.01 (s, 1H), 7.85 (s, 1H), 7.55-7.48 (m, 2H), 4 .24-4.16 (m, 2H), 3.40-3.34 (m, 3H), 3.27-2.23 (m, 1H), 3.00-2.96 (m, 1H) , 2.34 (s, 3H), 2.18-2.06 (m, 5H), 1.04-1.01 (m, 3H). MS (ER+) m/e 352.2 (M+H) ⁺ .

Example 23.

N-(2-(5-ethyl-1,4-diazepan-1-yl)-5,6-dimethylpyrimidin-4-yl)-1 H-indazol-5-amine n

XXz

ΗΝ yS __^NH

The reaction was carried out following General Protocol A. The reaction time in the first stage was 46 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(5-ethyl-1,4-diazepan-1-yl)-5,6dimethylpyrimidin-4-yl)-1H-indazol-5-amine as yellow solid (12%).

^1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.83 (d, J=0.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H) , 7.50 (dd, J=8.8, 1.6 Hz, 1H), 3.96-3.91 (m, 2H), 3.87-3.85 (m, 1H), 3.59 -3.58 (m, 1H), 3.30 (m, 2H), 3.21 (m, 1H), 2.49 (s, 3H), 2.22 (s, 3H), 2.12 ( m, 1H), 2.00-1.98 (m, 1H), 1.78-1.68 (m, 2H), 1.03 (t, J=7.2 Hz, 3H). MS (ER+) m/e 366.1 (M+H) ⁺ .

Example 24.

N-(2-(3,5-dimethylpiperazin-1-yl)-5,6-dimethylpyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 48 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,5-dimethylpiperazin-1-yl)-5,6dimethylpyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid ( 12%).

1H NMR (400 MHz, CD3OD) δ 8.50 (s, 2H), 8.01 (s, 1H), 7.89 (dd, J=1.6, 0.8 Hz, 1H), 7.56 -7.50 (m, 2H), 4.75-4.71 (m, 2H), 3.30-3.22 (m, 2H), 2.76-2.69 (m, 2H), 2 .34 (s, 3H), 2.15 (s, 3H), 1.29 (d, J=6.4 Hz, 6H). MS (ER+) m/e 352.1 (M+H) ⁺ .

Example 25.

N-(5,6-dimethyl-2-(5-methyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 48 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5,6-dimethyl-2-(5-methyl-1,4diazepan-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine in as a yellow solid (28%).

1H NMR (400 MHz, CD3OD) δ 8.39 (s, 2H), 8.01 (s, 1H), 7.92 (s, 1H), 7.57-7.50 (m, 2H), 4 .05-3.89 (m, 3H), 3.67-3.60 (m, 1H), 3.46-3.37 (m, 2H), 3.24-3.14 (m, 1H) , 2.36 (s, 3H), 2.16 (s, 3H), 2.12-2.04 (m, 1H), 1.971.87 (m, 1H), 1.34 (d, J=6 ,4 Hz, 3H). MS (ER+) m/e 352.1 (M+H) ⁺ .

- 22 044043

Example 26.

N-(2-(3-ethyl-1,4-diazepan-1-yl)-5,6-dimethylpyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 96 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-ethyl-1,4-diazepan-1-yl)-5,6dimethylpyrimidin-4-yl)-1H-indazol-5-amine as green solid (4%).

Ή NMR (400 MHz, CD ₃ OD) δ 7.97 (d, J=0.8 Hz, 1H), 7.93 (d, J=1.2 Hz, 1H), 7.56 (dd, J =8.8, 2.0 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 4.30-4.17 (m, 2H), 3.37-3.35 ( m, 1H), 3.16-3.09 (m, 1H), 2.98-2.92 (m, 1H), 2.77 (m, 1H), 2.65-2.53 (m, 1H), 2.31 (s, 3H), 2.13 (s, 3H), 2.05 (m, 1H), 1.89-1.75 (m, 1H), 1.40-1.32 (m, 2H), 0.87-0.70 (m, 3H). MS (ER+) m/e 366.1 (M+H) ⁺ .

Example 27.

N-(5,6-dimethyl-2-(2-methylpiperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 48 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5,6-dimethyl-2-(2-methylpiperazin1-yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (2 %).

Ή NMR (400 MHz, CD3OD) δ 7.96 (d, J=0.8 Hz, 1H), 7.91 (d, J=1.2 Hz, 1H), 7.57 (dd, J=8 ,8, 2.0 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 4.69-4.67 (m, 1H), 4.29-4.27 (m, 1H), 3.03-2.94 (m, 2H), 2.93-2.80 (m, 2H), 2.732.63 (m, 1H), 2.29 (s, 3H), 2.12 (s, 3H), 1.20 (d, J=6.8 Hz, 3H). MS (ER+) m/e 338.0 (M+H) ⁺ .

Example 28.

N-(5,6-dimethyl-2-(6-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 24 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5,6-dimethyl-2-(6-methyl-1,4diazepan-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine in as a white solid (11%).

Ή NMR (400 MHz, CD3OD) δ 7.99 (s, 1H), 7.97 (s, 1H), 7.59 (dd, J=8.8, 2.0 Hz, 1H), 748 (d , J=8.8 Hz, 1H), 4.19-4.08 (m, 2H), 3.51-3.48 (m, 1H), 3.22-3.15 (m, 1H), 3.03-2.86 (m, 3H), 2.60-2.55 (m, 1H), 2.31 (s, 3H), 2.14 (s, 3H), 2.10-2, 03 (m, 1H), 0.88 (d, J=6.8 Hz, 3H). MS (ER+) m/e 352.1 (M+H) ⁺ .

Example 29.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,6-dimethylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following general protocol A. The reaction time in the first stage was 16 h,

- 23 044043 and the crude material was further used without additional purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-8ul)-5,6-dimethylpyrimidin-4-yl)-1H-indazol-5-amine as a white solid (15%).

^1H NMR (400 MHz, DMSO- _d6 ) δ 13.18 (br s, 1H), 12.09 (br s, 1H), 9.72 (br s, 1H), 9.44 ( br s, 1H), 9.01 (b s, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.56 (d, J=8.8 Hz, 1H ), 7.49 (d, J=8.8, 1.6 Hz, 1H), 4.65 (s, 2H), 3.26-3.19 (m, 4H), 2.40 (s, 3H), 2.16 (s, 3H), 2.07-1.99 (m, 4H). MS (ER+) m/e 350.1 (M+H) ⁺ .

Example 30.

N-(5-methoxy-2-(piperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 64 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-methoxy-2-(piperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (20%).

Ή NMR (400 MHz, CD3OD) δ 8.38 (s, 2H), 8.05 (d, J=1.2 Hz, 1H), 8.01 (s, 1H), 7.66 (s, 1H ), 7.59 (dd, J=8.8, 2.0 Hz, 1H), 7.51 (d, J=9.2 Hz, 1H), 3.91 (s, 3H), 3.88 (t, J=5.2 Hz, 4H), 3.24 (t, J=5.2 Hz, 4H). MS (ER+) m/e 325.7 (M+H) ⁺ .

Example 31.

N-(5-methoxy-2-(3-methylpiperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 64 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-methoxy-2-(3-methylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (28%) .

Ή NMR (400 MHz, CD3OD) δ 8.36 (s, 2H), 8.06 (d, J=1.6 Hz, 1H), 8.01 (d, J=1.2 Hz, 1H), 7.66 (s, 1H), 7.58 (dd, J=8.8, 2.0 Hz, 1H), 7.51 (d, J=9.2 Hz, 1H), 4.56 (dd , J=14.0, 2.8 Hz, 2H), 3.91 (s, 3H), 3.43-3.36 (m, 1H), 3.35-3.32 (m, 1H), 3.25-3.06 (m, 2H), 2.99-2.93 (m, 1H), 1.33 (d, J=6.8 Hz, 3H). MS (ER+) m/e 339.8 (M+H) ⁺ .

Example 32.

N-(2-(3-isopropyl-1,4-diazepan-1-yl)-5-methoxypyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(2-(3-isopropyl-1,4-diazepan-1-yl)-5-methoxypyrimidin-4-yl)1H-indazole -5-amine as a light yellow oil (9%).

Ή NMR (400 MHz, CD3OD) δ 8.50 (s, 2H), 8.05 (s, 1H), 8.01 (s, 1H), 7.66 (s, 1H), 7.57-7 .52 (m, 2H), 4.32-4.28 (m, 1H), 4.14-4.10 (m, 1H), 3.92 (s, 3H), 3.56-3.47 (m, 3H), 3.25-3.19 (m, 1H), 3.07-3.02 (m, 1H), 2.20-1.84 (m, 3H), 0.89 (t , J=6.4 Hz, 6H). MS (ER+) m/e 382.1 (M+H) ⁺ .

- 24 044043

Example 33.

N-(2-morpholinopyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(2-morpholinopyrimidin-4-yl)-1H-indazol-5-amine as a white solid (37%).

^1H NMR (300 MHz, DMSO-dg) δ 12.95 (s, 1H), 9.21 (s, 1H), 8.00 (dd, J=3.0, 1.8 Hz, 2H), 7.92 (d, J=5.7 Hz, 1H), 7.54-7.39 (m, 2H), 6.05 (d, J=5.8 Hz, 1H). MS (ER+) m/e 297 (M+H) ⁺ .

Example 34.

N-(2-(piperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(piperazin-1-yl)pyrimudin-4yl)-1H-indazol-5-amine as a white solid (67%).

^1H NMR (300 MHz, DMSO-dg) δ 12.96 (s, 1H), 9.15 (s, 1H), 8.01 (d, J=6.0 Hz, 2H), 7.89 ( d, J=5.7 Hz, 1H), 7.54-7.40 (m, 2H), 6.00 (d, J=5.7 Hz, 1H), 3.65 (t, J=5 .0 Hz, 4H), 2.76 (t, J=5.1 Hz, 4H). MS (ER+) m/e 296 (M+H) ⁺ .

Example 35.

N-(2-(1,4-diazepan-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(1,4-diazepan-1-yl)pyrimidin-4ul)-1H-indazol-5-amine as a white solid (67%).

^1H NMR (500 MHz, DMSO-dg) δ 12.91 (s, 1H), 9.10 (s, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7. 87 (d, J=5.7 Hz, 1H), 7.46 (s, 2H), 5.97 (d, J=5.7 Hz, 1H), 3.75 (dt, J=23.6 , 5.8 Hz, 5H), 2.93-2.80 (m, 2H), 2.69 (t, J=5.8 Hz, 2H), 1.79 (s, 2H). MS (ER+) m/e 310 (M+H) ⁺ .

Example 36.

N-(2-(4-methoxypiperidin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl)-1H-indazol-5amine as a white solid ( 39%).

^1H NMR (300 MHz, DMSO-dg) δ 12.95 (s, 1H), 9.15 (s, 1H), 8.06-7.96 (m, 2H), 7.89 (d, J =5.7 Hz, 1H),

- 25 044043

7.55-7.38 (m, 2H), 5.99 (d, J=5.7 Hz, 1H), 4.26-4.11 (m, 2H), 3.42 (m, 2H) , 3.28 (s, 3H), 3.25-3.23 (m, 1H), 1.88 (m, 2H), 1.38 (m, 2H). MS (ER+) m/e 325 (M+H) ⁺ .

Example 37.

2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4-(pyridin-4-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3d]pyrimidine -4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4-(pyridin-4yl)phenyl)- 7,8-dihydro-5H-pyrano[4,3-th]pyrimidin-4-amine as a yellow solid (65%).

1H NMR (400 MHz, DMSO-66) δ 9.21 (br s, 1H), 8.90 (br s, 1H), 8.82 (d, J=6.0 Hz, 2H), 8 .15 (d, J=5.6 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.8 Hz, 2H), 4.70 (s, 2H), 4.64 (s, 2H), 3.94 (t, J=5.6 Hz, 2H), 3.21 (m, 4H), 2.72-2.67 (m, 2H), 2.11-2.02 (m, 4H). MS (ER+) m/e 361.1 (M+H).

Example 38.

N-(4-( 1 H-pyrazol-4-yl)phenyl)-2-(piperazin-1 -yl)pyrimidin-4-amine

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(piperazin-1-yl)pyrimidin-4amine as a white solid (41%). MS (ER+) m/e 322.1 (M+H).

Example 39.

2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1H-indazol-5-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1H-indazol-5yl)-5,7 -dihydrofuro[3,4-d]pyrimidin-4-amine as an off-white solid (23%).

1H NMR (400 MHz, DMSO-66) δ 13.01 (s, 1H), 9.01-8.89 (m, 2H), 8.88 (m, 1H), 8.04 (s, 1H) , 7.97 (s, 1H), 7.51-7.49 (m, 2H), 4.86 (m, 2H), 4.71 (m, 2H), 4.36 (d, J=13 .6 Hz, 2H), 4.14 (m, 2H), 3.22 (d, J=13.2 Hz, 2H), 1.94-1.91 (m, 2H), 1.77 (d , J=7.6 Hz, 2H). MS (ER+) m/e 364.1 (M+H).

Example 40.

2-(piperazin-1-yl)-N-(4-(pyridin-3-yl)phenyl)pyrimidin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(piperazin-1-yl)-N-(4-(pyridin-3-yl)phenyl)pyrimidine-26 044043

4-amine as a white solid (87%).

1H NMR (400 MHz, DMSO) δ 11.68 (s, 1H), 9.80 (s, 2H), 9.24 (s, 1H), 8.88-8.77 (m, 2H), 8 .06 (dd, J= 8.0, 5.6 Hz, 1H), 8.01-7.87 (m, 5H), 6.71 (d, J=7.2 Hz, 1H), 4, 11 (s, 4H), 3.28 (s, 4H). MS (ER+) m/e 330.0 (M+H).

Example 41.

N-(4-(1H-1,2,3-triazol-5-yl)phenyl)-2-(piperazin-1-yl)pyrimidin-4-amine

Into a mixture of the compound tert-butyl 4-(4-((4-bromophenyl)amino)pyrimidin-2-yl)piperazine-1carboxylate (998.96 mg, 2.30 mmol) and ethynyl(trimethyl)silane (6.78 g , 69.00 mmol) in DMF (10 ml), TEA (9.31 g, 92.00 mmol), CuI (43.85 mg) and Pd(PPh ₃ ) ₂ Cl ₂ (161.61 mg) were added in one portion 20°C in N2 atmosphere. The reaction mixture was then heated to 100°C for 16 hours. TLC (petroleum ether/EtOAc=1:1) indicated that the reaction was complete. The mixture was cooled to room temperature. Water (50 ml) was added and the mixture was extracted with EtOAc (40 ml x 3). The combined organic phase was washed with brine (50 ml x 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give the compound tert-butyl 4-(4-((4-((trimethylsilyl)ethynyl)phenyl)amino)pyrimidin-2yl)piperazine-1-carboxylate (800.00 mg, 77%) as a yellow solid.

A mixture of the compound tert-butyl 4-(4-((4-((trimethylsilyl)ethynyl)phenyl)amino)pyrimidin-2yl)piperazine-1-carboxylate (1.70 g, 3.76 mmol) and K2CO3 (1.04 g, 7.52 mmol) in MeOH (5 ml) was stirred at 80°C for 10 hours. TLC (petroleum ether/EtOAc = 1:1) showed that the reaction was complete. The reaction mixture was cooled to room temperature. Water (50 ml) was added and the mixture was extracted with EtOAc (100 ml x 3). The combined organic phase was washed with brine (50 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 4/1 to 2/1) to give tert-butyl 4-(4-((4-ethynylphenyl)amino)pyrimidin-2-yl)piperazin-1- carboxylate (1.40 g, 98%) as a yellow solid.

Into a mixture of the compound tert-butyl 4-(4-((4-ethynylphenyl)amino)pyrimidin-2-yl)piperazine-1carboxylate (500.00 mg, 1.32 mmol) and sodium ascorbate (261.50 mg, 1. 32 mmol), CuSO ₄ (42.14 mg, 264.00 µmol) in n-BuOH (5 ml) and H ₂ O (0.5 ml), NaN ₃ (257.44 mg, 3.96 mmol) was added in one portion in an N2 atmosphere. The mixture was then stirred at 20°C for 16 hours. LCMS indicated that the reaction was complete. The residue was poured into water (50 ml) and extracted with EtOAc mixture (40 ml x 3). The combined organic phase was washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give tert-butyl 4-(4-((4-(1H-1,2,3-triazole -5yl)phenyl)amino)pyrimidin-2-yl)piperazine-1-carboxylate (400 mg, crude). The residue was used in the next step without purification.

Mixture of the compound tert-butyl 4-(4-((4-(1H-1,2,3-triazol-5-yl)phenyl)amino)pyrimidin-2yl)piperazine-1-carboxylate (400.00 mg, crude) in HCl /EtOAc (3 ml) was stirred at 23°C for 3 hours. TLC (petroleum ether/EtOAc=1:1) showed that the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (basic) to give N-(4(1H-1,2,3-triazol-5-yl)phenyl)-2-(piperazin-1-yl)pyrimidin-4-amine (100.0 mg, yield 24%, two steps) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.23 (s, 1H), 7.93 (d, J=6.0 Hz, 1H), 7.79 (d , J=8.4 Hz, 2H), 7.72 (d, J=8.8 Hz, 2H), 6.04 (d, J=5.52 Hz, 1H), 3.63 (br. s , 4H), 2.73 (br. s, 4H). MS (ER+) m/e 323.1 (M+H).

Example 42.

N-(4-(1H-tetrazol-5-yl)phenyl)-2-(piperazin-1-yl)pyrimidin-4-amine

Into the mixture of the compound tert-butyl 4-(4-((4-cyanophenyl)amino)pyrimidin-2-yl)piperazin-1

- 27 044043 carboxylate (500.00 mg, 1.31 mmol) and NH ₄ Cl (70.30 mg, 1.31 mmol) in DMF (20 ml) added NaN ₃ (255.49 mg, 3.93 mmol) . The reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was diluted with H ₂ O (20 ml) and extracted with CH ₂ Cl ₂ (30 ml x 3). The organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated to obtain the compound tert-butyl 4-(4-((4-(1Htetrazol-5-yl)phenyl)amino)pyrimidin-2-yl)piperazine-1-carboxylate (650.00 mg, crude) as a brown oil. MS (ER+) m/e 424.2 (M+H).

Into a solution of the compound tert-butyl 4-(4-((4-(1H-tetrazol-5-yl)phenyl)amino)pyrimidin-2yl)piperazine-1-carboxylate (650.00 mg, 1.53 mmol) in CH ₂ Cl ₂ (10 ml) was added HCl/EtOAc (10 ml). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated and purified by preparative HPLC (basic) to give N-(4-(1H-tetrazol-5-yl)phenyl)-2(piperazin-1-yl) pyrimidine-4-amine (62.00 mg, 15%, two steps) as a white solid. 1H NMR: (400 MHz, DMSO-b ₆ ) δ 7.91 (d, J=8.4 Hz, 2H), 7.88 (d, J=5.6 Hz, 1H), 7.64 (d , J=8.8 Hz, 2H), 6.04 (d, J=5.6 Hz, 1H), 3.61 (t, J=4.4 Hz, 4H), 2.71 (t, J =4.8 Hz, 4H). MS (ER+) m/e 324.1 (M+H).

Example 43.

2-(3-methyl-1,4-diazepan-1-ul)-N-(4-(pyridin-4-yl)phenyl)pyrimidin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(3-methyl-1,4-diazepan-1-yl)-N-(4-(pyridin-4yl)phenyl)pyrimidine-4 -amine as a white solid (80%).

1H NMR (400 MHz, Methanol-b ₄ ) δ 8.57 (d, J=6.0 Hz, 2H), 8.32 (s, 2H), 7.99 (d, J=5.6 Hz, 1H), 7.84-7.78 (m, 4H), 7.74 (d, J=6.0 Hz, 2H), 6.20 (d, J=5.6 Hz, 1H), 4, 48-4.40 (m, 2H), 3.67-3.66 (m, 1H), 3.50-3.44 (m, 3H), 3.11-3.05 (m, 1H), 2.34-2.16 (m, 2H), 1.41 (d, J=6.8 Hz, 3H). MS (ER+) m/e 361.2 (M+H).

Example 44.

N-(4-( 1 H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1 -yl)pyrimidin-4-amine

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1-yl)pyrimidin-4amine as a beige solid ( 28%). MS (ER+) m/e 336.1 (M+H).

Example 45.

2-(5-methyl-1,4-diazepan-1-yl)-N-(4-(pyridin-4-yl)phenyl)pyrimidin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(5-methyl-1,4-diazepan-1-yl)-N-(4-(pyridin-4yl)phenyl)pyrimidine-4 -amine as a yellow solid (47%).

1H NMR (400 MHz, Methanol-b ₄ ) δ 8.57 (d, J=6.0 Hz, 2H), 8.32 (s, 3H), 7.99 (d, J=5.6 Hz, 1H), 7.86-7.78 (m, 4H), 7.75 (d, J=5.6 Hz, 2H), 6.20 (d, J=5.6 Hz, 1H), 4, 19-4.10 (m, 3H), 3.78-3.77 (m, 1H), 3.63-3.49 (m, 2H), 3.40-3.35 (m, 1H), 2.24-2.18 (m, 1H), 2.07-1.98 (m, 1H), 1.40 (d, J=6.8 Hz, 3H). MS (ER+) m/e 361.1 (M+H).

Example 46.

2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(1H-indazol-5-yl)-7,8-dihydro-5H-pyrano[4,3- 28 044043

d]pyrimidine-4-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)N-(1H-indazol-5-yl)-7,8-dihydro-5H- prano[4,3-d]pyrimidin-4-amine as a yellow solid (33%).

^1H NMR (400 MHz, DMSO- _d6 ) δ 13.11 (br s, 1H), 9.37 (s, 1H), 8.98 (s, 1H), 8.10 (s, 1H) , 7.85 (s, 1H), 7.56-7.48 (m, 2H), 4.63-4.61 (m, 2H), 3.96-3.93 (m, 2H), 3 .25-3.19 (m, 4H), 2.74 (m, 2H), 2.05-2.00 (m, 4H). MS (ER+) m/e 378.1 (M+H) ⁺ .

Example 47.

X-(2-(5-isopropyl-1,4-diazepan-1-yl)-5-methoxypyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give X-(2-(5-isopropyl-1,4-diazepan-1-yl)-5-methoxypyrimidin-4-yl)1H-indazole -5-amine as a white solid (29%).

1H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 8.15 (d, J=1.2 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H), 7.66 (s, 1H), 7.62 (dd, J=9.2, 2.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 4.62 (m , 1H), 4.15-4.05 (m, 1H), 4.02-3.96 (m, 1H), 3.92 (s, 3H), 3.90-3.83 (m, 1H ), 3.73-3.65 (m, 1H), 3.47-3.39 (m, 1H), 3.26-3.13 (m, 2H), 2.22-2.10 (m , 1H), 2.09-1.99 (m, 1H), 1.88-1.78 (m, 1H), 1.00 (t, J=6.8 Hz, 6H). MS (ER+) m/e 381.9 (M+H) ⁺ .

Example 48.

I-(5-methoxy-2-(3-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(5-methoxy-2-(3-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazole -5-amine as a white solid (33%).

1H NMR (400 MHz, CD ₃ OD) δ 8.52 (s, 1H), 8.02 (s, 1H), 7.70 (s, 1H), 7.68 (s, 1H), 7.53 (dd, J=8.8, 2.0 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7 .27 (t, J=7.2 Hz, 2H), 7.16-7.23 (m, 2H), 4.58-4.53 (m, 1H), 4.42-4.34 (m , 2H), 3.93 (s, 3H), 3.71-3.65 (m, 1H), 3.53-3.46 (m, 2H), 3.04-2.97 (m, 1H ), 2.39-2.31 (m, 1H), 2.23-3.14 (m, 1H). MS (ER+) m/e 416.1 (M+H) ⁺ .

Example 49.

N-(2-(3-ethylpinazin-1-yl)-5-methoxypyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(2-(3-ethylpiperazin-1-yl)-5-methoxypyrimidin-4-yl)-1H

- 29 044043 indazol-5-amine in the form of a white solid (33%).

1H NMR (400 MHz, CD3OD) δ 8.40 (s, 2H), 8.09 (dd, J=2.0, 0.8 Hz, 1H), 8.01 (d, J=1.2 Hz , 1H), 7.69 (s, 1H), 7.59 (dd, J=8.8, 1.6 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 4 .74-4.70 (m, 1H), 4.62-4.53 (m, 1H), 3.94 (s, 3H), 3.43-3.37 (m, 1H), 3.26 -3.18 (m, 1H), 3.17-3.09 (m, 2H), 2.97-2.90 (m, 1H), 1.78-1.59 (m, 2H), 1 .04 (t, J=7.2 Hz, 3H). MS (ER+) m/e 354.1 (M+H)+.

Example 50.

N-(5-methoxy-2-(5-phenyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(5-methoxy-2-(5-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazole -5-amine as a white solid (13%).

1H NMR (400 MHz, CD3OD) δ 8.44 (s, 2H), 8.15 (d, J=1.2 Hz, 1H), 7.97 (d, J=0.8 Hz, 1H), 7.69 (s, 1H), 7.64 (dd, J=8.8, 2.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.48-7 .41 (m, 5H), 4.44-4.41 (m, 1H), 4.23-4.03 (m, 3H), 3.95 (s, 3H), 3.80-3.73 (m, 1H), 3.59-3.49 (m, 1H), 3.42-3.36 (m, 1H), 2.46-2.36 (m, 1H), 2.33-2 .24 (m, 1H). MS (ER+) m/e 416.1 (M+H)+.

Example 51.

N-(2-(3-isopropylpiperazin-1-yl)-5-methoxypyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following general protocol C. The residue was purified by reverse phase preparative HPLC to give N-(2-(3-isopropylpiperazin-1-yl)-5-methoxypyrimidin-4-yl)-1Hindazol-5-amine as white solids (12%).

1H NMR (400 MHz, CD3OD) δ 8.46 (s, 2H), 8.10 (d, J=1.2 Hz, 1H), 8.00 (d, J=0.8 Hz, 1H), 7.69 (s, 1H), 7.59 (dd, J=8.8, 1.6 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 4.81 (m , 1H), 4.65-4.59 (m, 1H), 3.93 (s, 3H), 3.43-3.37 (m, 1H), 3.19-3.11 (m, 2H ), 2.96-2.87 (m, 2H), 1.93-1.85 (m, 1H), 1.09-1.04 (m, 6H). MS (ER+) m/e 368.1 (M+H) ⁺ .

Example 52.

N-(2-(3,5-dimethylpiperazin-1 -yl)-5-methoxypyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 100 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,5-dimethylpiperazin-1-yl)-5methoxypyrimidin-4-yl)-1H-indazol-5-amine as a white solid (15% ).

'll NMR (400 MHz, CD3OD) δ 8.52 (s, 2H), 8.10 (d, J=1.2 Hz, 1H), 8.02 (s, 1H), 7.68 (s, 1H), 7.60 (dd, J=8.8, 1.6 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 4.70-4.66 (m, 2H ), 3.93 (s, 3H), 3.32-3.25 (m, 2H), 2.82-2.76 (m, 2H), 1.34 (d, J=6.4 Hz, 6H). MS (ER+) m/e 354.1 (M+H) ⁺ .

- 30 044043

Example 53.

N-(5-methoxy-2-(5-methyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 52 hours, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-methoxy-2-(5-methyl-1,4-diazepan1-yl)pyrimidin-4-yl)-1H-indazol-5-amine as white solid matter (7%).

1H NMR (400 MHz, CD ₃ OD) δ 8.45 (br s, 2H), 8.15 (d, J=1.2 Hz, 1H), 8.02 (s, 1H), 7.66 (s, 1H), 7.62 (dd, J=8.8, 1.6 Hz, 1H), 7.53 (d, J=9.2 Hz, 1H), 4.02-3.98 ( m, 3H), 3.92 (s, 3H), 3.70-3.60 (m, 1H), 3.50-3.45 (m, 2H), 3.28-3.27 (m, 1H), 2.16-2.12 (m, 1H), 1.98-1.94 (m, 1H), 1.37 (d, J=6.8 Hz, 3H). MS (ER+) m/e 354.1 (M+H) ⁺ .

Example 54.

N-(2-(5-ethyl-1,4-diazepan-1-yl)-5-methoxypyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 80 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give K-(2-(5-ethyl-1,4-diazepan-1-yl)-5methoxypyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid substances (8%).

1H NMR (400 MHz, CD3OD) δ 8.41 (s, 2H), 8.13 (d, J=1.2 Hz, 1H), 8.00 (s, 1H), 7.64 (s, 1H ), 7.60 (dd, J=9.2, 2.0 Hz, 1H), 7.51 (d, J=9.2 Hz, 1H), 4.08-3.92 (m, 3H) , 3.90 (s, 3H), 3.69-3.62 (m, 1H), 3.48-3.43 (m, 1H), 3.28-3.22 (m, 2H), 2 .20 (m, 1H), 1.94-1.84 (m, 1H), 1.80-1.55 (m, 2H), 1.01 (t, J=7.6 Hz, 3H). MS (ER+) m/e 368.1 (M+H) ⁺ .

Example 55.

N-(5-methoxy-2-(3-methyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 96 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-methoxy-2-(3-methyl-1,4-diazepan1-yl)pyrimidin-4-yl)-1H-indazol-5-amine as yellow solids (6%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.10 (s, 1H), 7.97 (s, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.54 ( d, J=8.8, 1.6 Hz, 1H), 7.46 (s, 1H), 4.14-4.11 (m, 1H), 4.01 (s, 3H), 3.82 (m, 1H), 3.63-3.43 (m, 4H), 3.23-3.13 (m, 1H), 2.38-2.18 (m, 2H), 1.07 (d , J=4.0 Hz, 3H). MS (ER+) m/e 354.1 (M+H) ⁺ .

- 31 044043

Example 56.

N-(5-methoxy-2-(6-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give X-(5-methoxy-2-(6-methyl-1,4-diazepan1-yl)pyrimidin-4-yl)-1H-indazol-5-amine as yellow solid matter (13%).

^1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 8.00 (d, J=1.2 Hz, 1H), 7.66-7.58 (m, 2H), 7. 45 (s, 1H), 4.073.97 (m, 5H), 3.95-3.84 (m, 1H), 3.59-3.46 (m, 1H), 3.37 (s, 1H) , 3.31-3.19 (m, 2H), 3.10-3.04 (m, 1H), 2.37 (m, 1H), 1.01 (d, J=4.8 Hz, 3H ). MS (ER+) m/e 354.2 (M+H) ⁺ .

Example 57.

X-(2-(5-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(5-methyl-1,4-diazepan-1yl)nirumidin-4-yl)-1H-undazol-5-amine as a white solid (16 %).

^1H NMR (400 MHz, DMSO-de) δ 12.71 (s, 1H), 8.79 (s, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7. 87 (d, J=5.6 Hz, 1H), 7.49-7.44 (m, 2H), 5.96 (d, J=5.6 Hz, 1H), 3.94-3.89 (m, 2H), 3.69-3.50 (m, 2H), 3.10-3.07 (m, 1H), 2.822.75 (m, 1H), 2.73-2.63 (m , 1H), 1.97-1.87 (m, 1H), 1.47-1.35 (m, 1H), 1.03 (d, J=6.4 Hz, 3H). MS (ER+) m/e 324.1 (M+H) ⁺ .

Example 58.

N-(2-(3-ethylpiperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

N

ХХр

HN (S j

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give X-(2-(3-ethylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow gum (11%).

1H NMR (400 MHz, DMSO-b6) δ 9.29 (s, 1H), 8.30 (s, 2H), 8.08 (s, 1H), 7.96 (s, 1H), 7.92 (d, J=5.6 Hz, 1H), 7.50-7.43 (m, 2H), 6.06 (d, J=5.6 Hz, 1H), 4.67-4.64 ( m, 1H), 4.54-4.51 (m, 1H), 3.16-3.13 (m, 1H), 3.053.02 (m, 1H), 2.84-2.74 (m, 3H), 1.59-1.48 (m, 2H), 0.98 (t, J=7.6 Hz, 3H). MS (ER+) m/e 324.1 (M+H) ⁺ .

Example 59.

X-(2-(3-isopropylpiperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5 -amine

The reaction was carried out following general protocol A. The reaction time in the first stage was 16 h,

- 32 044043 and the crude material was further used without additional purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-isopropylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (12%).

1H NMR (400 MHz, DMSO-Y6) δ 12.98 (br s, 1H), 9.23 (s, 1H), 8.29 (s, 2H), 8.12 (s, 1H), 7 .92-7.89 (m, 2H), 7.49-7.43 (m, 2H), 6.02 (d, J=5.6 Hz, 1H), 4.67 (d, J=12 .0 Hz, 1H), 4.50 (d, J=12.0 Hz, 1H), 3.07-3.04 (m, 1H), 2.87 (m, 1H), 2.71-2 .68 (m, 1H), 2.65-2.59 (m, 1H), 2.43-2.41 (m, 1H), 1.69-1.66 (m, 1H), 0.99 (d, J=6.8 Hz, 6H). MS (ER+) m/e 338.1 (M+H) ⁺ .

Example 60.

N-(2-(5-ethyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 32 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give X-(2-(5-ethyl-1,4-diazepan-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a light brown solid (34%).

1H NMR (400 MHz, CD ₃ OD) δ 8.36 (s, 2H), 8.06 (s, 1H), 8.02 (s, 1H), 7.91 (d, J=6.0 Hz , 1H), 7.56-7.47 (m, 2H), 6.14 (d, J=6.0 Hz, 1H), 4.16-3.99 (m, 3H), 3.77- 3.69 (m, 1H), 3.57-3.49 (m, 1H), 3.32-3.27 (m, 2H), 2.27-2.23 (m, 1H), 1. 99-1.93 (m, 1H), 1.83-1.64 (m, 2H), 1.05 (t, J=7.6 Hz, 3H). MS (ER+) m/e 337.9 (M+H) ⁺ .

Example 61.

N-(2-(5-isopropyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(2-(5-isopropyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-indazol5-amine as a yellow solid (18%).

1H NMR (400 MHz, CD ₃ OD) δ 8.41 (s, 2H), 8.03 (s, 1H), 8.00 (s, 1H), 7.89 (d, J=6.0 Hz , 1H), 7.53-7.45 (m, 2H), 6.11 (d, J=6.0 Hz, 1H), 4.20-4.03 (m, 2H), 4.0- 3.93 (m, 1H), 3.76-3.69 (m, 1H), 3.53-3.45 (m, 1H), 3.293.21 (m, 2H), 2.22-1, 99 (m, 2H), 1.94-1.83 (m, 1H), 1.01 (dd, J=8.8, 7.2 Hz, 6H). MS (ER+) m/e 352.1 (M+H) ⁺ .

Example 62.

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

The reaction was carried out following General Protocol A. The reaction time in the first stage was 15 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-ethyl-1,4-diazepan-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (15 %).

1H NMR (400 MHz, CD3OD) δ 8.43 (s, 2H), 7.98 (s, 2H), 7.89 (d, J=6.0 Hz, 1H), 7.51 (d, J =8.8 Hz, 1H), 7.45 (d, J=8.8, 1.6 Hz, 1H), 6.10 (d, J=6.0 Hz, 1H), 4.44 (dd , J=14.4, 2.4 Hz, 1H), 4.35-4.25 (m, 1H), 3.48-3.38 (m, 4H), 3.09-2.99 (m , 1H), 2.22-2.11 (m, 2H), 1.67-1.63 (m, 2H), 0.93 (m, 3H). MS (ER+) m/e 338.1 (M+H) ⁺ .

- 33 044043

Example 63.

N-(2-(5-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(2-(5-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-indazol-5amine as a yellow solid (10%).

1H NMR (400 MHz, CD3OD) δ 8.36 (s, 2H), 8.05 (s, 1H), 7.97 (s, 1H), 7.92 (d, J=6.0 Hz, 1H ), 7.52-7.41 (m, 7H), 6.15 (d, J=6.0 Hz, 1H), 4.46 (dd, J=11.2, 2.0 Hz, 1H) , 4.31-4.22 (m, 1H), 4.17-4.14 (m, 2H), 3.84-3.77 (m, 1H), 3.62-3.56 (m, 1H), 3.41-3.38 (m, 1H), 2.49-2.39 (m, 1H), 2.34-2.24 (m, 1H). MS (ER+) m/e 386.1 (M+H) ⁺ .

Example 64.

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

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(2-(3-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-indazol-5amine as a yellow solid (39%).

1H NMR (400 MHz, CD3OD) δ 8.33 (m, 2H), 7.92 (d, J=6.0 Hz, 2H), 7.64 (s, 1H), 7.45-7.32 (m, 7H), 6.15 (d, J=6.0 Hz, 1H), 4.65 (d, J=14.4 Hz, 1H), 4.55-4.39 (m, 2H) , 3.85-3.79 (m, 1H), 3.56-3.51 (m, 2H), 3.16-3.10 (m, 1H), 2.44-2.33 (m, 1H), 2.31-2.18 (m, 1H). MS (ER+) m/e 386.1 (M+H) ⁺ .

Example 65.

N-(2-(3-isopropyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(2-(3-isopropyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-indazol5-amine as a yellow solid (11%).

1H NMR (400 MHz, DMSO-a ₆ , Т=8О°С) δ 10.75 (s, 1H), 9.24 (s, 2H), 8.04 (d, J=0.8 Hz, 1H ), 7.97 (s, 1H), 7.84 (d, J=7.2 Hz, 1H), 7.57 (d, J=9.2 Hz, 1H), 7.49 (d, J =8.8 Hz, 1H), 6.50 (d, J=6.4 Hz, 1H), 4.25-4.18 (m, 1H), 4.02-3.95 (m, 1H) , 3.78-3.64 (m, 1H), 3.42-3.41 (m, 1H), 3.34-3.31 (m, 2H), 3.10 (m, 1H), 2 .18 (d, J=4.8 Hz, 2H), 2.05 (m, 1H), 0.99-0.75 (m, 6H). MS (ER+) m/e 351.8 (M+H) ⁺ .

Example 66.

N-(2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following general protocol A. The reaction time in the first stage was 16 h,

- 34 044043 and the crude material was further used without additional purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(4,7-diazaspiro[2.5]octan-7yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (47 %).

1H NMR (400 MHz, CD3OD) δ 8.10 (d, J=0.8 Hz, 1H), 7.94 (s, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.48 (d, J=9.2 Hz, 1H), 6.40 (d, J=7.2 Hz, 1H), 4, 10 (t, J=5.2 Hz, 2H), 3.93 (s, 2H), 3.51 (t, J=5.2 Hz, 2H), 1.17 (t, J=7.2 Hz, 2H), 1.03 (t, J=6.4 Hz, 2H). MS (ER+) m/e 322.1 (M+H) ⁺ .

Example 67.

N-(2-(2,5-diazabicyclo[2.2.2]octan-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2,5-diazabicyclo[2.2.2]octan-2yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (18%).

^1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), 8.02 (s, 1H), 7.83 (d, J=7.2 Hz, 1H), 7.63-7, 48 (m, 2H), 6.40 (d, J=7.2 Hz, 1H), 4.84-4.77 (m, 1H), 4.04-3.97 (m, 2H), 3 .87-3.84 (m, 1H), 3.66-3.48 (m, 2H), 2.27-2.18 (m, 2H), 2.12-2.02 (m, 2H) . MS (ER+) m/e 322.1 (M+H) ⁺ .

Example 68.

N-(2-(2,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2,5-dimethylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (18%).

1H NMR (400 MHz, CD3OD) δ 8.10 (d, J=0.8 Hz, 1H), 7.98 (s, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 6.41 (d, J=7.2 Hz, 1H), 4, 76 (m, 1H), 4.24 (d, J=14.4 Hz, 1H), 3.89 (m, 1H), 3.73-6.69 (m, 1H), 3.64-3 .59 (m, 1H), 3.28-3.24 (m, 1H), 1.46 (d, J=6.8 Hz, 3H), 1.42 (d, J=6.8 Hz, 3H). MS (ER+) m/e 324.0 (M+H) ⁺ .

Example 69.

N-(2-(2-propylpiperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5 -amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 48 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2-propylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (15%).

1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.96 (s, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.62 (d, J =8.8 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 6.39 (d, J=7.2 Hz, 1H), 4.80 (m, 1H), 4.44-4.40 (m, 1H), 3.58-3.46 (m, 3H), 3.35 (m, 1H), 3.27-3.23 (m, 1H), 1. 82 (kv, J=8.0 Hz, 2H), 1.46-1.24 (m, 2H), 0.93 (t, J=7.2 Hz, 3H). MS (ER+) m/e 338.1 (M+H) ⁺ .

- 35 044043

Example 70.

N-(2-(2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2,7-diazaspiro[3.5]nonan-7yl)pyrimidin-4-yl)-1H-indazol-5-amine as an off-white solid (33%).

'H NMR (400 MHz, DMSO-d6) δ 13.19 (br s, 1H), 10.56 (br s, 1H), 8.94 (br s, 2H), 8.08 (s , 1H), 8.01 (s, 1H), 7.88 (d, J=5.8 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.48 (d , J=8.8 Hz, 1H), 6.30 (d, J=6.0 Hz, 1H), 3.813.78 (m, 4H), 3.67 (m, 4H), 1.88-1 .85 (m, 4H). MS (ER+) m/e 336.1 (M+H) ⁺ .

Example 71.

N-(2-(2,6-diazaspiro[3.4]octan-6-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2,6-diazaspiro[3.4]octan-6yl)pyrimidin-4-yl)-1H-indazol-5-amine as a light brown solid (21%).

^1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 8.11 (s, 1H), 7.76 (d, J=7.2 Hz, 1H), 7.61 (m, 2H), 6.36 (d, J=6.8 Hz, 1H), 4.25-4.23 (m, 2H), 4.13-4.10 (m, 2H), 3.94-3 .68 (m, 4H), 2.46 (m, 2H). MS (ER+) m/e 322.1 (M+H) ⁺ .

Example 72.

N-(2-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(1-oxa-4,9diazaspiro[5.5]undecan-9-yl)pyrimidin-4-yl)-1H-indazol-5-amine as dirty -white solid (15%).

¹ H NMR (400 MHz, DMSO-a ₆ ) δ 13.17 (br s, 1H), 10.54 (br s, 1H), 9.01 (s, 2H), 8.09 (s, 1H), 8.05 (s, 1H), 7.89 (d, J=6.0 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.48 (m, 1H), 6.28 (m, 1H), 4.09 (m, 2H), 4.04-4.02 (m, 2H), 3.33 (m, 2H), 3.09-3.04 (m, 4H), 2.03-2.00 (m, 2H), 1.69-1.64 (m, 2H). MS (ER+) m/e 366.1 (M+H) ⁺ .

Example 73.

N-(2-(2,7-diazaspiro[4.5]decan-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine

- 36 044043

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2,7-diαzaspiro[4.5]decan-2yl)pyrimidin-4-yl)-1H-indazol-5-amine as a light brown solid (17%).

1H NMR (400 MHz, DMSO- _d6 ) δ 13.18 (br s, 1H), 10.72 (br s, 1H), 8.87-8.80 (m, 2H), 8.31 (m, 1H), 8.10 (s, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.58 (s, 1H), 6.36 (m, 1H), 3 .76 (m, 1H), 3.61 (m, 3H), 3.10-3.07 (m, 4H), 2.14 (m, 1H), 1.95 (m, 1H), 1. 76-1.69 (m, 4H). MS (ER+) m/e 350.1 (M+H) ⁺ .

Example 74.

N-(2-(2,7-diazaspiro[4.5]decan-7-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2,7-diαzaspiro[4.5]decan-7yl)pyrimidin-4-yl)-1H-indazol-5-amine as a light brown solid (34%).

1H NMR (400 MHz, D2O) δ 8.07 (s, 1H), 7.80 (br s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.50 (d , J=8.8 Hz, 1H), 7.42-7.40 (m, 1H), 6.16 (d, J=7.2 Hz, 1H), 3.62-3.54 (m, 2H), 3.34-3.31 (m, 2H), 3.07 (m, 1H), 2.94-2.88 (m, 2H), 2.67 (m, 1H), 1.75 -1.60 (m, 6H). MS (ER+) m/e 350.1 (M+H) ⁺ .

Example 75.

N-(2-(2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2,6-diazaspiro[3.4]octan-2yl)pyrimidin-4-yl)-1H-indazol-5-amine as a light brown solid (18%).

1H NMR (400 MHz, CD ₃ OD) δ 8.22 (m, 1H), 8.07 (s, 1H), 7.76 (d, J=7.2 Hz, 1H), 7.60-7 .55 (m, 2H), 6.35 (d, J=6.4 Hz, 1H), 4.37 (d, J=9.6 Hz, 2H), 4.31 (d, J=9, 6 Hz, 2H), 3.60 (s, 2H), 3.42 (t, J=7.6 Hz, 2H), 2.42 (t, J=7.6 Hz, 2H). MS (ER+) m/e 322.1 (M+H) ⁺ .

Example 76.

N-(2-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2,7-diazaspiro[3.5]nonan-2yl)pyrimidin-4-yl)-1H-indazol-5-amine as an off-white solid (41%).

¹ H NMR (400 MHz, DMSO-d6) δ 13.17 (br s, 1H), 10.66 (br s, 1H), 8.63 (s, 2H), 8.19 (br s , 1H), 8.11 (s, 1H), 7.88 (d, J=6.8 Hz, 1H), 7.59-7.54 (m, 2H), 6.33 (m, 1H) , 3.99 (s, 4H), 3.09 (m, 4H), 1.97 (m, 4H). MS (ER+) m/e 336.1 (M+H) ⁺ .

- 37 044043

Example 77.

N-(2-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2,7-diazaspiro[3.5]heptan-2yl)pyrimidin-4-yl)-1H-indazol-5-amine as an off-white solid (45%).

Ή NMR (400 MHz, DMSO-d ₆ ) δ 13.22 (br s, 1H), 10.73 (s, 1H), 8.76 (s, 2H), 8.20 (br s, 1H ), 8.07 (s, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.59-7.52 (m, 2H), 6.34 (m, 1H), 4 .38 (s, 4H), 4.21-4.18 (m, 4H). MS (ER+) m/e 308.1 (M+H) ⁺ .

Example 78.

N-(2-(3,6-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.2.1]octan-3yl)pyrimidin-4-yl)-1H-indazol-5-amine as light brown solids (12%).

^1H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 8.07 (s, 1H), 7.82 (d, J=7.2 Hz, 1H), 7.64-7, 57 (m, 2H), 6.46 (m, 1H), 4.42-4.39 (m, 1H), 4.30 (m, 1H), 4.14 (m, 1H), 3.46 -3.37 (m, 4H), 2.94 (m, 1H), 2.20-2.12 (m, 2H). MS (ER+) m/e 322.1 (M+H) ⁺ .

Example 79.

N-(2-(3,7-diazabicyclo[3.3.1]nonan-3-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-2-(3,7-diazabicyclo[3.3.1]nonan-3yl)pyrimidin-4-yl)-1H-indazol-5-amine as a light brown solid substances (19%).

^1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 8.08 (s, 1H), 7.82 (d, J=7.2 Hz, 1H), 7.64-7, 62 (m, 2H), 6.43 (m, 1H), 4.40-4.37 (m, 2H), 3.54-3.45 (m, 4H), 3.37-3.34 ( m, 2H), 2.43 (m, 2H), 2.13-2.02 (m, 2H). MS (ER+) m/e 336.1 (M+H) ⁺ .

Example 80.

N-(2-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)nirimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified

- 38 044043 by reverse-phase preparative HPLC to obtain N-(2-(octahydro-5H-pyrrolo[3,2c]pyridin-5-yl)pyrimidin-4-yl)-1H-indazol-5-amine in the form of light -brown solid (18%).

^1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), 8.05 (s, 1H), 7.79 (d, J=7.2 Hz, 1H), 7.64-7, 53 (m, 2H), 6.37 (d, J=6.8 Hz, 1H), 4.06-3.90 (m, 2H), 3.92-3.90 (m, 2H), 3 .54-3.45 (m, 2H), 3.38-3.35 (m, 1H), 2.77-2.70 (m, 1H), 2.27-2.21 (m, 2H) , 2.05-1.84 (m, 2H). MS (ER+) m/e 336.1 (M+H) ⁺ .

Example 81.

N-(2-((1S,5S)-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-((1S,5S)-3,6diazabicyclo[3.2.0]heptαn-3-yl)pyrimidin-4-yl)-1H-indazol-5- amine as a light brown solid (11%).

1H NMR (400 MHz, CD3OD) δ 8.18 (s, 1H), 8.11 (s, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.63-7.58 (m, 2H), 6.46 (d, J=6.8 Hz, 1H), 5.13-5.10 (m, 1H), 4.56-4.52 (m, 1H), 4, 32-4.27 (m, 1H), 4.17 (m, 1H), 3.82-3.73 (m, 2H), 3.64-3.61 (m, 2H). MS (ER+) m/e 308.1 (M+H) ⁺ .

Example 82.

N-(2-((1R,6S)-3,7-diazabicyclo[4.2.0]octan-3-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-((1R,6S)-3,7diazabicyclo[4.2.0]octan-3-yl)pyrimidin-4-yl)-1H-indazol-5- amine as a light brown solid (9%).

1H NMR (400 MHz, CD3OD) δ 8.09 (m, 2H), 7.82 (d, J=7.2 Hz, 1H), 7.63-7.56 (m, 1H), 6.42 (m, 1H), 4.804.78 (m, 1H), 4.21-4.16 (m, 2H), 4.04-3.89 (m, 3H), 3.73-3.69 (m , 1H), 3.38 (m, 1H), 2.46-2.37 (m, 2H). MS (ER+) m/e 322.1 (M+H) ⁺ .

Example 83.

N-(2-(3 -(azetidin-3 -yl)pyrrolidin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5 -amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-(azetidin-3-yl)pyrrolidin-1yl)pyrimidin-4-yl)-1H-indazol-5-amineα as a light brown solid substances (13%).

1H NMR (400 MHz, CD ₃ OD) δ 8.27 (s, 1H), 8.08 (s, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.59 (m , 2H), 6.35 (d, J=6.4 Hz, 1H), 4.23-4.18 (m, 2H), 4.01-3.88 (m, 3H), 3.74- 3.60 (m, 2H), 3.18-3.16 (m, 1H), 3.05-3.03 (m, 1H), 2.84-2.75 (m, 1H), 2. 32-2.25 (m, 1H), 1.85-1.75 (m, 1H). MS (ER+) m/e 336.1 (M+H) ⁺ .

- 39 044043

Example 84.

N-(2-(octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse-phase preparative HPLC to obtain N-(2-(octahydro-2H-pyrazino[1,2a]pyrazin-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine as light -brown solid (13%).

^1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 8.05 (s, 1H), 7.80 (d, J=7.2 Hz, 1H), 7.64-7, 54 (m, 2H), 6.38 (m, 1H), 4.35 (m, 2H), 3.44-3.38 (m, 2H), 3.25-3.19 (m, 2H) , 3.10-2.90 (m, 4H), 2.53-2.40 (m, 3H). MS (ER+) m/e 351.1 (M+H) ⁺ .

Example 85.

X-(2-(octahydropyrrolo[3,4-d]azepin-6(1H)-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(octahydropyrrolo[3,4-d]azepin6(1H)-yl)pyrimidin-4-yl)-1H-indazol-5-amine as light brown solid (22%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.09 (m, 2H), 7.77 (d, J=7.2 Hz, 1H), 7.62-7.60 (m, 1H), 7.53 (m, 1H), 6.37 (d, J=6.4 Hz, 1H), 4.05 (m, 2H), 3.62-3.50 (m, 4H), 3.09 -3.05 (m, 2H), 2.71 (m, 2H), 2.07-2.04 (m, 2H), 1.95-1.87 (m, 2H). MS (ER+) m/e 350.1 (M+H) ⁺ .

Example 86.

X-(2-([3,3'-bipiperidin]-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give X-(2-([3,3'-bipiperidin]-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a light brown solid ( 31%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.10 (s, 1H), 8.04 (br s, 1H), 7.75 (d, J=7.2 Hz, 1H), 7, 62 (d, J=9.2 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 6.32 (d, J=7.2 Hz, 1H), 4.58 ( m, 1H), 4.12-4.08 (m, 1H), 3.43-3.40 (m, 1H), 3.293.18 (m, 2H), 2.91-2.63 (m, 3H), 1.97-1.87 (m, 3H), 1.61-1.35 (m, 6H), 0.97-0.86 (m, 1H). MS (ER+) m/e 378.1 (M+H) ⁺ .

Example 87.

N-(2-(spiro[indoline-3,4'-piperidine]-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following general protocol D. The reaction time in the first stage was 16 h,

- 40 044043 and the crude material was further used without additional purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(spiro[indolin-3,4'-piperidin]1-yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid substances (37%).

1H NMR (400 MHz, DMSO-d^δ 13.11 (br s, 1H), 9.81 (br s, 1H), 8.73-8.71 (m, 1H), 8.49- 8.47 (m, 1H), 8.18-8.07 (m, 4H), 7.59 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8, 1.6 Hz, 1H), 7.18-7.15 (m, 1H), 6.98 (m, 2H), 6.33 (d, J=6.0 Hz, 1H), 4.19 ( s, 2H), 3.42-3.34 (m, 2H), 3.08-2.99 (m, 2H), 2.06-2.00 (m, 2H), 1.87-1, 84 (m, 2H).MS (ER+) m/e 398.2 (M+H) ⁺ .

Example 88.

N-(2-(3-(piperidin-4-yl)indolin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol D. The reaction time for the first step was 16 hours, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-(piperidin-4-yl)indolin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid ( 43%).

1H NMR (400 MHz, DMSO-d6) δ 13.12 (br s, 1H), 10.03 (br s, 1H), 8.52-8.50 (m, 1H), 8.15- 8.07 (m, 5H), 7.61 (d, J=8.4 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.27-7.25 (m , 1H), 6.97-6.95 (m, 2H), 4.19-4.14 (m, 1H), 4.06-4.03 (m, 1H), 3.47 (m, 1H ), 3.46-3.45 (m, 2H), 3.32-3.23 (m, 2H), 1.97 (m, 1H), 1.84-1.81 (m, 2H), 1.44-1.39 (m, 2H). MS (ER+) m/e 412.1 (M+H) ⁺ .

Example 89.

N-(2-(3 -(piperidin-3 -yl)indolin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5 -amine

The reaction was carried out following General Protocol D. The reaction time for the first step was 16 hours, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-(piperidin-3-yl)indolin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid ( 38%).

1H NMR (400 MHz, DMSO- _d6 ) δ 13.16 (br s, 1H), 10.18 (br s, 1H), 8.77-8.62 (m, 1H), 8.38 -8.29 (m, 1H), 8.08-8.06 (m, 4H), 7.62 (d, J=8.8 Hz, 1H), 7.44-7.42 (m, 1H ), 7.27-7.22 (m, 1H), 7.01-6.94 (m, 2H), 6.396.37 (m, 1H), 4.13-4.12 (m, 2H), 3.53-3.49 (m, 1H), 3.46-3.32 (m, 1H), 3.24-3.21 (m, 1H), 2.78-2.67 (m, 2H ), 2.06-2.05 (m, 1H), 1.78-1.75 (m, 1H), 1.55-1.29 (m, 3H). MS (ER+) m/e 412.1 (M+H) ⁺ .

Example 90.

N-(5-chloro-2-(3-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-chloro-2-(3-methyl-1,4-diazepan-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as yellow solids (21%).

1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.94 (s, 1H), 7.57-7 .52 (m, 2H), 4.60 (m, 1H), 4.27-4.19 (m, 2H), 3.39-3.36 (m, 2H), 3.27-3.21 (m, 2H), 2.97-2.91 (m, 1H), 2.17-2.16 (m, 1H),

- 41 044043

2.04-1.99 (m, 1H), 1.11 (m, 3H). MS (ER+) m/e 358.0 (M+H) ⁺ .

Example 91.

N-(5-methyl-2-(3-methylpiperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 48 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-methyl-2-(3-methylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (26%) .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.96 (br s, 1H), 8.28 (s, 3H), 7.99 (d, J=0.8 Hz, 1H), 7 .97 (d, J=1.6 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H), 7.57 (dd, J=8.8, 2.0 Hz, 1H) , 7.47 (d, J=8.8 Hz, 1H), 4.40-4.34 (m, 2H), 3.063.03 (m, 1H), 2.94-2.82 (m, 2H ), 2.78-2.67 (m, 1H), 2.59-2.56 (m, 1H), 2.07 (s, 3H), 1.08 (d, J=6.4 Hz, 3H). MS (ER+) m/e 324.1 (M+H) ⁺ .

Example 92.

N-(2-(3-isopropyl-1,4-diazepan-1-yl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine

N XX?

N N\__/NH

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(2-(3-isopropyl-1,4-diazepan-1-yl)-5-methylpyrimidin-4-yl)-1Hindazol- 5-amine as a yellow oil (7%).

^1H NMR (400 MHz, CD3OD) δ 8.43 (s, 2H), 8.00 (s, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.53- 7.47 (m, 2H), 4.24-4.19 (m, 1H), 4.09-4.05 (m, 1H), 3.51-3.38 (m, 3H), 3. 14-3.08 (m, 1H), 3.03-2.96 (m, 1H), 2.13-1.75 (m, 6H), 0.75 (m, 6H). MS (ER+) m/e 365.9 (M+H) ⁺ .

Example 93.

N-(2-(5-isopropyl-1,4-diazepan-1-yl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(2-(5-isopropyl-1,4-diazepan-1-yl)-5-methylpyrimidin-4-yl)-1Hindazol- 5-amine as a white solid (17%).

1H NMR (400 MHz, CD3OD) δ 8.53 (s, 1H), 8.02 (d, J=0.8 Hz, 1H), 7.96 (d, J=1.2 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H), 7.59 (dd, J=8.8, 2.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H ), 4.09-4.00 (m, 1H), 3.99-3.91 (m, 1H), 3.86-3.80 (m, 1H), 3.68-3.61 (m , 1H), 3.40-3.35 (m, 1H), 3.21-3.15 (m, 2H), 2.15 (s, 3H), 2.07-2.03 (m, 2H ), 1.85-1.75 (m, 1H), 0.99 (t, J=6.8 Hz, 6H). MS (ER+) m/e 365.9 (M+H) ⁺ .

- 42 044043

Example 94.

N-(5-methyl-2 -(5-phenyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(5-methyl-2-(5-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazole -5-amine as a white solid (31%).

1H NMR (400 MHz, CD3OD) δ 8.44 (s, 2H), 7.98 (s, 1H), 7.97 (s, 1H), 7.80 (d, J=0.8 Hz, 1H ), 7.61 (dd, J=8.8, 1.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.46-7.40 (m, 5H) , 4.39-4.35 (m, 1H), 4.16-4.00 (m, 3H), 3.75-3.68 (m, 1H), 3.51-3.43 (m, 1H), 3.32-3.25 (m, 1H), 2.41-2.30 (m, 1H), 2.25-2.20 (m, 1H), 2.19 (s, 3H) . MS (ER+) m/e 400.2 (M+H) ⁺ .

Example 95.

N-(5-methyl-2-(piperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 48 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-methyl-2-(piperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as an off-white solid (14%) .

1H NMR (400 MHz, DMSO-66) δ 8.17 (s, 1H), 7.89 (s, 1H), 7.73 (s, 1H), 7.64 (d, J=8.8 Hz , 1H), 7.57 (d, J=9.2 Hz, 1H), 3.90 (t, J=4.8 Hz, 4H), 3.34 (s, 4H), 2.25 (s , 3H). MS (ER+) m/e 310.1 (M+H) ⁺ .

Example 96.

N-(2-(5-ethyl-1,4-diazepan-1-yl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 48 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(5-ethyl-1,4-diazepan-1-yl)-5methylpyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid substances (25%).

^1H NMR (400 MHz, CD3OD) δ 8.36 (s, 2H), 8.01 (d, J=0.8 Hz, 1H), 7.98-7.91 (m, 1H), 7, 75 (d, J=0.8 Hz, 1H), 7.58-7.50 (m, 2H), 4.03-3.82 (m, 3H), 3.64-3.57 (m, 1H), 3.43-3.36 (m, 1H), 3.27-3.15 (m, 2H), 2.20-2.10 (m, 4H), 1.90-1.80 ( m, 1H), 1.77-1.58 (m, 2H), 0.99 (t, J=7.6 Hz, 3H). MS (ER+) m/e 352.1 (M+H) ⁺ .

Example 97.

N-(5-methyl-2-(2-methylpiperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

- 43 044043

The reaction was carried out following General Protocol A. The reaction time in the first stage was 96 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-methyl-2-(2-methylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (21%) .

^1H NMR (400 MHz, CD3OD) δ 8.35 (s, 2H), 8.02-7.98 (m, 1H), 7.90 (d, J=1.2 Hz, 1H), 7, 78 (s, 1H), 7.577.49 (m, 2H), 4.93 (m, 1H), 4.53-4.49 (m, 1H), 3.36 (m, 1H), 3.29 -3.25 (m, 1H), 3.25-3.16 (m, 2H), 3.06-2.97 (m, 1H), 2.15 (s, 3H), 1.28 (d , J=7.2 Hz, 3H). MS (ER+) m/e 324.1 (M+H) ⁺ .

Example 98.

N-(2-(3,5-dimethylpiperazin-1 -yl)-5-methylpyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 50 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,5-dimethylpiperαzin-1-yl)-5methylpyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (11% ).

^1H NMR (400 MHz, CD3OD) δ 8.52 (s, 2H), 8.02 (s, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.58- 7.52 (m, 2H), 4.69 (d, J=2.4 Hz, 1H), 4.65 (d, J=2.0 Hz, 1H), 3.27-3.21 (m , 2H), 2.78-2.72 (m, 2H), 2.15 (s, 3H), 1.29 (d, J=6.4 Hz, 6H). MS (ER+) m/e 337.8 (M+H) ⁺ .

Example 99.

N-(2-(3-ethylpiperazin-1 -yl)-5 -methylpyrimidin-4-yl)-1 H-indazol-5 -amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 48 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-ethylpiperazin-1-yl)-5methylpyrimidin-4-yl)-1H-indazol-5-amine as a yellow oil (21%).

1H NMR (400 MHz, CD3OD) δ 8.34 (s, 2H), 8.01 (s, 1H), 7.91 (dd, J=2.0, 0.8 Hz, 1H), 7.80 (d, J=1.2 Hz, 1H), 7.58-7.51 (m, 2H), 4.69-4.67 (m, 1H), 4.56-4.53 (m, 1H ), 3.39-3.37 (m, 1H), 3.29-3.20 (m, 1H), 3.13-3.03 (m, 2H), 2.96-2.90 (m , 1H), 2.16 (s, 3H), 1.70-1.60 (m, 2H), 0.95 (t, J=7.2 Hz, 3H). MS (ER+) m/e 338.1 (M+H) ⁺ .

Example 100.

N-(5-methyl-2-(5-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 36 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-methyl-2-(5-methyl-1,4-diazepan-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as yellow solids (25%).

^1H NMR (400 MHz, CD3OD) δ 8.39 (br s, 2H), 8.02 (s, 1H), 7.97 (d, J=1.2 Hz, 1H), 7.77 ( s, 1H), 7.59 (dd, J=8.8, 1.6 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 4.02-3.93 (m , 3H), 3.62 (m, 1H), 3.43-3.38 (m, 2H), 3.21 (m, 1H), 2.16 (s, 3H), 2.11-2, 07 (m, 1H), 1.94-1.90 (m, 1H), 1.35 (d, J=6.8 Hz, 1H). MS (ER+) m/e 338.1 (M+H) ⁺ .

- 44 044043

Example 101.

N-(2-(3-isopropylpiperazin-1 -yl)-5 -methylpyrimidin-4-yl)-1 H-indazol-5 -amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 56 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-isopropylpiperazin-1-yl)-5methylpyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (43%).

^1H NMR (400 MHz, CD3OD) δ 8.42 (br s, 2H), 8.01 (s, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7. 57-7.51 (m, 2H), 4.80-4.76 (m, 1H), 4.62-4.59 (m, 1H), 3.39 (m, 1H), 3.18- 3.14 (m, 2H), 2.92-2.83 (m, 2H), 2.16 (s, 3H), 1.88-1.82 (m, 1H), 1.02 (d, J=6.8 Hz, 3H), 0.95 (d, J=6.8 Hz, 3H). MS (ER+) m/e 352.1 (M+H) ⁺ .

Example 102.

N-(5-methyl-2-(3 -methyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 96 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-methyl-2-(3-methyl-1,4-diazenan-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as yellow oils (31%).

1H NMR (400 MHz, CD3OD) δ 8.38 (s, 2H), 8.03 (s, 1H), 7.93 (s, 1H), 7.77 (s, 1H), 7.55 (s , 2H), 4.234.18 (m, 2H), 3.45-3.38 (m, 3H), 3.30-3.23 (m, 1H), 3.04-2.94 (m, 1H ), 2.22-2.09 (m, 5H), 1.10 (d, J=5.6 Hz, 3H). MS (ER+) m/e 338.1 (M+H) ⁺ .

Example 103.

N-(5-methyl-2-(3-phenyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(5-methyl-2-(3-phenyl-1,4-diazenan-1-yl)pyrimidin-4-yl)-1Hindazole -5-amine as a white solid (11%).

1H NMR (400 MHz, CD ₃ OD) δ 7.96 (s, 1H), 7.80 (s, 1H), 7.74 (d, J=0.8 Hz, 1H), 7.56 (d , J=8.8 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.27-6.87 (m, 5H), 4.46-4.43 (m, 1H), 4.25-4.23 (m, 1H), 3.84 (m, 1H), 3.46-3.39 (m, 1H), 3.22-3.15 (m, 2H) , 2.62-2.53 (m, 1H), 2.15 (m, 4H), 1.96-1.86 (m, 1H). MS (ER+) m/e 400.2 (M+H) ⁺ .

Example 104 (KL-01047)

N-(5-methyl-2-(2-methyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol B. The reaction time in the first stage was 48 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-methyl-2-(2-methyl-1,4-diazepan-1

- 45 044043 yl)pyrimidin-4-yl)-1H-indazol-5-amine in the form of a white solid (3%).

1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 7.99 (s, 1H), 7.72 (s, 1H), 7.64 (d, J=8.8 Hz, 1H ), 7.49 (d, J=9.2 Hz, 1H), 4.62 (m, 1H), 4.25-4.22 (m, 1H), 3.35-3.34 (m, 1H), 3.19-3.16 (m, 2H), 2.74-2.68 (m, 2H), 2.13 (s, 3H), 1.82-1.74 (m, 2H) , 1.10 (d, J=6.4 Hz, 3H). MS (ER+) m/e 338.1 (M+H) ⁺ .

Example 105 (KL-01048)

N-(2-(2-ethyl-1,4-diazepan-1-yl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol B. The reaction time in the first stage was 64 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2-ethyl-1,4-diazepan-1-yl)-5methylpyrimidin-4-yl)-1H-indazol-5-amine as a white solid substances (3%).

^1H NMR (400 MHz, CD3OD) δ 8.04 (s, 1H), 7.96 (d, J=0.8 Hz, 1H), 7.69 (s, 1H), 7.61 (dd, J=8.8, 2.0 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 4.51 (m, 1H), 4.20-4.16 (m, 1H ), 3.40-3.34 (m, 1H), 3.16-3.04 (m, 2H), 2.68-2.54 (m, 2H), 2.11 (s, 3H), 1.80 (m, 1H), 1.66-1.45 (m, 3H), 0.81 (m, 3H). MS (ER+) m/e 352.1 (M+H) ⁺ .

Example 106.

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

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-ethyl-1,4-diazepan-1-yl)-5methylpyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid substances (8%).

1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 7.83 (d, J=1.2 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 1.6 Hz, 1H), 4.16-4.14 (m, 1H), 3 .75 (m, 1H), 3.60-3.54 (m, 1H), 3.53-3.46 (m, 1H), 3.41-3.39 (m, 1H), 3.19 -3.15 (m, 2H), 2.26 (m, 5H), 1.34-1.20 (m, 2H), 0.42 (m, 3H). MS (ER+) m/e 352.2 (M+H) ⁺ .

Example 107.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 32 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-ethyl-1,4-diazepan-1-yl)-5methylpyrimidin-4-yl)-1H-indazol-5-amine as a white solid substances (2%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 13.11 (br s, 1H), 9.11 (br s, 1H), 8.83 (br s, 1H), 8.08 (s , 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.53 (s, 2H), 4.56 (s, 2H), 3.19 (m, 4H), 2 .16 (s, 3H), 2.11-1.92 (m, 4H). MS (ER+) m/e 336.1 (M+H) ⁺ .

- 46 044043

Example 108.

N-(6-methyl-2-(5-phenyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(5-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazole -5-amine as a yellow solid (24%).

1H NMR (400 MHz, CD3OD) δ 8.45 (s, 2H), 8.05 (s, 1H), 7.97 (s, 1H), 7.50-7.41 (m, 7H), 6 .04 (s, 1H), 4.45-4.42 (m, 1H), 4.27-4.17 (m, 3H), 3.85 (m, 1H), 3.59 (m, 1H ), 3.41-3.40 (m, 1H), 2.47-2.42 (m, 1H), 2.31-2.27 (m, 4H). MS (ER+) m/e 400.2 (M+H) ⁺ .

Example 109.

N-(2-(5-ethyl-1,4-diαzepαn-1-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 32 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(5-ethyl-1,4-diazepan-1-yl)-6methylpyrimidin-4-yl)-1H-indazol-5-αmine as a yellow solid substances (40%).

1H NMR (400 MHz, CD3OD) δ 8.36 (s, 2H), 8.02 (s, 1H), 7.99 (s, 1H), 7.52-7.44 (m, 2H), 5 .99 (s, 1H), 4.14-4.04 (m, 3H), 3.78-3.71 (m, 1H), 3.57-3.46 (m, 1H), 3.33 (m, 1H), 3.29-3.23 (m, 1H), 2.28-2.17 (m, 4H), 1.99-1.89 (m, 1H), 1.82-1 .61 (m, 2H), 1.03 (t, J=7.6 Hz, 3H). MS (ER+) m/e 352.1 (M+H) ⁺ .

Example 110.

N-(2-(3-isopropyl-1,4-diazepan-1 -yl)-6-methylpyrimidin-4-yl)-1 H-indazol-5-αmin

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(2-(3-isopropyl-1,4-diazepan-1-yl)-6-methylpyrimidin-4-yl)-1Hindazol- 5-amine as a yellow resin (14%).

^1H NMR (400 MHz, CD3OD) δ 8.45 (br s, 2H), 8.01-7.99 (m, 2H), 7.53-7.443 (m, 2H), 5.98 (s , 1H), 4.47-4.43 (m, 1H), 4.28 (m, 1H), 3.61-3.50 (m, 3H), 3.29-3.27 (m, 1H ), 3.07 (m, 1H), 2.24-2.13 (m, 5H), 2.00-1.99 (m, 1H), 1.02 (m, 6H). MS (ER+) m/e 366.1 (M+H) ⁺ .

Example 111.

N-(2-(5-isopronul-1,4-diazepan-1-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-αmin

- 47 044043

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(2-(5-isopropyl-1,4-diazepan-1-yl)-6-methylnirimidin-4-yl)-1Hindazol- 5-amine as a yellow solid (7%).

1H NMR (400 MHz, CD3OD) δ 8.48 (s, 2H), 8.04 (s, 1H), 8.00 (s, 1H), 7.56-7.46 (m, 2H), 5 .99 (s, 1H), 4.22 (m, 1H), 4.18-4.12 (m, 1H), 4.09-4.01 (m, 1H), 3.78-3.70 (m, 1H), 3.50-3.49 (m, 1H), 3.30-3.23 (m, 2H), 2.24-2.16 (m, 4H), 2.08-2 .05 (m, 1H), 1.91-1.88 (m, 1H), 1.05-1.01 (m, 6H). MS (ER+) m/e 366.1 (M+H) ⁺ .

Example 112.

N-(6-methyl-2-(3-phenyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(3-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazole -5-amine as a yellow solid (7%).

^1H NMR (400 MHz, CD3OD) δ 8.49 (s, 2H), 7.97 (s, 1H), 7.65 (br s, 1H), 7.46-7.33 (m, 7H ), 6.02 (s, 1H), 4.70-4.66 (m, 1H), 4.54 (m, 1H), 4.48-4.44 (m, 1H), 3.81- 3.74 (m, 1H), 3.54-3.50 (m, 2H), 3.10-3.07 (m, 1H), 2.38-2.37 (m, 1H), 2. 26-2.25 (m, 4H). MS (ER+) m/e 400.1 (M+H) ⁺ .

Example 113.

N-(2-(3,5-dimethylpiperazin-1-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine

N

XX?

Ν Ν

Χ^ΝΗ

The reaction was carried out following General Protocol A. The reaction time in the first stage was 50 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,5-dimethylpiperazin-1-yl)-6methylpyrimidin-4-yl)-1H-indazol-5-amine as a yellow oil (37%) .

1H NMR (400 MHz, CD ₃ OD) δ 8.39 (br s, 2H), 8.01 (s, 1H), 7.97 (s, 1H), 7.53 (d, J=8, 8 Hz, 1H), 7.45 (d, J=8.8, 2.0 Hz, 1H), 6.01 (s, 1H), 4.95-4.94 (m, 2H), 3, 37-3.36 (m, 2H), 2.88-2.82 (m, 2H), 2.24 (s, 3H), 1.38 (d, J=6.4 Hz, 6H). MS (ER+) m/e 338.1 (M+H)+.

Example 114.

N-(2-(3-ethylpiperazin-1 -yl)-6-methylpyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 36 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-ethylpiperazin-1-yl)-6methylpyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (9%).

1H NMR (400 MHz, CD ₃ OD) δ 8.43 (br s, 2H), 7.99 (s, 2H), 7.53-7.46 (m, 2H), 6.01 (s, 1H), 4.80-4.77 (m, 2H), 3.43-3.40 (m, 1H), 3.28 (m, 1H), 3.17-3.13 (m, 2H) , 3.04-3.01 (m, 1H), 2.24 (s, 3H), 1.75-1.68 (m, 2H), 1.09 (t, J=7.6 Hz, 3H ). MS (ER+) m/e 338.1 (M+H) ⁺ .

- 48 044043

Example 115.

N-(2-(3-isopropylpiperazin-1-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 36 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-uzonulpiperazin-1-yl)-6methylpyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (30%).

1H NMR (400 MHz, CD3OD) δ 8.46 (br s, 2H), 8.01 (s, 1H), 7.98 (s, 1H), 7.53-7.46 (m, 2H) , 6.01 (s, 1H), 5.02-4.97 (m, 1H), 4.83 (m, 1H), 3.43-3.40 (m, 1H), 3.21-3 .13 (m, 2H), 2.99-2.96 (m, 2H), 2.24 (s, 3H), 1.96-1.91 (m, 1H), 1.13-1.10 (m, 6H). MS (ER+) m/e 352.1 (M+H) ⁺ .

Example 116.

N-(6-methyl-2-(5-methyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 36 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(5-methyl-1,4-diazepan-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as yellow solids (8%).

^1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), 8.00 (br s, 1H), 7.63-7.61 (m, 1H), 7.51 (m, 1H ), 6.23 (s, 1H), 4.13-4.03 (m, 3H), 3.76-3.70 (m, 1H), 3.69 (m, 2H), 3.57 ( m, 1H), 2.43 (s, 3H), 2.19 (m, 2H), 1.43 (d, J=6.4 Hz, 3H). MS (ER+) m/e 338.1 (M+H) ⁺ .

Example 117.

N-(6-methyl-2-(2-methyl-1,4-diazepan-1-yl)nirimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol B. The reaction time in the first stage was 48 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(2-methyl-1,4-diazepan-1yl)pyrimidin-4-yl)-N-indazol-5-amine as white solids (6%).

1H NMR (400 MHz, CD3OD) δ 8.17 (s, 1H), 7.94 (s, 1H), 7.50-7.44 (m, 2H), 5.88 (s, 1H), 4 .59 (m, 1H), 4.45-4.42 (m, 1H), 3.41-3.36 (m, 1H), 3.17-3.13 (m, 2H), 2.76 -2.70 (m, 2H), 2.20 (s, 3H), 1.94-1.76 (m, 2H), 1.15 (d, J=5.6 Hz, 3H). MS (ER+) m/e 338.0 (M+H) ⁺ .

Example 118.

N-(6-methyl-2-(6-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following general protocol A. The reaction time in the first stage was 16 h,

- 49 044043 and the crude material was further used without additional purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(6-methyl-1,4-diazepan-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as white solids (4%).

1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.98 (m, 1H), 7.62-7.61 (m, 1H), 7.50 (m, 1H), 6 .23 (s, 1H), 4.17 (m, 2H), 3.97 (m, 1H), 3.62 (m, 1H), 3.39-3.36 (m, 1H), 3. 27-3.15 (m, 2H), 3.10 (m, 1H), 2.42 (m, 4H), 1.06 (m, 3H). MS (ER+) m/e 338.1 (M+H) ⁺ .

Example 119.

N-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-methylpyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-3yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine as white solid (18%).

1H NMR (400 MHz, DMSO-di) δ 13.06 (br s, 1H), 10.32 (s, 1H), 9.31-9.10 (m, 2H), 8.08 (s, 1H), 7.94 (s, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 6.17 (s, 1H), 4.32-4.22 (m, 4H), 3.40 (d, J=14.0 Hz, 2H), 2.30 (s, 3H), 1.96-1.95 (m , 2H), 1.86-1.84 (m, 2H). MS (ER+) m/e 336.1 (M+H) ⁺ .

Example 120.

N-(2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.1.1]heptan3-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine as white solid (13%).

^1H NMR (400 MHz, DMSO) δ 13.07 (br s, 1H), 10.55 (s, 1H), 9.71 (s, 1H), 8.29 (s, 1H), 8, 13-8.02 (m, 2H), 7.56-7.49 (m, 2H), 6.41 (s, 1H), 4.50 (d, J=5.2 Hz, 2H), 4 .18-3.90 (m, 4H), 2.94-2.86 (m, 1H), 2.37 (s, 3H), 1.88-1.84 (m, 1H). MS (ER+) m/e 322.1 (M+H) ⁺ .

Example 121.

N-(6-methyl-2-(2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse-phase preparative HPLC to give X-(6-methyl-2-(2,7diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)-1H-indazol-5-amine as dirty -white solid (23%).

1H NMR (400 MHz, DMSO-de) δ 13.13 (br.s, 1H), 11.78 (br.s, 1H), 10.61 (br.s, 1H), 8.80 (br.s. s, 2H), 8.06-8.01 (m, 2H), 7.58-7.47 (m, 2H), 6.10 (s, 1H), 3.80-3.70 (m, 8H), 2.29 (s, 3H), 1.85 (m, 4H). MS (ER+) m/e 350.1 (M+H) ⁺ .

- 50 044043

Example 122.

N-(6-methyl-2-(2,6-diazaspiro[3.4]octan-6-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse-phase preparative HPLC to give X-(6-methyl-2-(2,6diazaspiro[3.4]octan-6-yl)pyrimidin-4-yl)-1H-indazol-5-amine as dirty -white solid (31%).

¹ H NMR (400 MHz, DMSO-d6) δ 13.16 (br s, 1H), 11.91 (br s, 1H), 10.61 (br s, 1H), 9.09-8 .97 (m, 2H), 8.22-8.12 (m, 2H), 7.57 (s, 2H), 6.17 (s, 1H), 4.07 (m, 2H), 3. 95 (m, 2H), 3.84 (m, 2H), 3.62 (m, 2H), 2.32 (m, 5H). MS (ER+) m/e 336.1 (M+H) ⁺ .

Example 123.

N-(6-methyl-2-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give X-(6-methyl-2-(1-oxa-4,9diazaspiro[5.5]undecan-9-yl)pyrimidin-4-yl)-1H-indazol-5- amine in the form of a brown substance (38%).

1H NMR (400 MHz, DMSO-a ₆ ) δ 13.17 (br s, 1H), 11.84 (br s, 1H), 10.58 (br s, 1H), 9.12 (s , 2H), 8.08 (s, 1H), 8.02 (s, 1H), 7.58-7.48 (m, 2H), 6.13 (m, 1H), 4.17-4 .15 (m, 2H), 3.85 (m, 2H), 3.40-3.33 (m, 2H), 3.09-3.05 (m, 4H), 2.34 (s, 3H ), 2.03-2.00 (m, 2H), 1.69-1.64 (m, 2H). MS (ER+) m/e 380.1 (M+H) ⁺ .

Example 124.

N-(6-methyl-2-(2,7-diazaspiro[4.5]decan-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse-phase preparative HPLC to give X-(6-methyl-2-(2,7diazaspiro[4.5]decan-2-yl)pyrimidin-4-yl)-III-indazol-5-amine as dirty -white solid (41%).

1H NMR (400 MHz, DMSO- _d6 ) δ 13.12 (br s, 1H), 11.77 (br s, 1H), 10.63 (br s, 1H), 7.80 (m , 2H), 8.27 (br s, 1H), 8.08 (s, 1H), 7.56 (m, 2H), 6.18 (m, 1H), 3.68 (m, 4H) , 3.06 (m, 4H), 2.33 (s, 3H), 2.13 (m, 1H), 1.93 (m, 1H), 1.69 (m, 4H). MS (ER+) m/e 364.1 (M+H) ⁺ .

- 51 044043

Example 125.

N-(6-methyl-2-(2,7-diazaspiro[4.5]decan-7-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(2,7diazaspiro[4.5]decan-7-yl)pyrimidin-4-yl)-1H-indazol-5-amine as dirty -white solid (41%).

¹ H NMR (400 MHz, DMSO-d6) δ 13.11 (br s, 1H), 11.68 (br s, 1H), 10.62 (br s, 1H), 8.92 (br .s, 2H), 8.09-8.01 (m, 2H), 7.57-7.47 (m, 2H), 6.18-6.07 (m, 1H), 3.74 (m , 4H), 3.32 (m, 2H), 3.03-2.98 (m, 2H), 2.28 (s, 3H), 1.87-1.84 (m, 1H), 1. 72-1.65 (m, 5H). MS (ER+) m/e 364.1 (M+H) ⁺ .

Example 126.

N-(6-methyl-2-(2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(2,6diazaspiro[3.4]octan-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine as dirty -white solid (18%).

Ή NMR (400 MHz, D2O) δ 8.04 (s, 2H), 7.57-7.51 (m, 1H), 7.37-7.35 (m, 1H), 5.88 (s, 1H), 4.08-4.05 (m, 4H), 3.49 (s, 2H), 3.33 (t, J=7.2 Hz, 2H), 2.28 (m, 2H), 2.14 (s, 3H). MS (ER+) m/e 336.1 (M+H)+.

Example 127.

N-(6-methyl-2-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(2,7diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine as dirty -white solid (11%).

¹ H NMR (400 MHz, DMSO-d6) δ 13.16 (br s, 1H), 12.24 (br s, 1H), 10.59 (br s, 1H), 8.63 (s , 2H), 8.19 (br s, 1H), 8.11 (s, 1H), 7.56-7.49 (m, 2H), 6.15 (br s, 1H), 4, 00 (s, 4H), 3.08 (m, 4H), 2.30 (s, 3H), 1.97 (m, 4H). MS (ER+) m/e 350.1 (M+H)+.

- 52 044043

Example 128.

N-(6-methyl-2-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse-phase preparative HPLC to give N-(6-methyl-2-(2,6diazaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)-N-indazol-5-amine as dirty -white solid (34%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 13.16 (br s, 1H), 12.37 (br s, 1H), 10.61 (br s, 1H), 8.68 (s , 2H), 8.19 (br s, 1H), 8.06 (br s, 1H), 7.58-7.52 (m, 2H), 6.15 (s, 1H), 4, 37 (s, 4H), 4.21-4.18 (m, 4H), 2.29 (s, 3H). MS (ER+) m/e 322.1 (M+H) ⁺ .

Example 129.

N-(2-(3,6-diazabicyclo[3.2.1]octan-3-yl)-6-methylpyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.2.1]octan-3yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine as off-white solid (9%).

1H NMR (400 MHz, CD ₃ OD) δ 8.11 (s, 1H), 8.02 (s, 1H), 7.63-7.54 (m, 2H), 6.26 (br s, 1H), 4.49-4.46 (m, 1H), 4.28 (m, 2H), 3.44-3.40 (m, 4H), 2.93 (m, 1H), 2.43 (s, 3H), 2.20-2.12 (m, 2H). MS (ER+) m/e 336.1 (m+n) ⁺ .

Example 130.

N-(2-(3,7-diazabicyclo[3.3.1]nonan-3-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,7-diazabicyclo[3.3.1]nonan-3yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine as off-white solid (4%).

^1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), 8.06 (s, 1H), 7.61 (m, 2H), 6.25 (br s, 1H), 4, 49-4.46 (m, 2H), 3.55-3.44 (m, 4H), 3.37 (m, 2H), 2.42 (m, 5H), 2.13-2.02 ( m, 2H). MS (ER+) m/e 350.1 (M+H) ⁺ .

Example 131.

N-(6-methyl-2-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following general protocol A. The reaction time in the first stage was 16 h,

- 53 044043 and the crude material was further used without additional purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(octahydro-5Hpyrrolo[3,2-c]pyridin-5-yl)pyrimidin-4-yl)-1H-indazol-5- amine as an off-white solid (7%).

1H NMR (400 MHz, CD ₃ OD) δ 8.09 (s, 1H), 8.02 (br. s, 1H), 7.63-7.52 (m, 2H), 6.18 (br. s., 1H). s, 1H), 4.124.08 (m, 1H), 3.99-3.94 (m, 3H), 3.57-3.51 (m, 2H), 3.39-3.37 (m, 1H), 2.76-2.71 (m, 1H), 2.41 (s, 3H), 2.26-2.22 (m, 2H), 2.05-2.00 (m, 1H) , 1.93-1.87 (m, 1H). MS (ER+) m/e 350.1 (M+H) ⁺ .

Example 132.

N-(6-methyl-2-(octahydropyrrolo[3,4-d]azepin-6(1H)-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(octahydropyrrolo[3,4d]azepin-6(1H)-yl)pyrimidin-4-yl)-1H-indazol-5-amine as an off-white solid (13%).

1H NMR (400 MHz, CD3OD) δ 8.09 (m, 2H), 7.59-7.54 (m, 2H), 6.19 (s, 1H), 4.08 (m, 2H), 3 ,66-3.60 (m, 2H), 3.54-3.50 (m, 2H), 3.09-3.04 (m, 2H), 2.70 (m, 2H), 2.42 (s, 3H), 2.03 (m, 2H), 1.93-1.91 (m, 2H). MS (ER+) m/e 364.1 (M+H) ⁺ .

Example 133.

N-(6-methyl-2-(octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(octahydro-2Hpyrazino[1,2-a]pyrazin-2-yl)pyrimidin-4-yl)-1H-indazol-5- amine as a light brown solid (11%).

^1H NMR (400 MHz, CD ₃ OD) δ 8.10 (s, 1H), 8.02 (br s, 1H), 7.63-7.53 (m, 2H), 6.20 (s , 1H), 4.44 (m, 2H), 3.44-3.41 (m, 1H), 3.25-3.20 (m, 3H), 3.09-3.06 (m, 1H ), 3.03-3.00 (m, 1H), 2.96-2.90 (m, 2H), 2.54-2.41 (m, 6H). MS (ER+) m/e 365.1 (M+H) ⁺ .

Example 134.

N-(2-(3,6-diazabicyclo[3.2.0]gentan-3-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine g/l HN

Ha

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.2.0]heptan3-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine as light brown solid (19%).

1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 8.10 (s, 1H), 7.60 (m, 2H), 6.27 (s, 1H), 5.13-5 .10 (m, 1H), 4.62-4.59 (m, 1H), 4.29-4.26 (m, 2H), 3.82-3.72 (m, 2H), 3.64 -3.62 (m, 2H), 2.45 (s, 3H). MS (ER+) m/e 322.1 (M+H) ⁺ .

- 54 044043

Example 135.

N-(2-(3,7-diazabicyclo[4.2.0]octan-3-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,7-diαzabicyclo[4.2.0]octan-3yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine as light brown solid (21%).

^1H NMR (400 MHz, CD3OD) δ 8.09 (m, 2H), 7.59 (m, 2H), 6.23 (s, 1H), 4.80-4.77 (m, 1H), 4.18-4.05 (m, 3H), 3.97-3.92 (m, 2H), 3.75-3.71 (m, 1H), 3.38-3.37 (m, 1H ), 2.44-2.40 (m, 5H). MS (ER+) m/e 336.1 (M+H) ⁺ .

Example 136.

N-(2-([3,3'-bipiperidin]-1-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-([3,3'-bipiperidin]-1-yl)-6methylpyrimidin-4-yl)-1H-indazol-5-amine as light brown solids (6%).

1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 8.01 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.47 (d, J =8.0 Hz, 1H), 6.15 (s, 1H), 4.63-4.60 (m, 1H), 4.22-4.20 (m, 1H), 3.42-3, 39 (m, 1H), 3.27-3.19 (m, 2H), 2.88 (m, 1H), 2.75 (m, 1H), 2.62-2.60 (m, 1H) , 2.40 (s, 3H), 1.96-1.86 (m, 2H), 1.73 (m, 1H), 1.61-1.55 (m, 4H), 1.39-1 .32 (m, 2H), 0.92 (m, 1H). MS (ER+) m/e 392.1 (M+H) ⁺ .

Example 137.

N-(6-methyl-2-(3 -(piperidin-4-yl)indolin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol D. The reaction time for the first step was 16 hours, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(3-(piperidin-4yl)indolin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine as yellow solid (44%).

1H NMR (400 MHz, DMSO- _d6 ) δ 13.13 (br s, 1H), 9.93 (br s, 1H), 8.54-8.51 (m, 1H), 8.19 (m, 2H), 8.07 (m, 2H), 7.60 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.26 -7.24 (m, 1H), 6.96 (m, 2H), 6.20 (s, 1H), 4.214.18 (m, 1H), 4.10-4.07 (m, 1H), 3.46-3.44 (m, 1H), 3.32-3.24 (m, 2H), 2.85-2.80 (m, 2H), 2.33 (s, 3H), 1. 96 (m, 1H), 1.83-1.80 (m, 1H), 1.44 (m, 3H). MS (ER+) m/e 426.1 (M+H) ⁺ .

- 55 044043

Example 138.

N-(6-methyl-2-(spiro[indoline-3,4'-piperidin]-1-yl)pyrimidin-4-yl)-1H-indazol-5-αmin

The reaction was carried out following General Protocol D. The reaction time for the first step was 16 hours, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(spiro[indolin-3,4'piperidin]-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (39%).

1H NMR (400 MHz, DMSO-b ₆ ) δ 13.21 (br s, 1H), 9.97 (br s, 1H), 8.82 (m, 1H), 8.59-8.57 (m, 1H), 8.12-8.08 (m, 3H), 7.60 (d, J=8.8 Hz, 1H), 7.40 (dd, J=8.8, 1.6 Hz, 1H), 7.19-7.17 (m, 1H), 7.02-6.99 (m, 2H), 6.23 (s, 1H), 4.22 (s, 2H), 3 .43-3.40 (m, 2H), 3.08-3.02 (m, 2H), 2.35 (s, 3H), 2.07-2.01 (m, 2H), 1.87 -1.84 (m, 2H). MS (ER+) m/e 412.1 (M+H) ⁺ .

Example 139.

N-(6-methyl-2-(3 -(piperidin-3-yl)indolin-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol D. The reaction time for the first step was 16 hours, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(3-(piperidin-3yl)indolin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine as yellow solid (28%).

1H NMR (400 MHz, DMSO-ph) δ 13.13 (br s, 1H), 9.89 (br s, 1H), 8.73-8.59 (m, 1H), 8.35- 8.32 (m, 1H), 8.18 (m, 1H), 8.12-8.04 (m, 2H), 7.59 (d, J=8.8 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.26-7.21 (m, 1H), 6.97 (m, 2H), 6.20 (s, 1H), 4.19-4, 12 (m, 2H), 3.49-3.48 (m, 1H), 3.34-3.31 (m, 1H), 3.24-3.21 (m, 1H), 2.80- 2.77 (m, 2H), 2.34 (s, 3H), 1.79-1.75 (m, 1H), 1.48-1.44 (m, 1H), 1.32-1, 29 (m, 3H). MS (ER+) m/e 412.1 (M+H) ⁺ .

Example 140.

Ν-(5-Φτορ-2-(3-methylpiperazin-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-fluoro-2-(3-methylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (41%) .

1H NMR (400 MHz, DMSO-b ₆ ) δ 13.03 (br s, 1H), 9.29 (s, 1H), 8.30 (s, 2H), 8.07 (d, J=1 .2 Hz, 1H), 8.00 (d, J=0.8 Hz, 1H), 7.99 (d, J=3.6 Hz, 1H), 7.60 (dd, J=8.8 , 2.0 Hz, 1H), 7.49 (d, J=9.2 Hz, 1H), 4.33 (t, J=10.8 Hz, 2H), 3.01 (d, J=12 .0 Hz, 1H), 2.91-2.77 (m, 2H), 2.74-2.67 (m, 1H), 2.59-2.52 (m, 1H), 1.06 ( d, J=6.4 Hz, 3H). MS (ER+) m/e 328.1 (M+H) ⁺ .

- 56 044043

Example 141.

N-(5-φτορ-2-(3-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(5-φtor-2-(3-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazole -5-amine as a yellow solid (29%).

1H NMR (400 MHz, CD ₃ OD) δ 8.47 (s, 2H), 7.95 (s, 1H), 7.91 (d, J=3.6 Hz, 1H), 7.72 (s , 1H), 7.51 (d, J=9.2 Hz, 1H), 7.40-7.17 (m, 6H), 4.51 (dd, J=15.2, 2.8 Hz, 1H), 4.43-4.37 (m, 2H), 3.70 (dd, J=15.2, 10.8 Hz, 1H), 3.53-3.42 (m, 2H), 3 .08-2.98 (m, 1H), 2.39-2.27 (m, 1H), 2.25-2.12 (m, 1H). MS (ER+) m/e 404.1 (M+H) ⁺ .

Example 142.

N-(5-φtor-2-(5-φhenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(5-φtor-2-(5-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazole -5-amine as a yellow solid (19%).

1H NMR (400 MHz, CD3OD) 8.43 (s, 2H), 8.08 (d, J=1.2 Hz, 1H), 7.96 (s, 1H), 7.92 (d, J= 4.0 Hz, 1H), 7.61 (dd, J=9.2, 2.0 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.46-7, 38 (m, 5H), 4.42 (dd, J=11.2, 2.4, Hz, 1H), 4.20-4.17 (m, 1H), 4.14-4.04 (m , 2H), 3.79-3.71 (m, 1H), 3.56-3.47 (m, 1H), 3.36 (m, 1H), 2.42-2.32 (m, 1H ), 2.27-2.22 (m, 1H). MS (ER+) m/e 404.0 (M+H) ⁺ .

Example 143.

N-(2-(2-ethylpiperazin-1-yl)-5-φtorpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2-ethylpiperazin-1-yl)-5φtorpyrimidin-4-yl)-1H-indazol-5-amine as a white solid (5%).

^1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.91 (s, 1H), 8.68 (s, 1H), 8.08-8.04 (m, 2H ), 8.01 (s, 1H), 7.62-7.57 (m, 1H), 7.52-7.47 (m, 1H), 4.57 (d, J=13.6 Hz, 1H), 4.46 (d, J=12.80 Hz, 1H), 3.34 (d, J=12.4 Hz, 1H), 3.24-2.86 (m, 4H), 1, 68-1.50 (m, 2H), 0.94 (t, J=7.6 Hz, 3H). MS (ER+) m/e 342.2 (M+H) ⁺ .

Example 144.

N-(5-φtor-2-(3-isopropyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(5-φtor-2-(3-isopropyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazole -5-amine as a yellow solid (5%).

- 57 044043

1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.53 (s, 1H), 8.32 (s, 1H), 8.08-7.95 (m, 3H) , 7.62-7.47 (m,

2H), 4.14 (m, 1H), 4.00 (m, 1H), 3.61 (m, 1H), 3.53-3.51 (m, 2H), 3.19 (m, 1H ), 2.99 (m, 1H), 2.04 (m, 3H), 0.79 (m, 6H). MS (ER+) m/e 369.9 (M+H)+.

Example 145.

N-(5-fluoro-2-(5-isonpropyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(5-fluoro-2-(5-isopropyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazole -5-amine as a yellow solid (5%).

1H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 8.06 (d, J=1.2 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H), 7.88 (d, J=4.0 Hz, 1H), 7.59 (dd, J=9.2, 2.0 Hz, 1H), 7.52 (d, J=9.2 Hz, 1H ), 4.15-3.95 (m, 2H), 3.92-3.85 (m, 1H), 3.71-3.64 (m, 1H), 3.48-3.38 (m , 1H), 3.25-3.14 (m, 2H), 2.16-1.98 (m, 2H), 1.85-1.80 (m, 1H), 0.99 (t, J =7.2 Hz, 6H). MS (ER+) m/e 370.1 (M+H)+.

Example 146.

N-(2-(5-ethyl-1,4-diazepan-1-yl)-5-fluoropyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(2-(5-ethyl-1,4-diazepan-1-yl)-5-fluoropyrimidin-4-yl)-1H indazole -5-amine as a yellow solid (28%).

1H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), 8.07 (d, J=1.2 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H), 7.88 (d, J=4.0 Hz, 1H), 7.59 (dd, J=8.8, 1.6 Hz, 1H), 7.52 (d, J=9.2 Hz, 1H ), 4.08-3.89 (m, 3H), 3.69-3.62 (m, 1H), 3.48-3.40 (m, 1H), 3.27-3.20 (m , 2H), 2.22-2.12 (m, 1H), 1.92-1.82 (m, 1H), 1.78-1.60 (m, 2H), 1.01 (t, J =7.6 Hz, 3H). MS (ER+) m/e 356.1 (M+H)+.

Example 147.

N-(5-fluoro-2-(3-uzopropylpiperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 48 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-fluoro-2-(3-isopropylpinerazin1-yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (3%) .

1H NMR (400 MHz, CD3OD) δ 8.49 (s, 2H), 8.03 (d, J=1.2 Hz, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.90 (d, J=3.6 Hz, 1H), 7.56 (dd, J=9.2, 2.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H ), 4.82-4.80 (m, 1H), 4.66-4.63 (m, 1H), 3.37-3.34 (m, 1H), 3.11-3.04 (m , 2H), 2.91-2.88 (m, 2H), 1.91-1.80 (m, 1H), 1.06-1.00 (m, 6H). MS (ER+) m/e 356.1 (M+H)+.

- 58 044043

Example 148.

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

The reaction was carried out following General Protocol A. The reaction time in the first stage was 48 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-ethyl-1,4-diazepan-1-yl)-5fluoropyrimidin-4-yl)-1H-indazol-5-amineα as a yellow solid substances (4%).

^1H NMR (400 MHz, CD3OD) δ 8.50 (s, 2H), 8.00 (s, 2H), 7.88 (d, J=4.0 Hz, 1H), 7.56-7, 51 (m, 2H), 4.354.22 (m, 2H), 3.45-3.38 (m, 3H), 3.04-3.02 (m, 1H), 3.01-2.98 ( m, 1H), 2.20-2.18 (m, 1H), 2.17-2.06 (m, 1H), 1.58-1.54 (m, 2H), 0.81 (m, 1H), 3H). MS (ER+) m/e 356.1 (M+H) ⁺ .

Example 149.

N-(2-(3-ethylpiperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 32 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-ethylniperazin-1-yl)-5fluoropyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (22%).

^1H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), 8.02 (s, 1H), 8.00 (s, 1H), 7.90 (d, J=3.6 Hz, 1H), 7.57 (dd, J=8.8, 1.6 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 4.73 (d, J=12.4 Hz, 1H), 4.61 (d, J=14.0 Hz, 1H), 3.41-3.35 (m, 1H), 3.28-3.18 (m, 1H), 3.15 -3.05 (m, 2H), 2.96-2.92 (m, 1H), 1.71-1.58 (m, 2H), 1.00 (t, J=7.6 Hz, 3H ). MS (ER+) m/e 342.1 (M+H)+.

Example 150.

N-(2-(3,5-dimethylpiperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 50 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,5-dimethylpiperazin-1-yl)-5fluoropyrimidin-4-yl)-1H-indazol-5-amine as a white solid (14% ).

^1H NMR (400 MHz, CD3OD) δ 8.53 (s, 2H), 8.05-8.03 (m, 2H), 7.92 (d, J=4.0 Hz, 1H), 7, 61-7.53 (m, 2H), 4.73-4.70 (m, 2H), 3.31-3.26 (m, 2H), 2.82-2.75 (m, 2H), 1.32 (d, J=6.4 Hz, 6H). MS (ER+) m/e 342.1 (M+H) ⁺ .

Example 151.

N-(5-fluoro-2-(3-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-fluoro-2-(3-methyl-1,4-diazepan-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as yellow solids (10%).

- 59 044043

1H NMR (400 MHz, CD3OD) δ 8.49 (s, 2H), 8.05 (s, 1H), 8.01 (s, 1H), 7.88 (d, J=4.0 Hz, 1H ), 7.59-7.51 (m, 2H), 4.30-4.25 (m, 2H), 3.53-3.43 (m, 1H), 3.41-3.33 (m , 3H), 3.05-2.95 (m, 1H), 2.22-2.08 (m, 2H), 1.21 (d,

J=6.4 Hz, 3H). MS (ER+) m/e 342.1 (M+H) ⁺ .

Example 152.

N-(5-fluoro-2-(5-methyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 52 hours, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-fluoro-2-(5-methyl-1,4-diazepan-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as yellow solids (8%).

1H NMR (400 MHz, CD3OD) δ 8.07 (s, 1H), 8.05 (s, 1H), 8.00 (d, J=4.8 Hz, 1H), 7.60 (m, 2H ), 4.05-3.96 (m, 3H), 3.66 (m, 1H), 3.51-3.48 (m, 2H), 3.25 (m, 1H), 2.17- 2.13 (m, 1H), 2.06-2.01 (m, 1H), 1.39 (d, J=6.8 Hz, 3H). MS (ER+) m/e 342.1 (M+H) ⁺ .

Example 153.

N-(5-fluoro-2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse-phase preparative HPLC to give Na(5-fluoro-2-(4,7diazaspiro[2.5]octan-7-yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid substances (40%).

1H NMR (400 MHz, CD3OD) δ 8.05 (d, J=1.2 Hz, 1H), 8.00 (s, 1H), 7.83 (d, J=4.0 Hz, 1H), 7.60 (dd, J=8.8, 2.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 3.73-3.71 (m, 2H), 3 .58 (s, 2H), 2.94-2.92 (m, 2H), 0.61-0.59 (m, 4H). MS (ER+) m/e 340.2 (M+H) ⁺ .

Example 154.

N-(2-(2,5-diazabicyclo[2.2.2]octan-2-yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2,5-diazabicyclo[2.2.2]octan-2yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine as white solid (16%).

1H NMR (400 MHz, CD3OD) δ 8.07 (s, 2H), 8.01-8.00 (m, 1H), 7.62-7.56 (m, 2H), 4.73 (s, 1H), 3.96-3.91 (m, 2H), 3.79-3.76 (m, 1H), 3.55-3.45 (m, 2H), 2.20-2.12 ( m, 2H), 2.03-1.99 (m, 2H). MS (ER+) m/e 340.1 (m+n) ⁺ .

- 60 044043

Example 155.

N-(2-(2,5-dimethylpiperazin-1-yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2,5-dimethylpiperαzin-1-yl)-5fluoropyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (20% ).

^1H NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 8.02 (t, J=1.2 Hz, 1H), 7.98 (d, J=4.4 Hz, 1H) , 7.58 (d, J=1.2 Hz, 2H), 4.85-4.81 (m, 1H), 4.34-4.30 (m, 1H), 3.81-3.73 (m, 1H), 3.57-3.49 (m, 2H), 3.17-3.12 (m, 1H), 1.37 (t, J=7.6 Hz, 6H). MS (ER+) m/e 342.2 (M+H) ⁺ .

Example 156.

(1-(4-((1 H-indazol-5-yl)amino)-5-fluoropyrimidin-2-yl)piperazin-2-yl)methanol

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give (1-(4-((1H-indazol-5-yl)αmino)-5fluoropyrimidin-2-yl)piperazin-2-yl)methanol as a white solid (5 %).

^1H NMR (400 MHz, CD3OD) δ 8.12 (d, J=1.6 Hz, 1H), 8.02 (s, 1H), 7.86 (d, J=3.6 Hz, 1H) , 7.63 (dd, J=8.8, 2.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 4.59-4.55 (m, 1H), 4.32 (m, 1H), 3.96-3.92 (m, 1H), 3.74-3.70 (m, 1H), 3.30-3.27 (m, 1H), 3. 10 (m, 2H), 2.87-2.84 (m, 1H), 2.83-2.73 (m, 1H). MS (ER+) m/e 344.1 (M+H) ⁺ .

Example 157.

N-(2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.1.1]heptαn3-yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine as white solid (11%).

^1H NMR (400 MHz, CD3OD) δ 8.24 (d, J=1.2 Hz, 1H), 8.00 (s, 1H), 7.86 (d, J=4.0 Hz, 1H) , 7.70 (dd, J=9.2, 2.0 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 3.85-3.72 (m, 6H), 2.71-2.70 (m, 1H), 1.61 (d, J=9.2 Hz, 1H). MS (ER+) m/e 326.1 (M+H) ⁺ .

Example 158.

N-(5-fluoro-2-(2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified

- 61 044043 by reverse-phase preparative HPLC to obtain N-(5-φtor-2-(2,7diazaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)-1H-indazol-5-amine in the form of dirty -white solid (70%).

1H NMR (400 MHz, DMSOL) δ 13.04 (br s, 1H), 9.56 (s, 1H), 8.78 (br s, 2H), 8.05-8.03 (m, 3H), 7.60 (d, J=8.8, 1.6 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 3.76-3.73 (m, 4H ), 3.60-3.58 (m, 4H), 1.78-1.75 (m, 4H). MS (ER+) m/e 354.1 (M+H) ⁺ .

Example 159.

N-(5-φtor-2-(2,6-diazaspiro[3.4]octan-6-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse-phase preparative HPLC to obtain N(5-fluoro-2-(2,6diazaspiro[3.4]octan-6-yl)pyrimidin-4-yl)-1H-indazol-5-amine as dirty white solid (51%).

1H NMR (400 MHz, DMSO-Y6) δ 13.14 (br.s, 1H), 10.00 (br.s, 1H), 8.96 (br.s, 1H), 8.81 (br.s. s, 1H), 8.23 (s, 1H), 8.15 (d, J=4.8 Hz, 1H), 8.10 (s, 1H), 7.69 (dd, J=8.8 , 1.6 Hz, 1H), 7.55 (d, J=9.2 Hz, 1H), 4.04-4.00 (m, 2H), 3.93-3.92 (m, 2H) , 3.70 (m, 2H), 3.52-3.49 (m, 2H), 2.26-2.22 (m, 2H). MS (ER+) m/e 340.1 (M+H) ⁺ .

Example 160.

N-(5-φtor-2-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-φtor-2-(1-oxa-4,9diazaspiro[5.5]undecan-9-yl)pyrimidin-4-yl)-1H-indazol-5- amine as an off-white solid (42%).

^1H NMR (400 MHz, DMSO-d6) δ 13.02 (br s, 1H), 9.53 (br s, 1H), 8.94 (br s, 2H), 8.07-8 .03 (m, 3H), 7.60 (dd, J=9.2, 2.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 4.09-4, 06 (m, 2H), 3.84-3.81 (m, 2H), 3.28-3.23 (m, 2H), 3.07-3.02 (m, 4H), 1.91- 1.88 (m, 2H), 1.60-1.54 (m, 2H). MS (ER+) m/e 384.1 (M+H) ⁺ .

Example 161.

N-(5-fluoro-2-(2,7-diazaspiro[4.5]decan-2-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-φtor-2-(2,7diazaspiro[4.5]decan-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine as white solids (11%).

1H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 8.10 (s, 1H), 8.00 (d, J=5.2 Hz, 1H), 7.66 (dd, J =9.2, 2.0 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 3.72-3.70 (m, 2H), 3.61-3.58 ( m, 1H), 3.49-3.47 (m, 1H), 3.20-3.15 (m, 4H), 2.122.09 (m, 2H), 1.91-1.79 (m, 4H). MS (ER+) m/e 368.1 (M+H) ⁺ .

- 62 044043

Example 162.

N-(5-fluoro-2-(2,7-diazaspiro[4.5]decan-7-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse-phase preparative HPLC to give X-(5-fluoro-2-(2,7diazaspiro[4.5]decan-7-yl)pyrimidin-4-yl)-1H-indazol-5-amine as light -brown solid (37%).

1H NMR (400 MHz, DMSO-d6) δ 13.04 (br s, 1H), 9.45 (s, 1H), 8.83 (s, 2H), 8.08 (d, J=1, 2 Hz, 1H), 8.05 (s, 1H), 8.01 (d, J=4.0 Hz, 1H), 7.61 (dd, J=9.2, 2.0 Hz, 1H) , 7.53 (d, J=9.2 Hz, 1H), 3.65-3.56 (m, 2H), 3.30-3.29 (m, 2H), 3.28-3.18 (m, 2H), 2.98-2.95 (m, 2H), 1.84-1.82 (m, 1H), 1.70-1.57 (m, 5H). MS (ER+) m/e 368.1 (M+H) ⁺ .

Example 163.

N-(5-fluoro-2-(2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-4-ul)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse-phase preparative HPLC to give N(5-fluoro-2-(2,6diazaspiro[3.4]octan-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine as dirty white solid (31%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 13.11 (br s, 1H), 9.96 (s, 1H), 8.90 (s, 2H), 8.18 (d, J=1 .2 Hz, 1H), 8.14 (d, J=4.8 Hz, 1H), 8.04 (s, 1H), 7.64 (dd, J=9.2, 2.0 Hz, 1H ), 7.52 (d, J=8.8 Hz, 1H), 4.07 (d, J=8.8 Hz, 2H), 3.99 (d, J=8.8 Hz, 2H), 3.41-3.38 (m, 2H), 3.25-3.21 (m, 2H), 2.20 (t, J=7.2 Hz, 2H). MS (ER+) m/e 340.1 (M+H) ⁺ .

Example 164.

N-(5-fluoro-2-(2,7-diazaαspiro[3.5]nonan-2-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse-phase preparative HPLC to give N(5-fluoro-2-(2,7diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine as dirty white solid (24%).

1H NMR (400 MHz, DMSOC) δ 13.08 (br s, 1H), 9.82 (br s, 1H), 8.48 (br s, 2H), 8.19 (d, J= 1.6 Hz, 1H), 8.11 (d, J=4.4 Hz, 1H), 8.07 (s, 1H), 7.65 (dd, J=8.8, 2.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 3.82 (s, 4H), 3.07 (m, 4H), 1.93-1.91 (m, 4H). MS (ER+) m/e 354.1 (M+H) ⁺ .

- 63 044043

Example 165.

N-(5-fluoro-2-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse-phase preparative HPLC to obtain Na(5-fluoro-2-(2,6diαzaspiro[3.3]heptαn-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine as dirty white solid (29%).

1H NMR (400 MHz, DMSO-Y6) δ 13.11 (br s, 1H), 9.89 (s, 1H), 8.61 (br s, 2H), 8.20 (d, J= 1.2 Hz, 1H), 8.12 (d, J=4.4 Hz, 1H), 8.04 (s, 1H), 7.63 (dd, J=9.2, 2.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 4.20-4.14 (m, 8H). MS (ER+) m/e 326.1 (M+H) ⁺ .

Example 166.

N-(2-(3,6-diazabicyclo[3.2.1] octan-3-yl)-5-fluoropyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.2.1]octan-3yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine as off-white solid (34%).

1H NMR (400 MHz, D2O) δ 8.08 (s, 1H), 7.91-7.90 (m, 1H), 7.77 (d, J=5.2 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.50 (dd, J=8.8, 2.0 Hz, 1H), 4.13-4.09 (m, 2H), 3.88- 3.85 (m, 1H), 3.30-3.20 (m, 4H), 2.80 (m, 1H), 1.99 (m, 2H). MS (ER+) m/e 340.1 (M+H) ⁺ .

Example 167.

N-(2-(3,7-diazabicyclo[3.3.1]nonan-3-yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,7-diαzabicyclo[3.3.1]nonan-3yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine as off-white solid (7%).

^1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 8.07-8.05 (m, 2H), 7.67-7.61 (m, 2H), 4.35-4 .32 (m, 2H), 3.513.48 (m, 2H), 3.39-3.36 (m, 2H), 3.29 (m, 2H), 2.36 (m, 2H), 2, 09-1.97 (m, 2H). MS (ER+) m/e 354.1 (M+H) ⁺ .

Example 168.

N-(5-fluoro-2-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

- 64 044043

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-fluoro-2-(octahydro-5Hpyrrolo[3,2-c]pyridin-5-yl)pyrimidin-4-yl)-1H-indazol-5- amine as a light brown solid (4%).

^1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 8.04 (s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.63-7, 58 (m, 2H), 4.003.86 (m, 3H), 3.81-3.80 (m, 1H), 3.45-3.44 (m, 2H), 3.31-3.29 ( m, 1H), 2.67-2.65 (m, 1H), 2.19-2.15 (m, 2H), 1.95-1.86 (m, 2H). MS (ER+) m/e 354.1 (M+H) ⁺ .

Example 169.

N-(5-fluoro-2-(octahydropyrrolo[3,4-d]azepin-6(1H)-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-fluoro-2-(octahydropyrrolo[3,4d]azepin-6(1H)-yl)pyrimidin-4-yl)-1H-indazol-5-amine as a light brown solid (11%).

1H NMR (400 MHz, CD3OD) δ 8.09-8.08 (m, 2H), 7.89 (d, J=8.8 Hz, 1H), 7.61-7.60 (m, 2H) , 4.02-3.98 (m, 2H), 3.56-3.47 (m, 4H), 3.06-3.01 (m, 2H), 2.68-2.65 (m, 2H), 2.01-1.97 (m, 2H), 1.89-1.84 (m, 2H). MS (ER+) m/e 368.1 (M+H) ⁺ .

Example 170.

N-(2-(3,7-diαzabicyclo[4.2.0]octan-3-yl)-5-fluoropyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,7-diazabicyclo[4.2.0]octan-3yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine as light brown solid (7%).

1H NMR (400 MHz, CD3OD) δ 8.08-8.03 (m, 3H), 7.64-7.59 (m, 2H), 4.76-4.74 (m, 1H), 4, 17-4.06 (m, 2H), 3.93-3.91 (m, 2H), 3.82 (m, 1H), 3.65-3.60 (m, 1H), 3.37 ( m, 1H), 2.43-2.32 (m, 2H). MS (ER+) m/e 340.1 (M+H) ⁺ .

Example 171.

N-(2-([3,3'-bipiperidin]-1 -yl)-5-fluoropyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-([3,3'-bipiperidin]-1-yl)-5fluoropyrimidin-4-yl)-1H-indazol-5-amine as light brown solid matter (13%).

^1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 8.02-8.01 (m, 1H), 7.96 (d, J=5.2 Hz, 1H), 7, 63 (d, J=8.8 Hz, 1H), 7.54 (dd, J=8.0, 1.6 Hz, 1H), 4.46-4.43 (m, 1H), 4.08 -4.05 (m, 1H), 3.40-3.37 (m, 1H), 3.27 (m, 1H), 3.193.13 (m, 1H), 2.87-2.72 (m , 2H), 2.62-2.56 (m, 1H), 1.93-1.82 (m, 2H), 1.69-1.49 (m, 5H), 1.35-1.29 (m, 2H), 0.90-0.87 (m, 1H). MS (ER+) m/e 396.1 (M+H) ⁺ .

- 65 044043

Example 172.

N-(2-(3-(azetidin-3 -yl)pyrrolidin-1 -yl)-5 -fluoropyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-(azetidin-3-yl)nirrolidin-1yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine as light -brown solid (18%).

^1H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 8.09 (s, 1H), 8.00 (d, J=5.6 Hz, 1H), 7.66 (dd, J=9.2, 2.0 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 4.20-4.13 (m, 2H), 3.98-3.91 (m, 2H), 3.77-3.58 (m, 3H), 3.19-3.15 (m, 1H), 3.032.97 (m, 1H), 2.76 (m, 1H), 2.25 (m, 1H), 1.76 (m, 1H). MS (ER+) m/e 354.1 (M+H) ⁺ .

Example 173.

N-(5-fluoro-2-(octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-fluoro-2-(octahydro-2Hpyrazino[1,2-a]pyrazin-2-yl)pyrimidin-4-yl)-1H-indazol-5- amine as a light brown solid (19%).

1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), 8.03-8.01 (m, 2H), 7.63-7.57 (m, 2H), 4.33-4, 29 (m, 2H), 3.433.21 (m, 1H), 3.27-3.17 (m, 3H), 3.08-3.05 (m, 1H), 2.98-2.96 ( m, 1H), 2.90-2.84 (m, 2H), 2.52-2.34 (m, 3H). MS (ER+) m/e 369.1 (M+H) ⁺ .

Example 174.

N-(2-(3,6-diazabicyclo[3.2.0]heptan-3-yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.2.0]heptan3-yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine as light brown solid (19%).

1H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 8.06 (s, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.64 (dd, J =8.8, 2.0 Hz, 1H), 7.56 (d, J=9.2 Hz, 1H), 5.03-5.00 (m, 1H), 4.39 (d, J= 14.0 Hz, 1H), 4.25-4.20 (m, 1H), 4.08 (d, J=11.6 Hz, 1H), 3.74-3.70 (m, 1H), 3.56-3.52 (m, 2H), 3.46-3.41 (m, 2H). MS (ER+) m/e 326.3 (M+H) ⁺ .

- 66 044043

Example 175.

N-(5-fluoro-2-(3 -(piperidin-4-yl)indolin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol D. The reaction time for the first step was 16 hours, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-fluoro-2-(3-(piperidin-4yl)indolin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine as yellow solid (31%).

^1H NMR (400 MHz, DMSO- _d6 ) δ 13.10 (br s, 1H), 9.55 (s, 1H), 8.44-8.41 (m, 1H), 8.20- 8.16 (m, 2H), 8.07-8.05 (m, 3H), 7.61-7.56 (m, 2H), 7.20-7.18 (m, 1H), 6. 88-6.84 (m, 2H), 4.11-4.02 (m, 2H), 3.38-3.21 (m, 3H), 2.84-2.79 (m, 2H), 1.94 (m, 1H), 1.81-1.80 (m, 1H), 1.46-1.40 (m, 3H). MS (ER+) m/e 430.1 (M+H) ⁺ .

Example 176.

N-(5-fluoro-2-(spiro[indoline-3,4'-piperidin]-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol D. The reaction time for the first step was 16 hours, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-fluoro-2-(spiro[indolin-3,4'piperidin]-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (29%).

1H NMR (400 MHz, DMSO-46) δ 13.13 (br s, 1H), 9.58 (s, 1H), 8.72-8.69 (m, 1H), 8.49-8, 46 (m, 1H), 8.21-8.20 (m, 2H), 8.09 (s, 1H), 8.00 (m, 1H), 7.60-7.54 (m, 2H) , 7.12-7.10 (m, 1H), 6.91-6.87 (m, 2H), 4.14 (s, 2H), 3.38-3.35 (m, 2H), 3 .11-3.02 (m, 2H), 2.03-1.97 (m, 2H), 1.83-1.79 (m, 2H). MS (ER+) m/e 416.1 (M+H) ⁺ .

Example 177.

N-(5-fluoro-2-(3 -(piperidin-3-yl)indolin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol D. The reaction time for the first step was 16 hours, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-fluoro-2-(3-(piperidin-3yl)indolin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine as yellow solid (23%).

1H NMR (400 MHz, DMSO-d6) δ 13.11 (br s, 1H), 9.55 (s, 1H), 8.61-8.58 (m, 1H), 8.24-8, 15 (m, 3H), 8.07-8.02 (m, 2H), 7.58 (s, 2H), 7.20-7.15 (m, 1H), 6.88-6.87 ( m, 2H), 4.08-4.06 (m, 2H), 3.43-3.40 (m, 1H), 3.29-3.18 (m, 2H), 2.82-2, 79 (m, 2H), 2.02-2.01 (m, 1H), 1.79-1.77 (m, 1H), 1.53-1.27 (m, 3H). MS (ER+) m/e 430.1 (M+H) ⁺ .

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Example 178.

N-(5-chloro-2-(piperazin-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-chloro-2-(piperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (48%).

^1H NMR (400 MHz, DMSO- _d6 ) δ 13.04 (s, 1H), 8.79 (s, 1H), 8.29 (s, 1H), 8.05-8.01 (m, 2H), 7.89 (d, J=1.2 Hz, 1H), 7.45 (dd, J=8.8, 2.0 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 3.60 (t, J=4.8 Hz, 4H), 2.80 (t, J=4.8 Hz, 4H). MS (ER+) m/e 330.0 (M+H) ⁺ .

Example 179.

N-(5-chloro-2-(2-methylpiperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5 -amine

N

XX>

HN

Ύχλ

Ν Ν% k^NH

The reaction was carried out following General Protocol A. The reaction time in the first stage was 32 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-chloro-2-(2-methylpinerazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (11%) .

^1H NMR (400 MHz, DMSO- _d6 ) δ 13.05 (br s, 1H), 8.75 (s, 1H), 8.30 (s, 2H), 8.01 (s, 2H) , 7.93 (d, J=1.6 Hz, 1H), 7.55 (dd, J=9.2, 2.0 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 4.51 (m, 1H), 4.17-4.14 (m, 1H), 2.94-2.87 (m, 2H), 2.81-2.70 (m, 2H) , 2.56 (m, 1H), 1.15 (d, J=6.8 Hz, 3H). MS (ER+) m/e 344.0 (M+H) ⁺ .

Example 180.

N-(5-chloro-2-(3-methylninerasin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-chloro-2-(3-methylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (23%) .

^1H NMR (400 MHz, DMSO-66) δ 13.00 (br s, 1H), 8.80 (s, 1H), 8.28 (s, 2H), 8.02 (s, 2H), 7.92 (s, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.49 (d, J=9.2 Hz, 1H), 4.31 (t, J=12 .0 Hz, 2H), 2.99-2.54 (m, 5H), 1.03 (d, J=6.0 Hz, 3H). MS (ER+) m/e 344.1 (M+H) ⁺ .

Example 181.

N-(5-chloro-2-(3-isopropyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(5-chloro-2-(3-isopronyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazole -5-amine as a yellow solid (16%).

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1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.56-7 .54 (d, J=8.8

Hz, 1H), 7.51-7.48 (d, J=8.8 Hz, 1H), 4.24-4.14 (m, 2H), 3.49-3.39 (m, 3H) , 3.01-3.00 (m, 2H), 2.12-2.05 (m,

2H), 1.77 (m, 1H), 0.78 (m, 6H). MS (ER+) m/e 386.1 (M+H)+.

Example 182.

N-(5-chloro-2 -(5-isopropyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(5-chloro-2-(5-isopropyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazole -5-amine as a yellow solid (31%).

1H NMR (400 MHz, CD ₃ OD) δ 8.55 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.58 -7.52 (m, 2H), 4.05-4.00 (m, 2H), 3.98-3.95 (m, 1H), 3.67-3.64 (m, 1H), 3 .35 (m, 1H), 3.17-3.13 (m, 2H), 2.05-2.01 (m, 2H), 1.80 (m, 1H), 1.00-0.97 (t, J=7.2 Hz, 6H). MS (ER+) m/e 386.1 (M+H) ⁺ .

Example 183.

N-(5-chloro-2-(3-phenyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(5-chloro-2-(3-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazole -5-amine as a yellow solid (36%).

1H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 8.01 (s, 1H), 7.91-7.78 (m, 2H), 7.49-6.93 (m, 7H), 4.45-4.42 (m, 3H), 3.57-3.46 (m, 1H), 3.45-3.41 (m, 2H), 3.00-2.94 ( m, 1H), 2.27-2.26 (m, 1H), 2.16-2.14 (m, 1H). MS (ER+) m/e 420.1 (M+H) ⁺ .

Example 184.

N-(5-chloro-2-(5-phenyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(5-chloro-2-(5-phenyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazole -5-amine as a yellow solid (48%).

1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 7.99-7.97 (m, 3H), 7.60 (dd, J=8.8, 1.6 Hz, 1H) , 7.51 (d, J=9.2 Hz, 1H), 7.41-7.31 (m, 5H), 4.09-4.01 (m, 3H), 3.87 (m, 1H ), 3.76-3.74 (m, 1H), 3.35 (m, 1H), 3.18-3.15 (m, 1H), 2.18-2.13 (m, 2H). MS (ER+) m/e 420.1 (M+H) ⁺ .

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Example 185.

N-(5-chloro-2-(3-isopropylpiperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following general protocol C. The residue was purified by reverse phase preparative HPLC to give N-(5-chloro-2-(3-isopropylpiperazin-1-yl)pyrimidin-4-yl)-1Hindazol-5-amine as yellow solid (32%).

1H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 8.03 (s, 1H), 8.01 (s, 2H), 7.91 (s, 1H), 7.56-7 .51 (m, 2H), 4.81-4.75 (m, 1H), 4.67-4.63 (m, 1H), 3.36 (m, 1H), 3.15-3.05 (m, 2H), 2.89-2.85 (m, 2H), 1.85-1.80 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0, 93 (d, J=6.4 Hz, 3H). MS (ER+) m/e 372.1 (M+H) ⁺ .

Example 186.

N-(5-chloro-2-(3-ethyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol C. The residue was purified by reverse phase preparative HPLC to give N-(5-chloro-2-(3-ethyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazole -5-amine as a yellow solid (18%).

1H NMR (400 MHz, CD3OD) δ 8.45 (br s, 2H), 8.04 (s, 1H), 7.99 (s, 1H), 7.89 (s, 1H), 7.57 -7.50 (m, 2H), 4.25-4.22 (m, 2H), 3.42-3.36 (m, 3H), 3.18 (m, 1H), 3.03-3 .00 (m, 1H), 2.16-2.14 (m, 1H), 2.07-2.05 (m, 1H), 1.50-1.48 (m, 2H), 0.70 -0.65 (m, 3H). MS (ER+) m/e 372.2 (M+H) ⁺ .

Example 187.

X-(5-chloro-2-(2-ethylpiperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5 -amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 48 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give X-(5-chloro-2-(2-ethylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (19%) .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.53 (s, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.90 (s, 1H), 7. 57-7.54 (m, 2H), 4.75-4.64 (m, 2H), 3.34 (m, 1H), 3.33 (m, 1H), 3.28-3.20 ( m, 1H), 3.12-3.09 (m, 1H), 2.99-2.98 (m, 1H), 1.80-1.71 (m, 2H), 0.89 (t, J=7.6 Hz, 3H). MS (ER+) m/e 358.0 (M+H) ⁺ .

Example 188.

N-(5-chloro-2-(5-ethyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 48 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give X-(5-chloro-2-(5-ethyl-1,4-diazepan-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as dirty -white solid (19%).

1H NMR (400 MHz, CD3OD) δ 8.53 (s, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.59-7 .53 (m, 2H),

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4.06-3.94 (m, 3H), 3.65-3.58 (m, 1H), 3.42-3.35 (m, 1H), 3.25-3.13 (m, 2H ), 2.18-2.07 (m, 1H), 1.91-1.58 (m,

3H), 0.99 (t, J=7.6 Hz, 3H). MS (ER+) m/e 371.8 (m+H) ⁺ .

Example 189.

N-(5-chloro-2-(3,5-dimethylpiperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 48 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-chloro-2-(3,5-dimethylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (41 %).

^1H NMR (400 MHz, DMSO- _d6 ) δ 13.02 (br s, 1H), 8.78 (s, 1H), 8.29 (s, 2H), 8.00 (m, 2H) , 7.96 (d, J=1.2 Hz, 1H), 7.55 (dd, J=8.8, 1.6 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 4.36-4.34 (m, 2H), 2.72-2.68 (m, 2H), 2.362.30 (m, 2H), 0.99 (d, J=6.4 Hz , 6H). MS (ER+) m/e 358.0 (M+H)+.

Example 190.

N-(5-chloro-2-(3 -ethylpiperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5 -amine n

XΎρ °Ύ

Ν Ν ^/ γ ^Χ k^NH

The reaction was carried out following General Protocol A. The reaction time in the first stage was 36 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-chloro-2-(3-ethylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (22%) .

1H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 8.03 (s, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.55 (s , 2H), 4.694.66 (m, 1H), 4.60-4.56 (m, 1H), 3.30 (m, 1H), 3.21-3.20 (m, 1H), 3. 05-3.01 (m, 2H), 2.92-2.89 (m, 1H), 1.65-1.55 (m, 2H), 0.94 (t, J=7.6 Hz, 3H). MS (ER+) m/e 358.1 (M+H)+.

Example 191.

N-(5-chloro-2-(5-methyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 36 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-chloro-2-(5-methyl-1,4-diazepan-1 yl)pyrimidin-4-yl)-1H-indazol-5-amine as yellow solid (26%).

1H NMR (400 MHz, CD3OD) δ 8.48 (br s, 2H), 8.04 (s, 1H), 8.00 (s, 1H), 7.97 (s, 1H), 7.56 -7.55 (m, 2H), 4.04-3.94 (m, 3H), 3.62 (m, 1H), 3.45-3.41 (m, 2H), 3.23-3 .21 (m, 1H), 2.10-2.06 (m, 1H), 1.93-1.87 (m, 1H), 1.35 (d, J=6.8 Hz, 3H). MS (ER+) m/e 358.0 (M+H)+.

Example 192.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)-1H-indazol-5-amine

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The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-8yl)-5-chloropyrimidin-4-yl)-1H-indazol-5-amine as light yellow solid (71%).

^1H NMR (400 MHz, DMSO-yb) δ 13.00 (br s, 1H), 8.83 (s, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 8.03 (s, 1H), 7.94-7.93 (d, J=1.6 Hz, 1H), 7.58-7.48 (m, 2H), 4.39 (s, 2H) , 2.97 (d, J=12.0 Hz, 2H), 2.78 (d, J=12.0 Hz, 2H), 1.94-1.92 (m, 4H). MS (ER+) m/e 356.0 (M+H) ⁺ .

Example 193.

N-(5-chloro-2 -(6-methyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5 -amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-chloro-2-(6-methyl-1,4-diazepan-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as yellow solids (44%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.51 (s, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.97 (s, 1H), 7. 55-7.53 (m, 2H), 4.25-4.21 (m, 2H), 3.72-3.65 (m, 1H), 3.54-3.41 (m, 1H), 3.27-3.15 (m, 2H), 3.11-3.05 (m, 1H), 3.01-2.95 (m, 1H), 2.27-2.14 (m, 1H ), 0.96 (d, J=5.6 Hz, 3H). MS (ER+) m/e 358.0 (M+H) ⁺ .

Example 194.

N-(2-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-chloropyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give X-(2-(2,5-diazabicyclo[2.2.1]heptan2-yl)-5-chloropyrimidin-4-yl)-1H-indazol-5-amine as white solid (31%).

^1H NMR (400 MHz, CD3CN) δ 8.82 (s, 1H), 8.27 (s, 2H), 8.10 (s, 1H), 8.08 (s, 1H), 8.02 ( s, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 4.89 (s, 1H), 4.49 ( s, 1H), 3.77 (m, 1H), 3.65 (m, 1H), 3.51-3.45 (m, 1H), 3.39-3.37 (m, 1H), 2 .18-2.13 (m, 1H), 2.08-2.04 (m, 1H). MS (ER+) m/e 342.1 (M+H) ⁺ .

Example 195.

N-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloropyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-3yl)-5-chloropyrimidin-4-yl)-1H-indazol-5-amine as white solid (35%).

^1H NMR (400 MHz, DMSO-66) δ 9.06-8.79 (m, 3H), 8.07 (s, 1H), 8.04 (s, 1H), 7.89 (d, J =1.2 Hz, 1H), 7.57-7.48 (m, 2H), 4.26-4.22 (m, 2H), 4.09 (s, 2H), 3.17 (d, J=13.6 Hz, 2H), 1.95-1.84 (m, 2H), 1.73-1.71 (m, 2H). MS (ER+) m/e 356.1 (M+H) ⁺ .

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Example 196.

N-(5-methyl-2 -(6-methyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-methyl-2-(6-methyl-1,4-diazepan-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as white solids (26%).

1H NMR (400 MHz, CD3OD) δ 8.16 (d, J=0.8 Hz, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.71 (d, J=1 .2 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.57 (d, J=8.8, 1.6 Hz, 1H), 4.04-3.91 (m, 2H), 3.88-3.78 (m, 1H), 3.34 (m, 2H), 3.28-3.13 (m, 2H), 3.06 (m, 1H), 2.33-2.27 (m, 4H), 0.97 (m, 3H). MS (ER+) m/e 338.2 (M+H) ⁺ .

Example 197.

N-(5,6-dimethyl-2-(piperazin-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 32 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5,6-dimethyl-2-(piperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (31%) .

1H NMR (400 MHz, CD3OD) δ 8.35 (s, 2H), 7.99 (s, 1H), 7.85 (d, J=0.8 Hz, 1H), 7.55-7.48 (m, 2H), 3.86 (t, J=5.2 Hz, 4H), 3.18 (t, J=5.2 Hz, 4H), 2.33 (s, 3H), 2.14 (c, 3H). MS (ER+) m/e 324.1 (M+H) ⁺ .

Example 198.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-methoxypyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-8yl)-5-methoxypyrimidin-4-yl)-1H-indazol-5-amine as yellow solid (32%).

¹ H NMR (400 MHz, DMSO-dg) δ 13.08 (br s, 1H), 9.70 (br s, 1H), 9.13 (br s, 1H), 8.84 (br .s, 1H), 8.08 (s, 1H), 8.04 (s, 1H), 7.74 (s, 1H), 7.62 (dd, J=8.8, 2.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 4.60 (s, 2H), 3.91 (s, 3H), 3.21 (m, 4H), 2.10- 2.00 (m, 4H). MS (ER+) m/e 352.1 (M+H) ⁺ .

Example 199.

N-(2-(3,6-diazabicyclo[3.1.1]gentan-3-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.1.1]heptane

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3-yl)nirimidin-4-yl)-1H-indazol-5-amine as a yellow solid (52%).

^1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 8.10 (s, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.65-7, 55 (m, 2H), 6.49 (d, J=7.2 Hz, 1H), 4.61 (d, J=5.6 Hz, 2H), 4.17 (m, 4H), 3, 16-3.10 (m, 1H), 2.05-2.02 (m, 1H). MS (ER+) m/e 308.1 (M+H) ⁺ .

Example 200.

N-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 32 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.1.1]heπtan6-yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (38%).

^1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 8.10-7.94 (m, 3H), 7.56-7.44 (m, 2H), 6.26 (d , J=6.0 Hz, 1H), 4.51 (d, J=6.0 Hz, 2H), 3.92-3.89 (m, 2H), 3.41-3.38 (m, 2H), 3.02-2.93 (m, 1H), 1.92-1.90 (m, 1H). MS (ER+) m/e 308.1 (M+H) ⁺ .

Example 201.

N-(2-(2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 32 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2,5-diazabucyclo[2.2.1]heptan2-yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (38%).

^1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 8.10 (s, 1H), 7.82 (d, J=7.2 Hz, 1H), 7.66-7, 50 (m, 2H), 6.41 (d, J=6.4 Hz, 1H), 5.11 (s, 1H), 4.66 (s, 1H), 3.89-3.80 (m , 2H), 3.58-3.47 (m, 2H), 2.36 (d, J=11.2 Hz, 1H), 2.17 (d, J=11.2 Hz, 1H). MS (ER+) m/e 308.1 (M+H)+.

Example 202.

N-(2-(2,8-diazaspiro[4.5]decan-2-yl)πrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2,8-diazaspiro[4.5]decan-2yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (69 %). MS (ER+) m/e 349.1 (M+H)+.

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Example 203.

N-(2-(3-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-methyl-1,4-diazenan-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (29 %).

1H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 7.96 (s, 1H), 7.83 (d, J=6.0 Hz, 1H), 7.49 (s, 2H ), 6.02 (d, J=6.0 Hz, 1H), 4.36-4.24 (m, 2H), 3.43-3.36 (m, 1H), 3.15-3, 11 (m, 2H), 3.03-2.96 (m, 1H), 2.67-2.61 (m, 1H), 2.13-2.11 (m, 1H), 1.92- 1.85 (m, 1H), 1.16 (d, J=6.4 Hz, 3H). MS (ER+) m/e 323.9 (M+H).

Example 204.

N-(6-methyl-2-(3-methylpiperazin-1 -yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(3-methylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (56%) .

1H NMR (400 MHz, DMSO-d6) δ 12.90 (br s, 1H), 9.11 (s, 1H), 8.27 (s, 2H), 7.98 (s, 2H), 7 .48 (d, J=8.8 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 5.91 (s, 1H), 4.54 (d, J=13, 2 Hz, 2H), 3.15 (d, J=10.0 Hz, 1H), 3.00 (m, 2H), 2.88-2.67 (m, 2H), 2.13 (s, 3H), 1.16 (d, J=5.6 Hz, 3H). MS (ER+) m/e 324.1 (M+H).

Example 205.

N-(6-methyl-2-(niperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 32 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(piperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (46%).

1H NMR (400 MHz, CD3OD) δ 8.35 (s, 2H), 8.00 (s, 1H), 7.94 (s, 1H), 7.51 (d, J=8.8 Hz, 1H ), 7.45 (dd, J=8.8, 1.6 Hz, 1H), 6.00 (s, 1H), 4.03 (t, J=4.8 Hz, 4H), 3.25 (d, J=5.2 Hz, 4H), 2.22 (s, 3H). MS (ER+) m/e 310.1 (M+H).

Example 206.

N-(2-(3-ethyl-1,4-diazepan-1-yl)-6-methylpyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 36 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-ethyl-1,4-diazepan-1-yl)-6-75 044043 methylpyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (13%).

1H NMR (400 MHz, CD3OD) δ 8.38 (s, 2H), 7.99 (m, 2H), 7.53-7.44 (m, 2H), 5.99 (s, 1H), 4 .51-4.47 (m, 1H), 4.36-4.34 (m, 1H), 3.47-3.42 (m, 3H), 3.37-3.36 (m, 1H) , 3.05-3.02 (m, 1H), 2.27-2.24 (m, 4H), 2.14-2.13 (m, 1H), 1.68-1.65 (m, 2H), 0.99-0.97 (m, 3H). MS (ER+) m/e 352.1 (M+H).

Example 207.

N-(6-methyl-2-(2-methylpiperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 64 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(2-methylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (12%) .

1H NMR (400 MHz, CD3OD) δ 12.59 (s, 1H), 11.14 (s, 1H), 9.85 (s, 1H), 9.54 (s, 1H), 8.10 (s , 1H), 8.04 (s, 1H), 7.57 (s, 2H), 6.36 (s, 1H), 4.94 (m, 1H), 4.63-4.60 (m, 1H), 3.52-3.46 (m, 1H), 3.3-3.05 (m, 4H), 2.42 (s, 3H), 1.42 (d, J=6.8 Hz , 3H). MS (ER+) m/e 324.2 (M+H).

Example 208.

N-(6-methyl-2 -(3 -methyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(3-methyl-1,4-diazepan-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as yellow solid matter (37%).

1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), 7.95 (br s, 1H), 7.64-7.62 (d, J=8.8 Hz, 1H), 7 .48 (m, 1H), 6.24 (s, 1H), 4.26 (m, 1H), 3.95 (m, 1H), 3.67-3.51 (m, 4H), 3. 24-3.22 (m, 1H), 2.43 (s, 3H), 2.31 (m, 2H), 1.15 (m, 3H). MS (ER+) m/e 338.1 (M+H).

Example 209.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-8yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine as yellow solid (37%).

1H NMR (400 MHz, DMSO- _d6 ) δ 12.96 (br s, 1H), 9.09 (s, 1H), 8.26 (s, 2H), 8.02 (s, 1H), 8.00 (s, 1H), 7.49-7.42 (m, 2H), 5.91 (s, 1H), 4.58 (s, 2H), 2.98 (d, J=12, 0 Hz, 2H), 2.80 (d, J=12.0 Hz, 2H), 2.14 (s, 3H), 1.98-1.91 (m, 4H). MS (ER+) m/e 336.1 (M+H).

Example 210.

N-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidin-4-yl)-1H-indazol-5-amine

- 76 044043

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(hexahydronirrolo[3,4c]pyrrol-2(1H)-yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid substances (55%). MS (ER+) m/e 322.1 (M+H) ⁺ .

Example 211.

N-(2-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2,5-diazabicyclo[2.2.1]heptan2-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine as yellow solid (11%).

^1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 8.04 (s, 1H), 7.65-7.41 (m, 2H), 6.20 (s, 1H), 5.14 (s, 1H), 4.63 (s, 1H), 3.90-3.81 (m, 2H), 3.60-3.54 (m, 1H), 3.49-3, 43 (m, 1H), 2.39 (s, 3H), 2.34-2.31 (m, 1H), 2.18-2.11 (m, 1H). MS (ER+) m/e 338.1 (M+H).

Example 212.

N-(6-methyl-2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(6-methyl-2-(4,7diazaspiro[2.5]octan-7-yl)pyrimidin-4-yl)-N-indazol-5-amine as white solid matter (9%).

1H NMR (400 MHz, DMSO-66) δ 13.04 (br s, 1H), 9.90 (s, 1H), 9.37 (s, 2H), 8.05 (s, 1H), 7 .92 (s, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 6.09 (s, 1H), 4 .00 (m, 2H), 3.87 (s, 2H), 3.34 (m, 2H), 2.24 (s, 3H), 1.07-1.01 (m, 2H), 0. 95-0.88 (m, 2H). MS (ER+) m/e 336.1 (M+H).

Example 213.

N-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-6-methylpyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 32 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.1.1]heptan6-yl)-6-methylpyrimidin-4-yl)-1H-indazol-5-amine as white solid (10%).

^1H NMR (400 MHz, CD ₃ OD) δ 8.08 (s, 1H), 8.01 (s, 1H), 7.66-7.39 (m, 2H), 6.23 (s, 1H ), 4.76 (d, J=6.0 Hz, 2H), 3.89 (d, J=12.8 Hz, 2H), 3.59 (d, J=13.2 Hz, 2H), 3.16-3.04 (m, 1H), 2.38 (s, 3H), 2.00 (d, J=10.0 Hz, 1H). MS (ER+) m/e 322.1 (M+H).

Example 214.

N-(5-fluoro-2-(piperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

- 77 044043

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N(5-fluoro-2-(piperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (29%).

1H NMR (400 MHz, CD3OD) δ 8.44 (s, 2H), 8.02 (s, 1H), 8.00 (s, 1H), 7.91 (d, J=3.6 Hz, 1H ), 7.59-7.50 (m, 2H), 3.91 (t, J=5.2 Hz, 4H), 3.22 (t, J=5.2 Hz, 4H). MS (ER+) m/e 313.7 (M+H).

Example 215.

N-(2-(1,4-diazepan-1-yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(1,4-diazepan-1-yl)-5fluoropyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (28% ).

^1H NMR (400 MHz, CD3OD) δ 8.39 (s, 2H), 8.07 (d, J=1.2 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H) , 7.88 (d, J=4.0 Hz, 1H), 7.61-7.49 (m, 2H), 3.97 (t, J=5.2 Hz, 2H), 3.85 ( t, J=6.0 Hz, 2H), 3.35-3.32 (m, 2H), 3.28-3.25 (m, 2H), 2.13-2.07 (m, 2H) . MS (ER+) m/e 327.7 (M+H).

Example 216.

N-(5-fluoro-2-(2-methylpiperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

N

XA ⁿ λ

The reaction was carried out following General Protocol A. The reaction time in the first stage was 64 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(5-fluoro-2-(2-methylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (3%) .

1H NMR (400 MHz, CD3OD) δ 8.51 (s, 2H), 8.01 (m, 2H), 7.90 (d, J=3.6 Hz, 1H), 7.58 (dd, J =9.2, 2.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 4.53 (m, 2H), 3.35 (m, 1H), 3.27 -3.19 (m, 3H), 3.05-3.01 (m, 1H), 1.30 (d, J=7.2 Hz, 3H). MS (ER+) m/e 328.1 (M+H).

Example 217.

N-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoropyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-3yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine as off-white solid (9%).

1H NMR (400 MHz, CD ₃ OD) δ 8.49 (s, 1H), 8.05 (s, 2H), 7.91 (d, J=3.6 Hz, 1H), 7.60 (dd , J=8.8, 2.0 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 4.45-4.42 (m, 2H), 4.13 (m, 2H), 3.26-2.23 (m, 2H), 2.09-1.97 (m, 4H). MS (ER+) m/e 340.0 (M+H).

- 78 044043

Example 218.

N-(5-fluoro-2-(6-methyl-1,4-diazepan-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give X-(5-fluoro-2-(6-methyl-1,4-diazepan-1yl)pyrimidin-4-yl)-1H-indazol-5-αmine as yellow solids (46%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.52 (s, 2H), 8.11 (d, J=1.2 Hz, 1H), 8.02 (d, J=0.8 Hz, 1H), 7.90 (d, J=3.6 Hz, 1H), 7.61 (dd, J=8.8, 2.0 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 4.32-4.22 (m, 2H), 3.76-3.69 (m, 1H), 3.57-3.50 (m, 1H), 3.29-3, 19 (m, 2H), 3.15-3.09 (m, 1H), 3.04-2.98 (m, 1H), 2.32-2.21 (m, 1H), 1.03 ( d, J=6.8 Hz, 3H). MS (ER+) m/e 342.0 (M+H).

Example 219.

N-(2-(2,5-diazabicyclo[2.2.1] heptan-2-yl)-5-fluoropyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2,5-diαzabicyclo[2.2.1]heptan2-yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine as white solid (33%).

1H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 8.02 (d, J=0.8 Hz, 1H), 7.83 (d, J=4.0 Hz, 1H), 7.66 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 4.76 (s, 1H), 3.94 ( s, 1H), 3.63-3.56 (m, 1H), 3.55-3.48 (m, 1H), 3.123.06 (m, 2H), 2.01-1.98 (m, 1H), 1.85-1.82 (m, 1H). MS (ER+) m/e 326.3 (M+H).

Example 220.

N-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.1.1]heptan6-yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-αmine as yellow solid (20%).

1H NMR (400 MHz, CD3OD) δ 8.13 (d, J=1.6 Hz, 1H), 8.02-7.98 (m, 1H), 7.86 (d, J=4.2 Hz , 1H), 7.657.59 (m, 1H), 7.53-7.48 (m, 1H), 4.27 (d, J=6.0 Hz, 2H), 3.58-3.55 ( m, 2H), 2.89-2.86 (m, 2H), 2.74-2.67 (m, 1H), 1.79 (d, J=8.4 Hz, 1H). MS (ER+) m/e 326.2 (M+H).

Example 221.

N-(2-(3,8-diazaαbicyclo[3.2.1]octan-8-yl)-5-fluoropyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following general protocol A. The reaction time in the first stage was 16 h,

- 79 044043 and the crude material was further used without additional purification. The final residue was purified by reverse phase preparative HPLC to give X-(2-(3,8-diazabicyclo[3.2.1]octan-8yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine as white solid (5%).

1H NMR (400 MHz, DMSO-b ₆ ) δ 9.61 (s, 1H), 9.07 (s, 1H), 8.86 (s, 1H), 8.17-8.00 (m, 3H ), 7.61 (dd, J=8.8, 1.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 4.57 (s, 2H), 3.16 (m, 4H), 2.13-1.93 (m, 4H). MS (ER+) m/e 340.1 (M+H).

Example 222.

N-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-5-chloropyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.1.1]heptan6-yl)-5-chloropyrimidin-4-yl)-1H-indazol-5-amine as white solid (5%).

^1H NMR (400 MHz, DMSO-66) δ 13.02 (br s, 1H), 9.17 (s, 1H), 9.06 (s, 1H), 8.39 (m, 1H), 8.16 (s, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7.55-7.48 (m, 2H), 4.24 (m, 2H), 3 .65-3.62 (m, 2H), 3.31-3.26 (m, 2H), 2.74-2.68 (m, 1H), 1.82-1.80 (m, 1H) . MS (ER+) m/e 342.0 (M+H).

Example 223.

8-(4-((III-indazol-5-yl)amino)pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-ol

The reaction was carried out following General Protocol C. The reaction mixture was stirred for 48 hours at 110°C. The residue was purified by reverse phase preparative HPLC to give 8-(4((1H-indazol-5-yl)amino)pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-ol as a white solid substances (5%).

^1H NMR (400 MHz, DMSO-th ₆ ) δ 12.94 (br s, 1H), 9.13 (s, 1H), 8.10 (s, 1H), 7.98 (s, 1H) , 7.88 (d, J=6.0 Hz, 1H), 7.49-7.44 (m, 2H), 5.98 (d, J=6.0 Hz, 1H), 4.58 ( s, 1H), 4.58 (s, 1H), 4.51 (s, 2H), 3.89 (s, 1H), 2.28-1.64 (m, 8H). MS (ER+) m/e 337.1 (M+H).

Example 224.

N-(2-(3-phenylpiperazin-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol C. The reaction mixture was stirred for 16 hours. The residue was purified by reverse phase preparative HPLC to give N-(2-(3phenylpiperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5 -amine as a white solid (17%).

^1H NMR (400 MHz, DMSO-f,) δ 12.96 (br s, 1H), 9.20 (s, 1H), 8.10 (s, 1H), 7.91 (d, J= 6.0 Hz, 1H), 7.82 (s, 1H), 7.48-7.29 (m, 7H), 6.02 (d, J=5.6 Hz, 1H), 4.64 ( d, J=12.0 Hz, 1H), 4.57 (d, J=12.0 Hz, 1H), 3.70 (d, J=8.0 Hz, 1H), 3.06 (d, J=11.2 Hz, 1H), 2.91-2.67 (m, 4H). MS (ER+) m/e 372.1 (M+H).

- 80 044043

Example 225.

N-(2-(3-methylpiperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-methylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (10%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 13.0 (s, 1H), 9.15 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 7. 88 (d, J=5.6 Hz, 1H), 7.48 (d, J=9.2 Hz, 1H), 7.43 (d, J=9.2 Hz, 1H), 5.98 ( d, J=5.6 Hz, 1H), 4.45 (t, J=11.2 Hz, 2H), 2.91 (d, J=11.6 Hz, 2H), 2.78 (t, J=12.0 Hz, 1H), 2.64-2.57 (m, 2H), 2.42-2.37 (m, 1H), 1.01 (d, J=6.4 Hz, 3H ). MS (ER+) m/e 310.2 (M+H).

Example 226.

N-(2-(3,5-dimethylpiperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give K-(2-(3,5-dimethylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (10%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.15 (s, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.87 (d, J=5.6 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 5.97 (d, J=5.6 Hz, 1H), 4.51 (d, J=10.4 Hz, 2H), 2.70-2.64 (m, 2H), 2.302.27 (m, 2H), 2.21 (br s, 1H ), 1.02 (d, J=6.4 Hz, 6H). MS (ER+) m/e 324.2 (M+H).

Example 227.

N-(2-(3,3-dimethylpiperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,3-dimethylpiperazin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (35%).

^1H NMR (400 MHz, DMSO-th ₆ ) δ 13.0 (s, 1H), 9.12 (s, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7 .86 (d, J=5.6 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 5.95 (d, J=5.6 Hz, 1H), 3.65 (t, J=4.8 Hz, 2H), 3.47 (s, 2H), 2.77 (t, J=4.8 Hz , 2H), 1.88 (br. s, 1H), 1.04 (s, 6H). MS (ER+) m/e 324.1 (M+H).

- 81 044043

Example 228.

N(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)-III-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 16 hours at 110°C, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8diazabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)-N-indazol-5-amine as a white solid (12%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.04 (s, 1H), 8.00 (s, 1H), 7.86 (d, J=5.6 Hz, 1H), 7.51 ( s, 2H), 6.06 (d, J=5.6 Hz, 1H), 4.59 (m, 2H), 3.11-3.07 (m, 2H), 2.74-2.71 (m, 2H), 2.09-2.02 (m, 4H). MS (ER+) m/e 322.1 (M+H).

Example 229.

N-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first stage was 16 hours at 110°C, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8diazabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (16%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.95 (br s, 1H), 9.12 (s, 1H), 8.05 (s, 1H), 8.00 (s, 1H), 7.86 (d, J=5.2 Hz, 1H), 7.50-7.44 (m, 2H), 5.99 (d, J=6.0 Hz, 1H), 4.16 (d , J=11.2 Hz, 2H), 3.46 (s, 2H), 2.93 (d, J=12.0 Hz, 2H), 1.64-1.54 (m, 4n). MS (ER+) m/e 322.1 (M+H).

Example 230.

(1 -(4-(( 1 H-indazol-5-yl)amino)pyrimidin-2-yl)piperazin-2-yl)methanol

The reaction was carried out following General Protocol A. The reaction time in the first stage was 48 hours at 110°C, and the crude material was used without further purification. The final residue was purified by reverse phase preparative HPLC to give (1-(4-((1H-indazol-5yl)amino)pyrimidin-2-yl)piperazin-2-yl)methanol as a white solid (4%).

1H NMR (400 MHz, CD ₃ OD) δ 8.05 (s, 1H), 8.01 (s, 1H), 7.87 (d, J=6.0 Hz, 1H), 7.54-7 .46 (m, 2H), 6.05 (d, J=6.0 Hz, 1H), 4.68 (d, J=3.2 Hz, 1H), 4.45 (d, J=11, 6 Hz, 1H), 3.97 (dd, J=10.4 Hz, 8.4 Hz, 1H), 3.76 (dd, J=10.4 Hz, 5.2 Hz, 1H), 3, 20-3.04 (m, 2H), 2.90 (dd, J=12.8 Hz, 4.4 Hz, 1H), 2.78 (td, J=12.4 Hz, 3.6 Hz, 1H). MS (ER+) m/e 326.1 (M+H).

- 82 044043

Example 231.

(R)-N-(2-(3-aminopyrrolidin-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The reaction time in the first step was 16 hours, and the crude material was used further without further purification. The final residue was purified by reverse phase preparative HPLC to give (R)-N-(2-(3-aminopyrrolidin-1yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (17%) .

1H NMR (400 MHz, DMSO- _d6 ) δ 12.91 (br s, 1H), 9.17-9.04 (m, 1H), 8.26 (br s, 1H), 7.98 (s, 1H), 7.86 (d, J=5.6 Hz, 1H), 7.53-7.43 (m, 2H), 5.97 (d, J=5.6 Hz, 1H) , 3.68-3.51 (m, 4H), 3.18 (br. s, 1H), 2.091.97 (m, 1H), 1.74-1.63 (m, 1H). MS (ER+) m/e 296.1 (M+H).

Example 232.

N-(2-(2-methylpiperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following the general protocol E.

The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give N-(2(2-methylpiperazin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine as a white solid (32%) .

^1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.99 (s, 1H), 7.86 (d, J=5.6 Hz, 1H), 7.51 (s, 2H), 6.04 (d, J=5.6 Hz, 1H), 4.78-4.77 (m, 1H), 4.39-4.36 (m, 1H), 4.34-4 .32 (m, 1H), 3.00-2.91 (m, 2H), 2.79-2.71 (m, 2H), 1.30 (d, J=6.8 Hz, 3H). MS (ER+) m/e 310.1 (M+H).

Example 233.

N-(2-(3-((3-methoxybenzyl)amino)piperidin-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol F. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-((3-methoxybenzyl)amino)piperidin-1yl)pyrimidin-4-yl)-1H-indazol-5- amine as a white solid (38%).

1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 9.16 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.87 (d, J=5.6 Hz, 1H), 7.50-7.42 (m, 2H), 7.14 (t, J=7.6 Hz, 1H), 6.88-6.79 ( m, 2H), 6.74 (d, J=8.4 Hz, 1H), 5.96 (d, J=6.0 Hz, 1H), 4.68 (d, J=11.2 Hz, 1H), 4.37 (d, J=12.8 Hz, 1H), 3.86-3.81 (m, 1H), 3.73-3.64 (m, 3H), 2.95 (t , J=10.4 Hz, 1H), 2.84-2.73 (m, 1H), 2.45 (m, 1H), 1.93 (m, 1H), 1.68 (m, 1H) , 1.35-1.34 (m, 2H). MS (ER+) m/e 430.2 (M+H).

Example 234.

N-(2-(3 -(benzylamino)piperidin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol F. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-(benzylamino)piperidin-1-yl)pyrimidin-4-yl)

- 83 044043

Sh-indazol-5-amine as a white solid (2%).

1H NMR (400 MHz, DMSOA) δ 12.94 (s, 1H), 9.15 (s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.87 (d , J=5.6 Hz, 1H), 7.47 (s, 2H), 7.28-7.14 (m, 5H), 5.96 (d, J=5.6 Hz, 1H), 4 .67 (d, J=10.4 Hz, 1H), 4.37 (d, J=12.4 Hz, 1H), 3.87-3.78 (m, 1H), 3.76-3, 66 (m, 1H), 2.99-2.90 (m, 1H), 2.81-2.75 (m, 1H), 2.43 (m, 1H), 1.93 (m, 1H ), 1.67 (m, 1H), 1.34-1.32 (m, 2H). MS (ER+) m/e 400.2 (M+H).

Example 235.

X-(2-(2-ethylpiperazin-1 -yl)pyrimidin-4-yl)-1 H-indazol-5 -amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2-ethylpiperazin-1-yl)pyrimidin-4-yl)-1H-indazol5-amine as a white solid (42 %).

^1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 9.14 (s, 1H), 8.10 (s, 1H), 7.96 (s, 1H), 7. 87 (d, J=5.6 Hz, 1H), 7.49-7.42 (m, 2H), 5.96 (d, J=5.6 Hz, 1H), 4.44-4.37 (m, 2H), 2.94-2.86 (m, 3H), 2.67-2.63 (m, 1H), 2.522.51 (m, 1H), 1.87-1.85 (m , 1H), 1.58-1.55 (m, 1H), 0.88 (t, J=7.2 Hz, 3H). MS (ER+) m/e 324.2 (M+H).

Example 236.

2-(7-benzyl-1,4-diazepan-1-yl)-X-(1H-indazol-5-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine H

XX? HN osD j ΝΗ

M

The reaction was carried out following general protocol B. The final residue was purified by reverse phase preparative HPLC to give 2-(7-benzyl-1,4-diazepan-1-yl)-N-(1H-indazol-5-yl)-5,7dihydrofuro [3,4-th]pyrimidin-4-amine as a white solid (63%).

1H NMR (400 MHz, DMSO- _d6 ) δ 12.75 (s, 1H), 8.46 (s, 1H), 7.98 (s, 1H), 7.95 (s, 1H), 7. 53-7.46 (m, 2H), 7.19-7.01 (m, 5H), 4.88 (s, 2H), 4.83-4.73 (m, 1H), 4.68 ( s, 2H), 4.25 (d, J=14 Hz, 1H), 2.94-2.86 (m, 4H), 2.722.69 (m, 2H), 2.37-2.27 (m , 1H), 1.95-1.85 (m, 1H), 1.65-1.56 (m, 1H). MS (ER+) m/e 442.3 (M+H).

Example 237.

X-(2-(6-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following general protocol B. The final residue was purified by reverse phase preparative HPLC to give N-(2-(6-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazol-5-amine in as a white solid (25%).

1H NMR (400 MHz, Methanol ₄ ) δ 8.13 (s, 1H), 7.97 (s, 1H), 7.85 (d, J=5.6 Hz, 1H), 7.53- 7.46 (m, 2H), 6.04 (d, J=6.0 Hz, 1H), 4.36-4.15 (m, 2H), 3.57-3.53 (m, 1H) , 3.31-3.23 (m, 1H), 3.12-2.97 (m, 3H), 2.66 (dd, J=13.6 Hz, 9.2 Hz, 1H), 2, 18-2.15 (m, 1H), 0.99 (d, J=6.8 Hz, 3H). MS (ER+) m/e 324.1 (M+H).

- 84 044043

Example 238.

X-(2-(2-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following general protocol B. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazol-5-amine in as a white solid (12%).

^1H NMR (400 MHz, Methanol-dd δ 8.20 (s, 1H), 7.97 (s, 1H), 7.85 (d, J=6.0 Hz, 1H), 7.54-7 .48 (m, 2H), 6.03 (d, J=6.0 Hz, 1H), 4.72 (m, 1H), 4.33 (m, 1H), 3.40 (dd, J= 14.4 Hz, 6.0 Hz, 1H), 3.25-3.17 (m, 2H), 2.742.68 (m, 2H), 2.03-1.78 (m, 2H), 1, 17 (d, J=6.0 Hz, 3H) MS (ER+) m/e 324.2 (M+H).

Example 239.

2-(5-methyl-1,4-diazepan-1-yl)-K-(4-(pyridin-4-yl)phenyl)quinazolin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(5-methyl-1,4-diazepan-1-yl)-K-(4-(pyridin-4yl)phenyl)quinazoline-4 -amine as a yellow solid (56%).

1H NMR (400 MHz, Methanol-b ₄ ) δ 8.60 (d, J=6.0 Hz, 2H), 8.41 (br s, 1H), 8.24 (d, J=7.2 Hz, 1H), 7.99 (d, J=8.8 Hz, 2H), 7.87 (d, J=8.8 Hz, 2H), 7.78 (d, J=6.4 Hz, 2H), 7.72-7.66 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.32-7.29 (m, 1H), 4.29-4 .17 (m, 3H), 3.88-3.81 (m, 1H), 3.65-3.50 (m, 2H), 3.42-3.34 (m, 1H), 2.25 -2.20 (m, 1H), 2.09-1.99 (m, 1H), 1.39 (d, J=6.4 Hz, 3H). MS (ER+) m/e 411.0 (M+H).

Example 240.

K-(2-(7-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(7-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1Hindazol-5-amine in as a white solid (27%).

¹ H NMR (400 MHz, DMSO-a ₆ ) δ 12.97 (br s, 1H), 9.23 (s, 1H), 8.29 (s, 2H), 8.14 (br s, 1H), 8.00 (s, 1H), 7.90 (d, J=5.6 Hz, 1H), 7.49-7.43 (m, 2H), 6.03 (d, J=5 .6 Hz, 1H), 3.98-3.93 (m, 2H), 3.81-3.78 (m, 1H), 3.68-3.66 (m, 1H), 3.29 ( m, 1H), 3.11-3.05 (m, 2H), 1.99 (m, 1H), 1.75 (m, 1H), 1.17 (d, J=6.4 Hz, 3H ). MS (ER+) m/e 324.2 (M+H).

Example 241.

K-(2-(2-ethyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following general protocol B. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2-ethyl-1,4-diazepan-1-yl)pyrimidin-4-yl)-1H

- 85 044043 indazol-5-amine in the form of a white solid (30%).

1H NMR (400 MHz, Methanol^) δ 8.16 (br s, 1H), 7.96 (s, 1H), 7.83 (d, J=6.0 Hz, 1H), 7.52- 7.46 (m, 2H), 6.01 (d, J=6.0 Hz, 1H), 4.75-4.67 (m, 1H), 4.22 (m, 1H), 3. 50-3.45 (m, 1H), 3.19-3.14 (m, 2H), 2.71-2.67 (m, 2H), 1.89 (m, 1H), 1.76- 1.72 (m, 2H), 1.58-1.51 (m, 1H), 0.94 (t, J=7.6 Hz, 3H). MS (ER+) m/e 338.2 (M+H).

Example 242.

N-(2-(3-((3-methoxybenzyl)(methyl)amino)piperidin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol F. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-((3-methoxybenzyl)(methyl)amino)piperidin-1yl)pyrimidin-4-yl)-1H-indazole -5-amine as a white solid (12%).

1H NMR (400 MHz, DMSO-b ₆ ) δ 12.93 (s, 1H), 9.15 (s, 1H), 8.13 (br s, 1H), 7.91 (s, 1H), 7.88 (d, J=5.2 Hz, 1H), 7.47-7.45 (m, 2H), 7.18 (t, J=7.6 Hz, 1H), 6.87-6 .84 (m, 2H), 6.77 (d, J=8.0 Hz, 1H), 5.97 (d, J=5.6 Hz, 1H), 4.82 (d, J=12, 0 Hz, 1H), 4.56 (d, J=12.0 Hz, 1H), 3.68 (s, 3H), 3.66-3.56 (m, 2H), 2.88-2, 76 (m, 2H), 2.47-2.44 (m, 1H), 2.21 (s, 3H), 1.93 (d, J=10.8 Hz, 1H), 1.75 (d , J=13.2 Hz, 1H), 1.60-1.56 (m, 1H), 1.38 (m, 1H). MS (ER+) m/e 444.4 (M+H).

Example 243.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-7,8-dihydro-5H-pyrano[4,3b ]pyrimidine-4-amine

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,8-diazabicyclo[3.2.1]octan-8yl)-7,8- Dihydro-5H-pyrano[4,3-b]pyrimidin-4-amine as a white solid (19%).

1H NMR (400 MHz, DMSO-06) δ 9.26 (br s, 1H), 8.94 (br s, 1H), 8.04 (s, 1H), 7.61 (d, J= 8.4 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 4.69 (s, 2H), 4.60 (s, 2H), 3.93 (t, J= 5.6 Hz, 2H), 3.22 (m, 4H), 2.71 (m, 2H), 2.102.01 (m, 4H). MS (ER+) m/e 404.1 (M+H).

Example 244.

N-(2-(3-((2-methoxyphenyl)amino)piperidin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol F. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-((2-methoxyphenyl)amino)piperidin-1yl)pyrimidin-4-yl)-1H-indazol-5- amine as a white solid (6%).

1H NMR (400 MHz, Methanol-BD δ 8.31-8.66 (m, 1H), 7.98 (s, 1H), 7.79 (d, J=6.3 Hz, 1H), 7, 70 (s, 1H), 7.34-7.49 (m, 2H), 6.82-6.80 (m, 1H), 6.73-6.70 (m, 1H), 6.57- 6.54 (m, 2H), 6.12 (d, J=6.3 Hz, 1H), 4.50 (d, J=12.6 Hz, 1H), 4.11 (d, J=12 .9 Hz, 1H), 3.80 (s, 3H), 3.51 (d, J=3.9 Hz, 1H), 3.36-3.43 (m, 1H), 3.21 (dd , J=12.9, 8.4 Hz, 1H), 2.12 (s, 1H), 1.88 (s, 1H), 1.70 (t, J=9.3 Hz, 2H).MS (ER+) m/e 416.3 (M+H).

- 86 044043

Example 245.

6-methyl-2-(5-methyl-1,4-diazepan-1-yl)-N-(4-(pyridin-4-yl)phenyl)pyrimidin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 6-methyl-2-(5-methyl-1,4-diazepan-1-yl)-N-(4-(pyridin-4yl)phenyl )pyrimidin-4-amine as a yellow solid (50%).

1H NMR (400 MHz, Methanol^) δ 8.56 (d, J=6.0 Hz, 2H), 8.26 (s, 3H), 7.84-7.75 (m, 4H), 7, 74 (d, J=6.0 Hz, 2H), 6.08 (s, 1H), 4.20-4.11 (m, 3H), 3.83-3.77 (m, 1H), 3 .64-3.49 (m, 2H), 3.41-3.34 (m, 1H), 2.28 (s, 3H), 2.24-2.20 (m, 1H), 2.10 -1.97 (m, 1H), 1.40 (d, J=6.4 Hz, 3H). MS (ER+) m/e 374.8 (M+H).

Example 246.

(R)-N-(2-(3-((4-methoxyphenyl)amino)pyrrolidin-1-yl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol F. The final residue was purified by reverse phase preparative HPLC to give (R)-N-(2-(3-((4-methoxyphenyl)amino)pyrrolidin-1yl)pyrimidin-4-yl)-1H- indazole-5-amine as a white solid (13%).

1H NMR (400 MHz, DMSO-I6) δ 12.91 (s, 1H), 9.13 (s, 1H), 8.28 (s, 1H), 7.92-7.86 (m, 2H) , 7.46 (s, 2H), 6.75 (d, J=8.8 Hz, 2H), 6.61 (d, J=8.8 Hz, 2H), 5.99 (d, J= 5.6 Hz, 1H), 5.42 (d, J=6.8 Hz, 1H), 4.02 (m, 1H), 3.83 (m, 1H), 3.65-3.63 ( m, 5H), 3.44-3.42 (m, 1H), 2.26-2.23 (m, 1H), 1.93-1.91 (m, 1H). MS (ER+) m/e 402.1 (M+H).

Example 247.

6-methyl-2-(3-methyl-1,4-diazepan-1-yl)-N-(4-(pyridin-4-yl)phenyl)pyrimidin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 6-methyl-2-(3-methyl-1,4-diazepan-1-yl)-N-(4-(pyridin-4yl)phenyl )pyrimidin-4-amine as a yellow solid (56%).

^1H NMR (400 MHz, Methanol ₄ ) δ 8.56 (d, J=6.4 Hz, 2H), 8.36 (s, 2H), 7.82-7.76 (m, 4H) , 7.73 (d, J=6.4 Hz, 2H), 6.07 (s, 1H), 4.52-4.46 (m, 2H), 3.71-3.68 (m, 1H ), 3.50-3.42 (m, 3H), 3.09-3.06 (m, 1H), 2.34-2.15 (m, 5H), 1.41 (d, J=6 ,8 Hz, 3H). MS (ER+) m/e 374.8 (M+H).

Example 248.

2-(3-ethyl-1,4-diazepan-1-yl)-N-(4-(pyridin-4-yl)phenyl)pyrimidin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(3-ethyl-1,4-diazepan-1-yl)-N-(4-(pyridin-4

- 87 044043 yl)phenyl)pyrimidin-4-amine in the form of a yellow solid (65%).

1H NMR (400 MHz, Methanol-6 ₄ ) δ 8.55 (d, J=6.0 Hz, 2H), 8.32 (s, 2H), 7.97 (d, J=6.0 Hz, 1H), 7.81-7.75 (m, 4H), 7.71 (d, J=6.0 Hz, 2H), 6.17 (d, J=6.0 Hz, 1H), 4, 52 (d, J=12.80 Hz, 1H), 4.41-4.31 (m, 1H), 3.56-3.40 (m, 4H), 3.14-3.04 (m, 1H), 2.28-2.14 (m, 2H), 1.79-1.74 (m, 2H), 1.09 (t, J=7.6 Hz, 3H). MS (ER+) m/e 375.2 (M+H).

Example 249.

2-(5-ethyl-1,4-diazepan-1-yl)-N-(4-(pyridin-4-yl)phenyl)pyrimidin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(5-ethyl-1,4-diazepan-1-yl)-N-(4-(pyridin-4yl)phenyl)pyrimidine-4 -amine as a yellow solid (65%).

1H NMR (400 MHz, Methanol-6 ₄ ) δ 8.56 (d, J=6.1 Hz, 2H), 8.36 (br s, 2H), 7.99 (d, J=5.8 Hz, 1H), 7.86-7.78 (m, 4H), 7.74 (d, J=6.3 Hz, 2H), 6.20 (d, J=5.9 Hz, 1H), 4.22-4.03 (m, 3H), 3.81-3.75 (m, 1H), 3.633.54 (m, 1H), 3.40-3.34 (m, 2H), 2. 31-2.27 (m, 1H), 2.03-1.97 (m, 1H), 1.81-1.69 (m, 2H), 1.06 (t, J=7.5 Hz, 3H). MS (ER+) m/e 375.1 (M+H).

Example 250.

2-(5-isopropyl-1,4-diazepan-1-yl)-N-(4-(pyridin-4-yl)phenyl)pyrimidin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(5-isopropyl-1,4-diazepan-1-yl)-N-(4-(pyridin-4yl)phenyl)pyrimidine-4 -amine as a yellow solid (65%).

1H NMR (400 MHz, Methanol-64) δ 8.55 (d, J=6.0 Hz, 2H), 8.33 (s, 2H), 7.97 (d, J=6.0 Hz, 1H ), 7.82-7.76 (m, 4H), 7.72 (d, J=6.4 Hz, 2H), 6.18 (d, J=6.0 Hz, 1H), 4.26 -4.08 (m, 2H), 4.06-4.0 (m, 1H), 3.81-3.71 (m, 1H), 3.60-3.51 (m, 1H), 3 .29 (m, 2H), 2.23-2.19 (m, 1H), 2.14-2.03 (m, 1H), 1.95-1.86 (m, 1H), 1.05 -1.00 (m, 6H). MS (ER+) m/e 389.2 (M+H).

Example 251.

2-(3-isopropyl-1,4-diαzepαn-1-yl)-N-(4-(pyridin-4-yl)phenyl)pyrimidin-4-αmin

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(3-isopropyl-1,4-diazepan-1-yl)-N-(4-(pyridin-4yl)phenyl)pyrimidine-4 -amine as a yellow solid (66%).

1H NMR (400 MHz, Methanol-6 ₄ ) δ 8.55 (d, J=6.0 Hz, 2H), 8.30 (s, 2H), 7.97 (d, J=6.0 Hz, 1H), 7.80-7.72 (m, 4H), 7.71 (d, J=6.4 Hz, 2H), 6.17 (d, J=6.0 Hz, 1H), 4, 45 (dd, J=15.2, 3.2 Hz, 1H), 4.31-4.20 (m, 1H), 3.683.62 (m, 2H), 3.49-3.48 (m, 1H), 3.41-3.38 (m, 1H), 3.12 (m, 1H), 2.25-2.08 (m, 3H), 1.11 (dd, J=6.8, 2.0 Hz, 6H). MS (ER+) m/e 389.2 (M+H).

- 88 044043

Example 252.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3-methylpiperazin-1-yl)pyrimidin-4-amine

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give N(4-(1H-pyrazol-4-yl)phenyl)-2-(3-methylpiperazin-1yl)pyrimidin-4-amine as a white solid ( 24%).

1H NMR (400 MHz, DMSO-d^ δ 12.85 (s, 1H), 9.19 (s, 1H), 8.13-8.07 (m, 2H), 7.91 (d, J= 5.6 Hz, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 6.01 (d, J=5, 6 Hz, 1H), 4.44 (t, J=9.6 Hz, 2H), 2.92 (d, J=11.67 Hz, 1H), 2.82-2.75 (m, 1H) , 2.66-2.60 (m, 2H), 2.44-2.39 (m, 1H), 2.26 (lat s, 1H), 1.02 (d, J=6.4 Hz , 3H).MS (ER+) m/e 336.2 (M+H).

Example 253.

N-(4-( 1 H-pyrazol-4-yl)phenyl)-2-(2-methylniperazin-1 -yl)pyrimidin-4-amine

The reaction was carried out following General Protocol C. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give N-(4-(1H-nirazol-4-yl)phenyl)-2-(3-methylpinerazin-1yl)pyrimidin-4-amine as a white solid (10%).

^1H NMR (400 MHz, CD3OD) δ 7.93 (s, 1H), 7.89 (d, J=5.6 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H) , 7.53 (d, J=8.8 Hz, 2H), 6.06 (d, J=5.6 Hz, 1H), 4.79-4.74 (m, 1H), 4.39- 4.34 (m, 1H), 3.16-3.06 (m, 2H), 3.00-2.91 (m, 2H), 2.78-2.72 (m, 1H), 1. 30 (d, J=6.8 Hz, 3H). MS (ER+) m/e 336.2 (M+H).

Example 254.

(S)-N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3-aminopyrrolidin-1-yl)pyrimidin-4-amine

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give (S)-N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3aminopyrrolidin-1-yl)pyrimidin-4-amine in as a white solid (25%).

1H NMR (400 MHz, CD3OD) δ 7.92 (s, 1H), 7.83 (d, J=6.0 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 6.04 (d, J=6.0 Hz, 1H), 3.86-3.72 (m, 2H), 3.71-3 .57 (m, 2H), 3.39 (d, J=4.8 Hz, 1H), 2.31-2.20 (m, 1H), 1.92-1.84 (m, 1H). MS (ER+) m/e 322.1 (M+H).

Example 255.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,3-dimethylpiperazin-1-yl)nirimidin-4-amine

The reaction was carried out following general protocol A. The intermediate was purified by

- 89 044043 reverse-phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,3dimethylpiperazin-1-yl)pyrimidin-4-amine as yellow solids (42%).

1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 9.18 (s, 1H), 7.99 (s, 2H), 7.89 (d, J=5.6 Hz , 1H), 7.62 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 5.98 (d, J=5.6 Hz, 1H ), 3.64-3.62 (m, 2H), 3.47 (s, 2H), 2.78 (br s, 2H), 1.87 (br s, 1H), 1.04 ( s, 6H). MS (ER+) m/e 322.1 (M+H).

Example 256.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,5-dimethylpiperazin-1-yl)pyrimidin-4-amine

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,5dimethylpiperazin-1-yl)pyrimidin-4-amine as white solid matter (34%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.80 (s, 1H), 9.20 (s, 1H), 8.00 (s, 2H), 7.90 (d, J=5, 6 Hz, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 6.00 (d, J=5.6 Hz , 1H), 4.49 (d, J=10.4 Hz, 2H), 2.68 (br. s, 2H), 2.31 (t, J=12.4 Hz, 2H), 2.20 (lat s, 1H), 1.02 (d, J=6.4 Hz, 6H). MS (ER+) m/e 350.1 (M+H).

Example 257.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-4-amine

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,8diazabicyclo[3.2.1]octan-8-yl)pyrimidin- 4-amine as a white solid (14%).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.93 (s, 2H), 7.87 (d, J=6.0 Hz, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 6.07 (d, J=5.6 Hz, 1H), 4.58 (s, 2H), 3.06 (d, J=12.8 Hz, 2H), 2.68 (d, J=12.8 Hz, 2H), 2.08-2.01 (m, 4H). MS (ER+) m/e 348.2 (M+H).

Example 258.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-4-amine

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,8diazabicyclo[3.2.1]octan-3-yl)pyrimidin- 4-amine as a white solid (14%).

1H NMR (400 MHz, CD ₃ OD) δ 7.93 (s, 2H), 7.86 (d, J=6.0 Hz, 1H), 7.63 (d, J=8.8 Hz, 2H ), 7.55 (d, J=8.4 Hz, 2H), 6.08 (d, J=5.6 Hz, 1H), 4.25 (d, J=12.4 Hz, 2H), 3.61 (s, 2H), 3.11 (d, J=12.4 Hz, 2H), 1.86-1.76 (m, 4H). MS (ER+) m/e 348.1 (M+H).

- 90 044043

Example 259.

8-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-3-ol

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give 8-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2yl)-8-azabicyclo[3.2.1]octane -3-ol as a white solid (61%).

1H NMR (400 MHz, CD3OD) δ 7.94 (br s, 1H), 7.84 (d, J=6.0 Hz, 1H), 7.67 (d, J=8.4 Hz, 2H ), 7.54 (d, J=8.4 Hz, 2H), 6.04 (d, J=6.0 Hz, 1H), 4.61 (lat s, 2H), 4.06 (lat .s, 1H), 2.40-2.31 (m, 2H), 2.21 (d, J=14.4 Hz, 2H), 2.04 (dd, J=9.6 Hz, 4, 8 Hz, 2H), 1.78 (d, J=14.4 Hz, 2H). MS (ER+) m/e 363.1 (M+H).

Example 260.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3-phenylpiperazin-1-yl)pyrimidin-4-amine

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3-phenylpiperazin-1yl)pyrimidin-4-amine as a yellow solid (15% ).

1H NMR (400 MHz, DMSO-Y6) δ 12.87 (s, 1H), 9.25 (s, 1H), 8.11 (s, 1H), 7.93 (d, J=5.6 Hz , 1H), 7.86 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.52-7.46 (m, 4H), 7.40-7.30 ( m, 3H), 6.04 (d, J=5.6 Hz, 1H), 4.63 (d, J=11.6 Hz, 1h), 4.56 (d, J=12.4 Hz, 1H), 3.70 (d, J=7.6 Hz, 1H), 3.06 (d, J=11.6 Hz, 1H), 2.95-2.65 (m, 4H). MS (ER+) m/e 398.1 (M+H).

Example 261.

N-(4-( 1 H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1 -yl)-5-methylpyrimidin-4-amine

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1-yl)-5methylpyrimidin-4-amine as a white solid (16%).

^1H NMR (400 MHz, DMSO) δ 8.30 (s, 2H), 8.18 (s, 1H), 8.00 (s, 2H), 7.80 (s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 3.84 (s, 2H), 3.75 (t, J=5.6 Hz , 2H), 3.11 (s, 2H), 2.99 (s, 2H), 2.07 (s, 3H), 1.95 (s, 2H). MS (ER+) m/e 350.2 (M+H).

- 91 044043

Example 262.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1-yl)-5,7dihydrofuro[3 ,4-d]pyrimidin-4-amine as a yellow solid (35%).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.93 (s, 2H), 7.70 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 4.99 (s, 2H), 4.79 (s, 2H), 3.87 (t, J=5.6 Hz, 4H), 3.04 (t, J=5.2 Hz, 2H), 2.87 (t, J=6.0 Hz, 2H), 1.98-1.95 (m, 2H). MS (ER+) m/e 378.2 (M+H).

Example 263.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidin-4-amine r- NH__/NH

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1-yl)-5,7dihydrothieno[3 ,4-d]pyrimidin-4-amine as a yellow solid (40%).

^1H NMR (400 MHz, CD3OD) δ 8.60 (s, 2H), 7.81 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H) , 4.36-4.35 (m, 2H), 4.19 (br. s, 2H), 4.10 (t, J=4.8 Hz, 2H), 3.87 (br. s, 2H ), 3.45-3.42 (m, 4H), 2.34-2.28 (m, 2H). MS (ER+) m/e 394.1 (M+H).

Example 264.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1-yl)thieno[3,2-d]pyrimidin-4-amine

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1yl)thieno[3,2-d] pyrimidin-4-amine as a yellow solid (30%).

^1H NMR (400 MHz, CD3OD) δ 7.97 (s, 2H), 7.90 (d, J=5.6 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H) , 7.60 (d, J=8.8 Hz, 2H), 7.19 (d, J=5.2 Hz, 1H), 4.11 (t, J=5.6 Hz, 1H), 3 .98 (t, J=6.0 Hz, 1H), 3.42 (t, J=5.2 Hz, 1H), 3.30-2.29 (m, 2H), 2.20-2, 18 (m, 2H). MS (ER+) m/e 392.1 (M+H).

- 92 044043

Example 265.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1-yl)-6-methylpyrimidin-4-amine

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1-yl)-6methylpyrimidin-4-amine as a yellow solid (30%).

1H NMR (400 MHz, DMSO-Y6) δ 9.07 (d, J=16.8 Hz, 1H), 7.98 (s, 2H), 7.65 (t, J=8.0 Hz, 2H ), 7.51 (dd, J=8.4, J=3.6 Hz, 2H), 5.87 (d, J=11.2 Hz, 1H), 3.69-3.82 (m, 4H), 3.30 (d, J=5.6 Hz, 2H), 2.84 (s, 1H), 2.66 (t, J=5.6 Hz, 1H), 2.12 (s, 3H), 1.77 (s, 2H). MS (ER+) m/e 350.2 (M+H).

Example 266.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1-yl)-5,6-dimethylpyrimidin-4-amine

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1-yl)-5,6dimethylpyrimidin-4 -amine as a white solid (4%).

^1H NMR (400 MHz, CD3OD) δ 7.93 (s, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H) , 3.80-3.89 (m, 4H), 3.05 (s, 2H), 2.91 (s, 2H), 2.31 (s, 3H), 2.12 (s, 3H), 1.96 (s, 2H). MS (ER+) m/e 364.1 (M+H).

Example 267.

N-(4-( 1 H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1 -yl)-5-methoxypyrimidin-4-amine

The reaction was carried out following General Protocol A. The intermediate was purified by reverse phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1-yl)-5methoxypyrimidin-4-amine as a white solid (7%).

^1H NMR (400 MHz, CD3OD) δ 7.94 (s, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.63 (s, 1H), 7.55 (d, J=8.8 Hz, 2H), 3.90 (s, 3H), 3.81-3.87 (m, 4H), 3.04-3.12 (m, 2H), 2.91-2 .95 (m, 2H), 1.95-2.03 (m, 2H). MS (ER+) m/e 366.2 (M+H).

Example 268.

N-(4-( 1 H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1 -yl)quinazolin-4-amine

The reaction was carried out following general protocol A. The intermediate was purified by

- 93 044043 reverse-phase preparative HPLC. The final residue was purified by reverse phase preparative HPLC (main) to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(1,4-diazepan-1yl)quinazolin-4-amine as yellow solids (16%).

1H NMR (400 MHz, DMSO-66) δ 13.00 (br s, 1H), 11.12 (s, 1H), 9.56 (br s, 2H), 8.75 (d, J= 8.4 Hz, 1H), 8.32-8.17 (m, 3H), 7.89 (t, J=8.0 Hz, 1H), 7.74 (m, 4H), 7.54 ( t, J=7.6 Hz, 1H), 4.33 (m, 1H), 4.01-3.89 (m, 3H), 3.40-3.25 (m, 4H), 2.23 -2.08 (m, 2H). MS (ER+) m/e 386.1 (M+H).

Example 269.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3-(3-methoxyphenyl)pyrrolidin-1-yl)pyrimidin-4-amine g—NH iji

Y /=\

N V o

/

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3-(3-methoxyphenyl)pyrrolidin-1-yl) pyrimidin-4-amine as a white solid (10%).

^1H NMR (400 MHz, DMSO-66) δ 12.81 (s, 1H), 9.20 (s, 1H), 7.97 (s, 1H), 7.91 (d, J=5.6 Hz, 1H), 7.73 (s, 2H), 7.51 (d, J=7.2 Hz, 2H), 7.26 (t, J=7.6 Hz, 1H), 6.88- 6.95 (m, 2H), 6.82 (d, J=8.4 Hz, 1H), 6.02 (d, J=5.6 Hz, 1H), 4.00 (s, 1H), 3.75 (s, 4H), 3.44-3.58 (m, 3H), 2.33 (s, 1H), 2.07 (t, J=9.6 Hz, 1H). MS (ER+) m/e 413.2 (M+H).

Example 270.

X-(4-(1H-pyrazol-4-yl)phenyl)-2-(3-phenylpyrrolidin-1-yl)pyrimidin-4-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3-phenylpyrrolidin-1yl)pyrimidin-4-amine as yellow solid (33%).

1H NMR (400 MHz, DMSO-06) δ 12.82 (s, 1H), 9.21 (s, 1H), 8.09 (s, 1H), 7.91 (d, J=5.6 Hz , 1H), 7.85 (s, 1H), 7.73 (s, 2H), 7.52 (s, 2H), 7.35 (d, J=4.4 Hz, 4H), 7.25 (d, J=3.2 Hz, 1H), 6.02 (d, J=5.8 Hz, 1h), 4.01 (s, 1H), 3.77 (s, 1H), 3.42 -3.62 (m, 3H), 2.33 (s, 1H), 2.07 (t, J=9.6 Hz, 1H). MS (ER+) m/e 383.1 (M+H).

Example 271.

2-(5-phenyl-1,4-diazepan-1-yl)-X-(4-(pyridin-4-yl)phenyl)pyrimidin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(5-phenyl-1,4-diazepan-1-yl)-X-(4-(pyridin-4yl)phenyl)pyrimidine-4 -amine as a yellow solid (22%).

1H NMR (400 MHz, Methanol-b ₄ ) δ 8.52 (d, J=6.4 Hz, 2H), 8.43 (s, 2H), 8.00 (d, J=6.0 Hz, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.70 (d, J=6.4 Hz, 2H) , 7.49-7.39 (m, 5H), 6.21 (d, J=6.0 Hz, 1H), 4.494.43 (m, 1H), 4.32-4.29 (m, 1H ), 4.20 (m, 2H), 3.89-3.82 (m, 1H), 3.67-3.58 (m, 1H), 3.49-3.39 (m, 1H), 2.51-2.38 (m, 1H), 2.37-2.29 (m, 1H). MS (ER+) m/e 423.0 (M+H).

- 94 044043

Example 272.

2-(1,4-diazepan-1-yl)-N-(4-(pyridin-4-yl)phenyl)quinazolin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(1,4-diazepan-1-yl)-X-(4-(pyridin-4yl)phenyl)quinazolin-4-amine as yellow solid (24%). MS (ER+) m/e 397 (M+H).

Example 273.

2-(1,4-diazepan-1-yl)-N-(4-(pyridin-4-yl)phenyl)pyrimidin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(1,4-diazepan-1-yl)-X-(4-(pyridin-4yl)phenyl)pyrimidin-4-amine as yellow solid (29%). MS (ER+) m/e 447 (M+N).

Example 274.

2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(1H-indazol-5-yl)thieno[2,3-d]pyrimidin-4-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(1H-indazol-5yl)thieno[2, 3-d]pyrimidin-4-amine as a yellow solid (47%).

^1H NMR (400 MHz, DMSO- _d6 ) δ 13.06 (s, 1H), 9.59 (s, 1H), 8.90-8.79 (m, 2H), 8.09 (s, 2H), 7.69 (d, J=6.0 Hz, 1H), 7.65-7.63 (m, 1H), 7.55 (d, J=8.8 Hz, 1H), 7, 26 (d, J=6.0 Hz, 1H), 4.67 (s, 2H), 3.20-3.17 (m, 4H), 2.11-2.00 (m, 4H). MS (ER+) m/e 378.1 (M+H).

Example 275.

2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(1H-indazol-5-yl)-6,7-dihydro-5H-pyrrolo[3,4d]pyrimidin-4- amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-K-(1H-indazol-5yl)-6,7 -dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine as an off-white solid (38%).

1H NMR (400 MHz, DMSO-06) δ 13.11 (s, 1H), 9.49 (s, 2H), 9.21 (s, 1H), 9.16-9.14 (m, 1H) , 8.90 (s, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.55-7.50 (m, 2H), 4.64 (s, 2H), 4.36-4.28 (m, 4H), 3.22-3.12 (m, 4H), 2.08-2.00 (m, 4H). MS (ER+) m/e 363.2 (M+H).

Example 276.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6,7-dihydro-5H-pyrrolo[3,4 - 95 044043

d]pyrimidine-4-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,8diazabicyclo[3.2.1]octan-8-yl )-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine as a white solid (28%).

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.55 (s, 2H), 9.23-9.12 (m, 2H), 8.91 (s, 1H), 8.01 (s, 2H), 7.66-7.52 (m, 4H), 4.69 (s, 2H), 4.41 (s, 2H), 4.29 (s, 2H), 3.23-3013 (m , 4H), 2.07-2.02 (m, 4H). MS (ER+) m/e 389.3 (M+H).

Example 277.

N-(2-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-6-methylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-fluoro-6methylpyrimidin-4-yl) -1H-indazol-5-amine as a white solid (59%).

1H NMR (400 MHz, DMSOC) δ 13.04 (br s, 1H), 9.41 (br s, 1H), 9.04 (br s, 1H), 8.59 (br s, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 8.63 (dd, J=9.2, 2.0 Hz, 1H), 7.49 (d, J=9 .2 Hz, 1H), 4.78 (m, 1H), 4.44 (m, 1H), 3.66-3.63 (m, 1H), 3.56-3.53 (m, 1H) , 3.29-3.24 (m, 2H), 2.26-2.25 (m, 3H), 2.13-2.10 (m, 1H), 1.89-1.86 (m, 1H). MS (ER+) m/e 340.1 (M+H).

Example 278.

2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(1H-indazol-5-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(1H-indazol-5yl)-5,7 -dihydrofuro[3,4-d]pyrimidin-4-amine as a red solid (17%).

1H NMR (400 MHz, DMSO-d6) δ 13.00 (br s, 1H), 9.14 (s, 1H), 9.05-9.02 (m, 1H), 8.85 (s, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 7.51 (s, 2H), 4.89 (s, 2H), 4.76 (s, 2H), 4. 65 (m, 2H), 3.18 (m, 4H), 2.10-2.00 (m, 4H). MS (ER+) m/e 364.1 (M+H).

Example 279.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydrofuro[3,4d]pyrimidin-4 -amine

The reaction was carried out following general protocol A. The final residue was purified by reverse phase preparative HPLC to give K-(4-(N-pyrazol-4-yl)phenyl)-2-(3,8diazabicyclo[3.2.1]octane -8-yl)-5,7-dihydrofuro[3,4Apyrimidin-4-amine as a white solid (86%).

1H NMR (400 MHz, DMSO-dg) δ 9.06-8.99 (m, 2H), 8.81 (br s, 1H), 8.00 (s, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 4.95 (s, 2H), 4.76 (s, 2H), 4.68 (m, 2H), 3.19-3.18 (m, 4H), 2.14-2.01 (m, 4H). MS (ER+) m/e 390.1 (M+H).

Example 280.

X-(2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-chloropyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give X-(2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5chloropyrimidin-4-yl)-1H-indazole -5-amine as a white solid (77%).

^1H NMR (400 MHz, DMSO-dg) δ 13.06 (s, 1H), 8.77 (s, 1H), 8.29 (s, 1H), 8.10 (s, 2H), 8. 04 (s, 1H), 7.65 (dd, J=8.8 Hz, 1.6 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 3.97 (s, 2H), 3.81-3.75 (m, 4H), 2.68-2.63 (m, 1H), 1.56 (d, J=8.0 Hz, 1H). MS (ER+) m/e 342.0 (M+H).

Example 281.

2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-X-(4-(pyridin-4-yl)phenyl)-5,7-dihydrofuro[3,4d]pyrimidin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-X-(4-(pyridin-4ul)phenyl)- 5,7-dihydrofuro[3,4-d]pyrimidin-4-amine as a white solid (27%).

1H NMR (400 MHz, DMSO-dg) δ 9.36 (s, 1H), 9.09 (m, 1H), 8.87 (m, 1H), 8.82 (d, J=6.4 Hz , 2H), 8.16 (d, J=6.4 Hz, 2H), 8.03 (d, J=8.8 Hz, 2H), 7.93 (d, J=8.8 Hz, 2H ), 5.01 (s, 2H), 4.78 (s, 2H), 4.72 (m, 2H), 3.19 (m, 4H), 2.13-2.03 (m, 4H) . MS (ER+) m/e 401.1 (M+H).

Example 282.

2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(1H-indazol-5-yl)thieno[3,2-d]pyrimidin-4-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(1H-undazol-5yl)thieno[3, 2-d]pyrimidin-4-amine as a white solid (18%).

1H NMR (400 MHz, DMSO-dg) δ 13.15 (s, 1H), 10.15 (s, 1H), 9.14 (s, 1H), 8.93 (s, 1H), 8.15 -8.09 (m, 2H), 7.99 (s, 1H), 7.58 (s, 2H), 7.25 (d, J=5.2 Hz, 1H), 4.72 (s, 2H), 3.29-3.21 (m, 4H), 2.14-2.04 (m, 4H). MS (ER+) m/e 378.1 (M+H).

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Example 283.

2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-(1H-indazol-5-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-(1H-indazol-5yl)-5,7 -dihydrofuro[3,4-b]pyrimidin-4-amine as a white solid (18%).

^1H NMR (400 MHz, DMSO-Y6) δ 13.07 (s, 1H), 9.30-9.23 (m, 2H), 8.53 (s, 1H), 8.10 (s, 1H ), 8.06 (s, 1H), 7.50 (s, 2H), 4.90 (m, 2H), 4.77 (m, 2H), 4.37 (d, J=6.0 Hz , 2H), 3.72-3.69 (m, 2H), 3.34-3.33 (m, 2H), 2.80-2.75 (m, 1H), 1.89 (d, J =9.6 Hz, 1H). MS (ER+) m/e 350.1 (M+H).

Example 284.

2-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(1H-indazol-5-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(1H-indazol-5yl)-5,7 -dihydrofuro[3,4-th]pyrimidin-4-amine as a white solid (30%).

1H NMR (400 MHz, DMSO) δ 13.01 (s, 1H), 9.12 (s, 2H), 8.65 (s, 1H), 8.13-8.04 (m, 2H), 7 .56-7.49 (m, 2H), 4.89-4.85 (m, 3H), 4.78-4.75 (m, 2H), 4.47 (s, 1H), 3.71 -3.59 (m, 2H), 3.31-3.24 (m, 2H), 2.13 (d, J=9.6 Hz, 1H), 1.90 (d, J=10.8 Hz, 1H). MS (ER+) m/e 350.1 (M+H).

Example 292.

2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-(4-(pyridin-4-yl)phenyl)-6,7-dihydro-5H-pyrrolo[3,4d]pyrimidine -4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-(4-(pyridin-4yl)phenyl)- 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine as a yellow solid (16%).

1H NMR (400 MHz, DMSO-Y6) δ 8.76 (d, J=6.8 Hz, 2H), 8.24 (d, J=6.8 Hz, 2H), 8.01 (m, 4H ), 4.68-4.57 (m, 4H), 4.45 (s, 2H), 3.94 (d, J=12.8 Hz, 2H), 3.47 (d, J=12, 8 Hz, 2H), 3.05-2.99 (m, 1H), 1.97 (d, J=6.0 Hz, 1H). MS (ER+) m/e 386.0 (M+H).

Example 293.

N-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-5-chloropyrimidin-4-yl)-4-methyl-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-5chloropyrimidin-4-yl)-4-methyl -1H-indazol-5-amine as a yellow solid (16%).

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1H NMR (400 MHz, DMSO-d ₆ ) δ 8.25-8.05 (m, 2H), 7.42-7.40 (m, 1H), 7.29 (d, J=8.8 Hz , 1H), 4.29 (m,

2H), 3.70-3.68 (m, 2H), 3.31 (m, 2H), 2.86 (m, 1H), 2.49 (s, 3H), 1.80-1.78 (m, 1H). MS (ER+) m/e 356.3 (M+H).

Example 294.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)-4-methyl-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5chloropyrimidin-4-yl)-4-methyl -1H-indazol-5-amine as a white solid (22%).

1H NMR (400 MHz, DMSO) δ 8.19-8.10 (m, 2H), 7.47-7.39 (m, 1H), 7.35-7.26 (m, 1H), 4, 51 (m, 2H), 3.26 (m, 2H), 3.18-3.15 (m, 2H), 2.50 (s, 3H), 2.16-2.15 (m, 2H) , 2.00-1.98 (m, 2H). MS (ER+) m/e 370.1 (M+H).

Example 295.

N-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-5-chloropyrimidin-4-yl)-6-fluoro-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-5chloropyrimidin-4-yl)-6-fluoro -1H-indazol-5-amine as a white solid (45%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.15-8.11 (m, 1H), 8.08 (s, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.38 (d, J=10.4 Hz, 1H), 4.32 (m, 1H), 3.77 (d, J=12.8 Hz, 2H), 3.38-3.30 (m , 2H), 2.90-2.85 (m, 1H), 1.85-1.82 (m, 1H). MS (ER+) m/e 360.1 (M+H).

Example 296.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)-6-fluoro-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5chloropyrimidin-4-yl)-6-fluoro -1H-indazol-5-amine as a white solid (45%).

1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 8.09 (s, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.38 (d , J=10.4 Hz, 1H), 4.56 (m, 2H), 3.32-3.26 (m, 2H), 3.19-3.12 (m, 2H), 2.25- 2.10 (m, 2H), 2.00-1.92 (m, 2H). MS (ER+) m/e 374.1 (M+H).

Example 297.

N-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-5-chloropyrimidin-4-yl)-6-methoxy-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-5chloropyrimidin-4-yl)-6-methoxy -1H-indazol-5-amine as a white solid (53%).

1H NMR (400 MHz, DMSO- _d6 ) δ 8.42-8.27 (m, 1H), 8.15-8.11 (m, 1H), 7.98 (s, 1H), 7.11 (s, 1H), 4.52 (m, 2H), 4.04-3.96 (m, 3H), 3.83 (d, J=12.8 Hz, 2H), 3.46 (d, J=12.8 Hz, 2H), 3.03-2.88 (m, 1H), 1.97-1.87 (m, 1H).

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MS (ER+) m/e 372.0 (M+H).

Example 298.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5 -(trifluoromethyl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5(trifluoromethyl)pyrimidin-4-yl) -1H-indazol-5-amine in the form of a colorless resin (53%).

^1H NMR (400 MHz, DMSOL) δ 13.10 (s, 1H), 9.00 (s, 1H), 8.83 (m, 2H), 8.33 (s, 1H), 8.05 ( s, 1H), 7.75 (s, 1H), 7.50-7.43 (m, 2H), 4.79-4.74 (m, 1H), 4.28 (m, 1H), 3 .12 (m, 4H), 2.00-1.95 (m, 4H). MS (ER+) m/e 390.1 (M+H).

Example 299.

2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(1H-indazol-5-yl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3d] pyrimidine-4-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(1H-indazol-5yl)-6-methyl -5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine as a white solid (3%).

^1H NMR (400 MHz, DMSO) δ 10.69 (br s, 1H), 9.45 (s, 1H), 9.06-8.99 (m, 2H), 8.06 (s, 1H ), 7.88 (s, 1H), 7.54-7.49 (m, 2H), 4.60 (s, 2H), 3.61 (m, 4H), 3.19-3.12 ( m, 4H), 3.01-2.83 (m, 5H), 2.07-1.98 (m, 4H). MS (ER+) m/e 391.4 (M+H).

Example 300.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-6,7-dihydro-5H-pyrrolo[3,4d ]pyrimidine-4-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,6diazabicyclo[3.1.1]heptan-6-yl )-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine as a gray solid (4%).

1H NMR (400 MHz, CD3OD) δ 7.97 (s, 2H), 7.66 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H), 4.53-4.51 (m, 4H), 4.41 (s, 2H), 3.90 (d, J=12.8 Hz, 2H), 3.42 (d, J=12.4 Hz , 2H), 3.01-2.96 (m, 1H), 1.92 (d, J=10.0 Hz, 1H). MS (ER+) m/e 371.4 (M+H).

Example 301.

N-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-5-fluoro-6-methylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-5-fluoro-6methylpyrimidin- 4-yl)-1H-indazol-5-amine as an orange solid (23%).

1H NMR (400 MHz, CD3OD) δ 8.07 (s, 1H), 8.04 (s, 1H), 7.60-7.55 (m, 2H), 4.56 (m, 2H), 3 .87 (d, J=13.2

Hz, 2H), 3.46 (d, J=12.8 Hz, 2H), 3.04-2.98 (m, 1H), 2.41 (d, J=2.8 Hz, 3H), 1.91 (m, 1H). MS (ER+) m/e 340.0 (M+H).

Example 302.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-6-methylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-6methylpyrimidin-4-yl) -1H-indazol-5-amine as a pink solid (5%).

1H NMR (400 MHz, DMSO^) δ 13.0 (s, 1H), 9.44 (s, 1H), 9.07-9.04 (m, 1H), 8.85-8.84 (m , 1H), 8.05 (s, 1H), 8.03 (s, 1H), 7.60 (dd, J=9.2, 2.0 Hz, 1H), 7.50 (d, J= 8.8 Hz, 1H), 4.58 (s, 2H), 3.17-3.16 (m, 4H), 2.26 (s, 3H), 2.09-1.98 (m, 4H ). MS (ER+) m/e 354.3 (M+H).

Example 303.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6-methyl-5,6,7,8tetrahydropyrido[4 ,3-d]pyrimidine-4-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,8-diazabicyclo[3.2.1]octane-8 -yl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine as a pink solid (23%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.93 (s, 2H), 7.59 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 4.63 (m, 2H), 3.48 (s, 2H), 3.15-2.88 (m, 2H), 2.85-2.78 (m, 6H), 2.59 (s, 3H), 2.10-1.97 (m, 4H). MS (ER+) m/e 417.3 (M+H).

Example 304.

N-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-5(trifluoromethyl)pyrimidin-4-yl) -1H-indazol-5-amine as a white solid (52%).

1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 9.22 (s, 1H), 8.87 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 7.50-7.48 (m, 1H), 7.41-7.39 (m, 1H), 4.38 (s, 1H), 4.05 (s, 1H), 3.56 (m, 2H), 3.29 (m, 2H) 2.72-2.67 (m, 1H), 1. 78 (d, J=9.6 Hz, 1H). MS (ER+) m/e 376.1 (M+H).

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Example 305.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)-6-methoxy-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5chloropyrimidin-4-yl)-6-methoxy -1H-indazol-5-amine as a pink solid (40%).

1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.12 (s, 1H), 4.43 (m , 2H), 3.99 (s, 3H), 3.39-3.32 (m, 2H), 3.29-3.21 (m, 2H), 2.35-2.22 (m, 2H ), 2.15-2.01 (m, 2H). MS (ES+) m/e 386.0 (M+H).

Example 306.

[2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4-(pyridin-4-yl)phenyl)-6,7-dihydro-5H-pyrrolo[3,4th] pyrimidine-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4-(pyridin-4yl)phenyl)- 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine as a yellow solid (10%).

1H NMR (400 MHz, DMSO-I6) δ 9.76 (s, 2H), 9.57 (s, 1H), 9.43 (s, 1H), 9.09 (s, 1H), 8.85 (d, J=6.4 Hz, 2H), 8.22 (d, J=6.8 Hz, 2H), 8.06 (d, J=8.8 Hz, 2H), 7.94 (d , J=8.8 Hz, 2H), 4.73 (s, 2H), 4.49 (s, 2H), 4.34 (s, 2H), 3.25-3.16 (m, 4H) , 2.09-2.06 (m, 4H). MS (ER+) m/e 400.3 (M+H).

Example 307.

2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-(1H-indazol-5-yl)-7,8-dihydro-5H-pyrano[4,3d]pyrimidin-4- amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-(1H-indazol-5yl)-7,8 -dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine as a white solid (30%).

1H NMR (400 MHz, DMSOL) δ 13.12 (s, 1H), 9.44 (s, 1H), 8.78 (s, 1H), 8.09 (s, 1H), 7.90 (s , 1H), 7.557.53 (m, 1H), 7.548-7.46 (m, 1H), 4.61 (s, 2H), 4.43 (s, 2H), 3.94 (t, J= 5.6 Hz, 2H), 3.68 (d, J=12.4 Hz, 2H), 3.39 (d, J=9.6 Hz, 2H), 2.81-2.73 (m, 3H), 1.87 (d, J=9.6 Hz, 1H). MS (ER+) m/e 364.1 (M+H).

Example 308.

N-(2-(3,6-diazabicyclo[3.1.1]heptan-6-ul)-5-cyclopropylpyrimidin-4-yl)-1H-undazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-5cyclopropylpyrimidin-4-yl)-1H-indazole -5-amine as a white solid (9%).

^1H NMR (400 MHz, DMSO-I6) δ 13.19 (s, 1H), 9.87 (s, 1H), 9.52 (s, 1H), 9.02 (s, 1H), 8. 12 (d, J=0.8 Hz, 1H), 7.96 (s, 1H), 7.78 (d, J=0.8 Hz, 1H), 7.59-7.51 (m, 2H ), 4.46 (m, 2H), 3.65 (m, 2H), 3.42 (d, J=10.4 Hz, 2H),

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2.85-2.81 (m, 1H), 1.87 (d, J=10.4 Hz, 1H), 1.83-1.76 (m, 1H), 1.04-0.99 ( m, 2H), 0.73-0.69 (m, 2H). MS (ER+) m/e 348.0 (M+H).

Example 309.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-cyclopropylpyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5cyclopropylpyrimidin-4-yl)-1H-indazole -5-amine as a white solid (8%).

1H NMR (400 MHz, DMSO-66) δ 13.18 (s, 1H), 9.78 (s, 1H), 9.38 (s, 1H), 8.99 (s, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.73 (s, 1H), 7.60-7.54 (m, 2H), 4.60 (s, 2H), 3.22- 3.20 (m, 4H), 2.01-2.00 (m, 4H), 1.83-1.76 (m, 1H), 1.03-0.99 (m, 2H), 0. 71-0.67 (m, 2H). MS (ER+) m/e 362.1 (M+H).

Example 310.

2-(3,6-diazabicyclo[3.1.1]gentan-6-yl)-N-(1H-indazol-5-yl)-6,7-dihydro-5H-nirrolo[3,4d]πpyrimidin-4- amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-(1H-indazol-5yl)-6,7 -dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine as a brown solid (17%).

1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 9.59-9.40 (m, 3H), 9.24 (1, 1H), 8.70 (s, 1H) , 8.09-8.06 (m, 2H), 7.53-7.48 (m, 2H), 4.36-4.29 (m, 6H), 3.35 (m, 2H), 2 .78-2.75 (m, 1H) 1.89 (d, J=9.2 Hz, 1H). MS (ER+) m/e 349.1 (M+H).

Example 311.

2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-(4-(pyridin-4-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3d]pyrimidine -4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-(4-(niridin-4yl)phenyl)- 7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine as a yellow solid (30%).

^1H NMR (400 MHz, CD ₃ OD) δ 8.56-8.54 (m, 2H), 8.38 (s, 1H), 7.83-7.77 (m, 2H), 7.75 -7.71 (m, 4H), 4.66 (s, 2H), 4.48-4.46 (m, 2H), 4.02-3.99 (m, 2H), 3.87 (d , J=12.8 Hz, 2H), 3.37-3.33 (m, 2H), 2.96-2.90 (m, 1H), 2.75-2.73 (m, 2H), 1.88 (d, J=9.6 Hz, 1H). MS (ER+) m/e 401.1 (M+H).

Example 312.

2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-(4-(pyridin-4-yl)phenyl)-5,7-dihydrofuro[3,4d]pyrimidin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-(4-(pyridin-4yl )phenyl)-5,7-dihydrofuro[3,4-b]pyrimidin-4-amine as an off-white substance (28%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.53 (d, J=4.4 Hz, 2H), 7.93-7.90 (m, 2H), 7.75-7.71 (m , 4H), 5.02 (s, 2H),

4.81 (s, 2H), 4.38 (d, J=4 Hz, 2H), 3.57 (d, J=11.6 Hz, 2H), 2.89 (d, J=12.8 Hz, 2H), 2.78-2.2.73 (m, 1H), 1.85 (d, J=8.4 Hz, 1H). MS (ER+) m/e 387.0 (M+H).

Example 313.

2-(3,6-diazabucyclo[3.1.1]heptan-6-yl)-N-(1H-undazol-5-yl)-7-methyl-5,6,7,8-tetrahydropyrudo[3,4d] pyrimidine-4-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-N-(1H-indazol-5yl)-7-methyl -5,6,7,8-tetrahydropyrido[3,4-d]pyrimudin-4-amine as an off-white solid (18%).

1H NMR (400 MHz, DMSO-ph) δ 13.01 (s, 1H), 10.64-10.26 (m, 1H), 9.29 (s, 1H), 8.72-8.66 ( m, 2H), 8.05-8.01 (m, 2H), 7.55-7.48 (m, 2H), 4.27-4.13 (m, 4H), 3.85-3, 75 (m, 2H), 3.69-3.66 (m, 2H), 3.32 (s, 2H), 2.97 (s, 3H), 2.85 (m, 2H), 2.74 -2.71 (m, 1H), 1.85 (d, J=9.6 Hz, 1H). MS (ER+) m/e 377.1 (M+H).

Example 314.

1-(4-((1H-undazol-5-yl)amino)-2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5,7-dihydro-6H-pyrrolo[3, 4d]pyrimidin-6-yl)ethan-1-one

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 1-(4-((1H-undazol-5-yl)amino)-2-(3,8diazabicyclo[3.2.1]octane-8- yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one as a pink solid (33%).

1H NMR (400 MHz, DMSO-f) δ 13.00 (br s, 1H), 9.15-9.09 (m, 1H), 9.00 (s, 1H), 8.83 (s, 1H), 8.068.03 (m, 2H), 7.59-7.55 (m, 1H), 7.54-7.48 (m, 1H), 4.66-4.62 (m, 4H) , 4.47 (s, 1H), 4.37 (s, 1H), 3.18 (m, 4H), 2.08-1.99 (m, 7H). MS (ER+) m/e 405.2 (M+H).

Example 315.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6-chloro-5-methylpyrumidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6-chloro-5methylpyrimidin-4-yl) -1H-indazol-5-amine as a white solid (42%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 8.58 (s, 1H), 8.21 (s, 1H), 8.02 (s, 1H), 7, 89 (s, 1H), 7.547.46 (m, 2H), 4.35 (s, 2H), 2.94 (d, J=11.6 Hz, 2H), 2.75 (d, J=11 .2 Hz, 2H), 2.19 (s, 3H), 1.91-1.81 (m, 4H). MS (ER+) m/e 370.2 (M+H).

- 104 044043

Example 316.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-5,7-dihydrofuro[3,40]pyrimidin-4 -amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,6diazabicyclo[3.1.1]heptan-6-yl )-5,7-dihydrofuro[3,4-4]pyrimidin-4-amine as an off-white solid (55%).

^1H NMR (400 MHz, DMSO-06) δ 9.26 (s, 1H), 9.09 (s, 1H), 8.51 (s, 1H), 8.00 (s, 2H), 7. 67 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 4.96 (s, 2H), 4.77 (s, 2H), 4, 38-4.36 (m, 2H), 3.72-3.69 (m, 2H), 3.34 (m, 2H), 2.802.76 (m, 1H) 1.90-1.88 (m , 1H). MS (ER+) m/e 376.1 (M+H).

Example 317.

N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-7,8-dihydro-5H-pyrano[4.30 ]pyrimidine-4-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(3,6diazabicyclo[3.1.1]heptan-6-yl )-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine as an off-white solid (48%).

^1H NMR (400 MHz, DMSO-06) δ 9.55 (s, 1H), 9.28 (s, 1H), 8.90 (s, 1H), 8.04 (s, 2H), 7. 63-7.54 (m, 4H), 4.60-4.51 (m, 4H), 3.94 (t, J=5.6 Hz, 2H), 3.72-3.69 (m, 2H), 3.45-3.42 (m, 2H), 2.87-2.81 (m, 1H), 2.73 (m, 2H), 1.92-1.90 (m, 1H) . MS (ER+) m/e 390.1 (M+H).

Example 318.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)-6-methyl-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5chloropyrimidin-4-yl)-6-methyl -1H-indazol-5-amine as a white solid (27%).

^1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), 8.02 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 4.51 ( s, 2H), 3.243.21 (m, 2H), 3.14-3.11 (m, 2H), 2.39 (s, 3H), 2.18-2.15 (m, 2H), 1 .98-1.92 (m, 2H). MS (ER+) m/e 370.1 (M+H).

Example 319.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-6-methoxypyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-6methoxynirimidin- 4-yl)-1H-indazol-5-amine as an off-white solid (18%).

1H NMR (400 MHz, DMSO- _d6 ) δ 12.97 (br s, 1H), 9.15 (s, 1H), 9.01 (s, 1H), 8.80 (s, 1H), 8.03 (s, 1H),

7.97 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 4.57 (m, 2H), 3.91 (s, 3H), 3.18 (m, 4H), 2.07-1.99 (m, 4H). MS (ER+) m/e 370.1 (M+H).

Example 320.

6-((1H-indazol-5-yl)amino)-2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoropyrimidin-4-ol

IX ^f Xa but N

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 6-((1H-indazol-5-yl)amino)-2-(3,8diazabicyclo[3.2.1]octan-8-yl)- 5-fluoropyrimidin-4-ol as an off-white solid (32%).

1H NMR (400 MHz, DMSO) δ 13.01 (s, 1H), 11.28 (s, 1H), 9.12 (s, 1H), 8.90 (s, 2H), 8.01 (d , J=0.8 Hz, 1H), 7.81 (s, 1H), 7.50-7.43 (m, 2H), 4.55 (m, 2H), 3.27-3.13 ( m, 4H), 2.09-1.96 (m, 4H). MS (ER+) m/e 356.2 (M+H).

Example 321.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-chloro-6-methoxypyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give X-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-chloro-6methoxypyrimidin-4-yl) -1H-indazol-5-amine as a brown solid (41%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 13.02 (br s, 1H), 9.02 (d, J=11.2 Hz, 1H), 8.80 (s, 1H), 8, 70 (s, 1H), 8.05 (s, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.53-7.46 (m, 2H), 4.52 (m , 2H), 3.90 (s, 3H), 3.21-3.13 (m, 4H), 2.06-1.96 (m, 4H). MS (ER+) m/e 386.3 (M+H).

Example 322.

Ethyl (3aR,8aR)-2-(4-((1H-indazol-5-yl)amino)-5-fluoropyrimidin-2-yl)octahydropyrrolo[3,4d]azepine-3 a(1H)-carboxylate

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give ethyl (3aR,8aR)-2-(4-((1H-indazol-5-yl)amino)-5fluoropyrimidin-2-yl)octahydropyrrolo[ 3,4-d]azepine-3a(1H)-carboxylate as a yellow solid (10%).

1H NMR (400 MHz, CD3OD) δ 8.10-8.09 (m, 1H), 8.08 (s, 1H), 8.00 (d, J=5.2 Hz, 1H), 7.65 -7.57 (m, 2H), 4.25-4.18 (m, 3H), 3.93-3.87 (m, 1H), 3.51-3.45 (m, 4H), 3 .25-3.11 (m, 3H), 2.51-2.45 (m, 1H), 2.14-1.99 (m,

3H), 1.25 (t, J=6.8 Hz, 3H). MS (ER+) m/e 440.2 (M+H).

- 106 044043

Example 323.

Ethyl

d] azepin-3 a( 1 H)-carboxylate (3aR,8aR)-2-(4-((1H-indazol-5-yl)amino)-5-chloropyrimidin-2-yl)octahydropyrrolo[3,4-

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give ethyl (3aR,8aR)-2-(4-((1H-indazol-5-yl)amino)-5chloropyrimidin-2-yl)octahydropyrrolo[ 3,4-d]azepine-3a(1H)-carboxylate as a yellow solid (25%).

^1H NMR (400 MHz, CD3OD) δ 8.07 (s, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.60-7.54 (m, 2H), 4.26-4.11 (m, 3H), 3.87 (dd, J=11.2, 8.0 Hz, 1H), 3.49-3.41 (m, 3H), 3.22- 3.09 (m, 4H), 2.45 (dd, J=16.0, 6.8 Hz, 1H), 2.141.97 (m, 3H), 1.23 (t, J=6.8 Hz , 3H). MS (ER+) m/e 456.2 (M+H).

Example 324.

N-(2-((1,5)-9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-((1,5)-9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)- 5fluoropyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (28%).

^1H NMR (400 MHz, CD3OD) δ 8.06-8.05 (m, 2H), 8.02 (d, J=4.0 Hz, 1H), 7.64-7.55 (m, 2H ), 4.33 (d, J=13.6 Hz, 2H), 4.27 (s, 2H), 3.53-3.43 (m, 3H), 3.41-3.30 (m, 2H). MS (ER+) m/e 356.3 (M+H).

Example 325.

N-(2-((1,5)-9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)-5-chloropyrimidin-4-yl)-1H-indazol-5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-((1,5)-9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)- 5chloropyrimidin-4-yl)-1H-indazol-5-amine as a white solid (18%).

¹ H NMR (400 MHz, DMSO-b ₆ ) δ 13.02 (s, 1H), 9.05 (d, J=12.0 Hz, 1H), 8.95 (s, 1H), 8.16 (s, 1H), 8.057.99 (m, 3H), 7.64 (dd, J=9.2, 2.0 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H) , 4.26 (d, J=13.3 Hz, 2H), 4.20 (br. s, 2H), 3.34-3.28 (m, 4H), 3.21-3.18 (m , 2H). MS (ER+) m/e 372.1 (M+H).

Example 326.

Ethyl 3 -(4-(( 1 H-indazol-5-yl)amino)-5-chloropyrimidin-2-yl)-3,6-diazabicyclo[3.2.1]octane-7 carboxylate

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give ethyl 3-(4-((1H-indazol-5-yl)amino)-5-chloropyrimidine-2

- 107 044043 yl)-3,6-diazabicyclo[3.2.1]octane-7-carboxylate in the form of a yellow solid (23%).

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.06 (s, 1H), 8.02 (s, 1H), 7.95-7.94 (m, 1H), 7.56 (m, 2H), 4.60 (dd, J=14.0, 3.2 Hz, 1H), 4.50-4.45 (m, 2H), 4.19 (s, 1H), 4.09-3 .95 (m, 1H), 3.69 (m, 1H), 3.19-3.04 (m, 2H), 2.23 (s, 2H), 0.86 (m, 3H). MS (ER+) m/e 428.2 (M+H).

Example 328.

N-(2-(3a-((ethylperoxy)methyl)-6a-(trifluoromethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5fluoropyrimidin-4-yl)-1 H-indazol- 5-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3a-((ethylperoxy)methyl)-6a(trifluoromethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H) -yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine as a yellow solid (8%).

1H NMR (400 MHz, CD3OD) δ 8.09 (d, J=1.2 Hz, 1H), 8.05 (s, 1H), 8.02 (d, J=4.8 Hz, 1H), 7.62 (dd, J=9.2, 2.0 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 4.33-4.27 (m, 3H), 4 .15 (d, J=12.8 Hz, 2H), 3.99 (d, J=12.8 Hz, 1H), 3.94 (d, J=4.0 Hz, 1H), 3.92 -3.89 (m, 1H), 3.89-3.82 (m, 1H), 3.66 (d, J=12.8 Hz, 1H), 1.30 (t, J=7.2 Hz, 3H). MS (ER+) m/e 480.2 (M+H).

Example 329.

2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N ⁴ -(1H-indazol-5-yl)-N ⁶ -methylpyrimidin-4,6-diamine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N4-(1H-indazol-5yl)-N ⁶ - methylpyrimidine-4,6-diamine as a yellow solid (2%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 13.00 (s, 1H), 9.06 (s, 1H), 8.83 (s, 1H), 8.02 (s, 1H), 7. 82 (s, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 5.22 (s, 1H), 4, 69 (s, 2H), 3.21 (m, 4H), 2.74 (s, 3H), 2.11-2.00 (m, 4H). MS (ER+) m/e 351.2 (M+H).

Example 330.

2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(1H-indazol-5-yl)quinazolin-4-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(1H-indazol-5yl)quinazolin-4- amine as a yellow solid (42%).

1H NMR (400 MHz, DMSOL) δ 13.05 (br s, 1H), 9.74 (s, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.23 (s , 2H), 8.09-8.08 (m, 2H), 7.70 (d, J=9.2, 2.0 Hz, 1H), 7.69-7.62 (m, 1H), 7.55 (d, J=9.2 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.26 (t, J=8.4 Hz, 1H), 4, 65 (s, 2H), 3.12-3.00 (m, 4H), 2.07 (m, 4H). MS (ER+) m/e 372.4 (M+H).

- 108 044043

Example 331.

2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-^-(6-fluoro-III-indazol-5-yl)-^^ ^6- dimethylpyrimidin-4,6diamine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N ⁴ -(6-fluoro-1Hindazol-5-yl )-N ⁶ ,N ⁶ -dimetshirimidine-4,6-diamine as a white solid (29%).

^1H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 9.00 (s, 1H), 8.79 (s, 1H), 8.59 (s, 1H), 8. 06 (s, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.41 (d, J=10.8 Hz, 1H), 5.29 (s, 1H), 4, 62 (s, 2H), 3.15 (m, 4H), 2.95 (s, 6H), 2.10-1.90 (m, 4H). MS (ER+) m/e 383.3 (M+H).

Example 332.

2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N ⁴ -ethyl-N ⁶ -(1H-indazol-5-yl)-N ⁴ -methylpyrimidin-4,6diamine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N ⁴ -ethyl-N ⁶ -(1Hindazol-5- yl)-N ⁴ -methylpyrimidine-4,6-diamine as a yellow solid (10%).

1H NMR (400 MHz, DMSOL) δ 12.92 (br s, 1H), 8.87 (s, 2H), 8.72 (s, 1H), 7.99 (s, 1H), 7.89 (s, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 5.28 (m, 1H), 4.67 (m, 2H), 3.47 (m, 2H), 3.18 (m, 4H), 2.91 (s, 3H), 2.09-1.98 (m, 4H), 1.05 ( t, J=6.8 Hz, 3H). MS (ER+) m/e 379.3 (M+H).

Example 333.

6-((III-indazol-5-yl)amino)-2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-methylpyrimidin-4carbonitrile

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 6-((1H-indazol-5-yl)amino)-2-(3,8diazabicyclo[3.2.1]octan-8-yl)- 5-methylpyrimidine-4-carbonitrile as a yellow solid (4%).

1H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 9.02 (s, 2H), 8.79 (s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.567.51 (m, 2H), 4.51 (m, 2H), 3.14 (m, 4H), 2.32 (s, 3H), 2.08-1.95 ( m, 4H). MS (ER+) m/e 361.3 (M+H).

Example 334.

N-(5-fluoro-2-(5-(methylamino)-2-azabicyclo[2.2.1]heptan-2-yl)pyrimidin-4-yl)-1H-indazol-5-amine

Step 1. Solution of N-(2-chloro-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine (1 eq.), tert-butyl (2azabicyclo[2.2.1]heptan-2-yl)carbamatamine (1 eq.) and DIPEA (2 eq.) in DMSO were stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature and quenched by adding

- 109 044043 water, extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give tert-butyl (2-(4-((1H-indazol-5-yl)amino)-5-fluoronirimidin-2-yl)-2azabicyclo[2.2.1]heptan-5-yl )carbamate as a yellow oil (98% yield).

Step 2. Into a solution of tert-butyl (2-(4-((1H-indazol-5-yl)amino)-5-fluoropyrimidin-2-yl)-2azabicyclo[2.2.1]heptan-5-yl)carbamate ( 1 equiv.) LAG (2 equiv.) was added to THF. The mixture was stirred at 70°C for 19 hours. The reaction mixture was cooled to room temperature and diluted with H ₂ O (1 ml), 15% aqueous NaOH (1 ml) and H ₂ O (3 ml). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The final residue was purified by reverse phase preparative HPLC to give N-(5-fluoro-2-(5-(methylamino)-2-azabicyclo[2.2.1]heptan-2-yl)pyrimidin4-yl)-1H-indazol- 5-amine as a yellow solid (12%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.11 (s, 1H), 8.08 (s, 1H), 7.97 (d, J=5.2 Hz, 1H), 7.65- 7.56 (m, 2H), 4.60 (s, 1H), 3.77-3.69 (m, 1H), 3.67-3.61 (m, 1H), 3.60-3. 54 (m, 1H), 3.11 (m, 1H), 2.73 (s, 3H), 2.34-2.28 (m, 1H), 2.04-2.01 (m, 1H) , 1.90-1.87 (m, 1H), 1.74-1.68 (m, 1H). MS (ER+) m/e 354.4 (M+H).

Example 335.

N-(2-(5-(dimethylamino)-2-azabicyclo[2.2.1]gentan-2-yl)-5-fluoropyrimidin-4-yl)-1H-indazol-5 amine

The reaction was carried out following General Protocol F. The final residue was purified by reverse phase preparative HPLC to give N-(2-(5-(dimethylamino)-2-azabicyclo[2.2.1]heptan-2-yl)5-fluoropyrimidin-4-yl )-1H-indazol-5-amine as a white solid (8%).

1H NMR (400 MHz, CD ₃ OD) δ 8.24 (s, 1H), 7.98 (s, 1H), 7.76 (d, J=4.0 Hz, 1H), 7.68 (d , J=8.8 Hz, 1H), 7.49 (d, J=9.2 Hz, 1H), 4.47 (s, 1H), 3.62 (d, J=10.0 Hz, 1H ), 3.37 (d, J=10.9 Hz, 1H), 2.74 (s, 1H), 2.51-2.43 (m, 1H), 2.19 (s, 6H), 2 .01-1.95 (m, 1H), 1.81 (d, J=10.0 Hz, 1H), 1.70 (d, J=9.6 Hz, 1H), 1.44-1, 40 (m, 1H). MS (ER+) m/e 368.3 (M+H).

Example 336.

2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N ⁴ -(1H-indazol-5-yl)-N ⁶ ,N ⁶ -dimethylpyrimidin-4,6-diamine

XX?

jiS

I

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(3,8-d)diazabicyclo[3.2.1]octan-8-yl)-N ⁴ -(1H-indazol-5yl)- N ⁶ ,N ⁶ -dimethylpyrimidine-4,6-diamine as a yellow solid (33%).

1H NMR (400 MHz, DMSO-d6) δ 12.99 (br s, 1H), 9.13 (s, 2H), 8.88 (s, 1H), 8.01 (s, 1H), 7 .87 (s, 1H), 7.49-7.36 (m, 2H), 5.30 (s, 1H), 4.71 (s, 2H), 3.20 (m, 4H), 2. 97 (s, 6H), 2.16-1.94 (m, 4H). MS (ER+) m/e 365.3 (M+H).

Example 337.

N-(2-(3-(dimethylamino)-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)-1 H-indazol-5-amine

The reaction was carried out following General Protocol F. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3-(dimethylamino)-8-azabicyclo[3.2.1]octan-8yl)pyrimidin-4-yl)-1H- indazole-5-amine as a white solid (10%).

- 110 044043

1H NMR (400 MHz, CD ₃ OD) δ 8.09 (s, 1H), 7.98 (s, 1H), 7.83 (d, J=6.0 Hz, 1H), 7.53-7 .47 (m, 2H), 6.03 (d, J=6.0 Hz, 1H), 4.70 (s, 2H), 2.84-2.76 (m, 1H), 2.23 ( s, 6H), 2.12-2.01 (m, 2H), 1.91-1.81 (m, 4H), 1.79-1.70 (m, 2H). MS (ER+) m/e 364.3 (M+H).

Example 338.

Ethyl 2-(4-((1H-indazol-5-yl)amino)-5-chloropyrimidin-2-yl)-6a-(trifluoromethyl)hexahydropyrrolo[3,4-c]pyrrole-3 a(1H)- carboxylate

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give ethyl 2-(4-((1H-indazol-5-yl)amino)-5-chloropyrimidin-2yl)-6a-(trifluoromethyl)hexahydropyrrolo[ 3,4-c]pyrrole-3a(1H)-carboxylate as a yellow solid (38%).

1H NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.59-7.54 (m, 2H), 4 .30-4.25 (m, 3H), 4.12-4.09 (m, 2H), 3.93-3.79 (m, 4H), 3.62-3.60 (m, 1H) , 1.28 (t, J=7.2 Hz, 3H). MS (ER+) m/e 496.2 (M+H).

Example 339.

Ethyl 3-(4-((1H-indazol-5-yl)amino)-5-fluoropyrimidin-2-yl)-3,6-diazabicyclo[3.2.1]octane-7carboxylate

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give ethyl 3-(4-((1H-indazol-5-yl)amino)-5-fluoropyrimidin-2yl)-3,6-diazabicyclo[3.2 .1]octane-7-carboxylate as a yellow solid (30%).

1H NMR (400 MHz, CD3OD) δ 8.07 (s, 1H), 8.05-8.02 (m, 1H), 7.97 (d, J=4.4 Hz, 1H), 7.62 -7.56 (m, 2H), 4.56-4.43 (m, 3H), 4.24 (s, 1H), 4.08-3.98 (m, 1H), 3.71 (s , 1H), 3.26 (m, 1H), 3.19 (m, 1H), 3.08 (m, 1H), 2.25 (s, 2H), 0.85 (t, J=5, 6 Hz, 3H). MS (ER+) m/e 412.2 (M+H).

Example 340.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-1 H-inαzol-5 amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give X-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-chloro-6(trifluoromethyl)pyrimidin- 4-yl)-1H-indazol-5-amine as a white solid (41%).

1H NMR (400 MHz, DMSO-de) δ 13.11 (s, 1H), 9.49 (s, 1H), 8.91 (s, 2H), 8.08 (s, 1H), 7.87 (s, 1H), 7.53 (s, 2H), 4.49 (m, 2H), 3.22-3.13 (m, 4H), 2.09-1.95 (m, 4H). MS (ER+) m/e 424.1 (M+H).

- 111 044043

Example 341.

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-1H-indazol-5-amine

N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-1Hindazol-5-amine solution (1 eq.) and 10% Pd on carbon in MeOH were stirred at 50°C for 39 hours under H ₂ (50 psi). The reaction mixture was filtered through a celite filter, and the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH and 10% Pd on carbon was added, followed by HCl (36% purity). The reaction mixture was filtered through a celite filter, and the filtrate was concentrated under reduced pressure. The final residue was purified by reverse phase preparative HPLC to give N-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6-(trifluoromethyl)pyrimidin4-yl)-1H-indazol-5- amine as a white solid (41%).

^1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 9.73 (s, 1H), 8.27 (s, 2H), 8.09 (s, 1H), 8. 04 (s, 1H), 7.547.46 (m, 2H), 6.34 (s, 1H), 4.51 (m, 2H), 2.89-2.67 (m, 4H), 2.00 -1.92 (m, 4H). MS (ER+) m/e 390.3 (M+H).

Example 342.

Ethyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-N ⁴ -(1H-indazol-5-yl)-N ⁶ ,N ⁶ -dimethylpyrimidin-4,6- diamine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give ethyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-N ⁴ -(1Hindazol-5- yl)-N ⁶ ,N ⁶ -dimethylpyrimidine-4,6-diamine as a white solid (30%).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.98 (d, J=1.6 Hz, 1H), 7.94 (s, 1H), 7.56 (dd, J=8.8, 1 .6 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 4.50 (s, 2H), 3.15-3.12 (m, 8H), 2.74 (d , J=6.4 Hz, 2H), 2.09-1.90 (m, 4H). MS (ER+) m/e 383.4 (M+H).

Example 343.

4-((III-indazol-5-yl)amino)-2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6-methylpyrimidin-5carbonitrile

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 4-((1H-indazol-5-yl)amino)-2-(3,8-diazabicyclo[3.2.1]octan-8-yl )-6-methylpyrimidine-5-carbonitrile as a white solid (30%).

^1H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 9.40 (s, 1H), 9.08 (s, 1H), 8.84 (s, 1H), 8. 05 (s, 1H), 7.84 (s, 1H), 7.51-7.47 (m, 2H), 4.80 (m, 1H), 4.45 (m, 1H), 3.17 (m, 4H), 2.41 (s, 3H), 2.03-1.96 (m, 4H). MS (ER+) m/e 361.3 (M+H).

Example 344.

2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-chloro-N ⁴ -(1H-indazol-5-yl)-N ⁶ ,N ⁶ -dimethylpyrimidin-4,6diamine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-chloro-N ⁴ -(1Hindazole -5-yl)-N ⁶ ,N ⁶ -dimethylnirimidin-4,6-diamine as a brown solid (9%).

1H NMR (400 MHz, DMSO- _d6 ) δ 12.94 (br s, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.87 (s, 1H),

7.54-7.40 (m, 2H), 4.34 (s, 2H), 2.99 (s, 6H), 2.94-2.87 (m, 2H), 2.66-2, 64 (m, 2H), 1.92-1.78 (m, 4H). MS (ER+) m/e 399.1 (M+H).

Example 345.

2-(niperazin-1-yl)-N-(3-(pyridin-4-yl)phenyl)pyrimidin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(piperazin-1-yl)-N-(3-(pyridin-4-yl)phenyl)nirimidin4-amine as a white solid ( 33%).

¹ H NMR (400 MHz, DMSO-a ₆ ) δ 11.17 (s, 1H), 9.49 (s, 2H), 8.94 (d, J=6.0 Hz, 2H), 8.29 (s, 1H), 8.20 (d, J=5.6 Hz, 2H), 8.01 (d, J=6.8 Hz, 1H), 7.86 (d, J=7.2 Hz , 1H), 7.77 (d, J=7.6 Hz, 1H), 7.69-7.62 (m, 1H), 6.55 (d, J=6.4 Hz, 1H), 4 .02 (s, 4H), 3.25 (s, 4H). MS (ER+) m/e 333.0 (M+H).

Example 346.

2-(piperazin-1 -yl)-N-(3 -(pyridin-3 -yl)phenyl)pyrimidin-4-amine t

A

A

Ν ^ΝΗ

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give 2-(piperazin-1-yl)-N-(3-(pyridin-3-yl)phenyl)nirimidin4-amine as a white solid ( 35%).

1H NMR (400 MHz, DMSOL) δ 11.42 (s, 1H), 9.64 (s, 2H), 9.11 (s, 1H), 8.85 (s, 1H), 8.59 (d , J=8.2 Hz, 1H), 8.15 (s, 1H), 7.98 (d, J=7.2 Hz, 2H), 7.79 (s, 1H), 7.69-7 .58 (m, 2H), 6.63 (d, J=6.0 Hz, 1H), 4.06 (s, 4H), 3.26 (s, 4H). MS (ER+) m/e 333.2 (M+H).

Example 347.

N-(3-( 1 H-pyrazol-4-yl)phenyl)-2-(piperαzin-1 -yl)pyrimidin-4-amine

The reaction was carried out following General Protocol G. The final residue was purified by reverse phase preparative HPLC to give N-(3-(1H-pyrazol-4-yl)phenyl)-2-(piperazin-1yl)pyrimidin-4-amine as a white solid substances (18%).

1H NMR (400 MHz, DMSO- _d6 ) δ 9.26 (s, 1H), 8.04 (s, 1H), 7.98-7.88 (m, 3H), 7.37-7.18 (m, 3H), 6.04 (d, J=5.6 Hz, 1H), 3.66 (s, 4H), 2.73 (s, 4H). MS (ER+) m/e 322.2 (M+H).

- 113 044043

Example 349.

5-(4-((2-(piperazin-1-yl)pyrimidin-4-yl)amino)phenyl)pyridin-2(1H)-one

Step 1. Into a solution of tert-butyl 4-(4-((4-bromophenyl)amino)pyrimidin-2-yl)piperazine-1-carboxylate (1 eq.) and (6-methoxypyridin-3-yl)boronic acid compound (1 eq.) in dioxane and H ₂ O, Pd(dppf)Cl ₂ (84.15 mg) and K ₃ PO ₄ (732.33 mg) were added under N2 atmosphere at 23°C. The reaction mixture was heated to 100°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and quenched by adding water, extracted with EtOAc. The combined organics were dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to obtain tert-butyl 4-(4-((4-(6-methoxypyridin-3-yl)phenyl)amino)pyrimidin2-yl)piperazine-1-carboxylate.

Step 2: 4. A mixture of the compound tert-butyl 4-(4-((4-(6-methoxypyridin-3-yl)phenyl)amino)pyrimidin2-yl)piperazine-1-carboxylate (1 eq.) in HBr was stirred at 100°C for 16 hours. The final residue was purified by reverse phase preparative HPLC to give 5-(4-((2-(piperazin-1yl)pyrimidin-4-yl)amino)phenyl)pyridin-2(1H)- it is in the form of a white solid (53%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.29 (s, 1H), 7.92 (d, J=5.6 Hz, 1H), 7.82 (dd, J=9.6, 2.4 Hz, 1H), 7.68 (s, 1H), 7.66 (s, 2H), 7.50 (d, J=8.4 Hz, 2H), 6.41 (d, J= 9.2 Hz, 1H), 6.02 (d, J=5.6 Hz, 1H), 3.62 (br s, 4H), 2.72 (br s, 4H). MS (ER+) m/e 349.2 (M+H).

Example 350.

N-(4-(6-aminopyridin-3-yl)phenyl)-2-(piperazin-1-yl)pyrimidin-4-amine

Step 1. Mixture of compound tert-butyl 4-(4-((4-bromophenyl)amino)pyrimidin-2-yl)piperazine-1carboxylate (1 eq.), KOAc (3 eq.), B(Pin) ₂ (1 .5 eq.) and Pd(dppf)Cl ₂ (0.1 eq.) in dioxane were stirred at 100°C in an atmosphere of N ₂ for 16 hours. The reaction mixture was cooled to room temperature and quenched by adding water, extracted with EtOAc. The combined organics were dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give tert-butyl 4-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)phenyl)amino)pyrimidin-2-yl )piperazine-1-carboxylate.

Step 2. Mixture of the compound tert-butyl 4-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)amino)pyrimidin-2-yl)piperazin- 1-carboxylate (1 eq.), 5-bromopyridin-2-amine (0.1 eq.), Pd(PPh ₃ ) ₄ (0.1 eq.), K ₃ PO ₄ (3 eq.) in EDC and H ₂ O was stirred at 140°C under microwave irradiation for 20 minutes. The reaction mixture was cooled to room temperature and quenched by adding water, extracted with EtOAc. The combined organics were dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to obtain tert-butyl 4-(4-((4-(6-aminopyridin-3-yl)phenyl)amino)pyrimidin-2-yl)piperazine 1-carboxylate.

Step 3. A mixture of the compound tert-butyl 4-(4-((4-(6-aminopyridin-3-yl)phenyl)amino)pyrimidin-2yl)piperazine-1-carboxylate (1 eq.) in a mixture of HCl and methanol was stirred at 20°C for 2 hours. The final residue was purified by reverse-phase preparative HPLC to give N-(4-(6aminopyridin-3-yl)phenyl)-2-(piperazin-1-yl)pyrimidin-4-amine in as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.26 (s, 1H), 8.22 (s, 1H), 7.92 (d, J=5.6 Hz, 1H), 7.69 ( d, J=6.0 Hz, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 6.51 (d, J=5.6 Hz, 1H), 6.03 (d, J=6.0 Hz, 1H), 3.63 (t, J=4.4 Hz, 4H), 2.73 (t, J= 4.4 Hz, 4H). MS (ER+) m/e 348.0 (M+H).

- 114 044043

Example 351.

N-(4-(1H-imidazol-5-yl)phenyl)-2-(piperazin-1-yl)pyrimidin-4-amine

Step 1. Mixture of the compound tert-butyl 4-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)amino)pyrimidin-2-yl)piperazin- 1-carboxylate (1 eq.), K3PO4 (2 eq.), 4-bromo-1-((2(trimethylsilyl)ethoxy)methyl)-1H-imidazole (1 eq.) and Pd(dppf)Cl ₂ (0 .1 eq.) in dioxane was stirred at 100°C in an N2 atmosphere for 16 hours. The reaction mixture was cooled to room temperature and quenched by adding water, extracted with EtOAc. The combined organics were dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give tert-butyl 4-(4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1Himidazol-4-yl)phenyl)amino)pyrimidin-2-yl )piperazine-1-carboxylate.

Step 2. Mixture of the compound tert-butyl 4-(4-((4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4yl)phenyl)amino)pyrimidin-2-yl)piperazin- 1-carboxylate (1 eq.) in 6 M HCl was stirred at 100°C for 16 hours. The final residue was purified by reverse-phase preparative HPLC to give N-(4-(1H-imidazol-5-yl)phenyl)- 2-(piperazin-1-yl)pyrimidin-4-amine as a white solid (57%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.07 (s, 1H), 9.22 (s, 1H), 7.92 (d, J=5.6 Hz, 1H), 7.67 -7.61 (m, 5H), 7.51 (s, 1H), 6.03 (d, J=5.6 Hz, 1H), 3.64 (t, J=4.8 Hz, 4H) , 2.75 (t, J=4.8 Hz, 4H). MS (ER+) m/e 322.2 (M+H).

Example 353.

2-(piperazin-1-yl)-N-(4-(thiazol-5-yl)phenyl)pyrimidin-4-amine r-N iS k^NH

Step 1. Mixture of the compound tert-butyl 4-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)amino)pyrimidin-2-yl)piperazin- 1-carboxylate (1 eq.), K ₃ PO ₄ (2 eq.), 5-bromothiazole (1 eq.) and Pd(dppf)Cl2 (0.1 eq.) in dioxane and water were stirred at 100°C in atmosphere N2 for 16 hours. The reaction mixture was cooled to room temperature and quenched by adding water, extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give tert-butyl 4-(4-((4-(thiazol-5-yl)phenyl)amino)pyrimidin-2-yl)piperazin-1-carboxylate.

Step 2: A mixture of tert-butyl 4-(4-((4-(thiazol-5-yl)phenyl)amino)pyrimidin-2yl)piperazine-1-carboxylate (1 eq.) in TFA/DCM was stirred at 20 °C for 2 h. The final residue was purified by reverse phase preparative HPLC to give 2-(piperazin-1yl)-N-(4-(thiazol-5-yl)phenyl)pyrimidin-4-amine as a white solid (53%).

1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.02 (s, 1H), 8.23 (s, 1H), 7.96 (d, J=5.6 Hz , 1H), 7.74 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 6.05 (d, J=5.6 Hz, 1H ), 3.64 (t, J=4.8 Hz, 4H), 2.74 (t, J=4.8 Hz, 4H). MS (ER+) m/e 339.0 (M+H).

Example 354.

N-(4-(4H-1,2,4-triazol-3-yl)phenyl)-2-(piperazin-1-yl)pyrimidin-4-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(4-(4H-1,2,4-triazol-3-yl)phenyl)-2-(piperazin-1yl )pyrimidin-4-amine as a white solid (50%).

¹ H NMR (400 MHz, DMSO-dd δ 9.44 (s, 1H), 8.31 (s, 1H), 7.97-7.93 (m, 3H), 7.76 (d, J= 8.8 Hz, 2H), 6.07 (d, J=5.6 Hz, 1H), 3.64 (br s, 4H), 2.74 (br s, 4H).MS (ER+ ) m/e 323.1 (M+H).

Example 355.

4-(4-((2-(piperazin-1-yl)pyrimidin-4-yl)amino)phenyl)thiazol-2-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 4-(4-((2-(piperazin-1-yl)pyrimidin-4yl)amino)phenyl)thiazol-2-amine as a white solid substances (51%).

1H NMR (400 MHz, DMSO-dd δ 9.27 (s, 1H), 7.92 (d, J=5.6 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H) , 7.62 (d, J=8.8 Hz, 2H), 6.98 (s, 2H), 6.87 (s, 1H), 6.03 (d, J=5.6 Hz, 1H) , 3.63 (t, J=4.8 Hz, 4H), 2.74 (t, J=4.8 Hz, 4H).MS (ER+) m/e 354.1 (M+H).

Example 356.

5-(4-((2-(piperazin-1-yl)pyrimidin-4-yl)amino)phenyl)-1,3,4-thiadiazol-2-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 5-(4-((2-(piperazin-1-yl)pyrimidin-4-yl)amino)phenyl)1,3,4-thiadiazole -2-amine as a white solid (23%).

Ή NMR (400 MHz, DMSO-66) δ 9.59 (s, 1H), 8.25 (s, 2H), 8.00 (d, J=5.6 Hz, 1H), 7.74 (d , J=8.8 Hz, 2H), 7.70 (d, J=8.8 Hz, 2H), 7.31 (s, 2H), 6.13 (d, J=5.6 Hz, 1H ), 3.81 (t, J=4.8 Hz, 4H), 3.00 (t, J=4.8 Hz, 4H). MS (ER+) m/e 355.1 (M+H).

Example 357.

6-(4-((2-(piperazin-1 -yl)pyrimidin-4-yl)amino)phenyl)pyridazin-3 (2H)-one

Step 1. Into a solution of tert-butyl 4-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)pyrimidin-2-yl) piperazine-1-carboxylate (1 eq.) and 3-chloro-6-methoxypyridazine compound (1 eq.) in DMF and H ₂ O, Pd(dppf)Cl ₂ (0.1 eq.) and K ₂ CO ₃ ( 2 equiv.) in an N2 atmosphere at 23°C. The reaction mixture was heated to 100°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and quenched by adding water, extracted with EtOAc. The combined organics were dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to obtain tert-butyl 4-(4-((4-(6-methoxypyridazin-3yl)phenyl)amino)pyrimidin-2-yl)piperazin-1-carboxylate.

Step 2. A mixture of the compound tert-butyl 4-(4-((4-(6-methoxypyridazin-3-yl)phenyl)amino)pyrimidin2-yl)piperazin-1-carboxylate (1 eq.) in hydrochloric acid was stirred at 100 °C for 16 hours. The final residue was purified by reverse-phase preparative HPLC to give 6-(4-((2-(piperazin-1-yl)pyrimidin-4-yl)amino)phenyl)pyridazin-3(2H) -it is in the form of a yellow solid (8%).

- 116 044043 ¹ H NMR (400 MHz, DMSO-dg) δ 9.44 (s, 1H), 8.02 (d, J=10.0 Hz, 1H), 7.96 (d, J=5, 6 Hz, 1H), 7.82 (d,

J=8.8 Hz 2H), 7.75 (d, J=8.8 Hz, 2H), 6.95 (d, J=10.0 Hz, 1H), 6.06 (d, J=5 .6 Hz, 1H), 3.63 (br. s, 4H), 2.74 (br. s, 4H). MS (ER+) m/e 350.1 (M+H).

Example 358.

N-(4-(oxazol-5-yl)phenyl)-2-(piperazin-1-yl)pyrimidin-4-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(4-(oxazol-5-yl)phenyl)-2-(piperazin-1-yl)pyrimidin4-amine as a yellow solid ( 18%).

1H NMR (400 MHz, DMSO-dg) δ 9.45 (s, 1H), 8.36 (s, 1H), 7.94 (d, J=5.6 Hz, 1H), 7.78-7 .72 (m, 2H), 7.69-7.63 (m, 2H), 7.55 (s, 1H), 6.05 (d, J=5.6 Hz, 1H), 3.62 ( lat. s, 4H), 2.73 (lat. s, 4H). MS (ER+) m/e 323.1 (M+H).

Example 359.

N-(4-(2-aminopyridin-4-yl)phenyl)-2-(piperazin-1-yl)pyrimidin-4-amine

Step 1. Into a solution of tert-butyl 4-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)amino)pyrimidin-2-yl)piperazin- 1-carboxylate (1 eq.) and 4-bromopyridin-2-amine (1 eq.) in dioxane and H ₂ O added Pd(dppf)Cl ₂ (0.1 eq.) and K2CO3 (2 eq.) in atmosphere N2 at 23°C. The reaction mixture was heated to 100°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and quenched by adding water, extracted with EtOAc. The combined organics were dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to obtain tert-butyl 4-(4-((4-(2-aminopyridin-4yl)phenyl)amino)pyrimidin-2-yl)piperazine-1-carboxylate.

Step 2. A mixture of the compound tert-butyl 4-(4-((4-(2-aminopyridin-4-yl)phenyl)amino)pyrimidin-2yl)piperazine-1-carboxylate (1 eq.) in hydrochloric acid and ethyl acetate was stirred at 25°C for 2 hours. The final residue was purified by reverse-phase preparative HPLC to give N-(4-(2-aminopyridin-4-yl)phenyl)-2-(piperazin-1-yl)pyrimidin-4- amine as a yellow solid (37%).

1H NMR (400 MHz, CD3OD) δ 7.91 (t, J=5.6 Hz, 2H), 7.72 (d, J=8.8, 2H), 7.636 (d, J=8.8, 2H), 6.89 (dd, J=6.6, 1.6 Hz, 1H), 6.83 (s, 1H), 6.11 (d, J=5.6 Hz, 1H), 3, 76-3.86 (m, 4H), 2.90-3.02 (m, 4H). MS (ER+) m/e 348.1 (M+H).

Example 360.

4-(4-((2-(piperazin-1 -yl)pyrimidin-4-yl)amino)phenyl)pyridin-2(1H)-one

Step 1. Into a solution of tert-butyl 4-(4-((4-bromophenyl)amino)pyrimidin-2-yl)piperazine-1-carboxylate (1 eq.) and (2-methoxypyridin-4-yl)boronic acid ( 1 eq.) in dioxane and H ₂ O, Pd(dppf)Cl ₂ (0.1 eq.) and K ₃ PO ₄ (2 eq.) were added in an N2 atmosphere at 23°C. The reaction mixture was heated to 90°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and quenched by adding

- 117 044043 water, extracted with EtOAc. The combined organics were dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give tert-butyl 4-(4-((4-(2-methoxypyridin-4-yl)phenyl)amino)pyrimidin-2yl)piperazine-1-carboxylate.

Step 2. A mixture of the compound tert-butyl 4-(4-((4-(2-methoxypyridin-4-yl)phenyl)amino)pyrimidin-2yl)piperazine-1-carboxylate (1 eq.) in hydrochloric acid was stirred at 100 °C for 16 hours. The final residue was purified by reverse-phase preparative HPLC to give 4-(4((2-(piperazin-1-yl)nirimidin-4-yl)amino)phenyl)niridin-2(1H)- it is in the form of a white solid (9%).

1H NMR (400 MHz, DMSOL) δ 9.51 (br s, 1H), 7.96 (d, J=5.6 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H ), 7.67 (d, J=8.0 Hz, 2H), 7.41 (d, J=6.8 Hz, 1H), 6.57 (s, 1H), 6.54 (d, J =6.8 Hz, 1H), 6.08 (d, J=5.6 Hz, 1h), 3.64 (br s, 4H), 2.74 (br s, 4H). MS (ER+) m/e 349.1 (M+H).

Example 361.

5-(4-((2-(piperazin-1-yl)pyrimidin-4-yl)amino)phenyl)thiazol-2-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 5-(4-((2-(piperazin-1-yl)pyrimidin-4-yl)amino)phenyl)thiazol-2-amine as yellow solid (18%).

1H NMR (400 MHz, DMSO-b ₆ ) δ 9.41 (s, 1H), 8.27 (s, 2H), 7.97 (d, J=5.6 Hz, 1H), 7.96 ( d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 7.29 (s, 1H), 7.05 (s, 2H), 6.09 ( d, J=5.6 Hz, 1H), 3.83 (br. s, 4H), 3.04 (br. s, 4H). MS (ER+) m/e 354.1 (M+H).

Example 362.

5-(4-((2-(piperazin-1-yl)pyrimidin-4-yl)amino)phenyl)-1,3,4-oxadiazol-2-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 5-(4-((2-(piperazin-1-yl)pyrimidin-4-yl)amino)phenyl)1,3,4-oxadiazole -2-amine as a yellow solid (6%).

^1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.727 (d, J=8.8, 2H), 7.13 (s, 2H), 6.08 (d, J=5.6 Hz, 1H), 3.68-3.60 (m , 4H), 2.79-2.70 (m, 4H). MS (ER+) m/e 339.2 (M+H).

Example 363.

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 5-(4-((2-(piperazin-1-yl)pyrimidin-4-yl)amino)phenyl)1,3,4-oxadiazole -2-amine as a yellow solid (6%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.54 (s, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.727 (d, J=8.8, 2H), 7.13 (s, 2H), 6.08 (d, J=5.6 Hz, 1H), 3.68-3.60 (m , 4H), 2.79-2.70 (m, 4H). MS (ER+) m/e 339.2 (M+H).

- 118 044043

Example 364.

5-((2-(piperazin-1-yl)pyrimidin-4-yl)amino)-1,3-dihydro-2H-benzo[d]imidazol-2-one

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 5-((2-(piperazin-1-yl)pyrimidin-4-yl)amino)-1,3dihydro-2H-benzo[d]imidazole -2-one as a yellow solid (11%).

1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 10.45 (s, 1H), 9.03 (s, 1H), 7.86 (d, J=5.2 Hz , 1H), 7.50 (s, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 5.95 (d , J=5.6 Hz, 1H), 3.60 (t, J=4.4 Hz, 4H), 2.68 (t, J=4.4 Hz, 4H). MS (ER+) m/e 312.1 (M+H).

Example 365.

5-((2-(piperazin-1-yl)pyrimidin-4-yl)amino)indolin-2-one

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give 5-((2-(piperazin-1-yl)pyrimidin-4-yl)amino)indolin-2one as a white solid (24%) .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.28 (s, 1H), 9.00 (s, 1H), 7.86 (d, J=5.6 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 5.93 (d, J=6.0 Hz , 1H), 3.59 (t, J=4.4 Hz, 4H), 3.47 (s, 1H), 2.71 (t, J=4.4 Hz, 4H). MS (ER+) m/e 311.1 (M+H).

Example 366.

N-(4-(3H-imidazo[4,5-b]pyridin-7-yl)phenyl)-2-(piperazin-1-yl)pyrimidin-4-amine

Step 1. Into a solution of tert-butyl 4-(4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)amino)pyrimidin-2-yl)piperazin- 1-carboxylate (1 eq.) and 7-chloro-3-(4-methoxybenzyl)-3Himidazo[4,5-b]pyridine (1 eq.) in dioxane and H ₂ O, Pd(dppf)Cl ₂ (0 ,1 equiv.) and K ₂ CO ₃ (2 equiv.) in an N2 atmosphere at 23°C. The reaction mixture was heated to 100°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and quenched by adding water, extracted with EtOAc. The combined organics were dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to obtain tert-butyl 4-(4-((4-(3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl)phenyl)amino)pyrimidin-2yl )piperazine-1-carboxylate.

Step 2. Mixture of the compound tert-butyl 4-(4-((4-(3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7yl)phenyl)amino)pyrimidin-2-yl) piperazine-1-carboxylate (1 eq.) in trifluoroacetic acid and DCM was stirred at 25°C for 2 hours. The final residue was purified by reverse-phase preparative HPLC to give N-(4-(3H-imidazo[4,5- b]pyridin-7-yl)phenyl)-2-(piperazin-1yl)pyrimidin-4-amine as a white solid (20%).

1H NMR (400 MHz, DMSO-d6)δ 9.48 (s, 1H), 8.45 (s, 1H), 8.34 (d, J=5.2 Hz, 2H), 7.97 (d , J=5.6 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.52 (lat s, 1H), 6.09 (d, J=5.6 Hz , 1H), 3.66 (br. s, 4H), 2.75 (br. s, 4H). MS (ER+) m/e 373.1 (M+H).

- 119 044043

Example 367.

N-(4-(1,3,4-oxadiazol-2-yl)phenyl)-2-(piperazin-1-yl)pyrimidin-4-amine

The reaction was carried out following General Protocol A. The final residue was purified by reverse phase preparative HPLC to give N-(4-(1,3,4-oxadiazol-2-yl)phenyl)-2-(piperazin-1yl)pyrimidin-4-amine as a white solid (21%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.72 (s, 1H), 9.27 (s, 1H), 8.27 (br s, 1H), 8.02 (d, J=5 .6 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 6.14 (d, J=5.6 Hz, 1H), 3.73 (br s, 4H), 2.88 (br s, 4H). MS (ER+) m/z 324.1 (M+H).

Example 368.

N-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-2-(piperazin-1-yl)pyrimidin-4-amine

Step 1. Compound 4-(4-nitrophenyl)-1H-pyrrolo[2,3-b]pyridine (1 eq.), Fe powder (5 eq.) and NH4Cl (1.2 eq.) in ethanol:water mixture (5/1) was stirred at 90°C for 2 hours. The mixture was diluted with MeOH, filtered, and the solids were washed with MeOH. The filtrate was concentrated. The residue was dissolved in EtOAc and washed with water. The aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na ₂ SO ₄ and concentrated to give 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)aniline.

Step 2. Mixture of 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)aniline compound (1 eq.), 2,4dichloropyrimidine compound (1.3 eq.) and DIPEA (2 eq.) in n-BuOH was stirred at 100°C for 16 hours. The mixture was concentrated to give N-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-2chloropyrimidin-4-amine compound, which directly used in the next step.

Step 3. Mixture of N-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-2-chloropyrimidin-4-amine (1 eq.), tert-butyl piperazine-1- carboxylate (1.2 eq.) and DIPEA (2 eq.) in DMF (10.00 ml) were stirred at 110°C for 16 hours. The mixture was purified by preparative HPLC to give the compound tert-butyl 4-(4-( (4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)amino)pyrimidin-2-yl)piperazine-1carboxylate as a yellow solid.

Step 4. Mixture of the compound tert-butyl 4-(4-((4-(1H-pyrrolo[2,3-b]pyridin-4yl)phenyl)amino)pyrimidin-2-yl)piperazine-1-carboxylate (1 eq. .) in trifluoroacetic acid and DCM was stirred at 25°C for 2 hours. The final residue was purified by reverse phase preparative HPLC to give N-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl) phenyl)-2-(piperazin-1yl)pyrimidin-4-amine as a white solid (14%).

1H NMR (400 MHz, CD ₃ OD) δ 8.23 (d, J=4.8 Hz, 1H), 7.93 (d, J=6.0 Hz, 1H), 7.81-7.76 (m, 4H), 7.45 (d, J=3.6 Hz, 1H), 7.22 (d, J=5.2 Hz, 1H), 6.73 (d, J=3.6 Hz , 1H), 6.13 (d, J=5.6 Hz, 1H), 3.80 (t, J=5.2 Hz, 4H), 2.92 (t, J=5.2 Hz, 4H ). MS (ER+) m/e 372.1 (M+H).

Example 369.

N-(2-(piperazin-1 -yl)pyrimidin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-5-amine

The reaction was carried out following general protocol C. The final residue was purified by reverse phase preparative HPLC to give N-(2-(piperazin-1-yl)pyrimidin-4-yl)-1H-pyrrolo[2,3b]pyridin-5-amine in as a white solid (7%). MS (ER+) m/z 296.1 (M+H).

- 120 044043

Example 370.

N-(2-(1,4-diazepan-1-yl)pyrimidin-4-yl)-1 H-pyrrolo[2,3-b]pyridin-5-amine

The reaction was carried out following general protocol C. The final residue was purified by reverse phase preparative HPLC to give N-(2-(1,4-diazepan-1-yl)pyrimidin-4-yl)-1H-pyrrolo[2,3b]pyridin- 5-amine as a white solid (9%). MS (ER+) m/z 310.1 (M+H).

Example 371.

Ways.

Determination of ROCK inhibitory activity of a compound in vitro (Z'lyte assay): Recombinant proteins ROCK1 (amino acids 1-535) and ROCK2 (amino acids 1-552) were purchased from ThermoFisher Scientific. The activity of the compound was determined using the Z'-lyte kinase kit (ThermoFisher Scientific) and the IC50 was calculated.

Determination of ROCK inhibitory activity of compounds in A7R5 cells. A7R5 rat aortic smooth muscle cells were seeded at a density of 5000 cells/well in 96-well plates for 24 hours and then treated with the test compounds for 90 minutes. Cells were then fixed and processed according to the Intracellular Colorimetric ELISA kit manual (Thermo Scientific).

Analysis of NIH3T3 cells using an Acta2 promoter-driven luciferase reporter gene. An NIH3T3 cell line was created that stably expresses a luciferase reporter gene driven by the promoter of the human ACTA2 gene (-1000-1 bp) (NIH3T3-Acta2-luciferase). Cells were seeded to confluency and treated with test compounds plus TGFe1 for 24 h. Cells were then lysed and luciferase activity was measured using the LightSwitch Luciferase Kit from Active Motif.

Results.

The ROCK inhibitors of the invention effectively inhibited ROCK kinase activity in vitro and in cells.

As illustrated in FIG. 1a, ROCKi (Kadmon) at a concentration of less than 10 nanomoles effectively inhibited the activity of both ROCK isoforms in vitro as measured using the Z'-Lyte kit.

ELISA analysis was performed in A7R5 cells. A7R5 cells were treated with a 9-point 2-fold serial dilution of compounds and ppMlc levels (T18/S19) were determined to calculate cellular IC50 values of compounds. The compounds of the invention gave IC50 in cells of up to 100 nM. See fig. 1b.

A7R5 cells were treated with the compound from Example 192 for 90 min and ppMlc (T18/S19) levels were visualized by Western blotting. Example 192 at 110 nM effectively blocked phosphorylation of the ROCK targets MLC and MYPT1.

The in vitro activity of the compounds was determined using the Z'-lyte kinase kit (ThermoFisher Scientific). The percentage inhibition level was calculated by normalizing the kinase activity value obtained from treatment with 1 μM of the compound relative to the value of the DMSO control, and then plugging it into the formula [1-(compound/DMSO)] x 100%. IC50 was calculated using the fitted nonlinear regression curve function of GraphPad Prism software and kinase activity data obtained from treatment with 9-point 2-fold serial dilutions of compounds. The IC50 of pMLC in cells was calculated using data obtained from experiments with A7R5 cells. A7R5 cells were treated with a 9-point 2-fold serial dilution of compounds and ppMlc levels (T18/S19) were determined to calculate cellular IC50 values of compounds using the fitted nonlinear regression curve function of GraphPad Prism software. NIH3T3 cells stably expressing the ACTA2 promoter-driven luciferase gene were used to measure the functional IC50 significance of the compounds against ROCK in cells. Cells were seeded in 96-well plates until confluent and treated with a 9-point serial dilution of the compounds in combination in TGFe1 for 24 h. Luciferase activity was measured and the IC50 of the compounds was calculated using the fitted nonlinear regression curve function of GraphPad Prism software.

- 121 044043

The ex. No. % ING. ROCK2 @[conc.] IC50 ROCK2 (nM) % ING. ROCK1 @[conc.] IC50 ROCK1 (nM) % ING. pMLC A7R5 @[conc.] IC50 pMLC (nM), A7R5 NIH3T3A cta2-luc, IC50 (nM) 210 0 [3 µM] 41.9 [3 µM] 73.4 [10 µM] 589.0 202 88.3 [3 µM] 88.4 [3 µM] 13.8 [10 µM] 40 13.4 [10 µM] 41 >10000 9.96 [10 µM] 42 9.1 [10 µM] 225 98.3 [3 µM] 98 80.9 [3 µM] 78.0 [10 µM] 532.0 226 67.7 [10 µM] 227 83.4 [10 µM] 228 100.7 [3 µM] 3 98.5 [3 µM] 4 83.0 [10 µM] 69.0 151 229 77 81.0 [10 µM] 230 16.1 [10 µM] 232 103.7 [3 µM] 22 100.1 [3 µM] 75 93.0 [10 µM] 129.0 252 65.0 [10 µM] 1173.0 253 41.5 [10 µM] 255 72.0 [10 µM] 1355.0 256 84.5 [10 µM] 1557.0

- 122 044043

257 85.6 [10 µM] 2072.0 258 26.0 [10 µM] 224 48.0 [10 µM] 3348.0 3 54.4 [10 µM] 4 139 95.3 [10 µM] 312.0 5 102.3 [3 µM] 54 98.3 [3 µM] 86.0 [10 µM] 63.0 6 85.7 [1 µM] 94.6 [10 µM] 1800.0 7 96 [1 µM] 107 65 98.3 [10 µM] 460.0 8 83.3 [1 µM] 89.0 [10 µM] 1596.0 9 98.7 [1 µM] 93.5 [10 µM] 1200.0 10 98 [0.5 µM] 20 94 [0.5 µM] 90.0 [10 µM] 565.0 eleven 93 [0.5 µM] 31 76 [0.5 µM] 89.0 [10 µM] 1123.0 12 97.3 [1 µM] 95.0 [10 µM] 839.0 260 18.0 [10 µM] 261 74 [1 µM] 86.0 [10 µM] 1878.0 262 87.0 [10 µM] 3650.0

- 123 044043

263 101 [1 µM] 82.0 [10 µM] 1392.0 264 92.8 [1 µM] thirty 60.2 [10 µM] 514.0 265 71.2 [1 µM] 80.0 [10 µM] 1367.0 266 74.0 [10 µM] 3147.0 267 52.3 [1 µM] 70.0 [10 µM] 268 63.7 [10 µM] 3721.0 2 72.4 [10 µM] 2501.0 235 94.4 [1 µM] 54 510.0 236 80.8 [10 µM] 4688.0 237 104 63 68.2 [10 µM] 423.0 2348 238 17 55 70.0 [10 µM] 215.0 240 84.5 [1 µM] 78.1 [10 µM] 1108.0 241 85.2 [1 µM] 81.0 [10 µM] 954.0 203 98 [3 µM] 57 89.1 [3 µM] 46 63.5 [10 µM] 561 57 93.4 [3 µM] 17.4 [3 µM] 60.6 [10 µM] 1218 45 98.8 [3 µM] 649 99 [3 µM] 307 2121

- 124 044043

43 98.8 [3 µM] 120 99 [3 µM] 135 730 58 98.8 [3 µM] 144 99 [3 µM] 192 1079 239 100 [3 µM] > 1000 100 [3 µM] > 1000 6351 245 100 [3 µM] > 1000 100 [3 µM] > 1000 8222 247 100 [3 µM] 407 100 [3 µM] 132 1960 59 100 [3 µM] 902 100 [3 µM] 671 4778 60 100 [3 µM] 450 100 [3 µM] 660 3439 61 100 [3 µM] > 1000 100 [3 µM] > 1000 8166 62 100 [3 µM] 177.2 100 [3 µM] 179.3 1299 248 100 [3 µM] 43.92 100 [3 µM] 36.02 968 63 100 [3 µM] > 1000 100 [3 µM] > 1000 25130 249 > 1000 > 1000 33.6 [10 µM] 250 > 1000 > 1000 50.4 [10 µM] 5438 251 160 57 66.9 [10 µM] 614 271 > 1000 > 1000 28.3 [10 µM] 214 26 38 63 [10 µM] 323 1253

- 125 044043

215 37 40 68.5 [10 µM] 201 1221 1780 64 240 325 63.9 [10 µM] 1037 65 353 98 47.8 [10 µM] 1985 178 159 388 47.5 [10 µM] 706 18 206 332 eleven [10 µM] 179 77.6 [1 µM] 67.4 [10 µM] 1543 140 88 [1 µM] 63.5 [10 µM] 734 180 73.8 [1 µM] 62.6 [10 µM] 1455 204 85 20 70 [10 µM] 231 1780 205 61 55.05 [10 µM] 415 1275 91 47.9 [1 µM] 46.72 [10 µM] 141 54.87 [10 µM] 2892 142 37.45 [10 µM] thirty 90.6 [1 µM] 56.41 [10 µM] 1122 31 78.1 [1 µM] 57.97 [10 µM] 1854 181 36.50 [10 µM]

- 126 044043

182 30.22 [10 µM] 183 43.09 [10 µM] 184 34.13 [10 µM] 185 19.7 [1 µM] 41.60 [10 µM] 186 47.8 [1 µM] 47.72 [10 µM] 187 111 58 59.83 [10 µM] 665 108 47.29 [10 µM] 32 44.6 [1 µM] 53.71 [10 µM] 3949 47 33.1 [1 µM] 45.56 [10 µM] 48 51.08 [10 µM] 2579 49 50.6 [1 µM] 46.34 [10 µM] 92 19.64 [10 µM] 93 21.06 [10 µM] 94 19.25 [10 µM] 95 61 [1 µM] 46.73 [10 µM] 143 59.3 [1 µM] 49.78 [10 µM] 2151

- 127 044043

144 45.57 [10 µM] 145 42.36 [10 µM] 146 71.8 [1 µM] 50.24 [10 µM] 2063 188 44.9 [1 µM] 47.92 [10 µM] 96 27.2 [1 µM] 14.35 [10 µM] 109 68.4 [1 µM] 52.27 [10 µM] 1883 BY 67.5 [1 µM] 50.86 [10 µM] 1392 111 31.8 [1 µM] 43.98 [10 µM] 112 56.91 [10 µM] 1288 147 37.6 [1 µM] 47.8 [10 µM] 148 55.1 [1 µM] 46 [10 µM] 149 71.4 [1 µM] 49.4 [10 µM] 197 437 53.8 [10 µM] 581 13 58.1 [1 µM] 51.1 [10 µM] 1488 14 33.3 [1 µM] 48.9 [10 µM] 97 54 [1 µM] 52.5 [10 µM] 2337

- 128 044043

15 206 8 [1 µM] 198 — 26.4 [10 µM] 52.9 [10 µM] 519 16 32.1 [10 µM] 50 35.5 [10 µM] 51 29.3 [1 µM] 39.4 [10 µM] 98 0 [3 µM] 17.4 [10 µM] 19 4.6 [1 µM] 31.8 [10 µM] 20 37.6 [10 µM] 189 14 [0.5 µM] 18 [0.5 µM] 33.4 [10 µM] 637 52 29.5 [10 µM] 99 29.6 [10 µM] 113 58.1 [1 µM] 47.5 [10 µM] 2880 150 43.2 [1 µM] 44.4 [10 µM] 4971 207 91 [1 µM] 104 41 52.3 [10 µM] 351 1262 21 21.1 [10 µM] 151 87.4 [1 µM] 80 55.1 [10 µM]

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22 76.5 [1 µM] 54.2 [10 µM] 1390 190 41 [1 µM] 45.9 [10 µM] 114 82 [1 µM] 48.7 [10 µM] 115 64.2 [1 µM] 48.2 [10 µM] 152 77 [1 µM] 50.7 [10 µM] 1033 191 67 [1 µM] 50.6 [10 µM] 1852 100 47.5 [1 µM] 46.4 [10 µM] 116 81.9 [1 µM] 51.6 [10 µM] 1018 53 74.5 [1 µM] 51.3 [10 µM] 1718 23 29.5 [1 µM] 46.4 [10 µM] 208 135 49 58.3 [10 µM] 313 1512 90 73.8 [1 µM] 54.2 [10 µM] 2203 24 22.6 [10 µM] 25 52.9 [1 µM] 48.3 [10 µM] 101 19.2 [10 µM] 7527 102 48.5 [1 µM] 1095 43.5 [10 µM]

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54 58.5 [1 µM] 50.1 [10 µM] 1701 103 38.3 [10 µM] 55 83.3 [1 µM] 52.2 [10 µM] 998 199 151 49.6 [10 µM] 525 200 1.6 28 49.8 [10 µM] 275 1601 26 33.5 [1 µM] 39.9 [10 µM] 216 70 42.6 [1 µM] 517 1380 66 86.3 [1 µM] 380 17.5 [1 µM] 201 27 37 50.1 [1 µM] 168 1635 67 99.2 [1 µM] 45 31.4 [1 µM] 1363 27 71.3 [1 µM] 16.8 [1 µM] 117 45 15 50.6 [1 µM] 168 1274 68 294 35.4 [1 µM] 1009 69 52 [0.5 µM] 67 [0.5 µM] 19.3 [1 µM] 209 34 5 53.2 [1 µM] 47 332 192 12 5 53.5 [1 µM] 98 189

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104 82.9 [1 µM] 31.6 [1 µM] 997 105 53.9 [1 µM] 15.1 [1 µM] 217 28 6 51.2 [1 µM] 127 963 218 99.5 [1 µM] 65 53 [1 µM] 430 6113 193 84.4 [1 µM] 282 32.5 [1 µM] 788 106 34.1 [1 µM] 12.8 [1 µM] 153 556 23.8 [1 µM] 219 41 18 46.6 [1 µM] 77 613 154 98.5 [1 µM] 245 36.2 [1 µM] 433 2912 196 39 [0.5 µM] 37 [0.5 µM] 17.6 [1 µM] 56 87.1 [1 µM] 29 [1 µM] 155 82.1 [1 µM] 25 [1 µM] 220 5.9 3.1 45.1 [1 µM] 74 167 28 45 [1 µM] 11.8 [1 µM] 156 7.1 [1 µM] 157 89 27.2 [1 µM]

- 132 044043

221 3.7 39.6 [1 µM] 50 243 118 95.6 [1 µM] 90 32.9 [1 µM] 382 3727 211 103.8 [1 µM] 0.9 2.9 35.8 [1 µM] 66 437 119 90.1 [1 µM] 17.7 [1 µM] 212 91.9 [1 µM] 16.1 [1 µM] 120 93.1 [1 µM] 23.4 [1 µM] 158 -1.1 [1 µM] 121 -7.3 [1 µM] 70 -9.7 [1 µM] 159 -12.2 [1 µM] 71 -12.8 [1 µM] 107 98.3 [1 µM] 26 [1 µM] 194 98.3 [1 µM] 23 41 31.6 [1 µM] 176 1536 195 66 [1 µM] 405 -3.1 [1 µM] 213 101.2 [1 µM] 1.6 0.2 34 [1 µM] 60 230 122 -6.8 [1 µM]

- 133 044043

160 5.9 [1 µM] 161 2.6 [1 µM] 162 16.7 [1 µM] 163 -7.8 [1 µM] 164 -8.3 [1 µM] 165 -10.2 [1 µM] 72 -6.7 [1 µM] 73 -4.8 [1 µM] 74 2.7 [1 µM] 75 -8.7 [1 µM] 76 0 [1 µM] 77 -2.9 [1 µM] 123 -0.8 [1 µM] 124 -7.6 [1 µM] 125 0.7 [1 µM] 126 -12.3 [1 µM]

- 134 044043

127 -7.2 [1 µM] 128 -8.3 [1 µM] 29 102.4 [1 µM] 42 39.1 [1 µM] 147 1087 198 104.5 [1 µM] 5 4.1 38 [1 µM] 57 413 166 100.2 [1 µM] 34.3 [1 µM] 259 2043 167 88.2 [1 µM] 22.5 [1 µM] 168 12.2 [1 µM] 169 99.5 [1 µM] 30.9 [1 µM] 395 1832 170 99.1 [1 µM] 27 31.5 [1 µM] 274 572 78 99.1 [1 µM] 20.3 [1 µM] 79 9.8 [1 µM] 80 P,9 [1 µM] 81 13.2 [1 µM] 82 12 42.5 [1 µM] 572 3420 173 17.6 [1 µM] 1.3 [1 µM] 84 22.2 [1 µM] 0.7 [1 µM]

- 135 044043

174 35 26.3 [1 µM] 85 98 [1 µM] 17.3 [1 µM] 129 101.2 [1 µM] 18 50.6 [1 µM] 377 2918 130 93.4 [1 µM] 27.7 [1 µM] 131 74.1 [1 µM] 12.7 [1 µM] 132 81.8 [1 µM] 245 19.6 [1 µM] 133 15.2 [1 µM] 3.1 [1 µM] 134 eleven 29.9 [1 µM] 135 9.7 48.4 [1 µM] 400 2072 222 102.4 [1 µM] 4.9 58.2 [1 µM] 122 520 87 7.6 [1 µM] 5.8 [1 µM] 176 0 [3 µM] 14.5 [1 µM] 138 9.1 [1 µM] 15.2 [1 µM] 280 263 26.6 [1 µM] 284 thirty [0.5 µM] ND 25 [0.5 µM] 24.1 [1 µM] 283 101 [0.5 µM] <0.1 101 [0.5 µM] 25.8 [1 µM]

- 136044043

39 64 [0.5 µM] 67 [0.5 µM] 6.6 [1 µM] 277 3.7 63.4 [1 µM] 45 245 278 6.6 59.9 [1 µM] 199 1438 281 10 [0.5 µM] 2570 14 [0.5 µM] 10.4 [1 µM] 279 85 [0.5 µM] 40 76 [0.5 µM] 282 99 [0.5 µM] <0.1 101 [0.5 µM] 274 99 [0.5 µM] 0.4 101 [0.5 µM] 46 98 [0.5 µM] 1 98 [0.5 µM] 275 90 [0.5 µM] 1.2 95 [0.5 µM] 243 80 [0.5 µM] 56 67 [0.5 µM] 276 91 [0.5 µM] 2.3 88 [0.5 µM] 37 2873 7057 > 10,000 34 101.3 [3 µM] 29 101.7 [3 µM] 31 62.4 [10 µM] 393.0 35 98.9 [3 µM] 15 100 [3 µM] 16 68.1 [10 µM] 416.0 273 85.6 [3 µM] 89.1 [3 µM] 44.1 [10 µM] 272 85.8 [3 µM] 88.5 [3 µM] 53.3 [YumkM] 17 AND 2 [1 µM]

- 137 044043

38 63.1 [1 µM] 451 9.2 [1 µM] 44 72.7 [1 µM] 220 13.2 [1 µM] 83 2.1 [1 µM] 86 377.49 [1 µM] 88 13.8 [1 µM] 5.6 [1 µM] 89 12.7 [1 µM] 20.1 [1 µM] 136 1.1 [1 µM] 137 21.6 [1 µM] 24.4 [1 µM] 254 1230 16.24 [YumkM] 259 > 10000 6.48 [YumkM] 269 1653 -5.7,-7.2 [YumkM] 270 1426 -6.9,-8.9 [YumkM] 139 9.3 2.2 [1 µM] 171 -9.6 [1 µM] 172 -9.9 [1 µM] 175 10.5 [1 µM]

- 138044043

177 9.5 [1 µM] 10.2 [1 µM] 223 > 10000 15.76 [10 µM] 231 276 >10000 94.24, 63.4 [10 µM] 335 233 217 >10000 95.1 [10 µM] 712 234 1800 55.6 [10 µM] 242 747 41.2 [10 µM] 244 > 10000 0.8 [10 µM] 246 0 1.8 [10 µM] 33 > 10,000 292 10 [0.5 µM] 293 1 [0.5 µM] 294 0 [0.5 µM] 295 98 [0.5 µM] 45 646 2206 296 90 [0.5 µM] BY 860 3123 297 87 [0.5 µM] 84 1429 3791 298 75 1516 > 5000 299 70 [0.5 µM] 34 1196 > 10,000

- 139 044043

300 68 [0.5 µM] 54 > 10000 > 10,000 301 100 [0.5 µM] 0.4 16 178 302 98 [0.5 µM] 2.2 99 [0.5 µM] 35 229 303 257 > 10000 nd 304 17 413 980 305 83 [0.5 µM] 160 1411 3811 306 > 1000 > 10000 nd 307 2.6 977 2048 308 15 377 1241 309 117 917 3333 310 3.8 > 5000 > 5000 311 > 1000 N/A n/a 312 > 1000 n/a N/A 313 99 [0.5 µM] 14 94 [0.5 µM] 3033 314 94 [0.5 µM] 80 81 [0.5 µM] > 5000 > 5000 315 26 168 1949 316 85 [0.5 µM] 27 90 [0.5 µM] 2421 > 10000 317 75 [0.5 µM] 38 70 [0.5 µM] > 10,000 > 10,000 318 50 [0.5 µM] 319 100 [0.5 µM] 1.1 98 [0.5 µM] 18; 49 59 321 100 [0.5 µM] 8 98 [0.5 µM] 74 114

- 140 044043

322 29 [0.5 µM] 17 [0.5 µM] 320 97 [0.5 µM] 18 95 [0.5 µM] 8.7 >5000 > 5000 323 29 [0.5 µM] 17 [0.5 µM] 324 71 [0.5 µM] 268 2079 1373 325 25 [0.5 µM] 326 64 [0.5 µM] 305 6288 > 10,000 328 7 [0.5 µM] 8 [0.5 µM] 329 1.8 90 330 eleven 331 5.9 318 332 1.2 18 80 333 44 577 1597 334 121 889 1650 335 > 1000 336 103 [0.5 µM] 3.6 99 [0.5 µM] 25 116 337 > 1000 338 13 [0.5 µM] 3 [0.5 µM] 339 75 [0.5 µM] 211 56 [0.5 µM] 340 20 362 894 341 5.8 27 58 342 θ,ι 26 1950 343 5.6 127 223 344 1.7 82 192

- 141 044043

345 23.7 [10 µM] 346 > 10000 >10000 12.3 [10 µM] 349 4.21 [10 µM] 350 3700 14.81 [10 µM] 347 > 10000 16.96 [10 µM] 351 > 10000 7.8 [10 µM] 353 > 10000 25.55 [10 µM] 354 > 10000 6.4 [10 µM] 355 > 10000 21.93 [10 µM] 356 > 10000 6.59 [10 µM] 357 1900 6.35 [10 µM] 358 > 10000 24.32 [10 µM] 359 > 10000 21.75 [10 µM] 360 5200 1.69 [10 µM] 361 > 10000 2.02 [10 µM] 362 5.14 [10 µM] 363 10.22 [10 µM] 364 6.18 [10 µM] 365 > 10000 5.72 [10 µM] 366 4.95 [10 µM] 367 7.2 [10 µM] 368 1050 91.26 [10 µM] 1627 369 0.9 [10 µM] 370 6268 5.8 [10 µM]

- 142 044043

Example 372.

The ROCK inhibitors of the invention inhibited ROCK kinase-mediated polymerization

F-actin in cells.

The dynamic transition between monomeric globular (G-actin) and polymerized filamentous actin (F-actin) states in cells is driven primarily by the Rho/ROCK pathway. Inhibition of Rho GTPase or its effector kinase ROCK can lead to disruption of the filamentous actin structure of stress fibers in cells. In fig. Figure 2a illustrates that silencing ROCK expression in cultured fibroblasts by transfection of targeting siRNAs significantly reduced F-actin content. Pharmacological inhibition of ROCK activity in human CCD18lu lung fibroblasts using the ROCK inhibitor of the invention (Example 228) phenotypically replicated gene silencing as illustrated in FIG. 2b. This result highlights the importance of ROCK activity in regulating cellular actin dynamics and related nuclear signaling events.

Example 373.

The ROCK inhibitors of the invention prevent nuclear translocation of the fibrogenic transcriptional coactivator MKL1.

Monomeric G-actin binds to megakaryoblastic leukemia transcriptional coactivator 1 (MKL1 or MRTF) and prevents its nuclear translocation and transcriptional activation. Activation of the Rho/ROCK pathway reduces the amount of cellular G-actin by polymerizing into a filamentous form, leading to nuclear translocation of MKL1 and activation of MKL1-dependent serum response factor (SRF)-mediated gene expression.

The compound of Example 228 reduced the nuclear accumulation of MKL1 in cultured human lung fibroblasts. Human CCD18Lu lung fibroblasts were treated with ROCK inhibitor (3 μM) for 3 h, fixed, and stained with MKL1, F-actin, and DAPI. The ROCK inhibitor effectively abolished stress fiber formation while blocking the nuclear accumulation of MKL1. See fig. 3.

Example 374.

The ROCK inhibitors of the invention reduced the expression of profibrotic genes.

Expression of α-smooth muscle actin (aSMA or Acta2) by fibroblasts is a key marker indicating the transdifferentiation of fibroblasts into more profibrotic myofibroblasts, which are characterized by increased expression of fibrogenic factors such as connective tissue growth factor (CTGF) and collagen. Mechanotransduction along with fibrogenic cytokines, including TGFe signaling, lead to the expression of aSMA and are involved in the differentiation, proliferation and prolongation of myofibroblast survival.

As illustrated in FIG. 4a, ROCK inhibitor strongly inhibited stiff matrix-induced aSMA expression. HFF cells were cultured in Prime Coat plates coated with silicone gel of increasing stiffness (2 kPa or 30 kPa). Cells were treated with compounds for 24 h, and mRNA expression was quantified using Taqman qPCR.

TGFe1-induced aSMA expression was reduced by ROCK inhibitor. LL24 cells were treated for 24 h, and mRNA expression was quantified by Taqman qPCR. The ROCK inhibitor reduced basal as well as TGFe1-induced aSMA expression in human lung fibroblasts. See fig. 4b. Consistently, aSMA protein levels were reduced by longer incubation of ROCKi in a dose-dependent manner as seen in FIG. 4s. Human CCD18Lu lung fibroblasts were cultured on plastic substrate for 5 days with or without inhibitors. aSMA and control proteins were visualized by Western blotting.

ROCK inhibitors can be efficiently screened using a cell-based assay of the ACTA2 promoter-driven luciferase reporter gene. NIH3T3 cells stably expressing ACTA2 promoter-driven luciferase were seeded in 96-well plates until confluent and treated with a 9-point serial dilution of the compounds in combination in TGFe1 for 24 h. Luciferase activity was measured and the IC50 of the compounds was calculated. According to this analysis, many of the compounds of the invention gave IC50s of up to 200 nM. See fig. 4d.

Example 375.

ROCK inhibitors inhibited integrin-dependent latent activation of TGFe.

ROCK activity is required for ave6 integrin-mediated latent TGFe activation (Jenkins et al., 2006). Activation of the latent TGFe complex is a key step in regulating the bioavailability of this molecule and its subsequent activity. During tissue injury, cleavage of the cell membrane receptor protease-activated receptor 1 (par1) by extracellular proteases leads to activation of Rho/ROCK, which in turn activates ECM-associated TGFe via the cell membrane integrin ave6. Consequently, ROCK inhibition reduced par1 ligand thrombin-induced TGFe signaling in the ave6 integrin positive Detroit 562 cell line, as evidenced by decreased levels of phosphorylated smad2/3, as illustrated in FIG. 5. ανβ6 integrin positive Detroit 562 cells were seeded and treated with compounds in combination with the par1 ligand thrombin for 2 hours, lysed, and TGFe signaling was detected by phosphorylation of the Smad2/3 transcription factors.

Example 376.

ROCK inhibitors inhibited the expression of the extracellular matrix senescence protein CCN1.

Myofibroblasts isolated from the lungs of patients with IPF showed signs of aging. Although they were resistant to apoptotic signals, they had very active metabolism and continuously produced large amounts of ECM proteins (Kurundkar et al., 2016). In a fibrotic state driven by mechanotransduction and TGFe stimulation, aberrant myofibroblasts release the still poorly understood ECM-associated senescence proteins. One such protein is CCN1 (or CYR61).

Treatment of human lung fibroblasts with ROCK inhibitor upon induction of TGFe strongly inhibited the secretion of CCN1 proteins, as demonstrated by ELISA analysis of the cell culture medium, as illustrated in FIG. 6. CCD18Lu fibroblasts were treated with ROCK inhibitor in combination with TGFe for 40 hours. CCN1 content was measured using a human CCN1 ELISA kit from R&D Systems. These results suggest that ROCK inhibitors may attenuate prosurvival and aging signaling in myofibroblasts under fibrotic conditions.

Example 377.

ROCK inhibitors preserved the structural integrity of the epithelium and endothelium.

As fibrotic disease progresses, initial damage occurs in the epithelial layers of organs. Damaged epithelial cells undergo apoptosis, stimulate innate immune responses, and impair the function of the underlying vascular endothelial barrier. Nonvascular coagulation, caused by activation of the thrombin pathway, is a sign of tissue damage. Thus, protecting epithelial integrity, blocking thrombin-induced extravascular coagulation and related downstream signaling have important functions in preventing the initiation and spread of fibrosis.

Under conditions of shock due to calcium chelation, the ROCK inhibitors of the invention protected the integrity of polarized MDCK cells. See fig. 7a. MDCK cells were cultured at confluence for 3 days, and intracellular calcium was chelated by adding 5 mM EGTA under conditions with or without ROCK inhibitor. The integrity of cell junctions was visualized by immunofluorescent staining of the p120 adhesion molecule. Counter-staining of F-actin and nucleus was performed. ROCK inhibitors protected the integrity of epithelial junctions. See fig. 7a.

When stimulated with thrombin, the ROCK inhibitor (Example 228) effectively inhibited thrombin-induced phosphorylation of the contractile protein MLC in the endothelial cell line SVEC4-10. See fig. 7b. The murine endothelial cell line SVEC4-10 was cultured and treated with increasing doses of thrombin in combination with a ROCK inhibitor for 10 min. The ppMLC signal was detected by Western blotting. The ROCK inhibitor blocked thrombin-induced MLC phosphorylation. See fig. 7b. Together, the above data strongly confirm that the ROCK inhibitors of the invention are effective in fibrotic diseases.

Example 378.

Therapeutic efficacy of compounds in bleomycin-induced pulmonary fibrosis in mice.

Male C57B/L6 mice were kept for acclimatization for at least 7 days. After an acclimatization period, animals were randomly assigned to treatment groups. On day 0, mice were anesthetized with 5% isoflurane by inhalation for 10–15 min and then suspended by their anterior teeth from a wire attached to a fixed animal operating plate. 50 μl of saline or bleomycin was administered by intratracheal infusion. Mice in the treatment groups received an intratracheal infusion of 2.0 U/kg (mg/kg) bleomycin hydrochloride (BLM) in sterile saline. On day 7 after bleomycin administration, half of the animals in the basal solution treatment group were sacrificed to establish the baseline level of fibrosis at the start of treatment. Mice in the normal control group received saline po once a day, from day 7 to day 20. Mice in the treatment group received the compound orally once a day, from day 7 to day 20.

On day 20, 2-3 hours after the last dose, all mice were sacrificed. The lungs were gently washed through a tracheal cannula with 0.8 ml PBS containing 1% BSA and 0.6 mM EDTA. After washing, lung tissues were removed from each animal. Lung tissues were divided into 3 parts: the larger proportion of the right part was fixed in 10% neutral formalin for paraffin embedding and histopathology. The remaining right-hand portions were snap-frozen and protein lysates were prepared for target binding assays.

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Example 379.

Preventive efficacy of compounds against bleomycin-induced pulmonary fibrosis in mice.

Male C57B/L6 mice were ear-tagged and weighed before the start of the study. Animals from the treatment group were treated with the compound on day -1 before bleomycin administration and on all subsequent days after bleomycin administration. On day 0, animals from the disease groups received a dose of 1.5 U/kg bleomycin by the oropharyngeal route. The control group without bleomycin received sterile saline. The animals were closely monitored daily until the end of the study. On day 21 after bleomycin administration, all animals were sacrificed and blood, lungs, and bronchoalveolar lavage fluid (BAL) were obtained. Blood samples were used to obtain plasma; The total number of leukocytes in the BAL fluid was counted; and the lungs were fixed in 10% neutral buffered formalin for histopathological analysis.

Example 380.

A mouse model of ureteral obstruction (UO)-induced renal fibrosis.

Male C57B/L6 mice were anesthetized with isoflurane, placed in a flexed supine position, the abdominal area shaved, and prepared for surgery by alternately wiping with iodine- or chlorhexidine-70% isopropyl alcohol-soaked wipes. A small midline incision was made in the abdominal area, the left ureter was identified and cut out from the surrounding tissue. Double ligation was done (at a distance of 5 mm) directly below the left kidney, thus ligating the ureter. In the case of control animals, the ureter was identified and excised from the surrounding tissue, but not ligated. All animals were carefully observed for 3 days.

Beginning on day 0 and continuing until day 10, mice were dosed with the test compound or stock solution orally (PO) via gavage. Animals from the control drug group were dosed on days 0, 2, 4, 6 and 8. All animals were killed by CO ₂ asphyxia on the 10th day. After sacrifice, blood was collected for whole blood and plasma preparations, and both kidneys were removed, photographed, and weighed. Both kidneys were sectioned, fixed in 10% formaldehyde for histological analysis, and a portion was quickly frozen in liquid nitrogen and stored at -80°C. Formalin-fixed kidney sections were processed for standard histological evaluation. Longitudinal (coronal) sections were obtained from the samples and the slides were stained with hematoxylin and eosin and Masson's trichrome for histological examination of fibrosis.

Example 381.

A mouse model of histamine-induced vascular permeability.

7-8 week old female Balb/c mice were acclimatized for at least 3 days and randomly assigned to groups. Animals received an intravenous injection of 1% Evans blue at a dose of 100 μl/mouse. After 10 min, animals from the disease groups received an intradermal injection into the back of 1 μg of histamine in 20 μl of PBS and were sacrificed 20 min after injection. Animals from the control group were injected intradermally into the back of animals with 20 μl of PBS. Dosing of the base solution and test compounds was carried out through a gastric tube, respectively. The positive control salbutamol was administered 15 min before Evans blue.

Animals were sacrificed 20 min after histamine stimulation. The skin was then everted and the diameter of the lesions was measured. The area of lesions was calculated and expressed in square millimeters. After measuring the diameter, Evans blue dye was extracted from the skin tissue and the optical density was measured. Data were calculated relative to peak data on an Evans blue standard curve.

Example 382.

The ROCK inhibitor blocks the secretion of the inflammatory chemokine MCP-1 from endothelial cells.

Tissue damage-induced inflammation and wound healing responses aggravate the progression of fibrotic disease. Many fibrotic agents, including LPA and thrombin, not only activate the ROCK pathway in fibroblasts, but can also stimulate the release of cytokines and chemokines from endothelial cells to promote wound healing or the development of a fibrotic condition. Thus, inhibition of abnormal chemokine secretion is beneficial in the fight against fibrotic (and inflammatory) diseases. ROCK inhibitors could effectively block the increased secretion of MCP-1 in endothelial cells induced by exogenous factors. As shown in FIG. 8, increasing doses of ROCK inhibitor reduced MCP-1 detected in the cellular environment when murine endothelial cells SVEC4-10 were stimulated with LPA or thrombin in the presence of ROCK inhibitor for 24 h, as measured by ELISA. This highlights the potential application of ROCK inhibitors in the field of fibrotic and inflammatory diseases.

Example 383.

The ROCK inhibitor was effective in reducing some fibrotic parameters in a mouse model of bleomycin-induced pulmonary fibrosis.

- 145 044043

Given the potent antifibrotic cellular activity of the ROCK inhibitors of this invention, the ability of such inhibitors to reduce fibrosis in vivo has been assessed in several mouse disease models, including a model of bleomycin-induced pulmonary fibrosis. After intratracheal infusion of bleomycin, mice were orally administered ROCK inhibitor at a dose of 3 mg/kg, 10 mg/kg, or 30 mg/kg. Control animals received only the basic solution according to the same administration schedule once a day. After 20 days of treatment, the animals were sacrificed and the lungs were removed, weighed and fixed for histopathological evaluation. In fig. Figure 9a shows representative images of Masson's trichrome-stained lung sections at 10X magnification from each treatment group. While treatment groups still exhibited fibrous mass formation (arrowhead), alveolar septal thickening, and nodule-like formations (arrow), all were less severe compared to bleomycin-induced controls. (B = bronchiole). Overall, in this model, ROCK inhibitor improved lung architecture and collagen deposition in a dose-dependent manner. However, mice receiving doses > 10 mg/kg showed clear and statistically significant improvement.

Improvement in global lung fibrosis, percentage α-smooth muscle actin (aSMA) positive area, and total leukocyte count in bronchoalveolar lavage fluid were quantified by applying the Ashcroft grading scale to histopathological images, IGS quantification, and flow cytometry, respectively. Administration of >10 mg/kg ROCK inhibitor resulted in a significant reduction in fibrosis and less inflammatory leukocyte infiltration compared to basal-treated controls, as indicated by lower group mean fibrosis scores, aSMA-positive area, and total leukocyte counts in bronchoalveolar lavage fluid. . See fig. 9b.

Example 384.

ROCK inhibition is effective in reducing fibrosis scores when administered therapeutically in a mouse model of bleomycin-induced pulmonary fibrosis.

The activity of ROCK inhibitors in reducing pulmonary fibrosis at therapeutic dosing was assessed in a bleomycin-induced model following intratracheal infusion of bleomycin to induce lung tissue damage and subsequent pulmonary fibrosis. 7 days after bleomycin infusion, which ensured the development of fibrosis before treatment began, mice were treated with the compound or a control basal solution. All mice were sacrificed on day 20 and lungs were obtained. A large portion of the right lung was fixed in 10% neutral formaldehyde, sectioned, and stained with Masson's trichrome. Clear antifibrotic effects were observed in the 10 mg/kg and 30 mg/kg ROCK inhibitor treatment groups, as evidenced by lower collagen content and decreased Masson trichrome staining scores. See fig. 10a.

Improvement in overall pulmonary fibrosis was quantified for each animal in the control and treatment groups. See fig. 10b. Masson's trichrome-stained lung sections from individual mice are shown, with group averages and standard errors of the mean (SEM). The scores of normal control mice were 0. The amount of collagen in the lungs of mice treated with the compound of Example 192 was significantly less.

In addition to determining the therapeutic activity of ROCK inhibition in a model of pulmonary fibrosis, target binding and the extent of ROCK inhibition in the lungs of drug-treated animals were also determined. Protein extracts were prepared from snap-frozen lung samples, separated by SDS-PAGE, and analyzed by Western blotting. The expression levels of the direct target of ROCK kinase, phosphorylated myosin-binding subunit of myosin phosphatase (MYPT, pT853), and the ROCK pathway-regulated protein CCN1 were detected. Administration of the ROCK inhibitor of Example 192 blocked ROCK kinase activity in the lungs of bleomycin-treated mice, as indicated by decreased levels of phosphorylated MYPT and total CCN1 protein. Western blot results were quantified using Image J densitometry software. See FIG. 10s.

Example 385.

Administration of a ROCK inhibitor reduced the degree of fibrosis in a mouse model of ureteral obstruction (UO)-induced renal fibrosis.

To evaluate the activity of ROCK inhibitors in modulating fibrosis of accessory organs in vivo, the ROCK inhibitor was studied in an OM model of renal fibrosis. After surgical obstruction of the ureter, massive necrotic changes occur in the kidney along with the induction of fibrosis. The drug was administered via gastric tube in doses of 3 mg/kg twice daily, 6 mg/kg twice daily, and 10 mg/kg once daily, starting 2 hours before the ligation surgery. Animals were sacrificed on day 10 after surgery, and the degree of fibrosis was determined by histopathological analysis of fixed kidney sections stained with Masson's trichrome. The middle third of each kidney from the ROCK inhibitor or control groups was harvested, fixed in NBF, and processed for histopathology. See fig. 11a. The urinary part of the renal pelvis (U), medulla (M) and cortex (C) are labeled. Increased staining for collagen (arrows) is present between the tubules (interstitium) of the peripapillary zone near the urinary part and extends to the medulla.

Quantification of improvement in renal fibrosis after OM was performed by a pathologist blinded to group allocation based on individual image assessments. The scores assigned to each parameter in Masson's trichrome-stained sections of obstructed kidneys from individual mice, with group means and standard errors of the mean (SEM), are illustrated in FIG. 11b. Scores for each parameter in kidneys from mice in the sham-operated control group were 0. The amount of interstitial collagen (increased staining, interstitium) in obstructed kidneys was significantly lower (*p < 0.05 and **p < 0.01) in all groups treated with the ROCK inhibitor of Example 192. The improvement in the degree of renal fibrosis after treatment with the ROCK inhibitor suggests that in additional fibrotic indications, pharmacological manipulation of the ROCK signaling pathway may be beneficial.

Example 386.

Inhibition of ROCK stabilizes endothelial barrier function in a mouse model of histamine-induced vascular permeability.

In addition to damage to the organ epithelium, fibrotic diseases also cause damage to endothelial cells, leading to endothelial barrier destabilization and capillary leakage, which are hallmarks of fibrotic tissues. The ROCK signaling pathway is upregulated in damaged endothelial cells and leads to additional barrier destabilization and vascular leakage. The involvement of ROCK in the induction of vascular sweating led us to hypothesize that administration of a ROCK inhibitor may stabilize this vascular barrier function in vivo. We examined the efficacy of the blocking activity of a ROCK inhibitor following a single dose in a mouse model of histamine-induced dermal vascular sweating. In this model, intradermal injection of histamine rapidly induced sweating of Evans blue dye at the site of histamine injection. Administration of the ROCK inhibitor of Example 192 1 hour before histamine injection blocked histamine-induced vascular permeability in a dose-dependent manner, suggesting that in addition to antifibrotic activity, the ROCK inhibitors of this invention may also be used in diseases associated with induced vascular permeability. In fig. Figure 12a shows representative images of histamine-induced Evans blue dye sweating.

The degree of effectiveness of the compound was quantified by calculating the total area of the spot on the skin and the amount of Evans blue dye that penetrated the skin. Animals were sacrificed 20 min after histamine stimulation, and the diameter of the lesions was measured. The area of lesions was calculated and expressed in square millimeters. After measuring the diameter, Evans blue dye was extracted from the skin tissue and the optical density was measured. Data were calculated relative to peak data on an Evans blue standard curve. ** p < 0.01 compared with the basal solution group using one-way ANOVA followed by Dunnett's post hoc test. See fig. 12b.

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Laurent, G. J., Davis, G. E., Chambers, R. C., Matthay, M. A., and Sheppard, D. (2006). Ligation of protease-activated receptor 1 enhances alpha(v)beta6 integrin-dependent TGF-beta activation and promotes acute lung injury. J Clin Invest 116, 1606–1614.

Julian, L., and Olson, M.F. (2014). Rho-associated coiled coil containing kinases (ROCK): structure, regulation, and functions. Small GTPases 5, e29846.

Kurundkar, A.R., Kurundkar, D., Rangarajan, S., Locy, M.L.,

Zhou, Y., Liu, R.M., Zmijewski, J., and Thannickal, V.J. (2016). The matricellular protein CCN1 enhances TGF-betal/SMAD3-dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury. FASEB J 30, 2135-2150.

Moraes, C. (2015). Between a rock and a soft place: recent progress in understanding matrix mechanics. Integr Biol (Camb) 7, 736-739.

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Claims (3)

CLAIM 1. A compound having formula (IIj) where L ¹ represents CH; L ² represents N; R ² is selected from the group consisting of H, halogen, cyano, lower alkyl, C3-C6 cyclic alkyl, lower alkoxy and C ₁ -C ₃ -perfluoroalkyl; R ³ is selected from the group consisting of H, halogen, hydroxy, -NRR', cyano, lower alkyl, lower alkoxy and C ₁ -C ₃ -perfluoroalkyl; alternatively, R ² and R ³ together form a fused phenyl or a fused 5-6 membered ring having 0 to 3 ring heteroatoms, unsubstituted or substituted with -C(=O)-lower alkyl or lower alkyl; R ⁵ is selected from H, halogen, lower alkyl and lower alkoxy; R ⁶¹ represents H; each R is independently selected from H and lower alkyl; each R' is independently selected from H and lower alkyl; a selected from 1-10; and x is selected from 1-2; wherein the lower alkyl is C1- _C4 alkyl; lower alkoxy is -O-C ₁ -C ₄ -alkyl; and the heteroatom is nitrogen, oxygen or sulfur; or a pharmaceutically acceptable salt thereof. 2. Compound having formula (IIk) where R ² is selected from the group consisting of H, halogen, cyano, lower alkyl, C ₃ -C ₆ cyclic alkyl, lower alkoxy and C ₁ -C ₃ -perfluoroalkyl; R ³ is selected from the group consisting of H, halogen, hydroxy, -NRR', cyano, lower alkyl, lower alkoxy and C ₁ -C ₃ -perfluoroalkyl; alternatively, R ² and R ³ together form a fused phenyl or a fused 5-6 membered ring having 0 to 3 ring heteroatoms and unsubstituted or substituted with -C(=O)-lower alkyl or lower alkyl; R ⁵ is selected from H, halogen, lower alkyl and lower alkoxy; R ⁶¹ represents H; each R is independently selected from H and lower alkyl; each R' is independently selected from H and lower alkyl; a selected from 1-10; and x is selected from 1-2; wherein the lower alkyl is C1- _C4 alkyl; lower alkoxy is -O-C1-C ₄ -alkyl; and the heteroatom is nitrogen, oxygen or sulfur; or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 1 or 2, having the formula - 148 -