JAK1 selective inhibitors

Abstract

To provide compounds with selective JAK1 inhibition.SOLUTION: The invention provides a crystalline form of (R)-N-(3-(5-fluoro-2-(2-fluoro-3-(methylsulfonyl)phenylamino)pyrimidin-4-yl)-1H-indol-7-yl)-3-methoxy-2-(4-methylpiperazin-1-yl)propanamide represented by the structural formula in the figure, which has a powder x-ray diffraction pattern with characteristic peaks at 7.6, 12.7, 14.8, 19.3 and 25.5° 2-theta.SELECTED DRAWING: Figure 3

Description

[Background technology]

[0001] The JAK (Janus-associated kinase) family includes four non-receptor tyrosine kinases, JAK1, JAK2, JAK3, and Tyk2, which play important roles in cytokine- and growth factor-mediated signal transduction (Non-Patent Document 1). Kinase JAK1 interacts with receptors for type I interferons (e.g., IFN-α), type II interferons (e.g., IFN-γ), common gamma chain γc (e.g., IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21), and the interleukin-6 family (IL-10, IL-13, and IL-22), among others (Non-Patent Document 2). After binding of these cytokines to their receptors, receptor oligomerization occurs, which brings the cytoplasmic tails of associated JAK kinases into close proximity, promoting trans-phosphorylation and activation of tyrosine residues of JAK kinases. Phosphorylated JAK kinases bind to and activate various signal transducers and activators of transcription (STAT) proteins. These STAT proteins then dimerize and translocate to the nucleus, where they function as both signaling molecules and transcription factors, and ultimately bind to specific DNA sequences present in the promoters of cytokine-responsive genes (Non-Patent Document 3). Various immune deficiencies and autoimmune diseases, such as allergy, asthma, alopecia areata, graft (allogeneic) rejection, rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis, as well as solid and hematological cancers, arise from disruption of signal transduction in the JAK / STAT pathway. For example, see (Non-Patent Document 4), (Non-Patent Document 5), and (Non-Patent Document 6); (Non-Patent Document 7); (Non-Patent Document 8); (Non-Patent Document 9), (Non-Patent Document 10), and (Non-Patent Document 11).

[0002] An important element of JAK1 is its ability to pair with other JAK kinases at the intracellular domains of different subunits of the receptor. For example, JAK3 associates with the common γ chain (γc) of various cytokine receptors and pairs with JAK1 (Non-Patent Document 12). It has been shown that JAK1 is dominant over JAK3, and inhibition of JAK1 is sufficient to inactivate signaling by the common γ chain despite JAK3 activity (Non-Patent Document 13). Therefore, selective inhibition of JAK1 may be sufficient to treat some inflammatory and autoimmune diseases associated with cytokine signaling through the JAK1 / JAK3-STAT pathway. However, it has been a challenge to develop selective JAK1 inhibitors that have little or no off-target activity against other JAK kinases. Notably, compounds currently identified as JAK1-selective inhibitors in clinical development show only marginal JAK1 selectivity (Non-Patent Document 14). For example, the JAK1 / JAK2 selectivity ratios reported in biochemical assays for JAK1 inhibitors such as filgotinib (Non-Patent Document 15) and ABT-494 (Patent Document 1 - Figure 1), which are in active development for the treatment of autoimmune diseases, are approximately equal to the IC2 selectivity ratios measured at the Km of ATP. 50 2.8 based on the results of the present study. Therefore, it is expected that these compounds will have some target activity against other JAK kinases and therefore additional side effects that may be limited with more selective JAK1 inhibitors. Therefore, it is necessary to develop highly potent and selective JAK1 inhibitors that do not have any real or perceived side effects, such as anemia, associated with off-target activity to treat JAK1-related diseases, such as leukemia, lymphoma, transplant rejection (e.g., islet graft rejection, bone marrow transplant applications (e.g., graft-versus-host disease), autoimmune diseases (e.g., type 1 diabetes), and inflammation (e.g., asthma, allergic reactions). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2015061665 Brochure

Non-licensed literature

[0004] [Non-licensed document 1] Schindler C,and Darnell JE Jr.,Annu.Rev.Biochem.1995;64;621-651 [Non-licensed document 2] N Engl J Med 2013,368,161-170 [Non-licensed document 3] Leonard et al., (2000), J. Allergy Clin. Immunol. 105:877-888

Non-licensed Document 4

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Non-licensed Document 7

Non-licensed Document 8

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

[0005] The present disclosure relates to novel compounds with selective JAK1 inhibition. Thus, compounds of formula (I): [ka] (In the formula: R 1 , R 3 , and R 4 are each independently selected from hydrogen and methyl; R 2 is hydrogen, methyl, and -CH 2 CH 2 Selected from OH; n is 1 or 2; R 5 is methyl, ethyl, and -CH 2 OR 8 Selected from; R 6 is selected from methyl, chlorine, and fluorine; R 7 is selected from methyl, ethyl, and cyclopropyl; and R 8 is selected from methyl, ethyl, and benzyl; or a pharma- ceutically acceptable salt thereof is provided herein.

[0006] The disclosure also provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable diluent, excipient, or carrier.

[0007] Also disclosed is a method of treating a JAK1-associated disease (e.g., type 1 diabetes, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, COPD, vitiligo, and alopecia areata), comprising administering to a subject an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In another embodiment, disclosed is a use of a compound of formula (I) for treating a JAK1-associated disease, comprising administering to a subject an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In another embodiment, disclosed is a use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament or formulation for treating a JAK1-associated disease. In another embodiment, disclosed is a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof for treating a JAK1-associated disease.

[0008] Also disclosed is a method of inhibiting JAK1 in a subject, comprising administering to the subject an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In another embodiment, disclosed is the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof for inhibiting JAK1 in a subject, comprising administering to the subject an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In another embodiment, disclosed is the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament or formulation for inhibiting JAK1 in a subject. In another embodiment, disclosed is a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof for inhibiting JAK1 in a subject.

[0009] The disclosure also provides processes and intermediates useful in the preparation of compounds of formula (I). [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 depicts the powder X-ray diffraction diagram of the crystalline form of the title compound listed in Example 35. [Diagram 2]FIG. 2 depicts the Hair Index Score (HIS) of C3H / HeJ mice with established alopecia areata following treatment with 0.5 mg / kg of the compound of Example 35 compared to untreated mice. [Diagram 3] FIG. 3 depicts the percent reduction in eosinophils in bronchoalveolar lavage of OVA-exposed Brown Norway rats following treatment with the compound of Example 35 compared to exposed but untreated rats. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] compound In one embodiment, the compound of formula (I): [ka] (In the formula: R 1 , R 3 , and R 4 are each independently selected from hydrogen and methyl; R 2 is hydrogen, methyl, and -CH 2 CH 2 Selected from OH; n is 1 or 2; R 5 is methyl, ethyl, and -CH 2 OR 8 Selected from; R 6 is selected from methyl, chlorine, and fluorine; R 7 is selected from methyl, ethyl, and cyclopropyl; and R 8 is selected from methyl, ethyl, and benzyl; or a pharma- ceutically acceptable salt thereof is disclosed.

[0012] In some embodiments, R 1 ~R 4 Each of is independently selected from hydrogen and methyl.

[0013] In some embodiments, R 1 , R 3 , and R 4 are all hydrogen.

[0014] In some embodiments, n is 1.

[0015] In some embodiments, R 5 is methyl or -CH 2 OR 8 It is.

[0016] In some embodiments, R 6 is methyl or fluorine.

[0017] In some embodiments, R 7 is methyl.

[0018] In some embodiments, R 8 is methyl.

[0019] In at least one embodiment, R 1 , R 3 and R 4 is H;R 2 is methyl; R 6 is fluorine; R 7 is methyl; R 5 Ha-CH 2 OR 8 and R 8 is methyl.

[0020] In one embodiment, the compound of formula (I) is a compound of formula (Ia): [ka] (In the formula: R 1a , R 3a , and R 4a are each independently selected from hydrogen and methyl; R 2a is hydrogen, methyl, and -CH 2CH 2 Selected from OH; n is 1 or 2; R 5a is methyl, ethyl, and -CH 2 OR 8a Selected from; R 6a is selected from methyl, chlorine, and fluorine; R 7a is selected from methyl, ethyl, and cyclopropyl; and R 8a is selected from methyl, ethyl, and benzyl; or a pharma- ceutically acceptable salt thereof.

[0021] In some embodiments, R 1a ~R 4a Each of is independently selected from hydrogen and methyl.

[0022] In some embodiments, R 1a , R 3a , and R 4a are all hydrogen.

[0023] In some embodiments, n is 1.

[0024] In some embodiments, R 5a is methyl or -CH 2 OR 8a It is.

[0025] In some embodiments, R 6a is methyl or fluorine.

[0026] In some embodiments, R 7a is methyl.

[0027] In some embodiments, R 8a is methyl.

[0028] In at least one embodiment, R 1a , R3a and R 4a is H;R 2a is methyl; R 6a is fluorine; R 7a is methyl; R 5a Ha-CH 2 OR 8a and R 8a is methyl.

[0029] In one embodiment, the compound of formula (I) is a compound of formula (Ib): [ka] (In the formula: R 5b is methyl, ethyl, and -CH 2 OR 8b Selected from; R 6b is selected from methyl, chlorine, and fluorine; R 7b is selected from methyl, ethyl, and cyclopropyl; and R 8b is selected from methyl, ethyl, and benzyl; or a pharma- ceutically acceptable salt thereof.

[0030] In some embodiments, R 5b is methyl or -CH 2 OR 8b It is.

[0031] In some embodiments, R 6b is methyl or fluorine.

[0032] In some embodiments, R 7b is methyl.

[0033] In some embodiments, R 8b is methyl.

[0034] In at least one embodiment, R 6b is fluorine; R7b is methyl; R 5b Ha-CH 2 OR 8b and R 8b is methyl.

[0035] In some embodiments, a compound of Table 1 or a pharmaceutical salt thereof is disclosed.

[0036] [Table 1]

[0037] [Table 2]

[0038] [Table 3]

[0039] [Table 4]

[0040] [Table 5]

[0041] [Table 6]

[0042] [Table 7]

[0043] [Table 8]

[0044]

Table 9

[0045]

Table 10

[0046]

Table 11

[0047]

Table 12

[0048]

Table 13

[0049]

Table 14

[0050]

Table 15

[0051]

Table 16

[0052]

Table 17

[0053]

Table 18

[0054] The disclosed compounds of formula (I), (Ia), (Ib), or Table 1 can be prepared utilizing the methods and processes described herein. In one embodiment, the disclosed compounds of formula (I), (Ia), (Ib), or Table 1 are prepared according to the processes described in the Examples.

[0055] The compounds of formula (I), (Ia), (Ib), or Table 1 can exist in various stereoisomeric forms, and the present disclosure relates to each of the stereoisomeric forms that may exist in each compound and mixtures thereof, including racemates. It is understood that substituents may be attached to chiral centers of carbon atoms, and thus the disclosed compounds include enantiomers, diastereomers, and racemates. The term "enantiomer" includes a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture. The term is used to indicate a racemic mixture where appropriate. The term "diastereomer" or "diastereoisomer" includes stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is designated according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral center may be designated by R or S. Resolved compounds of unknown absolute configuration can be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) that they rotate plane polarized light at the wavelength of the sodium D line. Unless a structure or chemical name indicates chirality, the structure or name is intended to encompass any single stereoisomer corresponding to that structure or name as well as any mixture of stereoisomers, including racemates.

[0056] The term "pharmaceutically acceptable salts" includes acid addition salts which retain the biological effectiveness and properties of the compounds of Formula (I), (Ia), (Ib), or Table 1. Pharmaceutically acceptable salts may be formed with inorganic or organic acids and include acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, hydrogensulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, etc. Salts include, for example, salts of the following acids: lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, palmoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate, and trifluoroacetate. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, sulfosalicylic acid, and the like.

[0057] Pharmaceutically acceptable salts of the compounds of Formula (I), (Ia), (Ib), or Table 1 can be synthesized from a basic or acidic moiety by conventional chemical methods. Generally, such salts are prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (such as sodium hydroxide, carbonate, bicarbonate, etc.). + , Ca 2+ , Mg 2+ , or K +The free base forms of these compounds can be prepared by reacting with an appropriate acid such as ethyl acetate, ethanol, isopropanol, or the like, or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where feasible. Lists of additional suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences," 20th ed., Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0058] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds of formula (I), (Ia), (Ib), or Table 1. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of formula (I), (Ia), (Ib), or Table 1 include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 16 F, 31 P, 32 P, 35 S, 36 Cl, and 125 Compounds of formula (I), (Ia), (Ib), or Table 1 include 2 H, 3 H, 13 C, and 14These compounds may include various isotopically labeled compounds in which a radioactive isotope such as C is present. Isotopically labeled compounds of Formula (I), (Ia), (Ib), or Table 1 can generally be prepared by conventional techniques known to those of skill in the art, or by processes analogous to those described in the accompanying Examples, using the appropriate isotopically labeled reagent in place of the non-labeled reagent previously used.

[0059] Pharmaceutical Compositions The disclosure includes, in at least one embodiment, a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), or Table 1, and a pharma- ceutically acceptable excipient, carrier, or diluent.

[0060] The term "pharmaceutically acceptable excipient, carrier, or diluent" includes those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable excipients, carriers, and diluents are well known in the art, and the selection of the exact pharmaceutically acceptable excipient, carrier, and diluent will depend on the intended use and method of administration of the pharmaceutical composition.

[0061] The disclosed compositions may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, or intramuscular administration, or as a suppository for rectal administration).

[0062] The disclosed compositions can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents, and / or preservatives.

[0063] Suitable pharma- ceutically acceptable excipients for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate, or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid, or talc; preservatives such as ethyl or propyl p-hydroxybenzoate; and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or coated using conventional coating agents and procedures well known in the art to modify their disintegration in the gastrointestinal tract and subsequent absorption of the active ingredient or to improve their stability and / or appearance.

[0064] Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil, such as peanut oil, liquid paraffin, or olive oil.

[0065] Aqueous suspensions generally comprise the active ingredient in finely divided form, or in the form of nano- or micronized particles, in the presence of one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic; dispersing agents or wetting agents, such as lecithin or condensation products of alkylene oxides with fatty acids (e.g. polyoxethylene stearates), or condensation products of ethylene oxide with long chain aliphatic alcohols, such as heptadecaethyleneoxycetanoate; or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyoxyethylene sorbitol monooleate, or a condensation product of ethylene oxide with a long chain aliphatic alcohol, such as heptadecaethyleneoxycetanol, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyoxyethylene sorbitol monooleate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more of the following: a preservative, such as ethyl or propyl p-hydroxybenzoate; an antioxidant, such as ascorbic acid; a coloring agent; a flavoring agent; and / or a sweetening agent, such as sucrose, saccharin, or aspartame.

[0066] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil, such as liquid paraffin. Oily suspensions can also contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening and flavoring agents, such as those mentioned above, can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

[0067] Dispersible powders and granules suitable for preparing aqueous suspension by adding water generally contain an active ingredient together with a dispersing or wetting agent, a suspending agent, and one or more preservatives.Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.Additional excipients such as sweeteners, flavoring agents, and coloring agents may also be present.

[0068] The pharmaceutical composition may be in the form of an oil-in-water emulsion, the oil phase being a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or a mixture of any of these. Suitable emulsifiers may be, for example, natural gums such as gum arabic or gum tragacanth, natural phospholipids such as soybean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening agents, flavoring agents, and preservatives.

[0069] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension, which may be formulated according to known procedures using one or more of the suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.

[0070] Compositions for administration by inhalation and / or insufflation can be in the form of a conventional pressurized aerosol, which is configured to dispense active ingredient either as an aerosol containing finely divided solid or as liquid droplets.Conventional aerosol propellants such as volatile fluorohydrocarbons can be used, and the aerosol device is conveniently configured to dispense a metered amount of active ingredient.For further information on formulations, the reader is referred to Chapter 25.2, Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

[0071] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the host treated and the particular route of administration. For further information on routes of administration and Dosage Regimes, the reader is referred to Chapter 25.3, Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. For example, depending on the potency and physical properties of the compounds of formula (I), (Ia), (Ib) or Table 1 and their pharma- ceutically acceptable salts (i.e., active ingredients), pharmaceutical compositions that may be mentioned include those in which the active ingredient is present at least 1% (or at least 10%, at least 30%, or at least 50%) by weight. That is, the ratio of the active ingredient to other ingredients (i.e., the addition of excipients, carriers, and diluents) of the pharmaceutical composition is at least 1:99 (or at least 10:90, at least 30:70, or at least 50:50) by weight.

[0072] The compounds of formula (1), (Ia), (Ib), or Table 1 and pharma- ceutically acceptable salts thereof can be administered once, twice, three times per day, or as many times as medically necessary during a 24-hour period. Those skilled in the art can easily determine the amount of each individual dose based on the subject. In some embodiments, the compounds of formula (1), (Ia), (Ib), or Table 1 and pharma- ceutically acceptable salts thereof are administered in one dosage form, or in some embodiments, in multiple dosage forms.

[0073] method The compounds of formula (I), (Ia), (Ib), or Table 1, and their pharma- ceutically acceptable salts, may be useful in the treatment of conditions in which it is desired and / or required to inhibit JAK1 kinase and binding protein activity associated with JAK1 kinase, as may be shown, for example, in the tests exemplified below, and may therefore be useful in the treatment of conditions in which such inhibition is desired and / or required. Thus, the compounds of formula (I), (Ia), (Ib), or Table 1, and their pharma-ceutically acceptable salts, may be useful in the treatment of conditions in which it is desired and / or required to inhibit or reduce JAK1 kinase, or in some embodiments, in which it is desired and / or required to inhibit or reduce protein activity associated with JAK1 kinase. Thus, the compounds of formula (I), (Ia), (Ib), or Table 1, and their pharma-ceutically acceptable salts, are expected to be useful in the treatment of conditions that may benefit from inhibition of JAK1 kinase, such as respiratory diseases / disorders and / or inflammation and / or diseases having an inflammatory component.

[0074] Thus, in at least one embodiment, a method of inhibiting JAK1 kinase in a subject is disclosed, comprising administering to the subject an effective amount of a compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof.

[0075] In another embodiment, the use of a compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof, for inhibiting JAK1 kinase is disclosed.

[0076] In another embodiment, disclosed is the use of a compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting JAK1 kinase.

[0077] In yet another embodiment, a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof, for inhibiting JAK1 kinase is disclosed.

[0078] In at least one embodiment of the present disclosure, a compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof, has a JAK1 enzyme inhibitory activity (IC) of about 0.010 micromolar or less at a physiological ATP concentration of 5 mM. 50 In at least one other embodiment, the compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof, exhibits an inhibitory activity (IC) of about 0.050 micromolar or less in an IL-13-induced JAK-STAT6-luciferase cell assay. 50 ) is shown.

[0079] In another embodiment of the disclosure, a compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof, has a JAK1 enzyme inhibitory activity (IC) of about 0.010 micromolar or less at a physiological ATP concentration of 5 mM. 50 ) and exhibited JAK2 and JAK3 enzyme inhibitory activity of approximately 0.5 micromolar or more at a physiological ATP concentration of 5 mM (IC 50 In at least one other embodiment, the compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof, exhibits a JAK1 enzyme inhibitory activity (IC) of about 0.010 micromolar or less at a physiological ATP concentration of 5 mM. 50 ) and exhibited JAK2 and JAK3 enzyme inhibitory activity of approximately 0.5 micromolar or more at a physiological ATP concentration of 5 mM (IC 50 ) and showed inhibitory activity of approximately 0.050 micromolar or less in the IL-13-induced JAK-STAT6-luciferase cell assay (IC 50 ) is shown.

[0080] In another embodiment, a method of treating a JAK1 associated disease is disclosed, comprising administering to a subject an effective amount of a compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof.

[0081] In another embodiment, disclosed is a use of a compound of Formula (I), (Ia), (Ib), or Table 1 for treating a JAK1 associated disease, comprising administering to a subject an effective amount of a compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof.

[0082] In another embodiment, disclosed is the use of a compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament or formulation for treating a JAK1 associated disease.

[0083] In another embodiment, disclosed is the use of a compound of Formula (1), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a JAK-associated disease.

[0084] In another embodiment, a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof, for the treatment of a JAK1 associated disease is disclosed.

[0085] According to the present disclosure, the term "JAK1 associated disease" includes, for example, type 1 diabetes, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, COPD, vitiligo, and alopecia areata.

[0086] The compounds of formula (I), (Ia), (Ib), or Table 1, and pharma- ceutically acceptable salts thereof, can be administered in a variety of dosages depending on the route of administration. For example, oral doses can range from about 0.01 mg / kg of body weight per day (mg / kg / day) to about 100 mg / kg / day, such as about 0.01 to about 20 mg / kg / day, for example about 1.0 to about 15 mg / kg / day, for example about 12.5 mg / kg / day. Intravenous doses can range from about 0.5 mg / kg / day to about 50 mg / kg / day during constant rate infusion. Inhaled doses can range from about 0.0001 mg / kg / day to about 0.10000 mg / kg / day, such as about .0001 mg / kg / day to about 0.001 mg / kg / day, for example about 0.0006 mg / kg / day. Inhaled doses can also vary depending on the delivery device utilized. For example, the inhaled dose via a dry powder inhaler can range from about 0.010 mg / kg / day to about 0.020 mg / kg / day.

[0087] In any event, a physician, or person skilled in the art, will be able to determine the actual dosage which will be most suitable for an individual patient, but it is likely to vary with the route of administration, the type and severity of the condition being treated, and the species, age, weight, sex, renal function, hepatic function, and response of the particular patient being treated. The dosages set forth above are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

[0088] As used herein, the term "effective amount" includes an amount of a compound of Formula (I), (Ia), (Ib), or Table 1, or a pharmaceutical salt thereof, that elicits a biological or medical response in a subject, such as a reduction or inhibition of enzyme or protein activity associated with JAK1 and / or an amelioration of the symptoms of a JAK1-associated disease and / or a slowing or delay in the progression of a JAK1-associated disease. The effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of or feels an effect).

[0089] The term "subject" includes warm-blooded mammals, such as primates, cows, pigs, sheep, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, such as a human. In some embodiments, the subject suffers from a JAK1-associated disease. In some embodiments, the subject is in need of treatment (e.g., the subject would benefit biologically or medically from treatment).

[0090] The terms "inhibit", "inhibit", or "inhibiting" include a decrease in baseline activity of a biological activity or process. In some embodiments, a compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof, inhibits JAK1 kinase. In some embodiments, a compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof, is a selective JAK1 inhibitor. The term "selective JAK1 inhibitor" includes compounds of Formula (I), (Ia), (Ib), or Table 1, and pharma- ceutically acceptable salts thereof, that inhibit JAK1 but are inactive or have reduced activity against JAK2 or JAK3, or against both JAK2 and JAK3. Thus, in some embodiments, a compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof, inhibits JAK1 kinase but are inactive or have reduced activity against JAK2 or JAK3, or against both JAK2 and JAK3. For example, a compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof, has a JAK1 enzyme inhibitory activity (IC) of about 0.010 micromolar or less at a physiological ATP concentration of 5 mM. 50 ) and exhibited JAK2 and JAK3 enzyme inhibitory activity of approximately 0.5 micromolar or more at a physiological ATP concentration of 5 mM (IC 50 In at least one other embodiment, the compound of Formula (I), (Ia), (Ib), or Table 1, or a pharma- ceutically acceptable salt thereof, exhibits a JAK1 enzyme inhibitory activity (IC) of about 0.010 micromolar or less at a physiological ATP concentration of 5 mM. 50 ) and exhibited JAK2 and JAK3 enzyme inhibitory activity of approximately 0.5 micromolar or more at a physiological ATP concentration of 5 mM (IC50 ) and showed inhibitory activity of approximately 0.050 micromolar or less in the IL-13-induced JAK-STAT6-luciferase cell assay (IC 50 ) is shown.

[0091] The terms "treat," "treating," and "treatment" include reducing or inhibiting the activity of an enzyme or protein associated with JAK1 kinase, and ameliorating one or more symptoms of a JAK1-related disease in a subject, or slowing or delaying the progression of a JAK1-related disease in a subject. As such, the compounds of Formula (I), (Ia), (Ib), or Table 1, and pharma- ceutically acceptable salts thereof, are applicable to both therapeutic and / or prophylactic treatment of the above-mentioned conditions. EXAMPLES

[0092] The compounds of formula (I), (Ia), (Ib), or Table 1, and their pharma- ceutically acceptable salts, can be prepared using the methods and procedures described herein or by analogous methods and procedures. Where typical or exemplified process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, it will be recognized that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art.

[0093] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of suitable protecting groups for a particular functional group and suitable conditions for protection and deprotection are well known in the art. For example, many protecting groups and their introduction and removal are described in TW Greene and GM Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999 and references cited therein. The process for preparing the compounds of the present invention is provided as a further embodiment of the present invention and is illustrated by the following procedure. The stereochemical assignment of the isolated enantiomers was made based on the biological activity against JAK1 in the enzyme inhibition test as shown in Table 24.

[0094] Intermediate 1: 7-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole Process 1 A solution of NaOH (599 g, 14986.55 mmol) in water (1500 mL) was added over a period of 5 min under air to a stirred mixture of 7-nitro-1H-indole (243 g, 1498.65 mmol) and tetrabutylammonium hydrogen sulfate (50.9 g, 149.87 mmol) in DCM (3000 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 20 min. 4-Methylphenylsulfonyl chloride (371 g, 1948.25 mmol) was added under air and the resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with DCM (2000 mL) and diluted with water (2 x 500 mL), 10% K. 2 CO 3 The organic layer was washed successively with aqueous solution of NaCl (2×500 mL), 1M HCl (2×500 mL), and saturated NaCl (2×500 mL). 2 SO 4The precipitate was collected by filtration, washed with MTBE (1000 mL) and dried under vacuum to give 7-nitro-1-tosyl-1H-indole (402 g, 85%) as a white solid. 1 H NMR (300MHz, DMSO-d 6 )δ 2.39(s,3H),7.09(d,1H),7.40-7.55(m,3H),7.75-7.85(m,3H),7.95-8.00(m,1H),8.06(d,1H). m / z(ES+), [M+H] + =317.

[0095] Process 2 Bromine (81 mL, 1580 mmol) was dissolved in CCl 4 To 7-nitro-1-tosyl-1H-indole (50 g, 158 mmol) in 1000 mL of ethyl acetate was added dropwise. The resulting solution was stirred at 80° C. for 6 h. The mixture was cooled to room temperature, concentrated in vacuo, and the residue was washed with EtOAc to give 3-bromo-7-nitro-1-tosyl-1H-indole (53 g, 85%) as a brown solid. 1 H NMR (300MHz, DMSO-d 6 )δ 2.41(s,3H),7.55-7.62(m,2H),7.57(t,1H),7.85-7.92(m,3H),7.96(d,1H),8.49(s,1H). m / z(ES-), [MH] + =393.

[0096] Process 3 3-Bromo-7-nitro-1-tosyl-1H-indole (200 g, 506 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (193 g, 759 mmol), potassium acetate (99 g, 1012 mmol), and PdCl 2A solution of (dppf) (18.5 g, 25.3 mmol) in 1,4-dioxane (1500 mL) was degassed three times with nitrogen and the reaction mixture was stirred at 90 °C for 8 h. The mixture was cooled to room temperature and concentrated in vacuo. The solid was treated with water, filtered, washed with methanol, and dried in vacuo to give 7-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (150 g, 67%) as a grey solid. 1 H NMR (400 MHz, CDCl 3 )δ 1.41(s,12H),2.47(s,3H),7.38-7.43(m,3H),7.66(d,1H),7.87(d,2H),8.24(s,1H),8.29 -8.32(d,1H). m / z(ES+),[M+H] + =443.

[0097] Intermediate 2: 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1-tosyl-1H-indole 7-Nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole, intermediate 1 (50 g, 113 mmol) was placed in a 1 L reactor equipped with a condenser and nitrogen inlet. 2,4-Dichloro-5-methylpyrimidine (24 g, 147 mmol) and 2-methyltetrahydrofuran (200 mL, 4 volumes) were added to the reactor. A solution of potassium carbonate (46.9 g, 339 mmol) in water (10 mL, 2 volumes) was degassed and purged with N 2 The reactor was evacuated and backfilled (3×N 2 ), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct (4.62 g, 5.65 mmol) was added to the reaction mixture, degassed, and purified with N 2The mixture was backfilled again with ethyl acetate (3x) and then the reaction was slowly heated to 60°C. After 30 min a precipitate formed. The reaction was stirred for 1 h and the reactor temperature was set to 25°C. After 30 min cooling the internal temperature was 42°C and heptane (1 vol) was added. The reactor temperature was then set to +5°C. Water (4 vol) was added at 20°C and cooling was continued to +5°C for 1 h then stirred for 2 h. The reaction mixture was filtered on a Buchner funnel and the solid was washed with water (4 vol) and EtOAc (2 vol) to give a light yellow solid which was dried under a stream of nitrogen. The solid was stirred in EtOAc (1 vol), filtered and the resulting solid was dried under vacuum to give (42.8 g). The mother liquors were combined and evaporated in vacuum to give (20 g). 700 g of silica slurried in heptane was packed into a column (10x300 mm). The solids were dissolved in DCM, combined and loaded onto the column. After complete elution of DCM, the column was eluted with 20% EtOAc in heptane followed by a gradient of 20-50% EtOAc in heptane. The desired compounds were combined and evaporated in vacuo. The residue was slurried in 50% EtOAc in heptane (0.5 vol), filtered and dried under a stream of nitrogen to give 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1-tosyl-1H-indole (35.6 g, 71%) as a solid. 1 H NMR (400MHz, DMSO-d 6 )δ 2.40(s,3H),2.44(s,3H),7.54(d,2H),7.61(t,1H),7.91(d,2H),7.95-8.04(m,1H),8.40(dd,1H),8.62(s,1H),8.79(s,1H). m / z(ES+), [M+H] + =442.9.

[0098] Intermediate 3: 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1H-indole 3-(2-Chloro-5-methylpyrimidin-4-yl)-7-nitro-1-tosyl-1H-indole, intermediate 2 (2.477 g, 5.59 mmol) was dissolved in 1,4-dioxane / water (2:1) (75 mL) and 3.8 M sodium hydroxide (22 mL, 83.9 mmol) was added. The resulting reaction mixture was heated at 50° C. for 2 h. The reaction mixture was allowed to cool to room temperature and neutralized by the addition of 2 M HCl. The solid that formed was filtered off and extracted with EtOAc, Et 2 O and dried under vacuum to give 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1H-indole (1.894 g, 117% (wet)) as a solid. 1 H NMR (500MHz, DMSO-d 6 )δ 2.52(s,3H),7.47(t,1H),8.20(d,1H),8.25(d,1H),8.63(s,1H),8.90(d,1H),12.66(s,1H).m / z(ES+),[M+H] + =289.2.

[0099] Intermediate 4: 3-(2,5-dichloropyrimidin-4-yl)-7-nitro-1H-indole Process 1 PdCl 2 (dppf) * CH 2 Cl 2 (0.554 g, 0.68 mmol) was added to 7-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole, intermediate 1 (3.00 g, 6.78 mmol), 2,4,5-trichloropyrimidine (1.617 g, 8.82 mmol) and K in THF / water (4:1) (75 mL) at 25 °C. 2 CO 3 (2.81 g, 20.35 mmol) was added under nitrogen. The resulting mixture was stirred at 80° C. for 4 h. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (150 mL) and washed with brine (150 mL). The organic layer was extracted with Na 2 SO 4The mixture was dried at 70° C., filtered and evaporated in vacuo. The residue was purified by flash silica chromatography using a gradient of 8-30% EtOAc in petroleum ether as the mobile phase. Pure fractions were evaporated in vacuo and the residue was crystallized from acetonitrile to give 1-((4-chlorophenyl)sulfonyl)-3-(2,5-dichloropyrimidin-4-yl)-7-nitro-1H-indole (1.43 g, 43.4%) as a white solid. 1 H NMR (300MHz, DMSO-d 6 )δ 2.42(s,3H),7.52(d,2H),7.66(t,1H),7.91-8.14(m,3H),8.52(dd,1H),8.90(s,1H),9.08(s,1H). m / z(ES+), [M+H] + =463.

[0100] Process 2 A solution of NaOH (2.202 g, 55.05 mmol) in water (30 mL) was added to a stirred suspension of 3-(2,5-dichloropyrimidin-4-yl)-7-nitro-1-tosyl-1H-indole (1.7 g, 3.67 mmol) in 1,4-dioxane (30 mL) at 25° C. The resulting mixture was stirred at 50° C. for 1 h and then cooled to room temperature. The reaction mixture was diluted with EtOAc (200 mL) and diluted with water (50 mL), saturated NaHCO 3 (50 mL) and brine (50 mL). 2 SO 4 Drying at 40° C., filtration and evaporation in vacuo gave 3-(2,5-dichloropyrimidin-4-yl)-7-nitro-1H-indole, (0.500 g, 44.1%) as a yellow solid. 1 H NMR (300MHz, DMSO-d 6 )δ 7.34(t,1H),8.06(dd,1H),8.67(s,1H),8.78(s,1H),8.87(dd,1H). m / z(ES+), [M+H] + =309.

[0101] Intermediate 5: 2-Fluoro-3-(methylsulfonyl)aniline Process 1 Copper(I) iodide (1.002 g, 5.26 mmol) was added in one portion under nitrogen over a period of 1 min to 3-bromo-2-fluoroaniline (5 g, 26.31 mmol), N1,N2-dimethylethane-1,2-diamine (0.464 g, 5.26 mmol), and sodium iodide (7.89 g, 52.63 mmol) in 1,4-dioxane (10 mL) at 25 °C. The resulting suspension was stirred at 110 °C for 1 day. The reaction mixture was filtered through Celite and concentrated in vacuo. The crude product was purified by flash silica chromatography using a gradient of 5-30% EtOAc in petroleum ether as the mobile phase. Pure fractions were evaporated in vacuo to give 2-fluoro-3-iodoaniline (5.00 g, 80%) as a brown oil. 1 H NMR (400MHz, DMSO-d 6 )δ 5.32(bs,2H),6.59-6.83(m,2H),6.83-6.93(m,1H). m / z(ES+), [M+H] + =238.

[0102] Process 2 Copper(I) iodide (0.402 g, 2.11 mmol) was added to 2-fluoro-3-iodoaniline (5.00 g, 21.10 mmol), sodium methanesulfinate (3.23 g, 31.64 mmol), N1,N2-dimethylethane-1,2-diamine (0.558 g, 6.33 mmol) in DMSO (20 mL) under nitrogen. The resulting suspension was stirred at 95° C. for 18 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and evaporated in vacuo. The residue was purified by preparative TLC using EtOAc / petroleum ether (1:1) to give 2-fluoro-3-(methylsulfonyl)aniline (3.20 g, 80%) as a colorless oil that solidified upon standing. 1H NMR (400 MHz, CDCl 3 )δ 3.20(s,3H),3.96(bs,2H),6.97-7.13(m,2H),7.20-7.31(m,1H).m / z(ES+),[M+H] + =190.

[0103] The above procedure was repeated using the sulfinic acid salt indicated to give intermediate 6, as listed in Table 2.

[0104] [Table 19]

[0105] Intermediate 7: (3-bromo-2-fluorophenyl)(ethyl)sulfane Lithium diisopropylamide (17.14 mL, 34.29 mmol) was added dropwise over a period of 10 minutes to 1-bromo-2-fluorobenzene (5.00 g, 28.57 mmol) in THF (250 mL) at -78°C under nitrogen. The resulting mixture was stirred at -78°C for 60 minutes. 1,2-Diethyldisulfane (5.20 g, 42.54 mmol) was added dropwise over 20 minutes. The resulting mixture was stirred at -78°C for 60 minutes and then at room temperature overnight. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 250 mL). The combined organic extracts were washed with Na 2 SO 4 The mixture was dried at 70° C., filtered and evaporated in vacuo. The residue was purified by flash silica chromatography using a gradient of 0-10% EtOAc in pentane as eluent. The pure fractions were evaporated in vacuo to give (3-bromo-2-fluorophenyl)(ethyl)sulfane (5.27 g, 78%) as a colourless oil. 1 H NMR (300 MHz, CDCl 3 )1.32(t,3H),2.95(q,2H),6.90-7.04(m,1H),7.22-7.34(m,1H),7.35-7.47(m,1H).

[0106] Intermediate 8: tert-Butyl (3-(ethylthio)-2-fluorophenyl)carbamate (3-Bromo-2-fluorophenyl)(ethyl)sulfane, intermediate (4.14 g, 17.61 mmol) was added in one portion under nitrogen to cyclohexane-1,2-diamine (6.03 g, 52.82 mmol), phosphoric acid, potassium salt (3.74 g, 17.61 mmol), copper(I) iodide (8.38 g, 44.02 mmol), and tert-butyl carbamate (10.31 g, 88.04 mmol) in 1,4-dioxane (80 mL) at 25° C. The resulting mixture was stirred at 100° C. for 6 h and then allowed to cool to room temperature. The reaction mixture was filtered and evaporated in vacuo. The residue was purified by flash silica chromatography using a gradient of 0-10% EtOAc in pentane. Pure fractions were evaporated in vacuo to give tert-butyl (3-(ethylthio)-2-fluorophenyl)carbamate (1.412 g, 29.6%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ 1.31(t,3H),1.55(s,9H),2.94(q,2H),6.73(bs,1H),6.91-7.19(m,2H),7.92-8.05(m,1H).

[0107] Intermediate 9: tert-Butyl (3-(ethylsulfonyl)-2-fluorophenyl)carbamate tert-Butyl (3-(ethylthio)-2-fluorophenyl)carbamate, intermediate (1.4 g, 5.16 mmol) was added in one portion under nitrogen to 3-chlorobenzene-1-carboperoxyacid (2.67 g, 15.48 mmol) in DCM (15 mL) at 0° C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (50 mL), filtered and washed with saturated NaHCO 3 (2×50 mL) and brine (50 mL). 2 SO 4The mixture was dried at 70° C., filtered and evaporated in vacuo. The residue was purified by preparative TLC developed with petroleum ether / EtOAc (3:1) to give tert-butyl (3-(ethylsulfonyl)-2-fluorophenyl)carbamate, (1.650 g, 105%) as a yellow oil. m / z (ES-), [MH] + =302.

[0108] Intermediate 10: 3-(ethylsulfonyl)-2-fluoroaniline 2,2,2-Trifluoroacetic acid (10.0 g, 87.70 mmol) was added to tert-butyl (3-(ethylsulfonyl)-2-fluorophenyl)carbamate, intermediate 9 (1.65 g, 5.44 mmol) in DCM (20 mL) at 20° C. The resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was evaporated in vacuo, redissolved in DCM (50 mL) and washed with saturated NaHCO 3 (2×100 mL) and brine (100 mL). 2 SO 4 The mixture was dried at 40° C., filtered and evaporated in vacuo to give 3-(ethylsulfonyl)-2-fluoroaniline (0.786 g, 71.1%) as a yellow oil. 1 H NMR δ(CDCl 3 ,400MHz)δ 1.32(t,3H),3.32(q,2H),3.60-4.10(bs,2H),7.00-7.17(m,2H),7.17-7.34(m,1H).m / z(ES+),[M+H] + =204.

[0109] Intermediate 11: 3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine Process 1 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1-tosyl-1H-indole, intermediate 2 (20.0 g, 45.16 mmol), 2-fluoro-3-(methylsulfonyl)aniline hydrochloride, intermediate 5 (11.2 g, 49.68 mmol), cesium carbonate (30.9 g, 94.8 mmol), Pd2 (dba) 3 (4.14 g, 4.52 mmol) and 2'-(dicyclohexylphosphino)-N,N-dimethyl-[1,1'-biphenyl]-2-amine (3.55 g, 9.03 mmol) were placed in a 1 L reactor under nitrogen. 2-Methyltetrahydrofuran (200 mL) and water (100 mL) were added at room temperature. The reaction was degassed and flushed with N 2 (3x) and then backfilled at 72.5°C (T r =80°C) and stirred for 4 h (a brown precipitate formed after 3 h). Heptane (400 mL, 20 vol) was added, heating was stopped, and the reaction was cooled to 17°C over 30 min. The precipitate was stirred for 10 min and then filtered through a Buchner funnel. The filter cake was washed with water (2 vol x 3), EtOAc / heptane (1:2) (3 vol x 3) and then dried under vacuum / nitrogen to give N-(2-fluoro-3-(methylsulfonyl)phenyl)-5-methyl-4-(7-nitro-1-tosyl-1H-indol-3-yl)pyrimidin-2-amine (25.93 g, 96%) as a brown solid. Carried on without further purification. m / z (ES+), [M+H] + =596.2.

[0110] Process 2 A 1 L reactor was charged with 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1-tosyl-1H-indole (27.0 g, 45.3 mmol) at room temperature, 2-methyltetrahydrofuran (250 mL) and 3.8 M NaOH (aq) (250 mL) were added to give a brown insoluble mixture. The mixture was heated to 85° C. and stirred overnight. Heptane (10 vol) was charged to the reaction mixture, cooled to 17° C. over 40 min, and stirred for 30 min. The solid was filtered through a Buchner funnel and the filter cake was washed with water (3×40 mL). pH of the aqueous wash: 10-11 by pH paper. 40 mL of water was charged to the filter cake and slurried while adjusting the pH to 7 with 0.5 N HCl. The solid was filtered again through a Buchner funnel, washed with water (50 mL), dried under nitrogen / vacuum for 20 min, then washed with heptane / EtOAc (4×40 mL). (45% unreacted starting material by LCMS, compound was reacted again under the same conditions). The solid was placed in a 1 L reactor and 2-methyltetrahydrofuran (250 mL) and 3.8 M NaOH(aq) (250 mL) were added to give a brown insoluble mixture. The mixture was heated to 85° C. and stirred overnight. Heptane (10 vol) was charged to the reaction mixture, cooled to 17° C. over 40 min, and stirred for 30 min. The solid was filtered through a Buchner funnel and the filter cake was washed with water (3×40 mL). pH of aqueous wash: 10-11 by pH paper. 40 mL of water was charged to the filter cake and slurried while adjusting pH to 7 with 0.5 N HCl. The solid was again filtered through a Buchner funnel, washed with water (50 mL), dried under nitrogen / vacuum for 20 min, then washed with heptane / EtOAc (4×40 mL) and dried to give N-(2-fluoro-3-(methylsulfonyl)phenyl)-5-methyl-4-(7-nitro-1H-indol-3-yl)pyrimidin-2-amine (20.0 g, 100%). m / z(ES+), [M+H] + =442.1.

[0111] Process 3 N-(2-fluoro-3-(methylsulfonyl)phenyl)-5-methyl-4-(7-nitro-1H-indol-3-yl)pyrimidin-2-amine (11.0 g, 24.9 mmol) was placed in a 1 L reactor and 2-methyltetrahydrofuran / EtOH (2:1) (330 mL) was added. The reactor was heated to 80° C., stirred for 10 min for solubility, and then cooled slowly to 30° C. A solution of 10% Pd-C (2.00 g, 24.9 mmol, 50% wet) and ammonium formate (9.43 g, 149.5 mmol) in water (10 mL) (endothermic) was added at room temperature under nitrogen. The reaction mixture was slowly heated to 80° C. and stirred for 15 min. It was then allowed to cool to 40-50 °C, filtered through a Buchner funnel under nitrogen (causion), the cake washed with hot THF / EtOH (1:1) (50 mL), and the filtrate concentrated and co-evaporated in vacuo with DCM (50 mL) to give 3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine 10.0 g, 98%) as a brown solid. m / z(ES+), [M+H] + =412.4.

[0112] Intermediate 12: N-(3-(ethylsulfonyl)-2-fluorophenyl)-5-methyl-4-(7-nitro-1H-indol-3-yl)pyrimidin-2-amine Pd 2 (dba) 3(159 mg, 0.17 mmol) and 2'-(dicyclohexylphosphino)-N,N-dimethyl-[1,1'-biphenyl]-2-amine (136 mg, 0.35 mmol) were added under nitrogen to 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1H-indole, intermediate 3 (500 mg, 1.73 mmol), 3-(ethylsulfonyl)-2-fluoroaniline, intermediate (352 mg, 1.73 mmol), and cesium carbonate (1693 mg, 5.20 mmol) in DMF (15 mL) at 23° C. The resulting solution was stirred at 80° C. for 3 h. The reaction mixture was filtered through Celite and the solvent was evaporated in vacuo to give N-(3-(ethylsulfonyl)-2-fluorophenyl)-5-methyl-4-(7-nitro-1H-indol-3-yl)pyrimidin-2-amine (1.22 g, 155%) as a dark solid. Used without further purification. m / z (ES+), [M+H] + =456.

[0113] The above procedure was repeated using the starting intermediates indicated to give intermediates 13-14, as listed in Table 3:

[0114] [Table 20]

[0115] Intermediate 15: 3-(2-((3-(ethylsulfonyl)-2-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine N-(3-(ethylsulfonyl)-2-fluorophenyl)-5-methyl-4-(7-nitro-1H-indol-3-yl)pyrimidin-2-amine, intermediate (1.406 g, 3.09 mmol), ammonium chloride (0.991 g, 18.52 mmol), and iron (1.034 g, 18.52 mmol) in MeOH / THF / water (1:1:1) (75 mL) were stirred at 60° C. for 3 h. The reaction mixture was filtered through Celite and the solvent was removed under reduced pressure. The residue was purified by preparative TLC using DCM / MeOH (10:1) as eluent to give 3-(2-((3-(ethylsulfonyl)-2-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine (0.600 g, 46%) as a brown solid. 1 H NMR (300MHz, DMSO-d 6 )δ 1.11(t,3H),2.37(s,3H),3.33(q,2H),5.12(bs,2H),6.39(d,1H),6.74(t,1H),7.38(t,1H),7.44-7. 66(m,2H),7.94(d,1H),8.25(s,1H),8.34(t,1H),9.03(s,1H),11.34(s,1H).m / z(ES+),[M+H]+=426.

[0116] The above procedure was repeated using the starting intermediates indicated to give intermediates 16-17, as listed in Table 4:

[0117] [Table 21]

[0118] Intermediate 18: 3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-amine Process 1 A solution of potassium carbonate (40.9 mL, 678.28 mmol) was placed in a 1 L reactor equipped with a thermometer and a nitrogen inlet. The mixture was then rinsed three times with N 2The mixture was degassed with nitrogen at room temperature (23° C.). 7-Nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole, intermediate 1 (100 g, 226.09 mmol), 2,4-dichloro-5-fluoropyrimidine (49.1 g, 293.92 mmol), and methyl THF (1000 mL) were added and stirred at room temperature for 10 minutes. The resulting mixture was degassed three times with nitrogen. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct (9.23 g, 11.30 mmol) was added to the reaction mixture and the resulting mixture was degassed and backfilled again (3×N 2 ) and stirred at 23° C. overnight to give a yellow precipitate. Heptane (500 mL) was charged to the reaction mixture at room temperature and stirred for 10 min. Stirring was then stopped and the precipitate was allowed to settle. The reaction mixture was cooled to 5° C. and stirred for 1 h. The precipitate was filtered through a glass funnel and washed with water until the water reached a neutral pH (13 vol, displacement wash, 1.3 L). The filter cake was then washed with room temperature EtOAc / heptane mixture (1:1) (5×2 vol, 1 L), heptane (2×200 mL, 2×2 vol) and the solid was dried under vacuum at 35° C. overnight to give 3-(2-chloro-5-fluoropyrimidin-4-yl)-7-nitro-1-tosyl-1H-indole (97 g, 89% effective yield). 1 H NMR (400MHz, DMSO-d 6 )δ 2.41(s,3H),7.51(d,2H),7.69(t,1H),7.95(d,2H),8.01(dd,1H),8.75(d,1H),8.81(dd,1H),9.01(d,1H).m / z(ES+),[M+H] + =447.2.

[0119] Process 2 3-(2-chloro-5-fluoropyrimidin-4-yl)-7-nitro-1-tosyl-1H-indole (89.5 g, 200.30 mmol), 2-fluoro-3-(methylsulfonyl)aniline hydrochloride, intermediate 5 (54.2 g, 240.36 mmol), Pd 2 (dba) 3(9.17 g, 10.01 mmol), and 2'-(dicyclohexylphosphino)-N,N-dimethyl-[1,1'-biphenyl]-2-amine (7.88 g, 20.03 mmol) were added to a 2 L reactor under nitrogen. A degassed solution of 2-methyltetrahydrofuran (1000 mL) and cesium carbonate (137 g, 420.62 mmol) in water (450 mL) was added at room temperature and the reaction mixture was degassed (×7). The reaction was then heated to 72.6 °C and then stirred overnight. The reaction was cooled to 4-5 °C and stirred for at least 30 minutes. The solid was filtered through a Buchner funnel, washed with cold 2-methyltetrahydrofuran (300 mL, 3 volumes), water (3×300 mL, 3 volumes), and a mixture of EtOAc / heptane (1:2) (3×300 mL, 3 volumes), and dried under vacuum at 40° C. to give 5-fluoro-N-(2-fluoro-3-(methylsulfonyl)phenyl)-4-(7-nitro-1-tosyl-1H-indol-3-yl)pyrimidin-2-amine (77.89 g, 65% effective yield) as a brown solid. 1 H NMR (400MHz, DMSO-d 6 )δ 2.56-2.64(m,3H),3.42(d,3H),7.52-7.64(m,4H),7.73(t,1H),7.98-8.0 9(m,3H),8.22(t,1H),8.71(s,1H),8.79(d,1H),8.94(d,1H),9.89(s,1H). m / z(ES+), [M+H] + =600.2.

[0120] Process 3 5-Fluoro-N-(2-fluoro-3-(methylsulfonyl)phenyl)-4-(7-nitro-1-tosyl-1H-indol-3-yl)pyrimidin-2-amine (97.7 g, 129.87 mmol) was placed in a 5 L reactor at room temperature. A mixture of THF (100 mL) and 3.8 M NaOH (aq) (1000 mL) was added to give a brown insoluble mixture. The mixture was heated to 75° C. under reflux and stirred over the weekend. THF (10 vol) and heptane (10 vol) were charged to the reaction mixture. It was then allowed to cool to 17° C. over 40 min, stirred for 60 min, and the solid was filtered through a Buchner funnel. The filter cake was washed with 1 M citic acid (500 mL, until pH neutral), water (5×300 mL, until pH neutral), followed by heptane / EtOAc (4×400 mL). The solid was dried under vacuum to give 5-fluoro-N-(2-fluoro-3-(methylsulfonyl)phenyl)-4-(7-nitro-1H-indol-3-yl)pyrimidin-2-amine (55.0 g, 95%). 1 H NMR (400MHz, DMSO-d 6 )δ 3.27-3.38(m,3H),7.30(t,1H),7.47(t,1H),7.64(t,1H),8.11-8.29(m,3H),8.52(d,1H),8.98(d,1H),9.60(s,1H),12.57(s,1H). m / z(ES+), [M+H] + =446.2.

[0121] Process 4 To a stirred suspension of 5-fluoro-N-(2-fluoro-3-(methylsulfonyl)phenyl)-4-(7-nitro-1H-indol-3-yl)pyrimidin-2-amine (59.5 g, 123.5 mmol, 92.5 wt%) in THF / EtOH (2:1) (600 mL) at room temperature and under nitrogen was added a solution of 10% Pd / C (12.0 g, 123.5 mmol, 50% wet) and ammonium formate (46.8 g, 741.4 mmol) in water (50 mL). The reaction mixture was slowly heated to 70° C. and stirred for 30 min. 12 g of activated charcoal was added and the mixture was stirred for 15 min. The reaction mixture was cooled to 40° C. and filtered under nitrogen through a Buchner funnel (paper). The filter cake was washed with THF / EtOH (160 mL). The filtrate was concentrated to 4 volumes and the resulting slurry was cooled to room temperature and filtered under nitrogen. The solid was washed with water (2 volumes), ethanol (2 volumes) and dried under nitrogen / vacuum at 40° C. to give 3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-amine (44.3 g, 86%) as a light brown solid. 1 H NMR (400MHz, DMSO-d 6 )δ 3.28(s,3H),5.20(bs,2H),6.43(dd,1H),6.78(t,1H),7.44(t,1H),7.57-7.63(m,1H),7 .66(d,1H),8.09-8.25(m,2H),8.38(d,1H),9.34(s,1H),11.57(s,1H).m / z(ES+),[M+H] + =416.3.

[0122] Intermediate 19: 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole Sodium hydride (60% dispersion in mineral oil) (1.32 g, 33.10 mmol) was added in portions to a stirring yellow suspension of 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1H-indole, intermediate 3 (6.37 g, 22.07 mmol) in anhydrous THF (150 mL) at 0° C. After stirring for 25 min (gas evolution ceased) (2-(chloromethoxy)ethyl)trimethylsilane (4.10 mL, 23.17 mmol) was added dropwise rapidly. After 5 min, the cooling bath was removed and the reaction was left stirring at ambient temperature for 1.5 h. Additional sodium hydride (60% dispersion in mineral oil) (130 mg, 3.3 mmol) and (2-(chloromethoxy)ethyl)trimethylsilane (0.4 mL, 2.3 mmol) were added. The reaction was stirred for an additional 40 min and then saturated NaHCO 3 (aq) and the pale yellow mixture was quenched with Et 2 The layers were separated and the aqueous layer was diluted with Et 2 The combined organic layers were washed with brine and MgSO 4 The mixture was dried at 70° C., filtered and evaporated in vacuo. The residue was dissolved in chloroform and purified by automated silica gel flash chromatography using a 120 g column. 5% EtOAc in hexanes for 3 min followed by a gradient of 5-45% EtOAc in hexanes over 25 min was used as the mobile phase. The product was collected using a wavelength of 254 nm to give 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole (9.21 g, 100%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 )δ -0.16(s,9H)0.60-0.73(m,2H)2.51-2.52(m,3H)3.11-3.22(m,2H)5.72(s,2H)7.48(t,1H)7.94(d,1H)8.57(s,1H)8.64(s,1H)8.84(d,1H). m / z(ES+), [M+H] + =419.2.

[0123] Intermediate 20: 3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-amine Process 1 Cesium carbonate (2.333 g, 7.16 mmol) was dissolved in 3-(2-chloro-5-methylpyrimidin-4-yl)-7-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole, Intermediate 19 (1.0 g, 2.39 mmol), 2-fluoro-3-(methylsulfonyl)aniline, Intermediate 5 (0.542 g, 2.86 mmol), Pd in ​​DMF (20 mL) at 25 °C. 2 (dba) 3 (0.219 g, 0.24 mmol) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (Davephos) (0.188 g, 0.48 mmol) were added under nitrogen. The resulting mixture was stirred at 80 °C for 3 h and allowed to cool to room temperature. The reaction mixture was diluted with EtOAc (200 mL) and diluted with water (50 mL), saturated NaHCO 3 (50 mL), and brine (100 mL). 2 SO 4 The mixture was dried at 70° C., filtered and evaporated in vacuo. The residue was purified by flash silica chromatography using a gradient of 5-60% EtOAc in petroleum ether as the mobile phase. Pure fractions were evaporated in vacuo to give N-(2-fluoro-3-(methylsulfonyl)phenyl)-5-methyl-4-(7-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)pyrimidin-2-amine (0.940 g, 69%) as a yellow solid. 1 H NMR (300 MHz, CDCl 3)δ -0.08(s,9H),0.74-0.87(m,2H),2.44(s,3H),3.22-3.38(m,5H),5.67(s,2H),7.21-7.33(m,2H), 7.42(s,1H),7.48-7.60(m,1H),7.72(s,1H),7.89(d,1H),8.39(s,1H),8.62(d,1H),8.89(t,1H). m / z(ES+), [M+H] + =572.2.

[0124] Process 2 N-(2-fluoro-3-(methylsulfonyl)phenyl)-5-methyl-4-(7-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)pyrimidin-2-amine (2.76 g, 4.83 mmol), iron (11.59 g, 207.59 mmol), and ammonium hydrochloride (11.10 g, 207.59 mmol) were dissolved in MeOH / THF / water (1:1:1) (120 mL) and stirred at 70° C. for 4 h. The reaction mixture was allowed to cool to room temperature. The solids were filtered off and the filtrate was poured into water (200 mL) and extracted with DCM (8×40 mL). The combined organic extracts were filtered through a phase separator and evaporated in vacuo to give 3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-amine (2.52 g, 96%) as an orange gum. 1 H NMR (500MHz, DMSO-d 6 )δ -0.05(s,9H),0.87-0.93(m,2H),2.37(s,3H),3.22(s,3H),3.56-3.65(m,2H),5.05(s,2H),5.73(s,2H),6.53(d, 1H),6.78(t,1H),7.38(t,1H),7.53(d,1H),7.58(d,1H),8.03(s,1H),8.28(d,2H),9.13(s,1H).m / z(ES+),[M+H] + =542.3.

[0125] Intermediate 21: (S)-2-Bromo-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)propanamide DIPEA (0.679 mL, 3.89 mmol) was added in one portion to 3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine, intermediate (200 mg, 0.49 mmol) and (S)-2-bromopropanoic acid (149 mg, 0.97 mmol) in DMF (3 mL) at 25° C. The resulting solution was cooled to −40° C. and 1-propanephosphonic acid cyclic anhydride (619 mg, 0.97 mmol) was added dropwise at −40° C. and stirring was continued for 30 min. The reaction mixture was diluted with DCM (25 mL) and washed with brine (2×50 mL). The organic layer was extracted with Na 2 SO 4 The residue was purified by preparative TLC using MeOH / DCM (1:20) as eluent to give (S)-2-bromo-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)propanamide, (224 mg, 84%) as a brown solid. 1 H NMR (300MHz, DMSO-d 6 )δ 1.86(d,3H),2.42(s,3H),3.26(s,3H),4.78-4.90(m,1H),7.01(t,1H),7.38-7.52(m,2H),7.57(t,1H), 8.09(d,1H),8.18(d,1H),8.25-8.34(m,2H),9.21(s,1H),10.20(s,1H),11.37(s,1H).m / z(ES+),[M+H] + =546.

[0126] Intermediate 22: (R)-2-(4-methylpiperazin-1-yl)propanoic acid dihydrochloride Process 1 (S)-Methyl 2-hydroxypropanoate (250 g, 2.40 mol), DCM (1500 mL), and 2,6-dimethylpyridine (656.7 g, 6.13 mol) were placed in a 3000 mL four-neck round bottom flask and the mixture was cooled to -78°C. Trifluoromethanesulfonic anhydride (630 g, 2.23 mol) was added dropwise with stirring at -78°C, and the resulting solution was then stirred at room temperature for 3 h. The reaction mixture was diluted with water (1000 mL) and washed with 1M HCl (3 x 500 mL) and brine (1 x 500 mL). The organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried over 1000 mL, filtered, and concentrated in vacuo. The residue was then added dropwise to a stirred 3000 mL four-neck round bottom flask containing 1-methylpiperazine (213.3 g, 2.13 mol), DCM (800 mL), water (400 mL), and potassium carbonate (491.3 g, 3.53 mol) at 0° C. The resulting solution was stirred at room temperature overnight and then diluted with DCM (500 mL). The resulting mixture was washed with water (1×500 mL) and brine (500 mL). The organic phase was diluted with Na 2 SO 4 The mixture was dried at 70° C., filtered and concentrated in vacuo. The residue was purified by preparative silica gel chromatography using a gradient of 17-50% ethyl acetate in petroleum ether as the mobile phase to give (R)-methyl 2-(4-methylpiperazin-1-yl)propanoate (226 g, 68%) as a pale yellow oil. m / z (ES+), [M+H] + =187.

[0127] Process 2 In a 3000 mL four-neck round bottom flask was placed hydrogen chloride (2000 mL, 60.34 mol, 6 M / L) followed by (R)-methyl 2-(4-methylpiperazin-1-yl)propanoate (226 g, 1.21 mol). The resulting solution was stirred overnight at 100° C. and then concentrated in vacuo. The resulting mixture was diluted with acetonitrile (1000 mL) and the solid was collected by filtration. The product was recrystallized (×5) from ethanol (1 g / 20 mL) at room temperature to give (R)-2-(4-methylpiperazin-1-yl)propanoic acid dihydrochloride (124 g, 42%) as a white solid. 1 H NMR (300 MHZ, CD 3 OD)δ1.69-1.71(d,3H),3.04(s,3H),3.83(m,8H),4.35-4.42(m,1H). m / z(ES+),[M+H] + =173.

[0128] Intermediate 23: (R)-Methyl 2-((S)-3,4-dimethylpiperazin-1-yl)propanoate 2,6-Dimethylpyridine (0.672 mL, 5.77 mmol) was added to a cooled -78°C solution of (S)-methyl 2-hydroxypropanoate (500 mg, 4.81 mmol) in DCM (5 mL). The mixture was stirred for 5 min and then trifluoromethanesulfonic anhydride (0.974 mL, 5.77 mmol) was added dropwise. The reaction was stirred for 30 min, the cooling was removed and the reaction mixture was allowed to reach room temperature over 30 min. The solution was washed with 1M HCl (aq) (20 mL), dried through a phase separator and then added slowly to a mixture of (S)-1,2-dimethylpiperazine dihydrochloride (0.944 g, 5.05 mmol) and potassium carbonate (1.993 g, 14.42 mmol) in water (10 mL) suspended in DCM (10 mL). The reaction was stirred at room temperature for 18 h. The phases were allowed to separate. The organic phase was washed with brine (25 mL), dried by phase separator and evaporated in vacuo to give (R)-methyl 2-((S)-3,4-dimethylpiperazin-1-yl)propanoate (0.726 g, 75%) as a pale orange oil. 1H NMR (500 MHz, CDCl 3 )δ 1.05(d,3H),1.29(d,3H),2.1-2.25(m,2H),2.25-2.37(m,4H),2.46(t,1H),2.69-2.83(m,3H),3.28(q,1H),3.70(s,3H).

[0129] The above procedure was repeated using the amines indicated to give intermediates 24, as listed in Table 5:

[0130] [Table 22]

[0131] Intermediate 25: (R)-2-((S)-3,4-Dimethylpiperazin-1-yl)propanoic acid dihydrochloride (R)-Methyl 2-((S)-3,4-dimethylpiperazin-1-yl)propanoate, intermediate (726 mg, 3.62 mmol) was stirred at reflux in 6M HCl (6 mL, 36.00 mmol) for 16 h. (The reaction was dried). Water (6 mL) was added and stirred for 2 h. The reaction was cooled to room temperature and the solvent was concentrated in vacuo. The residue was suspended in acetonitrile and stirred at room temperature for 1 h. The solid was filtered off, washed with acetonitrile and dried in vacuo to give (R)-2-((S)-3,4-dimethylpiperazin-1-yl)propanoic acid dihydrochloride (626 mg, 66.6%) as a solid. 1 H NMR (500MHz, D 2 O)δ 1.33(d,3H),1.37-1.48(m,3H),2.88(s,3H),3.07-3.23(m,1H),3.28-3.85(m,7H).

[0132] The above procedure was repeated using the starting intermediates indicated to give intermediates 26, as set forth in Table 6:

[0133] [Table 23]

[0134] Intermediate 27: (R)-2-((R)-2,4-dimethylpiperazin-1-yl)propanoic acid dihydrochloride Process 1 2,6-Dimethylpyridine (0.868 mL, 7.45 mmol) was added to a cooled -78°C solution of (S)-methyl 2-hydroxypropanoate (0.646 g, 6.21 mmol) in DCM (10 mL). The mixture was stirred for 5 min and then trifluoromethanesulfonic anhydride (1.259 mL, 7.45 mmol) was added dropwise. The reaction was stirred for 45 min, the cooling was removed and the reaction mixture was allowed to reach room temperature and stirred for 1 h. The solution was washed with 1M HCl (aq) (20 mL), dried through a phase separator and concentrated in vacuo. The residue was dissolved in acetonitrile (5 mL) and added to a suspension of (R)-1,3-dimethylpiperazine dihydrochloride (1.22 g, 6.52 mmol) and potassium carbonate (2.57 g, 18.63 mmol) in acetonitrile (10 mL). The reaction was cooled to -78°C and stirred for 1 h. 2 The reaction was heated under atmosphere to 60° C. for 20 h. The reaction was cooled to room temperature, the solids were filtered off, washed with acetonitrile, and the filtrate was evaporated in vacuo. The residue was dissolved in DCM (10 mL) and 8% NaHCO 3 (aq) (10 mL), shaken and the phases separated. The aqueous phase was extracted with DCM (10 mL). The combined extracts were dried through a phase separator and evaporated in vacuo to give (R)-methyl 2-((R)-2,4-dimethylpiperazin-1-yl)propanoate (0.589 g, 47.4%, 80% de) as a pale oil. 1 H NMR (500MHz, DMSO-d 6 ) δ 0.94(d,3H), 1.06(d,3H), 1.82(t,1H), 2.03(t,1H), 2.10(s,3H), 2.37-2.55(m,3H), 2.55-2.67(m,2H), 3.61(s,3H), 3.66-3.74(m,1H). (The most abundant diastereoisomer is listed.)

[0135] Process 2 (R)-Methyl 2-((R)-2,4-dimethylpiperazin-1-yl)propanoate (589 mg, 2.94 mmol) was dissolved in 6 M HCl (aq) (5 mL, 30.00 mmol) and refluxed for 18 h. The reaction was cooled to room temperature and the solvent was evaporated in vacuo to a semi-solid residue. Diethyl ether was added to the residue and stirred for 30 min, the solid was filtered off and dried in vacuo to give (R)-2-((R)-2,4-dimethylpiperazin-1-yl)propanoic acid dihydrochloride (623 mg, 82%) as a pale solid. 1 H NMR (500MHz, D 2 O) δ 1.32(d,3H), 1.41(d,3H), 2.89(s,3H), 3.08-3.91(m,7H), 4.25-4.51(m,1H). (The most abundant diastereoisomer is listed.)

[0136] Intermediate 28: Methyl 3-methoxy-2-(4-methylpiperazin-1-yl)propanoate 1-Methylpiperazine (100 g, 988.4 mmol) and potassium carbonate (164 g, 1186 mmol) were slurried in dry acetonitrile (800 mL) under nitrogen. Methyl 2-bromo-3-methoxypropanoate (201 g, 988.4 mmol) was added to the slurry at 50-60° C. over a period of 40 min. The resulting mixture was heated at 61° C. under nitrogen for 23 h and then cooled to 20° C. The solids were filtered off. The filtrate was evaporated to an oily residue which was dissolved in 1M HCl (1000 mL). The pH was then adjusted to 1 with 4M HCl (approximately 300 mL). The resulting solution was extracted with DCM (200 mL). The aqueous solution was washed with saturated Na 2 CO 3 (1000 mL) and extracted with DCM (2 x 500 mL). The pH of the aqueous phase was then raised to 10-11 with sodium hydroxide and extracted with DCM (2 x 500 mL). The four organic phases were combined and evaporated in vacuo to give methyl 3-methoxy-2-(4-methylpiperazin-1-yl)propanoate (181 g, 85%). 1 H NMR (400 MHz, CDCl3 )δ 2.07(s,3H),2.14-2.34(m,4H),2.39-2.52(m,4H),3.14(s,3H),3.22(dd,1H),3.42(dd,1H),3.48-3.56(m,4H).

[0137] Intermediate 29: Methyl 2-(4-methylpiperazin-1-yl)propanoate Potassium carbonate (1.987 g, 14.38 mmol) was added to methyl 2-bromopropanoate (2.041 g, 12.22 mmol) and 1-methylpiperazine (1.20 g, 11.98 mmol) in acetonitrile (20 mL) at 20° C. under nitrogen. The resulting mixture was stirred at 60° C. for 18 h. The bright orange mixture was cooled to room temperature, diluted with ethyl acetate, and filtered. The orange solution was concentrated in vacuo. The residue was dissolved in diethyl ether and filtered. The filtrate was evaporated in vacuo to give methyl 2-(4-methylpiperazin-1-yl)propanoate, (2.2 g, 99%) as an oil. 1 H NMR (400 MHz, CDCl 3 )δ 1.23(dd,3H),2.21(d,3H),2.28-2.65(m,8H),3.16-3.27(m,1H),3.63(s,3H).m / z(ES+),[M+H] + =187.

[0138] Repeating the above procedure using the indicated reactants gave intermediates 30-44, as described in (Error! Reference source not found):

[0139] [Table 24]

[0140] [Table 25]

[0141] [Table 26]

[0142] [Table 27]

[0143] [Table 28]

[0144] [Table 29]

[0145] Intermediate 45: 2-(4-Methylpiperazin-1-yl)propanoic acid dihydrochloride Methyl 2-(4-methylpiperazin-1-yl)propanoate, intermediate 29 (6.00 g, 32.21 mmol) was added dropwise to 6M HCl (70 mL, 420.00 mmol) at 0° C. The resulting mixture was stirred at 100° C. for 12 h. The mixture was cooled to room temperature and washed with DCM (2×2000 mL). The aqueous phase was removed under reduced pressure to give 2-(4-methylpiperazin-1-yl)propanoic acid dihydrochloride (6.00 g, 76%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ 1.54(d,3H),2.83(s,3H),3.47-3.90(m,8H),4.25-4.45(m,1H),12.21(bs,1H).m / z(ES+),[M+H] + =173.

[0146] The above procedure was repeated using the starting intermediates indicated to give intermediates 46-47, as listed in Table 7:

[0147] [Table 30]

[0148] Intermediate 48: Lithium 3-methoxy-2-(4-methylpiperazin-1-yl)propanoate A solution of lithium hydroxide (0.321 g, 13.39 mmol) in water (5 mL) was added to a solution of methyl 3-methoxy-2-(4-methylpiperazin-1-yl)propanoate, intermediate 28 (1.93 g, 8.92 mmol) in THF (5 mL). A few drops of MeOH were added until the reaction mixture became clear. The reaction was heated at 40° C. for 24 h. The organic liquid was evaporated in vacuo. The residue was diluted with water and lyophilized (×3) to give lithium 3-methoxy-2-(4-methylpiperazin-1-yl)propanoate (1.92 g, 103%) as a solid. 1 H NMR (500MHz, D 2 O)δ 2.06(s,3H),2.48(bs,8H),2.99(t,1H),3.20(s,3H),3.46-3.57(m,2H).

[0149] The above procedure was repeated using the starting intermediates indicated to give intermediates 49-59 as listed in Table 8:

[0150] [Table 31]

[0151] [Table 32]

[0152] [Table 33]

[0153] Intermediate 60: (S)-Methyl 3-ethoxy-2-hydroxypropanoate Magnesium trifluoromethanesulfonate (1.577 g, 4.90 mmol) was added to (S)-methyloxirane-2-carboxylate (2.00 g, 19.59 mmol) dissolved in ethanol (10 mL) at 25° C. under nitrogen. The resulting mixture was stirred at 50° C. for 30 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc (50 mL) and washed with brine (25 mL). The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and evaporated in vacuo. The residue was purified by preparative TLC using EtOAc / petroleum ether (1:1) to give (S)-methyl 3-ethoxy-2-hydroxypropanoate (1.788 g, 61.6%) as a colorless oil. 1 H NMR (300 MHz, CDCl 3 )δ 1.20(t,3H),2.46(bs,1H),3.45-3.67(m,2H),3.74(d,2H),3.83(s,3H),4.19-4.41(m,1H).m / z(ES+),[M+H] + =203.

[0154] Intermediate 61: (S)-Methyl 3-ethoxy-2-(((trifluoromethyl)sulfonyl)oxy)propanoate 2,6-Dimethylpyridine (1.643 mL, 14.11 mmol) was added to (S)-methyl 3-ethoxy-2-hydroxypropanoate, intermediate 60 (1.9 g, 12.82 mmol) in DCM (30 mL) at -78 °C under nitrogen. After again maintaining complete cooling, trifluoromethanesulfonic anhydride (2.341 mL, 14.11 mmol) was added dropwise over 1 h via syringe pump. The resulting solution was stirred at -78 °C for 30 min, subsequently warmed to room temperature and stirred for an additional 1 h. The reaction mixture was diluted with DCM (100 mL), washed with 1 M HCL (75 mL) and the organic phase was dried under vacuum to give (S)-methyl 3-ethoxy-2-(((trifluoromethyl)sulfonyl)oxy)propanoate (3.30 g, 92%) as a light brown oil. 1 H NMR (300 MHz, CDCl3 )δ 1.23(t,3H),3.48-3.75(m,2H),3.82-4.01(m,3H),4.23-4.46(m,2H),5.22-5.36(m,1H).

[0155] Intermediate 62: (R)-Methyl 3-ethoxy-2-(4-methylpiperazin-1-yl)propanoate Potassium carbonate (3.26 g, 23.55 mmol) was dissolved in water (420 mL) and added dropwise over a period of 5 min to a solution of (S)-methyl 3-ethoxy-2-(((trifluoromethyl)sulfonyl)oxy)propanoate, Intermediate 61 (3.3 g, 11.78 mmol) and 1-methylpiperazine (1.769 g, 17.66 mmol) in DCM (15 mL) at 0° C. The resulting mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with DCM (500 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was concentrated to Na 2 SO 4 The mixture was dried at 40° C., filtered and evaporated in vacuo. The residue was purified by preparative TLC using petroleum ether / EtOAc (1:1) to give (R)-methyl 3-ethoxy-2-(4-methylpiperazin-1-yl)propanoate (2.40 g, 88%) as a yellow oil. 1 H NMR (300 MHz, CDCl 3 )δ 1.18(t,3H),2.30(s,3H),2.36-2.60(m,4H),2.60-2.79(m,4H),3.35-3.60(m,3H),3.61-3.84(m,4H),4.21(q,1H). m / z(ES+), [M+H] + =231.

[0156] Intermediate 63: (R)-3-ethoxy-2-(4-methylpiperazin-1-yl)propanoic acid lithium salt Lithium hydroxide (204 mg, 8.51 mmol) in water (6 mL) was added to (R)-methyl 3-ethoxy-2-(4-methylpiperazin-1-yl)propanoate, intermediate 62 (980 mg, 4.26 mmol) in THF / MeOH (1:1) (12 mL) at 25° C. The resulting solution was stirred at room temperature for 15 h. The solvent was removed under reduced pressure. The residue was diluted with MeOH (50 mL), washed with petroleum ether (2×50 mL), and evaporated in vacuo to give (R)-3-ethoxy-2-(4-methylpiperazin-1-yl)propanoic acid (421 mg, 45.7%). 1 H NMR (300 MHz, CDCl 3 )δ 1.19(t,3H),2.27(s,3H),2.34-2.78(m,8H),2.97-3.08(m,1H),3.42-3.59(m,2H),3.70(dd,1H),3.76-3.87(m,1H).m / z(ES+),[M+H] + =217.

[0157] Intermediate 64: Sodium 3-(benzyloxy)-2-(4-methylpiperazin-1-yl)propanoate Process 1 In a round bottom flask equipped with a thermometer, (S)-2-amino-3-(benzyloxy)propanoic acid (3.00 g, 15.37 mmol) was dissolved in sulfuric acid (18.44 mL, 36.88 mmol) and cooled to 0° C. with an ice bath. A solution of sodium nitrite (1.696 g, 24.59 mmol) in water (10 mL) was added in small portions over 60 min, keeping the internal temperature below 3° C. The reaction mixture was stirred at 0° C. and allowed to warm slowly to room temperature overnight. NaOH (50%, aq., w / w, 2.8 mL) was added until pH 4. Ethyl acetate (25 mL) was then added and 2M H 2 SO 4 The reaction mixture was stirred vigorously while the pH was lowered to pH 3 by addition of (aqueous). The phases were separated and the aqueous phase was extracted with EtOAc (3×25 mL). The combined organic phases were washed with MgSO 4The extract was dried over rt, filtered through a phase separator and concentrated in vacuo to give (S)-3-(benzyloxy)-2-hydroxypropanoic acid (2.55 g, 85%, 98.0% ee). 1 H NMR (500 MHz, CDCl 3 ) δ 3.78 (dd, 1H), 3.83 (dd, 1H), 4.37 (t, 1H), 4.61 (d, 2H), 7.28-7.4 (m, 5H). No exchangeable protons observed.

[0158] Process 2 Acetyl chloride (4.28 mL, 60.14 mmol) was added dropwise to cold methanol (14 mL) at 0° C. in an ice bath. The mixture was stirred at 0° C. for 5 min and then transferred to a solution of (S)-3-(benzyloxy)-2-hydroxypropanoic acid (2.36 g, 12.03 mmol) in methanol (14.00 mL) at 0° C. The resulting mixture was stirred at room temperature for 40 min. Trimethyl orthoformate (2.66 mL, 24.06 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 50 g column using 50% EtOA in heptane as the mobile phase over 12 CV. The compounds were detected using a wavelength of 257 nm. The product was collected and evaporated in vacuo to give (S)-methyl 3-(benzyloxy)-2-hydroxypropanoate (1.94 g, 77%). 1 H NMR (500 MHz, CDCl 3 )δ 3.04(d,1H),3.76(d,2H),3.79(s,3H),4.31-4.36(m,1H),4.54(d,1H),4.61(d,1H),7.27-7.37(m,5H).

[0159] Process 3 Trifluoromethanesulfonic anhydride (1.543 mL, 9.13 mmol) was added dropwise to a cold solution of (S)-methyl 3-(benzyloxy)-2-hydroxypropanoate (1.92 g, 9.13 mmol) and DIPEA (1.595 mL, 9.13 mmol) in toluene (20 mL) at 0° C. in an ice bath. The reaction was stirred at 25° C. for 30 min and then cooled to −78° C. A mixture of 1-methylpiperazine (1.013 mL, 9.13 mmol) and DIPEA (1.595 mL, 9.13 mmol) in toluene (20 mL) was added (keeping the temperature below −70° C.). The reaction mixture was stirred overnight with cooling, during which time the cooling bath had reached −40° C. The reaction mixture was allowed to warm to room temperature, filtered, and concentrated in vacuo. The residue was purified using 66% EtOAc in heptane over 12 CV as the mobile phase followed by 0.2M NH 3 over 10 CV. The product was detected using a wavelength of 250 nm. The product fractions were collected and evaporated in vacuo to give (R)-methyl 3-(benzyloxy)-2-(4-methylpiperazin-1-yl)propanoate (1.32 g, 66%, 96.0% ee). 1 H NMR (500 MHz, CDCl 3 )δ 2.42(s,3H),2.5-2.71(m,4H),2.71-2.83(m,4H),3.49(t,1H),3.66-3.7 4(m,4H),3.78(dd,1H),4.53(dd,2H),7.24-7.39(m,5H).m / z(ES+),[M+H] + =293.6.

[0160] Process 4 (R)-Methyl 3-(benzyloxy)-2-(4-methylpiperazin-1-yl)propanoate (308 mg, 1.05 mmol) was dissolved in methanol (1.5 mL) and 1 M aqueous sodium hydroxide (1.05 mL) and stirred at room temperature for 16 h. Additional 1 M aqueous sodium hydroxide (0.2 mL) was added and the reaction mixture was stirred for an additional 2 h at room temperature and 3 h at 45° C. The reaction was then allowed to reach room temperature, diluted with water (5 mL) and lyophilized to give crude sodium 3-(benzyloxy)-2-(4-methylpiperazin-1-yl)propanoate (356 mg) as a solid. 1 H NMR (500MHz, DMSO-d 6 )δ 2.10(s,3H),2.16-2.34(m,4H),2.52-2.63(m,4H),2.91(dd,1H),3.58(dd,1H),3.6 5(dd,1H),4.39-4.48(m,2H),7.23-7.28(m,1H),7.28-7.36(m,4H).m / z(ES+),[M+H] + =279.2.

[0161] Intermediate 65: Lithium 2-(4-methylpiperazin-1-yl)butanoate Lithium hydroxide (0.335 g, 14.00 mmol) was added to ethyl 2-(4-methylpiperazin-1-yl)butanoate, intermediate 30 (2.00 g, 9.33 mmol) in THF (6 mL), water (6 mL) and MeOH (1 mL) under nitrogen. The resulting suspension was stirred at 40° C. for 24 h. The reaction mixture was concentrated in vacuo. The residue was diluted with water (10 mL), extracted with diethyl ether (2×10 mL) and the aqueous layer was lyophilized to give lithium 2-(4-methylpiperazin-1-yl)butanoate (1.680 g, 97%) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d 6 )δ 0.82(t,3H),1.38-1.68(m,2H),2.11(s,3H),2.16-2.48(m,4H),2.49-2.67(m,5H).

[0162] Intermediate 66: Lithium 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)propanoate Process 1 Potassium carbonate (0.890 g, 6.44 mmol) was added to methyl 2-bromopropanoate (0.897 g, 5.37 mmol) and tert-butyl piperazine-1-carboxylate (1.00 g, 5.37 mmol) in acetonitrile (10 mL) at 20° C. under nitrogen. The resulting mixture was stirred at 60° C. for 18 h. The reaction mixture was diluted with ethyl acetate (50 mL), filtered through Celite, and the filtrate was evaporated in vacuum. The reaction mixture was diluted with diethyl ether (50 mL). The reaction mixture was filtered through Celite, and the filtrate was evaporated in vacuum to give tert-butyl 4-(1-methoxy-1-oxopropan-2-yl)piperazine-1-carboxylate (1.80 g, 123%) as a colorless oil, which was taken directly to the next step. 1 H NMR (300 MHz, CDCl 3 )1.33(d,3H),1.46(s,9H),2.45-2.75(m,4H),3.25-3.60(m,5H),3.72(s,3H).m / z(ES+),[M+H] + =273.

[0163] Process 2 A solution of lithium hydroxide (0.158 g, 6.61 mmol) in water (5 mL) was added to a stirred solution of tert-butyl 4-(1-methoxy-1-oxopropan-2-yl)piperazine-1-carboxylate (1.80 g, 6.61 mmol) in THF / MeOH 1:1 (10 mL). The resulting solution was stirred at 60° C. for 4 h. The solvent was evaporated in vacuo. The residue was diluted with water (15 mL) and lyophilized to give lithium 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)propanoate, intermediate 66 (1.60 g, 91%) as a white solid. 1 H NMR (300MHz, D 2O)1.13(d,3H),1.35(s,9H),2.40-2.55(m,4H),2.89(q,1H),3.26-3.47(m,4H).m / z(ES+),[M+H] + =259.

[0164] Example 1 (R)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)propanamide Potassium carbonate (101 mg, 0.73 mmol) was added to (S)-2-bromo-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)propanamide, Intermediate 21 (200 mg, 0.37 mmol) and 2-(piperazin-1-yl)ethanol in DMF (5 mL) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 18 h, then cooled to room temperature, filtered through Celite and evaporated in vacuo. The product was purified by elution with water (0.05% NH 3 ) at a flow rate of 30 mL / min over 7 min. 3 xH 2 The crude product was purified by preparative achiral-HPLC on an XBridge C18 OBD column using a gradient of 41-58% acetonitrile in 2H2O. The product was collected and evaporated in vacuo to give (R)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)propanamide (100 mg, 50%) as a white solid. 1 H NMR (300MHz, CD 3OD)δ 1.47(d,3H),2.47(s,3H),2,85-3.43(m, 13H),3.45 -3.60(m,1H),3.86(t,2H),7.06(t,1H),7.20(d,1H),7.30-7.54(m,1H),7.54-7.72(m, 1H),7.94(s,1H),8.14(d,1H),8.31(s,1H),8.47(bs,1H),8.58(t,1H).m / z(ES+),[M+H] + =596.

[0165] Example 2 (R)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide DIPEA (13.9 mL, 78.08 mmol) was added in one portion to (R)-2-(4-methylpiperazin-1-yl)propanoic acid dihydrochloride, intermediate (3.34 g, 13.64 mmol) and 3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine, intermediate (4.00 g, 9.72 mmol) in DCM (70 mL) at 25 °C. The resulting solution was stirred at 25 °C for 10 min. Then, 1-propanephosphonic acid cyclic anhydride, T3P (50 wt%) (12.37 g, 19.44 mmol) was added dropwise at 0 °C. The solution was stirred at 0 °C for 1 h and then concentrated in vacuo. The residue was purified by C18-flash chromatography using a gradient of 5-60% MeOH in water as the mobile phase. Pure fractions were pooled and evaporated in vacuo. The residue was purified by CO 2The mixture was purified by preparative chiral-HPLC on a ChiralCel OD-H (20×250 mm) using 40% EtOH in 100 ml of water and a flow rate of 40 mL / min. The enantiomers were detected using a wavelength of 220 nm. The major isomer (isomer 1) was collected to give (R)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide (1.85 g, 30%) as a yellow solid. 1 H NMR (300MHz, DMSO-d 6 )δ 1.26(d,3H),2.16(s,3H),2.30-2.75(m,11H),3.25(s,3H),3.27-3.40(m,1H),6.97(t,1H),7.30-7.48(m,2 H),7.48-7.65(m,1H),8.03(d,1H),8.13(d,1H),8.23-8.40(m,2H),9.16(s,1H),9.66(s,1H),11.38(s,1H). 19 F NMR (282MHz, DMSO-d 6 ) δ -121.22.m / z(ES+),[M+H] + =566.

[0166] The procedure described for Example 2 was repeated using the intermediates indicated to give Examples 3-5, as set forth in Table 17 below:

[0167] [Table 34]

[0168] [Table 35]

[0169] Example 6 (S)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide Isomer 2 from the reaction of Example 2 was collected and evaporated in vacuum. The residue was repurified by C18-flash chromatography using a gradient of 10-60% MeOH in water (0.1% FA). Pure fractions were evaporated in vacuum. 2 The residue was repurified by preparative SFC on a ChiralCel OD-H (20×250 mm) using 40% EtOH in 100 ml of water and a flow rate of 40 mL / min. The isomers were detected using a wavelength of 220 nm. Isomer 2 was collected to give (S)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide (40 mg) as a white solid. 1 H NMR (400MHz, CD 3 OD)δ 1.41(d,3H), 2.33(s,3H),2.43(s,3H),2.49-2.87(m,8H),3.15(s,3H),3.39(q,1H),7.02(t,1H),7.14(dd,1H) ,7.28-7.38(m,1H),7.53-7.63(m,1H),7.91(s,1H),8.09(dd,1H),8.27(s,1H),8.51-8.61(m,1H). 19 F NMR (400MHz, CD 3 OD) δ -125.65. m / z (ES+), [M+H] + =566.

[0170] Example 7 (R)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-((3S,5S)-3,4,5-trimethylpiperazin-1-yl)propanamide Process 1 (R)-2-((3S,5S)-3,4,5-trimethylpiperazin-1-yl)propanoic acid dihydrochloride, intermediate 26 (113.0 mg, 0.42 mmol) and di(1H-imidazol-1-yl)methanone (127 mg, 0.78 mmol) were dissolved in DMF (3 mL) and stirred at room temperature for 1 h. 3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-amine, intermediate (90.0 mg, 0.17 mmol) was added and the mixture was stirred at 50° C. for 16 h. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (10.0 mL) and diluted with saturated Na 2 CO 3 (30 mL). The phases were shaken, separated and the aqueous phase was extracted with EtOAc (3×15 mL). The combined organic extracts were filtered through a phase separator and evaporated in vacuo. 0.1M HCO 2 The residue was purified by reverse-phase preparative HPLC on a Waters Sunfire C18 ODB (5 μm, 19 × 150 mm) column using a gradient of 5-95% acetonitrile in H(aq), pH 3. Product fractions were collected and lyophilized to give (R)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)-2-((3S,5S)-3,4,5-trimethylpiperazin-1-yl)propanamide (125 mg, 104% (water present)) as a pale yellow solid. 1 H NMR (500MHz, DMSO-d 6)δ -0.07(s,9H),0.85-0.92(m,2H),0.98(d,6H),1.24(d,3H),2.17(s,3H),2.20-2.3 3(m,2H),2.39(s,3H),2.64(d,2H),2.72-2.82(m,2H),3.10(q,1H),3.25(s,3H),3. 45-3.57(m,2H),5.68(d,1H),5.78(d,1H),7.06(t,1H),7.33(d,1H),7.40(t,1H),7 .55(t,1H),8.16-8.22(m,2H),8.28(t,1H),8.33(s,1H),9.23(s,1H),9.45(s,1H). m / z(ES+), [M+H] + =724.

[0171] Process 2 (R)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)-2-((3S,5S)-3,4,5-trimethylpiperazin-1-yl)propanamide (97.0 mg, 0.13 mmol) was dissolved in DCM (1.3 mL) and TFA (0.25 mL, 3,37 mmol) was added. The reaction mixture was stirred at room temperature for 60 h. The reaction was diluted with DCM and saturated NaHCO 3 (10 mL). The phases were shaken, separated and the aqueous phase was extracted with DCM (3×5 mL). The organic extracts were combined, filtered through a phase separator and concentrated in vacuo. 2 The residue was purified by chiral SFC on a Cellucoat (250×30 mm, 5 μm) column using 35% EtOH / DEA (100:0.5) in water and a flow rate of 140 mL / min. The product peak was detected at 270 nm. The product was collected and evaporated in vacuo. 2 Medium 20mM MeOH / NH 3The residue was repurified by SFC on a Waters BEH (5 μm, 30 × 250 mm) column using a mobile phase of 1000 μl. The product fractions were collected and lyophilized to give (R)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-((3S,5S)-3,4,5-trimethylpiperazin-1-yl)propanamide, Example 6. (S)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide Isomer 2 from the reaction of Example 2 was collected and evaporated in vacuum. The residue was repurified by C18-flash chromatography using a gradient of 10-60% MeOH in water (0.1% FA). Pure fractions were evaporated in vacuum. 2 The residue was repurified by preparative SFC on a ChiralCel OD-H (20×250 mm) using 40% EtOH in 100 ml of water and a flow rate of 40 mL / min. The isomers were detected using a wavelength of 220 nm. Isomer 2 was collected to give (S)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide (40 mg) as a white solid. 1 H NMR (400MHz, CD 3 OD)δ 1.41(d,3H), 2.33(s,3H),2.43(s,3H),2.49-2.87(m,8H),3.15(s,3H),3.39(q,1H),7.02(t,1H),7.14(dd,1H) ,7.28-7.38(m,1H),7.53-7.63(m,1H),7.91(s,1H),8.09(dd,1H),8.27(s,1H),8.51-8.61(m,1H). 19 F NMR (400MHz, CD 3 OD) δ -125.65. m / z (ES+), [M+H] +=566. This gave Example 7 (21 mg, 27%). 1 H NMR (600MHz, DMSO-d 6 )δ 0.98(d,6H),1.28(d,3H),2.17(s,3H),2.21-2.35(m,2H),2.40(s,3H), 2.62-2.69(m,2H),2.71-2.81(m,2H),3.19(q,1H),3.25(s,3H),6.98(t, 1H),7.35-7.44(m,2H),7.51-7.58(m,1H),8.03(d,1H),8.13(d,1H),8.2 5-8.35(m,2H),9.17(s,1H),9.57(s,1H),11.39(s,1H).m / z(ES+),[M+H] + =594.

[0172] Example 8 (R)-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)-2-((3S,5S)-3,4,5-trimethylpiperazin-1-yl)propanamide (R)-2-((3S,5S)-3,4,5-trimethylpiperazin-1-yl)propanoic acid dihydrochloride, Intermediate 26 (199 mg, 0.73 mmol) and 1,1'-carbonyldiimidazole (91 mg, 0.56 mmol) were dissolved in DMF (2 mL) and stirred at room temperature for 1.5 h. 3-(5-Fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-amine, Intermediate 18 (202 mg, 0.49 mmol) was added and the reaction was heated to 60° C. for 3 h. The reaction was allowed to cool to room temperature. DCM (25 mL) was added and the organic phase was washed with 8% NaHCO 3 (3×25 mL), dried by phase separator and evaporated in vacuum. 2 O / ACN / NH 3The residue was purified by preparative HPLC on an XBridge C18 column (10 μm, 250×50 mm) using a gradient of 25-65% acetonitrile in (95 / 5 / 0.2) buffer. The compound was detected by UV at 229 nm. The product was collected and lyophilized to give (R)-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)-2-((3S,5S)-3,4,5-trimethylpiperazin-1-yl)propanamide, Example 8 (188 mg, 65%, 99.4% de) as a white solid. 1 H NMR (500MHz, DMSO-d 6 )δ 0.98(d,6H),1.28(d,3H),2.17(s,3H),2.2-2.34(m,2H),2.65(d,2H),2.7-2.81(m,2H),3.19(q,1H),3.27-3.34(m,3H),7.03(t,1H),7. 38-7.5(m,2H),7.58-7.66(m,1H),8.14-8.25(m,2H),8.28(d,1H),8.43(d,1H),9.45(s,1H),9.62(s,1H),11.60(s,1H).m / z(ES+),[M+H] + =598.3.

[0173] Example 9 (R)-2-((3S,5S)-3,5-Dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)propanamide, isomer 1 Process 1 3-(2-((2-Fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-amine, Intermediate (225 mg, 0.42 mmol), lithium 2-((3S,5S)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)propanoate, Intermediate 55 (143 mg, 0.50 mmol), and pyridine (0.088 mL, 1.04 mmol) were dissolved in DCM (5.0 mL) and the resulting reaction mixture was cooled to 0 °C. To the cooled reaction mixture was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide, T3P (0.371 mL, 1.25 mmol) and the reaction mixture was allowed to slowly reach room temperature. The reaction was stirred for 16 h. The reaction was quenched with water, diluted with DCM (5 mL) and diluted with 10% Na 2 CO 3 (30 mL), shaken, the phases separated and the aqueous phase extracted with DCM (3×10 mL). The combined organic extracts were filtered through a phase separator and evaporated in vacuo. H 2 at a flow rate of 100 mL / min for 20 min was added. 2 O / ACN / NH 3 The residue was purified by preparative HPLC on an XBridge C18 column (10 μm, 250 × 50 mm) using a gradient of 45-95% acetonitrile in (95 / 5 / 0.2) buffer. The compound was detected by UV at 270 nm. The product fractions were collected and lyophilized to give (2S,6S)-tert-butyl 4-(1-((3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)amino)-1-oxopropan-2-yl)-2,6-dimethylpiperazine-1-carboxylate (256 mg, 76%) as a solid. 1 H NMR (500MHz, DMSO-d 6)δ -0.08(d,9H),0.78-0.97(m,2H),1.18-1.31(m,9H),1.39(s,9H),2.32-2.47(m,5 H),2.61-2.78(m,2H),3.18-3.36(m,4H),3.42-3.57(m,2H),3.77-3.89(m,2H),5. 70(d,1H),5.75-5.86(m,1H),7.06(t,1H),7.27-7.45(m,2H),7.55(t,1H),8.14- 8.23(m,2H),8.27(t,1H),8.33(s,1H),9.24(s,1H),9.53(d,1H).m / z(ES+),[M+H] + =810.

[0174] Process 2 To (2S,6S)-tert-butyl 4-(1-((3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)amino)-1-oxopropan-2-yl)-2,6-dimethylpiperazine-1-carboxylate (179.8 mg, 0.22 mmol) dissolved in DCM (2.0 mL) was added TFA (0.5 mL, 6.73 mmol) and the mixture was stirred at room temperature for 96 h. The reaction was diluted with DCM and quenched by the addition of water and saturated NaHCO 3 (10 mL), shaken, the phases separated and the aqueous phase extracted with EtOAc (3×5 mL). The combined organic extracts were filtered through a phase separator and concentrated in vacuo. 2 The isomers were purified by chiral SFC on a Chiralpak IB (250×30 mm, 5 μm) column using 30% EtOH / DEA (100:0.5) in water and a flow rate of 150 mL / min. Isomer 1 was collected and evaporated in vacuo to give (R)-2-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)propanamide isomer 1, Example 9 (50 mg, 41%, 97% ee). 1H NMR (500 MHz, CDCl 3 ) δ 1.22-1.33(m,6H), 1.39(d,3H), 2.19-2.36(m,2H), 2.43(s,3H), 2.69-2.8(m,2H), 3.14-3.28(m,4H), 3.29-3.41(m,2H), 6.77(d,1H), 7.12(t,1H), 7.20-7.31(m,1H), 7.38(s,1H), 7.50(t,1H), 7.73(d,1H), 8.20(d,1H), 8.31(s,1H), 8.99(t,1H), 9.83(s,1H), 11.45(s,1H). Not one exchangeable proton is observed.

[0175] Example 10 (S)-2-((3S,5S)-3,5-Dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)propanamide Isomer 2 from the synthesis of Example 9, step 2 was collected and evaporated in vacuo to yield (S)-2-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)propanamide, Example 10 (48 mg, 36%, 90% ee). 1 H NMR (500 MHz, CDCl 3 ) δ 1.24-1.32(m,6H), 1.35(d,3H), 2.33-2.47(m,5H), 2.61-2.78(m,2H), 3.24(s,3H), 3.33-3.44(m,3H), 6.79(d,1H), 7.11(t,1H), 7.2-7.31(m,1H), 7.38(d,1H), 7.50(t,1H), 7.72(d,1H), 8.19(d,1H), 8.31(s,1H), 8.99(t,1H), 9.87(s,1H), 11.45(s,1H). Not one exchangeable proton is observed.

[0176] Example 11 (R)-2-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)propanamide isomer 1 Process 1 3-(5-Fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-amine, intermediate 18 (318 mg, 0.77 mmol), lithium 2-((3S,5S)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)propanoate, intermediate 55 (235 mg, 0.80 mmol), and DIPEA (0.535 mL, 3.06 mmol) were dissolved in DMF (2 mL) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (306 mg, 0.80 mmol) was added. The reaction was heated to 50° C. for 1.5 h and then cooled to ambient temperature. The reaction mixture was diluted with DCM (25 mL) and 5% Na 2 CO 3 (aq) (25 mL), shaken and the phases separated. The aqueous phase was extracted with DCM (2×25 mL). The combined organic phases were washed with Na 2 SO 4 The mixture was dried at 40° C. for 20 min at a flow rate of 100 mL / min, filtered and evaporated in vacuo. 2 O / ACN / NH 3 The compounds were purified by preparative HPLC on an XBridge C18 column (10 μm, 250×50 mm) using a gradient of 45-85% acetonitrile in (95 / 5 / 0.2) buffer. The compounds were detected by UV at 230 nm. The products were collected and lyophilized. CO at 120 bar was used as eluent. 2Diastereoisomers were separated using chiral SFC on a CelluCoat (250×20 mm, 5 μm) column using 35% EtOH / DEA (100:0.5) in water and a flow rate of 70 ml / min. Diastereoisomers were detected at 300 nm. The first eluting compound was collected and evaporated in vacuum as isomer 1. The residue was dissolved in acetonitrile / water and lyophilized to give (2S,6S)-tert-butyl 4-(1-((3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)amino)-1-oxopropan-2-yl)-2,6-dimethylpiperazine-1-carboxylate isomer 1 (62.0 mg, 25.3%, 99.9% de) as a white solid. 1 H NMR (500MHz, DMSO-d 6 )δ 1.19-1.34(m,9H),1.39(s,9H),2.40(dd,2H),2.75(dd,2H),3.26-3.37(m,4H),3.75-3.87(m,2H),7.04(t,1H),7. 39-7.51(m,2H),7.62(t,1H),8.14-8.25(m,2H),8.28(d,1H),8.44(d,1H),9.45(s,1H),9.68(s,1H),11.54(s,1H). m / z(ES+), [M+H] + =684.3.

[0177] Process 2 tert-Butyl (2S,6S)-4-(1-((3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)amino)-1-oxopropan-2-yl)-2,6-dimethylpiperazine-1-carboxylate (62 mg, 0.09 mmol) was dissolved in DCM (4 mL) and TFA (1 mL, 12.98 mmol) was added. The reaction was stirred at room temperature for 1 h and then evaporated in vacuo. The residue was dissolved in DCM (25 mL), 8% NaHCO 3(aq) (25 mL), shaken and the phases separated. The aqueous phase was extracted with DCM (25 mL). The combined organic phases were dried through a phase separator and evaporated in vacuo. MeOH / NH 3 The residue was purified by SFC on a Waters BEH 2-EP (5 μm, 30 × 250 mm) column using 1,2-dimethylpiperazin-1-yl (20 mM) as eluent. The product was collected and evaporated in vacuo to give (R)-2-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)propanamide, Example 11 (32.7 mg, 61.8%). 1 H NMR (600MHz, DMSO-d 6 )δ 1.06(d,6H),1.26(d,3H),2.12-2.21(m,2H),2.61(dd,2H),3.06-3.14(m,2H),3.20(q,1H),3.30(s,3H),7.03(t,1H),7.41(d,1H),7. 46(t,1H),7.59-7.65(m,1H),8.16-8.24(m,2H),8.27(d,1H),8.43(d,1H),9.45(s,1H),9.65(s,1H),11.63(bs,1H).m / z(ES+),[M+H] + =584.2.

[0178] Example 12 (S)-2-((3S,5S)-3,5-Dimethylpiperazin-1-yl)-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)propanamide isomer 2 Process 1 The second eluting compound from the reaction of step 1 of Example 11 was collected and evaporated in vacuum. The residue was dissolved in acetonitrile / water - a white solid crashed out. The solid was filtered, washed with acetonitrile / water, and dried in vacuum to give (2S,6S)-tert-butyl 4-(1-((3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)amino)-1-oxopropan-2-yl)-2,6-dimethylpiperazine-1-carboxylate isomer 2 (89 mg, 36.3%, 99.3% de) as a white solid. 1 H NMR (500MHz, DMSO-d 6 )δ 1.18-1.31(m,9H),1.39(s,9H),2.44(dd,2H),2.69(dd,2H),3.26-3.36(m,3H),3.49(q,1H),3.78-3.89(m,2H),7.03(t,1 H),7.38-7.51(m,2H),7.62(t,1H),8.15-8.24(m,2H),8.27(d,1H),8.44(d,1H),9.45(s,1H),9.73(s,1H),11.60(s,1H). m / z(ES+), [M+H] + =684.2.

[0179] Process 2 tert-Butyl (2S,6S)-4-(1-((3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)amino)-1-oxopropan-2-yl)-2,6-dimethylpiperazine-1-carboxylate isomer 2 (89 mg, 0.13 mmol) was dissolved in DCM (4 mL) and TFA (1 mL, 12.98 mmol) was added. The reaction was stirred at room temperature for 1 h and then evaporated in vacuo. The residue was dissolved in DCM (25 mL), 8% NaHCO 3(aq) (25 mL), shaken and the phases separated. The aqueous phase was extracted with DCM (25 mL). The combined organic phase was dried through a phase separator and evaporated in vacuo. The residue was dissolved in DMSO and diluted with MeOH / NH 3 The mixture was purified by SFC on a Waters BEH 2-EP (5 μm, 30×250 mm) column using 1,2-dichloro-1,3-diphenyl-2,4-dichloro-1,3-diphenyl-2,4-diphenyl-2,5-diphenyl-2,6-diphenyl-2,7-diphenyl-2,8-diphenyl-2,9 ... 1 H NMR (600MHz, DMSO-d 6 )δ 1.06(d,6H),1.19(d,3H),2.21(dd,2H),2.52-2.59(m,2H),3.08-3.17(m,2H),3.30(s,3H),3.37-3.5(m,1H),7.03(t,1H),7.40 (d,1H),7.46(t,1H),7.58-7.67(m,1H),8.13-8.23(m,2H),8.26(d,1H),8.43(d,1H),9.45(s,1H),9.72(s,1H),11.67(bs,1H). m / z(ES+), [M+H] + =584.2.

[0180] Example 13 (S)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)butanamide DIPEA (2.54 mL, 14.58 mmol) was added to lithium 2-(4-methylpiperazin-1-yl)butanoate, intermediate 65 (1.81 g, 9.72 mmol) and 3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine, intermediate (2.00 g, 4.86 mmol) in DCM (50 mL) at 15° C. under nitrogen. The mixture was stirred for 10 min and T3P (50% in EtOAc) (6.18 g, 9.72 mmol) was added dropwise at 0° C. and the reaction was stirred at 0° C. for 1 h. The solvent was then concentrated in vacuo. Water (NH 4 HCO 3 The residue was purified by flash C18-flash chromatography using a gradient of 5-80% MeOH in water (%NH 4 HCO 3 The residue was repurified by preparative HPLC on a SunFire Prep C18 OBD column (5 μm, 30×100 mm) using decreasingly polar mixtures of 1,2-dichlorophenyl 2,4-dichlorophenyl 2,5-dichlorophenyl 2,6-dichlorophenyl 2,7-dichlorophenyl 2,7-dichlorophenyl 2,8-dichlorophenyl 2,7 ... 2 The enantiomers were separated by preparative chiral SFC on a ChiralPak AD-H (50×250 mm, 5 μm) column using 50% IPA in 0.1% DEA and a flow rate of 150 mL / min. The enantiomers were detected using UV at 254 nm. The first eluting isomer was collected and evaporated in vacuo to give (S)—N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)butanamide, Example 13 (200 mg, 7%, 96.4% ee) as a white solid. 1 H NMR (400MHz, CD 3OD) δ 1.05(t,3H), 1.77-1.99(m,2H), 2.30(s,3H), 2.43(s,3H), 2.45-2.90(m,8H), 3.11-3.23(m,4H), 7.02(t,1H), 7.18(d,1H), 7.32(t,1H), 7.52-7.62(m,1H), 7.91(s,1H), 8.06-8.15(m,1H), 8.27(s,1H), 8.51-8.61(m,1H). No exchangeable protons observed. 19 F NMR (400MHz, CD 3 OD) δ -125.77.m / z(ES+),[M+H] + =580.

[0181] Example 14 (R)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)butanamide The second eluting isomer from the synthesis of Example 13 was collected and evaporated in vacuo to give (R)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)butanamide isomer 2, Example 14 (200 mg, 7%, 92.8% ee) as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 1.05(t,3H), 1.77-1.99(m,2H), 2.30(s,3H), 2.43(s,3H), 2.45-2.95(m,8H), 3.11-3.23(m,4H), 7.02(t,1H), 7.18(d,1H), 7.33(t,1H), 7.52-7.62(m,1H), 7.91(s,1H), 8.06-8.15(m,1H), 8.27(s,1H), 8.51-8.61(m,1H). No exchangeable protons observed. 19 F NMR (400MHz, CD 3 OD) δ -125.72. m / z (ES+), [M+H] +=580.

[0182] The procedures described above for Examples 13 and 14 were repeated using the intermediates indicated to give Examples 15-18, as set forth in Table 18 below:

[0183] [Table 36]

[0184] [Table 37]

[0185] [Table 38]

[0186] Example 19 (S)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-((3S,5S)-3,4,5-trimethylpiperazin-1-yl)butanamide 3-(2-((2-Fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine, intermediate (300 mg, 0.73 mmol) was added to lithium 2-((3S,5S)-3,4,5-trimethylpiperazin-1-yl)butanoate, intermediate 49 (313 mg, 1.46 mmol), 1-propanephosphonic acid cyclic anhydride, T3P (50% in EtOAc) (928 mg, 1.46 mmol), and DIPEA (1.019 mL, 5.83 mmol) in DCM (1 mL) under nitrogen. The resulting solution was stirred at 25° C. for 1 h. The reaction mixture was diluted with DCM (50 mL) and washed with saturated NaHCO 3 (2 × 100 mL), brine (2 × 100 mL), and Na 2 SO 4The mixture was dried at 75° C., filtered and evaporated in vacuum. The residue was purified by preparative TLC using DCM / MeOH (10:1). The product fraction was evaporated in vacuum. The diastereoisomers were separated by preparative chiral-HPLC on a ChiralPak-AD-H-SL001 (20×250 mm) column using 50% IPA in hexane (0.1% DEA) as the mobile phase and a flow rate of 15 mL / min. The diastereoisomers were detected using UV at 254 and 220 nm. The first eluting isomer was collected and evaporated in vacuo to give (S)—N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-((3S,5S)-3,4,5-trimethylpiperazin-1-yl)butanamide, Example 19 (30 mg, 24%, 99.9% ee) as a white solid. 1 H NMR (300MHz, CD 3 OD) δ 1.07(t,3H), 1.17(d,6H), 1.75-1.98(m,2H), 2.39(s,3H), 2.45(s,3H), 2.52-2.70(m,2H), 2.89(dd,2H), 2.93-3.10(m,2H), 3.11-3.25(m,4H), 7.03(t,1H), 7.17(dd,1H), 7.35(dd,1H), 7.54-7.64(m,1H), 7.93(s,1H), 8.10(dd,1H), 8.29(s,1H), 8.52-8.62(m,1H). No exchangeable protons observed. 19 F NMR (282MHz, DMSO-d 6 ) δ -121.25.m / z(ES+),[M+H] + =608.

[0187] Example 20 (R)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-((3S,5S)-3,4,5-trimethylpiperazin-1-yl)butanamide The second eluting isomer from the synthesis of Example 19 was collected and evaporated in vacuo to give (R)—N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-((3S,5S)-3,4,5-trimethylpiperazin-1-yl)butanamide isomer 2, Example 20 (5 mg, 4%, 90% ee) as a white solid. 1 H NMR (300MHz, CD 3 OD) δ 1.09(t,3H), 1.25-1.45(m,6H), 1.70-1.98(m,2H), 2.45(s,3H), 2.74(s,3H), 2.98-3.13(m,2H), 3.16(s,3H), 3.15-3.60(m,5H), 7.03(t,1H), 7.21(d,1H), 7.35(t,1H), 7.53-7.65(m,1H), 7.93(s,1H), 8.10(d,1H), 8.30(s,1H), 8.50-8.65(m,1H). No exchangeable protons observed. 19 F NMR (282MHz, DMSO-d 6 ) δ -121.11.m / z(ES+),[M+H] + =608.

[0188] The procedures described above for Examples 19 and 20 were repeated using the intermediates indicated to give Examples 21-23, as set forth in Table 19 below:

[0189] [Table 39]

[0190] [Table 40]

[0191] Example 24 (R)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(piperazin-1-yl)propanamide Process 1 DIPEA (0.637 mL, 3.65 mmol) was added to 3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine, Intermediate (500 mg, 1.22 mmol), lithium 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)propanoate, Intermediate 66 (628 mg, 2.43 mmol), EDC (349 mg, 1.82 mmol), and HOBT (279 mg, 1.82 mmol) in DMF (10 mL) under nitrogen. The resulting solution was stirred at 25° C. for 15 h. The reaction mixture was poured into water (75 mL) and extracted with EtOAc (2×75 mL). The combined organic layers were washed with brine (3×100 mL) and concentrated under nitrogen. 2 SO 4 The residue was purified by preparative TLC using DCM / MeOH (8:1) to give tert-butyl 4-(1-((3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-1-oxopropan-2-yl)piperazine-1-carboxylate (440 mg, 55.6%) as a light yellow solid. m / z(ES+), [M+H] + =652.

[0192] Process 2 TFA (0.050 mL, 0.64 mmol) was added dropwise to tert-butyl 4-(1-((3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-1-oxopropan-2-yl)piperazine-1-carboxylate (420 mg, 0.64 mmol) in DCM (20 mL) at 20° C. The resulting solution was stirred at 20° C. for 2 h. The solvent was evaporated in vacuo. The residue was diluted with DCM (50 mL) and diluted with NaHCO3 (2×50 mL) and the organics were evaporated in vacuo. The enantiomers were separated by preparative chiral-HPLC on a Phenomenex Lux 5u Cellulose-4, AXIA Packed (250×21.2 mm, 5 μm) using 100% MeOH (0.1% DEA) as eluent and a flow rate of 20 mL / min. The isomers were detected at wavelengths of 254 and 220 nm. The first eluting isomer was collected and evaporated in vacuo to give (R)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(piperazin-1-yl)propanamide isomer 1, Example 24 (53 mg, 27%, 99.9% ee) as a white solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 1.26(d,3H), 2.41(s,3H), 2.45-2.65(m,4H), 2.73-2.85(m,4H), 3.22-3.40(m,4H), 6.98(t,1H), 7.35-7.50(m,2H), 7.50-7.62(m,1H), 8.03(s,1H), 8.14(d,1H), 8.25-8.37(m,2H), 9.18(s,1H), 9.73(s,1H), 11.48(bs,1H). Not one exchangeable proton is observed. 19 F NMR (376MHz, DMSO-d 6 )-121.21.m / z(ES+),[M+H] + =552.

[0193] Example 25 (S)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(piperazin-1-yl)propanamide The second eluting isomer from the reaction of Example 24, step 2 was collected and evaporated in vacuo to give (S)—N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(piperazin-1-yl)propanamide, Example 25 (47 mg, 24%, 92.6% ee) as a white solid. 1 H NMR (300MHz, DMSO-d 6 ) δ 1.25(d,3H), 2.39(s,3H), 2.43-2.65(m,4H), 2.68-2.85(m,4H), 3.22-3.40(m,4H), 6.97(t,1H), 7.35-7.50(m,2H), 7.50-7.62(m,1H), 8.02(s,1H), 8.12(d,1H), 8.25-8.37(m,2H), 9.17(s,1H), 9.69(s,1H), 11.43(bs,1H). Not one exchangeable proton is observed. 19 F NMR (282MHz, DMSO-d 6 )-121.20.m / z(ES+),[M+H] + =552.

[0194] Example 26 (R)-2-((3R,5R)-3,5-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)butanamide Process 1 DIPEA (1.02 mL, 5.83 mmol) was added in one portion to lithium 2-((3R,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)butanoate, intermediate 56 (438 mg, 1.46 mmol) and 3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine, intermediate (300 mg, 0.73 mmol) in DCM (5 mL) at 25° C. The resulting solution was stirred at 25° C. for 10 min. 1-Propanephosphonic acid cyclic anhydride, T3P (928 mg, 1.46 mmol) was added dropwise at 0° C. and the reaction was stirred for 1 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC using MeOH / DCM (1:10) to give (2R,6R)-tert-butyl 4-(1-((3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-1-oxobutan-2-yl)-2,6-dimethylpiperazine-1-carboxylate (200 mg, 39.5%) as a yellow solid. 1 H NMR (400MHz, CD 3 OD) δ 1.03-1.11(m,3H), 1.18-1.52(m,15H), 1.81-1.92(m,2H), 2.35-2.80(m,5H), 2.82-2.93(m,2H), 3.15(s,3H), 3.75-3.99(m,2H), 4.08-4.21(m,1H), 7.02(t,1H), 7.18(dd,1H), 7.32(t,1H), 7.52-7.61(m,1H), 7.91(d,1H), 8.09(d,1H), 8.26(s,1H), 8.51-8.61(m,1H). No exchangeable protons observed. Mixture of diastereoisomers. m / z(ES+), [M+H] + =694.

[0195] Process 2 TFA (5 mL, 64.90 mmol) was added to (2R,6R)-tert-butyl 4-(1-((3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)amino)-1-oxobutan-2-yl)-2,6-dimethylpiperazine-1-carboxylate (370 mg, 0.53 mmol) in DCM (20 mL) at 25° C. The resulting mixture was stirred at room temperature for 2 h. The solvent was concentrated in vacuo. Water (0.03% NH 3 ) was added at a flow rate of 30 mL / min over 7 min. 3 H 2 The residue was purified by reverse phase preparative chromatography on an XBridge Prep C18 OBD column (5 μm, 19×150 mm) using a gradient of 30-50% acetonitrile in 2H2O. Compounds were detected using wavelengths of 220 and 254 nm. Diastereoisomers were separated by preparative chiral-HPLC on a ChiralPak-AD-H-SL001 (20×250 mm) using 50% EtOH in hexane (0.1% DEA) over 85 min and a flow rate of 15 mL / min. Compounds were detected using wavelengths of 220 and 254 nm. The first eluted compound was collected and evaporated in vacuo to give R-2-((3R,5R)-3,5-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)butanamide, Example 26 (78 mg, 28%, 99.0% ee). 1 H NMR (400MHz, CD 3 OD)δ 1.09(t,3H),1.41(d,6H),1.80-2.00(m,2H),2.44(s,3H),2.77(dd,2H),3.07(dd,2H),3.15(s,3H),3.28-3.40(m,1H),3.55- 3.72(m,2H),7.02(t,1H),7.23(d,1H),7.33(t,1H),7.53- 7.62(m,1H),7.92(d,1H),8.05-8.13(m,1H),8.28(s,1H),8.40-8.49(m,2H),8.50-8.60(m,1H). 19 F NMR (376MHz, CD 3 OD) δ -125.59. m / z (ES+), [M+H] + =594.

[0196] Example 27 (S)-2-((3R,5R)-3,5-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)butanamide The second eluting compound from the reaction of Example 26, step 2 was collected and evaporated in vacuo to give (S)-2-((3R,5R)-3,5-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)butanamide Example 27 (30.0 mg, 13%, 99.9% ee) as a white solid. 1 H NMR (400MHz, CD 3 OD) δ 1.07(t,3H), 1.22(d,6H), 1.80-1.93(m,2H), 2.40-2.58(m,5H), 2.81(dd,2H), 3.07-3.18(m,4H), 3.19-3.29(m,2H), 7.03(t,1H), 7.19(d,1H), 7.35(t,1H), 7.53-7.63(m,1H), 7.94(s,1H), 8.05-8.15(m,1H), 8.29(s,1H), 8.52-8.62(m,1H). No exchangeable protons observed. m / z(ES+), [M+H] + =594.

[0197] The procedures described above for Examples 26 and 27 were repeated using the intermediates indicated to give Examples 28-33, as set forth in Table 20 below:

[0198] [Table 41]

[0199] [Table 42]

[0200] [Table 43]

[0201] [Table 44]

[0202] Example 34 (S)-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)-3-methoxy-2-(4-methylpiperazin-1-yl)propanamide Lithium 3-methoxy-2-(4-methylpiperazin-1-yl)propanoate, Intermediate 48 (430 mg, 2.06 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (785 mg, 2.06 mmol), and DIPEA (1.068 mL, 6.11 mmol) were dissolved in DMF (10 mL) and stirred at room temperature for 5 min, then 3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-amine, Intermediate 18 (635 mg, 1.53 mmol) was added. The reaction was stirred at room temperature for 2 h and then diluted with DCM (75 mL) and 5% Na 2 CO 3 (aq) (50 mL), shaken and the phases separated. The aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were dried through a phase separator, filtered and evaporated in vacuo. H 2 was added at a flow rate of 100 mL / min for 20 min. 2 O / ACN / NH 3The compound was purified by preparative HPLC on an XBridge C18 column (10 μm, 250×50 mm) using a gradient of 15-65% acetonitrile in (95 / 5 / 0.2) buffer. The compound was detected by UV at 220 nm. The product peak was collected and lyophilized. It was then crystallized from acetonitrile and the solid was collected by filtration, washed with a minimal amount of acetonitrile and dried in vacuum. The mixture was eluted at 150 bar CO with a flow rate of 140 mL / min. 2 The enantiomers were separated by chiral-SFC on a CelluCoat (250×30 mm, 5 μm) column using 25% IPA / DEA (100:0.5) in water. The enantiomers were detected by UV at 270 nm. The first eluting enantiomer was collected and lyophilized to give N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)-3-methoxy-2-(4-methylpiperazin-1-yl)propanamide, Example 34 (213 mg, 23%, 99.9% ee) as a white solid. 1 H NMR (500MHz, DMSO-d 6 )δ 2.14(s,3H),2.24-2.44(m,4H),2.56-2.67(m,2H),2.68-2.8(m,2H),3.24-3.35(m,6H),3.50(t,1H),3.67(dd,1H),3.79(dd,1H),7.04(t, 1H),7.41-7.55(m,2H),7.62(t,1H),8.19(t,1H),8.22-8.32(m,2H), 8.44(d,1H),9.46(s,1H),9.84(s,1H),11.47(s,1H).m / z(ES+),[M+H] + =600.2.

[0203] Example 35 (R)-N-(3-(5-fluoro-2-(2-fluoro-3-(methylsulfonyl)phenylamino)pyrimidin-4-yl)-1H-indol-7-yl)-3-methoxy-2-(4-methylpiperazin-1-yl)propanamide The second eluting enantiomer of Example 34 was collected and lyophilized. The residue was recrystallized by stirring a suspension in EtOH / water (3:1) (5 mL), heating to 70° C. with an oil bath and seeding. The oil bath temperature was then set to 23° C. and the suspension was allowed to slowly reach room temperature. Stirring was continued for 5 days to give a milky slurry containing short needles along with a mix in of longer needles. The suspension was heated to 70° C. with stirring, then heating and stirring were stopped and the mixture was allowed to slowly reach room temperature (2×). Only nice long needles. The suspension was left unstirred for another week. The solid was filtered off and dried in vacuum at 40 °C to give (R)-N-(3-(5-fluoro-2-(2-fluoro-3-(methylsulfonyl)phenylamino)pyrimidin-4-yl)-1H-indol-7-yl)-3-methoxy-2-(4-methylpiperazin-1-yl)propanamide, Example 35 (186 mg, 20%, 99.4% ee) as white needles. 1 H NMR (500MHz, DMSO-d 6 )δ 2.14(s,3H),2.23-2.45(m,4H),2.57-2.67(m,2H),2.69-2.78(m,2H),3.26-3.34(m,6H),3.50(t,1H),3.67(dd,1H),3.79(d d,1H),7.03(t,1H),7.4-7.55(m,2H),7.62(t,1H),8.13-8.33(m,3H),8.44(d,1H),9.46(s,1H),9.84(s,1H),11.48(s,1H). 19 F NMR (470MHz, DMSO-d 6 )δ -120.52,-147.75.m / z(ES+),[M+H] + =600.5.

[0204] The sample of Example 35 was mounted on a silicon single crystal (SSC) wafer mount and powder X-ray diffraction was recorded on a Theta-Theta PANalytical X'Pert PRO (X-ray wavelength 1.5418 Å nickel filtered Cu radiation, voltage 45 kV, filament emission 40 mA). Automatic variable divergence and anitscatter slits were used and the sample was rotated during the measurement. The sample was scanned from 2 to 50° 2-theta with a PIXCEL detector (effective length 3.35° 2-theta) using a step width of 0.013° and a step measurement time of 233 seconds. The characteristic peak positions of the crystals are listed in Table 21 below (measured by XRPD) and shown in Figure 1:

[0205] [Table 45]

[0206] Those skilled in the art will recognize that the diffraction pattern data presented herein should not be construed as absolute, and that any crystalline form that gives a power diffraction pattern substantially identical to that disclosed herein is within the scope of the present disclosure (for further information see Jenkins, R & Snyder, RL 'Introduction to X-Ray Powder Diffractometry' John Wiley & Sons, 1996).

[0207] Example 36 (S)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methyl-1,4-diazepan-1-yl)butanamide HATU ((1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (832 mg, 2.19 mmol) was added to 3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine, intermediate (300 mg, 0.73 mmol), lithium 2-(4-methyl-1,4-diazepan-1-yl)butanoate, intermediate 58 (511 mg, 2.55 mmol), and DIPEA (1.273 mL, 7.29 mmol) in DMF (1 mL). The resulting solution was stirred at 25 °C for 16 h. Water (0.03% NH) was used as the eluent. 3 H 2 The crude product was purified by reversed-phase preparative chromatography on an XBridge Prep C18 OBD column (5 μm, 19 × 150 mm) using a gradient of 30-55% acetonitrile in CO and a flow rate of 30 mL / min. Compounds were detected using wavelengths of 220 and 254 nm. 2 The enantiomers were separated by chiral SFC on a (R,R)WHELK-01 5 / 100 Kromasil (250×21.1 mm) column using 50% MeOH / acetonitrile (1:1) (0.1% DEA) in water and a flow rate of 50 mL / min. Compounds were detected using a wavelength of 220 nm. The first eluting isomer was collected and evaporated in vacuo to give (S)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methyl-1,4-diazepan-1-yl)butanamide, Example 36 (40 mg, 6%, 99.9% ee). 1 H NMR (400MHz, CD 3OD) δ 1.08(t,3H), 1.72-2.02(m,4H), 2.38-2.50(m,6H), 2.70-2.85(m,4H), 2.88-3.10(m,4H), 3.15(s,3H), 3.27-3.40(m,1H), 7.02(t,1H), 7.26(d,1H), 7.34(t,1H), 7.52-7.65(m,1H), 7.92(s,1H), 8.08,(d,1H), 8.28(s,1H), 8.52-8.63(m,1H). No exchangeable protons observed. 19 F NMR (376MHz, CD 3 OD) δ -125.64. m / z (ES+), [M+H] + =594.

[0208] Example 37 (R)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methyl-1,4-diazepan-1-yl)butanamide The second eluting isomer from the synthesis of Example 36 was collected and evaporated in vacuo to give (R)—N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methyl-1,4-diazepan-1-yl)butanamide, (40 mg, 6%, 99.9% ee). 1 H NMR (400MHz, CD 3 OD) δ 1.07(t,3H), 1.73-2.03(m,4H), 2.39-2.49(m,6H), 2.68-2.83(m,4H), 2.88-3.09(m,4H), 3.15(s,3H), 3.27-3.40(m,1H), 7.02(t,1H), 7.25(d,1H), 7.34(t,1H), 7.52-7.62(m,1H), 7.92(s,1H), 8.08,(d,1H), 8.28(s,1H), 8.50-8.63(m,1H). No exchangeable protons observed. 19 F NMR (376MHz, CD 3 O.D.)δ -125.70. m / z(ES+), [M+H] + =594.

[0209] The procedures described above for Examples 36 and 37 were repeated using the intermediates indicated to give Examples 38-45, as set forth in Table 22 below:

[0210] [Table 46]

[0211] [Table 47]

[0212] [Table 48]

[0213] [Table 49]

[0214] [Table 50]

[0215] Example 46 (R)-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methyl-1,4-diazepan-1-yl)propanamide 2-(4-Methyl-1,4-diazepan-1-yl)propanoic acid dihydrochloride, Intermediate 47 (175 mg, 0.68 mmol) and CDI (84 mg, 0.52 mmol) were dissolved in DMF (2 mL) and stirred at room temperature for 1.5 h. 3-(5-Fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-amine, Intermediate 18 (187 mg, 0.45 mmol) was added and the reaction was heated to 60° C. for 4 h. The reaction was allowed to cool to room temperature. DCM (25 mL) was added and the organic phase was washed with 8% NaHCO 3 (3×25 mL), dried by phase separator and evaporated in vacuum. 2 O / ACN / NH 3 The compounds were purified by preparative HPLC on an XBridge C18 column (10 μm, 250×50 mm) using a gradient of 25-70% acetonitrile in (95 / 5 / 0.2) buffer. The compounds were detected by UV at 228 nm. The products were collected and lyophilized. CO at 120 bar was used as eluent. 2 The enantiomers were separated using chiral SFC on a CelluCoat (250×20 mm, 5 μm) column using 40% IPA / DEA (100:0.5) in water and a flow rate of 140 ml / min. Compounds were detected by UV at 270 nm. The first eluting compound was collected and evaporated in vacuum. H2O was added at a flow rate of 19 mL / min for 20 min. 2 O / ACN / NH 3 The residue was repurified by preparative HPLC on an XBridge C18 column (10 μm, 250×19 mm) using a gradient of 25-70% acetonitrile in (95 / 5 / 0.2) buffer. Compounds were detected by UV at 228 nm. Product fractions were collected and lyophilized to give (R)-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methyl-1,4-diazepan-1-yl)propanamide, Example 46 (40 mg, 30%, 99.9% ee) as a white solid. 1 H NMR (500MHz, DMSO-d6 )δ 1.25(d,3H),1.71-1.82(m,2H),2.26(s,3H),2.52-2.67(m,4H),2.77-2.89(m,4H),3.23-3.39(m,3H),3.57(q,1H),7.03(t, 1H),7.37-7.51(m,2H),7.62(t,1H),8.13-8.24(m,2H),8.27(d,1H),8.44(d,1H),9.45(s,1H),9.77(s,1H),11.61(bs,1H). 19 F NMR (470MHz, DMSO-d 6 )δ -120.55,-147.73.m / z(ES+),[M+H] + =584.4.

[0216] Example 47 (S)-2-((R)-2,4-Dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)propanamide Process 1 3-(2-((2-Fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-amine, intermediate (300 mg, 0.55 mmol) and lithium 2-((R)-2,4-dimethylpiperazin-1-yl)propanoate, intermediate (103 mg, 0.55 mmol) were suspended in DCM (5 mL) and pyridine (0.134 mL, 1.66 mmol) was added. The mixture was cooled to 0° C. and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide, T3P (0.989 mL, 1.66 mmol) was added dropwise. The reaction mixture was stirred at 22° C. for 1 h. Another portion of lithium 2-((R)-2,4-dimethylpiperazin-1-yl)propanoate, intermediate 53 (20 mg, 0.11 mmol) and T3P (200 μL, 0.34 mmol) were added. The mixture was stirred for 30 min. The reaction mixture was diluted with DCM (15 mL) and saturated NaHCO 3(5 mL) and stirred at room temperature for 5 min. The organic layer was separated and the aqueous layer was extracted with DCM (2×5 mL). The combined organic phase was washed with MgSO 4 Drying at 40° C., filtering, and concentrating under reduced pressure to give 2-((R)-2,4-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)propanamide (377 mg, 96%). m / z(ES+), [M+H] + =710.5.

[0217] Process 2 2-((R)-2,4-Dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)propanamide (335 mg, 0.47 mmol) was dissolved in DCM (3.5 mL), cooled in an ice bath and TFA (1.083 mL, 14.16 mmol) was added. The reaction mixture was stirred at room temperature overnight. DCM (5 mL) was added followed by TFA (1 mL) and stirring was continued for 5 h. The reaction mixture was then heated at 40° C. overnight. DCM (25 mL) was added followed by NaHCO 3 (10 mL) and MeOH (1 mL) were added. The organic layer was separated and the aqueous layer was extracted with DCM (2×20 mL). The combined organic phase was washed with MgSO 4 The residue was dissolved in DCM (25 mL), saturated NaHCO 3 (10 mL) and MeOH (1 mL), shaken and the organic layer separated. The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic phases were washed with MgSO 4 The mixture was dried at 40° C. for 20 min at a flow rate of 19 mL / min, filtered and evaporated in vacuo. 2 O / ACN / NH 3The residue was purified by preparative HPLC on an XBridge C18 column (10 μm, 250 × 19 mm) using a gradient of 20-80% acetonitrile in (95 / 5 / 0.2) buffer. The compounds were collected by UV at 269 nm and evaporated in vacuum. 120 bar CO was used as the mobile phase. 2 Diastereoisomers were separated by chiral-SFC on a Chiralpak IB (30×250 mm, 5 μm) column using 35% EtOH / TEA (100:0.5) in 100 ml of water and a flow rate of 80 mL / min. Compounds were detected by UV at 260 nm. The first eluting isomer was collected and evaporated in vacuum to give (S)-2-((R)-2,4-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)propanamide, Example 47 (20 mg, 8%, 99.9% de). 1 H NMR (500MHz, DMSO-d 6 )δ 1.03(d,3H),1.30(d,3H),1.86(t,1H),2.07-2.23(m,4H),2.40(s,3H),2.54 -2.63(m,2H),2.68-2.78(m,1H),2.79-2.91(m,2H),3.25(s,3H),3.69(q,1H) ,6.97(t,1H),7.32-7.47(m,2H),7.49-7.61(m,1H),8.03(d,1H),8.13(d,1H) ,8.22-8.35(m,2H),9.17(s,1H),9.65(s,1H),11.38(s,1H).m / z(ES+),[M+H] + =580.4.

[0218] Example 48 (R)-2-((R)-2,4-Dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)propanamide The second eluting isomer from the reaction of Example 47, step 2 was collected and evaporated in vacuo to give (R)-2-((R)-2,4-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)propanamide (22 mg, 9%, 99.2% de). 1 H NMR (500MHz, DMSO-d 6 )δ 1.11(d,3H),1.16(d,3H),2.02(t,1H),2.11-2.23(m,4H),2.40(s,3H),2.44-2. 49(m,1H),2.54-2.66(m,3H),2.66-2.78(m,1H),3.25(s,3H),3.76-3.89(m,1H), 6.97(t,1H),7.27(d,1H),7.40(t,1H),7.51-7.59(m,1H),8.00(s,1H),8.14(d, 1H),8.23-8.36(m,2H),9.16(s,1H),9.58(s,1H),11.37(s,1H).m / z(ES+),[M+H] + =580.4.

[0219] Example 49 (R)-2-((R)-2,4-Dimethylpiperazin-1-yl)-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)propanamide (R)-2-((R)-2,4-Dimethylpiperazin-1-yl)propanoic acid dihydrochloride, intermediate (573 mg, 2.21 mmol) and CDI (275 mg, 1.70 mmol) were stirred in DMF (2 mL) at room temperature for 1 h (gas evolution). 3-(5-Fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-amine, intermediate 18 (816 mg, 1.47 mmol) dissolved in DMF (2 mL) was added and the reaction was stirred at 50° C. for 5 h. The reaction was diluted with DCM (25 mL) and 5% Na 2 CO 3(aq) (25 mL), shaken and the phases separated. The aqueous phase was extracted with DCM (2×25 mL). The combined organic phases were dried using a phase separator and concentrated in vacuo. H 2 O was added at a flow rate of 100 mL / min for 20 min. 2 O / ACN / NH 3 The residue was purified twice by preparative HPLC on an XBridge C18 column (10 μm, 250×50 mm) using a gradient of 15-65% acetonitrile in (95 / 5 / 0.2) buffer. The compound was detected by UV at 235 nm. The product was lyophilized to give (R)-2-((R)-2,4-dimethylpiperazin-1-yl)-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)propanamide, Example 49 (234 mg, 32%) as a white solid. 1 H NMR (500MHz, DMSO-d 6 )δ 1.11(d,3H),1.16(d,3H),2.02(t,1H),2.1-2.23(m,4H),2.42-2.54(m,1H),2 .54-2.67(m,3H),2.67-2.78(m,1H),3.25-3.36(m,3H),3.77-3.88(m,1H),7.0 3(t,1H),7.28(d,1H),7.46(t,1H),7.57-7.68(m,1H),8.15-8.24(m,2H),8.29 (d,1H),8.43(d,1H),9.45(s,1H),9.63(s,1H),11.55(s,1H).m / z(ES+),[M+H] + =584.3.

[0220] Example 50 (S)-2-((R)-2,4-Dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)butanamide 3-(2-((2-Fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine, intermediate (387 mg, 0.94 mmol) and 2-((R)-2,4-dimethylpiperazin-1-yl)butanoic acid dihydrochloride, intermediate 46 (300 mg, 1.10 mmol) were suspended in anhydrous DCM (25 mL) and pyridine (0.3 mL, 3.71 mmol) was added. The mixture was cooled to 0° C. in an ice bath and T3P (1.5 mL, 2.52 mmol) was added dropwise. The ice bath was removed and the reaction mixture was stirred at 23° C. for 20 min. The reaction mixture was diluted with saturated NaHCO 3 (20 mL) and stirred at 23° C. for 30 min. The organic layer was separated and the aqueous phase was extracted with DCM (2×20 mL). The combined organic phase was filtered through a phase separator and evaporated in vacuo. H 2 O was added at a flow rate of 100 mL / min for 25 min. 2 O / ACN / NH 3 The residue was purified by preparative HPLC on an XBridge C18 column (10 μm, 250×50 mm) using a gradient of 20-70% acetonitrile in (95 / 5 / 0.2) buffer in two injections. Compounds were detected by UV at 269 nm. The first eluting isomer was collected and lyophilized to give (S)-2-((R)-2,4-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)butanamide, Example 50 (205 mg, 37%). 1 H NMR (500MHz, DMSO-d 6)δ 0.97(t,3H),1.10(d,3H),1.65-1.77(m,2H),1.77-1.87(m,1H),1.91-2.01(m,1H), 2.11(s,3H),2.40(s,3H),2.55-2.67(m,2H),2.67-2.77(m,1H),2.81-2.94(m,2H),3 .25(s,3H),3.55(t,1H),6.97(t,1H),7.40(t,1H),7.47(d,1H),7.5-7.58(m,1H),8 .05(d,1H),8.12(d,1H),8.24-8.34(m,2H),9.17(s,1H),9.62(s,1H),11.20(s,1H). m / z(ES+), [M+H] + =594.4.

[0221] Example 51 (R)-2-((R)-2,4-Dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)butanamide The second eluting isomer from the reaction of Example 50 was collected and lyophilized to give (R)-2-((R)-2,4-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)butanamide, Example 51 (210 mg, 38%). 1 H NMR (500MHz, DMSO-d 6)δ 0.95(t,3H),1.13(d,3H),1.57-1.69(m,1H),1.72-1.86(m,1H),2.00-2.09(m,1H) ),2.09-2.23(m,4H),2.38-2.58(m,6H),2.72-2.81(m,1H),2.81-2.91(m,1H),3.2 5(s,3H),3.44-3.53(m,1H),6.98(t,1H),7.35-7.45(m,2H),7.51-7.6(m,1H),8.0 3(d,1H),8.13(d,1H),8.24-8.36(m,2H),9.16(s,1H),9.61(s,1H),11.32(s,1H). m / z(ES+), [M+H] + =594.4.

[0222] The procedures described above for Examples 50-51 were repeated using the intermediates shown to give Examples 52-57, as set forth in Table 23 below.

[0223] [Table 51]

[0224] [Table 52]

[0225] [Table 53]

[0226] Example 58 (R)-2-((S)-2,4-Dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)propanamide Process 1 3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-amine, intermediate (210 mg, 0.39 mmol) and lithium 2-((S)-2,4-dimethylpiperazin-1-yl)propanoate, intermediate 51 (97 mg, 0.44 mmol, approximately 84 wt%) were suspended in DCM (10 mL) and pyridine (0.10 mL, 1.24 mmol) was added. The mixture was cooled to 0° C. and T3P (0.9 mL, 1.51 mmol, 50 wt% in EtOAc) was added dropwise. The reaction mixture was stirred at 22° C. for 1 h. Lithium 2-((S)-2,4-dimethylpiperazin-1-yl)propanoate, intermediate 51 (24 mg, 0.11 mmol) was added, followed by T3P (0.2 mL, 0.34 mmol) and the reaction mixture was stirred at 22 °C for 30 min. The reaction mixture was diluted with saturated NaHCO 3 (20 mL) and stirred at 22° C. for 15 min. The organic layer was separated and the aqueous layer was extracted with DCM (2×10 mL). The combined organic phases were filtered through a phase separator and concentrated in vacuo. 2 Diastereoisomers were separated by chiral SFC on a CelluCoat (5 μm, 250×30 mm) column using 32% EtOH / DEA (100:0.5) in water and a flow rate of 140 mL / min. Compounds were detected by UV at 220 nm. The first eluting isomer was collected and evaporated in vacuum to give 2-((S)-2,4-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)propanamide isomer 1 (125 mg, 45%, 99.9% de). 1 H NMR (500MHz, DMSO-d 6)δ -0.09(s,9H),0.77-0.89(m,1H),0.92-1.17(m,4H),1.25(d,3H),1.81-1.95(m,1H),2.1 3(s,3H),2.22-2.34(m,1H),2.39(s,3H),2.43-2.62(m,3H),2.67-2.86(m,2H),3.07-3. 65(m,6H),5.72(d,1H),5.87(d,1H),7.05(t,1H),7.35-7.48(m,2H),7.51-7.6(m,1H),8 .15(d,1H),8.19(s,1H),8.23-8.31(m,1H),8.31-8.41(m,1H),9.23(s,1H),9.86(s,1H).

[0227] Process 2 2-((S)-2,4-Dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)propanamide isomer 1 (123 mg, 0.17 mmol) was dissolved in anhydrous DCM (2 mL) and TFA (3 mL) was added. The reaction mixture was stirred at ambient temperature for 19 h. DCM (10 mL) was added followed by NaHCO 3 (10 mL) and MeOH (1 mL) were added. The organic layer was separated and the aqueous layer was extracted with a mixture of DCM / MeOH (5:1) (2×6 mL). The combined organic phases were filtered through a phase separator and concentrated in vacuo. H 2 was added at a flow rate of 19 mL / min for 20 min. 2 O / ACN / NH 3 The residue was purified by preparative HPLC on an XBridge C18 column (10 μm, 250×19 mm) using a gradient of 20-80% acetonitrile in (95 / 5 / 0.2) buffer. The compound was detected by UV at 269 nm. The product was collected and lyophilized to give (R)-2-((S)-2,4-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)propanamide, Example 58 (63 mg, 63%) as a white solid. 1 H NMR (500MHz, DMSO-d 6 )δ 1.03(d,3H),1.30(d,3H),1.86(t,1H),2.08-2.22(m,4H),2.40(s,3H),2.46 -2.62(m,2H),2.68-2.78(m,1H),2.79-2.91(m,2H),3.25(s,3H),3.69(q,1H) ,6.97(t,1H),7.33-7.45(m,2H),7.5-7.59(m,1H),8.03(s,1H),8.12(d,1H) ,8.25-8.36(m,2H),9.16(s,1H),9.64(s,1H),11.36(s,1H).m / z(ES+),[M+H] + =580.3.

[0228] Example 59 (S)-2-((S)-2,4-Dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)propanamide isomer 2 Process 1 The second eluting isomer from the reaction of Example 58, step 1 was collected and evaporated in vacuo to give 2-((S)-2,4-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)propanamide isomer 2 (120 mg, 43%, 99.7% de). 1 H NMR (500MHz, DMSO-d 6)δ -0.09(s,9H),0.81-0.91(m,1H),0.95-1.16(m,7H),1.95(t,1H),2.03-2.18(m,4H) ,2.33-2.43(m,4H),2.43-2.57(m,1H),2.58-2.72(m,3H),3.25(s,3H),3.4-3.56(m, 2H),3.84(s,1H),5.73(d,1H),5.87(d,1H),7.04(t,1H),7.40(t,1H),7.48(d,1H), 7.55(t,1H),8.11-8.22(m,2H),8.27(t,1H),8.33(s,1H),9.23(s,1H),9.84(s,1H).

[0229] Process 2 2-((S)-2,4-Dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)propanamide isomer 2 (118 mg, 0.17 mmol) was dissolved in anhydrous DCM (2 mL) and TFA (3 mL) was added. The reaction mixture was stirred at ambient temperature for 19 h. DCM (10 mL) was added followed by NaHCO 3 (10 mL) and MeOH (1 mL) were added. The organic layer was separated and the aqueous layer was extracted with a mixture of DCM / MeOH (5:1) (2×6 mL). The combined organic phases were filtered through a phase separator and concentrated in vacuo. H 2 was added at a flow rate of 19 mL / min for 20 min. 2 O / ACN / NH 3 The residue was purified by preparative HPLC on an XBridge C18 column (10 μm, 250×19 mm) using a gradient of 20-80% acetonitrile in (95 / 5 / 0.2) buffer. The compound was detected by UV at 269 nm. The product fractions were lyophilized to give (S)-2-((S)-2,4-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)propanamide, Example 59 (74 mg, 77%) as a white solid. 1 H NMR (500MHz, DMSO-d 6 )δ 1.12(d,3H),1.16(d,3H),2.02(t,1H),2.15(s,3H),2.16-2.22(m,1H),2.40(s ,3H),2.43-2.48(m,1H),2.54-2.66(m,3H),2.67-2.77(m,1H),3.25(s,3H),3.7 6-3.88(m,1H),6.97(t,1H),7.27(d,1H),7.40(t,1H),7.51-7.59(m,1H),8.00( s,1H),8.14(d,1H),8.26-8.34(m,2H),9.16(s,1H),9.58(s,1H),11.36(s,1H). m / z(ES+), [M+H] + =580.5.

[0230] Example 60 (R)-2-((S)-2,4-Dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)butanamide Process 1 Lithium 2-((S)-2,4-dimethylpiperazin-1-yl)butanoate, intermediate 52 (104 mg, 0.52 mmol) and 3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-amine, intermediate (210 mg, 0.39 mmol) were dissolved in DCM (10 mL) and pyridine (0.1 mL, 1.24 mmol) was added followed by T3P (1.0 mL, 1.68 mmol). The reaction mixture was stirred at 22° C. overnight. The reaction mixture was diluted with NaHCO 3 (15 mL), stirred for an additional 10 min, and extracted with DCM (3×7 mL). The combined organic phase was filtered through a phase separator and concentrated in vacuo. H 2 O at a flow rate of 100 mL / min for 20 min was added. 2 O / ACN / NH 3The residue was purified by preparative HPLC on an XBridge C18 column (10 μm, 250×50 mm) using a gradient of 20-80% acetonitrile in (95 / 5 / 0.2) buffer. Compounds were detected by UV at 269 nm. Pure fractions were pooled and lyophilized. 120 bar CO 2 Diastereoisomers were separated by chiral SFC on a ChiralPak IB column (5 μm, 250×30 mm) using 23% EtOH / DEA (100:0.5) in water and a flow rate of 150 mL / min. Compounds were detected using UV at 270 nm. The first eluting isomer was collected and evaporated in vacuum to give 2-((S)-2,4-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)butanamide isomer 1 (69 mg, 24%, 99.3% de). 1 H NMR (500MHz, DMSO-d 6 )δ -0.08(s,9H),0.80-0.96(m,2H),0.99(t,3H),1.06(d,3H),1.63-1.87(m,3H),2. 06-2.16(m,4H),2.39(s,3H),2.56(d,2H),2.73-2.86(m,3H),3.25(s,3H),3.31( s,1H),3.47-3.56(m,2H),5.78(dd,2H),7.05(t,1H),7.37-7.44(m,2H),7.52-7. 59(m,1H),8.13-8.21(m,2H),8.28(t,1H),8.33(s,1H),9.23(s,1H),9.61(s,1H).

[0231] Process 2 2-((S)-2,4-Dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)butanamide isomer 1 (67 mg, 0.09 mmol) was dissolved in DCM (2 mL) and TFA (3 mL) was added. The reaction mixture was stirred at 22° C. for 17 h. DCM (10 mL) and NaHCO 3 (15 mL) was added, shaken, the phases were separated and the aqueous layer was extracted with DCM (2×5 mL). The combined organic phases were filtered through a phase separator and concentrated in vacuo. H was added at a flow rate of 19 mL / min for 20 min. 2 O / ACN / NH 3 The residue was purified by preparative HPLC on an XBridge C18 column (10 μm, 250×19 mm) using a gradient of 20-80% acetonitrile in (95 / 5 / 0.2) buffer. The compound was detected by UV at 269 nm. The product peak was collected and lyophilized to give (R)-2-((S)-2,4-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)butanamide, Example 60 (31 mg, 56%) as a white solid. 1 H NMR (500MHz, DMSO-d 6 )δ 0.97(t,3H),1.10(d,3H),1.62-1.88(m,3H),1.97(t,1H),2.11(s,3H),2.39(s, 3H),2.55-2.67(m,2H),2.67-2.77(m,1H),2.82-2.95(m,2H),3.25(s,3H),3.56( t,1H),6.97(t,1H),7.40(t,1H),7.48(d,1H),7.55(t,1H),8.05(d,1H),8.12(d, 1H),8.24-8.37(m,2H),9.16(s,1H),9.63(s,1H),11.22(s,1H).m / z(ES+),[M+H] + =594.4.

[0232] Example 61 (S)-2-((S)-2,4-Dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)butanamide Process 1 The second eluting isomer from Example 60, step 1 was collected and evaporated in vacuo to give 2-((S)-2,4-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)butanamide (133 mg, 47%, 95.9% de). 1 H NMR (500MHz, DMSO-d 6 )δ -0.09(s,9H),0.82-0.91(m,1H),0.92-1.02(m,4H),1.12(d,3H),1.53-1.66(m,1H),1.69-1.84(m,1H) ),1.91-2.02(m,1H),2.02-2.1(m,1H),2.12(s,3H),2.39(s,3H),2.43-2.66(m,4H),2.74-2.84(m,1H ),3.25(s,3H),3.48-3.56(m,3H),5.77(d,1H),5.84(d,1H),7.05(t,1H),7.40(t,1H),7.49(d,1H),7 .52-7.59(m,1H),8.15(d,1H),8.18(s,1H),8.24-8.31(m,1H),8.33(s,1H),9.23(s,1H),9.73(s,1H).

[0233] Process 2 2-((S)-2,4-Dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)butanamide isomer 2 (131 mg, 0.18 mmol) was dissolved in DCM (2 mL) and TFA (3 mL) was added. The reaction mixture was stirred at 22° C. for 17 h. DCM (10 mL) and NaHCO 3 (15 mL) was added, shaken, the phases were separated and the aqueous layer was extracted with DCM (2×5 mL). The combined organic phases were filtered through a phase separator and concentrated in vacuo. H was added at a flow rate of 19 mL / min for 20 min. 2 O / ACN / NH 3 The residue was purified by preparative HPLC on an XBridge C18 column (10 μm, 250×19 mm) using a gradient of 20-80% acetonitrile in (95 / 5 / 0.2) buffer. The compound was detected by UV at 269 nm. The product was collected and lyophilized to give (S)-2-((S)-2,4-dimethylpiperazin-1-yl)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)butanamide isomer 2, Example 61 (65 mg, 60%) as a white solid. 1 H NMR (500MHz, DMSO-d 6 )δ 0.95(t,3H),1.13(d,3H),1.56-1.70(m,1H),1.72-1.85(m,1H),2.01-2.09(m,1H) ,2.09-2.23(m,4H),2.34-2.58(m,6H),2.73-2.81(m,1H),2.81-2.91(m,1H),3.25 (s,3H),3.45-3.54(m,1H),6.98(t,1H),7.36-7.46(m,2H),7.50-7.59(m,1H),8.0 3(d,1H),8.13(d,1H),8.25-8.37(m,2H),9.16(s,1H),9.62(s,1H),11.33(s,1H). m / z(ES+), [M+H] + =594.5.

[0234] Example 62 (R)-3-Ethoxy-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide DIPEA (688 μl, 3.94 mmol) was added in one portion to (R)-3-ethoxy-2-(4-methylpiperazin-1-yl)lithium propanoate, intermediate (237 mg, 1.09 mmol) and 3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-amine, intermediate (180 mg, 0.44 mmol) in DCM (1 mL) at 0° C. The resulting solution was stirred at 0° C. for 10 min. Then, 1-propanephosphonic acid cyclic anhydride, T3P (835 mg, 1.31 mmol) was added dropwise at 0° C. The solution was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (50 mL) and washed with saturated NaHCO 3 The organic layer was washed with water (2×50 mL) and brine (2×50 mL). 2 SO 4 The mixture was dried at 37° C., filtered and evaporated in vacuum. The residue was purified by preparative TLC using DCM / MeOH (20:1) as eluent. The product (50% ee) was purified by preparative chiral-HPLC on a Chiralpak IA (20×250 mm, 5 μm) using 20% ​​IPA in MTBE (0.1% DEA) as eluent at a flow rate of 20 mL / min for 19 min. The product was detected using wavelengths of 254 and 220 nm. The major isomer was collected to give (R)-3-ethoxy-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide, Example 62 (40 mg, 15%, 99.7% ee) as a white solid. 1 H NMR (300MHz, CD 3OD)δ 1.21(t,3H),2.33(s,3H),2.42(s,6H),2.50-2.73(m,4H),2.74-3.02(m,2H),3.15(s,3H),3.45-3.65(m,3H),3.86(dd,1H),3.9 7(dd,1H),7.02(t,1H),7.13(d,2H),7.31(t,1H),7.49-7.63(m,1H),7.90(s,1H),8.10(d,1H),8.25(s,1H),8.47-8.52(m,1H). 19 F NMR (282MHz, CD 3 OD) δ -125.71.m / z(ES+),[M+H] + =610.

[0235] Example 63 (R)-3-Ethoxy-N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide The procedure described above for Example 62 was repeated using Intermediates 18 and 63 to give Example 63 (80 mg, 24%, 97.9% ee) as a white solid. Purification was performed by preparative chiral-HPLC on a ChiralPak-AD-H-SL002, (20×250 mm) using 50% IPA in hexanes (0.1% DEA) over 56 min and a flow rate of 14 mL / min. Compounds were detected using 254 and 220 nm. The major isomer was evaporated in vacuo. 1 H NMR (300MHz, CD 3 OD)δ 1.21(t,3H),2.32(s,3H),2.45-2.72(m,4H),2.73-3.02(m,4H),3.21(s,3H),3.44-3.66(m,3H),3.78-4.0 4(m,2H),7.00-7.21(m,2H),7.42(t,1H),7.58-7.73(t,1H),8.16(s,1H),8.23-8.37(m,2H),8.42(t,1H). No exchangeable protons observed 19 F NMR (282MHz, CD3 OD)δ -149.01, -124.61 m / z(ES+), [M+H] + =614.

[0236] Example 64 (R)-3-(benzyloxy)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide Process 1 Sodium 3-(benzyloxy)-2-(4-methylpiperazin-1-yl)propanoate, intermediate 64 (317 mg, 0.93 mmol) and 3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-amine, intermediate (448 mg, 0.83 mmol) were suspended in ethyl acetate (20 mL) and pyridine (0.25 mL, 3.09 mmol) was added. The reaction mixture was cooled to 0° C. and T3P (1.0 mL, 1.68 mmol, 50 wt % in ethyl acetate) was added dropwise. The reaction mixture was stirred at 0° C. for 10 min and then at 22° C. for 14 h. The reaction mixture was cooled to 0° C., T3P (1.0 mL, 1.68 mmol) was added dropwise, and stirring was continued at 22° C. for 3 h. The reaction mixture was cooled again to 0° C., T3P (0.5 mL, 0.84 mmol) was added dropwise, and stirring was continued at 22° C. for 2 h. The reaction mixture was cooled again to 0° C., T3P (0.5 mL, 0.84 mmol) was added dropwise, and stirring was continued at 22° C. for 16 h. Water (5 mL) was added, and the mixture was stirred at 22° C. for 30 min. NaHSO 4 (20 mL) was added followed by DCM (10 mL) and the phases were separated. The aqueous phase was extracted with DCM (2×10 mL). The combined organic phase was washed with Na 2 SO 4Drying at 40° C., filtration and concentration in vacuo gave 3-(benzyloxy)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide (690 mg, quantitative), which was taken on directly to the next step. m / z (ES+), [M+H] + =802.3.

[0237] Process 2 3-(Benzyloxy)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide isomer 2 (600 mg, 0.75 mmol) was dissolved in anhydrous DCM (3 mL) and TFA (3 mL, 26 mmol) was added to the stirred solution at ambient temperature. The reaction mixture was stirred at 22° C. for 4 h. TFA (2 mL) was added and the reaction mixture was stirred at 22° C. for 3 days. TFA (2 mL) was added and stirring was continued for 4 days. TFA (2 mL) was added and the mixture was stirred at 22° C. overnight. DCM (20 mL) was added and the mixture was diluted with saturated NaHCO 3 (50 mL) and MeOH (3 mL) was added. The organic layer was separated and the aqueous phase was extracted with 10% MeOH in DCM (2×11 mL). The combined organic phase was filtered through a phase separator followed by a small plug of silica, which was washed with a mixture of DCM and MeOH. The combined filtrate was concentrated in vacuo. H was added at a flow rate of 100 mL / min for 30 min. 2 O / ACN / NH 3 The residue was purified by preparative HPLC on an XBridge C18 column (10 μm 250×50 mm) using a gradient of 20-80% acetonitrile in (95 / 5 / 0.2) buffer. Compounds were detected by UV at 269 nm. The product peak was collected and lyophilized. 100% MeOH / NH as eluent. 3The enantiomers were separated by preparative chiral HPLC on a Lux C4 column (30×250 mm, 5 μm) using a 2×2 ratio of 1:1 (100:0.1) and a flow rate of 40 mL / min. Compounds were detected by UV at 260 nm. The second eluting isomer was collected and evaporated in vacuo. H 2 O / ACN / NH 3 The residue was repurified by preparative HPLC on an XBridge C18 column (10 μm, 250×50 IDmm) using a gradient of 25-75% acetonitrile in (95 / 5 / 0.2) buffer. Compounds were detected by UV at 270 nm. Pure fractions were lyophilized to give (R)-3-(benzyloxy)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide, Example 64 (161 mg, 32%) as a solid. 1 H NMR (500MHz, DMSO-d 6 )δ 2.15(s,3H),2.26-2.44(m,7H),2.59-2.69(m,2H),2.71-2.82(m,2H),3.25 (s,3H),3.58(t,1H),3.79(dd,1H),3.91(dd,1H),4.54(s,2H),6.98(t,1H) ,7.24-7.36(m,5H),7.40(t,1H),7.44(d,1H),7.52-7.58(m,1H),8.01(d,1 H),8.14(d,1H),8.26-8.33(m,2H),9.17(s,1H),9.83(s,1H),11.21(s,1H). m / z(ES+), [M+H] + =672.5.

[0238] Example 65 (S)-3-(benzyloxy)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide The first eluting isomer from the reaction of Example 64, Step 2 was collected and evaporated in vacuo. The residue was dissolved in acetonitrile / water and lyophilized to give (S)-3-(benzyloxy)-N-(3-(2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-indol-7-yl)-2-(4-methylpiperazin-1-yl)propanamide Example 65 (63 mg, 12%) as a solid. 1 H NMR (500MHz, DMSO-d 6 ) δ 2.15(s,3H),2.27-2.44(m,7H),2.59-2.69(m,2H),2.72-2.82(m,2H),3.25(s, 3H),3.58(t,1H),3.79(dd,1H),3.91(dd,1H),4.54(s,2H),6.98(t,1H),7.24-7 .37(m,5H),7.40(t,1H),7.44(d,1H),7.51-7.58(m,1H),8.01(d,1H),8.14(d,1 H),8.26-8.33(m,2H),9.17(s,1H),9.83(s,1H),11.21(s,1H).m / z(ES+),[M+H] + =672.4.

[0239] Example 66 (R)-N-(3-(5-fluoro-2-(2-fluoro-3-(methylsulfonyl)phenylamino)pyrimidin-4-yl)-1H-indol-7-yl)-3-methoxy-2-(piperazin-1-yl)propanamide Process 1 Potassium carbonate (4.21 g, 30.45 mmol) was added to methyl 2-bromo-3-methoxypropanoate (3 g, 15.23 mmol) and tert-butyl piperazine-1-carboxylate (3.12 g, 16.75 mmol) in acetonitrile (60 mL) at 25 °C under air. The resulting mixture was stirred at room temperature for 15 h. The reaction mixture was filtered through Celite and the filter cake was washed with additional acetonitrile. The filtrates were combined and the solvent was removed under reduced pressure. The crude product was purified by flash alumina chromatography, elution gradient 0-100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give tert-butyl 4-(1,3-dimethoxy-1-oxopropan-2-yl)piperazine-1-carboxylate (2.300 g, 50.0%) as a colorless oil. m / z(ES+), [M+H] + =303.

[0240] Process 2 Lithium hydroxide (0.238 g, 9.92 mmol) was added to a slurry of tert-butyl 4-(1,3-dimethoxy-1-oxopropan-2-yl)piperazine-1-carboxylate (1.0 g, 3.31 mmol) in a solvent mixture of MeOH (5 mL), THF (5.00 mL), and water (25 mL), then stirred at room temperature for 1 h. The solvent was concentrated in vacuo to give crude lithium 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-methoxypropanoate (1.200 g) as a yellow solid. m / z (ES+), [M+H] + =289.

[0241] Process 3 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane (5398 mg, 9.99 mmol) was added to a solution of Intermediate 33 (415 mg, 1.00 mmol), lithium 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-methoxypropanoate (588 mg, 2.00 mmol), and DIPEA (1.745 mL, 9.99 mmol) in DCM (30 mL) at room temperature and then stirred at room temperature overnight. The reaction was diluted with water (100 mL) and extracted with DCM (3×20 mL). The combined organic phase was washed with water (10 mL) and brine (10 mL) and then diluted with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated in vacuo. The eluent was water (0.05% NH 3 The crude product was purified by preparative HPLC (XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 150 mm length) using decreasingly polar mixtures of 5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)amino)-3-methoxy-1-oxopropan-2-yl)piperazine-1-carboxylate (305 mg, 44.5%) as a yellow solid. m / z (ES+), [M+H] + =686.

[0242] Process 4 tert-Butyl 4-(1-((3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)amino)-3-methoxy-1-oxopropan-2-yl)piperazine-1-carboxylate (300 mg, 0.44 mmol) was added to a solution of 1:3 TFA-DCM (10 mL) and then stirred at room temperature for 1 h. The solvent was then concentrated in vacuo and the crude product was purified by preparative HPLC (XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. The appropriate fractions were concentrated to dryness to give N-(3-(5-fluoro-2-((2-fluoro-3-(methylsulfonyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-7-yl)-3-methoxy-2-(piperazin-1-yl)propanamide (200 mg, 78%) as a yellow solid. The compound was further purified by preparative chiral-HPLC on a chiralpak ID-3 column, eluting isocratically with 10% MeOH in MTBE (modified with 0.1% DEA) as eluent. The fractions containing the first eluted compound were concentrated to dryness to give Example 66, (R)—N-(3-(5-fluoro-2-(2-fluoro-3-(methylsulfonyl)phenylamino)pyrimidin-4-yl)-1H-indol-7-yl)-3-methoxy-2-(piperazin-1-yl)propanamide (39.0 mg, 19.43%) as a white solid. 1 H NMR (300MHz, DMSO-d 6 )δ 2.50(s,3H),2.68-2.71(m,2H),2.80-2.90(m,6H),3.30(s,3H),3.62-3.69(m,2H),3.76-3.83(m,1H),7.00-7.06(t,1H) ),7.44-7.49(t,1H),7.60-7.65(m,2H),8.16-8.27(m,3H),8.40-8.44(m,2H),9.47(s,1H),10.25(s,1H),12.20(s,1H). m / z(ES+), [M+H] +=586.

[0243] Example 67 The second eluting isomer fraction of Example 66 was concentrated to dryness to give Example 67, (S)—N-(3-(5-fluoro-2-(2-fluoro-3-(methylsulfonyl)phenylamino)pyrimidin-4-yl)-1H-indol-7-yl)-3-methoxy-2-(piperazin-1-yl)propanamide (35.0 mg, 17.50%) as a white solid. 1 H NMR (300MHz, DMSO-d 6 )δ 2.50(s,3H),2.73(m,2H),2.83-2.92(m,6H),3.30(s,3H),3.64-3.69(m,2H),3.76-3.82(m,1H),7.00-7.06(t,1H),7 .44-7.49(t,1H),7.60-7.65(m,2H),8.16-8.27(m,3H),8.41-8.44(m,2H),9.47(s,1H),10.30(s,1H),12.29(s,1H). m / z(ES+), [M+H] + =586.

[0244] Example 68: Enzyme Inhibition Test Enzyme inhibition studies were performed by incubating recombinant JAK1 (amino acids 866-1154, Life Technologies, #PV4774, Carlsbad, CA), JAK2 (amino acids 831-1132, AstraZeneca R&D Boston), or JAK3 (amino acids 781-1124, AstraZeneca R&D Boston) in 50 mM HEPES pH 7.3, 1 mM DTT, 0.01% Tween-20, 50 μg / ml BSA, and 10 mM MgCl 2 The assay was performed using buffer conditions of 0.1 mM. JAK enzymes were expressed in insect cells as N-terminal GST fusions and purified by glutathione-affinity and size-exclusion chromatography. Enzymes were assayed at their estimated upper limit of physiological ATP concentration of 5 mM in the presence of inhibitors dosed at 30, 3, 0.3, 0.03, 0.003 and 0 μM final test concentrations.

[0245] For JAK1, 4 nM enzyme was incubated with 1.5 μM peptide substrate (FITC-C6-KKHTDDGYMPMSPGVA-NH2 (SEQ ID NO: 1), Intonation, Boston, MA). For JAK2, 0.3 nM enzyme was incubated with 1.5 μM peptide substrate (5FAM-GEEPLYWSFPAKKK-NH2 (SEQ ID NO: 2), Intonation, Boston, MA). For JAK3, 0.1 nM enzyme was incubated with 1.5 μM peptide substrate (5FAM-GEEPLYWSFPAKKK-NH2 (SEQ ID NO: 2), Intonation, Boston, MA). Phosphorylated and non-phosphorylated peptides were separated and quantified by Caliper LC3000 system (Caliper Life Sciences, MA) and percent inhibition was calculated. The results of this assay are shown in Table 24.

[0246] Example 69: Interleukin-inducible JAK-STAT6-luciferase cellular assay (pSTAT6) A stable cell line based on U937 monocytes was generated that harbors a genomically incorporated luciferase reporter gene under the control of the STAT6 promoter (U937-STAT6-Luc). Cells were grown in growth medium (RPMI 1640 containing GlutaMAX and 25 mM Hepes, 10% FCS, 1% sodium, 1% non-essential amino acids, and 0.5 mg / ml geneticin (for selection)) at 37°C and 5% CO. 2 The strain was grown in suspension at 67° C.

[0247] Cells were harvested by centrifugation at 250g for 5 min and resuspended at 1000 cells per μl (pr) in assay buffer (20 mM HEPES, 1xHBSS and 0.1%BSA). Cells were stimulated with interleukin-13 (IL-13), also dissolved in assay buffer at 300 pM or 7 nM, respectively, giving 150 pM and 3.5 nM in the final assay, respectively, and increasing the signal to Emax Test and control compounds were applied to assay plates (low volume white 384-well plates) in serial dilutions from 10 mM to 0.5 nM in DMSO at 5 nl per well.

[0248] To each well, 4 μl of cells and 4 μl of interleukin (IL-13) were added, the plates were sealed and incubated for 4.5 hours at 37° C., then for 30 minutes at room temperature. The assay was developed by the addition of 4 μl of SteadyGlo (Promega) per well, and after 20 minutes the plates were read on an Envision plate reader equipped with a luminescence filter.

[0249] In the assay, the compounds were thus diluted 1600-fold and the IC of the compounds was determined by a dose-response curve for inhibition of interleukin-induced signaling. 50 The assay determines IC values ​​between 2 nM and 2 μM appropriate for control and test compounds. 50 A range of compounds was determined.

[0250] [Table 54]

[0251] [Table 55]

[0252] Example 70 - Alopecia Areata In Vivo Dose Escalation Study Compounds within the scope of the present disclosure were given orally at increasing doses to C3H / HeJ mice with established alopecia areata (AA) until obvious hair growth was observed. Hair growth was expressed as a Hair Index Score (HIS) evaluated weekly and compared to healthy mice (complete fur = HIS of 300) and mice with complete AA (no fur = HIS of 0).

[0253] A. Fauna Group 1 - (n=6) Alopecia areata treatment group Group 2 - (n=6) Untreated alopecia areata mice (control group) Group 3 - (n=6) healthy controls

[0254] B. Treatment All three groups were housed 6 by 6 in macrolon cages in the facility with a 12 h / 12 ​​h light / dark cycle at 21±2° C. and 55±15% relative humidity. Rodent food and water were available ad libitum. Photographs were taken before the start and immediately before the end of the study. Body weight (BW) and HIS were monitored weekly. Once a day, Group 1 mice were fed 5 g of crushed rodent food soaked in increasing doses of the compound of Example 35 in 10 mL tap water (BW and HIS were monitored weekly): 1. 0.5 mg / kg body weight (BW) for 2 weeks, 2. 2.5 mg / kg BW for 2 weeks, and 3. 12.5 mg / kg BW for 2 weeks.

[0255] C. Termination By the time of the last dose of the highest concentration of compound of Example 35, clear hair growth was observed and a hair growth score was recorded, but 1-2 hours after the last dose, mice from group 1 were sacrificed. Blood was collected from behind the eyes into EDTA-coated tubes (Multivette 300, Sarstedt) and kept on ice. Plasma was obtained by centrifugation (4°C, 4000G, 5 min) and 50 μL was transferred to a 96-well NUNC plate and stored at -20°C until analyzed for drug concentration by LC-MSMS.

[0256] D. Results The results for all three groups are presented in Figure 2 as a graph with HIS on the Y-axis and time (weeks) on the X-axis.

[0257] E. Results The mean plasma exposure (total concentration) of the compound of Example 35 at the termination time point was 338 nM with a HIS of 218.

[0258] The results are shown below. 1. The compound of Example 35 produced the desired response at the highest dose, but longer treatment was required to achieve a HIS=300. 2. For a full study (12 weeks) to demonstrate full efficacy (HIS=300), 12.5 mg / kg BW would be the preferred dose.

[0259] Example 71 - OVA lung inflammation model in vivo pharmacodynamic properties test Brown Norway rats were sensitized and challenged with chicken egg albumin (OVA) (Clinical and Experimental Allergy, 37 (2007) 973-988). After inhaling a dose of a micronized compound within the scope of the present disclosure, reduction in airway inflammation in the lungs of OVA-exposed Brown Norway rats was measured as the % reduction in eosinophils in bronchoalveolar lavage (BAL) compared to exposed but untreated rats using the following protocol. As a model control, an it overdose (2 x 300 μg / kg) of the model reference compound, budesonide, was used.

[0260] A. Fauna 74 animals were divided into 8 experimental groups and treated as follows: Group 1 (saline / saline / air), n=6 - Sham (saline) sensitization on days 0 (S1) and 7 (S2), and sham (saline) exposure on day 14 (P1). Treatment - room air Group 2 (OVA / saline / lactose), n = 8 - Al(OH) on days 0 (S1) and 7 (S2) 3 / OVA mixture followed by it sham (saline) exposure (P1) on day 14. Treatment - DPI lactose. Group 3 (OVA / OVA / lactose), n = 12 - Al(OH) on days 0 (S1) and 7 (S2) 3 / OVA mixture followed by itOVA challenge (P1) on day 14. Treatment - DPI lactose. Group 4 (OVA / OVA / Example 35), n=10 - Al(OH) on days 0 (S1) and 7 (S2) 3 / OVA mixture, followed by itOVA challenge on day 14 (P1). Treatment - DPI; compound of Example 35, target dose 0.03 μg / kg Group 5 (OVA / OVA / Example 35), n=10 - Al(OH) on days 0 (S1) and 7 (S2) 3 / OVA mixture, followed by itOVA challenge on day 14 (P1). Treatment - DPI; compound of Example 35, target dose 0.3 μg / kg Group 6 (OVA / OVA / Example 35), n=10 - Al(OH) on days 0 (S1) and 7 (S2) 3 / OVA mixture, followed by itOVA challenge on day 14 (P1). Treatment - DPI; compound of Example 35, target dose 3 μg / kg Group 7 (OVA / OVA / Example 35), n=10 - Al(OH) on days 0 (S1) and 7 (S2) 3 / OVA mixture, followed by itOVA challenge on day 14 (P1). Treatment - DPI; compound of Example 35, target dose 30 μg / kg Group 8 (OVA / OVA / budesonide), n=8 - Al(OH) on days 0 (S1) and 7 (S2) 3 Sensitization with / OVA mixture followed by it OVA challenge (P1) on day 14. Treatment - 2 x 300 μg / kg budesonide (model reference compound) it on day 14. Twice daily.

[0261] B. Experimental Procedure Before the start of the first sensitization (S1), body weight (BW) was recorded and all rats were marked on the tail with an identification number. BW was further recorded before S2 and before the termination time point (D15). BAL was measured in all animals. At the time of termination, the investigator was blinded to the status of the individual rats.

[0262] i. Sensitization On days 0 and 7, rats were administered OVA / Al(OH) 3A mixture of 100 μg OVA in 1 ml saline:100 mg Al / rat was injected subcutaneously (sc) and 0.5 ml / rat of B. pertussis toxin (0.1 μg / ml) was injected intraperitoneally (ip). Sham sensitization was performed by subcutaneous and intraperitoneal injection of isotonic saline of the same volume and dosage.

[0263] ii. Compound Administration Dry Powder Inhalation (DPI) Operating Procedure Each exposure system consisted of a flow-past exposure inhalation chamber, a rat restraining tube, and a Modified Wright Dust Feed mechanism. Measurements of aerosol concentrations in the inhalation chamber for each dose step were performed by filter sampling at one of the inhalation ports (AP40, 47 mm, Millipore). Different doses of the compound of Example 35 were achieved by varying the exposure time while keeping the test article concentration and flow rate in the exposure chamber constant. Rats in groups 2 and 3 were exposed to lactose in a restraining tube (Battelle chamber). The target inhalation dose (μg / kg) was calculated using the following formula, assuming an exposure duration of 2-10 minutes and a body weight of 250 g:

number

[0264] Intratracheal administration of a model reference compound (budesonide) Rats were weighed the day before OVA exposure. At the time of exposure, rats were anesthetized with an isoflurane mixture (air and 4% isoflurane) and in a supine position at an angle of 30-40° before injection of vehicle or compound. The intratracheal injection was performed using a modified metal cannula with a bolus-bulb at the end. Rats were placed in their cages in a head-up supine position until consciousness was regained. Reference compounds were administered twice daily, with the second daily administration 6 hours after the first daily administration. Injection volume: 0.25 mL / rat.

[0265] iii. Exposure (challenge with OVA) Five minutes (5') before OVA exposure, blood was drawn from the lingual vein (0.2 ml) and plasma (60 ul / well) was collected in a 96-deep well plate. Induction occurred on day 14 (P1) and was applied 2 hours after compound administration. Rats were anesthetized with an isoflurane mixture (air and 4% isoflurane), placed in supine position at an angle of 30-40°, and injected with isotonic saline or OVA (0.1 mg / ml). Intratracheal injection was performed using a modified metal cannula with a bolus bulb at the end. Rats were placed in their cages in a head-up supine position until consciousness was regained. Sham exposure was performed by it injection of isotonic saline of the same volume and manner. Injection volume: 0.25 ml / rat.

[0266] iv. Termination and bronchoalveolar lavage 22 hours after OVA exposure (P1), rats were euthanized by intraperitoneal injection of 1 ml pentobarbital (50 mg / ml). Blood was collected from the jugular vein into EDTA-coated tubes, centrifuged (Rotanta 46R, 480xg, 10 min, 20°C), and plasma samples were collected into 2x96-deep-well plates (60ul / well) placed on dry ice and will be stored at a minimum of -70°C for further analysis. Bronchoalveolar lavage (BAL) was performed by manually perfusing the whole lung with PBS. After exposing the trachea, a polyethylene tube (PE120) was inserted and tied with a suture. The tube was connected to a syringe pre-filled with 4.2 ml of room temperature PBS and slowly injected into the lungs for a duration of 10 seconds. Fluid was recollected by slow aspiration into the syringe. This procedure was performed twice. The final BAL fluid was transferred to a test tube (4 ml, polypropylene (PP)). The tube containing the BAL sample was weighed (assuming 1 ml of BALF equals 1 g). The BAL was kept on ice until centrifugation (Rotanta 46R, 300xg, 10 min, 4°C). After centrifugation, the supernatant was aliquoted into 4x96-well plates (0.1 ml / well) placed on dry ice and kept and stored at a minimum of -70°C until mediator analysis. The cell pellet was then resuspended in 0.5 ml of PBS and kept on ice until cell counting. The total and differential numbers of cells were counted using a semi-automated SYSMEX XT-1800i Vet (Sysmex, Kobe, Japan) with a gated program: BALrOVAi.

[0267] C. Results Based on filter analysis, the following pulmonary doses (μg / kg body weight) of micronized Example 35 were achieved: Group 4: 0.08 Group 5: 0.11 Group 6: 0.6 Group 7: 4.76

[0268] The results are presented in FIG. 3 as a bar graph with p-value or ns indicating non-significance above the bar, and the % reduction in eosinophils in each experimental group compared to the untreated third group (OVA / OVA).

[0269] The results show: 1. The compound of Example 35 reduced eosinophils in the BAL by 7% (non-significant), 28% (non-significant), 68% (p<0.01), and 61% (p<0.01) at lung doses of 0.08, 0.11, 0.6, and 4.76 μg / kg, respectively. 2. OVA challenge (group 3) significantly increased the number of eosinophils in the BAL. 3. The compound of Example 35 significantly reduces the presence of eosinophils in a dose-dependent manner with a maximum inhibition of 68% compared to the OVA control (Group 3), with a plateau in inhibition observed from the 0.6 μg / kg dose. 4. An overdose of 2*300 mg / kg of the model reference compound budesonide (group 8) showed a 97% inhibition of eosinophils in the range observed in this model. Furthermore, the present invention includes the following aspects. 1. A compound of formula (I): [ka] (In the formula: R 1 、R 3 , and R 4 are each independently selected from hydrogen and methyl; R 2 is hydrogen, methyl, and -CH 2 CH 2 Selected from OH; n is 1 or 2; R 5 is methyl, ethyl, and -CH 2 OR 8 Selected from; R 6 is selected from methyl, chlorine, and fluorine; R 7 is selected from methyl, ethyl, and cyclopropyl; and R 8 is selected from methyl, ethyl, and benzyl; or a pharma- ceutically acceptable salt thereof. 2. R 1 ~R 4 Each of is independently selected from hydrogen and methyl. 3. R 1 、R 3 , and R 4 are all hydrogen. Item 3. The compound according to any one of Items 1 and 2. 4. R 2 The compound according to any one of items 1 to 3, wherein is methyl. 5. R 5 is methyl or -CH 2 OR 8 Item 3. The compound according to item 1, wherein 6. R 8 6. The compound according to any one of items 1 to 5, wherein is methyl. 7. R 6 is a methyl or fluorine atom. 8. R 6 8. The compound according to any one of items 1 to 7, wherein is a fluorine atom. 9. R 7 is methyl. 10. The compound according to item 1, having the structure of formula (Ia):

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Claims

1. (R)-N-(3-(5-fluoro-2-(2-fluoro-3-(methylsulfonyl)phenylamino)pyrimidin-4-yl)-1H-indol-7-yl)-3-methoxy-2-(4-methylpiperazin-1-yl)propanamide, having an X-ray powder diffraction pattern with characteristic peaks at 7.6, 12.7, 14.8, 19.3 and 25.5 degrees 2-theta: 【Chemistry 1】 Crystalline form of.

2. 13. A medicament comprising the crystalline form of claim 1 for use in therapy.

3. 3. The agent of claim 2 for use in the treatment of a JAK1 associated disease.

4. 4. The method of claim 3, wherein the JAK1 associated disease is selected from type 1 diabetes, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, COPD, vitiligo and alopecia areata.

5. 10. A pharmaceutical composition comprising the crystalline form of claim 1 and a pharma- ceutically acceptable diluent, excipient or carrier.

6. 6. A pharmaceutical composition according to claim 5 for use in therapy.

7. 6. The pharmaceutical composition of claim 5 for use in treating a JAK1 associated disease.

8. 8. The pharmaceutical composition of claim 7, wherein the JAK1 associated disease is selected from type 1 diabetes, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, COPD, vitiligo, and alopecia areata.

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