Preparation of pyrimidinyl-3,8-diazabicyclo[3.2.1]octanylmethanone derivatives and their salts

Abstract

A process for preparing ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone and intermediates used in the process for its preparation.

Description

[Technical Field]

[0001] The present invention relates to a process for preparing ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone, a compound useful for inhibiting Janus kinases (JAKs). The present invention also relates to intermediates for preparing said compound. [Background technology]

[0002] ((S)-2,2-Difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone has the chemical formula C 18 H 21 F2N7O and the following structural formula:

[0003] [ka]

[0004] It has. A prior synthesis of ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone is described in commonly assigned U.S. Pat. No. 9,663,526, the contents of which are incorporated herein by reference in their entirety. Crystalline forms of ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimid-in-4-yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone free base are useful as inhibitors of protein kinases such as the enzyme Janus kinase, and as such are therapeutically useful as immunosuppressants for organ transplantation, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease (IBD), psoriasis, type 1 diabetes and diabetic complications, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia, and other indications where immunosuppression is desirable.

[0005] Therefore, it is desirable to provide a more efficient method for producing ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone and its p-toluenesulfonate salt, which provides the product in high yield and excellent purity. Summary of the Invention

[0006] The present invention relates to a compound of formula I:

[0007] [ka]

[0008] 1. A method for preparing a compound of formula (I), comprising: (a)(i) Structure:

[0009] [ka]

[0010] Compounds and structures having the following structure:

[0011] [ka]

[0012] wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, halo, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy; or (ii) Structure:

[0013] [ka]

[0014] (Wherein, R is C6 to C 12 aryl and C4-C9 heteroaryl, wherein the C6-C 12 preparing an activated ester having an aryl and a C4-C9 heteroaryl optionally substituted with a C1-C6 alkyl, -S(=O)-R0, -S(=O)2-R0, cyano, nitro, a C1-C6 alkoxy, or a halo, where R0 is a C1-C6 alkyl; (b) treating said activated ester or said salt with a compound having the structure:

[0015] [ka]

[0016] under appropriate conditions to form a compound of formula I The method includes: The present invention will be further understood from the following description, which is given by way of example only. The present invention is directed to processes for the preparation of ((S)-2,2-difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)methanone and novel intermediates thereof. While the present invention is not so limited, an appreciation of various aspects of the present invention will be gained through the following discussion and examples.

[0017] As used herein, the term "alkyl" refers to a group of the formula -C n H (2n+1) " refers to a straight or branched chain monovalent hydrocarbon radical of the formula: Non-limiting examples include methyl, ethyl, propyl, butyl, 2-methyl-propyl, 1,1-dimethylethyl, pentyl, and hexyl.

[0018] The term "alkoxy" as used herein means an alkyl substituent attached through an oxygen atom. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexyloxy.

[0019] As used herein, the term "benzyl" refers to a phenylmethyl group. The term "aryl" as used herein means an aromatic or partially unsaturated 6- to 8-membered monocyclic or 6- to 12-membered bicyclic carbocyclic ring, said carbocyclic ring being optionally substituted with one or more groups R. Examples include phenyl or naphthalenyl.

[0020] The term "heteroaryl," as used herein, refers to a monocyclic or bicyclic aromatic hydrocarbon containing 5 to 10 ring atoms in which at least one ring carbon atom is replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. Such heteroaryl groups may be bonded through a ring carbon atom or, where valence allows, a ring nitrogen atom. General examples of 10-membered heteroaryl groups include quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl, and pyrimido[4,5-d]pyrimidinyl.

[0021] As used herein, the term "halogen" or "halo" refers to fluoride, chloride, bromide, or iodide. The term "amino" as used herein refers to --NH.sub.2.

[0022] When a substituent is defined as a combination of two groups (e.g., alkoxyalkyl), the moiety is always attached through the second of the two named groups (in this case, the alkyl). Thus, for example, ethoxymethyl corresponds to CH3CH2-O-CH2-.

[0023] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. When substituents are described as being "independently selected" from a group, each substituent is selected independently of the others. Each substituent can therefore be the same or different from the other substituents. [Brief explanation of the drawings]

[0024] [Figure 1] FIG. 1 provides the powder X-ray diffraction pattern obtained for crystalline 2,2-difluorocyclopropane-1-(S)-carboxylate (R)-N-benzyl-1-phenylethan-1-aminium salt as described in Preparation 3 herein below. [Figure 2] structure:

[0025] [ka]

[0026] FIG. 1 provides a powder X-ray diffraction pattern obtained for the crystalline bis[(1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane][1,1′-biphenyl]-4,4′-diol complex having the formula: [Figure 3] FIG. 1 provides the powder X-ray diffraction pattern obtained for crystalline (1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane as described in Preparation 1 herein below. DETAILED DESCRIPTION OF THE INVENTION

[0027] According to a first aspect of the present invention, a compound of formula I:

[0028] [ka]

[0029] 1. A method for preparing a compound of formula (I), comprising: (a)(i) Structure:

[0030] [ka]

[0031] Compounds and structures having:

[0032] [ka]

[0033] wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, halo, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy; or (ii) Structure:

[0034] [ka]

[0035] (Wherein, R is C6 to C 12 aryl and C4-C9 heteroaryl, wherein the C6-C 12 preparing an activated ester having an aryl and a C4-C9 heteroaryl optionally substituted with C1-C6 alkyl, -S(=O)-R0, -S(=O)2-R0, cyano, nitro, C1-C6 alkoxy, or halo, where R0 is C1-C6 alkyl; (b) reacting the activated ester or salt with a compound of Formula IV:

[0036] [ka]

[0037] under appropriate conditions to form a compound of formula I The method includes: Below we describe several embodiments (E) of this first aspect of the invention, which for convenience are identified as E1.

[0038] E1. A method for preparing a compound of formula I as defined above. E2. The method of E1, wherein R1, R2, R3, and R4 are hydrogen. E3. The method of E1 or E2, wherein R is p-cyanophenyl or isoquinolin-3-yl.

[0039] E4. Formula I:

[0040] [ka]

[0041] 1. A process for preparing the p-toluenesulfonate salt of a compound of the formula: (a)(i) Structure:

[0042] [ka]

[0043] Compounds and structures having the following structure:

[0044] [ka]

[0045] wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, halo, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy; or (ii) Structure:

[0046] [ka]

[0047] (Wherein, R is C6 to C 12 aryl and C4-C9 heteroaryl, wherein the C6-C 12preparing an activated ester having an aryl and a C4-C9 heteroaryl optionally substituted with cyano, -S(=O)-R0, -S(=O)2-R0, nitro, C1-C6 alkoxy, or halo, where R0 is a C1-C6 alkyl; (b) reacting the activated ester or salt with a compound of Formula IV:

[0048] [ka]

[0049] under appropriate conditions to form a compound of formula I:

[0050] [ka]

[0051] forming a compound of (c) treating said compound with p-toluenesulfonic acid under appropriate conditions to obtain a compound of formula IA:

[0052] [ka]

[0053] Step of obtaining the p-toluenesulfonic acid salt of The method comprising: E5. The method of E4, wherein R1, R2, R3, and R4 are hydrogen.

[0054] E6. The method of any one of E4 or E5, wherein R is p-cyanophenyl or isoquinolin-3-yl. E7.Formula II:

[0055] [ka]

[0056] 1. A process for preparing a salt of (a) Structure:

[0057] [ka]

[0058] preparing a carboxylic acid having (b) treating the carboxylic acid with a compound having the structure:

[0059] [ka]

[0060] under appropriate conditions to form a salt of formula II. E8. Carboxylic acid having the structure:

[0061] [ka]

[0062] (Wherein, R5 is C1-C6 alkyl, C3-C6 cycloalkyl, benzyl, C6-C 12 aryl, or C4-C9 heteroaryl) to form a compound having the structure:

[0063] [ka]

[0064] (Wherein, R6 is C1-C5 alkyl, benzyl, C6-C 12 The method according to E7, wherein the compound is prepared by treating the compound with an ester compound having a C4-C9 aryl or C4-C9 heteroaryl.

[0065] E9. The method of E8, wherein R5 is n-propyl or n-butyl, and R6 is methyl or ethyl. E10. The method of any one of E7 to E9, wherein the reaction is carried out using n-Bu4NBr, n-Bu4NI, or n-Bu4NOH.

[0066] E11. Carboxylic acid is (a) Structure:

[0067] [ka]

[0068] (Wherein, R7 is C2-C6 alkyl, C3-C6 cycloalkyl, benzyl, C6-C 12 aryl, and C4-C9 heteroaryl) to form a compound having the structure:

[0069] [ka]

[0070] (Wherein, R6 is C1-C5 alkyl, benzyl, C6-C 12 aryl, or C4-C9 heteroaryl) under appropriate conditions to obtain an ester compound with the structure:

[0071] [ka]

[0072] forming an intermediate having (b) treating the intermediate produced in step (a) with a Lewis acid selected from the group consisting of FeCl3 and AlCl3 under appropriate conditions to obtain a compound of the structure:

[0073] [ka]

[0074] forming an alcohol compound having the formula: (c) reacting the alcohol compound with an oxidizing agent under appropriate conditions to form a carboxylic acid. The method according to E7, prepared by

[0075] E12.R7 is C5H 11 and R6 is methyl or ethyl. E13. The method of any one of E7 to E12, wherein the reaction is carried out using n-Bu4NBr, n-Bu4NI, or n-Bu4NOH.

[0076] E14. The method of any one of E7 to E13, wherein the Lewis acid is FeCl3. E15. The method of any one of E7 to E14, wherein the oxidizing agent is selected from periodate, chromate, peroxide, sodium hypochlorite, and potassium hypochlorite.

[0077] E16. The method of any one of E7 to E15, wherein the oxidizing agent is sodium hypochlorite. E17. Carboxylic acid is (a) Structure:

[0078] [ka]

[0079] (Wherein, R7 is C4-C6 alkyl, C1-C6 alkyl, C3-C6 cycloalkyl, benzyl, C6-C 12 aryl, or C4-C9 heteroaryl) to form a compound having the structure:

[0080] [ka]

[0081] (Wherein, R6 is C1-C5 alkyl, benzyl, C6-C 12and C4-C9 heteroaryl), under appropriate conditions to obtain an ester compound having the structure:

[0082] [ka]

[0083] forming an intermediate having (b) treating the intermediate produced in step (a) under appropriate conditions with a base selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, cesium carbonate, lithium carbonate, potassium carbonate, ammonium sodium carbonate, ammonium carbonate, lithium bicarbonate, sodium bicarbonate, potassium carbonate, metal or ammonium carboxylates, monobasic, dibasic, and tribasic metal phosphates to produce a compound of the structure:

[0084] [ka]

[0085] forming an alcohol compound having (c) reacting the alcohol compound with an oxidizing agent selected from the group consisting of periodate, chromate, peroxide, sodium hypochlorite, and potassium hypochlorite under appropriate conditions to provide a carboxylic acid. The method according to E7, prepared by

[0086] E18.R7 is C5H 11 and R6 is methyl or ethyl. E19. The method of either E17 or E18, wherein the reaction is carried out using n-Bu4NBr.

[0087] E20. The method of any one of E17 to E19, wherein the base is potassium hydroxide. E21. The method of any one of E17 to E20, wherein the oxidizing agent is selected from periodate, chromate, peroxide, sodium hypochlorite, and potassium hypochlorite.

[0088] E22. The method of any one of E17 to E21, wherein the oxidizing agent is sodium hypochlorite. E23.Formula III:

[0089] [ka]

[0090] or a salt thereof, or a solvate thereof, wherein R8 is an optionally substituted arylmethylene, and the salt is a dihydrochloride or dihydrobromide salt.

[0091] E24. The compound according to E23, wherein R8 is benzyl and the salt is the dihydrochloride salt. E25. A compound or salt thereof according to any one of aspects E23 or E24, wherein said solvate is a hydrate.

[0092] E26.Formula III:

[0093] [ka]

[0094] or a salt thereof, or a solvate thereof, wherein R8 is an optionally substituted arylmethylene, and the salt is a dihydrochloride or dihydrobromide salt, and the compound has the structure:

[0095] [ka]

[0096] wherein R8 is an optionally substituted arylmethylene and X is methoxy, ethoxy, Cl, Br, or I, by reacting a compound having the structure:

[0097] [ka]

[0098] under appropriate conditions to form a compound of formula III. E27.Formula IV:

[0099] [ka]

[0100] is converted under appropriate conditions into a compound of formula III:

[0101] [ka]

[0102] or a salt or solvate thereof, wherein R8 is optionally substituted arylmethylene, and said salt is a dihydrochloride or dihydrobromide salt.

[0103] E28. The method according to E27, wherein R8 is benzyl and said suitable conditions comprise a hydrogenating agent or a reducing agent. E29.Formula IV:

[0104] [ka]

[0105] is converted under appropriate conditions into a compound of formula III:

[0106] [ka]

[0107] or a salt or solvate thereof, wherein R8 is optionally substituted arylmethylene, and said salt is a dihydrochloride or dihydrobromide salt.

[0108] E30. The process according to E29, wherein R8 is benzyl and said suitable conditions comprise a hydrogenating agent or a reducing agent. E31. (a)(i) Structure:

[0109] [ka]

[0110] A compound having and structure:

[0111] [ka]

[0112] wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, halo, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy; or (ii) Structure:

[0113] [ka]

[0114] (Wherein, R is C6 to C 12 aryl and C4-C9 heteroaryl, wherein the C6-C 12 preparing an activated ester having an aryl and a C4-C9 heteroaryl optionally substituted with cyano, -S(=O)-R0, -S(=O)2-R0, nitro, C1-C6 alkoxy, or halo, where R0 is a C1-C6 alkyl; (b) reacting the salt with a compound of Formula IV:

[0115] [ka]

[0116] under appropriate conditions to form a compound of formula I:

[0117] [ka]

[0118] forming a compound of 1. A compound of formula I prepared by a process comprising: E32. The compound according to E31 or a salt thereof, wherein R1, R2, R3, and R4 are hydrogen.

[0119] E33. A compound according to any one of aspects E31 or E32, or a salt thereof, wherein R is p-cyanophenyl or isoquinolin-3-yl. E34.Formula IV:

[0120] [ka]

[0121] is converted under appropriate conditions into a compound of formula III:

[0122] [ka]

[0123] or a salt thereof, wherein R8 is optionally substituted arylmethylene, and said salt is a dihydrochloride or dihydrobromide salt.

[0124] E35. A compound according to any one of aspects E31 to E34, or a salt thereof, wherein R8 is benzyl and said suitable conditions comprise a hydrogenating agent or a reducing agent. E36.Formula I:

[0125] [ka]

[0126] p-toluenesulfonic acid salt of the compound (a)(i) Structure:

[0127] [ka]

[0128] Compounds and structures having the following structure:

[0129] [ka]

[0130] wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, halo, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy; or (ii) Structure:

[0131] [ka]

[0132] (Wherein, R is C6 to C 12 aryl and C4-C9 heteroaryl, wherein the C6-C 12 preparing an activated ester having an aryl and a C4-C9 heteroaryl optionally substituted with cyano, -S(=O)-R0, -S(=O)2-R0, nitro, C1-C6 alkoxy, or halo, where R0 is a C1-C6 alkyl; (b) reacting the salt with a compound of Formula IV:

[0133] [ka]

[0134] under appropriate conditions to form a compound of formula I:

[0135] [ka]

[0136] forming a compound of (c) treating said compound with p-toluenesulfonic acid under appropriate conditions to obtain a compound of formula IA:

[0137] [ka]

[0138] Step of obtaining the p-toluenesulfonic acid salt of 1. A p-toluenesulfonic acid salt prepared by a process comprising: E37. The p-toluenesulfonate salt prepared according to E36, wherein R1, R2, R3, and R4 are hydrogen.

[0139] E38. The p-toluenesulfonic acid salt prepared according to any one of the embodiments E36 or E37, wherein R is p-cyanophenyl or isoquinolin-3-yl. E37.Structure:

[0140] [ka]

[0141] wherein A is C1-C6 alkyl, comprising: (a) reacting a compound having the structure:

[0142] [ka]

[0143] wherein X is halo, is reacted with acetamide under appropriate conditions in the presence of a catalyst to produce a compound of the formula:

[0144] [ka]

[0145] preparing a protected compound having (b) treating the protected compound under appropriate conditions to obtain a compound of the structure:

[0146] [ka]

[0147] forming a compound having The method comprising: E38. The method according to E37, wherein A is methyl and X is bromo.

[0148] E39. The method of any one of E37 or E38, wherein the catalyst is CuI and a ligand selected from the group consisting of rac-trans-N,N'-dimethylcyclohexane-1,2-diamine and N,N-dimethylethylenediamine.

[0149] E40. The method of any one of E37 to E39, wherein step (b) is carried out under acidic conditions. Synthesis method The following schemes and written descriptions provide general details for the preparation of compounds of Formula I, or their p-toluenesulfonic acid salts. In particular, the compounds or salts may be prepared by the procedures described with reference to the schemes that follow, or by specific methods described in the Examples, or by processes similar to any of the above.

[0150] Those skilled in the art will appreciate that the experimental conditions illustrated in the following schemes are illustrative of conditions suitable for effecting the transformations shown, and that it may be necessary or desirable to vary the exact conditions used for the preparation of compounds of formula I or their p-toluenesulfonic acid salts.

[0151] Furthermore, those skilled in the art will understand that at any stage in the synthesis of the compound of Formula I or its p-toluenesulfonate salt, it may be necessary or desirable to protect one or more sensitive groups to prevent undesired side reactions. In particular, it may be necessary or desirable to protect amino or carboxylic acid groups. The protecting groups used in the preparation of the compounds of the present invention may be used in a conventional manner. See, for example, "Greene's Protective Groups in Organic Synthesis," 3rd Edition, by Theodora W Greene and Peter GM Wuts (John Wiley and Sons, 1999), which is incorporated herein by reference and which also describes methods for the removal of such groups, particularly those described in Chapter 7 ("Protection for the Amino Group") and Chapter 5 ("Protection for the Carboxyl Group").

[0152] Thus, the compound of formula I or its p-toluenesulfonic acid salt can be prepared by the procedures described in the general method set forth below, or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing derivatives of formula I, as well as any novel intermediates used therein. Those skilled in the art will understand that the following reactions may be heated thermally or under microwave irradiation. It will further be understood that it may be necessary or desirable to carry out transformations in a different order than those described in the schemes, or to modify one or more transformations, to provide the desired compounds of the present invention.

[0153] Those skilled in the art will also recognize that some compounds of the present invention are chiral and therefore can be prepared as racemic or scalemic mixtures of enantiomers. There are several methods for separating enantiomers and they are well known to those skilled in the art. The preferred method for routinely separating enantiomers is supercritical fluid chromatography using a chiral stationary phase.

[0154] The compound of formula I or its p-toluenesulfonate salt can be prepared from compounds A-1, A-2, and C-3 as illustrated by Scheme A. Compounds of formula A-1, A-2, and C-3 are commercially available or can be synthesized by those skilled in the art according to the preparation methods described in the literature or herein. For these purposes, PG is a protecting group, and may be, for example, tert-butoxycarbonyl, as known to those skilled in the art. Compounds of formula A-3 can be prepared from compounds of formula A-1 and A-2 according to step (i), an aromatic nucleophilic substitution reaction in the presence of an organic base. Preferred conditions include triethylamine in methanol at 0°C to room temperature. This reaction (i) can be carried out in various solvents, including methanol, 2-MeTHF, DMSO, THF, or combinations thereof. Organic bases used in the reaction include bases such as tertiary amines, DBN, guanidine, amidine, NMI, potassium carbonate, potassium phosphate, lithium hydroxide, lithium methoxide, and lithium carbonate.

[0155] Compounds of formula A-5 can be prepared from compounds of formula A-3 by following process steps (ii) and (iii), nucleophilic substitution with compounds of formula C-3 under Buchwald-Hartwig cross-coupling conditions or via acid and elevated temperatures, followed by deprotection via either inorganic or organic acids. Typical Buchwald-Hartwig conditions involve the use of a suitable palladium catalyst and a suitable chelating phosphine ligand, along with an inorganic base in a suitable organic solvent at elevated temperatures, either thermally or under microwave irradiation. Preferred conditions include a) palladium(II) acetate and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl or Xantphos with sodium tert-butoxide; b) potassium phosphate or cesium carbonate in DMA at 120-140 °C under microwave irradiation; or c) BrettPhos Pd G3 with cesium carbonate as the base and DMA or dioxane as the solvent at 40 °C. Typical acidic conditions include a suitable inorganic acid in a suitable alcoholic solvent at elevated temperatures, either thermally or under microwave irradiation. Preferred conditions include concentrated hydrochloric acid in isopropanol at 140°C under microwave irradiation. Alternatively, deprotection occurs in situ during step (ii) of the process. Compounds of formula A-6 can be prepared from compounds of formula A-5 according to step (iv) of the process, an amide bond formation reaction with a compound of formula BC(O)X, where X can be chloro, hydroxy, a suitable leaving group, or an anhydride (e.g., (S)-2,2-difluorocyclopropane-1-carboxylic acid). When the compound of formula BC(O)X is an acid chloride (e.g., Example 2), preferred conditions include triethylamine in dichloromethane at room temperature. When the compound of formula BC(O)X is a carboxylic acid (e.g., Example 1), activation of the carboxylic acid using a suitable organic base and a suitable coupling agent is used. Preferred conditions include DIPEA or triethylamine and HATU in dichloromethane or DMF at room temperature. Many other amide bond-forming reagents are effective for this transformation, including acid chlorides, CDI / HOPO, T3P, EDCl, and DPPCl. Trifluoroethanol is a good alternative solvent.

[0156] [ka]

[0157] Alternatively, the compound of formula I or its p-toluenesulfonic acid salt can be prepared from compounds A-3 and C-3 as illustrated by Scheme B. The compound of formula A-3 is prepared as described in Scheme A. The compound of formula C-3 is commercially available or can be synthesized by those skilled in the art according to the preparation methods described in the literature or herein. The compound of formula B-1 can be prepared from the compound of formula A-3 by following process step (i): deprotection reaction via either an inorganic or organic acid in a suitable organic solvent. Preferred conditions include hydrochloric acid or TFA in dioxane or DCM. This reaction can be carried out in trifluoroethanol. Other acids such as acetic acid, phosphoric acid, citric acid, L-tartaric acid, methanesulfonic acid, and sulfuric acid can also be used.

[0158] Compounds of formula B-2 can be prepared from compounds of formula B-1 and BC(O)X according to process step (ii), an amide bond formation reaction, as described in Scheme A. Compounds of formula A-6 can be prepared from compounds of formula B-2 according to process step (iii), a nucleophilic substitution reaction with compounds of formula C-3 under Buchwald-Hartwig cross-coupling conditions or via acid and elevated temperature, as described in Scheme A.

[0159] [ka]

[0160] The compound of formula C-3 used in Scheme A and Scheme B can be prepared from the compound of formula C-1 as illustrated in Scheme C. The compound of formula C-1 is commercially available or can be synthesized by one skilled in the art according to the preparation methods described in the literature or herein. The compound of formula C-2 can be prepared from the compound of formula C-1 according to process step (i) an alkylation reaction with an appropriately substituted alkyl halide of formula AX (wherein X is Cl, Br, or I) in the presence of an inorganic or organic base and a solvent such as DMF, or an addition reaction to an epoxide in the presence of an inorganic or organic base. The compound of formula C-3 can be prepared from the compound of formula C-2 according to process step (ii) a reduction, which is typically carried out in the presence of a metal catalyst such as palladium or nickel, hydrogen gas at a pressure of 1 to 50 atmospheres, and a protic solvent such as methanol.

[0161] [ka] [Example]

[0162] Preparation and Examples The following non-limiting preparations and examples illustrate the preparation of compounds and salts of the present invention. In the examples and preparations presented below, and in the schemes described above, the following abbreviations, definitions, and analytical procedures may be referenced. Other abbreviations common in the art may also be used. Compounds of the present invention have been named using ChemDraw Professional™ version 18.0 (Perkin Elmer) or have been given names believed to be consistent with IUPAC nomenclature.

[0163] 1H nuclear magnetic resonance (NMR) spectra were consistent with the proposed structures in all cases. Characteristic chemical shifts (δ) are given in parts per million downfield from tetramethylsilane, and conventional abbreviations are used to designate major peaks, e.g., s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and br, broad. The following abbreviations are used for common NMR solvents: CD3CN, deuteroacetonitrile; CDCl3, deuterochloroform; DMSO-d6, deuterodimethyl sulfoxide; and CD3OD, deuteromethanol. Where appropriate, tautomers may be recorded in the NMR data, and some exchangeable protons may be invisible. Some resonances in the NMR spectrum appear as complex multiplets because the isolate is a mixture of two conformers.

[0164] Mass spectra were recorded using electron impact ionization (EI), electrospray ionization (ESI), or atmospheric pressure chemical ionization (APCI). The observed ions are reported as MS m / z and are the positive ions of the compounds [M]. + , compound plus proton [MH] + , or the compound plus sodium ions [MNa] + In some cases, [MH-(missing fragment)] + In some cases, only fragment ions reported as chlorine ( 35 Cl and / or 37 Cl), bromine ( 79 Br and / or 81 Br), and tin ( 120 Sn) isotopes.

[0165] When TLC, chromatography, or HPLC is used to purify a compound, one skilled in the art can select any suitable solvent or combination of solvents to purify the desired compound. Chromatographic separations (except HPLC) were performed using silica gel adsorbent unless otherwise noted.

[0166] All reactions were carried out under a nitrogen or argon gas atmosphere with continuous stirring unless otherwise noted. In some cases, the reaction was purged with nitrogen or argon gas before initiation. In this case, nitrogen or argon gas was bubbled through the liquid phase of the mixture for approximately the specified time. Solvents used were commercially available anhydrous grades. All starting materials were commercially available products. In some cases, Chemical Abstracts Service® (CAS) identification numbers are provided for clarity. Those skilled in the art will appreciate that the term "concentration," as used herein, generally refers to evaporation of the solvent under reduced pressure, typically accomplished using a rotary evaporator.

[0167] The following abbreviations are used herein: ACN: acetonitrile; BrettPhos Pd G3: [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; CDI: 1,1′-carbonyldiimidazole; Cs2CO3: Cesium carbonate; DMF: N,N-dimethylformamide; ESI: electrospray ionization; EtOAc: ethyl acetate; g: grams; HPLC: high performance liquid chromatography; HRMS: high-resolution mass spectrum; KOH: potassium hydroxide; MeOH: methanol; MIBK: methyl isobutyl ketone; mg: milligram; mL: milliliter; mmol: millimolar; Mpa: megapascal; MTBE: methyl tert-butyl ether; Pd / C: palladium on carbon; THF: tetrahydrofuran T3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide. Preparation 1: 4-((1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (a) (1R,5S)-8-benzyl-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane

[0168] [ka]

[0169] Dissolve (1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane (5.0 g, 18 mmol) in methanol (50 mL) and 2-methyltetrahydrofuran (25 mL) and cool the solution to 0 °C. Add 2,4-dichloropyrimidine (2.99 g, 20 mmol). Add N,N-diisopropylethylamine (10.8 mL, 62 mmol). Stir the reaction until complete. Allow the solution to warm to room temperature. Add water (50 mL) and heat the reaction to 55 °C. The reaction may be seeded. Cool the reaction and isolate the product by filtration and dry under vacuum. Isolate (1R,5S)-8-benzyl-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane (5.3 g) as a crystalline white solid. 1 H NMR (400 MHz, DMSO) δ 8.06 (d, J = 6.1 Hz, 1H), 7.59 - 6.97 (m, 5H), 6.72 (d, J = 6.2 Hz, 1H), 4.15 (s, 1H), 3.56 (s, 3H), 3.26 (s, 2H), 3.07 (s, 2H), 1.99 (dd, J = 8.8, 4.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 2H). 13C NMR (101 MHz, DMSO) δ 164.2, 159.8, 157.5, 139.8, 128.9, 128.6, 127.3, 102.7, 57.9, 56.0, 25.6. mp: 117.6 °C. Alternative procedure: (1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1] dihydrochloride (5 g, 18.17 mmol) and methanol (25 mL) were charged to a 50 mL reactor. N,N-diisopropylethylamine (9.8 mL, 56 mmol, 3.1 equiv.) was added to the slurry. A solution of 2,4-dichloropyrimidine (2.6 g, 17 mmol, 0.96 equiv) in 2-methyltetrahydrofuran (25 mL) and methanol (5 mL) was added over 30 min. The reaction was stirred until complete and then carried on directly to Step 2. (b) 4-((1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

[0170] [ka]

[0171] (1R,5S)-8-benzyl-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane (24 g, 76.2 mmol) was dissolved in methanol (175 mL) and 2-methyltetrahydrofuran (110 mL) and water (12 mL) was added. 1-Methyl-1H-pyrazol-4-amine hydrochloride (12.2 g, 91.5 mmol, 1.2 equiv.) was charged. The solution was heated to 60°C until the reaction was complete. The reaction was cooled to 45°C and water (190 mL) was added. 45 wt% aqueous potassium hydroxide (16 mL) was added. The reaction was optionally seeded. The slurry was cooled to 15°C. The product was isolated by filtration. 4-((1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (85% yield) is isolated as a white crystalline solid. 1H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 7.88 (d, J = 5.9 Hz, 1H), 7.73 (s, 1H), 7.42 (t, J = 4.0Hz, 3H), 7.38 - 7.30 (m, 2H), 7.26 (t, J = 7.3 Hz, 1H), 6.03 (d, J = 6.0 Hz, 1H), 3.88 (s, 2H), 3.76 (d, J = 1.3 Hz, 3H), 3.57 (s, 2H), 3.33 (s, 3H), 3.03 (d, J = 11.9 Hz, 2H), 1.99 (dd, J = 7.6, 3.7 Hz, 2H), 1.55 (t, J = 6.9 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 163.9, 159.4, 156.7, 139.9, 130.0, 128.9, 128.6, 127.2, 124.3, 120.2, 94.1, 58.2, 56.2, 50.5, 39.0, 25.7. mp: 153.6 °C. Alternative Procedure: To the solution from Step 1, add methanol (15 mL) and water (2.5 mL). Add 1-methyl-1H-pyrazol-4-amine hydrochloride (2.8 g, 1.2 equiv., 21 mmol) and heat the reaction to 65 °C until complete. Cool the reaction to 45 °C. Add 1 M aqueous potassium hydroxide solution (46 mL, 46 mmol). The solution may be seeded. The slurry is cooled to 15° C. The product is isolated by filtration. The solid is dried in a vacuum oven to give 4-((1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (5.2 g, 14 mmol, 82% yield). Preparation 2. 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

[0172] [ka]

[0173] 4-((1R,5S)-8-Benzyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (10 g, 23.9 mmol) is combined with water (25 mL) and concentrated hydrochloric acid (3.53 mL, 43.02 mmol, 1.8 equiv.). Isopropanol (11 mL) is added and the pH is adjusted to pH 4 using 1 M aqueous HCl (4.78 mL, 4.78 mmol, 0.2 equiv.). Palladium hydroxide (10%) on carbon (0.3 g) is added and the mixture is heated to 40 °C. Hydrogen gas is added under pressure and the mixture is stirred until the reaction is complete. The mixture is brought to 25 °C and the catalyst is filtered. Water (47 mL) and isopropanol (10 mL) are added and the mixture is cooled. Potassium hydroxide solution in water (2.5 M, 21 mL, 2.2 equivalents) is added. The mixture is then isolated by filtration and washed with water. 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine is isolated as a crystalline white solid. 1 H NMR (400 MHz, DMSO) δ 8.77 (s, 1H), 7.86 (d, J = 5.9 Hz, 1H), 7.72 (s, 1H), 7.44 (s, 1H), 6.01 (d, J = 6.0 Hz, 1H), 3.85 (s, 2H), 3.77 (s, 3H), 3.52 - 3.46 (m, 2H), 2.93 (d, J = 11.9 Hz, 2H), 1.66 (dd, J = 8.2, 4.3 Hz, 2H), 1.54 (t, J = 6.5 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 164.0, 159.3, 156.6, 130.0, 124.3, 120.3, 94.1, 53.5, 51.3, 39.0, 28.9.mp:243.2℃. Preparation 3. (S)-2,2-Difluorocyclopropane-1-carboxylic acid 2,2',2''-nitrilotris(ethan-1-ol) salt

[0174] [ka]

[0175] A 100 mL reactor was charged with ACN (50.0 mL) and triethanolamine (12.2 g, 1.0 equiv.). The solution was heated to 45° C., and a premixed solution of (S)-2,2-difluorocyclopropane-1-carboxylic acid (10.1 g, 1.0 equiv.) in MTBE (50.0 mL, approximately 20% w / w), prepared as described in Preparation 68 of U.S. Pat. No. 9,663,526, was added dropwise over 100 minutes. After the addition, the reaction was held at 45° C. for 30 minutes and then cooled to 20° C. at a rate of 0.25° C. / min. The mixture was granulated for 30 minutes, filtered, washed with MTBE (40.0 mL), and dried under vacuum at 50° C. 1 H NMR (400 MHz, DMSO-d6) δ 6.85 (s, 4H), 3.61 (t, J = 5.7 Hz, 6H), 2.97 (t, J = 5.7 Hz, 6H), 2.38 (ddd, J = 15.4, 10.8, 7.9 Hz, 1H), 1.84 - 1.62 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 169.0, 115.9, 113.1 (dd, J = 285.9, 281.2 Hz), 113.1, 110.3, 57.4, 56.5, 27.7, 27.6 (dd, J = 12.0, 9.2 Hz), 27.6, 27.5, 16.2, 16.1 (t, J = 9.8 Hz), 16.0.mp:82.4℃. Preparation 4. 2,2-Difluorocyclopropane-1-(S)-carboxylate (R)-N-benzyl-1-phenylethan-1-aminium salt

[0176] [ka]

[0177] To a 250 mL vessel was added MTBE (134 mL), (S)-2,2-difluorocyclopropane-1-carboxylic acid 2,2',2''-nitrilotris(ethan-1-ol) salt (20.0 g, 1.0 equiv.), and a premixed solution of sulfuric acid (4.3 mL, 1.1 equiv.) in water (86.0 mL). The mixture was stirred until all solids dissolved, and the layers were allowed to settle. The layers were separated, and the bottom (aqueous) layer was back-extracted with MTBE (58 mL). The combined organic layers were dried by azeotropic distillation to a final concentration of approximately 15% (w / w) (S)-2,2-difluorocyclopropane-1-carboxylic acid in MTBE. To this solution was added the chiral amine (R)-(+)-N-benzyl-α-methylbenzylamine (13.0 g, 0.85 equiv.) dropwise over approximately 1 h. After approximately 25% of the amine had been added, the reaction was seeded with previously purified (R)-N-benzyl-1-phenylethan-1-amine(S)-2,2-difluorocyclopropane-1-carboxylate (50 mg, 0.002 equiv.). After the amine had been added, the slurry was granulated, filtered, washed with MTBE (12.0 mL) pre-cooled to 10°C, and the solid was dried under vacuum at 50°C. The crude solid (10.57 g) was returned to the same vessel, and MeCN (35.0 mL) was added. The slurry was heated to 80°C until the solid was completely dissolved. The solution was cooled to 22°C at a rate of 0.2°C / min and granulated. The product was collected by filtration, washed with MeCN (13.0 mL), and then dried under vacuum at 50°C. 1 H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 2H), 7.46 (d, J = 6.9 Hz, 2H), 7.43 - 7.24 (m, 9H), 4.00 (q, J = 6.7 Hz, 1H), 3.74 (d, J = 13.3 Hz, 1H), 3.65 (s, 1H), 2.50 - 2.39 (m, 1H), 1.90 - 1.66 (m, 2H), 1.43 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 168.5, 142.4, 137.1, 129.3, 129.0, 128.7, 128.0, 127.9, 127.6, 116.0, 113.2, 113.1 (dd, J = 286.1, 281.3 Hz), 110.3, 57.2, 49.8, 27.6, 27.5, 27.5 (dd, J = 12.0, 9.3 Hz), 27.4, 22.5, 16.2, 16.1 (t, J = 9.8 Hz), 16.07.mp:138.6℃. Preparation 5 Alternative Procedure: (R)-N-benzyl-1-phenylethan-1-amine (S)-2,2-difluorocyclopropane-1-carboxylate A solution containing butyl acrylate (200 g), ethyl bromdifluoroacetate (1426 g), and tetrabutylammonium bromide (9.8 g) was slowly added to a solution of anisole (2.0 kg) preheated to 140 °C. The mixture was stirred and cooled, and the desired product was purified by distillation to give butyl 2,2-difluorocyclopropane-1-carboxylate as a solution in anisole. This solution was added to aqueous NaOH, and the biphasic mixture was heated to 40 °C. The mixture was cooled and filtered through Celite™ to separate the layers. The aqueous layer was washed with MTBE, acidified to pH 1-2, and washed twice with MTBE. The combined organic phases were solvent-exchanged to MeCN by distillation to give 2,2-difluorocyclopropane-1-carboxylic acid as a solution in MeCN. To this solution was added the chiral amine (R)-N-benzyl-1-phenylethan-1-amine, the mixture was heated to 40°, MTBE was added, and the mixture was cooled to 10° C., resulting in crystallization of the desired 2,2-difluorocyclopropane-1-(S)-carboxylate (R)-N-benzyl-1-phenylethan-1-aminium salt. The solid was isolated by filtration and recrystallized from MeCN to give material containing less than 0.5% of the desired acid enantiomer. Preparation 6 Alternative Procedure: (R)-N-Benzyl-1-phenylethan-1-amine (S)-2,2-difluorocyclopropane-1-carboxylate To a 26.5% m / m eutectic mixture of biphenyl in diphenyl ether (1497 g) previously heated at 130 °C, a solution of tetrabutylammonium bromide (6.8 g), butyl acrylate (1615 g), and ethyl bromodifluoroacetate (853 g) in a eutectic mixture of biphenyl in diphenyl ether (748 g) was added, and the mixture was maintained at 130–135 °C. Additional tetrabutylammonium bromide (6.8 g) was added. The reaction was cooled, 1,2-dichlorobenzene (1976 g) was added, and the mixture was distilled to obtain the desired butyl 2,2-difluorocyclopropane-1-carboxylate as a solution in 1,2-dichlorobenzene. To this solution, tetrabutylammonium bromide (5 mol%) and aqueous NaOH (15% m / m, 4 equiv.) were added, and the biphasic mixture was stirred at room temperature. Additional tetrabutylammonium bromide (1.25 mol%) was added. The phases are separated, and the aqueous phase is washed with MTBE, acidified to pH 1 with aqueous HCl, and extracted twice with MTBE. The combined organic phases are solvent-switched to MeCN to give a 15% m / m solution of 2,2-difluorocyclopropane-1-carboxylic acid. The solution is heated to 40°C, and (R)-(+)-N-benzyl-1-phenylethan-1-amine (1.1 equiv.) is added. The reaction is then further heated to 80°C, and the reaction mixture is seeded to promote crystallization of the title salt and cooled. The solid is isolated by filtration, washed with MeCN, and recrystallized using MeCN to give the desired material containing less than 0.5% of the undesired acid enantiomer. Preparation 7 Alternative Procedure: (R)-N-Benzyl-1-phenylethan-1-amine (S)-2,2-difluorocyclopropane-1-carboxylate To a solution of allyl hexanoate (225 L, 1.28 mol) in anisole (400 L) at 130 °C, ethyl bromodifluoroacetate (328 L, 2.56 mol) and tetrabutylammonium bromide (2.06 L, 0.006 mol) were added slowly. Additional portions of EBDFA (82.1 L, 0.64 mol) and tetrabutylammonium bromide (2.00 L, 0.006 mol) were added until complete conversion of the allyl hexanoate was observed. The mixture was cooled, THF (1600 L) was added, and the THF was distilled from the system to remove volatile by-products, yielding (2,2-difluorocyclopropyl)methyl hexanoate as a solution in anisole. Aqueous KOH (301 L of 48 wt % KOH in 470 L of HO) was added to this solution, and the mixture was heated to 60 °C. Add 0.5 wt% K2HPO4 (100 L) and separate the layers. Wash the aqueous layer twice with methylene chloride (600 mL each). To the combined organic layers, add TEMPO (9.94 g, 0.064 mol), potassium bromide (75.7 g, 0.636 mol), sodium bicarbonate (506.7 g, 6.03 mol), tetrabutylammonium bromide (20.51 L, 0.064 mol), and water (397.6 L) to form a biphasic mixture. Cool the reaction mixture to 10 °C and add 14.8 wt% NaOCl (1777.5 L, 4.07 mol). Add sodium thiosulfate (100.6 g, 0.636 mol), remove the solids by filtration, and rinse the cake with methylene chloride (179 L). The layers are separated and the organic layer is washed with aqueous NaOH (4.51 L of 30% NaOH in 795 L of HO). The pH of the aqueous layer is adjusted to pH 2 with HCl and extracted twice with methylene chloride (596 L each). The aqueous layer is washed twice with methyl tert-butyl ether (600 L each). The solvent is exchanged to give a solution of 2,2-difluorocyclopropane-1-carboxylic acid in acetonitrile. To this solution is added the chiral amine (R)-N-benzyl-1-phenylethan-1-amine and the reaction is stirred at 40°C before being cooled to 20°C to crystallize the title salt. The solid is collected by filtration, washed twice with MeCN, and then recrystallized in MeCN to give the title salt, which contains 0.5% of the undesired acid enantiomer.

[0178] Example 1 ((S)-2,2-Difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone p-tosylate (R)-N-benzyl-1-phenylethan-1-amine (S)-2,2-difluorocyclopropane-1-carboxylate (65.7 g, 197 mmol) is slurried in methyl t-butyl ether (441 mL) at 25° C. and treated with aqueous sulfuric acid (22 g, 217 mmol, 1.375 equiv.). The phases are separated, the aqueous phase is washed with methyl t-butyl ether (189 mL), and the organic phases are combined. The combined organic phases are concentrated, tetrahydrofuran (THF) (550 mL) is added, and the solution is concentrated. A second addition of tetrahydrofuran (550 mL) and concentration are performed.

[0179] A solution of (S)-2,2-difluorocyclopropane-1-carboxylate in THF (approximately 430 mL) was cooled to 0°C and 1,1'-carbonyldiimidazole (CDI) (36.9 g, 205 mmol, 1.3 equiv.) was added. Water (22.5 g) was then added. 2-Hydroxypyridine n-oxide (HOPO) (0.9 g, 7.9 mmol, 0.05 equiv.) and 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (45 g, 158 mmol) were added at 0°C until the reaction was complete. The mixture was then warmed to 55°C. To the reaction is added a solution of p-toluenesulfonic acid monohydrate (52.8 g, 278 mmol, 1.75 equiv) in THF (99 mL). The solution is seeded with the title compound salt. A second portion of p-toluenesulfonic acid monohydrate (79.2 g, 416 mmol, 2.25 equiv) in THF (148 mL) is added over 4 hours. The slurry is then cooled to 10° C. The solid title compound salt is collected by filtration, washed twice with a premixed solution of 95:5 v / v THF / water (5 volumes), and then dried under vacuum at 50±5° C. The title compound salt is isolated as a white crystalline solid (79.8 g, 90%).

[0180] Example 2 Alternative Procedure: ((S)-2,2-Difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone p-tosylate Chiral 2,2-difluorocyclopropane-1-(S)-carboxylic acid was prepared by salt break of 2,2-difluorocyclopropane-1-(S)-carboxylate (R)-N-benzyl-1-phenylethan-1-aminium salt. The acid chloride was prepared and reacted with isoquinolin-3-ol to give isoquinolin-3-yl (S)-2,2-difluorocyclopropane-1-carboxylate. 1 H NMR (400 MHz, DMSO) δ 9.23 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.83 (dd, J = 8.4, 6.8 Hz, 1H), 7.75 - 7.66 (m, 2H), 3.22 (ddd, J = 12.3, 10.9, 7.9 Hz, 1H), 2.35 - 2.13 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 165.8, 153.5, 152.4, 138.3, 131.8, 128.2, 127.9 (d, J = 2.6 Hz), 127.8, 126.9, 115.07, 112.2, 112.2 (dd, J = 286.3, 284.4 Hz), 111.2, 109.3, 31.7, 28.8, 25.5, 25.4 (dd, J = 12.8, 10.1 Hz), 25.3, 25.2, 17.4, 17.3 (t, J = 10.0 Hz), 17.2. 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (1.50 g, 5.26 mmol) was combined with tetrahydrofuran (21.4 mL) and water (1.13 mL). To this reaction was added isoquinolin-3-yl (S)-2,2-difluorocyclopropane-1-carboxylate (1.57 g, 6.30 mmol) and 2-hydroxypyridine N-oxide (0.029 g, 0.26 mmol). The reaction was stirred at room temperature until completion. The solution was heated to 50 °C. p-Toluenesulfonic acid monohydrate (2.44 g, 12.6 mmol) was dissolved in tetrahydrofuran (7.13 mL) and water (0.375 mL). Approximately 1.7 mL of this solution is added to the reaction. The reaction may be seeded. The remaining acid solution is added. The slurry is cooled to room temperature. The solid is isolated by filtration and washed with THF / water. The title compound salt is isolated as a white crystalline solid (2.72 g). 1 H NMR (400 MHz, DMSO) δ 9.23 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.83 (dd, J = 8.4, 6.8 Hz, 1H), 7.75 - 7.66 (m, 2H), 3.22 (ddd, J = 12.3, 10.9, 7.9 Hz, 1H), 2.35 - 2.13 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 165.8, 153.5, 152.4, 138.3, 131.8, 128.2, 127.9 (d, J = 2.6 Hz), 127.8, 126.9, 115.07, 112.2, 112.2 (dd, J = 286.3, 284.4 Hz), 111.2, 109.3, 31.7, 28.8, 25.5, 25.4 (dd, J = 12.8, 10.1 Hz), 25.3, 25.2, 17.4, 17.3 (t, J = 10.0 Hz), 17.2.mp:99.3℃.

[0181] Example 3 Alternative Procedure: ((S)-2,2-Difluorocyclopropyl)-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone p-tosylate A reactor is charged with the title compound salt (20.0 g, 35 mmol) and methyl isobutyl ketone (MIBK) (160 mL). A solution of sodium carbonate (4.52 g, 42 mmol, 1.2 equiv.) in water (55 mL) is added. The reaction is stirred until a homogeneous two-phase mixture is obtained. The aqueous layer is separated and back-extracted with MIBK (100 mL). The organic phases are combined and washed with water (55 mL). The organic phase is concentrated to a volume of 100 mL. The solution is heated to 85° C. and heptane (67 mL) is added. The solution may be seeded. The solution is cooled to 25° C. The solid is isolated by filtration and washed with 30% heptane in MIBK. The title compound salt is isolated as a white crystalline solid.

[0182] Example 4 1-Methyl-1H-pyrazol-4-amine hydrochloride (a) N-(1-methyl-1H-pyrazol-4-yl)acetamide To a 100 mL vessel equipped with a reflux condenser, temperature probe, and overhead stirrer, 4-bromo-1-methyl-1H-pyrazole (7.0 g), acetamide (7.47 g, 3 equiv.), K2CO3 (8.83 g, 1.5 equiv.), ligand, and 2-methyl-2-butanol (70.0 mL) were added to give a yellowish slurry. Nitrogen was sparged through the mixture for approximately 20 minutes to remove oxygen. The vessel was then evacuated and refilled with nitrogen three times. CuI was added under a strong nitrogen flow, and the vessel was heated to an internal temperature of 100 °C. After 26 h, the reaction was cooled to 25 °C. The reaction was diluted with a premixed solution of sodium citrate (31.0 g, 2.5 equiv.) in water (70 mL), which dissolved all solids. The layers were allowed to settle, and the bottom (aqueous) layer was removed. The resulting organic layer was extracted again with a premixed solution of sodium citrate (49.6 g, 4 equiv.) in water (70 mL), and the layers were separated. The resulting organic layer (approximately 90 mL) was concentrated and distilled under vacuum to approximately 40 mL, during which time a solid crystallized in the vessel, and then toluene (75 mL) was added. This organic solution was further concentrated (from approximately 115 mL to approximately 60 mL), and then the mixture was cooled to 20 °C, filtered, and dried under vacuum at 50 °C. N-(1-methyl-1H-pyrazol-4-yl)acetamide was isolated as a light gray to tan solid. 1 H NMR (400 MHz, DMSO) δ 9.89 (s, 1H), 7.84 (s, 1H), 7.36 (s, 1H), 3.77 (s, 3H), 1.97 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 166.9, 129.8, 122.2, 121.5, 39.0, 23.2.mp:149.0℃. (b) N-(1-methyl-1H-pyrazol-4-amine hydrochloride To a 50 mL vessel fitted with a reflux condenser, temperature probe, and overhead stirrer, N-(1-methyl-1H-pyrazol-4-yl)acetamide (3.97 g) was added, followed by 1-BuOH (32.0 mL), water (2.0 mL), and 12 M HCl (2.60 mL, 1.2 equiv.). A slight exotherm was observed during the addition of HCl. The mixture was heated to an internal temperature of 80 °C and held until complete conversion of the starting material was observed (usually within 16-24 h). The reaction mixture was concentrated by distillation to remove water, during which the desired product, PF-05602633-01, crystallized as shimmering white flakes. The slurry was cooled to 20 °C, and the product was isolated by filtration, washed with 1-BuOH, and dried under vacuum at 50 °C.

[0183] Example 5 (S)-2,2-Difluorocyclopropane-1-carboxylic acid 2,2',2''-nitrilotris(ethan-1-ol) salt

[0184] [ka]

[0185] A 100 mL reactor was charged with MeCN (50.0 mL) and triethanolamine (12.2 g, 1.0 equiv.). The solution was heated to 45°C, and a premixed solution of 2,2-difluorocyclopropane-1-carboxylic acid (10.1 g, 1.0 equiv.) in MTBE (50.0 mL, approximately 20% w / w) was added dropwise over 100 min. After the approximately 40% MTBE solution was added, the reaction was seeded with (S)-2,2-difluorocyclopropane-1-carboxylic acid 2,2',2''-nitrilotris(ethan-1-ol) salt (42 mg, 0.002 equiv.). After the addition, the reaction was held at 45°C for 30 min and then cooled to 20°C at a rate of 0.25°C / min. The mixture was granulated for 30 minutes, then filtered, washed with MTBE (40.0 mL), and dried under vacuum at 50° C. The difluoroacids can then be resolved by crystallization of the diastereoisomers. 1 H NMR (400 MHz, DMSO) δ 6.85 (s, 4H), 3.61 (t, J = 5.7 Hz, 6H), 2.97 (t, J = 5.7 Hz, 6H), 2.38 (ddd, J = 15.4, 10.8, 7.9 Hz, 1H), 1.84 - 1.62 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 169.0, 115.9, 113.1(dd, J = 285.9, 281.2 Hz), 113.1, 110.3, 57.4, 56.5, 27.7, 27.6 (dd, J = 12.0, 9.2 Hz), 27.6, 27.5, 16.2, 16.1 (t, J = 9.8 Hz), 16.0.mp:82.4℃. The present invention includes, but is not limited to, the following aspects. [Aspect 1] Formula I: [ka] 1. A method for preparing a compound of formula (I), comprising: (a)(i) Structure: [ka] Compounds and structures having the following structure: [ka] wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, halo, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy; or (ii) Structure: [ka] (Wherein, R is C6 to C 12 aryl and C4-C9 heteroaryl, wherein the C6-C 12Aryl and C4-C9 heteroaryl are optionally C1-C6 alkyl, -S(=O)-R0, -S(=O)2-R0, cyano, nitro , C1-C6 alkoxy, or halo, wherein R0 is C1-C6 alkyl; (b) reacting the activated ester or salt with a compound of Formula IV: [ka] under appropriate conditions to form a compound of formula I The method comprising: [Aspect 2] The method of embodiment 1, wherein R1, R2, R3, and R4 are hydrogen. [Aspect 3] The method of embodiment 1, wherein R is p-cyanophenyl or isoquinolin-3-yl. [Aspect 4] Formula I: [ka] 1. A process for preparing the p-toluenesulfonate salt of a compound of the formula: (a)(i) Structure: [ka] Compounds and structures having the following structure: [ka] wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, halo, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy; or (ii) Structure: [ka] (Wherein, R is C6 to C 12 aryl and C4-C9 heteroaryl, wherein the C6-C12 preparing an activated ester having an aryl and a C4-C9 heteroaryl optionally substituted with cyano, -S(=O)-R0, -S(=O)2-R0, nitro, C1-C6 alkoxy, or halo, where R0 is a C1-C6 alkyl; (b) reacting the activated ester or salt with a compound of Formula IV: [ka] under appropriate conditions to form a compound of formula I: [ka] forming a compound of (c) treating said compound with p-toluenesulfonic acid under appropriate conditions to obtain a compound of formula IA: [ka] Step of obtaining the p-toluenesulfonic acid salt of The method comprising: [Aspect 5] The method of embodiment 4, wherein R1, R2, R3, and R4 are hydrogen. [Aspect 6] The method of embodiment 4, wherein R is p-cyanophenyl or isoquinolin-3-yl. [Aspect 7] Formula II: [ka] 1. A process for preparing a salt of (a) Structure: [ka] preparing a carboxylic acid having (b) treating the carboxylic acid with a compound having the structure: [ka] under appropriate conditions to form a salt of formula II The method comprising: [Aspect 8] The carboxylic acid has the structure: [ka] (Wherein, R5 is C2-C6 alkyl, C3-C6 cycloalkyl, benzyl, C6-C 12 aryl, or C4-C9 heteroaryl) to form a compound having the structure: [ka] (Wherein, R6 is C1-C5 alkyl, benzyl, C6-C 12 8. The method of claim 7, wherein the compound is prepared by treating the compound with an ester compound having a C4-C9 aryl, or C4-C9 heteroaryl. [Aspect 9] The method of embodiment 8, wherein R5 is n-propyl or n-butyl, and R6 is methyl or ethyl. [Aspect 10] The method of embodiment 7, wherein the reaction is carried out using n-Bu4NBr, n-Bu4NI, or n-Bu4NOH. [Aspect 11] The carboxylic acid is (a) Structure: [ka] (Wherein, R7 is C2-C6 alkyl, C3-C6 cycloalkyl, C6-C 12 aryl, or C4-C9 heteroaryl) to form a compound having the structure: [ka] (Wherein, R6 is C1-C5 alkyl, benzyl, C6-C 12 aryl, or C4-C9 heteroaryl) under appropriate conditions to obtain an ester compound with the structure: [ka] forming an intermediate having (b) treating the intermediate produced in step (a) with a Lewis acid selected from the group consisting of FeCl3 and AlCl3 under appropriate conditions to obtain a compound of the structure: [ka] forming an alcohol compound having the formula: (c) reacting the alcohol compound with an oxidizing agent under appropriate conditions to form a carboxylic acid. 8. The method of embodiment 7, wherein the compound is prepared by [Aspect 12] R7 is C5H 11 and R6 is methyl or ethyl. [Aspect 13] 12. The method of embodiment 11, wherein the reaction is carried out using n-Bu4NBr, n-Bu4NI, or n-Bu4NOH. [Aspect 14] 12. The method of claim 11, wherein the Lewis acid is FeCl. [Aspect 15] 12. The method of embodiment 11, wherein the oxidizing agent is selected from the group consisting of periodate, chromate, peroxide, sodium hypochlorite, and potassium hypochlorite. [Aspect 16] 12. The method of embodiment 11, wherein the oxidizing agent is sodium hypochlorite. [Aspect 17] The carboxylic acid is (a) Structure: [ka] (Wherein, R7 is C4-C6 alkyl, C1-C6 alkyl, C3-C6 cycloalkyl, benzyl, C6-C 12 aryl, or C4-C9 heteroaryl) to form a compound having the structure: [ka] (Wherein, R6 is C1-C5 alkyl, benzyl, C6-C 12and C4-C9 heteroaryl), under appropriate conditions to obtain an ester compound having the structure: [ka] forming an intermediate having (b) treating the intermediate produced in step (a) under appropriate conditions with a base selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, cesium carbonate, lithium carbonate, potassium carbonate, sodium ammonium carbonate, ammonium carbonate, lithium bicarbonate, sodium bicarbonate, potassium carbonate, metal or ammonium carboxylate salts, monobasic, dibasic, and tribasic metal phosphates to obtain a compound having the structure: [ka] forming an alcohol compound having the formula: (c) reacting the alcohol compound with an oxidizing agent selected from the group consisting of periodate, chromate, peroxide, sodium hypochlorite, and potassium hypochlorite under appropriate conditions to provide a carboxylic acid. 8. The method of embodiment 7, wherein the compound is prepared by [Aspect 18] R7 is C5H 11 and R6 is methyl or ethyl. [Aspect 19] The method of embodiment 7, wherein the reaction is carried out using n-Bu4NBr. [Aspect 20] The method of embodiment 7, wherein the base is potassium hydroxide. [Aspect 21] 8. The method of embodiment 7, wherein the oxidizing agent is selected from periodate, chromate, peroxide, sodium hypochlorite, and potassium hypochlorite. [Aspect 22] 8. The method of embodiment 7, wherein the oxidizing agent is sodium hypochlorite. [Aspect 23] Formula III: [ka] or a salt thereof, or a solvate thereof, wherein R8 is an optionally substituted arylmethylene, and the salt is a dihydrochloride or dihydrobromide salt. [Aspect 24] 24. A compound according to aspect 23, or a salt thereof, wherein R8 is benzyl, and the salt is a dihydrochloride salt. [Aspect 25] 24. The compound or salt thereof according to aspect 23, wherein the solvate is a hydrate.

Claims

1. Formula I: 【Chemistry 1】 1. A method for preparing a compound of formula (I), comprising: (a)(i) Structure: 【Chemistry 2】 Compound (A) having the formula and structure: 【Transformation 3】 A base (B) having the formula From the structure: 【Chemistry 4-1】 and preparing a salt of formula II having the structure: 【Chemistry 4-2】 isolating a chiral compound having the formula: or, (ii) Structure: 【Transformation 5】 (Wherein R is C ６ ~C １２ Aryl and C ４ ~C ９ heteroaryl, wherein said C ６ ~C １２ Aryl and C ４ ~C ９ Heteroaryl is optionally C １ ~C ６ Alkyl, —S(═O)—R ０ , -S(=O) ２ -R ０ , cyano, nitro, C １ ~C ６ substituted with alkoxy, or halo, where R ０ is C １ ~C ６ preparing an activated ester having a hydroxyl group, wherein the hydroxyl group is alkyl; (b) reacting the activated ester or the chiral compound with a compound of Formula IV: 【Transformation 6】 under appropriate conditions to form a compound of formula I The method comprising:

2. 2. The method of claim 1, wherein R is p-cyanophenyl or isoquinolin-3-yl.

3. Formula I: 【Transformation 7】 1. A process for preparing the p-toluenesulfonate salt of the compound of formula (I), comprising: (a)(i) Structure: 【Chemistry 8-1】 Compound (A) having the formula and structure: 【Chemistry 8-2】 A base (B) having the formula From the structure: 【Chemistry 8-3】 and preparing a salt of formula II having the structure: 【Chemistry 9】 isolating a chiral compound having the formula: or, (ii) Structure: 【Chemistry 10】 (Wherein R is C ６ ~C １２ Aryl and C ４ ~C ９ heteroaryl, wherein said C ６ ~C １２ Aryl and C ４ ~C ９ Heteroaryl is optionally cyano, —S(═O)—R ０ , -S(=O) ２ -R ０ , Nitro, C １ ~C ６ substituted with alkoxy, or halo, where R ０ is C １ ~C ６ preparing an activated ester having a hydroxyl group, wherein the hydroxyl group is alkyl; (b) reacting the activated ester or the chiral compound with a compound of Formula IV: 【Chemistry 11】 under appropriate conditions to form a compound of formula I: 【Chemistry 12】 forming a compound of (c) treating said compound with p-toluenesulfonic acid under appropriate conditions to produce a compound of formula IA: 【Chemistry 13】 obtaining the p-toluenesulfonic acid salt of The method comprising:

4. 4. The method of claim 3, wherein R is p-cyanophenyl or isoquinolin-3-yl.

5. Formula II: 【Chemistry 14】 1. A process for preparing a salt of (a) Structure: 【Chemistry 15】 preparing a carboxylic acid having (b) reacting the carboxylic acid with a compound having the structure: 【Chemistry 16】 under appropriate conditions to form a salt of formula II The method comprising:

6. The carboxylic acid has the structure: 【Chemistry 17】 (In the formula, R ５ is C ２ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, benzyl, C ６ ~C １２ aryl, or C ４ ~C ９ heteroaryl) to form a compound having the structure: [Chemistry 18] (In the formula, R ６ is C １ ~C ５ Alkyl, benzyl, C ６ ~C １２ aryl, or C ４ ~C ９ with an ester compound having a heteroaryl group, The method of claim 5.

7. R ５ is n-propyl or n-butyl, and R ６ The method of claim 6, wherein is methyl or ethyl.

8. The reaction is ４ NBr, n-Bu ４ NI, or n-Bu ４ 6. The method of claim 5, carried out using NOH.

9. The carboxylic acid is (a) Structure: 【Chemistry 19】 (In the formula, R ７ is C ２ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C ６ ~C １２ aryl, or C ４ ~C ９ heteroaryl) to form a compound having the structure: 【Chemistry 20】 (In the formula, R ６ is C １ ~C ５ Alkyl, benzyl, C ６ ~C １２ aryl, or C ４ ~C ９ and treating the compound with an ester compound having the structure: 【Chemistry 21】 forming an intermediate having (b) The intermediate produced in step (a) is reacted with FeCl ３ and AlCl ３ and treating under appropriate conditions with a Lewis acid selected from the group consisting of: 【Chemistry 22】 forming an alcohol compound having the formula: (c) reacting the alcohol compound with an oxidizing agent under appropriate conditions to form a carboxylic acid. The method of claim 5, wherein the compound is prepared by

10. R ７ But C ５ H １１ and R ６ The method of claim 9, wherein is methyl or ethyl.

11. The reaction is ４ NBr, n-Bu ４ NI, or n-Bu ４ 10. The method of claim 9 carried out using NOH.

12. The Lewis acid is FeCl ３ The method of claim 9, wherein

13. 10. The method of claim 9, wherein the oxidizing agent is selected from the group consisting of periodate, chromate, peroxide, sodium hypochlorite, and potassium hypochlorite.

14. 10. The method of claim 9, wherein the oxidizing agent is sodium hypochlorite.

15. The carboxylic acid is (a) Structure: 【Chemistry 23】 (In the formula, R ７ is C ４ ~C ６ Alkyl, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, benzyl, C ６ ~C １２ aryl, or C ４ ~C ９ heteroaryl) to form a compound having the structure: 【Chemistry 24】 (In the formula, R ６ is C １ ~C ５ Alkyl, benzyl, C ６ ~C １２ Aryl, and C ４ ~C ９ and treating the compound with an ester compound having the structure: 【Chemistry 25】 forming an intermediate having the formula: (b) treating the intermediate produced in step (a) under appropriate conditions with a base selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, cesium carbonate, lithium carbonate, potassium carbonate, sodium ammonium carbonate, ammonium carbonate, lithium bicarbonate, sodium bicarbonate, potassium carbonate, metal or ammonium carboxylate salts, monobasic, dibasic, and tribasic metal phosphates to obtain a compound of the structure: 【Chemistry 26】 forming an alcohol compound having the formula: (c) reacting the alcohol compound with an oxidizing agent selected from the group consisting of periodate, chromate, peroxide, sodium hypochlorite, and potassium hypochlorite under suitable conditions to provide a carboxylic acid. The method of claim 5, wherein the compound is prepared by

16. R ７ But C ５ H １１ and R ６ 16. The method of claim 15, wherein is methyl or ethyl.

17. The reaction is ４ 16. The method of claim 15 carried out using NBr.

18. 16. The method of claim 15, wherein the base is potassium hydroxide.

19. 16. The method of claim 15, wherein the oxidizing agent is selected from periodate, chromate, peroxide, sodium hypochlorite, and potassium hypochlorite.

20. 16. The method of claim 15, wherein the oxidizing agent is sodium hypochlorite.

21. Formula III: 【Chemistry 27】 or a salt or solvate thereof, wherein R ８ is optionally substituted arylmethylene, and said salt is a dihydrochloride or dihydrobromide salt, or a salt thereof, or a solvate thereof.

22. R ８ 22. The compound or salt thereof according to claim 21, wherein is benzyl and the salt is a dihydrochloride salt.

23. 22. The compound or salt thereof according to claim 21, wherein the solvate is a hydrate.

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