Substitute pyrrolo[2,3-D]pyrimidines, their manufacture and therapeutic applications

Abstract

Disclosed are compounds of formula (I), or pharma- ceutically acceptable salts thereof, wherein R1 and R2 are as defined herein. Methods of using said compounds as inhibitors of LRRK2, and pharmaceutical compositions comprising said compounds, are also disclosed. These compounds are useful in neurodegenerative diseases, such as Parkinson's disease.

Description

[Technical Field]

[0001] Substituted pyrrolo[2,3-d]pyrimidine compounds, methods for producing them, pharmaceutical compositions containing these compounds, and their therapeutic uses are disclosed herein. [Background technology]

[0002] background Parkinson's disease (PD) is an age-dependent neurodegenerative disorder with specific unmet medical needs in the context of an aging population. Mutations in several genes separate PD into different lineages. In particular, seven leucine-rich repeat kinase 2 (LRRK2) mutations are associated with the autosomal dominant form of PD. LRRK2 polymorphisms have been identified as risk factors for sporadic PD in genome-wide association studies (Non-Patent Literature 1). LRRK2 carriers share similar clinical symptoms, disease onset, and progression with sporadic patients (Non-Patent Literature 2), suggesting that the LRRK2 signaling pathway may be central to the processes underlying both familial and sporadic late-onset PD. All pathogenic LRRK2 mutations, as well as VPS35 D620N, another target genetically associated with PD, induce increased LRRK2 kinase activity (Non-Patent Literature 3; Non-Patent Literature 4). In addition to familial PD, increased LRRK2 activity or levels have been reported in human brains derived from idiopathic PD patients (Non-Patent Literature 5). These results support the hypothesis that dysregulated LRRK2 kinase activity may contribute to pathogenesis and suggest the therapeutic potential of LRRK2 kinase inhibitors that block abnormal LRRK2-dependent signaling in both PD and idiopathic forms (Non-Patent Literature 6). Accumulation of synuclein aggregates and loss of dopaminergic neurons are major features of PD. Blockade of these phenotypes after LRRK2 kinase inhibitor treatment has been demonstrated in numerous reports (Non-Patent Literature 7). These results support the hypothesis that potent brain-penetrating LRRK2 kinase inhibitors have therapeutic efficacy in treating PD.

[0003] Successive evidence suggests a role for LRRK2 in regulating lysosomal activity (Non-Patent Literature 8). Increased bis(monoacylglycerol) phosphate levels, a marker of lysosomal storage disorders such as Pick's disease, have been observed in the fluids of LRRK2 gain-of-function mutant carriers (Non-Patent Literature 9). Lysosomal glucocerebrosidase (GBA) mutations are the greatest risk factor for developing PD (GBA-PD). Reduced glucocerebrosidase activity has been reported in neurons derived from GBA and LRRK2 mutant carriers (Non-Patent Literature 10). Conversely, normalization of glucocerebrosidase activity and levels has been achieved in vitro and in vivo after treatment with LRRK2 kinase inhibitors, suggesting potential benefits in patients with lysosomal storage disorders such as GBA-PD (Non-Patent Literature 11).

[0004] Immunofluorescence experiments in the human brain showed co-localization of LRRK2 with neurofibrillary tangles (Non-Patent Literature 12). Furthermore, LRRK2 has been reported to phosphorylate microtubule-associated Tau (Non-Patent Literature 13), and Tau hyperphosphorylation has been observed in LRRK2 kinase-activated mutant transgenic mice (Non-Patent Literature 14). These data suggest that LRRK2 kinase inhibitor treatment may be useful in treating tauopathic disorders such as Pick's disease, progressive supranuclear palsy, and frontotemporal dementia.

[0005] LRRK2 is expressed in brain glial cells, and attenuation of neuroinflammation has been achieved after treatment with LRRK2 kinase inhibitors in various in vivo models (Non-Patent Literature 15). Neuroinflammation is often observed in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, HIV-induced dementia, and amyotrophic lateral sclerosis; therefore, LRRK2 kinase inhibitors may be useful in treating these conditions.

[0006] Patent Document 1 discloses compounds having pyrrolopyrimidine nuclei substituted with (hetero)arylamine groups and pyrrolopyrimidine nuclei substituted with cyano groups. These compounds have the ability to inhibit certain protein kinases, and in particular the leucine-rich repeat kinase 2 (LRRK2) protein, and can be used to treat disorders, including neurodegenerative diseases such as Parkinson's disease.

[0007] Patent Document 2 discloses novel pyrrolo-pyrimidine derivative compounds for preventing or treating protein kinase-related diseases.

[0008] Patent Document 3 discloses compounds having pyrrolopyrimidine nuclei substituted with (hetero)arylamino groups and cyano groups, which may be advantageously used to treat or prevent protein kinase-related diseases, cancer and degenerative brain diseases. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] WO2017106771 [Patent Document 2] US2020239474 [Patent Document 3] WO2020149715 [Non-patent literature]

[0010] [Non-Patent Document 1] JHKluss, Biochemical Society Transactions 2019 [Non-Patent Document 2] H.Tomiyama, Hum.Mov.Disord.2006 [Non-Patent Document 3] M. Steger et al., eLife 2016 [Non-Patent Document 4] R, Mir et al., Biochem J. 2018. [Non-Patent Document 5] R.Di Maio et al., Sci.Transl.Med.2018 [Non-Patent Document 6] ABWest Exp.Neurol.2017 [Non-Patent Document 7] EMRocha et al., Neurobiol.Of Disease 2019. [Non-Patent Document 8] J. Schapansky et al. Neurobiol.of Disease 2018 [Non-Patent Document 9] RNAlcalay, Movement Disorders, 2020 [Non-Patent Document 10] D. Ysselstein, Nature com.2019 [Non-Patent Document 11] A. Sanyal et al., Mov. Disorders 2020 [Non-Patent Document 12] J.Miklossy, J Neuropathol.Exp.Neurol.2006 [Non-Patent Document 13] F. Kawakami et al., PloS One 2012 [Non-Patent Document 14] Y. Li et al., Nat. Neurosci. 2009. [Non-Patent Document 15] MSMoehle et al., J. Neurosci. 2012. [Overview of the Initiative] [Problems that the invention aims to solve]

[0011] There is a need to provide LRRK2 kinase inhibitors that exhibit good efficacy. [Means for solving the problem]

[0012] Summary of the Invention According to one embodiment, equation (I): [ka] [In formula: R1 is selected from the group consisting of an aryl group, an ortho-condensed bicyclic heteroaryl group, and a heteroaryl group, where the ortho-condensed bicyclic heteroaryl group is unsubstituted or substituted with one or more -(C1-C3)-alkyl groups; and where the aryl group and the heteroaryl group are unsubstituted or a) Fluorine atom, b) Deuterium atom, c) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. d) Unsubstituted or cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. e) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. f) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, g) Unsubstituted, or -O-cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. h) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, hydroxyl groups, and alkylcarbonyl groups, i) -O-spiro ring group, j) Alkylsulfonylalkyl groups, and k) Alkyl sulfonyl group Substituted with one or more substituents independently selected from the group consisting of; and R2 is selected from the group consisting of alkyloxylalkyl groups and heterocycloalkyl groups, where the heterocycloalkyl group represented by R2 is bonded via carbon atoms and is either unsubstituted or substituted with an alkyl group, an alkyloxyl group, or one or more fluorine atoms. Compounds of or pharmaceutically acceptable salts thereof are disclosed herein.

[0013] Another aspect of the present disclosure is a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0014] The compound of formula (I) and its pharmaceutically acceptable salts exhibit inhibitory activity against wild-type and mutant LRRK2 and are useful in the treatment of neurodegenerative diseases. [Modes for carrying out the invention]

[0015] description As used herein, the following abbreviations shall be understood to have the following meanings unless otherwise indicated: As used herein, the term “alkyl” means a linear or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms in the chain. In another embodiment, alkyl has 1 to 4 carbon atoms in the chain. “Lower alkyl” means an alkyl group having 1 to about 3 carbon atoms in an alkyl chain which may be linear or branched. Branching means that one or more lower alkyl groups, such as methyl, ethyl, or propyl, are bonded to the linear alkyl chain. Furthermore, the term “(C1-C4)-alkyl” refers to a linear or branched alkyl group having 1 to 4 carbon atoms. The term “(C1-C3)-alkyl” refers to a linear or branched alkyl group having 1 to 3 carbon atoms. Examples of alkyl groups include methyl, ethyl, i-propyl, and t-butyl.

[0016] As used herein, the term “alkylamino” means alkyl-N(H)-, where alkyl is as defined herein.

[0017] As used herein, the term “dialkylamino” means an amino group having two linear or branched alkyl groups, as defined herein and independent of each other. The term “dialkylamino” includes, for example, dimethylamino, diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, and Nt-butyl-N-methylamino.

[0018] As used herein, the term “alkylcarbonyl” means alkyl-C(=O)- such that alkyl is as defined herein. Examples of alkylcarbonyls include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, and isobutylcarbonyl.

[0019] As used herein, the term “alkyloxyl” means alkyl-O- such that alkyl is as described herein. Examples of alkyl-O- include methoxyl, ethoxyl, n-propoxyl, isopropoxyl, n-butoxyl, isobutoxyl, sec-butoxyl, tert-butoxyl, and the like.

[0020] As used herein, the term “alkyloxylalkyl” means alkyl-O-alkyl groups having two linear or branched alkyl groups that are independent of each other and as defined herein.

[0021] As used herein, the term “alkylsulfonyl” means alkyl-S(=O)2-, where alkyl is as defined herein. Examples of alkylsulfonyls include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, and isobutylsulfonyl.

[0022] As used herein, the term "alkylsulfonylalkyl" means alkyl-S(=O)2-alkyl-, where alkyl is as defined herein.

[0023] As used herein, the term "aryl" refers to an aromatic monocyclic or bicyclic ring system consisting of about 5 to about 10 carbon atoms. Examples of aryls include phenyl and naphthyl.

[0024] As used herein, the term “cycloalkyl” refers to a non-aromatic monocyclic ring system of 3 to 6 carbon atoms. (C3-C6)-cycloalkyl is a cycloalkyl having 3, 4, 5, or 6 ring carbon atoms. Examples of cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0025] As used herein, the term “heteroaryl,” whether used alone or with other terms such as “heteroaryl group,” means a cyclic aromatic group containing 2 to 10 carbon atoms and a heteroatom such as nitrogen, oxygen, or sulfur between positions 1 and 4. This heteroaryl group may be monocyclic or bicyclic. As used herein, the term “monocyclic heteroaryl” means a cyclic aromatic group containing 2 to 5 carbon atoms and a heteroatom such as nitrogen, oxygen, or sulfur between positions 1 and 3. Examples of monocyclic heteroaryl groups include, but are not limited to, benzimidazole, benzothiazole, benzothiadiazole, benzofuran, benzotriazole, benzoxazole, furan, furazan, indole, imidazole, isoxazole, isothiazole, oxadiazole, oxazole, pyridine, pyrimidine, pyrrolo[2,3-b]pyridine, pyrazine, pyrazole, pyridazine, pyrrole, 1,2,4-thiadiazole, 1,2,4-triazine, 1,3,4-thiadiazole, thiazole, triazole, and thiophene.

[0026] As used herein, the term “heterocycloalkyl” means a four-membered, five-membered, six-membered, or seven-membered non-aromatic monocyclic ring system having at least one carbon atom and at least one heteroatom other than carbon, such as nitrogen, oxygen, or sulfur. Examples of heterocycloalkyls include azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, iisothiazolidinyl, dioxolanil, dioxepanil, dithiolanil, piperidinyl, tetrahydropyranil, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanil, dithianyl, hexahydro-1,3,5-triazinyl, trioxanil, trithianil, azepanil, oxepanil, thiepanil, and diazepanil.

[0027] As used herein, the term “ortho-condensed” means a ring system in which two adjacent rings share two adjacent atoms, and the second ring system is alpha with respect to the branching carbon atoms. The term “ortho-condensed heteroaryl” means a bicyclic ring system containing 7 to 10 carbon atoms and 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. Bicyclic ring systems in which one ring is a monocyclic heteroaryl and the other ring is an aryl ring or a heterocycloalkyl ring, or bicyclic ring systems in which both rings are monocyclic heteroaryls, fall within the definition of an ortho-condensed heteroaryl group. Examples include indolyl and benzimidazolyl.

[0028] As used herein, the term “spiro ring” or “spiro ring formula” means a carbogenic bicyclic ring system in which both rings are connected via a single atom. The rings may be of different sizes and properties, or of the same size and properties. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both rings in a spiro ring may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more carbon atoms in a spiro ring may be substituted with heteroatoms (e.g., O, N, S, or P). C5-C 12 A spiro ring is a spiro ring containing between 5 and 12 carbon atoms. One or more carbon atoms may be substituted with heteroatoms.

[0029] As used herein, the term “substituted” means that the hydrogen radical of a specified part is replaced by the radical of a particular substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise noted, substituents may be in any position, provided that each compound is sufficiently stable and suitable as a pharmaceutically active compound. The requirement that a particular group and compound of formula I be sufficiently stable and suitable as a pharmaceutically active compound generally applies to the definition of all groups in a compound of formula (I).

[0030] As used herein, the term “one or more substituents” means a number of substituents equal to one, up to the maximum number of substituents possible based on the number of available bonding sites, provided that the above conditions for stability and chemical feasibility are met. Unless otherwise indicated, optionally substituted groups may have substituents at each of the substitutable positions of the group, and the substituents may be the same or different.

[0031] As used herein, the terms “independently” or “independently selected” mean that the same or different values ​​can be selected for multiple cases of a given variable in a single compound.

[0032] As used herein, the term “unsubstituted” indicates that each group does not have any particular substituents.

[0033] As used herein, the term “pharmaceutically acceptable salt” refers to relatively non-toxic inorganic and organic acid addition salts and base addition salts of the compound of formula (I). These salts can be prepared in situ during the final isolation and purification of the compound.

[0034] If a compound of formula (I) contains one or more acidic or basic groups, such as basic heterocyclic groups, the corresponding physiologically or toxicologically acceptable salts, in particular pharmaceutically acceptable salts, are also included in this disclosure. Accordingly, compounds of formula (I) may be deprotonated on an acidic group and used, for example, as alkali metal salts or ammonium salts. Compounds of formula (I) containing at least one basic group may be prepared and used, for example, in the form of pharmaceutically acceptable salts with inorganic and organic acids, or in the form of their acid addition salts. Generally, salts can be prepared from acidic and basic compounds of formula (I) by reaction with an acid or base in a solvent or diluent according to a standard procedure. If a compound of formula (I) contains both an acidic and a basic group in its molecule, this disclosure also includes intramolecular salts (betaines, zwitterions) in addition to the salt forms described above. The disclosure also includes all salts of the compound of formula (I), which, due to their low physiological tolerability, are not directly suitable for pharmaceutically acceptable use, but are suitable as intermediates for chemical reactions or for the production of physiologically acceptable salts, for example, using anion exchange or cation exchange.

[0035] As used herein, the term “pharmaceutically acceptable excipient” means a non-toxic solvent, dispersant, excipient, adjuvant, or other material that is mixed with the compounds of this disclosure to enable the formation of a pharmaceutical composition, i.e., a drug form that can be administered to a patient. These excipients are selected from common excipients known to those skilled in the art, according to the pharmaceutical form and the desired method of administration.

[0036] As used herein, the terms “pharmaceutically effective dose” or “therapeutic dose” mean the amount of a compound / composition according to this disclosure that is effective in producing the desired therapeutic effect.

[0037] As used herein, the term “to treat” or “treatment” means to halt, slow down or reduce the progression of a disease; to cause regression of its biological signs and / or clinical symptoms; that is, to inhibit the further progression or worsening of at least one symptom by reducing the severity or frequency of at least one symptom.

[0038] As used herein, the term "patient" refers to a person suffering from a disease.

[0039] As used herein, the term “compound of formula (I)” and its equivalent expression are intended to include, where circumstances permit, racemic compounds of formula (I), as well as their enantiomers, epimers, diastereomers, geometric isomers, tautomers, and mixtures thereof.

[0040] As used herein, the term "isomer" refers to a compound having the same molecular formula but differing in the nature or arrangement of the bonding of its atoms, or in the spatial arrangement of its atoms. The terms "isomer 1" and "isomer 2" may be assigned to isomers with known absolute configurations or may be used to describe stereoisomers with unknown absolute configurations. Therefore, the use of the terms "isomer 1" and "isomer 2" should not be interpreted as indicating that the absolute configurations of both isomers are known. The term "isomer mixture" refers to a mixture of isomers.

[0041] As used herein, the term “stereoisomer” is a general term used for all isomers of individual molecules that differ only in the spatial orientation of their atoms. The term “diastereomer” refers to stereoisomers that are not mirror images of each other, and the term “enantiomer” refers to stereoisomers that are mirror images of each other but cannot be superimposed. Enantiomers can be characterized by the absolute configuration of their chiral centers and are described by the R- and S-prioritization rules of Cahn, Ingold, and Prelog, or by the rotation of the molecule’s plane of polarization, and are designated as dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as any individual enantiomer, individual diastereomers, or as mixtures thereof. A mixture containing enantiomers in equal proportions is called a “racemic mixture.” A mixture containing diastereomers in any proportion is called a “diastereomer mixture.” For compounds having two chiral centers in a ring system, "trans" refers to the chiral center substituents (other than hydrogen) being on opposite sides of the ring; "cis" refers to the chiral center substituents being on the same side of the ring. "Rasemic trans" refers to two trans enantiomers in equal proportions, and "rasemic cis" refers to two cis enantiomers in equal proportions. Diastereomer mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can also be separated directly using chiral chromatography techniques or indirectly using enzymatic methods. Naturally, all such isomers and mixtures thereof in any proportion are included within the scope of this disclosure.

[0042] Equation (I): [ka] [In formula: R1 is selected from the group consisting of an aryl group, an ortho-condensed bicyclic heteroaryl group, and a heteroaryl group, where the ortho-condensed bicyclic heteroaryl group is unsubstituted or substituted with one or more -(C1-C3)-alkyl groups; and where the aryl group and the heteroaryl group are unsubstituted or a) Fluorine atom, b) Deuterium atom, c) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. d) Unsubstituted, or cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. e) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. f) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, g) Unsubstituted, or -O-cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. h) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, hydroxyl groups, and alkylcarbonyl groups, i) -O-spiro ring group, j) Alkylsulfonylalkyl groups, and k) Alkyl sulfonyl group Substituted with one or more substituents independently selected from the group consisting of; and R2 is selected from the group consisting of alkyloxylalkyl groups and heterocycloalkyl groups, where the heterocycloalkyl group represented by R2 is bonded via a carbon atom and is either unsubstituted or substituted with an alkyl group, an alkyloxyl group, or one or more fluorine atoms. Compounds of or pharmaceutically acceptable salts thereof are provided herein.

[0043] Equation (I): [ka] [In formula: R1 is selected from the group consisting of an aryl group, an ortho-condensed bicyclic heteroaryl group, and a heteroaryl group, where the ortho-condensed bicyclic heteroaryl group is unsubstituted or substituted with one or more -(C1-C3)-alkyl groups; and where the aryl group and the heteroaryl group are unsubstituted or a) Fluorine atom, b) Deuterium atom, c) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. d) Unsubstituted or cycloalkyl groups substituted with one or more fluorine atoms or -(C1-C3)-alkyl groups, e) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. f) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, g) Unsubstituted or -O-cycloalkyl groups substituted with one or more fluorine atoms or -(C1-C3)-alkyl groups, h) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, and alkylcarbonyl groups, i) -O-spiro ring group, j) Alkylsulfonylalkyl groups, and k) Alkyl sulfonyl group Substituted with one or more substituents independently selected from the group consisting of; and R2 is selected from the group consisting of alkyloxylalkyl groups and heterocycloalkyl groups, where the heterocycloalkyl group represented by R2 is bonded via a carbon atom and is either unsubstituted or substituted with an alkyl group, an alkyloxyl group, or one or more fluorine atoms. Compounds of or pharmaceutically acceptable salts thereof are provided herein.

[0044] One embodiment is given by formula (I), [wherein R1 is selected from the group consisting of phenyl groups and heteroaryl groups, where the aryl group and heteroaryl group are either unsubstituted or a) Fluorine atom, b) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. c) Unsubstituted or cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. d) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups, e) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, f) Unsubstituted or -O-cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. g) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, hydroxyl groups, and alkylcarbonyl groups, h) -O-spiro ring group, i) Alkylsulfonylalkyl groups, and j) Alkyl sulfonyl group Substituted with one or more substituents independently selected from the group consisting of; and R2 is selected from the group consisting of alkyloxylalkyl groups and heterocycloalkyl groups, where the heterocycloalkyl group represented by R2 is bonded via a carbon atom and is either unsubstituted or substituted with an alkyl group, an alkyloxyl group or one or more fluorine atoms; a compound of or a pharmaceutically acceptable salt thereof.

[0045] One embodiment is given by formula (I), [wherein, R1 is a substituted or unsubstituted phenyl group, an ortho-condensed bicyclic heteroaryl group, and [ka] Selected from a group consisting of elements; Here, the ortho-condensed bicyclic heteroaryl group is either unsubstituted or substituted with one or more -(C1-C3)-alkyl groups; R2 is selected from the group consisting of alkyloxylalkyl groups and heterocycloalkyl groups, wherein the heterocycloalkyl group is bonded via a carbon atom and is either unsubstituted or substituted with an alkyl group, an alkyloxyl group, or one or more fluorine atoms; R4 is a) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, b) Unsubstituted or -O-cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups, c) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, alkylcarbonyl groups, and hydroxyl groups, and d) -O-spiro ring group Selected from the group consisting of; R5 is a) Hydrogen atom, b) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. c) Unsubstituted or cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. d) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. e) Alkylsulfonylalkyl groups, and f) Alkylsulfonyl group Selected from the group consisting of; and R6 is selected from the group consisting of hydrogen atoms and deuterium atoms. It is a compound of or a pharmaceutically acceptable salt thereof.

[0046] One embodiment is given by formula (I), [wherein, R1 is [ka] It is the basis;

[0047] R2 is alkyloxylalkyl and [ka] Selected from a group consisting of elements; Here, R3 is selected from the group consisting of a hydrogen atom, a -(C1-C3)-alkyl group, and a -(C1-C3)-alkyloxyl group; m represents 1, 2, or 3; n represents either 0 or 1; R4 is a) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, b) Unsubstituted or -O-cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. c) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, hydroxyl groups, and alkylcarbonyl groups, and d) -O-spiro ring group Selected from the group consisting of; R5 is a) Hydrogen atom, b) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. c) Unsubstituted or cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups, d) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. e) Alkylsulfonylalkyl groups, and f) Alkylsulfonyl group Selected from the group consisting of; and R6 is selected from the group consisting of hydrogen atoms and deuterium atoms. It is a compound of or a pharmaceutically acceptable salt thereof.

[0048] One embodiment is given by formula (I), [wherein, R1 is selected from the group consisting of phenyl groups and heteroaryl groups, where the phenyl group and heteroaryl group are either unsubstituted or a) Fluorine atom, b) Deuterium atom, c) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. d) Unsubstituted or cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. e) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. f) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, g) Unsubstituted or -O-cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups h) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, hydroxyl groups, and alkylcarbonyl groups, i) -O-spiro ring group, j) Alkylsulfonylalkyl groups, and k) Alkyl sulfonyl group Substituted with one or more substituents independently selected from the group consisting of; and R2 is a heterocycloalkyl group bonded via a carbon atom and is either unsubstituted or substituted with an alkyl group, an alkyloxyl group, or one or more fluorine atoms. It is a compound of or a pharmaceutically acceptable salt thereof.

[0049] One embodiment is given by formula (I), [wherein, R1 is [ka] It is the basis; R2 is a heterocycloalkyl group bonded via a carbon atom and is either unsubstituted or substituted with an alkyl group, an alkyloxyl group, or one or more fluorine atoms; R4 is a) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, b) Unsubstituted or -O-cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. c) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, alkylcarbonyl groups, and hydroxyl groups, and d) -O-spiro ring group Selected from the group consisting of; R5 is a) Hydrogen atom, b) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. c) Unsubstituted or cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. d) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. e) Alkylsulfonylalkyl groups, and f) Alkylsulfonyl group Selected from the group consisting of; and R6 is selected from the group consisting of hydrogen atoms and deuterium atoms. It is a compound of or a pharmaceutically acceptable salt thereof.

[0050] One embodiment is given by formula (Ia) [ka] [In formula: R1 is selected from the group consisting of an aryl group, an ortho-condensed bicyclic heteroaryl group, and a heteroaryl group, where the ortho-condensed bicyclic heteroaryl group is unsubstituted or substituted with one or more -(C1-C3)-alkyl groups; the aryl group and the heteroaryl group are unsubstituted or a) Deuterium atom, b) Fluorine atom, c) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. d) Unsubstituted or cycloalkyl groups substituted with one or more fluorine atoms, hydroxyl groups, or -(C1-C3)-alkyl groups, e) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, or alkylcarbonyl groups. f) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, g) Unsubstituted or -O-cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups h) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, alkylcarbonyl groups, and hydroxyl groups. i) -O-spiro ring group, j) Alkylsulfonylalkyl groups, and k) Alkyl sulfonyl group Substituted with one or more substituents independently selected from the group consisting of; R3 is selected from the group consisting of a hydrogen atom, a -(C1-C3)-alkyl group, and a -(C1-C3)-alkyloxyl group; m represents 1, 2, or 3; and n represents either 0 or 1; It is a compound of or a pharmaceutically acceptable salt thereof.

[0051] One embodiment is given by formula (Ia) [ka] [In formula: R1 is selected from the group consisting of an aryl group, an ortho-condensed bicyclic heteroaryl group, and a heteroaryl group, where the ortho-condensed bicyclic heteroaryl group is unsubstituted or substituted with one or more -(C1-C3)-alkyl groups; the aryl group and the heteroaryl group are unsubstituted or a) Deuterium atom, b) Fluorine atom, c) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. d) Unsubstituted or cycloalkyl groups substituted with one or more fluorine atoms or -(C1-C3)-alkyl groups, e) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, or alkylcarbonyl groups. f) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, g) Unsubstituted or -O-cycloalkyl groups substituted with one or more fluorine atoms or -(C1-C3)-alkyl groups, h) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, and alkylcarbonyl groups, i) -O-spiro ring group, j) Alkylsulfonylalkyl groups, and k) Alkyl sulfonyl group Substituted with one or more substituents independently selected from the group consisting of; R3 is selected from the group consisting of a hydrogen atom, a -(C1-C3)-alkyl group, and a -(C1-C3)-alkyloxyl group; m represents 1, 2, or 3; and n represents either 0 or 1; It is a compound of or a pharmaceutically acceptable salt thereof.

[0052] One embodiment is given by formula (Ia), [wherein, R1 is selected from the group consisting of phenyl groups and heteroaryl groups, where the phenyl group and heteroaryl group are either unsubstituted or a) Fluorine atom, b) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. c) Unsubstituted or cycloalkyl groups substituted with one or more fluorine atoms, hydroxyl groups, or -(C1-C3)-alkyl groups, d) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. e) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, f) Unsubstituted or -O-cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. g) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, alkylcarbonyl groups, and hydroxyl groups, h) -O-spiro ring group, i) Alkylsulfonylalkyl groups, and j) Alkyl sulfonyl group Substituted with one or more substituents independently selected from the group consisting of; m represents 1 or 2; and n represents either 0 or 1; It is a compound of or a pharmaceutically acceptable salt thereof.

[0053] One embodiment is given by formula (Ib) [ka] [In formula: R3 is selected from the group consisting of a hydrogen atom, a -(C1-C3)-alkyl group, and a -(C1-C3)-alkyloxyl group; R4 is a) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, b) Unsubstituted or -O-cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. c) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, alkylcarbonyl groups, and hydroxyl groups, and d) -O-spiro ring group Selected from the group consisting of; m represents 1, 2, or 3; n represents either 0 or 1; R5 is a) Hydrogen atom, b) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. c) Unsubstituted or cycloalkyl groups substituted with one or more fluorine atoms, hydroxyl groups, or -(C1-C3)-alkyl groups, d) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. e) Alkylsulfonylalkyl groups, and f) Alkylsulfonyl group Selected from the group consisting of; and R6 is selected from the group consisting of hydrogen atoms and deuterium atoms. It is a compound of or a pharmaceutically acceptable salt thereof.

[0054] One embodiment is given by formula (Ib) [ka] [In formula: R3 is selected from the group consisting of a hydrogen atom, a -(C1-C3)-alkyl group, and a -(C1-C3)-alkyloxyl group; R4 is a) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, b) Unsubstituted or -O-cycloalkyl groups substituted with one or more fluorine atoms or -(C1-C3)-alkyl groups, c) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, and alkylcarbonyl groups, and d) -O-spiro ring group Selected from the group consisting of; m represents 1, 2, or 3; n represents either 0 or 1; R5 is a) Hydrogen atom, b) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. c) Unsubstituted or cycloalkyl groups substituted with one or more fluorine atoms or -(C1-C3)-alkyl groups, d) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. e) Alkylsulfonylalkyl groups, and f) Alkylsulfonyl group Selected from the group consisting of; and R6 is selected from the group consisting of hydrogen atoms and deuterium atoms. It is a compound of or a pharmaceutically acceptable salt thereof.

[0055] One embodiment is given by formula (Ib) [ka] [In formula: R3 is selected from the group consisting of -(C1-C3)-alkyl groups and -(C1-C3)-alkyloxyl groups; R4 is a) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, b) Unsubstituted or -O-cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. c) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, alkylcarbonyl groups, and hydroxyl groups, and d) -O-spiro ring group Selected from the group consisting of; m represents 1 or 2; n represents either 0 or 1; R5 is a) Hydrogen atom, b) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. c) Unsubstituted or cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. d) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. e) Alkylsulfonylalkyl groups, and f) Alkylsulfonyl group Selected from the group consisting of; and R6 is a hydrogen atom. It is a compound of or a pharmaceutically acceptable salt thereof.

[0056] One embodiment is given by formula (Ib) [ka] [In formula: R3 is selected from the group consisting of -(C1-C3)-alkyl groups and -(C1-C3)-alkyloxyl groups; R4 is a) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, b) Unsubstituted or one or more fluorine atoms, -(C1-C3)-alkyl groups or -O-cycloalkyl groups substituted with hydroxyl groups, and c) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, alkylcarbonyl groups, and hydroxyl groups. Selected from the group consisting of; m represents 1; n represents 1; R5 is a) an alkyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group. b) Unsubstituted or cycloalkyl groups substituted with one or more fluorine atoms, hydroxyl groups, or -(C1-C3)-alkyl groups, c) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. Selected from the group consisting of; and R6 is a hydrogen atom. It is a compound of or a pharmaceutically acceptable salt thereof.

[0057] One embodiment is given by formula (Ib) [ka] [In formula: R3 is a -(C1-C3)-alkyl group; R4 is a) Unsubstituted or -O-cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. b) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, alkylcarbonyl groups, and hydroxyl groups, Selected from the group consisting of, m represents 1; n represents 1; R5 is either unsubstituted or an alkyl group substituted with one or more substituents independently selected from the group consisting of a hydroxyl group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group, and R6 is a hydrogen atom. It is a compound of or a pharmaceutically acceptable salt thereof.

[0058] One embodiment is given by formula (Ic) [ka] [In formula: R4 is a) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, b) Unsubstituted or -O-cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. c) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, alkylcarbonyl groups, and hydroxyl groups, and d) -O-spiro ring group Selected from the group consisting of; R5 is a) Hydrogen atom, b) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. c) Unsubstituted or cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl groups, or hydroxyl groups. d) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. e) Alkylsulfonylalkyl groups, and f) Alkylsulfonyl group Selected from the group consisting of; R6 is selected from the group consisting of hydrogen atoms and deuterium atoms; R7 is a -(C1-C3)-alkyl group; and R8 is a -(C1-C3)-alkyl group; It is a compound of or a pharmaceutically acceptable salt thereof.

[0059] One embodiment is given by formula (Ic) [ka] [In formula: R4 is a) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, b) Unsubstituted or -O-cycloalkyl groups substituted with one or more fluorine atoms or -(C1-C3)-alkyl groups, c) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, and alkylcarbonyl groups, and d) -O-spiro ring group Selected from the group consisting of; R5 is a) Hydrogen atom, b) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. c) Unsubstituted or cycloalkyl groups substituted with one or more fluorine atoms or -(C1-C3)-alkyl groups, d) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. e) Alkylsulfonylalkyl groups, and f) Alkylsulfonyl group Selected from the group consisting of; R6 is selected from the group consisting of hydrogen atoms and deuterium atoms; R7 is a -(C1-C3)-alkyl group; and R8 is a -(C1-C3)-alkyl group; It is a compound of or a pharmaceutically acceptable salt thereof.

[0060] One embodiment is a compound of formula (I) in which R1 represents a substituted or unsubstituted aryl group.

[0061] One embodiment is a compound of formula (I) in which R1 represents a substituted or unsubstituted phenyl group.

[0062] One embodiment is a compound of formula (I) in which R1 represents an ortho-condensed bicyclic heteroaryl group that is either unsubstituted or substituted with one or more -(C1-C3)-alkyl groups.

[0063] In one embodiment, R1 is as follows: [ka] It is a compound of formula (I) representing an ortho-condensed bicyclic heteroaryl group selected from the following.

[0064] One embodiment is a compound of formula (I) in which R1 represents a substituted or unsubstituted heteroaryl group.

[0065] In one embodiment, R1 is [ka] Group [wherein: R4 is a) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, b) Unsubstituted or -O-cycloalkyl groups substituted with one or more fluorine atoms, -(C1-C3)-alkyl or hydroxyl groups, c) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, alkylcarbonyl groups, and hydroxyl groups, and d) -O-spiro ring group Selected from the group consisting of; R5 is a) Hydrogen atom, b) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. c) Unsubstituted or hydroxyl-substituted cycloalkyl groups d) Heterocycloalkyl groups, e) Alkylsulfonylalkyl groups, and f) Alkylsulfonyl group Selected from the group consisting of; and R6 is selected from the group consisting of hydrogen atoms and deuterium atoms. It is a compound of formula (I) or a pharmaceutically acceptable salt thereof that represents [the specified value].

[0066] One embodiment is a compound of formula (I) in which R2 represents an alkyloxylalkyl group.

[0067] One embodiment is a compound of formula (I) in which R2 represents a heterocycloalkyl group.

[0068] In one embodiment, R2 is [ka] It is a compound of formula (I) that represents a group.

[0069] In one embodiment, R2 is listed below: [ka] It is a compound of formula (I) representing a heterocycloalkyl group selected from the following.

[0070] One embodiment is a compound of formula (Ia) in which R3 represents a hydrogen atom.

[0071] One embodiment is a compound of formula (Ia) in which R3 represents a -(C1-C3)-alkyl group.

[0072] One embodiment is a compound of formula (Ia) in which R3 represents a -(C1-C3)-alkyloxyl group.

[0073] One embodiment is a compound of formula (Ia) where m represents 1.

[0074] One embodiment is a compound of formula (Ia) where m represents 2.

[0075] One embodiment is a compound of formula (Ia) where m represents 3.

[0076] One embodiment is a compound of formula (Ia) where n represents 0.

[0077] One embodiment is a compound of formula (Ib) where n represents 1.

[0078] One embodiment is a compound of formula (Ib) in which R4 represents an alkyloxyl group that is either unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom.

[0079] One embodiment is a compound of formula (Ib) in which R4 is unsubstituted or represents an O-cycloalkyl group substituted with one or more fluorine atoms, a lower alkyl group, or a hydroxyl group.

[0080] One embodiment is a compound of formula (Ib) in which R4 is unsubstituted or represents an -O-heterocycloalkyl group substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, alkylcarbonyl groups, and hydroxyl groups.

[0081] One embodiment is a compound of formula (Ib) in which R4 represents an -O-spiro ring group.

[0082] In one embodiment, R4 is listed below: [ka] It is a compound of formula (Ib) that represents a group selected from among the following.

[0083] One embodiment is a compound of formula (Ib) in which R5 represents a hydrogen atom.

[0084] One embodiment is a compound of formula (Ib) in which R5 is either unsubstituted or represents an alkyl group substituted with one or more substituents independently selected from the group consisting of a hydroxyl group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group.

[0085] One embodiment is a compound of formula (Ib) in which R5 represents an unsubstituted or hydroxyl-substituted cycloalkyl group.

[0086] One embodiment is a compound of formula (Ib) in which R5 represents a heterocycloalkyl group.

[0087] One embodiment is a compound of formula (Ib) in which R5 represents an alkylsulfonylalkyl group.

[0088] One embodiment is a compound of formula (Ib) in which R5 represents an alkylsulfonyl group.

[0089] In one embodiment, R5 is listed below: [ka] It is a compound of formula (Ib) that represents a group selected from among the following.

[0090] In one embodiment, the compound of formula (I) is: 2-[[3-(1-acetylazetidine-3-yl)oxy-1-methylpyrazole-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-[[1-methyl-3-[(3S,4R)-4-methyltetrahydrofuran-3-yl]oxy-1H-pyrazole-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-[[1-methyl-3-[(3R,4S)-4-methyltetrahydrofuran-3-yl]oxy-1H-pyrazole-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-[[1-methyl-3-[(trans)-4-methyltetrahydrofuran-3-yl]oxy-1H-pyrazole-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-[[1-[(1R)-2,2-difluoro-1-methyl-ethyl]-3-(oxetane-3-yloxy)pyrazole-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-[[1-[(1S)-2,2-difluoro-1-methyl-ethyl]-3-(oxetane-3-yloxy)pyrazole-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-[[1-(2,2-difluoro-1-methyl-ethyl)-3-(oxetane-3-yloxy)pyrazole-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-methyl-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-methyl-3-(((trans)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-[[1-Methyl-3-(oxetan-3-yloxy)pyrazol-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-[[1-[2-Hydroxy-1-methyl-ethyl]-3-(oxetan-3-yloxy)pyrazol-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(3R,4R)-4-Methyltetrahydrofuran-3-yl]-2-[[1-(oxetan-3-yl)-3-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(3R,4R)-4-Methyltetrahydrofuran-3-yl]-2-[[1-(oxetan-3-yl)-3-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(3R,4R)-4-Methyltetrahydrofuran-3-yl]-2-[[1-(oxetan-3-yl)-3-(2,2,2-trifluoro-1-methyl-ethoxy)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-[[3-[(3S,4S)-4-Methoxytetrahydrofuran-3-yl]oxy-1-methyl-pyrazol-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-[[3-[(3R,4R)-4-Methoxytetrahydrofuran-3-yl]oxy-1-methyl-pyrazol-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-[[3-[(trans)-4-Methoxytetrahydrofuran-3-yl]oxy-1-methyl-pyrazol-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-[[1-(Methylsulfonylmethyl)-3-(oxetan-3-yloxy)pyrazol-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(Methyl-d3)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(Methyl-d3)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(Methyl-d3)-3-(((trans)-2-methyloxetan-3-yl)oxy)-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((R)-1-acetyl-2,2-dimethylazetidin-3-yl)oxy)-1-methyl-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((S)-1-acetyl-2,2-dimethylazetidin-3-yl)oxy)-1-methyl-1H-pyrazol-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((1-acetyl-2,2-dimethylazetidine-3-yl)oxy)-1-methyl-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(methyl-d3)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((4-(2-hydroxypropan-2-yl)-2-(oxetane-3-yloxy)phenyl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(((R)-1,1,1-trifluoropropane-2-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(((S)-1,1,1-trifluoropropane-2-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-((1,1,1-trifluoropropane-2-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(((2R,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(((2S,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(((cis)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-isopropoxy-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-isopropoxy-1-methyl-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(2-cyanopropan-2-yl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-cyclopropoxy-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(2-cyanopropan-2-yl)-3-isopropoxy-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-cyclopropoxy-1-(oxetan-3-yl)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-isopropoxy-1-(oxetan-3-yl)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(methoxymethyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methylsulfonyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-cyclopropoxy-1-(methoxymethyl)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-cyclopropoxy-1-((methylsulfonyl)methyl)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-Cyclopropyl-3-(Oxetane-3-yloxy)-1H-Pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-Pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-ethyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-[[1-(methoxymethyl)-3-[(trans)-2-methyloxetane-3-yl]oxy-pyrazole-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-[[1-methyl-3-[(2-oxaspiro[3,3]heptan-7-yl)oxy]pyrazole-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((2-cyclopropoxy-4-((dimethylamino)methyl)phenyl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-isopropoxy-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-cyclopropoxy-1-(1,1-difluoropropan-2-yl)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3S,4S)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3S,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4S)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((cis)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-isopropoxy-1-methyl-1H-pyrazole-4-yl)amino)-7-((cis)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-((R)-1-cyanoethyl)-3-isopropoxy-1H-pyrazole-4-yl)amino)-7-((3S,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(1-cyanoethyl)-3-isopropoxy-1H-pyrazole-4-yl)amino)-7-((cis)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-((S)-1-cyanoethyl)-3-isopropoxy-1H-pyrazole-4-yl)amino)-7-((3S,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-((R)-1-cyanoethyl)-3-isopropoxy-1H-pyrazole-4-yl)amino)-7-((3R,4S)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-((S)-1-cyanoethyl)-3-isopropoxy-1H-pyrazole-4-yl)amino)-7-((3R,4S)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; (R)-2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; (S)-2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-2-((1-(oxetane-3-yl)-3-((1,1,1-trifluoropropane-2-yl)oxy)-1H-pyrazole-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((4-(2-hydroxypropan-2-yl)-2-(oxetane-3-yloxy)phenyl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-((S)-1-cyanoethyl)-3-isopropoxy-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-((R)-1-cyanoethyl)-3-isopropoxy-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(1-cyanoethyl)-3-isopropoxy-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(1-cyanoethyl)-3-cyclopropoxy-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(2-cyanopropan-2-yl)-3-cyclopropoxy-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(2-cyanopropan-2-yl)-3-isopropoxy-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-cyclopropoxy-1-isopropyl-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-isopropoxy-1-methyl-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-isopropoxy-1-(oxetan-3-yl)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-cyclopropoxy-1-(oxetan-3-yl)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-(3,3-difluorocyclobutoxy)-1-methyl-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-((R)-sec-butoxy)-1-methyl-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-((S)-sec-butoxy)-1-methyl-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine-8-yl)amino)-7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 7-((3R,4R)-4-methoxytetrahydrofuran-3-yl)-2-(((R)-2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridine-9-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-((trans)-4-methoxytetrahydrofuran-3-yl)-2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((4-(2-hydroxypropan-2-yl)-2-(oxetane-3-yloxy)phenyl)amino)-7-((trans)-4-methoxytetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-((cis)-4-ethyltetrahydrofuran-3-yl)-2-((3-isopropoxy-1-methyl-1H-pyrazole-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-((trans)-4-ethyltetrahydrofuran-3-yl)-2-((3-isopropoxy-1-methyl-1H-pyrazole-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(2-Cyanopropan-2-yl)-3-isopropoxy-1H-pyrazol-4-yl)amino)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-Isopropoxy-1-methyl-1H-pyrazol-4-yl)amino)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(2S,3R)-2-Methyloxetan-3-yl]-2-[[1-methyl-3-(oxetan-3-yloxy)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(2R,3S)-2-Methyloxetan-3-yl]-2-[[1-methyl-3-(oxetan-3-yloxy)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(trans)-2-Methyloxetan-3-yl]-2-[[1-methyl-3-(oxetan-3-yloxy)pyrazol-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(2R,3S)-2-Methyloxetan-3-yl]-2-[(1-methyl-3-propan-2-yloxypyrazol-4-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(2S,3R)-2-Methyloxetan-3-yl]-2-[(1-methyl-3-propan-2-yloxypyrazol-4-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(trans)-2-Methyloxetan-3-yl]-2-[(1-methyl-3-propan-2-yloxypyrazol-4-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-Methyl-3-(oxetan-3-yloxy)-1H-pyrazol-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (R)-2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (S)-2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((trans)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3S,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; ((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((cis)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[1-methyl-3-[(2S,3R)-2-methyloxetane-3-yl]oxy-pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[1-methyl-3-[(2R,3S)-2-methyloxetane-3-yl]oxy-pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[1-methyl-3-[(trans)-2-methyloxetane-3-yl]oxy-pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(2S,3R)-2-methyloxetane-3-yl]oxy-1-(methyl-d3)pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(2R,3S)-2-methyloxetane-3-yl]oxy-1-(methyl-d3)pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(trans)-2-methyloxetane-3-yl]oxy-1-(methyl-d3)pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(2S)-1-methoxypropan-2-yl]-2-[[3-(oxetane-3-yloxy)-1-(methyl-d3)pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-[[3-(cyclopropoxy)-1-(methoxymethyl)pyrazole-4-yl]amino]-7-[(1S)-2-methoxy-1-methyl-ethyl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[1-(methylsulfonylmethyl)-3-(oxetane-3-yloxy)pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl-5-d)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (S)-2-((3-cyclopropoxy-1-(methoxymethyl)-1H-pyrazole-4-yl-5-d)amino)-7-(1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl-5-d)amino)-7-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-((2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl-5-d)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(methyl-d3)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl-5-d)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-(((R)-2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropane-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((S)-2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-((S)-1-methoxypropan-2-yl)-2-((1-(methyl-d3)-3-(((R)-tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-((S)-1-methoxypropan-2-yl)-2-((1-(methyl-d3)-3-(((S)-tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-((S)-1-methoxypropan-2-yl)-2-((1-(methyl-d3)-3-((tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (S)-2-((3-cyclopropoxy-1-(2-methoxyethyl)-1H-pyrazole-4-yl)amino)-7-(1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; cis-2-((1-(4-hydroxy-4-methylcyclohexyl)-3-isopropoxy-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; trans-2-((1-(4-hydroxy-4-methylcyclohexyl)-3-isopropoxy-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; cis-2-((3-cyclopropoxy-1-(4-hydroxy-4-methylcyclohexyl)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; trans-2-((3-cyclopropoxy-1-(4-hydroxy-4-methylcyclohexyl)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(3-hydroxy-2,2-dimethylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((S)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-(((R)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((5,5-dimethyltetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(methyl-d3)-3-(((S)-tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(((R)-tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-((tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-cyclopropoxy-1-(2-methoxyethyl)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((3R,4R)-4-hydroxytetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((trans-4-hydroxytetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((3R,4R)-4-hydroxytetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((trans-4-hydroxytetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((S)-2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-(((R)-2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (S)-2-((3-((2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (R)-2-((3-((2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-((2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-cyclopropoxy-1-(2-methoxyethyl)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-((trans-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (R)-2-((3-cyclopropoxy-1-(1-methoxypropan-2-yl)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (S)-2-((3-cyclopropoxy-1-(1-methoxypropan-2-yl)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-cyclopropoxy-1-(1-methoxypropan-2-yl)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(1-methoxypropan-2-yl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 7-((S)-1-methoxypropan-2-yl)-2-((1-((S)-1-methoxypropan-2-yl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-((S)-1-methoxypropan-2-yl)-2-((1-((R)-1-methoxypropan-2-yl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-((S)-1-methoxypropan-2-yl)-2-((1-(1-methoxypropan-2-yl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((cis-4-hydroxy-4-methyltetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(cis-3-hydroxy-2,2,4,4-tetramethylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(trans-3-hydroxy-2,2,4,4-tetramethylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(3-hydroxy-2,2,4,4-tetramethylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(3-hydroxy-2,2-dimethylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (isomer 1); 2-((3-(3-hydroxy-2,2-dimethylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (isomer 2); 2-((3-(3-hydroxy-2,2-dimethylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((3S,4R)-4-hydroxytetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((3R,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((cis-4-hydroxytetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (S)-2-((1-(2-hydroxyethyl)-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazole-4-yl)amino)-7-(1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (S)-2-((1-(2-hydroxyethyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-(1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((1S,2R)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-((1R,2S)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(cis-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-((trans-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-((1S,2S)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-((1R,2R)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(cis-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((1S,2R)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((1R,2S)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(trans-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((1S,2S)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((1R,2R)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(2-hydroxyethyl)-3-((tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(2-hydroxyethyl)-3-(((R)-tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(2-hydroxyethyl)-3-(((S)-tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (S)-2-((2-cyclopropoxy-4-(2-hydroxypropan-2-yl)phenyl)amino)-7-(1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-(trans-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-cyclopropoxy-1-((methylsulfonyl)methyl)-1H-pyrazole-4-yl)amino)-7-(trans-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-cyclopropoxy-1-((methylsulfonyl)methyl)-1H-pyrazole-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-cyclopropoxy-1-((methylsulfonyl)methyl)-1H-pyrazole-4-yl)amino)-7-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(2-hydroxyethyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(2-hydroxyethyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; and 2-((1-(2-hydroxyethyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-(trans-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; Alternatively, it is selected from the group consisting of pharmaceutically acceptable salts thereof.

[0091] In one embodiment, the compound of formula (I) is: 2-((1-methyl-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-[[1-methyl-3-(oxetane-3-yloxy)pyrazole-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(methyl-d3)-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(methyl-d3)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-isopropoxy-1-methyl-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[1-methyl-3-[(2S,3R)-2-methyloxetane-3-yl]oxy-pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[1-methyl-3-[(2R,3S)-2-methyloxetane-3-yl]oxy-pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(2S,3R)-2-methyloxetane-3-yl]oxy-1-(methyl-d3)pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(2R,3S)-2-methyloxetane-3-yl]oxy-1-(methyl-d3)pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (S)-2-((1-(2-hydroxyethyl)-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazole-4-yl)amino)-7-(1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(((S)-tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(((R)-tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; (S)-2-((2-cyclopropoxy-4-(2-hydroxypropan-2-yl)phenyl)amino)-7-(1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((S)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-(((R)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((1S,2S)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((1R,2R)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(cis-3-hydroxy-2,2,4,4-tetramethylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(trans-3-hydroxy-2,2,4,4-tetramethylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-((1S,2S)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-((1R,2R)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((3R,4R)-4-hydroxytetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-(((S)-2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-(((R)-2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(2-hydroxyethyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(2-hydroxyethyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; and 2-[[3-(cyclopropoxy)-1-(methoxymethyl)pyrazole-4-yl]amino]-7-[(1S)-2-methoxy-1-methyl-ethyl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; Alternatively, it is selected from the group consisting of pharmaceutically acceptable salts thereof.

[0092] In one embodiment, the compound of formula (I) is: 2-((1-methyl-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-[[1-methyl-3-(oxetane-3-yloxy)pyrazole-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(methyl-d3)-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-(methyl-d3)-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(methyl-d3)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((3-isopropoxy-1-methyl-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[1-methyl-3-[(2S,3R)-2-methyloxetane-3-yl]oxy-pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[1-methyl-3-[(2R,3S)-2-methyloxetane-3-yl]oxy-pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(2S,3R)-2-methyloxetane-3-yl]oxy-1-(methyl-d3)pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(2R,3S)-2-methyloxetane-3-yl]oxy-1-(methyl-d3)pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; and 2-[[3-(cyclopropoxy)-1-(methoxymethyl)pyrazole-4-yl]amino]-7-[(1S)-2-methoxy-1-methyl-ethyl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; Alternatively, it is selected from the group consisting of pharmaceutically acceptable salts thereof.

[0093] In one embodiment, the compound of formula (I) is 2-((1-methyl-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0094] In one embodiment, the compound of formula (I) is 2-((1-methyl-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0095] In one embodiment, the compound of formula (I) is 2-[[1-methyl-3-(oxetane-3-yloxy)pyrazole-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0096] In one embodiment, the compound of formula (I) is 2-((1-(methyl-d3)-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0097] In one embodiment, the compound of formula (I) is 2-((1-(methyl-d3)-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0098] In one embodiment, the compound of formula (I) is 2-((1-(methyl-d3)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0099] In one embodiment, the compound of formula (I) is 2-((3-isopropoxy-1-methyl-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0100] In one embodiment, the compound of formula (I) is 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0101] In one embodiment, the compound of formula (I) is 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0102] In one embodiment, the compound of formula (I) is 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0103] In one embodiment, the compound of formula (I) is 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[1-methyl-3-[(2S,3R)-2-methyloxetan-3-yl]oxy-pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0104] In one embodiment, the compound of formula (I) is 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[1-methyl-3-[(2R,3S)-2-methyloxetan-3-yl]oxy-pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0105] In one embodiment, the compound of formula (I) is 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(2S,3R)-2-methyloxetane-3-yl]oxy-1-(methyl-d3)pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0106] In one embodiment, the compound of formula (I) is 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(2R,3S)-2-methyloxetane-3-yl]oxy-1-(methyl-d3)pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0107] In one embodiment, the compound of formula (I) is 2-[[3-(cyclopropoxy)-1-(methoxymethyl)pyrazole-4-yl]amino]-7-[(1S)-2-methoxy-1-methyl-ethyl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0108] In one embodiment, the compound of formula (I) is (S)-2-((1-(2-hydroxyethyl)-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazole-4-yl)amino)-7-(1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0109] In one embodiment, the compound of formula (I) is 2-((1-(methyl-d3)-3-(((S)-tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0110] In one embodiment, the compound of formula (I) is 2-((1-(methyl-d3)-3-(((R)-tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0111] In one embodiment, the compound of formula (I) is (S)-2-((2-cyclopropoxy-4-(2-hydroxypropan-2-yl)phenyl)amino)-7-(1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0112] In one embodiment, the compound of formula (I) is 2-((3-(((S)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0113] In one embodiment, the compound of formula (I) is 2-((3-(((R)-5,5-dimethyltetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0114] In one embodiment, the compound of formula (I) is 2-((3-((1S,2S)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0115] In one embodiment, the compound of formula (I) is 2-((3-((1R,2R)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0116] In one embodiment, the compound of formula (I) is 2-((3-(cis-3-hydroxy-2,2,4,4-tetramethylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0117] In one embodiment, the compound of formula (I) is 2-((3-(trans-3-hydroxy-2,2,4,4-tetramethylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((S)-1-methoxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0118] In one embodiment, the compound of formula (I) is 2-((3-((1S,2S)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0119] In one embodiment, the compound of formula (I) is 2-((3-((1R,2R)-2-hydroxy-2-methylcyclobutoxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0120] In one embodiment, the compound of formula (I) is 2-((3-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0121] In one embodiment, the compound of formula (I) is 2-((3-(((3R,4R)-4-hydroxytetrahydrofuran-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0122] In one embodiment, the compound of formula (I) is 2-((3-(((S)-2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0123] In one embodiment, the compound of formula (I) is 2-((3-(((R)-2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; or a pharmaceutically acceptable salt thereof.

[0124] In one embodiment, the compound of formula (I) is 2-((1-(2-hydroxyethyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0125] In one embodiment, the compound of formula (I) is 2-((1-(2-hydroxyethyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0126] Compounds of formula (I) may contain one or more chiral carbon atoms. Therefore, they may exist in the form of enantiomers or diastereomers. These enantiomers and diastereomers, as well as mixtures thereof, including racemic mixtures, are also provided herein.

[0127] Some of the compounds of formula (I) may exist in the form of a base or an acid addition salt. Such addition salts form part of the disclosure. These salts are advantageously prepared using pharmaceutically acceptable acids, but salts of other acids useful for the purification or isolation of the compounds of formula (I), for example, also form part of the disclosure.

[0128] Another embodiment is a method for producing a compound of formula (I), the method comprising reacting a compound of formula (11X) with a compound of formula (15X): [ka] In the formula, R1 and R2 are as defined herein for the compound of formula (I).

[0129] Another embodiment is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0130] Another embodiment is a pharmaceutical composition comprising an effective dose of the compound of formula (I) as an active ingredient, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0131] One embodiment is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is 2-((1-methyl-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitride.

[0132] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is 2-((1-methyl-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitride.

[0133] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is 2-[[1-methyl-3-(oxetane-3-yloxy)pyrazole-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitride.

[0134] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is 2-((1-(methyl-d3)-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

[0135] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is 2-((1-(methyl-d3)-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile.

[0136] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is 2-((1-(methyl-d3)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitride.

[0137] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is 2-((3-isopropoxy-1-methyl-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitride.

[0138] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitride.

[0139] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitride.

[0140] One embodiment is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitride.

[0141] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[1-methyl-3-[(2S,3R)-2-methyloxetan-3-yl]oxy-pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitride.

[0142] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[1-methyl-3-[(2R,3S)-2-methyloxetan-3-yl]oxy-pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitride.

[0143] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(2S,3R)-2-methyloxetane-3-yl]oxy-1-(methyl-d3)pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitride.

[0144] One embodiment is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(2R,3S)-2-methyloxetane-3-yl]oxy-1-(methyl-d3)pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitride.

[0145] One embodiment is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is 2-[[3-(cyclopropoxy)-1-(methoxymethyl)pyrazole-4-yl]amino]-7-[(1S)-2-methoxy-1-methyl-ethyl]pyrrolo[2,3-d]pyrimidine-6-carbonitride.

[0146] One embodiment is a method for treating a disease or disorder selected from the group consisting of neurodegenerative diseases, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0147] One embodiment is a method for treating a neurodegenerative disease selected from the group consisting of Parkinson's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, Lewy body dementia, Pick's disease, progressive supranuclear palsy, and frontotemporal dementia, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0148] One embodiment is a method for treating a neurodegenerative disease selected from the group consisting of Parkinson's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, and Lewy body dementia, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0149] One embodiment is a method for treating a tauopathic disorder selected from the group consisting of Pick's disease, progressive supranuclear palsy, and frontotemporal dementia, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0150] One embodiment is a method for treating Parkinson's disease, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need.

[0151] One embodiment is a drug characterized by containing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0152] One embodiment is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder selected from the group consisting of neurodegenerative diseases.

[0153] One embodiment is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of neurodegenerative diseases selected from the group consisting of Parkinson's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, Lewy body dementia, Pick's disease, progressive supranuclear palsy, and frontotemporal dementia.

[0154] One embodiment is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of neurodegenerative diseases selected from the group consisting of Parkinson's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, and Lewy body dementia.

[0155] One embodiment is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of tauopathic disorders selected from the group consisting of Pick's disease, progressive supranuclear palsy, and frontotemporal dementia.

[0156] One embodiment is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Parkinson's disease.

[0157] General procedure: The starting materials and solvents used in the synthesis were obtained from chemical suppliers such as ABCR, Aldrich, Acros, Apollo, Fluka, Netchem, and Lancaster.

[0158] Typically, the crude product was purified by column chromatography or flash chromatography.

[0159] The compounds of formula (I) as used herein can be prepared by the methods outlined in the following reaction schemes and examples.

[0160] The compound of formula (11X) can be prepared according to scheme 1.

[0161] Scheme 1 [ka]

[0162] Commercially available 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde (1X) can be converted to its derivative (3X) by reacting a protected glycine methyl ester (2X) with a protected glycine methyl ester (2X) in a polar aprotic solvent such as DCM or THF in the presence of a base such as triethylamine. The derivative (3X) was then cyclized in a polar aprotic solvent such as acetonitrile, DMF, or THF in the presence of an organic base such as DBU or an inorganic base such as sodium hydride to obtain compound (4X). The derivative (5X) can be obtained by removing the protecting group according to methods known to those skilled in the art.

[0163] The compound (5X) is subjected to the Mitsunobu reaction with the alcohol R2-OH of formula (6X) in a polar aprotic solvent such as THF in the presence of a diazodicarboxylate (DIAD or DEAD) and triphenylphosphine at a temperature between ambient temperature and 60°C, followed by hydrolysis of the ester (7X) using a hydroxide source such as NaOH or LiOH to obtain the carboxylic acid (8X) [where R2 is as defined above]. The carboxylic acid (8X) is reacted with NH4OH in a solvent such as DMF in the presence of a coupling agent such as CDI, HATU, or HBTU to obtain the amide (9X). The nitrile derivative (10X) can be obtained by dehydrating the carboxamide (9X) using phosphorus oxychloride or ethyl phosphorodichloride in a solvent such as DCM in the presence of DBU, or using trifluoroacetic anhydride in a solvent such as THF in the presence of triethylamine, or using propanephosphonic anhydride such as T3P. Finally, the derivative (11X) is obtained by oxidation of sulfur using an oxidizing agent such as 3-chloroperbenzoic acid, an aqueous solution of hydrogen peroxide, sodium perborate tetrahydrate, sodium bromate, or oxone.

[0164] The compound of formula (7X) can also be prepared according to scheme 2 [where R2 is as defined above].

[0165] Scheme 2 [ka]

[0166] Commercially available 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde (11X) can be converted to compound (13X) [where R2 is as defined above] by reacting it with a substituted glycine methyl ester of formula (12X) in a polar aprotic solvent such as DCM or THF in the presence of a base such as triethylamine. Compound (7X) is obtained by cyclization of compound (13X) in a polar aprotic solvent such as acetonitrile, DMF or THF in the presence of an organic base such as DBU or an inorganic base such as sodium hydride.

[0167] The compound of formula (15X) can be prepared according to scheme 3.

[0168] Scheme 3 [ka]

[0169] Compounds of formula (15X) [where R1 is as defined above] can be prepared by reacting compound (14X) with formic acid at a temperature between 0°C and ambient temperature, optionally in the presence of acetic anhydride. Most compounds of formula (14X) can be prepared according to methods known to those skilled in the art.

[0170] The following scheme (Scheme 4) provides a process for producing a compound of formula (14X) in which R1 is a substituted pyrazole.

[0171] Scheme 4 [ka]

[0172] Pyrazoles of general formula (14X) [wherein R4 is an alkyloxyl group, and R5 is defined herein in the compound of formula (Ib)] can be synthesized from commercially available 3,4-dinitro-1H-pyrazole (16X). Pyrazole (16X) can be alkylated to compound (21X) in a polar aprotic solvent such as DMF, NMP, or DMSO at a temperature between ambient temperature and 80°C in the presence of a base such as potassium carbonate, cesium carbonate, or sodium hydride, using a halide R5X [wherein X is Cl, Br, or I], or a sulfonate R5OSO2R' such as mesylate (R'=CH3), tosylate (R'=PhMe), triflate (R'=CF3), or nonaflate (R'=CF2CF2CF2CF3). Alternatively, 3,4-dinitro-1H-pyrazole (16X) can be converted to pyrazole (21X) via Chan-Lam coupling by reacting it with boronic acid R5B(OH)2 under reflux in an aprotic solvent such as dichloromethane or 1,2-dichloroethane in the presence of Cu(OAc)2 and a base such as pyridine or 4'-di-tert-butyl-2,2'-bipyridine. If R5 is an alkylsulfonyl group, pyrazole (16X) can be sulfonylated with sulfonyl chloride in an aprotic solvent such as dichloromethane at a temperature between 0°C and ambient temperature in the presence of a base such as triethylamine.

[0173] Compound (20X) can be obtained by treating dinitropyrazole (21X) with the alcohol R4H in a polar aprotic solvent such as DMF, NMP, or DMSO at a temperature between ambient temperature and 80°C in the presence of a base such as potassium carbonate, cesium carbonate, or sodium hydride.

[0174] Alternatively, 4-dinitro-1H-pyrazole (16X) can be protected with a para-methoxybenzyl group under alkylation conditions to obtain compound (17X). The resulting protected pyrazole (17X) can be treated with an alcohol of formula R4H to obtain compound (18X) in the same manner as the conversion from (21X) to (20X). Deprotection of compound (18X) to pyrazole (19X) can be achieved, for example, by a reaction using cerium ammonium nitrate under conditions known to those skilled in the art. The resulting deprotected pyrazole (19X) can be alkylated to compound (20X) using conditions similar to those used for the conversion from compound (16X) to (21X).

[0175] Nitro-substituted pyrazole (20X) can be reduced, for example, in an aprotic or protic solvent under hydrogen pressure in the presence of carbon-supported palladium to obtain the corresponding amino-pyrazole (14X).

[0176] The compound of general formula (I) can be prepared according to scheme 5.

[0177] Scheme 5 [ka]

[0178] Compound (15X) is reacted with pyrrolopyrimidine (11X) in a polar aprotic solvent such as DMF or DMSO at a temperature between ambient temperature and 60°C in the presence of an organic base such as DBU or BTTP, or an inorganic base such as cesium carbonate, potassium tert-butyrate (tertiobutylate), or sodium hydride, to obtain the compound of general formula (I).

[0179] The embodiments provided herein will be described more specifically with reference to the following examples, but the scope of the embodiments provided herein is not limited to these examples.

[0180] Abbreviation Unless otherwise stated, the following abbreviations have the meanings described in the following examples: Acetic acid (ACOH) BTTP tert-butylimino-tri(pyrrolidino)phosphoran HCl (hydrogen chloride) CDI 1,1'-Carbonyldiimidazole DBU 1,8-Diazabicyclo[5.4.0]Undeca-7-Ene DCM Dichloromethane DIAD Diisopropyl Azodiformate DEAD Dietoxycarbonyldiazene DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) eq. equivalent amount Et ethyl EtOH Ethanol Et2O Diethyl ether HCl ethyl acetate HAUT 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HPLC (High-Performance Liquid Chromatography) LC / MS Liquid Chromatography-Mass Spectrometry LiOH (Lithium Hydroxide) NaOH (Sodium Hydroxide) NH4OH Ammonium hydroxide NMP 1-methyl-2-pyrrolidone Me methyl MeOH methanol nM nanomolar concentration NMR nuclear magnetic spectroscopy rt room temperature THF (Tetrahydrofuran) T3P 1-Propanephosphonic Acid Anhydride

[0181] LC / MS analysis was performed using the following method. Method A: UPLC waters and SQD2 Waters mass spectrometer The purity is measured using a UV diode array detector (192-400 nm). Eluent A: H2O (+ 0.1%HCO2H) Eluent B: CH3CN (+ 0.1%HCO2H) Gradient: [Table 1] Flow rate: 0.8mL / min Column: Acquity UPLC CSH Waters C18, 2.1 x 50 mm, 1.7 μm

[0182] Method B: Waters UPLC-SQD2 Eluent A: H2O (+ 0.1%HCO2H) Eluent B: CH3CN (+ 0.1%HCO2H) Gradient (2.5 min): B 3% to 100% at 2.1 min; 2.45 min: B 100%; 2.5 min: B 3% Flow rate: 1mL / min Column: ACQUITY CSH C18, 1.7 μm, 2.1 x 50 mm

[0183] Method C: HPLC Waters XeVo - QTof Eluent A: H2O (+ 0.1%HCO2H) Eluent B: CH3CN (+ 0.1%HCO2H) Gradient (5.3 min): B 5% 0-0.3 min; B 5% to 100% at 4 min; B 100% 4-4.6 min; 5.3 min: B 5% Flow rate: 0.5mL / min Column: ACQUITY CSH C18, 1.7 μm, 2.1 x 100 mm

[0184] Method D: UPLC waters and SQD waters mass analyzer Dissolution solution A: H₂O (+ 0.1% HCO₂H₂O) Dissolution solution B: CH3CN (+ 0.1% HCO2H) グラジエント: Table 2 Flow rate: 1 mL / min カラム:Acquity CORTECS C18, 2.1x50mm, 1.6μm

[0185] Method E: UPLC HCLASS and SQD2 Waters mass analyzer Dissolution solution A: H₂O (+ 0.1% HCO₂H₂O) Dissolution solution B: CH3CN (+ 0.1% HCO2H) グラジエント: Table 3 Flow rate: 0.8 mL / min カラム:Cortecs UPLC C18, 2.1x50mm, 1.6μm

[0186] Method F: UPLC HCLASS and SQD2 Waters mass analyzer Dissolution solution A: H₂O (+ 0.1% HCO₂H₂O) Dissolution solution B: CH3CN (+ 0.1% HCO2H) グラジエント: Table 4 Flow rate: 0.8 mL / min カラム:Cortecs UPLC C18, 2.1x50mm, 1.6μm

[0187] Method G: UPLC HCLASS and SQD2 Waters mass analyzer Dissolution solution A: H₂O (+ 0.1% HCO₂H₂O) Eluent B: CH3CN (+ 0.1%HCO2H) Gradient: [Table 5] Flow rate: 0.8mL / min Column: Cortecs UPLC C18, 2.1 x 50 mm, 1.6 μm

[0188] Method H: UPLC waters and SQD Waters mass spectrometer The purity is measured using a UV diode array detector (192-400 nm). Eluent A: H2O (+ 0.1%HCO2H) Eluent B: CH3CN (+ 0.1%HCO2H) Gradient: [Table 6] Flow rate: 0.8mL / min Column: Acquity UPLC CSH Waters C18, 2.1 x 50 mm, 1.7 μm

[0189] Method I: LCMS waters and SQD mass spectrometer waters Eluent A: H2O (+ 0.1%HCO2H) Eluent B: CH3CN (+ 0.1%HCO2H) Gradient: t=0 min: B 5%, t=1.5 min: B 99%, t=1.9 min: B 99% Flow rate: 1mL / min Column: Cortecs UPLC C18, 2.1 x 50 mm, 1.6 μm.

[0190] intermediate Intermediate 1: 2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate methyl Step 1: Preparation of (4-methoxybenzyl)glycine methyl ester [ka] 53 mL (1 eq.) of methyl 2-bromoacetate in 225 mL of tetrahydrofuran was slowly added under argon at 0°C (ice water / methanol bath) for 35 minutes to a solution of 71 mL (1 eq.) of (4-methoxyphenyl)methaneamine and 116 mL of triethylamine (1.5 eq.) in 750 mL of tetrahydrofuran. After 5 hours at room temperature, the reaction was complete and the mixture was filtered. The filtrate was placed in 975 mL of ethyl acetate and 375 mL of water was added. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The residue was then eluted with 100% dichloromethane, then dichloromethane / ethyl acetate (90 / 10), then dichloromethane / ethyl acetate (70 / 30), and purified on silica gel to obtain 60.9 g of (4-methoxybenzyl)glycine methyl ester.

[0191] Step 2: Preparation of N-(5-formyl-2-(methylthio)pyrimidine-4-yl)-N-(4-methoxybenzyl)glycine methyl ester [ka] 52.5 mL (1.5 eq.) of triethylamine was added at 0°C to a solution of 49 g (1 eq.) of 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde in 500 mL of tetrahydrofuran and 50 mL of dichloromethane. 63 g (1.1 eq.) of (4-methoxybenzyl)glycine methyl ester was added dropwise. The mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with 500 mL of ethyl acetate and water. The organic layer was separated, washed twice with 1000 mL of water, and then washed with 1000 mL of 0.5 N HCl aqueous solution. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was placed in 500 mL of heptane and stirred for 12 hours. The resulting precipitate was filtered and dried under vacuum to obtain 90 g of N-(5-formyl-2-(methylthio)pyrimidine-4-yl)-N-(4-methoxybenzyl)glycine methyl ester. MS (Method B) m / z362[M+1]+;t=1.53 min.

[0192] Step 3: Preparation of 7-(4-methoxybenzyl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate methyl [ka] 167 mL (4 eq.) of 1,8-diazabicyclo[5.4.0]undeca7-ene was added dropwise to a solution of 99 g (1 eq.) of N-(5-formyl-2-(methylthio)pyrimidine-4-yl)-N-(4-methoxybenzyl)glycine methyl ester in 1000 mL of acetonitrile. The reaction mixture was heated at 85°C for 40 minutes. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was placed in 800 mL of ethyl acetate and 500 mL of water. The organic layer was washed with 300 mL of 1N HCl aqueous solution, 300 mL of saturated sodium bicarbonate aqueous solution, 500 mL of water, and then 300 mL of brine, and concentrated under reduced pressure to obtain 82.4 g of 7-(4-methoxybenzyl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate methyl. MS (Method B) m / z344[M+1]+;t=1.74 min.

[0193] Step 4: Preparation of methyl 2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate [ka] 169 mL (10 eq.) of trifluoromethanesulfonic acid was added dropwise to a solution of 62.8 g (1 eq.) of 7-(4-methoxybenzyl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate methyl in 604 mL (44 eq.) of trifluoroacetic acid. The reaction mixture was heated to 75°C for 90 minutes. After cooling to room temperature, the trifluoroacetic acid was concentrated under reduced pressure. The reaction mixture was diluted with 500 mL of dichloromethane and cooled to -15°C. 360 mL of 5 M sodium hydroxide solution was added dropwise while maintaining the temperature below 5°C. A precipitate formed when the pH reached 6. This precipitate was filtered, then washed with water (twice with 250 mL) and then with 250 mL of heptane, and then dried under vacuum to obtain 37.72 g of 2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate methyl. MS (Method B) m / z224[M+1]+;t=1.18 min.

[0194] Intermediates 2 and 3: (3S,4S)-4-methyltetrahydrofuran-3-ol (Intermediate 2) and (3R,4R)-4-methyltetrahydrofuran-3-ol (Intermediate 3) [ka]

[0195] Step 1: Preparation of cis-4-methyltetrahydrofuran-3-ol (a racemic mixture of (3S,4S)-4-methyltetrahydrofuran-3-ol and (3R,4R)-4-methyltetrahydrofuran-3-ol) [ka] A solution of 20 g (1 eq.) of 4-methyldihydrofuran-3(2H)-one (commercially available) in 100 mL of anhydrous tetrahydrofuran was added over 30 minutes under argon to a solution of 68 g (1.06 eq.) of (+)-β-chlorodiisopinocampheylborane [(+)-DIP chloride] in 270 mL of anhydrous tetrahydrofuran, cooled to -25°C. The mixture was stirred at -25°C for 2 hours. Then, a suspension of 46 g (2.16 eq.) of diethanolamine in tetrahydrofuran was added gradually. The mixture was stirred at room temperature for 18 hours, then diluted with 200 mL of pentane and filtered. The filter cake was washed twice with 50 mL of diethyl ether, and the filtrate was carefully concentrated at 40°C under reduced pressure of 120 mbar. The residue was dissolved in 50 mL of dichloromethane and 50 mL of cyclohexane, filtered, and eluted with 10%, 30%, 50%, and 100% diethyl ether in cyclohexane, and purified on silica gel. The pure fraction was concentrated at 40°C under reduced pressure of 120 mbar to obtain 17 g of a racemic mixture of (3S,4S)-4-methyltetrahydrofuran-3-ol and (3R,4R)-4-methyltetrahydrofuran-3-ol. 1 H NMR (400MHz, CDCl3)δ ppm:1.05 (d, J=7 Hz, 3 H);2.21 (m, 1 H);2.24 (s, 1 H);3.44 (dd, J=8 Hz and J=11 Hz, 1 H);3.74 (dd, J=1.4 Hz and J=10 Hz, 1 H);3.90 (t, J=8 Hz, 1 H); 3.93 (dd, J=4 Hz and J=10 Hz, 1 H); 4.19 (m, 1 H).

[0196] Step 2: Preparation of intermediate 3 - (3S,4S)-4-methyltetrahydrofuran-3-yl acetate (precursor to intermediate 2) and enantiopurine (3R,4R)-4-methyltetrahydrofuran-3-ol [ka] To a solution of 14.7 g (1 eq.) of a racemic mixture of (3S,4S)-4-methyltetrahydrofuran-3-ol and (3R,4R)-4-methyltetrahydrofuran-3-ol in 130 mL of vinyl acetate and 130 mL of pentane, 1.5 g of lipase AMANO AK (reference ALDRICH: Amano lipase from fluorescent bacterium (Pseudomonas fluorescens) 20,000 U / g; catalog number: 534730-50G) was added, and the suspension was stirred at 22°C for 16 hours, then filtered through a decalite pad. The filter cake was rinsed twice with 50 mL of diethyl ether, and the filtrate was carefully concentrated at 40°C under reduced pressure of 180 mbar. The residue was eluted with 0-50% ether in cyclohexane and purified with silica to subsequently obtain 9.15 g of (3S,4S)-4-methyltetrahydrofuran-3-yl acetate (precursor of intermediate 2) and 5.64 g of enantiopurine (3R,4R)-4-methyltetrahydrofuran-3-ol (intermediate 3).

[0197] (3S,4S)-4-methyltetrahydrofuran-3-yl acetate: 1 H NMR (400MHz, CDCl3) δ ppm:1.01 (d, J=7 Hz, 3 H);2.09 (s, 3 H);2.39 (m, 1 H);3.45 (dd, J=8 Hz and J=10 Hz, 1 H);3.79 (dd, J=2 Hz and J=10 Hz, 1 H);3.98 (t, J=8 Hz, 1 H); 4.05 (dd, J=4 Hz and J=10 Hz, 1 H); 5.25 (m, 1 H).

[0198] (3R,4R)-4-methyltetrahydrofuran-3-ol-intermediate 3: 1¹H NMR (400MHz, CDCl3) δ ppm: 1.05 (d, J=7 Hz, 3 H); 2.21 (m, 1 H); 2.24 (s, 1 H); 3.44 (dd, J=8 Hz and J=11 Hz, 1 H); 3.74 (dd, J=1.4 Hz and 10 Hz, 1 H); 3.90 (t, J=8 Hz, 1 H); 3.93 (dd, J=4 Hz and 10 Hz, 1 H); 4.19 (m, 1 H).

[0199] Step 3: Preparation of (3S,4S)-4-methyltetrahydrofuran-3-ol intermediate 2 [ka] 94 mL (1.09 eq.) of a 1N methanol solution of pre-cooled (0°C) sodium methoxide was added at 0°C to 12.4 g (86 mmol; 1 eq.) of (3S,4S)-4-methyltetrahydrofuran-3-yl acetate (precursor of intermediate 2) in 20 mL of methanol. The mixture was stirred at 0°C for 1 hour and 30 minutes, and then quenched with 47 mL (1.09 eq.) of a 2N diethyl ether solution of hydrogen chloride. After adding another 100 mL of diethyl ether, the suspension was filtered through a decalite pad, and the filter cake was rinsed with 50 mL of diethyl ether. The filtrate was concentrated at 40°C under reduced pressure of 120 mbar, and the residue was dissolved in 50 mL of dichloromethane and 50 mL of cyclohexane, filtered, and purified by elution with silica gel using 10%, 30%, 50%, and 100% diethyl ether in cyclohexane to obtain 7.2 g of enantiopurine (3S,4S)-4-methyltetrahydrofuran-3-ol (intermediate 2) (after concentration at 40°C under reduced pressure of 120 mbar). 1¹H NMR (400MHz, CDCl3) δ ppm: 1.05 (d, J=7 Hz, 3 H); 2.21 (m, 1 H); 2.24 (s, 1 H); 3.44 (dd, J=8 Hz and J=11 Hz, 1 H); 3.74 (dd, J=1.4 Hz and 10 Hz, 1 H); 3.90 (t, J=8 Hz, 1 H); 3.93 (dd, J=4 Hz and 10 Hz, 1 H); 4.19 (m, 1 H).

[0200] Intermediate 4: N-(1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 1-methyl-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole [ka] 2.03 g (1.3 eq.) of oxetan-3-ol and 13.74 g (2 eq.) of cesium carbonate were added to a solution of 3.63 g (1 eq.) of 1-methyl-3,4-dinitro-1H-pyrazole (commercial) in 12 mL of acetonitrile. This mixture was heated at 50°C for 2 hours, then allowed to cool to room temperature and poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was suspended in 15 mL of diethyl ether, filtered, concentrated under vacuum, eluted with a gradient of 0-50% ethyl acetate in heptane, and purified on silica gel to obtain 3.7 g of 1-methyl-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole. MS (Method B) m / z 200 [M+1]+; t=0.98 min.

[0201] Step 2: Preparation of N-(1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide [ka] A solution of 3.5 g (1 eq.) of 1-methyl-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole in 170 mL of methanol was treated with 0.1 g of carbon-supported palladium (10%) for 2 hours under 2.5 bar of hydrogen. The mixture was filtered, washed with dichloromethane, and concentrated under reduced pressure. The residue was concentrated twice in dichloromethane under reduced pressure. A solution of 6.63 mL of acetic anhydride mixed with 12.13 mL of formic acid for 30 minutes was added dropwise to the residue solution in 12 mL of tetrahydrofuran at 0°C. The reaction mixture was stirred for 2 hours and then heated to room temperature. This was then poured into a 10% sodium bicarbonate aqueous solution and stirred for 15 minutes, and extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 0-100% ethyl acetate in heptane and purified with silica gel to obtain 2.02 g of N-(1-methyl-3-(oxetan-3-yloxy)-1H-pyrazole-4-yl)formamide. MS (Method B) m / z 198[M+1]+; t=0.62 min.

[0202] Intermediate 5: N-(1-methyl-3-(((3S,4R)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)formamide and N-(1-methyl-3-(((3R,4S)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)formamide (racemic mixture) Step 1: Preparation of a racemic mixture of 1-methyl-3-(((3S,4R)-4-methyltetrahydrofuran-3-yl)oxy)-4-nitro-1H-pyrazole and 1-methyl-3-(((3R,4S)-4-methyltetrahydrofuran-3-yl)oxy)-4-nitro-1H-pyrazole [ka] 1.54 g (1.3 eq.) of trans-4-methyltetrahydrofuran-3-ol (commercial) and 7.34 g (2 eq.) of cesium carbonate were added to a solution of 2 g (1 eq.) of 1-methyl-3,4-dinitro-1H-pyrazole (commercial) in 40 mL of acetonitrile. This mixture was heated at 80°C for 4 hours, then allowed to cool to room temperature and poured into ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 10-50% ethyl acetate in heptane and purified with silica gel to obtain 1.1 g of a racemic mixture of 1-methyl-3-(((3S,4R)-4-methyltetrahydrofuran-3-yl)oxy)-4-nitro-1H-pyrazole and 1-methyl-3-(((3R,4S)-4-methyltetrahydrofuran-3-yl)oxy)-4-nitro-1H-pyrazole. MS (Method A) m / z 228[M+1]+; t=1.68 min.

[0203] Step 2: Preparation of a racemic mixture of 1-methyl-3-(((3S,4R)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-amine and 1-methyl-3-(((3R,4S)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-amine [ka] In a microwave vial, a solution of 1.09 g (1 eq.) of a racemic mixture of 1-methyl-3-(((3S,4R)-4-methyltetrahydrofuran-3-yl)oxy-4-nitro-1H-pyrazole and 1-methyl-3-(((3R,4S)-4-methyltetrahydrofuran-3-yl)oxy-4-nitro-1H-pyrazole in 32 mL of methanol was treated with 1.15 g (7 eq.) of ammonium formate and 0.326 g of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 10 minutes. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The residue was filtered in dichloromethane, and the filtrate was concentrated under reduced pressure to obtain 904 mg of a racemic mixture of 1-methyl-3-(((3S,4R)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-amine and 1-methyl-3-(((3R,4S)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-amine. MS (Method A) m / z 198[M+1]+; t=0.26 min.

[0204] Step 3: Preparation of a racemic mixture of N-(1-methyl-3-(((3S,4R)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)formamide and N-(1-methyl-3-(((3R,4S)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)formamide [ka] A solution of 904 mg (1 eq.) of a racemic mixture of 1-methyl-3-(((3S,4R)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-amine and 1-methyl-3-(((3R,4S)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-amine in 34 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 1.29 mL (3 eq.) of acetic anhydride in 1.07 mL (6 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at 5°C for 5 minutes and then at room temperature for 1.5 hours, and then concentrated under vacuum. The residue was eluted with a gradient of 0-40% acetone in dichloromethane and purified with silica gel to obtain 810 mg of a racemic mixture of N-(1-methyl-3-(((3S,4R)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)formamide and N-(1-methyl-3-(((3R,4S)-4-methyltetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)formamide. MS (Method B) m / z 226[M+1]+; t=0.94 min.

[0205] Intermediate 6: N-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazole-4-yl)formamide Step 1: Production of 2-methyl-1-((1-methyl-4-nitro-1H-pyrazole-3-yl)oxy)propan-2-ol [ka] 409 mg (1.3 eq.) of 2-methylpropane-1,2-diol and 3.44 g (3 eq.) of cesium carbonate were added to a solution of 600 mg (1 eq.) of 1-methyl-3,4-dinitro-1H-pyrazole (commercially available) in 30 mL of acetonitrile. This mixture was heated at 80°C for 2 hours, then allowed to cool to room temperature and poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with 50% ethyl acetate in heptane and purified on silica gel to obtain 358 mg of 2-methyl-1-((1-methyl-4-nitro-1H-pyrazole-3-yl)oxy)propane-2-ol. MS (Method A) m / z 216[M+1]+; t=1.45 min.

[0206] Step 2: Preparation of N-(3-(2-hydroxy-2-methylpropoxy)-1-methyl-1H-pyrazole-4-yl)formamide [ka] In a microwave vial, a solution of 115 mg (1 eq.) of 2-methyl-1-((1-methyl-4-nitro-1H-pyrazole-3-yl)oxy)propan-2-ol in 4 mL of methanol was treated with 98 mg (2.8 eq.) of ammonium formate and 57 mg (0.1 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 10 minutes. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude substance, dissolved in 2 mL of tetrahydrofuran, was added dropwise to a cooled (0°C) solution of 204 μL (4 eq.) of acetic anhydride in 373 μL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at 5°C for 1 hour and then concentrated under vacuum. The residue was used in the next step without further purification. MS (Method A) m / z 214[M+1]+; t=1.1 min.

[0207] Intermediate 7: N-(1-methyl-3-((1,1,1-trifluoropropan-2-yl)oxy)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 1-methyl-4-nitro-3-((1,1,1-trifluoropropan-2-yl)oxy)-1H-pyrazole (racemic) [ka] 819 mg (1.3 eq.) of racemic 1,1,1-trifluoropropan-2-ol and 3.67 g (2 eq.) of cesium carbonate were added to a solution of 1 g (1 eq.) of commercially available 1-methyl-3,4-dinitro-1H-pyrazole in 20 mL of acetonitrile. This mixture was heated at 65°C for 2 hours, then allowed to cool to room temperature and poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 20-50% ethyl acetate in heptane and purified with silica gel to obtain 1.25 g of racemic 1-methyl-4-nitro-3-((1,1,1-trifluoropropan-2-yl)oxy)-1H-pyrazole. MS (Method A) m / z 240[M+1]+; t=1.48 min.

[0208] Step 2: Preparation of 1-methyl-3-((1,1,1-trifluoropropan-2-yl)oxy)-1H-pyrazole-4-amine (racemic) [ka] In a microwave vial, a solution of 1.2 g (1 eq.) of 1-methyl-4-nitro-3-((1,1,1-trifluoropropan-2-yl)oxy)-1H-pyrazole in 15 mL of methanol was treated with 904 mg (2.8 eq.) of ammonium formate and 0.267 g (0.05 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 10 minutes. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was incorporated into the next step without further purification.

[0209] Step 3: Preparation of N-(1-methyl-3-((1,1,1-trifluoropropan-2-yl)oxy)-1H-pyrazole-4-yl)formamide (racemic) [ka] A solution of 1050 mg (1 eq.) of racemic 1-methyl-3-((1,1,1-trifluoropropan-2-yl)oxy)-1H-pyrazole-4-amine in 7 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 1.9 mL (4 eq.) of acetic anhydride in 3.87 mL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at 5°C for 5 minutes and then at room temperature for 1.5 hours, and then concentrated under vacuum to obtain 895 mg of racemic N-(1-methyl-3-((1,1,1-trifluoropropan-2-yl)oxy)-1H-pyrazole-4-yl)formamide. MS (Method A) m / z 238[M+1]+; t=1.61 min.

[0210] Intermediate 8: N-(3-isopropoxy-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 3-isopropoxy-4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole [ka] 3.35 g (1.5 eq.) of 2,2,2-trifluoroethyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid and 2.45 g (3 eq.) of potassium carbonate were added to a solution of 1 g (1 eq.) of commercially available 3-isopropoxy-4-nitro-1H-pyrazole in 16 mL of dimethylformamide. This mixture was heated at 80°C for 1.5 hours, then allowed to cool to room temperature and poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 20-50% ethyl acetate in heptane and purified on silica gel to obtain 1.22 g of 3-isopropoxy-4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole. MS (Method B) m / z254[M+1]+;t=1.59 min.

[0211] Step 2: Preparation of 3-isopropoxy-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-amine [ka] In a microwave vial, a solution of 885 mg (1 eq.) of 3-isopropoxy-4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole in 17 mL of methanol was treated with 630 mg (2.8 eq.) of ammonium formate and 186 mg (0.05 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 10 minutes. This mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was incorporated into the next step without further purification.

[0212] Step 3: Preparation of N-(3-isopropoxy-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)formamide [ka] A solution of 780 mg (1 eq.) of 3-isopropoxy-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-amine in 5 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 1.33 mL (4 eq.) of acetic anhydride in 2.7 mL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at 5°C for 5 minutes and then at room temperature for 1 hour, followed by concentration under vacuum. The residue was eluted with 18% ethyl acetate / MeOH with 32% 7N NH4 / 80% heptane and 45% ethyl acetate / MeOH with 35% 7N NH4 / 50% heptane, and purified on silica gel to obtain 730 mg of N-(3-isopropoxy-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)formamide. MS (Method A) m / z 252[M+1]+; t=1.94 min.

[0213] Intermediate 9: N-(3-((1-acetylazetidine-3-yl)oxy)-1-methyl-1H-pyrazole-4-yl)formamide Step 1: Production of 3-((1-methyl-4-nitro-1H-pyrazole-3-yl)oxy)azetidine-1-carboxylate tert-butyl [ka] 13.71 g (1.1 eq.) of tert-butyl 3-iodoazetidine-1-carboxylate and 12.17 g (2 eq.) of potassium carbonate were added to a solution of 6.3 g (1 eq.) of 1-methyl-4-nitro-1H-pyrazole-3-ol (commercial) in 125 mL of dimethylformamide. This mixture was heated at 90°C for 30 hours, then at room temperature for 70 hours, and then poured over ethyl acetate (100 mL) and water (10 mL). The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 10-60% ethyl acetate in heptane and purified with silica gel to obtain 8 g of tert-butyl 3-((1-methyl-4-nitro-1H-pyrazole-3-yl)oxy)azetidine-1-carboxylate. MS (Method A) m / z243[M-tBu]+;t=1.87 min.

[0214] Step 2: Production of 3-(azetidine-3-yloxy)-1-methyl-4-nitro-1H-pyrazole (TFA salt) [ka] 32 mL of trifluoroacetic acid was added at 0°C to a solution of 8 g (1 eq.) of tert-butyl 3-((1-methyl-4-nitro-1H-pyrazole-3-yl)oxy)azetidine-1-carboxylate in 160 mL of dichloromethane. The mixture was stirred at room temperature for 1.5 hours and then cooled to 0°C. 10 mL of MeOH and then 150 mL of 7N NH3 in MeOH were slowly added to the reaction mixture. The mixture was concentrated under vacuum. The residue was eluted using a mixture of dichloromethane / MeOH / 7N methanolic ammonia in a ratio of (95 / 4.5 / 0.5) to (80 / 18 / 2) and purified on silica gel to obtain 9.9 g of 3-(azetidine-3-yloxy)-1-methyl-4-nitro-1H-pyrazole (TFA salt). MS (Method A) m / z 199[M+1]+; t=0.26 min.

[0215] Step 3: Production of 1-(3-((1-methyl-4-nitro-1H-pyrazole-3-yl)oxy)azetidine-1-yl)ethane-1-one [ka] 13.4 mL (10 eq.) of triethylamine was added to a solution of 3 g (1 eq.) of 3-(azetidine-3-yloxy)-1-methyl-4-nitro-1H-pyrazole (TFA salt) in 100 mL of tetrahydrofuran. The mixture was cooled to 0°C, and 1.4 mL (2 eq.) of acetyl chloride was added dropwise. The reaction mixture was stirred at 0°C for 5 minutes, then at room temperature for 1 hour, and then poured over ethyl acetate (100 mL) and water (10 mL). The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted using a gradient of 10-50% acetone in dichloromethane and purified on silica gel to obtain 1.34 g of 1-(3-((1-methyl-4-nitro-1H-pyrazole-3-yl)oxy)azetidine-1-yl)ethane-1-one. MS (Method A) m / z241[M+1]+;t=1.22 min.

[0216] Step 4: Production of 1-(3-((4-amino-1-methyl-1H-pyrazole-3-yl)oxy)azetidine-1-yl)ethane-1-one [ka] In a microwave vial, a solution of 1.34 g (1 eq.) of 1-(3-((1-methyl-4-nitro-1H-pyrazole-3-yl)oxy)azetidine-1-yl)ethane-1-one in 32 mL of methanol was treated with 2.18 g (6 eq.) of ammonium formate and 403 mg (0.07 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 10 minutes. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was incorporated into the next step without further purification.

[0217] Step 5: Preparation of N-(3-((1-acetylazetidine-3-yl)oxy)-1-methyl-1H-pyrazole-4-yl)formamide [ka] A solution of 1.29 g (1 eq.) of 1-(3-((4-amino-1-methyl-1H-pyrazole-3-yl)oxy)azetidine-1-yl)ethane-1-one in 20 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 2.32 mL (4 eq.) of acetic anhydride in 1.88 mL (8 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. 15 mL of tetrahydrofuran was added, and the reaction mixture was stirred at room temperature for 35 minutes. The residue was concentrated under vacuum, and the residue was triturated in a mixture of dichloromethane and diisopropyl ether. The solid was filtered, and the filtrate was evaporated under reduced pressure to obtain 1.08 g of N-(3-((1-acetylazetidine-3-yl)oxy)-1-methyl-1H-pyrazole-4-yl)formamide. MS (Method A) m / z 239[M+1]+; t=0.87 min.

[0218] Intermediate 10: N-(2-cyclopropoxy-4-((dimethylamino)methyl)phenyl)formamide Step 1: Preparation of 1-(3-cyclopropoxy-4-nitrophenyl)-N,N-dimethylmethaneamine [ka] A solution of 1 g (1 eq.) of 3-cyclopropoxy-4-nitrobenzaldehyde, 4.6 mL of acetic acid, and 2.41 mL of 2N dimethylamine solution in tetrahydrofuran was mixed in 23 mL of dichloromethane and stirred at room temperature for 15 minutes. 2.05 g (2 eq.) of sodium triacetoxyborohydride was added, and the reaction mixture was stirred at room temperature for 70 hours. 40 mL of dichloromethane and 40 mL of saturated sodium bicarbonate solution were added. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with a mixture of dichloromethane / ethyl acetate / 7N NH3 in MeOH (80 / 18 / 2) and purified on silica gel to obtain 471 mg of 1-(3-cyclopropoxy-4-nitrophenyl)-N,N-dimethylmethaneamine. MS (Method A) m / z 237[M+1]+; t=0.72 min.

[0219] Step 2: Production of 2-cyclopropoxy-4-((dimethylamino)methyl)aniline [ka] In a microwave vial, a solution of 471 mg (1 eq.) of 1-(3-cyclopropoxy-4-nitrophenyl)-N,N-dimethylmethaneamine in 12 mL of methanol was treated with 363 mg (2.8 eq.) of ammonium formate and 212 mg (0.1 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 80°C for 15 minutes. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude product was triturated in diisopropyl ether, and the filtrate was evaporated to obtain 337 mg of 2-cyclopropoxy-4-((dimethylamino)methyl)aniline. The crude product was incorporated into the next step without further purification.

[0220] Step 3: Preparation of N-(2-cyclopropoxy-4-((dimethylamino)methyl)phenyl)formamide [ka] A solution of 337 mg (1 eq.) of 2-cyclopropoxy-4-((dimethylamino)methyl)aniline in 10 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 468 μL (3 eq.) of acetic anhydride in 779 μL (12 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour. The residue was concentrated under vacuum to obtain 337 mg of N-(2-cyclopropoxy-4-((dimethylamino)methyl)phenyl)formamide. MS (Method A) m / z 235[M+1]+; t=0.36 min.

[0221] Intermediate 11: N-(3-cyclopropoxy-1-(oxetan-3-yl)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 3-cyclopropoxy-4-nitro-1-(oxetan-3-yl)-1H-pyrazole [ka] 653 mg (1.2 eq.) of 3-iodooxetane and 817 mg (2 eq.) of potassium carbonate were added to a solution of 0.5 g (1 eq.) of 3-cyclopropoxy-4-nitro-1H-pyrazole (intermediate 15, step 2) in 20 mL of 1-methyl-2-pyrrolidinone. This mixture was heated at 80°C for 24 hours, then allowed to cool to room temperature, and poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 20-50% ethyl acetate in heptane and purified on silica gel to obtain 296 mg of 3-cyclopropoxy-4-nitro-1-(oxetan-3-yl)-1H-pyrazole. MS (Method A) m / z 226[M+1]+; t=1.68 min.

[0222] Step 2: Preparation of 3-cyclopropoxy-1-(oxetan-3-yl)-1H-pyrazole-4-amine [ka] In a microwave vial, a solution of 296 mg (1 eq.) of 3-cyclopropoxy-4-nitro-1-(oxetan-3-yl)-1H-pyrazole in 9 mL of methanol was treated with 240 mg (2.8 eq.) of ammonium formate and 140 mg (0.1 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 10 minutes. This mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was incorporated into the next step without further purification.

[0223] Step 3: Preparation of N-(3-cyclopropoxy-1-(oxetan-3-yl)-1H-pyrazole-4-yl)formamide [ka] A solution of 250 mg (1 eq.) of 3-cyclopropoxy-1-(oxetan-3-yl)-1H-pyrazole-4-amine in 5 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 484 μL (4 eq.) of acetic anhydride in 884 μL (18 eq.) of formic acid, which had been stirred at room temperature for 30 minutes prior. The reaction mixture was stirred at 0°C for 1 hour. The residue was concentrated under vacuum to obtain 200 mg of N-(3-cyclopropoxy-1-(oxetan-3-yl)-1H-pyrazole-4-yl)formamide. MS (Method A) m / z 224[M+1]+; t=1.17 min.

[0224] Intermediate 12: N-(3-isopropoxy-1-(oxetan-3-yl)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 3-isopropoxy-4-nitro-1-(oxetan-3-yl)-1H-pyrazole [ka] 653 mg (1.2 eq.) of 3-iodooxetane and 817 mg (2 eq.) of potassium carbonate were added to a solution of 0.5 g (1 eq.) of 3-isopropoxy-4-nitro-1H-pyrazole (commercially available) in 20 mL of 1-methyl-2-pyrrolizinone. This mixture was heated at 80°C for 24 hours, then allowed to cool to room temperature and poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 20-50% ethyl acetate in heptane and purified with silica gel to obtain 564 mg of 3-isopropoxy-4-nitro-1-(oxetan-3-yl)-1H-pyrazole. MS (Method A) m / z 228[M+1]+; t=1.86 min.

[0225] Step 2: Preparation of 3-isopropoxy-1-(oxetan-3-yl)-1H-pyrazole-4-amine [ka] In a microwave vial, a solution of 150 mg (1 eq.) of 3-isopropoxy-4-nitro-1-(oxetan-3-yl)-1H-pyrazole in 4 mL of methanol was treated with 120 mg (2.8 eq.) of ammonium formate and 71 mg (0.1 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 10 minutes. This mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was incorporated into the next step without further purification.

[0226] Step 3: Preparation of N-(3-isopropoxy-1-(oxetan-3-yl)-1H-pyrazole-4-yl)formamide [ka] A solution of 130 mg (1 eq.) of 3-isopropoxy-1-(oxetan-3-yl)-1H-pyrazole-4-amine in 3 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 249 μL (4 eq.) of acetic anhydride in 455 μL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at 0°C for 1 hour. The residue was concentrated under vacuum to obtain 200 mg of N-(3-isopropoxy-1-(oxetan-3-yl)-1H-pyrazole-4-yl)formamide. MS (Method A) m / z 226[M+1]+; t=1.36 min.

[0227] Intermediate 13: N-(1-((methylsulfonyl)methyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 1-(4-methoxybenzyl)-3,4-dinitro-1H-pyrazole [ka] 11.77 g (1.2 eq.) of 4-methoxybenzyl chloride, 27.15 g of tetrabutylammonium iodide, and 36.02 g (1.8 eq.) of cesium carbonate were added to a solution of 10 g (1 eq.) of 3,4-dinitro-1H-pyrazole in 50 mL of dimethylformamide. The mixture was stirred at room temperature for 50 minutes and then poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 10-50% ethyl acetate in heptane and purified on silica gel to obtain 15.25 g of 1-(4-methoxybenzyl)-3,4-dinitro-1H-pyrazole. MS (Method A) m / z 277 [M-1]; t=1.61 min.

[0228] Step 2: Preparation of 1-(4-methoxybenzyl)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole [ka] 2.16 g (1.25 eq.) of oxetan-3-ol and 15.24 g (2 eq.) of cesium carbonate were added to a solution of 6.5 g (1 eq.) of 1-(4-methoxybenzyl)-3,4-dinitro-1H-pyrazole in 80 mL of acetonitrile. This mixture was heated at 80°C for 3 hours, then allowed to cool to room temperature, and then poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was triturated in diisopropyl ether to obtain 7.1 g of 1-(4-methoxybenzyl)-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole. MS (Method A) m / z 306[M+1]+; t=2.16 min.

[0229] Step 3: Production of 4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole [ka] 32.33 g (2.5 eq.) of cerium ammonium nitrate was added to a solution of 7.1 g (1 eq.) of 1-(4-methoxybenzyl)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole in 170 mL of acetonitrile and 170 mL of water. The mixture was stirred at room temperature for 16 hours. 4.5 g of cerium ammonium nitrate was then added, and the reaction mixture was stirred at room temperature for 30 minutes, and then poured over 85 mL of ethyl acetate and 85 mL of saturated sodium thiosulfate solution. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was triturated in diethyl ether, and the precipitate was filtered to obtain 2.38 g of 4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole. MS (Method A) m / z 186[M+1]+; t=0.90 min.

[0230] Step 4: Production of 1-((methylthio)methyl)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole [ka] 937 μL (1.4 eq.) of (chloromethyl)(methyl)sulfan and 2.24 g (2 eq.) of potassium carbonate were added to a solution of 1.5 g (1 eq.) of 4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole in 50 mL of dimethylformamide. This mixture was heated at 80°C for 2.5 hours, then allowed to cool to room temperature and poured onto ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 20-50% ethyl acetate in heptane and purified on silica gel to obtain 935 mg of 1-((methylthio)methyl)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole. MS (Method A) m / z 246[M+1]+; t=1.15 min.

[0231] Step 5: Production of 1-((methylsulfonyl)methyl)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole [ka] 2.55 g of 3-chloroperbenzoic acid (77% purity, 3 eq.) was added at 0°C to a solution of 931 mg (1 eq.) of 1-((methylthio)methyl)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole in 40 mL of dichloromethane. The mixture was heated to room temperature and then quenched with 50 mL of DCM and 20 mL of 10% aqueous sodium thiosulfate solution. The mixture was stirred for 15 minutes. The organic layer was successively washed with 50 mL of saturated aqueous sodium carbonate solution, 50 mL of water, and 50 mL of brine, then dried over magnesium sulfate and concentrated under reduced pressure. The precipitate formed at the interface between the aqueous and organic layers was filtered and dried under vacuum to obtain 255 mg of 1-((methylsulfonyl)methyl)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole. The residue from the evaporation of the organic layer was eluted with 7N NH3(80 / 18 / 2) in heptane / ethyl acetate / MeOH and purified with silica to obtain 291 mg of 1-((methylsulfonyl)methyl)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole. MS (Method B) m / z 278[M+1]+; t=0.85 min.

[0232] Step 6: Preparation of 1-((methylsulfonyl)methyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-amine [ka] A solution of 546 mg (1 eq.) of 1-((methylsulfonyl)methyl)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole in 50 mL of methanol was treated with 0.42 g of carbon-supported palladium (10%) under 4 bar of hydrogen for 1 hour. The mixture was filtered, washed with methanol, and concentrated under reduced pressure to obtain 450 mg of 1-((methylsulfonyl)methyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-amine. MS (Method A) m / z 248[M+1]+; t=0.24 min.

[0233] Step 7: Preparation of N-(1-((methylsulfonyl)methyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide [ka] A solution of 486 mg (1 eq.) of 1-((methylsulfonyl)methyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-amine in 3 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 742 μL (4 eq.) of acetic anhydride in 1.36 mL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour. The residue was concentrated under vacuum and eluted with 7N NH3 (50 / 45 / 5) in heptane / ethyl acetate / MeOH, and purified with silica to obtain 450 mg of N-(1-((methylsulfonyl)methyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide. MS (Method A) m / z 276[M+1]+; t=0.52 min.

[0234] Intermediate 14: N-(1-(methoxymethyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 1-(methoxymethyl)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole [ka] 121 mg (1.4 eq.) of sodium hydride (60% purity) was added at 0°C to a solution of 400 mg (1 eq.) of 4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole (intermediate 13, step 3) in 12 mL of tetrahydrofuran. The reaction mixture was stirred at 0°C for 30 minutes and then at room temperature for 15 minutes. The mixture was cooled to 0°C and 244 mg (1.4 eq.) of chloro(methoxy)methane was added. The mixture was stirred at 0°C for 30 minutes and then slowly poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 20-50% ethyl acetate in heptane and purified on silica gel to obtain 373 mg of 1-(methoxymethyl)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole. MS (Method A) m / z230[M+1]+;t=1.34 min.

[0235] Step 2: Preparation of 1-(methoxymethyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-amine [ka] In a microwave vial, a solution of 453 mg (1 eq.) of 1-(methoxymethyl)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole in 15 mL of methanol was treated with 356 mg (2.8 eq.) of ammonium formate and 210 mg (0.05 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 10 minutes. This mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was incorporated into the next step without further purification.

[0236] Step 3: Preparation of N-(1-(methoxymethyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide [ka] A solution of 393 mg (1 eq.) of 1-(methoxymethyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-amine in 3 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 745 μL (4 eq.) of acetic anhydride in 1.36 mL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at 0°C for 1 hour. The residue was concentrated under vacuum, eluted with 7N NH3 (50 / 45 / 5) in heptane / ethyl acetate / MeOH, and purified with silica to obtain 312 mg of N-(1-(methoxymethyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide. MS (Method A) m / z 228 [M+1]+; t=0.74 min.

[0237] Intermediate 15: N-(3-cyclopropoxy-1-(methoxymethyl)-1H-pyrazole-4-yl) Step 1: Preparation of 4-cyclopropoxy-1-(4-methoxybenzyl)-3-nitro-1H-pyrazole [ka] 2.51 g (1.5 eq.) of cyclopropanol and 19.2 g (2 eq.) of cesium carbonate were added to a solution of 8 g (1 eq.) of 1-(4-methoxybenzyl)-3,4-dinitro-1H-pyrazole (intermediate 13, step 1) in 100 mL of acetonitrile. The mixture was heated at 50°C for 3 hours, then allowed to cool to room temperature and poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 20-50% ethyl acetate in heptane and purified with silica gel to obtain 5.1 g of 4-cyclopropoxy-1-(4-methoxybenzyl)-3-nitro-1H-pyrazole as a yellow oil. MS (Method A) m / z 290 [M+1]+; t=1.59 min.

[0238] Step 2: Preparation of 3-cyclopropoxy-4-nitro-1H-pyrazole [ka] 18.35 g (2.5 eq.) of cerium ammonium nitrate was added to a solution of 5.1 g (1 eq.) of 4-cyclopropoxy-1-(4-methoxybenzyl)-3-nitro-1H-pyrazole in 100 mL of acetonitrile and 100 mL of water. The mixture was stirred at room temperature for 16 hours. A further 4 g of cerium ammonium nitrate was added, and the reaction mixture was stirred at room temperature for 30 minutes, then poured over 85 mL of ethyl acetate and 85 mL of saturated aqueous solution of sodium thiosulfate. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with 5% methanol in dichloromethane and purified on silica gel to obtain 2.5 g of 3-cyclopropoxy-4-nitro-1H-pyrazole. MS (Method A) m / z 170 [M+1]+; t=1.3 min.

[0239] Step 3: Preparation of 3-cyclopropoxy-1-(methoxymethyl)-4-nitro-1H-pyrazole [ka] 667 mg (1.4 eq.) of chloro(methoxy)methane was added at 0°C to a solution of 1 g (1 eq.) of 3-cyclopropoxy-4-nitro-1H-pyrazole and 1.65 g (2 eq.) of potassium carbonate in 30 mL of acetonitrile. The mixture was heated to room temperature, stirred for 1.5 hours, and then poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 20-50% ethyl acetate in heptane and purified on silica gel to obtain 815 mg of 3-cyclopropoxy-1-(methoxymethyl)-4-nitro-1H-pyrazole. MS (Method B), m / z 170[M+1]+; t=1.18 min.

[0240] Step 4: Preparation of 3-cyclopropoxy-1-(methoxymethyl)-1H-pyrazole-4-amine [ka] In a microwave vial, a solution of 815 mg (1 eq.) of 3-cyclopropoxy-1-(methoxymethyl)-4-nitro-1H-pyrazole in 10 mL of methanol was treated with 689 mg (2.8 eq.) of ammonium formate and 204 mg (0.05 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 100°C for 10 minutes. This mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was incorporated into the next step without further purification.

[0241] Step 5: Preparation of N-(3-cyclopropoxy-1-(methoxymethyl)-1H-pyrazole-4-yl)formamide [ka] A solution of 700 mg (1 eq.) of 3-cyclopropoxy-1-(methoxymethyl)-1H-pyrazole-4-amine in 7 mL of tetrahydrofuran was added dropwise to a solution of 1.45 mL (4 eq.) of acetic anhydride in 1.31 mL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred for 1 hour. The residue was concentrated under vacuum and eluted with dichloromethane, then with 2% methanol in dichloromethane, and purified on silica gel to obtain 620 mg of N-(3-cyclopropoxy-1-(methoxymethyl)-1H-pyrazole-4-yl)formamide. MS (Method B) m / z 212[M+1]+; t=0.86 min.

[0242] Intermediate 16: N-(3-cyclopropoxy-1-((methylsulfonyl)methyl)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 3-cyclopropoxy-1-((methylthio)methyl)-4-nitro-1H-pyrazole [ka] 820 μL (1.4 eq.) of (chloromethyl)(methyl)sulfan and 1.96 g (2 eq.) of potassium carbonate were added to a solution of 1.2 g (1 eq.) of 3-cyclopropoxy-4-nitro-1H-pyrazole (intermediate 15, step 2) in 45 mL of dimethylformamide. The mixture was heated at 50°C for 2 hours, then allowed to cool to room temperature, and poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with 20% ethyl acetate in heptane and purified on silica gel to obtain 800 mg of 3-cyclopropoxy-1-((methylthio)methyl)-4-nitro-1H-pyrazole.

[0243] Step 2: Preparation of 3-cyclopropoxy-1-((methylsulfonyl)methyl)-4-nitro-1H-pyrazole [ka] 2.50 g of 3-chloroperbenzoic acid (70% purity, 3 eq.) was added to a solution of 800 mg (1 eq.) of 3-cyclopropoxy-1-((methylthio)methyl)-4-nitro-1H-pyrazole in 10 mL of dichloromethane. The mixture was stirred for 3 hours and then quenched with 50 mL of dichloromethane and 20 mL of 10% sodium thiosulfate sodium carbonate aqueous solution. The mixture was stirred for 15 minutes. The organic layer was successively washed with 50 mL of saturated sodium carbonate aqueous solution, 50 mL of water, and 50 mL of brine, then dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated in diisopropyl ether, the solid was filtered, and dried under vacuum to obtain 830 mg of 3-cyclopropoxy-1-((methylsulfonyl)methyl)-4-nitro-1H-pyrazole. MS (Method A) m / z 263[M+1]+; t=2.36 min.

[0244] Step 3: Preparation of 3-cyclopropoxy-1-((methylsulfonyl)methyl)-1H-pyrazole-4-amine [ka] A solution of 730 mg (1 eq.) of 3-cyclopropoxy-1-((methylsulfonyl)methyl)-4-nitro-1H-pyrazole in 70 mL of methanol was treated with 595 mg of carbon-supported palladium (10%) for 1 hour under 4 bar of hydrogen. The mixture was filtered, washed with methanol, and concentrated under reduced pressure to obtain 680 mg of 3-cyclopropoxy-1-((methylsulfonyl)methyl)-1H-pyrazole-4-amine. The crude material was incorporated into the next step without further purification.

[0245] Step 4: Preparation of N-(3-cyclopropoxy-1-((methylsulfonyl)methyl)-1H-pyrazole-4-yl)formamide [ka] A solution of 680 mg (1 eq.) of 3-cyclopropoxy-1-((methylsulfonyl)methyl)-1H-pyrazole-4-amine in 7 mL of tetrahydrofuran was added dropwise to a solution of 1.12 mL (4 eq.) of acetic anhydride in 1.01 mL (8 eq.) of formic acid, which had been mixed beforehand at room temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour. The residue was concentrated under vacuum and eluted with dichloromethane, then with 2% methanol in dichloromethane, and purified with silica to obtain 490 mg of N-(3-cyclopropoxy-1-((methylsulfonyl)methyl)-1H-pyrazole-4-yl)formamide. MS (Method B) m / z 260[M+1]+; t=0.79 min.

[0246] Intermediate 17: N-(3-(((3R,4R)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazole-4-yl)formamide and N-(3-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazole-4-yl)formamide Step 1: Production of (3S,4S)-4-methoxytetrahydrofuran-3-ol and (3R,4R)-4-methoxytetrahydrofuran-3-ol [ka] 929 μL (0.05 eq.) of sulfuric acid was added dropwise to a solution of 30 g (1 eq.) of 3,4-epoxytetrahydrofuran in 450 mL of methanol. The reaction mixture was stirred at room temperature for 48 hours. 60 mL of saturated aqueous solution of sodium bicarbonate was added, and the reaction mixture was stirred for 30 minutes. 150 mL of ethyl acetate and 60 mL of water were added. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum to obtain 31.47 g of a racemic mixture of (3S,4S)-4-methoxytetrahydrofuran-3-ol and (3R,4R)-4-methoxytetrahydrofuran-3-ol. The aqueous layer was further extracted with dichloromethane. The organic layers were dried over magnesium sulfate and concentrated under vacuum to obtain a further 4.88 g of a racemic mixture of (3S,4S)-4-methoxytetrahydrofuran-3-ol and (3R,4R)-4-methoxytetrahydrofuran-3-ol. The crude material was incorporated into the next process without further purification.

[0247] Step 2: Preparation of 3-(((3R,4R)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-4-nitro-1H-pyrazole and 3-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-4-nitro-1H-pyrazole [ka] 1.37 g (1.3 eq.) of a racemic mixture of (3S,4S)-4-methoxytetrahydrofuran-3-ol and (3R,4R)-4-methoxytetrahydrofuran-3-ol, along with 7.58 g (2 eq.) of cesium carbonate, were added to a solution of 2 g (1 eq.) of 1-methyl-3,4-dinitro-1H-pyrazole (commercially available) in 40 mL of acetonitrile. This mixture was heated at 80°C for 6 hours, then allowed to cool to room temperature, and poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 10-20% ethyl acetate in dichloromethane and purified with silica gel to obtain 1.4 g of a racemic mixture of 3-(((3R,4R)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-4-nitro-1H-pyrazole and 3-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-4-nitro-1H-pyrazole. MS (Method B) m / z 244[M+1]+; t=1.08 min

[0248] Step 3: Preparation of 3-(((3R,4R)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazole-4-amine and 3-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazole-4-amine [ka] A racemic mixture of 3-(((3R,4R)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-4-nitro-1H-pyrazole and 3-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-4-nitro-1H-pyrazole was dissolved in 32 mL of ethanol and 6.6 mL of water, and treated with 1.11 g (5 eq.) of ammonium chloride. The reaction mixture was heated at 80°C, and 1.15 g (5 eq.) of iron was added. This reaction mixture was heated at 80°C for 2 hours, 10 mL of ethanol was added, and the mixture was filtered through Celite and washed with ethanol. The filtrate was concentrated under reduced pressure. The crude material was diluted with 20 mL of ethyl acetate and 10 mL of saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum to obtain 0.9 g of a racemic mixture of 3-(((3R,4R)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazole-4-amine and 3-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazole-4-amine. MS (Method A) m / z 214[M+1]+.

[0249] Step 4: Production of N-(3-(((3R,4R)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazole-4-yl)formamide and N-(3-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazole-4-yl)formamide [ka] A solution of 1.3 g (1 eq.) of a racemic mixture of 3-(((3R,4R)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazole-4-amine and 3-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazole-4-amine in 8 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 2.33 mL (4 eq.) of acetic anhydride in 2.09 mL (8 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at 0°C for 15 minutes. The residue was concentrated under vacuum, eluted with 5% methanol in dichloromethane, and purified with silica to obtain 300 mg of a racemic mixture of N-(3-(((3R,4R)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazole-4-yl)formamide and N-(3-(((3S,4S)-4-methoxytetrahydrofuran-3-yl)oxy)-1-methyl-1H-pyrazole-4-yl)formamide. MS (Method B) m / z 242[M+1]+; t=0.87 min.

[0250] Intermediate 18: N-(1-(methylsulfonyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 1-(methylsulfonyl)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole [ka] 502 μL (1.5 eq.) of methanesulfonyl chloride was added at 0°C to a solution of 0.8 g (1 eq.) of 4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole (intermediate 13, step 3) in 40 mL of dichloromethane and 1.21 mL (2 eq.) of triethylamine. The mixture was stirred at room temperature for 2 hours and then poured over 20 mL of saturated aqueous solution of ammonium chloride. The aqueous layer was separated and extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with 5% ethyl acetate in chloromethane and purified on silica gel to obtain 600 mg of 1-(methylsulfonyl)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole. MS (Method B) m / z 264[M+1]+; t=2.21 min.

[0251] Step 2: Preparation of N-(1-(methylsulfonyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide [ka] 610 mg (5 eq.) of ammonium chloride and 600 mg (5 eq.) of iron were added to a solution of 0.6 g (1 eq.) of 1-(methylsulfonyl)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole in 18 mL of ethanol and 2 mL of water. The reaction mixture was heated at 80°C for 10 minutes under vigorous stirring, filtered through Celite, washed with ethanol, and concentrated under reduced pressure. The crude material was diluted with 20 mL of ethyl acetate and washed with 20 mL of saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated under vacuum.

[0252] The residue solution in 3 mL of tetrahydrofuran was added dropwise to a solution of 1.08 mL (5 eq.) of acetic anhydride in 1.55 mL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The residue was eluted with 5% methanol in dichloromethane and purified with silica to obtain 250 mg of N-(1-(methylsulfonyl)-3-(oxetan-3-yloxy)-1H-pyrazole-4-yl)formamide. MS (Method B) m / z 262[M+1]+; t=0.78 min.

[0253] Intermediate 19: N-(1-methyl-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide and N-(1-methyl-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide (racemic trans)

[0254] Step 1: Preparation of 1-methyl-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole and 1-methyl-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole (racemic trans) and 1-methyl-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole and 1-methyl-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole (racemic cis) [ka] 2.53 g (1.3 eq.) of 2-methyloxetan-3-ol and 14.68 g (2 eq.) of cesium carbonate were added to a solution of 4 g (1 eq.) of 1-methyl-3,4-dinitro-1H-pyrazole (commercially available) in 100 mL of acetonitrile. This mixture was heated at 65°C for 3 hours, then allowed to cool to room temperature and poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 10-50% ethyl acetate in heptane and purified with silica gel to obtain 2.18 g of the first mixture and 1.18 g of the second mixture.

[0255] The first mixture was characterized by NMR as a racemic trans mixture of 1-methyl-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole and 1-methyl-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole. MS (Method B) m / z 214[M+1]+; t=1.05 min (racemic trans).

[0256] The second mixture was characterized as a racemic mixture of 1-methyl-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole and 1-methyl-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole. MS (Method B) m / z 214[M+1]+; t=1.02 min (racemic).

[0257] Step 2: Preparation of N-(1-methyl-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide and N-(1-methyl-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide (racemic trans) [ka] A solution of 535 mg (1 eq.) of a racemic trans mixture of 1-methyl-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole and 1-methyl-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole in 170 mL of methanol was treated with 0.26 g of carbon-supported palladium (10%) for 1.5 hours under 2.5 bar of hydrogen. The mixture was filtered, washed with methanol, and concentrated under reduced pressure. A solution of 943 μL (4 eq.) of acetic anhydride, pre-mixed for 30 minutes, in 1.73 mL (18 eq.) of formic acid was added dropwise at 0°C to a solution in 12 mL of tetrahydrofuran of the residue. The reaction mixture was stirred for 1 hour, the temperature was raised to room temperature, and then concentrated under vacuum. The residue was eluted with a gradient of 0-100% ethyl acetate in heptane and purified with silica gel to obtain 410 mg of a mixture (racemic trans) of N-(1-methyl-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide and N-(1-methyl-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide. MS (Method B) m / z 212[M+1]+; t=0.81 min.

[0258] Intermediate 20: N-(1-methyl-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide and N-(1-methyl-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide (racemic cis) [ka] A solution of 350 mg (1 eq.) of a mixture (racemic cis) of 1-methyl-3-(((2S,3S)-2-methyloxetan-3-yl)oxy-4-nitro-1H-pyrazole and 1-methyl-3-(((2R,3R)-2-methyloxetan-3-yl)oxy-4-nitro-1H-pyrazole prepared in intermediate step 19 was dissolved in 40 mL of methanol and treated with 0.1 g of carbon-supported palladium (10%) under 2.5 bar of hydrogen for 1 hour. The mixture was filtered, washed with methanol, and concentrated under reduced pressure. A solution of 619 μL (4 eq.) of acetic anhydride, pre-mixed for 30 minutes, in 1.13 mL (18 eq.) of formic acid was added dropwise at 0°C to a solution of the residue in 10 mL of tetrahydrofuran. The reaction mixture was stirred for 1 hour, raised to room temperature, and then concentrated under vacuum. The residue was eluted with a gradient of 0-100% ethyl acetate in heptane and purified with silica gel to obtain 143 mg of a mixture (racemic cis) of N-(1-methyl-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide and N-(1-methyl-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide. MS (Method B) m / z 212[M+1]+; t=0.75 min.

[0259] Intermediate 21: N-(1-(methyl-d3)-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)formamide and N-(1-(methyl-d3)-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)formamide (racemic trans) Step 1: Preparation of 1-(methyl-d3)-3,4-dinitro-1H-pyrazole [ka] 6.42 g (1.4 eq.) of iodomethane-d3 and 8.83 g (2 eq.) of potassium carbonate were added at 0°C to a solution of 5 g (1 eq.) of 3,4-dinitro-1H-pyrazole (commercially available) in 150 mL of acetonitrile. The mixture was stirred at room temperature for 6.5 hours and then poured onto ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 20-50% ethyl acetate in heptane and purified with silica gel to obtain 4.8 g of 1-(methyl-d3)-3,4-dinitro-1H-pyrazole. 1 H NMR (400MHz, DMSO-d6) δ ppm:9.1 (s, 1H).

[0260] Step 2: Preparation of 1-(methyl-d3)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole and 1-(methyl-d3)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole (racemic trans) and 1-(methyl-d3)-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole and 1-(methyl-d3)-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole (racemic cis) [ka] 3.16 g (1.5 eq.) of 2-methyloxetan-3-ol and 15.63 g (2 eq.) of cesium carbonate were added to a solution of 4.2 g (1 eq.) of 1-(methyl-d3)-3,4-dinitro-1H-pyrazole f in 115 mL of acetonitrile. This mixture was heated at 65°C for 7 hours, then allowed to cool to room temperature and poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with 20% ethyl acetate in heptane and purified with silica gel to obtain 2.2 g of the first mixture and 1.25 g of the second mixture.

[0261] The first mixture was characterized by NMR as a racemic trans mixture of 1-(methyl-d3)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole and 1-(methyl-d3)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole. MS (Method B) m / z 217[M+1]+; t=1.05 min.

[0262] The second mixture was characterized by NMR as a racemic mixture of 1-(methyl-d3)-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole and 1-(methyl-d3)-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole. MS (Method B) m / z 217[M+1]+; t=1.02 min.

[0263] Step 3: Preparation of 1-(methyl-d3)-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-amine and 1-(methyl-d3)-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-amine (racemic trans) [ka] In a microwave vial, a solution of 2.2 g (1 eq.) of 1-(methyl-d3)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole and 1-(methyl-d3)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole (racemic trans) in 40 mL of methanol was treated with 1.83 g (2.8 eq.) of ammonium formate and 541 mg (0.05 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 85°C for 30 minutes. This mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to obtain 1-(methyl-d3)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-amine and 1.9 g of 1-(methyl-d3)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-amine (racemic trans). The crude material was incorporated into the next step without further purification.

[0264] Step 4: Preparation of N-(1-(methyl-d3)-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)formamide and N-(1-(methyl-d3)-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)formamide (racemic trans) [ka] A solution of 1-(methyl-d3)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-amine and 1-(methyl-d3)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-amine (racemic trans) in 15 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 3.87 mL (4 eq.) of acetic anhydride in 3.5 mL (8 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under vacuum. The residue was eluted with 2% methanol in dichloromethane and purified with silica gel to obtain N-(1-(methyl-d3)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide and N-(1-(methyl-d3)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide (racemic trans) 1.7 g. MS (Method B) m / z 215[M+1]+; t=1.62 min.

[0265] Intermediate 22: 1-(methyl-d3)-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-amine and 1-(methyl-d3)-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-amine (racemic cis) Step 1: Preparation of 1-(methyl-d3)-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-amine and 1-(methyl-d3)-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-amine (racemic cis) [ka] In a microwave vial, a solution of 1.25 g (1 eq.) of 1-(methyl-d3)-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole and 1-(methyl-d3)-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole (racemic cis) (intermediate 21, step 2) in 20 mL of methanol was treated with 1.04 g (2.8 eq.) of ammonium formate and 308 mg (0.05 eq.) of carbon-supported palladium. The reaction mixture was heated at 85°C for 30 minutes. This mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to obtain 1-(methyl-d3)-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-amine and 1 g of 1-(methyl-d3)-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-amine (racemic cis). The crude material was incorporated into the next step without further purification.

[0266] Step 2: Preparation of N-(1-(methyl-d3)-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide and N-(1-(methyl-d3)-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide (racemic cis) [ka] A solution of 1-(methyl-d3)-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-amine and 1-(methyl-d3)-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-amine (racemic cis) in 7 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 2.2 mL (4 eq.) of acetic anhydride in 2 mL (8 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under vacuum. The residue was eluted with 2% methanol in dichloromethane and purified with silica gel to obtain 0.95 g of N-(1-(methyl-d3)-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide and N-(1-(methyl-d3)-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide (racemic cis) as beige solids. MS (Method B) m / z 215[M+1]+; t=1.55 min.

[0267] Intermediate 23: N-[1-(oxetan-3-yl)-3-[(2,2,2-trifluoro-1-methylethoxy]pyrazole-4-yl]formamide (racemic) Step 1: Preparation of 1-[(4-methoxyphenyl)methyl]-4-nitro-3-[2,2,2-trifluoro-1-methylethoxy]pyrazole (racemic) [ka] 0.66 g (1.05 eq.) of racemic 1,1,1-trifluoro-2-propanol and 3.55 g (2 eq.) of cesium carbonate were added to a solution of 1.5 g (1 eq.) of 1-(4-methoxybenzyl)-3,4-dinitro-1H-pyrazole (intermediate 13, step 1) in 15 mL of acetonitrile. The mixture was heated at 80°C for 4 hours, then allowed to cool to room temperature, and poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was triturated in 10 mL of isopropyl ether, the precipitate was filtered, and dried under vacuum to obtain 2.0 g of racemic 1-[(4-methoxyphenyl)methyl]-4-nitro-3-[2,2,2-trifluoro-1-methyl-ethoxy]pyrazole. MS (Method B) m / z346[M+1]+;t=1.86 min.

[0268] Step 2: Preparation of 4-nitro-3-[2,2,2-trifluoro-1-methylethoxy]-1H-pyrazole (racemic) [ka] 8.1 g (2.5 eq.) of cerium(IV) ammonium nitrate dissolved in 40 mL of water was added to a solution of 2 g (1 eq.) of racemic 1-[(4-methoxyphenyl)methyl]-4-nitro-3-[2,2,2-trifluoro-1-methyl-ethoxy]pyrazole in 40 mL of acetonitrile. The mixture was stirred at room temperature for 2 hours and poured over 20 mL of 1 M sodium thiosulfate solution and 20 mL of dichloromethane. The aqueous layer was separated and extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was triturated in 40 mL of diethyl ethyl ether, the solid was filtered, and dried under vacuum to obtain 1.1 g of racemic 4-nitro-3-[2,2,2-trifluoro-1-methyl-ethoxy]-1H-pyrazole. MS (Method B) m / z 226[M+1]+; t=1.39 min.

[0269] Step 3: Preparation of racemic 4-nitro-1-(oxetan-3-yl)-3-[2,2,2-trifluoro-1-methylethoxy]pyrazole [ka] 588 μL (1.3 eq.) of 3-iodooxetane and 1.3 g (2 eq.) of potassium carbonate were added to a solution of 1.1 g (1 eq.) of racemic 4-nitro-3-[2,2,2-trifluoro-1-methylethoxy]-1H-pyrazole in 16 mL of N,N-dimethylformamide. This mixture was heated at 80°C for 24 hours, then allowed to cool to room temperature and poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under vacuum. The residue was eluted with a gradient of 0-5% ethyl acetate in dichloromethane and purified on silica gel to obtain 700 mg of racemic 4-nitro-1-(oxetane-3-yl)-3-[2,2,2-trifluoro-1-methylethoxy]pyrazole. MS (Method B) m / z282[M+1]+;t=1.57 min.

[0270] Step 4: Preparation of racemic 1-(oxetan-3-yl)-3-[2,2,2-trifluoro-1-methylethoxy]pyrazole-4-amine [ka] In a microwave vial, a solution of 450 mg (1 eq.) of racemic 4-nitro-1-(oxetan-3-yl)-3-[2,2,2-trifluoro-1-methylethoxy]pyrazole in 15 mL of methanol was treated with 620 mg (6 eq.) of ammonium formate and 170 mg of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 20 minutes. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The residue was placed in dichloromethane, the solid was filtered, and the filtrate was concentrated under reduced pressure to obtain 500 mg of racemic 1-(oxetan-3-yl)-3-[2,2,2-trifluoro-1-methylethoxy]pyrazole-4-amine. The crude material was incorporated into the next step without further purification.

[0271] Step 5: Preparation of racemic N-[1-(oxetan-3-yl)-3-[2,2,2-trifluoro-1-methylethoxy]pyrazole-4-yl]formamide [ka] A solution of 500 mg (1 eq.) of racemic 1-(oxetan-3-yl)-3-[2,2,2-trifluoro-1-methylethoxy]pyrazole-4-amine in 3 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 750 μL (3 eq.) of acetic anhydride in 700 μL (6 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at 5°C for 30 minutes and then at room temperature for 1 hour, and then concentrated under vacuum. The residue was diluted with ethyl acetate and poured over a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and then concentrated under vacuum. The residue was eluted with a 0-5% methanol gradient in dichloromethane and purified with silica gel to obtain 530 mg of racemic N-[1-(oxetan-3-yl)-3-[2,2,2-trifluoro-1-methylethoxy]pyrazole-4-yl]formamide. MS (Method B) m / z 280[M+1]+; t=1.20 min.

[0272] Intermediate 24: N-(1-cyclopropyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 1-cyclopropyl-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole [ka] 0.59 g (2 eq.) of cyclopropylboronic acid, 0.87 g (1 eq.) of 4'-di-tert-butyl-2,2'-bipyridine, 0.7 g (2 eq.) of sodium carbonate, and 0.59 g (1 eq.) of copper(II) acetate were added to a solution of 0.6 g (1 eq.) of 4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole (intermediate 13, step 3) in 22 mL of 1,2-dichloroethane. The mixture was refluxed for 3 hours, then allowed to cool to room temperature, poured over dichloromethane and water, and filtered through a Celite pad. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted in cyclohexane with 10% to 50% ethyl acetate and purified by silica gel to obtain 0.6 g of 1-cyclopropyl-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole. MS (Method A) m / z 226[M+1]+; t=1.69 min.

[0273] Step 2: Preparation of 1-cyclopropyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-amine [ka] A solution of 0.6 g (1 eq.) of 1-cyclopropyl-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole in 15 mL of methanol was treated with 442 mg (2.8 eq.) of ammonium formate and 261 mg (0.05 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 15 minutes. This mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to obtain 1-cyclopropyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-amine, which was used in the next step without further purification.

[0274] Step 3: Preparation of N-(1-cyclopropyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide [ka] A solution of 478 mg (1 eq.) of 1-cyclopropyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-amine in 2 mL of tetrahydrofuran was added dropwise at 0°C to 1.69 mL (18 eq.) of formic acid in 0.924 mL (4 eq.) of acetic anhydride, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at 0°C for 30 minutes and then concentrated under vacuum. The residue was eluted with 7N NH3 (50 / 45 / 5) in heptane / ethyl acetate / MeOH and purified on silica gel to obtain 390 mg of N-(1-cyclopropyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide. MS (Method B) m / z 224[M+1]+; t=1.26 min.

[0275] Intermediate 25: N-[1-[2,2-difluoro-1-methyl-ethyl]-3-(oxetane-3-yloxy)pyrazole-4-yl]formamide Step 1: Production of 1,1-difluoropropane-2-yl methanesulfonic acid (racemic) [ka] 1.5 mL (1.05 eq.) of triethylamine was added to a solution of 1 g (1 eq.) of racemic 1,1-difluoropropan-2-ol in 20 mL of dichloromethane. The mixture was cooled to 0°C, and 1.8 g (1 eq.) of methanesulfonic anhydride was added. The reaction mixture was heated to room temperature and stirred for 2 hours, then poured into 50 mL of ethyl acetate and 50 mL of diethyl ether. The organic layer was washed three times with 10 mL of water, then dried over sodium sulfate, and concentrated under vacuum to obtain 1.5 g of racemic methanesulfonic acid 1,1-difluoropropan-2-yl. 1 H NMR (400MHz, CDCl3) δ ppm: 1.45 (m, 3 H); 2.98 (s, 3 H); 4.80 (m, 1 H); 5.75 (dt, J=4.5 and 53 Hz, 1 H).

[0276] Step 2: Preparation of 1-[2,2-difluoro-1-methyl-ethyl]-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole (racemic) [ka] 282 mg (1.5 eq.) of racemic methanesulfonic acid 1,1-difluoropropan-2-yl and 704 mg of cesium carbonate were added to a solution of 200 mg (1 eq.) of 4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole (intermediate 13, step 3) in 10 mL of acetonitrile. The mixture was heated at 80°C for 18 hours. The mixture was filtered through decalite, washed twice with 5 mL of acetonitrile, and concentrated under reduced pressure. The residue was eluted with a gradient of 0-40% ethyl acetate in cyclohexane and purified on silica gel to obtain 100 mg of racemic 1-[2,2-difluoro-1-methyl-ethyl]-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole. MS (Method E) m / z 264[M+1]+; t=1.1 min.

[0277] Step 3: Preparation of N-[1-[2,2-difluoro-1-methyl-ethyl]-3-(oxetane-3-yloxy)pyrazole-4-yl]formamide (racemic) [ka] 101 mg of ammonium chloride (5 eq.) and 106 mg of iron (5 eq.) were added to a solution of 100 mg of racemic 1-[2,2-difluoro-1-methyl-ethyl]-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole in 8 mL of ethanol and 1.2 mL of water. The reaction mixture was stirred vigorously at 80°C for 10 minutes, filtered through Celite, washed with ethanol, and concentrated under reduced pressure. The crude material was diluted with 20 mL of ethyl acetate and washed with 20 mL of saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate and concentrated under vacuum. The solution of the residue in 3 mL of tetrahydrofuran was added dropwise to a solution of 179 μL (5 eq.) of acetic anhydride in 258 μL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The residue was eluted with 5% methanol in dichloromethane and purified with silica to obtain 60 mg of racemic N-[1-[2,2-difluoro-1-methyl-ethyl]-3-(oxetane-3-yloxy)pyrazole-4-yl]formamide as a brown oily substance. MS (Method E) m / z 262[M+1]+; t=0.92 min.

[0278] Intermediate 26: N-(1-(methyl-d3)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 1-(methyl-d3)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole [ka] 126 μL (1.5 eq.) of iodomethane-d3 (commercial) and 880 mg of cesium carbonate were added to a solution of 250 mg (1 eq.) of 4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole (intermediate 13, step 3) in 10 mL of N,N-dimethylformamide. The mixture was stirred at room temperature for 1 hour and then poured into a mixture of 20 mL of ethyl acetate and 20 mL of diethyl ether. The organic layer was washed three times with 10 mL of water, then dried over sodium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 0-80% ethyl acetate in cyclohexane and purified on silica gel to obtain 215 mg of 1-(methyl-d3)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole. MS (Method B) m / z 280[M+1]+; t=1.20 min.

[0279] Step 2: Preparation of N-(1-(methyl-d3)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide [ka] 284 mg (5 eq.) of ammonium chloride and 297 mg (5 eq.) of iron were added to a solution of 215 mg of 1-(methyl-d3)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole in 8 mL of ethanol and 1.2 mL of water. The reaction mixture was heated at 80°C for 10 minutes under vigorous stirring, filtered through Celite, washed with ethanol, and concentrated under reduced pressure. The crude material was diluted with 20 mL of ethyl acetate and washed with 20 mL of saturated sodium chloride solution. The organic layer was dried over sodium sulfate and concentrated under vacuum.

[0280] A solution of the residue in 5 mL of tetrahydrofuran was added dropwise to a solution of 503 μL (5 eq.) of acetic anhydride in 722 μL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The residue was eluted with 5% methanol in dichloromethane and purified with silica to obtain 150 mg of N-(1-(methyl-d3)-3-(oxetan-3-yloxy)-1H-pyrazole-4-yl)formamide. MS (Method B) m / z 201[M+1]+; t=0.62 min.

[0281] Intermediate 27: N-(1-(2-cyanopropan-2-yl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide Step 1: Preparation of methyl 2-(3,4-dinitro-1H-pyrazole-1-yl)-2-methylpropanoate [ka] 1.6 mL (1 eq.) of methyl 2-bromo-2-methylpropanoate and 8.2 g (2 eq.) of cesium carbonate were added to a solution of 2 g (1 eq.) of 3,4-dinitro-1H-pyrazole (commercially available) in 30 mL of N,N-dimethylformamide. This mixture was heated at 80°C for 4 hours, then allowed to cool to room temperature, and poured into 50 mL of ethyl acetate and 100 mL of diethyl ether. The organic layer was washed three times with 50 mL of water, dried over sodium sulfate, and concentrated under vacuum. The residue was eluted with a gradient of 0-40% ethyl acetate in cyclohexane and purified on silica gel to obtain 1 g of methyl 2-(3,4-dinitro-1H-pyrazole-1-yl)-2-methylpropanoate. MS (Method E) m / z 257[M+1]+; t=1.23 min.

[0282] Step 2: Production of methyl 2-methyl-2-(4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole-1-yl)propanoate [ka] 574 mg (2 eq.) of oxetane-3-ol and 3.1 g (2.5 eq.) of cesium carbonate were added to a solution of 1 g (1 eq.) of methyl 2-(3,4-dinitro-1H-pyrazole-1-yl)-2-methylpropanoate in 50 mL of acetonitrile. This mixture was heated at 130°C for 1 hour, then allowed to cool to room temperature, and poured onto 30 mL of ethyl acetate and 50 mL of diethyl ether. The organic layer was washed twice with 20 mL of water, dried over sodium sulfate, and concentrated under vacuum. The residue was eluted with a gradient of 0-40% ethyl acetate in cyclohexane and purified on silica gel to obtain 602 mg of methyl 2-methyl-2-(4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole-1-yl)propanoate. MS (Method E) m / z 286[M+1]+; t=1.12 min.

[0283] Step 3: Production of 2-methyl-2-(4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole-1-yl)propanamide [ka] 2.34 mL (4 eq.) of 12N sodium hydroxide aqueous solution was added to a solution of 2 g (1 eq.) of methyl 2-methyl-2-(4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole-1-yl)propanoate in 8 mL of methanol. This mixture was heated at 40°C for 1 hour, then allowed to cool to room temperature, and the pH was adjusted to approximately 1 with 2N HCl aqueous solution. This mixture was concentrated under vacuum. The residue was eluted with a gradient of 0-10% methanol in dichloromethane and purified with silica gel to obtain 1.8 g of the corresponding acid. To the residue solubilized in 100 mL of dichloromethane, 1.3 g (1.18 eq.) of 1,1'-carbonyldiimidazole was added. This mixture was stirred at room temperature for 18 hours, then 2.9 mL (5 eq.) of ammonium hydroxide (12N) was added. This mixture was stirred for a further 15 minutes and then concentrated under vacuum. The residue was eluted with a gradient of 0-10% methanol in dichloromethane and purified with silica gel to obtain 1.5 g of 2-methyl-2-(4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole-1-yl)propanamide. MS (Method E) m / z 271[M+1]+; t=0.91 min.

[0284] Step 4: Production of 2-methyl-2-(4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole-1-yl)propanenitrile [ka] 4.64 mL (6 eq.) of triethylamine was added to a solution of 1.5 g (1 eq.) of 2-methyl-2-(4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole-1-yl)propanamide in 15 mL of tetrahydrofuran. The mixture was cooled to 0°C, and 3.14 mL (4 eq.) of trifluoroacetic anhydride was added. The reaction mixture was heated to room temperature and stirred for 1 hour, then poured over 50 mL of diethyl ether and 20 mL of water. The organic layer was dried over sodium sulfate and concentrated under vacuum to obtain 1 g of 2-methyl-2-(4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole-1-yl)propanenitrile. MS (Method E) m / z 253[M+1]+; t=1.11 min.

[0285] Step 5: Preparation of N-(1-(2-cyanopropan-2-yl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide [ka] 1.06 g (5 eq.) of ammonium chloride and 1.11 g (5 eq.) of iron were added to a solution of 1 g of 2-methyl-2-(4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole-1-yl)propanenitrile in 16 mL of ethanol and 4 mL of water. The reaction mixture was heated at 80°C for 10 minutes under vigorous stirring, filtered through Celite, washed with ethanol, and concentrated under reduced pressure. The crude material was diluted with 20 mL of ethyl acetate and washed with 20 mL of saturated sodium chloride solution. The organic layer was dried over sodium sulfate and concentrated under vacuum.

[0286] The residue solution in 10 mL of tetrahydrofuran was added dropwise to a solution of 1.87 mL (5 eq.) of acetic anhydride in 2.69 mL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The residue was eluted with 5% methanol in dichloromethane and purified with silica to obtain 750 mg of N-(1-(2-cyanopropan-2-yl)-3-(oxetan-3-yloxy)-1H-pyrazole-4-yl)formamide. MS (Method E) m / z 251[M+1]+; t=0.94 min.

[0287] Intermediate 28: (3-cyclopropoxy-1-(1,1-difluoropropan-2-yl)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 3-cyclopropoxy-1-(1,1-difluoropropan-2-yl)-4-nitro-1H-pyrazole (racemic) [ka] Racemic 3-cyclopropoxy-1-(1,1-difluoropropan-2-yl)-4-nitro-1H-pyrazole 200 mg was prepared by starting with 300 mg of 3-cyclopropoxy-4-nitro-1H-pyrazole according to the basic procedure described in intermediate 25, step 2. MS (Method E) m / z 248[M+1]+; t=1.27 min.

[0288] Step 2: Preparation of N-(3-cyclopropoxy-1-(1,1-difluoropropan-2-yl)-1H-pyrazole-4-yl)formamide (racemic) [ka] 216 mg (5 eq.) of ammonium chloride and 226 mg (5 eq.) of iron were added to a solution of 200 mg of racemic 3-cyclopropoxy-1-(1,1-difluoropropan-2-yl)-4-nitro-1H-pyrazole in 8 mL of ethanol and 1.2 mL of water. The reaction mixture was heated at 80°C for 10 minutes under vigorous stirring, filtered through Celite, washed with ethanol, and concentrated under reduced pressure. The crude material was diluted with 20 mL of ethyl acetate and washed with 20 mL of saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate and concentrated under vacuum.

[0289] The residue solution in 4 mL of tetrahydrofuran was added dropwise to a solution of 382 μL (5 eq.) of acetic anhydride in 549 μL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The residue was eluted with 5% methanol in dichloromethane and purified with silica to obtain 45 mg of racemic N-(3-cyclopropoxy-1-(1,1-difluoropropan-2-yl)-1H-pyrazole-4-yl)formamide. MS (Method E) m / z 246[M+1]+; t=1.01 min.

[0290] Intermediate 29: N-[3-(cyclopropoxy)-1-(methyl-d3)pyrazole-4-yl]formamide Step 1: Preparation of trimethyl-[2-[(4-nitropyrazole-1-yl)methoxyethyl]silane [ka] 10 g (1 eq.) of 4-nitro-1H-pyrazole (commercial) was dissolved in 100 mL of dry tetrahydrofuran under an argon atmosphere. The mixture was cooled to -5°C, and 4.24 g (1.2 eq.) of sodium hydride (60% in mineral oil) was added gradually. After stirring at room temperature for 10 minutes, the mixture was cooled to 0°C, and then 18 mL (1.15 eq.) of 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) was added dropwise. The mixture was stirred at room temperature for 1.5 hours, and then quenched by adding ice and diethyl ether. The organic layer was separated, washed twice with water, dried over magnesium sulfate, and concentrated under vacuum. The residue was eluted with 20% ethyl acetate in heptane and purified on silica gel to obtain 21.34 g of trimethyl-[2-[(4-nitropyrazole-1-yl)methoxy]ethyl]silane. MS (Method E) m / z242[MH];t=1.95 min.

[0291] Step 2: Production of 2-[(3-chloro-4-nitropyrazole-1-yl)methoxy]ethyl-trimethyl-silane [ka] 53 mL (1.2 eq.) of 1N lithium bis(trimethylsilyl)amide in tetrahydrofuran was added dropwise at -78°C to a solution of 10.8 g (1 eq.) of trimethyl-[2-[(4-nitropyrazole-1-yl)methoxy]ethyl]silane in 80 mL of dry tetrahydrofuran. The mixture was stirred at -50°C for 30 minutes, then cooled to -78°C, and a solution of 13.66 g (1.3 eq.) of perchloroethane in 50 mL of anhydrous tetrahydrofuran was added dropwise. After stirring at -70°C for 2 hours, the mixture was quenched with 10% aqueous citric acid solution and diethyl ether. The organic layer was separated and washed with 10% aqueous citric acid solution, water, and brine, then dried over sodium sulfate and sodium bicarbonate, and concentrated under vacuum. The residue was eluted with 5% ethyl acetate in cyclohexane and purified with silica gel to obtain 10 g of 2-[(3-chloro-4-nitropyrazole-1-yl)methoxy]ethyl-trimethyl-silane. MS (Method E), no ionization, t=1.60 min.

[0292] Step 3: Preparation of 2-[[3-(cyclopropoxy)-4-nitropyrazole-1-yl]methoxy]ethyl-trimethyl-silane [ka] A suspension of 576 mg (2 eq.) of sodium hydride (60% in mineral oil) in 20 mL of anhydrous tetrahydrofuran was cooled to -10°C, and 837 mg (2 eq.) of cyclopropanol was added. After stirring for 30 minutes, 2 g (1 eq.) of 2-[(3-chloro-4-nitro-pyrazole-1-yl)methoxy]ethyl-trimethyl-silane in 10 mL of anhydrous tetrahydrofuran was added. This mixture was stirred at 5°C for 30 minutes and then quenched with 10% aqueous citric acid solution and diethyl ether. The organic layer was separated, washed twice with water, dried over magnesium sulfate, and concentrated under vacuum to obtain 2.1 g of 2-[[3-(cyclopropoxy)-4-nitro-pyrazole-1-yl]methoxy]ethyl-trimethyl-silane. The residue was used in the next step without further purification. MS (Method H), no ionization, t=1.25 min.

[0293] Step 4: Production of [3-(cyclopropoxy)-4-nitropyrazole-1-yl]methanol [ka] 100 mL (4.8 eq.) of 1N hydrochloric acid solution was added to a solution of 6.28 g (1 eq.) of 2-[[3-(cyclopropoxy)-4-nitropyrazole-1-yl]methoxy]ethyl-trimethyl-silane in 200 mL of dry acetonitrile. After heating at 40°C for 3 hours, the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The aqueous layer was extracted four times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 0-50% ethyl acetate in cyclohexane and purified with silica gel to obtain 4.72 g of [3-(cyclopropoxy)-4-nitropyrazole-1-yl]methanol. MS (Method G), m / z 200[M+1]+; t=1.49 min.

[0294] Step 5: Preparation of 3-(cyclopropoxy)-4-nitro-1H-pyrazole [ka] A solution of 2.86 g (1 eq.) of 3-(cyclopropoxy)-4-nitropyrazole-1-yl]methanol in 20 mL of methanol and 100 mL of 7N NH3 in MeOH was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum to obtain 2.5 g of 3-(cyclopropoxy)-4-nitro-1H-pyrazole. MSm / z 170[M+1]+; t=0.88 min.

[0295] Step 6: Preparation of 3-(cyclopropoxy)-4-nitro-1-(methyl-d3)pyrazole [ka] 46 μL (1.5 eq.) of iodomethane-d3 (commercial) and 308 mg (2 eq.) of cesium carbonate were added to a solution of 80 mg (1 eq.) of 3-(cyclopropoxy)-4-nitro-1H-pyrazole in 10 mL of dry acetonitrile. This mixture was heated at 80°C for 1 hour. After cooling to room temperature, the mixture was filtered and washed with acetonitrile, and the solvent was concentrated. The residue was eluted with a gradient of 0-40% ethyl acetate in cyclohexane and purified with silica gel to obtain 75 mg of 3-(cyclopropoxy)-4-nitro-1-(methyl-d3)pyrazole. MS (Method E), m / z 187[M+1]+; t=0.94 min.

[0296] Step 7: Preparation of N-[3-(cyclopropoxy)-1-(methyl-d3)pyrazole-4-yl]formamide [ka] 112.5 mg (5.0 eq.) of iron powder and 108.0 mg (5.0 eq.) of ammonium chloride were added to a solution of 75 mg (1 eq.) of 3-(cyclopropoxy)-4-nitro-1-(methyl-d3)pyrazole in a mixture of 8 mL of ethanol and 2 mL of water. This mixture was heated at 80°C for 30 minutes and then allowed to cool to room temperature. The reaction mixture was filtered through Celite and washed with ethanol, and the filtrate was concentrated under reduced pressure. The residue was placed in 10 mL of dry tetrahydrofuran and added dropwise to a solution of 190 μL (5 eq.) of acetic anhydride in 273 μL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The residue was eluted with a 0-10% methanol gradient in dichloromethane and purified with silica gel to obtain 25 mg of N-[3-(cyclopropoxy)-1-(methyl-d3)pyrazole-4-yl]formamide. MS (Method E) m / z 214[M+1]+; t=1.37 min.

[0297] Intermediate 30: N-[1-(1-cyano-1-methyl-ethyl)-3-(cyclopropoxy)pyrazole-4-yl]formamide Step 1: Preparation of 2-[3-(cyclopropoxy)-4-nitropyrazole-1-yl]-2-methylpropanoate methyl [ka] 2.6 g (2.5 eq.) of potassium carbonate was added to a solution of 1.5 g (1 eq.) of [3-(cyclopropoxy)-4-nitropyrazole-1-yl]methanol (intermediate 29, step 4) in 45 mL of dry N,N-dimethylformamide. The reaction mixture was heated at 70°C for 2 hours, followed by the addition of 1.3 mL (1.3 eq.) of methyl 2-bromo-2-methylpropanoate. The resulting mixture was stirred at 70°C for a further 3 hours, after which water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate / diethyl ether. The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was eluted with a gradient of 0-10% ethyl acetate in cyclohexane and purified on silica gel to obtain 1.78 g of methyl 2-[3-(cyclopropoxy)-4-nitropyrazole-1-yl]-2-methylpropanoate as a colorless oil. MS (Method E) m / z270[M+1]+;t=1.63 min.

[0298] Step 2: Production of 2-[3-(cyclopropoxy)-4-nitropyrazole-1-yl]-2-methylpropanenitrile [ka] A solution of 1.78 g (1 eq.) of 2-[3-(cyclopropoxy)-4-nitropyrazole-1-yl]-2-methylpropanoate in 360 mL of 7N NH3 in MeOH was stirred at room temperature for 2 days, and the reaction mixture was concentrated under vacuum. The residue was placed in 30 mL of dry tetrahydrofuran, and 1 mL (1.1 eq.) of trifluoroacetic anhydride and 2 mL (2.2 eq.) of triethylamine were added at 0°C. After stirring the reaction mixture for 1 hour, water and diethyl ether were added to quench the reaction. The aqueous layer was separated and extracted with diethyl ether. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum to obtain 1.35 g of 2-[3-(cyclopropoxy)-4-nitropyrazole-1-yl]-2-methylpropanenitrile. The residue was used without further purification. MS (Method E) m / z 237[M+1]+; t=1.25 min.

[0299] Step 3: Preparation of N-[1-(1-cyano-1-methyl-ethyl)-3-(cyclopropoxy)pyrazole-4-yl]formamide [ka] 58.0 mg (5.0 eq.) of iron powder and 59.0 mg (5.0 eq.) of ammonium chloride were added to a solution of 50 mg (1 eq.) of 2-[3-(cyclopropoxy)-4-nitropyrazole-1-yl]-2-methylpropanenitrile in 4 mL of ethanol and 2 mL of water. This mixture was heated at 80°C for 30 minutes and then allowed to cool to room temperature. The reaction mixture was filtered through Celite and washed with ethanol, and the filtrate was concentrated under reduced pressure. The residue was placed in 10 mL of dry tetrahydrofuran and added dropwise to a solution of 100 μL (5 eq.) of acetic anhydride in 144 μL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The residue was eluted with a 0-10% methanol gradient in dichloromethane and purified with silica gel to obtain 46 mg of N-[1-(1-cyano-1-methyl-ethyl)-3-(cyclopropoxy)pyrazole-4-yl]formamide. MSm / z 235[M+1]+; t=1.03 min.

[0300] Intermediate 31: N-[1-(1-cyano-1-methyl-ethyl)-3-isopropoxypyrazole-4-yl]formamide Step 1: Preparation of 2-(3-isopropoxy-4-nitropyrazole-1-yl)-2-methylpropanoate methyl [ka] 3-Isopropoxy-4-nitro-1H-pyrazole (commercial) (1 eq.) was dissolved in 70 mL of dry N,N-dimethylformamide under an argon atmosphere. The mixture was cooled to -5°C, and 941 mg (1.35 eq.) of sodium hydride (60% in mineral oil) was added gradually. The reaction mixture was stirred at 0°C for 30 minutes, and then 3.04 mL (1.35 eq.) of methyl 2-bromo-2-methylpropanoate was added. The resulting mixture was stirred for 2 days, and then the reaction was quenched with water. The aqueous layer was extracted twice with a 50 / 50 mixture of ethyl acetate and diethyl ether. The organic layer was washed twice with water, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was eluted with a gradient of 0-60% ethyl acetate in cyclohexane and purified with silica gel to obtain 3.3 g of methyl 2-(3-isopropoxy-4-nitro-pyrazole-1-yl)-2-methylpropanoate. MS (Method E) m / z 272[M+1]+; t=1.76 min.

[0301] Step 2: Production of 2-(3-isopropoxy-4-nitropyrazole-1-yl)-2-methylpropanenitrile [ka] A solution of 3 g (1 eq.) of methyl 2-(3-isopropoxy-4-nitropyrazole-1-yl)-2-methylpropanoate in 100 mL of 7N NH3 in MeOH was heated at 100°C for 18 hours. The reaction mixture was then cooled to room temperature and concentrated under vacuum. The residue was added to 50 mL of anhydrous tetrahydrofuran and cooled to 0°C. Then, 2.06 mL (1.2 eq.) of anhydrous trifluoroacetic acid and 4.24 mL (2.5 eq.) of triethylamine were added. The reaction mixture was stirred at room temperature for 1 hour, and then the reaction was quenched with water and diethyl ether. The aqueous layer was separated and extracted with diethyl ether. The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was eluted with 10-15% ethyl acetate in cyclohexane, purified with silica gel, and concentrated under vacuum to obtain 2.6 g of 2-(3-isopropoxy-4-nitropyrazole-1-yl)-2-methyl-propanenitrile. MS (Method F): m / z 239[M+1]+; t=1.67 min.

[0302] Step 3: Preparation of N-[1-(1-cyano-1-methyl-ethyl)-3-isopropoxypyrazole-4-yl]formamide [ka] 3.05 g (5 eq.) of iron was added at 80°C to a solution of 2.6 g of 2-(3-isopropoxy-4-nitropyrazole-1-yl)-2-methylpropanenitrile in 90 mL of ethanol, 10 mL of water, and 5 mL of acetic acid. The reaction mixture was vigorously stirred at 80°C for 20 minutes, then cooled, filtered through Celite, washed with ethanol, and concentrated under reduced pressure. The crude material was diluted with 100 mL of ethyl acetate and washed with 50 mL of saturated sodium chloride solution. The organic layer was dried over sodium sulfate and concentrated under vacuum.

[0303] The residue solution in 15 mL of tetrahydrofuran was added dropwise to a solution of 4.12 mL (4 eq.) of acetic anhydride in 3.35 mL (8 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour, and then quenched with 100 mL of ethyl acetate and 100 mL of 10% sodium carbonate for 30 minutes with vigorous stirring. The organic layer was separated and washed twice with 50 mL of 10% aqueous sodium carbonate solution, and then concentrated under vacuum. The residue was added to 100 mL of toluene and concentrated under vacuum. The residue was triturated in 100 mL of a 70 / 30 pentane / ether mixture, and the solid was filtered to obtain 2.06 g of N-[1-(1-cyano-1-methyl-ethyl)-3-isopropoxypyrazole-4-yl]formamide. MS (Method F): m / z 237[M+1]+; t=1.37 min.

[0304] Intermediate 32: N-(3-((1-acetyl-2,2-dimethylazetidine-3-yl)oxy)-1-methyl-1H-pyrazole-4-yl)formamide (racemic) Step 1: 2,2-dimethyl-3-((1-methyl-4-nitro-1H-pyrazole-3-yl)oxy)azetidine-1-carboxylate tert-butyl (Race Seminar) Manufacturing [ka] 482 mg (1.3 eq.) of racemic 3-hydroxy-2,2-dimethylazetidine-1-carboxylate tert-butyl and 1.5 g (2 eq.) of cesium carbonate were added to a solution of 400 mg (1 eq.) of 1-methyl-3,4-dinitro-1H-pyrazole (commercially available) in 8 mL of acetonitrile. This mixture was heated at 80°C for 5 hours, then allowed to cool to room temperature, and poured into ethyl acetate and water. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with 20 mL of saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under vacuum. The residue was eluted with a gradient of 0-20% ethyl acetate in dichloromethane and purified on silica gel to obtain 460 mg of racemic 2,2-dimethyl-3-((1-methyl-4-nitro-1H-pyrazole-3-yl)oxy)azetidine-1-carboxylate tert-butyl. MS (Method B) m / z237[M+1]+;t=1.69 min.

[0305] Step 2: Preparation of 3-((2,2-dimethylazetidine-3-yl)oxy)-1-methyl-4-nitro-1H-pyrazole (racemic) [ka] 5.5 mL (19 eq.) of trifluoroacetic acid was added to a solution of 1.2 g (1 eq.) of racemic 2,2-dimethyl-3-((1-methyl-4-nitro-1H-pyrazole-3-yl)oxy)azetidine-1-carboxylate tert-butyl in 30 mL of dichloromethane. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, then dissolved in 10 mL of methanol, treated with 30 mL of 7 M methanolic ammonia solution for 1 hour, and concentrated under vacuum. The residue was eluted with a gradient of 0-5% 7 M methanolic ammonia solution in dichloromethane and purified on silica gel to obtain 460 mg of racemic 3-((2,2-dimethylazetidine-3-yl)oxy)-1-methyl-4-nitro-1H-pyrazole. MS (Method B) m / z 227[M+1]+; t=0.22-0.27 min.

[0306] Step 3: Production of 1-(2,2-dimethyl-3-((1-methyl-4-nitro-1H-pyrazole-3-yl)oxy)azetidine-1-yl)ethane-1-one (racemic) [ka] 1.14 mL (4 eq.) of triethylamine was added to a solution of 460 mg (1 eq.) of racemic 3-((2,2-dimethylazetidine-3-yl)oxy)-1-methyl-4-nitro-1H-pyrazole in 23 mL of tetrahydrofuran. The mixture was cooled to 0-5°C, and 292 μL (2 eq.) of acetyl chloride was added. The mixture was stirred at 0°C for 5 minutes, then at room temperature for 30 minutes. The mixture was poured into ethyl acetate and water. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with 20 mL of saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under vacuum. The residue was eluted with a 0-5% methanol gradient in dichloromethane and purified with silica gel to obtain 360 mg of racemic 1-(2,2-dimethyl-3-((1-methyl-4-nitro-1H-pyrazole-3-yl)oxy)azetidine-1-yl)ethane-1-one. MS (Method B) m / z 269[M+1]+; t=1.13 min.

[0307] Step 4: Production of 1-(3-((4-amino-1-methyl-1H-pyrazole-3-yl)oxy)-2,2-dimethylazetidine-1-yl)ethane-1-one (racemic) [ka] In a microwave vial, a solution of 310 mg (1 eq.) of racemic 1-(2,2-dimethyl-3-((1-methyl-4-nitro-1H-pyrazole-3-yl)oxy)azetidine-1-yl)ethane-1-one in 12 mL of methanol was treated with 515 mg (7 eq.) of ammonium formate and 86 mg of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 10 minutes. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The residue was filtered in chloromethane, and the filtrate was concentrated under reduced pressure to obtain 260 mg of racemic 1-(3-((4-amino-1-methyl-1H-pyrazole-3-yl)oxy)-2,2-dimethylazetidine-1-yl)ethane-1-one. MS (Method A) m / z 239[M+1]+; retention time: dead volume.

[0308] Step 5: Preparation of N-(3-((1-acetyl-2,2-dimethylazetidine-3-yl)oxy)-1-methyl-1H-pyrazole-4-yl)formamide (racemic) [ka] A solution of 264 mg (1 eq.) of racemic 1-(3-((4-amino-1-methyl-1H-pyrazole-3-yl)oxy)-2,2-dimethylazetidine-1-yl)ethane-1-one in 2.6 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 416 μL (3 eq.) of acetic anhydride in 374 μL (6 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at 5°C for 30 minutes and then concentrated under vacuum. The residue was placed in toluene and concentrated under vacuum. The residue was eluted with a gradient of 0-5% methanol in dichloromethane and purified with silica gel to obtain 250 mg of racemic N-(3-((1-acetyl-2,2-dimethylazetidine-3-yl)oxy)-1-methyl-1H-pyrazole-4-yl)formamide. MS (Method B) m / z267[M+1]+;t=0.92 min.

[0309] Intermediate 33: Methyl 2-(4-formamide-3-(oxetane-3-yloxy)-1H-pyrazole-1-yl)propanoate (racemic) Step 1: Preparation of methyl -2-(4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole-1-yl)propanoate (racemic) [ka] 923 μL (1 eq.) of racemic methyl 2-bromopropionate was added to a solution of 1500 mg (1 eq.) of 4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole (intermediate 13, step 3) and 5280 mg (2 eq.) of cesium carbonate in 45 mL of acetonitrile. The mixture was heated at 80°C for 2.5 hours and then allowed to cool to room temperature. The mixture was poured into ethyl acetate and water. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with 20 mL of saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under vacuum. The residue was eluted with a gradient of 10-50% ethyl acetate in heptane and purified on silica gel to obtain 594 mg of racemic methyl 2-(4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole-1-yl)propanoate. MS method B: m / z272[M+1]+;t=1.19 min.

[0310] Step 2: Production of methyl 2-(4-amino-3-(oxetane-3-yloxy)-1H-pyrazole-1-yl)propanoate (racemic) [ka] 335 mg (3 eq.) of iron and 321 mg (3 eq.) of ammonium chloride were added to a solution of 542 mg (1 eq.) of racemic 2-(4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole-1-yl)propanoate methyl in 20 mL of ethanol and 5 mL of water. The reaction mixture was vigorously stirred at 90°C for 2.5 hours, then cooled to room temperature, filtered through Celite, washed with ethanol, and concentrated under reduced pressure. The crude material was diluted with 100 mL of ethyl acetate and washed with 50 mL of saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and concentrated under vacuum to obtain 454 mg of racemic 2-(4-amino-3-(oxetane-3-yloxy)-1H-pyrazole-1-yl)propanoate methyl, which was used in the next step without further purification.

[0311] Step 3: Production of 2-(4-formamide-3-(oxetane-3-yloxy)-1H-pyrazole-1-yl)propanoate methyl (racemic) [ka] A solution of 454 mg (1 eq.) of racemic 2-(4-amino-3-(oxetan-3-yloxy)-1H-pyrazole-1-yl)propanoate in 14 mL of tetrahydrofuran was added dropwise at 5°C to a solution of 0.71 mL (4 eq.) of acetic anhydride in 0.57 mL (8 eq.) of formic acid, which had been mixed at room temperature for 55 minutes prior. The reaction mixture was stirred at 5°C for 5 minutes and then at room temperature for 1.5 hours, followed by concentration under vacuum. The residue was eluted with a gradient of 10-30% acetone in dichloromethane and purified with silica gel to obtain 366 mg of racemic 2-(4-formamido-3-(oxetan-3-yloxy)-1H-pyrazole-1-yl)propanoate. MS method A: m / z 270 [M+1]+; t=1.26 min.

[0312] Intermediate 34: 3-(cyclopropoxy)-4-formamido-methyl benzoate Step 1: Production of methyl 3-(cyclopropoxy)-4-nitrobenzoate [ka] A solution of 0.843 mL (2 eq.) of cyclopropanol in 35 mL of anhydrous tetrahydrofuran was stirred under argon to 0°C. 7.83 mL (1.2 eq.) of a solution of [bis(trimethylsilyl)amino]lithium (1 M in THF) was added dropwise. The resulting mixture was stirred at 0°C for 30 minutes, and then 1.3 g (1 eq.) of methyl 3-fluoro-4-nitrobenzoate in 40 mL of anhydrous tetrahydrofuran was added dropwise. The mixture was stirred at room temperature for 4 hours, cooled to 0°C, quenched with 50 mL of saturated ammonium chloride solution, and extracted with ethyl acetate (three times with 50 mL). The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, eluted with 20% ethyl acetate in heptane, and purified on silica gel to obtain 380 mg of methyl 3-(cyclopropoxy)-4-nitrobenzoate. MS (Method H): m / z238[M+1]+;t=1.53 min.

[0313] Step 2: Production of methyl 4-amino-3-(cyclopropoxy)benzoate [ka] 186 mg (3 eq.) of ammonium chloride and 194 mg (3 eq.) of iron were added to a stirred solution of 275 mg (1 eq.) of methyl 3-(cyclopropoxy)-4-nitrobenzoate in 7 mL of ethanol and 2 mL of water. The reaction mixture was heated at 90°C for 1 hour. The mixture was filtered through Celite, washed with ethanol, and concentrated under reduced pressure. The residue was placed in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum, eluted with a 2-5% methanol gradient in dichloromethane, and purified on silica gel to obtain 280 mg of 4-amino-3-(cyclopropoxy)benzoate. MS (Method H) m / z 208[M+1]+; t=1.69 min.

[0314] Step 3: Production of 3-(cyclopropoxy)-4-formamidomethyl benzoate [ka] A solution of 280 mg (1 eq.) of methyl 4-amino-3-(cyclopropoxy)benzoate in 4 mL of tetrahydrofuran was added dropwise to a solution of 0.510 mL (4 eq.) of acetic anhydride in 0.414 mL (8 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at room temperature for 2 hours and 30 minutes, and then concentrated under vacuum. The residue was placed in ethyl acetate and washed with a saturated solution of sodium bicarbonate, and then with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum to obtain 250 mg of methyl 3-(cyclopropoxy)-4-formamidobenzoate. MS (Method A) m / z 236[M+1]+; t=1.99 min.

[0315] Intermediate 35: 4-Formamide-3-(oxetane-3-yloxy)methyl benzoate Step 1: Production of methyl 4-nitro-3-(oxetane-3-yloxy)benzoate and 4-nitro-3-(oxetane-3-yloxy)benzoic acid [ka] 1.4 g (1.9 eq., 60% oil dispersion) of sodium was gradually added to a solution of 2.23 g (2 eq.) of oxetane-3-ol in 50 mL of anhydrous tetrahydrofuran cooled to 0°C. The reaction mixture was stirred at 0°C for 1 hour, and then 3 g (1 eq.) of methyl 3-fluoro-4-nitro-benzoate in 15 mL of anhydrous tetrahydrofuran was added. The mixture was raised to room temperature and stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted three times with 50 mL of ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was eluted with a gradient of 20-50% heptane and purified on silica gel to obtain 900 mg of methyl 4-nitro-3-(oxetane-3-yloxy)benzoate. MS (Method A) m / z 254[M+1]+; t=1.97 min. The aqueous layer was acidified to pH=5 using a 5N hydrochloric acid solution, and then extracted three times with 50 mL of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was eluted with a gradient of 5-10% methanol in dichloromethane and purified with silica gel to obtain 1.5 g of 4-nitro-3-(oxetan-3-yloxy)benzoic acid. MS (Method A) m / z 240 [M+1]+; t=1.69 min.

[0316] Step 2: Production of methyl 4-amino-3-(oxetane-3-yloxy)benzoate [ka] In a microwave vial, a solution of 500 mg (1 eq.) of methyl 4-nitro-3-(oxetane-3-yloxy)benzoate in 10 mL of methanol was treated with 355 mg (2.8 eq.) of ammonium formate and 210 mg (0.1 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 85°C for 15 minutes. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to obtain 440 mg of methyl 4-amino-3-(oxetane-3-yloxy)benzoate. MS (Method A) m / z 254[M+1]+; t=1.55 min.

[0317] Step 3: Production of methyl 4-formamide-3-(oxetane-3-yloxy)benzoate [ka] A solution of 440 mg (1 eq.) of methyl 4-amino-3-(oxetane-3-yloxy)benzoate in 4 mL of tetrahydrofuran was added dropwise to a solution of 0.75 mL (4 eq.) of acetic anhydride in 0.68 mL (8 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under vacuum to obtain 435 mg of methyl 4-formamido-3-(oxetane-3-yloxy)benzoate. MS (Method A) m / z 252[M+1]+; t=1.59 min.

[0318] Intermediate 36: (N-(3-((2-Oxaspiro[3,3]heptan-5-yl)oxy)-1-methyl-1H-pyrazole-4-yl)formamide Step 1: Preparation of 3-((2-oxaspiro[3,3]heptan-5-yl)oxy)-1-methyl-4-nitro-1H-pyrazole [ka] 430 mg (1.3 eq.) of 2-oxaspiro[3.3]heptan-5-ol (commercial) and 1.9 g (2 eq.) of cesium carbonate were added to a solution of 500 mg (1 eq.) of 1-methyl-3,4-dinitro-1H-pyrazole (commercial) in 25 mL of acetonitrile. This mixture was heated overnight at 70°C, then allowed to cool to room temperature and poured into ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted in heptane with 50% ethyl acetate and purified on silica gel to obtain 595 mg of 3-((2-oxaspiro[3.3]heptan-5-yl)oxy)-1-methyl-4-nitro-1H-pyrazole. MS (Method A) m / z 240[M+1]+; t=1.67 min.

[0319] Step 2: Preparation of N-(3-((2-oxaspiro[3,3]heptan-5-yl)oxy)-1-methyl-1H-pyrazole-4-yl)formamide [ka] In a microwave vial, a solution of 600 mg (1 eq.) of 3-((2-oxaspiro[3,3]heptan-5-yl)oxy)-1-methyl-4-nitro-1H-pyrazole in 16 mL of methanol was treated with 448 mg (2.8 eq.) of ammonium formate and 267 mg (0.1 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 10 minutes. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The residue was dissolved in 2 mL of tetrahydrofuran, and this solution was added dropwise to a cooled (0°C) solution of 946 μL (4 eq.) of acetic anhydride in 1.73 mL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at 5°C for 5 minutes, then at room temperature for 1 hour, and then concentrated under vacuum. The residue was added to 50 mL of toluene and concentrated under vacuum to obtain 395 mg of N-(3-((2-oxaspiro[3.3]heptan-5-yl)oxy)-1-methyl-1H-pyrazole-4-yl)formamide. MS (Method A) m / z 238[M+1]+; t=1.39 min.

[0320] Intermediate 37: N-(1-(methoxymethyl)-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)formamide and N-(1-(methoxymethyl)-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)formamide (racemic trans ) Step 1: Preparation of 1-(methoxymethyl)-3,4-dinitro-1H-pyrazole [ka] 357 mg (1.4 eq.) of chloro(methoxy)methane and 883 mg (2 eq.) of potassium carbonate were added to a solution of 0.5 g (1 eq.) of 3,4-dinitro-1H-pyrazole (commercially available) in 15 mL of acetonitrile. This mixture was stirred at room temperature for 2 hours, then poured into ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with 20-50% ethyl acetate in heptane and purified on silica gel to obtain 485 mg of 1-(methoxymethyl)-3,4-dinitro-1H-pyrazole. 1 H NMR (400MHz, DMSO-d6) δ ppm: 3.35 (s, 3H); 5.5 (s, 2H); 9.32 (s, 1H).

[0321] Step 2: Preparation of 1-(methoxymethyl)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole and 1-(methoxymethyl)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole (racemic trans) [ka] 714 mg (1.25 eq.) of 2-methyloxetan-3-ol and 4.23 g (2 eq.) of cesium carbonate were added to a solution of 1310 mg (1 eq.) of 1-(methoxymethyl)-3,4-dinitro-1H-pyrazole in 17 mL of acetonitrile. This mixture was heated at 80°C for 2 hours, then allowed to cool to room temperature, and poured into ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with 10% to 50% ethyl acetate in heptane and purified with silica gel, and NMR characterized the mixture of 1-(methoxymethyl)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole and 1-(methoxymethyl)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole as racemic trans. 501 mg (MS (Method A) m / z 24 A mixture of 1-(methoxymethyl)-3-(((2S,3S)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole and 1-(methoxymethyl)-3-(((2R,3R)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole was obtained (MS (Method A) m / z 244[M+1]+; t=1.17 min), characterized as racemic cis by NMR.

[0322] Step 3: Preparation of 1-(methoxymethyl)-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-amine and 1-(methoxymethyl)-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-amine (racemic trans) [ka] In a microwave vial, a solution of 501 mg (1 eq.) of a racemic mixture of 1-(methoxymethyl)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole and 1-(methoxymethyl)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-4-nitro-1H-pyrazole in 15 mL of methanol was treated with 371 mg (2.8 eq.) of ammonium formate and 220 mg (0.05 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 15 minutes. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was incorporated into the next step without further purification.

[0323] Step 4: Preparation of N-(1-(methoxymethyl)-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)formamide and N-(1-(methoxymethyl)-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)formamide (racemic trans) [ka] A solution of 439 mg (1 eq.) of a racemic mixture of 1-(methoxymethyl)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-amine and 1-(methoxymethyl)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-amine in 2 mL of tetrahydrofuran was added dropwise to a solution of 779 μL (4 eq.) of acetic anhydride in 1.76 mL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes beforehand. The reaction mixture was stirred at 0°C for 1 hour. The residue was concentrated under vacuum and eluted with 7NNH3(50 / 45 / 5) in heptane / AcOEt / MeOH, then purified on silica gel to obtain 387 mg of a mixture (racemic trans) of N-(1-(methoxymethyl)-3-(((2R,3S)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide and N-(1-(methoxymethyl)-3-(((2S,3R)-2-methyloxetan-3-yl)oxy)-1H-pyrazole-4-yl)formamide. MS (Method B) m / z 242[M+1]+; t=0.85 min (racemic trans).

[0324] Intermediate 38: N-(3-isopropoxy-1-methyl-1H-pyrazole-4-yl)formamide Step 1: Preparation of 3-isopropoxy-1-methyl-4-nitro-1H-pyrazole [ka] 438 μL (1.2 eq.) of iodomethane and 1.61 g (2 eq.) of potassium carbonate were added to a solution of 1 g (1 eq.) of 3-isopropoxy-4-nitro-1H-pyrazole (commercially available) in 30 mL of N-methylpyrrolidinone. This mixture was heated at 70°C for 1 hour and then poured into a mixture of 100 mL of ethyl acetate and 100 mL of diethyl ether. The organic layer was washed three times with 100 mL of water, then dried over sodium sulfate and concentrated under vacuum. The residue was eluted with a cyclohexane / ethyl acetate 85 / 15 mixture and purified on silica gel to obtain 1 g of 3-isopropoxy-1-methyl-4-nitro-1H-pyrazole as a white solid. MS (Method E) m / z 186[M+1]+; t=1.08 min.

[0325] Step 2: Preparation of 3-isopropoxy-1-methyl-1H-pyrazole-4-amine [ka] 1.51 g (5 eq.) of iron was added at 80°C to a solution of 1 g of 3-isopropoxy-1-methyl-4-nitro-1H-pyrazole in 50 mL of ethanol, 1 mL of water, and 10 mL of acetic acid. The reaction mixture was vigorously stirred at 80°C for 20 minutes, then cooled to room temperature, filtered through Celite, washed with ethanol, and concentrated under reduced pressure. The crude material was diluted with 100 mL of ethyl acetate and washed with 50 mL of saturated aqueous sodium carbonate solution. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was eluted with 5% methanol in dichloromethane and purified on silica gel to obtain 650 mg of 3-isopropoxy-1-methyl-1H-pyrazole-4-amine. MS (Method E); m / z 156[M+1]+; t=0.78 min.

[0326] Step 3: Preparation of N-(3-isopropoxy-1-methyl-1H-pyrazole-4-yl)formamide [ka] A solution of 3-isopropoxy-1-methyl-1H-pyrazole-4-amine in 10 mL of tetrahydrofuran was added dropwise to a solution of 5.91 mL (4 eq.) of acetic anhydride in 4.8 mL (8 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at room temperature for 1 hour, and then quenched with 100 mL of ethyl acetate and 100 mL of 10% aqueous sodium carbonate solution for 30 minutes with vigorous stirring. The organic layer was separated and washed twice with 50 mL of 10% aqueous sodium carbonate solution, and then concentrated under vacuum. The residue was eluted with a 70 / 30 cyclohexane / ethyl acetate mixture and purified on silica gel to obtain 2.18 g of N-(3-isopropoxy-1-methyl-1H-pyrazole-4-yl)formamide. MS (Method E); m / z 184[M+1]+; t=0.80 min.

[0327] Intermediate 39: (R)-N-(1-(1-cyanoethyl)-3-isopropoxy-1H-pyrazole-4-yl)formamide and (S)-N-(1-(1-cyanoethyl)-3-isopropoxy-1H-pyrazole-4-yl)formamide Step 1: Production of (R)-2-(3-isopropoxy-4-nitro-1H-pyrazole-1-yl)propanenitrile and (S)-2-(3-isopropoxy-4-nitro-1H-pyrazole-1-yl)propanenitrile [ka] 1.21 mL (1.2 eq.) of 2-bromopropanenitrile and 3.23 g (2 eq.) of potassium carbonate were added to a solution of 2 g (1 eq.) of 3-isopropoxy-4-nitro-1H-pyrazole (commercial) in 20 mL of 1-methyl-2-pyrrolizinone (NMP). The mixture was stirred at room temperature for 1 hour and then poured over ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was eluted with 50% ethyl acetate in heptane and purified on silica gel to obtain 2.2 g of a racemic mixture of (R)-2-(3-isopropoxy-4-nitro-1H-pyrazole-1-yl)propanenitrile and (S)-2-(3-isopropoxy-4-nitro-1H-pyrazole-1-yl)propanenitrile. MS (Method B) m / z225[M+1]+;t=1.34 min.

[0328] Step 2: Production of (R)-2-(4-amino-3-isopropoxy-1H-pyrazole-1-yl)propanenitrile and (S)-2-(4-amino-3-isopropoxy-1H-pyrazole-1-yl)propanenitrile [ka] 680 mg of ammonium chloride (3 eq.) and 710 mg of iron (3 eq.) were added to a solution of 950 mg (1 eq.) of a racemic mixture of (R)-2-(3-isopropoxy-4-nitro-1H-pyrazole-1-yl)propanenitrile and (S)-2-(3-isopropoxy-4-nitro-1H-pyrazole-1-yl)propanenitrile in 25 mL of ethanol and 7 mL of water. The reaction mixture was heated at 90°C for 7 hours and then allowed to cool to room temperature. The mixture was filtered through Celite, washed with ethanol, and concentrated under reduced pressure. The residue was washed in ethyl acetate with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude material was eluted with 5% methanol in dichloromethane and purified with silica gel to obtain 850 mg of a racemic mixture of (R)-2-(4-amino-3-isopropoxy-1H-pyrazole-1-yl)propanenitrile and (S)-2-(4-amino-3-isopropoxy-1H-pyrazole-1-yl)propanenitrile. MS (Method B) m / z 195[M+1]+; t=0.59 min.

[0329] Step 3: Preparation of (R)-N-(1-(1-cyanoethyl)-3-isopropoxy-1H-pyrazole-4-yl)formamide and (S)-N-(1-(1-cyanoethyl)-3-isopropoxy-1H-pyrazole-4-yl)formamide [ka] A solution of 1.4 g (1 eq.) of a racemic mixture of (R)-2-(4-amino-3-isopropoxy-1H-pyrazole-1-yl)propanenitrile and (S)-2-(4-amino-3-isopropoxy-1H-pyrazole-1-yl)propanenitrile in 15 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 2.72 mL (4 eq.) of acetic anhydride in 2.21 mL (8 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue was washed in ethyl acetate with saturated sodium bicarbonate aqueous solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude material was eluted with 2% methanol in dichloromethane and purified on silica gel. The resulting oily substance was triturated in diisopropyl ether, and the precipitate was filtered to obtain 1.1 g of a racemic mixture of (R)-N-(1-(1-cyanoethyl)-3-isopropoxy-1H-pyrazole-4-yl)formamide and (S)-N-(1-(1-cyanoethyl)-3-isopropoxy-1H-pyrazole-4-yl)formamide. MS (Method B) m / z 223[M+1]+; t=2.27 min.

[0330] Chiral separation was performed on 1.1 g of a racemic mixture, yielding 488 mg of the first eluted isomer and 503 mg of the second eluted isomer (conditions: column Chiralpak AY, 20 μm, 230 x 100 mm; liquid phase: heptane 90 / ethyl alcohol 10; flow rate 400 mL / min). Peak 1 (first isomer): MS (Method B) m / z 223[M+1]+; t=2.27 min. Peak 2 (second isomer): MS (Method B) m / z 223[M+1]+; t=2.27 min.

[0331] Intermediate 40: N-(1-(1-cyanoethyl)-3-cyclopropoxy-1H-pyrazole-4-yl)formamide Step 1: Production of (R)-2-(3-cyclopropoxy-4-nitro-1H-pyrazole-1-yl)propanenitrile and (S)-2-(3-cyclopropoxy-4-nitro-1H-pyrazole-1-yl)propanenitrile [ka] 491 μL (1.2 eq.) of 2-bromopropanenitrile and 1.31 g (2 eq.) of potassium carbonate were added to a solution of 0.8 g (1 eq.) of 3-cyclopropoxy-4-nitro-1H-pyrazole (intermediate 29, step 5) in 8 mL of N,N-dimethylformamide (DMF). The mixture was stirred at room temperature for 3.5 hours and then poured into ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was eluted with 50% ethyl acetate in heptane and purified on silica gel to obtain 755 mg of a racemic mixture of (R)-2-(3-cyclopropoxy-4-nitro-1H-pyrazole-1-yl)propanenitrile and (S)-2-(3-cyclopropoxy-4-nitro-1H-pyrazole-1-yl)propanenitrile. MS (Method A) m / z223[M+1]+;t=1.96 min.

[0332] Step 2: Production of (R)-2-(4-amino-3-cyclopropoxy-1H-pyrazole-1-yl)propanenitrile and (S)-2-(4-amino-3-cyclopropoxy-1H-pyrazole-1-yl)propanenitrile [ka] 545 mg of ammonium chloride (3 eq.) and 570 mg of iron (3 eq.) were added to a solution of 755 mg (1 eq.) of a racemic mixture of (R)-2-(3-cyclopropoxy-4-nitro-1H-pyrazole-1-yl)propanenitrile and (S)-2-(3-cyclopropoxy-4-nitro-1H-pyrazole-1-yl)propanenitrile in 20 mL of ethanol and 5 mL of water. The reaction mixture was heated at 90°C for 1.5 hours and then allowed to cool to room temperature. The mixture was filtered through Celite, washed with ethanol, and concentrated under reduced pressure. The residue was washed in ethyl acetate with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude material was incorporated into the next step without further purification.

[0333] Step 3: Preparation of (R)-N-(1-(1-cyanoethyl)-3-cyclopropoxy-1H-pyrazole-4-yl)formamide and (S)-N-(1-(1-cyanoethyl)-3-cyclopropoxy-1H-pyrazole-4-yl)formamide [ka] A solution of 0.65 g (1 eq.) of (R)-2-(4-amino-3-cyclopropoxy-1H-pyrazole-1-yl)propanenitrile and (S)-2-(4-amino-3-cyclopropoxy-1H-pyrazole-1-yl)propanenitrile in 7 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 1.28 mL (4 eq.) of acetic anhydride in 2.33 mL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure to obtain 620 mg of a racemic mixture of (R)-N-(1-(1-cyanoethyl)-3-cyclopropoxy-1H-pyrazole-4-yl)formamide and (S)-N-(1-(1-cyanoethyl)-3-cyclopropoxy-1H-pyrazole-4-yl)formamide. MS (Method A) m / z221[M+1]+;t=1.42 min.

[0334] Intermediate 41: N-(3-cyclopropoxy-1-isopropyl-1H-pyrazole-4-yl)formamide Step 1: Preparation of 3-cyclopropoxy-1-isopropyl-4-nitro-1H-pyrazole [ka] 603 mg (1.2 eq.) of 2-iodopropane and 817 mg (2 eq.) of potassium carbonate were added to a solution of 0.5 g (1 eq.) of 3-cyclopropoxy-4-nitro-1H-pyrazole (intermediate 29, step 5) in 15 mL of N,N-dimethylformamide (DMF). This mixture was heated at 80°C for 1 hour and then poured into a mixture of 100 mL of ethyl acetate and 100 mL of diethyl ether. The organic layer was washed three times with 100 mL of water, dried over sodium sulfate, and concentrated under vacuum. The residue was eluted with an 80 / 20 heptane / ethyl acetate mixture and purified on silica gel to obtain 273 mg of 3-cyclopropoxy-1-isopropyl-4-nitro-1H-pyrazole. MS (Method A) m / z 212[M+1]+; t=2.17 min.

[0335] Step 2: Preparation of 3-cyclopropoxy-1-isopropyl-1H-pyrazole-4-amine [ka] In a microwave vial, a solution of 273 mg (1 eq.) of 3-cyclopropoxy-1-isopropyl-4-nitro-1H-pyrazole in 8 mL of methanol was treated with 236 mg (2.8 eq.) of ammonium formate and 138 mg (0.1 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 10 minutes. This mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude material was incorporated into the next step without further purification.

[0336] Step 3: Preparation of N-(3-cyclopropoxy-1-isopropyl-1H-pyrazole-4-yl)formamide [ka] A solution of 234 mg of 3-cyclopropoxy-1-isopropyl-1H-pyrazole-4-amine in 2 mL of tetrahydrofuran was added dropwise to a solution of 488 μL (4 eq.) of acetic anhydride in 892 μL (18 eq.) of formic acid, which had been pre-mixed at 0°C for 30 minutes. The reaction mixture was stirred at 0°C for 1 hour and then concentrated under vacuum. The residue was eluted with a 50 / 50 heptane / ethyl acetate mixture and purified on silica gel to obtain 155 mg of N-(3-cyclopropoxy-1-isopropyl-1H-pyrazole-4-yl)formamide. MS (Method A); m / z 210[M+1]+; t=1.55 min.

[0337] Intermediate 42: N-(3-(3,3-difluorocyclobutoxy)-1-methyl-1H-pyrazole-4-yl)formamide Step 1: Preparation of 5-(3,3-difluorocyclobutoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [ka] A suspension of 288 mg (2 eq.) of sodium hydride (60% in mineral oil) in 10 mL of dry tetrahydrofuran was cooled to -10°C, and 779 mg (2 eq.) of 3,3-difluorocyclobutan-1-ol was added. After stirring for 30 minutes, 1 g (1 eq.) of 2-[(3-chloro-4-nitropyrazole-1-yl)methoxy]ethyl-trimethylsilane (intermediate 29, step 2) in 5 mL of dry tetrahydrofuran was added. This mixture was stirred at 5°C for 30 minutes and then quenched with 10% aqueous citric acid solution and diethyl ether. The organic layer was separated, washed twice with water, dried over magnesium sulfate, and concentrated under vacuum to obtain 1.5 g of 5-(3,3-difluorocyclobutoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. The crude material was used in the next step without further purification. MS (Method A): No ionization; t=3.13 min.

[0338] Step 2: Preparation of 3-(3,3-difluorocyclobutoxy)-1-methyl-4-nitro-1H-pyrazole [ka] 32 mL (7.5 eq.) of 1N hydrochloric acid solution was added to a solution of 1.5 g (1 eq.) of 5-(3,3-difluorocyclobutoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole in 32 mL of dry acetonitrile. After heating at 40°C for 4 hours, the reaction mixture was cooled to room temperature and neutralized to pH 7 by adding 32 mL of 1N aqueous sodium hydroxide solution. The reaction mixture was extracted twice with 50 mL of ethyl acetate. The combined organic layer was dried over magnesium sulfate and concentrated under vacuum to obtain 711 mg of a yellow solid, which was dissolved in 25 mL of N-methylpyrrolidinone. 244 μL (1.2 eq.) of iodomethane and 897 mg (2 eq.) of potassium carbonate were added to this solution. The mixture was heated at 80°C for 2 hours and then poured into a mixture of 200 mL of ethyl acetate and 200 mL of diethyl ether. The organic layer was washed three times with 100 mL of water, then dried over magnesium sulfate, and concentrated under vacuum. The residue was eluted with an 80 / 20-50 / 50 heptane / ethyl acetate mixture and purified on silica gel to obtain 725 mg of 3-(3,3-difluorocyclobutoxy)-1-methyl-4-nitro-1H-pyrazole. MS (Method B) m / z 234[M+1]+; t=1.25 min.

[0339] Step 3: Preparation of 3-(3,3-difluorocyclobutoxy)-1-methyl-1H-pyrazole-4-amine [ka] 946 mg (5 eq.) of ammonium chloride and 988 mg (5 eq.) of iron were added to a solution of 825 mg (1 eq.) of 3-(3,3-difluorocyclobutoxy)-1-methyl-4-nitro-1H-pyrazole in 25 mL of ethanol and 3.8 mL of water. The reaction mixture was heated at 80°C for 1 hour and then allowed to cool to room temperature. The mixture was filtered through Celite, washed with ethanol, and concentrated under reduced pressure. The residue was washed in ethyl acetate with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 579 mg of 3-(3,3-difluorocyclobutoxy)-1-methyl-1H-pyrazole-4-amine as an orange viscous substance. The crude material was incorporated into the next step without further purification.

[0340] Step 4: Preparation of N-(3-(3,3-difluorocyclobutoxy)-1-methyl-1H-pyrazole-4-yl)formamide [ka] A solution of 579 mg of 3-(3,3-difluorocyclobutoxy)-1-methyl-1H-pyrazole-4-amine in 7 mL of tetrahydrofuran was added dropwise to a solution of 1.08 mL (4 eq.) of acetic anhydride in 875 μL (8 eq.) of formic acid, which had been mixed for 30 minutes and cooled to 0°C. The reaction mixture was stirred at 0°C for 10 minutes, then stirred at room temperature for 30 minutes and concentrated under vacuum. The residue was eluted with a 50 / 50 heptane / ethyl acetate mixture and purified on silica gel to obtain 374 mg of N-(3-(3,3-difluorocyclobutoxy)-1-methyl-1H-pyrazole-4-yl)formamide. MS (Method B); m / z 232[M+1]+; t=0.97 min.

[0341] Intermediate 43: 2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile Step 1: Preparation of 2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide [ka] In a sealed tube, 2 g (1 eq.) of 2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate methyl (intermediate 1) in 200 mL of 7N ammonia solution in methanol was stirred at room temperature for 3 days. The mixture was then concentrated under reduced pressure. The residue was triturated in 50 mL of diethyl ether, and the insoluble matter was filtered off. The mixture was then dried under vacuum to obtain 1.8 g of 2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide. MS (Method B) m / z 209[M+1]+; t=0.88 min.

[0342] Step 2: Preparation of 2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile [ka] 4.25 mL (3.6 eq.) of anhydrous trifluoroacetic acid and 5.31 mL (4.5 eq.) of triethylamine were added under argon at 0°C to a solution of 1.75 g of 2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (1 eq.) in 31 mL of anhydrous tetrahydrofuran. The mixture was stirred at 0°C to room temperature for 1 hour, and then poured into 200 mL of water. The precipitate was filtered by vacuum and triturated with diethyl ether to obtain 1.3 g of 2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile. MS (Method A) m / z 191[M+1]+; t=1.72 min.

[0343] Intermediate 44: N-(1-ethyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 1-ethyl-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole [ka] 228 μL (1.5 eq.) of iodoethane and 1.23 g (2 eq.) of cesium carbonate were added to a solution of 350 mg (1 eq.) of 4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole (intermediate 13, step 3) in 10 mL of N,N-dimethylformamide. The mixture was stirred at room temperature for 1 hour and then poured into a mixture of 100 mL of ethyl acetate and 100 mL of diethyl ether. The organic layer was washed three times with 150 mL of water, dried over sodium sulfate, and concentrated under vacuum. The residue was eluted with a gradient of 0-80% ethyl acetate in cyclohexane and purified on silica gel to obtain 374 mg of 1-ethyl-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole. MS (Method E) m / z 214[M+1]+; t=0.97 min.

[0344] Step 2: Preparation of N-(1-ethyl-3-(oxetan-3-yloxy)-1H-pyrazole-4-yl)formamide [ka] N-(1-ethyl-3-(oxetan-3-yloxy)-1H-pyrazole-4-yl)formamide 200 mg was prepared starting from 1-ethyl-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole 373 mg, following the basic procedure described in Intermediate 26, Step 2. MS (Method E) m / z 212[M+1]+; t=0.78 min.

[0345] Intermediate 45: N-[3-isopropoxy-1-(methyl-d3)pyrazole-4-yl]formamide Step 1: Preparation of 3-isopropoxy-4-nitro-1-(methyl-d3)pyrazole [ka] 1.43 g of 3-isopropoxy-4-nitro-1-(methyl-d3)pyrazole was prepared starting from 1.5 g of 3-isopropoxy-4-nitro-1H-pyrazole, following the basic procedure described in Intermediate 26, Step 1. MS (Method E) m / z 189 [M+1]+; t = 1.11 mins.

[0346] Step 2: Preparation of N-[3-isopropoxy-1-(methyl-d3)pyrazole-4-yl]formamide [ka] 170 mg of ammonium chloride (5 eq.) and 178 mg of iron (5 eq.) were added to a solution of 120 mg of 3-isopropoxy-4-nitro-1-(methyl-d3)pyrazole in 8 mL of ethanol and 1.2 mL of water. The reaction mixture was heated at 80°C for 10 minutes with vigorous stirring, and the mixture was filtered through Celite, washed with ethanol, and concentrated under reduced pressure. The crude material was diluted with 20 mL of ethyl acetate and washed with 20 mL of saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate and concentrated under vacuum to form a residue.

[0347] The residue solution in 3 mL of tetrahydrofuran was added dropwise to a solution of 301 μL (5 eq.) of acetic anhydride in 433 μL (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The residue was eluted with 5% methanol in dichloromethane and purified on silica gel to obtain 95 mg of N-[3-isopropoxy-1-(methyl-d3)pyrazole-4-yl]formamide. MS (Method E) m / z 187[M+1]+; t=0.83 min.

[0348] Intermediate 46: (S)-N-(3-(2-butoxy)-1-methyl-1H-pyrazole-4-yl)formamide Step 1: Preparation of (S)-5-(2-butoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [ka] (S)-5-(2-butoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole 785 mg was prepared starting from 1 g of 5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole, following the basic procedure described in step 3 of intermediate 29. MS (Method F) m / z without ionization; t = 2.14 min.

[0349] Step 2: Production of (S)-(5-(2-butoxy)-4-nitro-1H-pyrazole-1-yl)methanol [ka] Following the basic procedure described in step 4 of intermediate 29, 785 mg of (S)-5-(2-butoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole was converted to 495 mg of (S)-(5-(2-butoxy)-4-nitro-1H-pyrazole-1-yl)methanol. The crude product was incorporated into the next step without further purification.

[0350] Step 3: Preparation of (S)-3-(2-butoxy)-1-methyl-4-nitro-1H-pyrazole [ka] 230 μL (1.1 eq.) of iodomethane and 1.16 g (2.5 eq.) of potassium carbonate were added to a solution of 495 mg (1 eq.) of (S)-(5-(2-butoxy)-4-nitro-1H-pyrazole-1-yl)methanol in 30 mL of N,N-dimethylformamide. The mixture was stirred at 60°C for 2 hours, then allowed to cool to room temperature, and poured into a mixture of 100 mL of ethyl acetate and 100 mL of diethyl ether. The organic layer was washed three times with 150 mL of water, then dried over sodium sulfate, and concentrated under vacuum. The residue was eluted with a gradient of 0-60% ethyl acetate in cyclohexane and purified on silica gel to obtain 367 mg of (S)-3-(2-butoxy)-1-methyl-4-nitro-1H-pyrazole. MS (Method E) m / z 200 [M+1]+; t = 1.23 min.

[0351] Step 4: Preparation of (S)-N-(3-(2-butoxy)-1-methyl-1H-pyrazole-4-yl)formamide [ka] Following the basic procedure described in step 7 of intermediate 29, 375 mg of (S)-3-(2-butoxy)-1-methyl-4-nitro-1H-pyrazole was converted to 179 mg of (S)-N-(3-(2-butoxy)-1-methyl-1H-pyrazole-4-yl)formamide. MS (Method E) m / z 198[M+1]+; t=0.95 min.

[0352] Intermediate 47: (R)-N-(3-(2-butoxy)-1-methyl-1H-pyrazole-4-yl)formamide Step 1: Preparation of (R)-5-(2-butoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole [ka] Following the basic procedure described in step 3 of intermediate 29, 1 g of 5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole was converted to 889 mg of (R)-5-(2-butoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. MS (Method F) m / z without ionization; t=2.14 min.

[0353] Step 2: Production of (R)-(5-(2-butoxy)-4-nitro-1H-pyrazole-1-yl)methanol [ka] (R)-5-(2-butoxy)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole 890 mg was converted to (R)-(5-(2-butoxy)-4-nitro-1H-pyrazole-1-yl)methanol 607 mg. MS (Method E) m / z 216[M+1]+; t=1.09 min.

[0354] Step 2: Preparation of (R)-3-(2-butoxy)-1-methyl-4-nitro-1H-pyrazole [ka] (R)-(5-(2-butoxy)-4-nitro-1H-pyrazole-1-yl)methanol 620 mg was converted to (R)-3-(2-butoxy)-1-methyl-4-nitro-1H-pyrazole 440 mg. MS (Method E) m / z 200[M+1]+; t=1.23 min.

[0355] Step 3: Preparation of (R)-N-(3-(2-butoxy)-1-methyl-1H-pyrazole-4-yl)formamide [ka] (R)-3-(2-butoxy)-1-methyl-4-nitro-1H-pyrazole 440 mg was converted to (R)-N-(3-(2-butoxy)-1-methyl-1H-pyrazole-4-yl)formamide 175 mg. MS (Method E) m / z 198[M+1]+; t=0.95 min.

[0356] Intermediate 48: (N-(2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine-8-yl)formamide Step 1: Preparation of 2,2-dimethyl-2,3-dihydro-4H-pyrano[3,2-b]pyridine-4-one [ka] In a sealed container, 4.52 mL of pyrrolidine (1.5 eq.) was added to a solution of 5 g (1 eq.) of 1-(3-hydroxypyridine-2-yl)ethane-1-one in 100 mL of toluene. The mixture was stirred at room temperature for 15 minutes. Then, 5.4 mL (2 eq.) of acetone was added, and the reaction mixture was stirred at 40°C for 24 hours. A further 4 mL (1.5 eq.) of acetone was added, and the mixture was stirred again at room temperature for 15 hours. The mixture was then filtered through a silica gel pad and eluted with a gradient of 0-100% ethyl acetate in cyclohexane to obtain 3.29 g of 2,2-dimethyl-2,3-dihydro-4H-pyrano[3,2-b]pyridine-4-one. MS (Method F) m / z 178[M+1]+; t=1.63 min.

[0357] Step 2: Production of 2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-ol [ka] A solution of 1 g (1 eq.) of 2,2-dimethyl-2,3-dihydro-4H-pyrano[3,2-b]pyridine-4-one in 10 mL of ethanol was added dropwise to a solution of 160 mg (0.75 eq.) of sodium borohydride in 5 mL of ethanol under stirring. The reaction mixture was stirred under reflux for 2 hours, then cooled to room temperature, and concentrated under vacuum. The residue was dissolved in 200 mL of ethyl acetate and washed with 150 mL of saturated aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, then concentrated under vacuum, and the residue was eluted with a gradient of 0-5% methanol in dichloromethane and purified on silica gel to obtain 820 mg of 2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-ol. MS (Method E) m / z 180[M+1]+; t=0.34 min.

[0358] Step 3: Preparation of 2,2-dimethyl-2H-pyrano[3,2-b]pyridine [ka] In a Dean-Stark apparatus, a solution of 820 mg (1 eq.) of 2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine-4-ol and 87 mg (0.1 eq.) of p-toluenesulfonic acid hydrate in 50 mL of toluene was refluxed for 5 hours while continuously removing water. After cooling to room temperature and concentrating under vacuum, the residue was eluted with a gradient of 0-5% methanol in dichloromethane and purified with silica gel to obtain 442 mg of 2,2-dimethyl-2H-pyrano[3,2-b]pyridine. MS (Method E) m / z 162[M+1]+; t=0.83 min.

[0359] Step 4: Production of 2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine [ka] A solution of 440 mg (1 eq.) of 2,2-dimethyl-2H-pyrano[3,2-b]pyridine in 15 mL of methanol was treated with 286 mg (0.1 eq.) of 10% by mass of carbon-supported palladium in a Parr apparatus under 2.5 bar of hydrogen for 1.5 hours. After filtration with decalite and rinsing with 30 mL of methanol, the solution was concentrated under vacuum. The residue was eluted with a gradient of 0-70% ethyl acetate in cyclohexane and purified with silica gel to obtain 445 mg of 2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine. MS (Method E) m / z 164[M+1]+; t=0.68 min.

[0360] Step 5: Preparation of 2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine 5-oxide [ka] 1.78 g (2.1 eq.) of 3-chloroperbenzoic acid (70% purity by mass) was added at 0°C to a solution of 560 mg (1 eq.) of 2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine in 250 mL of dichloromethane. The reaction mixture was stirred at room temperature for 18 hours, then washed with 100 mL of saturated sodium carbonate aqueous solution, and the organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 0-5% methanol in dichloromethane and purified on silica gel to obtain 290 mg of 2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine 5-oxide. MS (Method E) m / z 359[M+1]+; t=0.95 min.

[0361] Step 6: Production of 2,2-dimethyl-8-nitro-3,4-dihydro-2H-pyrano[3,2-b]pyridine and 2,2-dimethyl-8-nitro-3,4-dihydro-2H-pyrano[3,2-b]pyridine 5-oxide [ka] 2 mL (28.6 eq.) of nitric acid was added dropwise to a solution of 280 mg (1 eq.) of 2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine 5-oxide in 2 mL of acetic acid. The reaction mixture was stirred at 85°C for 5 hours, then cooled to room temperature, and poured into a mixture of 200 g of ice and 10 mL of 12N sodium hydroxide aqueous solution. The aqueous layer was saturated with sodium chloride and extracted three times with 150 mL of ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated under vacuum, and obtained 290 mg of an inseparable mixture of 2,2-dimethyl-8-nitro-3,4-dihydro-2H-pyrano[3,2-b]pyridine and 2,2-dimethyl-8-nitro-3,4-dihydro-2H-pyrano[3,2-b]pyridine 5-oxide. MS (Method E) m / z209[M+1]+;t=1.26 min and m / z225[M+1]+;t=1.03 min.

[0362] Step 7: Preparation of N-(2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine-8-yl)formamide [ka] Following the basic procedure described in step 3 of intermediate 31, 290 mg of 2,2-dimethyl-8-nitro-3,4-dihydro-2H-pyrano[3,2-b]pyridine and 2,2-dimethyl-8-nitro-3,4-dihydro-2H-pyrano[3,2-b]pyridine 5-oxide were reduced and formylated to obtain 150 mg of N-(2,2-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine-8-yl)formamide. MS (Method E) m / z 207[M+1]+; t=1.07 min.

[0363] Intermediate 49: N-(3-isopropoxy-1-[(1R)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-4-yl)formamide and N-(3-isopropoxy-1-[(1S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-4-yl)formamide Step 1: Preparation of 3-isopropoxy-4-nitro-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole (racemic) [ka] Racemic 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid 1,1,1-trifluoropropan-2-yl (commercial) 1.74 g (1.5 eq.) and potassium carbonate 1.22 g (3 eq.) were added to a solution of 3-isopropoxy-4-nitro-1H-pyrazole (commercial) 0.5 g (1 eq.) in 2 mL of dimethylformamide. This mixture was heated at 80°C for 1.5 hours, then allowed to cool to room temperature, and poured into ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was placed in diethyl ether and water. The organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated under vacuum to obtain 360 mg of racemic 3-isopropoxy-4-nitro-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole. MS (Method D) m / z 268[M+1]+; t=1.29 min.

[0364] Step 2: Preparation of N-(3-isopropoxy-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-yl)formamide (racemic) [ka] A solution of 550 mg (1 eq.) of racemic 3-isopropoxy-4-nitro-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole in 80 mL of methanol was hydrogenated for 1 hour under 2.5 bar of hydrogen in the presence of 100 mg (0.05 eq.) of carbon-supported palladium (10%). The mixture was filtered through decalite, washed with dichloromethane, and concentrated under reduced pressure. A solution of the crude material dissolved in 12 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 777 μL (4 eq.) of acetic anhydride in 632 μL (8 eq.) of formic acid, which had been mixed at room temperature for 30 minutes. The reaction mixture was stirred at 0°C for 1 hour, then heated to room temperature, and then poured into a 10% sodium carbonate aqueous solution and stirred for 15 minutes. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was eluted with a gradient of 0-20% ethyl acetate in heptane and purified with silica gel to obtain 510 mg of racemic N-(3-isopropoxy-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-yl)formamide. MS (Method D) m / z 266[M+1]+; t=0.99 min.

[0365] Intermediate 50: (3S,4S)-4-methoxytetrahydrofuran-3-ol [ka] 7.5 g of lipase Amano AK (reference ALDRICH: Amano lipase derived from Pseudomonas fluorescens, 20,000 U / g; catalog number: 534730 - 50G) was added to a solution of 30 g (1 eq.) of a racemic mixture of (3S,4S)-4-methoxytetrahydrofuran-3-ol and (3R,4R)-4-methoxytetrahydrofuran-3-ol (intermediate 1, step 1) and 150 mL of vinyl acetate in 300 mL of heptane. The suspension was stirred at 22 °C for 5 days and then filtered through a pad of decalite. The filter cake was rinsed twice with 50 mL of ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel eluting with 30 - 90% ethyl acetate in heptane to give 11.72 g of (3S,4S)-4-methoxytetrahydrofuran-3-ol. 1 1H NMR (400 MHz, CDCl3) δ ppm: 2.61 (broad s, 1 H); 3.39 (s, 3 H); 3.76 (m, 3 H); 3.94 (dd, J = 4.04 and 10 Hz, 1 H); 4.05 (dd, J = 4.3 and 9.7 Hz, 1 H); 4.29 (m, 1 H).

[0366] Intermediate 51: (R)-N-(2-Methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridin-9-yl)formamide Step 1: Preparation of (S)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol

Chemical Structure

[0367] Step 2: Production of (R)-3-((2-chloropyridine-3-yl)oxy)butan-1-ol [ka] 9.11 g (1.1 eq.) of triphenylphosphine and 6.45 mL (1.05 eq.) of diisopropyl azodicarboxylic acid were successively added dropwise at 0°C to a solution of 6.78 g (1.05 eq.) of (S)-4-((tert-butyldimethylsilyl)oxy)butan-2-ol and 4.09 g (1 eq.) of 2-chloropyridine-3-ol in 80 mL of tetrahydrofuran. The reaction mixture was stirred at 0°C to room temperature for 1 hour, and then diluted with 150 mL of diethyl ether and 100 mL of water. The organic layer was washed with 50 mL of water, dried over sodium sulfate, and concentrated under vacuum. The residue was eluted with a gradient of 0-10% ethyl acetate in cyclohexane and purified on silica gel to obtain 8.24 g of the silylated intermediate. The obtained compound was dissolved in 250 mL of acetonitrile and 50 mL of 1N hydrogen chloride aqueous solution, and the reaction mixture was stirred for 1 hour. Then, it was carefully poured into 200 mL of saturated sodium bicarbonate aqueous solution and 400 mL of dichloromethane. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was eluted with a gradient of 0-70% ethyl acetate in cyclohexane and purified with silica gel to obtain 4.4 g of (R)-3-((2-chloropyridine-3-yl)oxy)butan-1-ol. MS (Method F) m / z 202[M+1]+; t=1.17 min.

[0368] Step 3: Production of (R)-2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridine [ka] A solution of 2.5 g (1 eq.) of (R)-3-((2-chloropyridine-3-yl)oxy)butan-1-ol in 40 mL of 1-methyl-2-pyrrolidinone was added to a suspension of 644 mg (1.3 eq.) of sodium hydride (60% by mass in mineral oil) in 50 mL of 1-methyl-2-pyrrolidinone at 95°C under argon for 30 minutes. The reaction mixture was stirred at 90-100°C for 2 hours, then cooled to room temperature, and poured into 200 mL of a 50 / 50 mixture of diethyl ether and ethyl acetate and 100 mL of water. The aqueous layer was extracted with 50 mL of ethyl acetate, and the organic layers were washed four times with 50 mL of water, then dried over sodium sulfate, and concentrated under vacuum. The residue was eluted with a gradient of 0-50% ethyl acetate in cyclohexane and purified with silica gel to obtain 1 g of (R)-2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridine. MS (Method F) m / z 166[M+1]+; t=1.11 min.

[0369] Step 4: Preparation of (R)-2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridine-9-carboxylic acid [ka] 5.7 mL (1.5 eq.) of 1.6N butyllithium solution in heptane was slowly added to a solution of 1 g (1 eq.) of (R)-2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridine in 30 mL of anhydrous tetrahydrofuran at -60°C under argon, while maintaining the temperature below -55°C. The reaction mixture was stirred at -60°C for 1 hour and 30 minutes. The temperature was slowly raised to room temperature while stirring, and then diluted with 50 mL of diethyl ether and 20 mL of water. The organic layer was discarded, and the basic aqueous layer was acidified with 10 mL of 10% citric acid aqueous solution. After extraction five times with a 75 / 25 mixture of dichloromethane / isopropanol, the organic layers were dried together over sodium sulfate and concentrated under vacuum. The residue was triturated in 10 mL of a 60 / 40 pentane / diethyl ether mixture to obtain 390 mg of (R)-2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridine-9-carboxylic acid. MS (Method F) m / z 210[M+1]+; t=0.81 min.

[0370] Step 5: Preparation of (R)-(2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridine-9-yl)carbamate tert-butyl [ka] 316 μL (1.2 eq.) of triethylamine and 503 μL (1.2 eq.) of diphenyl phosphoryl azide were added under argon to a solution of 395 mg (1 eq.) of (R)-2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridine-9-carboxylic acid in 10 mL of anhydrous toluene and 10 mL of tert-butanol. The reaction mixture was stirred at room temperature for 2 hours and 30 minutes. Then, 7.6 mg (0.03 eq.) of copper(II) chloride and a further 10 mL of tert-butanol were added, and the mixture was stirred at 110°C for 1 hour and 30 minutes, then cooled to room temperature, and diluted with 30 mL of diethyl ether, 30 mL of ethyl acetate, and 20 mL of water. The organic layer was washed with 10 mL of water and 10 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The residue was eluted with a gradient of 0-30% ethyl acetate in cyclohexane and purified with silica gel to obtain 450 mg of (R)-(2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridine-9-yl)carbamate tert-butyl. MS (Method F) m / z 281[M+1]+; t=1.52 min.

[0371] Step 6: Preparation of (R)-N-(2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridine-9-yl)formamide [ka] A solution of 450 mg (1 eq.) of (R)-(2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridin-9-yl)carbamate tert-butyl was stirred at room temperature for 1 hour, then concentrated under vacuum. The residue was azeotropically mixed three times with a 50 / 50 mixture of toluene / tetrahydrofuran, then added to 5 mL of tetrahydrofuran and to a pre-mixed solution of 492 μL (8 eq.) formic acid and 606 μL (4 eq.) acetic anhydride. After stirring at room temperature for 2 hours, the reaction mixture was poured into 20 mL of dichloromethane and 10 mL of 10% aqueous sodium carbonate solution. The two-phase mixture was vigorously stirred for 10 minutes, and the aqueous layer was further extracted with 20 mL of dichloromethane. The organic layers were dried together over sodium sulfate and concentrated under vacuum. The residue was triturated in 10 mL of a 50 / 50 pentane / diethyl ether mixture to obtain 238 mg of (R)-N-(2-methyl-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridine-9-yl)formamide. MS (Method F) m / z 209[M+1]+; t=0.84 min.

[0372] Intermediate 52: N-(3-((2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)formamide (racemic) Step 1: Preparation of 3-((2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-4-nitro-1H-pyrazole (racemic) [ka] 0.365 g (1.25 eq.) of 2,2-dimethyloxetan-3-ol and 1.86 g (2 eq.) of cesium carbonate were added to a solution of 0.5 g (1 eq.) of 1-(methyl-d3)-3,4-dinitro-1H-pyrazole (intermediate 21, step 1) in 25 mL of acetonitrile. This mixture was heated at 80°C for 7 hours, then allowed to cool to room temperature, and poured into ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with 20% ethyl acetate in heptane and purified on silica gel to obtain 470 mg of 3-((2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-4-nitro-1H-pyrazole (racemic). MS (Method A) m / z 231[M+1]+; t=1.66 min.

[0373] Step 2: N-(3-((2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)formamide (racemic) [ka] In a microwave vial, a solution of 0.66 g (1 eq.) of 3-((2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-4-nitro-1H-pyrazole (racemic) in 15 mL of methanol was treated with 1.26 g (7 eq.) of ammonium formate and 202 mg (0.07 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 15 minutes. This mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to obtain 0.62 g of 3-((2,2-dimethyloxetane-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-amine (racemic). The crude material was incorporated into the next step without further purification.

[0374] A solution of 0.57 g (1 eq.) of 3-((2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-amine (racemic) in 20 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 1.16 g (4 eq.) of acetic anhydride in 2.4 g (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under vacuum. The residue was eluted with 5% methanol in dichloromethane and purified on silica gel to obtain 0.51 g of N-(3-((2,2-dimethyloxetan-3-yl)oxy)-1-(methyl-d3)-1H-pyrazole-4-yl)formamide (racemic). MS (Method A) m / z 229[M+1]+; t=1.26 min.

[0375] Intermediate 53: N-(3-cyclopropoxy-1-(2-methoxyethyl)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 1-(2-methoxyethyl)-3,4-dinitro-1H-pyrazole [ka] 1.21 g (1.4 eq.) of 1-bromo-2-methoxyethane and 1.75 g (2 eq.) of potassium carbonate were added to a solution of 1 g (1 eq.) of 3,4-dinitro-1H-pyrazole (commercially available) in 10 mL of dimethylformamide. The mixture was stirred at 80°C for 5 hours, then allowed to cool to room temperature and poured into ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with dichloromethane, then with 1% methanol in dichloromethane, and purified on silica gel to obtain 1.0 g of 1-(2-methoxyethyl)-3,4-dinitro-1H-pyrazole. MS (Method B) t=1.19 min; no mass detection.

[0376] Step 2: Preparation of 3-cyclopropoxy-1-(2-methoxyethyl)-4-nitro-1H-pyrazole [ka] 1.25 eq. of cyclopropanol and 2 eq. of cesium carbonate were added to a solution of 0.98 g (1 eq.) of 1-(2-methoxyethyl)-3,4-dinitro-1H-pyrazole in 20 mL of acetonitrile. This mixture was heated at 80°C for 8 hours, then allowed to cool to room temperature and poured into ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted in 10% ethyl acetate in dichloromethane and purified on silica gel to obtain 825 mg of 3-cyclopropoxy-1-(2-methoxyethyl)-4-nitro-1H-pyrazole. MS (Method B) m / z 228[M+1]+; t=1.22 min.

[0377] Step 3: Preparation of N-(3-cyclopropoxy-1-(2-methoxyethyl)-1H-pyrazole-4-yl)formamide [ka] In a microwave vial, a solution of 0.825 g (1 eq.) of 3-cyclopropoxy-1-(2-methoxyethyl)-4-nitro-1H-pyrazole in 10 mL of methanol was treated with 1.6 g (7 eq.) of ammonium formate and 100 mg (0.025 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 15 minutes. This mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to obtain 715 mg of 3-cyclopropoxy-1-(2-methoxyethyl)-1H-pyrazole-4-amine. The crude material was incorporated into the next step without further purification.

[0378] A solution of 0.71 g (1 eq.) of 3-cyclopropoxy-1-(2-methoxyethyl)-1H-pyrazole-4-amine in 15 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 1.47 g (4 eq.) of acetic anhydride in 3 g (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at room temperature for 20 minutes and then concentrated under vacuum. The residue was eluted with 5% methanol in dichloromethane and purified on silica gel to obtain 455 mg of N-(3-cyclopropoxy-1-(2-methoxyethyl)-1H-pyrazole-4-yl)formamide. MS (Method A) m / z 226[M+1]+; t=1.21 min.

[0379] Intermediate 54: N-(1-(methyl-d3)-3-((tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)formamide (racemic) Step 1: Preparation of 1-(methyl-d3)-4-nitro-3-((tetrahydrofuran-3-yl)oxy)-1H-pyrazole (racemic) [ka] 0.38 g (1.25 eq.) of tetrahydrofuran-3-ol and 2.23 g (2 eq.) of cesium carbonate were added to a solution of 0.6 g (1 eq.) of 1-(methyl-d3)-3,4-dinitro-1H-pyrazole (intermediate 21, step 1) in 12 mL of acetonitrile. This mixture was heated overnight at 80°C, then allowed to cool to room temperature and poured into ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted in 10% ethyl acetate in dichloromethane and purified on silica gel to obtain 245 mg of 1-(methyl-d3)-4-nitro-3-((tetrahydrofuran-3-yl)oxy)-1H-pyrazole. MS (Method B) m / z 217[M+1]+; t=0.97 min.

[0380] Step 2: Preparation of N-(1-(methyl-d3)-3-((tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)formamide (racemic) [ka] In a microwave vial, a solution of 0.245 g (1 eq.) of 1-(methyl-d3)-4-nitro-3-((tetrahydrofuran-3-yl)oxy)-1H-pyrazole in 4 mL of methanol was treated with 0.5 g (7 eq.) of ammonium formate and 30 mg (0.025 eq.) of carbon-supported palladium (10%). The reaction mixture was heated at 100°C for 10 minutes. This mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to obtain 1-(methyl-d3)-3-((tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-amine. The crude material was incorporated into the next step without further purification.

[0381] A solution of 0.21 g (1 eq.) of 1-(methyl-d3)-3-((tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-amine in 5 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 0.47 g (4 eq.) of acetic anhydride in 0.9 g (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at room temperature for 90 minutes and then concentrated under vacuum. The residue was placed in a mixture of ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with dichloromethane 5% methanol and purified on silica gel to obtain 140 mg of N-(1-(methyl-d3)-3-((tetrahydrofuran-3-yl)oxy)-1H-pyrazole-4-yl)formamide. MS (Method A) m / z 215[M+1]+; t=0.98 min.

[0382] Intermediates 55 and 56: cis N-(1-((4-hydroxy-4-methylcyclohexyl)-3-isopropoxy-1H-pyrazole-4-yl)formamide and trans N-(1-((4-hydroxy-4-methylcyclohexyl)-3-isopropoxy-1H-pyrazole-4-yl)formamide Step 1: Preparation of 3-isopropoxy-4-nitro-1-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole [ka] 4.6 g (1.5 eq.) of triphenylphosphine was added to a solution of 2 g (1 eq.) of 3-isopropoxy-4-nitro-1H-pyrazole (commercially available) and 1.85 g (1 eq.) of 1,4-dioxaspiro[4.5]decane-8-ol in 30 mL of tetrahydrofuran. The mixture was cooled to 0°C, and 3.55 g (1.5 eq.) of diisopropyl azodicarboxylate (DIAD) was added. The mixture was stirred overnight at room temperature and then diluted with 100 mL of ethyl acetate and 50 mL of water. The two phases were separated. The organic layer was dried over magnesium sulfate, concentrated under vacuum, eluted with 10% ethyl acetate in dichloromethane, and purified with silica to obtain 1.45 g of 3-isopropoxy-4-nitro-1-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole. MS (Method B) m / z312[M+1]+;t=1.61 min.

[0383] Step 2: Preparation of 4-(3-isopropoxy-4-nitro-1H-pyrazole-1-yl)cyclohexane-1-one [ka] In a microwave vial, a solution of 0.7 g (1 eq.) of 3-isopropoxy-4-nitro-1-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole in 12 mL of acetone and 2.5 mL of water was treated with 0.68 g (1.2 eq.) of pyridinium-p-toluenesulfonic acid (PPTS). The reaction mixture was heated at 120°C for 30 minutes. This mixture was concentrated under reduced pressure and placed in 50 mL of ethyl acetate and 20 mL of water. The two phases were separated. The organic layer was dried over magnesium sulfate, concentrated under vacuum, eluted with 10% ethyl acetate in dichloromethane, and purified with silica to obtain 500 mg of 4-(3-isopropoxy-4-nitro-1H-pyrazole-1-yl)cyclohexane-1-one. MS (Method B) m / z 268[M+1]+; t=1.41 min.

[0384] Step 3: Preparation of N-(3-isopropoxy-1-(4-oxocyclohexyl)-1H-pyrazole-4-yl)formamide [ka] 800 mg of ammonium chloride (5 eq.) and 836 mg of iron (5 eq.) were added to a solution of 800 mg of 4-(3-isopropoxy-4-nitro-1H-pyrazole-1-yl)cyclohexane-1-one in 20 mL of ethanol and 2.5 mL of water. The reaction mixture was heated at 80°C under vigorous stirring for 90 minutes, and the mixture was filtered through Celite, washed with ethanol, and concentrated under reduced pressure.

[0385] The residue solution in 5 mL of tetrahydrofuran was added dropwise at 0°C to a solution of 2.24 g (8 eq.) of acetic anhydride in 4.4 g (35 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at room temperature for 50 minutes and then concentrated under vacuum. The residue was eluted with 5% methanol in dichloromethane and purified with silica gel to obtain 170 mg of N-(3-isopropoxy-1-(4-oxocyclohexyl)-1H-pyrazole-4-yl)formamide. MS (Method A) m / z 266[M+1]+; t=1.55 min.

[0386] Step 4: Preparation of cis N-(1-((4-hydroxy-4-methylcyclohexyl)-3-isopropoxy-1H-pyrazole-4-yl)formamide and trans N-(1-((4-hydroxy-4-methylcyclohexyl)-3-isopropoxy-1H-pyrazole-4-yl)formamide [ka] 311 μL (1.5 eq.) of methylmagnesium bromide (3M in tetrahydrofuran) was added at -78°C to a solution of 165 mg of N-(3-isopropoxy-1-(4-oxocyclohexyl)-1H-pyrazole-4-yl)formamide in 8 mL of tetrahydrofuran. The reaction mixture was stirred at -78°C for 10 minutes, then 104 μL (0.5 eq.) of methylmagnesium bromide (3M in tetrahydrofuran) was added, and the mixture was stirred at -78°C for 1 hour. The reaction was quenched with 3 mL of saturated aqueous solution of ammonium chloride, and then extracted with 20 mL of ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, eluted with 3% methanol in dichloromethane, and purified with silica to obtain N-(1-((4-hydroxy-4-methylcyclohexyl)-3-isopropoxy-1H-pyrazole-4-yl)formamide 50 mg (cis) = intermediate 55, MS (Method B) m / z 282[M+1]+; t=1.19 min, and N-(1-((4-hydroxy-4-methylcyclohexyl)-3-isopropoxy-1H-pyrazole-4-yl)formamide 30 mg (trans) = intermediate 56, MS (Method B) m / z 282[M+1]+; t=1.1 min.

[0387] Intermediates 57 and 58: cis N-(3-cyclopropoxy-1-(hydroxy-4-methylcyclohexyl)-1H-pyrazole-4-yl)formamide and trans N-(3-cyclopropoxy-1-(hydroxy-4-methylcyclohexyl)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 3,4-dinitro-1-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole [ka] 10 g (1.5 eq.) of triphenylphosphine was added to a solution of 4 g (1 eq.) of 3,4-dinitro-1H-pyrazole and 4 g (1 eq.) of 1,4-dioxaspiro[4.5]decane-8-ol in 60 mL of tetrahydrofuran. This mixture was cooled to 0°C, and 7.68 g (1.5 eq.) of diisopropyl azodicarboxylate (DIAD) was added. This mixture was stirred at room temperature for 72 hours, then diluted with 200 mL of ethyl acetate and 100 mL of water. The organic layer was washed with water and brine, dried over magnesium sulfate, concentrated under reduced pressure, eluted with 10% ethyl acetate in dichloromethane, and purified with silica to obtain 1.6 g of 3,4-dinitro-1-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole. MS (Method A) t=1.47 min - No mass.

[0388] Step 2: Preparation of 3-cyclopropoxy-4-nitro-1-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole [ka] 220 mg (1.25 eq.) of cyclopropanol and 2 g (2 eq.) of cesium carbonate were added to a solution of 900 mg (1 eq.) of 3,4-dinitro-1-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole in 20 mL of acetonitrile. This mixture was heated at 80°C for 5 hours, allowed to cool to room temperature, and then diluted with ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was eluted with 10% ethyl acetate in dichloromethane and purified on silica gel to obtain 700 mg of 3-cyclopropoxy-4-nitro-1-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole. MS (Method B) m / z 310[M+1]+; t=1.51 min.

[0389] Step 3: Production of 4-(3-cyclopropoxy-4-nitro-1H-pyrazole-1-yl)cyclohexane-1-one [ka] In a microwave vial, a solution of 0.7 g (1 eq.) of 3-cyclopropoxy-4-nitro-1-(1,4-dioxaspiro[4.5]decane-8-yl)-1H-pyrazole in 12 mL of acetone and 2.5 mL of water was treated with 0.68 g (1.2 eq.) of pyridinium p-toluenesulfonate (PPTS). The reaction mixture was heated at 120°C for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was then placed in 50 mL of ethyl acetate and 20 mL of water. The organic layer was dried over magnesium sulfate, concentrated under vacuum, eluted with 10% ethyl acetate in dichloromethane, and purified with silica to obtain 500 mg of 4-(3-cyclopropoxy-4-nitro-1H-pyrazole-1-yl)cyclohexane-1-one. MS (Method B) m / z 266[M+1]+; t=1.3 min.

[0390] Step 4: Preparation of N-(3-cyclopropoxy-1-(4-oxocyclohexyl)-1H-pyrazole-4-yl)formamide [ka] 363 mg of ammonium chloride (5 eq.) and 380 mg of iron (5 eq.) were added to a solution of 360 mg of 4-(3-cyclopropoxy-4-nitro-1H-pyrazole-1-yl)cyclohexane-1-one in 12 mL of ethanol and 2 mL of water. The reaction mixture was heated at 80°C for 90 minutes with vigorous stirring, and the mixture was filtered through Celite, washed with ethanol, and concentrated under reduced pressure.

[0391] The residue solution in 12 mL of tetrahydrofuran was added dropwise at 0°C to a solution of 1.1 g (8 eq.) of acetic anhydride in 2.2 g (35 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at room temperature for 4 hours and then concentrated under vacuum. The residue was eluted with 5% methanol in dichloromethane and purified with silica gel to obtain 80 mg of N-(3-cyclopropoxy-1-(4-oxocyclohexyl)-1H-pyrazole-4-yl)formamide. MS (Method A) m / z 264[M+1]+; t=1.09 min.

[0392] Step 5: Preparation of cis N-(3-cyclopropoxy-1-(hydroxy-4-methylcyclohexyl)-1H-pyrazole-4-yl)formamide and trans N-(3-cyclopropoxy-1-(hydroxy-4-methylcyclohexyl)-1H-pyrazole-4-yl)formamide [ka] 380 μL (2.5 eq.) of methylmagnesium bromide (3M in tetrahydrofuran) was added at -78°C to a solution of 120 mg of N-(3-cyclopropoxy-1-(4-oxocyclohexyl)-1H-pyrazole-4-yl)formamide in 6 mL of tetrahydrofuran. The reaction mixture was stirred at -78°C for 1 hour. 3 mL of saturated aqueous ammonium chloride and 20 mL of ethyl acetate were added. The two phases were separated. The organic layer was dried over magnesium sulfate, concentrated under vacuum, eluted with 5% methanol in dichloromethane, and purified with silica to obtain N-(3-cyclopropoxy-1-(hydroxy-4-methylcyclohexyl)-1H-pyrazole-4-yl)formamide 35 mg (cis) = intermediate 57, MS (Method A) m / z 280 [M+1]+; t = 1.53 min, and N-(3-cyclopropoxy-1-(hydroxy-4-methylcyclohexyl)-1H-pyrazole-4-yl)formamide 25 mg (trans) = intermediate 58, MS (Method A) m / z 280 [M+1]+; t = 1.39 min.

[0393] Intermediate 59: N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3,4-dinitro-1H-pyrazole [ka] 1.97 g (1.3 eq.) of 2-bromoethoxy-tert-butyl-dimethyl-silane and 1.75 g (2 eq.) of potassium carbonate were added to a solution of 2 g (1 eq.) of 3,4-dinitro-1H-pyrazole (commercially available) in 20 mL of dimethylformamide. This mixture was heated overnight at 80°C, then allowed to cool to room temperature and diluted with ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was heptane.

number

[0394] Step 2: Preparation of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazole [ka] 1.3 g (2 eq.) of tetrahydropyran-4-ol and 4.2 g (2 eq.) of cesium carbonate were added to a solution of 2 g (1 eq.) of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3,4-dinitro-1H-pyrazole in 100 mL of acetonitrile. This mixture was heated overnight at 80°C, allowed to cool to room temperature, and then diluted with ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was heptane.

number

[0395] Step 3: Preparation of N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazole-4-yl)formamide [ka] In a microwave vial, a solution of 0.54 g (1 eq.) of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazole in 10 mL of methanol was treated with 641 mg (7 eq.) of ammonium formate and 150 mg of carbon-supported palladium (10%). The reaction mixture was heated at 70°C for 15 minutes. This mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure to obtain 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazole-4-amine. The crude material was incorporated into the next step without further purification.

[0396] A solution of (2-((tert-butyldimethylsilyl)oxy)ethyl)-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazole-4-amine in 10 mL of tetrahydrofuran was added dropwise to a cooled (0°C) solution of 618 mg (4 eq.) of acetic anhydride in 1.26 g (18 eq.) of formic acid, which had been mixed at room temperature for 30 minutes prior. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was eluted with 5% methanol in dichloromethane and purified on silica gel to obtain 324 mg of N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazole-4-yl)formamide. MS (Method B) m / z 370[M+1]+; t=4.05 min.

[0397] Intermediate 60: N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide Step 1: Preparation of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-3-(oxetane-3-yloxy)-1H-pyrazole [ka] 176 mg (1.5 eq.) of oxetan-3-ol and 1.03 g (2 eq.) of cesium carbonate were added to a solution of 500 mg (1 eq.) of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3,4-dinitro-1H-pyrazole (step 1 of intermediate 59) in 25 mL of acetonitrile. The mixture was heated overnight at 80°C, then allowed to cool to room temperature, and poured into ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The residue was eluted with 20% ethyl acetate in heptane, then with 50% ethyl acetate in heptane, and purified on silica gel to obtain 476 mg of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-3-(oxetan-3-yloxy)-1H-pyrazole. MS (Method A) m / z344[M+1]+;t=2.8 min.

[0398] Step 2: Preparation of N-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)formamide [ka] In a microwave vial, a solution of 0.48 g (...

Claims

1. Equation (I) 【Chemistry 1】 [In the formula: R1 is selected from the group consisting of aryl groups and heteroaryl groups, where the heteroaryl group is an ortho-condensed bicyclic heteroaryl group, and the ortho-condensed bicyclic heteroaryl group is unsubstituted or has one or more -(C 1 -C 3 ) - Substituted with an alkyl group; and where the heteroaryl group is other than the aryl group and the ortho-condensed bicyclic heteroaryl group, each is either unsubstituted or a) Deuterium atom, b) Fluorine atom, c) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. d) Unsubstituted or containing one or more fluorine atoms, hydroxyl groups, or -(C 1 -C 3 ) - Cycloalkyl groups substituted with alkyl groups, e) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. f) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, g) Unsubstituted, or one or more fluorine atoms, hydroxyl groups, or -(C) 1 -C 3 )-O-cycloalkyl group substituted with an alkyl group, h) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, hydroxyl groups, and alkylcarbonyl groups, i) -O-spiro ring group, j) Alkylsulfonylalkyl groups, and k) Alkyl sulfonyl group Substituted with one or more substituents independently selected from the group consisting of; and R2 is selected from the group consisting of alkyloxylalkyl groups and heterocycloalkyl groups, where the heterocycloalkyl group represented by R2 is bonded via a carbon atom and is either unsubstituted or substituted with an alkyl group, an alkyloxyl group, or one or more fluorines. A compound of or a pharmaceutically acceptable salt thereof.

2. R1 is selected from the group consisting of aryl groups and heteroaryl groups, where the heteroaryl group is an ortho-condensed bicyclic heteroaryl group, and the ortho-condensed bicyclic heteroaryl group is either unsubstituted or has one or more -(C 1 -C 3 ) - Substituted with an alkyl group; and where the heteroaryl group is other than the aryl group and the ortho-condensed bicyclic heteroaryl group, each is either unsubstituted or a) Deuterium atom, b) Fluorine atom, c) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. d) is non-substituted or is a cycloalkyl group substituted with one or more fluorine atoms or a -(C 1 -C 3 )-alkyl group, e) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. f) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, g) Unsubstituted or one or more fluorine atoms or -(C) 1 -C 3 )-O-cycloalkyl group substituted with an alkyl group, h) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, and alkylcarbonyl groups, i) -O-spiro ring group, j) Alkylsulfonylalkyl groups, and k) Alkyl sulfonyl group Substituted with one or more substituents independently selected from the group consisting of; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R1 is selected from the group consisting of a phenyl group and a heteroaryl group other than an ortho-condensed bicyclic heteroaryl group, where the phenyl group and the heteroaryl group are either unsubstituted or a) Fluorine atom, b) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. c) Unsubstituted or containing one or more fluorine atoms, hydroxyl groups or -(C 1 -C 3 ) - Cycloalkyl groups substituted with alkyl groups, d) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. e) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, f) Unsubstituted, or one or more fluorine atoms, hydroxyl groups, or -(C) 1 -C 3 )-O-cycloalkyl group substituted with an alkyl group, g) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, hydroxyl groups, and alkylcarbonyl groups, h) -O-spiro ring group, i) Alkylsulfonylalkyl groups, and j) Alkyl sulfonyl group Substituted with one or more substituents independently selected from the group consisting of; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. Equation (Ia) 【Chemistry 2】 [In the formula: R3 is a hydrogen atom, -(C 1 -C 3 )-alkyl groups and -(C 1 -C 3 ) Selected from the group consisting of alkyloxyl groups; m represents 1, 2, or 3; and n represents 0 or 1]; A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the above.

5. Equation (Ia) 【Transformation 3】 [In the formula, R1 is selected from the group consisting of a phenyl group and a heteroaryl group other than an ortho-condensed bicyclic heteroaryl group, where the phenyl group and the heteroaryl group are either unsubstituted or a) Fluorine atom, b) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. c) Unsubstituted or containing one or more fluorine atoms, hydroxyl groups or -(C 1 -C 3 ) - Cycloalkyl groups substituted with alkyl groups, d) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. e) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom, f) Unsubstituted, or one or more fluorine atoms, hydroxyl groups, or -(C) 1 -C 3 )-O-cycloalkyl group substituted with an alkyl group, g) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, hydroxyl groups, and alkylcarbonyl groups, h) -O-spiro ring group, i) Alkylsulfonylalkyl groups, and j) Alkyl sulfonyl group Substituted with one or more substituents independently selected from the group consisting of; m represents 1 or 2; and n represents 0 or 1]; A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

6. Formula (Ib) 【Chemistry 4】 [In the formula: R3 is a hydrogen atom, -(C 1 -C 3 )-alkyl groups and -(C 1 -C 3 ) Selected from the group consisting of alkyloxyl groups; R4 is, a) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups and fluorine atoms. b) Unsubstituted or containing one or more fluorine atoms, hydroxyl groups, or -(C 1 -C 3 )-O-cycloalkyl group substituted with an alkyl group, c) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, hydroxyl groups, and alkylcarbonyl groups, and d) -O-spiro ring group Selected from the group consisting of; R5 is, a) Hydrogen atom, b) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. c) Unsubstituted or containing one or more fluorine atoms, hydroxyl groups or -(C 1 -C 3 ) - Cycloalkyl groups substituted with alkyl groups, d) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. e) Alkylsulfonylalkyl groups, and f) Alkyl sulfonyl group Selected from the group consisting of; R6 is selected from the group consisting of hydrogen atoms and deuterium atoms; m represents 1, 2, or 3; and n represents 0 or 1. A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the above.

7. R3 is -(C 1 -C 3 )-alkyl groups and -(C 1 -C 3 ) Selected from the group consisting of alkyloxyl groups; R6 is a hydrogen atom; m represents 1 or 2; and n represents 0 or 1; The compound according to claim 6 or a pharmaceutically acceptable salt thereof.

8. R3 is -(C 1 -C 3 )-alkyl groups and -(C 1 -C 3 ) Selected from the group consisting of alkyloxyl groups; R4 is, a) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom. b) Unsubstituted or containing one or more fluorine atoms, hydroxyl groups, or -(C 1 -C 3 -O-cycloalkyl groups substituted with -alkyl groups, and c) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, hydroxyl groups, and alkylcarbonyl groups. Selected from the group consisting of; R5 is, a) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. b) Unsubstituted or containing one or more fluorine atoms, hydroxyl groups, or -(C 1 -C 3 )-Cycloalkyl groups substituted with alkyl groups, and c) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. Selected from the group consisting of; R6 is a hydrogen atom; m represents 1; and n represents 1; The compound according to claim 6 or a pharmaceutically acceptable salt thereof.

9. R3 is - (C 1 -C 3 ) - is an alkyl group; R4 is, a) Unsubstituted or containing one or more fluorine atoms, hydroxyl groups, or -(C) 1 -C 3 -O-cycloalkyl groups substituted with -alkyl groups, and b) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, hydroxyl groups, and alkylcarbonyl groups. Selected from the group consisting of, R5 is an alkyl group that is either unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group, a fluorine atom, a deuterium atom, a cyano group, an alkyloxyl group, an alkylamino group, and a dialkylamino group; R6 is a hydrogen atom; m represents 1; and n represents 1; The compound according to claim 6 or a pharmaceutically acceptable salt thereof.

10. Formula (Ic) 【Transformation 5】 [In the formula: R4 is, a) An alkyloxyl group that is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxyl group and a fluorine atom. b) Unsubstituted or containing one or more fluorine atoms, hydroxyl groups, or -(C 1 -C 3 )-O-cycloalkyl group substituted with an alkyl group, c) -O-heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of alkyl groups, alkyloxyl groups, hydroxyl groups, and alkylcarbonyl groups, and d) -O-spiro ring group Selected from the group consisting of; R5 is, a) Hydrogen atom, b) Alkyl groups that are unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxyl groups, fluorine atoms, deuterium atoms, cyano groups, alkyloxyl groups, alkylamino groups, and dialkylamino groups. c) Unsubstituted or one or more fluorine atoms, hydroxyl groups or -(C 1 -C 3 ) - Cycloalkyl groups substituted with alkyl groups, d) Heterocycloalkyl groups that are unsubstituted or substituted with one or more substituents independently selected from alkyl groups, alkyloxyl groups, and alkylcarbonyl groups. e) Alkylsulfonylalkyl groups, and f) Alkyl sulfonyl group Selected from the group consisting of; R6 is selected from the group consisting of hydrogen atoms and deuterium atoms; R7 is - (C 1 -C 3 ) - is an alkyl group; and R8 is - (C 1 -C 3 ) - is an alkyl group; A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the above.

11. 2-((1-methyl-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-methyl-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-[[1-methyl-3-(oxetane-3-yloxy)pyrazole-4-yl]amino]-7-[(3R,4R)-4-methyltetrahydrofuran-3-yl]pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(methyl-d3)-3-(((2R,3S)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(methyl-d3)-3-(((2S,3R)-2-methyloxetane-3-yl)oxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-(methyl-d3)-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((3-isopropoxy-1-methyl-1H-pyrazole-4-yl)amino)-7-((3R,4R)-4-methyltetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriel; 2-((1-methyl-3-(oxetan-3-yloxy)-1H-pyrazole-4-yl)amino)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 2-((1-methyl-3-(oxetane-3-yloxy)-1H-pyrazole-4-yl)amino)-7-((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[1-methyl-3-[(2S,3R)-2-methyloxetan-3-yl]oxypyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[1-methyl-3-[(2R,3S)-2-methyloxetan-3-yl]oxypyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(2S,3R)-2-methyloxetane-3-yl]oxy-1-(methyl-d3)pyrazole-4-yl]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; 7-[(1S)-2-methoxy-1-methyl-ethyl]-2-[[3-[(2R,3S)-2-methyloxetane-3-yl]oxy-1-(methyl-d3)pyrazole-4-yl] [Lu]amino]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; and 2-[[3-(cyclopropoxy)-1-(methoxymethyl)pyrazole-4-yl]amino]-7-[(1S)-2-methoxy-1-methyl-ethyl]pyrrolo[2,3-d]pyrimidine-6-carbonitrile; A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

12. Reacting the compound of formula (11X) with the compound of formula (15X): 【Transformation 6】 A method for producing the compound according to claim 1, comprising [wherein R1 and R2 are as defined in claim 1 for the compound of formula (I)].

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

14. A drug for treating neurodegenerative diseases, comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

15. The agent according to claim 14, wherein the neurodegenerative disease is selected from the group consisting of Parkinson's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, Lewy body dementia, Pick's disease, progressive supranuclear palsy, and frontotemporal dementia.

16. The agent according to claim 14, wherein the neurodegenerative disease is Parkinson's disease.

17. A drug comprising a compound of formula (I) as described in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

18. A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use in the treatment of neurodegenerative diseases.

19. The neurodegenerative disease is selected from the group consisting of Parkinson's disease, multiple sclerosis, HIV-induced dementia, amyotrophic lateral sclerosis, Lewy body dementia, Pick's disease, progressive supranuclear palsy, and frontotemporal dementia, and is a compound of formula (I) for use according to claim 18, or a pharmaceutically acceptable salt thereof.

20. The neurodegenerative disease is Parkinson's disease, a compound of formula (I) for use according to claim 18, or a pharmaceutically acceptable salt thereof.

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